Title of Invention	PYRIDO(2,1-A)ISOQUINOLINE DERIVATIVES AS DPP-IV INHIBITORS
Abstract	The present invention relates to compounds of formula (I) wherein R<sup>1</sup>, R<sup>2</sup>, R<sup>3</sup>, R<sup>4</sup>, R<sup>5</sup> and R<sup>6</sup> are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prophylaxis of diseases which are associated with DPP-IV, such as diabetes, particularly non-insulin dependent diabetes mellitus, and impaired glucose tolerance.

Title of Invention

PYRIDO(2,1-A)ISOQUINOLINE DERIVATIVES AS DPP-IV INHIBITORS

Abstract

The present invention relates to compounds of formula (I) wherein R1, R2, R3, R4, R5 and R6 are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prophylaxis of diseases which are associated with DPP-IV, such as diabetes, particularly non-insulin dependent diabetes mellitus, and impaired glucose tolerance.

Full Text	PYRIDO(2,1-A)ISOQUINOLINE DERIVATIVES AS DPP-IV INHIBITORS Novel Pyrido[2J-a1isoquinQline Derivatives The present invention is concerned with novel pyrido [2,l-a] isoquinoline derivatives, their manufacture and their use as medicaments. In particular, the invention relates to compounds of the formula (I) wherein R’ is lower alkyl, aryl, heteroaryl or lower alkyl substituted by cycloalkyl, by’ aryl or by heteroaryl; R’, R’ and R’ are each independently hydrogen,, halogen, hydroxy, lower alkyi, lower alkoxy) or lower alkenyl, wherein lower alkyl, lower alkoxy and lower alkenyl may optionally be substituted by lower alkoxycarbonyl, aryl or heterocyclyl; R is hydrogen, fluorine, lower alkyl, or aryl; R is hydrogen, lower alkyl or hydroxy-lower alkyl, or R’ and R’ together with the carbon atoms to which they.are attached form a five or six membered saturated carbocyclic ring; R is hydrogen, fluorine or lower alkyl; and pharmaceutically acceptable salts thereof. The enzyme dipeptidyl peptidase IV (EC.3.4.14.5, abbreviated in the following as DPP-IV) is involved in the regulation of the activities of several hormones. In particular DPP-IV is degrading efficiently and rapidly glucagons like peptide 1 (GLP-1), which is one of the most potent stimulator of insulin production and secretion. Inhibiting DPP-IV would potentiate the effect of endogenous GLP-l, and lead to higher plasma insulin concentrations. In patients suffering from impaired glucose tolerance and type 2 diabetes mellitus, higher plasma insulin concentration would moderate the dangerous hyperglycaemia and accordingly reduce the risk of tissue damage. Consequently, DPP-IV inhibitors have been suggested as drug candidates for the treatment of impaired glucose tolerance and type 2 diabetes emeritus (e.g. Villagers, W098/1999S). Without disclosing any medical use, Buzas et al., Lab. Chime. Org. V, Fac. Sci., Orleans, Fr. Chim. Ther. (1992), 7(5), 404-7 describe synthesis of the compounds of Examples 41 and 42 below. We have found novel DPP-IV inhibitors that very efficiently lower plasma glucose levels. Consequently, the compounds of the present invention are useful for the treatment and/or prophylaxis of diabetes, particularly non-insulin dependent diabetes mellitus, and/or impaired glucose tolerance, as well as other conditions wherein the ampUfication of action of a peptide normally inactivated by DPP-IV gives a therapeutic benefit. Surprisingly, the compounds of the present invention can also be used in the treatment and/or prophylaxis of Bowl disease. Colitis Ulcerous, Morbus Crown, obesity and/or metabolic syndrome. Furthermore, the compounds of the present invention can be used as diuretic agents and for the treatment and/or prophylaxis of hypertension. Unexpectedly, the compounds of the present invention exhibit improved therapeutic and T’harmacological ‘properties compared to other DPP-IV inhibitors known in the art, such as e.g. in context with pharmacokinetic and bioavailability. Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein. In this specification the term "lower" is used to mean a group consisting of one to six, preferably of one to four carbon atom(s). The term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably to chlorine. The term "alkyl", alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms. The term "lower-alkyl", alone or in combination with other groups, refers to a branched or straight-chain monovalent alkyl radical of one to six carbon atoms, preferably one to four carbon atoms. This term is further exemplified by radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-pentyl, 3-methylbutyl, n-hexyl, 2-ethylbutyl and the like. The term "cycloalkyl" refers to a monovalent carbocyclic radical of three to six carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, with cyclopropyl being preferred. The term "alkoxy" refers to the group R'-O-, wherein R' is alkyl. The term "lower-alkoxy" refers to the group R'-O-, wherein R' is lower-alkyl. Examples of lower-alkoxy groups are e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy, with methoxy being especially preferred. The term "lower alkoxycarbonyl" refers to the group R'-O-C(O)-, wherein R' is lower alkyl. The term "heterocyclyl" refers to a 5- or 6-membered aromatic or saturated N-heterocyclic residue, which may optionally contain a further nitrogen or oxygen atom, such as imidazolyl, pyrazolyl, thiazolyl, phenyl, pyridyl, pyrimidyl, morpholino, piperazino, piperidino or pyrrolidino, preferably pyridyl, thiazolyl or morpholino. Such heterocyclic rings may optionally be mono-, di- or tri-substituted, independently, by lower alkyl, lower alkoxy, halo, cyano, azido, amino, di-lower alkyl amino or hydroxy. Preferable substituent is lower alkyl, with methyl being preferred. The term "aryl" refers to an aromatic monovalent mono- or polycarbocyclic radical, such as phenyl or naphthyl, preferably phenyl, which may optionally be mono-, di- or tri-substituted, independently, by lower alkyl, lower alkoxy, halo, cyano, azido, amino, di-lower alkyl amino or hydroxy. The term "heteroaryl" refers to a 5- or 6-membered, unsaturated aromatic monovalent cyclic radical containing one to three, preferably one or two, heteroatoms independently selected from nitrogen, sulfur and oxygen, with nitrogen being preferred. Examples of heteroaryl residues are pyrrolyl, pyridinyl and pyrimidinyl, with pyrrolyl and pyridinyl being preferred. Said heteroaryl residues may be mono-, di- or tri-substituted, independently, by halogen, amino, perfluoro-lower alkyl, lower alkyl or lower alkoxy.The term "pharmaceutically acceptable salts" embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulphonic acid, salicylic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms. Preferred salts with acids are formats, maleate, citrates, hydrochlorides, hydro bromides and methanesulfonic acid salts, with hydrochlorides being especially preferred. In one embodiment, the present invention relates to a compound of formula (I) as defined above, wherein R’ is lower alkyl, aryl or lower alkyl substituted by cycloalkyl or by aryl; R , R and R are each independently hydrogen, hydroxy, lower alkyl, lower alkoxy or lower alkenyl, wherein lower alkyl, lower alkoxy and lower alkenyl may optionally be substituted by lower alkoxycarbonyl, aryl or heterocyclyl; R and R are each independently hydrogen, lower alkyl, aryl or, together with the carbon atoms to which they are attached form a five or six membered saturated carbocyclic ring; and pharmaceutically acceptable salts thereof In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein R’ is lower alkyl, phenyl, or cycloalkyl-lower alkyl; R’, R’ and R’ are each independently hydrogen, hydroxy, lower alkoxy; or lower alkoxy substituted by aryl, heterocyclyl or lower alkoxycarbonyl. Preferable aryl residues in R , R and R are phenyl or phenyl substituted by di-lower aDcyl amino or cyano. Preferable heterocyclyl residues in R , R and R are morpholino, pyridyl, thiazolyl or thiazolyl substituted by lower alkyl Preferable lower alkoxycarbonyl residues in R', R and R are ethoxycarbonlymethoxy. In another preferable embodiment, the present invention relates to a compound of formula (I) as defined above, wherein R is lower alkyl, phenyl, phenyl substituted by lower alkyl or by lover alkoxy, or R’ is heteroaryl such as Truly and pyridinyl, or cycloalkyl-lower alkyl; R , R and R are each independently hydrogen, hydroxy, lower alkoxy; or lower alkoxy substituted by aryl, by heterocyclyl or by lower alkoxycarbonyl; R’ is hydrogen, lower alkyl or phenyl mono- or di-substituted by lower alkyl, lower alkoxy or halogen; R’ is hydrogen, lower alkyl or hydroxy-lower alkyl; or R’ and R’ together with the carbon atoms to which they are attached form a five or six membered saturated carbocyclic ring; and R is hydrogen or lower alkyl. In one embodiment, residue R’ is lower alkyl or lower alkyl substituted by cycloalkyl, preferably cyclopropyl. Preferable lower residues R’ are n-propyl, n-butyl, isobutyl, 3-methylbutyl and 2-ethylbutyl, most preferred are n-propyl, n-butyl and 3-methylbutyl. Preferable lower Al substituted by cycloalkyl is cyclopropylmethyl. In another embodiment, R’ is aryl, preferably phenyl. Aryl residues R’ maybe mono-, di- or tri-substituted, independently, by lower alkyl, lower alkoxy or hydroxy, preferably by lower alkyl or lower alkoxy. Preferably, aryl residues R’ are unsubstituted. In still another embodiment, R is a heteroaryl residue selected from pyridinyl, pyrimidinyl and pyrrolyl. Preferred heteroaryl residues R’ are pyridinyl or pyrrolyl. The said heteroaryl residues R’ may be mono-, di- or