NZ266525A

NZ266525A - 4,5,6,7-tetrahydro-1h-pyrazolo[3,4-c]pyridine derivatives and medicaments

Info

Publication number: NZ266525A
Application number: NZ266525A
Authority: NZ
Inventors: Allen Jacob Duplantier
Original assignee: Pfizer
Priority date: 1993-07-06
Filing date: 1994-06-16
Publication date: 1997-10-24
Also published as: NO960056L; HU9503934D0; ZA944844B; AU6805794A; RU2131876C1; NO960056D0; IL110175A0; WO1995001980A1; CN1048015C; TW316904B; HUT74170A; JP2944048B2; EG20513A; JPH08507084A; KR100228949B1; NO305029B1; EP0707585A1; CA2166721C; FI943208A0; KR960703852A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £66525 New Zealand No. 266525 International No. PCT/IB94/00156 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 06.07.1993; Complete Specification Filed: 16.06.1994 Classification:^) C07D471/04; A61K31/445,435 Publication date: 24 October 1997 Journal No.: 1421 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: Bicyclic tetrahydro pyrazolopyridines NO DRAWIN Name, address and nationality of applicant(s) as in international application form: PFIZER INC., a Delaware corporation of 235 East 42nd Street, New York, NY 10017, United States of America New Zealand No. International No. 266525 PCT/IB94/00156 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: Bicyclic tetrahydro pyrazolopyridines Name, address and nationality of applicant(s) as in international application form: PFIZER INC, a Delaware corporation of 235 East 42nd Street, New York, NY 10017, United States of America WO 95/01980 PCT/EB94/00156 -1- 266525 5 BICYCLIC TETRAHYDRO PYRAZOLOPYRIDINES Background of the Invention This invention relates to a series of bicyclic tetrahydro pyrazolopyridines which are selective inhibitors of phosphodiesterase (PDE) type IV or the production of tumor 10 necrosis factor (hereinafter TNF) and as such are useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases; and AIDS, septic shock and other diseases involving the production of TNF. This invention also relates to a method of using such compounds in the 15 treatment of the above diseases in mammals, especially humans and to pharmaceutical compositions useful therefor. Since the recognition that cyclic AMP is an intracellular second messenger (E.W. Sutherland, and T. W. Rail, Pharmacol. Rev.. 1960, 12, 265), inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic 20 intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized (J.A. Beavo and D. H. Reifsnyder, TiPS. 1990, H, 150), and their selective inhibition has led to improved drug therapy (C.D. Nicholson, R. A. Challiss and M. Shahid, TiPS. 1991, 12,19). More particularly, it has been recognized that inhibition of PDE type IV can lead to inhibition of inflammatory mediator release (M.W. Verghese 25 et al.. J. Mol. Cell Cardiol., 1989, 12! (Suppl. II), S 61) and airway smooth muscle relaxation (T. J. Torphy in Directions for New Anti-Asthma Drugs, eds S. R. O'Donnell and C. G. A. Persson, 1988, 37, Birkhauser-Verlag). Thus, compounds that inhibit PDE type IV, but which have poor activity against other PDE types, would inhibit the release of inflammatory mediators and relax airway smooth muscle without causing 30 cardiovascular effects or antiplatelet effects. TNF is recognized to be involved in many infectious and auto-immune diseases (W. Friers, FEBS Letters. 1991, 285, 199). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C.E. Spooner et al., Clinical Immunology and Immunopatholoov. 1992, 62, S11). WO 95/01980 PCT/IB94/00156 -2- 20 25 Summary of the Invention The present invention relates to compounds of the formula R1 1 7 10 and the pharmaceutical^ acceptable salts thereof; wherein R1 is (C -C )alkyl, (CJ-CJ)alkenyl, (CJ-C5)cycloalkyl or methylene (C3-C5)cydoalkyl wherein each alkyi or alkenyl group may be optionally substituted with up to two (C'-C^alkyl ortrifluoromethyl 3 groups or up to three halogens; X is oxygen or two hydrogen atoms; R is selected from the group consisting of hydrogen, (C1-C14)alkyll 15 (C2-C7)alkenyl, (C^-C'jheterocydic group containing oxygen, sulphur, SOa or NR5 wherein R5 ;s hydrogen or (C'-C^alkyl, or a group of the formula i V (R4)a -<Y)b-CZ)c II 30 wherein a is an integer firm 1 to 5; b and c are each independently O or 1 4 1 R is hydrogen, hydroxy, (C - C5)alkyl, (CJ-C5)alkenyt, (C'-C5)aIkoxy, (C3-C6)cycloaIkoxy, halogen, trifluoromethyl, COjR8, C0NR6R', NR®R7, N02 or S02NR6R7 wherein R6 and R' are each independently hydrogen or (C'-C)alkyl; wherein Z is oxygen, sulphur, SOa or NR* wherein R" is hydrogen or (C1-C4)alkyl; and Y is (C'-C5)alkylene or (CJ-C8)alkenyl optionally substituted with up to two (C'-C')alkyl or (C3-C7)cycloalkyl groups; or R3 is a group of the formula R9 U ^WO 95/01980 O _ 3 _ O PCT/IB94/00156 ™ 9 13 wherein p is an integer from 1 to 3, W is oxo or hydroxy, and R is (C -C )alkyl; wherein each said alkyl, alkenyl, cycloalkyl, aJkoxyalkyl or heterocyclic group may be optionally substituted with one or more _ _ of the>group consisting of (C1- C2)alkyl, trifluoromethyl or halogen? and R^ is either mono-substituted phenyl, substituted in the 2 or 3 positions of the phenyl ring, or R is disubstituted phenyl, di.substituted in the 2 and 3 positions of the phenyl ring, wherein the g substituents for R2 are selected from the group consisting of hydroxy, (C*- C5)alkylt (C2-Cs)alkenyl, (C'-C5)alkoxy, (C3-C8)cycloaIkoxy, halogen, trifluoromethyl, COjR6, CONR'R7, NR'R7, N02 or SOjNR*R7 wherein R6 and R7 are each independently hydrogen or (C'-C^alkyl. 