Title of Invention	A METHOD OF TRANSMISSION IN A TRANSMISSION AND RECEPTION SYSTEM
Abstract	ABSTRACT lN/PCT/2002/01151/CH E •1,3-DISUBSTITUTED PYRROLIDINES AS ALPHA-2-ADRENOGEPTOR ANTAGONISTS* The-invention provides compounds of formula I wherein R0, R1, R2 and A are as defined In the description, and the preparation thereof. The compounds of formula I are useful as pharmaceuticals.

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I The present invention relates to novel 1,3-disubstitutecl pyrrolidines, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them. More particularly the invention provides a compound of formula I wherein Ro is hydrogen or (CM)alkyl, Ri is halogen, hydroxy, (Ci^)alkyl, (Ci.4)alkoxy, (C2.5)alkenyloxy, trifluoromethyl or trifluoromethoxy, and can also be hydrogen if A is a group of formula (b), (c), (f) or (g), Rz is hydrogen or as defined for Ri, or, when in ortho position to Ri, can also form with Ri a methylenedioxy group, and A is tetrahydropyran-4-yl or a group of formula wherein m is 1 to 3, X is O. Sor CH=CH, R3 is hydrogen, halogen, hydroxy, (CM)alkyl, hydroxy(CM)alkyl, (CM)alkoxy, trifluoromethyl, (CM)alkylsulfonylamlno, benzyloxy, carbamoyl. (C1.4)aiKyicarDamoyl or cli(C1.4)alkylcarbamoyl, R4and R5 are hydrogen, halogen, (CM)alkyl or (C1.4)alkoxy, R6 is hydrogen, halogen or (C1.4)alkyl, R7 Is hydrogen, (C1.6)alkyl or (C3.7)cycloalkyl(C1^)alkyl, R8 is hydrogen, halogen, hydroxy, (C1.4)alkyl, (CM)alkoxy, amino, (C2.5)alkanoylamlno, benzoylamino, (C1.4)alkylsulfonylannlno, benzylsulfonylamino.furylcarbonylamino, carbamoyl, (Ci.4)alkylcarbamoyl or di(CM)alkylcarbamoyl, and R9 is hydrogen, halogen, (Ci-4)alkyl or phenyl, or R8and R9 together are -0-(CH2)m-0- wherein m is as defined above, R10 is hydrogen, (C1.4)alkyl, (C3-5)cycloalkyl(C1.4)alkyl, (C1.4)alkylcarbonyl, (C3-5)cycloalkylcarbonyl, (C1.4)alkoxycarbonyl, benzyl, benzyloxycarbonyl, benzoyl, (C1.4)alkyIsulfonyl, phenylsulfonyl, benzylcarbonyl, benzylsulfonyl, 2-furylcarbonylamino or N-(C1-4)alkyl-N-(2-furylcarbonyl)amino, and R11 is hydrogen or (CM)alkoxy, in free base or acid addition salt form. On account of the asymmetical carbon atom(s) present in the compounds of formula I and their salts, the compounds may exist in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures. All optical isomers and their mixtures including the racemic mixtures are part of the present invention. Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. Any alkyl and alkoxy radicals are branched or straight chain radicals. They are preferably methyl or methoxy groups. In a further aspect the invention provides a process for the production of the compounds of formula I and their salts, whereby a compound of fomnula n I wherein R1 and R2 are as defined above, is alkylated and the resulting compound is recovered in free base form or as an acid addition salt. The alkylation can be effected in accordance to conventional procedures, for example using an appropriate compound of formula Y-CHRo-A, wherein Ro and A are as defined above and Y is iodine, bromine, chlorine, mesyloxy or tosyloxy, in the presence of a base and in an inert solvent, preferably at elevated temperature, e.g. as described in Example 1. Alternatively a compound RQ-CO-A, wherein Ro and A are as defined above, can be used (reductive alkylation), e.g. as described in Example 4. For