| Title of Invention | NOVEL DERIVATIVES AND ANALOGUES OF GALANTHAMIN |
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| Abstract | The invention discloses novel compounds of general formula (I), wherein R1, R2, R3, R4, R5 G1, G2, G3 and W are defined in the specification. The compound of the invention have superior therapeutic effects in view of their high slectivity for acetycholin-esterase (AchE) and butyrylcholinesterase (BuChE) Compared to the parent compound. The invention also discloses the process for preparation of these compounds and Pharmaceuticals composition comprising them. |
| Full Text | New Derivatives and Analogs of Galanthamine This invention relates to new substituted benzofuran derivatives, process for their production, their salts as well as the use for a) Treatment of Alzheimer's disease, b) treatment of Parkinson's disease, c) treatment of Huntington's disease (chorea), d) treatment of multiple sclerosis, e) treatment of amyotrophic lateral sclerosis, f) treatment of epilepsy, g) treatment of the sequelae of stroke, h) treatment of the sequelae of cranio-cerebral trauma, i) treatment and prophylaxis of the sequelae of diffuse oxygen and nutrient deficiency in the brain, as they are observed after hypoxia, anoxia, asphyxia, cardiac arrest, poisonings, as well as in the case of complications in difficult deliveries of infants or in the case of anesthesia, j) especially also prophylactic treatment of apoptotic degeneration in neurons that were or are damaged by local radiotherapy or chemotherapy of brain tumors, and k) treatment of bacterial meningitis and 1) treatment of diseases with apoptotic components, especially in the wake of an amyloid-associated cell degeneration, 2 m) treatment of diabetes mellitus, especially if the disease is accompanied by amyloid degeneration of islet cells. The new derivatives and analogs of galanthamine according to the invention increase the muscular power and the perseverance of Alzheimer patients. The new compounds according to the invention are those of general formula I in which the substituents have the meanings that are explained below: R1 and R2 are the same or different and mean: a) hydrogen, F, Cl, Br, I, CN, NC, OH, SH, N02, SO3H, PO3H, NH2, CF3, OSO2 (CH2)nCF3/ in which n is equal to 0, 1 or 2), OSO2- aryl, OSO2-vinyl or OSO2-ethinyl; b) a low (C1-C6) , optionally branched, optionally substituted alkyl, alkoxy group, cycloalkyl or cycloalkyloxy group; c) an amino group, which optionally is substituted by one or two identical or different low (C1-C6) , optionally branched, optionally substituted alkyl, alkylcarbonyl, alkoxycarbonyl 3 groups or has an amino group in which a cyclic substitution in the form of a pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, homopiperazine radical that is substituted in any case, d) a COOH, COO alkyl, CO-amino, with the definition of the amino group as in the last paragraph under c) or a CHOHalkyl, group; e) a -(CH2)nX (in which X = Br, Cl, F or I), -(CH2)nOH, -(CH2)nCHO, -(CH2)nCOOH, -(CH2)nCN, -(CH2)nNC, - (CH2) nCOalkyl, -(CH2) nCOaryl group, in which n means 1-4; f) a - (CHz)nvinyl, (CH2) nethinyl group, or (CH2)ncycloalkyl group in which n describes 0, 1 or 2, and cycloalkyl describes an aliphatic ring of the ring size of 3-7; g) a C3-C6-substituted alkenyl group (optionally substituted with H, F, Br, Cl, CN, CO2alkyl, COalkyl, COaryl); h) a C3-C6-substituted alkinyl group (optionally substituted with H, F, Br, Cl, CN, CO2alkyl, COalkyl, COaryl) ; or i) R1 and R2 together mean -CH=CH-CH=CH-, -O(CH2)nO~ (n = 1 to 3), -CH=CH-A1 or -CH2-CH2-A1, whereby NH, 0 or S can stand for Al; R3 has the same meaning as R2, especially OH and OCH3 and in addition R2_and_R3 together mean -A2(CH2)n A2, in which n is 1 to 3 and A2 means two identical or different radicals that are selected from NH, 0 or S; 4 R4 and R5, are either a) both hydrogen, or b) a combination of hydrogen or an alkyl, alkenyl, alkinyl group with i) 0R6, in which R6 means hydrogen, a low (C1-C10, optionally branched or substituted) alkyl group or cycloalkyl group, a C3-C10 substituted silyl group (for example, triethylsilyl, trimethy1silyl, t-butyldimethylsilyl or dimethylphenylsilyl), a C2-C10 "-alkoxyalkyl group, for example tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, ethoxymethyl, (2-methoxypropyl), ethoxyethyl, phenoxymethyl or (l~phenoxyethyl); ii) O-CS-NHR6 (thiourethane) , in which R6 has the above-mentioned meaning iii) O-CO-NHR7 with the meaning below: iv) O-CO-HR6, in which R6 has the above-mentioned meaning, especially ester with the substitution pattern of amino acids (both enantiomers), such as 5 v) NR7R7, in which two substituents R7 are the same or different and mean hydrogen, a low (C1-C4) , optionally branched or cyclic alkyl group, or the two substituents R7 together are -(CH2)n_, in which n is 3 to 5; vi) NH-COR6 (amide), in which R6 has the above mentioned meaning; vii) S-R6, in which R6 is hydrogen or a low (C1-C10) , optionally branched, optionally substituted alkyl group, and in which R6 has the above-mentioned meaning; viii) SOnR8, in which n is 0, 1 or 2, in which R3 is a (C1-C10) , optionally branched or cyclic, optionally substituted alkyl group. If R4 is hydrogen, R5 can be OH, CN, CO2-alkyl, CONRaRb, in which Ra is hydrogen, a low (C1-C6) , optionally branched, cyclic alkyl group that is substituted in any case, and Rb is hydrogen, a low (C1-C6), optionally branched or substituted alkyl group, or Ra+Rb together are -(CH2)n-, in which n means 2 to 6, or - (CH2)nE (CH2)n-, in which E is the same as NH, N-alkyl, O, or S, and n is 0 to 5, aryl (phenyl or naphthyl), 6-B heterocycle, (such as, for example, imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl and substituted variants thereof) , or imidazolinyl, thiazolinyl or oxazolinyl. For the case that R5 is not hydrogen, R4 can also be OH. R4 and R5 together can be carbonyl (=0), hydrazone (=N-NH-R9, =N-NR9R10 or oxime (=N-OR10) , in which R9 is hydrogen, a low (C1- 6 C6), optionally branched or cyclic, optionally substituted alkyl, alkylcarbonyl, alkylcarbonyloxy group or a sulfonic acid group, such as tosyl or mesyl, and R10 is hydrogen, a low (C1-C6) , optionally branched or cyclic, optionally substituted alkyl, alkinyl, alkoxy, alkyllcarbonyl, alkoxycarbonyl, alkylcarbonyloxyalkyl- or alkyl, alkinyl, alkoxy, alkyllcarbonyl, alkoxycarbonyl, alkylcarbonyloxyalkylcarbonyl group, a sulfonic acid group, such as a tosyl group or mesyl group. R4 and R5 together can be substituents of the type in which Yl,Y2 are the same or different and mean O, S, NH or N-R0 (free valences are in any case hydrogen), or for the case that Y1 is NH and Y2 is N-R9, R4 and R5 can be connected by -(CH2)n- (n = 2, 3, or 4) . G1: - (CH2)x-, in which x is 1 or 2; G2_: -(CH2)y-, in which y is 0 to 2; G3_ : - (CH2)2-, in which z is 0 to 3, is carbonyl or thiocarbonyl, provided that x+y+z together are at least 2 and at most 4 or in which G3 means -CH(OH)- or -C(0H)=. G1_ and G2 together or separately can also mean: -C (R11 R12)-, in which Rn and R12 mean hydrogen, OH, a low, optionally branched or cyclic, optionally substituted alkyl, aryl, alkyloxy or aryloxy group or together an alkylspiro group (C3-C7 spiro ring) or G1 and G2 together mean 7 in which m is 1 to 7, W can have the following meanings: a) CR13R14, in which R13 means hydrogen and R14 means the radicals - (CH2) nNR7R7 or -CO-NR7R7 or -COOR7, whereby n can assume the values 0 to 2 and R7 is as defined above, or R7R7 form a ring by -(CH2)n (in which n is 3 to 5) , whereby substituents R13 and R14 can be exchanged. b) N-Phenyl (whereby the phenyl radical optionally is substituted with fluorine, bromine, chlorine, (C1-C4) alkyl, CO2 alkyl, CN, CONH2, or alkoxy) means or N-thien-2 or 3-yl, or N-fur-2 or 3-yl or an N-l,3,5-triazinyl, whereby the triazine radical can then be substituted with Cl, CR6 or NR7R7,and R6 or R7 have the meaning indicated above; c) One of the substituents that is presented below in which I means no bond or -(CH2)n-, with n = 0 to 3, carbonyl, thiocarbonyl 0, S, -SO- or S02, R6 has the meaning that is indicated above, and in addition, Q is defined as -(CH2)n-M+-(CH2)m, whereby n = 0 to 4 and m = 0 to 4 and M+ represents alkinyl, alkenyl, disubstituted phenyl, disubstituted thiophene, disubstituted furan, disubstituted pyrazine, disubstituted pyridazine, a peptide spacer L or a heterocyclic spacer HS, whereby this definition of the spacer is defined in addition by the following graphic formulas in which R15 means the side chain of D-, L-, D, L-aminoacids or unnatural amino acids, and for the case of n > 1, R15 in the individual radicals in each case means the same or a different side chain of D-, L-, D, L-amino acids or unnatural amino acids, whereby these formulas are defined such that atom N in addition to Q is connected in each case to G2 and G3 of formula I; 9 d) W can also be connected to a tricyclic substituent (Tr) via spacer Q, whereby the tricyclic substituents are defined by the following graphic formulas, and these formulas are defined such that atom N in addition to Q is connected in each case with G2 and G3 of formula I, and Q and Z have the meaning indicated under c). The tricyclic substituent (Tr) means a tricyclic ring system, with at least one heterocyclic ring as a ring component and a binding site to a carbon atom of an anellated benzene ring thereof, whereby Tr optionally is substituted at least in one place, in which ring A is an optionally substituted benzene ring and one of rings B and C is an optionally substituted heterocyclic ring and the other can contain a substituted 4- to 14-membered, preferably a 5- to 7-nembered ring, which can contain one or more heteroatoms in the ring. The benzene ring is optionally further substituted in at least one place, whereby these substituents can be halogens, such as fluorine and chlorine, halo-C1-C3 alKyl groups, such as trifluoromethyl, C1-C3 alkyl groups, such as methyl, C1-C3 alkoxy groups, such as methoxy, and the hydrcxy group, whereby halogens, such as fluorine, are preferred. Heterocyclic ring B or C that is optionally substituted is, for example, a 4- to 14-membered ring, preferably a 5- to 7-membered ring. At least one heteroatom of the heterocyclic ring (1 to 3 heteroatoms are possible} can be nitrogen, oxygen, sulfur. In particular, rings B and C are pyridine, pyrazine, pyrimidine, imidazole, furan, thiophene, pyrrolidine, piperidine, hexamethylethylenimine, tetrahydrofuran, piperazine, morpholine and thiomorpholine, whereby 5- to 7-membered nonaromatic rings, which can have one or two heteroatoms that are the same or : different, are preferred. Ring 3 or C can also be a non-aronatic, heterocyclic ring that contains 1-3 heteroatoms, such as nitrogen, oxygen or sulfur, and nonaromatic heterocyclic rings with a nitrogen atom and another heteroatom, which is nitrogen, oxygen or sulfur. i "5- to 8-membered rings 3 or C" are 5- to 8-membered. heterocyclic or alicyclic rings or carbon rings, which are substituted at least in one place. These 5- to 8-membered carbon rings can be a benzene ring or a saturated or unsaturated ring, for example, benzene, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene and cycloheptadiene. If rings B or C contain at least one heteroatom (e.g., 1-3 heteroatoms, such as nitrogen, oxygen, sulfur, etc.), i.e., if ring B or C is a heterocyclic ring, it may or may not be aromatic. Such aromatic heterocyclic rings are, for example, pyridine, furan, thiophane. Preferred nonaromatic, heterocyclic rings are the above-indicated examples of rings B or C. Accordingly, tricyclic substituent Tr can be a condensed benzene ring of general formula Examples in this respect are: Carbazole, 1,2,3,4-4a,Sa-hexahydrocarbazoie, 9,10-dihydroacridine, 1,2,3,4-tetrahydroacridine, 10,ll-dihydro-5H-dibenz[b,f]azepine, 5,6,11,12-tetrahydrodibenz[b,g]azocine, S,ll-dihydro-5H-dibenz[b,e,]azepine, 6,7-dihydro-5H-dibenz[c,e]azepine, 5,6,11,12-tetrahydrodibenz[b, flazocine, 12 dibenzofuran, 9H-xanthene, 1-O-ll-dihydrobenz[b,f]oxepin, 6,11-dihydrobenz[b,e]oxepin, 6,7-dihydro-5H-dibenz[b,g]oxacine, dibenzothiophene, 9H-thioxanthene, 10,11-dihydrodibenzo[b,f]thiepin, 6,11-dihydrodibenzo[b,e] thiepin, 6,7-dihydro-5H-dibenzo[b,g]thiocin, 10H-phenothiazine, 10H-phenoxazine, 5,10-dihydrophenazine, 10,11-dibenzo[b,f]-[1,4] thiazepine, 2,3,5,6,11,lla-hexahydro-IH-pyrrolo[2, 1-b] [3] benzazspine, 1-0,ll-dihydro-5H-dibenzo[b,e][1,4]diazepine, 5,11-dihdyrodibenz[b,e] [1,4]oxazepine, 5,11-dihydrodibenzo[b,f] [1,4]thiazepine, 10,ll-dihydro-5H-dibsnzo[b,e][1,4]diazepine, 1, 2 , 3 , 3a,8,8a-hexahydropyrrolo[2,3b]indole. Tricyclic substituent Tr can be a condensed benzene ring of general formula and can mean, for example: 1H,3H-Naphth[l,8-cd] [1,2]oxazine, naphth[l,8-de]-l,3-oxazine, naphthtl,8-de]-l,2-oxazine, 1, 2,2a,3,4,5-hexahydrobenz[cd]indole, 2, 3 ,3a,4,5, 6-hexahydro-lH-benzo[de] quinoline, 4H-pyrrolo[3,2,l-ij]quinoline, 1,2,5,6-tetrahydro-4H-pyrrolo[3,2, l-ij] quinoline, 5, 6-dihydro-4H-pyrrolo[3,2,l-ij]quinoline, 1H,5H-benzo[ij]quinolizine, 2,3,6,7-tetrahydro-lH,5H-benzo[ij ] quinolizine, azepino[3,2,1-hi]indole, 1,2,4,5,6,7-hexahydroazepino[3,2,1-hi] indole, IH-pyrido[3,2,1-jk][1]benzazepine, 5,6,7,8-tstrahydro-lH-pyrido[3,2,1-jk] [1] benzazepine, 1,2,5,6,7,8-hexahydro-5H-pyrido[3,2,1-jk] [1] benzazepins, 2,3-dihydro-lH-benz[de]isoquinoline, l,2,3,4,4a,5,6,7-octahydronaphth[l,8-be]azepine, 2,3,5,6,7, 8-hexah.ydro-1H-pyrido [3 , 2,1-jk] [1] benzazepine. Tricyclic substituent Tr can be a condensed benzene ring of 'general formula 14 Examples of these compounds are: 1,2,3,5,6,7-Kexahydrobenzo[1,2-b:4 , 5b' ] dipyrrole, 1,2,3,5,6,7-hexahydrocyclopent[f]indole, 1,2,3,6,7,8-hexahydrocyclopentan[e] indole or 2,3,4,7,8-hexahydro-lE-cyclopenta[f] guinoline. Tricyclic substituent Tr can be a condensed benzene ring of general formula Examples of this are: 1,2,3,6,7,8-Hexahydrocyclopent[e]indole or 2,3,4,7,8,9-hexahydro-lH-cyclopenta[f]quinoline. Additional examples of tricyclic substituents Tr are condensed benzene rings of the following formulas, whereby the binding site to Q can take up the space of any hydrogen atom: 15 In addition, Tr can be a. cyclic or bicyclic hydrocarbon which is referred to by the following formula: 16 In addition, each substituent Tr can be substituted by one or more substituents Rl, whereby the definition of substituent R2 is the same as in formula I. e) In addition, W can mean -NH-, -S-, -SO- or -S02-- In addition, the invention relates to compounds of general formula II in which D stands for NH, N-alkyl, N-acyl, oxygen or sulfur, and in which substituents R3 to R5, G2 to G3 and W can have the meanings that are indicated above in general formula I. In addition, the invention relates to compounds of general formula III in which X-R15 is a substituent in which X is oxygen or sulfur and RJ5 is hydrogen or a low (C.-C^) , optionally branched or cyclic, optionally substituted alkyl group, and in which 17 substituents R1 to R5, G, to G3 and w can have the meanings that are indicated above in general formula I. The invention extends to compounds of general formula IV in which W represents CK or N, and H13 and R19 mean hydrogen, alkyl, aryl or aralkyl, and in which the C atoms that carry substituents R1S and R19 are linked to one another via a single bond or a double bond and in which substituents R1 to R- as well as G1 and G3 have the meanings that are indicated above in general formula I. It is preferred if in the compound of general formula IV substituent w is nitrogen and/or substituent G1 is -(CE2) -, in which x is equal to 1 or 2 and G2 means - (CK2) -, in which y is equal to 0 to 2, provided that x + y together mean at least 2 and at most 4. Separation of Optical Isomers from rac. Norgalanthamine: In acditicn, the invention includes a process for chiral separation of (6R)-3-methoxy-5, 6,9,10,11,12-hexahydro-4aH [1]benzofuro[3a, 3 , 2-ef ] [2benzazepin-6-ol (norgalanthamine) (4) 18 The separation of ( + ) and {-} isomers is carried cut by-fractionated crystallization in such a way that • a solution or suspension of the optical isomer mixture in which 3 to 50 x the amount is added to or introduced into • a solvent, such as water, methanoi, ethanoi, propanol, isopropanol, acetone or mixtures of this solvent, mainly methanoi • with the equimolar amount or excess chiral acid (unsubstituted, (+) or (-) tartaric acid, citric acid, lactic acid, preferably {+)-O,0-di-p-toluoyl tartaric acid that is substituted in one or more places and that is dissolved in one of the above-mentioned solvents -- and the solution or suspension of the optical isomer mixture is added, • that the solution is inoculated with crystals produced from the natural (-) galanthamine derivatives and chiral organic acids, such as (+)-0,O-di-p-toluoyl tartaric acid, • and is allowed to stand at -40 to +20 degrees, preferably 0 degrees for 2-24 hours or longer, • that the formed crystals are filtered and dried, • ther. mixed with excess NK^OH and extracted with an organic solvent, such as chloroform, msthylsne chloride, ethyl acetate, butyl acetate, diethyl ether, t-butylmethyl ether, dibutyl ether, petroleum ether, xylene, benzene, toluene or similar solvents, and the 19 corresponding (-) norgalanthamine is isolated by-distillation of the solvent. In this process, concentration by evaporation of the mother liquor, uptake of excess NH4OE, extraction with an organic solvent (as indicated above) and concentration by evaporation yield additional fractions of norgalanthamine, from which in the same way as above, the (+) norgalanthamine can be produced with chiral organic acids, such as (-)-0,0-di-p-toluoyl tartaric acid. The products that are obtained according to the invention can be purified by a suitable process, for example, sublimation, fractionated crystallization or chromatography. Among the compounds according to the invention, especially the compounds that are mentioned below are considered: In the survey below, "AchS" means acetylcholinesterase, n3chS" means butyrylcholinesterase, "hr" means human recombinann, "mH11 means pre-ir.cubacion of the enzyme with inhibitor, and "ICg" means concentration, in which 50% inhibition takes place. 20 Substance Structure IC50 IC50 Laboratory Patent Code (AChE, (3ChE, Code Example m2, hr) m2, hr) Nmnber ,llh,.nn, lc50 "C50 Patent Subs'anz* pl It Labor- Struktur (AChE, (3ChE, Beispie!- Code Code mE, hr) mt, hr) Nummer 21 Substance Structure IC50 IC50 Laboratory Patent Code (AChE, (BChE, Code Example mE, hr) mS, hr) Number 22 Substance Structure rr^n men T I. l>uure icio IC50 Laboratory Patent C°de (AChS, (BChE, Code Example mE, hr) mE, hr} Number 23 Substance Structure IC50 IC50* Laboratory Patent Code (AChE, (BChE, Code Example mE, hr) mE, hr) Number 24 Substance Structure IC50 IC50 Laboratory Patent Code (&ChE, {BChS, Coda Example mH, hr) mS/ hr) Kumber 25 Substance Structure IC50 IC50 Laboratory Patent Code (AChE, (BChS, Cods Example KL3, hr) mS, hr) Number 26 Substance Structure IC50 IC50 Laboratory Patent Code (AChS, (BChE, Code Example mE, hr) m2, hr) Number !C50 IC50 Patent Substanz- Labor- Strukiur (AChE, (BChE, Beispiel- Code Code rnE, hr) mE, hr) Nummer 27 Substance Structure IC50 IC50 Laboratory Patent Code (AChE, (BChE, Code Example mE, hr) mE, hr) Number IC50' IC50 Patent Substanz- Labor- Struktur (AChE, (BChE, Belspiel- Code Code mE, hr) mE, hr) Nummer 28 Substance Structure IC5 0 IC5 0 Laboratory Patent Code (AChE, (BChE, Code Example mS, hr) mE, hr) Number IC50 IC50 Patent Substanz- Labor- Struktur (ACh£, (3ChE, Beispiel- n~A~ Code mE, hr) mE, hr) Nummer 29 Substance Structure IC5 0 IC5 0 Laboratory Patent Code (AChE, (BChE, Code Example raE, hr) aiE, hr) Number 1C50 IC50 Patent Substanz- Labor- Struktur (AChE, (3ChE, Beispie!- Cods Code mE, hr) m=, hr) Nummer 30 Substance Structure IC50 IC50 Laboratory Patent Code (AChE, (BChE, Code Example mE, hr) mE, hr) Number IC50 IC50 Patent Substanz- Labor- Struktur (AChE, (BChE, Beispiel- Code Code mE, hr) mE, hr) Nummer 31 Substance Structure IC50 IC50 Laboratory Patent Code (AChE, (BChE, Code Example mE, hr) mE, hr) Number 1C50 IC50 Patent Substanz- Labor- Struktur (AChE, (BChE, Belspiel- Code Code mE, hrt mE, hr) Nummer 3 2 Substance Structure IC5 0 IC5 0 Laboratory Patent Code (AChE, (BChE, Code Example mE, hr) mE, hr) Number IC50 IC50 Patent , Labor- Substam- ^^ (AChE {3ChE> c^s Beispiel- Code mE, hr) mE, hr) Nummer 33 Substance Structure IC50 IC50 Laboratory Patent Code (AChE, (BChE, Code Example mE, hr) mE, hr) Number IC50 IC50 Patent Substanz- Labor- Struktur (AChE, . (BChE, Beispiel- Code Code mE, hr) mE, hr) Nummer 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 SPH -Number Structure IC50 AChE fiK IC50 BChE fiK SPH-Nummer Struktur IC50 AChE ,M ICSO BChE pM Within the scope of the invention, i.a., the compound (6R)-3-methoxy-5,6,9,10,11,12-hexahydro-4a[HI]benzofuro [3a, 3 ,2-ef][2]benzazepin-6-ol (norgalanthamine), specifically racemic nbrgalanthamine, (-) norgalanthamine and (+) norgalanthamine, is especially to be considered. Both racemic norgalanthamine and its (+)- and (-)-isomers can be used in pharmaceutical agents for treatment of the diseases mentioned above under a) to m) as active ingredients per se or in combination with other active ingredients. The compounds according to the invention can be synthesized with proper use of the process and modes of operation for the production of galanthamine and galanthamine derivatives described in WO 96/12692 and WO 97/40049. An addition to the above-mentioned synthesis methods, some of the compounds according to the invention can be produced with u;se of the combinatory (or parallel) synthesis technology. With tiiis synthesis method, the skeleton of interest (or nuclear 51 molecule) is immobilized in a solid phase (e.g., glass pellets, polymer pellets or another inert vehicle) , which facilitates the' separation of excess reactants from a modified skeleton. The solid phase that is used in each case depends on the concentration capacity, the reactants that are used and the reaction solvents. In particular, polymer pellets, such as, for example, Merrie,field resin, Wang resin or TentaGel (Rapp) resin, are considered. The immobilization of the skeleton is carried out by a functional group that can be recovered in the last step of the synthesis under suitable reaction conditions. The last step consists in the cleavage of the desired product from the solid phase. The selection of the linker unit, which couples the basic molecule to the solid phase, depends on the combination and/or the series of reactants and the reaction conditions that are necessary to obtain maximum yields and/or purity. Moreover, with different linkers, the products can be cleaved off from the same solid phase under different conditions. This technology allows a quick¦synthesis including automated syntheses of compounds according to the invention. Relative to the combinatory and/or parallel synthesis, reference is made to the bibliographic references below, in which general process descriptions are included: 1) Abelson, J. N., Combinatorial Chemistry. Academic Press, San Diego (1996). 52 2) Epton, R., Innovation and Perspectives in Solid Phase Synthesis and Combinatorial Libraries, Mayflower Scientific Limited, Birmingham (1996) . 3) Wilson, S. R. and Czarnik, A. W., Combinatorial Chemistry. Synthesis and Applications. John Wiley &, Sons, Inc., New York (1997). 4) Gordon, E. M. and Kerwin, J. F. J., Combinatorial Chemistry and Molecular Diversity in Drug Discovery. John Wiley and Sons, Inc., New York (1998). 5) Thompson, L. A., Elltnan, J. A. Chem. Rev. 96, 555 (1996) . 6) Special Issue on Combinatorial Chemistry, cf., Ace. Chem. Res., 29, 111 (1996). 7) Fruchtel, J. S.; Jung, G. Angew. Chem. [Applied Chemistry] Int. Ed. Engl. 35, 17 (1996). 8) Cheng, S.; Comer, D. D.; Williams, J. P.; Myers, P. L. ; Bbger, D. L. J. Am. Chem. Soc., 118, 2567 (1996) . 9) For additional information regarding this quickly developing field, see: A Dynamic Database of References in Molecular Diversity at http://www.5z.com. 10) Bayer, E.,- Angew Chem. Int. Ed., 30, 113-129 (1991). 11) Mayer, J. P.; Zhang, J.; Bjergarde, K.; Lentz, D. M. ; Gaudino, J. J.; Tetrahedron Letters, 37, 8081 (1996) . 12) Bayer, E.; Angew. Chem. Int. Ed., 30, 113-129 (1991). 13) DE 19745628 Al. In the example of a norgalanthamine skeleton (G1 = G2 = G3 = methylene; W = NH) or "homogalanthamine (G1 = G2 = G3 = methylene; 53 W = CH-NH2) , a bond between the molecule and the solid phase can be obtained either via a carbon center (C-linked), a nitrogen center (N"-linked) or an oxygen center (O-linked) . The linkage points depend on the type of structural modification desired. In the reaction diagrams mentioned below by way of example, various transformations of skeletons linked by linkers to various solid phases are depicted. O-Linker Transformations of Skeletons of the Norganlanthamine Type and the "Homogalanthamine" Type 54 Linker = X(CH2)nCO (X = CH2, O, NH, SOM), X(CH2)nCS (X = CH2, O, NH, SO0.2), X(CH2)nJCO (X = CH2, O, NH, SO^; J = NH, 0, S), XC6H4CH2 (X = CH2, O, S), N-Linker Transformations of a Molecule Skeleton of the Norgalanthamine- Type C-Linker Transformations of a Skeleton of the Norgalanttiamine Type 55 C-Linker Transformations of the "Homogalanthamine Skeleton" The compounds according to the invention, as well as pharmaceutically acceptable acid addition salts thereof can be used as active ingredients in pharmaceutical agents, for example, for treating diseases with apoptotic components. Neurodegenerative diseases of the human nervous system belong to the syndromes for which few or no causal treatment methods are now available. Neurological diseases of this type with chronic course are primarily defined as follows: Primary degenerative dementias (primarily Alzheimer's disease), 56 Cerebral and spinal paralysis (amyotrophic lateral sclerosis, multiple sclerosis), Centrally induced motor disturbances (Parkinson's disease and Huntington's disease) and Diseases of the epileptic group. Neurodegeneration, however, also plays a role in the immediate wake of acute neurological cases, among which primarily the following can be mentioned: Ischemic stroke (obstruction of an artery supplying the brain), ' hemorrhagic stroke (internal cerebral hemorrhage), cranio-cerebral trauma, and brain damage after cardiac failure or respiratory arrest (hypoxia/anoxia). The compounds of the invention as well as pharmaceutically acceptable acid addition salts thereof can use active ingredients of pharmaceutical agents for treatment of neurodegenerative processes, whereby the primary aim is not to bring about an improvement of the acute symptoms and signs but rather a slowing a!nd modification of the associated processes. Within the framework of diabetes mellitus type II, there is increasing evidence of a role of amyloid fragments in the cell degeneration of the insulin-producing Langerhans' islet cells. The cell degeneration can be aggravated by a non-controlled cialcium inflow.1' 2/ 3 The compounds according to the invention as well as pharmaceutically acceptable acid addition salts thereof can be 57 used as active ingredients in pharmaceutical agents, for example for treating degenerative diseases of the islet cells (such as, e.g., diabetes mellitus type II). The compounds of the invention can be used as active ingredients in pharmaceutical agents that can be used as follows: a) for treatment of Alzheimer's disease, b) for treatment of Parkinson's disease, c) for treatment of Huntington's disease (chorea), d) for treatment of multiple sclerosis, e) for treatment of amyotrophic lateral sclerosis, f) for treatment of epilepsy, g) for treatment of the sequelae of stroke, h) for treatment of the sequelae of cranio-cerebral trauma, i) for treatment and prophylaxis of the sequelae of diffuse oxygen and nutrient deficiency in the brain, as they are observed after hypoxia, anoxia, asphyxia, cardiac arrest, poisonings, as well as in the case of complications in difficult deliveries of infants or in the case of anesthesia, j) especially also for prophylactic treatment of apoptotic degeneration in neurons that were or are damaged by local radiotherapy or chemotherapy of brain tumors, and k) for treatment of bacterial meningitis and 1) for treatment of diseases with apoptotic components, especially in the wake of an amyloid-associated cell degeneration, 58 m) for treatment of diabetes mellitus, especially if it is accompanied by amyloid degeneration of islet cells. The compounds according to the invention or their pnarmaceutically acceptable acid addition salts, e.g., hydrobromide, hydrochloride, methyl sulfate, methiodide, tartrate, fumarate, oxalate, etc. (see table below) can be administered to patients orally, rectally or by subcutaneous, intramuscular, intravenous or intrathecal injection or infusion, or intracerebroventricularly, e.g., using an implanted container. 59 60 Typical dosage rates in administration of these active ingredients depend on the nature of the compound that is used and in intravenous administration are in the range of 0.01 to 2.0 mg per day and per kilogram of body weight based on the physical condition and other medications of the patient, The following specific formulations can be used: Tablets and capsules that contain 0.5 to 50 mg Solution for parenteral administration that contains 0.1 to 30 mg of active ingredient/ml Liquid formulations for oral administration at a concentration of 0.1 to 15 mg/ml Liquid formulations for intracerebroventricular administration, at a concentration, of l or 5 mg of active ingredient/ml. The compounds according to the invention can also be a transdermal system, in which 0.1 to 10 mg/day is released. A transdermal dosage system consists of a storage layer that Contains 0.1 to 3 0 mg of the active substance as a free base or salt in any case together with a penetration accelerator, e.g,. 61 dimethyl sulfoxide, or a carboxylic acid, e.g., octanoic acid, and a realistic-looking polyaerylate, e.g., hexylacrylate/vinyl acetate/acrylic acid copolymer including softeners, e.g., isopropylmyristate. As a covering, an active ingredient-impermeable outside layer, e.g., a metal-coated, siliconized polyethylene patch with a thickness of, for example, 0.35 mm, is used. To produce an adhesive layer, e.g., a dimethylaminomethacrylate/methacrylate copolymer in an organic solvent is used. The invention also relates to pharmaceutical compositions that in a pharmaceutically acceptable adjuvant contains a therapeutically effective amount of at least one of the compounds that are proposed according to the invention. The invention also extends to the use of these compounds for the production of pharmaceutical agents and processes for the production of such compounds. In particular, the compounds according to the invention, which in many cases show a cholinesterase-inhibiting action, are suitable as therapeutic and/or prophylactic active ingredients for senile dementia, Alzheimer's disease, etc. The compounds that are proposed according to the invention are new tetracyclic, condensed, heterocyclic compounds. In addition to the therapeutic and/or prophylactic properties, the compounds and compositions according to the invention can also be used in the diagnosis of disease conditions of the above-mentioned type. 62 Literature: 1) Kawahara, M.; Kuroda, Y. ; Arispe, N.; Rojas, E.; "Alzheimer's Beta-Amyloid, Human Islet Amylin, and Prion Protein Fragment Evoke Intracellular Free Calcium Elevations by a Common Mechanism in a Hypothalamic BnRH Neuronal Cell Line." J Biol Chem 2000 May 12; 275 (19): 14077-83 2) Ma, Z.: Westermark, P.; Westermark, GT; "Amyloid in Human Islets of Langerhans: Immunologic Evidence that Islet Amyloid Polypeptide is Modified in Amyloidogenesis." Pancreas 2000 August; 21(2): 212-8 3) Rhoades, E.; Agarwal, J.; Gafni, A-; "Aggregation of an Amyloidogenic Fragment of Human Islet Amyloid Polypeptide." Biotin Biophys Acta 2000 February 9; 1476(2): 230-8 Below, operating instructions and examples for the production of compounds according to the invention are indicated. 63 General Remarks "Concentration" refers to the removal of solvents under reduced pressure by means of a rotary evaporator. "MPLC" refers to a chromatographic purification on silica gel 20-60 /an with use of Buchi chromatography columns, a Shimadzu LC-8A pump and a Shimadzu 6AV UV detector. Example 1: Step l: 4-Bromo-2-methoxy-5-(2-nitroethenyl)-phenol 40.0 g {173 mmol) of 2-bromo-5-hydroxy-4-methoxybenzaldehyde and 13.3 g (173 mmol) of ammonium acetate are refluxed in 400 nil of nitromethane for 15 minutes. The reaction mixture is evaporated to the dry state, the residue is digested in about 70 ml of methanol and then suctioned off. To obtain a second fraction of the product, the methanol solution is concentrated by evaporation to about 30 ml and then poured onto 500 ml of water. The precipitated solid is filtered off by suction, washed with about 100 ml of water and dried together with the first fraction at 50°C/50 mbar, by which a total of 43.6 g (92% of theory) of yellow crystals is obtained on 4-bromo-2-methoxy-5-(2-nitroethenyl)-phenol with a melting point of 152-154°C. 64 TLC: CH2C12: MeOH = 9:1 1H-NMR (CDC13; 6 (ppm) : 3.85 (s, 3H, OCH3) ; 7.30 (s, 1H, H- 6); 7.38 (S, 1H, H-3); 8.03 (d, 3JU1 HI = 13.41 Hz, 1H, ArCH=); 8.16 (d, 3JHH = 13.41 Hz, 1H, =CHNO2) 13C-NMR (CDC13; 6 (ppm): 56.3 (q, OCH3) ; 114.7 (d, C-6); 116.1 (d, C-3) ; 116.6 137.6 (&, =CHNO2) ; 146.5 (s, C-5) ; 152.1 (s, C-4) Step 2: 4-Bromo-2-methoxy-5-(2-aminoethyl)-phenol Method A: 7.2 g (74 mmol) of concentrated sulfuric acid is added in drops at 0°C under nitrogen atmosphere to 16 8 ml (14 8 mmol) of a 0.88N lithium aluminum hydride solution in diethyl ether. 10.0 g (36.5 mmol) of 4-bromo-2-methoxy-5-{2-nitroethenyl)-phenol is partially dissolved in one liter of absolute diethyl ether in boiling heat, and then the supernatant solution is added with a transfer needle and dry nitrogen to the aluminum hydride solution 65 at room temperature. After the addition is completed, 700 ml oE diethyl ether from the reaction mixture is distilled in undissolved 4-bromo-2-methoxy-5-(2-nitroethenyl)-phenol in the receiving flask. By heating to reflux, a saturated solution is produced that is fed to the reaction mixture as above. This process is repeated (three to four times) until the addition of * 4-bromo-2-methoxy-5-(2-nitroethenyl)-phenol is completed. Then, it is hydrolyzed with water at 0°C, and the ethereal phase is extracted twice with 300 ml each of 4N hydrochloric acid. The acid solution is mixed with 22.2 g (148 mmol) of L-( + )-tartaric acid, made basic with concentrated aqueous ammonia and exhaustively extracted with chloroform. The combined organic phases are washed with saturated aqueous sodium chloride solution, dried (Na2SO4), filtered and concentrated by evaporation, by which 2.2 0 g (24% of theory) of colorless crystals is obtained on 4-bromo-2-methoxy-5-(2-aminoethyl)-phenyl with a melting point of 170-172°C. Method B: A solution of 18.0 g (65.7 mmol) of 4-bromo-2-methoxy-5~ (2-nitroethenyl)-phenol in 200 ml of absolute tetrahydrofuran is added in drops over the course of 2 hours under nitrogen to a reflux-heated solution of 15.0 g (394.2 mmol) of lithium aluminum hydride in 1 1 of absolute tetrahydrofuran. Then, while being cooled with ice, the reaction mixture is hydrolyzed with about 2 0 ml of water and evaporated to the dry state. The residue is taken up in 500 ml of 2K hydrochloric acid and washed with 500 ml 66 of ethyl acetate. The washing phase is shaken back with 200 ml of 2N hydrochloric acid, the combined aqueous phases are mixed with 70 g (467 mmol) of L-(+)-tartaric acid, made basic with concentrated aqueous ammonia and extracted three times with 800 ml of chloroform each. The combined organic phases are dried on sodium sulfate, filtered and concentrated by evaporation, by which 9.92 g (61% of theory) of colorless crystals is obtained on 4^bromo-2-methoxy-5-(2-aminoethyl)-phenol with a melting point of lftO-172°C. S|tep 3: 4-Bromo-5-{N- [ (4-hydroxyphenyl)methyl] -2~aminoethyl} -2-m'e t hoxypheno 1 6.4 g (26.0 mmol) of 4-bromo-2-methoxy-5-(2-aminoethyl) -phenol and 3.2 g (26.0 mmol) of p-hydroxy-benzaldehyde are refluxed for 2 hours in 150 ml of absolute ethanol. Then, while being cooled with ice, 5.0 g (132.0 mmol) of sodium borohydride Is added and refluxed for another half hour, the excess sodium borohydride is destroyed by adding approximately 1 ml of glacial acetic acid as well as 50 ml of water while being cooled with jice, and the solution is concentrated by evaporation. The residue is acidified with 2N hydrochloric acid and washed with 50, 67 ml of chloroform. During hydrolysis, optionally larger solid fragments can form, which must be ground before extraction sincje they include large amounts of product. The washing phase is shaken back with 3 0 ml of 2N hydrochloric acid, the combined aqueous phases are made basic with concentrated aqueous ammonia and extracted three times with 8 0 ml each of ethyl acetate. The organic phases are combined, dried on sodium sulfate, filtered and concentrated by evaporation, by which 8.9 g (97% of theory) of colorless crystals is obtained on 4-bromo-5-{N-[(4-hydroxyphenyl)methyl]-2-aminoethyl}-2-methoxyphenol with a melting point of 69-72°C. TLC: CHC13 : MeOH =9:1 + 2% NH3 1H-NMR (DMSO; 6 (ppm) ) : 2.55-2.78 (m, 4H, ArCH2CH2NH) ; 3.58 (s, 2H, NHCH2Ph) ; 3.73 [s,1 3H, OCH3) ; 6.60-6.76, 7.02-7.14 (2*m, 6H, 2* Ph) 13C-NMR (DMSO; 5 {ppm)): 35.2 (t, ArCH2) ; 48.7 (t, CH2CH2NH) ; 52.2 (t, NHCH2Ph) ; 55.9 (q, OCH3) 111.3 (s, C-4); 114.8 (d, C-3'); 115.9 (d, C-6);.117.3 (d, C-3); 129.1 (d, C-2'); 130.7 (s, C-5); 131.3 (S, C-l'); 146.0 (S, C-2); 146.8 (S, C-l); 156.0 (s, C-4') 68 Step 4: N- [2- (2-Bromo-5-hydroxy-4-methoxyphenyl)ethyl]-N- [ (4-hydroxyphenyl) methyl]formamide: 8.5 g (24.1 ramol) of 4-bromo-5-{N-[(4-hydroxyphenyl)methyl]-2 -aminoethyl}-2-methoxyphenol and 10 ml (123.8 mmol) of ethyl formate are refluxed with "2.5 rnl of formic acid, 10 ml of N,N-dlimethylformamide and a spatula-tip full of dimethylaminopyridine iln 150 ml of absolute dioxane for 24 hours. Toward the end of tlhe reaction, the initially white suspension turns clear, and the mixture is mixed with 50 ml of water. The dioxane is distilled off, the white precipitate that is produced is filtered off by suction and washed with water, by which the first fraction product is obtained. The filtrate is extracted three times with 50 ml each of ethyl acetate, the combined organic phases are dried on sodium sulfate, filtered and concentrated by evaporation. By subsequent column chromatography (50 g of silica djel, mobile solvent: CHC13 : MeOH = 97:3), another fraction is Obtained. Both fractions are dried at 50°C/50 mbar until a constant weight is reached, by which a total of 6.6 g (72% of 69 theory) of colorless crystals is obtained on N-[2 -(2-bromo-5-hydroxy-4-methoxyphenyl)ethyl]-N-[(4-hydroxyphenyl)methyl]-formamide with a melting point of 104-106°C. TLC: CHC13 : MeOH = 9:1 1H-NMR (DMSO; 3 (ppm) ) : 2.56-2.7B (m, 2H, ArCH2) ; 3.43-3.53 (m, 2H, CH2N) ; 3.72 (s, 3H, OCH3) ; 4.14 (dd, 2H, NCH2Ph) ; 6.67-6.80, 7.00-7.11 (2*m, 6H, Ar, Ph) ; 9.30, 9.4 8 (2* s, 1H, CHO) 13C-NMR (DMSO; 6 (ppm)): 32.6, 34.2 (2* t, ArCH2) ; 41.5, 44.3 (2* t, CH2N) ; 46.1, 50.4 (2* t, NCH2Ph) ; 56.1 (q, OCH3) ; 111.4, 111.6 (2* S, C-4) ; 115.1, 115.2 (2* d, C-G); 115.6, 115.7 (2* d, C-3'); 117.7, 118.0 {2* d, C-3); 126.8, 127.0 {2* s, C-5) ; 129.4 (d, C-2'); 130.0 (s, C-l'); 146.5, 146.6 (2* S, C-2); 147.5, 147.6 {2* S, C-l); 157.1, 157.5 {2* s, C-4'); 162.7, 163.0 (2* d, CHO) Step 5: (4aa,8aa)-4a,5,9,10,ll-Hexahydro-l-bromo-3-methoxy-6-oxo-6H-benzofuro[3a,3,2-ef3 -[3] benzazepine-io-carboxyaldedyde: 70 A mixture of 13 g (39.5 mmol) of potassium hexacyanoferrate(III), 300 ml of chloroform and 50 ml of aqueous 10% potassium carbonate solution is heated to 60°C, mixed with 3 g (7.9 mmol) of N-[2-(2-bromo-5-hydroxy-4-methoxyphenyl) ethyl]-N-[(4-hydroyphenylyl)methyl]-formamide while being stirred vigorously and then mechanically stirred vigorously for another 10 minutes. Then, the brown solid that is produced is filtered off on Hyflo, rewashed three times wich 30 ml each of chloroform and pressed out solid. The filtrate is then washed with about 150 ml of water, the washing phase is shaken back with 150 ml of chloroform, the combined organic phases are dried on magnesium sulfate, filtered and concentrated by evaporation. By purification on column chromatography (15 g of silica gel, mobile solvent: CHC13 : MeOH. = 97:3), 580 mg (19% of theory) of colorless crystals with a melting point of 218-22O°C is obtained. TLC: CHC13 : MeOH =9:1 ^-NMR (CDC13; 6 (ppm) ) : 2.58-4.27 (m, 8H, H- 5/5'/S/9•111/11'/12/12') ; 3.80 (s, 3H, OCH3) ; 4.85 (dd, IK, H-4a) ; 6.09 (dd, 1H, H-8); 6.53 (dd, IK, H-7); 7.01 (s, 1H, H-2); 8.10, 8.30 (2* s, IK, CHOConf>A/3) 13C-NMR (CDC13; 5 (ppm)): 33.4, 35.3 (2*t, C- 9Conf _ A/B) ; 37.2, 37.4 (2*t, C-5Conf. A/3); 43.7 {t, C-11) ; 48. 7, 49.0 (2*t, C-12Conf_ A/3) ; 50.9, 51.4 (2*s, C-8aConf_ A/B) ; 56.2 (q, OCH3) ; 83.8, 84.3 (2*s, C-4aConf_ 71 A/B); 115.3, 115.7 (2*s# C-lConf#VB); 116.8, 117.0 (2*d, C-8Conf>A/B); 127.6, 128.9 128.0, 128.8 (2*d, C-7Conf_A/BJ; 129.8, 130.8 (2*s, C-12bConf_ A/B) ; 141.5, 141.7 A/3) ; 143.8, 144.0 (2*s, C-3aConf_ A/B) ; 146.8 {S, C-3); 161.7, 162.3 {2*d, CHO); 193.0, 193.4 (2*s, C-6) C17Hl6BrN04 (JOS 1526) 378.23 g/mol Cld.: C 53.99 H 4.26 N 3.70 Fnd.: C 53.70 H4.47 N3.41 Step 6: (4aa,8aa)-4a,5,9,10,ll-Kexahydro-l-bromo-3-methoxy-6H-benzofuro[3a,3,2-ef]-[3]benzazepin-6-ol: 4 ml (4.00 mmol) of IN L-selectride solution is added in drops at -12GC under nitrogen to a solution of 500 mg (1.32 mmol) of (4aa,8aa)-4a,5,9,10, ll~hexahydro-l-bromo-3-methoxy-6-oxo-6H- benzofuro [3a, 3,2-ef ] [3] benzazepine-10-carboxaldehyde in -2 ml °- absolute tetrahydrofuran, and the reaction mixture is then 72 stirred for one hour at -1O°C. Then, it is hydrolyzed with 3 ml of methanol, the solution is evaporated to the dry state, taken up in 5 0 ml of 2N hydrochloric acid and stirred vigorously for another hour. The aqueous solution is washed with 5 0 ml of ethyl acetate, the washing phase is shaken back with 2 0 ml of 2N hydrochloric acid, the combined aqueous phases are made basic with concentrated aqueous ammonia and extracted three times with 50 ml each of ethyl acetate. The combined organic phases are dried on magnesium sulfate, filtered and concentrated by evaporation, by which 380 mg (82% of theory) of light yellow crystals is obtained on (4aa,8aa)-4a, 5, 9 ,10 , 11-hexahydro-l-bromo-3-methoxy-6H-benzofuro[3a,3,2-ef][3][benzazepin-6-ol with a melting point of 132-136°C. TLC: CKC13 : MeOH =9:1 ^-NMR (t, C-ll); 51.6 (s, C-8a); 56.0 (q, OCH3) ; 57.3 (t, C-12); 62.0 (d, C-6); 85.5 (d, C-4a); 114.9 (s, C-l); 115.7 (d, C-8); 127.3 (d, C-2); 127.7 (d, C-7); 130.5 (s, C-12a); 73 134.2 (s, C-12b); 143.5 (s, C-3a); 145.4 (s, C-3) Step 7: (4aot, 8aa) -4a, 5, 9,10, ll-Hexahydro-l-bromo-3 -methoxy-10-methyl-6H-benzofuro[3a,3,2-ef]-[3]benzazepin-6-ol In succession, 1 ml of 35% aqueous formaldehyde solution and, in portions, 165 mg (2.63 mmol) o£ sodium cyanoborohydride are added while being stirred vigorously to a solution of 370 mg (1.05 mmol) of (4aa,8aa)-4a,5,9,10,ll-hexahydro-l-bromo-3-methoxy-6H-benzofuro[3a,3,2-ef][3]benzazepin-6-ol in 12 ml of acetonitrile, and the reaction mixture is stirred vigorously at room temperature for one hour. The solution is then acidified with 2N hydrochloric acid, washed with 15 ml of dichlorornethane, and the washing phase is shaken back with 15 ml of 2N hydrochloric acid. The combined organic phases are made basic with concentrated aqueous ammonia and extracted three times with 3 0 ml of dichlorornethane each. The combined organic phases are 74 dried on magnesium sulfate, filtered and concentrated by i evaporation, by which 355 mg {92% of theory) of yellow crystals is obtained on (4aa,8aa)-4a,5,9,10,ll-hexahydro-l-bromo-3-methoxy-10-methyl-6H~benzofuro[3a,3,2-ef][3]benzazepin-6-ol with a melting point of 158-161°C. TLC: CHC13 : MeOH =9:1 1H-NMR (CDC13; a (ppm) ) : 1.91-2.04 (m, 1H, H-5) ; 2.27-2.48 (m, 2H, H-5'/H); 2.41 (s, 3H, NCH3); 2.60-2.81 {m, 2H, H-9/11'); 2.92-3.16 (m, 2H, 9'/12); 3.34 (dd, 3J11/12, = 6.37 Hz, *J12/12, = 16.48 Hz, 1H, H-12'); 4.13-4.25 (m, 1H, H-6); 4.58 (b, 1H, K-4a) ; 6.02 (dd, 3J7/a = 10.17 Kz, 4J6/8 = 5.08 Hz, 1H, H-8); 6. IS (d, 3J7/8 = 10.17 H2, 1H, E-7); 6.92 (s, 1H, H-2) Step 8 : (4aa, 8ao;) -4a, 5 , 9,10, ll-Hexahydro-3-methoxy-10-methyl-6H-benzofuro[3a,3,2-ef] -[3]benzazepin-6-ol 75 A mixture that consists of 340 mg (0.93 mmol) of (4aot,8aa)-4a, 5, 9, 10, ll-hexahydro-l-bromo-3-methoxy-lO-methyl-6H-benzofuro[3a,3,2-ef][3]benzazepin-6-ol and 722 mg {6.51 mmol) of calcium chloride in 40 ml of 50% ethanol is mixed with 1.4 g (22.32 mmol) of freshly activated zinc powder1 and refluxed for 5 hours. Then, the zinc is filtered out, it is rewashed with methanol, and the residual solution is concentrated by evaporation. The residue is taken up in 50 ml of IN hydrochloric acid, washed with 30 ml of ethyl acetate, and the washing phase is shaken back with 20 ml of hydrochloric acid. The combined ;iaqueous phases are made basic with concentrated aqueous ammonia and extracted three times with 50 ml each of ethyl acetate. The combined organic phases are dried on magnesium sulfate, filtered and .concentrated by evaporation, by which 230 mg (86% of theory) of yellow crystals is obtained on (4aa, 8ao:) -4a, 5, 9,10 ,11-hexahydro-3-methoxy-10-methyl-6H-benzofuro[3a, 3, 2-ef][3]benzazepin-6-ol with a melting point of 152-155°C. TLC: EE : EtOH = 9:1 (visible by oxidation in the iodine chamber) ^K-NHR (CDC13; 5 (ppm)): 1.90-2.04 (m, 1H, K-5); 2.26-2.46 (m, 2E, H-ll/11'); 2.42 (s, 3H, NCH3) ; 2.62-2.80 (m, 3H, H-5'/9/9'); 3.01-3.12 (m, IE, H-12); 3.12-3.29 (m, 1H, H-12'); 3.83 (s, 3Zinc powder (Aldrich Company) mixed with 2N hydrochloric acid, thoroughly mixed, filtered off and first washed neutral with distilled water, then thoroughly rewashed with methanol 76 3H/ OCH3) ; 4.12-4.22 (m, 1H, H-6); 4.57 (b, 1H, H-4a) ; 6.01 {ddd, 3J7/8 = 10.16 Hz, \j6/a = 5.18 Hz, 3J5/8 = 0.95 Kz; 1H, H-8); 6.22 {dd,, 3J?