10 In one embodiment, the invention relates to a compound of formula I wherein R1 is (C1-C3)alkyl R3 is selected from the group consisting of (C3-C7)cycloalkyl, (C4-C7)heterocyclic group containing SOj or a group of the formula (R") „ 15 I I I 4 15 wherein a is an integer frcm 1 to 5 and R is hydrogen, hydroxy, (C -C )alkyl, 15 2 (C -C )alkoxy or halogen, and the substituents for R are selected from 15 15 the group consisting of hydroxy, (C -C )alkyl, (C -C ) alkoxy and halogen. 20 In another embodiment, the invention relates to a compound of formula I wherein R1 is ethyl or isopropyl; R2 is 2-methyiphenyl, 3-methyiphenyi, 2* methoxyphenyl, 3-methoxyphenyl or 3-trifluoromethylphenyl and R3 is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolanyl, 4-fluorophenyi or 3,4-dichlorophenyt. The present invention further relates to a pharmaceutical composition for the 25 inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) comprising a pharmaceutical^ effective amount of a compound according to formula I and the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. Also described herein is a method for the inhibition of 30 phosphodiesterase .(PDE) type IV and the production of tumor necrosis factor (TNF) comprising administering to a patient an effective amount of a compound according to formula I and the pharmaceutically acceptable salts thereof. WO 95/01980 o PCT/IB94/00156 5 -4- Also described herein is a method of treating an inflammatory condition in mammals which comprises administering to said mammal an antiinflammatory amount of a compound of the formula I and the pharmaceutically acceptable salts thereof. 5 The present invention further relates to a pharmaceutical composition for the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF comprising a pharmaceutically effective amount of a compound according to formula I and the pharmaceutically acceptable 10 salts thereof together with a pharmaceutically acceptable carrier. Also described herein is a method of treating or preventing a condition selected from the group consisting of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF comprising 15 administering to a patient an effective amount of a compound according to formula I and the pharmaceutically acceptable salts thereof. Specific preferred compounds of the invention are: 20 3-ethyl-1-(3,4-dichiorophenyl)-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine; 3-ethyl-1-cyclopentyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-25 pyrazolo[3,4-c]pyridine; 3-ethyl-1-(4-fiuorophenyl)-6-(2-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazo!o[3,4-c]pyridine; 3-ethyl-l -cyclopentyl-6-(3-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c] pyridine; 30 3-ethyl-1 -cyclopentyl-e-fS-trifluoromethylphenylJ^-oxo^.S.ej-tetrahydro-l H- pyrazolo [3,4-c] pyridine; 3-ethyl-1-cyclohexyl-6-(3-methoxyphenyl)-7-oxo-4,5,^7-tetrahydro-1 H- pyrazolo [3,4-c] pyridine; _W0 95/01980 PCT/IB94/00156 -5- 3-isopropyl-1-cyclopentyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyra2olo[3,4-c]pyridine; 3-ethyl-l-cyclobutyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine; 5 3-ethyl-1 -cyclopentyl-6-(2-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazo!o[3,4-c]pyridine; 3-ethyl-1-(3-sulfolanyl)-6-(3-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine; 10 3-ethyl-1 -(3-sulfolanyl)-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H- pyra2olo[3,4-c]pyridine; 3-ethyl-1-cyclabutyl-6-(3-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyra2olo[3,4-c]pyridine; 3-ethyl-1-(3-sulfolanyl)-6-(3-trifluoromethylphenyl)-7-oxo-4(5,6,7-tetrahydro-1 H- 15 pyrazolo[3,4-c]pyridine; 3-ethyl-1-cyclobutyl-6-(3-trifluoromethylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazo!o[3,4-c]pyridine; 3-ethyl-1-cyclobutyl-6-(2-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrBZolo[3l4-c] pyridine. 20 Detailed Description of the Invention The term "halogen", as used herein, unless otherwise indicated, includes chloro, fluoro and bromo. Unless indicated otherwise, the alkyl, alkoxy and alkenyl groups referred to herein may be straight chained or if comprising three or more carbons may be straight 25 chained, branched, cyclic or a combination of cyclic and branched or straight chained moieties. The "inflammatory diseases" which can be treated according to this invention include, but are not limited to asthma, chronic obstructive pulmonary disease, bronchitis and arthritis. 30 R\ R2 and R3, as used herein, unless otherwise indicated, are as defined above with reference to formula I. The following reaction schemes illustrate, but are not limiting to the preparation / of the compounds of the present invention. yV WO 95/01980 PCT/EB94/00156 WO 95/01980 PCT/IB94/00156 -7- 5 In Reaction 1 of Scheme 1, the 2-pyrrolidinone compound of formula IV is converted to the corresponding N-(aryl)-2-pyrrolidone compound V wherein "aryl" is a group of the formula II by reacting IV with an aryl halide neat in the presence of copper power and potassium carbonate. Suitable aryl halides include 1-iodo- or 1-bromo- 4-methoxybenzene, 3-methoxybenzene, 2-methoxybenzene, 3-methylbenzene, 4-10 methylbenzene, 2-methylbenzene, 3-trifluoromethylbenzene, 2-trifluoromethylbenzene, 3,4-dimethoxybenzeneor3-cyclopentoxy-4-methoxybenzene. The reaction temperature will generally be in the range of about 110°Cto about 170°C, preferably about 150°C, for a time period of about 14 hours to about 22 hours, preferably about 18 hours, under inert reaction conditions. 