the preparation of a compound of formula I wherein Ro is hydrogen, the alkylation can also be effected by acylation with an acid A-COOH, wherein A is as defined above, and subsequent reduction, e.g. as described in Example 2. For the preparation of a compound of formula I wherein A is a group of formula (c) or (e), the substituent R7 or R10 may suitably be introduced after the alkylation or acylation/reduction of the compound of formula n, e.g. as described in Example 3, Compounds of formula I wherein A is as defined above but free from reduceable functional groups (hereinafter A'), can also be obtained by reduction of a compound of fomnula ill m wherein Ro, R1, R2 and A' are as defined above, obtained by ring closure of a diacid of formula IV IV wherein R1 and R2 are as defined above, with an amine H2N-CHR0-A', wherein Ro and A' are as defined above. Worl Compounds of formula I in optically pure form can be obtained from the corresponding racemates according to well-l Acid addition salts may be produced in known manner from the free base forms and vice-versa. The starting compounds of formulae H, IV, Y-CHRo-A and H2N-CHR0-A are known or may be obtained from known compounds, using conventional procedures. The compounds of fomiula I and their pharmaceutically acceptable acid addition salts, hereinafter referred to as agents of the invention, exhibit valuable pharmacological properties when tested in vitro and in animals, and are therefore useful as pharmaceuticals. In binding assays, the agents of the invention display high affinity at 02 adrenoceptor subtypes, with selectivity to 020, as shown in a radioligand binding assay using ^H-RX821002 as a ligand and membranes from CHO K1 cells expressing the recombinant human 02 adrenoceptor subtypes. In this assay, agents of the invention exhibit pKd values of about 6 to about 10. in la vitro antagonist experiments using cAMP-based luciferase reporter gene assays based on transfected CHO K1 cells stably expressing the recombinant human 02 receptors, in presence of the α2 agonists UK 14,304 or noradrenaline, agents of the invention act as competitive antagonists at the cfe receptors with pKe values of about 6 to about 9. In vivo, the agents of the invention inhibit loxapine-induced catalepsy in rats [cf. Kalkman H.O. et a!., Br. J. Pharmacol. 124:1550-1556 (1998)] at doses of about 0.3 to about 30mg/kg s.c. Furthermore the agents of the invention inhibit amphetamine induced locomotion in rats at doses of about 0.3 to abotit 30mg/Kg s.c. Locomotion (ambulatory activity) Is measured as the number of consecutive infrared interruptions in an appropriate device during a period of 15 min. directly following s.c. injection of amphetamine (Img/kg) or solvent (physiological saline) at t=0. The compound or the solvent are administered at t= -30 min. in view of the above, the agents of the invention are useful as antipsychotics in the treatment of schizophrenia, in the treatment of depressiort (including bipolar disorders) and more generally in the treatment of any condition associated with a deficiency of noradrenaline in the central or peripheral nervous system which Is compensated by a-antagonists via blockade of presynaptic a2 receptors, such as cognition deficits, Parkinson disease, drug abuse, attention deficit hyperactivity disorders, glaucoma, diabetes and erectile