/8 = 10.16 Hz, 4J5/7 = 1.09 Hz, 1H, H-7) ; 6.61 (d, 3J1/2 = 8.21 Hz, 1H, H-2); 6.66 (d, 3J1/2 = 8.21 Hz, 1H, H-l) 13C-NMR (CDC13; 5 (pptn) ) : 30.0 (t, C-5); 34.5 (t, C-9); 48.9 (S, C-8a); 49.3 (q, NCH3) ; 55.6 (q, OCH3) ; 59.1 (t, C-ll) ; 62.0 (d, C-6); 66.3 (t, C-12); 85.6 (d, C-4a); 111.1 (d, C-l); 121.5 (d, C-8) ; 126.5 (d, C-2); 128.3 {d, C-7); 130.9 (s; C-12a); 132.7 (s, C-12b); 142.9 (s, C-3a); 145.3 (s, C-3b) r| Example 2: '! (4aa, 8ao;) -4a, 5, 9,10, n-Hexahydro-l-bromo-6- [ (4-bromophenyl)methyl]-3-methoxy-6H-bensofuro[3a,3,2-ef] [3]benzazepin-6-ol 77 A mixture of 23 mg (0.068 mmol) of (4aa,8aa)-4a,5,9,10,11- hexahydro-l-bromo-3-methoxy-6H-benzofuro[3a,3,2-et] [3]benzazepin-6-ol, 19 rag (0.136 mmol) of potassium carbonate and 12 mg (0.082 mmol) of sodium iodide is mixed in 20 ml of absolute acetone with 21 mg (0.082 mmol) of 4-bromobenzyl bromide and refluxed. After one hour, the reaction mixture is concentrated by evaporation, the residue is taken up in 10 ml of 2N hydrochloric acid, washed with ethyl acetate, made basic with concentrated aqueous ammonia and extracted three times with 5 ml each of ethyl acetate. The combined organic phases are washed once with saturated aqueous sodium chloride solution, dried (Na2SO4, activated carbon), filtered and concentrated by evaporation. Further purification is carried out via'flash chromatography (15 g of silica gel; mobile solvent: CHC13 - CKC13 : MeOH = 95:5), by which 10 mg (29% of theory} of oily substance on (4aa,8aa)-4a,5,9,10,11-hexahydro-l-bromo-6-[(4-bromophenyl)methyl]-3-methoxy-6H-benzofuro[3a,3,2-ef] [3]benzazepin-6-ol is obtained. TLC: CHC13 : MeOH = 9:1 1H-NMR (CDC13; 6 (ppm)): 1.78 (ddd, 1H, H-5); 1.98-2.31 (m, 4K, H-5'/9/ll/ll' ) ; 2.70 (ddd, IK, E-9'); 3.57 (ddd, 1H, H-12); 3.82 (s, 3H, OCH3) ; 3.86 (ddd, 1H, H-12'); 4.15 (b, 1H, H-6); 4.42 (d, IE, NCH2) ; 4.65 (b, 1H, H-4a); 5.00 (d, 1H, NCH2'); 5.91 (d, 1H, H-7); 6.06 (dd, 1H, H-8); 6.92 (s, 1H, H- 78 2); 7.28 (d, 2H, Ph-2/6); 7.43 (d, 2H, Ph-3/5) Diagrams for Examples 1 and 2 79 Example 3: 2- [4- [(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9 ,10 , 11,12-hexahydro-4aH-benzofuro[3a,3,2-e,f] [2]benzazepine-11-yl] butyl]-1,2-benzoisothiazol-3(2H)-one, 1,1-dioxide tartrate, dihydrate (SPH-1374) 2- (6-Bromohexyl) -1, 2-benzisothiazol-3 (2H) -one-1, 1-dioxide (2.33 g, 7,32 mmol), produced according to Hamor, G. H.; Rubessa, F.; Farmaco Ed. Sci. 1970, 25, 36-39, Norgalanthamine (2.00 g, 7.32 mmol) and N-ethyldiisopropylamine (2.84 g, 22.0 mmol) in absolute chloroform (20 ml) are stirred at boiling temperature for 24 hours. The solvent is drawn off, and the residue is purified by column chromatography (150 g of silica gel, chloroform : ¦methanol : ammonia : 96.5 : 3 : 0.5), by which the product is obtained as a colorless foam (2.67 g, 5.23 mmol, 71.4%). TLC: Chloroform : methanol : ammonia = 89 : 10 : 1; Rf = 0.5 1E-NMR (CDC13) : 5 8.05-7.72 (m, 4H) , 6.63-6.55 (m, 2H) , 6.10-5.90 (m, 2H) , 4.56 (b, 1H) , 4.15-4.01 (m, 2H) , 3.84-3.70 (m, 80 6E) , 3.42-3.04 (m, 2H) , 2.71-2.35 (m, 4H) , 2.10-1.72 (m, 4H) , 1.65-1.40 (m, 2H); 13C-NMR (CDC13) : 5 158.8 (s), 145.7 (s), 143.9 s), 137.5 {s}, 134.6 (d) , 134.1 (d) , 133.0 (s) , 129.4 (s), 127.4 (d) , 127.2 (s), 126.8 (d) , 124.9 (d) , 121.8 (d) , 120.7 (d) , 111.0 (d) , 88.5 (d) , 61.9 (d) , 57.5 (t) , 55,7 (q) , 51.4 (t), 50.5 (t), 48.3 (s), 39.1 (t), 32.9 (t), 29.8 (t), 26.0 (t), 24.5 (t) The base {SPH-1369, 2.50 g, 4.90 mmol) and ( + )-tartaric acid (0.80 g, 5.33 mmol, 1.09 equivalents) is heated in EtOH (95%, about 10 ml) until the solution turns clear (about 50°C), and this solution is added still hot drop by drop within 5 minutes to absolute ether (about 200 ml) that is stirred with a magnet, whereby a white precipitate is produced. After standing overnight at room temperature, the crystals that are obtained are filtered off by suction and washed with absolute ether (3 x 50 ml), and the product is dried in a vacuum desiccator at room temperature/50 mbar on calcium chloride, whereby the tartrate dihydrate is obtained in the form of a colorless powder (3.184 g, 93.3% of theory) . A sample quantity is dried at 2 mbar and 40°C for 8 hours on phosphorus pentoxide. C27H3QN2O6S . C4H4O4 . 2 H2O (JOS 1659) (697.7) Fnd. C 56.18 H 5.78 N 4.23 Cld. a) C 55.74 H 5.81 N 4.15 b) C 55.76 H 5.79 N 4.26 81 Example 4: 2- [5- [ {4aS, 6R, 8aS) -6-Hydroxy-3-methoxy-5, 6, 9, 10,11,12-hexahydro-4aH-benzofuro[3a,3,2-e,f][2]benzazepine-ll-yl]pentyl]-1,2-benzoisothiazol-3(2H)-one, i,1-dioxide (SPH-1372) 2-(5-Bromopentyl)-1,2-benzisothiazol-3{2H)-one-l,1-dioxide (1.66 g, 5.00 mmol), norgalanthamine (1.37 g, 5.00 tnmol) and N-ethyldiisopropylamine (1.94 g, 15.0 mmol) in absolute chloroform (15 ml) are stirred for 24 hours at boiling temperature. The solvent is drawn off, and the residue is purified by column chromatography (150 g of silica gel, chloroform : methanol : ammonia : 96.5 : 3 : 0.5), by which the product is obtained as a colorless foam (2.09 g, 3.99 mmol, 79.7%). TLC: Chloroform : methanol : ammonia =89 : 10 : 1; Rf = 0.5 1H-NMR (CDC13) : 6 8.05-7.70 (m, 4H) , 6.63-6.50 (m, 2H) , 6.09-5.85 (m, 2H) , 4.55 (b, 1H) , 4.15-3.99 (m, 2H) , 3.82-3.60 (m, 5H) , 3.41-2.92 (m, 2H) , 2.70-2.32 (m, 3H) , 2.09-1.70 (m, 4H) , 1.58-1.23 (m, 6H); 13C-NMR (CDCI3) : 5 158.7 (s), 145.6 (s), 143.8 (s), 137.5 (s), 134.5 (d) , 134.1 (d) , 133.0 (q) , 129.4 (s) , 127.3 (d) , 127.2 82 (s) , 12 6.8 (d) , 124.8 (d) , 121.8 (d) , 120.7 (d) , 111.0 (d) , 88.5 (d), 61.8 (d), 57.5 (t), 55.7 (q), 51.4 (t), 51.0 (t), 48.2 (s), 39.1 (t), 32.8 (t), 29.8 (t), 28.1 (t), 26.6 (t), 24.3 (t), 20.3 (d) Production of Fumarate (UJ-1682) A hot (about 50°C) solution of the base (1.686 g, 3.21 mmol) in EtOH (95%, 10 ml) is combined with saturated fumaric acid solution (10 ml, about 0.5 M in 95% ethanol), heated at about 60°C until a clear solution is obtained, and this solution that is still hot is fed in drops within 5 minutes to absolute ether (about 200 ml) that is stirred with a magnet, whereby a white precipitate is produced. After standing overnight at room temperature, the crystals that are obtained are filtered off by suction and washed with absolute ether (3 x 50 ml), and the product is dried in a vacuum desiccator at room temperature/50 mbar on calcium chloride, whereby the fumarate is obtained in the form of a colorless powder (1.394 g, 67.7% of theory). A sample cruantity is dried at 2 mbar and at 40°C for 8 hours on phosphorus pentoxide. A second fraction is obtained from the mother liquor (= UJ-1682-1-2) . C28H32N2O6S . C4H4O^ . %C4H10O (JOS 1657) (677.8) Cld. C 59.54 H 6.21 N 4.21 Fnd. C 59.49 H6.18 N 4.20 83 Example 5: 2-[6-[(4aS/6R/8aS)-6-Hydroxy-3-methoxy-5, 6, 9,10,11,12-hexahydro-4aH-benzofuro[3a,3,2-e,f][2]benzazepine-11-yl]hexyl]-1,2-benzoisothiasol-3(2H)-one, 1,1-dioxide fumarate (SPH-1373) 2-(6-Bromohexyl)-i,2-benzisothiazol-3(2H)-one-1,1-dioxide (1.50 g, 4.33 mmol), produced according to Kim, Sung-Kyu; Cho, Su-Dong; Moon, Jung-Kyen; Yoon, Yong-Jin. J. Heterocycl. Chem. (1996), 33(3), 615-618, norgalanthamine (1.18 g, 4.33 ramol) and N~ethyldiisopropylamine (1.68 g, 13.0 mmol) in absolute chloroform (15 ml) is stirred for 24 hours at boiling temperature. The solvent is drawn off, and the residue is purified by column chromatography (150 g of silica gel, chloroform : methanol : ammonia : 96.5 : 3 : 0.5), by which the base is obtained as a colorless foam (1.91 g, 3.52 mmol, 81.4%). TLC: Chloroform : methanol : ammonia =89 : 10 : 1; Rf = 0.5 1H NMR (CDC13) : 5 8.08-7.72 (m, 4H) , 6.68-6.55 (m, 2K) , 6.12-5.90 (m, 2H) , 4.57 (b, 1H) , 4.16-4.01 (m, 2H) , 3.82-3.65 (tn, 6H) , 3.52-3.03 (m, 2H) , 2.71-2.28 (m, 3H) , 2.10-1.71 (m, 4H) , 1.55-1.25 (m, 7H); 84 158.8 (s) , 145.7 (s), 143.9 (s) , 137.6 (s), 134.6 (d) , 134.2 (d) , 133.1 (s), 129.5 (s), 127.4 (d) , 127.3 (s) , 126.9 (d) , 125.0 (d), 121.9 (d), 120.8 (d), 111-1 (d), 88.6 (d), 62.0 (d), 57.6 (t), 55.8 (q), 51.5 (t), 48.3 (t), 39.3 (tj, 32.9 (t), 29.9 (t) , 28.2 (t), 27.1 (t), 26.7 (t), 26.6 A clear solution that is obtained by heating the base (1.33 g, 2.47 mmol) in fumaric acid solution (8 ml, saturated solution in 95% ethanol) to about 60°C is added drop by drop within 5 minutes to absolute ether that is stirred with a magnet, whereby a white precipitate is produced. After standing overnight at room temperature, the crystals that are obtained are filtered off by suction and washed with absolute ether (3 x 50 ml), and the product is dried in a vacuum desiccator at room temperature/50 mbar on calcium chloride, whereby the fumarate is obtained in the form of a colorless powder (1.170 g, 72% of theory). A sample quantity is dried at 2 mbar and 40°C for 8 hours on phosphorus pentoxide. C2gH34N2O6S . C4H4O4 (JOS 1658) Cld.: C 60.54, H 5.85, N 4.28 Fnd.: C 60.49, H 5.97, N 4.22 85 Example 6: Step 1: 2-(4-Bromobutyl)-5,6-dimethoxy-i-oxoindane-2-carboxylic acid methyl ester 5,6-Dimethoxy-l-oxoindane-2-carboxylic acid methyl ester (4.0 g, 16.0 mmol), produced according to Fukushi, Hideto; Mabuchi, Hiroshi; Itoh, Katsumi; Terashita, Zen-ichi; Nishikawa, Kohei; Sugihara, Hirosada; Chem. Pharm. Bull. 1994, 42(3), 541-550, is added in substance at room temperature to a suspension of sodium hydride (0.84 g, 17.6 mmol, 50% in white oil, released from white oil by digestion with absolute petroleum ether (3 x 50 ml) in absolute DMF, and the solution is stirred for 45 minutes at room temperature. Then, it is mixed with 1,4-dibromobutane (24.2 g, 112.0 mmol) and stirred for 18 hours at room temperature. It is dispersed between water and ether, the aqueous phase is extracted quantitatively with ether, the combined organic phases are washed with water (5 x), saturated common salt solution (1 x) and dried (sodium sulfate/activated carbon). Excess dibromoalkane under high vacuum is separated by 86 bulb tube distillation {100°C/0.05 tnbar) from the residue that is ¦obtained after concentration by evaporation and the residue that is obtained is recrystallized from boiling tert-butylmethyl ether (25 ml), by which the product is obtained in the form of colorless crystals (5.02 g, 13.0 mmol, 81.6%). TLC: Petroleum ether : ethyl acetate = 3:1; Rf = 0.15 Melting point: 92-93°C 1H NMR (CDC13) : 6 7.13 (s, 1H) , 6.88 (s, 1H) , 3.94 (s, 3H) , 3.87 (s, 3H) , 3.65 (s, 3H) , 3.58 (d, J = 18.3 Hz, 1H) , 3.33 {t, J = 6.7 Hz, 2H) , 2.97 (d, J = 17,2 Hz, 1H) , 2.20-1.99 (m, 1H) , 1.95-1.73 (m, 3H), 1.53-1.26 (m, 2H) ; 13C NMR (CDC13) : 6 200.7 (s), 171.6 (s), 156.1 (s), 149.7 (s), 14S.5 (s), 127.7 (s) , 107.1 (d) , 104.8 (d) , 60.6 (s), 56.2 (q) , 56.0 (q) , 52.6 (q) , 36.3 (t) , 33.6 (t) , 33.2 (t), 32.6 ft), 23.1 (t) Number, chemical displacement and multiplicity of the peaks found confirm the postulated structure Step 2: 2-(4-Bromobutyl)-5 , 6-dimethoxyindan-l-one 87 2- (4-Bromobutyl) -5 , 6-dimethoxy-l-oxoindane-2-carboxylic acid methyl ester {3.0 g, 7.79 mmol) is stirred in concentrated hydrochloric acid (10 ml) and acetic acid (30 ml) for 12 hours at |60oC. It is mixed with saturated sodium carbonate solution, neutralized with sodium carbonate and extracted quantitatively with ether, the combined organic phases are washed with saturated sodium carbonate solution (3 x), water (1 x), saturated common salt solution (1 x), dried {sodium sulfate/activated carbon) and the residue that is obtained after concentration by evaporation is crystallized from tert-butylmethyl ether (10 ml). In this way, the product is obtained in the form of colorless crystals (1.85 g, 5.65 mmol, 72.5%). TLC: Petroleum ether : ethyl acetate = 3 : 1; Rf = 0.2 Melting point: 72-73°C 1ENMR (CDC13) : 5 7.15 (s, 1H) , 6.85 (s, IK), 3.95 (s, 3K) , 3.8 8 (s/ 3H) , 3.4 0 (t, J = S.8 Hz, IE) , 3.23 (dd, J = 18.0 Hs, J = 8.0 Hs, 1H) , 2.78-2.57 ,(m, 2H) , 2.00-1.72 (m, 3H) , 1.65-1.35 (m, 3H) ; 13C NMR (CDCl3) : 6 207.1 (s), 155.5 (s), 149.4 (s), 148.8 (s) , 129.3 (s) , 107.3 (d) , 104.3 (d) , 56.1 (t) , 56.0 (t) , 47.4 (d) , 33.5 (t) , 32.6 (t) , 32.5 (t) , 30.6 (t), 25.8 (t) 88 Step 3 : 2- [4- [ (4aS,6R,8aS)-6-Hydroxy-3-methoxy-5 , 6, 9, 10,11,12-hexahydro- 4aH-benzofuro[3a,3,2-e,f][2]benzazepine-11-yl]butyl]-5,6- !dimethoxyindan-l-one 2- (4-Bromobutyl)-5,6-dimethoxyindan-l-one (1.0 g, 3.01 mmol), norgalanthamine (919 mg, 3.36 mmol) and potassium carbonate (1.26 g, 9.09 mmol, anhydrous, finely ground) are ,stirred at boiling temperature for 24 hours as in absolute i acetonitrile (10 ml). The reaction mixture is filtered, the solvent is drawn off, and the residue is purified by column chromatography (150 g of silica gel, chloroform : methanol : ammonia : 96.5 : 3 : 0.5), by which the product is obtained as a colorless foam (1.21 g, 2.32 mmol, 77.6%). TLC: Chloroform : methanol : ammonia : 8.95 : 10 : 0.5, Rf = 0 . 65 1H-NMR (CDC13) : a 7.14 (s, IK), 6.83 (s, IK), 6.67-6.52 (m, 2H) , 6.12-5.90 {in, 2H) , 4.57 (b, 1H) , 4.02-4.18 (m, 2H) , 3.93 (s, 3H) , 3.87 (s, 3H) , 3.80 (s, 3H) , 3.75 (d, J = 13.7 Hz, 1H) , 3.43- 89 3.06 (m, 3H) , 2.75-2.35 (m, 5H) , 2.11-1.83 (m, 3H) , 1-59-1.29 (m, 6H) ; 13C NMH (CDC13) : 6 207.5 (s), 155.4 (s) , 149.3 (s), 148.9 (s), 145.7 (s), 144.0. (S), 133.1 (s), 129.4 (s), 127.5 (d), 126.9 (d), 121.9 (d), 111.1 (d), 107.3 (d), 104.2 (d), 88.6 (d) , 62.0 (d), 57.7 (t), 56.1 (q), 56.0 (q), 55.8 (q) , 51.5 (t), 51.2 (t), 48.3 (t) , 47.5 (d) , 32.8 (t) , 32.5 (t) , 31.5 (t) , 29.9 (t), 27.4 (t) , 25-.1 (t) Example 7: Step 1: 2- (5-Bromopentyl) -5, 6-dimethoxy-l-oxoindane-2-carboxylic acid methyl ester 5,6-Dimethoxy-i-oxoindane-2-carboxylic acid methyl ester (3.0 g, 12.0 mmol) is added in substance at room temperature to a suspension of sodium hydride (0.62 g, 13.2- mmol, 50% in white oil, released from white oil by digestion with absolute petroleum ether (3 x 50 ml)) in absolute DMF, and the solution is stirred for 45 minutes at room temperature. Then, it is mixed with 1,5-dibromopentane (19.3 g, 84.0 mmol) and stirred for 18 hours at' room temperature. it is dispersed between water and ether, the 90 aqueous phase is extracted quantitatively with ether, the combined organic phases are washed with water {5 x), saturated common salt solution (1 x) and dried (sodium sulfate/activated carbon). Excess dibromoalkane is separated under high vacuum by bulb tube distillation (100°C/0.05 mbar) from the residue that is obtained after concentration by evaporation, and the residue that is obtained is recrystallized from boiling tert-butylmethyl ether (20 ml), by which the product is obtained in the form of colorless crystals {3.75 g, 9.4 mmol, 78.3%). TLC: Petroleum ether : ethyl acetate = 3 : 1; Rf = 0.15 Melting point: 108.5-110°C 1H NMR (CDC13) : 6 7.15 (s, 1H) , 6.89 (s, 1H) , 3.96 (s, 3H) , ,3.89 (S, 3H), 3.67 (s, 3H), 3.60 (d, J = 19.1 Hz, 1H), 3.35 (t, J = 7.0 Hz, 2H) , 2.96 (d, J = 19.1 Hz, 1H) , 2.20-1.15 (m, 8H) ; 13C NMR (CDCI3) : 5 200.9 (s), 171.8 (s), 156.1 (s), 149.7 (s), 148.4 (s), 12 7.9 (s), 107.1 (d), 104.9 (d) , 60.8 (s), 56.2 (q), 56.1 (q) , 52.6 fg), 36.4 (t), 34.5 (t), 33.5 (t), 32.3 (t), 28.3 (t), 26.9 (d), 23.7 (t) Step 2: 2-{5-Bromopentyl)-5,6-dimethoxyindan-l-one 91 2- (5-Bromopentyl) -5, 6-dimethoxy-l-oxoindane-2 -carboxylic acid methyl ester (3.0 g, 7.51 mmol) is stirred in concentrated hydrochloric acid (io ml) and acetic acid (30 ml) for 12 hours at 60°C. It is mixed with saturated sodium carbonate solution, neutralized with sodium carbonate and extracted quantitatively with ether, the combined organic phases are washed with saturated sodium carbonate solution (3 x), water (1 x), saturated common salt solution (1 x), dried (sodium sulfate/activated carbon), and the residue that is obtained after concentration by evaporation is crystallized from tert-butylmethyl ether (10 ml). In this way, the product is obtained in the form of colorless crystals (1.78 g, 5.22 mmol, 69.5%). TLC: Petroleum ether : ethyl acetate = 3 : 1; Rf = 0.2 Melting point: 67.5-68.5°C 1H NMR (CDC13) : 5 7.15 (s, 1H) , 6.85 (s, 1H) , 3.95 (s, 3H) , 3.89 (S, 3H), 3.50 (t, J = 7.0 Hz, 2H) , 3.20 (dd, J = 6.4 Hz, J = 9.5 Hz, 1H), 2.72 (d, J = 3.2 Hz, IK), 2.60 (d, J = 3.2 Hz, 1H), 2.00-1.65 (m, 3H), 1.55-1.35 (m, 5H); 13C NMR (CDC13) : 5 207.4 (s), 155.5 (s), 149.4 (s) , 148.8 (s), 129.4 (s) , 107.4 (d) , 104.3 (d) , 56.2 (q) , 56.0 (q) , 47.5 (d) , 44.9 (t), 32.5 (t), 32.3 (t), 31.4 (t), 26.8 (t), 2S.5 (t) 92 Step 3: 2-[5-[(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-benzofuro [3a,3,2-e,f] [2] benzazepine-ll-yl] pentyl] -5,6-dimethoxyindan-1-one (S PH-13 5 9) 2- (4-Bromopentyl)-5,6-dimethoxyindan-l-one (1.66 g, 4.86 mmol), norgalanthanamine (1.46 g, 5.35 mmol) and potassium carbonate (2.01 g, 14.6 mmol, anhydrous, finely ground) are stirred for 24 hours at boiling temperature as in absolute acetonitrile (10 ml). The reaction mixture is filtered, the solvent is drawn off, and the residue is purified by column chromatography {150 g of silica gel, chloroform : methanol : ammonia : 96.5 : 3 : 0.5), by which the product is obtained as a colorless foam (1.84 g, 2.32 mmol, 70.9%) TLC: Chloroform ; methanol : ammonia : 8 9.5 : 10 : 0.5, Rf = 0.65 1H NMR (CDC13) : 6 7.11 A solution of the base {1.00, 1.874 mmol) in saturated fumaric acid solution (6 ml, about 0.5 M in 95% ethanol) is heated at about 60°C until a clear solution is obtained, and this solution that is still hot is added drop by drop within 5 minutes to absolute ether (about 150 ml) that is stirred with a magnet, whereby a white precipitate is produced. After standing overnight at room temperature, the crystals that are obtained are filtered off by suction and washed with absolute ether (3 x 50 ml), and the product is dried in a vacuum desiccator at room temperature/50 mbar on calcium chloride, whereby the fumarate is obtained in the form of a colorless powder {0.694, 57.0% of theory). A sample quantity is dried at 2 mbar and 40°C for 8 hours on phosphorus pentoxide. A second fraction is obtained from the mother liquor. 94 Cs&J*0* ¦ CA°4 " * H2° (658.7) Cld. C 65.64 H 6.73 N 2.13 Fnd.: C 65.83 H 6.72 N 2.10 95 Formulas and Table for Examples 8-79 Galanthamin Derivate * gaXasthamisa derivatives 96 97 93 Example 8 Step 1 (6R)-l-Bromo-3~methoxy-5,6,9,10,11,12-hexahydro-4aH- [1]benzofuro[3a,3,2-ef[2]benzazepin-6-one (2a) Water (660 ml) and concentrated hydrochloric acid (400 ml) were added to a stirred solution of (6R)-5,6,9,10,11,12,1-bromo-3-methoxy-6-oxo-4aH-hexahydro-benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxaldehyde (2) (100.0 g, 0.26 mol) in toluene (2.6 1). The reaction mixture was refluxed for 48 hours while being stirred. The precipitate was filtered off and washed with water (3 x 500 ml). The phases of the hydrate were separated, and the organic phase was extracted with water (3 x 500 ml). The precipitate was heated with the combined, aqueous solutions of the hydrate and hot-filtered. The solution was set at pH = 12 with 30% sodium hydroxide. The precipitate was filtered and dried (50°C/50 mbar) to obtain 64.5 g (70%) of title compound (2a) at about a melting point of 228-231°C. 1H-NMR (CDC13 6 6.94 (dd, J, = 10.3, 1.9 Hz, 1H), 6.62 (s, 1H), 6.00 (d, J = 10.5 Hz, IE), 4.69 (m, 1H), 4.04 (d, J = 15.9 Hz, 1H), 3.83 (d, J = 15.9 Hz, IK) , "3.80 (S, 3H) , 3.29 (m, 2H) , 3.07 (d, J = 1.9 Hz, 1H) , 2.70 (dd, J, = 17.8 Hz, J2 = 3.7 Hz, 1H) , 2.16 (m, 1H) , 1.80 (dt, J1 = 14.0 Hz, J2 = 2.9 Hz, 1H) ; 13C-NMR (CDCl3) 5 194.3 (s>, 146.9 (s) , 143 .8 (s) , 135.3 (d)', 13 0.5 (s) , 12 9.3 (s) , 126.9 (d) , 121.9 (d) , 111.8 (s) , 87.9 (d),. 56.3 (t), 55.9 (q) , 51.8 (t), 49.0 (s), 37.2 (t) , 33.0 (t) . Anal. (C,6H16BrKO3.0.4 H2O) C, H, N. 99 Step 2: (6R)-l-Bromo-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[33,3,2-ef [2]benzazepin-6-ol (3) An L-selectride solution {1 M, 276 ml, 0.276 mol) was added at -10°C to a solution of (6R)-l-bromo-3-methoxy-5,6,9,10,11,12-hexahydro-4aH[1]benzofuro[3a,3,2-ef3 [2]benzazepin-6-one (2a) {64.5 g, 0.184 mol) in dry THF (1.3 1). After 30 minutes of stirring at -10 to -5°C, the reaction mixture was hydrolyzed with MeOH (80 ml) and concentrated by evaporation. The residue that was obtained was dissolved in 2N hydrochloric acid and stirred for 18 hours at room temperature. The solution was set at pK = 9 with concentrated ammonia and extracted with EtOAc (3 x 500 ml), the combined, organic layers were washed with brine and dried (Na2SO4) to produce 55.9 g (90.6%) of the product. 1H-NMR (CDC13) 6 6.85 (S, 1H), 6.05 (m, 2H), 4.56 (b, 1H), 4.48 (d, J = 14.7 Hz, 1H), 4.10 (m, 1H), 3.85 (d, J = 14.7 Hz, 1H), 3.80 (s, 3H), 3.35-3.05 (m, 2H) , 2.62 (m, 1H), 2.25 (m, 1H), 1.98 (d, J = 13.2 Hz, 1H) , 1.85-1.65 (m, 2H) ; 13C-NMR (CDC13) 6 145.8 (s), 144.0 (s) , 134.1 (s), 131.6 (s), 12 7.9 (d), 126.8 (d), 115.5 (d), 113.0 (s), 88.4 (d) , 61.7 (d) , 56.0 (q) , 52.7 (t) , 49.3 (s) , 46.6 (t) , 29.7 (t) . ¦Step 3: (6R)-3-Methoxy-5,6,9,10,11,12-hexahydro-4aH- [1]benzofuro [3a, 3 , 2-sf][2]benzazepin-6-ol {= {+/-)norgalanthamine) (4) Activated zinc (89.0 g, 1.36 mol) and calcium chloride (44.0 g, 0.40 mol) were added to a solution of (6R)-l-bromo-3-niethoxy- 100 5, 6, 9,10,11,12-hexahydro-4aH-[l]benzofuro[3a,3,2-ef][2]benzazepin~6-oi (3) (20,0 g, 56.3 mmol) in 50% EtOH {1000 ml). The reaction mixture was refluxed for 18 hours and filtered on Celite. The filtrate was concentrated by evaporation, the residue was diluted with 2N hydrochloric acid (500 ml) and extracted with EtOAc (3 x 400 ml). The pH of the aqueous phase was set at above 8.5 with concentrated ammonia and extracted with CH2C12 (3 x 100 ml) and with CH2Cl2:Me0K =9:1 (3 x 100 ml) . The combined organic extraccs were washed with brine (200 ml), dried (Na2SO4) and concentrated by evaporation to produce 12.3 g (79.0% of compound 4: 1H-NMR (CDC13) 5 6.62 (b, 2H) , 6.02 (m, 2H) , 4.61 (b, 1H), 4.14 (t, J = 4.3 Hz, 1H), 3.98 (d, J = 5.0 Hz, 2H), 3.83 (s, 3H) , 3.30 (m, 1H) , 2.69 (t, J = 15.7, 1H) , 2.10-1.63 (m, 4H) ; l3C-NMR (CDC13) 5 146.2 (s), 144.1 (s), 133.1 (s), 131.7 (s), 127.8 (d), 126.8 (d), 120.8 (d) , 111.1 (d), 88.4 (d), 61.9 (d) , 55.9 (q), 53.3 (t) , 48.5 (s) , 46.7 (t), 39.4 (t) , 29.9 (t). Anal. (C20H26N2O4) C, H, N. Step 4: Methyl(6R)-l-bromo-N^-cyano-e-hydroxy-a-methoxy-S,6,9,10- tetrahydro-4aH[1]benzofuro[3a,3,2-ef][2]ben2azepine- 11(12H)carboximidothioate (3bi) 0.21 g, 1.4 mmol) of N-cyanodithiocarbonimidic acid dimethyl ester (0.21 g, 1.4 mmol) was added to a solution of {+/-)-norgalanthamine (0.5 g, 1.4 mmol) in EtOH:DMF = 4:1 (20 ml). The reaction mixture was refluxed for 4 days and concentrated by evaporation. The residue was crystallized in EtOH to produce 101 0.25 g (41.7%) of compound 3bi: 1H-NMR (CDC1,) : 6 6.90 (s, 1H) , 6.05 Example 9: (6R) -3-Methoxy-n- (2-pyrimidinyl) -5, 6, 9,10,11,12-hexahydro-4aK[l]benzofuro[3a,3,2-ef[2]benzazepin-6-ol (4a) 0.21 g, 1.8 mmol) of 2-chloropyrimidine and sodium bicarbonate (0.61 g, 7.2 mmol) were added to a solution of (+/-)-norgalanthamine (0.5 g 1.8 mmol) in EtOH (30 ml). The reaction mixture was refluxed for 2 days and concentrated. The residue was diluted with water (30 ml), and EtOAc (3 x 20 ml) was extracted. The combined, organic extracts were washed with common salt solution (2 0 ml) , dried (Na2SO4) and concentrated by evaporation to produce 0.51 g (80.8%) of 4a: ^-NMR (DMSO-d) 5 7.82 (d, J = 4.0 Hz, 2H), 6.42 (d, J = 12.0 Hz 1H), 6.23 (d, J = 12.0 Hz, 1H), 6.03 (t, J = 4.0 Hz, 1H), 5.83 (d, J = 8.0 Hz, 1H), 5.54 (dd, J, = 8.0 Hz, J2 = 3.0 Hz, IE), 4.98 (d, J = 14.0 Hz, 1H) , 428 (d, J = 16.0, 1H) , 4.09 (b, 1H) , 3.94 (d, J = 14.0 Hz, 1H) , 3.72 (m, 1H), 3.38 (s, 3H) , 3.21 (t, J = 14.0 Hz, 1H) , 2.54 (d, J = 12.0 Hz, 1H) , 2.15 (m, 1H) , 1.55 (m, 3H) , 13C-NMR (DMSO- 102 d) 5 159.5 (d), 61.3 (d), 54.8 (q), 50.2 (t), 47.3 {s}, 47.4 (t), 34.6 (t), 29.2 (t) . Anal. (C20H21N3O3. 0.15 EtOH) C, H, N. Example 10 : (6R)-11-(2-Chloro-4-pyrimidinyl)-3-methoxy-5,6,9,10,11, 12-hexahydro-4aH-[1] benzofuro[3a,3,2-ef] [2]benzazepin-6-ol (4b) was produced analogously to Example 9. Reaction time 40 hours, yield 0.62 g (88.6%). ^-KMR (CDC13) 6 7.84 (d, J = 4.0 Hz, 1H) , 6.88 (d, J = 12.0 Hz, 1H) , 6.69 (d, J = 12.0 Hz, IK), 6.05 (b, 2H) , 5.90 (d, J = 4.0 Hz, 1H), 5.58 (b, 1H), 4.34 (m, 2H) , 4.18 (b, 1H) , 3.80 (s, 3K) , 3.60 (t, J = 16.0 Hz, 1H) , 2.73 (d, J = 16.0 Hz, 1H) , 2.39 (m, 1H) , 2.04 (d, J = 18 Hz, 1H) , 1.87 (m, 2H) ; 13C-NT^R (CDC13) 6 160.5 (s) , 158.4 (s), 157.0 (s), 145.0 (s), 144.1 (s) , 132.2 (s), 128.2 (d) , 127,8 (s), 126.6 (d) , 126.1 (d) , L11.0 (d) , 107.1 (d) , 88.1 (d) , 61.6 (d) , 55.8 (q) , 53.8 (t) , 48.3 (s), 46.0 (t), 34.9 (t), 29.6 (t). Example 11: (6R) -11- (2-Diethylamino) -4-pyrimidinyl) 3-methoxy-5, 6,9,10,11,12-hexahydro-4aK-[1] benzofuro]3a,3,2-ef] [2] benzazepin-6-ol (4c) . 0.1 g (1.30 mmol) of potassium hydroxide was added to a solution of compound 4b (0.5 g, 1.3 0 mmol) in diethylamine (6 ml, 57.6 mmol). The reaction mixture was refluxed for 22 hours and concentrated by evaporation. The residue was diluted with saturated solution of potassium carbonate (30 ml) and extracted 103 with EtOAc {3 x 20 ml). The combined, organic phases were washed with common salt solution (20 ml), dried (Na,SO,) and concentrated by evaporation. Flash chromatography yielded 0.21 g (38,5%) of 4c. Below, only the different NTMR signals are described: 1H-NMR (CDC13) a 2.97 (d, J = 16.0 Hz, 4H) , 1.34 (m, 6H) ; 13C~NMR (CDC13) 6 36.3 (t), 14.0 (q) . Example 12: (6R)-11-(2-(3-(Dimethylsminojpropoxy)-4-pyrimidinyl)-3-methoxy-5,6,9,10,ll,12-hexahydro-4aH-[l]benzofuro[3 a,3,2-ef][2]benzazepin-6-ol (4d): The production was carried out analogously to Example 11. Reaction time 2 hours, yield 0.15 g ¦ (41.0%) . Only the different NMR signals are described: 1H-NMR (CDC13) 5 4.34 (m, 2H) , 2.28 (s, 6H) , 2.00 {m, 4H) ; 13C-NMR (CDC13) 65.0 (t), 56.3 (t), 45.2 (q), 27.0 (t). Example 13: (6R)-11-(4,6-Dichloro-l,3,5-triazine-2-yl)-3-methoxy- 5,6,9,10,11,12-hexahydro-4aH-[l]benzofuro[3a,3,2- ef] [2]benzazepin-6-ol (4e) : A solution of 2,4,6-trichloro-l,3,5- triazine (0.66 g, 3.7 mmol) in acetone (16 ml) was poured onto ice water (35 ml) and added in small portions at 0°C to (+/-)- norgalanthamine (1.0 g, 3.7 mmol). After the addition of 2N- sodium hydroxide (2 ml) , the reaction mixture was refluxed for 40 hours. The aqueous phase was extracted with EtOAc {3 x 30 ml). The combined, organic phases were washed with common salt solution (30 ml) , dried (Na2SO4) and concentrated by evaporation, 104 to produce 0.90 g (59.5%) of compound 4e: 1K-NMR (CDC13) 5 6.82 (d, J = 10.0 Hz, IK), 6.63 (d, J = 10.0 Hz, I'd) , 6.02 (b, 2H) , 5.30 (d, J = 11.0 Hz, 1H), 4.75 (d, J = 16.0, 1H), 4.50 (b, 1H), 4.22 (d, J = 11.0 Hz, 1H) , 4.11 (b, 1H) , 3.78 (s, 3H) , 3.59 (m, 1H) , 3.06 (m, 1H) , 2.61 (d, J = 16.0 Hz, IK), 1.90 (m, 3H) ; 13C-NMR (CDC13) 5 207.0 (s) 171.2 (s), 163.7 (s), 146.2 (s), 143.9 (s), 132.3 (d), 129.5 (s), 127.6 (s), 12S.7 (d), 121.5 (d), 110.8 (d), 88.0 (d), 61.7 (d), 55.7 (q), 51.3 (t), 48.2 (s), 43.4 (t), 35.9 (t), 29.7 (t). Compounds 4f-4i contain the basic galanthamine skeleton, such as 4e, but are different in the nitrogen substituent. Since the proton and carbon signal of the gaianthamine core are not significantly different, the NMR signals of the nitrogen substituent are relayed below. Example 14: (6R) -11- (4,6-Bis-(diethylamino-l,3,5-triazine-2-yl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef] [2]benzazepin-6-ol (4f) : A solution of compound 4e {0.30 g, 0.71 mmol) in 40 ml of acetone was poured onto 100 ml of ice Water, and at 0°C, a solution of diethylamine (5.7 ml, 54.7 mraol) in acetone (10 ml) was added. The reaction mixture was refluxed for 2 hours and then poured onto 200 ml of ice water. The aqueous phase was extracted with 3 x 100 ml of EtOAc. The combined organic phases were washed with common salt solution (100 ml), dried on sodium sulfate and concentrated by 105 evaporation. Flash chromatography yielded 0.17 g {47.8%) of compound 4f: ^-NMR (CDC13) 6 3.54 {m, 8H) , 1.18 (m, 12H) ; 13C-NMR {CDC13) 6 41.7 (t), 13.4 (q) . Example 15: (6R)-11-(4,S-Diphenoxy-1,3,5-triazine-2-yl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (4 g): 6.5 g (18.3 mmol) of 2,4,6-triphenoxy-1,3,5-triazine was added to a solution of (+/-)-norgalanthamine (1.0 g, 3.74 mmol) in dioxane {60 ml). The reaction mixture was refluxed for 20 hours. The precipitate was filtered off and washed with dioxane. The filtrate was concentrated by evaporation, and flash chromatography yielded 0.91 g (45.9%) of compound 4g: ^-NMR (CDC13) Example 16: (6R) -11- (4, 6-Bis- (2aminoethoxy) -1,3, 5-triazine-2-yl) -3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2- ef] [2]benzazepin-6-ol (4H) : The compound was produced according to the procedure indicated in Example 11, whereby the reaction time was 3 hours. 0.15 g {67.9%) of compound 4H was obtained. 1E-NMR (CDC13) a 3.64 (m, 4H) , 3.42 (m, 4H) ; 13C-NMR (CDCl3) 5 61.3 (t), 42.1 (t). 106 Example 17: (6R)-11-(4,6-Bis-(2-(dimethylamino)ethoxy)-1,3, 5-triazina-2-yl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[l]benzofuro[3a, 3, 2-ef][2]benzazepin-6-ol (4i). According to the procedure indicated in Example 11, compound 4i was obtained at a reaction time of 3 hours in a yield of 0.16 g (59.5%): 1H-NMR (CDC13) 6 4.12 (q, J = 6.0 Hz, 4K) , 2.29 (d, J = 4.0 Hz, 12H) , 1.29 (m, 8H) ; 13C-NMR {CDC13) 5 65.6 (t), 56.0 (t), 45.2 (q), 29.2 (t). Example 18: 2-Chloro-l-((6R)-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12K)-yl)-l~ethanone (4j): 0.82 g of chloroacetyl chloride (7.3 mmol) and 0.81 g (8.0 mtnol) of triethylamine were added to a solution of ( + /-)-norgalanthamine {2.0 g, 7.3 mmol) in dry TRF (100 ml). The reaction mixture was refluxed for 3 hours and concentrated by evaporation. The residue was diluted with 2N hydrochloric acid (100 ml) and extracted with EtOAc (3 x 75 ml). The aqueous phase was set at pH > 8.5 with concentrated ammonia and extracted with 3 x 75 ml of CH2C12. The combined, organic phases were washed with common salt solution, dried on sodium sulfate and concentrated by evaporation. Flash chromatography yielded 0.20 g (7.7% of compound 4j): 1H-NMR (CDC13) 5 6.78 (b, IE) , 6.12 (m, 2H), 5.30 (d, J = 11.0 H2, IK), 4.65 (m, 2H), 4.32-4.01 (m, 3H), 3.78 (s, 3H), 3.59 (m, 1H), 3.06 (m, 1H), 2.61 (d, J = 16.0 Hz, 1H) , 1.90 (m, 3H) , 13C-NMR (CDCl3) 6 166.0 (s) 146.2 (s) , 144.9 (s), 132.3 (d), 128.3 (s), 127.3 (s), 126.0 (d), 120.2 (d), 111.2 107 (d) , 88.2 (d) , 61.7 (d), 55.8 (q), 52.8 (t), 48.1 (s), 45.5 ft), 41.4 (t), 35.4 (tj, 29.6 (t). Example 19: (6R) -6-Kydroxy-N1l-isopropyl-3-methoxy-5 ,6,9, 10-tetrahydro-4aH-[l]benzofuro[3a,3,2-ef [2]benzazepine-11(12H)carboxamide (41) : According to the procedure that is indicated in Example 11, 0.50 g of compound 4H was obtained at a reaction time of 4 hours with a melting point of 106-108°C: 1H-NMR (CDC13) 5 6.68 (dd, J = 10.3; 8.3 Hz, 2H) , 6.00 (m, 2H) , 4.59 (b, 1H) , 4.47 (d, J = 16.4 HZ, 1H) , 4.31 (d, J = 16.4, 1H) , 4.16 (m, 1H) , 3.86 (m, 1H) , 3.83 (s, 3H), 3.36 (dt, J = 12.6; 2.0 Hz, 1H), 2.69 (dd, J 15.7; 3.4 Hz, 1H), 2.28 (d, J = 11.3 Hz, 1H), 2.02 (m, 1H), 1.88 {dd, J = 12.3; 3.4 H2, 1H), 1.77 m, 1H), 1.07 (dd, J = 21.8; 6.4 Hz, 6H) ; 13C-NMR (CDC13) 5 156.4 (s) , 146.8 (s), 144.5 (s) , 132.4 (s), 12 9.0 (s) , 127.9 (d) , 12 6.4 (d) , 12 0.1 (d) , 111.0 (d) , 88 .3 (d) , 61.7 (d) , 55.8 (q) , 51.5 (t) , 48.3 (s) , 45.4 108 Example 20: (6R)-Nn-t-Butyl-e-hydroxy-S-methoxy-S,6, 9,10-tetrahydro-4aH-[ljbenzofuro[3a,3,2-ef[2]benzazepine-ll(12H)-carboxamide (4m): Process according to Example 11, reaction time 3 hours, yield 0.57 g (85%); melting point 204-205°C; 1H-NMR (CDC13) 5 1.24 (s, 9H); 13C-NMR (CDC13) 5156.4 (s) , 50.7 (s) , 29.3 (q) . Anal. (C21H2SN2O4) C, H, N. Example 21: (6R)-N11-Ethyl-6-hydroxy-3-methoxy-5,6,9, 10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef[2]benzazepine-11(12H)-carboxamide (4n) : Process according to Example 11, reaction time 3 hours, yield 0.61 g (98%); melting point 137-139°C; iR-NMR (CDC13) 5 3.14 (q, J - 4.0 Hz, 2H), 1.04 (t, J = 10 Hz, 3H) ; 13C-NMR (CDC13) 5 157.0 (s), 35.6 (t), 15.3 (q). Example 22: (6R) -Ni:L-Cyclohexyl-6~hydroxy-3-niethoxy-5, 6, 9, 10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11-(12H)-carboxamide (4o): Process according to Example 11, reaction time 5 hours, yield 0.56 g (79%); melting point 225-228°C; ^-NMR (CDC13) 5 1.24 (s, 9H) ; 13C-NMR (CDC13) 5 48.8 (d) , 33.4 (t), 33.2 (t) , 25.5 (t), 24.8 (t), 24.6 (t) . 109 Example 23: (6R)-e-Hydroxy-a-methoxy-N^-phenyl-S,6,9,10-tetrahydro-4aH-[ljbenzofuro[3a,3,2-ef][2]benzazepine-11-(12H)-carboxamide (4p): Process according to Example 11, reaction time 4 hours, yield 0.34 g (47%); melting point 198-199°C; JH-NMR (CDC13) * 7.24 (m, 4H) , 6.99 (q, J = 4.2 Hz, 1H) ; 13C-NMR Example 25: (eRJ-e-Hydroxy-S-methoxy-N^-tS)-(-)"-methylbenzyl-5,6,9, 10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef] [2]benzazepine-11- (12H)-carboxamide (4r): Process according to Example 11, reaction time 6 hours, yield 0.66 g (58%); iH-NMR (d), 126.5 and 126.4 (d), 125.9 and 125.5 (d), 46.1 (d), 22.9 and 22.6 (q). 110 Example 26: (6R)-6-Hydroxy-3-methoxy-N11- (S)- {-)a-methylbenzyl-5,S,9,10-tetrahydro-4aH-[13benzofuro[3a,3,2-ef ] [2] benzazepine-11-(12H)-carboxamide (4s): Process according to Example 11, reaction time 6 hours, yield 0.66 g (58%); 1H-NMR (CDC13) 6 7.82 (d, J = 8.0 Hz, 1H) , 7.61 (d, J = 6.0 Hz, 2H) , 7.43 (m, 4H) ; 13C-NMR (CDC13) 5 155.4 (s), 134.0 (s), 133.6 (s), 132.5 (s), 128.6 (d) , 127.9 111 Example 28: (6R)-6-Hydroxy-3-methoxy-N11-allyl-5,6,9,10-tetrahydro-4aK-[1]benzofuro[3a,3,2-ef] [2]benzazepine-11-(12H)-carbothioamide (4u): Process according to Example 11, reaction time 5 hours, yield 0.47 g (70%); melting point 192-194°C; same skeleton as 47, only the different NMR signals are relayed: ^-NMR (CDC13) 6 6.85 (m, 1H) , 5.13 (m, 2H) , 4.14 (m, 2H) ; 13C-NMR (CDC13) 3 181.2 (s), 133.7 (d) , 116.6 (t) , 48.3 (t). Anal. (C^H^N^S) C, H, N. Example 29: ( (6R) -fi-Hyuxuxy^s-methoxy-S ,0,9,10 tebrafaydr-o—^£e3f ¦[1] benzofuro [3 a, 3, 2-ef ] [2] benzazepine-11- (12H) -yl-fumaric acid dimethyl ester (4v): Process according to Example 11. 0.37 g (2.61 mmol) of but-2-enedionic acid dimethyl ester was added to a solution of (+/-)-norgalantharaine (0.5 g, 1.74 mmol} in 40 ml of CE2C12, and it was stirred for 20 hours. The solvent was removed to obtain an oily product, whose flash chromatography yielded 0.28 g (39.1%) of 4v. Melting point 112-115°C, 1H-NMR (CDC13) 5 6.63 (dd, J^ = 12.6 Hz, u2 = 8.1 Hz, 2E) , 6.02 (dd, J1 = 15.9 Hz, J2 = 11.5 Hz, 2H) , 4.77 (b, IK), 4.59 (b, 1H), 4.22 (d, J = 15.9, 1H), 4.13 (b, IK), 3.92 (s, 3H), 3.83 (s, 3H), 3.72 112 (d), 88.6 (d), 86.6 (d), 61.9 (d) , 56.9 (t), 55.8 (q) , 55.0 (q), 50.2 (q), 48.3 (s) , 33.0 (t) , 29.3 (t) . Anal. (C22H25NO7) C, H, N. Example 30: {6R)-11-{3-2-(4-Fluoro)phenyl-2,5-diazabicyclo[2.2.1]heptane-5-yl-propyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (4w): Process according to Example 11, reaction time 4 days, yield 0.14 g (63.0%); iH-NMR (CDC13) 5 7.21 (m, 2H) ; 6.68 (m, 3H) , 5.0 (s, 1H) , 4.47 (d, J - 14.0 Hz, 1H), 3.90 (m, 1H), 3.63 (m, 3H), 3.24 (m, 1H) , 2.04 (m, 3H) ; 13C-NMR (CDC13) 5168.0 and' 167.6 (s) , 146.4 (d) , 144.1 (s), 127.7 and 127.5 (d), 112.5 and 112.4 (d), 67.0 (t), 57.0 and 56.8 (d), 56.8 and 56.6 (t), 51.8 and 51.6 (t) , 36.6 (t); 33.7 and 33.6 (t) . Example 31: 2-{(6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH~ [l]benzofuro[3a,3,2-ef][2]benzazepine-ll(12H)-ylmethylene)-malononitrile (4x): Process according to Example 11, reaction time 6 hours, yield 0.41 g (64.8%); ^H-NMR (CDC13) 5 7.12 (m, 1H), 6.63 (dd, Jx = 12.6 Hz, J2 - 8.1 Hz, 2H), 6.02 (dd, J1 = 15.9 Hz, J2 = 11.5 Hz, 2H), 4.59 (b, 1H), 4.22 (d, J - 15.9, 1H), 4.13 (b, 1H), 3.83 (s, 3H), 3.72 (d, J = 15.9 Hz, 1H), 3.46 (m, 1H), 3.19 (dt, Jj_ = 15.1 Hz, J2= 3.1 Hz, 3H) , 2.68 (dd, Jx - 15.8 Hz, J2 = 2.2 Hz, 1H), 2.00 (m, 1H) , 1.54 (m, 1H) ; 13C-NMR (CDC13) 5 157.2 and 156.8 (d), 146.0 (s), 144.3 (s), 132.9 (s), 128.5 (s), 127.8 (d), 126.4 (d), 124.2 (s), 121.8 (d), 116.8 and 116.5 (s), 113 115.0 and 114.7 (s), 111.2 (d) , 88.6 (d) , 61.9 (d) , 56.9 (t) , 55.8 (q), 48.3 (s), 33.0 (t), 29.8 (t). Example 32: 2- ( (6R) -6-Hydroxy-3-methoxy-5, 6, 9,10-tetrahydro-4aH-[llbenzofuro[3a, 3, 2-ef ] [2]benzazepine-11(12H)-ylmethylene) -malonic acid diethyl ester (4y): Process according to Example 11, reaction time 21 hours, yield 0.46 g (63.3%), melting point 145-146°C, same skeleton as compound 4v, only the different NMR signals are described: ^-NMR (CDC13) 6 6.83 (s, 1H) , 3.43 (m, 6H) ; 13C-NMR (CDCl3) 5 181.2 (s), 133.7 (d) , 116.6 (t), 48.3 (t). Anal. (C22H25NO70.25 CfiH14O) C, H, N. Example 33: >j3- ( (6R) -6-Hydroxy-3 -methoxy-5 ,6,9,10~tetrahydro-4aH-[1]benzofuro[3a,3,2-ef] [2]benzazepine-11(12H)-yl-acrylic acid ethyl ester (4z): Process according to Example 11, reaction time 20 hours, yield 0.30 g (46.2%), melting point 121-122°C, same skeleton as compound 4v, only the different NMR signals are ;i described: 1H-NMR (CDC13) 6 7.40 {dd, J1 = 16.0 Hz, J2 = 2.0 Hz, 1H) , 4.68 (d, J = 16.0 Hz, 1H) , 4.10 (m, 2H) , 1.28 8m, 3H) ; 13C-NMR (CDCI3) 5 169.3 and 167.8 (s) , 161.1 (d) , 97.5 (d) , 59.0 (t) , 14.5 and 14.3 (q). Process E: A solution (+/-)-norgalanthamine (0.5 g, 1.83 i mmol), 0.51 g (3.66 mmol) of potassium carbonate, (2.20 mmol) of sodium iodide and alkyl halide (2.20 mmol) in acetone (20 ml) were refluxed for 12 hours and concentrated by evaporation. The 114 residue was dissolved in 30 ml of 2N hydrochloric acid and extracted with 1 x 20 ml of AcOEt. The aqueous solution was set at pH > 8.5 with concentrated ammonia and extracted with AcOEt (3 x 20 ml). The combined, organic extracts were washed with common salt solution, dried (Na2SO4) , concentrated by evaporation and purified by MPLC. Compounds 4ab-4ah and 4an-4aq contain the basic galantharaine skeleton such as 4aa, but are different with respect to the nitrogen substituent. Since the proton and carbon signals of the galanthamine core are not essentially different from one another, only the NMR signals of the nitrogen substituent are relayed below. Example 34: Ethyl-2- ( (6R)-6-Hydroxy-3-methoxy-5,6,9, l0-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef] [2]bensazepine-11(12H)-yl)acetate (4ac) : According to process e with use of ethyl chloroacetate and a reaction time of 1 hour, 0.48 g of the compound (73%) was obtained; 'H-NMR (CDC13) 5 4.10 (m, 2K) , 3.32 (s, 2H) , 1.21 (t, J = 7.3 Hz, 3H) ; 13C-NMR (CDCl3) 5 170.7 (s) , 60.4 (t), 58.0 (t), 14.1 (q)- 115 Example 35: Instructions: SUBSTITUTION IN POSITION 1 Direct Introduction of New Substituents 3.2.1.1 [4aS-(4aa,6£,8aR*) ] -4 a,5r9,10 ,11,12-Hexahydro-l- (N,N- dimethylamino)-3-methoxy-ll-methyl-6H-benzofuro[3a, 3,2- ef][2]benzazepin-S-ol, 1-(N,N-dimethylamino)-galanthamine (MH-7) 320 mg (1.06 mmol) 1-aminogalanthamine (4) 0.50 ml formic acid in 2 ml of water 0.2 5 ml formaldehyde (3 7%) While being stirred with a magnet, all reactants, dissolved in 10 ml of water, were heated together to 70°C. After 4.5 hours, it was made basic with concentrated aqueous ammonia, whereby a white precipitate in yellow solution precipitated. The reaction mixture was exhaustively extracted with ethyl acetate, the combined organic phases were dried on sodium sulfate, filtered, and the solvent was drawn off. 116 .i The resulting substance mixture was separated on a silica gel column (CHC13 : MeOE = 1:1) and then distilled under high vacuum by means of a bulb tube. Yield: 0.17 g (0.52 mmol = 49% of theory) of a light yellow oil C19H26N2°3 [3 3 0.43] TLC: Rf = 0.49 (CHCl3 : MeOH =1:1) Boiling point: 180°C/0.01 Torr aB20 [c = 0.1, CHCI3] = -15 6.3 6° FID Numbers: 1H: MHEMOF.016, 13C: MHEM1F.002, DEPT: MHEM2F.002 1H-NMR (200 MHz, CDCI3) : 5 6.57 (s, 1H) , 6.08 (dd, J = 10.3, 1.0 Hz, 1H) , 5.97 (dd, J = 10.3, 4.8 Hz, 1H) , 4.56 (bs, 1H) , 4.45 (d, J.= 15.1 Hz, 1H) , 4.12 (bs, 1H) , 3.83 (s, 3H) , 3.55 (d, J = 15.1 Hz, 1H), 3.12 (td, J = 13.1, 1.7 Hz, 1H), 2.97 (dt, J.= 14.1, 3.5 Hz, 1H), 2.72-2.53 (m, IE), 2.58 (s, 6H), 2.44 (s, 3H) , 2.12-1.98 (m, 2H) , 1.62 (ddd, J = 13.6, 3.8, 2.1 Hz, 1H) ; 13C-NMR (50 MHz, CDCI3) : 5 147.1 (s), 143.2 (s), 142.0 (s), 133.7 (s), 127.3 (d), 127.2 (d), 124.2 (s), 103.9 (d), 88.3 (d), 62.0 (d) , 55.9 (q), 54.4 (t) , 54.1 (t) , 48.4 (s) , 45.7 (q), 44.2 (q) , 34.8 (t), 29.8 (t) 117 Example 37: (4aS/6R,8aS)-11-(3-Aminoethyl)-3-methoxy-5,6,9,10,11,12 -hexahydro-4aH-[1]benzofuro[3a,3,2-ef] [2]benzazepin-6-ol (4af), Process F, reactant compound 4ad, reaction time 1 hour; yield 0.31 g (59.2%); melting point 47-51°C; 1H-NMR- (CDC13) 5 2.69 (m, 2H) , 1-92 (b, 2H) ; 13C-NMR (CDC13) 5 51.9 (s), 38.0 (t). Example 40: Ethyl-3-((6R)-6-hydroxy-3-methoxy-5,6, 9,10-tetrahydro-4aH- [1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)propanoate (4ai): Process B, reaction time 4 hours; yield 0.64 g (47.5%); 1H-NMR (CDC13) 5 4.15 (q, J = 6.0 Hz, 2H) , 2.81 (t, 7.0 Hz, 2K) , 2.47 (t, J = 7.0 HZ, 2H) , 1.23 (t, J = 6 Hz, 3H) ; 13C-NMR (CDC13) 5 172.4 (s), 60.3 (t), 57.3 t-Butyl-3- ( (6R) -S-Hydroxy-3-methoxy~5,6,9, 10-tetrahydro-4aK-[1] benzofuro [3a,3,2-ef] [2] benzazepine-11 (12H) -yl) propanoate (4aj): Process B, reaction time 5 hours; yield 0.83 g (60.0%); ^I-NMR (CDCI3) a 2.82 (t, J = 7.0 Hz, 2H) , 2.40 (t, J = 7.0 Hz, 2H) , 1.43 (s, 91-:); 13C-NMR (CDCl.) 0 172.0 (s), 80.5 (s) , 57.7 (t), 34.2 (t), 28.0 (q) . Anal. (C24H33NO5) C, H, N. 118 Example 42: 3-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aK-[l]benzofuro [3a,3,2-ef ] [2] benzazepine-11 (12H) -yl) -N11- isopropylpropanamide (4ak) : Process B, reaction time 18 hours; yield 0.55 g (78.7%); 'H-NMR (CDC13) 5 3.81 (m, 1H) , 2.79 (t, J = 6Hz, 2H) , 2.32 (t, J = 6.0 Hz, 2H) , 1.10 (t, J = 12.0 Hz, 6H) ; 13C-NMR (CDClj) 5 171.4 (s) , 56.9 (t) , 40.7 (d) , 33.2 (t), 22.7 (qJ- Example 43: 3-((6R)-6-Hydroxy-3-methoxy-5, 6,9,10-tetrahydro-4aH- [1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)-Nl--t-butylpropanamide (4al): Process B, reaction time 24 hours; yield 0.37 g (51.2%); 1E-NMR (CDCI3) 5 2.76 (t, 6.0 Hz, 2H) , 2.29 (m, 2H) , 1.28 (s, 9H) ; 13C-NMR (CDCI3) 6 171.4 (s), 51.4 (t), 50.3 (s), 33.5 (t), 28.7 (q). Example 44: 3- ( (6R)-6-Hydroxy-3-methoxy-5, 6,9,10-tetrahydro-4aH-¦ [1] benzofuro [3a, 3, 2-ef] [2] benzazepine-11 (12H) -yDpropanitrile (4am): Process B, reaction time 4 hours; yield 0.53 g (90.6%); 'H-NMR (CDCI3) 6 2'.82 (t, J = 7.1 Hz, 2E) , 2.47 (t, J = 6.8 Hz, 2H) ; 13C-NMR (CDClj) 6 118.7 (s) , 51.6 (t) , 46.6 (t) , 16.7 (t). 119 Example 45: (6R)-11-(3-Hydroxypropyl)-3-methoxy-5, 6, 9,10, 11,12-hexahydro-4aH-[1] benzofuro [3a,3, 2-ef] [2] benzazepin-6-ol (4an) : Process F, reactant compound 4ai, reaction time 7 hours; yield 0.21 g (47.7%); 'H-NMR (CDC13) 5 3.77 (m, 2H) , 2.72 (m,-2H), 2.02 (m, 2H) ; 13C-NMR (CDCl3) 5 63.9 (t), 57.3 (t), 29.8 (t). Example 46: (6R) -11- (3-Aminopropyl) -3-Tnethoxy-5 , 6, 9,10-tetrahydro-4aH-[l]benzofuro[3a,3,2-ef] [2]benzazepin-6-ol (4ao) : Process F, reactant compound 4am, reaction time 1 hour; yield 78 mg (52.8%); ^H-NMR (CDCI3) 5 3.22 (m, 2H) , 2.68 (m, 2H) , 1.72 (m, 2H) ; 13C-NMR (CDCI3) 6 51.3 (t) , 37.8 (t) , 29.3 (t). Example 47: (6R) -11- (3-Piperidine-l-yl-propyl) -3-methoxy-5 ,6,9,, 10-hexahydro-4aH-[ljbenzofuro[3a,3,2-ef3 [2]benzazepin-6-ol (4ap): Process e, reaction time 3 days; yield 0.36 g (53.2%); ^-NMR (CDC13) 6 2.68 (m, 8H) , 1.77 {m, SH) , 1.50 (m, 2H) ; 13C-NMR (CDCI3J 6 57.4 (t), 1 44.1 (t), 49.2 (t), 24.7 (t), 23.4 (t), 23.3 (t). Example 48: Step 1: (4a,S,SR8aS)-3-Methoxy-5,6,9,10,11,12-hexahydro- 5 4aH[l] benzofuro [3a,3,2-ef[2] benzazepin-6-ol, {-) -norgalarithamine (8) . 120 Method l: A solution of 7.72 g {20.0 mmol) of (+)-0,O-di-p-toluoyl tartaric acid in 15 ml of methanol is added in drops to a solution of 10.92 g (40.0 mmol) of rac.norgalanthamine (4) in 40 ml of methanol, and it is then rewashed with 1 ml of methanol. The solution is mixed with a seed crystal (without a seed crystal, crystal formation can take several weeks), and it is allowed to stand for two days at 4°C. Then, it is thoroughly ground with a glass rod and allowed to stand for another two to five days at 4°C, whereby it is always thoroughly ground again with a glass rod. Then, the precipitated salt is suctioned off, rewashed three times with ice-cold methanol and taken up in 100 mi of water. The aqueous phase is made basic with concentrated aqueous ammonia and extracted three times with 60 ml each of ethyl acetate. The combined organic phases are washed once with saturated aqueous sodium chloride solution, dried (Na2SO4, activated carbon), filtered and concentrated by evaporation, by which 2.9 g (37.5% of theory) of colorless crystals is obtained on {-)-norgalanthamine (8). Method 2: m-CPBA (peroxide content 76%, 15.6 g 70 mmol) was added to a solution of galanthamine (1) (20.0 g, 70 mmol) in CH2C12 (350 ml), and the clear solution was stirred for 4 0 minutes at room temperature. In this stage, the conversion into the N-oxide was quantitative, as was found by HPLC. Then, a solution of FeS04.7H2O {9.7 g 35 mmol) in MeOH (100 ml) was added. The 121 mixture was stirred for 20 minutes, mixed with 2N hydrochloric acid (200 ml), the volatile portions (CH2C12 and MeOH) were evaporated at reduced pressure and then washed with ether (3 x 100 ml). The aqueous solution was set at pH > 8.5 with concentrated ammonia and extracted with CH2C12 (3 x 100 ml) and with CH2Cl2:Me0H = 9:1 (3 x 100 ml). The combined, organic extracts were washed with common salt solution (200 ml), dried on Na2SO4 and concentrated by evaporation to produce a crystalline product (18.2 g, 96%), which consisted of a 92:8 mixture of norgalanthamine and galanthamine. KPLC (CHCl3:Me0H:Et3N = 98:1.25:0.5), 16.1 g (84.7%) of norgalanthamine (8): ^-NMR (CDC13) 6 6.62 (b, 2H), 6.02 (m, 2H), 4.61 (b, 1H), 4.14 (t, J = 4.3 Ez, 1H), 3.98 (d, J = 5.0 Hz, 2K), 3.83 (s, 3H), 3.30 (m, IK), 2.69 (d, J = 15.7, 1H) , 2.10-1.63 (m, 4H) ; 13C-NMR (CDC13 6 146.2 (s) , 144.1 (s) , 13 3.1 (s) , 131.7 (s) , 127.8 (d) , 12 6.8 (d) , 120.8 (d), 111.1 (d), 88.4 (d), 61.9 (d), 55.9 (q), 53.3 (t), 48.5 (s), 45.7 (t), 39.4 (t), 29.9 (t). Step 2: '(4a, S,6R8aS) -3-Methoxy-ll-phenyl-S, 6,9,10,11,12-hexahydro-4aH[l]benzofuro[3a,3,2-ef[2]benzazepin-6-ol (8a). 