tri-substituted, independently, by lower alkyl, lower alkoxy, or hydroxy, preferably by lower alkyl or lower alkoxy. Preferably, heteroaryl residues R are unsubstituted. Most preferred R’ are lower alkyl, preferably n-butyl, or unsubstituted phenyl. In one preferable embodiment, residue R is lower alkoxy, preferably methoxy, hydrogen or hydroxy. Most preferable residue R is methoxy. In another preferable embodiment, residue R is lower alkoxy, with methoxy, ethoxy, propoxy, n-butoxy and isobutoxy being preferred, hydrogen, hydroxy; or lower alkoxy, preferably methoxy or ethoxy, substituted by aryl, by heterocyclyl or by lower alkoxycarbonyl. Preferable aryl substituents in R are unsubstituted phenyl or phenyl mono-substituted by di-lower alkyl amino, with dimethylamino being preferred, or by cyano. Most preferable aryl substituents in R is unsubstituted phenyl. More preferable residues R are lower alkoxy, preferably methoxy, hydrogen or hydroxy. Most preferred residue R’ is methoxy or hydroxy, with methoxy being especially preferred. In another preferable embodiment, residue R is lower alkoxy, preferably methoxy, hydrogen or hydroxy. Most preferable residue R’ is hydrogen. In one embodiment, R’ is hydrogen, lower alkyl, with methyl being preferred, or aryl. Preferable aryl residues R’ are unsubstituted phenyl or phenyl mono-, di- or tri-substituted, independently, by lower alkyl, lower alkoxy or halogen. Most preferable aryl residue R’ is unsubstituted phenyl. In another embodiment, R’ is hydrogen, lower alkyl, with methyl being preferred, or hydroxy-lower alkyl, with 2-hydroxy-ethyl being preferred. Preferably, R’ is hydrogen. In still another embodiment, R and are hydrogen or, together with the carbon atoms to which they are attached, form a six membered saturated carbocyclic ring. The present invention also relates to a process for the manufacture of compounds of formula (I) as defined above, which process comprises reducing an oxide of formula (II) > optionally followed by conversion into a pharmaceutically acceptable salt thereof Hydrogenation of the above oxime of formula II can be performed according to methods known in the art. For example, the reaction can be performed in the presence of a catalyst such as Raney nickel, platin or palladium in an inert solvent, such as ethanol, at a temperature of about 20°C to SO'‘C. Hydroxy groups in the compounds of formula II can be present in a protected form, for example as a benzyl ether. Such protecting groups can be removed according to processes known in the art, e.g. in case of benzyl ether by catalytic hydrogenation. Oximes of formula II are known in the art or can be prepared starting from ketones of the formula III by methods known in the art and as exemplified or in analogy thereto. Compounds of formula (III): manufactured according to a process as defined above. As described above, the compounds of formula (I) of the present invention can be used as medicaments for the treatment and/or prophylaxis of diseases which are associated with DPP-IV such as diabetes, particularly non-insulin dependent diabetes mellitus, impaired glucose tolerance, Bowl disease, Colitis Ulcerosa, Morbus Crohn, obesity, and/or metabolic syndrome, preferably non-insulin dependent diabetes mellitus and/or impaired glucose tolerance. Furthermore, the compounds of the present invention can be used as diuretic agents or for the treatment and/or prophylaxis of hypertension. The invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant Further, the invention relates to compounds as defined above for use as therapeutic active substances, particularly as therapeutic active substances for the treatment and/or prophylaxis of diseases which are associated with DPP-IV such as diabetes, particularly non-insulin dependent diabetes mellitus, impaired glucose tolerance, Bowl disease, Coatis Ulcerosa, Morbus Crohn, obesity, and/or marabou syndrome, preferably for use as therapeutic active substances for the treatment and/or prophylaxis of non-insulin dependent diabetes mellitus and/or impaired glucose tolerance. Furthermore, the invention relates to compounds as defined above for use as diuretic agents or for use as therapeutic active substances for the treatment and/or prophylaxis of hypertension. In another embodiment, the invention relates to a method for the treatment and/or prophylaxis of diseases which are associated with DPP-IV such as diabetes, particularly non-insulin dependent diabetes mellitus, impaired glucose tolerance. Bowl disease, Colitis Ulcerosa, Morbus Crohn, obesity, and/or metabolic syndrome, preferably for the treatment and/or prophylaxis of non-insulin dependent diabetes mellitus and/or impaired glucose tolerance, which method comprises administering a compound as defined above to a human being or animal. Furthermore, the invention relates to a method for the treatment and/or prophylaxis as defined above, wherein the disease is hypertension or wherein a diuretic agent has a beneficial effect. The invention further relates to the use of compounds as defined above for the treatment and/or prophylaxis of diseases which are associated with DPP-IV such as diabetes, particularly non-insulin dependent diabetes mellitus, impaired glucose tolerance, Bowl disease. Colitis Ulcerosa, Morbus Crohn, obesity, and/or metabolic syndrome, preferably for the treatment and/or prophylaxis of non-insulin dependent diabetes merits and/or impaired glucose tolerance. Furthermore, the invention relates to the use as defined above, wherein the disease is hypertension or to the use as diuretic agent. In addition, the invention relates to the use of compounds as defined above for the preparation of medicaments for the treatment and/or prophylaxis of diseases which are associated with DPP-IV such as diabetes, particularly non-insulin dependent diabetes mellitus, impaired glucose tolerance. Bowl disease. Colitis Ulcerosa, Morbus Crohn, obesity, and/or metabolic syndrome, preferably for the treatment and/or prophylaxis of non-insulin dependent diabetes merits and/or impaired glucose tolerance. Such medicaments comprise a compound as defined above. Furthermore, the invention relates to the use as defined above, wherein the disease is hypertension or the use for the preparation of diuretic agents. In context with the methods and uses defined above, the following diseases relate to a preferred embodiment: diabetes, particularly non-insulin dependent diabetes mellitus, impaired glucose tolerance, obesity, and/or metabolic syndrome, preferably non-insulin dependent diabetes meUitus and/or impaired glucose tolerance. The compounds of formula (I) can be manufactured by the methods given below, by the methods given in the Examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to the person skilled in the art. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below or in the Examples or by methods known in the art. The following tests were carried out in order to determine the activity of the compounds of formula I. Activity of DPP-IV inhibitors are tested with natural human DPP-IV derived from a human plasma pool or with recombinants human L>PP-IV. Human citrate plasma from different donors is pooled, filterted through a 0.2 micron membrane under sterile conditions and aliquots of 1 ml are shock frozen and stored at -120°C until used. In the colorimetric DPP-IV assay 5 to 10 pi human plasma and in the fluorometric assay 1.0 \x\ of human plasma in a total assay volume of 100 Jul is used as an enzyme source. The cDNA of the human DPP-IV sequence of amino acid 31 — to 766, restricted for the N-terminus and the Tran membrane domain, is cloned into pichia pastoris. Human DPP-IV is expressed and purified from the culture medium using conventional column chromatography including size exclusion and anion and cation chromatography. The purity of the final enzyme preparation of Compassed blue SDS-PAGE is > 95 %. In the colorimetric DPP-IV assay 20 ng rec.-h DPP-IV and in the fluorometric assay 2 ng reek DPP-IV in a total assay volume of 100 is used as an enzyme source. In the fluorogenic assay Ala-Pro-7-amido-4-trifluoromethylcoumarin (Caliches No 125510) is used as a substrate. A 20 mM stock solution in 10 % DMF/H2O is stored at- 20°C until use. In IC50 determinations a final substrate concentration of 50 used. In assays to determine kinetic parameters as Km, Amax Kj, the substrate concentration is varied between 10 p-M and 500 In the colorimetric assay H-Ala-Pro-pNA.HCl (Sachem L-1115) is used as a substrate. A 10 mM stock solution in 10% MeOH/HiO is stored at-20X until use. In IC50 determinations a final substrate concentration of 200 is used. In assays to determine kinetic parameters as Km, Amax Kii, the substrate concentration is varied between 100 \|iM and 2000 . Fluorescence is detected in a Perkin Elmer Luminescence Spectrometer LS SOB at an excitation wavelength of 400 nm and an emission wavelength of 505 nm continuously every 15 seconds for 10 to 30 minutes. Initial rate constants are calculated by best fit linear regression. The absorption of pNA liberated from the colorimetric substrate is detected in a Packard SpectraCount at 405 nM continuo sly every 2 minutes for 30 to 120 minutes. Initial rate constants are calculated by best fit linear regression. DPP-IV activity assays are performed in 96 well plates at 37°C in a total assay volume of 100 Jil. The assay buffer consists of 50 mM Tris/HCl pH 7.8 containing 0.1 mg/ml BSA and 100 mM NaCl. Test compounds are solved in 100 % DMSO, diluted to the desired concentration in 10% DMSO/H2O. The final DMSO concentration in the assay is 1 % (v/v). At this concentration enzyme inactivation by DMSO is IC50 determinations of test compounds are calculated by non-linear best fit regression of the DPP-IV inhibition of at least 5 different compound concentrations. Kinetic parameters of the enzyme reaction are calculated at least 5 different substrate concentrations and at least 5 different test compound concentrations. The preferred compounds of the present invention exhibit IC50 values of 1 nM to 10 more preferrably of 1 - 100 nM, as shown in the following table. The compounds of formula I and/or their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils. Oral administration is preferred. The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants. Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers might, however, be required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols’ polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives. Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants. The dosage of the compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 to 1000 mg, especially about 1 to 100 mg, comes into consideration. Depending on severity of the disease and the precise pharmacokinetic profile the compound could be administered with one or several daily dosage units, e.g. in 1 to 3 dosage units. The pharmaceutical preparations conveniently contain about 1-500 mg, preferably 1-100 mg, of a compound of formula I. The following Examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner. Examples Abbreviations: MS = mass spectrometry, ISP = ion spray (positive ion) corresponds to ESI (electrospray, positive ion), b.p. = boiling point, m.p. = melting point, aq. = aqueous, r.t = room temperature. Example 1 mc-3\|3-Butyl-9,10-dimethoxy-l,3,4,6,7,llbp-hexahydro-2H-pyrido[2,l-a]isoquinolin-2P-ylamine and rac-3P-butyl-9,10-dimethoxy-l,3,4,6,7,llb\|3-hexahydro-2H-pyrido[2,l-a]isoquinoHn-2a-ylamine (i) A solution of 6.8 g of 3,4-dihydro-6,7-dimethoxy-isoquinoline in 70 ml of ethanol is treated with 11.4 g of (2-acetylhexyl)trimethylammonium iodide and heated under reflux for 1.5 hours. The reaction mixture is cooled down and treated with a solution of 6.8 g of potassium hydroxide in 70 ml of water. The ethanol is evaporated and the aq. solution is extracted three times with 80 ml of dichlormethane. The combined organic solutions are dried over anhydrous sodium sulfate and evaporated. The solid red residue is purified by chromatography (silica gel, hexane/ethyl acetate 4:1) and crystallized from isopropyl ether. 7.0 grac-3p-Butyl-9,10-dimethoxy-l,3,4,6,7,llbp-hexahydro-pyrido[2,l-a]isoquinolin-2-one are obtained, m.p. = 117°C. (ii) A solution of 5.5 g hydroxylamine hydrochloride in 50 ml of water and 20 ml of ethanol is made alkaline (pH 9) with 7.27 ml of N sodium hydroxide solution and a solution of 3.35 g rac-3p-butyl-9,10-dimethoxy-l,3,4,6,7,llbp-hexahydro-pyrido[2,l-a]isoquinolin-2-one in 50 ml of ethanol is added. The reaction mixture is stirred for 45 minutes at 45°C, half concentrated and then cooled to 0°C. The precipitated product is filtered and washed with ethanol/water (1:1), subsequently with water. 3.26 g rac-3P-butyl-9,10-dimethoxy-l,3,4,6,7,llbP-hexahydro-pyrido[2,l-a]isoquinolin-2-oneoximeare obtained, m.p. = 143-145°C. (iii) A suspension of 1.5 g rac-3\|3-butyl-9,10-dimethoxy-l,3,4,6,75llbp-hexahydro-pyrido[2,l-a]isoquinolin-2-one oxime in 40 ml of ethanol and 40 ml of water is treated with 1.25 g of a nickel-aluminum alloy and 4.935 ml of an aq. 32% sodium hydroxide solution are added dropwise.The mixture is stirred thoroughly for four hours at room temperature, then filtered and washed with ethanol/water (1:1). The filtrate is extracted twice with dichloromethane and the combined organic solutions are washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated. The solid residue is purified by chromatography (silica gel, dichloromethane- Trifluoroacetic acid (18 mL) was added at CC to a solution of 2-aInino-9,10-dimethoxy-l,6,7,llb-tet’ahydro-4H-py’ido[2,l-a]isoquinoline-3-ca’box7lic acid ethyl ester (LOO g, 3.01 mmol) in tetrahydrofuran (9 mL), then after 30 rain the homogeneous solution was treated with sodium borohydride (237 mg, 6.02 mmol) and stirred for another 45 min. The reaction mixture was poured onto 2 M aq. sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried (MgS04) and evaporated. The residue was dissolved in dichloromethane (10 mL), di-tert-butyl-dicarbonate (711 mg, 319 mmol) was added, the solution was stirred at r.t. for 16 h, then evaporated. Chromatography of the residue (SiOz, CH2Cl2/MeOH/NH40H 97.5:2.5:0.25) produced the title compound (1.14 g, 87%). Light yahoo solid, MS (ISP) 435.4 (M+H)"". (iii) rflc-(2a-tert-Butoxycarbonylamino-9,10-dimethoxy-l,3,4,6,7,llbP-hexahydro-2H-pyrido[2,l-a]isoquinolin-3P-yl)-carbamic acid benzyl ester A solution ofmc-2a-tert-butoxycarbonylamino-9,10-dimethoxy-l,3,4,6,7,llbP-hexahydro-2H-pyrido[2,l-a]isoquinoline-3p-carboxyhc acid ethyl ester (1.00 g, 2.30 mmol) in tetrahydrofuran (10 mL) was treated with 1 M aq. sodium hydroxide solution (2.30 mL, 2.30 mmol), and the resultant mixture was stirred at r.t. After 16 h, another portion of 1 M aq. sodium hydroxide solution (0.23 mL, 0.23 mmol) was added, and stirring was continued for 4 h. The solvent was then evaporated, the residue was suspended twice in toluene (50 mL) and concentrated to remove residual water azeotropically. The residue was suspended in toluene (20 mL) and treated with diphenylphosphoryl azide (669 mg, 2.30 mmol) and triethylamine (234 mg, 2.30 mmol). The reaction mixture was stirred at r.t. for 30 min, then heated at 80°C for 45 min, then benzyl alcohol (374 mg, 3.47 mmol) was added, and the reaction mixture was heated at 100°C for 72 h. After cooling and partitioning between dichloromethane and water, the organic layer was washed with brine, dried (MgS04), and evaporated. Chromatography of the residue (Si02, CH2Cl2/MeOH/NH40H 95:5:0,25) produced the title compound (278 mg, 24%). White solid, MS (ISP) 512.5 (M+H)"". (iv) rac-(3b-Amino-9,10-dimethoxy-l,3,4,6,7,llbj3-hexahydro-2H-pyrido[2,l-a]isoquinolin-2a-yl)-carbamic acid tert-butyl ester A solution of rac-(2a-tert-butoxycarbonylamino-9,10-dimethoxy-l,3,4,6,7,llbj3-hexahydro-2H-pyrido[2,l-a]isoquinolin-3P-yl)-carbamic acid benzyl ester (275 mg, 0.538 mmol) in acetic acid (10 mL) was hydrogenated at r.t. and atmospheric pressure in the presence of palladium (10% on activated charcoal, 15 mg). After 30 min, the solvent was evaporated, the residue was treated with toluene (20 mL), the suspension concentrated and the residue dried in vacuo to afford the title compound (247 mg, ca, 85% purity), which was directly used in the next step. Light yellow shod, MS (ISP) 378.4 (M+H)"‘. (v) mc-(9,10-Dimethoxy-3\|3-pyrrol-l-yl-13>4,6,7,llb\|3-hexahydro-2H-pyTido[2,l-a]isoquinolin-2a-yl)-carbamic acid tert-butyl ester 2,5-dimethoxytetrahydrofuran (41 mg, 0.30 mmol) was added to a solution of rac-(3P- amino-9,10-dimethox)’-l,3A6,7,llb(3-hexahydro-2H-pyrido[2,l-a]isoquinolin-2a-yl)-carbamic acid tert-butyl ester (120 mg, 0.27 mmol/85% purity) in acetic acid (1.2 mL, 21 mmol) and pyridine (0.76 mL, 9.5 mmol). The homogeneous solution was heated at 100°C for 105 min, then evaporated, and the residue was chromatographed (Si02, heptane/ethyl acetate gradient) to afford the title compound (87 mg, 75%). White shod, MS (ISP) 428.3 (M+H)’. (vi) rac-9,10-Dimethoxy-3P-pyrrol-l-yI-l,3,4>6,7,llb\|3-hexahydro-2H-pyrido[2,l-a] isoquinolin-2a-ylamine rac-(9,10-Dimethoxy-3P-pyrrol-l-yl-l,3,4,6,7,llb\|3-hexahydro-2H-pyrido[2,l-a]isoquinolin-2a-yl)-carbamic acid tert-butyl ester (86 mg, 0.20 mmol) was dissolved in hydrogen chloride solution (4 M in dioxane, 1 mL), stirred at r.t. for 1 h, and evaporated. Chromatography of the residue (SiOa, CH2Cl2/MeOH/NH40H 95:5:0.25) produced the title compound (58 mg, 88%). White solid, MS (ISP) 328.3 (M+H)’. Examples 61 and 62 The following compounds are prepared in analog)'‘ to Example 1: 61. rac-9,10-Dim.ethox)’-3P-p-tolyl-l,3,4,6,7,llbP-hexahydro-2H-pyrido[2,l-a]isoquinolin-2P-ylamine as a yellow powder, MS (ISP) 353.3 (M+H)"‘. 62. rac~9y 10-Dimethoxy-3p-p-tolyl-l,3,4,6,7,llb\|3-hexahydro-2H-pyrido[2,l-a]isoquinolin-2a-ylamine as a yellowish powder, MS (ISP) 353.3 (M+H)"‘. The educts used in Examples 61 and 62 (compounds of formulae II, III and VI) which have not been described above can be prepared according to the procedures described below or in analogy thereto. Oxime derivative (compound of formula II) The forewing compound is prepared in analogy to the procedure for the preparation ofrac-3P-Butyl-9,10-dimethoxy-I,3,4,6,7,llbP-hexahydro-pyrido[2,l-a]isoquinolin-2-one oxime described in above Example 1: mc-9,10-Dimethoxy-3(3-p-tolyl-l,354,6,7,llbP-hexahydro-pyrido[2,l-a]isoquinolin-2-one oxime as a yellowish powder, MS (ISP) 367.2 (M-hH)"‘. Ketone derivative (compound of formula III) The following compound is prepared in analogy to the procedure for the preparation ofrflc-3(3-Butyl-9,10-dimethoxy-l,354,6>7,llbp-hexahydro-pyrido[2,l-a]isoquinolin-2-one described in above Example 1: rac-9,10-Dimethoxy-3p-p-toiyl-l,3,4,637,llb-hexahydro-pyrido[2,l-a]isoquinolin-2-one as an off-white powder, MS (ISP) 352.3 (M+H)"". Ammonium iodide derivative (compound of formula V) A mixture of 4-methylphenylacetone (3.01 g), par formaldehyde (0.489 g) and dimethylamine hydrochloride (1.49 g) in MeOH (2 ml) is stirred under reflux for 3 h. The reaction mixture is diluted with 20 ml of water and the product is extracted with two portions of ether. After addition of 1 M aqueous NaOH solution, the aqueous layer is extracted with two more portions of ether. The combined organic layers are dried (Na2S04) and the solvent is evaporated to obtain 4-dimethylamino-3-p-tolyl-butan-2-one (compound of formula VI) as a yellowish liquid, MS (ISP) 206.2 (M+H)’ 4-Dimethylamino-3-p-tolyl-butan-2-one is dissolved in AcOEt (17 ml) and diazomethane (L46) is added. After 1 h the formed solid is collected by filtration, washed with AcOEt and dried on the vacuum. 