15 In Reaction 2 of Scheme 1, R1 halide is added to a suspension of magnesium in an anhydrous aprotic solvent. The reaction mixture is heated to reflux until all the magnesium is consumed'and thereafter cooled to a temperature between about -15°C to about 15°C, preferably about 0°C. The N-(aryl)-2-pyrrolidone compound of formula V is then added and the reaction mixture is warmed to room temperature while being 20 stirred for a time period between about 1.5 hours to about 2.5 hours, preferably about 2 hours. Suitable alkyl halides include bromomethane, bromoethane or bromopropane. The preferred anhydrous aprotic solvent is anhydrous ether. Upon completion of the reaction, the desired intermediate may be isolated in a conventional manner, e.g., by first washing the combined organics with water and brine, then drying 25 over sodium sulfate, filtering and concentrating under reduced pressure to afford a readily-recoverable precipitate in the form of a white solid. The above precipitate is converted to the corresponding 1,2,5,6-tetrahydropyridine compound of formula VI by dispersing the precipitate in a mixture of a non-polar aprotic solvent and base. Upon vigorous stirring, ethyl oxalyl chloride 30 is added and the reaction mixture is heated to reflux for a time period between about 1.5 hours to about 4.5 hours, preferably about 3.0 hours. The preferred non-polar aprotic solvent is benzene and the preferred base is sodium hydroxide. The solvents are removed and the resulting residue is treated with a solution of sodium alkoxide in ethanol. After heating at reflux for a time period between about 1 hour and about 3 35 hours, preferably about 1.5 hours, the mixture is concentrated under reduced pressure and acidified to pH=3 with hydrochloric acid. WO 95/01980 PCT/IB94/00156 -8- ln Reaction 3 of Scheme 1, the compound of formula VI is converted to the corresponding 3-methoxy-1,2,5,6-tetrahydropyridine compound VII by heating to reflux a reaction mixture of VI and 3-methyl-1-p-tolyltriazene in an aprotic solvent. The preferred aprotic solvent is 1,2-dichloroethane. The time period for the reaction is 5 between about 30 minutes to about 120 minutes, preferably about 45 minutes. In Reaction I of Scheme 2, the 1,2,5,6-tetrahydropyridine compound of formula VIII, wherein R5 is hydrogen or methyl, is converted to the corresponding 4,5,6,7-tetrahydro-7-oxo-1H-pyrazolo[3,4-c]pyridine compound IX by reacting VIII with a hydrazine of the formula R3HNNH2. Both derivatives of the compound of formula VIII, 10 3-hydroxy and 3-methoxy, may be used as starting materials under one of three different sets of reaction conditions. Under one set of reaction conditions, the 1,2,5,6-tetrahydropyridine compound of formula VIII is converted to the corresponding compound of formula IX by reacting VIII with a hydrazine hydrochloride and sodium alkoxide in an anhydrous polar protic 15 solvent. The preferred sodium alkoxide is sodium methoxide and the preferred anhydrous polar protic solvent is anhydrous ethanol. The reaction mixture is heated to reflux for a time period between about 9 hours to about 15 hours, preferably about 12 hours. Under a second set of reaction conditions, the 1,2,5,6-tetrahydro-pyridine 20 compound VIII is converted to the corresponding compound of formula IX by reacting VII] with hydrazinobenzoic acid in an anhydrous polar protic solvent, preferably ethanol. The reaction mixture is heated to reflux for a time period between about 16 hours to about 24 hours, preferably about 20 hours. The compound IX so formed may be further reacted to give the corresponding 1-(4-benzamide)-7-oxo-4,5,6,7-tetrahydro-1 H-25 pyrazolo[3,4-c]pyridine compound by reacting IX with sodium methoxide in a polar protic solvent, preferably methanol, for a time period between about 15 minutes to about 45 minutes, preferably 30 minutes. The polar protic solvent is removed under reduced pressure, the solid residue is suspended in a non-polar aprotic solvent, perferably benzene, and thereafter, the non-polar solvent is removed under reduced 30 pressure. The resulting dry solid is suspended in cold ether and treated with oxaiyl chloride and N,N-dimethylformamide and allowed to stir for a time period between about 30 minutes to about 90 minutes, preferably 60 minutes. The solvent is then removed and the crude residue is dissolved in dry tetrahydrofuran. The resulting WO 95/01980 PCT/IB94/00156 -9- solution is added diopwise to stirred ammonium hydroxide at a temperature between about -10°C to about 10°C, preferably 0°C. Under a third set of reaction conditions, the 1,2,5,6-tetrahydropyridine compound of formula VIII is converted to the corresponding compound of formula IX 5 by reacting VIII with a hydrazine hydrochloride in a polar protic solvent, preferably methanol. The reaction mixture is heated to a temperature between about 70°C to about 110°C, preferably about 90°C, under a gentle stream of nitrogen until all of the solvent is removed. The neat mixture is then heated to a temperature between about 12Q°C to about 180°C, preferably about 150°C, for a time period between about 30 10 minutes to about 90 minutes, preferably 60 minutes. The compounds so formed of formula IX may be converted to the corresponding 6-R2-4,5,6,7-tetrahydro-7-oxo-1H-pyrazolo [3,4-c]pyridine compound, wherein R2 is other than the group of formula II, by reacting a solution of IX in a polar aprotic solvent, preferably acetonitrile, with a solution of ammonium cerium (IV) nitrate 15 in water at a temperature between about -15°C to about 15°C, preferably about 0°C, tor a time period between about 20 minutes to about 50 minutes, preferably about 35 minutes. Upon completion of the reaction, the mixture is diluted with water