0.28 g of phenylboric acid (7.2 mmol), 0.6 ml of pyridine (7.2 mmol) , 0.67 g of copper acetate (3.6 mmol) and one molecular sieve (L.O g) were added to a solution of 1.0 g of compound 8 (-)-norgalanthamine in 50 ml of CH2C12. The reaction mixture was stirred at room temperature for 3 days. The precipitate was filtered off and washed with 3 x 10 ml of CK2C12. The filtrate 122 was extracted 3 x with 50 ml of dilute ammonia solution. The combined, aqueous phases were extracted with 3 x 50 ml of CH2C12, the organic phases were washed with common salt solution, dried on sodium sulfate and concentrated by evaporation. MPLC yielded 0.33 g (26.4%) of compound 8a. Melting point 178-180°C; iH-NMR (CDC13) 57.18 (m, 2H) , 6.82 (m, 3H) , 6.67 (dd, Jx = 33.8 Hz, J2 = 7.6 Hz, 2H) , 6.05 Example 4 9: (4a,S,6R,8aS)-3-Methoxy-ll-thiophenyl-5,6, 9, 10,11,12-hexahydro-4aH-[ljbenzofuro[3a,3,2-ef][2]benzazepin-6-ol (8b). The compound was produced as in compound 8a, and the reaction time was 3 days, yield 0.14 g (28.0%). Only the NMR signals that are different from 8a are described: iH-NMR (CDC13) 57.23 (m, 1H) , 6.92 {t, J = 3.0 Hz, 1H), 6.83 (d, J = 2.7 Hz, 1H) ; 13C-NMR (CDC13 * 145.7 (s) , 127.6 (d), 126.2 (d) , 125.0 (d). Anal. (C20H21NO3S) C, H, N. 123 Example 50: (4a,S,6R,8aS)-ll-Benzoyl-piperidine-4-yl)-3-methoxy-5,6,9,10,11, 12-hexahydro-4aH-[l]benzofuro[3a,3,2 -ef][2]benzazepin-6-ol (8c). l-Benzoyl-piperidin-4-one (0.34 g, 1.7 mmol'i , 0.47 g of titanium isopropylate (1.7 mmol) and 3.6 g (1.3 mmol) of compound 8 were melted for 30 minutes at 110°C. After cooling at room temperature, a solution of sodium cyanoborohydride (65 mg, 0.9 mmol) in dry EtOH (10 ml) was added, and the reaction mixture was stirred at room temperature for 24 hours. After 2 ml of water was added, the precipitate was filtered off, the filtrate was concentrated by evaporation, and the residue was diluted with 20 ml of EtOAc and filtered again. The clear solution was concentrated by evaporation. MPLC yielded 0.24 g (38.8%) of compound 8c. 2H-NMR (CDC13) 5 7.52-7.31 (m, 5H), 6.65 (b, 2H) , 6.0 8 (m, 2H), 4.64 (b, 1H), 4.22-3.90 (m, 4H), 3.82 (s, 3H), 3.37 (m, 2H), 3.01-2.62 (m, 5H), 2.10-1.82 (m, 5H), 1.67-1.42 (m, 2H) ; 13C-NMR (CDC13) 5170.1 (s) , 145.8 (s) , 144.0 (s), 136.0 (s), 133.1 (s), 12 9.4 (d), 12 8.8 (d), 12 8.4 (d), 12 8.3 (d), 127.6 (d), 12 6.7 (d), 121.6 (d) , 111.2 (d) , 88.6 (d) , 61.9 (d), 55.8 (g), 55.6 (t), 48.3 (t), 30.8 (t), 29.8 (t). Example 51: (4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[l]benzofuro[3a,3,2-ef][2]benzazepine-ll(12H)-carboxylic acid phenyl ester (8e): 2.5 g of sodium bicarbonate (29.8 mmol) and 1.84 ml of phenyl chloroformate (14.6 mol) were added to a solution of 0.50 g of compound 8 (1.74 mmol) in 50 ml of CHC13. 124 The mixture was vigorously stirred and refluxed for two hours and then diluted with water {30 ml). The phases were separated. The aqueous phase was extracted with 2 x 3 0 ml of CH2C12, and the combined organic phases were washed with IN hydrochloric acid (30 ml), dried on sodium sulfate and concentrated by evaporation under reduced pressure to produce the crude product. MPLC (CH2Cl2:Me0H = 99:1) yielded 0.53 g (84.2%) of compound 8e: 1H-NMR (CDC13) 6 7.51-7.04 (m, 5H) , 6.82 (dd, J1 = 24.0 Hz, J2 = 6.0 Hz, 2H) , S.04 (b, 2H) , 4.91 (b, 1H) , 4.69 (d, J = 6.0 Hz, 2H) , 4.20 (b, 1H), 3.83 (s, 3H), 3.42 (m, 1H), 3.19 (m, 1H), 2.43-1.90 (m, 4H) ; 13C-NMR (CDC13) 5 151.3 (s) , 146.6 (s) , 145.7 (s), 130.5 (s) , 13 0.1 (s) , 12 9.4 (d) , 12 9.3 (d) , 125.9 (d) , 12 5.3 (d) , 125.0 (d) , 121.6 (d) , 111.9 (d) , 3 8.3 (d) , 62.8 (d) , 57.7 (t) , 55.9 (q) , 53.4 (t), 49.3 (s), 43.3 (t), 32.7 (t). Example 52: (4a,S,6R,8aS)-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[l]benzofuro[3a,3 , 2-ef ] [2]benzazepine-ll(12H)-carbothionic acid-O-phenyl ester {8f) : 0.24 ml of chlorothionoformate (1.74 mmol) was added to a solution of 0.50 g of compound 8 (1.74 mmol) in 25 ml of CHC13, and the reaction mixture was stirred for 1 hour under nitrogen. The solvent was separated to produce a colorless oil that was flash-chromatographed to produce 0.50 g (71.2%) of compound 8a: 1H-NMR (CDCl3) 125 (s), 146.7 and 146.6 (s), 145.8 and 145.7 (s), 131.3 and 130.6 (s), 130.2 and 129.5 (s), 129.2 and 129.1 (d) , 126.0 and 125.9 (d) , 125.0 and 124.9 (d) , 122.7 and 122.6 (d) , 121.6 and 120.4 (d), 115.3 (d) , 112.0 (d), 84.4 and 84.2 (d) , 63.1 and 62.9 (d), 55.9 (q), 51.5 (t), 49.5 and 49.3 (s), 47.8 (t), 36.9 (t), 33.1 (t) . Example 53: (4a,s,6R,8aS)-6-Hydroxy-3-methoxy-S,6,9,10-tetrahydro-4aH-[llbenzofuro[3a, 3 ,2-ef ] [2]benzazepine-11(12H)-carboxylic acid-9-H-fluor-9-ylmethyl ester (8g): 0.5 g of 9- fluorenylmethyloxycarbonyl chloride (20 mmol) was added to a solution of 0.5 g of compound 8 (1.8 mmol) and 2.5 ml of triethylamine (1.8 mmol) in 20 ml of CH2C12, and it was stirred for 3 0 minutes at room temperature. The reaction mixture was concentrated by evaporation, the residue was diluted with 80 ml of 2N hydrochloric acid and extracted with 5 x 50 ml of CH2Cl2. The organic phases were combined, washed with common salt solution, dried on sodium sulfate and concentrated by evaporation to produce 0.88 g (99.2%) of compound 8g. Melting point 76-79°C; O!D = -33.0°; 1H-NMR (CDCl3) 6 1.72 (dd, J = 13.5; 5.0 Hz, 1H) , 1.80-2.10 (m, 2H) , 2.69 (dd, J = 13.5; 5.0 Hz, 1H) , 3.20-3.45 (m, 2H) , 3.85 (s, 3H) , 3.95-4.35 (m, 3K) , 4.40-4.52 (m, 2H) , 5.78-6.05 (m, 2K) , 6.22-6.82 (m, 2H), 7.1S-7.82 (m, 8H); 13C-NMR (CDCI3) 5 155.1 (s), 144.4 (s), 144.0 (s), 141.4 (s), 134.0 (s), 129.1 (S) , 128.1 (s), 128.0 (d) , 127.6 (d) , 126.4 (d) , 124.9 (d) , 124.7 (d) , 121.0 (d) , 119.9 (d), 111.1 (d) , 88.3 (d) , 66.9 (t) , 126 61-.9 (d) , 56.0 (q) , 51.5 1-{{4a,S,6R, 8aS)-6-Hydroxy-3-methoxy-5, 6, 9,10-tetrahydro-4aH-[l]benzo£uro[3a,3,2-ef] [2]benzazepine-11(12H)-yl)pent-4-en-1-one (8h): 0.97 ml (5.1 mmol) of pent-4-enoic anhydride was added at 0°C to a solution of 1.0 g of compound 8 (3.7 mmol) and 0.51 ml (3.7 mmol) of triethylamine in 40 ml of CH2Cl2Me0H = 5:2, and it was stirred for 20 minutes. The reaction mixture was diluted with 20 ml of CH2Cl2, extracted with 2 x 20 ml of saturated sodium bicarbonate solution. The combined aqueous phases were extracted with 2 x 40 ml of CH2C12, the combined organic phases were washed with common salt solution, dried on sodium sulfate and concentrated by evaporation to produce 1.24 g (95.3%) of compound 8h: ^-NMR (CDC13) 5 6.6G (b, 2H) , 5.98 (m, 2H) , 5.78 (m, 1H) , 4.98 (m, 2H) , 4.66 (d, J = 12.8 Hz, 1H), 4.55 (s, 1H) , 4.41 (d, J = 16.5 Hz, 1H) , 4.11 127 Example 55: 1-((4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5, 6, 9, 10-tetrahydro-4aH-[l]benzofuro[3a,3,2-ef][2]benzazepine-ll(12H)-carboxamide Example 56: (4a,S,6R,8aS)-6-Hydroxy-3-methoxy-N1I-methyl-5,6,9,10-tetrahydro-4aH-[l]benzofuro[3a,3,2-ef][2]benzazepine-ll(12H)-carbothioamide (8j): Process according to Example 142, reaction time 4 hours, yield 1.02 g (88%); melting point 229-230°C, iH-NMR and 13C-NMR 128 were identical to compound 4t. Anal. CiaK22N2O3S .0.2 CH3C6H5 C, H, N. Example 57: (4a,S,6R,8aS)-S-Hydroxy-N^-isopropyl-S-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef] [2]benzazepine-11(12H)-carboxamide (8k): Process A, reaction time 3 hours, yield 1.86 g (71%); 1H-NNR and 13C-NMR were identical to compound 4i. Example 58: (4a,S,6R,8aS) -N11-t-Butyl-6-hydroxy-3-methoxy-5, 6 , 9,10-tetrahydro-4aH-[1] benzofuro[3a,3,2-ef ] [2]benzazepine-11(12H)-carboxamide (81): Process A, reaction time 3 hours, yield 1.63 g (60%) ; melting point 106-108°C; ^-NMR and 13C-NMR were identical to compound 4m. Example 59: (4a,S,6R,SaS)-6-Hydroxy-3-methyl-N11-2-trifluoromethyl-5,6,9,10-tetrahydro-4aH-[1] benzofuro[3a,3,2-ef] [2]benzazepine-11(12H) -carboxamide (8m): Process A, reaction time 5 hours, yield 0.60 g (59%); 1H-NMR (CDC13) 5 8.20. (t, J = 8.0 Hz, 1H) , 7.24 (m, 2H) , 7.02 £m, 1H) ; 13C-NMR {CDC13) 5 153.6 (s) , 137.6 (s) , 127.6 (d) ; 126.1 (d), 123.0 and 117.8 (s), 122.3 (d), 119.8 (s), 111.3 (d). 129 Example 60: Methyl- (4a,S,6R, 8aS), -Nn-Cyano-6-hydroxy-=3-methoxy-5 , 6, 9, 10-tetrahydro-4aH-[i]benzofuro[3a,3, 2-ef] [2]benzazepine-11 (12H) -carboximidothioate (8n). The compound was produced as described for compound 3bi. Reaction time 3 days, yield 0.90- g (33.2%); 1H-NMR (CDC13) 6 6.72 (m, 2H} , 5.98 (d, J = 10.2 Hz, 2H), 4.62 (m, 2H) , 4.14 (b, 1H) , 3.92 (d, J = 11.8 Hz, 1H) , 3.84 (s, 3H) , 3.44 (m, 2H), 2.74 (s, 3H), 2.63 (m, 1H), 1.99 (m, 3H); 13C-NMR (CDC13) 5 146.2 (s) , 144.9 (s) , 131.7 (s)",' 128.7 (d) , 125.8 (s) , 125.5 (d) , 121.8 (d) , 111,2 (d) , 88.1 (d) , 61.6 (d) , 55.8 (q) , 5TT2—Ct-)^-4-9-7—(ti-—4-7T9"(-s)-r-2-9~6—(-t-)^-l-6--l~(-q)-r Example 61: (4a,S,6R,8aS)-11-(Cyclopropylmethyl)-3-methoxy-5,6,9,10-tetrahydro-4aH-[1] benzofuro[3a, 3 , 2-ef ] [2] benzazepin-6-ol (80) : Process according to Example E, reaction time 36 hours, yield 0.12 g (29.0%); same skeleton as 4aa, only the different NMR signals are described. ^-KMR (CDC13) 6 3.48 (t, J = 8.0 Ez, 2E) , 0.91 (m, 1H) , 0.53 (d, J = 12 Hz, 2H) , 0.11 (d, J = 6 Hz, 2H) ; 13C-NMR (CDC1-) 6 57.2 (t) , 9.8 (d) , 4.7 (t) , 4.1 (t) . Example 63: 3- ( (4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3, 2-ef ] [2]benzazepine-11(12K)-yl)ethanonitrile (3r) : Process as in Example E, reaction time 2 hours, yield 1.67 130 g (61.1%); melting point 169-171°C; 'E-NMR and 13C-NMR were identical to compound 4ad. Anal. (CtflH2QN2O3.0. 6 7 H20) C, H, N. Example 64: 1-(2-Phenyl-2,5-diazabicyclo[2.2.1]heptane-5-yl)-2-((4a,S,6R,8aS)-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a, 3 , 2-ef ] [2]benzazepine-11(12H)-yl)-1-ethanone (8s): Process as in Example E, reaction time 3 days, yield 0.68 g (37.8%); melting point 85-89°C; c Example 65: (4a,S,6R,8aS)-11-(3-Aminoethyl)-3-methoxy-5,6,9,10,11,12-) hexahydro-4aK-[1]benzofuro[3a,3,2-ef] [2] benzazepin-6-ol { 8t) : Process according to Example F, reactant compound 8r; reaction time 18 hours, yield 1.01 g (66.1%); melting point 72-75°C; aD = -71.58°, 'H-NMR and 13C-NMR were identical to compound 4af- Anal. (C1SK24N203.0.6 5 EtOH.0.05 CK2Cl2) ) C, H, M. 131 Example 66: (4a,S,6R,8aS)-11-(2-Morpholine-4-yl-ethyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[l]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (8u): Process according to Example E, reaction time 2 days, yield 1.77 g (63.6%); melting point 101-104°C; aD20 = -110.9°, ^-NMR and 13C-NMR were identical to compound 4ag. Anal. (C22H30N2O40.15 CH2C12) C, H, N. Example 67: (4a,S,6R,8aS)-ll-(2-Phenyl-2,5-diazabicylo[2.2.1]heptane-5-yl-ethyl)-3-methoxy-5,6,9,10,11, 12-hexahydro-4aH- [l]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (8v): Process according to Example F, reactant compound 8s, reaction time 30 minutes, yield 0.26 g (50.8%); melting point 72-75°C; aD20 = -131.6°, XH-NMR and 13C-NMR were identical to compound 4ah. Anal. (C29H35N3O3.0.35 CH2Cl2.0.5 Et3N) C, H, N. Example 68: 3-((4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[ljbenzofuro[3a,3,2-ef][2]benzazepine-ll(12H)-yl)propanoic acid (8w): A solution of 8w (0.5 g, 1.25 mmol) was added to CH2C12 (20 ml) in trifluoroacetic acid (5 ml). The reaction mixture was stirred at room temperature for 2 hours and yielded a concentrate of 0.37 g (64.5%) of 8w: same skeleton as 4aa, only different NMR signals are described: ^-NMR (CDC13) 58.95 (b, 1H) , 2.82 (m, 2H), 2.25 (m, 2H). 132 Example 69: t-Butyl-3- ( (4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5, 6, 9, 10-tetrahydro-4aH-[l]benzofuro[3a,3,2-ef][2]benzazepine-11(12E)-propanoate (8x): Process B, reaction time S hours, yield 0.74 g (53.2%); ^-NMR and 13C-NMR were identical to compound 4aj . Example 70: (4a,S,6R,SaS)-11-(3-Hydroxypropyl)-3-methoxy-5,6,9,10,11, 12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef] [2]benzazepin-6-oi (8z) ; Process E, reaction time 4 days, yield 0.32 g (56.7%); aQ ~ 90.0°; 1H-NMR and 13C-NMR were identical to compound 4an. Example 71: (4a,S,6R,8aS)-ll-{(3-Dimethylamino)propyl-3-methoxy-5/6,9,10,ll,12-hexahydro-4aK-[1]bensofuro[3a,3,2-ef][2]benzazepin-S-ol (8aa): Process E, reaction time 24 hours, yield 0.45 g (51.6%); same skeleton as 4aa, only the different NMR signals are described. 1H-W1R (CDC13) d 2.50 (mf 2H) , 2.30 (m, 2H) , 2.22 {s, 3H) , , 2.18 (s, 3H), 1-82 (m, 2H> ; "C-NMR (CDC13) 5 55.6 (t) , 53.4 It), 45.0 (q); 25.3 (t) . 133 Example 72: (4a,S,6R,8aS)-3-Methoxy-11-(3-piperidine-l-yl-propyl)- 5,6, 9,10, ll,12-hexahydro-4aH-[1]benzofuro[3a,3,2- ef][2]benzazepin-6-ol (8ab): Process E, reaction time 3 days, yield 1.77 g (54.7%); melting point 84-92°C; aD20 = -50.64; 1H-NMR and 13C-NMR were identical to compound 4an. Anal. (C24H34N2O3.3C4H6O6) C, H, N. Example 73: (4a,S,6R,8aS)-11-{3-2-(4-Fluoro)phenyl-2,5- draiza±xrcyc±oi[2 .2.1] lrepfcaite—5—yl— -p^ropyi-)—3—me-bfooxy 5 , G , D , i-&r4r3rr3.-3- hexahydro-4aH-[l]benzofuro [3a,3,2-ef] [2]benzazepin-6-ol (8ac) : Process E, reaction time 4 days, yield 1.77 g (59.3%); melting point 84-92°C; aD20 = -50.64; ^-NMR and 13C-NMR were identical to compound 4aq. Anal. (C30H36FN3O3.2CH2Cl2.2 Et3N) C, H, N. Example 74: (4a,R,6S/8aR)-3-Methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro [3a,3,2-ef] [2]benzazepin-6-ol, { + ) norgalanthamine (9) was prepared and described for 8: yield 5.35 g (74.2%); 1H-NMR and 13C-NMR were identical to compound 8. Example 75: (4a,R,6S,3aR)-6-Hydroxy-N11-isopropyl-3~methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef] [2] benzazepine-11(12H) -carboxamide (9aJ : Process A, reaction time 3 hours; yield 1.03 g (79%); 1K-NMR and 13C-NMR were identical to compound 41. 134 Example 76; (4a, R, 6S, SaR) -N'1-t-Butyl-6-hydroxy-3-ir.ei:hoxy-5, 6, 9, 10-tetrahydro-4aK-[1]benzofuro[3a,3,2-e£J [2]benzazepine-11 [12KJ-carboxamide Ob): Process Af reaction time 3 hours; yield 0.35 c (S3%); ^-NMR and 13C-*WIR were identical to compound 4m. Example 77 i (4a,R,€S,BaH)-3-Hethoxy-ll- (2-morphoiine-4-yl-ethylJ- 5,6,9,l0,ll,l2-hexahydro-4aH- [1]benzofuro[3a,3,2- ef] [2]benzazepin-S-ol (9c): Process 2, reaction time 2 days; yield 0.12 g (53.2%); ^-NMR and 13C-NMH were identical to compound 4ag, Example 78: (4a,R, 6S, 8aR) -11- ( (3-Dimethylamino)propyl) -3-rnethoxy- 5,G,5,10,11,i2-hexahydro-4aK- fl]benzofuro [3 a,3,2- ef] [2] ber.zasepin-6-ol (9d) : Process E, reaction time 22 hours; yield 0.13 g (44.6%); ^K-NMR and -3C-NXR were identical to compound 3aa. Exajaple 79 i (4a,R,6S,SaR)-11-(3-Piperidine-i-yl-propyl)-3-rcethoxy- 5, 6, 9, 10,11, 12-hexaJiydro-4aH- fl] benzofuro [3a, 3 , 2- ef] [2]benzazepin-6-ol (9e): Process S, reaction time 20 hours; yield 0.33 g (75.0%); ^-CTIR and 13C-NTviR were identical to compound 4ap. 135 Example SO: Step 1: 2-Bromo-4-methoxy-5-(1-methylethoxy)benzaldehyde 2-Bromo-5~hydroxy-4-methoxybenzaldehyde (100.0 g, 433 mmol), 2-bromopropane {160.0 g, 1.30 mol) and potassium carbonate (300 g, 2.16 mol, anhydrous, freshly ground) are stirred in acetonitrile (1200 ml) for 48 hours at 60°C. The reaction mixture is filtered, the solvent is distilled off in a rotary evaporator, and the residue is dispersed between water (800 ml) and ether (800 ml). The aqueous phase is extracted with ether (2 x 300 ml) , the combined organic phases are washed with water (2 x 500 ml) and saturated common salt solution (1 x 500 ml), dried (sodium sulfate/activated carbon), filtered, and the residue that is obtained after the solvent was distilled off is recrystallized from methanol (500 ml). In this way, the product is obtained in the form of pale rose-colored crystals (98.1 g, 83%). Melting point: 75-76°C 136 TLC: Petroleum ether : ethyl acetate = 3:1, Rf = 0.75 1H NMR (CDC13) : 6 10.13 (s, 1H) , 7.40 (s, 1H) , 7.03 (s, 1H) , 4.61 (septet, J = 6.4 Hz, 1H) , 3.92 (s, 3H) , 1.38 (d, J = 6.4 HZ 6H); 13C NMR (CDC13) : 5 190.8 (d) , 15.6 (s), 147.1 (s), 126.4 (S), 120.0 (S), 115.8 (d), 113.7 (d), 71.5 (d), 56.4 (q), 21.8 (q) Step 2: 2-Bromo-4-metb.oxy-5- (1-methylethoxy) benzenemethanol 2-Bromo~4-methoxy-5-(1-methylethoxy)benzaldehyde (6.0 g, 22.0 mmol) is added in substance at X5°C within 15 minutes to a suspension of sodium borohydride (1.67 g, 44.1 mmol) in anhydrous .ethanol (60 ml) , and the mixture is stirred for one hour at room temperature. The residue that remains after the solvent is distilled off is dispersed between saturated sodium bicarbonate solution (60 ml) and ether (100 ml) . The aqueous phase is extracted with 137 ether (3 x 40 ml),-the combined organic phases are washed with saturated sodium bicarbonate solution (1 x 100 mi}, water (1 x 100 ml) and saturated common salt solution (1 x 100 ml), dried (sodium sulfate/activated carbon) and filtered. After the solvent is distilled off in a rotary evaporator, the product is obtained in the form of colorless crystals (5.575 g, 95). Melting point: 67-69°C TLC: Petroleum ether : ethyl acetate = 4:1, Rf = 0.25 1H NMR (CDC13) : 6 7.00 (s, 2H) , 4.64 {s, 2H) , 4.50 (septet, J = 6.4 Hz, 1H), 3.85 (s, 3H), 2.05 (s, 1H), 1.34 (d, J = 6.4 Hz, 6H) ; 13C NMR (CDC13) : 6 150.1 (s), 14S.5 (s), 131.8 (s), 116.1 (s) , 115.9 (d) , 112.6 (s) , 71.7 (t), 64.3 (d) , 56.0 (q) , 21.8 (q) MT-44 JOS 1693 CiiH15BrO3 Cld.: C, 48.02; H, 5.50 Fnd.: C, 48.11: H, 5.29 Step 3: l-Bromo-2- (chloromathyl) -5-methoxy-4- (1-methylethoxy) -benzene 138 Thionyl chloride (20 ml) in absolute CH2Cl2 (10 ml) is added in drops within 10 minutes to 2-bromo-4~methoxy-5-(1-methylethoxy)benzenemethanol (5.63 g, 20.5 mmol) in absolute CH2C12 (60 ml), and it is stirred for 90 minutes at room temperature. The residue that is obtained after solvent is removed in a rotary evaporator is dispersed between ether (100 ml) and saturated sodium bicarbonate solution (100 ml), the combined organic phases are washed with saturated sodium bicarbonate solution (2 x 100 ml), water (1 x 100 ml) and saturated common salt solution {1 x 100 ml), dried {sodium sulfate/activated carbon), filtered, and the solvent is distilled off in a rotary evaporator. In this way, the product is obtained in the form of colorless crystals (5.72 g, 95%). Melting point: 68-70°C TLC: Petroleum ether : ethyl acetate = 3:1, Rf = 0.9 'll NMR (CDC13) : 6 7.05 (s, 1H) , 6.97 (s, 1H) , 4.66 (s, 2H) , 4.51 (septet, J = 6.4Hz, 1H) , 3.85 (s, 3H) , 1.37 (d, J = 6.4 Hz, 6EJ ; 13C NMR (CDC13) : 6 151.2 (s), 146.8 (s) , 128.5 (s) , 117.7 (s), 116.1 (d), 114.8 (s), 71.9 (t), 56.2 (d), 64.4 (q), 21.9 (q) MT-45 JOS 1760 C14H20°3 Cld.: C, 71.16; H, 8.53 Fnd.: C, 70.90; H, 8.28 139 Step 4: 1-[4-(l-Methylethoxy)phenylJethanone 1-(4-Hydroxyphenyl)ethanone (12.7 g, 93.2 mmol), 2-bromopropane (57.3 g, 466 mmol) and potassium carbonate (62.2 g, 4 66 mmol, anhydrous, freshly ground) are stirred in absolute acetonitrile (150 ml) for 24 hours.at 60°C. The reaction mixture is filtered, the solvent is distilled off in a rotary evaporator, and the residue is dispersed between water (200 ml) and ether (200 ml). The aqueous phase is extracted with ether (2 x 80 ml) , the combined organic phases are washed with water (2 x 100 ml) and saturated common salt solution (1 x 100 ml), dried (sodium sulfate/activated carbon) and filtered. In this way, after the solvent is distilled off, the product is obtained in the form of colorless crystals (16.8 g, 99%) . Melting point: 36-80°C TLC: Petroleum ether : ethyl acetate = 4:1, Rf = 0.5 140 'H NMR (CDC13) : 5 7.82 (d, J = 9.5 Hz, 2H) , 6.88 (d, J = 9.5 Hz, 2H) , 4.63 (septet, J = 6.4 Hz, 1H) , 2.52 (s, 3H) , 1.33 (d, J = 6.4 Hz, 6H) ; 13C NMR (CDC13) : 6 196.7 (s), 161.9 (s), 130.5 (d) , 129.8 (s), 115.0 (d), 70.0 (d), 26.2 (q), 21.8 (q) Step 5: 2-Bromo-l-[4-(1-methylethoxy)phenyl]ethanone Bromine (11.7 g, 73.5 mmol) in absolute dioxane (70 ml)/absolute ether (100 ml) is added in drops within one hour to a solution of 1-[4-(1-methylethoxy)phenyl]ethanone (10.0 g, 56.0 mmol) in absolute dioxane (100 ml), and it is stirred for 2 hours at room temperature. The reaction mixture is mixed with sodium sulfite (5.0 g) in water (100 ml), the phases are separated, and the aqueous phase is extracted with ether (3 x 100 ml), the combined organic phases are washed with water (2 x 100 ml) , saturated sodium bicarbonate solution (2 x 150 ml) and saturated common salt solution (1 x 200 ml), dried {sodium 141 sulfate/activated carbon), filtered, and the residue that is obtained after the solvent is distilled off is crystallized unde a mixture that consists of petroleum ether (25 ml) and cyclohexane (25 ml) at -20°C. In this way, the product is obtained in the form of colorless crystals that rapidly become dark in color (8.80 g, 59%). Melting point: 36-37°C TLC: Petroleum ether : ethyl acetate = 4:1, Rf = 0.7 'H NMR (CDC13) : 5 7.93 (d, J = 9.5 Hz, 2H) , 6.92 (d, J = 9.5 Hz, 2H) , 4.63 (septet, J = 6.4 Hz, 1H) , 4.40 (s, 2H) , 1.35 (d, J = 6.4 Hz, 6H); 13C NMR (CDC13) : 6 189.8 (s), 162.7 (s), 131.4 (d) , 126.4 (s), 115.3 (d), 70.3 (d), 30.7 (t), 21.9 (q) Step 6: 1-(2-Bromoethyl)-4-(l-methylethoxy)benzene Tert-butylamine-borane complex (7.45 g, 85.0 mmol, pellets or powder) is added at 5°C to a suspension of anhydrous aluminum 142 chloride {5.70 g, 43.0 mmol) in absolute CK2C12 {100 ml). After 15 minutes, 2-bromo-l-[4-(1-methylethoxy)phenyl]-ethanone (7.30 g, 28.4 mmol} in anhydrous CH2C12 (50 ml) is added in drops within 3 0 minutes. The mixture is stirred for three hours at room temperature, mixed with 0.IN hydrochloric acid {100 ml), and the aqueous phase is extracted with CH2C12 (2 x 30 ml). The combined organic phases are washed with 0.IN hydrochloric acid (2 x 50 ml), saturated sodium bicarbonate solution (2 x 5 0 ml) and saturated common salt solution {1 x 100 ml), dried (sodium sulfate/activated carbon) , and the residue that is obtained after the solvent is concentrated by evaporation is purified by bulb tube distillation (0.05 mbar/80°C) , whereby the product is obtained as a colorless oil (5.81 g, 83%) . TLC: Petroleum ether, Rf =0.35 'H NMR (CDC13) : 5 7.18 (d, J = 9.5 Hz, 2H) , 6.87 (d, J = 9.5 Hz, 2H) , 4.53 (septet, J = 6.4 Hz, IK), 3.53 (t, J = 6.9 Hz, 2H) , 3.08 (t, J = 6.9 Hz, 2K) , 1.33 (d, J = 6.4Hz, 6H) ; 13C NMP. (CDC13) : 5 156.7 (s) , 130.7 (s) , 129.5 (d) , 115.8 (d), 69.8 (d), 38.5 (t), 33.2 (t), 21.9 (q) MT-35 JOS 1760 Cl1Hl5BrO Cld.: C, 54.34; H, 6.22 Fnd.: C, 54.34; E, 6.0 9 143 Step 7: 2-[2-[4-(l-Methylethoxy)phenyl]ethyl]propanedioic acid dimethyl ester 1-(2-Bromoethyl)-4-(1-methylethoxy)benzene [19.0 g, 78.1 mtnol) , malonic acid dimethyl ester (40.0 g, 300 mmol) and potassium carbonate {42.0 g, 3 00 mmol, anhydrous, freshly ground) in absolute DMF (400 ml) are stirred for 10 hours at 70°C. The solvent is removed in a rotary evaporator, and the residue is dispersed between water (250 ml) and ether (250 ml). The aqueous phase is extracted with ether (1 x 100 ml), the combined organic phases are washed with water (3 x 200 ml) and saturated common salt solution (1 x 150 ml), dried (sodium sulfate/activated carbon) and excess malonic acid dimethyl ester is distilled off from the residue that is obtained after the solvent is removed from the rotary evaporator {160°C/15 mbar). The crude product is purified by means of bulb tube distillation (140°C/0.001 mbar), by which the product is obtained as a colorless oil (18.9 g, 82%). 144 TLC: Petroleum ether : ethyl acetate = 9:1, Rf = 0.4 1H NMR (CDC13) : 5 7.08 (d, J = 10 Hz, 2H) , 6.81 (d, J = 10 Hz, 2H) , 4.50 (septet, J = 6.5 Hz, 1H) , 3.71 (s, 6K) , 3.32 Step 8: 2- [2-Bromo-4-methoxy-5- (l-methylethoxy)phenyl] methyl-2- [2- [4- (1- methylethoxy)phenyl] ethyl] propane-dioic acid methyl ester 2- [2 [4- (l-Methylethoxy)phenyl]ethyl]propanedioic acid dimethyl ester {18.9 g, 64,2 mmol), l-bromo-2-(chloromethyl)-4-(1-methylethoxy)-5-methoxybenzene {18.9 g, 64.2 mmol) and potassium carbonate (45.0 g, 32 1 mmol, anhydrous, freshly 145 ground) in absolute DMF {300 ml) are stirred for 12 hours at 60°C. The residue that remains after the solvent is removed is dispersed between water (250 ml) and ether {250 ml). The aqueous phase is extracted with ether {1 x 100 ml), the combined organic phases are washed with water (3 x 200 ml) and saturated common salt solution (150 ml), dried (sodium sulfate/activated carbon), filtered, and the solvent is removed in a rotary evaporator. After drying under high vacuum, the product is obtained as a colorless oil (33.7 g, 95%). TLC: Petroleum ether : ethyl acetate = 9:1, Rf = 0.5 1H NMR (CDC13) : 6 7.04 (s, IK), 7.01 (d, J = 10 Hz, 2H) , 6.79 {d, J = 10 Hz, 2H), 6.73 (s, IE); 4.47 (septet, J = 6.5 Hz, IK), 4.36 (septet, J = 6.5 Hz, 1H), 3.80 (s, 3H) , 3.72 (s, 6H) , 3.48 (s, 2H), 2.65-2.47 (m, 2H) , 2.26-2.06 (m, 2H), 1.31 (d, J= 6.5 Hz, 12H); 13C MR (CDCI3) : 6 171.4 (s) , 156.1 (s), 149.8 (s), 146.2 (s), 133.0 (s), 129.3 (s), 129.1 (d), 118.2 (s), 116.2 (d), 116.0 (d), 115.8 (d) , 69.7 (d) , 53.7 (s) , 55.9 (q) , 52.3 (q) , 37.4 (t), 34.5 (t), 29.9 (t), 21.95 (q), 21.9 (q) MT-54 JOS 1698 C27K35BrO7 Cld.: C, 58.31; H, 6.4 0 Fnd.: C, 59.00: H, 6.26 146 Step 9: Alpha- [ [2-bromo-4-methoxy-5- (1-methylethoxy) phenyl] methyl] -4- (1- methylethoxy)benzenebutanoic acid 2- [2-Bromo-4-methoxy-5- {1-methylethoxy) phenyl] methyl-2 - [2-[4-(1-methylethoxy}-phenyl]ethyl]propanedioic acid dimethyl ester (33.7 g, 61.1 mmol) and potassium hydroxide (17.5 g, 312 mmol) are stirred in ethanol (150 ml)/water (30 ml) for 12 hours at boiling temperature. The reaction mixture is acidified with concentrated hydrochloric acid up to a pH of 1 and kept under reflux for one hour. The residue that remains after the solvent is removed is dispersed between water (250 ml) and ether (250 ml) . The aqueous phase is extracted with ether (2 x 100 ml) , the combined organic phases are washed neutral with water, washed with saturated common salt solution (150 ml), dried (sodium sulfate/activated carbon) and filtered. The residue that remains after the solvent is removed is decarboxylated in a bulb tube for 3 0 minutes at 147 140°C and then distilled at 150cC/0.005 mbar. In this way, the product is obtained in the form of colorless crystals (27.5 g, 94%) . Melting point: 114-116°C TLC; Chloroform : methanol = 9:1, Rf - 0.65 *H NMR (DMSO-d6) : 6 7.09, (s, 1H) , 7.01 (d, J - 7.3 Hz, 2H) , 6.80 (s, 1H), 6.78 (d, J = 7.3 Hz, 2H), 4.69-4.37 (m, 2H), 372 (s, 3H), 3.00-2.33 (m, 5H), 1.99-1.58 (m, 211), 1.18 (d, J = 6.4 Hz, 12H); 13C NMR (DMSO6) : 5176.0 (s) , 155.6 (s) , 149.3 (s) , 145.8 (s), 133.1 (s), 130.3 (s), 129.1 (d) , 118.1 (d), 116.0 (d) , 115.5 (s), 114.1 (d), 70.6 (d), 69.0 (d), 55.8 (q), 44.9 (d), 33.5 (t), 31.9 (t), 21.85 (q), 21.8 (q) MT-100 JOS 1592 C2 Step 10: Alpha[[2-bromo-4-methoxy-5-(1-methylethoxy)phenyl]methyl3-4-(1- methylethoxy)benzenebutanoic acid amide 148 Thionyl chloride (50 ml) is added in drops at 0°C within 15 minutes to alpha[[2-bromo-4-methoxy-5- methylethoxy)phenyl]methyl]~4-(1-methylethoxy)-benzenebutanoic acid (10.0 g, 20.8 mmol) in CH2C12 (100 ml), and the mixture is stirred for two hours at this temperature. The solvent is removed in a rotary evaporator, the residue is taken up in absolute formamide (15 ml) and mixed at 0°C with ammonia in formamide (100 ml of a solution that is saturated at this temperature). The mixture is stirred for one hour at 0°C and poured onto water (1500 ml). The precipitated crystals are filtered off and digested with water (4 x 400 ml). In this way, the product is obtained in the form of colorless crystals (9.21 g, 92%). Melting point: 154-156°C TLC: CH2C12 : methanol =9:1, Rf = 0.7 2H NMR (DMSO-d6) : 5 7.32 (s, 1H) , 7.08 (s, 1H) , 7.02 (s), 133.5 (s), 130.9 (s), 12 9.9 (d), 118.1 (d), 115.8 (d), 115.5 (s), 114.1 (d), 70.9 (d), 69.0 (d), 55.8 (q), 45.9 (d), 34.2 (t), 32.1 (t), 21.85 (q), 21.8 (q) MT-112 JOS 1591 C24H32BrNO4 Cld.: C, 60.25; H, 6.74; N, 2.93 Fnd.: C, 59.99; H, 6.56; N, 2.82 Step 11: Production of alpha [ [2-bromo-5-hydroxy-4-methoxyphenyl]methyl]-4- hydroxybenzenebutanoic acid amide Boron trichloride (4 0 ml, 1.6 M in CH2C12) is added in drops at -78°C to a solution of alpha[[2-bromo-5-hydroxy-4-methoxyphenyl]methyl]-4-hydroxybenzenebutanoic acid amide (9.30 g, 19.4 mmol) in absolute CH2C12 (150 ml), and it is stirred for one hour at this temperature. Then, the mixture is heated to room temperature and stirred for two hours. It is mixed with water (300 ml), and the organic solvent is distilled off in a rotary evaporator, whereby the crude product precipitates as crystals, the latter is filtered off and is digested with water (6 x 200 ml) and diisopropyl ether (2 x 40 ml) . In this case, the product is obtained in the form of colorless crystals (6.76 g, 88%). 150 Melting point: 177-179°C TLC: CH2C12 ; methanol = 9:1, Rf = 0.4 1H NMR (DMSO-d6) : 6 9.18 (s, 2H) , 7.18 (s'. III), 7.04 (s, 1H), 6.97 (d, J = 7.3 Hz, 2H), 6.72 (s, 1H), 6.65 (s, 1H), 6.66 (d, J = 7.3 HZ, 2H), 3.77 (s, 3H), 3.48 (s, 3H), 2.92-2.38 (m, 4K) ; 13C NMR (DMSO-d6) : 5 175.6 (s) , 155.5 (s), 147.0 (s), 145.8 (s) , 131.3 (s) , 129.9 (s) , 12 9.8 (d) , 117.9 (s) , 115.8 (d) , 115.' (d), 11.9 C13H20BrO4 Cld.: C, 54.84; H, 5.11; N, 3.55 Fnd.: C, 54.55; H, 4.90; N, 3.28 Step 12: l-Bromo-4a/5,9,10,11,12-hexahydro-3-methoxy-6-oxa-6H- benzo[a]cyclohepta[hi]benzofuran-ll-carboxylic acid amide 151 a-[[2-Bromo-5-hydroxy-4-methoxyphenyl]methyl]-4-hydroxybenzenebutanoic acid amide {3.00 g, 7.61 mmol) is suspended in chloroform (300 ml) and mixed with a solution of potassium hexacyanoferrate (III) (13.2 g, 40.0 mmol) in potassium carbonate solution (75 ml, ten percent). The mixture is stirred vigorously at room temperature for 40 minutes and filtered on Hyflo. The aqueous phase is extracted with chloroform (3 x 5 0 ml), the combined organic phases are washed with water (2 x 20>0 ml) and saturated common salt solution (1 x 150 ml), dried (sodium sulfate/silica gel), filtered, and the crude product that is obtained after the solvent is concentrated by evaporation is purified by column chromatography (50 g of silica gel, ethyl acetate). In this way, the product is obtained in the form of colorless crystals (0.36 g, 12%). TLC: Chloroform : methanol = 9:1, Rf = 0.4 and 0.5 1H NMR (CDC13) : 5 7.00 (s, 1H) ; 6.86 (dd, J = 12 Hz, J = 1 Hz, 1H) , 6.06 (d, J = 1 Hz, 1H) , 5.02 (bs, 2H) , 4.70 (s, 1H) , 3.82 (s, 3H), 3.62 (d, J = 16 Hz, 1H), 3.23 (dd, J = 16 Hz, J = 3 Hz, 1H) , 3.08-2.89 (m, 1H), 2.77 (dd, J = 16 Hz, J = 6 Hz, 1H) , 2.62-1.70 (rn, 5K) 13C NMR (DMS0-d6) : 5 202.5 (s), 1S4.S and 179.1 (s), 146.5 and 146.1 (d) , 145.0 and 145.9 (s) , 143.3 and 142.0 (s) , 132.0 and 131.8 (s), 128.9 and 128.0 (s), 126.7 and 126.2 (d), 116.3 and 115.0 (s), 114.4 (d) , 87.4 and 87.3 (d) , 56.0 (q), 49.5 and ; 49.3 (s), 45.3 (d), 37.3 and 37.0 (t), 35.4 (t), 34.4 (t), 30.4 (t) 152 Deeper-Running Diastereomer ]H KMR (CDC13) : 8 6.70-6.85 {m, 2H) , 6.07-5.91 {tn, 2H) , 4.54 (s, 1H) , 4.12 (s, 1H) , 3.82 (s, 3H) , 2.99 (s, IE), 2.86 (t, J = 15 Hz, 1H), 2.72 (d, J = 16 Hz, 1H), 2.63 (dd, J = 16 Hz, J = 3 Hz, IK) , 2.30-1.60 (m, 9H) ; 13C NMR {CDC13) : 6 146.4 (s), 143.9 (s), 133.7 (s), 128.5 (s) , 128.1 (d) , 127.5 (d) , 123.3 (d) , 111.7 (d) , 88.9 (d) , 62.4 (d) , 56.3 (q), 52.8 (d) , 48.3 (s), 45.1 (t), 35.8 (t), 35.6 (t) , 30.4 (t) MT-115 JOS 1585 C18H18BrNO4 Cld.: C, 55.12; H, 4.63; N, 3.57 Fnd.: C, 54.91; H, 4.66; N, 3.41 Example 81: l-Bromo-4a/ 5, 9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H- benzo [a] cyclohepta [hi] benzofuran.-11-carboxylic acid amide 153 L-Selectride(R) (6.S ml, 6.6 mmol, 1 M in THF) is added at 0QC within 15 minutes to a suspension of l-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxa-6H-benzo[a]cyclohepta[hi]benzofuran-ll-carboxylic acid amide (860 mg, 2.19 mmol) in absolute THF {5 ml), and the mixture is stirred for 12 hours at room temperature. It is hydrolyzed with water (3 ml) and dispersed between water (10 ml) and ethyl acetate (10 ml), the aqueous phase is extracted with ethyl acetate (3x5 ml), the combined organic phases are washed with IN hydrochloric acid (3 x 10 ml), water (2 x 10 ml), saturated sodium bicarbonate solution (1 x 10 ml) and saturated common salt solution (1 x 10 ml), dried (sodium sulfate/activated carbon), filtered, and the crude product that is obtained after the solvent is distilled off is purified by column chromatography {50 g of silica gel, ethyl acetate). In this way, the product is obtained in the form of colorless crystals (741 mg, 86%). TLC: Chloroform : methanol = 9:1, Rf = 0.35 and 0.4 5 1H NMR (CDC13) : 6 6.92 (s, IK), 6.10-5.89 (m, 2H) , 5.82-5.53 (m, 2H), 4.54 (s, 1H) , 4.13 (s, 1H) , 3.81 (s, 3H) , 3.51 (d, J = 15 HZ, IK), 3.05 (dd, J = 17 Hz, J = 6 Kz, IK), 2.96-2.84 (m, 1H), 2.65 (d, J = 16 Hz, IK), 2.83 (dd, J = 16 Hz, J = 6 Kz, IK), 2.44-1.40 (m, 9H); 13C NMR (CDC13) : 5 177.7 and 175.2 (s) , 145.3 (s) , 145.7 (s), 144.2 (s) , and 143.9 (s) , 133.3 and 134.2 (s) , 128.3 and 128.2 (d) , 126.5 (d), 116.1 and 115.9 (s), 115.3 and 115.1 (d), 83.5 (d), 61.8 (d), 56.1 (q), 49.1 and 49.0 (s), 46.0 (d), 41.9 (t), 35.9 and 35.7 (t), 29.8 and 29.6 (t), 23.8 and 26.2 (t) 154 MT-120 JOS 1710 C18H2QBrNO4 Cld.: C, 54.84; H, 5.11; N, 3.55 Fnd.: C, 54.84; H, 5.18; N, 3.43 Example 82: ll-Amino-l-bromo-4a/5/ 9,10,11,12-hexahydro-3-methoxy-S-hydroxy- 6H-benzo[a] cyclohepta[hi]benzo-furan-6-ol (SPH-1459) gel, chloroform : methanol : ammonia = 96:3:1). In this way, the product is obtained in the form of colorless crystals (490 mg, 75%) . TLC: Chloroform : methanol = 9:1, Rf = 0.2 and 0.25 1H NMR (MeOH-d4) : 8 7.07 (s, 1H) , 6.12-5.87 {m, 2H) , 5.82-5.53 (m, 2H), 4.53 (s, 1H), 4.14 (s, 1H) , 3.80 (s, 3H), 3.59 (d, J = 20 Hz, 1H), 3.14-2.92 (m, 1H), 2.47 (d, J = 17 Hz, 1H), 2.16 (S, 3H), 2.01-2.62 (m, 2H); 13C NMR (MeOH-d4) : 5 148.3 and 148.2 (s) , 146.5 and 146.1 (s), 135.8 (s), 129.9 and 129.3 (s), 128.5 and 127.9 (d), 125.9 and 123.9 (d), 118.4 and 118.1 (s) , 116.9 and 116.0 (d) , 118.4 and 118.0 (s), 116.8 and 116.0 (d), 89.0 and 88.9 (d), 62.4 and 62.3 (d) , 57.2 (g) , 50.6 and 50.4 (s) , 49.8 (d) , 38.5 (t) , 36.0 and 33.0 (t) , 31.8 and 31.0 (t), 31.4 and 2 8.3 (t) JOS 1707 C17H20BrNO3*l CHC13 Cld.: C, 44.52; H,.4.36; N, 2.88 Fnd.: C, 44.90; H, 4.30; N, 2.67 156 Example 83: ll-Amino-4a/5/9,10/ll/12-hexahydro-3-methoxy-6~hydroxy-6H- benzo[a]cyclohepta[hi]benzof-uran-6-ol Production of the Copper-Zinc Alloy Zinc powder (600 mg) and copper(I) iodide are reacted under argon in water (4 ml) and ethanol (4 ml) for 45 minutes in an ultrasonic bath, whereby a dark-black, fine-powder suspension is produced. Debromination ll-Amino-l-bromo-4a,5,9,10,11,12-hexahydro~3-methoxy-6-hydroxy-6H-benzo[a]cyclohepta[hi]benzofuran-6-ol (8 0 mg, 0.22 mmol) and calcium chloride (300 mg, 2.7 mmol) are added in substance to the suspension that is produced, and the mixture is stirred for 12 hours at boiling temperature. It is mixed with concentrated aqueous ammonia solution (1 ml), the solvent is removed in a rotary evaporator, the residue is taken up in chloroform (15 ml) , filtered, and the residue that is obtained 157 after the filtrate is concentrated by evaporation in a rotary evaporator is purified by column chromatography {30 g of silica gel, chloroform : methanol : ammonia = 56:3:1). In this way, the two optical isomers can be separated (10 mg, 0.04 mmol of isomer A: 26 mg, 0.09 mmol of isomer B; a total of 36 mg, 59%) and obtained as a colorless foam. Higher-Running Diastereomer 1H NMR (CDC13) : 5 5.73-6.62 (m, 2H) , 6.05 (s, 2H) , 4.62 (s, 1H) , 4.14 (s, 1H) , 3.82 (s, 3H) , 3.57 (s, 1H) , 3.22 (d, J = 16 Hz, 1H), 2.83 13C MR (CDC13) : a 146.2 (s), 144.3 (s), 133.6 (s), 128.4 (s) , 128.1 (d) , 127.2 (d) , 124.8 (d) , 111.9 (d) , 89.0 (d) , 62.6 (d), 56.3 (q) 49.0 (s), 48.3 (d), 41.8 1H NMR (CDC13) : 5 6.70-6.58 (m, 2H) , 6.07-591 {m, 2HJ , 4.54 (S, 1H), 4.12 (s, IK), 3.82 Diagram for Example 83: 158 159 Example 84: Step 1: Condensation and Reduction: General Operating Instructions 1 equivalent 2 -methyl-4-methoxy-5-hydroxybenzaldehyde or 2,4-dimethoxy-5-hydroxybenzaldehyde 1 equivalent tyramine 0.8 equivalent sodium borohydride 10 ml ethanol (96%)/l g of aldehyde The educt was suspended in ethanol, and the tyramine was added while being stirred, then the reaction mixture was refluxed for 8.5 hours. Since the Schiff base (MH-16' or 34') that formed on the TLC plate breaks back down into the starting materials, the reaction progress was determined by reduction of a small 'sample with sodium borohydride, conventional working-up and application of the product obtained. After 8.5 hours, the reaction mixture was cooled in an ice bath to 0°C, and the sodium borohydride, dissolved in 4 ml of water/I g, was slowly added in drops, then stirred in an ice bath for 30 minutes. Then, it was poured onto 150 ml of ice/water/1 g of aldehyde while being stirred vigorously, the white precipitate that was produced was filtered off and dried in a vacuum drying 160 oven. A second fraction of the product, which was collected and dried, was precipitated from the mother liquor. Example 84: Step la: 5- (N- [2- [4-Hydroxyphenyl].ethyl] aminomethyl) -2-methoxy-4- raethylphenol (MH-16) 27.8 g {168 mmol) 2-methyl-4-methoxy-5- hydroxybenzaldehyde (6) 2 3.0 g (16 8 mmol) tyramine 5.20 g (134 mmol) = 0.8 equivalents sodium faorohydride Yield: 43.4 g {161 mmol = 3$% of theory) of a beige powder C17H21NO3 [287.36] TLC: Rf = 0.21 (CHCl3 : MeOH = 9:1 + 1% concentrated NH4OH) Melting point: 122-124°C % C % H % N Cld.: 71.06 7.37 4.87 Fnd.: 71.07 7.41 4.86 ^-NMR (200 MHz, DMSO-dJ : 5 6.90 (m, 2H) , 6.67 (s, 1H) , o 6.62 (ra, 2H) , 6.55 (s, 1H) ; 3.72 (s, 3H) ; 3.51 (s, 2H) ; 2.73 (t, J = 6.5 Hz, 2H) ; 2.60 (t, J = 6.5 Hz, 2H) ; 2.10 (s, 3H) ; 13C-NMR 161 (50 MHz, DMSO-d6) : 5 155.4 (s), 145.8 (s), 143.9 (s), 130.9 (s), 130.4 (s>, 129.3 (d), 126.0 (s), 116.2 (d) , 115.0 (d) , 114.3 5~(N-[2-[4-Hydrbxyphenyl]ethyl]aminomethyl)-2, 4-dimethoxyphenol (MH-34) 18.85 g (103.47 mmol) 5-hydroxy-2,4-dimethoxy- benzaldehyde (8) 14.21 g (103.47 mmol) tyramine 3.13 g (82.74 mmol) =0.8 equivalent NaBH,, 200 ml ethanol 96% Yield: 28.lg = 92.63 mmol = 89.5% of theory C17H21NO4 [303.36] TLC: Rf = 0.14 (CHCI3 : MeOH = 9:1 + 1% concentrated NH4OH) Melting point: 170-173°C C17H21NO4 [303.36] (contaminated with aliphatic substance about C15H32, Schliffett) 162 % C % H % N Cld.: 67.31 6.98 4 . 62 Fnd.: 68.10 7.04 4.66 1H-NMR (200 MHz, DMSO-d&) : 5 6.95 (m, 2H) , 6.70 (s, 1H) , 6.64 (m, 2H) , 6.57 (s, 1H) , 3.75 Step 2: Formylation: General Operating Instructions 1 equivalent amine 2 equivalents formic acid ester (ethyl formate or methyl formate) 10 ml 1,4-dioxane, distilled/i g of arnine 0.2 ml dimethylformamxde/l g of amine Catalytic amount of formic acid All reagents were refluxed together (formic acid optionally was added several times), and the reaction mixture was evaporated to the dry state in a vacuum after the end of the reaction. The 163 solid residue was taken up in 10 ml of methanol/1 g of amine, and 50 ml of ice/water/1 g of amine was added in portions while being stirred, whereby the suspension of the intermediate product was converted under hydrolysis into the flocculent end product, which was suctioned off and dried. Example 84/Step 2a N-((5-Hydroxy-4-methoxy-2-phenylmethyl)-N-(2-[4- hydroxyphenyljethyl)1formamide (MH-18) 55.0 g (191 mmol) 5-(N-[2-[4- hydroxyphenyl]ethyl]aminomethyl)-2-methoxy-4-methylphenol (XVII) 23.5 ml (383 mmol = 2 equivalents) methyl formate 11.0 ml DMF 1.50 ml formic acid 400 ml 1,4-dioxane. The working-up is carried out after 7 hours. Yield: 49.8 g (158 mmol = 82.6% of theory) of a beige powder C18H21NO4 [315.37] TLC: Rf = 0.35 (CHC13 : MeOH = 9:1 + 1% concentrated NH4OH) Melting point: 170-171°C % C % H % N Cld.: 68.55 6.71 4.44 Fnd.: 68.77 6.86 4.14 ^-NMR (200 MHz, DMSO-d6) : 5 9.20 (s, 1H) , 8.74 (d, J = 15.3 Kz, 1H) , 8.19 (s, 0.5H),7.88 (s, 0.5K) , 7.00-6.87 (m, 2H) , .6.74 (s, 1H), 6.72-6.56 (m, 2H), 6.59 (S, 1H), 4.31 (s, 1H), 4.23 (s, 1H), 3.73 (s, 3H), 3.21 (dd, J = 15.3, 7.6 Hz, 2H), 2.60 (t, J = 7.6 Hz, 2H) , 2.12 (s, 3K) ; 13C-NMR (50 MHz, DMSO-d6) : 6 162.7 and 162.3 (d), 155.7 (s), 146.7 and 146.5 (s), 144.4 and 144.2 (s), 129.7 and 129.4 (d), 128.9 and 128.4 (s), 126.5 (s), 126.4 and 126.3 (s), 116.3 and 115.9 (d) , 115.1 (d), 114.6 and 114.4 i (d), 55.6 (q), 48.0 and 47.4 (t), 43.3 and 41.6 (t), 33.2 and 31.9 (t), 18.1 and 18.0 (q). Example 84/Step 2b N-(2-(4-Hydroxyphenyl)ethyl)-N-((5-hydroxy-2,4-) dimethoxyphenyi)methyl) -formamide (MH-35) 165 27 g (89 ramolj 5-{N-[2-[4- hydroxyphenyl] ethyl] aminomethyl) - 2,4-dimethoxyphenol (XXV) 14.4 ml (178 mmol) ethyl formate 200 ml 1,4-dioxane 5 . 