2.61 g of trimethyl-(3-oxo-2-p-tolyl-but}d)-ammonium iodide are obtained as an oft'-white shod, MS (ISP) 220.3 M’. Examples 63 and 64 (i) 21.5 mg of palladium acetate, 276 mg of sodium tert-butoxide and 23 mg of tri-tert-butylphosphine are placed in a flask, which is evaporated and charged with argon three times. 2 ml of tetrahydrofurane is added under argon. To this solution 177 mg of 4-bromoxylene and 250 mg of rac-9,10-dimethoxy-1,3,4,6,7,1 lb-hexahydro-2H-benzo[a]quinolizin-2-one (D. Bake, C. Szantay, Chem. Ber. 95, 2132 (1962)) dissolved in 1 ml of tetrahydrofurane are added. The reaction is stirred at room temperature under argon over night. The crude reaction is diluted with diethyl ether, washed "vetch water and sat. aq. sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and the solvent is evaporated. The residue is purified by column chromatography (silica gel, diethyl ether) to yield 92.0 mg of rac:-9,10-dimethoxy-3P-(3,4-dimethyI-phenyl)- l,3,4,6,7,llb\|3-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-one as a light yellow solid. ‘H NMR (CDCI3): 5 = 7.16-6.90 (m, 3 K), 6.64 (s, 1 H), 6.59 (s, 1 H), 3.93-3.71 (m, 8 H, 2 MeO + 2 H), 3.40-3.36 (m, 1 H), 3.17-2.6 (m, 7 H), 2.4-2.2 (m, 6 H, 2 Ar-CHs). MS (ISP): 366.2 (M+H)’. (ii) To a yellow suspension of 86 mg of mc-9,10-dimethoxy-3(3-(3,4-dimethyl-phenyl)-1,3,4,6,7,1 lb(3-hexahydro-pyrido[2.1-a]isoquinolin-2-one in 4 ml of ethanol is added 21.2 mg sodium acetate and 18.0 mg hydroxylamine hydrochloride. The reaction mixture is stirred for four hours at room temperature. 4 ml. of water and 150 mg of nickel-aluminum alloy are added. 0.7 ml of an aq. 32 % sodium hydroxide solution is added dropwise. The mixture is stirred at room temperature over night, filtered and the solution is extracted three times with dichloromethane. The organic layers are dried over sodium sulfate and the solvent is evaporated. The residue is purified by chromatography (silica gel, dichloromethane/methanol/sat. aq. ammonia = 97/3/0.3). Two products are obtained. They are dissolved independently in dichloromethane and saturated etheral hydrochloric acid solution is added until a solid precipitated. 63. rac-9,10-dimeth6xy-3\|3-(3,4-dimethyl-phenyl)-l,3,4,6,7,llbP-hexahydro-2H- pyrido[24-a]isoquinolin-2\|3-ylamine chlorohydrate (1:2) 14.4 mg of the title compound are obtained as a light yellow solid. This product is eluted first during chromatography. ‘H NMR (CDCI3): 5 = 7.17-6.95 (m, 3 H), 6.70 (s, 1 H), 6.60 (s, 1 H), 3.85 (s, 3 H, MeO), 3, 84 (s, 3 H, MeO), 3.6-2.2 (m, 17 H), 2.0- 1.8 (m, 1 H). MS (ISP): 367.3 (M+H)"". 64. rac-9,10-dimethoxy-3P-(3,4-Dimethyl-phenyl)-l,3,4,6,7,llbP-hexahydro-2H- pyrido[2,l-a]isoquinolin-2a-ylamine chlorohydrate (1:2) 39.5 mg of the title compound are obtained as a light yellow sohd.This product is eluted second during chromatography. ‘H NMR (CDCI3): 5 = 7.15-6.99 (m, 3 H), 6.75 (s, 1 H), 6.60 (s, 1 H), 3.85 (s, 3 H, Ar-CHs), 3.83 (s, 3 H, MeO), 3.4-2.9 (m, 5 H), 2.7-2.2 (m, 12 H). MS (ISP): 367.3 (M+H)’. Examples 65-68 The following compounds are prepared in analogy to Examples 63 and 64: 65. rac-9,10-Dimethoxy-3P-(3-methox7-phenyl)-l,3,4,6,7,nb\|3-hexah7dro-2H- pyTido[2,l-a]isoquinolin-2P-ylainine chlorohydrate (1:2). The tide compound was obtained as a light yellow solid. This product is eluted first during chromatography. ‘H NMR (CDCI3): 5 = 7.29-7.24 (m, 1 H), 6.84-6.74 (m, 3 H), 6.70 (s, 1 H), 6.60 (s, 1 H), 3.94-3.82 (m, 10 H, 3 MeO +1 H), 3.60-2.36 (m, 10 H), 2.00-1.95 (m, 1 H). MS (ISP): 369.3 (M+H)’ 66. rac-9,10-Dimethoxy-3P-(3-methoxy-phenyl)-1,3,4,6,7,1 lb\|3-hexahydro-2H- pyTido[2,l-a]isoquinolin-2a-ylamine chlorohydrate (1:2). The title compound was obtained as a light yellow solid. This product is eluted second during chromatography. ‘H NMR (CDCls): 5 = 7.30-7.24 (m, 1 H), 6.89-6.79 (m, 3 H), 6.75 (s, 1 H), 6.60 (s, 1 H), 3.85-3.82 (m, 6 H, 2 MeO), 3.82 (m, 4 H, 1 MeO + 1 H), 3.4-2.2 (m, 11 H). MS (ISP): 369.3 (M+H)"". ()1. rac-9,10-Dimethoxy-3\|3-pyridin-l,3,4,6,7,llbP-hexahydro-2H-pyrido[2,l-a]isoquinolin-23-ylamine chlorohydrate (1:2). The title compound is obtained as a light meow solid. This product is eluted first during chromatography. 'H NMR (CDCI3): 6 = 8.60-8.57 (m, 1 H), 7.68-7.63 (m, 1 H), 7.27-7.15 (m, 2 H), 6.71 (s, 1 H), 6.60 (s, 1 H), 3.85-3.84 (m, 7 H, 2 MeO), 3.8-3.0 (m, 7 H), 2.8-2.6 (m, 1 H), 2.45-2.39 (m, 1 H), 2-1.92 (m, 1 H). MS (ISP): 340.3 (M+H)"". 68. rac-9,10-Dimethoxy-3\|3-pyridin-l,3,4,6,7,llbP-hexahydro-2H-pyrido[2,l-a]isoquinolin-2a-ylamine chlorohydrate (1:2). The title compound was obtained as a light yellow solid. This product is eluted second during chromatography. ‘H NMR (CDCI3): 5 = 8.63-8.61 (m, 1 H), 7.68-7.62 (m, 1 H), 7.26-7.16 (m, 2 H), 6.75 (s, 1 H), 6.60 (s, 1 H), 3.87-3.80 (m, 7 H), 3.5-2.5 (m, 11 H). MS (ISP): 340.3 (M+H)"". The following compounds are prepared in analogy to the procedure used for the preparation of rac-9,10-dimethoxy-3\|3-(3,4-dimethyl-phenyl)-1,3,4,6,7,1 IbP-hexahydro-2H-pyTido[2,l-a]isoquinolin-2-one described above in Examples 63 and 64: rac-9,10-dimethoxy-3P-(3-methoxy-phenyl)-l,3,4,6,7,llbP-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-one obtained as a light yellow solid. ‘H NMR (CDCl): 5 = 7.43-6.56 (m, 5 H), 3.95-3.72 (m, 11 H, 3 MeO + 2 H), 3.45-3.40 (m, 1 H), 3.2-2.6 (m, 8 H). MS (ISP): 368.3 (M+H)'. rac-9,10-dimethoxy-3\|3-pyridin-2-yl-l,3,4,6,7,llb(3-hexah7dro-2H-p7rido[2,l-a]isoqumolin-2-one obtained as an orange solid. ‘H NMR (CDCI3): 5 = 8.38-8.35 (m, 1 H), 7.72-7.67 (m, 1 H), 7.07-6.96 (m, 2 H), 6.68 (s, 1 H), 6.62 (s, 1 H), 3.93-3.75 (m, 8 H, 2 MeO + 2 H), 3.65-3.60 (m, 1 H), 3.40-3.26 (m, 7 H). MS (ISP): 339.3 (M+H)’ Examples 69-81 The following compounds were prepared in analogy to Example 1: 69. rac-4-(2j’-Amino-3/?-butyl-9,10-dimethoxy-l,3,4,6,7,Ilb/9-hexahydro-2H-pyrido[2,l-a]isoquinolin-7/?-yl)-phenol, MS (ISP) 411.5 (M+H)’. 70. rac-3y?-Butyl-9,10-dimethoxy-6-methyl-l,3,4,6,7,llb;/?-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-ylamine, MS (ISP) 333.4 (M+H)*. 71. rac-3y5-Butyl-7j5-(4-chloro-phenyl)-9,10-dimethoxy-l,3,4>6,7,llb)5-hexahydro-2H-pyrido[2,l-a]isoquinolin-2a-ylamine, MS (ISP) 429.6 (Mi-H)’ 72. rac-3;5-Butyl-7«-(4-chloro-phenyl)-9,10-dimethoxy-l,3,4,6,7,llb/?-hexahydro-2H-pyrido[2,l-a]isoquinolin-2«r-yIamine, MS (ISP) 429.6 (M-l-H)"‘. 73. rac-3/?-Butyl-7;’-(3,4-dimethoxy-phenyI)-9,10-dimethoxy- l,3,4,6,7,nb/?-liexahydro-2H-pyrido[2,l-a]isoquinolin-2Qr-ylamine, MS (ISP) 455.6 (M+H)’. 74. rac-3/?-But5’1-9,10-dimethoxy-7,7-dimethyl-l,3,4,6,7,llby5-liexahydro-2H-pyrido[2,l-a]isoquinolin-2a-yIamine, MS (ISP) 347.5 (M-hH)"‘. 75. rflc-3y5-Butyl-9,10-dimethoxy-7,7-dimethyl-l,3,4,6,7,llb;5-liexahydro-2H-pyrido[2,l-a]isoquinolin-2y5-ylamine, MS (ISP) 347.5 (M+H)"‘. 76. rflc-7yS-But)4-ll,12-dimethoxy-2,3,4,4aA6,7,8,9,9ao;13by’-decahydro-lH-pyrido[l,2-f]phenanthridin-8/?-ylamine,MS (ISP) 373.5 (M+H)’. 77. rflc-7/?-Butyl-ll,12-dimethoxy-2,3A4ay5,6,7,8,9,9aal3b/?-decahydro-lH-pyrido[l,2-flphenanthridin-8a-ylamine, MS (ISP) 373.5 (M+H)"". Example D Soft gelatin capsules containing the following ingredients can be manufactured in a conventional manner: Capsule contents Compound of formula (I) 5.0 m’- Yellow wax 8.0 mg Hydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0 mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg Gelatin capsule Gelatin 75.0 mg Glycerol 85 % 32.0 mg Karin 83 8.0 mg (dry matter) Titan dioxide 0.4 mg Iron oxide yellow 1.1 mg The active ingredient is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures. Example E Sachets containing the following ingredients can be manufactured in a conventional manner: Compound of formula (I) 50.0 mg Lactose, fine powder 1015.0 mg Microcristalline cellulose (AVICEL PH 102) 1400.0 mg Sodium carboxymethyl cellulose 14,0 mg Polyvinylpyrrohdon K 30 10.0 mg Magnesiumstearate 10.0 mg Flavoring additives 1.0 mg The active ingredient is mixed with lactose, microcristalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrohdon in water. The granulate is mixed with magnesiumstearate and the flavorings additives and filled into sachets. WE CLAIM: 1, Compounds of formula (I) with an alcohol R-OH wherein R is C1-C6-alkyl substituted by aryl, heterocyclyl or lower alkoxycarbonyl; in the presence of triphenylphosphine and di-r-butyl azodicarboxylate, followed by deprotection. 17. Pharmaceutical compositions comprising a compound according to any of claims 1 to 15 and a pharmaceutically acceptable carrier and/or adjuvant. 18. Compounds of formula (I), wherein R\ R^, R^, R"^ R^, R^ and R^ are as defined in claim 1 and pharmaceutically acceptable salts thereof for use as therapeutic active substances. 19. Compounds according to any of claims 1 to 15 for use as therapeutic active substances. 20. Compounds according to any of claims 1 to 15 for use as therapeutic active substances for the treatment and/or prophylaxis of diseases which are associated with DPP-IV.