and extracted with ethyl acetate. The combined organics are then washed with saturated sodium bicarbonate followed by sodium sulfite. The compound so formed in a polar 20 aprotic solvent, preferably tetrahydrofuran, is treated with sodium hydride, heated to reflux and stirred for a time period between about 30 minutes to about 60 minutes, preferably 45 minutes. The reaction mixture is cooled to a temperature between about 20°C to about 30°C, preferably about 25°C, and an alkyl halide of formula R2 halide, wherein R2 is as defined with reference to formula I other than a group of formula II, is 25 added. The reaction mixture is stirred and heated to reflux for a time period between about 12 hours to about 20 hours, preferably 16 hours. In Reaction 2 of Scheme 2, the 2-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine compound IX is converted to the corresponding compound of formula X by reacting IX with a reducing agent, preferably lithium aluminum hydride, in a non-polar 30 aprotic solvent, preferably ether. The reaction is stirred for a time period between about 12 hours to about 20 hours, preferably 16 hours. Water and base, preferably sodium hydroxide, is then added and the reaction mixture is stirred for a time period between WO 95/01980 PCT/EB94/00156 -10- about 1.5 hours to about 2.5 hours, preferably 2 hours, and filtered. The filtrate is concentrated to a white solid. The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit phosphodiesterase IV (PDE4) and, consequently, demonstrate their 5 effectiveness for treating inflammatory diseases is shown by the following in vitro assay. BIOLOGICAL ASSAY (Human lung PDE,V) Thirty to forty grams of human lung tissue is placed in 50 ml of pH 7.4 Tris/phenylmethylsulfonyl fluoride (PMSF)/sucrose buffer and homogenized using a 10 Tekmar Tissumizer® (Tekmar Co., 7143 Kemper Road, Cincinnati, Ohio 45249) at full speed for 30 seconds. The homogenate is centrifuged at 48,000 x g for 70 minutes at 4°C. The supernatant is filtered twice through a 0.22 //m filter and applied to a Mono-Q FPLC column (PharmacialKB Biotechnology, 800 Centennial Avenue, Piscataway, New Jersey 08854) pre-equilibrated with pH 7.4 Tris/PMSF buffer. A flow rate of 1 ml/minute 15 is used to apply the sample to the column, followed by a 2 ml/minute flow rate for subsequent washing and elution. Sample is eluted using an increasing, step-wise NaCI gradient in the pH 7.4 Tris/PMSF buffer. Eight ml fractions are collected. Fractions are assayed for specific PDEIV activity, determined by [3H]cAMP hydrolysis and the ability of a known PDEIV inhibitor (e.g. rolipram) to inhibit that hydrolysis. Appropriate 20 fractions are pooled, diluted with ethylene glycol (2 ml ethylene glycol/5 ml of enzyme prep) and stored at -20°C until use. Compounds are dissolved in DMSO at a concentration of 10 mM and diluted 1:25 in water (400 /jM compound, 4% DMSO). Further serial dilutions are made in 4% DMSO to achieve desired concentrations. Final DMSO concentration in assay tube is 25 1%. In duplicate the following are added, in order, to a 12 x 75 mm glass tube (all concentrations are given as final concentrations in assay tube). i) 25 (j\ compound or DMSO (1%, for control and blank) ii) 25 fj\ pH 7.5 Tris buffer iii) [3H]cAMP (1 //M) 30 iv) 25 //I PDEIV enzyme (for blank, enzyme is preincubated in boiling water for 5 minutes) The reaction tubes are shaken and placed in a water bath (37 °C) for 20 minutes, at which time the reaction is stopped by placing the tubes in a boiling water WO 95/01980 PCT/IB94/00156 -11- bath for 4 minutes. Washing buffer (0.5 ml, 0.1 M 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid (HEPES)/0.1 M NaCI, pH 8.5) is added to each tube on an ice bath. The contents of each tube are applied to an Affi-Gel 601 column (Biorad Laboratories, P.O. Box 1229, 85A Marcus Drive, Melville, New York 11747) (boronate affinity gel, 1 5 ml bed volume) previously equilibrated with washing buffer. [3H]cAMP is washed with 2 x 6 ml washing buffer, and [3H]5'AMP is then eluted with 4 ml of 0.25M acetic acid. After vortexing, 1 ml of the elution is added to 3 ml scintillation fluid in a suitable vial, vortexed and counted for [3H]. % inhibition = 1 - average com (test compound) - average com (blank) 10 average cpm (control) - average cpm (blank) IC50 is defined as that concentration of compound which inhibits 50% of specific hydrolysis of [3H]cAMP to [3H]5'AMP. (TNF) 15 The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit the production of TNF and, consequently, demonstrate their effectiveness for treating diseases involving the production of TNF is shown by the following in vitro assay: Peripheral blood (100 mis) from human volunteers is collected in 20 ethylenediaminetetraacetic acid (EDTA). Mononuclear cells are isolated by Ficoll/Hypaque and washed three times in incomplete HBSS. Cells are resuspended in a final concentration of 1 x 106 cells per ml in pre-warmed RPMI (containing 5% FCS, glutamine, pen/step and nystatin). Monocytes are plated as 1 x 10® cells in 1.0 ml in 24-well plates. The cells are incubated at 37°C (5% carbon dioxide) and allowed to 25 adhere to the plates for 2 hours, after which time non-adherent cells are removed by gentle washing. Test compounds (10//I) are then added to the cells at 3-4 concentrations each and incubated for 1 hour. LPS (10^1) is added to appropriate wells. Plates are incubated overnight (18 hrs) at 37°C. At the end of the incubation period TNF was analyzed by a sandwich ELISA (R&D Quantikine Kit). IC50 30 determinations are made for each compound based on linear regression analysis. Pharmaceutically-acceptable acid addition salts of the compounds of this invention include, but are not limited to, those formed with HCI, HBr, HN03, H2S04, H3P04, CH3SO3H, p-CH3C6H4S03H, CH3COjH, gluconic acid, tartaric acid, maleic acid and succinic acid. Pharmaceutically-acceptable cationic salts of the compounds of this WO 95/01980 PCT/IB94/00156 -12- invention of formula I wherein R4 is COjR6 and R6 is hydrogen include, but are not limited to, those of sodium, potassium, calcium, magnesium, ammonium, N,N'-dibenzylethylenediamine, N-methylglucamine (meglumine), ethanolamine and diethanolamine. 