5 ml dimethylf ormamicie 2 ml formic acid The working-up was carried out after 24 hours, and the formic acid was added in 3 portions at intervals of several hours. Yield: 26.13 g (78.85 mmol = 88.6% of theory) of a beige powder C18H21NO5 [3 31.3 7] TLC: Rf = 0.53 (.CHC13 : MeOH = 9:1 + 1% concentrated NH40H) Melting point: 130-132°C % C % K % N Cld.: 65.24 6.39 4.23 Fnd.: 64.97 6.40 4.18 1H-NMR (200 MHz, DMSO-d6) : 6 9.18 (bs, 1H) , 8.48 {d, J = 7.4 Hz, 1H) , 8.16 (s, 0.5H), 7.86 (s, 0.SH) , 6.98-6.87 (ra, 2E) , 6.71-6-58 (m, 4H) , 4.31 (s, 1H) , 4.19 (s, 1H) , 3.78 (s, 3H) , 3.75 (s, 3H) , 3.21 (dd, J = 16.4, 7.7 Hz, 2H) , 2.69-2.55 (m, 2H) ; 13C-NMH (50 MHz, DMSO-d6) : 6 162-7 and 162.5 (d) , 155.7 and 155.6 (s) , 150.6 and 150.3 (s) , 146.7 and 147.3 (s), 140.1 and 139.9 (s), 129.6 and 129.3 (d) , 129.0 and 128.4 (s), 116.8 and 116.4 (d) , 116.2 and 115.9 (s), 115.1 (d) , 98.5 and 98.4 (d) , 56.3 and 56.2 (q), 55.9 (q), 47.9 and 45.2 (t), 43.0 and 38.3 (t), 33.4 and 31.9 (t) Example 84/Step 3 Phenolic Oxidative Coupling: 1-Methylqalanthamine (XV) [ (±) ~ (4aa, 8aR*) ] -4a, 5, 9,10,11,12-Hexahydro-3 -methoxy-l-methyl-6-oxo-SH-benzofuro[3a,3,2-ef][2]benzazepine-ll-carboxaldehyde, 1-Methyl-N-formylnarwedine {MH-19) 11.4 g {69.8 mmol) N-((5-hydroxy-4-methoxy~2- phenylmethyl)-N-(2- [4-hydroxyphenyl]ethyl] formamide (XVIII) 47.0 g (338 mmol) potassium carbonate 47.0 g (142 mmol) potassium hexacyanoferrate (III) 1.60 1 toluene 470 ml water 4 0.0 g Hyflo Potassium carbonate, potassium hexacyanoferrate (III), water and toluene were heated in a 4 liter-four-neck flask to 80°C, and 157 then the educt was sprinkled while being mechanically stirred vigorously. The temperature was kept at 8 0°C for 1 hour, then Hyflo was added and stirred for 10 more minutes. The reaction mixture was suctioned off, and the solid residue was rewashed 1 x with water and 3 x with hot toluene. The toluene phase was separated from the aqueous phase, and the latter was extracted with toluene. The organic phases were combined, the solvent was drawn off, and the product was dried in a vacuum drying oven. Yield: 6.17 g (19.7 mmol = 55.0% of theory) of a light yellow powder C18H19NO,h [313.3 9] TLC: Rf = 0.48 and 0.42 (2 rotamers) (CHC13 : MeOH = 9:1 + 1% concentrated NH4OH) Melting point: Decomposition > 215°C % C % H % N Cld.: 69.00 6.11 4.47 Fnd.: 68.78 6.33 4.40 1H-NMR (Mixture that consists of 2 rotamers, 200 MHz, DMSO-d6) : 6 8.18 (s, 0.2H), 8.10 (s, 0.8H) , 7.25 (dd, J = 10.4, 1.9 Hz, 0.8H), 7.15 (dd, J = 10.4, 1.9 Hz, 0.2H), 6.73 (s, 0.2H), 6.69 (s, 0.8H), 5.95 (d, J = 10.3 Hz, 0.SH), 5.93 (d, J = 10.3 Hz, 0.2H), 5.14 (d, J = 15.4 Hz, 0.8H), 4.83 (d, J = 15.4 Hz, 0.2H), 4.67 (bs, 1H), 4.51 (d, J = 15.4 Hz, 0.2K), 4.07 (d, J = 15.4 Hz, O.SH), 3.97 (bs, 1H), 3.78-3.60 (m, 4H), 3.07 (dd, J= ; 17.4, 3.4 Hz, 1H) , 2.78 (dd, J = 17.4, 1.9 Hz, IK), 2.33 (s, 3H) , 2.30 (s, 0.3H), 2.22 (s, 0.2H), 1.86 (dt, J = 13.5, 3.7 Hz, 1H) ; 13C-NMR (mixture that consists of 2 rotamers, 50 MHz, DMSO-d6) : 5 168 194.9 [(±)-(4aa,6£,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-l-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol, 1-methyl-N-demethylgalanthamine (MH-20) 500 mg (1.60 mmol) 1-Methyl-N-formylnarwedine (XIX) 6.00 ml (6.06 mmol = 3.78 equivalents) L-selectride 1 M in THF 12.0 ml absolute THF A suspension of finely ground educt in absolute THF was cooled to 0°C, and then L-selectride was added in drops, whereby 15 5 a temperature increase of 5°C was to be observed. At 0°C, it was stirred for 1 hour, whereby a clear solution formed. After 70 minutes, 5 drops of water and 1 ml of concentrated aqueous ammonia were added, stirred for 10 minutes, and then the reaction mixture was concentrated by evaporation by 50% in a vacuum. Then, 10 ml of ammonia were added once more, and the solution was extracted with methylene chloride. The combined organic phases were rewashed once with dilute ammonia solution, dried on sodium sulfate, filtered, and the solvent was drawn off. The luminous red oil that was produced was purified on a silica gel column. Yield: 440 mg (1.53 mmol = 96.0% of theory) of a colorless oil C17H21NO3 [287.3 6] TLC: Rf = 0.3 9 (CKC13 : MeOK = 9:1 + 1% NH^OH) C17H21NO3 X 0.8 H2O [301.76] % C % H % N Cld.: 67.66 7.55 4.64 Fnd.: 67.60 7.40 4.65 'H-NMR (200 MHz, CDCl3) : 5 6.51 (s, IK), 6.06 (d, J = 10.2 Hz, 1H) , 5.97 (dd, J = 10.2, 4.5 Kz, 1H) , 4.57 (bs, 1H) , 4.27 (d, J = 16.0 Hz, IE), 4.11 (t, J = 4.4 Hz, 1H) , 3.80 (s, 3H) , 3.77 (d, J = 16.0 Hz, 1H) , 3.40-3.10 (m, 2K) , 2.65 (dd, J = 15.6, 3.2 Hz, 1H) , 2.23 (s, 3H) , 1.99 (ddd, J = 15.6, 4.9, 2.3 Hz, 1H) , 1.89-1.63 (m, 2K) ; 13C-NMR (50 MHz, CDC1-) : 5 144.4 (s), 142.9 (s) , 133.4 (s), 130.5 17 0 Example 8 6 [( + ) - (4aa,8aR*)3 -4a, 5, 9,10,11,12-Hexahydro-3-methoxy-1, 4' -dimethyl-spiro [-SH-benzofuro [3a,3,2-ef] [2] benzazepine] -6,2'- [1,3]-dioxolane]-ll~carboxaldehyde, 1-methyl-N-formyl-narwedine ketal (MH-21) 6.17 g (19.7 mtnol) 1-methyl-N-formylnarwedine (XIX) 40.0 ml toluene 375 mg (1.97 mmol) p-toluenesulfonic acid 11.1 ml (149 mmol) propylene glycol In a flask with a water separator, the educt was introduced into toluene, and 1/3 of the p-toluenesulfonic acid was added to 2/3 of propylene glycol. The reaction mixture was refluxed, and after 2 hours, the solution of the residual p-toluenesulfonic acid in propylene glycol was added in portions over 5 hours, then refluxed for another 6 hours. After the end of the reaction (HPLC study necessary, since TLC has little informational value), the toluene phase was separated, and the propylene glycol phase was exhaustively extracted with toluene. The collected toluene 171 phases were extracted 2 x with acetic acid {8% in water), 2 x with saturated sodium bicarbonate solution and 2 x with water, then the solvent was drawn off. Yield: 5.34 g (14.38 mmol = 73% of theory) of a beige foam C21H25NOS [371.44] TLC: Rf = 0.71 (CHCl, : MeOH = 9:1) C21H25NO5 X 0.8 5 H2O [3 8 6.74] % C % H % N Cld.: 65.22 6.96 3.62 Fnd.: 65.39 7.19 3.52 ^-NMR (mixture that consists of diastereomers and rotamers, 200 MHz, CDC13) : 5 8.14-8.01 (m, 1H) , 7.30-7.09 (m, 2H) , 6.51 (s, 1H) , 6.22-5.97 (m, 1H) , 5.85-5.61 (m, 1H) , 5.38 and 4.77 (d, J = 15.7 Hz, 1H) , 4.49 (bs, 1H) , 4.37-4.01 (m, 2H) , 3.93-3.74 (m, 5H), 3.71-3.10 (m, 1H), 2.79-2.58 (m, 1H), 2.41 (s, 2H), 2.32 (d, J = 10.2 Hz, 3K) , 2.25-1.74 (in, 3H) ; 13C-NMR (mixture that consists of diastereomers and rotamers, 50 MHz, CDCl3) : 172 Example 87 [ (±) - (4aor,8aR*) 3 -4a,5,9,10,11,12-Hexahydro-3-methoxy-l, 1 dimethyl-6H-benzofuro [3a,3,2-ef ] [2]benzazepin-6-one, 1-methylnarwedine (MH-22) 5.34 g {14.4 mmol) 1-methyl-N-formylnarwedine ketal (XX) 2 5.2 ml (25.2 mmol) = 1.75 equivalents lithium aluminum hydride 1 M in THF 2 0 ml absolute THF 1-Methyl-N-formylnarwedine (V) was dissolved in absolute THF, and lithium aluminum hydride was added in portions while being stirred. After 15 minutes, the reaction mixture was mixed with 10 ml of toluene, then hydrolyzed with 1.5 ml of water, and after 1.5 ml of sodium hydroxide solution (15% in water) was added, it was stirred for 15 minutes. After 1.5 g of Hyflo was added, it was refluxed for 1 hour, filtered off, the filter cake was boiled up 3 x with 10 ml of toluene : THF =1:1 each and in each case suctioned off. The organic phases were evaporated to 173 the dry state, taken up with 25 ml of 4N HC1 and stirred for 25 minutes at 60°C, then exhaustively extracted with ethyl acstate. The collected organic phases were backwashed with dilute HC1. The collected acidic, aqueous phases were released by distillation of excess ethyl acetate, then made basic with concentrated aqueous ammonia and exhaustively extracted with chloroform. The collected chloroform phases were washed with saturated common salt solution, dried on sodium sulfate, filtered, and the solvent was drawn off. The purification was carried out by recrystallization from diisopropyl ether : ethyl acetate = 9:1. Yield: 4,01 g (13.36 mmol = 93% of theory) of light yellow, very fine needles C1SH21NO3 E2 99.37] TLC: Rf = 0.43 (CHCl3 : MeOH = 95:5) Melting point: 121-122°C % C % H % N Cld.: 72.22 7.07 4.68 Fnd.: 71.95 7.08 4.57 ^-NMR (200 MHz, CDC13) : 6 7.01 (dd, J = 10.4, 1.6 Hz, IK), 6.56 (s, 1H), 5.99 (d, J = 10.4 Hz, 1H), 4.68-4.62 (m, IK), 3.97 (d, J = 15.7 Hz, 1H) , 3.80 (s, 3H) , 3.79 (d, J = 15.7 Hz, 1H)., 3.22-2.95 (m, 3H), 2.71 (dd, J = 17.8, 3.7 Hz, 1H), 2.44 (s, 3H), 2.23 {s, 3H), 2.20-2.01 (m, 1H), 1.87 (dt; J = 13.8, 3.4 Hz, 1H); 13C-NMR (50 MHz, CDC13): 6 194.4 (s), 145.2 (s), 142.9 (s) , 131.0 (s) , 128.9 (s), 126.8 (d + d + s), 114.3 (d) , 87.7 (d) , 55.9 (q) , [74 55.8 (t), 54.1 (t), 48.9 (s), 43.5 (q), 37.1 (t), 33.4 (q) Example 88 [ (±) - (4aa, 6(5, 8aR*) ] -4a, 5, 9,10,11,12-Hexahydro-3-methoxy-l, 11-dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol, 1-methylgalanthamine (MH-3 0) 170 mg {0.57 mmol) 1-methyl-narwedine (XXI) 0.70 ml (0.68 mmol) = 1.2 equivalents L-SelectridetR> 1 M in -THF 5 ml absolute THF The educt was introduced into THF under N2 atmosphere and cooled to -25°C, then L-Selectride was slowly added in drops- It was stirred for 30 minutes at -15°C, whereby the initial suspension was in a clear solution. Then, the reaction mixture was brought to room temperature over 1 hour, hydrolyzed with 5 drops of water, stirred for 30 minutes, 0.5 ml of concentrated aqueous NH,,OH was added, stirred for another 10 minutes, 2 ml of concentrated NH4OH was added again and finally it was extracted with methylene chloride. The combined organic phases were washed 175 with saturated common salt solution, dried on sodium sulfate, filtered, and the solvent was drawn off, whereby 3 50 mg of crude product was produced. This crude product was purified on a silica gel column (CHC13 : MeOH = 9:1); whereby a yellow oil was produced, which solidified by adding ether. Yield: 120 mg (0.398 mmol = 70% of theory) of a colorless powder C18H23NO3 [3 01.3 9] TLC: Rf = 0.43 (CKC13 : MeOH = 95:5), not to be separated from educt 1H-NMR (200 MHz, CDCl3) : 6 6.54 (s, 1H) , 6.10 (dd, J = 10.2, 1.2 Hz, 1H), 5.98 (dd, J = 10.2, 4.7 Hz, 1H), 4.56 (bs, 1H), 4.12 (bs, 1H) , 3.99 (d, J = 15.6 Hz, 1H) , 3.82 (s, 3H) , 3.81 (d, J = 15.6 Hz, 1H), 3.20 (ddd, J = 14.2, 12.1, 2.1 Hz, 1H), 2.96 (dt, J = 14.2, 3.4 Hz, 1H), 2.65 (ddd, J = 15.7, 3.2, 1.5 Hz, 1H), 2.41 (S, 3H), 2.24 (s, 3H), 1.99 (ddd, J = 15.5, 5.0, 2.5 Hz, 2H), 1.6 0 (ddd, J = 13.7, 4.0, 2.4 Hz, 1H) ; 13C-NMR (50 MHz, CDC13) : 6 144.0 (s) , 143.0 (s), 133.4 (s) , 128.9 (s), 127.4 (d + d), 127.0 (s), 126.6 (s), 113.6 (d), 88.3 (d) , 61.9 (d) , 55.7 (q) , 55.4 (t), 53.8 (t) , 48.2 (s), 42.7 (q) , 33.8 (t), 29.8 (t), 19.4 (q) Production of Hydrobromide: The reaction solution is hydrolyzed with ethanol (about half the reaction volume), stirred for 30 minutes, then brought to pE 17 5 Melting point: 246-250°C (hydrobromide) C18H24£TO3Br x 0.5 H2O [391.30] % C % H % N Cld.: 55.25 6.44 3.58 Fnd.: 55.21 6.39 3.56 Example 8 9 [ (±) - {4aa, 6a, 8aR*) 3 -4a, 5, 9,10 ,11,12-Hexahydro-3-methoxy-1,11-dimethyl-6H-benzofuro[3a,3,2-ef] [2]benzazepin-6-ol, 1-methylepigalanthamine (MH-31) 2.0 0 g (6.68 mmol) l-methylnarwedine (XXI) 150 ml methanol 2.50 g (6.63 mmol) cerium trichloride heptahydrate 0.5 0 g (13.4 mmoi) = 2 equivalents NaBH4 The educt was dissolved in methanol with heating and then cooled to 0°C, CeCl3 x 7H2O was added and stirred at 0°C for about 30-60 minutes. Then, NaBH4 was added in portions, it was stirred 177 ¦for another 2 hours at 0-5°C, whereby a precipitate formed. The reaction mixture was hydrolyzed with 5 ml of 2N HC1, methanol was distilled off in a vacuum, the residue was taken up with another 150 ml of 2N HC1, made basic with concentrated NH4OH (violet precipitate), extracted with ethyl acetate, the collected organic phases were washed with saturated common salt solution, dried on sodium sulfate, filtered, and the solvent was drawn off. As a crude product, an isomer mixture of 1-methylepigalanthamine and 1-methylgalanthamine at a ratio of about 5:1 was produced, which could be separated by chromatography {silica gel, CHC13 : MeOH = 9:1 + 0.5% NH4OH) . Yield: 1.34 g (4.45 mmol = 66.6% of theory) of a colorless oil CiaH23NO3 [3 01,3 9] TLC: Rf = 0.2 0 (CHCl3 : MeOH =9:1) ^-NMR (200 MHz, CDCl3) : 5 6.51 (s, 1H) , 6.10 (d, J = 10.2 HZ, IK), 5.79 (d, J = 10.2 Hz, 1H), 4.69-4.56 (m, 1H), 4.55 (bs, 1H) , 3.96 (d, J = 15.3 Hz, 1H) , 3.82 (s, 3H) , 3.79 (d, J = 15.3 Hz, 1H) , 3.21 (td, J = 13.1, 1.7 Hz, 1H) , 2.97 (dt, J = 14.1, 3.3 Kz, 1H), 2.75 (dddd, J = 14.1, 5.3, 4.0, 1.2 Hz, 1H), 2.33 (s, 3H) , 2.23 (S, 3H) , 2.10 (dd, J = 13.1, 3.2 Hz, 1H) , 2.03 (bs, 1H) , 1.69 (ddd, J = 13.6, 10.7, 2.6 Hz, 2H) ; 13C-KMR (50 MHz, CDCI3) : 6 145.0 (S) , 142.9 (s), 133.5 (s), 131.7 (d) , 123.5 (s), 12 6.7 (d) , 12 6.6 (s) , 113.5 (d) , 88.3 (d) , 63.1 (d) , 55.8 (q) , . 55.2 (t), 54.1 (t), 48.3 (s), 42.6 (q), 34.6 (t), 32.4 (t), 19.5 (q) 178 Production of Hvdrobromide: The 1-methylepigalanthamine that was obtained was taken up in ethanol and brought to pH s 1 with concentrated HBr. The hydrobromide was brought to crystallization under cold conditions and the precipitate that was produced was suctioned off, washed with cold ethanol and dried. Melting point: 254-255°C (hydrobromide) CiaH24NO3Br x 0.5 H20 [391.30] % C % H % N Cld.: 56.25 6.44 3.58 Fnd.: 56.28 6.21 3.57 Example 9 0 [( + ) - (4aa,6a,8aR*)] -4a, 5, 9 ,10,11,12-Hexahydro-3-methoxy-l-inethyl-6E-benzofuro[3a,3,2-ef][2]benzazepin-6-ol, 1-methyl-N-demethylepigalanthajtiine Method A (Epimerization o£ l-methyl-K-demethylgalanthamine (XXII)) 179 Step 1 (Acetylation) : [ (±)-(4aa, 6a, 8aR*) ]-6-0-Acetyloxy-4a, 5,9,10,11,12-hexahydro-3-methoxy-l-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepine (MH-67) 100 mg (0.35 mmol) 1-methyl-N-demethylgalanthamine (XXII) 0.50 ml (1.74 mmol) = 5 equivalents N,N-dimethylformamide- bis(2,2-dimethylpropyl)-acetal 0.10 ml (1.74 mmol) = 5 equivalents glacial acetic acid 12 ml toluene The educt was heated in 10 ml of toluene under N2 atmosphere to 80°C and over 1 hour, a mixture that consists of N,N-dimethylformamide-bis-(2,2-dimethylpropyl)acetal and glacial acetic acid in 2 ml of toluene was added in drops. After 22 hours at 80°C, the cooled toluene phase was extracted 1 x with water, then with 2N hydrochloric acid, the acidic aqueous phase was made basic with concentrated ammonia solution, it was extracted with ethyl acetate, the organic phases were washed with / 180 saturated common salt solution, dried on sodium sulfate, filtered, and the solvent was drawn off. The residue was purified by column chromatography. (CHCI3 : MeOH = 95:5) . Yield: 45 mg (0.14 mmol = 39% of theory) of a colorless oil C19H23HO4 [329.40] TLC: Rf = 0.2 0 (CHCl3 : MeOH = 95:5) 1K-NMR (200 MHz, CDC13) : 6 6.50 (s, 1H) , 6.14 (d, J = 10.2 Hz, 1H) , 5.72 (d, J = 10.2 Hz, 1H) , 5.67-5.58 (m, 1H) , 4.57 (bs, 1H) , 4.24 (d, J = 16.0 Hz, 1H) , 3.83 (s, 3H) , 3.75 (d, J = 16.0 Hz, 1H) , 3.40-3.09 (m, 2H) , 2.90-2.70 (m, 1H) , 2.23 (s, 3H) , 2.07 (s, 3H) , 2.01-1.73 (m, 3H) ; 13C-NMR (50 MHz, CDCl3) : 6 170.2 (s), 145.3 (s) , 142.8 (s) , 133.0 (s) , 13 0.5 (s) , 12 8.4 181 17 mg (0.05 mmol) 6-O-acetyl-l-methyl-N- demethylepigalanthamine (XXIla) 0.5 ml methanol 0.1 ml 2N KOH 17 mg (0.12 mmol) =2.4 equivalents potassium carbonate The reagents were stirred together at room temperature. After the end of the reaction, it was mixed with 1 ml of water, methanol was drawn off, it was acidified with 4 ml of 2N hydrochloric acid, the aqueous phase was washed with ethyl acetate, then made basic with concentrated aqueous ammonia solution and extracted with ethyl acetate. The organic phases were washed with saturated common salt solution, dried on sodium sulfate, filtered, and the solvent was drawn off. C17H2iNO3 [287.36] TLC: Rf = 0.07(CHCl3 : MeOH = 9:1) Method B (Demethylation of 1-Methylepigalanthamine) (MH-94) 182 0.80 g (2.65 mmol) 1-methylepigalanthamine (XXIII) 1.50 g (6.63 mmol) = 2.5 equivalents azodicarboxylic acid- bis-(2-methyl-2-propylester) 80 ml tetrahydrofuran The reagents were stirred together at room temperature for 24 hours, then the solvent was drawn off. The residue.was taken up in trifluoroacetic acid in methylene chloride, stirred for 30 minutes, made basic in an ice bath with concentrated aqueous ammonia solution and extracted with methylene chloride. The organic phases were washed with saturated common salt solution, dried on sodium sulfate, filtered, and the solvent was removed. The crude product was purified by column chromatography (CHC13 : MeOH = 9:1). Yield: 400 mg (1.39 mmol = 53% of theory) of a colorless oil C17H21NO3 [287.36] TLC: Rf = 0.10 (CHCI3 : MeOH = 9:1) ^-NMR (200 MHz, CDCI3) : . 6.50 (s, 1H) , 6.08 (d, J = 10.3 Hz, 1H), 5.80 (d, J = 10.3 Hz, 1H), 4.70-4.62 (m, 1H), 4.57 (bs, 1H), 4.26 (d, J = 15.7 Hz, 1H), 3.83 (s, 3H), 3.75 (d, J = 15.7 Hz, 1H), 3.35-3.20 (m, 1H) , 2.85-2.70 (m, 1H) , 2.50-2.29 (m, 2H), 2.23 (s, 3H), 2.00-1.64 (m, 2H) ; 13ONMR (50 MHz, CDC13) : 145.4 (s), 142.9 (s>, 133.5 (s) , 131.6 (d) , 130.7 (s), 127.2 (d), 126.8 (s), 113.3 (d), 88.2 (d) , 63.1 (d) , 55.9 (q) , 48.9 (t), 48.8 (s), 47.2 (t), 32.2 (t), 28.2 (t), 19.5 (q) 183 General Operating Instructions for Quaternary 1-Methyl- and 1-Methylepi-galanthamine Derivatives (Examples 90-99) The educt was dissolved* in very little DMF, added to the alkyl halide, and the reaction mixture was heated (generally not above the boiling temperature of the alkyl halide, but at most 70°C) . By means of TLC, the end of the reaction was determined, then the reaction mixture was slowly added in drops to ether while being stirred (in many cases easily extrudes oil), the precipitate was suctioned off and washed with ether. For purification and for removing residual DMF, the precipitate was dissolved in ethanol and once more precipitated in ethyl acetate, then dried in a vacuum drying oven at 5 0°C. TLC: CHCL3 : MeOH = 9:1, Rf generally slightly over the starting value. *With R = CH2C1, methylene chloride (p.A. 99.5%) is used as a solvent and reagent. 184 Example 91 [(±)-(4aa,6p,8aR*)]-4a,5,9,10,ll,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-ll-(2-methyl-2-propenyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium, chloride (MH-33) 280 mg (0.94 mmol) 1-methylgalanthamine (XV) 0.30 ml (3.08 mmol) = 3 equivalents l-chloro-2-methylprop-2-ene 5.00 ml dimethylformamide The reaction was performed at 70°C and worked up after 2 hours, by the reaction mixture having been added in drops to 25 ml of diethyl ether. Yield: 270 mg (0.69 mmol = 73% of theory) of a colorless powder C22H30CINO3 [391.94] TLC: Rf - 0.10 (CHCI3 : MeOH - 9:1) Melting point: 239-241°C C22H30CINO3 x 1.4 H2O [417.14] 185 % C % H % N Cld.: 63.34 7.92 3.36 Fnd.: 63.22 7.85 3.59 13C-NMR (50 MHz, DMSO-d6) : 5 144.6 (s), 134.2 (s), 133.5 (s), 131.1 (s), 130.9 (d), 127.5 (t) , 124.9 (d), 115.9 (s), 114.4 (d), 86.3 (d), 73.0 (t), 60.8 (t), 59.4 (d), 55.5 (q), 46.3 [ (±)-(4a, , 6p,8aR*)]-4a,5,9,10,ll,12-Hexahydro-6-hydroxy-3-methoxy—1,11—dimethyl—11-(2-propinyl)-6H-benzofuro[3a,3,2— ef][2]benzazepinium, bromide (MH-38) 349 mg (1.16 mmol) 1-methylgalanthamine (XV) 0.13 ml (1.16 mmol) 3-bromo-l-propine (propargyl bromide) 4.00 ml dimethylformamide 186 The reaction was performed at 60°C and worked up after 19 hours by the reaction mixture having been added in drops to 80 ml of diethyl ether. Yield: 300 mg (0.71 mmol = 62% of theory) of a beige powder C21H26BrNO3 [420.35] TLC: Rf = 0.09 (CHCl3 : MeOH = 9:1) Melting point: 216-218°C C21H26BrNO3 x 0.35 H2O x 0.25 C3H7NO [444.93] % C % H % N Cld.: 58.72 6.44 3.90 Fnd.: 58.70 6.37 3.94 13C-NMR (50 MHz, DMSO-d6) : ? 144.8 (s) , 144.7 (s), 133.4 (s), 131.0 (s>, 125.2 (d), 115.3 (s), 114.5 (d) , 86.2 (d), 83.7 (d), 72.6 [ (±) - (4aa, 6fS, 8aR*) ] -4a, 5, 9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,ll-dimethyl-ll-phenylmethyl-6H-benzofuro[3a,3,2-ef][2]benzazepinium, bromide (MH-39) 187 242 mg (0.80 mmol) 1-methylgalanthamine (XV) 0.25 ml (1.01 mmol) = 1.4 equivalents benzyl bromide 4.00 ml dimethylformamide The reaction was performed at 60°C and worked up after 10 minutes. Yield: 262 mg (0.55 mmol = 69% of theory) of a beige powder C25H3oBrN03 [472.42] TLC: Rf = 0.08 (CHC13 : MeOH = 9:1) Melting point: 246-248°C % C % H ' % N Cld.: 63.56 6.40 2.96 Fnd.: 63.35 6.34 2.93 13C-NMR (50 MHz, DMSO-d6) : 5 144.7 (s), 133.4 (d) , 130.7 (s), 130.4 (d) , 129.0 (d), 128.1 (s), 114.5 (d), 86.3 (d), 59.7 (t), 5 9.5 (d), 55.6 (q), 4 6.2 (s) , 18.6 (q) Example 94 [ (±)-(4aa, 6(3, 8aR*) ]-4a,5, 9,10,11,12-Hexahydro-6-hydroxy-3-methoxy—1,11,11—trimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepinium, iodide (MH-83) 188 140 mg (0.46 mmol) 1-methylgalanthamine (XV) 198 mg (1.39 mmol) = 3 equivalents methyl iodide 4.00 ml dimethylformamide The reaction was performed at 40°C and worked up after 1.5 hours, by the reaction mixtue having been added in drops to 30 ml of diethyl ether. Yield: 146 mg (0.54 mmol = 71% of theory) of a light brown powder C19H26INO3 [443.32] TLC: Rf = 0.05 (CHCI3 : MeOH = 9:1) Melting point: 278-280°C C19H26lNO3 x 0.3 H2O [448.72] % C % H % N Cld.: 50.86 5.97 3.12 Fnd.: 50.57 5.85 3.43 13C-NMR (50 MHz, DMSO-d6) : 5 144.6 (s), 144.1 (s), 132.8 (s), 131.6 (s), 114.2 (d), 86.3 (d), 62.6 (t), 59.5 (d), 55.4 (q), 45.9 (s), 31.0 (t), 18.4 (q) 189 Example 95 [ (±) - (4aa, 6(3, 8aR*) ]-4a, 5, 9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-ll-(2-methyl-2-propenyl)-6H-benzofuro[3a,3,2-ef] [2]benzazepinium, chloride (MH-66) 150 mg (0.50 mmol) 1-methylepigalanthamine (XXIII) 45.0 mg (1.50 mmol) = 3 equivalents l-chloro-2-methylprop- 2-ene 4.00 ml dimethylformamide The reaction was performed at 70°C and worked up after 100 minutes, by the reaction mixture having been added in drops to 50 ml of diethyl ether. Yield: 160 mg (0.41 mmol = 82% of theory) of a colorless powder C22H30CINO3 [391.94] TLC:' Rf = 0.09 (CHC13 : MeOH - 9:1) Melting point: 162-164°C C22H30CINO3 x 0.7 H2O x 0.15 C3H7NO [415.51] 190 % C , % H % N Cld-: 64.90 7.87 3.88 Fnd. : 64.77 7.68 3.95 13C-NMR (50 MHz, DMSO-d6): 5 144.7 (s), 134.2 (s), 134.1 (s), 131.1 (d), 127.5 (t), 114.4 I (±) -(4aa,6|3, 8aR*) 1-43,5, 9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-ll-(2-propinyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium, bromide (MH-71) 150 mg (0.50 mmol) 1-methylepigalanthamine (XXIII) 180 mg (1.50 mmol) = 3 equivalents 3-bromo-l-propine (propargyl bromide) 4.00 ml dimethylformamide 191 The reaction was performed at 70°C and worked up after 2.5 hours, by the reaction mixture having been added in drops to 30 ml of diethyl ether. Yield: 167 mg (0.40 mmol = 82% of theory) of a light brown powder C2iH26BrNO3 [420.35] TLC: Rf = 0.09 (CHC13 : MeOH - 9:1) Melting point: 158-162°C 13C-NMR (50 MHz, DMSO-d6) : 5 144.8 (s), 133.9 (s), 131.2 (s), 114.5 (d) , 87.2 (d), 83.7 (d), 72.6 (d), 55.6 (q), 46.3 (s), 31.9 (t), 18.8 (q) Example 97 E (±) - 192 150 mg (0.50 mmol) 1-methylepigalanthamine (XXIII) 0.13 ml (1.50 mmol) = 3 equivalents 3-bromo-l-propene (allyl bromide) 4.00 ml dimethylformamide The reaction was performed at 60°C and worked up after 2 hours. Yield: 150 mg (0.36 mmol = 64% of theory) of a light brown powder C2iH28BrNO3 [422.36] TLC: Rf = 0.11 (CHC13 : MeOH = 9:1) Melting point: 140-145°C C2iH2eBrNO3 x 1 H2O x 0.25 C3H7NO [458.64] % C % H % N Cld.: 56.96 6.98 3.82 Fnd.: 56.69 6.65 4.05 13C-NMR (50 MHz,. DMSO-d6) : 5 144.7 (s) , 134.5 (d) , 134.0 (s) , 131.1 (s), 12 8.3 (s), 126.1 (d), 115.3 (d), 114.4 (d), 87.2 (d), 60.7 (d), 59.8 (t), 55.6 (q) , 46.3 (s), 31.5 (t), 18.8 (q) 193 Example 98 [ (±) - (4aa, 6a, 8aR*) ]-4a, 5, 9,10,11,12~Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-ll-(4-(trifluoromethyl)phenylmethyl)-6H-benzofuro[3a,3,2-ef] £2]benzazepinium, bromide (MH-75) 150 mg (0.50 ramol) 1-methylepigalanthamine (XXIII) 357 mg (1.50 mmol) = 1.4 equivalents 4-trifluoromethyl- benzyl bromide 4.00 ml dimethylformamide The reaction was performed at 70°C and worked up after 1 hour. Yield: 142 mg (0.26 mmol = 53% of theory) of a light yellow powder C26H29BrF3NO3 [540.42] TLC: Rf = 0.10 (CHC13 : MeOH = 9:1) Melting point: 178-182°C 13C-NMR (50 MHz, DMSO-de) : 5 144.8 (s), 134.4 (d + d), 134.2 (d), 132.6 (s), 131.2 (s), 130.9 (s), 130.3 (s), 126.6 (d), 125.8 194 (s>, 121.2 Example 99 [ (±) - (4aa, 6a, 8aR*) ] -4a, 5, 9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-ll-(phenylmethyl)-6H-benzofuro[3a,3,2-ef J[2]benzazepinium, bromide (MH-76) 153 mg (0.51 mmol) 1-methylepigalanthamine (XXIII) 92 mg (0.51 mmol) benzyl bromide 4.00 ml dimethylformamide The reaction was performed at 70°C and worked up after 3 hours. Yield: 150 mg (0.32 mmol = 63% of theory) of a light brown powder C25H3oBrN03 [472.42] TLC: Rf = O.11(CHC13 : MeOH = 9:1) Melting point: 169-175°C 195 13C-NMR (50 MHz, DMSO-d6) : 5 144.6 (s), 134.1 (s), 133.4 (d), 131.0 (s), 130.4 (d) , 128.9 (d) , 128.1 (s), 114.4 (d) , 87.2 (d), 61.8 (d), 59.4 (t), 55.6 (q), 46.3 (s), 31.5 (t), 18.6 (q) Example 100 [ (±)-(4aa, 6a,8aR*) ]-4a,5, 9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11,ll-trimethyl-6H-benzofuro[3a,3,2-ef] [2]benzazepinium, iodide (MH-81) 210 mg (0.70 mmol) 1-methylepigalanthamine (XXIII) 290 mg (2.10 mmol) = 3 equivalents methyl iodide 4.00 ml , dimethylformamide The reaction was performed at 70°C and worked up after 2 hours, by the reaction mixture having been added in drops to 30 ml of diethyl ether. Yield: 240 mg (0.54 mmol = 77% of theory) of a light-brown powder /C19H26INO3 [443.32] 196 TLC: Rf = 0.05 (CHC13 : MeOH = 9:1) Melting point: decomposition > 280°C % C % H % N Cld.: 51.48 5.91 3.16 Fnd.: 51.25 5.75 3.32 13C-NMR (50 MHz, DMSO-d6) : 5 144.7 (s) , 133.6 (s) , 131.1 (s) , 114.4 (d), 87.1 (d), 62.2 (t), 60.7 (q), 55.5 (q), 48.4 (d), 46.2 (s), 31.5 (t), 18.9 (q) General Operating Instructions for the Production of Galanthamine-N-Oxides (Examples 101-102) 1 equivalent galanthamine derivative 1-1.5 equivalents 3-chloroperbenzoic acid 100 ml chloroform/1 g of galanthamine derivative 0.7 ml H2O2 (35%)/I g of galanthamine derivative The 3-chloroperbenzoic acid is dissolved in 1/3 chloroform, mixed with hydrogen peroxide and stirred for 2 minutes. Then, this solution is added to a solution of the galanthamine derivative in 2/3 chloroform, it is stirred for 15 minutes, concentrated by evaporation and purified by means of column chromatography (gradient: CHCl3 : MeOH = 9:1 ? MeOH). 197 Example 101 [4aS- (4aa,6a,8aR*) ] -4a, 5, 9,10,11,12-Hexahydro-3 -methoxy- lime thyl-6H-benzof uro [3a,3,2-ef] [2]benzazepin-6-ol, 11-oxide, epigalanthamine-N-oxide (Pi-23) 49.7 mg (0.17 mmol) epigalanthamine (26) 29.9 mg (0.17 mmol) 3-chloroperbenzoic acid 0.03 ml hydrogen peroxide (35%) 5 ml chloroform Yield: 37 mg (71% of theory) C17H2.NO6 [3 03.3 6] " TLC: Rf = 0.05 (CHCl3 : MeOH =9:1) 1H-NMR (200 MHz, CDCl3) : 6 6.67 (s, 2H) , 5.96 (bs, 2H) , 4.78 (d, J = 15.0 Hz, 1H) , 4.67-4.50 (m, 2H) , 4.26 (d, J = 15.0 Hz, 1H) , 3.83 (s, 3H) , 3.67-3.41 (m, 2H) , 3.41 (s, 2H) , 2.96 (s, 3H) , 2.77 (dt, J = 13.1, 3.7 Hz, 1H), 2.05 (bs, 1H), 1.74 (t, J = 11.3 Hz, 1H) 198 C-spectra could not be taken up because of the quick solvate formation and crystallization in chloroform, but the structural determination was made by x-ray crystallography. General Operating Instructions for the Production of N-Substituted 1-Methylgalanthamine Derivatives (Examples 102-106) 200 mg (0.70 mmol) 1-methyl-N-demethylgalanthamine (or -epigalanthamine) 192 mg (1.39 mmol) = 2 equivalents potassium carbonate 117 mg (0.78 mmol) = 1.1 equivalents sodium iodide (0.84 mmol) = 1.2 equivalents substituted alkyl halide 10 ml acetone, dried on a 4 A molecular sieve Sodium iodide, potassium carbonate and educt were thoroughly pulverized'in a friction column, the mixture together with some / 199 glass pellets were introduced into the flask and suspended in absolute acetone. The substituted alkyl halide was added in measured quantities, and the reaction mixture was refluxed. After the end of the reaction, the reaction mixture was evaporated to the dry state in a vacuum, and the residue was taken up with 2N HC1, the aqueous phase was washed with ethyl acetate, then made basic with concentrated aqueous ammonia and in turn extracted with ethyl acetate. The collected organic phases were washed with saturated common salt solution, dried on sodium sulfate, filtered, and the solvent was drawn off. The crude product was purified on a silica gel column (mobile solvent: CHC13 : MeOH = 9:1 + 1% NH^OH) . Example 102 [(±) _ (4aa,6£,8aR*) ] -4a, 5, 9 ,10,11,12-Kexahydro-3-methoxy-l-methyl-11-(2-propenyl)-6H-benzofuro[3a,3,2-ef][2]benzazepin-S-ol, 1-methyl-N-allylgalanthamine (MH-25) 200 200 mg (0.70 mmol) 1-methyl-N-demethylgalanthamine (XXII) 0.07 ml (0.84 mmol) = 1.2 equivalents l-bromo-2-propene (allyl bromide) After 10 hours, the reaction was worked up. Yield: 50 mg (0.15 mmol = 22% of theory) of a yellow oil C20H25NO3 [327.43] TLC: Rf = 0.17 (CHC13 : MeOH = 9:1 + 1% NH4OH) C20H25NO3 x 0.8 H2O [341.83] % C % H % N Cld.: 70.27 7.84 4.10 Fnd.: 70.18 7.60 4.05 2H-NMR (200 MHz, CDCI3) : 5 6.52 (s, 1H) , 6.12 (d, J = 10.3 Hz, 1H), 6.03-5.78 (m, 2H), 5.18 (bs, 1H), 5.11 (q) 201 Example 103 [ 200 mg (0.70 mmol) 1-methyl-N-demethylgalanthamine (XXII) 0.1 ml (0.84 mmol) = 1.2 equivalents bromomethylbenzene (benzyl bromide) After 24 hours, the reaction was worked up. Yield: 140 mg (0.37 mmol = 53% of theory) of a yellow oil C24H27NO3 [377.48] TLC: Rf = 0.36 (CHC13 : MeOH = 9:1 + 1% NH^OH) 1H-NMR (200 MHz, CDC13) : 5 7.30 (m, 5H) , 6.50 (s, 1H), 6.16 (d, J = 10.2 Hz, 1H), 5.99 (dd, J = 10.2, 4.9 Hz, 1H), 4.61 (bs, 1H), 4.13 (bs, 1H), 4.00 (d, J - 15.7 Hz, 1H), 3.82 (s, 3H), 3.81 202 13C-NMR (50 MHz, CDC13) : 6 143.9 (s), 143.0 (s), 138.9 (s) , 133.6 (s) , 12 9.2 (s) , 128.7 (d) , 12 8.2 (d) , 12 7.4 (d) , 127.3 (d) , 127.2 C (±) - (4aa, 6£, 8aR*) 3 -4a, 5, 9,10,11,12-Hexahydro-3-methoxy-l-inethyl-11- (2- (4-morpholin.yl)ethyl)-6H-benzofuro t3a,3,2-ef] [2]benzazepin-6-ol, 1-methyl-N-morpholinoethyl-galanthamine (MH-28) 200 mg (0.70 mmol) 1-methyl-N-demethylgalanthamine (XXII) 155 mg (0.84 mmol) = 1.2 equivalents 4-(2-chloroethyl)morpholine hydrochloride After 24 hours, the reaction was worked up. Yield: 210 mg {0.52 mmol = 75% of theory) of a yellow oil C23E3EN2°4 [400-52] TLC; Rf = 0.51 {CHCl3 : MeOH =9:1 + 1% NH^OH) 203 C23H32N2°4 X °*9 H2° [416.72] % C % H % N Cld.': 66.29 8 . 17 6.72 Fnd.: 66.28 8.09 6.85 ^-NMR (200 MHZ, CDCl3) : 5 6.52 (s, 1H) , 6.10 (d, J = 10.3 Hz, 1H), 5.97 (dd, J = 10.3, 4.8 Hz, 1H), 4.55 (bs, 1H), 4.13 (bs, 1H) , 4.12 (d, J = 15.9 Hz, 1H) , 3.88 (d, J = 15.9 Hz, 1H) , 3.81 (s, 3H), 3.75-3.65 (m, 4H), 3.30 (ddd, J = 14.3, 12.4, 2.0 Hz, 1H) , 3.10 (dt, J = 14.3, 3.3 Hz, 1H) , 2.76-2.58 (m, 4H) , 2.55-2.41 (m, 5H), 2.25 (s, 3H), 2.08-1.90 (m, 2H), 1.55 (dd, J= 13.7, 2.8 Hz, 1H) ; 13C-NMR (50 MHz, CDCl3) : 5 144.1 (s), 143.0 (s) , 133.5 (s) , 12 8.9 (s) , 127.4 (d) , 127.1 (d) , 12 6.9 (s) , 113.7 (d) , 88.4 (d) , 66.7 (t + t) , 66.6 (t) , 61.9 (d) , 57.1 (t), 55.8 (q) , 54.0 (t + t), 53.4 (t) , 52.0 (t) , 48.4 (s), 33.4 (t), 29.8 (t), 19.4 (q) Example 105 E(±) - (4ao;/6fi/8aR*) ] -4a, 5, 9,10,11,12-Hexahydro-3-methoxy-l-methyl-11- {3- (l-piperidinyl)propyl)-6H-benzofuro[3a,3,2-ef] [2 3benzazepin-6-ol, 1-methyl-N-piperidinopropyl-galanthamine (MH-29) 204 200 mg (0.70 mmol) 1-methyl-N-demethylgalanthamine (XXII) 166 mg (0.84 mmol) = 1.2 equivalents 1-(3- chloropropyl)piperidine hydrochloride After 24 hours, the reaction was worked up. Yield: 180 mg (0.44 mmol = 63% of theory) of a yellow oil C25H36N2O3 [412.58] TLC: Rf = 0.27 (CHCI3 : MeOH = 9:1 + 1% NH^OH) C25H36N2O3 x 0.50 H2O [421.58] % C % H % N Cld.: 71.23 8.85 6.64 Fnd.: 71.33 8.97 6.60 ^-NMR (200 MHz, CDCI3) : 5 6.52 (s, 1H) , 6.10 (d, J = 10.4 Hz, 1H), 5.96 (dd, J - 10.4, 4.7 Hz, 1H), 4.55 (bs, 1H), 4.12 (bs, 1H), 4.08 (d, J = 15.7 Hz, 1H), 3.83 (d, J = 15.7 Hz, 1H) , 3.81 205 Example 106 [ (±)-(4aa, 6a, 8aR*) ]-4a,5, 9,10,11,12-Hexahydro-3-methoxy-l-methyl- 11-(3-(l-piperidinyl)propyl)-6H-benzofuro[3a,3,2- ef][2]benzazepin-6-ol, 1-methyl-N-piperidinopropyl- epigalanthamine (MH-117) 100 rag (0.35 mmol) 1-methylepigalanthamine (XXIV) 83 mg (0.42 mmol) = 1.2 equivalents (l-(3- chloropropyl)piperidine hydrochloride After 28 hours, the reaction was worked up. Yield: 60 mg (0.15 mmol = 42% of theory) of a light yellow oil C25H36N2O3 [412.58] TLC: Rf = 0.12 (CHC13 : MeOH = 9:1) 2H-NMR (200 MHz, CDC13) : 5 6.50 206 13.5, 2.5 Hz, 1H), 2.75 (dt, J = 13.7, 4.1 Hz, 1H) , 2.56-2.27 (m, ¦8H) , 2.23 (s, 3H) , 2.08 (td, J = 13.1, 4.0, 2H) , 1.81-1.38 (m, 9H) ; 13C-1STMR (50 MHz, CDC13) : 5 144.9 (s), 142.7 (s), 133.4 19.4 (q) General Operating Instructions for the Production o£ Galanthaminium Bromide Derivatives (Examples 107-109) 1 equivalent a galanthamine derivative 1 equivalent N-bromosuccinimide 50 ml methylene chloride or chloroform, distilled via P20-/l g of a galanthamine derivative The educt is dissolved in a solvent, and K"-bromosuccinimide is added while being stirred. A precipitate is immediately 207 formed that is auctioned off after an appropriate length of time, washed and sectioned off in the dry state. The products that are thus obtained are generally very pure, but the large amount of solvent rather than a small amount is important since otherwise succinimide is pulled into the substances and the latter are subsequently difficult to purify. Example 107 [4aS- (iao:, 6£, 8aR*) ] -4a, 5,9,10-Tetrahydro-6-hydroxy-3-methoxy-ll-methyl-SH-benzofuro[3a,3,2-efj [2]benzazepinium, bromide, galanthaminiiun bromide (MH-119) 200 mg (0.7 mmol) galanthamine (1) 124 mg (0.7 mmol) N-bromosuccinimide 10 ml methylene chloride or chloroform, distilled via P2O5 The precipitate that was produced was suctioned off after 10 minutes. Yield: 230 mg (0.63 mmol = 90% of theory) of a light yellow powder C17H20BrNO3 [366.25] 208 TLC: Rf = 0.58 (CHC13 : MeOH = 9:1 + 1% NH^OH) . Melting point: 216-219°C C17H2QBrNO3 x 0.1 HBr [374.34] % C % H % N Cld.: 54.55 5.41 3.74 Fnd. : 54 .52 5.36 3.66 1H-NMR {200 MHZ, CDCl3) : 5 9.10 (s, IK), 7.54 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.5 Ez, 1H), 5.92 (dd, J = 10.3, 4.5 Hz, 1H), 5.73 {d, J = 10.3 Hz, 1H), 4.74 (s, 1H), 4.59 (s, 1H), 4.11 (s, 2H), 3.94 (s, 3H), 3.79 (s, 3H), 2.38 (d, J = 15.3 Hz, 1H), 2.15 (m, 3H) ; 13C-NMR (50 MHz, CDC13) : 5 1S7.3 (d) , 151.3 (s) , 146.2 (s), 136.9 (s) , 133.0 (d) , 129.8 (d) , 126.4 (d) , 115.0 (s), 112.9 (d) , 87.0 (d) , 58.9 [(±) - (4aa,6£,8aR*) ] -4a, 5, 9,10-Tetrahydro-S-hydroxy-3-methoxy-^ll-dimethyl-SH-benzofuropa/S^-ef] [23 benzazepinium, bromide/ l-iuethylgalanthaminiiiiti bromide {Pi-8) 209 200 rag (0.66 mmol) l-methylgalanthamine (XV) 118 mg (0.66 mmol) N-bromosuccinimide 5 ml chloroform After 5 minutes, an orange-yellow precipitate was produced, which, was suctioned off after 15 minutes. The precipitate 162 mg) was washed twice with diethyl ether. The filtrate was concentrated by evaporation, taken up in a little ethanol and precipitated in diethyl ether (54 mg). Yield: 216 mg (0.57 mmol = 86% of theory) of an orange-yellow powder C18H22BrNO3 [3 80.28] TLC: Rf = 0.02 (CHC13 : MeOH = 9:1) Melting point: 223-226°C C1RH^BrNO, x 0.35 HBr [408.60] % C % H % N Cld.: 52.91 5.51 3.43 Fnd.: 52.99 5.52 3.48 1H-NMR (200 MHz, DMSO-d6) : 6 9.06 (s, IK), 7.04 (s, 1H) , 5.81 (dd, J = 10.1, 4.5 Hz, 1H) , 5.54 (d, J = 10.2 Hz, 1H) , 4.74 (s, 1H) , 4.17-3.95 (m, 4H) , 3.91 (s, 3H) , 3.86 (s, 3H) , 2.53 (s, 3H) , 2.40-1.96 (m, 4H) ; 13C-NMR (50 MHz, DMSO-d6) : 5 166.4 (d) , 150.5 (s) , 144.7 (s) , 140.4 (s), 136.7 (s), 128.4 (d) , 127.9 (d) , 114.9 (d) , 113.9 (s) , 86.5 (d) , 58.7 (d)', 56.3 (q) , 54.4 (t) , 50.5 (q) , 47.0 (s), 35.1 (t), 29.4 (t), 18.9 (q) 210 Example 10 9 [4aS- (4aa,6a,8aR*)] -4a, 5, 9,10-Tetrahydro-6-hydroxy-3 -methoxy-lime thyl-6H-benzofuro E3a,3,2-ef] [2]benzazepinium, bromide, epigalanthaminium bromide (Pi-13) 0.78 g {2.71 mmol) epigalanthamine (26) 0.48 g (2.71 mmol) N-bromosuccinimide 6 ml absolute chloroform After 3 minutes, a yellow precipitate was produced, which was suctioned off and washed twice with diethyl ether. A seconc fraction was obtained by concentration by evaporation of the filtrate.and adding in drops of diethyl ether to a level of 60 ml. The second fraction was dissolved in a little ethanol for purification and added in drops to diethyl ether. Yield: 0.91 g.(2.48 mmol = 92% of theory) C17K20BrNO3 [366.25] TLC: Rf = 0.05 (CHCl3 : MeOH =9:1 + 1% NH40H) Melting point: 205-210°C C17H20BrNO3 X 0.3 HBr £390.52] 211 % C % H % N Cld. : 52 .28 5.24 3.59 Fnd. : 52 .12 5.18 3.88 ^-NMR (200 MHz, DMSO-d6) : 5 9.10 {s, 1H) , 7.51 (d, J = 11.5 Hz, 1H), 7.20 (d, J = 11.5 HZ, 1H), 5.82 (d, J = 12.7 Hz, 1H), 5.68 (d, J = 12.7 Hz, 1H) , 4.80 1 equivalent a galanthaminium derivative 3 equivalents potassium cyanide 30 ml water/l g of a galanthaminium derivative 212 10 ml diethyl ether/1 g of a galanthaminium derivative The educt was dissolved in a separatory funnel in water, and the solution was covered with a layer of ether, than solid potassium cyanide (freshly pulverized) was added thereto, whereby a white precipitate immediately formed in the aqueous phase. After about 2-3 minutes, the product was extracted by shaking in the ether phase. The aqueous phase was exhaustively extracted with ether and with sparingly soluble derivatives with chloroform, the organic phases were combined, washed with saturated aqueous common salt solution, dried on Na2SO4, filtered, and the" solvent was drawn off. If necessary, the product that was obtained was purified on a silica gel column .(mobile solvent: CHCl3 : MeOH = 9:1, unless otherwise indicated). Example 110 [4aS- {4aa,6S,8aR*)J -4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-ll-methyl-6H-benzo£uro[3a,3,2-ef][2]benzazepine-12-carbonitrile, galanthamine-12-carbonitrile (MH-123) 213 3.50 g {9.56 mmol) galanthaminium bromide (L) 1.90 g (28 . 7 mmol) = 3 equivalents potassium cyanide 100 ml water 40.0 ml diethyl ether The reaction was performed according to the general operating instructions. Raw yield > 2 g The oily raw mixture, consisting of an isomer ratio of about 9:1, was dissolved in as little ethanol as possible, and the main isomer was brought to crystallization while being stirred. The precipitate was suctioned off, washed with ethanol, and the filtrate was combined with the washing solution and concentrated by evaporation. The process was repeated until the main amount of pure main isomer was isolated. Yield: 990 mg (3.28 mmol = 34% of theory) of a white powder Ci8H20N2O3 [312.37] A mixture that consists of two isomers (ratio 9:1) and galanthamine remains, and said mixture is produced during the isolation of the main isomer, which could be purified by columns. The isomer mixture is eluted again at a ratio of 9:1 from the column, since it is converted into one another on the column. TLC: Rf = 0.77 main isomer 0.63 Secondary isomer (CHC13 : MeOH = 9:1) Melting point: 151-155°C CI8H2ON2Q/X 0.1 H2O [314.17] 2 14 % C % H % N Cld. : 68 .82 6.48 8.92 Fnd. : 68.85 6.32 8.69 ]H-NMR (200 MHz, CDC13) : 5 6.70 (s, 2H) , 6.35 (d, J = 10.2 Hz, 1H) , 6.07 {dd, J = 10.2, 5.3 Hz, 1H) , 4.71 (s, 1H) , 4.61 {m, 1H), 4.15 (dt, J = 11.1, 5.0 Hz, lH)y 3.85 (s, 3H), 3.50 (dd, J = 15.0, 13.6 Hz, 1H), 2.91 (dt, J = 15.0, 3.2 Hz, 1H), 2.74-2.61 {m, IK), 2.61 (s, 3H), 2.38 (d, J = 11.4 Hz, 1H), 1.98-2.08 (m, 2K) , 1.78 (ddd, J = 13.7, 5.0, 1.2 Hz, 1H) ; 13C-NMR (50 MHz, CDC13) : 5 146.7 (s), 145.6 (s), 132.9 (s), 128.2 (d) , 126.9 (d) , 124.2 (s) , 122.5 (s) , 111.6 (d) , 88.9 (d) , 61.6 (d + d) , 55.9 (q) , 49.9 (t) , 48.1 (s), 46.1 (q) , 36.4 (t), 29.7 [( + ) -(4aa,6£,8aR*)3-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-msthoxy-1,11-dimethyl-6H-benzofuro[3a,3,2-efI[2]benzazepine-12-carbonitrile, l-methylgalanthamine-12-carbonitrile (Pi-12) 215 300 mg (0.79 mmol) l-methylgalanthaminium bromide (LI) 154 mg {2.36 mmol) = 3 equivalents potassium cyanide 20.0 ml water 205 mg of a white crude product was isolated. An attempt was made to achieve column-chromatographic separation of the diastereomers with a pure ethyl acetate as a mobile solvent. In this case, however, no separation of the diastereomer mixture could be accomplished. Yield: 151 mg (0.46 mmol = 59% of theory) C19H22N2O3 [32 6.3 9] TLC: Rf = 0.30/0.65 (diastereomer mixture; ethyl acetate) Melting point: 72-73°C C19H22N2°3 X °'5 H2° [335.39] % C % H % N Cld.: 68.04 6.91 8.35 Fnd.: 67.91 6.62 8.20 1H-NMR (Mixture that consists of 2 isomers, 200 MHz, CDC13) : 6 6.59 (s, 1H), 6.31 (d, J = 8.9 Hz, 0.4H), 6.27 (d, J = 8.9 Hz, 0.6H)", 6.01 (dd, J = 9.2, 5.0 Hz, 1H) , 4.96 (s, 0. 6H) , 4.83 (s, 0.4H), 4.57 (bs, 0.6H), 4.50 (bs, 0.4H), 4.12 (dt, J = 15.5, 4.9 Hz, IK), 3.83 (s, 3H), 3.47 (ddd, J = 13.9, 9.8, 3.4 Hz, 1H), 2.38 (dt, J = 14.6, 3.8 Hz, 1H), 2.70 (bs, 1H), 2.62 (s, 1.8H), 2.60 (s, 1.2E) , 2.31 (s, 3H) , 2.10-1.92 (m, 2H), 1.87-1.68 (m, 1H) ; 13C-NMR (mixture that consists of 2 isomers, 100 MHz, CDCl3) : 5 145.5 (s), 145.4 (s), 145.3 (s), 144.8 (s), 135.7 (s), 133.6 (s) , 129.7 (d) , 129.3 (d) , 129.6 (s), 128.7 (s), 128.4 (d) , 127.7 216 (d), 122.9 (s) , 122.8 (s), 116.7 (s), 115.3 (s), 114.5 (d), 114.4 (d), 89.4 (d), 88.9 (d) , 62.3 (d) , 62.2 (d) , 57.9 (d) , 56.6 (d) , 56.5 (q), 56.3 (q) , 51.0 (t), 50.3 (t), 49.0 (s), 47.9 (s), 47.2 (q), 47.2 (s), 36.8 (t), 33.7 (t), 30.2 (t), 2 0.3 (q), 19.3 (q) Example 112 [4aS-(4aa, 6a, 8aR*) ]-4a,5, 9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-ll-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepine-12-carbonitrile, epigalanthamine-12-carbonitrile (Pi-14) 500 mg (1.37 mmol) epigalanthaminium bromide (LII) 270 mg {4.10 mmol) = 3 equivalents potassium cyanide 15.0 ml water Yield: 0.33 g (1.06 mmol = 77% of theory) C18H20N2O3 [312.37] TLC: Rf = 0.75 (CHCI3 : MeOH = 9:1) Melting point: 90-96°C 217 ^-NMR (Mixture that consists of 2 isomers, 200 MHz, CDC13) : 5 6.92 (d, J = 8.3 Hz, 0.3H), 6.72 (d, J = 8.0 Hz, 0.3H), 6.63 (d, J = 8.0 Hz, 0.7H), 6.62 (d, J = 8.3 Hz, 0.7H), 6.31 (dt, J= 10.5, 1.6 Hz, 0.7H); 6.03 (d, J = 10.5 Hz, 0.3H), 5.85 (d, J = 10.3 Hz, 1H), 5.22 {s, 0.3H), 4.64 (s, 0.7H), 4.58 (bs, 1H), 3.8S (s, 0.9H), 3.85 (S, 2.1H), 3.12 (dt, J= 14.8, 3.2 Hz, 0.3H), 2.98-2.70 (m, 1.7H), 2.58 (s, 2.1H), 2.38 (s, 0.9H), 2.27-2.04 (m, 1.2H), 1.85 (dd, J = 13.5, 4.2 Hz, 1.4H), 1.71 (ddd, J = 13.5, 10.7, 2.5 Hz, 1.4H); 13C-NMR (mixture that consists of 2 isomers, 50 MHz, CDC13) : 5 147.5 and 147.2 (s) , 145.2 and 145.0 (s), 132.6 (s), 132.5 and 131.9 (d), 126.6 (d), 124.0 and 123.3 (s), 121.8 and 120.1 (d), 116.5 (s), 111.3 and 111.2 (d), 88.7 and 88.4 (d) , 62,8 (d) , 61.4 and 58.4 (d) , 55.8 (q) , 50.0 (t) , 47.9 (s), 45.9 (q), 36.9 (t), 32.0 and 31.7 (t) Example 113 [ (±) - (4aa, 60!/ 8aR*) ] -4a, 5, 9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1, ll-ddjnethyl-6H-benzofuro [3a,3,2-ef ] [2]benzazepine-12-carbonitrile, l-methylepigalanthamine-12-carbonitrile (Pi-19) 218 1-Methylepigalanthaminium bromide was produced according to general operating instructions for the production of galanthaminium derivatives, whereby no precipitate formed, however. The reaction solution was therefore evaporated to the dry state, the remaining residue was taken up in ether, suctioned off and washed. The remaining crude product was used directly in the subsequent reaction according to NMR analysis. 500 mg (1.32 mmol) 1-methylepigalanthaminium bromide (LIII) 260 mg (3.96 mmol) = 3 equivalents potassium cyanide 50 ml water The purification was carried out by means of column chromatography (CHC13 : MeOH = 9:1). Yield: 220 mg (0.67 mmol = 51% of theory) of a white foam C19H22N2O3 [326.39] TLC: Rf = 0.70/0.60 (diastereomer mixture; CHC13 : MeOH = 9:1) XH-NMR (Mixture that consists of 2 isomers, 200 MHz, CDC13) : 5 6.57 (s, 1H), 6.26 (d, J = 10.4 Hz, 1H), 5.82 (d, J = 10.4 Hz, 1H), 4.94 and 4.82 (s, 1H), 4.74-4.55 (m, 1H), 4.50 and 4.45 (m, 1H), 3.87 and 3.84 (s, 3H), 3.55-3.32 (m, 1H), 3.05-2.68 (m, 2H) , 2.58 and 2.57 (s, 3H), 2.33 and 2.30 (s, 3H), 2.23-2.07 (m, 1H), 1.93-1.63 (m, 2H); 13C-NMR (mixture that consists of 2 isomers, 50 MHz, CDCI3) : 5146.0 (s), 145.8 (s), 144.5 (s), 144.1 (s), 135.0 (s), 133.0 (s), 132.2 (d), 131.7 (d) , 129.5 (d), 128.5 (s), 127.6 (&/, 127.1 (d), 122.4 (s), 122.2 (s), 116.4 (s), 114.8 (s), 219 113.9 (d) , 113.8 (d) , 88.5 (d) , 88.4 (d) , 63.0 (d) , 62.6 (d) , 57.2 (d), 56.4 (d), 56.0 (q), 55.8 (q), 50.7 (t), 50.0 (t), 48.4 (s), 47.3 (s), 46.7 (q), 36.9 ft), 34.1 1 equivalent a galanthaminium derivative 2-4 equivalents methylmagnesium iodide (3M in diethyl ether) 20 ml absolute diethyl ether/1 g of a galanthaminium derivative The entire amount of Grignard reagent was introduced under N2 atmosphere, and then the solid galanthaminium derivative was added without solvent. After the length of time indicated in each case, diethyl ether was added and stirred for a specific length of time, whereby the solid material dissolved. Then, it 220 was hydrolyzed with water, the reaction solution was made basic with concentrated ammonia and extracted with ethyl acetate. The organic phases were washed with saturated common salt solution, dried on sodium sulfate, filtered, and the solvent was drawn off. Example 114 [4aS- (4aa, 6p, 8aR*) ]-4a, 5,9,10,11, 12-Hexahydro-3-methoxy-ll,12-dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol, 12-methylgalanthamine (Pi-4) 2.00 g (5.46 mmol) galanthaminium bromide (L) 6.70 ml {20.2 mmol) = 3.7 equivalents methylmagnesium iodide (3 M in diethyl ether) 40 ml absolute diethyl ether After 40 minutes, the solvent was added and stirred for 5 hours, before it was hydrolyzed. Yield: 760 mg (2.52 mmol = 46% of theory) of a light yellow foam X 221 C18H23NO3 [3 01.3 8] TLC: Rf = 0.65 {CHC13 : MeOK =9:1 + 1% NH4OH) Melting point: 46-43°C ^-NMR {Mixture that consists of 2 isomers,.200 MHz, CDC13) 5 6.6S (d, J = 8.3 Hz, 0.8H), 6.65 (s, 0.2H), 6.64 (s, 0.2H), 6.57 (d, J = 8.3 Hz, 0.8H), 6.13 (d, J = 10.1 Hz, 0.2H), 6.07 (c J = 10.1 Hz, 0.8H), 5.94 (dd, J = 10.1, 4.4 Hz, 1H), 4.54 (bs, 1H), 4.26 (q, J = 7.0 Hz, 0.2K), 4.08 (t, J = 4.4 Hz, 1H), 3.88 (q, J = 7.4 Hz, 0.8H), 3.80 (s, 0.6H), 3.78 (s, 2.4H), 3.62 (ddc J = 14.6, 13.2, 1.0 HZ, 0.8H), 3.45 (d, 14.2 Hz, 0 -2H) , 3.12 (dt J = 14.8, 3.3'Hz, 0.2H), 2.85 (td, J = 15.5, 3.5 Hz, 0.8H), 2.7* (bs, 1H), 2.63 (d, J = 15.6 Hz, 1H), 2.43 (s, 3H), 2.16 (d, J = 2.7 Hz, 0.2H), 1.98 (dt, J = 15.5, 2.3 Hz, 0.8H), 1.95 {dd, J = 15.5, 2.3 Hz, 0.2H), 1.51 (d, J = 7.3 Hz, 2.4H), 1.47 (d, J = 7, Hz, 0.6H); 13C-NMR (mixture that consists of 2 isomers, 50 MHz, CDC13) : 6 146.1 and 145.6 (s), 143.8 and 143.4 (s) , 134.9 and 132.6 (s), 132.4 and 131.3 (s) , 129J3 (d) , 127.6 and 127.3 (d) , 126.9 (d), 122.0 and 119.9 (d), 111.5 and 110.8 (d), 88.6 and 83.5 (d) , 64.0 (d), 61.9 and 61.6 (d) , 58.3 and 55.7 (q) , 48.8 (s) , 44.1 (t) , 41.3 (q), 31.5 and 31.0 (t) , 29.9 and 29.7 (t) , 21.8 and 17.5 (q) 222 Example 115 [4 aS- (4a?, 6? , 8aR*, 12R*)] -4a,5 , 9 ,10 ,11,12 -Hexahydro-3 -tnethoxv-11/12-dimethyl-6H-benzofuroF3a, 3,2-e£l [21benzazepin-6-ol, ( = 12-methvlgalanthajniiie) i (main isomer) The isomer mixture v;as purified by column chromatography on silica gel (CHC13 : MeOH = 9:1 + 1% NH^OH) , whereby a pure isomer was obtained. 