Full Text

PYRIDO(2,1-A)ISOQUINOLINE DERIVATIVES AS DPP-IV INHIBITORS
Novel Pyrido[2J-a1isoquinQline Derivatives
The present invention is concerned with novel pyrido [2,l-a] isoquinoline derivatives, their manufacture and their use as medicaments. In particular, the invention relates to compounds of the formula (I)

wherein
R’ is lower alkyl, aryl, heteroaryl or lower alkyl substituted by cycloalkyl, by’ aryl or by heteroaryl;
R’, R’ and R’ are each independently hydrogen,, halogen, hydroxy, lower alkyi, lower alkoxy) or lower alkenyl, wherein lower alkyl, lower alkoxy and lower alkenyl may optionally be substituted by lower alkoxycarbonyl, aryl or heterocyclyl;
R is hydrogen, fluorine, lower alkyl, or aryl;
R is hydrogen, lower alkyl or hydroxy-lower alkyl, or
R’ and R’ together with the carbon atoms to which they.are attached form a five or six membered saturated carbocyclic ring;
R is hydrogen, fluorine or lower alkyl; and pharmaceutically acceptable salts thereof.

The enzyme dipeptidyl peptidase IV (EC.3.4.14.5, abbreviated in the following as DPP-IV) is involved in the regulation of the activities of several hormones. In particular DPP-IV is degrading efficiently and rapidly glucagons like peptide 1 (GLP-1), which is one of the most potent stimulator of insulin production and secretion. Inhibiting DPP-IV would potentiate the effect of endogenous GLP-l, and lead to higher plasma insulin concentrations. In patients suffering from impaired glucose tolerance and type 2 diabetes mellitus, higher plasma insulin concentration would moderate the dangerous hyperglycaemia and accordingly reduce the risk of tissue damage. Consequently, DPP-IV inhibitors have been suggested as drug candidates for the treatment of impaired glucose tolerance and type 2 diabetes emeritus (e.g. Villagers, W098/1999S). Without disclosing any medical use, Buzas et al., Lab. Chime. Org. V, Fac. Sci., Orleans, Fr. Chim. Ther. (1992), 7(5), 404-7 describe synthesis of the compounds of Examples 41 and 42 below.
We have found novel DPP-IV inhibitors that very efficiently lower plasma glucose levels. Consequently, the compounds of the present invention are useful for the treatment and/or prophylaxis of diabetes, particularly non-insulin dependent diabetes mellitus, and/or impaired glucose tolerance, as well as other conditions wherein the ampUfication of action of a peptide normally inactivated by DPP-IV gives a therapeutic benefit. Surprisingly, the compounds of the present invention can also be used in the treatment and/or prophylaxis of Bowl disease. Colitis Ulcerous, Morbus Crown, obesity and/or metabolic syndrome. Furthermore, the compounds of the present invention can be used as diuretic agents and for the treatment and/or prophylaxis of hypertension. Unexpectedly, the compounds of the present invention exhibit improved therapeutic and T’harmacological ‘properties compared to other DPP-IV inhibitors known in the art, such as e.g. in context with pharmacokinetic and bioavailability.
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
In this specification the term "lower" is used to mean a group consisting of one to six, preferably of one to four carbon atom(s).
The term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably to
chlorine.
The term "alkyl", alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon
atoms.

The term "lower-alkyl", alone or in combination with other groups, refers to a branched or straight-chain monovalent alkyl radical of one to six carbon atoms, preferably one to four carbon atoms. This term is further exemplified by radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-pentyl, 3-methylbutyl, n-hexyl, 2-ethylbutyl and the like.
The term "cycloalkyl" refers to a monovalent carbocyclic radical of three to six carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, with cyclopropyl being preferred.
The term "alkoxy" refers to the group R'-O-, wherein R' is alkyl. The term "lower-alkoxy" refers to the group R'-O-, wherein R' is lower-alkyl. Examples of lower-alkoxy groups are e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy, with methoxy being especially preferred.
The term "lower alkoxycarbonyl" refers to the group R'-O-C(O)-, wherein R' is lower alkyl.
The term "heterocyclyl" refers to a 5- or 6-membered aromatic or saturated N-heterocyclic residue, which may optionally contain a further nitrogen or oxygen atom, such as imidazolyl, pyrazolyl, thiazolyl, phenyl, pyridyl, pyrimidyl, morpholino, piperazino, piperidino or pyrrolidino, preferably pyridyl, thiazolyl or morpholino. Such heterocyclic rings may optionally be mono-, di- or tri-substituted, independently, by lower alkyl, lower alkoxy, halo, cyano, azido, amino, di-lower alkyl amino or hydroxy. Preferable substituent is lower alkyl, with methyl being preferred.
The term "aryl" refers to an aromatic monovalent mono- or polycarbocyclic radical, such as phenyl or naphthyl, preferably phenyl, which may optionally be mono-, di- or tri-substituted, independently, by lower alkyl, lower alkoxy, halo, cyano, azido, amino, di-lower alkyl amino or hydroxy.
The term "heteroaryl" refers to a 5- or 6-membered, unsaturated aromatic monovalent cyclic radical containing one to three, preferably one or two, heteroatoms independently selected from nitrogen, sulfur and oxygen, with nitrogen being preferred. Examples of heteroaryl residues are pyrrolyl, pyridinyl and pyrimidinyl, with pyrrolyl and pyridinyl being preferred. Said heteroaryl residues may be mono-, di- or tri-substituted, independently, by halogen, amino, perfluoro-lower alkyl, lower alkyl or lower alkoxy.The term "pharmaceutically acceptable salts" embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulphonic acid, salicylic acid, p-toluenesulphonic

acid and the like, which are non toxic to living organisms. Preferred salts with acids are formats, maleate, citrates, hydrochlorides, hydro bromides and methanesulfonic acid salts, with hydrochlorides being especially preferred.
In one embodiment, the present invention relates to a compound of formula (I) as defined above, wherein R’ is lower alkyl, aryl or lower alkyl substituted by cycloalkyl or by aryl; R , R and R are each independently hydrogen, hydroxy, lower alkyl, lower alkoxy or lower alkenyl, wherein lower alkyl, lower alkoxy and lower alkenyl may optionally be substituted by lower alkoxycarbonyl, aryl or heterocyclyl; R and R are each independently hydrogen, lower alkyl, aryl or, together with the carbon atoms to which they are attached form a five or six membered saturated carbocyclic ring; and pharmaceutically acceptable salts thereof
In another embodiment, the present invention relates to a compound of formula (I) as defined above, wherein R’ is lower alkyl, phenyl, or cycloalkyl-lower alkyl; R’, R’ and R’ are each independently hydrogen, hydroxy, lower alkoxy; or lower alkoxy substituted by aryl, heterocyclyl or lower alkoxycarbonyl. Preferable aryl residues in R , R and R are phenyl or phenyl substituted by di-lower aDcyl amino or cyano. Preferable heterocyclyl residues in R , R and R are morpholino, pyridyl, thiazolyl or thiazolyl substituted by

lower alkyl Preferable lower alkoxycarbonyl residues in R', R and R are ethoxycarbonlymethoxy.
In another preferable embodiment, the present invention relates to a compound of formula (I) as defined above, wherein R is lower alkyl, phenyl, phenyl substituted by lower alkyl or by lover alkoxy, or R’ is heteroaryl such as Truly and pyridinyl, or cycloalkyl-lower alkyl; R , R and R are each independently hydrogen, hydroxy, lower alkoxy; or lower alkoxy substituted by aryl, by heterocyclyl or by lower alkoxycarbonyl; R’ is hydrogen, lower alkyl or phenyl mono- or di-substituted by lower alkyl, lower alkoxy or halogen; R’ is hydrogen, lower alkyl or hydroxy-lower alkyl; or R’ and R’ together with the carbon atoms to which they are attached form a five or six membered saturated carbocyclic ring; and R is hydrogen or lower alkyl.
In one embodiment, residue R’ is lower alkyl or lower alkyl substituted by cycloalkyl, preferably cyclopropyl. Preferable lower residues R’ are n-propyl, n-butyl, isobutyl, 3-methylbutyl and 2-ethylbutyl, most preferred are n-propyl, n-butyl and 3-methylbutyl. Preferable lower Al substituted by cycloalkyl is cyclopropylmethyl.

In another embodiment, R’ is aryl, preferably phenyl. Aryl residues R’ maybe mono-, di- or tri-substituted, independently, by lower alkyl, lower alkoxy or hydroxy, preferably by lower alkyl or lower alkoxy. Preferably, aryl residues R’ are unsubstituted.
In still another embodiment, R is a heteroaryl residue selected from pyridinyl, pyrimidinyl and pyrrolyl. Preferred heteroaryl residues R’ are pyridinyl or pyrrolyl. The said heteroaryl residues R’ may be mono-, di- or tri-substituted, independently, by lower alkyl, lower alkoxy, or hydroxy, preferably by lower alkyl or lower alkoxy. Preferably, heteroaryl residues R are unsubstituted.
Most preferred R’ are lower alkyl, preferably n-butyl, or unsubstituted phenyl.
In one preferable embodiment, residue R is lower alkoxy, preferably methoxy, hydrogen or hydroxy. Most preferable residue R is methoxy.
In another preferable embodiment, residue R is lower alkoxy, with methoxy, ethoxy, propoxy, n-butoxy and isobutoxy being preferred, hydrogen, hydroxy; or lower alkoxy, preferably methoxy or ethoxy, substituted by aryl, by heterocyclyl or by lower alkoxycarbonyl. Preferable aryl substituents in R are unsubstituted phenyl or phenyl mono-substituted by di-lower alkyl amino, with dimethylamino being preferred, or by cyano. Most preferable aryl substituents in R is unsubstituted phenyl.
More preferable residues R are lower alkoxy, preferably methoxy, hydrogen or hydroxy. Most preferred residue R’ is methoxy or hydroxy, with methoxy being especially preferred.
In another preferable embodiment, residue R is lower alkoxy, preferably methoxy, hydrogen or hydroxy. Most preferable residue R’ is hydrogen.
In one embodiment, R’ is hydrogen, lower alkyl, with methyl being preferred, or aryl. Preferable aryl residues R’ are unsubstituted phenyl or phenyl mono-, di- or tri-substituted, independently, by lower alkyl, lower alkoxy or halogen. Most preferable aryl residue R’ is unsubstituted phenyl.
In another embodiment, R’ is hydrogen, lower alkyl, with methyl being preferred, or hydroxy-lower alkyl, with 2-hydroxy-ethyl being preferred. Preferably, R’ is hydrogen.
In still another embodiment, R and are hydrogen or, together with the carbon atoms to which they are attached, form a six membered saturated carbocyclic ring.