5 For administration to humans in the curative or prophylactic treatment of inflammatory diseases, oral dosages of the compounds of formula I and the pharmaceutically acceptable salts thereof (hereinafter also referred to as the active compounds of the present invention) are generally in the range of from 0.1-100 mg daily for an average adult patient (70 kg). Thus for a typical adult patient, individual 10 tablets or capsules contain from 0.1 to 50 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration are typically within the range of 0.1 to 10 mg per single dose as required. For intranasal or inhaler administration, the dosage is generally formulated as a 0.1 to 1% (w/v) solution. In practice the physician will determine the actual dosage which will be 15 most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and all such dosages are within the scope of this invention. For administration to humans for the inhibition of TNF, a variety of conventional 20 routes may be used including orally, parenterally and topically. In general, the active compound will be administered orally or parenterally at dosages between about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration 25 will, in any event, determine the appropriate dose for the individual subject. For human use, the active compounds of the present invention can be administered alone, but will generally be administered in an admixture with a pharmaceutical diluent or carrier selected with regard to the intended rout© of administration and standard pharmaceutical practice. For example, they may be 30 administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovales either alone or iii admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally; for example, intravenously, intramuscularly or subcutaneously. o o * WO 95/01980 • ) \_J PCT/IB94/00156 CW -13- For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances; for example, enough salts or glucose to make the solution isotonic. Thus in a further aspect the invention provides pharmaceutical compositions 5 comprising a compound of the formula I and the pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable diluent or carrier. The present invention is illustrated by the following examples, but it is not limited to the details thereof. Example 1 10 *3-Ethvl-1-(4-methoxvphenvh-6-phenvl-7-oxo-4.5.6.7-tetrahvdro-1H-Dvra2olof3.4- clovridine A mixture of 3-hydroxy-2-oxo-1-phenyl-4-propionyl-1,2,5,6-tetrahydro-pyridine (1.0 g, 4.1 mmole), 4-methoxyphenylhydrazine hydrochloride (0.8 g, 4.6 mmole) and sodium methoxide (0.11 grams, 2 mmole) in 35 ml anhydrous ethanol (distilled from Mg) was 15 heated at reflux. After 12 hours, the solvent was removed by rotory evaporation under reduced pressure, and the crude residue was chromatographed on a 4x20 cm silica column using 1:1 ether/hexane as eluent to give 345 mg of the title compound as a red oil that crystallized upon standing at room temperature. The desired 1-(4-methoxyphenyl) regioisomer is less polar than the 2-(4-methoxyphenyl) byproduct. 20 M.P. 43-45°C, IR (chloroform) lactam C=0, 1665 cm1; 'H NMR (300 MHz, CDCI3) d 1.32 (t,J = 7.6 Hz, 3H), 2.74 (q, J = 7.6 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H), 3.79 (s, 3H), 4.10 (t,J = 6.6 Hz, 2H), 6.89 (d.J = 9.0 Hz, 2H), 7.22-7.39 (m, 5H), 7.45 (d.J = 9.0 Hz, 2H); Anal, calcd. for C2,H21N302: C, 72.60; H, 6.09; N, 12.09. Found: C, 72.48; H, 6.08; N, 11.66; MS m/z (M+) 347. 25 Examples 2-15 Reaction of the appropriate hydrazine hydrochloride with the requisite 4-alkanoyl-3-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine, analogous to the procedure of Example 1, affords the following compounds. Ex.# R' R2 R3 M.p.°C Mass Spectra or Analysis (calcd.) %C, %H, %N Mass Spectra or Analysis (found) %C, %H, %N 30 * 2 ethyl phenyl methyl 80-83 70.56, 6.71, 16.46 70.61, 6.77, 15.51 * 3 ethyl phenyl (erf-butyl 120-121 72.70, 7.79. 14.13 72.50/7-436, 14.16 Not ccnpounds of the invention / / o \ ' ✓1 ' y "V «p WO 95/01980 o -14- o FCT/IB94/00156 4 ethyl 4-methoxy phenyl 4-methoxy phenyl 42-45 70.01, 6.14, 11.13 70.05, 6.07, 11.00 5 ethyl 4-fluoro phenyl tert-butyl 92-94 (M*) 315.1747 HRMS (M+) 315.1741 6 ethyl phenyl 3,4- dichloro-phenyl (oil) [M*] 386.26 MS mtz [M+] 386 7 ethyl 4-fluoro phenyl 4-methoxy phenyl 129-130* 69.03, 5.52, 11.50 68.75, 5.37, 11.43 8 methyl phenyl 4-fluoro phenyl 139-140" [M4] 321.3 MS mfz [M+] 322 9 ethyl phenyl cyclopent yi 73-75 (M+) 309.1841 HRMS (M+) 309.1823 10 methyl phenyl 4-methoxy phenyl 167-168 (M+) 333.1477 HRMS (M+) 333.1477 11 ethyl phenyl 5-phenyl pentyl (oil) (M+) 388.2389 HRMS (M+) 388.2395 12 methyl 4-methoxy phenyl 4-fluoro phenyl 140-142" 68.36, 5.16, 11.96 67.92, 5.03, 11.72 13 methyl 4-methoxy phenyl 3-fiuoro phenyl 133-138 68.36, 5.16, 11.96 68.04, 5.04, 11.75 14 ethyl 4-methoxy phenyl 3.4- dichloro-phenyl 50-60 60.59. 