1H-NMR (200 MHz, CDC13) : 6 6.66 (d, J = 8.3 Hz, 1H) , 6.57 (d, J = 8.3 Hz, 1H), 6.07 (d, J = 10.1 Hz, 1H), 5.94 (dd, J = 10.1, 4.4 Hz, 1H) , 4.54 (bs, 1H) , 4.OS (t, J = 4.4 Hz, 1H) , 3.88 (q, J = 7.4 Hz, 1H), 3.78 (s, 3H), 3.62 (dd, J = 14.6 (13.2 Hz, IE), 2.85 (td, J = 15.5, 3.5 Hz, 1H), 2.63 (d, J = 15.6 Hz, IE), 2.43 (s, 3H), 2.11 (dt, J = 13.3, 2.4 Hz, 1H), 1.95 (ddd, J = 16.5, 5.0, 1.8 Hz, 1H) , 1.51 (d, J = 7.3 Hz, 3H) , 1.47 (dd, J = 13.3 Hz, IK); 13C-NMR (50 MHz, CDC13) : 5 146.2 (s), 143.5 (s), 135.1 (s), 131.4 (S), 129.4 (d) , 127.4 (d) , 122.2 (d) , 111.6 (d) , 88.8 (d), 64.0 (d), 61.8 (d), 55.8 (q), 48.9 (s), 44.2 (t), 41.5 (q), 31.7 (t), 29.8 (t), 21.9 (q) 223 Example 116 [ (±) - (4aa, 6(3, 8aR*) ]-4a, 5, 9,10,11,12-Hexahydro-3-methoxy-6H-l,ll,12-trimethyl-benzofuro[3a,3,2-ef] £2]benzazepin-6-ol, 1,12-dimethylgalanthamine (Pi-21) 500 mg (1.31 mmol) 1-methylgalanthaminium bromide (LI) 1.00 ml (3.00 mmol) = 2.3 equivalents methylmagnesium iodide (3 M in diethyl ether) 15 ml absolute diethyl ether During the addition of educt, 5 ml of diethyl ether was added to keep the reaction mixture stirrable. After the addition of educt was completed (30 minutes), another 10 ml of diethyl ether was added. After 2.5 hours, the reaction mixture was hydrolyzed. Yield: 73 mg (0.23 mmol - 18% of theory) C19H25NO3 [315.41] TLC: Rf = 0.50 (CHC13 : MeOH = 9:1 + 1% NH4OH) Melting point: 45-50°C 224 1H-NMR (Mixture that consists of 2 isomers, 200 MHz, CDCl.) : 6 6.57 (s, 1H) , 6.06 (d, J = 10.2 Hz, 1H) , 5.95 (dd, J = 10.2, 4.5 Hz, 1H) , 4.59-4.44 (m, IK), 4.17-4.03 (m, 2H) , 3.81 {s, 3H) , 3.75-3.5S (m, 1H), 2.97-2.77 (m, 1H), 2.73-2.55 (m, 1H), 2.51 (s, O.SH)> 2.46 (s, 2.5H), 2.25 (s, 3H) , 2,15-1.87 (m, 2H) , 1.51 (d, J = 7.3 Hz, 3K) , 1.30-1.13 (m, 1H) ; 13C-NMR (mixture that consists of 2 isomers, 50 MHz, CDC13) : 6 144.7 (s) , 142,9 (s) , 132.5 and 131.7 (s) , 130.4 and 129.0 (s) , 129.3 (d) , 127.8 and 126.8 (s) , 127.5 (d), 114.3 and 114.0 (d) , 88.7 and 88.4 (d) , 62.2 and 61.8 (d) , 59.3 and 58.8 (d), 56.0 and 55.8 (q) , 49.4 and 48.4 (s), 44.3 (t) , 41.5 (q) , 31.7 (t) , 29.9 (t) , 19.7 and 19-2 (q), 18.8 (q) Example 117 [4aS- (4aa; Sa,8aR*) ] -4a, 5, 9,10,11,12-Hexahydro-3-methoxy-ll, 12-dimethyl-SH-benzofuro[3a,3,2-ef][2]b&nzazepin-6-ol, 12-methylepigalaxithamine (Pi-22) 225 300 mg (0.82 nunol) epigalanthaminium bromide (LII) 1.00 ml (3.00 mmol) = 3.70 equivalents methylmagnesium iodide (3 M in diethyl ether) The Grignard reagent was added over 30 minutes, then 5 ml of ether was added. After 20 minutes, another 15 ml of ether was added and hydrolyzed for 3 hours. The purification was carried out by column chromatography (CHC13 : MeOH = 9:1) . Yield: ¦ 60 mg (0.20 mmol = 24% of theory) C18H23NO3 [301.39] TLC: Rf = 0.78 (CHC13 : MeOH = 9:1 + 1% NH4OH) XH-NMR {200 MHz, CDCI3) : 66.65 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 8.3 Hz, 1H), 6.04 (d, J = 10.4 Hz, 1H), 5.76 (d, J = 10.4 Hz, 1H), 4.7 0-4.57 (m, 1H), 4.54 (bs, 1H), 3.93-3.82 (m, 1H), 3.81 (s, 3H), 3.61 (t, J - 13.6 Hz, 1H), 2.94-2.67 (m, 3H), 2.41 (s, 3H), 2.20 (td, J - 13.2, 2.4 Hz, 1H), 1.69 (ddd, J = 13.6, 10.6, 2.0 Hz, 1H), 1.52 (d, J = 7.3 Hz, 3H), 1.59-1.44 (m, 1H) ; 13C-NMR (50 MHz, CDCI3) : 5 147.0 226 Example 118 [4aS- (4aa, 6£, 8aR*) ] -4a, 5, 9,10-Tetrahydro-6-hydroxy-3 -methoxy-lime thyl-6H-benz of uro [3a,3,2-ef] [2]benzazepin-12(11H)-one (MH-12 8) 200 g (0.64 mmol) galanthamine-12-carbonitrile (LV) 0.64 ml (0.64 mmol) sodium trimethylsilanolate (1 M in CH2C12) 5 ml absolute tetrahydrofuran The educts were stirred under N2 atmosphere at room temperature for 72 hours, whereby a precipitate formed, which was suctioned off, washed with tetrahydrofuran and dried. Yield: 177 mg (0.59 mmol = 92% of - theory) of a light yellow powder C17H19NO4 [301.35] TLC: Rf = 0.65 (CHCl3 : MeOH =9:1) Melting point: 251-255°C ^-NME (200 MHz, CDC13) : 5 7.49 (d, J = 8.5 Hz, 1H) , 6.89 (d, J = 8.5 Hz, 1H) , 5.87 (dd, J = 9.8, 5.3 Hz, 1H) , 5.53 (d, J = 9.8 Hz, 1H) , 4.74 (bs, 1H) , 4.13 (dt, J = 10.1, 4.8 Hz, 1H) , 3.91 227 (S, 3H), 3.80 (dt, J = 14.1, 2.1 Hz, 1H), 3.25-3.16 {m, 1H) , 3.19 (s, 3H) , 2.71 (dt, J = 15.7, 1.7 Hz, 1H) , 2.31 {dt, J =r 14.1, 3.3 Hss, 1H) , 2.06 (ddd, J = 15,7, 5.0, 2.3 Hz, 1H) , 1.83 (dt, J = 14.6, 2.5 Hz, 1H) ; 13C-NMR (50 MHz, CDCl3) : 5 168.3 (s) , 146.9 (S), 145.1 (S), 131.7 (s)) 131.6 (d), 125.2 (d), 124.4 (d), 123.4 (a), 111.9 (d) , 89.2 (d)/61,0 (d) , 55.8 (q) , 49.5 (t) , 48.0 (s) , 38.3 (tj, 34.9 (q), 29.3 (t) Example 119 [4aS- (4aa,6£,8aR*)] -4a, 5, 9,10-Tetrahydro-3-methoxy-6H-Treim-u£m.u [3a, 3,2--e-f ] Ulbengagcpin -6-oJU,—li*oxd 4.25 g (15.55 mmol) demsthylgalanthamine (27) 85 mg (0.77 mmol) = 5% selenium dioxide 70 ml 10% aqueous H2O2 solution (35%) in acetone (oxidation solution) Deraethylgalanthamine was dissolved in the oxidation solution in an environment devoid of atmospheric humidity and cooled to 228 0°C. Then, SeO2 was added, and it was stirred first for 2 0 minutes at 0°C and then for 4 hours at room temperature, whereby a white precipitate settled out, which was suctioned off, washed with acetone and dried. The filtrate was mixed with water, the acetone was distilled off in a vacuum, and the remaining aqueous phase was extracted with methylene chloride. The collected organic phases were washed with saturated common salt solution, dried on sodium sulfate, filtered, and the solvent was drawn off. The oily residue was taken up in acetone, whereby a precipitate settled out, which could be obtained as a second fraction. By repeated concentration by evaporation of the filtrate and taking-up in acetone, other fractions were obtained. Yield: 3.53 g (12.29 mmol = 79% of theory) of a white powder C16H1?NO4 [287.31] TLC: Rf = 0.42 (CHC13 : MeOH = 9:1 + 1% concentrated NH40H) Melting point: 232-233°C (CHC13) ; release of a liquid starting from 215°C C16H17NOA X 0.2 H2O [290.91] % C % H % N Cld.: 66.06 6.03 4.81 Fnd.: 66.11 6.05 4.73 TK-NMR (200 MHZ, DMSO-d6) : 6 7.82 (s, 1H) , 6.90 (s, 2H) , 5.81 (dd, J = 10.1,' 4.4 Hz, IK), 5.54 (d, J = 10.1 Hz, 1H) , 4.64 (bs, 1H), 4.36 (d, J = 5.5 Hz, 1H), 4.14-4.02 (m, 2H), 3.79 (s, 3H) , 2.39-1.99 (m, 4H) ; 13C-NMR (50 MHz, DMSO-d6) : 6 146.1 (s) , 229 144.6 (s) , 134.6 (d) , 131.8 (s), 128.3 (d) , 127.6 (d) , 122.4 (d) , 118.3 (s) , 112.6 (d) , 86.7 (d) , 61.8 (d) , 59.1 (t), 55.7 (q) , 45.3 (s), 34.2 (t), 29.7 (t) Example 119 [4aS- (4aa,6£,8aR*)] -4a, 5, 9,10,13 ,14a-Hexahydro-6-hydroxy-3-methoxy-SH, 14H-benzofu.ro [3a,3,2-ef] isoxazolo [3,2-a][2]benzazepine-13{or 14)-carboxylic acid, methyl ester (MH-143) 175 rag (0.61 ramol) galanthamine nitrone (LXXXIV) 0.05 ml (0.61 mmol) acrylic acid methyl ester 6 ml absolute toluene The reagents were refluxed for 48 hours under argon atmosphere, then the solvent was drawn off. The residue was purified by column chromatography (CHC13 : MeOH = 9:1 + 1% concentrated NK40H) . Yield: 225 mg (0.60 mmol = 99% of theory) of a light brown, glass-like solidifying oil C2QH23NO6 137 3.40] 230 TLC: Rf = 0.74 (CHC13 : MeOH = 9:1 + 1%"concentrated NH^OH) C20H23NO6 X 0.5 H2O [382.40] % C % H % N Cld. : 62.82 6.33 3 .66 Fnd.: 62.88 6.17 3.65 Mixture that consists of stereoisomers and regioisomers. The more specific treatment of spectra is found in Chapter 2.2, Strukturaufklarungen [Structural Explanations]. Example 12 0 [4aS- (4aa, 6fi, 8aR*, 14aS*) ] -4a, 5, 9,10-Tetrahydro-6-hydroxy-3-methoxy-6H, 14aH-benzofuro [3a, 3, 2-ef ] isoxazolo [3,2-a] [2]benzazepine-14-carboxylic acid, methyl ester (MH-145) 200 mg (0.70 ramol) galanthamine nitrone (LXXXIV) 0.06 ml (0.70 mmol) acetylenecarboxylic acid methyl ester (propiolic acid methyl ester) 5 ml absolute toluene 231 The reagents were refluxed for 10 minutes under argon atmosphere, whereby the solution was already colored'orange during heating, then the solvent was drawn off. The residue was purified by column chromatography (CEC13 : MeOH = 9:1} . The oily residue was recrystallized from ethanol, whereby yellow- needles were obtained. Yield: 261 mg (0.70 mmol = 100% of theory) of light yellow needles C20H21NO6 [371.3 9] TliC: Rf = 0.73 (CHC13 : MeOH =9:1) Melting point: 151-154°C % C % H % N Cld.: 64.68 5.70 3.77 Fnd.: 64.59 5.89 3.67 ^-NMR (200 MHz, CDC13} : a 7.54 (s, 1H) , 6.96 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.9S-5.77 (m, 2H), 5.67 (s, 1H) , 4.55 (bs, 1H) , 4.10 (bs, 1H) , 3.85 (s, 3H) , 3.68 (s, 3H) , 3.59 (ddd, J = 14.3, 6.8, 3.8 Hz, 1H), 3.30 (ddd, J = 12.9, 9.3, 3.4 Hz, 1H), 2.64 (dd, J = 15.7, 3.7 Hz, IK), 2.15 (td, J = 1.1, 3.4 Hz, 1H), 2.01 (ddd, J = 15.6, 5.3, 1.9 Hz, 1H), 1.54 (ddd, J = 15.6, 6.7, 3.5 Hz, 2H) ; 13C-NMR (50 MHz, CDC13) : 5 163.9 (s), 154.6 (d) , 14 6.8 (s) , 145.1 (s) , 13 3.3 (s) , 13 0.3 (d) , 126.9 (d) , 12 5.3 (s), 123.3 (d), 111.3 (d), 10 9.9 (s) , 8 9.1 (d), 68.7 (d), 61.4 (d), 55.8 (q), 52.4 (t), 51.4 (q), 47.2 (s), 29.2 (t), 28.0 (t) 232 Example 121 [4aS- (4aa,6E, 8aR*) 1-43,5,9,10,13, 14a-Hexahydro-6-hydroxy-3-methoxy-6H,14H-benzofuro[3a,3,2-ef]isoxazolo [3,2-a] [2]benzazepine-13(or 14)-carbonitrile (MH-146) 200 mg (0.70 mmol) galanthamine nitrone (LXXXTV) 0.05 ml (0.70 mmol) acrylonitrile 5 ml absolute toluene The reagents were refluxed for 2 hours under argon atmosphere, then the solvent was drawn off. The residue was purified by column chromatography {CKCl- : MeOH = 9:1) . Yield:- 230 mg (0.68 mmol = 97% of theory) of a light yellow oil C19H2QN2O4 [340.38] TLC: Rf = 0.74 (CHC13 : MeOH =9:1) C19H20N2O4 X 0.2 H2O [343.98] % C % H % N Cld.: 66.34 5.98 8.14 Fnd. : 66 .22 6.03 7.86 233 Mixture that consists of 4 stereoisomers and regioisomers. The more specific treatment of spectra is found in Chapter 2.2, Strukturaufklarungen. Example 122 [4aS- 200 mg (0.70 mmol) galanthamine nitrone (LXXXIV) 0.24 ml (2.10 mmol) = 4 equivalents vinyl acetate 5 ml absolute toluene The reagents were refluxed for 4 days under N2 atmosphere, whereby each day, 1 equivalent of vinyl acetate was added. The solvent was then drawn off, and the residue was purified by column chromatography {CHCI3 : MeOH = 9:1). The purified oil was crystallized from methanol. Yield: 256 rng (0.69 mmol = 98% of theory) of beige crystals 234 C20H23NO6 [3 73.41] TLC: Rf = 0.70 (CHC13 : MeOH =9:1) Melting point: 132-134°C C2QH23NO6 X 0.6 H2O [384.21] % C % H % N Cld.: 62.52 6.35 3.65 Fnd.: 62.59 6.12 3.61 ^-NMR (Mixture that consists of 2 isomers, 2 00 MHz, CDC13) : 5 S.76 and 6.73 (d, J = 8.3 Hz, 1H), 6.68 and 6.60 (d, J = 7.7 Hz, 1H) , 6.36 (d, J = 4.1 Hz, 1H) , 6.30 (d, J = 10.6 Hz, 1H) , 6.08-5.91 (m, 1H), 4.60 and 4.50 (bs, 1H) , 4.32 (dd, J = 11.3, 5.6 Hz, 1H) , 4.13 (bs, 1H) , 3.84 (s, 3H) , 3.80 (dd, J = 19.1, 9.8 Hz, 1H) , 3.22 (ddd, J = 10.0, 6.8, 2.8 Hz, 1H) , 2.92 (dd, J = 12.3, 5.8 HZ, 1H) , 2.78-2.57 (m, 2H) , 2.09 (s, 3H) , 2.07-1.79 (m, 2H) ; 13C-NMR (Mixture that consists of 2 isomers, 50 MHz, CDC13) : 6 169.6 (s), 145.8 (s), 143.8 (s), 134.1 (s), 129.8 (d), 128.0 and 127.7 (d) , 127.0 (s), 118.7 and 118.5 (d) , 111.4 and 110.9 (d), 95.3 and 94.5 (d), 88.7 and 88.2 (d), 61.4 (d + d), 55.7 and 55.5 (q) , 54.5 (t) , 47.3 (s), 41.7 (t), 29.7 (t) , 29.3 (t), 21.0 and 2 0.9 (q) 235 Example 12 3 [4aS- (4aa,6£,8aR*,14aS*)] -4a,5,9,10-Tetrahydro-6-hydroxy-3-methoxy-6H,14aH-benzofuro[3a,3,2-ef]isoxazolo [3,2-a][2]benzazepine-14-carbonitrile (MH-159) 500 mg (1.74 mmol) galanthamine nitrone (LXXXIV) 90 mg (1.74 mmol) acetylene carbonitrile 10 ml absolute toluene The reagents were stirred for 7 days under argon atmosphere at room temperature, whereby the solution was colored yellow, then the solvent was drawn off. The residue was crystallized from methanol, suctioned off, and washed with methanol. The filtrate was concentrated by evaporation and a second product fraction was obtained from the residue by column chromatography (CHC13 : MeOH = 9:1) . Yield: 570 mg (1.68 mmol = 97% of theory) of colorless crystals C19H13N2O4 [338.37] 235 TLC: Rf = 0.60 (CHC13 : MeOH = 9:1) Melting point: 137-139°C % C % H % N Cld.: 67.45 5.36 8.28 Fnd.: 67.17 5.41 8.19 ^-NMR (200 MHz, CDC13) : 6 7.09 (d( J = 8.6 Hz, 1H) , 6.76 (d, J = 8.6 Hz, 1H) , 5.98 (s, 2H) , 5.54 (s, 1H) , 4.52 (bs, 1H) , 4.11 (bs, 1H), 3.83 (s, 3H), 3.75-3.59 (m, 1H), 3.42-3.25 (m, 1H), 2.64 (dd, J = 15.9, 3.2 Hz, IK), 2.44 (d, J = 11.5 Hz, 1H)', 2.11-1.94 (m, 2H) , 1.71-1.52 (m, 1H) ; 13C-NMR (50 MHz, CDCI3) : 5 156.5 (d) , 14 7.1 (s) , 145.5 (s) , 132.7 (s) , 12 9.6 (d) , 12 7.9 (d) 123.8 (s) , 120.8 (d) , 114.0 (s), 111.7 (d) , 88.9 (d) , 88.6 (s), 68.4 (d) , 61.3 (d) , 55.9 (q) , 52.5 (t), 47.2 (s), 29.3 (t), 28.3 Step 1: l-Bromo-5-methoxy-2-(2-methoxyethen-l-yl)-4-(1- methylethoxy)benzene While being cooled with ice, potassium-tert-butylate (20.S g, 183 mmol) is added to a suspension of (methoxymethyl) -triphenylphosphonium chloride (50.0 g, 152 mmol) in absolute THF (330 ml). After 15 minutes, 2-bromo-4-methoxy-5-(1-methylethoxy)benzaldehyde (33.1 g, 121 mmol) is added in portions. After 15 minutes, the residue that is obtained after the solvent is removed in a rotary evaporator is dispersed between water (300 ml) and ether (300 ml). The organic phase is dried (sodium sulfate), filtered, and the residue that is obtained after concentration by evaporation {37.3 g) is purified by means of MPLC (petroleum ether : ethyl acetate = 2:1, flow 70 ml/min). In this way, the product is obtained in the form of colorless crystals (32.5 g, 85%). Melting point: 43-45°C TLC: Petroleum ether : ethyl acetate =2:1 Rf = 0.75 1H: NMR (CDC13) 5 7.00 (s, 1H) ; 6.90 (s, 1H) , 6.83 (d, J = 12.7 Hz, II* J , 6.13 (d, J = 7.6 Hz, 1H- ) , 5.98 (d, J = 12.7 Ifd [15 C I 5 Hz, 1I3L n ) , 5.50 (d, J = 7.6 Hz, 1H . ) , 4.49 (septet, J = 6.4 Hz, %,i DMS CIS IK), 3.81 (s, 3H) , 3.74 (s, 3Htran3) , 3.70 (s, 3Hcis) , 1.35 (d, J = 6.4 Hz, 6H); 13C-NMR (CDC13) 5 149.2 and 149.6 (s), 147.6 and 148.9 (s) , 146.0 and 146.7 (d), 127.5 and 128.4 (s) , 115.7 and 117.2 (d) , 113.6 and 116.2 (d), 113.3 and 113.7 (s), 103.8 and 104.2 (d), 71.5 and 71.9 (d) , 56.1 and 56.4 (q) , 56.0 and 60.6 (q) , 21.9 and 22.0 (q) 238 Step 2: 2-Bromo-4-methoxy-5- (1-methylethoxy)benzene acetaldehyde l-Bromo-5-methoxy-2-(2-methoxyethen-l-yl)-4-(1-methylethoxy)benzene (20.0 g, 66.4 mmol) is stirred in tetrahydrofuran {250 ml)/2N Hcl (10 ml) for three hours at boiling temperature. After the solvent is drawn off in a rotary evaporator, the residue is dispersed between water (200 ml) and ether (200 ml), the aqueous phase is extracted with ether {3 x 100 ml), the combined organic phases are washed with water (4 x 150 ml), saturated sodium bicarbonate solution (2 x 200 ml) and saturated common salt solution (1 x 200 ml), dried (sodium sulfate/activated carbon) and filtered. After concentration by evaporation, the product is obtained as a yellow oil (18.7 g, 93%) . TLC: Petroleum ether : ethyl acetate = 4:1, Rf = 0.77 239 1H: NMR (CDC13) 5 9.71 (t, J = 1.71 Hz, 1H) , 7.06 (s, 1H) , 6.80 (s, 1H) , 4.49 (septet, J = 6.4 Hz, 1H) , 3.90 (s, 3H) , 3.73 {d, J = 1.71 HZ, 2H), 1.35 (d, J = 6.4 Hz, 6H); 13C NMR (CDC13) 5 191.8 (d) , 146.6 (s), 145.1 (s) , 125.4 (s), 118.1 {s), 115.3 (d) , 113.7 (d) , 71.5 (d) , 5S.4 (q) , 49.8 (t), 21.8 (q) Step 3: 2-Bromo-4-methoxy-5- (1-iaethylethoxy)benzene ethanol 2-Bromo-5- (1-methylethoxy) -4-methoxybenzene acetaldehyde (2.60 g, 9.05 mmol) is added at 15°C within 30 minutes to a suspension of sodium borohydride (0.341 g, 9.05 mmol) in absolute ethanol (40 ml), and it is stirred for two hours at this temperature. The ethanol is removed in a rotary evaporator, and the residue is dispersed between saturated sodium bicarbonate solution (200 ml) and ether (200 ml). The aqueous phase is extracted with ether (3 x 50 ml) . The combined organic phases 240 are washed with water (31 x 200 ml) and saturated common salt solution (1 x 200 ml), dried (sodium sulfate/activated carbon), dried and filtered. After concentration by evaporation, the product is obtained in the form of colorless crystals (2.60 g, 99%) . TLC: PE : EE = 9:1, 0.25 1H NMR (CDC13) 6 6.98 (s, 1H) , 6.80 (s, 1H) , 4.47 (septet, J = 6.3 Hz, 1H) , 3.82 (t, J = 7.0 Hz, 2H) , 3.80 (s, 3K) , 2.90 (t, J = 7.0 Hz, 2H), 1.32 (d, J = 7.3 Hz, 6H) ; 13C NMR (CDCI3) 5 149.7 (s) , 146.4 (s) , 129.6 (s) , 118.5 (d) , 116.3 (d) , 114.8 (s) , 71.8 (d) , 62.2 (t) , 56.1 (q) , 3 8.8 (t) , 21.9 (q) MT-163 JOS 1682 C12H17BrO3 Cld.: C, 49.84; H, 5.93 Fnd.: C, 49.69; H, 5.79 Step 4: l-Bromo-2- (2-iodoethyl) -5-methoxy-4- (1-methylethoxy)benzene 241 Triphenylphosphine (24.7 g, 94.0 mmol), imidazole {12.8 g, 183.0 mmol) and iodine {23.05 g, 90.9 mmol) are stirred in absolute CH2C12 (150 ml) for one hour at 15°C. 2-Bromo-5-(1-methylethoxy)-4-methoxybenzene ethanol (18.0 g, 62.2 mmol) in absolute CH2Cl2 (100 ml) is added in drops at this temperature within 10 minutes, and the mixture is stirred for two hours at room temperature. The mixture is filtered, and the filtrate is washed with water {1 x 200 ml). The aqueous phase is extracted with CH2C12 (2 x 50 ml), and the combined organic phases are washed with sodium thiosulfate solution (1 x 200 ml) , water (1 x 200 ml) , copper sulfate solution (1 x 200 ml), water (1 x 200 ml) and saturated common salt solution {1 x 200 ml) , dried {sodium sulfate/activated carbon), filtered, and the solvent is removed in a rotary evaporator. After purification by column chromatography (1000 g of silica gel/petroleum ether : ethyl acetate = 96:4), the product is obtained in the form of colorless needles {19.0 g, 77%). 1H NMR (CDC13) 5 7.00 (s, 1H), 6.77 (s, 1H), 4.49 (septet, J = 6.3 Hz, 1H) , 3.81 (s, 3H) , 3.39-3.24 (m, 2H) , 3.24-3.09 (m, 2H), 1.36 (d, J = 7.3 Hz, 6H); 13C NMR £CDC13) : 5 150.0 (s), 146.5 (s), 131.7 (s), 118.0 (d), 116.3 (d), 114.3 (s), 71.8 (d), 56.1 (q), 40.0 (t), 22.0 (q) , 4.2 (t) MT 164 JOS 1704 C12H16BrIO2 242 Cld. : C, 36.12;_ H, 4.04 Fnd.: C, 36.38; H, 3.91 Step 5: 2-[2-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]ethyl]- propanedioic acid dimethyl ester l-Bromo-2- (2-iodoethyl) -4- (l-methylethoxy) ~5-methoxybenzene (18.0 g, 45.1 mmol), potassium carbonate (32.0 g, 321 mmol, anhydrous, freshly ground) and malonic acid dimethyl ester (50.0 g, 373 mmol) are stirred in absolute DMF (200 ml) for 12 hours at 8 0°C. The mixture is filtered, the solvent is removed in a rotary evaporator, and the residue is dispersed between water (300 ml) and ether (300 ml). The aqueous phase is extracted with ether (3 x 50 ml), the combined organic phases are washed with water (4 x 150 ml) and saturated common salt solution (1 x 200 ml), dried (sodium sulfate/activated carbon), filtered, excess malonic ester is removed by distillation, from the residue that is obtained 243 after the solvent is distilled off (16O°C/15 mbar), and it is purified by means of bulb tube distillation {170°C/0.06 mbar), by which the product is obtained as a colorless oil (18.9 g, 72%) . 1K: NMR (CDC13) 5 6.99 (s, 1H) , 6.73 (s, 1H) , 4.49 (septet, J = 6.3 Hz, 1H), 3.81 (s, 3K), 3.76 (s, 6H), 3.39 (t, J = 7.9 Hz, 1H) , 2.68 {t, J = 7.9 Hz, 2H) , 2.18 (q, J = 7.9 Hz, 2H) , 1.34 d, J = 6.3 Hz, 6H) ; 13C NMR (CDC13) 6 169.6 (s) , 149.7 (s), 146.6 (s), 131.7 (s), 117.8 (d) , 116.3 (d) , 114.6 (s) , 71.8 (d) , 56.2 (q) , 52.5 (q) , 50.9 (d), 33.1 (t), 29.0 (t), 22.0 (q) MT-165 JOS 1771 Cl7H23BrO6 Cld.: C, 50.63; H, 5.75 Fnd.: C, 50.87; H, 5.62 Step 6: 2- [2- [2-Bromo-4-methoxy-5- (1-methylethoxy) phenyl] ethyl] -2- [4- (1- methylethoxy)phenylmethyl]propanedioic acid methyl ester 244 l-aromo-2- (2 - iodoethyl) -4- (l-mathylethoxy) -5-methoxyberizer.e (13.0 g, 45.1 nmol) , potassium carbonate (32.0 g, 321 rr.mcl, anhydrous, freshly ground) and (50.0 g, 378.4 mmol) of malsnic acid dimethyl ester are stirred (200 rr.l) in anhydrous DM? for 12 hours at 8 0=C. The mixture is filtered, the solvent is drawn off, and the residue is dispersed between 300 ml of water and 3G0 rr.l of ether. The aqueous phase is extracted three times with 50 ml each, the cci?.bined organic phases are washed four times with 150 ml of water each and once with 200 ml of saturated common salt solution, dried on sodium sulfate/activated carbon, filtered, ar.d the solvent is drawn off. Excess malo.nic acid dimethyl ester is separated by distillation (1SO°C/15 mbar), and the residue is purified by means of bulb tube distillation (170=C (0.06 mbar), by which the product is obtained in the form of a colorless oil (18.9 g, 72%). KT IS6 JOS 1594 C27H3.3r0r Cld.: C, 53.31; K, G.40 ?nd. : C, 59. 03; K, S.24 245 Step 7: 4- [2-Bromo-4-methoxy-5- (1-methylethoxy) ] -a- [4- (1-methylethoxy) - phenylmethyl]benzenebutanoic acid 2-[2-[2-Bromo-5-{1-methylethoxy)-4-methoxyphenyl]ethyl]-2-[4- (1-methylethoxy)phenylmethyl]propanedioic acid dimethyl ester (18.1 g, 32.8 mmol) and potassium hydroxide (17.5 g, 312 mmol) are stirred in a mixture that consists of ethanol (100 ml) and water (20 ml) for 12 hours at boiling temperature. The~reaction mixture is acidified with concentrated hydrochloric acid to a pH of 1 and kept under reflux for one hour. The residue that remains after the solvent is removed is dispersed between water (250 ml) and ether (250 ml) . The aqueous phase is extracted with ether (2 x 100 ml) , the combined, organic phases are washed neutral with water, washed with saturated common salt solution (150 ml) and dried (sodium sulfate/activated 246 carbon). The residue that remains after the solvent is removed is decarboxylated in a bulb tube for 30 minutes at 160°C under high vacuum and then distilled at 210°C/0.008 mbar. In this way, the product is obtained in the form of colorless crystals (13.3 g, 84%). 1H: NMR (CDC13) 6 7.04 (d, J = 9.5 Hz, 2H) , 6.99 (s, 1H) , 6.80 (d, J = 9.5 HZ, 2H) , 6.77 {s, 1H) , 4.60-4.39 (m, 2H) , 3.79 (s, 3H) , 3.09-2.58 (m, 5H) , 2 .09-1.72 (m, 2H) , 1.43-1.29 (m, 1H) ; 13C NMR (CDC13) : 131.0 (s) , 156.2 (s) , 149.3 (s) , 14 6.3 (s) , 132.3 (s) , 13 0.7 (s) , 12 9.6 (d) , 117.6 (d) , 116.1 (d) , 115.7 (d) , 114.3 (s), 71.6 (d) , 69.6 (d) , 55.9 (q) , 46.7 (d) , 37.0 (t), 33.1 (t), 317 (t), 21.8 (q). Step 8: 4- [2-Bromo-4-methoxy-5- (1-meth.ylethoxy) ] -a- [4- (1-methylethoxy) - phenylmethyllbenzenebutanoic acid amide Oxalic acid dichloride (15 ml) is added in drops at 0°C within 15 minutes to 4- [2-bromo-4-methoxy-5- (1-methylethoxy) ] -a- 247 [4- (1-methylethoxy)-phenylmethyl]benzenebutanoic acid (24.0 g, 50.1 mmol) in absolute CH2Cl2 (200 ml), and the mixture is stirred for two hours at this temperature. The solvent is removed in a rotary evaporator, the residue is taken up in absolute THF (100 ml), and ammonia is introduced at 0°C for two hours. The mixture is stirred for one hour at 0°C and poured onto water (1000 ml). The precipitated crystals are filtered off and digested with water (4 x 500 ml). In this way, the product is obtained in the form of colorless crystals (19.9 g, 83%). *H NMR (CDC13) 5 7.04 (d, J = 9.5 Hz, 2H), 6.96 (s, 1H), 6.72 (d, J - 9.5 Hz, 2H), 6.70 (s, 1H), 6.00 (b, 1H), 5.55 (b, 1H), 4.60-4.30 (m, 2H) , 3.7 7 (s, 3H), 2.96-2.52 (m, 4H), 2.51-2.28 (m, 1H), 2.03-1.60 (m, 2H), 1.36-1.20 (m, 12H); I3C NMR (CDC13) : 51774, (s) , 156.2 (s) , 149.2 (s) , 146.4 (s), 132.7 (s), 131.1 (d) , 129.7 (d), 117.5 (s), 116.1 (d), 115.7 (d) , 114.4 (d), 71.6 (d), 69.6 (d), 56.0 (q), 48.6 (d) , 38.0 (t), 33.3 (t), 32.5 (t), 21.9 (q). MT-168 JOS 1770 C24H32BrNO4 Cld.: C, 60.25; H, 6.74; N, 2.93 Fnd.: C, 60.15; H, 6.55; N, 2.77 248 carbon). The residue that remains after the solvent is removed is decarboxylated in a bulb tube for 30 minutes at 160°C under high vacuum and then distilled at 210°C/0.008 mbar. In this way, the product is obtained in the form of colorless crystals (13.3 g, 84%) . 1ti: NMR (CDC13) 57.04 (d, J - 9.5 Hz, 2H), 6.99 (s, 1H), 6.80 (d, J = 9.5 Hz, 2H) , 6.77 4-[2-Bromo-4-methoxy-5-(1-methylethoxy)]-.-[4-(1-methylethoxy)- phenylmethyl]benzenebutanoic acid amide Oxalic acid dichloride (15 ml) is added in drops at 0°C within 15 minutes to 4-[2-bromo-4-methoxy-5-(1-methylethoxy)]~a~ 249 Cld.: C, 54.22; H, 5.18; N, 3.5X Fnd.: C, 54.05; H, 4.95; N, 3.54 Step 10: l-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxa-6H- benzo[a]cyclohepta[h]benzofuran-10-carboxylic acid amide (SPH- 1478) a- [ [2~Bromo-5~hydroxy-4-methoxyphenyl]methyl] -4-hydroxybenzenebutanoic acid amide (3.00 g, 7.61 mmol) is suspended in chloroform (300 ml) and mixed with a solution of potassium hexacyanoferrate (III) (13.2 g, 40.0 mmol) in potassium carbonate solution (75 ml, ten percent). The mixture is stirred vigorously at room temperature for 40 minutes and filtered on Hyflo. The aqueous phase is extracted v/ith chloroform (2 x 50 ml) , the combined organic phases are washed with water (2 x 200 ml) and saturated common salt solution (1 x 150 ml), dried (sodium sulfate/silica gel), and the crude 250 product that is obtained after the solvent is concentrated by evaporation is purified via column chromatography (50 g of silica gel, ethyl acetate). In this way, the product is obtained in the form of colorless crystals (179 mg, 6%). TLC: ethyl acetate, R = 0.6 nH NMR 13C NMR (CDC13) : 5 193.8 (s), 176.7 (s), 146.7 (d) , 143.5 (s), 143.2 (s) , 131.0 (s) , 129.9 (s), 127.7 (d) , 116.5 (s) , 115.1 (d), 87.6 (d), 56.1 (q) , 49.1 (s), 44.2 (d), 39.4 (t), 37.0 (t), 32.0 (t), 31.7 (t) 251 Example 12 S: l-Bromo-4a,5, 9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H- benzo[a]cyclohepta[hi]benzofuran-10-carboxylic acid amide {SPH- L-SelectrideR (2.0 ml, 2.0 mmol, l M in THF) is added at 0°C within 15 minutes to a suspension of l-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxa-SH-benzo[a] cyclohepta[hi] benzofuran-10-carboxylic acid amide (160 mg, 0.41 mmol) in absolute THF (5 ml), and the mixture is stirred for 12 hours at room temperature. It is hydrolyzed with water (2 ml) and dispersed between water (10 ml) and ethyl acetate (10 ml), the aqueous phase is extracted with ethyl acetate (3x5 ml), the combined organic phases are washed with IN hydrochloric acid (3 x 10 ml), water (2 x 10 ml) , saturated sodium bicarbonate solution (1 x 10 ml) and saturated common salt solution (1 x 10 ml), dried (sodium sulfate/activated carbon), filtered, and the crude product that is obtained, after the solvent is distilled off is' purified by means of column chromatography (10 g of silica gel, ethyl acetate) . In this way, 252 the product is obtained in the form'of colorless crystals (137 mg, 8 5%). MT-194 JOS 1712 C18H2QBrNO4 ClcL : C, 54,84; H, 5.11; N, 3.55 Fnd.; C, 54.55; H, 5.22; N, 3,34 TLC: ethyl acetate, Rf = 0.5 ^ MR (MeOH-d45 : 6 6.99 (s, 1H) , €.03 (d, J = 16.5 Hz, 1H) , 5.94 (dd, J = 16.5 Hz, J = 5.9 Hz, 1H) , 4.52 (s, 1H) , 4.16 253 Diagram for Examples 125 and 12S [Key:] Schritt = Step Beispiel = Example 254 Example 12 7 Step 1 5- (6-Acetyloxy-l-oxohexyl) -5, 6-dihydro-4H-pyrrolo [3,2,1- ij] guinolin-2(1H)-one 6-Acetyloxyhexanoic acid chloride (16.7 g, 86.6 mmol) in absolute CH2C12 (50 ml) is added in drops at 0°C within 10 minutes to a suspension of anhydrous aluminum chloride (61,5 g, 461.6 mmol) in absolute CH2C12 (500 ml), and it is stirred for 15 minutes at this temperature. 5,6-Dihydro-4H-pyrrolo [3,2 ,1-ij]guinolin-2(1H) -one (10.0 g (57.7 mmol) in absolute CH2C12 (100 mi) is added in drops within 15 minutes at 0°C, then it is heated to boiling temperature and stirred for 3 0 minutes. It is cooled to 0°C, hydrolyzed with ice and dispersed between water (300 ml) and CK2C12 (100 ml) . The aqueous phase is extracted with CH2Cl2 (2 x 100 ml), the combined organic phases are washed with 2N hydrochloric acid (2 x 250 ml), water (2 x 250 ml), semi- 255 concentrated aqueous Na2CO3 solution (2 x 250 ml) concentrated aqueous Na2CO3 solution (2 x 250 ml) and concentrated common salt solution (1 x 250 ml), dried (sodium sulfate/activated carbon), and the solvent is removed in a rotary evaporator. After recrystallization from methanol {150 ml) , the product is obtained in the form of light yellow crystals (14.3 g, 75.5%). MT-304 JOS 1675 C19H23NO4 Cld.: C, 69.28; H, 7.04; N, 4.25 Fnd.: C, 69.27; H, 6.99; N, 4.25 1K NMR (CDC13) : 5 7.72 (s, 2H) , 4.0 6 {t, J = 6.5 Hz, 2H) , 3.72 (t, J = 5.7 Hz, 2H), 3.54 (s, 2H), 2.90 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 6.0 Hz, 2H), 2.09-1.93 (m, 5H), 1.85-1.56 (m, 4H), 1.50-1.30 (m, 2H); 13C NMR (CDCl3) : 5 198.9 (s) , 174.2 (s), 171.1 (s), 145.5 (s) , 131.3 (s), 127.8 (d) , 122.9 (s), 122.4 (d) , 119.5 (s), 64.3 (t), 38.9 (t), 38.0 (t), 36.1 (t), 2S.5 (t), 25.7 (t), 24.4 (t), 24.1 (t), 21.0 (q), 20.9 (t) Step 2 5- (6-Hydroxy-l-oxohexyl) -5, 6-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-2(1H)-one 256 5- (6-Acetyloxy-l-oxohexyl)-5,6-dihydro-4H-pyrrolo [3,2,1-ij]quinolin-2(1H)-one (10.0 g, 30.6 mmol) is suspended in anhydrous ethanol (150 ml), mixed with catalyst amounts of 4-methylbenzenesulfonic acid monohydrate and stirred for five hours at boiling temperature. The solvent volume is concentrated by evaporation to one third, and the product is obtained in the form of light yellow needles (8.22 g, 93.5%) by crystallization at -20°C. MT-305.JOS 1672 CVK21NO3 Cld.: C, 71.06; K, 7.37; N, 4.87 Fnd.: C, 71.30; K, 7.37; N, 4.87 ]K NMR (CDC13) : 6 7.67 (s, 2H) , 3.80-3.52 (m, 4H) , 3.48 (s, 2E-) , 2.97-2.66 257 Step 3 5- (6-Iodo-l-oxohexyl) -5, 6-dihydro-4H-pyrrolo [3 , 2,1-ij] Triphenylphosphine {2.02 g, 7.74 mmol), iodine (3.08 g, 12.12 mmol) and imidazole (0.618 g, 9.08 mmol) are stirred in absolute CH2Cl2 (30 ml) for 30 minutes at 15°C. S-(6-Hydroxy-l-oxohexyl)-5,6-dihydro~4H-pyrrolo [3,2, 1-ij]quinolin-2(1H)-one (2.0 g, 6.96 mmol) in anhydrous CH2C12 (10 ml) is added in drops within 5 minutes at this temperature, then it is stirred for 40 minutes at room temperature. It is mixed with semisaturated sodium sulfate solution (50 ml), the phases are separated, the aqueous phase is extracted with CH2C12, the combined organic phases are washed with 2N hydrochloric acid (3 x 100 ml), water (2 x 100 ml), saturated sodium bicarbonate solution (2 x 100 ml) and saturated common salt solution (1 x 100 ml), dried (sodium sulfate/activated carbon), filtered, and the crude product that is obtained after 258 the solvent is removed in a rotary evaporator is recrystallized from methanol (10 ml). Variant A: The residue is purified by column chromatography (100 g of silica gel, chloroform), by which the product is obtained in the form of light yellow crystals (2.44 g, 88.3%) . Variant B: The residue is recrystallized one additional time from methanol (10 ml), by which the product is obtained in the form of light yellow crystals (2.28 g, 82.4%). MT-3 0 8 JOS 1670 C17H20INO2 Cld.: C, 51.40; H, 5.07; N, 5.53 Fnd.: C, 51.56; H, 4.97; N, 3.46 1K KMR (CDC1,) : 5 7.70 (s, 2H) , 3.72 (t, J = 5.7 Hz, 2H) , 3.52 (s, 2H), 3.18 (t, J = 6.9 Hz, 2K), 2.91 (t, J = 7.2 Hz, 2H), 2.80 (t, J = 6.1 HZ, 2K), 2.12-1.61 (m, 6H) , 1.57-1.36 (m, 2H) ; 13C NMR (CDC13) : 6 198.7 (s), 174.1 (s), 145.5 (s), 131.2 (s), 127.8 (d), 122.9 (s), 122.3 (d), 119.4 (s), 38.8 (t), 37.9 (t), 36.0 (t), 33.2 (u), 30.1 (t), 24.0 (t), 23.3 (t), 20.9 (t), i €.6 (t) 259 Step 4 5- (6-Methylsulfonyloxy-l-oxohexyl) -5, 6-dihydro-4H-pyrrolo[3,2,1-ij] c[uinolin-2 (1H) -one Methanesulfonic acid chloride {458 mg, 4.00 mmol) is added in drops within 5 minutes at 15°C to 5-(6-hydroxy-l-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (1.0 g, 3.48 mmol) and N-ethyldiisopropylamine (550 mg, 4.35 mmol) in anhydrous CH2C12 (10 ml) , and it is then stirred for two hours at room temperature. It is mixed with water (20 ml) , the phases are separated, the aqueous phase is extracted with CH2Cl2 (1 x 10 ml) , the combined organic phases are washed with 2N hydrochloric acid (3 x 10 ml), water (2 x 10 ml) , saturated sodium bicarbonate solution (2 x 10 ml) and saturated common salt solution {1 x 10 ml) , dried (sodium sulfate/activated carbon), filtered, and the crude product that is obtained after the solvent is removed in a rotary evaporator is digested with diisopropyl ether (10 ml) , by which the product is obtained in the form of light yellow crystals (1.17 g, 92.2%). 260 H NNR (CDCI3) : 6 7.70 (s, 2H) , 4.22 (t, J = 6 . 5 -Hz, 2H) , 3.71 (t, J = 5.8 HZ, 2H), 3.52 (s, 2K), 2.99 (s, 3H) , 2.92 (t, J = 7.0 Hz, 2H) , 2.80 (t, J = 6.0 Hz, 2H) , 2.17-1.92 (m, 5H) , 1.90-1.64 (m, 4H), 1.60-1.37 (m, 2H); 13C NMR (CDC13) : 5 198.7 (s), 174.2 (s), 145.6 (s), 131.2 (s) , 127.8 (d) , 123.0 (s) , 122.4 (d) , 119.5 (s), 69.8 (t), 38.8 (t), 37.8 (t), 37.3 (q) , 36.1 (t), 23.9 (t), 25.1 (t), 24.3 (t), 23 .7 (t) , 20.9 (t) Step 5 5- [6- [ (4aS, 6R, 8aS) -4a, 5 , 9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-6H-benzofuro[3a,3,2-ef3 [2]benzazepine-11-yl] -1-oxohexyl]-5,6-dihydro-4H-pyri:olo [3,2,1-ij] quinolin-2- (1H) -one (SPH-150 0) Worgalanthamine (1.13 g, 1.64 mmol), 5-(6-iodo-1-oxohexyl)-5,6-dihydro-4E-pyrrolo[3,2,l-ij]quinolin-2(1H)-one (1.50 g, 3.75 mmol) and N-ethyldiisopropylamine (1.46 g, 11.3 mmol) are stirred 261 in absolute chloroform (20 ml) for 54 hours at boiling temperature. The residue that is obtained after the solvent is removed in a rotary evaporator is purified by column chromatography (200 g of silica gel, chloroform : methanol : ammonia = 96:3:1), by which the product is obtained as a light yellow foam (1.31 g, 64.3%). 1H NMR (CDC13) : a 7.63 (s, 2H) , 6.68-6.46 (m, 2H) , 6.00 (d, J = 10.3 Hz, 1H), 5.90 (dd, J = 10.3 Hz, J = 4.6 Hz, 1H), 4.51 (s, 1H) , 4.19-3.96 (m, 2H) , 3.75 (s, 1H) , 3.73 (s, 3H) , 3.70-3.58 Cm, 2H) , 3.44 (s, 2H) , 3.35-2.98 (m, 2H) , 2.96-6.67 (m, 4H) , 2.66-2.29 (m, 4H) , 2.15-1.84 (m, 4K) , 1.82-1.11 (m, 6H) ; 13C NMR (CDC13) : 6 199.1 (s), 174.1 (s), 145.6 (s), 145.3 (s), 143.8 (s), 133.0 (s) , 131.2 (s) , 12 9.3 (s), 127.7 (d), 127.4 (d), 126.8 (d), 122.8 (s), 122.3 (d), 121.7 (d), 119.4 (s), 111.0 (d) , 88.5 (d) , 61.8 (d) , 57.6 (t) , 55.7 (q) , 51.4 (t), 51.2 (t), 48.2 (s) , 38.7 (t) , 38.0 (t) , 36.0 (t) , 32.8 (t), 29.8 (t), 27.1 (t), 26.9 (t), 24.3 (t), 24.2 (t), 20.8 (t) Step 6 5- [6- [ (4aS, 6R, 8aS) -4a, 5 , 9,10,11,12-Hexahydro-6-hydroxy-3-methoxy- 6H-benzofuro[3a,3,2-ef][2]benzazepine-ll-yl]-1-oxohexyl]-5,6- dihydro-4H-pyrrolo[3, 2,1-ij]quinolin-2(1H)-one fumarate (SPH- 1499) The precipitation of the fumarate was carried out analogously to Example 4. 262 MT-311 JOS 1762 C37H42N2O9*H2O Cld.: C, 65.67; H, 6.55; N, 4.14 Fnd.: C, 65.93; H, 6.54; N, 4.03 Example 12 8a Step 1 2- [ [4- (l-Methylethoxy)phenyl] methyl]propanedioic acid dimethyl ester 1-(Chloromethyl)-4-(1-methylethoxy)benzene (20.5 g, 111 mmol), malonic acid dimethyl ester {102.5 g, 776 mmol) and potassium carbonate (46.5 g, 332 mmol, anhydrous, freshly ground) are stirred in absolute D.MF (250 ml) for 24 hours -at 70QC. The mixture is filtered, and the residue that is obtained after the filtrate is concentrated by evaporation in a rotary evaporator is dispersed between ether (250 ml) and water (250 ml) ; The organic phase is washed with water (3 x 2,00 ml) and saturated common salt solution (1 x 200 ml), dried {sodium sulfate/activated carbon), filtered, and the solvent is removed. The excess malonic acid dimethyl ester is separated by vacuum distillation (85QC/l5 mbar), and the crude product that remains in the residue is purified by bulb tube distillation (130°C/0.001 mbar). In this way, the product is obtained as a colorless oil (23.6 g, 78%}. MT-67 JOS 1774 C1SH2O°5 Cld.: C, 64.27; H, 7.19 Fnd.: C, 64.28; H, 7.07 Step 2: 4-(l-Methylethoxy)benzenepropanoic acid 2- [ [4- {1-Methylethoxy)phenyl]methyl]-propanedioic acid dimethyl ester (23.6 g, 84.2 mmol) is stirred into 2N potassium 264 hydroxide solution (15 ml)/ethanol (25 ml) for 18 hours at boiling temperature. The ethanol is distilled off in a rotary evaporator/ the residue is brought to a pH of 1 with concentrated hydrochloric acid and extracted with ether (3 x 150 ml) . The combined organic phases are washed with water (6 x 200 ml) and saturated common salt solution (200 ml), dried (sodium sulfate/activated carbon) and filtered. The residue that is obtained after concentration by evaporation in a rotary evaporator is decarboxylated in a bulb tube (140°C/0.08 mbar) and then distilled {155°C/0.08 mbar) . In this way, the product is obtained in the form of colorless crystals (14.4 g, 82%). 1H NMR (CDC13) : 6 7.12 (d, J= 9.5 Hz, 2H) , 6.82 (d, J = 9.5 Hz, 2H) , 4.50 (septet, J = 6.3 Hz, 1H) , 2.89 (t, J = 7.9 Hz, 2H) , 2.63 (t, J = 7.9 Hz, 2H), 1.32 (d, J = 6.3 Hz, 6H); 13C NMR (CDC13) : 5 178.8 (s), 156.4 (s), 132.1 (s), 129.2 (d), 116.0 (d), 69.9 (d), 35.8 (t), 29.7 (t), 22.1 (g) Step 3 2-Bromo-4-methoxy-5-{1-methylethoxy)benzene acetonitrile 265 l-Bromo-2-(chloromethyl)-5-methoxy-4-(1-methylethoxy)benzene (7.00 g, 23.8 mmol) and potassium cyanide (1.70 g, 26.1 mmol, freshly ground) are stirred in absolute DMSO (70 ml) for 12 hours at room temperature. The mixture is poured onto water (700 ml), the aqueous phase is extracted with ether (3 x 150 ml), the combined organic phases are washed with water (5 x 150 ml) and saturated common salt solution (1 x 200 ml), dried (sodium sulfate/activated carbon), filtered, and the residue that is obtained after concentration by evaporation is digested with diisopropyl ether (15 ml). In this way, the product is obtained in the form of colorless crystals (6.46 g, 95%). MT-72 JOS 1695 c12H14BrNO2 Cld.: C, 50.72; K, 4.97; N, 4.93 Fnd.: C, 50.73; H, 4.84; N, 4.89 1K NMR (CDC13) : 5 7.02 (s, 1H) , 6.97 (s, 1H) , 4.50 (septet, J = 6.3 Hz, IK), 3.81 (s, 3H), 3.72 (s, 2H), 1.36 (d, J = 6.3 Hz, SH) ; 13C NMR (CDC13) : 5 150.8 (s), 147.1 (s), 12.1 5 (s), 117.3 (s), 116.7 (d), 116.3 (d), 113.9 (s), 72.1 (d), 56.2 (g), 24,2 (t), 21.9 (q) 266 Step 4 4-(l-Methylethoxy)benzenepropanoic acid-(1-methyl)ethyl ester 4-Hydroxybenzenepropanoic acid (50.0 g, 300 mmol), potassium carbonate (210 g, 1.5 mol, anhydrous, freshly ground) and 2-bromopropane (221 g, 1.8 mol) are stirred in absolute DMF (500 ml) for 24 hours at 60°C. The solution is filtered, and the residue that is obtained after the concentration by evaporation in a rotary evaporator is dispersed between ether (500 ml) and 2N sodium hydroxide solution (500 ml) . The organic phase is washed with 2N sodium hydroxide solution (2 x 200 ml), water (3 x 500 ml) and saturated common salt solution (200 ml), dried (sodium sulfate/activated carbon) and filtered. The residue that is obtained after the solvent is distilled off in a rotary evaporator is purified by bulb tube distillation (139-142°C/o. 025 mbar) , by which the product is obtained as a colorless oil (70.8 g, 94%). 267 MT-159 JOS 1768 C15H22O3 Cld.: C, 71.97; H, 8.8 6 Fnd.: C, 71.84; H, 8.75 *'H NMR (CDC13) : 5 7.10 (d, J= 9.5 Hz( 2H) , 6.81 (d, J = 9.5 Hz, 2H), 4.99 (septet, J = 6.3 Hz, 1H) , 4.48 (septet, J = 6.3 Hz, 1H), 2.87 (t, J = 7.9 Hz, 2H), 2.54 (t, J = 7.9 Hz, 2H), 1.20 (d, J = 6.3 Hz, 6H), 1.31 (d, J = 6.3 Hz, 6H) ; 13C NMR (CDC13) : 5 172.4 (s) , 156.2 (s), 132.4 (s), 129.1 (d), 115.8 (d), 69.7 (d), 67.4 (d), 36.4 (t), 30.1 (t), 22.0 (q), 21.7 (q) Step 5 4-(l-Methylethoxy)benzenepropanol 1. From 4-(1-methylethoxy)benzenepropanoic acid 4- (l-Methylethoxy)benzenepropanoic acid (7.57 g, 36.3 mmol) in absolute THF (80 ml) is added in drops at 0°C to a suspension of lithium aluminum hydride (4.17 g, 110 mmol) in absolute THF 268 (80 ml) within 30 minutes, and it is stirred for 12 hours at room temperature. It is hydrolyzed with water (30 ml) and mixed with concentrated hydrochloric acid until the solution becomes clear, dispersed between water (30 ml) and ether (60 ml), the aqueous phase is extracted with ether (2 x 20 ml) , the combined organic phases are washed with 2N hydrochloric acid (3 x 100 ml), water (1 x 100 ml), saturated sodium bicarbonate solution (2 x 100 ml) and saturated common salt solution (1 x 100 ml), dried (sodium sulfate/activated carbon) and filtered. After the solvent is distilled off in a rotary evaporator, the product is obtained in the form of colorless crystals (6.84 g, 97%). 2. From 4- (l-Methylethoxy)benzenepropanoic acid-(1-methyl)ethyl ester 4-(l-Methylethoxy)benzenepropanoic acid-(1-methyl)ethyl ester (10.0 g, 39.9 mmol) in absolute THF (100 ml) is added in drops at 0°C to a suspension of lithium aluminum hydride (3.04 g, 269 80 mmol) in absolute THF (100 ml) within 30 minutes, and it is stirred for 12 hours at room temperature. It is hydrolyzed with water (30 ml) and mixed with concentrated hydrochloric acid, until the solution becomes clear, dispersed between water {30 ml) and ether (SO ml), the aqueous phase is extracted with ether (2 x 20 ml), the combined organic phases are washed with 2N hydrochloric acid (3 x 100 ml), water (1 x 100 ml), saturated sodium bicarbonate solution (2 x 100 ml) and saturated common salt solution {I x 100 ml), dried (sodium sulfate/activated carbon) and filtered. After the solvent is distilled off in a rotary evaporator, the product is obtained in the form of colorless crystals (7.04 g, 99%)¦ MT-39 JOS 1700 C12H1S°2 Cld.: C, 74.19; H, 9.34 Fnd. : C, 73 .93; H, 9.07 ]K NMR (CDC13) : 6 7.10 (d, J = S.5 H2, 2H) , 6.82 (d, J=9.5 Hz, 2H), 4.50 (septet, J = 6.3 Hz, IE), 3.68 (t, J = 7.9 Hz, 2K) , 2.66 (t, J = 7.9 Hz, 2H), 2.0 (b, 1H), 1.93-1.78 (m, 2H), 1.32 (d, J = 6.3 HZ, 6H); 13C NMR (CDC13) : 6 155.9 (s) , 133.7 (s), 129.2 (d) , 115.9 (d), 69.9 (d), 62.0 (t), 34.3 (t), 31.1 (t), 22.0 (q) 270 Step 6 1- (3-Iodopropyl) -4- {1-methylethoxy) benzene Triphenylphosphine (13.1 g, 49.9 mmol), iodine (19.9 g, 78.4 raraol) and imidazole (4.0 g, 58.8 mmol) are stirred in absolute CH2C12 (250 ml) for 20 minutes at room temperature. 4-(l-Methylethoxyjbenzenepropanol (8.74 g, 45.0 mmol) in CH2C12 (100 ml) is added in drops at 15°C and stirred for 12 hours at room temperature. It is dispersed between water (300 ml) and CH2C12 (150 ml) , the aqueous phase is extracted with CH2C12 (2 x 50 ml) , the combined organic phases are washed with water (1 x 200 ml) , semisaturated copper(II) sulfate solution (2 x 200 ml), water (1 x 200 ml), 10% sodium sulfite solution (1 x 200 ml), saturated common salt solution (1 x 200 ml), dried (sodium sulfate/activated carbon), filtered, and the residue that is obtained after concentration by evaporation in a rotary evaporator is taken up in diisopropyl ether (200 ml). The 271 residue that is obtained from the filtrate after the solvent is drawn off in a rotary evaporator is filtered and purified by column chromatography (900 g of silica gel; petroleum ether : ethyl acetate =95:5). In this way, the product is obtained as a colorless oil (10.9 g, 79%). MT-151 JOS 1755 C12K17IO Cld. : C, 47 .35; H, 5. 63 Fnd.: C, 47.37; H, 5.41 1H NMR {CDC13) : 6 7.11 (d, J = 9.5 Hz, 2H) , 6.82 (d, J = 9.5 Hz, 2H) , 4.53 (septet, J = 6.3 Hz, 1H) , 3.18 (t, J = 7.9 Hz, 2H) , 2.67 (t, J = 7.9 Kz, 2E) , 2.10 (quintet, J = 7.9 Hz, 2H), 1.35 (d, J = 6.3 HZ, 6H); 13C NMR (CDCI3) : 5 156.2 (s), 132.2 (s), 129.4 (d) , 115.9 (d), 69.8 (d), 35.2 (t), 35.0 (t), 22.1 (q), 6.5 (t) Step 7 a- [2~Bromo-4-methoxy-5- (1-meth.ylethoxy) phenyl] 4- (1-methylethoxy) - bsnzenepentane nitrile 272 n-Butyllithium (12.7 ml, 2 7.5 mmol, 2.2 M in hexane) is added within 15 minutes at a temperature of -78°C to a solution of diisopropylamine {3.55 g, 35.03 mmol) in absolute TKF (50 ml}, then the mixture is heated to -30°C and stirred for 30 minutes at 5 this temperature. The solution is cooled to -78°C, mixed with 2-bromo-4-methoxy-5-(1-methylethoxy)-benzene acetonitrile (7.94 g, 27.9 mmol) in absolute THF (100 ml), stirred for 20 minutes at this temperature, heated to room temperature, and stirred for another 10 hour. The mixture is cooled to -78°C, then 1-(3-iodopropyl) -4-(1-methylethoxy)benzene (8.50 g, 27.9 mmol) in absolute THF (50 ml) is added in drops with 15 minutes, and the mixture is stirred for 45 minutes. It is mixed with saturated ammonium chloride solution (50 15 ml) and heated to room temperature. The residue that is obtained after concentration by evaporation is dispersed between 2N hydrochloric acid (200 ml) and ether (200 ml) . The aqueous phase is extracted with ether (3 x 50 ml) , the combined organic phases are washed with water (3 x 200 ml) , saturated sodium bicarbonate 20 solution {1 x 200 ml) and saturated common salt solution (1 x 200 ml), dried (sodium sulfate/activated carbon), filtered, and the residue that remains after the solvent is removed in a rotary evaporator is purified by column chromatography (1000 g of silica gel, petroleum ether : ethyl acetate = 98:2) . The product is 2 5 thus obtained as a colorless oil (11.46 g, 71%). MT-158 JOS 1S99 273 C24H30SrNO3 Cld.: C, 62.61; H, 6.57; N, 3.04 Fnd.: C, 62.32; H, 6.31; N, 2.97 Step 8 a- [2-Bromo-4-methoxy-5- (1-methylethoxy) phenyl] -4- (1- methylethoxy)-benzene pentanoic acid amide a- [2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]-4- (l-rnethylethoxy) benzene pentane nitrile (30.0 g, 65.2 mmol) in ethanol (600 ml) is mixed with potassium hydroxide (60.0 g, 1.07 mol) in water (100 ml) and stirred for 6 hours at boiling temperature, The residue that is obtained after concentration by evaporation is dispersed between 2N hydrochloric acid {2O0 ml) and ether (300. ml) . The aqueous phase is extracted with ether (3 x 75 ml). The combined organic phases are washed with water (3 x 200 ml), saturated sodium bicarbonate solution (1 x 200 ml) and saturated common salt solution (1 x 200 ml), dried (sodium 274 sulfate/activated carbon)1, filtered, and the residue that remains after the solvent is removed is purified by column chromatography (1000 g of silica gel, petroleum ether : ether = 1:2). The higher-running fraction is taken up in absolute CH2C12 {100 ml) , mixed at 0°C with oxalic acid chloride (3 ml) and a drop of DMF and stirred for two hours. The residue that is obtained after the solvent is drawn off in a rotary evaporator is suspended in absolute THF {100 ml), whereupon ammonia is introduced under the surface for two hours. The mixture is filtered, and the residue that is obtained after concentration by evaporation is dispersed between water (100 ml) and ether (100 ml) . The aqueous phase is extracted with ether (3 x 50 ml), the combined organic phases are washed with water (3 x 200 ml) and saturated common salt solution (1 x 200 ml), dried (sodium sulfate/activated carbon), filtered, and the residue that is obtained after concentration by evaporation is combined with the deeper-running fraction that is obtained by column chromatography, crystallised under diisopropyl ether and digested with diisopropyl ether (100 ml) . In this way, the product is obtained in the form of colorless crystals (26.0 g, 83.5%). ]H NMH {CDC13} : 6 7.01 [d, J = 8.9 Hz, 2H) , 6.98 (s, 1H) , 6.92 (3, IE), 6.75 (d, J = 8.9 Hz, 2H) , 5.98 (b, 1H) , 5.52 (b, 1H) , 4.47 (septet, J = 6.3 Hz, 2H), 3.91 (t, J = 7.0 Hz, 1H) , 3.82 (S, 3H), 2.74-2.40 (m, 2H), 2.22-2.00 (m, 1H), 1.91-1.36 (m, 3K), 1.35-1.22 (m, 6H); 13C NMR (CDCI3) : 6 175.2 (s), 155.8 (s) , 149.9 (s) , 147.0 (s), 133.9 (S), 130.8 (s), 129.1 (d), 115.7 (d), 114.8 (d), 114.7 275 (d) , 71.4 (d), 69.7 (d) , 56.0 (q) , 49.7 (d) , 34.6 (t), 31.9 (t), 29.1 (t), 22.0 (q), 21.8 (q), 21.7 (q) Step 9 or- [2-Bromo-5-hydroxy-4-inethoxypheiiyll -4-hydroxyben2enepentanoic acid amide a-[2-Bromo-4-methoxy-5-[l-methylethoxy)phenyl]-4- (1-methylethoxy)benzenepentanoic acid amide (24.0 g, 50.2 mmol) in absolute CH2Cl2 (300 ml) is mixed at -78°C with boron trichloride (150 ml, 150 mmol, 1 M in CH2C12) and stirred for four hours at room temperature. Water (200 ml) is added in drops, and the organic phase is removed in a rotary evaporator. The precipitated crystals are digested with water (6 x 200 ml), by which the product is obtained in the form of colorless crystals (19.3 g, quant.) . MT-161 JOS 1713 CiaK20BrNO4 276 Cld.: C, 54.84; E, 5.11; N, 3.55 Fnd.: C, 54.56; H, 5.40; N, 3.25 Step 10 l-Bromo-4a# 5,9,10,11,12-hexahydro-3-methoxy-S-oxa-6H- benzo[a]cyclohepta[hi]benzofuran-12-carboxylic acid amide (SPH- 1484) a-[2-Bromo-5-hydroxy-4-methoxyphenyl)-5- hydroxybenzenepentanoic acid amide (3.00 g, 7.61 mmol) is suspended in chloroform (300 ml) and mixed with a solution of potassium hexacyanoferrate(III) (13.2 g, 40.0 mmol) in potassium carbonate solution (75 ml, ten percent). The mixture is vigorously stirred at room temperature for 40 minutes and filtered on Hyflo. The aqueous phase is extracted with chloroform (2 x 50 ml) , the combined organic phases are washed with 2N hydrochloric acid (2 x 100 ml) , water (2 x 200 ml) and saturated common salt solution (1 x 150 ml) , dried (sodium sulfate/activated carbon), and the crude product that is obtained 277 after concentration by evaporation of the solvent is purified via column chromatography (50 g of silica gel, ethyl acetate). In this way, the product is obtained as a mixture that consists of two diastereomeric enantiomer pairs, whereby the deeper-running is isomerized to the higher-running. By column chromatography (chloroform : methanol = 96:4), the enantiomer pair with the higher Rf-value is obtained in the form of colorless crystals (0.24 g, 8% of theory). MT-162/OF JOS 1679 C18H18BrNO4 Cld.: C, 55.12; H, 4.63; N, 3.57 Fnd.: C, 55.15; H, 4.71; N, 3.38 ^ NMR (DMSO~d6) : 6 7.5 7 (s, 1H) , 7.4 8 (d, J = 14.5 Hz, IK) , 7.14 (s, 2H) , 5.89 (d, J = 14.5 Hz, 1H) , 4.66 (s, 1H) , 4.32 (s, 1H), 4.01 (q, J = 7.7 Kz, 1H), 3.78 {s, 3H), 3.02 (d, J = 19.6 Hz, 1H) , 2.79 (d, J = 19.6 Hz, 1H) , 2.52 (d, J = 16.5 Hz, 1H) , 2.14 (d, J = 16.5 Hz, 1H), 1.96-1.67 (m, 2H), 1.14 (t, J = 7.7 Hz, 1H) 13C MR (DMSO-d6) : 6 195.6 (s), 174.6 (s), 149.5 (d) , 147.9 (s) , 144.4 (s), 133.6 (s) , 130.6 (s) , 126.5 (d) , 117.5 (s) , 117.1 (d) , 88.4 (d) , 56.8 (q) , 52.1 (s) , 51.6 (d) , 37.9 (t), 36.6 (t), 33.3 (t), 21.5 (t) 278 Example 12 8b (6R) -l-Bromo-4a,5/9#10,ll,12-hexahydro-3-inethoxy-6-hydroxy-6H-benzo[a]cyclohepta[hi]benzofuran-12-carboxylic acid amide (SPH-1483) L-SelectrideCR) (4.6 ml, 4.6 mmol, 1 H in THF) is added at 0°C within 15 minutes to a suspension of l-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxa-SH-benzo[a] cyclohepta[hi] benzofuran-12-carboxylic acid amide (600 rag, 1.52 mmol) in absolute THF (5 ml), and the mixture is stirred for 12 hours at room temperature. It is hydrolyzed with water (3 ml) and dispersed between water (10 ml) and ethyl acetate (10 ml), the aqueous phase is extracted with ethyl acetate (3x5 ml), the combined organic phases are washed with IN hydrochloric acid (3 x 10 ml), water (2 x 10 ml), saturated sodium bicarbonate solution (1 x 10 ml) and saturated common salt solution (1 x 10 ml}, dried (sodium sulfate/activated carbon), filtered, and the crude product that is obtained after the solvent is distilled off is purified by means of column chromatography (50 g of silica gel, ethyl acetate). In this way, 279 the product is obtained in the form of colorless crystals (798 nig, 83%) . MT-169/0F JOS 1677 C13H2QBrNOA Cld.: C, 54.84; H, 5.11; N, 3.55 Fnd.: C, 54.67; H, 5.10; N, 3.46 1H NMR (CDCl3/DMSO-d6) : 6 6.97 (s, 1H) , 6.79 (b, 1H) , 6.49 (b, 1H), 6.12 (d, J = 11.4 Hz, 1H) , 5.83 (dd, J = 11.4 Hz, J = 5.1 Hz, 1H), 4.42 (s, 1H), 4.31-4.21 (m, 1H), 3.78 (s, 3H), 3.42-3.18 (m, 2H), 2.68-2.29 (m, 2H), 2.14-1.38 (m, 5H); 13C NMR (CDCl3/DMSO-d6) : 6 173.4 (s), 146.3 (s), 143.6 (s), 134.2 (s), 12 8.8 (d), 12 8.6 (d), 12 6.8 (s), 116.1 (s), 115.6 (d), 87.1 £d), 60.1 (q), 55.6 (d), 50.1 (s), 49.5 (d), 37.5 (t), 31.0 ft), 29.8 (t), 20.3 (t) Example 12 8c (6R)-10-Amino-l-bromo-4a/5/9,10,11,12-hexahydro-3-methoxy-6- hydroxy-6H-benzo[a]cyclohepta[hi]benzofuran-6-ol (SPH-14 82) 280 Bis (trifluoroacetoxy) iodobenzene (300 mg, 0.75 rr.mcl) is dissolved in acetonitrile (1.5 ml, HPLC-quality) and rr.ixed with water {1.5 ml, H?LC-quality). Then, (SR)-1-brorr.o-43,5,9,10,11, 12-hexahydro MT-170 JOS 1705 C17H233rNO3-0.SS H20 Cld.: C, 54.02; fi, 5.68; X, 3,71 Fnd.: C, 53.96; H, 5.52; N, 3,60 'H NWR (MeOH-dJ : 6 7.OS (s, IK), 6.41 (d, J = 14.5 Hz, IK), 5.8833 (dd, u = 14.5 HZ, J = 5.1 Kz, 1H); 4.72 (s( IK), 4.5a (S, 1H), 4.13 (t, J = 3,6 Kz, IK), 3.82 (s, 3H), 2.49 (d, J = 17.2 KZ, IK), 2.45-2.07 (m, 4K) , 1.92-1.58 (m, 4K) ; 13C NMR (MeOH-dJ : 5 147.2 (s), 144,7 (s), 134.5 (s), 133.3 (B), 130.9 (d) , 126.4 (d) , 116.6 (d) , 115.5 (s), 87.8 (d) , 51.2 (d), 57.3 (g), 54.0 (d), 46.6 (s), 38.3 (t), 35.2 (t), 30.1 (t), 17.3 (t) 281 Example 128d (SR) -10-Amino-4a, 5 9,10,11,12 -hexah.ydro-3 -methoxy- 6-hydroxy-6H-benzo[a]cyclohepta[hi]benzofuran-6-ol (6R) -l0-Amino-l-bromo-4a, 5, 9, 10, 11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]cyclohepta[hi]benzofuran-S-ol (70 mg, 0 .19 mmol) and calcium chloride (300 mg, 2.7 mmol) are added in substance to a black suspension of zinc (production: zinc powder (500 mg) and copper (I) iodide (500 mg) are treated under argon in water (4 ml) and ethanol (4 ml) for 45 minutes in an ultrasound bath), and the mixture is stirred for 5 hours at boiling temperature. It is mixed with concentrated aqueous ammonia ¦¦solution (1 ml) , the solvent is removed in a rotary evaporator, the residue is taken up in chloroform (15 ml) , filtered, and the residue that is obtained after the filtrate is concentrated by evaporation in a rotary evaporator is purified by column chromatography (30 g of silica gel, chloroform : methanol : ammonia = 96:3:1). In this way, the product is obtained in the form of colorless crystals (42 mg, 78%). 