The present invention also relates to a process for the manufacture of compounds of formula (I) as defined above, which process comprises reducing an oxide of formula (II)
>
optionally followed by conversion into a pharmaceutically acceptable salt thereof
Hydrogenation of the above oxime of formula II can be performed according to methods known in the art. For example, the reaction can be performed in the presence of a catalyst such as Raney nickel, platin or palladium in an inert solvent, such as ethanol, at a temperature of about 20°C to SO'‘C.
Hydroxy groups in the compounds of formula II can be present in a protected form, for example as a benzyl ether. Such protecting groups can be removed according to processes known in the art, e.g. in case of benzyl ether by catalytic hydrogenation.
Oximes of formula II are known in the art or can be prepared starting from ketones of the formula III by methods known in the art and as exemplified or in analogy thereto.
Compounds of formula (III):

manufactured according to a process as defined above.
As described above, the compounds of formula (I) of the present invention can be used as medicaments for the treatment and/or prophylaxis of diseases which are associated with DPP-IV such as diabetes, particularly non-insulin dependent diabetes mellitus, impaired glucose tolerance, Bowl disease, Colitis Ulcerosa, Morbus Crohn, obesity, and/or metabolic syndrome, preferably non-insulin dependent diabetes mellitus and/or impaired glucose tolerance. Furthermore, the compounds of the present invention can be used as diuretic agents or for the treatment and/or prophylaxis of hypertension.
The invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant
Further, the invention relates to compounds as defined above for use as therapeutic active substances, particularly as therapeutic active substances for the treatment and/or prophylaxis of diseases which are associated with DPP-IV such as diabetes, particularly non-insulin dependent diabetes mellitus, impaired glucose tolerance, Bowl disease, Coatis Ulcerosa, Morbus Crohn, obesity, and/or marabou syndrome, preferably for use as therapeutic active substances for the treatment and/or prophylaxis of non-insulin dependent diabetes mellitus and/or impaired glucose tolerance. Furthermore, the invention relates to compounds as defined above for use as diuretic agents or for use as therapeutic active substances for the treatment and/or prophylaxis of hypertension.
In another embodiment, the invention relates to a method for the treatment and/or prophylaxis of diseases which are associated with DPP-IV such as diabetes, particularly non-insulin dependent diabetes mellitus, impaired glucose tolerance. Bowl disease, Colitis Ulcerosa, Morbus Crohn, obesity, and/or metabolic syndrome, preferably for the treatment and/or prophylaxis of non-insulin dependent diabetes mellitus and/or impaired glucose tolerance, which method comprises administering a compound as defined above to a human being or animal. Furthermore, the invention relates to a method for the treatment and/or prophylaxis as defined above, wherein the disease is hypertension or wherein a diuretic agent has a beneficial effect.
The invention further relates to the use of compounds as defined above for the treatment and/or prophylaxis of diseases which are associated with DPP-IV such as diabetes, particularly non-insulin dependent diabetes mellitus, impaired glucose tolerance, Bowl disease. Colitis Ulcerosa, Morbus Crohn, obesity, and/or metabolic syndrome, preferably for the treatment and/or prophylaxis of non-insulin dependent diabetes merits and/or impaired glucose tolerance. Furthermore, the invention relates to the use as defined above, wherein the disease is hypertension or to the use as diuretic agent.

In addition, the invention relates to the use of compounds as defined above for the preparation of medicaments for the treatment and/or prophylaxis of diseases which are associated with DPP-IV such as diabetes, particularly non-insulin dependent diabetes mellitus, impaired glucose tolerance. Bowl disease. Colitis Ulcerosa, Morbus Crohn, obesity, and/or metabolic syndrome, preferably for the treatment and/or prophylaxis of non-insulin dependent diabetes merits and/or impaired glucose tolerance. Such medicaments comprise a compound as defined above. Furthermore, the invention relates to the use as defined above, wherein the disease is hypertension or the use for the preparation of diuretic agents.
In context with the methods and uses defined above, the following diseases relate to a preferred embodiment: diabetes, particularly non-insulin dependent diabetes mellitus, impaired glucose tolerance, obesity, and/or metabolic syndrome, preferably non-insulin dependent diabetes meUitus and/or impaired glucose tolerance.
The compounds of formula (I) can be manufactured by the methods given below, by the methods given in the Examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to the person skilled in the art. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below or in the Examples or by methods known in the art.
The following tests were carried out in order to determine the activity of the compounds of formula I.
Activity of DPP-IV inhibitors are tested with natural human DPP-IV derived from a human plasma pool or with recombinants human L>PP-IV. Human citrate plasma from different donors is pooled, filterted through a 0.2 micron membrane under sterile conditions and aliquots of 1 ml are shock frozen and stored at -120°C until used. In the colorimetric DPP-IV assay 5 to 10 pi human plasma and in the fluorometric assay 1.0 \x\ of human plasma in a total assay volume of 100 Jul is used as an enzyme source. The cDNA of the human DPP-IV sequence of amino acid 31 — to 766, restricted for the N-terminus and the Tran membrane domain, is cloned into pichia pastoris. Human DPP-IV is expressed and purified from the culture medium using conventional column chromatography including size exclusion and anion and cation chromatography. The purity of the final enzyme preparation of Compassed blue SDS-PAGE is > 95 %. In the colorimetric DPP-IV assay 20 ng rec.-h DPP-IV and in the fluorometric assay 2 ng reek DPP-IV in a total assay volume of 100 is used as an enzyme source.
In the fluorogenic assay Ala-Pro-7-amido-4-trifluoromethylcoumarin (Caliches No 125510) is used as a substrate. A 20 mM stock solution in 10 % DMF/H2O is stored at-

20°C until use. In IC50 determinations a final substrate concentration of 50 used. In assays to determine kinetic parameters as Km, Amax Kj, the substrate concentration is varied between 10 p-M and 500
In the colorimetric assay H-Ala-Pro-pNA.HCl (Sachem L-1115) is used as a substrate. A 10 mM stock solution in 10% MeOH/HiO is stored at-20X until use. In IC50 determinations a final substrate concentration of 200 is used. In assays to determine kinetic parameters as Km, Amax Kii, the substrate concentration is varied between 100 |iM and 2000 .
Fluorescence is detected in a Perkin Elmer Luminescence Spectrometer LS SOB at an excitation wavelength of 400 nm and an emission wavelength of 505 nm continuously every 15 seconds for 10 to 30 minutes. Initial rate constants are calculated by best fit linear regression.
The absorption of pNA liberated from the colorimetric substrate is detected in a Packard SpectraCount at 405 nM continuo sly every 2 minutes for 30 to 120 minutes. Initial rate constants are calculated by best fit linear regression.
DPP-IV activity assays are performed in 96 well plates at 37°C in a total assay volume of 100 Jil. The assay buffer consists of 50 mM Tris/HCl pH 7.8 containing 0.1 mg/ml BSA and 100 mM NaCl. Test compounds are solved in 100 % DMSO, diluted to the desired concentration in 10% DMSO/H2O. The final DMSO concentration in the assay is 1 % (v/v). At this concentration enzyme inactivation by DMSO is IC50 determinations of test compounds are calculated by non-linear best fit regression of the DPP-IV inhibition of at least 5 different compound concentrations. Kinetic parameters of the enzyme reaction are calculated at least 5 different substrate concentrations and at least 5 different test compound concentrations.
The preferred compounds of the present invention exhibit IC50 values of 1 nM to 10 more preferrably of 1 - 100 nM, as shown in the following table.

The compounds of formula I and/or their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils. Oral administration is preferred.
The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers might, however, be required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols’ polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and

cellulose derivatives.
Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 to 1000 mg, especially about 1 to 100 mg, comes into consideration. Depending on severity of the disease and the precise pharmacokinetic profile the compound could be administered with one or several daily dosage units, e.g. in 1 to 3 dosage units.
The pharmaceutical preparations conveniently contain about 1-500 mg, preferably 1-100 mg, of a compound of formula I.
The following Examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.

Examples Abbreviations:
MS = mass spectrometry, ISP = ion spray (positive ion) corresponds to ESI (electrospray, positive ion), b.p. = boiling point, m.p. = melting point, aq. = aqueous, r.t = room temperature.
Example 1
mc-3|3-Butyl-9,10-dimethoxy-l,3,4,6,7,llbp-hexahydro-2H-pyrido[2,l-a]isoquinolin-2P-ylamine and rac-3P-butyl-9,10-dimethoxy-l,3,4,6,7,llb|3-hexahydro-2H-pyrido[2,l-a]isoquinoHn-2a-ylamine
(i) A solution of 6.8 g of 3,4-dihydro-6,7-dimethoxy-isoquinoline in 70 ml of ethanol is treated with 11.4 g of (2-acetylhexyl)trimethylammonium iodide and heated under reflux for 1.5 hours. The reaction mixture is cooled down and treated with a solution of 6.8 g of potassium hydroxide in 70 ml of water. The ethanol is evaporated and the aq. solution is extracted three times with 80 ml of dichlormethane. The combined organic solutions are dried over anhydrous sodium sulfate and evaporated. The solid red residue is purified by chromatography (silica gel, hexane/ethyl acetate 4:1) and crystallized from isopropyl ether. 7.0 grac-3p-Butyl-9,10-dimethoxy-l,3,4,6,7,llbp-hexahydro-pyrido[2,l-a]isoquinolin-2-one are obtained, m.p. = 117°C.
(ii) A solution of 5.5 g hydroxylamine hydrochloride in 50 ml of water and 20 ml of ethanol is made alkaline (pH 9) with 7.27 ml of N sodium hydroxide solution and a solution of 3.35 g rac-3p-butyl-9,10-dimethoxy-l,3,4,6,7,llbp-hexahydro-pyrido[2,l-a]isoquinolin-2-one in 50 ml of ethanol is added. The reaction mixture is stirred for 45 minutes at 45°C, half concentrated and then cooled to 0°C. The precipitated product is filtered and washed with ethanol/water (1:1), subsequently with water. 3.26 g rac-3P-butyl-9,10-dimethoxy-l,3,4,6,7,llbP-hexahydro-pyrido[2,l-a]isoquinolin-2-oneoximeare obtained, m.p. = 143-145°C.
(iii) A suspension of 1.5 g rac-3|3-butyl-9,10-dimethoxy-l,3,4,6,75llbp-hexahydro-pyrido[2,l-a]isoquinolin-2-one oxime in 40 ml of ethanol and 40 ml of water is treated with 1.25 g of a nickel-aluminum alloy and 4.935 ml of an aq. 32% sodium hydroxide solution are added dropwise.The mixture is stirred thoroughly for four hours at room temperature, then filtered and washed with ethanol/water (1:1). The filtrate is extracted twice with dichloromethane and the combined organic solutions are washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated. The solid residue is purified by chromatography (silica gel, dichloromethane-