4.60, 10.09 60.34, 4.56, 9.86 15 ethyl 3-methoxy phenyl methyl (oil) [W] 285.35 MS m/z IM+] 286 5* 10* Recrystailizing solvents: *isopropyl ether. b5% Ethyl acetate in petroleum ether. 15 Example 16 * 3-Ethvl-1 -(4-phenvlcarboxvlic acic0-6-phenvl-7-oxo-4.5.6.7-tetrahvdro-1 H-pvrazolof3.4-c1pvridine A mixture of 3-hydroxy-2-oxo-1-phenyl-4-propionyM,2,5,6-tetrahydro-pyridine (1.0 grams, 4,08 mmole), 4-hydrazinobenzoic acid (0.68 grams, 4.49 mmole) and 30 ml of 20 anhydrous ethanol was heated at reflux. After 20 hours, the mixture was concentrated by rotory evaporation under reduced pressure, and the solid residue was suspended in a mixture of ethyl acetate (500 ml) and pH 4 buffer (200 ml). The organic layer was separated (leaving behind most of the 2-(4-phenylcarboxylic acid) byproduct), washed with brine, dried over sodium sulfate, filtered and concentrateduntteq-educed pressure. * Not compounds of the invention WO 95/01980 n O PCT/IB94/001'i6' r; -15- Recrystallization from methanol gives 0.64 grams of the title compound as an orange solid. M.P. 261-263°C, 1H NMR (300 MHz, DMSO-dfi) d 1.23 (t,J = 7.6 Hz, 3H), 2.68 (q.J - 7.6 Hz, 2H), 2.94 (t.J = 6.5 Hz, 2H), 4.05 (t,J = 6.5 Hz, 2H), 7.20-7.41 (m, 5H), 7.65 (d.J = 8.6 Hz, 2H), 7.96 (d,J = 8.6 Hz, 2H), 13.05 (s, 1H); MS m/z (M+) 362. 5 Example 17 * 1-(4-Benzamide)-3-ethvl-6-(4-methoxvphenvn-7-oxo-4.5.6.7-tetrahvdro-1H-pvrazolof3.4-c1 pyridine To a stirred solution of sodium methoxide in methanol (prepared from 6.6 mg Na) is added 3-ethyl-6-(4-methoxyphenyl)-1-(4-phenylcarboxylic acid)-7-oxo-4,5,6,7-10 tetrahydro-1 H-pyrazolo[3,4-c]pyridine (96 mg, 0.25 mmole). After 30 minutes, methanol was removed under reduced pressure, the solid residue was suspended in benzene, and the benzene was removed under reduced pressure. The resulting dry solid was suspended in cold ether (ice-bath) and treated with oxalyl chloride (31 pi, 0.35 mmole) and anhydrous N,N-dimethylformamide (1 drop). After stirring for 1 hour the vaiatiies 15 are removed under reduced pressure, and the crude residue was dissolved in dry tetrahydrofuran. The resulting solution was added dropwise to briskly stirred ammonium hydroxide at 0°C. After warming to ambient temperature over 2 hours the reaction mixture was concentrated under reduced pressure until a yellow solid begins to precipitate. At this time the mixture was diluted with water to approximately 100 ml 20 and filtered, and the precipitate was washed with water to give 81 mg of the title compound. Decomposition point 243-245°C; 1H NMR (DMSO-cy 1.24 (t,J = 7.6 Hz, 3H), 2.68 (q,J = 7.6 Hz, 2H), 2.93 (t,J = 6.5 Hz, 2H), 3.75 (s, 3H), 3.99 (t,J = 6.5 Hz, 2H), 6.94 (d,J = 9.1 Hz, 2H), 7.27 (d,J = 9.0 Hz, 2H), 7.43 (s, 1H), 7.59 (d,J = 8.5 Hz, 2H), 7.90 (d,J = 8.6 Hz, 2H). 8.04 (s, 1H); Anal, calcd. for C22H22N403: C, 67.68; H. 25 5.68; N, 14.35. Found: C, 67.19; H. 5.31; N, 13.55. HRMS calcd. for C22H22N403 [M+] 391.1770. Found 391.1781. The starting 3-ethyl-6-(4-methoxyphenyl)-1-(4-phenylcarboxylic acid)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo [3,4-cJ pyridine was prepared using the appropriate reagents according to the procedure of example 16. 30 *Not a compound of the invention WO 95/01980 l J U PCT/IB94/00156 * -16- Example 18 W3.4-dichloroDhenv0-3-ethvl-6-(3-methoxvDhenv1}-7-oxo-4.5.6.7-tetrahvdro-1 H-ovrazolof3.4-c1 pyridine A stirred mixture of 3-methoxy-1-(3-methoxyphenyl)-2-oxo-4-propionyl-1,2,5,6-5 tetrahydro-pyridine (0.49 grams, 1.7 mmole), 3,4-dichlorophenyihydrazine hydrochloride (0.40 grams, 1.87 mmole) and sodium metnoxide (46 mg, 0.85 mmole) in anhydrous ethanol was heated to reflux. After 16 hours, the mixture was concentrated under reduced pressure and chromatographed on a silica gel column using 1:4 ethyl acetate/hexane as eluent to give a white solid. Recrystallization from ether gave 0.46 10 grams of white needles. M.P. 97-99°C, 'H NMR (250 MHz, CDCI,) 1.31 (t.J = 7.5 Hz, 3H), 2.73 (q,J = 7.6 Hz, 2H), 2.96 (t.J = 6.6 Hz, 2H), 3.79 (s, 3H), 4.09 (t,J = 6.6 Hz, 2H), 6.78-6.91 (m, 3H), 7.29-7.49 (m, 3H), 7.73 (d,J = 1.8 Hz, 1H); MS m/z [M+] 416. Examples 19-42 Reaction of the appropriate hydrazine hydrochloride with the requisite 4-15 alkanoyl-3-methoxy-2-oxo-1,2,5,6-tetrahydropyridine, analogous to the procedure of Example 18, affords the following compounds. * 20 * * * * 25* Ex.# R' R2 R3 M.p.°C Mass Spectra or Analysis (calcd.) %C, %H, %N Mass Spectra or Analysis (found) %C, %H, %N 19 methyl 4-methoxy phenyl 3-4- dichloro-phenyl 143-144* 59.71, 4.26, 10.45 56.13, 4.02, 9.65 20 ethyl 3-methoxy phenyl cyclo-pentyl 64-65 [M*] 340.2025 HRMS [M+] 340.2046 21 ethyl 4-methoxy phenyl cyclo-pentyl 96-98 70.77, 7.42, 12.38 70.44, 7.68, 11.69 22 methyl 4-methoxy phenyl cyclo-pentyl 121-122 70.13, 7.12, 12.91 69.48, 7.10, 12.70 23 iso-propyl phenyl 3,4- dichloro phenyl oil [M*] 400.0983 HRMS [M+] 400.0966 24 ethyl 3,4-dimeth-oxyphenyl cyclo-pentyt 107-10B [M*] 369.46 MS m/z [M*] 369 25 ethyl 3.4-dimeth-oxyphenyl 3.4- dichloro-phenyl 190-191" 59.20, 4.74, 9.41 59.41, 4.46, 9.71 * Not corrpounds of the invention 1 I WO 95/01980 o PCT/TB94/00156 -17- Ex.# R1 R* R3 M.p.°C Mass Spectra or Analysis (calcd.) %C. %H, %N Mas9 Spectra or Analysis (found) %C. %H. %N 26 iso-propyl 4-methoxy phenyl 3.4- dichloro phenyl 145-147' 61.40. 4.92, 9.76 61.29, 4.81, 9.53 27 propyl 4-methoxy phenyl cyclo-pentyl 102-103' 71.36. 7.70, 11.89 70.98, 7.66, 11.73 28 iso-propyt 3-methoxy phenyl 3,4- dichloro-phenyl 126-127" 61.40, 4.92, 9.76 61.55, 5.10, 9.97 29 ethyl 4-methoxy-3-cyclo-pentoxy-phenyl 3.4- dichloro-phenyl 54-56 62.40. 5.44. 