282 }K NMR (CDC13) : 6 6.81-6.61 (m, 3H) , 6.97 (dd, J = 14 Hz, J = 4 Hz, 1H), 4.44 (s, 1H) , 4.30 (s, 1H) , 4.24 (t, J = 3 Hz, 1H) , 3.85 (s, 3H), 2.63 (dd, J = 17 Hz, J = 6 Hz, 1H) , 2.40 (q, J = 15 Hz, 1H), 2.19-2.08 (m, 1H), 2.02 (dd, J = 13 Hz, J = 4 Hz, 1H), 1.97-1.52 (m, 9H) • 13C NMR (CDC13) : 6 145.4 (s), 143.2 (s), 134.1 (s), 132.6 (S), 129.9 (d), 125.4 (d), 121.9 (d), 109.9 (d), 87.7 (d), 61.1 (d), 54.8 (q), 48.5 (s), 37.0 (t), 34.4 (t), 29.0 (t), 25.8 (t), 16.9 (t) EXAMPLE 12 9 8-[6-[(4aS,6R,8aS)-4a,5,9,10,ll, 12-Hexahydro-6-hydroxy-3 -methoxy-6H-benzofuro[3a, 3 , 2-ef ] [2]benzazepine-11-yl]-1-oxohexyl]- 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]CTuinolin-4-one (SPH-1516) 1. Synthesis in Solution: Norgalanthamine (1.13 g, 4.13 mmol), 8-(6-iodo-l-oxohexyl) -1,2,5, S-tetrahydro-4K-pyrrolo [3 , 2 ,1-ij ] quin.olin-4-one (1.50 gr 3.75 mmol) and N-ethyldiisopropylamine (1.46 g, 11.3 rnmol) are 283 stirred in absolute chloroform (20 ml) for 54 hours at boiling temperature. The residue that is obtained after the solvent is removed in a rotary evaporator is purified by column chromatography (200 g of silica gel, chloroform : methanol : ammonia = 96:3:1), by which the product is obtained as a light yellow foam (1.87 g, 92%) . TLC: CHC13 : MeOH : KH3 = 89:10:1, Rf - 0.5 1H NMR (CDC13) : 5 7.52 (s, 1H) , 7.67 (s, 1H) , 6.68-6.43 (m, 2H) , 6.00 (d, J = 9.7 Hz, 1H) , 5.93-5.81 (m, 1H) , 4.51 Production of fumarate (SPH-1519) analogously to Example 4 MT-407 JOS 1761 C37H42N2°2X° Cld.: C, 65.67; H, 6.55; N, 4.14 Fnd.: C, 65.69; K, 6.49; N, 4.02 284 2. By Solid-Phase Synthesis 0.300 g (0.102 mmolj of norgalanthamine-6-yloxy)-1,5-dioxopentyloxymethyl-Merrifield resin is steeped in a 5-ml-polyethylene frit that is sealed on both sides for 3 0 minutes in 3 ml of dimethylformamide/acetone (l/l) and after filtering, it is suspended in a solution of 0.125 g (0.315 mmol) of 8-(6-iodo-1-oxohexyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one and 54 p.1 (0.041 g, 0.315 mmol) of ethyldiisopropylamine in 3 ml of dimethylformamide/acetone (1/1). The suspension is shaken at room temperature for 19 hours. A negative chloranil test indicates the complete conversion of the secondary amine. The resin is washed three times with dimethylformamide (2 minutes, 3 ml) and six times with tetrahydrofuran/methanol (4/1, 2 minutes, 3 ml). The resin is suspended below in a solution that consists of 0.113 g (0.63 mmol) of 30% sodium methanolate-methanol solution and 3.0 ml of tetrahydrofuran/methanol (4/1). After 15 hours, the solution is filtered off, and the resin is extracted six times with 3 ml each of dichloromethane. The combined filtrates are neutralized with methanolic hydrochloric acid, diluted with 10 ml of dichloromethane, washed twice with 15 ml of saturated sodium chloride solution, dried on sodium sulfate, filtered and concentrated by evaporation in a rotary evaporator under reduced pressure. The crude product is i separated by means of MPLC (200 g of silica gel, v = 285 nm, chloroform/methanol/concentrated ammonia = 96/3/1) . After the concentration by evaporation, a yellow oil that crystallizes 285 while standing is obtained: 0.043 g (0.041 g, 0.075 mmol, 74%) of yellowish crystals (Mw = 542.7), HPLC, TLC identical to a reference sample: TLC: Rf = 0.55 (chloroform/methanol = a/2 + 2% concentrated ammonia) HPLC: tRef =13.7 minutes, 95.7% {Merck Purospher column, 4.0 mm x 125 mm, RP-l8e, 5.0 /an, 1 ml/min, 285 nm, acetonitrile/20 mmol of C13CCO2H in H2O (5/95 v/v for 5 minutes, 5/95 -» 60/40 v/v in 18 minutes (convex), 60/40 w for 5 minutes) Example 13 0a (4aS,6R/8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl- 6H-benzofuro[3a,3,2-ef3 [2]benzazepin-6-ol, galanthamine (HM 424) Lithium aluminum hydride (104 nc, 2.73 mmol) was added to a susoension of galanthaminium bromide HM 40 7 (1.0 g, 2.7 3 mmol) in absolute tetrahydrofuran (50 ml) and stirred for 3 hours at room temperature. Then, excess lithium aluminum hydride, annihilated 286 with ethyl acetate, was added to water (49 rag, 2.73 mmol) to form a precipitate that could be filtered, and precipitated. The A12O3 that was produced was filtered off, the filtrate was dried on sodium sulfate, and the solvent was removed in Rotavapor. 750 mg {96% of theory) of galanthamine was obtained as a white foam. TLC : CHC13 : MeOH/NH3 (9:1) 1H NMR (CDCI3) : 6 6.66-6.58 (m, 2H) , 6.08-5.94 (m, 2H) , 4.58 {b, 1H) , 4.15 (b, 1H) , 4.06 (d, J = 15.2 Hz, IK), 3.78 (s, 3H) , 3.66 (d, J = 15.2 Hz, 1H), 3.25 (ddd, J = 14.4, 2.2, 1.9 Hz, 1H), 3.05 (ddd, J = 14.9, 3.1, 3.1 Hz, 1H), 2.68 (ddd, J = 15.7, 1.8, 1.8, 1H) , 2.40 (s, 3H) , 2.15-1.90 (m, 2H), 1.55 (ddd, J = 13.7, 4.1, 2.0 Hz, 1H) ; 13CNMR (CDCI3) : 5 145.8 (s), 144.1 (s), 133.1 (s) , 12 9.2 (s), 127.6 (d) , 126.8 (d) , 122.1 (d) , 111.1 (d) , 8 8.7 (d), 62.0 (d), 60.4 (t), 55.8 (q), 53.7 (t), 48.2 (s), 41.9 (q), 33.4 (t), 29.9 (t) Example 13 0b: (4aS,6R,8aS)-43,5,9,10,ll-Pentahydro-12-deutero-3-methoxy- lime thyl-6H-benzofuro [3a,3,2-ef][2]benzazepin-S-ol, (12-¦ deuterogalanthamine, SPH-1520) 267 Lithium aluminum deuteride (28 mg, 0.68 mmol) was added to a suspension of galanthaminium bromide HM 407 (250 mg, 0.633 mmol) in absolute tetrahydrofuran (15 ml) and stirred for 3 hours at room temperature. Then, excess lithium aluminum deuteride was destroyed with ethyl acetate and precipitated with deuterium oxide (12 mg, 0.6 8 mmol) of Al2O3. The Al2O3 that was produced was filtered off, the filtrate was dried on sodium sulfate, and the solvent was removed in Rotavapor. 100 mg (51% of theory) of HM 427 was obtained as a white foam. TLC : CHC13 : MeOH/NH3 (9:1) *H NMR (CDCI3) : 6 6.66-6.58 (m, 2H) , 6.08-5.94 (m, 2H) , 4.58 (b, 1H), 4.14 (b, 1H), 4.06 (d, J = 15.2 Hz, 0.5H), 3.78 (s, 3H), 3.66 (d, J = 15.2 Hz, 0.5H), 3.25 (ddd, J = 14.4, 2.2, 1.9 Hz, IE), 3,05 (add, J = 14.3, 3.1, 3.1 Hz, 1H) , 2.68 (ddd, J = 15.7, • 1.8, 1.8, 1H), 2.40 (s, 3H), 2.15-1.90 (m, 2H), 1.55 (ddd, J= 13.7, 4.1, 2.0 HZ, 1H) ; 13C NMR (CDCI3) : 6 145.8 (s), 144.1 (s), 133.1 (s) , 129.2 (s) , 127.6 (d), 126.8 (d) , 122.1 and 122.0 (d), 111.1 (d), 88.7 (d), 62.0 (d), 60.4 (t), 55.8 (q), 53.8 and 53.7 (t), 48.2 (s), 42.1 and 4.1.9 (q), 33.8 and 33.7 (t), 29.9 (t) LC/MS:30*2.1 mm of Zorbax SB C18 3 ^m, 40% MeOH for 2 minutes to 100% © 10 minutes for 10 minutes; remainder of H2O at 0.5 ml/minute, UV 210, 250, 280 and 310 nm, a single peak (RT about 6.0 minutes). PI-MS m/z 289 ([M+H]+), 271 ( [M+H'H2O]+) . NI-MS m/z 287 ([M-H]-), 269 ( [M"H-H2O] ) . 288 Example 131: Norsanguinine {SPH-14 8 6) A solution of norgalanthamine (1.0 g, 3.66 mmol) in 40 ml of absolute THF is mixed at room temperature with 17 ml of L-selectrideR (1 M in THF) and stirred for 24 hours at boiling temperature. It is cooled to room temperature, mixed with ethyl acetate (20 ml) , then with water (100 ml) , and the phases are separated. The organic phase is extracted with water (4 x 20 ml), the combined aqueous phases are extracted with ethyl acetate (2 x 20 ml) and the residue that remains after concentration by evaporation is purified via column chromatography (100 g) of silica gel, chloroform : ammonia = 90:9:1) and crystallized under acetone. In this way, the product is obtained in the form of colorless crystals (0.78 g, 82.3%). ^ NMR -(DMSO-d6) : 5 6.52-6.37 (m, 2H) , 6.03 {d, J = 10.3 Hz, 1H) , 5.78 (dd, J = 10.3 Hz, J = 4.6 Hz, 1H) , 4.43 (s , 1H) , 4.09 (s, 1H) , 3.30 (d, J= 16 Hz, 1H) , 3.71 (d, J = 16 Hz, 1H) , 3.25-2.92 (m, 2H) , 2.24-2.90 (m, 2H) , 2.39 (d, J = 14 Hz, 2H) ; 289 13C NMR (DMSO-d6) : 6 145.6 (s), 140.4 (s), 133.0 (s), 132.3 (S), 127.7 (d) , 127.6 (d) , 119.6 (d), 114.8 (d) , 86.5 (d) , 60.1 (d) , 53.1 (t), 48.3 (s), 46.6 (t), 40.2 (t), 30.8 (4a,S,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol (SPH-1487) (4aS,6R,8aS)-4a,5,9,10,ll,12-Hexahydro-3- trifluoromethylsulfonyloxy-6H-benzofuro[3a,3,2-ef[2]benzazepin-6-ol (200 mg, 0.49 mmol), tetramethylstannane (106 mg, 0.59 mmol), anhydrous lithium chloride (62 mg, 1.47 mmol) and tetrakis triphenylphosphine palladium (28 mg, 0.025 mmol, 0.05 equivalent) are stirred in absolute DMF {3 ml) for 24 hours at 1OO°C. It is dispersed between water (20 ml) and ethyl acetate (30 ml) , the aqueous phase is extracted with ethyl acetate (5 x 30 ml), the combined organic phases are washed with water (3 x 10 ml) and saturated common salt solution (15 ml), and the residue that is obtained after concentration by evaporation is purified by column 290 chromatography (20 g of silica gel, chloroform : methanol : ammonia =96:3:1). In this way, the product is obtained in the form of colorless crystals (102 mg, 77%). MT-298 JOS 1711 C17H21NO2'0.25 H2O Cld.: C, 74.02; H, 7.86; N, 5.08 Fnd.: C, 73.77; H, 7.67; N, 5.04 1H NMR (CDC13) : 6 6.90 (d, J = 7.0 Hz, 1H) , 6.4 6 (d, J = 7.0 Hz, 1H), 6.08 (d, J = 11.5 Hz, 1H), 6.00 (dd, J = 8.5 Hz, J = 5.2 Hz, 1H), 4.54 (s, 1H), 4.13 (s, 1H), 4.11 (d, J = 16.5 Hz, 1H), 3.70 (d, J = 16.5 Hz, 1H), 3.30 (t, J = 12.7 Hz, 1H), 3.08 (d, J = 12.7 Hz), 2.66 (dd, J = 15.2 Hz, J = 5.0 Hz, 1H), 2.42 (s, 3H), 2.18 (s, 3H), 2.17-2.00 (m, 2H), 1.57 (dd, J = 13.3 Hz, J = 5.0 Hz, 1H); 13C NMR (CDCI3) : 6 156.4 (s) , 135.3 (s), 131.6 (s), 130.1 (d) , 127.7 (d) , 127.6 (d) , 122.0 (d) , 119.8 (s), 88.1 (d) , 62.7 (d), 61.3 (t), 54.2 (t), 48.5 (s), 42.4 (d), 33.9 (t), 30.4 (t), 15.3 (q)- Example t**re I 2>3 ] \s SPH-1146 IK 66/1 (-) Cyclopropylmethylgalanthaminium bromide 291 Production analogously to Examples 90-99, melting point 230-2 3 7°C aD20 = -110 (C = 1.5 in water) Example 3t37-r 12>L{> * I yS SPH-1149 HM 104 IS (-) (3-Methylbut-2-en-l-yl)-galanthaminium bromide Production analogously to Examples 90-99, melting point 198-2 01°C aD20 = -118.2 (1.5 in water) 292 Example 13*-: ^2*5'. SPH-1162 Cl 2-1 3au 3-({6R)-l-Bromo-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-- [l]benzofuro[3a,3,2-e£3 [2] benzazepin-11 (12H) -yUpropanoic acid ethyl ester Production analogously to Example 143 Reaction time: 8 hours, yield: 80% colorless foam Same skeleton as in Example 143, here only the signals that are different are indicated: 1H NMR (CDC13) k 4.13 (q, J = 6.0 Hz, 2H) , 2.85 (t, 7.0 Hz, 2H), 2.58 (t, J = 7.0 Hz, 2H), 1.27 (t, J = 6 Hz, 3H); 13C NMR {CDCI3) 5 172.4 (s) , 60.3 (t) , 57.3 (t) , 32.9 (t) , 14.1 (q). 293 Example 1W* l V£> '. SPH-1184 LC2 225/1 (-) (4-Bromophenyl)methylgalanthaminium bromide hemihydrate Production analogously to Examples 90-99, Cld.: C 52.77, H 5.17, N 2.56 Fnd.: C 52.45, H 5.15, N 2.52 Example 3rt^: *3^> SPH-1191 LCz 205 (-) (3-Chloropropyl)-galanthaminium bromide, 1.25 H20 294 Production analogously to Examples 90-99, Cld.: C 51.40, H 6.36, N 3.00 Pnd.: C 51.08, H 6.07, N 2.92 Example 14A+ V 2>% / SPH-1208 CB 2 (6R)-l-Bromo-6-hydroxy-N11-isopropyl-3-methoxy-5/6,9,10- tetrahydro-4aH-[1]benzofuro[3a,3,2-ef ] [2]benzazepine-11 (12H) - carboxylic acid amide Production analogously to Example 142, yield: 96%; 1H NMR (CDC13) 5 6.87 (s, 1H) , 6.04 (dd, J = 16.0; 10.0 Hz, 2H), 4.88 (d, J = 18.0 Hz, 1H), 4.61 (m, 1H), 4.28 (d, J = 18.0, 1H) , 4.-13 (b, 1H) , 3.90 (m, 1H) , 3.85 (s, 3H) , 3.26 (t, J - 12.0 Hz, 1H) , 2.67 (dd, J = 16.0; 3.0 Hz, 1H) , 2.29 (d, J = 10.0 Hz, 1H), 1.99 (m, 2H) , 1.72 (d, J = 17 Hz, 1H) ; 1.12 {dd, J = 20.0; 5.0 Hz, 6H) ; t3CNMR 295 (t), 42.7 (d), 36.5 (t), 29.6 (t), 23.4 (q), 23.0 (q). Anal. [C20H25BrN2O4"0.3 H2O) Cld.: C 54.26 H 5.83 N 6.33 Fnd.: C 54.28 H 5.79 N 6.14 Example 142-t 13^ ¦ SPH-12 0 9 CB 5 (6R)-l-Bromo-6-hydroxy-3-methoxy-Nll-methyl 5,6,9,10-tetrahydro-4aH-tUbenzofuro[3a,3,2-ef][2]benzazepine-11(12H)-thiocarboxylic acid amide Methyl isothiocyanate {42.0 mg, 0.57 mmol) was added in drops to a stirred solution of bromonorgalanthamine (0.2 g, 0.57 mmol) in toluene (10 ml), and it was refluxed for three hours. After concentration by evaporation, the residue was taken up in 2N HC1 (20 ml) and washed with AcOEt (1 x 10 ml). The aqueous solution was brought to a pH > 8.5 with concentrated ammonia and extracted with AcOEt (3 x 10 ml). The combined organic phases were washed with saturated common salt solution, dried (Na2SOA) 296 and concentrated by evaporation, by which the product was obtained in the form of colorless crystals with a melting point of 183-185°C (0.22 g, 99%); ^ NMR (CDC13) 6 7.35 (b, 1H) , 6.89 (m, 1H) , 6.10 (m, 2H) , 5.50 (d, J = 12.0 Hz, 1H), 5.11 (d, J = 12.0 Hz, 1H), 4.69 (b, -1H) , 4.52 (d, J = 12.0 Hz, 1H) , 4.17 (b,"lH), 3.85 (s, 3H) , 3.60 (t, J = 18.0 Hz,. 1H) , 3.10 (d, J= 3.4 Hz, 3H) , 2.72 (dd, J = 18.8; 2.0 Hz, 1H) , 2.13 (m, 2H) , 1.79 (d, J = 12.0 Hz, 1H) ; 13C-NMR (CDC13) 5 181.5 (s), 146.8 (s) , 145.4 (s), 133.9 (s), 128.9 (d), 128.2 (s), 125.5 (d), 115.3 (d), 112.5 (d), 88.6 (d), 61.5 (d) , 56.2 (q), 51.7 (t) , 51.2 (t) , 48.9 (s) , 35.8 (t) , 33.0 (q) , 29.6 (t). Anal. (C18H2lBrN2O3S-0.5 H-,0) Cld.: C 50.83 H 4.98 N 6.59 Fnd.: C 50.73 H 5.02 N 6.63 Example £43t \U0 I ^\/ SPH-1210 CB 4 3-((6R)-l-Bromo-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[l]benzofuro[3a,3,2-ef ] [2] benzazepine-11(12H)-yljpropanenitrile 297 Acrylonitrile (0.05 ml, 0.85 mtnol) and calcium chloride (200 mg, 1.80 mmol) were added to a solution of norgalanthamine (200 mg, 0.57 mmol) in 50% EtOK (20 ml), and the reaction was refluxed for 3 hours. The reaction was concentrated, the residue was taken up in 2N HCl (50 ml) and washed with EtOAc (3 x 25 ml, the organic phase was discarded). The aqueous solution was brought to pH > 3.5 with concentrated NH3 and extracted with methylene chloride (3 x 2 5 ml). The combined organic phases were washed with saturated sodium chloride solution (200 ml) , dried (Na2SO4) and concentrated by evaporation, and the product, 220 mg (95.7%), was obtained as a colorless foam. 'H NMR (CDC13) 5 6.90 (s, 1H) , 6.04 (dd, J, = 16.0 Hz, J2 = 10.0 KZ, 2H) , 4.60 (b, IK), 4.33 (d, J = 16.0, 1H) , 4.12 (b, IK), 4.08 (d, J = 16.0 HZ, 1H) , 3.83 (s, 3H) , 3.47 (t, J = 10.0 Hz, 1H) , 3.18 (d, J = 18.0 Hz, 1H) , 2.80 (t, J = 10.0 Hz, 2K) , 2.63 (m, 2H), 2.61 (m, 1H), 2.03 (m, 2H), 1.60 (d, J = 10.0 Hz, 1H); 13C-NMR {CDC13) 5 145.6 (s) , 144.5 (s) , 134.1 (s), 128.4 (d), 127.1 (S), 126.1 (d), 118.6 (s), 115.8 (d) , 114.3 (d), 88.7 (d), 61.7 (d), 56.1 (q) , 54.9 (t), 52.0 (t), 48.9 £s), 47.2 (t), 33.3 (t), 29.7 (t), 16.8 (t). Anal. (Cl9H21BrN2O3) Cld.: C 56.31 H 5.22 N 6.91 Fnd.: C 56.53 H 5.44 N 6.64 298 Example ±44 \ lp \ SPH-1227 [4aS- (4aa,6a,8aR*) ] -4a, 5, 9,10,11,12-Hexahydro-3-methoxy-ll-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepine-6-amine Step 1 A solution- of 300 mg (1.05 mmol) of galanthamine, 208 mg (1.20 mmol) of azadicarboxylic acid diethyl ester, 314 mg (1.20 mmol) of triphenylphosphine and 1.20 mmol of phthalimide in 30 ml of absolute tetrahydrofuran is stirred for 24 hours at room temperature. Then, the tetrahydrofuran is spun off, the residue is taken up in 30 ml of 2N hydrochloric acid, washed three times with 30 ml each, of ethyl acetate and made basic with concentrated aqueous ammonia. Then, the solution is extracted three times with 3 0 ml each of ethyl acetate, the combined organic phases are washed once with saturated aqueous sodium chloride solution, dried (Na2SO4) , filtered and concentrated by evaporation. The crude product is purified by FLC (15 g of silica gel, mobile solvent: CHC13 : MeOH = 97:3). 299 83% colorless crystals, melting point: 60-63°C TLC: CHC13 : MeOH =9:1 Step 2 146 mg (1.44 mmol) of triethylamine and 162 mg (1.58 ramol) of 3-(dimethylamino)propylamine are added in drops to a solution, cooled to -5°C, of 0.72 mmol of educt in 5 ml of absolute methanol. Then, the reaction mixture is allowed to stir at room temperature for 24 hours, and then methanol, triethylamine and 3-(dimethylamino)propylamine are spun off. The crude product that is obtained is purified by FLC (15 g of silica gel, mobile solvent: CHCl3 : MeOH = 9:1 with 0.5% concentrated aqueous ammonia), by which colorless crystals with a melting point of 119-121°C with a rotation of aD20 [c = 0.1, CHCl3] = -264° of product are obtained. TLC: CHC13 : MeOH =9:1 300 1H NMR (CDCI3) : 5 1.56-1.89, m, 2H; 2.78, m, 1H; 3.02, m, 1H; 3.24, m, 1H; 3.48, m, 1H; 2.32, s, 1H; 3.83, s, 1H; 3.63, d, 1H; 4.07, d, 1H; 4.62, b, 1H; 4.98, b, 1H; 5.74, d, 1H; 6.11, d, 1H; 6.54, d, 1H; 6.64, d, 1H. Example £4-5-* 1 If 2..' SPH-1273 CB 99 (4aS,6R,8aS) -li-Methyl-3-phenoxy-5, 6, 9,10 ,11,12-hexahydro-4aH- [1]benzofuro[3a,3,2-ef] [2]benzazepin-6-ol 0.44 g (3.6 mmol) of benzeneboric acid, 2.5 ml (9 mtnol) of triethylamine, 0.67 g (3.6 mmol) of copper (II) acetate and 1 g of molecular sieve (4 A, crushed) were added to a solution of 1.0 g (3.6 mmol) of O-demethylgalanthamine in 50 ml of dichloromethane. The reaction mixture was stirred for 44 hours at room temperature. The solid was filtered off. The filtrate was extracted twice with 3 0 ml each of saturated sodium bicarbonate solution. The aqueous phase was re-extracted three times with 30 ml of methylene chloride in each case. The combined organic phases were dried on sodium sulfate, and the solvent was 301 distilled off. The crude product (0.55 g, 43.7% of theory) was purified by means of column chromatography (CHC13 : MeOH = 95:5). Yield: 0.3 g (23.8% of theory) TLC: CHC13 : CHjOH = 9:1 CB 99: ]H NMR (CDCI3) : 6 7.29 [m, 2H) , 7.04 (t, J = 7 . 2 Hz, 1H) , 6.89 (d, J = 8.7 Hz, 2H), 6.73 (dd, J1 = 31.6 Hz, J2 = 8.7 Hz, 2H) , 6.03 (m, 2H) , 4.59 (s, 1H) , 4.51 (b, 1H) , 4.17 {d, J = 15.3' Hz, 1H) , 3.77 (d, J = 15.3 Hz, 1H) , 3.33 (t, J = 13.0 Hz, 1H) , 3.10 (d, J = 14.5 Hz, 1H) , 2.53 (m, 1H) , 2.43 (s, 3H) , 2.15 (m, 1H) , 1.89 (m, 1H) , 1.62 (d, J = 13.8, 1H) ; 13C-NMR (CDCl3) : 6 157.3 (S), 14 8.1 (s), 13 9.6 (s), 134.2 (s), 12 9.6 (2*d), 128.1 (d) , 126.2 (d) , 122.8 (d) , 122.7 (d) , 120.2 (d) , 116.8 (d) , 88.7 (d) , 61.7 (d) , 59.9 (t) , 53.2 (t) , 48.1 (s) , 41.2 (q) , 32.8 (t), 29.7 (t). Anal. (C22H23NO3*0.2 CHC13) Cld.: C 71.43 H 6.26 N 3.75 Fnd.: C 71.43 H 6.61 N 3.84 302 Example 4«-s ^ [p 2? ' SPH-12S8 HM 122.DD 13 (6R)-3,6-Dihydroxy-Nl1-isopropyl~5,6,9,l0-tetrahydro-4aH-[l]benzofuro[3a,3,2-ef] [2] benzazepine-11 (12H) -carboxylic acid amide A solution of 0.42 ml (4.3 mmol) of boron tribromide in 4 ml of absolute dichloromethane was slowly added in drops under argon at -5°C to a solution of 1.6 mmol of educt in 17 ml of absolute dichloromethane. After 3 hours of stirring at -5 to 0°C, the reaction mixture was poured onto 2 0 ml of water and saturated with sodium bicarbonate. The aqueous phase was extracted four times with 15 ml each of n-butanol, and the solvent was distilled off. The residue was purified by means of column chromatography (LM: CHC13 : CH3OH =,97:3) and dried at 50°C/50 mbar. ^ NMR (CDC13) : 6 6.57 {dd, J1 = 18.7 Hz, J2 = 8.0 Hz, 2H) , 5.94 (dd, J, = 21.4 Hz, J2 = 10.4 Hz, 2H) , 4.90 (dd, J,, = 10.6 Hz, J2 = 6.0 Hz, 1H), 4.36 (m, 3H), 3.85 (m, 1H) , 3.33 (t, J = 12.1 Hz, 1H) , 2.93 (m, 1H) , 2.25 (m, 1H) , 1.87 (m, 2H} , 1.24 (m, 1H) , 303 1.06 Cdd, J2 = 21.3 Hz, Jz = 6.5 Hz, 6H) ; 13C-NMR (CDC13) : 6 156.7 (s), 146.5 (s), 141.0 (s), 131.5 (s), 130.1 (s), 128.1 (d), 127.1 (d), 120.1 (d), 115.5 (d), 88.2 (d), 51.6 (t), 48.0 (s), 45.9 (t), 42.8 (d), 42.0 Cld.: C 54.0 H 5.68 N 6.37 Fnd.: C 54.08 H5.61 N 6.33 Example 14-7-: llf L$ SPH-1302 HM 203 {4aa, 6£, 8aR*) -4a, 5, 9, 10-Tetrahydro-6-hydroxy-3-methoxy-6H- benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxylic acid-1,1- dimethylethyl ester (8d) A solution of 9.00 g {41.30 mmol) of pyrocarbonic acid-di-tert-butyl ester in 150 ml of absolute tetrahydrofuran was added in drops while being cooled with ice to a solution of 12.0 g of a mixture of norgalanthamine and galanthamine at a ratio of 94:6 (corresponding to 41.3 mmol of norgalanthamine) and 7.10 g (70.2 mmol) of triethylamine in 400 ml of absolute tetrahydrofuran. After 10 minutes, the ice-cooling was removed, and it was stirred 304 for 16 hours at room temperature. Then, the organic solvent was evaporated, the residue was taken up in ethyl acetate, and it was washed three times with 150 ml each of IN aqueous hydrochloric acid, three times with 200 ml each of saturated sodium bicarbonate solution and twice with 200 ml each of saturated sodium chloride solution. The solvent was dried on sodium sulfate, concentrated by evaporation, and the crude product was purified by means of MPLC: mobile solvent: chloroform : methanol 99:1 6 90:10. 11.2 g of white foam was obtained at HM 203 (73% of theory). TLC: CHC13 : MeOH/NH3 9:1 JH-NMR (CDCI3, 200 MHz): 51.35-1.45 (m, 9H) , 1.75 (m, 1H) , 1.97 (m, 1H), 2.05 (m, 1H), 2.40 (m, 1H), 2.69 (b, 1H), 3.30 (b, 1H), 3.85 (OCH3, s, 3H) , 4.0 8-4.17 (m, 3H), 4.60 (b, 1H), 5.97- 6.06 (m, 2H), 6.70-6.78 {m, 2H) Anal. (C21H27NO5, 0.4 MeOH) Cld.: C 66.54 H 7.46 N 3.63 Fnd.: C 66.59 H 7.59 N 3.47 305 Example &t9~. MfS' SPH-1339 HM 264-1 (4aS,6R,8aS)-ll-Propyl-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[l]benzofuro[3a,3,2-ef] [2]benzazepin-6-ol Method 1: A solution of 250 mg {0.92 mmol) of (-)-norgalanthamine and 160 mg (2.76 mmol) of propanal in 20 ml of absolute acetonitrile were mixed in portions with 145 mg (2.3 mmol) of sodium cyanoborohydride and stirred for 12 hours at room temperature. Then, 145 mg (2.3 mmol) of sodium cyanoborohydride was repeatedly added in portions, and the reaction mixture was stirred for another 6 hours. After the solvent was evaporated, the working-up was carried out according to instructions Al. Further purification was carried out by means of MPLC (mobile solvent: chloroform : methanol/NH3 = 95:5). 200 mg (70% of theory) of HM 2 64 was obtained. TLC: CHC1, : MeOH/NH, 9:1 306 Method 2: A solution of 200 mg (0.73 mmol) of (-) norgalanthamine and 120 mg (1.46 mmol) of sodium acetate in 12 ml of water, 4 ml of 'absolute ethanol and 0.S2 ml of glacial acetic acid was cooled to 0°C, mixed with 211 mg (3.65 mmol) of propanal and stirred for 5 minutes. Then, 138 mg (3.65 mmol of sodium borohydride in 10 mg portions was added. After 20 minutes, another 211 mg (3.65 mmol) of propanal and 138 mg (3.65 mmol) of sodium borohydride were added and stirred for 30 minutes. Then, the reaction mixture was worked up as described in Instructions Al. 210 mg (91% of theory) of HM 2 64 was obtained. TLC: CHC13 : MeOH/NH3 9:1 1H-NMR 307 Example ISO: 1^ SPH-1340 HM 265-1 N-Demethyl-N-propargyl-galanthamine A solution that consists of 0.50 g (1.83 mmol) of (-)demethylgalanthamine, 0.51 g (3.66 mmol) of potassium carbonate and 0.55 g (3.66 mmol). of sodium iodide in 25 ml of dimethylformamide was mixed with 2.20 mmol of reagent and heated for six hours to 70-80°C. Then, the solvent was evaporated. The residue was taken up in 50-100 ml of 2N aqueous hydrochloric acid and washed twice with 40-70 ml each of ethyl acetate. Then, it was made basic with concentrated aqueous ammonia and extracted three times with 40-70 ml each of dichloromethane. The combined organic phases were washed twice with 4 0-70 ml each of saturated sodium chloride solution, dried on sodium sulfate, and the solvent was evaporated. The further purification was carried out by means of MPLC (mobile solvent: chloroform : methanol/NH3 = 95:5). Yield: 0.26 g (46% of theory) of a colorless oil 308 TLC: CHC13 : MeOH/NH3 9:1 1H-NMR (CDC13, 200.13 MHz): 5 1.53 (ddd, J = 13.8, J = 3.7, J = 2.1, 1H), 1.89-2.09 13C-NMR (CDC13, 50.32 MHz): 5 29.9 (t) , 34.5 (t) , 44.2 (t), 48.0 (s), 51.5 (t), 55.8 (q), 58.2 (t), 61.9 (d) , 72.8 (s), 79.4 (d), 88.6 (d), lli;3 (d), 122.0 (d), 12 6.8 (d), 127.6 (d), 128.7 (s), 132.9 (s), 144.1 (s), 145.8 (s) Example -£53r: I U}%r '• SPH-1357 MF 8 Production analogously to Example 6/step 3, but with use of 2- (4-bromobutyl)-5-methoxyindan-l-one, colorless foam. 1H-NMR (pptn, CDC13) : 5 7.65 (d, J = 8.1 Hz, 1H) , 6.8 7 {d, J = 7.7 Hz, 2H), 6.62 (dd, J1 =12.9 Hz, J2 = 8.4 Hz, 2H), 6.04 (m, 2H) , 4.60 (b, 1H) , 4.14 (m, 2H) , 3.85 (s, 3H) , 3.83 (s, 3H) , 3.81 (m, 1H), 3.61 (d, J = 6.24 Hz, 1H), 3.25 309 15.1, 5H), 2.52 (b, 1H), 2.07 (m, 3H), 1.93 (m, 1H), 1.64-1.48 (m, 4H); "C-NMR (ppm, CDC13) : 5207.0 (s) , 165.3 (s) , 162.5 (s), 156.6 (s), 145.8 (s), 144.1 (s) , 133.1 (s), 129.5 (s), 127.6 (d), 126.9 (d) , 32.8 (t), 31.5 (t), 29.9 (t), 29.6 (t) , 27.4 (t), 25.1 (t). Example 455fLfg ; SPH-1377 BK-34-2 2~[4-[(4aS, 6R, 8aS)-4a, 5, 9, 10, 11,12-Hexahydro-6-hydroxy-3-methoxy- 6H-benzofuro[3a,3,2-ef][2]benzazepine-11-yl]butyl]-5- methoxyindan-1-one, fumarate Production of Example 151 analogously to Example 7/production of fumarate. Melting point: 107-110°C C3aH35NO5 5/4C4H,O4 1 H2O 310 Cld.: C, 64.07 H, 6.4 4 N, 2.11 Fnd.: C, 64.26 H, 6.41 N, 2.23 m NMR (ppiri, CDC13) : 5 7.56 (d, J = 10 Hz, 1H) , 7.10 (s, 1H), 6.98 (d, J = 10 Hz, 1H), 6.80 (m, 2H), 6.63 (s, 2H), 6.13 (d, J = 12.0 Hz, 1H) , 5.89 (m, 1H) , 4.61 (s, 1H) , 4.50 (d, J = 8.0 Hz, 1H), 4.07 (b, 2H), 3.88 (s, 3H), 3.72 (s, 3H), 3.52 (t, J = 12 Hz, 1H), 3.31 (m, 2H), 2.69 (m, 5H) , 2.30 (d, J = 12 Hz, 1H), 2.07 (m, 2H), 1.74 (m, 4H) , 1.38 (m, 3H) ; 13C-NMR (ppm, CDCI3) : 5206.3 (s), 166.9 (s) , 165.3 (s) , 157.2 (s), 146.3 (s), 144.6 (s), 133.1 (d), 129.7 (s), 129.4 (s), 126.4 (d), 125.1 (d), 122.5 (d), 115.8 (d), 112.7 SPH-1S1S (4aS,6R,8aS)-3,6-Dihydroxy-5,6,9,10-tetrahydro-4aH-[l]benzofuro[3a,3,2-ef][2]benzazepine-ll(12H)-yl)carboxylic acid allyl ester (ML-7) 311 2.11 ml (1.538 g, 19.3 tnraol) of triethylamine and 0.81 ml (0.693 g, 6.384 mmol) of trimethylsilyl chloride are sprayed under inert-gas atmosphere by means of a syringe through a septum into a suspension of 0.788 g (0.552 g, 2.13 mmol) of norsanguinine (HPLC purity 70%) and 10 ml of absolute dichloromethane, and the suspension is stirred for three hours at room temperature. In the meantime, a flocculent precipitate settles out. Then, 0.34 ml (0.385 g, 3.192 mmol) of allyl chloroformate is added while being cooled in an ice bath (exothermic). The reaction mixture is heated within two hours to room temperature while being stirred, by the ice bath being allowed to thaw. The reaction is halted by adding 13 ml of 2N hydrochloric acid, and the phases are separated. The organic phase is washed four times with 10 ml each of 2N hydrochloric acid and once with common salt solution, the combined aqueous phases are re-extracted once with 20 ml of dichloromethane. The combined organic phases are dried on sodium sulfate and filtered. After the solvent is distilled off in a rotary evaporator, the crude product (HPLC purity 87.5%) is purified by means of MPLC (50 g of silica gel, v = 285 nin, chloroform/methanol = 95/5) . After concentration by evaporation and drying in a high vacuum, the product is obtained as a yellowish, highly viscous oil, which crystallizes during concentration by evaporation from dichloromethane. Yield: 0.443 g (1.29 mmol, 61%) of colorless crystalline solid, (Mw = 343.4), TLC: Rf = 0.55 (chlorofcrm/methanol = 9/1). Melting point: 197-198°C (dichioromethane). 312 1H-NMR: (200.13 MHz, CDC13, TMS) 5 7.66 (bs, 0.3H), 6.52-6.76 (m, 2H) , 5.95 (bs, 2K) , 5.72-5.90 (m, 1H) , 5.06-5.36 (m, 2H) , 4.90 (d, J = 12.7 Hz, 0.5H), and 4.79 (d, J = 12.7 Hz, 0.5H) , 4.51 (bs, 3H) , 4.00-4.41 (m, 3H) , 3.22-3 .53 (m, 1H) , 3.13 (bs, 0.3H), 2.58 {bd, J = 13.4 Hz, IK), 1.63-2.10 (m, 3H) , 13C-NMR: (50.32 MHz, CDC13/ TMS), 6 155.4 and 155.2 (s) , 145.4 (s), 140.6 (s) , 132.7 and 132.6 (d) , 131.9 and 131.7 (s) , 128.3 (s) , 127.1 (d) , 127.0 (d) , 121.6 and 121.1 (d) , 117.4 and 116.8 (t) , 115.8 and 115.7 (d), 87.7 (d), 66.1 and 65.9 (t), 61.8 (d), 51.9 and 51.5 (t), 48.4 (s), 45.9 and 45.4 (t), 37.0 and 36.0 (t), 29.5 (t) . 313 Diagram for Examples 158 and 159 314 Example t&6 I §0 '. SPH-1522 (4aS,6R,8aS) -N11- (N-tert-Butoxycarbonyl-6-aminohexyl) -6-hydroxy-3~meth.oxy-5,6,9,10-tetrahydro-4aH~ [l]benzofuro- [3a,3,2-efJ-E2]benzazepine-11(12H> carboxamide (CK-52-6) 0.600 g (0.426 mmol) of N-tert- butoxycarbonylnorgalanthamine-6-yloxy-l,5-dioxopentyloxymethyl-Merrifield resin is steeped in a 10-ml-polyethylene frit that can be sealed on both sides for 3 0 minutes in a sufficient amount of dichloromethane and demasked analogously to the protection removal instructions to immobilize N-tert- butoxycarbonylnorgalanthamine (Example 14 7) and washed (in each case 6 ml of solvent). Then, the resin is reacted analogously to the above instructions with 730 ^tl (0.551 g, 4.260 mmol) of ethyldiisopropylamine and.0.379 g (1.278 mmol) of triphosgene in 6 ml of absolute dichloromethane. After the resin is washed and dried in a vacuum overnight, 0.653 g of N- 315 chclorocarbonylnorgalanthamine-6-yloxy-l, 5-dioxopentyloxymethyl-Merrifield resin is obtained. After the resin (0.103 g, 0.065 mmol) is steeped and filtered, it is suspended in a solution that consists of 0.1S4 g (0.650 mmol) of N-tert-butoxycarbonyl-1,6- diaminohexanehydrochloride, 222 /zl (0.168 g, 1.300 mmol) of ethyldiisopropylamine, 0.053 fil (0.051 g, 0.650 mmol) of pyridine and 2.0 ml of dimethylforinamide (to dissolve the hydrochloride, the solution is heated beforehand). Then, the suspension is shaken at room temperature for 5.5 hours. The resin is washed three .times with dimethylformamide (2 minutes, 1 ml) and six times with dichloromethane (2 minutes, 1 ml) . After drying in a vacuum, the resin is shaken in 2 ml of tetrahydrofuran for 3 0 minutes, and after filtering, it is mixed with a solution that consists of 0.059 g (0.018 g, 0.325 mmol), 30% of sodium methanolate-methanol solution and 1.5 ml of tetrahydrofuran/methanol (4/1). After 9.5 hours of shaking at room temperature, the solution is filtered off, and the resin is extracted three times with 1.5 mi each of dichloromethane/methanol (l/l) and three times with 1.5 ml each of dichloromethane. The combined filtrates are neutralized with methanolic hydrochloric acid, diluted with 10 ml of dichloromethane, washed once with 15 ml of 2N hydrochloric acid and twice with 15 ml each of saturated sodium chloride solution, dried on sodium sulfate, filtered and concentrated by evaporation under reduced pressure in a rotary evaporator. The crude product 316 (0.051 g) is separated by means of column chromatography (5 g of silica gel, chloroform/methanol = 50/1). After concentration by evaporation, a colorless oil is obtained. Yield: 0.030 g (0.058 mmol, 89%), colorless oil (M^ = 515.7) TLC: Rf = 0.47 (chloroform/methanol = 9/1) ^-NMR: (200.13 MHz, CDC13, TMS) 56.73 (d, J = 8.1 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 5.90-6.07 (m, 2H) , 4.23-4.70 (m, 5H), 4.13 (bs, 1H), 3.82 (s, 3H), 3.35 (t, J = 13.5 Hz, 1.0 H) , 2.96-3.20 (m, 4H), 2.67 (bd, J = 15.7 Hz, 1H); 1.65-2.10 (m, 3H), 1.42 (s, 9H), 1.06-1.40 (m, 8H) 13C NMR: (50.32 MHz, CDC13, TMS) 5 157.2, 156.0, 147.0, 144.7, 132.5, 129.2, 12 8.1, 126.5, 120.2, 111.2, 88.4, 61.9, 55.9, 51.7, 48.5, 45.7, 42.1, 40.5, 39.3, 36.6, 30.0, 29.7, 28-4, 26.1, 23.5 HPLC: tBef = 17.8 minutes, 98.7% (Merck Purospher column, 4.0 mm x 125 mm, RP-18e, 5.0 urn, 1 ml/minute, 285 nm, acetonitrile/20 mmol of C13CCO2H in H20 (20/80 for 5 minutes, 20/80 6 60/40 in 12 minutes, 60/40 for 5 minutes, v/v) 317 Example £5-3 *£>! - N-tert-Butyloxycarbonylglycine-E4-E(4aS,6R,8aS)-6-hydroxy-3- methoxy-5, 6,9,10-tetrahydro-4aH- [l]benzofuro [3a, 3, 2- ef] [2]benzazepine-ll(12H) -yl] -3-aza-4-oxob-utyl] amide (CK-58-2) 0.199 g (0.102 mmol) of norgalanathamine-6-yloxy-l,5-dioxopentyloxymethyl-Merrifield resin is steeped in a 5-ml-polyethylene frit that can be sealed on both sides for 3 0 minutes in 2 ml of dichloromethane/ and after filtering, it is suspended in a solution-of 120 fil (0.091 g, 0.700 mmol) of ethyldiisopropylamine in 1.5 ml of dichloromethane. Then, the suspension is mixed with a solution, cooled to 0°C, that consists of 0.0 62 g (0.210 mmol) of triphosgene and 0.5 ml of dichloromethane and shaken at room temperature for two hours. The resin is washed three times with dichloromethane (2 minutes, 2 ml) and three times with dimethylformamide (2 minutes, 2 ml) . A solution that consists of 47 \i1 (0.042 g, 0.700 mmol) of ethylenediamine and 2.0 ml of dimethylformamide is subsequently added, and the suspension is shaken at room temperature. After three hours, the solution is filtered off, and the resin is washed six times with 2 ml each of dimethylformamide (2 minutes). 318 (The Kaiser Test cannot be evaluated. The beads exhibit brown-red staining.) The resin is mixed with a solution that consists of 0.037 g (0.210 mmol) of N-BOC-glycine, 0.028 g (0.210 mmol) of 1-hydroxybenzotriazole and 1 ml of dimethylformamide, and the suspension is shaken for five minutes. Then, 0.043 g (0.210 mmol) of dicyclohexylcarbodiimide, dissolved in 1 ml of dichloromethane, is added. The suspension is shaken for three ¦ hours at room temperature, the resin is filtered, and it is washed three times with dimethylformamide (2 ml, 2 minutes) and six times with dichloromethane (2 ml, 2 minutes). After drying in a vacuum, 0.239 g of resin, which is shaken in tetrahydrofuran for 30 minutes, is obtained, and after filtering, it is mixed with a solution that consists of 0.07S g {0.023 g, 0.63 mmol) of 30% sodium methanolate-methanol solution and 2.0 ml of tetrahydrofuran/methanol (4/1). After 8.25 hours of shaking, the solution is filtered off, and the resin is extracted three .times with 2 ml each of dichloromethane/methanol (1/1) and three times with 2 ml each of dichloromethane. The combined filtrates are neutralized with methanolic hydrochloric acid, diluted with 10 ml of dichloromethane, washed twice with 15 ml of saturated sodium chloride solution, dried on sodium suifate, filtered and concentrated by evaporation in a rotary evaporator under reduced pressure. The crude product (0.0 64 g) is separated by means of column chromatography (5 g of silica gel, chloroform/methanol = 25/l 15/1). After the concentration by evaporation, a colorless oil is obtained. 319 Yield: 0.030 g (0.025 g, 0.048 mmol, 47%), colorless oil (Mw = 516.6) TLC: Rf = 0.38 (chloroform/methanol = 9/1) ^-NMR: (200.13 MHz, CDC13/ TMS) 5 6.90 (bs, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.60-6.71 (m, 1H), 5.88-6.08 (m, 2H) , 5.3 9 (bs, 1H), 5.19 (bs, 1H), 4.50-4.7 0 (m, 2H) , 4.04-4.34 (m, 3H) , 3.82 (s, 3H), 3.70 (d, J = 6.1 Hz, 1H), 3.65 (d, J = 5.6 Hz, 1H), 3.11-3.49 (m, 5H), 2.68 (d, J = 15.9 Hz, 1H), 2.41 (d, J ¦¦= 10.9 Hz, 1H) , 1.65-2.09 (m, 3H), 1.44 (s, 9H) HPLC: tRef = 15.2 minutes, 82.3% (Merck Purospher column, 4.0 mm x 125 mm, RP-18e, 5.0 um, 1 ml/minute, 285 nm, MeOH/H2O (5/95 for 5 minutes, 5/95 6 100/0 in 15 minutes (convex), 100/0 for 10 minutes, v/v) LC/MS: tRef = 30.6 minutes, (Phenomenex Luna column, 3.0 mm x 50 mm, RP-18, 3.0 um, 0.8 ml/minute, methanol/H2O (10/90 for 2 minutes, 10/90 6 100/0 in 15 minutes, 100/0 for 5 minutes, vv) APCI-PI-MS 517 (17), 499 (5), 461 (55), 443 (39), 417 (100), 399 (18), 274 (43), 256 (16) 320 Example Sr€-0- I ££- * SPH-1524 (4aS,6R,8aS) -6- (Benzoyloxy) -3 -xnethoxy-5, 6, 9, lO-tetrahydro-4aH- [l]benzofuro[3a,3,2-ef] E2]benzazepine-11(12H) -yl) carboxylic acid allyl ester (CK-65-1) 0.075 g (0.210 mmol) of N-allyloxycarbonylnorgalanthamine, 0.475 g (2.098 mmol) of benzoic acid anhydride and 0.013 g (0.105 mmol) of dimethylaminopyridine are introduced into 2 ml of dichloromethane and then mixed with 0.185 ml (0.136 g, 1.049 mmol) of ethyldiisopropylamine, After 13 hours at room temperature, the solution is taken up with 5 ml of saturated sodium bicarbonate solution, and extracted three times with 5 ml each of ethyl acetate. The combined organic extracts are washed with 10 ml of saturated sodium bicarbonate solution, twice with 10 ml of 2N hydrochloric acid and twice with 10 ml of saturated sodium chloride solution, dried on sodium sulfate, filtered and concentrated by evaporation in a rotary evaporator under reduced pressure. The residue is digested twice in each case with 10 ml 321 of petroleum ether, and the solution is decanted off. The residue (0.100 g) is purified by column chromatography (10 g of silica gel, mobile solvent = petroleum ether/ethyl acetate = 2/1) . Yield: 0.066 g (0.080 mmol, 68%), colorless foam (M = 461.5) TLC: Rf = 0.52 (ethyl acetate/petroleum ether = 2/1) Melting point: 45-49°C (ethyl acetate/petroleum ether = 2/1) IR: KBr v (cm"1) 2946 (m) , 1708 (s) , 1509 (m) , 1483 (m) , 1276 (s) , 1108 (m) , 10S6 (m) , 714 (m) 1H-NMR: (200.13 MHz, CDC13, TMS) 5 8.06 (d, J = 7.1 Hz, 1H), 7.29-7,61 (m, 3H), 6.59- 6.84 (m, 2H), 6.28 (d, J = 10.3 Hz, 5H), 6.07 (dd, J = 5.0 Hz, J = 10.2 Hz, 1H), 5.76-5.99 (m, 1H), 5.59 (t, J = 4,4 HZ, 1H), 5.09-5.35 (m, 2H), 4.87 (dd, J = 15.7 HZ, J = 22.0 HZ, 1H) , 4.05-4.70 (tn, 5H) , 3,89 (s, 3K) , 3.29-3.60 (m, IK), 2.81 (bd, J = 16.1 Hz, 1H), 1.74- 2.25 (m, 3H) 13C-NMH: (50.32 MHz, CDC13/ TMS) 6 166.2 (s), 155.3 and 155.1 (s), 147.4 and 147.3 (s), 144.3 (s) , 132.99 and 132.85 (d) , 131.7 (d) , 131.4 and 131.0 (s) , 13 0.4 (s) , 12 9.9 (d) , 12 8.4 (d) , 12 7.1 (d) , 120.7 and 120.2 (d), 117.4 and 116.8 (t), 111.4 and 111.3 (d) , 86 ,(d) , 66.1 and 66.0 (t) , 63 .4 (d) , 56.0 322 (q) , 63.8 (d) , 51.9 and 51.4 (t) , 48.3 (s), 45.8 and 45.4 (t), 37.9 and 37.0 (t), 27.8 (t) 323 Diagram for Examples 151 and 162 324 Example i£3r I &2> ' SPH-1525 Immobilization of (4aS,6R/8aS)-3,6-Dihydroxy-5,6,9,10-tetrahydro-4aH-[l]benzofuro[3a,3,2-ef]-[2]benzazepine-ll(12H)-yl)carboxylic acid allyl ester on a para-hydroxymethylphenoxy-polystyrene resin (Wang resin) Method A (CK-63-2) 0.257 g (0.244 mmol) of Wang resin2 is stirred under argon atmosphere in 3 ml of absolute dichloromethane for 15 minutes. Then, 86 \il (0.141 g,'1.19 mmol) of thionyl chloride is added in drops within five minutes at 0°C. The suspension is stirred at 0°C for one hour. Then, the resin is moved to a polyethylene frit that can be sealed on both sides, and it is washed five times with dichloromethane (2 minutes, 2.5 ml), twice with methanol (2 minutes, 2.5 ml), once with dichloromethane (2 2P-Alkoxybenzyl alcohol resin, D-1250, Bachem Feinchemikalien AG 325 minutes, 2.5 ml) and once with diethyl ether (2 minutes, 2.5 ml). The resin is then dried in a vacuum on phosphorus pentoxide. Step 1 0.2334 g of the chlorine-Wang resin that is thus produced, 0.232 g (0.713 mmol) of cesium carbonate, 0.088 g (0.238 mmol) of tetra-n-butylammonium iodide and 0.245 g (0.713 mmol) of N-alloc-norsanguinine are suspended in 3 ml of absolute dimethylformamide while being stirred. Then, the suspension is stirred for 24 hours at 60°C. After five hours, 1 ml of dimethylf ormamide is added to suspend the deposited precipitate. Then, the resin is moved to a polyethylene frit that can be sealed on both sides with dimethylformamide/water solution (2/1), and it is washed twice with dimethylformamide/water solution (2/1, 2 minutes, 2.5 ml), twice with dimethylformamide/water solution (1/2, 2 minutes, 2.5 ml), twice with methanol/water solution (l/l, 2 minutes, 2.5 ml), twice with methanol (2 minutes, 2.5 ml) and six times with dichloromethane (2 minutes, 2.5 ml). Method B (CK-63-1) 0.121 ml (0.192 g, 1.247 mmol) of carbon tetrachloride is introduced into 2.0 ml of absolute dichloromethane at 0°C. While being stirred (KPG-stirrer) , 0.311 g (1.188 mmol) of triphenylphosphine, dissolved in 1.0 nl of absolute dichloromethane, is added in drops within 15 minutes at 0°C. It is stirred for another ten minutes at 0°C and then for another ten hours at room temperature, until triphenylphosphine can no 326 longer be detected by thin-layer chromatography. 0.2506.g (0.238 mmol) of Wang resin1 and 1.5 ml of dichloromethane are subsequently added, and the suspension is stirred for 35 hours at room temperature (3 00 s"1) . The working-up of the chlorinated Wang resin is carried out analogously to method A. After drying, 0.2403 g of chlorine-Wang resin, which is reacted analogously to step 1 above with the same amounts of cesium carbonate, tetra-n-butylammonium iodide and N-alloc-norsanguinine, is obtained. Example 3*2 » ?Zp '. SPH-1526 Determination of Concentration, (4aS,6R,8aS)-6-(Benzoyloxy)-3-hydroxy-5,6,9,10-tetrahydro-4aH-[llbenzofuro [3a, 3,2-ef ] [2]-benzazepine-ll(12H) -yl) carboxylic acid allyl ester 1.1-1 Step 1 (CK-63-2) To determine the concentration and to detect that the N-alloc-norsanguinine is bonded via the phenol function to the resin, the resin, which is obtained by method A and step 1, is mixed successively with a solution that consists of 0.537 g (2.375 mmol) of benzoic acid anhydride and 2 ml of dichloromethane and a solution that consists of 0.015 g (0.119 mmol) of dimethylaminopyridine, 0.203 ml (0.154 g, 1.188 mmol) of ethyldiisopropylamine and 0.5 ml of dichloromethane. Then, the suspension is shaken out at room temperature. After 18 hours, the resin is filtered off, washed six times with 2.5 ml each of dichloromethane (2 minutes) and once with 2.5 ml of diethyl ether (2 minutes) and dried in a vacuum on phosphorus pentoxide. 