dysfunction. For the above-mentioned indications, the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.1 to about 100, preferably from about 0.5 to about 100 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 1 to about 500, preferably from about 1 to about 300 mg of an agent of the invention, conveniently administered, for example, in divided doses up to four times a day or in sustained release form. The agent of the invention may be administered by any conventional route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions. In accordance with the foregoing, the present invention also provides an agent of the invention, for use as a pharmaceutical, e.g. for the treatment of schizophrenia. The present invention furthermore provides a pharmaceutical composition comprising an agent of the invention in association with at least one pharmaceutical carrier or diluent. Such compositions may be manufactured In conventional manner. Unit dosage forms contain, for example, from about 0.25 to about 150, preferably from 0.25 to about 25 mg of a compound according to the invention. For all the above indications, the preferred compounds are (R)-1-isopropyl-5-[3-(2-methoxyphenyl)pyrrolidin-1 -ylmethyl]-1 H-pyridin-2-one and (R)-1 -(2,3,-dihydro-benzo-[1,4]dioxin-6-ylmethyl)-3-(2-methoxyphenyl)pyrrolidine. In the above-mentioned loxapine-induced catalepsy test, both compounds show with 0.3-3mg/kg s.c. a long lasting, dose-dependent inhibition of catalepsy. An oral dose of 10mg/kg produces similar inhibition as 3mg/kg s.c. In the above mentioned amphetamine-induced locomotion test, both compounds dose-dependently reduce locomotion at 0.1, 0.3 and Img/kg s.c. (first mentioned compound) and 1, 3 and lOmg/kg s.c, (second compound). The preferred indications are schizophrenia and depression. Moreover the present invention provides the use of an agent of the invention, for the manufacture of a medicament for the treatment of any condition mentioned above. In still a further aspect the present invention provides a method for the treatment of any condition mentioned above, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of an agent of the invention. The following examples illustrate the invention. The temperatures are given in degrees Celsius and are uncorrected. Example 1:1 -d .4-Dioxaspirof4.51dec-8-vlmethvl)-3-(2-methoxvphenvl)pvrrolicline 1 g of 3-(2-Methoxyphenyl)pyrrolidine is dissolved in 60 ml of dioxane and 0.85 g Nal, followed by 1.2 ml of N,N-ethyldiisopropylamine and 1.5 g of 8-bromomethyl-1.4-dioxaspiro[4.5]decane, dissolved in 5 ml of dioxane, are added. The reaction mixture is stirred overnight at 80°, evaporated and the residue extracted with ethylacetate/2N Na2C03, followed by aqueous NaCI. The combined, dried and evaporated organic phases yields an oily residue which is purified by flash chromatography on silica gel using t-butylmethylether as a solvent system providing the product as an oil. MS (El): M* = 331; NMR (DMSO): 1.1 (2H, m), 1.45 (3H, m), 1.6-1.8 (5H, m), 2.15 (1H, m), 2.25 (2H, m), 2.4 (1H, t), 2.6 (2H, m), 2.8 (1H, t), 3.6 (1H, t), 3.75 (3H, s), 3.85 (4H, s), 6.9 (2H, dd), 7.15 (1H, t), 7.3 (1H, d). Example 2: (+)-5-f3-(2-methoxvphenyl)pvrrolidin-1 -vlmethvl]-1 H-pvridin-2-one 10.5 g of (-)-5-[3-(2-methoxyphenyl)pyrrolidin-1-carbonyl]-1H-pyridin-2-one dissolved in 100 ml of THF are added at 0° to a