8.40 62.15, 5.50, 7.97 30 ethyl 4-methoxy-3-cyclo-pentoxy-phenyl cyclo-pentyl 88-89 [M*] 423.55 MS mh. [M*] 423 31 ethyl 3-methoxy phenyl 4-fiuoro-phenyl 139-140* 69.03, 5.79, 11.50 69.05, M2, 11.57 32 ethyl 2-methoxy phenyl cyclo-pentyl 119-120 70.77, 7.42. 12.38 70.63, 7.16, 12.01 33 ethyl 2-methoxy phenyl 4-fiuoro-phenyl 103-104' [M*] 365.41 MS m/z [M*] 366 34 ethyl 3-methyl phenyl cyclo-pentyl oil 74.27, 7.79, 12.99 74.54, 7.89, 12.63 35 ethyl 3-methyl phenyl 4-fluoro-phenyl oil 72.19,5.77. 12.02 72.06, 5.55, 11.52 36 ethyl 3-trifluoro- methyl- phenyl cyclo-pentyl oil 63.65. 5.87, 11.13 63.95, 5.73, 10.97 37 ethyl 3-trifluoro- methyl- phenyl 4-fluoro-phenyl 139-140' 62.53, 4.25, 10.42 62.60, 4.08, 10.41 38 ethyl 4-methyl-phenyl cyclo-pentyl 93-94 74.27, 7.79, 12.99 74.10, 7.52, 12.59 39 ethyl 2-methyl-phenyl 4-fluoro-phenyl 141-142" 72.19, 5.77, 12.03 72.36, 5.52, 12.09 40 ethyl 2-methyl-phenyl cyclo-pentyl 130-131 MW 323.44 MS m/z 323 10 15 * Not ccrrpounds of the invention WO 95/01980 .) o PCT/IB94/00156 -13- Ex.# R1 R' R3 M.p.°C Mass Spectra or Analysis (calcd.) %C, %H, %N Mass Spectra or Analysis (found) %C, %H, %N 41 ethyl 2-trifluoro- methyl- phenyl 4-fluoro-phenyl 48-50 MW 403.38 MS m/z 404 42 ethyl 3-methyl-phenyl 3-sulfo-lan/l oil MW 373.47 MS mlz 374 Recrystallizing solvents: * 5% Ethyl acetate/petroleum ether. b Isopropyl ether. 5 c Ethyl acetate/hexane. "Ethyl ether. *5% Ethyl acetate/pentane. 'Pentane. Example 43 1-Cvclohexvl-3-ethvl-6-(3-methoxvphenvn-7-oxo-4.5.6.7-tetrahvdro-1 H-pvra2Qlof3.4-clpvridine A solution of 3-methoxy-1 -(3-methoxyphenyl)-2-oxo-4-propionyl-1,2,5,6-pyridine 10 (0.80 grams, 2.8 mmole) and cyclohexylhydrazine hydrochloride (0.54 grams, 3.6 mmole) in methanol (15 ml) was warmed to 90 °C under a gentle stream of nitrogen until all of the solvent was removed. The neat mixture was then heated to approximately 150°C under nitrogen for 1 hour. After cooling to room temperature, the mixture was dissolved in ether and washed with 1N hydrochloric acid followed by brine, 15 dried over sodium sulfate, filtered and concentrated under reduced pressure. Chromatography on silica gel using 1:1 ethyl acetate/hexane as eluent gives 0.47 grams of the title compound as a yellow oil. ^ NMR (250 MHz, CDCI3) 1.20-1.52 (m, 6H, including t at 1.23, J = 7.6 Hz, 3H), 1.64-1.74 (m, 1H), 1.80-2.06 (m, 6H), 2.67 (q,J = 7.6 Hz, 2H), 2.87 (t,J = 6.7 Hz, 2H), 3.82 (s, 3H), 3.97 (t,J = 6.7 Hz, 2H), 5.13 (tt, J 20 « 4.3 and 11.3 Hz, 1H), 6.79-6.93 (m, 3H), 7.31 (t,J = 8.1 Hz, 1H); HRMS calculated forC21H27N3Oj[M+]: 353.2103. Found: 353.2094. Examples 44-57 Reaction of the appropriate hydrazine hydrochloride with the requisite 4-alkanoyl-3-methoxy-2-oxo-1,2,5,6-tetrahydropyridine, analogous to the procedure of 25 Example 43, affords the following compounds. Ex.# R1 R' R3 M.p.°C Mass Spectra or Analysis (calcd.) %C, %H, %N Mass Spectra or Analysis (found) %C, %H, %N * 44 isopropyl 4-methoxy phenyl cyclo-pentyl 102-103* [M+] 354 MS [M*] 354 I—\ ~v ■ * Not" a comopund of the invention o WO 95/01980 ) V.) PCT/IB94/0C156 -19- . .* 5* 10 * Ex.# R1 R3 R3 M.p.°C Mass Spectra or Analysis (calcd.) %C, %H, %N Mass Spectra or Analysis (found) %C, %H, %N 45 iso-propyl 3-methoxy phenyl cyclo-pentyl 99-100" 71.36, 7.70, 11.89 71.10, 7.56, 11.73 46 ethyl 3-methoxy phenyl cyclobutyl 73-74" 70.13, 7.12, 12.91 70.10, 7.22, 12.93 47 ethyl phenyl methylene cyclo- propyl 60-62e 73.19, 7.17. 14.23 73.34, 7.08, 13.95 48 ethyl 3-methoxy phenyl methylene cyclo- propyl oil [M"] 326 MS [M*] 326 49 ethyl 4-methoxy-phenyl phenyl 156-157" 72.60, 6.09, 12.10 72.35, 5.91, 12.02 50 ethyl 3-methoxy-phenyl 3-sulfo-lanyl oil 58.59, 5.95, 10.79 58.46, 6.03. 9.82 51 ethyl 3-methoxy-phenyl 4-trifluoro- methyl- phenyl 124-125" 63.61, 4.85. 10.12 63.40, 4.51, 10.09 52 ethyl 3-methyl-phenyl cyclobutyl oil 73.75, 7.49, 13.58 73.22, 7.56, 13.03 53 ethyl 3-trifluoro- methyl- phenyl 3-sulfo-lanyl oil MW 427.44 MS m/z 428 54 ethyl 3-trifluoro- methyl- phenyl cyclobutyl oil 62.80, 5.55, 11.56 63.01.5.54. 11.19 55 ethyl phenyl 2-indanyl 155-156* 77.28, 6.49, 11.76 77.35, 6.48, 11.08 56 ethyl 2-methyl-phenyl cyclobutyl 100-102 MW 309.41 MS mfc 310 57 ethyl 3-methoxy-phenyl 2-indanyl 60-62' MW 387.48 MS m/z 388, 389, 390 15 Recrystallization solvents: "Ethyl acetate/pentane. bEthyl ether/pentane. clsopropyl ether/pentane. dEthyl/acetate/petroleum ether. 'Ethyl acetate. 'Ethyl acetate/hexane. * Not compounds of the invention I t 4 sr. 1997 -20- - 4 St? W RECEIVED Example 58 * 3-Ethvl-6-(4-fluorophenvn-1-(4-methoxvphenvn-4.5.6.7-tetrahvdro-1H-pvrazolo T3.4-c1 pyridine To a stirred solution of 3-Ethyl-6-(4-fluorophenyl)-1-(4-methoxyphenyl)-7-oxo-5 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (0.3 grams, 0.82 mmole) in 50 ml ether was added lithium aluminum hydride (33 mg, 0.86 mmole). After stirring for 16 hours water (0.5 ml) was added followed by 3N sodium hydroxide (1 ml). After stirring for 2 hours the white precipitate was filtered through celite and the filtrate is concentrated under reduced pressure. Chromatography on a silica gel column using 1:3 ethyl 10 acetate/hexane as eluent gives 0.12 grams of the title compound as a pale yellow paste. 'H NMR (250 MHz, CDCI3) 1.28 (t.J = 7.6 Hz, 3H), 2.66 (q,J = 7.6 Hz, 2H), 2.71 (t.J = 5.7 Hz, 2H), 3.49 (t,J = 5.7 Hz, 2H), 3.84 (s, 3H), 4.23 (s, 2H), 6.84-6.99 (m, 6H), 7.36 (d,J = 9.0 Hz, 2H); MS m/z [M+] 352. Examples 59-63 15 Reaction of the appropriate 7-oxo-2,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine with lithium aluminum hydride, analogous to the procedure of Example 58, affords the following compounds. 20 * Ex.# R1 R2 R3 M.p.