327 0.3085 g of substituted resin, which is suspended in absolute dichloromethane for 15 minutes and then is thoroughly filtered, is obtained. Step 2 For cleavage, the resin is mixed with 2.5 ml of trifluoroacetic acid/dichloromethane solution (15/85), shaken for 30 minutes at room temperature, filtered and shaken again with 2.5 ml of trifluoroaceuic acid/dichloromethane solution (15/85), filtered and finally extracted four times with 2.5 ml of dichloromethane in each case. The combined filtrates or extracts are taken up with 10 ml of distilled water and set at pH 6 with sodium bicarbonate. The phases are separated, and the aqueous phase is extracted three times with 10 ml of dichloromethane. The combined organic extracts are washed twice with 10 ml each of saturated sodium chloride solution, dried on sodium sulfate, filtered and concentrated. The purification of the crude product (0.078 g) is carried out by means of column chromatography (10 g of silica gel, ethyl acetate/petroleum ether = 2/1). After concentration by evaporation and drying under high vacuum, 0.078 g of a colorless' foam is obtained that is 95% pure according to HPLC analysis. The colorless foam can be purified by recrystallization from diethyi ether at -22°C (deep freeze from the refrigerator). Yield: 0.059 g (0.055, 0.0125 mmol, thus a concentration of 0.41 mmol/g, 61% of theoretical maximum 328 concentration2 is calculated), colorless foam (M = 447.5) TLC; Rf = 0.29 (ethyl acetate/petroleum ether'= 1/1) Melting point: 158-159°C (diethyl ether) 1H-NMR: (200.13 MHz, d6-DMSO} 5 7.99 (d, J = 6.5 Hz, 2H) , 7.38-7.71 (m, 3H) , 6.39-6.63 (m, 3H) , 5.73-6.17 (m, 2H) , 5.47 (t, J = 4.3 Hz, 1H) , 5.04-5.33 (m, 2H) , 4.00-4.72 (m", 6H) , 2.60-2.89 (m, 1H), 2.55 (bd, J = 18.6 Hz, 1H) , 2.25 (bd, J = 15.7 Hz, 1H) , 1.70-1.93 {m, 2H) 13C-NMR: (50.32 MHz, d6-DMSO) 5 165.4 (s), 154.6 and 154.4 (s), 146.3 (s), 141.3 (s), 133.5 (d) , 133.3 (d) , 133.2 (d) , 131.8 (d) , 131.5 (s) , 13 0.2 (s), 12 9.5 (d), 12 8.6 (d), 128.0 (s) , 122.2 (d) , 120.4 and 120.0 (d) , 117.0 and 116.1 (t), 115.0 (d), 84.7 (d), 65.2 and 65.0 (t), 63.8 (d) , 51.0 and 50.5 (t) , 48.0 (s) , 45.1 and 44.7 (t), 37.3 and 36.4 (t), 27.4 (t) HPLC: tRef = 21.41 minutes, 95.1% (Merck Purospher column, 4.0 mm x 125 mm, RP-18e, 5 fim, 235 nm, 1 ml/minute, acetonitrile/20 mmol of C13CCO2H in E2O (15/85 for 5 minutes, 15/85 -> 60/40 in 12 minutes, 60/40 for 5 minutes, v/v) (CK-63-1) 2 0.67 mmol/g =0.95 mmol/g/(l g + 1 g * 0.95 mol/g * (447.5 g/mol - 18 g/mol)/l000 329 The resin, which is obtained by method 3 and step l, is reacted analogously to step 1 with benzoic acid anhydride, and after drying under vacuum, 0.3 004 g of the substituted resin is obtained. The cleavage of the product and the aqueous working-up are carried out analogously to step 2. After the concentration by evaporation and the drying in a vacuum, 0.070 g of crude product, which is purified by means of column chromatography (10 g of silica gel, ethyl acetate/petroleum ether = 2/1), is obtained. After concentration by evaporation and drying under high vacuum, 0.051 g of a colorless foam, which is 93% pure according to HPLC analysis, is obtained. Yield: 0.051 g (0.047 g, 0.0106 mmol, thus a concentration of 0.35 mmol/g, 52% of the theoretical maximum concentration3, is calculated), colorless foam (MH = 447.5) HPLC: tRef = 21.42 minutes, 92.7% (Merck Purospher column, 4.0 mm x 125 mm, RP-lSe, 5 fim, 285 nm, 1 ml minute, acetonitrile/20 mmol of C13CCO2H in H2O (15/85 for 5 minutes, 15/85 -» S0/40 in 12 minutes, 60/40 for 5 minutes, v/v) 3 0.67 mmol/g = 0.95 mmol/g / (1 g + 1 g * 0.95 mol/g * (447.5 g/mol - 18 g/mol)/1000) 330 155 Example 1S3-: Synthesis of the Solid Phase/Manual Diagram for Example 163 Steps 8-13 a) 3 equivalents of TBTU, 3 equivalents of Fmoc-Phe- OH, 6 equivalents of DIEA, DMF, RT, 3 hours b) Pip/DMF (2/8) , RT, 2 and 10 minutes c) 3 equivalents of TBTU, 3 equivalents of Fmoc-Phe- OH, 6 equivalents of DIEA, DMF, RT, 0.5 hour 331 d) Pip/DMF (2/8), RT, 2 and 10 minutes e) 3 equivalents of TBTU, 3 equivalents of p-MeO-C6H4- C02H, 6 equivalents of DIEA, DMF, RT, 12 hours f) 0.5 M NaOMe, THF/MeOH (4/1), RT, 8 hours Example 163/Steps 1-7 Immobilization of (4aR,6S,8aR)-3-Methoxy-5,6,9,10,11,12-hexahydro-4aH-[l]benzofuro I3a,3,2-ef3 [2]benasepin-6-ol on a Kydroxymethyl-Polystyrene Resin (Merrifield Resin) 332 Method A (CK-41-1) Steps 1-2 and 5-7 5.000 g {5.2 mmol) of hydroxymethyl-Merrifield resin4 is stirred in a three-neck glass reactor with a frit that is recessed in the bottom and a KPG stirrer in 60 ml of dichloromethane for one hour (300 s"1) . After filtering, the suspension is mixed with a solution of 2.373 g (20.8 mmol) of glutaric acid anhydride, 4.45 ml (3.362 g, 26.0 mmol) of ethyldiisopropylamine in 3 0 ml of absolute dichloromethane. The suspension is stirred at room temperature for ten hours, filtered, washed once with 50 ml of dichloromethane, once with 50 ml of methanol and three times with 50 of dichloromethane in each case. The resin is then dried in a vacuum. 4.385 g of the 4-carboxy-l-oxobut-l-yloxymethyl-Merrifield resin that is thus produced is suspended for 30 minutes in 50 ml of absolute dichloromethane while being stirred, and it is filtered. Then, 4.569 g (12.23 mmol) of N-tert-butoxycarbonylnorgalanthamine and 0.249 g (2.04 mmol) of dimethylaminopyridine, both dissolved in 15 ml of dichloromethane, and 2.10 ml (1.582 g, 12.23 mmol) of ethyldiisopropylamine, dissolved in 5 ml of dichloromethane, are added. While being stirred, a solution that consists of 1.89 ml (1.544 g, 12.23 mmol) of diisopropylcarbodiimide and 5 ml of dichloromethane is added in drops within five minutes at room temperature. After 24 hours, the resin is filtered off, washed with 40 ml of methanol and filtered. Then, the resin is washed 4Hydroxymethyl resin, D-1160, Bachem Feinchemikalien AG 333 six times with 40 ml of dichloromethane in each case (5 minutes) and dried in a vacuum. The resin is mixed with 42 ml of absolute dichloromethane and 3 ml of anisole and stirred for 30 minutes {150 s1) . Then, while being stirred (300 s1) , 15 ml of trifluoroacetic acid is added within 15 minutes. Then, the suspension is stirred for 60 minutes (150 s1) , filtered and washed with dichloromethane (2 x 40 ml, 5 minutes), with dichloromethane/dimethylformamide/ triethylamine (5/4/1) (3 x 40 ml, 5 minutes) and finally with dichloromethane (5 x 40 ml, 5 minutes). After drying in a vacuum, 4.353 g of resin is obtained. To determine the concentration, 0.23 84 g of resin in 3 ml of dimethylformide is suspended in a polyethylene frit that can be sealed on both sides. After filtering, the resin is shaken in a solution that consists of 177 \il (0.1S1 g, 1.S75 mmol) of acetic acid anhydride, 180 p.\ (0.136 g, 1.050 mmol) of ethyldiisopropylamine and 2 ml of dimethylformamide for nine hours at room temperature. After washing (dimethylformamide (3 x 2.5 ml, 2 minutes) and tetrahydrofuran/methanol (4/1)* (5 x 2.5 ml, 2 minutes), the resin shows no reaction with the 'chloranil test. The polymer is suspended in a 0.3 M sodium methane-late solution in tetrahydrofuran/methanol (4/1) . The resin is shaken for 8 hours at room temperature, filtered and extracted with methanol/dichloromethane (l/l, 3 x 2.5 ml) and with dichloromethane (3 x 2.5 ml). The combined filtrates are neutralized with methanolic hydrochloric acid. The solution is diluted with about 10 ml of dichloromethane, washed with 25 ml of 334 saturated sodium bicarbonate solution, IN hydrochloric acid and saturated sodium chloride solution in each case, dried on sodium sulfate, filtered and concentrated. The purification is carried out by means of column chromatography (10 g of silica gel, diethyl ether/ethanol = 100/15). After concentration by evaporation and drying under high vacuum, 0.028 g of a yellowish foam, which contain 10% other contaminants according to HPLC analysis, is obtained. Yield: 0.025 g (0.080 mmol. A concentration of 0.34 mmol/g, 45% of the theoretical maximum concentration5thus is calculated) , yellowish foam (Mw = 315.4) TLC: Rf = 0.29 (diethyl ether/ethanol = 100/15) IR: KBr v (cm"1) 3551 (v) , 3305 (bm) , 2926 (m) , 2864 (v) , 1650 (m), 1615 (s), 1443 (m), 1257 (m), 1070 (m) ^-NMR: (200.13 MHz, CDC13/ TMS) 5 6.54-6.89 (m, 2H), 5.75-6.09 (m, 2H), 5.14-5.33 (m, 0.3H), 4.32-4.74 (m, 3.3H), 4.12 (bs, IK), 3.86-4.00 (m, 0.3H), 3.81 and 3.79 (s, 3H) , 3.56-3.76 (m, 0.8H), 3.23 (bt, J = 12.6 Hz, 0.8H), 2.67 (bd, J = 15.9 Hz, 1H), 2.38 (bs, 0.7H), 2.06 (m, 3H), 1.62-2.00 (m, 3H), HPLC: tRef = 13.9 minutes, 89.8% (Merck Purospher column, 4.0 mm x 12 5 mm, RP-18e, 5 fxm, 2 85 nm, 1 50.75 mmol/g = 1.04 mmol/g/(l g + 1 g * 1.04 mol/g * (387.4 g/mol = 18 g/mol)/l000) 335 ml/minute, acetonitrile/20 mmol of C13CCO2H in K.o (05/9S for 5 minutes, 05/95 -* 60/40 in 10 minutes, 10/40 for 10 minutes, v/v, pH 10) Method B (CK-43-2), Steps 1 and 3-7 3.500 g (3.64 mmol) of hydroxymethyl-Merrifield resin6 is reacted analogously to the method that is described under method A with 1.661 g (14. S mmol) of glutaric acid anhydride, 3.15 ml (2.378 g, 13.39 mmol) of ethyldiisopropylamine and 0.044 g (o.3£4 nunol) of dimethylaminopyridine in 2 0 ml of absolute dichlorcmethane. After washing, the resin is stirred successively with a solution that consists of 3.15 ml (2.373 g, 13.3 9 mmol) of ethyldiisoprcpylamine, and 10 ml of absolute dichloromethane and with a solution that consists of 1.34 ml (1.317 g, 10.92 mmol) of pivaloyl chloride and for nine hours, at room temperature. After washing (dichloromethane (4 x 30 ml, 5 minute3), tetrahydrofuran (30 ml, 5 minutes) and dichloromethane (2 x: 30 ml, 5 minutes), the resin is successively treated with 4.0S1 g (10.87 mmol) of N-tert-butoxycarbonylnorgalanchamine and 0.222 g (1.32 mmol) of dimethyiamirvopyridine, both dissolved in 15 ml of dichloronethane, and 3,15 ml (2.378 g, 18.33 mmol) of ethyldiisopropylamine, dissolved in 15 ml of dichloromethane. After 24 hours at room temperature, the solution is filtered off, and the resin is mixed with 40 ml of a dry solution that consists of msthanol and dichloromethane, and it is stirred for ten 6Hydrcxymethyl resin, D-1150, 3achem Feinchemikalier. AG 336 minutes at room temperature. After filtering, six cycles of washing with dichloromethane and drying in a vacuum, the resin is washed and dried with 40 ml of trifluoroacetic acid/dichloromethane/anisole (25/70/5) analogously to method A. 4.145 g of a yellow resin is obtained. 0.2214 g of the resin is reacted to determine the concentration analogously to the method, and it is purified. 0.024 g of a yellowish foam, which is 90% pure according to HPLC analysis, is obtained. Yield: 0.022 g (0.069 mmol. This corresponds to a concentration of 0.31 mmol/g, 41% of the theoretical maximum concentration). HPLC: tRef = 14.4 minutes, 89.0% (Merck Purospher column, 4.0 mmx 125 mm, RP-18e, 5 jim, 285 nm, 1 ml/minute, acetonitrile/20 mmol of C13CCO2H in K20 (05/95 for 5 minutes, 05/95 -* 60/40 in 10 minutes, 60/40 for 10 minutes, v/v, pH 10) 337 Example 163/Steps 8-13 SPH-152 8 1,2 N-P-METHOSCYBENZOYL-PHENYXALAin-L-PHENYLALANINE- ( C4AS, 6R, 8AS) -6-HYDROXY-3-METHOXY-5,6,9,10-TETRAHYPRO-4AH- riiBEN2;OFURO[3A,3,2-EFi [23 BENZAZEPIKE-11 (12H) -YD -AMIDE (CK-47-1) 0.245 g (0.076 mmol) of N-tert- butoxycarbonylnorgalanthamine-6-yloxy-1, 5-dioxopentyloxymethyl-Merrifield resin is steeped twice in a 5-ml-polyethylene frit that is sealed on both sides for 15 minutes in 3 ml of dimethylformamide, and after filtering, it is suspended in a solution of 0.0S5 g (0.169 mmol) of Fmoc-phsnylalanine and 0.062 g (0.169 mmol) of 2-(lH-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 1 ml of dimethyl£ormamide each, and it is shaken for five minutes at room temperature. Then, 58 /zl (0.044 g, 0.338 mmol) of ethyldiisopropylamine in 0 .5 ml of dimethylformamide is added. The suspension is shaken at room temperature for 3 hours. The resin is washed six times with 338 dimethylformamide (1 minute, 2.5 ml) and suspended in a 2 0% piperidine solution in dimethylformamide for two and ten minutes in each case at room temperature. After six washing cycles with dimethylformamide (1 minute, 2.5 ml), the resin is reacted analogously to the first peptide coupling step with 0.065 .g (0.169 mmol) of Fmoc-phenylalanine and 0.062 g (0.169 mmol) of 2-(lH-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 1 ml of dimethylformamide in each case and 58 y.1 (0.044 g, 0.333 mmol) of ethyldiisopropylamine in 0.5 ml of dimethylformamide, washed with dimethylformamide, shaken in 20% piperidine-dimethylformamide solution and in turn washed six times with dimethylformamide (l minute, 2.5 ml). Then, solutions of 0.065 g (0.169 mmol} of Fmoc-Phe-OH in 1 ml of dimethylformamide, 0.062 g (0.169 mmol) of 2-(lH-benzotriazol-1-yl)-1,lf3,3-tetramethyluronium tetrafluoroborate in 1 ml of dimethylformamide and 53 fil (0.044 g, 0.338 mmol) of ethyldiisopropylamine in 0.5 ml of dimethylformamide are added successively, and the suspension is shaken for 3 0 minutes at room temperature. The Kaiser test indicates complete reaction. Then, it is washed analogously to the above-described procedure, suspended in piperidine-dimethylformamide solution and washed in turn with dimethylformamide. After renewed successive addition of 0.026 g (0.169 mmol) of p-methoxybenzoic acid in 1 ml of dimethylformamide, 0.062 g (0.169 mmol) of 2-{iH-benzotriazol-i-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 1 ml of dimethylformamide and 58 /il (0.044 g, 0.338 mmol) of ethyldiisopropylamine in 0.5 ml of dimethylformamide, the resin 339 is shaken overnight, since the Kaiser test was not unambiguous after 30 minutes because of a green-bluish staining. The resin is filtered, washed three times with dimethylformamide, five times with dichloromethane and with methanol and then dried in a vacuum. The resin (0.251 g) is suspended for 30 minutes in THF, filtered and suspended in a solution that consists of 0.250 g (1.39 tnmol) of 30% sodium methanolate-methanol solution and 2.5 ml of tetrahydrofuran/methanol (4/1). After eight hours, the solution is filtered off, and the resin is extracted six times with 3 ml of dichloromethane/methanol in each case. The combined filtrates are neutralized with 106 jil (0.158 g, 1.39 mmol) of trifluoroacetic acid, concentrated and separated with preparative thin-layer chromatography (silica gel, chloroform/methanol = 100/5). The product-containing silica gel fraction is extracted with chloroform/methanol (9/1), and the combined extracts are filtered repeatedly with a filter (pore diameter 0.2 /zm) , concentrated by evaporation and dried in a vacuum. Yield: 0.041 g (0.029 g, 0.041 mmol, 53%), rose-colored wax (M = 701.8). The product contains a byproduct (0.006 g, 0.008 mmol, 10%) that is a diastereomer of the main product according to LC/MS. TLC: Rf = 0.43 (chloroform/methanol = 20/1) HPLC: ta , = 2.7 minutes, 70.4% (Phenomenex Luna column, 3.0 mm x 50 mm, RP-18, 3.0 fim, 0.5 ml/minute, 285 nm, methanol/20 mmol of C13CCO2H in H2O (30/70 v/v) 340 LC/MS: tRef = 30.6 minutes, 73%, (Phenomenex Luna column 3.0 mm x 50 mm, RP-18, 3.0 ^m, 0.5 ml/minute, methanol/H20 (5/95 v/v for 2 minutes, 5/95 -* 4C v/v in 15 minutes, 40/60 v/v for 5 minutes) APCI-PI-MS 702 (56), 421 (100), 274 (6), 256 (13) APCI-NI-MS 700 tRef = 35.6 minutes, 8%, (diastereomeric byproduct) APCI-PI-MS 702 (56), 421 (100), 274 (6), 256 (13) APCI-NI-MS 700 1.3 1.4 EXAMPLES ±e3^tt7: SYNTHESIS ON ROBOTS 341 1-6 M-P-C&RBOXYIi-DIPEPTOYIi- f (4AS,6R,8AS) -6-HYDROXY-3 -METHOXY-5,6,9, 10-TETRAHYDRO-4AH- [1] BENZOFTJRO [3A, 3 , 2 -EF] [2 ] BENZAZEPINE-1K12H) -YD AMIDE (CK-59-1) In each case, 0.300 g (0.102 mmol) of norgalanthamine-6-yloxy-1,5-dioxopentyloxymethyl-Merrifield resin is introduced into polyethylene reactors with frits of a synthesis robot (Syro II MultiSynTech) and mixed with 3 ml of absolute dimethylformamide. After five minutes of standing, the suspensions are stirred at intervals for 25 minutes at 23°C. All subsequent operations are carried out at this temperature. Then, the resins are washed once with 3 ml of dimethylformamide and mixed successively with a solution that consists of 0.119 g (0.306 mmol) of Fmoc-phenylalanine or 0.117 g (0.306 mmol) of N-Fmoc-O-tert-butylserine and 1.5 ml of dimethylformamide and with a solution that consists of 0.112 g (0.306 mmol) of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate and 1 ml of dimethylformamide. Then, the resin suspensions are stirred for five minutes. Then, 105 \L\ (0.079 g, 0.612 mmol) of ethyldiisopropylamine in 0.5 ml of dimethylformamide is added. The suspensions are stirred for 3 hours, suctioned off for two 342 minutes and in each case mixed with a solution that consists of 241 fil (0.260 g, 2.550 mmol) of acetic anhydride, 437 fil (0.330 g, 2.550 mmol) of ethyldiiospropylamine and 3 ml of dimethylformamide. After 15 minutes of stirring and two minutes of filtering, the resins are washed six times with dimethylformamide (3 ml, 2 minutes), and suspended or stirred in a 20% piperidine solution in dimethylformamide for six and 15 minutes in each case. After six cycles of washing with dimethylformamide (2 minutes, 3 ml), the resins are reacted analogously to the first peptide coupling step with Fmoc-phenylalanine or N-Fmoc-0-tert-butylserine/ the unreacted arnine groups are masked with acetic anhydride, and the Fmoc-protective group is cleaved off with 20% piperidine-dimethylformide solution. It is then washed analogously to the above-described procedure, mixed with a solution that consists of 0.047 g (0.306 mmol) of p-methoxybenzoic acid or 0.038 g (0.306 mmol) of isonicotinic acid in 2.5 ml of dimethylformamide and stirred for five minutes. Then, in each case, solutions of 48 (j.1 (0.039 g, 0.306 mmol) of diisopropylcarbodiimide 241 fil and 0.5 ml of 1,2-dichloroethane are added. It is stirred for three hours. The resins are filtered (2 minutes), washed three times with dimethylformamide (2 minutes, 3 ml), six times with dichloromethane (2 minutes, 3 ml), dried for ten minutes at 40°C, suctioned off and then dried in a vacuum on phosphorus pentoxide. The Kaiser test is negative in all resins (0.250 to 0.377 g) . The resins that contain O-tert-butyl-protected serine radicals are mixed successively with 1 ml of dichloromethane, 343 0.125 ml of phenol, 0.125 ml of anisole and 3.75 ml of trifluoroacetic acid, and it is stirred for three hours at room temperature. Then, the solutions are filtered off, and the resins are washed three times with dichloromethane (2 minutes, 3 ml), three times with dichloromethane/ethyldiisopropylamine (95/5, 2 minutes, 3 ml), three times with dichloromethane (2 minutes, 3 ml) in each case, and three times with tetrahydrofuran (2 minutes, 3 ml) and dried under reduced pressure. The resins are transferred to 5-ml polyethylene frits that are sealed on both sides, suspended for 3 0 minutes in THF, filtered and suspended in a solution that consists of 0.092 g (0.028 g, 0.510 mmol) of 30% sodium methanolate-methanol solution and 3 ml of tetrahydrofuran/methanol (4/1). After six hours, the solution is filtered off, and the resin is extracted five times with 3 ml of tetrahydrofuran/methanol (4/1) in each case. The combined filtrates are neutralized with Dowex 50W (one spatula tip full) and NaHCO3 (one spatula tip full) . The suspensions are filtered on some Celite, and the filter Celite is flushed twice with 5 ml of dichloromethane. The filtrates are concentrated and purified with preparative thin-layer chromatography (mobile solvent: chloroform/methanol = (10/1) for CK-49-1-IPP-3, CK-59-MPP-1, CK-59-IPP-2, CK-5 9-ACPP-3, chloroform/methanol = (4/1) for CK-59-IPP-4 and chloroform/methanol = (6/1) for CK-59-MPP-5). The produce-containing silica gel fractions are extracted with chloroform/methanol (9/1) and filtered. The extracts that are concentrated by evaporation are filtered repeatedly with a filter 344 (pore diameter 0.2 ptm) , further concentrated by evaporation and dried in a vacuum. HPLC: Phenomenex Synergi Polar-RP-column, 4.6 mm x 150 mm, 4.0 jim, 1.0 ml/minute, methanol/2 0 mm of C13CCO2H in H2O (20/80 for 5 minutes, 20/80 -» 80/20 in 20 minutes, 80/20 for 10 minutes, v/v) LC/MS Phenomenex Luna column, 3.0 mm x 50 mm, RP-18, 3.0 /im, 0.8 ml/minute, methanol/H20 (10/90 for 2 minutes, 10/90 -> 100/0 in 15 minutes, 100/0 for 5 minutes, v/v) Result 345 [Key to Table:] Beispiel = Example SPH-Nummer = SPH Number Aminosaure 1 und 2 = Amino acid 1 and 2 Carboxylrest 3 = Carboxyl radical 3 Rf-Wert = Rf value Yields 346 347 348 [Key to Table:] Beispiel = Example HPLC (tRef, Reinheit) = HPLC (tRef, purity) Ausbeute und Bemerkung = Yield and Remarks racemisiertes Product = Racemized product Example *€-?i> l£>° ^ ^ / SPH-1543 r As a by-product, N-acetyl-phenylalanine-((4aS,6R,8aS)-6-hydroxy-S-methoxy-B^.g,10-tetrahydro-4aH- [1]benzo-furo- [3a,3,2-ef] - [2]benzazepine-n (12H) -yl) amide was obtained: 349 [Key to Table:] EPLC (tRef, Reinheit) = HPLC (tRef, purity) LC/MS und Rf-Wert = LC/MS and Rf value Ausbeute und Bemerkung = Yield and remarks racemisiertes Produkt = Racemized product 350 Example Att- \& { SPH-1371 (4aa,6b,8aR*) -4a, 5, 9,10,11,12-Hexahydro-3-methoxy-ll- [3- (1- piperidinyl)propyl]-6H-benaofuro[3a, 3,2-ef3 [2]benzazepin-6-ol, Dihydrobromide, Dihydrate Production from the free base by treatment with Hbr/EtOH [a]D20 = -92.5° (c 0.24, H2O) General Instructions -- "Thiophene Derivatives" (Examples 3rM- 1.1 equivalents of norgalanthamine and 1 equivalent of the corresponding thienyl-halide were heated to reflux temperature together with 3 equivalents of fine-powder, anhydrous KJCOJ in dry acetonitrile (10% by weight of solution) for 24 hours. Complete conversion was examined by means of TLC. After the solution was cooled/ it was filtered, and the KJCOJ residue was washed several times with dry acetonitrile while being monitored by TLC. The crude product that was obtained after concentration by evaporation was purified by means of flash chromatography. 351 Example 121 \£>1— SPH-1490 6,7-Dihydro-5~(4-((4aS,6R,8aS)-6-hydroxy-3-methoxy~4a,5,9,10-tetrahydro-6H-benzofuro[3a,3,2-ef] [2]benzazepine-11 (12H) -yl)-butyl)-benzo[b]thiophene-4(5H)-one C28H33NO4S (479.64) Norgalantharaine: 500 mg (1.83 tnmol) 5 (4-bromobutyl)-6,7-dihydro- benzo [b] thiophene-4 (5H)-one: 479 trig (1.67 ramol) K2CO3: 693 mg (5.01 mtnol) about 4 ml of acetonitrile Crude product: 450 mg Flash chromatography: Ethyl acetate : triethylamine = 100:2 Yield: 44 0 mg (50%) of a light yellow powder 352 1H (400 MHz, CDCI3) : 6 7.34 (d, J = 5.26, 1H), 7.04 (d, J = 5.26, 1H), 6.66 (d, J = 8.18, 1H), 6.62 (d, J = 8.18, 1H) , 6.09 (m, 2H), 4.61 (m, 1H) , 4.25-4.07 (m, 2H) , 3.92-3.84 (m, 1H) , 3.84-3.79 (m, 1H) , 3.80. (s, 3H) , 3.4 6-3.56 (m, 1H) , 3.3 0-3.18 (m, 1H) , 3.13-3 .03 (m, 1H) , 3.02-2.91 (m, 1H), 2.73-2.65(m, 1H), 2.64-2.47 (m, 2H), 2.45-2.36 (m, 1H), 2.32-2.23 (m, 1H), 2.11-1.83 (m, 4H), 1.63-1.09 (m, 6H) 13C (100 MHz, CDC13) : 5*95.2 (s) , 154.8 (2*s) , 145.8 (s) , 144.4 (s) , 136.8 (s) , 132.9 (s) , 127.9 (d), 12 6.4 (d) , 125.1 (d) , 123.2 (d) , 122.4 (d) , 111.3 (d) , 88.6 (d) , 61.9 (d) , 58.1 (t) , 55.9 (q) , 51.4 (t) , 51.3 (t), 48.2 (S), 46.2 (d), 29.9 (t), 29.5 (t), 28.9 (t), 28.8 (t), 28.5 (t), 24.8 (t), 24.2 (t) Example 3#2* ^3 SPH-1491 6,7-Dihydro-5-(5-((4aS,6R,8aS)-6-hydroxy-3-methoxy-4a,5,9,10-tetrahydro-6H-benzofuro[3a,3,2-ef] [2] benzazepine-11(12H)-yl)-pentyl)-benzo[b]thiophen-4(5H)-one C2gH35WO4S (493.67) 353 Norgalanthamine: 200 mg (0.73 tnmol) 5-(5-bromopentyl)-6,7-dihydro-benzo[b]- thiophen-4(5H)-one: 201 mg (0.67 mmol) K2CO3: 277 mg (2.00 mmol) about 4 ml of acetonitrile Crude product: 43 0 mg Flash chromatography: ethyl acetate : triethylamine = 100:2 Yield: 240 mg (66.3%) of a light yellow powder ^ NMR (400 MHz, CDCl3) : a 7.35 (d, J = 5.2 Hz, 1H), 7.03 (d, J= 5.2 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H) , 6.61 (d, J = 8.1 Hz, 1H) , 6.05 (d, J = 10.2 Hz, IK), 5.99 (dd, J = 10.2, 4.6 Hz, 1H), 4.60 {m, 1H), 3.83 (d, J = 15.2, 1H), 4.14-4.10 (m, 1H), 3.83 (d, J = 15.2 Hz, IK), 3.81 (s, 3H), 3.41-3.31 (m, 1H), 3.22-3.14 (m, 1H), 3.07 (dt, J= 17.2, 5.2 Hz, 1H), 2.96 (ddd, J = 17.2, 9.1, 4.7 Hz, 1H), 2.70-2.62 (m, 1H) , 2.56-2.34 (m, 4H) , 2.26 (m, 1H) , 2.10-1.8 (m, 4K) , 1.61-1.21 (m, 8H) 15C NMR: (100 MHZ, CDC13) : 5 195.7 (s) , 155.1 (2*s) , 146.2 (s), 144.5 (s), 137.3 (s), 133 .5 (s) , 128.0 (d) , 12 7.3 (d) , 125.5 (d) , 123.6 (d) , 122.5 (d) , 111.5 (d) , 89.1 (d) , 62.5 (d) , 58.1 (t) , 56.3 (q) , 51.3 (t), 48.8 (s) , 46.7 (d) , 33.2 (t) , 30.3 (t) , 30.0 (t) , 29.9 (t), 29.4 (t), 27.8 (t), 27.6 (t), 27.5 (t), 24.6 (t) 354 General Instructions -- "Azacycloalkyl Derivatives" (Examples 173-17 6) One equivalent of norgalanthamine and 3 equivalents of the corresponding aminoalkyl halide was heated to reflux temperature together with 3 equivalents of fine-powder, dry KjCO^ in dry acetonitrile (about 10% by weight of solution) for 24 hours. Complete conversion was controlled by means of TLC. After the solvent was distilled off, the remaining residue was dissolved in 2N HC1. After two extraction cycles with diethyl 'ether, it was made alkaline with 10% NaOH solution and extracted exhaustively with chloroform. After drying on Na2SO4, it was concentrated by evaporation and purified by means of flash chromatography (CHCl3 : MeOH : NH3 = 10 : 1 : 0.5). The indicated yields of the reactions relate to 500 mg (1.83 mmol) of norgalanthamine as a starting product and were determined according to flash chromatography. 355 Example 3sTS~ I £>£}> SPH-1492 (4aS,6R,8aS)-3-Methoxy-ll-(6-piperidin-l-yl-hexyl)-5,6,9,10,11,12-hexahydro-4aH-[1] benzofuro[3a,3,2-ef][2]benzazepin-6-ol C27H40N2O3 (440.63) Yield: 161 mg (20%) of a yellowish oil 1H (400 MHz, CDC13) : 6 6.6€ (d, J = 8.0 Hz, 1H), 6.62 (d, J= 8.0 Hz, 1H), 6.10 (d, J = 10.0 Hz, 1H), 6.01 (dd, J = 10.0, 5.4 Hz, 1H), 4.62 (m, 1H) , 4.14 (m, 1H) , 4.13 (d, J = 15.6, 1H) , 3.84 (s, 3H) , 3.81 (d, J = 15.6, 1H), 3.4-3.3 (m, 1H), 3.2-3.15 (m, 1H), 2.69 (ddt, J = 15.7, 3.4, 1.6 Hz, 1H), 2.55-2.25 (m, 8H) , 2.10-2.0 (m, 1H), 2.01 (ddd, J = 12.9, 5.0, 2.6 Hz, 1H), 1.65-1.2 (m, 16H) 13C (100 MHz, CDC13) : 6 146.2 (s) , 144.4 (s), 133.6 (e) , 12 9.9 (s) , 127.9 (d) , 127-.4 (d) , 122.4 (d) , 111.5 (d) , 89.1 (d) , 62.5 (d) , 59.9 (t) , 356 58.1 (t) , 56.3 (q), 54.9 (4*t), 51.9 (t) , 48.8 (s) , 33.3 (t) , 30.3 (t), 28.0 (t), 27.9 (t), 27.8 (t), 27.1 (t), 26.2 (t), 24.8 (t) Example i*4 I t>P • SPH-1493 (4aS,6R,8aS)-3-Methoxy-ll-(6-(4-methylpiperazine)-1-yl-hexyl)-5,6,9,10/11,12-hexahydro-4aH-[1]benzofuro [3a,3,2-ef][2]benzazepin-6-ol C27H41N3O3 (455.65) Yield: 208 mg (25%) of a yellowish oil ]K (400 MHz, CDC13) : 5 6.66 (d, J = 8.18, 1H), 6.61 (d, J = 8.18, 1H), 6.09 (d, J = 10.23, 1H), 6.0 (dd, J = 9.94, 4.97, 1H), 4.61 (m, 1H), 4.20-4.08 (m, 2H) , 3.84 (s, 3H) , 3.80 (d, J = 15.8, 1H) , 3.40-3.30 (m. 357 1H) , 3.23-3.10 (m, 1H) , 2.73-2.63 (m, 1H) , 2.63-2.30 (m, 12H) , 2.29 (s, 3H), 2.10-1.94 (m, 2H), 1.57-1.17 (m, 10H) 13C (100 MHz, CDC13) : 5 146.2 (s), 144.4 (s), 133.6 (s), 129.9 (s), 127.9 (d), 12 7.4 (d) , 122.4 (d) , 111.5 (d) , 8 9.1 (d) , 62.5 (d) , 5 9.1 (t) , 58.2 (t), 56.3 (q) , 55.5 (2*t), 53.6 (3*t), 51.9 (t), 48.8 (s), 46.5 (q), 33.3 (t), 30.4 (t) , 27.98 (t), 27.83 (t), 27.74 (t), 27.23 (t) Example V« I *>(* SPH-1494 (4aS,6R,8aS)-3-Methoxy-ll-(6-[4-hydroxypiperidine)-1-yl-hexyl)-5,6,9,10,11,12-hexahydro-4aH-[l]benzofuro[3a, 3 ,2-ef] [2]benzazepin-6-ol C27H60H2O4 (456.63) Yield: 200 mg (24%) of a yellowish oil 1H (400 MHz, CDC13) : 6 6.64 (d, J = 8.1 Hz, 1H) , 6.59 (d, J = 8.1 Hz, 1H), 6.07 (d, J = 10.2 Hz, 1H), 5.97 (dd, J = 10.2, 4.9 Hz, 1H), 4.58 (m, 1H), 4.11 (m, 1H), 4.07 (m, 1H), 3.81 (s+m, 4H), 3.71-3.61 (m, 1H) , 3.35 (m, 1H) , 3.15 (m, 1H) , 2.81-2.71 (m, 2H) , 2.67 (d, J = 15.4, 1H), 2.52-2.36 (m, 4H), 2.34-2.26 (m, 2H), 2.20-2.08 (m, 2H) , 2.06-1.94 (m, 2H) , 1.93-1.84 (m, 2H) , 1.63-1.53 (m, 2H) , 1.52-1.38 (m, 5H), 1.32-1.20 (m, 4H) 13C (100 MHz, CDC13) : 6 146.2 (s) , 144.5 (s) , 133.6 (s) , 129.9 SPH-1521 [/ 1- (6-((4aS,6R,8aS)-6-Hydroxy-3-methoxy-4a,5,9,10-tetrahydro-6H-benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)-hexyl)-piperidin-4-one C27H3«NzO4 (454-61) 359 Yield: 125 mg (15%) of a yellowish oil 1H (400 MHz, CDC13) : 6 6.65 (d, J = 8.18 Hz, 1H), 6.60 5 209.7 (s), 146.2 (s), 144.5 (s), 13 3.5 (s), 12 9.7 (s), 128.1 (d), 127.4 (d), 122.4 (d), 111.5 (d), 89.0 (d), 62.4 (d), 58.1 (2*t) , 57.9 (2*t), 56.4 (g) , 56.3 (t) , 53.4 (t) , 52.2 (t), 51.9 (t), 48.8 (s), 41.5 (t), 33.4 (t), 30.4 (t), 27.9 (t), 27.8 (t), 27.7 (t) Example KHJ- ' fcS SPH-1363 (4aS,6R,8aS)-6-hydroxy-3-roethoxy-5,6,9,10-tetrahydro-4aH-[l]benzofuro[3a,3,2-ef] [2]benzazepine-ll(12H)-yl) methyl -azodicarboxylic acid-di-tort-butyl ester (CK-24-2) 360 A solution that consists of 0.300 g (0.104 mmol) of galanthamine in 3 ml of dichloromethane is introduced at room temperature, mixed with 0.264 g (1.150 mmol) of di-tert-butylazodicarboxylate and stirred for four days at room temperature. After concentration by evaporation in a rotary evaporator, the residue (0.258 g) is purified by means of flash chromatography on silica gel (25 g, mobile solvent dichloromethane/petroleum ether = 2/3 + 4% triethylamine). After drying under high vacuum, 0.2 92 g of a white foam is obtained. Yield: 0.292 g (0.56 mmol, 54%), colorless foam, (Mw = 517.6) TLC: Rf = 0.71 (dichloromethane/methanol = 9/l + 2% concentrated NH- solution) Melting point: 59-62°C (petroleum ether/dichloromethane = 1/1 + 4% triethylamine) IR: KBr V {cm'1) 3557 (v) , 3340 (bra), 2932 (s) , 2915 (s) , 172S (s), 1711 (s) 1H-NMR: (200.13 MHz, CDC13, TMS) 6 6.49-6.66 (m, 2H), 6.39 (s, 0.6 H), 5.84-6.06 (m, 2K), 4.52 (s, 1H), 4.35 (bs, 1H), 3.99-4.17 (m, 2K) , 3.71-3.88 (m, 1H) , 3.76 (s, 3K) , 3.07-3.40 (m, 2H), 2.61 (bd, J = 15.7 Hz, IK), 2.40 (bd, J = 11.8 Hz, 0.3H), 1.79-2.05 (m, 2H), 1.5S-1.72 (m, 1H), 1.46 (s, 9H), 1.45 (s, 9H) 13C NMR: (50.32 MHz, CDC13, TMS) 361 6 156.7 (s), 155.9 (s), 145.9 (s), 144.0 (s), 132.8 (d) , 129.8 (3), 127.6 (d) , 126.7 (d) , 121.5 (d) , 111.1 (d) , 88.5 (d) , 68.9 (t) , 62.4 (t) , 61.8 (t) 61.8 (d), 56.6 (t), 55.8 (q), 49.7 (t), 48.1 (s), 35.2 (t) , 29.8 (t) , 14.32 (q) , 14.26 (q) LC/MS: tRef = 9.56 minutes, (Zorbax SB column, 2.1 mm x 30 mm, RP-18, 3 (im, 0.5 ml/minute, methanol/H20 {40/60 -» 100/0 (v/v) in 2 minutes) APCI-PI-MS 518 (100), 500 (25), 462 (9), 285 (13), 274 (11), 256 (26) APCI NI-MS 516 Example i&± I G>J p/ SPH-1362 (4aS,6R, 8aS) -S-Hydroxy-S-inethoxy-S, 6,9,10-tetrahydro-4aH- [llbenzofuro [3a,3,2-ef] [2]benzazepine-ll (12H) -yl)methyl- azodicarboxylic acid diethyl ester (CK-21-3) 362 89 fil (0.100 g, 0.57 mmol) of diethylasodicarboxylate is added to a solution that consists of 0.150 g (0.52 mmol) of galanthamine in 2 ml of dichloromethane, and the solution is stirred for 72 hours at room temperature. After concentration by evaporation in a rotary evaporator, the residue (0.258 g) is purified by means of -flash chromatography on silica gel (25 g, mobile solvent dichloromethane/petroleum ether = l/l + 4% triethylamine). After drying under high vacuum, 0.168 g of a white foam is obtained. Yield: 0.168 g (0.36 mmol, 70%), white foam, (Mw = 461.6) TLC: Rf = 0.66 (dichloromethane/methanol = 9/1 + 2% concentrated NH3 solution) Melting point: 40-42°C (petroleum ether/dichloromethane = l/l + 4% triethylamine) IR: KBr v (cm"1) 3553 (v) , 3305 (m) , 2981 (s), 2935 (s) , 1742 (s), 1722 (s) 1H-NMR (200.13 MHz, CDCl3, TMS) 6 6.77 (bs, 1H) , 6.64 (d, J = 8.3 Ez, 1H) , 6.58 (d, J = 8.1 Hz, 1H) , 5.84-6.06 (m, 2H) , 4.53 (s, 1H) , 3.98-4.23 (m, 6H), 3.69-3.87 (m, 1H), 3.76 (s, 3H), 3.01-3.42 (m, 2H), 2.66 (bd, J = 15.7 Hz, 1H), 2.33 (bs, 0.2H), 1.65-1.77 (m, 2H), 1.35-1.47 (m, 1H), 1.09-1.35 (m, 6H) 13C-NKR: (50.32 MHz, CDC13, TMS) 5 155.1 (s), 145.9 (s), 143.9 (s), 132.8 (d), 130.2 (s), 127.5 (d), 126.9 (d), 121.4 (d), 111.1 (d), 363 81.2 (s) , 80.9 (s) , 69.5 (t) , 61.9 (d) , 56.8 (t), 55.8 (q) , 49.8 (t), 48.1 (s), 35.6 (t), 29.8 (t), 28.1 (1), 28.0 LC/MS: tRef = 8.0 8 minutes, (Zorbax SB column, 2.1 mm x 3 0 mm, RP-18, 3 /an, 0.5 ml/minute, methanol/K20 (40/60 -* 100/0 (v/v) in 2 minutes) APCI-PI-MS 462 (100), 444 (32), 286 (34), 274 (12), 256 (29) APCI-NI-MS 460 Process for Synthesis of Norgalanthamine Method A 20 g (70 mmol) of galanthamine is reacted with 14.206 g (0.07 mol) of m-chloroperbenzoic acid (85%) in 350 ml of dichloromethane and subsequent addition of 9.730 g (35 mmol) of Fe (II) SO4*7 H20 in 100 ml of methanol. The reaction is terminated after 2 0 minutes with 200 ml of 2N hydrochloric acid. After the slightly volatile solvent is distilled off, after the acids and bases are separated and after the I e(OH)x precipitate is 364 filtered off by means of a Hyflo nutsch, the filtrate is dried on Na2SO4, filtered and concentrated by evaporation. About 18 g of the crude product is obtained in the form of a yellow foam. Working-up Variant 1 (CK-1-1) The crude product (18.46 g) is taken up in about 200 ml of ethyl acetate/methanol/triethylamine (90/10/2) while being heated slightly. During cooling, I e(0H)x is again precipitated, which is filtered off. The purification is carried out by means of MPLC chromatography (silica gel, h = 25 cm, d = 3.6 cm, v = 300 nm) with an altered mobile solvent mixture {ethyl acetate/methanol/triethylamine = 95/5/2 -» 90/10/2 -* 80/20/2) . The norgalanthamine content is only 68% according to an HPLC quantification (caffeine as an internal standard). Yield: 10.34 g (38 mmol, 54%), yellowish, amorphous solid (Mw = 273.3) Working-up Variant 2 (CK-l-11) The crude product (16.48 g) is dissolved in 100 ml of methanol, mixed with a solution that consists of 12.86 g (102 mmol) of oxalic acid dihydrate in 100 ml of methanol and carefully heated to homogenize the solution. Then, the solution is allowed to cool to room temperature and then to cool to about 5°C, the crystallized product is filtered off, and the precipitate is washed with methanol. The combined methanol solutions that are concentrated by evaporation are again, subjected to recrystallization. 365 Yield: 16.108 g (43 mmol, 62%}, colorless crystalline solid Cld. for C16H19NO3 . C2H2O4 . 0 .5 H.,0 C, 58.06 H, 5.95 N, 3.76 Fnd. C, 57.91 H, 5.88 N, 3.69 Method B (CK-1-10) 2.000 g (6.96 mmol) of galanthamine and 0.981 g (10.44 mmol) of hydrogen peroxide-urea-adduct are stirred for two days in 25 ml of dichloromethane and 5 ml of methanol at room temperature, then mixed with 0.03 0 g of platinum/activated carbon and stirred for one; hour at room temperature. When the catalyst is added, a strong gas development can be observed. Then, 0.967 g (3.48 mmol} of Fe(II}SO4*7 H2O in 5 ml of MeOH is added, and the brown suspension is vigorously stirred. The reaction is terminated after 2 0 minutes with 5 0 ml of saturated NaHCO3 solution. The reaction solution is filtered by means of a Hyflo filter aid. The phases are separated, and the aqueous phase is extracted exhaustively with dichloromethane. The combined organic extracts are washed with saturated NaHCO3 solution (50 ml) and with saturated NaCi solution (50 ml) , dried on Na2SO4/ filtered and concentrated by evaporation. The crude product (1.325 g) is dissolved in 10 ml of methanol, mixed with a solution that consists of 1.332 g (10.6 mmol) of oxalic acid dihydrate in 10 ml of methanol and carefully heated to homogenize the solution. Then, the solution is allowed to cool to room temperature and then to about 5°C/ the crystallized product is filtered off, and the precipitate is washed with methanol. The combined methanol 366 solutions that are "concentrated by evaporation are again subjected to recrystallization. Yield: 1.010 g (2.7 mmol, 39%), colorless crystalline solid (MH = 371.4), according to HPLC 97% Method C: Demethylation of Norgalanthamine By Means of Diethylazodicarboxylate (CK-1-7) 178 fil (0.199 g, 1.144 mmol) of diethylazodicarboxylate is added to a solution that consists of 0.300 g (1.04 mmol) of galanthamine in 3 ml of dichloromethane, and the solution is stirred for three days at room temperature. After concentration by evaporation in a rotary evaporator at 40°C, the residue is dissolved in 5 ml of ethanol and 5 ml of 4N hydrochloric acid and stirred at 80°C for one and one-half hours. The reaction is cooled to room temperature, and the solution is diluted with 5 ml of water. The ethanol portion is distilled off in a rotary evaporator, and the aqueous phase is extracted three times with 10 ml of diethyl ether in each case. The aqueous phase is set at pH 10-11 by adding sodium carbonate and sodium hydroxide, and it is extracted four times with 20 ml of dichloromethane in each case. The combined phases are washed with 40 ml of saturated common salt solution and dried on Na2SO4. After filtering and concentration by evaporation, the residue (0.268 g) is purified by means of MPLC on silica gel (60 g, mobile solvent ethyl acetate/ethanol/triethylamine = 19/1/0.4). After drying under high vacuum, 0.13 6 g of a yellowish foam is obtained. Yield: 0.136 g (0.495 mmol, 48%), white-yellowish foam, (MH = 273.3), HPLC identical to a reference sample EPLC: tRef = 3.79 minutes, 96.3% {Merck Purospher column, 4.0 mm x 125 mm, RP-lSe, 5 fim, 250 nm, 1 ml/minute, acetonitriie/20 mmol of trichloroacetic acid in H2O {15/80 v/v) Method D: Demetnylation of Norgalanthamine by Means of Di-tert- butylazodicarboxylate (CK-1-6) 0.300 g {1.04 mmol) of galanthamine and 0.264 g (1.144 mmol) of di~tert-butylazodicarboxylate in 3 ml of dichloromethane are reacted analogously to the above-described procedure for three days at room temperature, concentrated by evaporation and stirred in 5 ml of ethanol and 5 ml of 4N hydrochloric acid for 3 0 minutes at 8 0°C. The reaction is cooled to room temperature, and the solution is diluted with 5 ml of water. After the aqueous working-up, the residue {0.259 g) is purified by means of MPLC on silica gel {60 g, mobile solvent ethyl acetate/ethanol/triethylamine = 19/1/0.4). After drying under high vacuum, 0.132 g of a white-yellowish foam is obtained. Yield: 0.132 g (0.48 mmol, 46%), white-yellowish foam, (MH = 273.3), HPLC identical to a reference sample HPLC: tRftf = 3.74 minutes, 100% (Merck Purospher column, 4.0 mm x 125 mm, RP-l3e, 5 /im, 250 nm, 1 ml/minute, acetonitrile/20 mmol of trichloroacetic acid in H2O (15/80 v/v) 368 Method E: Saponification of (4aS,6R,8aS)-3-Methoxy-12-trifluoroacetyl- 5,6; 9,10,ll,12-hexahydro-4aH-[1]benzofuro[3a,3,2- ef][2]benzazepin-6-ol Method A (CK-40-2) 3,3 ml of a 0.25 M potassium hydroxide solution (0.045 g (0,81 mmol) in dioxane/methanol/water (10/2/5) is mixed with 0.100 g (0.27 mmol) of N-trifluoroacetylnorgalanthamine and stirred for one hour at room temperature. Then, the solution is diluted with 0.4 ml of 2N hydrochloric acid, and the volatile components are distilled off in a rotary evaporator. The residue is taken up with saturated sodium carbonate solution and extracted five times with dichloromethane. The combined extracts are washed with saturated sodium chloride solution, dried oh sodium sulfate, filtered and concentrated by evaporation in a rotary evaporator under reduced pressure. 0.070 g of a white-yellowish foam with a purity of 95% (HPLC, caffeine as an internal standard) is obtained. Yield: 0.070 g (0.067, 0.25 mmol, 91%), white-yellowish foam (MH = 2 73.3) Method B (CK-40-3) A solution that consists of 0.100 (0.27 mmol) of N-trifluoroacetylnorgalanthamine and 0.243 g (1.35 mmol) of 30% sodium methanolate-methanol solution in 3 ml of tetrahydrofuran/methanol (l/l) is stirred for three hours at room 369 temperature. The solution is neutralized with 0.7 ml of 2N hydrochloric acid, and the solution is evaporated to the dry state, the residue is taken up with 25 ml of dichloromethane and washed with saturated sodium carbonate solution and with saturated sodium chloride solution, dried on sodium sulfate, filtered and concentrated by evaporation in a rotary evaporator under reduced pressure. After drying in a vacuum, a yellowish foam (0.067 g) with a purity of 76% {HPLC, caffeine as an internal standard) is obtained. Yield: 0.067 g (0.051 g, 0.19 mmol, 69%), white-yellowish 'foam (MH = 2 73.3) Method G: Separation of ( + ) and {-) Isoiaers from rac.Norgalanthamine (4) Production of (-J Norgalanthamine (8) A solution of 7.72 g (20.0 mmol) of (+)-O,O-di-p-toluoyltartaric acid in 15 ml of methanol is added in drops to a solution of 10.92 g (40.0 mmol) of rac.norgalanthamine (4) in 40 ml of methanol and then rewashed with 1 ml of methanol. The solution is mixed with a seed crystal and allowed to stand for two days at 4°C. Then, a glass rod is passed vigorously through the solution, and it is allowed to stand for another two to five days at 4°C, whereby a glass rod is always passed vigorously through the solution again. Then, the precipitated salt is auctioned off, rev/ashed three times with ice-cold methanol and taken up in 100 ml of water. The aqueous phase is made iasic with concentrated aqueous ammonia and extracted three times with 370 .60 ml of ethyl acetate each. The combined organic phases are washed once with saturated aqueous sodium chloride solution, dried (Na2SO4, activated carbon), filtered and concentrated by evaporation, by which 2.90 g (37.5% of theory) of colorless crystals with an angle of rotation of aD22 [CHC13] = -62.4 of (-) norgalanthamine (8) is obtained. The methanolic mother liquor is concentrated by evaporation, the residue is taken up in 100 ml of water and treated like the pure salt above, by which 4.1 g (53.1% of theory) of crude product can be recovered, which is used as follows for recovering (+) norgalanthamine. Production of (+) Norgalanthamine A solution of 2.9 g (7.5 mmol) of {-)-O,O-di-p- toluoyltartaric acid in 5.6 ml of methanol is added in drops to a solution of 4.1 g (15.0 mmol) of recovered norgalanthamine (this is concentrated in (+) isomers) in 21 ml of methanol, whereby it is rewashed with 0.5 ml of ethanol. The solution is mixed with a seed crystal and treated as in the recovery of {-) norgalanthamine, by which 3.0 g (39% of theory) of colorless crystals is obtained with an angle of rotation of c*D22 [CHC13] = +57.5° (+) norgalanthamine. As an alternative, (+) norgalanthamine is also obtained by reaction of rac.norgalanthamine (4) with (-)-0,O-di-p-toluoyltartaric acid analogously to the above instructions with an angle of rotation of o>D2Z [CHC13] = +6 0.5°. 371 Example iftfi 1^0 SPH-1534 (4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro~4aH-[l]benzofuro]3a,3,2-ef] [2]benzazepine-ll(12H) -yl) carboxylic acid triisopropyl silyl ester (CK-9-2) 0.200 g (0.732 mmol) of norgalanthamine (68% (HPLC, CK-1-1)) and 0.47 ml (0.341 g, 3.37 mmol) of triethylamine are introduced at -80°C in 6 ml of dichloromethane in a single-neck flask with a septum and a C02 tank, which is filled by evacuation and flushing with carbon dioxide. Then, the solution is cooled to the point that solid carbon dioxide precipitates in the reaction solution. After one and one-half hours at about -80 to -90°C, triisopropyl silyl chloride (0.155 ml, 0.141 g, 0.732 mmol) is added via a syringe. Then, the reaction solution is slowly heated overnight to room temperature. In this case, a colorless precipitate settles out. The reaction solution is taken up with 10 ml of IK hydrochloric acid, the phases are separated, and the aqueous phase is extracted twice with 10 ml of dichloromethane. The 372 combined organic phases are washed with 10 ml of IN hydrochloric acid and with 10 ml of saturated common salt solution, dried on Na2SO4, filtered'and concentrated by evaporation. The yellow viscous; oil (0.315 g) is purified by means of column chromatography on silica gel with the mobile solvent petroleum ether/ethyl acetate. After concentration by evaporation, 0.208 g of the product is obtained in the form of a colorless foam. Yield: 0.208 g (0.44 mmol, 60%), colorless foam, (Mu = 473.7) TLC: Rf = 0.35 (petroleum ether/ethyl acetate = 1/1) Melting point: 53-54°C (petroleum ether/ethyl acetate = 1/D IR: KBr v (cm"1) 3556 (m) , 3454 (m) , 2946 (s) , 1679 (sj 1K-NMR (200.13 MHz, CDCl3, TMS) 5 6.60-6.85 (m, 2H), 5.93-6.09 (m, 2K}, 4.90 (d, J = 15.3 Hz, 0.4H), 4.80 (d, J = 15.7 Hz, 0.6H), 4.57 (s, 1H), 4.06-4.40 (m, 3H), 3.83 (s, 3H), 3.27- 3.57 (m, 0.4K), 2.70 (bd, J = 16.3 Hz, 1H), 2.41 (bd, J = 11.0 Hz, 0.6H), 1.60-2.11 (m, 3H), 1.29 (bh, J = 5.1 Hz, 3H), 1.05 (d, J = 6.8 Hz, 8H), 0.98 Id, J = 6.9 Hz, 10H) 13C-NMR: (50.32 MHz, CDCl3, TMS) 6 154.4 and 153.9 (s), 146.5 and 146.2 (s), 144.3 and 144.1 (s), 132.2 and 131.8 (d) , 129.4 and 129.2 (s) , 127.9 (d) , 126.5 (d) , 121.6 and 120.9 (d) , 111.1 and 110.9 (d), 88.2 (d), 61.8 (d), 55.8 and 373 55.7 (q), 52.5 and 51.7 (t), 48.3 (s), 46.4 and 45". 