suspension of 6.7 g of LiAIH4 in 200 ml of THF. The temperature of the reaction mixture is allowed to reach room temperature while stirring is continued for 17 hours. Subsequently, the reaction mixture is hydrolysed with NH4CI solution and filtered. The filtrate is evaporated and partitioned between CH2CI2 and 1N Na2C03, followed by aqueous NaCI. The combined organic phases are dried and evaporated and the resulting oil purified by flash chromatography on silica gel using CHaCla/MeOH 9/1 as solvent system providing the product as an oil: [oo^^] = + 31.4° (c=1.0, EtOH); MS (El): M* = 284; NMR (DMSO): 1.75 (1H, m), 2.15 (1H, m), 2.4 (1H, t), 2.6 (2H, m), 2.8 (1H. t), 3.3-3.4 (2H, m), 3.6 (1H, m), 3.75 (3H, s), 6.3 (1H, d), 6.85-6.95 (2H, m), 7.15 (1H, t), 7.2 (1H, s), 7.25 (1H, d), 7.45 (1H, dd), 11.4 (1H, s). The starting (-)-5-[3-(2-methoxyphenyl)pyrrolldin-1 -carbonyl]-1 H-pyridin-2-one is prepared as follows: 6.26 g of 6-hydroxynicotinic acid are suspended in 300 ml of DMF and 9.3 g N,N'-dicyclohexylcarbodlimide, followed by 6.1 g of 1-hydroxybenztriazole are added. After 30 minutes of stirring at room temperature, 8.0 g of (-)-3-(2-methoxyphenyl)pyrrolldine, dissolved in 45 ml of DMF, is added to the resulting solution and stining continued overnight. Dicyclohexylurea is filtered off, the resulting filtrate evaporated and the residue partitioned between ethylacetate and 2N HCI, followed by aqueous NaCI solution. The combined organic phases are dried and evaporated and the resulting residue purified by flash chromatography on silica gel using CH2Cl2/MeOH/conc. aqueous NH4OH 95/4.5/0.5 as solvent system providing the product as a white foam: [ αD 25] = - 34.7° (c=1.0, EtOH); MS (CI): MH* = 299; NMR (DMSO): 2.05 (1H, m), 2.15 (1H, m), 3.45-3.9 (8H, m), 6.35 (1H, d), 6.9-7.05 (2H, m), 7.25 (2H, m), 7.65 (1H, dd), 7.75 (1H, s), 11.9 (1H, s). Example 3: (+)-1 -lsopropyl-5-[3-(2-methoxvphenvl)pyrrolidin-1 -ylmethvl]-1 H-pvridin-2-one and (+)-2-lsopropoxv-5-[3-(2-methoxvphenyl)pvrrolidin-1-vlmethyl]-1H-pvridine 9.75 g of (+)-5-[3-(2-methoxyphenyl)pyrrolidin-1 -ylmethyl]-1 H-pyrldin-2-one (example 2) are dissolved in 170 ml of toluene. 14.2 g of Na2C03, followed by 6.9 ml of isopropyl-iodide are added to the solution which is stirred at 100° overnight. Subsequently, another 3.4 g of isopropyliodide are added and stirring continued for additional 17 hours. The reaction solution is extracted with water and the combined organic phases dried and evaporated resulting in an oily residue which is purified by flash chromatography on silica gel using CHaCla/MeOH/conc. aqueous NH4OH 95/4.5/0.5 as solvent system which provides (+)-1-lsopropyl-5-[3-(2-methoxyphenyl)pyrrolidin-1 -ylmethyl]-1 H-pyridin-2-one {[ αD = +19.7° (c=1.0, EtOH); MS (CI): MH* = 327; NMR (DMSO, 120°): 1.3 (6H. d), 1.95 (1H, m), 2.3 (1H. m), 2.7-3.4 (4H, m), 3.6-3.8 (3H, m), 3.8 (3H. s), 5.0 (1H, q), 6.35 (1H, d). 6.9-7.0 (2H, m), 7.2 (1H, t), 7.3 (1H, m), 7.4 (1H, m), 7.6 (1H, m)} and (+)-2-lsopropoxy-5-[3-(2-methoxyphenyl)pyrrolidln-1-ylmethyl]-1H-pyridlne {[ αD 25] = + 22.8° (c=1.0, EtOH); MS (El): M* = 326; NMR (DMSO): 1.3 (6H, d), 1.75 (1H, m), 2.15 (1H, m), 2.4 (1H, t), 2.65 (2H, m), 2.8 (1H, t), 3.5-3.65 (3H. m), 3.75 (3H, s), 5.2 (1H. m), 6.7 (1H, d), 6.85-6.95 (2H, m), 7.15 (1H, t), 7.3 (1H, d), 7.6 (1H. m). 