Trifluoroacetic acid (18 mL) was added at CC to a solution of 2-aInino-9,10-dimethoxy-l,6,7,llb-tet’ahydro-4H-py’ido[2,l-a]isoquinoline-3-ca’box7lic acid ethyl ester (LOO g, 3.01 mmol) in tetrahydrofuran (9 mL), then after 30 rain the homogeneous solution was treated with sodium borohydride (237 mg, 6.02 mmol) and stirred for another 45 min. The reaction mixture was poured onto 2 M aq. sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried (MgS04) and evaporated. The residue was dissolved in dichloromethane (10 mL), di-tert-butyl-dicarbonate (711 mg, 319 mmol) was added, the solution was stirred at r.t. for 16 h, then evaporated. Chromatography of the residue (SiOz, CH2Cl2/MeOH/NH40H 97.5:2.5:0.25) produced the title compound (1.14 g, 87%). Light yahoo solid, MS (ISP) 435.4 (M+H)"".
(iii) rflc-(2a-tert-Butoxycarbonylamino-9,10-dimethoxy-l,3,4,6,7,llbP-hexahydro-2H-pyrido[2,l-a]isoquinolin-3P-yl)-carbamic acid benzyl ester
A solution ofmc-2a-tert-butoxycarbonylamino-9,10-dimethoxy-l,3,4,6,7,llbP-hexahydro-2H-pyrido[2,l-a]isoquinoline-3p-carboxyhc acid ethyl ester (1.00 g, 2.30 mmol) in tetrahydrofuran (10 mL) was treated with 1 M aq. sodium hydroxide solution (2.30 mL, 2.30 mmol), and the resultant mixture was stirred at r.t. After 16 h, another portion of 1 M aq. sodium hydroxide solution (0.23 mL, 0.23 mmol) was added, and stirring was continued for 4 h. The solvent was then evaporated, the residue was suspended twice in toluene (50 mL) and concentrated to remove residual water azeotropically. The residue was suspended in toluene (20 mL) and treated with diphenylphosphoryl azide (669 mg, 2.30 mmol) and triethylamine (234 mg, 2.30 mmol). The reaction mixture was stirred at r.t. for 30 min, then heated at 80°C for 45 min, then benzyl alcohol (374 mg, 3.47 mmol) was added, and the reaction mixture was heated at 100°C for 72 h. After cooling and partitioning between dichloromethane and water, the organic layer was washed with brine, dried (MgS04), and evaporated. Chromatography of the residue (Si02, CH2Cl2/MeOH/NH40H 95:5:0,25) produced the title compound (278 mg, 24%). White solid, MS (ISP) 512.5 (M+H)"".
(iv) rac-(3b-Amino-9,10-dimethoxy-l,3,4,6,7,llbj3-hexahydro-2H-pyrido[2,l-a]isoquinolin-2a-yl)-carbamic acid tert-butyl ester
A solution of rac-(2a-tert-butoxycarbonylamino-9,10-dimethoxy-l,3,4,6,7,llbj3-hexahydro-2H-pyrido[2,l-a]isoquinolin-3P-yl)-carbamic acid benzyl ester (275 mg, 0.538 mmol) in acetic acid (10 mL) was hydrogenated at r.t. and atmospheric pressure in the presence of palladium (10% on activated charcoal, 15 mg). After 30 min, the solvent was evaporated, the residue was treated with toluene (20 mL), the suspension concentrated and the residue dried in vacuo to afford the title compound (247 mg, ca, 85% purity), which was directly used in the next step. Light yellow shod, MS (ISP) 378.4 (M+H)"‘.

(v) mc-(9,10-Dimethoxy-3|3-pyrrol-l-yl-13>4,6,7,llb|3-hexahydro-2H-pyTido[2,l-a]isoquinolin-2a-yl)-carbamic acid tert-butyl ester
2,5-dimethoxytetrahydrofuran (41 mg, 0.30 mmol) was added to a solution of rac-(3P-
amino-9,10-dimethox)’-l,3A6,7,llb(3-hexahydro-2H-pyrido[2,l-a]isoquinolin-2a-yl)-carbamic acid tert-butyl ester (120 mg, 0.27 mmol/85% purity) in acetic acid (1.2 mL, 21 mmol) and pyridine (0.76 mL, 9.5 mmol). The homogeneous solution was heated at 100°C for 105 min, then evaporated, and the residue was chromatographed (Si02, heptane/ethyl acetate gradient) to afford the title compound (87 mg, 75%). White shod, MS (ISP) 428.3 (M+H)’.
(vi) rac-9,10-Dimethoxy-3P-pyrrol-l-yI-l,3,4>6,7,llb|3-hexahydro-2H-pyrido[2,l-a] isoquinolin-2a-ylamine
rac-(9,10-Dimethoxy-3P-pyrrol-l-yl-l,3,4,6,7,llb|3-hexahydro-2H-pyrido[2,l-a]isoquinolin-2a-yl)-carbamic acid tert-butyl ester (86 mg, 0.20 mmol) was dissolved in hydrogen chloride solution (4 M in dioxane, 1 mL), stirred at r.t. for 1 h, and evaporated. Chromatography of the residue (SiOa, CH2Cl2/MeOH/NH40H 95:5:0.25) produced the title compound (58 mg, 88%). White solid, MS (ISP) 328.3 (M+H)’.
Examples 61 and 62
The following compounds are prepared in analog)'‘ to Example 1:
61. rac-9,10-Dim.ethox)’-3P-p-tolyl-l,3,4,6,7,llbP-hexahydro-2H-pyrido[2,l-a]isoquinolin-2P-ylamine as a yellow powder, MS (ISP) 353.3 (M+H)"‘.
62. rac~9y 10-Dimethoxy-3p-p-tolyl-l,3,4,6,7,llb|3-hexahydro-2H-pyrido[2,l-a]isoquinolin-2a-ylamine as a yellowish powder, MS (ISP) 353.3 (M+H)"‘.
The educts used in Examples 61 and 62 (compounds of formulae II, III and VI) which have not been described above can be prepared according to the procedures described below or in analogy thereto.
Oxime derivative (compound of formula II)
The forewing compound is prepared in analogy to the procedure for the preparation ofrac-3P-Butyl-9,10-dimethoxy-I,3,4,6,7,llbP-hexahydro-pyrido[2,l-a]isoquinolin-2-one oxime described in above Example 1:

mc-9,10-Dimethoxy-3(3-p-tolyl-l,354,6,7,llbP-hexahydro-pyrido[2,l-a]isoquinolin-2-one oxime as a yellowish powder, MS (ISP) 367.2 (M-hH)"‘.
Ketone derivative (compound of formula III)
The following compound is prepared in analogy to the procedure for the preparation ofrflc-3(3-Butyl-9,10-dimethoxy-l,354,6>7,llbp-hexahydro-pyrido[2,l-a]isoquinolin-2-one described in above Example 1:
rac-9,10-Dimethoxy-3p-p-toiyl-l,3,4,637,llb-hexahydro-pyrido[2,l-a]isoquinolin-2-one as an off-white powder, MS (ISP) 352.3 (M+H)"".
Ammonium iodide derivative (compound of formula V)
A mixture of 4-methylphenylacetone (3.01 g), par formaldehyde (0.489 g) and dimethylamine hydrochloride (1.49 g) in MeOH (2 ml) is stirred under reflux for 3 h. The reaction mixture is diluted with 20 ml of water and the product is extracted with two portions of ether. After addition of 1 M aqueous NaOH solution, the aqueous layer is extracted with two more portions of ether. The combined organic layers are dried (Na2S04) and the solvent is evaporated to obtain 4-dimethylamino-3-p-tolyl-butan-2-one (compound of formula VI) as a yellowish liquid, MS (ISP) 206.2 (M+H)’ 4-Dimethylamino-3-p-tolyl-butan-2-one is dissolved in AcOEt (17 ml) and diazomethane (L46) is added. After 1 h the formed solid is collected by filtration, washed with AcOEt and dried on the vacuum. 2.61 g of trimethyl-(3-oxo-2-p-tolyl-but}d)-ammonium iodide are obtained as an oft'-white shod, MS (ISP) 220.3 M’.
Examples 63 and 64
(i) 21.5 mg of palladium acetate, 276 mg of sodium tert-butoxide and 23 mg of tri-tert-butylphosphine are placed in a flask, which is evaporated and charged with argon three times. 2 ml of tetrahydrofurane is added under argon. To this solution 177 mg of 4-bromoxylene and 250 mg of rac-9,10-dimethoxy-1,3,4,6,7,1 lb-hexahydro-2H-benzo[a]quinolizin-2-one (D. Bake, C. Szantay, Chem. Ber. 95, 2132 (1962)) dissolved in 1 ml of tetrahydrofurane are added. The reaction is stirred at room temperature under argon over night. The crude reaction is diluted with diethyl ether, washed "vetch water and sat. aq. sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and the solvent is evaporated. The residue is purified by column chromatography (silica gel,
diethyl ether) to yield 92.0 mg of rac:-9,10-dimethoxy-3P-(3,4-dimethyI-phenyl)-

l,3,4,6,7,llb|3-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-one as a light yellow solid. ‘H NMR (CDCI3): 5 = 7.16-6.90 (m, 3 K), 6.64 (s, 1 H), 6.59 (s, 1 H), 3.93-3.71 (m, 8 H, 2 MeO + 2 H), 3.40-3.36 (m, 1 H), 3.17-2.6 (m, 7 H), 2.4-2.2 (m, 6 H, 2 Ar-CHs). MS (ISP): 366.2 (M+H)’.
(ii) To a yellow suspension of 86 mg of mc-9,10-dimethoxy-3(3-(3,4-dimethyl-phenyl)-1,3,4,6,7,1 lb(3-hexahydro-pyrido[2.1-a]isoquinolin-2-one in 4 ml of ethanol is added 21.2 mg sodium acetate and 18.0 mg hydroxylamine hydrochloride. The reaction mixture is stirred for four hours at room temperature. 4 ml. of water and 150 mg of nickel-aluminum alloy are added. 0.7 ml of an aq. 32 % sodium hydroxide solution is added dropwise. The mixture is stirred at room temperature over night, filtered and the solution is extracted three times with dichloromethane. The organic layers are dried over sodium sulfate and the solvent is evaporated. The residue is purified by chromatography (silica gel, dichloromethane/methanol/sat. aq. ammonia = 97/3/0.3). Two products are obtained. They are dissolved independently in dichloromethane and saturated etheral hydrochloric acid solution is added until a solid precipitated.
63. rac-9,10-dimeth6xy-3|3-(3,4-dimethyl-phenyl)-l,3,4,6,7,llbP-hexahydro-2H-
pyrido[24-a]isoquinolin-2|3-ylamine chlorohydrate (1:2)
14.4 mg of the title compound are obtained as a light yellow solid. This product is
eluted first during chromatography. ‘H NMR (CDCI3): 5 = 7.17-6.95 (m, 3 H), 6.70
(s, 1 H), 6.60 (s, 1 H), 3.85 (s, 3 H, MeO), 3, 84 (s, 3 H, MeO), 3.6-2.2 (m, 17 H), 2.0-
1.8 (m, 1 H). MS (ISP): 367.3 (M+H)"".
64. rac-9,10-dimethoxy-3P-(3,4-Dimethyl-phenyl)-l,3,4,6,7,llbP-hexahydro-2H-
pyrido[2,l-a]isoquinolin-2a-ylamine chlorohydrate (1:2)
39.5 mg of the title compound are obtained as a light yellow sohd.This product is
eluted second during chromatography. ‘H NMR (CDCI3): 5 = 7.15-6.99 (m, 3 H),
6.75 (s, 1 H), 6.60 (s, 1 H), 3.85 (s, 3 H, Ar-CHs), 3.83 (s, 3 H, MeO), 3.4-2.9 (m, 5
H), 2.7-2.2 (m, 12 H). MS (ISP): 367.3 (M+H)’.
Examples 65-68
The following compounds are prepared in analogy to Examples 63 and 64:

65. rac-9,10-Dimethoxy-3P-(3-methox7-phenyl)-l,3,4,6,7,nb|3-hexah7dro-2H-
pyTido[2,l-a]isoquinolin-2P-ylainine chlorohydrate (1:2).
The tide compound was obtained as a light yellow solid. This product is eluted first during chromatography. ‘H NMR (CDCI3): 5 = 7.29-7.24 (m, 1 H), 6.84-6.74 (m, 3 H), 6.70 (s, 1 H), 6.60 (s, 1 H), 3.94-3.82 (m, 10 H, 3 MeO +1 H), 3.60-2.36 (m, 10 H), 2.00-1.95 (m, 1 H). MS (ISP): 369.3 (M+H)’
66. rac-9,10-Dimethoxy-3P-(3-methoxy-phenyl)-1,3,4,6,7,1 lb|3-hexahydro-2H-
pyTido[2,l-a]isoquinolin-2a-ylamine chlorohydrate (1:2).
The title compound was obtained as a light yellow solid. This product is eluted second during chromatography. ‘H NMR (CDCls): 5 = 7.30-7.24 (m, 1 H), 6.89-6.79 (m, 3 H), 6.75 (s, 1 H), 6.60 (s, 1 H), 3.85-3.82 (m, 6 H, 2 MeO), 3.82 (m, 4 H, 1 MeO + 1 H), 3.4-2.2 (m, 11 H). MS (ISP): 369.3 (M+H)"*".
()1. rac-9,10-Dimethoxy-3|3-pyridin-l,3,4,6,7,llbP-hexahydro-2H-pyrido[2,l-a]isoquinolin-23-ylamine chlorohydrate (1:2).
The title compound is obtained as a light meow solid. This product is eluted first during chromatography. 'H NMR (CDCI3): 6 = 8.60-8.57 (m, 1 H), 7.68-7.63 (m, 1 H), 7.27-7.15 (m, 2 H), 6.71 (s, 1 H), 6.60 (s, 1 H), 3.85-3.84 (m, 7 H, 2 MeO), 3.8-3.0 (m, 7 H), 2.8-2.6 (m, 1 H), 2.45-2.39 (m, 1 H), 2-1.92 (m, 1 H). MS (ISP): 340.3 (M+H)"".
68. rac-9,10-Dimethoxy-3|3-pyridin-l,3,4,6,7,llbP-hexahydro-2H-pyrido[2,l-a]isoquinolin-2a-ylamine chlorohydrate (1:2).
The title compound was obtained as a light yellow solid. This product is eluted second during chromatography. ‘H NMR (CDCI3): 5 = 8.63-8.61 (m, 1 H), 7.68-7.62 (m, 1 H), 7.26-7.16 (m, 2 H), 6.75 (s, 1 H), 6.60 (s, 1 H), 3.87-3.80 (m, 7 H), 3.5-2.5 (m, 11 H). MS (ISP): 340.3 (M+H)"*".
The following compounds are prepared in analogy to the procedure used for the preparation of rac-9,10-dimethoxy-3|3-(3,4-dimethyl-phenyl)-1,3,4,6,7,1 IbP-hexahydro-2H-pyTido[2,l-a]isoquinolin-2-one described above in Examples 63 and 64:
rac-9,10-dimethoxy-3P-(3-methoxy-phenyl)-l,3,4,6,7,llbP-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-one obtained as a light yellow solid. ‘H NMR (CDCl): 5 =

7.43-6.56 (m, 5 H), 3.95-3.72 (m, 11 H, 3 MeO + 2 H), 3.45-3.40 (m, 1 H), 3.2-2.6 (m, 8 H). MS (ISP): 368.3 (M+H)'.
rac-9,10-dimethoxy-3|3-pyridin-2-yl-l,3,4,6,7,llb(3-hexah7dro-2H-p7rido[2,l-a]isoqumolin-2-one obtained as an orange solid. ‘H NMR (CDCI3): 5 = 8.38-8.35 (m, 1 H), 7.72-7.67 (m, 1 H), 7.07-6.96 (m, 2 H), 6.68 (s, 1 H), 6.62 (s, 1 H), 3.93-3.75 (m, 8 H, 2 MeO + 2 H), 3.65-3.60 (m, 1 H), 3.40-3.26 (m, 7 H). MS (ISP): 339.3 (M+H)’
Examples 69-81 The following compounds were prepared in analogy to Example 1:
69. rac-4-(2j’-Amino-3/?-butyl-9,10-dimethoxy-l,3,4,6,7,Ilb/9-hexahydro-2H-pyrido[2,l-a]isoquinolin-7/?-yl)-phenol, MS (ISP) 411.5 (M+H)’.
70. rac-3y?-Butyl-9,10-dimethoxy-6-methyl-l,3,4,6,7,llb;/?-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-ylamine, MS (ISP) 333.4 (M+H)*.
71. rac-3y5-Butyl-7j5-(4-chloro-phenyl)-9,10-dimethoxy-l,3,4>6,7,llb)5-hexahydro-2H-pyrido[2,l-a]isoquinolin-2a-ylamine, MS (ISP) 429.6 (Mi-H)’
72. rac-3;5-Butyl-7«-(4-chloro-phenyl)-9,10-dimethoxy-l,3,4,6,7,llb/?-hexahydro-2H-pyrido[2,l-a]isoquinolin-2«r-yIamine, MS (ISP) 429.6 (M-l-H)"‘.
73. rac-3/?-Butyl-7;’-(3,4-dimethoxy-phenyI)-9,10-dimethoxy- l,3,4,6,7,nb/?-liexahydro-2H-pyrido[2,l-a]isoquinolin-2Qr-ylamine, MS (ISP) 455.6 (M+H)’.
74. rac-3/?-But5’1-9,10-dimethoxy-7,7-dimethyl-l,3,4,6,7,llby5-liexahydro-2H-pyrido[2,l-a]isoquinolin-2a-yIamine, MS (ISP) 347.5 (M-hH)"‘.
75. rflc-3y5-Butyl-9,10-dimethoxy-7,7-dimethyl-l,3,4,6,7,llb;5-liexahydro-2H-pyrido[2,l-a]isoquinolin-2y5-ylamine, MS (ISP) 347.5 (M+H)"‘.

76. rflc-7yS-But)4-ll,12-dimethoxy-2,3,4,4aA6,7,8,9,9ao;13by’-decahydro-lH-pyrido[l,2-f]phenanthridin-8/?-ylamine,MS (ISP) 373.5 (M+H)’.
77. rflc-7/?-Butyl-ll,12-dimethoxy-2,3A4ay5,6,7,8,9,9aal3b/?-decahydro-lH-pyrido[l,2-flphenanthridin-8a-ylamine, MS (ISP) 373.5 (M+H)"".

Example D
Soft gelatin capsules containing the following ingredients can be manufactured in a conventional manner:
Capsule contents
Compound of formula (I) 5.0 m’-
Yellow wax 8.0 mg
Hydrogenated Soya bean oil 8.0 mg
Partially hydrogenated plant oils 34.0 mg
Soya bean oil 110.0 mg
Weight of capsule contents 165.0 mg
Gelatin capsule
Gelatin 75.0 mg
Glycerol 85 % 32.0 mg
Karin 83 8.0 mg (dry matter)
Titan dioxide 0.4 mg
Iron oxide yellow 1.1 mg
The active ingredient is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.
Example E
Sachets containing the following ingredients can be manufactured in a conventional manner:
Compound of formula (I) 50.0 mg
Lactose, fine powder 1015.0 mg
Microcristalline cellulose (AVICEL PH 102) 1400.0 mg
Sodium carboxymethyl cellulose 14,0 mg
Polyvinylpyrrohdon K 30 10.0 mg
Magnesiumstearate 10.0 mg
Flavoring additives 1.0 mg
The active ingredient is mixed with lactose, microcristalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrohdon in water. The granulate is mixed with magnesiumstearate and the flavorings additives and filled into sachets.

WE CLAIM:
1, Compounds of formula (I)

with an alcohol
R-OH
wherein R is C1-C6-alkyl substituted by aryl, heterocyclyl or lower alkoxycarbonyl;
in the presence of triphenylphosphine and di-r-butyl azodicarboxylate, followed by deprotection.
17. Pharmaceutical compositions comprising a compound according to any of claims 1 to 15
and a pharmaceutically acceptable carrier and/or adjuvant.
18. Compounds of formula (I), wherein R\ R^, R^, R"^ R^, R^ and R^ are as defined in claim 1
and pharmaceutically acceptable salts thereof for use as therapeutic active substances.
19. Compounds according to any of claims 1 to 15 for use as therapeutic active substances.
20. Compounds according to any of claims 1 to 15 for use as therapeutic active substances for the treatment and/or prophylaxis of diseases which are associated with DPP-IV.

Documents:

1416-chenp-2004-abstract.pdf

1416-chenp-2004-claims filed.pdf

1416-chenp-2004-claims granted.pdf

1416-chenp-2004-correspondnece-others.pdf

1416-chenp-2004-correspondnece-po.pdf

1416-chenp-2004-description(complete) filed.pdf

1416-chenp-2004-description(complete) granted.pdf

1416-chenp-2004-form 1.pdf

1416-chenp-2004-form 26.pdf

1416-chenp-2004-form 3.pdf

1416-chenp-2004-form 5.pdf

1416-chenp-2004-other documents.pdf

1416-chenp-2004-pct.pdf

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Patent Number

209390

Indian Patent Application Number

1416/CHENP/2004

PG Journal Number

38/2007

Publication Date

21-Sep-2007

Grant Date

28-Aug-2007

Date of Filing

23-Jun-2004

Name of Patentee

M/S. F. HOFFMANN-LA ROCHE AG

Applicant Address

124 Grenzacherstrasse, CH-4070 Basel

Inventors:

#	Inventor's Name	Inventor's Address
1	GOBBI Luca Claudio	Rohrhagstrasse 14, CH-4104 Oberwil
2	LUEBBERS Thomas	Talweg 10a, 79540 Loerrach
3	MATTEI Patrizio	Doernliweg 33, CH-4125 Riehen
4	NARQUIZIAN Robert	9, rue de la Gare, F-68870 Barthenheim
5	WYSS Pierre	Im Hofacker 15, CH-4106 Therwil

PCT International Classification Number

A61 K 31/445

PCT International Application Number

PCT/EP2002/014685

PCT International Filing date

2002-12-20

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	01130882.2	2001-12-27	EUROPEAN UNION