8 (t) , 37.3 and 36.1 (t) , 29.7 ft) , 17.77 17.75, 17.68 and 17.65 (g), 11.9 (d) Example A93 \ I SPH-1535 (4aS,6R/8aS)-6-Hydroxy-3-methoxy-5,6,$,10-tetrahydro-4aH-[l]benzofuro £3a,3,2-e£] [2]benaazepine-ll{12H)-yl)carboxylic acid-tert-butyldiphenylsilyl ester Analogously to the instructions for the N-triisopropylsilyloxycarbonylnorgalanthamine (TBDP-C1), norgalanthamine (68% (HPLC, CK-1-1)) is reacted with 1 or 1.1 equivalents of tert-butyldiphenylsilyl chloride and 5 equivalents of triethylamine. Then, the reaction is terminated with water or dilute hydrochloric acid, the phases are separated, and the ¦aqueous phase is extracted with dichloromethane. After drying :with Na2SO4, filtering and concentration by evaporation, the .amorphous foam is purified by means of column chromatography 374 (silica gel, ethyl acetate/petroleum ether = l/i) . A colorless foam is obtained. TLC: Rf = 0.40 (petroleum ether/ethyl acetate = l/l) Melting point: 71-80°C (petroleum ether/ethyl acetate = l/l) IR: KBr v (cm-1) 3553 5 7.20-7.68 (m, 10H) , 6.56-6.77 (m, 2H) , 4.83-5.03 (m, 1H), 5.03 (s, 1H), 4.02-4.40 (m, 3H), 3.83 (s, 3H) , 3.63 (bt, J = 13.1 Hz, 0.3H), 3.41 (bf, J = 12.9 Hz, 0.7E), 2.70 (bt, J = 15.6 Hz, 1H), 2.41 (bd, J = 19.7 Hz, 1H), 1.78-2.10 (m, 2H), 1.54-1.76 (m, 1H) , 1.05 (s, 9H) 375 13C-OTR: (50.32 MHz, CDC13, TMS) 5 153.7 and 153.2 (s)', 146.6 and 146.1 (s) , 144.4 and 144.2 (s), 135.0 and 134.7 (d), 132.4 and 132.3 (s), 132.4 (s), 132.3 and 131.8 (s), 129.7 and 129.6 (d) , 129.2 and 129.0 (s), 126.5 (s) , 121.8 and 121.2 (d), lll.l and 110.9 (d), 88.3 and 88.1 (d), 61.8 (d); 55.9-(q), 52.7 and 51.8 (t), 48.3 (s), 46.5 and 46.1 (t), 37.4 and 35.8 (t), 29.7 (t), 27.0 and 26.9 (q), 19.1 and 18.9 (d) Example 104 \~1~%-' SPH-1536 (4aS,GR,8aS)-3-Methoxy-12-trifluoroacetyl-5,6,9,10,11,12 -hexahydro-4aH-[llbenzofuro[3a,3,2-ef]-[2]benzazepin-6-ol Method A (CK-32-1) A solution that consists of 5 ml of dichloromethane and 4.6 ml {3,333 g, 32.9 mmol) of trifluoroacetic acid anhydride is added in drops at 0°C within 15 minutes to a solution of 1.00 g 376 (3.66 mmol) of norgalanthamine (68% (HPLC, CK-1-1)), 1.5 ml (1.095 g, 10.8 mmol) of triethylamine in 5 ml of absolute dichloromethane. Then, the solution is stirred for 1.75 hours at 0°C, and the reaction .is then terminated by adding 5.5 ml of 2N hydrochloric acid. The phases are separated, and the aqueous phase is extracted three times with 20 ml of dichloromethane in each case. The combined organic phases are washed with 3 0 ml of saturated common salt solution, dried on Na2SO4, filtered and concentrated by evaporation. The crude product (0.866 g) is purified by means of MPLC (silica gel, h = 25 cm, d = 3.6 cm, v = 300 nm, mobile solvent petroleum ether/ethyl acetate = 2/1) . After concentration by evaporation and drying in a vacuum, the product is obtained as a white-yellowish foam (0.866 g) . Yield: 0.866 g (1.95 mmol, 53%), white-yellowish foam, Mw = 369.3 Method B (CK-32-2) 2.52 g of norgalanthamine (= 90%, 2.268 g, 8.30 mmol) and 3.45 ml (2.520 g, 24.9 mmol) of triethylamine are dissolved in 20 ml of absolute dichloromethane. Then, a solution that consists of 1.211 ml (1.830 g, 8.71 mmol) of trifluoroacetic acid anhydride and 10 ml of dichloromethane is added in drops within 30 minutes at 0°C. It is heated to room temperature, additional trifluoroacetic acid anhydride (1.2 ml, 1.830 g, 8.71 mmol) is added in portions, and the reaction solution is stirred overnight. The solution is diluted with 120 ml of ethyl acetate and washed with 50 ml of IN hydrochloric acid in each case, with 377 50 ml of saturated NaHC03 solution and twice with 50 ml-of saturated common salt solution in each case, dried on Na2SO4 and filtered. After the concentration by evaporation, the residue is dissolved in 150 ml of dichloromethane, and 141.1 g of a 5% NH, solution is added. The two-phase solution is vigorously stirred at room temperature. After 3 0 minutes, the phases are separated, and the aqueous phase is extracted with dichloromethane (twice, 50 ml). The combined organic phases are washed with IN "hydrochloric acid (twice, 50 ml) and with saturated common salt solution (twice, 50 ml), dried on Na2SO4, filtered and concentrated by evaporation. The residue (2.77 g) is purified by means of MPLC {450 g of silica gel, v = 300 nm, mobile solvent petroleum ether/ethyl acetate = l/l) . After concentration by evaporation and drying in a vacuum, the product is obtained as a white-yellowish foam (2.6171 g). Yield: 2.6171 g (7.09 mmol, 85%), white-yellowish foam (MH = 369.3) TLC: Rf = 0.23 (petroleum ether/ethyl acetate = l/l) Melting point: 65-63°C (petroleum ether/ethyl acetate = 1/1) IR: K3r v (cm"1) 3546.3 (v) , 3417 (bv) , 2924 (m) , 1690 (s) 1H-NMR: (2 00.13 MHz, CDCl3, TMS) 6 6.62-6.92 (m, 2H), 5.88-6.16 (m, 2H), 5.25 (d, J = 15.2 Hz, 0.5H), 4.85 (d, J = 16.6 Hz, 0.5H) , 4.42-4.77 (m, 2H) , 4.02-4.34 (m, 2H) , 3.84 (s, 3H) , 3.60-3.83 (m, 0.5H), 3.27-3.50 (m, 0.5H), 2.72 (d, 378 J = 16.0 Hz, 1.0H), 2.29 (bs, 0.7H), 1.80-2.13 (m, 3H) 13C-NMR: (50.32 MHz, CDC13, TMS) 6/156.1 (m) , 146.4 and 146. (s), 144.8 and 144.7 SPH-1537 (4aS,6R,8aS)-6-Hydroxy-3~methoxy-5,6,9,10-tetrahydro-4aH- EHbenzofuro [3a,3,2-ef] [2] benzazepine-ll{12H) -yl) carboxylic acid allyl estor 379 Variant A (CK-17-1) 3.000 g (11.0 mmol) of norgalanthamine is introduced at 0°C into a solution that consists of 10 ml of absolute dichloromethane and 4.6 ml (3.333 g, 32.9 mmol) of triethylamine. At 0°C, a solution that consists of 1.454 g (12.1 mmol} of allyl chloroformate and 5 ml- of absolute dichloromethane is added in drops within 20 minutes. The reaction solution is stirred overnight and in this case heated to room temperature. The reaction solution is taken up with 50 ml of IN hydrochloric acid and 50 ml of dichloromethane. The phases are separated, and the aqueous phase is extracted three' times with 50 ml of dichloromethane in each case. The combined organic phases are washed with 100 ml of saturated common salt solution, dried on Na2SO4, filtered and concentrated by evaporation. The crude produce (3.2 g) is separated by means of MPLC (silica gel, h = 25 cm, d"= 3.6 cm, v = 300 nm, mobile solvent petroleum ether/ethyl acetate = 2/1). After concentration by evaporation and drying in a vacuum, the product is obtained as a white-yellowish foam (2.594 g) and 0.232 g of a by-product, which was identified as N,O-diallyloxycarbonylnorgalanthamine. Yield: 2.594 g (7.25 mmol, 66%) TLC: Rf = 0.30 (petroleum ether/ethyl acetate = l/l) Melting point: 44-46°C (petroleum ether/ethyl acetate = 1/1) IR: KBr v (cm"1) 3550 (m) , 3458 (m) , 1700 (s) ^-NMR: (200.13 MHz, CDC13, TMS) 380 5 f. 62-6.86 (m, 2H) , 5.95-6.09 (m, 2H) , 5.76-5.94 (m, 1H) , 5.10-5.33 (m, 2H) , 4.93 and 4.83 (d and d, J = 15.1 Hz, and J = 15.7 Hz, 1H), 4.45-4.68 (m, 3H) , 4.05-4.44 (m, 3H) , 3.83 (s, 3H) , 3.27-3.55 (m, 1H), 2.70 (bdd, J = 15.1 Hz, and J = 15.7 Hz, 1H) , 2.26 (bs, O.5H) , 1.93-2.11 (m, 1H) , 1.69-1.92 (m, 1H) 13C-NMR: (50.32 MHz, CDCl3, TMS) 5 155.1 and 155.0 (s), 146.4 (s), 144.3 (s), 132.7 (d) , 132.3 and 132.0 (s), 129.1 (s), 128.0 (d) , 126.2 (d) , 121.4 and 120.8 (d), 117.3 and 116.7 (t), 111.1 and 110.9 (d), 88.1 and 88.0 (d), 65.9 and 65.8 (t), 61.7 (d), 55.7 (q), 51.8 and 51.3 (t), 48.2 (s), 45.8 and 45.3 (t), 37.2 and 36.3 (t), 29.7 (t) Example t&tf H"^ SPH-1538 {4aS,6R,8aS)-6 -(2-Allyloxycarbonyloxy)-3-methoxy-5,6,9,10 -tetrahydro-4aH-[l]benzofuro£3ar3,2-ef][2]benzazepine-ll(12H) yl)carboxylic acid allyl ester 381 Colorless wax, (Mw = 441.5) TLC: Rf = 0.51 (petroleum ether/ethyl acetate = 1/1) IR: KBr v (cm'1) 2947 (m) , 1739 (s) , 1700 (s) 1H-NMR: (200.13 MHz, CDClj, TMS) 6 6.56-6.81 (m, 2H) , 6.22 (d, J = 10.3 Hz, 1H), 5.73- 6.04 (m, 3H), 5.08-5.40 {m, 5H), 4.90 (d, J = 15.5 Hz, 0.5H), 4.80 (d, J = 15.9 Hz, 0.5H), 4.44-4.64 (m, 5H), 4.04-4.43 {m, 2H), 3.82 (s, 3H), 3.24-3.54 (m, 1H), 2.78 (bd, J = 16.4 Hz, 1H), 1.65-2.21 (m, 3H) 13C-NMR: (50.32 MHz, CDCl3, TMS) 5 155.0 and 154.8 (s), 154.4 (s), 147.2 (s), 144.1 (s), 132.7 (d), 131.5 (d), 130.9 (s), 130.6 (d), 128.9 and 128.8 (s), 122.3 (d) , 120.6 and 120.1 (d) , 118.3 (t), 117.2 and 116,6 (t), 111.5 and 111.3 (d) , 85.3 (d) , 68.1 (t) , 66.5 (d) , 65.8 and 65.7 (t), 55.8 (q), 51.6 and 51.2 (t), 47.8 (s), 45.6 and 45.2 (t), 37.6 and 36.7 (t), 27.5 (t) Variant B (CK-17-2) 1.000 g (3.66 mrnol) of norgalanthamine (68% (HPLC, CK-1-1) ) , dissolved in 3 ml of absolute dichloromethane, and 0.441 g (3.66 mmol) of allyl chloroformate, dissolved in 2 ml of absolute dichloromethane, are reacted analogously to method A with 1.48 ml (1.443 g, 18.3 mmol) of pyridine. After aqueous working-up analogously to method A and column chromatography (50 g of silica 382 gel, mobile solvent petroleum ether/ethyl acetate = 2/1 -» l/l) , 0.784 g of a colorless foam and 0.214 g of the same by-product are obtained. Yield: 0.784 g (2.19 mmol, 60%) Example 187 Diagram for Example l&f- ^ T~3 383 384 Steps 1-4 Immobilization of (4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9/ 10-tetrahydro-4aH-[l]benzofuro-[3a,3,2-ef ] [2]benzoazepine-ll (12H) -yl) carboxylic Acid Allyl Ester on a Hydroxymethyl-Folystyrene Resin (Merrifield Resin) In a 5-ml-polyethylene frit that is sealed on both sides, 0.200 g {0.20a mmol) of hydroxymethylpolystyrene resin (1.04 mmol/g, Merrifield resin3) is suspended in 3 ml of dichloromethane, and it is shaken for 30 minutes at about 40'x per minute. After filtering, 0.095 g (0.832 mmol) of glutaric acid anhydride, and 178 /il (0.134 g, 1.04 mmol} of ethyldiisopropylamine in 2 ml of dichloromethane are added, and the suspension is shaken for 16 hours at room temperature at about 40 x per minute. The reaction solution is filtered off, and the resin is washed once with dichloromethane, once with methanol and five times with dichloromethane with 2.5 ml in each case. The resin is subsequently suspended in 77 /il {0.075 g, 0.624 mmol) of pivaloyl chloride, 178 /il (0,134 g, 1.04 mmol) of ethyldiisopropylamine in 1.7 5 ml of dichloromethane and shaken for six hours at room temperature. After filtering and washing with dichloromethane (1 x 2.5 ml), tetrahydrofuran (1 x 2.5 ml) and dichloromethane (5 x 2.5 ml), the resin is shaken in a solution that consists of 0.230 g (0.624 mmol) of N-allyloxycarbonylnorgalanthamine, 0.013 g (0.104 mmol) of 4-dimethylaminopyridine and 178 p.1 (0.134 g, 1.04 mmol) of ethyldiisopropylamine in 2 ml of dichloromethane at room temperature. After 22 hours,- the reaction is terminated by 385 filtering off the reaction solution, the resin is washed with dichloromethane (1 x 2.5 ml), with dimethylformamide (2 x 2.5 ml) and with dichloromethane (5 x 2.5 ml), dried, auctioned off and dried overnight in a vacuum at 3 0 to 50 mbar. To determine the concentration, an aliquot of resin (0.262 g) in 2.5 ml of methanol/tetrahydrofuran (1/3) is steeped for 30 minutes, filtered and suspended in a solution of 0.168 g (0.933 mmol) of 30% sodium methanolate-methanol solution in 0.5 ml of methanol and 1.5 ml of tetrahydrofuran. The mixture is shaken for 15.5 hours at room temperature, filtered off, and the resin is extracted three times with methanol/dichloromethane (1/1, 2.5 ml) and three times with dichloromethane (2.5 ml). The combined filtrates are neutralized with 95 /U (0.067 g, 1.248 mmol) of trifluoroacetic acid and concentrated by evaporation in a rotary evaporator. The residue is purified by means of column chromatography (5 g of silica gel, mobile solvent petroleum ether/ethyl acetate = l/l). After concentration by evaporation and drying under high vacuum, 0.04 8 g of a colorless, vitreous solid is obtained. Yield: 0.048 g (0.13 mmol, 65% relative to the degree of substitution of the hydroxymethyl resin), ^-NMR spectrum identical to the starting material 386 Example 187/Steps 5-8 SPH-1539 1-(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH- [l]benzofuro [3a, 3,2-ef] - [2]benzazepine-ll(12H) -yl) -6- (4-h.ydroxy- l-piperidyl)hexaii-l-one (CK-3 6-1) 0.273 g of resin, produced from 0.200 g (0.208 ramol) of hydroxymethylpolystyrene resin7 (1.04 mmol/g) according to the above-described method A, 0.120 g (0.104 mmol) of PcKPhjP),,, and 0.2 92 g (2.08 mmol) of dimedone are shaken in 1.2 ml of tetrahydrofuran in a 5-ml-polyethylene frit that is sealed on both sides for six hours at room temperature at about 40 x per minute. The resin is filtered and washed with dichloromethane (1 x 2.5 ml), with dichloromethane/methanol/ethyldiisopropylamine (5/4/1) (3 x 2.5 ml) and finally with dichloromethane (5 x 2.5 ml). The resin is subsequently mixed with a solution that consists of 96 /xl (0.133 g, 0.624 mmol) of 6-bromocaproyl 7Hydroxymethyl resin, D-1160, Bachem Feinchemikalien AG 387 chloride and 178 /tl (0.134 g, 1.04 mmol) of ethyldiisopropylamine in 2 ml of dichloromethane and shaken for five hours at room temperature. After washing with dimethylformamide (6 x 2.5 ml), the resin is shaken in a solution that consists of 0.210 g (2.08 mmol) of 4-hydroxypiperidine and 2 ml of dimethylformamide for twelve hours at room temperature. The resin is washed three times with 2.5 ml of dichloromethane in each case and three times with 2.5 ml of tetrahydrofuran in each case and subsequently suspended in a solution of 0.168 g (0.933 mmol) of 30% sodium methanolate-methanol solution in 0.5 ml of methanol and 1.5 ml of tetrahydrofuran. After twelve hours at room temperature, the resin is filtered and extracted with methanol/dichloromethane (l/l, 3x2.5 ml) and with dichloromethane (3 x 2.5 ml). The combined filtrates are neutralized with 95 p.1 (0.067 g, 1.248 mmol) of trifluoroacetic acid and concentrated by evaporation in a rotary evaporator at about 2 ml volumes. The crude product is purified by means of preparative thin-layer chromatography (PSC chromatoplate8, mobile solvent dichloromethane/methanol = 9/1 + 3% triethylamine). Triethylammonium trifluoroacetate is then separated from the product fraction that is concentrated by evaporation by means of column filtration via aluminum oxide (pH 9-10, mobile solvent dichloromethane/methanol = 20/1). After concentration by evaporation and drying under high vacuum, 0.012 g of the product is obtained in the form of a yellowish foam. BPSC chromatoplate by Merck, Art. No.: 113 895, 20 x 20 cm, l mm, silica gel 60 F254 388 Yield: 0.012 g {0.025 mmol, 12% relative to the degree of substitution of the hydroxymethyl resin), white-brownish wax (M =470.6) TLC: Rf = 0.32 (dichloromethane/methanol = 8/2 + 2% triethylamine) HPLC: tRef = 5.38 minutes, 98.6% (Waters Xterra column, 3.9 mm x 100 mm, RP-18, 3.5 pa, 250 nm, 1 ml/minute, acetonitrile/2 0 mmol of Na2B4O7 in K2O (20/80 v/v, pH 10) ^-NMR: (200.13 MHz, CDCl3, TMS) 5 6.81-6.88 and 6.61-6.71 (m, 2H) , 5.90-6.10 (m, 2H) , 4.52-4.75 (m, 2H), 4.51 (d, J = 16.5 Hz, 1H), 4.15 (bs, 1H), 3.84 (s, 3H), 3.82 (s, 1H), 3.40-3.60 and 3.10-3.30 (m, 1H), 2.81-3.03 (m, 2H), 2.70 (bd, J = 16.3 Hz,- IK) , 2.33-2.62 (m, 4H) , 1.15-2.30 (M, 21H) LC/MS: tRef = 8.7 minutes, 98%, (Zorbax SB C 13-column, 2.1 mm x 30 mm, RP-18, 3 fim, 0.5 ml/minute, Methanol/H20 (40/60 -* 100/0 (v/v) in 2 minutes) APCI-NI-MS 470 Example 188 Diagram for Example £6-8 W^o 389 390 Example 188/Steps 1-7 SPH-1540 (4aS,6R,8aS) -6-Hydroxy-3-methoxy-N11- (1-naphthyl) -5,6,9,10-tetrahydro-4aH- EUbenzofuro- [3a,3,2-ef] - [2]benzazepine-ll(12H) -carboxamide Variant A (CK-41-3), Steps 1, 4 and 6-7 0.228 g (0.212 mmol) of 4-carboxy-l-oxobut-l-yloxymethyl-Merrifield resin is steeped in a 5-ml-polyethylene frit that is sealed on both sides for 3 0 minutes in 3 ml of dichloromethane, and after filtering, it is mixed in a solution of 0.234 g (0.628 mmol) of N-tert-butoxycarbonylnorgalanthamine, 0.013 g (0.105 mmol) of 4-dimethylaminopyridine and 108 p.1 (0.082 g, 0.628 mmol) of ethyldiisopropylamine in 1 ml of dichloromethane. Then, 97 /zl (0.079 g, 0.628 mmol) of diisopropylcarbodiimide, dissolved in 1 ml of dichloromethane, is added, and the suspension is shaken for .24 hours at about 40 x per minute at room temperature. After filtering, the resin is suspended for ten minutes in 2.5 ml of dichloromethane/methanol ' (l/l) while being shaken, filtered and 391 washed with dichloromethane (5 x 2.5 ml) . The resin is subsequently suspended once for ten minutes and once for 50 minutes in each case in 2.5 ml of a solution that'consists of trifluoroacetic acid, dichloromethane, and anisole (25/70/5). After filtering, it is washed with dichloromethane (2 x 2.5 ml), with dichloromethane/methanol/triethylamine (5/4/1, 3 x 2.5 ml) and finally with dichloromethane (5 x 2.5 ml). The resin, is shaken for eleven hours in a solution that consists of 0.208 p.1 (0.245 g, 1.45 mmol) of 1-naphthylisocyanate, 113 ptl (0.085 g, 0.657 mmol) of ethyldiisopropylamine and 2 ml of dichloromethane at room temperature. After three cycles of washing in each case with dichloromethane (2.5 ml) and tetrahydrofuran (2.5 ml), the polymer is suspended in a solution of 1.88 g (1.045 mmol) of 30% sodium methanolate-methanol solution in 0.4 ml of methanol and 1.6 ml of tetrahydrofuran. After the resin was shaken for 24 hours at room temperature, the resin is filtered and extracted with methanol/dichloromethane (1/1, 3 x 2.5 ml) and with dichloromethane (3 x 2.5 ml). The combined filtrates are neutralized with concentrated hydrochloric acid. The suspension is filtered on a silica gel column (10 g, dichloromethane/ methanol = 9/1), and the filtrate is concentrated by evaporation in a rotary evaporator. The crude product is purified by means of preparative thin-layer chromatography (silica gel, mobile solvent dichloromethane/methanol = 4//3) . After concentration by evaporation and drying under high vacuum, 0.091 g of a yellowish foam is obtained. To remove triethylammonium salts, the residue is taken up in dichloromethane and extracted twice with IN 392 hydrochloric acid and once with saturated common salt solution, dried on MgSO4, filtered and concentrated by evaporation. Yield: 0.042 g (0.095 mmol, 45% relative to the degree of substitution of the 4-carboxy-l-oxobut-l-yloxymethyl-Merrifield resin), brown-yellowish wax (Mw = 442.5) TLC: Rf = 0.21 (dichloromethane/methanol = 48/2) HPLC: tRef = 5.15 minutes, 100% (Merck purospher column 4.0 mm x 125 mm, RP-18e, 5 um, 250 nm, 1 ml/minute, acetonitrile/20 mmol of C13CCO2H in H2O (40/60 v/v) ^-NMR: (200.13 MHz, CDC13, TMS) 5 7.71 (d, J - 6.9 Hz, 1H), 7.20-7.66 (m, 6H), 6.85 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 5.96 (bs, 2H), 4.91 (d, J = 16.7 Hz, 1H), 4.25-4.62 (m, 3H), 4.0 9 (bs, 1H), 3.78 (s, 3H), 3.25-3.50 (m, 2H), 2.55-2.67 (m, 1H), 1.87-2.0 4 (m, 2H), 1.60-1.75 (m, 1H) 13C-NMR: (50.32 MHz, CDC13, TMS) 5 155.7, 146.9, 144.6, 134.4, 133.8, 132.5, 129.0, 12 8.7, 128.1, 128.0, 126.3, 125.6, 125.5, 124.8, 122.1, 120.7, 111.0, 88.2, 62.9, 55.9, 51.8, 48.3, 46.1, 36.4, 29.7 Variant B, Steps 2-5 and 7 0.250 g (0.233 mmol) of 4-carboxy-l-oxobut-l-yloxymethyl- Merrifield resirx is introduced into a frit reactor of synthesis 393 robot (Syro II MultiSynTech). Then, the resin is steeped in a reactor for 30 minutes in dichloromethane, suctioned off, washed three times with dichloromethane and mixed successively with 0.150 g (1.163 mmol) of ethyldiisopropylarnine in 1 ml of dichloromethane and 0.084 g (0.698 mmol) of pivaloyl chloride in "1.5 ml of dichloromethane. After six hours of stirring at 23°C, the solution is suctioned off, and the polymer is washed in each ¦case with 3 ml of dichloromethane (6x2 minutes). After the addition of 0.260 g (0.698 mmol) of N-tert- Ibutoxycarbonylnorgalanthamine, 0.014 g (0.116 mmol) of 4- dimethylaminopyridine and 0.150 g (1.163 mmol) of i ethyldiisopropylamine in 2.5 ml of dichloromethane, the suspension is stirred at 23°C for 15 hours. After suctioning off, the resin is stirred in 2.5 ml of dichloromethane/methanol i (l/l) for ten minutes, suctioned off, washed three times with ¦ dichloromethane/methanol (1/1) (3 ml, 2 minutes) and five times with dichloromethane (3 ml, 2 minutes). The polymer is subsequently suspended once for ten minutes and once for 5 0 , minutes in each case in 2.5 ml of a solution that consists of trifluoroacetic acid, dichloromethane and anisole (25/70/5) . After suctioning off, it is washed with dichloromethane (3x3 ¦ ml), with dichloromethane/methanol/triethylamine (5/4/1, 3x3 ml) and finally with dichloromethane (5 x) in each case for two minutes. Then, the residue is mixed with 0.197 g (1.163 mmol) of l-naphthylisocyanate, 0.150 g (1.163 mmol) of ethyldiisopropylarnine and 2.5 ml of dimethylformamide and stirred for six hours at 5 0°C. The reaction is terminated by the 394 solution being suctioned off, the resin being washed with 3 ml of dichloromethane at 23°C six times for two minutes in each case, and the resin being suctioned off in the dry state at 40°C for ten minutes. For cleavage, the resin is transferred into a 5-ml-polyethylene frit that is sealed on both sides and steeped in 2.5 ml of tetrahydrofuran for 30 minutes. After filtering, the polymer is suspended in a solution that consists of 0.209 g (1.163 mmol) of 30% sodium methanolate-methanol solution in 0.75 ml of methanol and 1.2 5 ml of tetrahydrofuran, and it is shaken for 15 hours at about 40 x per minute at room temperature. The resin is filtered and extracted three times with methanol/dichloromethane (l/l, 2.5 ml) and three times with dichloromethane (2.5 ml). The combined extracts are neutralized with concentrated hydrochloric acid, filtered and concentrated by evaporation. Then, the crude product is purified by means of column chromatography on 10 g of silica gel' (mobile solvent dichloromethane/methanol = 99/1). After concentration by evaporation and drying in a vacuum, 0.029 g of a rose-colored wax with a purity of 75% (HPLC), identical to the product that is produced according to method A, is obtained. Yield: 0.029 g (0.021 g( 0.047 mmol, 20% relative to the degree of substitution of the 4-carboxy-l-oxobut-1-yloxymethyl-Merrifield resin) HPLC: tRef = 14.32 minutes, 75% (Merck purospher column 4.0 mm x 125 mm, RP-lSe, 5 fim, 250 nm, 1 ml/minute, acetonitrile/20 mmol of C13CCO2H in H2O (30/70 v/v) Diagram for Examples 189-190 395 396 Example tea- \^~1—-SPH-1541 Steps 1-2 (4aS,6R,8aS)-3-Methoxy-ll-tert-butoxycarbonyl-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef] [2]benzazepine-6(12H)-yloxy)-5-oxopentanoic acid (CK-48-1) 5.000 g (18.295 mmol) of norgalanthamine (98% (HPLC)) and 3.804 ml (2.777 g, 27.442 mraol) of triethylamine in 75 ml of absolute dichloromethane are introduced at 0°C. While being stirred, a solution that consists of 4.393 g (20.124 mmol) of di-tert-butyldicarbonate is added in drops within 15 minutes at 0°C. After 40 minutes at 0°C, the reaction solution is stirred for three days at room temperature. After two days, 1.598 g (7.318 mmol) of di-tert-butyldicarbonate and 1.27 ml (0.926 g, 9.147 mmol) of triethylamine are added again. The reaction solution is taken up with 150 ml of dichloromethane, and the organic phase is washed three times with 100 ml of IN hydrochloric acid in each case, three times with 100 ml of a saturated NaHCO3 solution in 397 each case and twice with 10 0 ml of saturated common salt solution, dried on Na2SO4, filtered and concentrated by evaporation under reduced pressure. The residue (7.065 g, 18.9 mmol, 103% raw yield) is dissolved in 75 ml of absolute dichloromethane, and 4.175 g (36.590 mmol) of glutaric acid anhydride, 0.224 g (1.829 mmol) of 4-dimethylaminopyridins and 3.S04 ml (2.777 g, 27.442 mmol) of triethylamine are added to this solution. The solution is stirred for three days at room temperature. The reaction is terminated by adding 200 ml of diethy1 ether and 500 ml of aqueous ammonia solution (pH 10-11). The cloudy aqueous phase is separated {poor phase separation, addition of some methanol, optionally before the dichloromethane solution is distilled off) and extracted three times with 200 ml of diethyl ether and then set at pH 2 with concentrated hydrochloric acid. In this case, the cloudy solution becomes clear. The aqueous phase is extracted four times with 400 ml of dichloromethane in each case. The combined organic extracts are washed three times with 300 ml of distilled water in each case and twice with 300 ml of saturated common salt solution, dried on Na2SO4, filtered, mixed with 50 ml of diisopropyl ether and concentrated under reduced pressure until the product crystallizes out. The solution is allowed to stand for a little while and then the crystallized colorless solid is filtered off, which is dried in a vacuum. Yield: 7.546 g {15.48 mmol, 84.6 % over two stages), colorless crystalline solid, {Mw = 487.6) TLC: R = 0.45 (petroleum ether/ethyl acetate = 1/2) 398 Rf = 0.28 (aluminum oxide, petroleum ether/ethyl acetate = 1/2) Melting point: 159-163°C (dichloromethane/diisopropyl ether = 1/D IR: KBr v (cm'1) 3245 (bs) , 2978 (s) , 1715 (s) , 1683 (s) ^-NMR: (200.13 MHz, CDC13/ TMS) 5 6.53-6.79 (m, 2H) , 6.13-6.29 (m, 1H) , 5.82-5.97 (m, 1H), 5.33 (1, J = 4.9 Hz, 1.OH), 4.87 (d, J = 15.S Hz, 0.3H), 4.67 (d, J = 15.7 Hz, 0.7H), 4.53 (s, 1H), 3.99-4.38 (m, 2H), 3.83 (s, 3H), 3.19-3.50 (m, 1H), 2.68 (d, J = 16.0 Hz, 1.0H), 2.40 (t, J = 7.3 H2, 2.OH), 2.39 (t, J = 7.0 Hz, 2.OH), 2.01-2.17 (m, 1H) , 1.93 (qui, J = 7.1 Hz, 2.OH), 1.66-1.84 (m, 1H), 1.41 (s, 3H),'1.37 (s, 6H) 13C-NMR: (50.32 MHz, CDC13, TMS) 5 178.2 (s), 172.6 (s), 154.9 (s), 147.1 (s), 144.0 (s) , 131.3 (s) , 130.5 (d) , 129.6 (s) , 123.0 (d) , 120.2 (d), 111.0 (d), 85.8 (d), 79.9 (s), 63.2 (d), 55.8 (q), 51.8 and 51.2 (t), 48.0 (s), 45.2 (t), 3 7.9 and 37.0 (t), 33,4 (t), 32.9 (t), 28.2 (q), 27.5 (t), 19.7 (t) Example -&&0 t^rT" SPH-1542 (See Diagram, Step 3) Immobilization of (4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[l]benzofuro-[3a,3,2-e£] [2]benzoazepine-ll(12H) -yl)carboxylic acid-tert-butyl Ester on a Hydroxymethyl-Polystyrene Resin (Merrifield Resin) (CK-43-5) 5.00 g (5.2 mmol) of hydroxymethylpolystyrene resin (1.04 mmol/g, Merrifield resin9) is stirred in a three-neck glass reactor with a frit that is recessed in the bottom and a KPG stirrer in 50 ml of dimethylformamide (300 s"1) . After filtering, a solution that consists of N-tert- butoxycarbonylnorgalanthamine-6-yloxy-5-oxopentanoic acid (7.607 gf 15.6 mmol), 4-dimethylaminopyridine (0.635 g, 5.2 mmol) in 30 ml of absolute ditnethylformamide is added to the resin. At room temperature, a solution that consists of diisopropylcarbodiimide 9Hydroxymethyl resin, D-1160, Bachem Feinchemikalien AG 400 (2.42 ml, 1.969 g, 15.6 mmol) and 10 ml of dimethylformamide is then added in portions. After 2 0 hours of stirring at room temperature, it is filtered, the resin is washed six times with dichloromethane {40 ml, 5 minutes) and once with diethyl ether (40 ml, 5 minutes) and dried in a vacuum. To determine the concentration, an aliquot of resin (0.2465 g) in a polyethylene frit that can be sealed on both sides in 2.5 ml of methanol/tetrahydrofuran (1/4) is steeped for 30 minutes, filtered, and suspended in a solution of 0.280 g (1.56 mmol) of 30% sodium methanolate-methanol solution in 0.5 ml of methanol and 2 ml of tetrahydrofuran. The mixture is shaken for nine hours at room temperature, filtered off, and the resin is extracted three times with methanol/dichloromethane (l/l, 2.5 ml) and three times with dichloromethane (2.5 ml). The combined filtrates are neutralized with 119 (xl (0.178 g, 1.56 mmol) of trifluoroacetic acid and concentrated by evaporation in a rotary evaporator. The residue is taken up in 3 0 ml of ethyl acetate, washed twice with saturated NaHCO5 solution (10 ml), with distilled water (10 ml) and with saturated common salt solution (10 ml), dried on Na2SO4, filtered and concentrated by evaporation again. The residue (0.080 g) is purified by means of column chromatography (10 g of silica gel, mobile solvent petroleum ether/ethyl acetate = l/l -* 1/2). After concentration by evaiporation and drying under high vacuum, 0.0661 g of a colorless, vitreous solid is obtained. Yield: 0.0661 g (0.177 mmol. A concentration of 0.718 mmol/g, 103% of the theoretical maximum 401 concentration10 thus is calculated) , 1H-NM"R spectrum that is identical to the starting material H?LC: tRef = 9.18 minutes, 93.8% (270 ntn) , 97.7% (285 nm), (Phenomenex Luna column, 3.0 mm x 50-mm, RP-18, 3.0 /im, 0.5 ml/minute, methanol/20 mmol of trichloroacetic acid in K2O (50/50 v/v) Step 4 Recycling Excess (4aS, 6R, 8aS) -3-Methoxy-ll-tert-bufcoxycarbonyl- 5,6,9,10-tetrahydro-4aH-[l]benzo£uro[3a,3,2-ef] t2]benzazepine- 6 (12H)-yloxy)-5-oxopentanoic Acid from the Resin Immobilization (CK-51-1) The filtrate of the reaction solution and the first five dichloromethane filtrates are combined and washed three times with 100 ml of IN hydrochloric acid, three times with 100 ml of distilled water and twice with saturated sodium chloride solution, dried with Na2SO4, filtered and concentrated by evaporation. The amorphous residue (6.806 g) is suspended in 50 ml of ethanol and 30 ml of distilled water, then 1.97 g (46.9 mmol} of lithium hydroxide monohydrate is added. The suspension is stirred for three days at room temperature. The reaction solution is extracted three times with 100 ml of dichloromethane in each case, and the combined extracts are extracted in each case three times with 100 ml of IN hydrochloric acid and twice 10=l.04 mmol/g/(1 g + 1 g * 1.04 mol/g * (487.6 mol/g - 18 mol/g)/1000) 402 with 100 ml of saturated common salt solution. After drying on Ma2S04, filtering and concentration by evaporation under reduced pressure, the organic phase produces 5.0 5 g of a colorless foam, which contains about 60% N-tert-butoxycarbonylnorgalanthamine according to HPLC. The residue is reacted analogously to the above-described procedure with 0.164 g (1.339 mmol) of dimethylaminopyridine, 3.055 g (26.78 mmol) of glutaric acid anhydride and 2.8 ml (2.033 g, 20.09 mmol) of triethylainine in 50 ml of dichloromethane. The reaction is terminated by the addition of 200 ml of diethyl ether and 250 ml of aqueous ammonia solution {pH 10-11) . The cloudy, aqueous phase is separated and extracted twice with 200 ml of diethyl ether and then set to pH 2 with concentrated hydrochloric acid. The aqueous phase is extracted three times with 200 ml of dichloromethane in each case. The combined organic extracts are washed three times with 200 ml of distilled water in each case and twice with 200 ml of saturated common salt solution, dried on Na2S0A, filtered, concentrated by evaporation to about 50 ml, mixed with 50 ml of diisopropyl ether and further concentrated under reduced pressure until the product crystallizes out. The solution is allowed to stand for a little while, and then the crystallised colorless solid is filtered off, which is dried in a vacuum. Yield: 4.909 g (10.07 mmol, 96.6% relative to the excess that is used in the immobilization) HPLC: tRef = 13.9 minutes, 99.8% (Merck Purospher column, 4.0 mm x 125 mm, RP-18e, 5 nm, 285 nm, 1 403 ml/minute/ acetonitrile/2 0 mmol of C13CCO2H in H20 (40/60 v/v, pH 10) Example £93- t T-tf Step 1 N-(Adamantan-1-yl)-6-bromohexanoic acid amide Adamantane-1-amine, tiydrochloride (2.50 g, 13,3 mmol) and N-ethyldiisopropylamine (3.79 g, 29.3 mmol) are stirred in absolute CH2C12 (50 ml) for 15 minutes at room temperature. Then, 6-bromohexanoic acid chloride (3.13 g, 14.7 mmol) in CH2C12 (10 ml) is added in drops at 0°C and stirred for one hour at room temperature. It is extracted with 2N HCl (2 x 50 ml), water (1 x 50 ml), saturated sodium bicarbonate solution (2 x 50 ml) and saturated common salt solution (1 x 100 ml), dried (sodium sulfate/activated" carbon), filtered, and the residue that is obtained after the solvent is removed in a rotary evaporator is recrystallized from petroleum ether (25 ml)/diisopropyl ether (25 ' ml) , by which tjie product is obtained in the form of colorless crystals wi/a melting point of 73-75°C (3.51 g, 80%). 404 TLC: CHCI3 : MeOH = 9:1, Rf = 0.9 ]H NMR (CDCL,) : 6 5.43 (b, IK), 3.33 (t, J = 6.0 Kz, 2H) , 2.21-1.15 (m, 23K); 13C NMR (CDC13) : 5 171.6 (s), 51.4 (s), 41.3 (t), 37.0 (t), 36.1 (t) , 33.5 (t), 32.2 (t), 29.1 (d), 27.4 (t), 24.6 (t) Step 2 ¦ SPH-1517 N- (Adajnantan-1-yl) -6-[(4aS,6R,8aS)-4a,5/9/10/ll/12-hexahydro-6- hydroxy-3-methoxy-6H-benzofuro [3a, 3, 2-ef 3 [2] benzazepine-11-yl] - bromohexanoic acid amide, fumarate Norgalar.thamins (1.0C g, 3.66 HITT.OI) , N-(adamantan-l-yl)-S-broir.ohexanoic acid amide (1.2G g, 3.G6 mmol) and potassium ¦ carbonate (anhydrous, freshly ground, 1.52 g, 11.3 mmol) are ¦ stirred in absolute acetcnitrile (1C nl) for 8 hours at boiling temperature. 405 The residue that is obtained after the solvent is removed in a rotary evaporator is purified by column chromatography (2 00 g of silica gel, chloroform : methanol : ammonia = 96:3:1), by which the product is obtained as a light yellow foam (1.73 g, 91%) . The conversion into fumarate was carried out analogously to the production of MT-311 and MT-407 and yielded the product in the form of light yellow crystals with a melting point of 109-114°C. TLC: CHC13 : MeOH : NH3 = 89:10:1, Rf = 0.6 Microelement analysis (JOS 1763}: C37H42N2°9*H2° Cld.: C, 66.03; K, 7.70; N, 4.28 Fnd.: C, 66.27; H, 7.61; N, 4.22 ^MR (DMSO-d6) : 6 = 7.20 (b, IK), 6.90-6.63 (m, 2H) , 6.51 (s, 2H), 6.11 (d, J = 10.2 Hz, 1H), 5.82 (dd, J = 11.4 Hz, J = 4.7 Hz, 1H), 4.56 (s, 1H), 4.41 (d, J = 14.8 Hz, 1H), 4.22-3.86 (m, 2H) , 3.76 (s, 3H) , 3.62-3.12 (m, 3H) , 2.81-2.47 (m, 3H) , 2.44-1.04 (m, 26K); 13C NMR (DMSO-d,) : 5 171.6 (s) , 167.4 (s) , 146.3 (s) , 144.1 0 (s), 134.7 (d), 132.9 (s), 129.0 (d) , 126.3 (d) , 124.6 (s) , 122.0 (d), 111.7 (d), 86.7 (d) , 59.8 (d) , 55.5 (q) , 50.7 (t) , 50.5 (t) , 47.3 (s), 41.1 (t), 36.1 (t), 36.0 (s), 32.0 (t), 31.0 (t), 28.9 (d), 26.0 (t), 25.2 (t), 24.9 (t) 406 Example iS-3 I £& Step 1 2-(5-brcmopentyl)-lH-benz[de]isoquinoline-1,3(2H)-dione IH-Benz[de]isoquinoline-1,3(2H)-dione (10.0 g, 50.7 mmol) in DMF (50 ml) is slowly added in drops at room temperature to a suspension of sodium hydride (2.33 g, 55.8 mmol of a 55% dispersion, white oil is removed by washing with absolute petroleum ether) in absolute DMF (50 ml). It is stirred for 30 minutes, heated to 60°C, 1.5 dibromopentane (46.64 g, 202.8 mmol) is added once, and it is stirred for 12 hours at this temperature. It is filtered, and the residue that is obtained after the solvent is removed in a rotary evaporator is dispersed between water (200 ml) and ether (200 ml). The aqueous phase is extracted with ether (3 x 50 ml) , the combined organic phases are washed with water (3 x 200 ml), 2N NaOH (2 x 100 ml) and saturated common salt solution (1 x 200 ml), dried (sodium 407 sulfate), and solvent is removed in a rotary evaporator. Excess dibromopentane is separated by distillation (100°C/20 mbar), the residue is recrystallized from methanol (200 ml) , by which the product is obtained in the form of colorless crystals (15.45 g, 88%) of melting point 114-116°C. TLC: Petroleum ether : ethyl acetate = 4:1, Rf = 0.35 1H NMR (CDC13) : 6 8.48 {dd, u = 7.0 Hz, J = 1.3 Hz, 2H) , 8.13 (dd, J = 7.0 Hz, J = 1.3 Hz, 2H) , 8.48 (t, J = 7.0 Hz, 2H) , 4.21 (t, J = 7.6 Hz, 2H), 3.89 (t, J = 6.6 Hz, 2H), 1.89 (quintet, J = 6.6 Hz, 2H), 1.79-1.43 (m, 4H); 13C NMR (CDC13) : 5 163.8 (s), 133.7 (d) , 131.3 (s), 130.9 (d), 127.8 (s), 126.7 (d), 122.4 (d), 39.8 (t), 33.5 (t), 32.2 (t), 27.0 (t), 25.5 (t) Step 2 SPH-14 9 6 2- [5- ![(4aS,6R,8aS) -4a, 5, 9 ,10,11,12-Hexahydro-6-hydroxy-S-methoxy-SH-benzofuro [3ai3,2-ef3 [2]benzazepine-ll-yl]pentyl]-1H-benz[de]isoquinoline-l,3(2H)-dione, fumarate 408 Nargalanthamine (1.00 g, 3.66 mmol), 2 -(5-bromopentyl)-1H-ber.z [de] isoquinoline-1, 3 (2K) -dione (1.15 g, 3.33 mmol) and potassium carbonate (anhydrous, freshly gound, 1.15 g, 10.0 rr.mol) are stirred in absolute acetonitrile (10 ml) for 12 hours at boiling temperature. The residue that is obtained after the solvent is removed in a rotary evaporator is purified by column chrorr.atography (100 g of silica gel, chloroform : methanol : ammonia = 96:3:1), by which the product is obtained as a light yellow foam (1.58 g, 88%) . The conversion into fumarate was carried out analogously to the production of MT-311 and MT-407 and yielded the product in the form of light yellow crystals with a melting point of 12S-134CC. TLC: CHC13 : MeOH : NH3 =89:10:1, Rf =0.5 Microelement analysis (JOS 1790): Cld.: C, 65.19; K, 6.06; N, 4.11 Fnd.: C, 65.02; H, 5.82; N, 3. 58 ^ NMR (DMSO d,) : 6 8.34 (d, J = 7.0 Hz, 4H) , 7.76 7.0 Hz, 2H) , 6.81-6.49 (m, 4H) , 6.07 (a, J = 11.4 Kz, 1H) , 5.81 (dd, J = 11.4 Hz, J = 4.7 HZ, 1H), 4.49 (s, IE), 4.29 (d, J = 14.0 Hz, IK), 4.16-3.74 (m, 4K) , 3.70 (s, 3H) , 3.43-3.01 (m, 2H) , 2.50 (b, 2K), 2.27 (d, J = 14.8 Hz, IE), 2.12-1.88 (m, 2H), 1.78-1.12 (m, 8K); 409 13C NMR (DMSO-d6) : 6 167.3 (s) , 163.3 (s), 146.2 (s) , 143.8 (s), 134.7 (d), 134.2 (d), 132.8 (s), 131.2 (s), 130.6 (d), 128.7 (d), 127.2 (d), 127.1 (s), 126.5 (d), 126.1 (s) , 121.9 (s) , 121.6 (d), 111.5 (d), 86.7 (d), 59.8 (d), 56.0 (t), 55.5 (q), 50.7 (t), 50.2 (t), 47.4 (s), 39.S (t) , 32.2 (t) , 3 0". 9 (t) , 27.3 (t), 25.3 (t), 24.1 (t) Example 3^4" I ^ / >r Step 1 6-Bromo-l-(3,4-dimethoxyphenyl)-1-hexanone 6-Bromohexanoic acid chloride (4.9 g, 22.7 mmol) is added in drops within 10 minutes at a temperature of 0 to 5°C to a mixture that consists of 1,2-dimethoxybenzene (3.10 g, 22.7 mmol) and aluminum chloride (3.0 g, 22.7 mmol) in absolute carbon disulfide (50 ml). It is heated within 30 minutes to 40°C, and it is stirred for one hour at this temperature. It is hydrolyzed with 2N hydrochloric acid (20 ml), dispersed between benzene (30 ml) and 2N hydrochloric acid (30 ml) , and the aqueous phase is extracted with benzene (2 x 15 ml), the combined organic phases are washed with 2N hydrochloric acid (3 x 50 ml), water (1 x 50 410 ml), saturated sodium bicarbonate solution (3 x 50 ml), saturated common salt solution (1 x 50 ml), dried {sodium sulfate/activated carbon), filtered, and the residue that is obtained after concentration by evaporation in a rotary evaporator recrystallizes from pentane (35 ml), by which the product is obtained in. the form of colorless crystals with a melting point of 44-45°C (3.2 g, 44.7%) . TLC: Petroleum ether : ethyl acetate = 4:1; Rf = 0.85 1K NMR (CDC13) : 5 7.54 (dd, J = 1.9 Hz, J = 8.9 Hz, 1H) , 7.51 (d, J = 1.9 Hz, 1H), 6.89 (d, J = 8.9 Hz, 1H), 3.97 (s, 6H), 3.40 (t, J = 6.4 Hz, 2H), 2.92 (t, J = 7.0 Hz, 2H), 1.90 (quintet, J = 6.4 Hz, 2H), 1.73 (quintet, J = 7.0 Hz, 2H), 1.63-1.48 (m, 2H); 13C NMH (CDClj) : 6 198.6 (s), 153.2 (s) , 149.0 (s), 130.2 (s) , 122.6 (d) , 110.1 (d) , 110.0 (d) , 56.0 (q) , 55.9 (q) , 37.7 (t), 33.6 (t), 32.6 (t), 27.9 (t), 23.6 (t) 411 Step 2 SPH-1497 1- (3,4-Dimethoxyphenyl) -6- [ (4aS, 6R, 8aS) -4a, 5/ 9,10,11,12- hexahydro-6-hydroxy-3-methoxy-6H-benzofuro[3a,3 , 2- et] [2]benzazepine-ll-yl]hexan-1-one, fumarate Norgalanthamine (1.00 g, 3.66 mmol), 6-bromo-l-(3,4-dimethoxyphenyl)-l-hexanone (1.15 g, 3.66 mmol) and potassium carbonate (anhydrous, freshly ground, 1.15 g, 10.0 mmol) is stirred in absolute acetonitrile (15 ml) for 12 hours at boiling temperature. The residue that is obtained after the solvent is removed in a rotary evaporator is purified by column chromatography (100 g of silica gel, chloroform : methanol : ammonia = 96:3:1), by which the product is obtained as a light yellow foam (1.70 g, 91%) • The conversion into fumarate was carried out according to standard instructions. The conversion into fumarate was carried out analogously to the production of MT-311 and MT-407 and yielded the product in 412 the form of light yellow crystals with a melting point of 88-94°C. TLC: CHC13 : MeOH : NH3 = 89:10:1, Rf = 0.5 Microelement analysis (JOS 1782}: Cld.: C, 65.00; H, 6.86; N, 2.17 Fnd.: C, 64.81; H, 6.64; N, 2.09 1H NMR (DMSO-d6) : 5 5 7.61 (d, J = 8.9 Hz, 1H) , 7.43 (s, 1H) , 7.01 (d, J = 8.9 Hz, 1H) , 6.81-6.66 {m, 2H) , 6.58 (s, 2H) , 6.11 (d, J = 11 Hz, 1H), 5.82 (dd, J = 11 Hz, J = 5 Hz, 1H), 4.61-4.33 (m, 2H), 4.20-3.92 (m, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.72 (s, 3H) , 3.62-3.12 (m, 2H), 3.10-2.81 (m, 2H), 2.78-2.43 {m, 3H) , 2.39-1.86 413 We claim : 1. New compounds of general formula (I): Where Rl is H or Br; R2 is H; R3 is methoxy; R4 is OH; R5 is H; Gl and G2 considered together are CH2; G3 is CH2; and W is any of the following, where the first-mentioned nitrogen atom establishes the bonds between G2 and G3: a) N-Phenyl {optionally substituted with fluorine, bromine, chlorine, (C1-C4) alkyl, C02 alkyl, CN, C0NH2r or C2-C4 alpha alkoxy) ; b) N-thien-2-yl or N-thien-3-yl; c) N-fur-2-yl or N-fur-3-yl; 414 d) N-1,3,5-10 triazinyl, whereby the triazine radical can be substituted with Cl, 0R6 (in which R6 means hydrogen, a Cl- C10,optionally branched or substituted alkyl group or cycloalkyl group, a C3-C10 substituted silyl group, or a C2- C10 alpha-alkoxyalkyl group) or NR7R7 (where the two substituents R7 are the same or different and are hydrogen, or a C1-C4, optionally branched, alkyl group or cycloalkyl group, or substituents R7 together are - (CH2) n-, in which n is 3 to 5); e) a tricyclic substituent (Tr) as per below that is optionally substituted at least in one place with at least one heterocyclic ring as a ring component and a binding site to a carbon atom of an anellated benzene ring thereof, which is connected via a spacer Q to the nitrogen atom that establishes the bonds between G2 and G3; 415 whereby A is imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolinyl, thiazolinyl or oxazolinyl, rings B and C each are optionally substituted 5-to 7-membered, nonaromatic rings, each of which contains one or two identical or different heteroa'toms selected from the group containing nitrogen, oxygen, and sulfur; and whereby Q is a linker -(CH2)n,-M*-(CH2)m- with n = 0 to 4 and m = 0 to 4, and M* means alkinyl (triple C-C bbnd), alkenyl (C-C double bond), disubstituted phenyl, disubstituted thiophene, or disubstituted furan, or any of the following: 2. Compound as claimed in claim 1, in which Tr is a cyclic or bicyclic hydrocarbon. 416 3. Compound as claimed in claim 2, in which Tr has one of the formulas below: 4. Compound as claimed in any one of claims 1-3, in which substituent Tr is substituted at least in one place with Rlr and R-L has the meanings indicated in claim 1. 5. Compound as claimed in any one of claims 1-4, in which substituent W is nitrogen and/or substituent Gx is -(CH2) x-, in which x is equal to 1 or 2 and G2 means -(CH2) y-, in which y is equal to 0 to 2, provided that x + y together mean at least 2 and at most 4. 6. Compound as claimed in any one of claims 1-5, in which substituents G± and G2 together or separately have the meaning of ~CR11R12-, in which R1± and R12 mean hydrogen, hydroxy, a low, optionally branched or cyclic, optionally substituted (Ar)alkyl, aryl, (Ar)alkoxy or aryloxy group. 7. Compound as claimed in any one of claims 1-6, in which GL and G2 together are an alkylspiro group (C3-Cj spiro ring). 8. Process for the production of the compounds as claimed in claims 1-7, wherein the combinatory or parallel-synthesis 417 technology such as herein described is used, whereby the basic molecule is immobilized by a functional group (linker) in a solid phase, which implements the synthesis of the target compound and then this target compound is separated from the solid phase - 9. Process as claimed in claim 8, wherein the basic molecule is immobilized in the solid phase via a carbon center, a nitrogen center or an oxygen center. 10. Process as claimed in claim 8 or 9, wherein -X(CH2)nCO(X = CH2, CO, O, S, NH) , -X(CH2)nOCO (X = CH2, CO, 0, S, NH), -XC6H,CH2- (= CHZ, CO, 0, S, NH) , THP, or - X(CH2)nSi(alkyl)a is used as a functional group (linker). 11. Process as claimed in claim 8 or 9, wherein -X(CH2)nCO(X = CH2, 0, NH, So0_2) , -X(CH2)nCS (X = CH2, 0, NH, So0. 2), X(CH2)nJCO (X = CH2, 0, NH, So0_2; J = NH, 0, S) , or XC6H4CH2 (X = CH2, 0, S) is used as a functional group (linker). 12. Process as claimed in claim 8, wherein -(CH2)nSi(alkyl)2-, -C6H4Si (alkyl) 2-, - (CH2) nSn (alkyl) 2-, -C6H4Sn (alkyl) 2, -(CH2)nS, or -C6H4S is used as a functional group (linker). 13. Pharmaceutical composition comprising a compound of the general formula I as claimed in clam 1 or its pharmaceutically acceptable salt as active ingredient in association with a pharmaceutically acceptable vechile and/or formulation adjuvant. 14. Process for the production of pharmaceutical composition as claimed in claim 13 wherein said active ingredient is mixed with a pharmaceutically acceptable vehicle and/or formulation adjuvant. The invention discloses novel compounds of general formula (I), wherein R1, R2, R3, R4, R5 G1, G2, G3 and W are defined in the specification. The compound of the invention have superior therapeutic effects in view of their high slectivity for acetycholin-esterase (AchE) and butyrylcholinesterase (BuChE) Compared to the parent compound. The invention also discloses the process for preparation of these compounds and Pharmaceuticals composition comprising them. |
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in-pct-2001-01225-kol abstract.pdf
in-pct-2001-01225-kol assignment.pdf
in-pct-2001-01225-kol claims.pdf
in-pct-2001-01225-kol correspondence.pdf
in-pct-2001-01225-kol description(complete).pdf
in-pct-2001-01225-kol form-1.pdf
in-pct-2001-01225-kol form-13.pdf
in-pct-2001-01225-kol form-18.pdf
in-pct-2001-01225-kol form-3.pdf
in-pct-2001-01225-kol form-5.pdf
in-pct-2001-01225-kol g.p.a.pdf
in-pct-2001-01225-kol letters patent.pdf
in-pct-2001-01225-kol priority document others.pdf
in-pct-2001-01225-kol priority document.pdf
in-pct-2001-01225-kol reply f.e.r.pdf
IN-PCT-2001-1225-KOL-CORRESPONDENCE 1.1.pdf
IN-PCT-2001-1225-KOL-FORM 27.pdf
in-pct-2001-1225-kol-granted-abstract.pdf
in-pct-2001-1225-kol-granted-claims.pdf
in-pct-2001-1225-kol-granted-description (complete).pdf
in-pct-2001-1225-kol-granted-specification.pdf
in-pct-2001-1225-kol-priority document.pdf
in-pct-2001-1225-kol-translated copy of priority document.pdf
| Patent Number | 212737 | ||||||||||||||||||||||||
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| Indian Patent Application Number | IN/PCT/2001/1225/KOL | ||||||||||||||||||||||||
| PG Journal Number | 50/2007 | ||||||||||||||||||||||||
| Publication Date | 14-Dec-2007 | ||||||||||||||||||||||||
| Grant Date | 12-Dec-2007 | ||||||||||||||||||||||||
| Date of Filing | 21-Nov-2001 | ||||||||||||||||||||||||
| Name of Patentee | SANOCHEMIA PHARMAZEUTIKA AKTIENGESELLSCHAFT | ||||||||||||||||||||||||
| Applicant Address | BOLTZMANNGASSE 9A-11 A-1091 WIEN AUSTRIA | ||||||||||||||||||||||||
Inventors:
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| PCT International Classification Number | A61L2/00 | ||||||||||||||||||||||||
| PCT International Application Number | PCT/AT01/00082 | ||||||||||||||||||||||||
| PCT International Filing date | 2001-03-22 | ||||||||||||||||||||||||
PCT Conventions:
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