8.05 (1H, s)} Example 4: (+)-1-(2.3-Dihvdroben2ri.41dloxln-6-methvl)-3-(2-methoxvphenvnpvrrolldine 1.77 g of (-)-3-(2-methoxyphenyl)pyrrolidine, followed by 1.8 g of 2,3-dihydroben2[1.4]-dioxlne-6-carbaldehyde are dissolved in 40 ml of MeOH. 1.26 g of NaCNBHs is added and the reaction mixture stirred during 3 hours at room temperature. The solvent is evaporated and the residue partitioned between ethylacetate and water. The organic phases are combined, dried and evaporated and the resulting oily residue purified by flash chromato¬graphy on silica gel using ethylacetate/hexane 1/9 as solvent system. The product is . obtained as an oil which is transformed into the hydrochloride salt: mp 201-202°; [ αD20] = + 9.7° (c=1.0, MeOH); MS (ES): MH* = 326; NMR (DMSO/NaOD): 1.7 (1H, m), 2.15 (1H, m). 2.35 (1H, q), 2.6-2.7 (2H, m), 2.8 (1H, t), 3.45 (1 H,q), 3.55 (1H, q), 3.75 (3H, s), 4.2 (4H, s), 6.75-6.95 (5H, m), 7.15 (1H, t), 7.25 (1H, d). Example 5: (-)-2-[1-(2.3-Dihydrobenzof1.41dioxin-6-ylmethvnpvrrolidin-3-vl1phenol 450 mg of (-)-2-pyrrolidin-3ylphenol, followed by 520 mg of of 2,3-dihydrobenz[1.4]-dioxine-6-carbaldehyde are dissolved in 10 ml of MeOH. The pH is adjusted to 5.5 by addition of acetic acid and the reaction solution is stirred for 2 hours, before 443 mg of NaCNBHa is added in portions. Stirring Is continued overnight, the solvent subsequently evaporated and the residue purified by flash chromatography on silica gel with CH2Cl2/EtOH/conc. aqueous NH4OH 95/4.5/0.5 which provides the product as an oil: [ αD 20] = - 35.6° (c=0.75, EtOH); MS (El): M^ = 311; NMR (DMSO): 1.7 (1H, m), 2.2-2.4 (2H, m), 2.6 (1H, t), 2.75 (1H, dd), 2.95 (1H, t), 3.4 (1H, m), 3.6 (2H, q), 4.25 (4H, s), 6.65 (1H, t), 6.7 (1H, d), 6.75-6.85 (3H, m), 6.95-7.05 (2H, m). The starting (-)-5-[3-(2-methoxyphenyl)pyrrolidin-1-carbonyl]-1H-pyridin-2-one is prepared as follows: 500 mg of (-)-3-(2-methoxyphenyl)pyrrolldine are dissolved In 12 ml of CH2CI2, 8.5 ml of a 1 M BBra solution in CH2CI2 is addded dropwise at 0° and stirring continued overnight. The reaction mixture is poured on IN Na2C03 solution, extracted with CH2CI2 and the organic phases washed with brine, dried, evaporated and purified by flash chromatography on silica gel with CH2Cl2/EtOH/conc. aqueous NH4OH 88/10.8/1.2 providing the product as an oil: MS (El): M* = 163; NMR (DMSO, 120°): 1.85 (1H, m), 2.2 (1H, m), 2.8 (2H, broad), 2.95-3.05 (2H, m), 2.2-2.4 (2H. m), 3.5 (1H, m), 6.7 (1H, t), 6.8 (1H, d), 7.05 (1H, m), 7.1 (1H, dd). Example 6:1-Benzv!-3-(5-ch!oro-2-methoxvphenvnpvrrolidine 730 mg of 1-benzyl-3-(5-chloro-2-methoxyphenyl)pyrroline-2,5-dione are dissolved in 2 mi of acetyichioride and stirred at room temperature for 24 hours. The acetylchioride is evaporated, the residue dried and added to a suspension of 295 mg of LiAIH4 in 15 ml of ether. The reaction mixture is stirred during 30 minutes, hydrolyzed, filtered and partitioned between CH2CI2 and 2N Na2COs, followed by aqueous NaCI. The combined, dried and evaporated organic phases yield an oil which is purified by flash chromatography using ethylacetate/hexane 1/1 providing the product as a colorless oil: MS (CI): MH* = 302; NMR (DMSO): 1.7 (1H, m), 2.2 (1H, m), 2.4-2.8 (5H, m), 3.6 (2H, q), 3.75 (3H, s), 6.95 (1H, d). 7.15-7.35 (7H, m). The starting 1-Benzyl-3-(5-chloro-2-methoxyphenyl)pyrroline-2,5-dione is prepared as follows: 1.0 g of 2-(5-chloro-2-methoxyphenyl)succinic acid is suspended In 50 ml of xylene, 0.47 ml of benzylamine is added and the mixture refluxed for 8 hours with separation of water. The solvent is evaporated and the residue taken up in ethylacetate and extracted with 2N HCI, followed by 2N NaOH and aqueous NaCI. The organic layer is dried, filtered and the solvent evaporated. The dried residue is purified by flash chromatography using t-butylmethylether/hexane 1/1 providing the amorphous product: MS (El): M* = 329; NMR (DMSO): 2.65 (1H, dd), 3.1 (1H, dd), 3.45 (3H, s), 4.2 (1H, dd), 4.6 (2H, s), 7.0 (1H, d), 7.25-7.4 (7H, m). The following compounds of formula I wherein Ro, Ri, R2 and A have the significancies indicated in the table are produced analogously to Example 1. The compounds marked "A" under "Remarks" are preferably produced analogously to Example 2, the compounds marked "B" preferably analogously to Example 4 or 5, and the compounds marked "C preferably analogously to Example 3. .WE CLAIM: wherein F?o is hydrogen or (CM)alkyl, Ri is (Gi^)alkoxy or (C2.8)all trifiuoromethyl or trifluoromethoxy if A is a group of formula (b), (c), (e), (f) or (g), and can also be hydrogen if A is a group of formula (c), (0 or (g) or if A is a group of formula (b) and R2 is not hydrogen, R2 is hydrogen, halogen, hydroxy, (C1-4)alkyl, (C1-4)alkoxy, (C2,s)alkenyloxy. trifiuoromethyl or trifluoromethoxy, or, when in ortho position to R1, can also form with R1 a methylenedioxy group, and A is tetrahydropyran-4-yl or a group of formula wherein m is 1 to 3, X is O, S or CH=CH, R3 is hydrogen, halogen, hydroxy, (C1-4)alkyl, hydroxy(C1-4)alkyl, (CM)alkoxy, trifiuoromethyl, {CM)alkylsulfonyIamino, benzyloxy, carbamoyl, (C1-4)alkylcarbamoyl or di(CM)alkylcarbamoyl, R4and R5 are hydrogen, halogen, {CM)alkyl or (C1-4)alkoxy, R6 is hydrogen, halogen or (C1-4)a!kyl, R7 is hydrogen(C1-4))alkyl or (C3.7)cycloalkyl(CM)alkyl, Ra is hydrogen, halogen, hydroxy, (C1-4)alkyl, (CM)alkoxy, amino, {C2.5)alkanoylamino, benzoylannino, (C1-4)alkylsu[fonyIannino, benzylsulfonylamincfurylcarbonylamino, carbamoyl, (C1-4)alkylcarbamoyi or dl(C1-4)alkylcarbamoyl, and R9 Is hydrogen, halogen, (C1-4,)alkyl or phenyl, or Ra and R9 together are -0-(CH2)m-0- wherein m is as defined above, R10 is hydrogen, (CM)alkyl, (C3-6)cycloa!kyl(C1-4)alkyl, (C1-4)alkylcarbonyl, (C3.6)cycloalkylcarbonyl, (C1-4)alkoxycarbonyl, benzyl, benzyloxycarbonyl, benzoyl, (CM)alkylsulfonyl, phenylsulfonyl, benzylcarbonyl, benzylsulfonyl, 2-furylcarbonylamino or N-(CM)alkyl-N-(2- furylcarbonyl)amino, and R11 is hydrogen or (CM)alkoxy, in free base or pharmaceutically acceptable acid addition salt form. 2. The compound as claimed in claim 1, which is selected from (a) (S)-1-lsopropyl-5-[3-(2-methoxyphenyl)pyn'olidin-1-ylmethyl]-lH-pyridin-2- one. (b) (S)-1 -(2,3-Dihydrobenzo[1,4]dioxin-6-ylmethyl)-3-(2-methoxyphenyl)pyrrolidine . 3. A process for the production of a compound of formula I as defined in claim 1. which comprises alkylating a compound of formula II II wherein R1 and R2 are as defined in claim 1, and recovering the resulting compound in free base form or as an acid addition salt. 4, A pharmaceutical composition comprising a compound of any one of claims 1 to 3 in free base or pharmaceutically acceptable acid addition salt form, in association with a

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