°C Mol. Weight Mass Spectra [M*] (found) 59 ethyl 4-methoxy-3-cyclopentoxy phenyl cyclopentyl oil 409.57 409 60 ethyl phenyl 3,4-dichloro-phenyl oil 372.30 371.373 61 ethyl phenyl cyclopentyl oil 295.43 296 62 ethyl 3-methoxy phenyl cyclobutyl oil 311.43 312 63 ethyl 3-methoxy phenyl cyclohexyl oil 339.48 340 25 Example 64 * 1-cvclopentvl-3-ethvl-7-oxo-4.5.6.7-tetrahvdro-1 H-pvrazolor3.4-c1 pyridine A stirred solution of 1-cyclopentyl-3-ethyl-6-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (2.58 grams, 7.60 mmoles) in acetonitrile (90 ml) at 0°C is treated with a solution of eerie ammonium nitrate (12.5 grams, 22.8 mmoles) * Not compounds of the invention WO 95/01980 O Q- "PCT/IB94/00r56rm*w*1 - 4 bet3 ws/ -21- RECEIVED in water (110 ml). After stirring for 35 minutes the mixture is diluted with water (550 ml) and extracted with ethyl acetate (100 ml x 4). The combined organics are washed with 50% saturated sodium bicarbonate (250 ml) followed by 10% sodium sulfite until the aqueous wash becomes pale yellow. The organic layer is then washed further with 5 saturated bicarbonate and brine, and treated with decolorizing charcoal. After stirring for 30 minutes the mixture is dried over sodium sulfate, filtered through celite and concentrated under reduced pressure. The brown residue is recrystefllized from ether to give .814 grams of a tan solid. M.P. 143-145°C; MS (M/Z) 234; 'H NMR (250 MHz, CDCI3) 1.21 (t, J = 7.6 Hz, 3H), 1.62-2.13 (m, 8H), 2.62 (q, J = 7.6 Hi, 2H), 2.73 (t, J 10 =6.8 Hz, 2H), 3.51 (dt, J = 2.7 and 6.8 Hz, 2H), 5.47 (s, 1H), 5.61 (pentet, J = 7.7 Hz, 1H). Example 65 * i-cvclopentvl-3-ethvl-6-cvclopropvlmethvl-7-oxo-4.5.6.7-tetrahvdro-1 H-pyrazolo f3.4-c1 pyridine 15 A solution of 1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4- cjpyridine (0.21 grams, 0.92 mmoles) in THF (5 ml) is treated with 60% sodium hydride in mineral oil (40 mg, 1.01 mmoles). After stirring at reflux over 45 minutes the reaction mixture is cooled to 25 °C and (bromomethyl) cyclopropane (0.31 grams, 2.29 mmoles) is added. The mixture is stirred at reflux for 16 hours and then cooled to 25°C before 20 concentrating under reduced pressure. Chromatography on silica gel eluting with 1:1 ethyl acetate/hexane gives 0.19 grams of the title compound as a colorless oil. MS m/z [M+] 288; 'H NMR (300 MHz, CDCI3) 0.26-0.31 (m, 2H), 0.50-0.56 (m, 2H), 0.85-1.06 (m, 1H), 1.20 (t, J = 7.6 Hz, 3H), 1.62-2.08 (m, 8H), 2.61 (q, J = 7.6 Hz, 2H), 2.74 (t, J = 6.8 Hz, 2H), 3.39 (d, J = 6.9 Hz, 2H), 3.63 (t, J = 6.8 Hz, 2H), 5.67 (pentet, J = 25 7.8 Hz, 1H). Preparation 1 4-lsobut,- 'l-3-methoxv-1 -phenvl-2-oxo-1.2.5.6-tetrahvdropvridine A stirred solution of freshly distilled diisopropylamine (0.16 ml, 2.21 mmole) in anhydrous tetrahydrofuran (4 ml) was cooled to 0°C and treated with 2.5 M n-butyl 30 lithium (0.85 ml, 2.11 mmole). After 15 minutes the mixture was cooled to -78°C and a pre-cooled solution of 4-propionyl-3-methoxy-1-phenyl-2-oxo-1,2,5,6-tetrahydropyridine (0.52 grams, 2.0 mmole) in tetrahydrofuran (4 ml) was added dropwise via cannula. After approximately 20 minutes methyl iodide (0.20 ml, 3.0 * Not a compound of the invention WO 95/01980 PCT/IB94/00156 -22- mmole) was added to the bright orange-red solution and the mixture was allowed to come to room temperature over 2.5 hours. The reaction mixture is poured into saturated aqueous ammonium chloride and the organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. 5 Chromatography on a silica gel column using 1:4 ethyl acetate/hexane as eluent gives 0.12 grams of the title compound as a yellow oil and 0.1 grams of recovered starting material. 'H NMR (250 MHz, CDCI3) 1.15 (d, 6H), 2.72 (t, 2H), 3.47 (heptet, 1H), 3.82 (t, 2H), 3.97 (s. 3H), 7.21-7.45 (m, 5H); MS m/z [M+] 274. Preparations 2-3 10 Reaction of the appropriate 3-methoxy-2-oxo-4-propionyl-1,2,5,6- tetrahydropyridine with lithium diisopropylamine and methyl iodide, analogous to the procedure of preparation 1, affords the following compounds of formula VII. Prep# E RJ m.p. °C M.W. Mass Spectra [M+] 2 4-methoxyphenyl oil 303.36 304 3 3-methoxyphenyl oil 303.36 304 Preparation 4 3-Methoxv-1-(4-methvlphenvn-2-oxo-4-propionvl-1.2.5.6-tetrativdropvridine 20 A solution of 3-hydroxy-1-(4-methylphenyl)-2-oxo-4-propionyl-1,2,5,6- tetrahydropyridine (5.9 grams, 23 mmole) and 3-methyl-1-p-tolyltriazine (5.1 grams, 34 mmole) in 1,2-dichloroethane was heated to reflux for 45 minutes. The mixture was allowed to cool to room temperature and was poured into water and acidified with 6N hydrochloric acid. The aqueous layer was extracted 3 times with methylene chloride, 25 and the combined organics are washed with 1N hydrochloric acid followed by water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting quantitative brown oil was clean by thin layer chromatography and *H NMR and was used without purification. 'H NMR (300 MHz, CDCI3) 1.12 (t,J = 7.2 Hz, 3H), 2.34 (s, 3H), 2.71 (t,J = 6.7 Hz, 2H), 2.93 (q,J = 7.2 Hz, 2H), 3.77 (t,J = 30 6.8 Hz, 2H), 3.94 (s. 3H), 7.20 (s, 4H); MS [M+] 273. Preparations 5-14 WO 95/01980 PCT/EB94/00156 -23- Reaction of the appropriate 3-hydroxy-1-aryI-2-oxo-4-alkanoyl-1,2,5,6-tetrahydropyridine with 3-methyl-1-p-tolyltriazine, analogous to the procedure of Preparation 4, affords the following compounds of formula VI. Prep# R1 R2 m.p. °C M.W. Mass Spectra [M+] 5 ethyl phenyl oil 259.31 260 6 methyl 4-methoxyphenyl oil 275.30 275 7 ethyl 4-methoxyphenyl 81-82 289.33 289 8 n-propyl 4-methoxyphenyl oil 303.36 303 9 ethyl 3-methoxyphenyl 59-60 289.33 289, 290 10 ethyl 2-methoxyphenyl oil 289.33 289 11 * ethyl 3,4-dimethoxyphenyl oil 319.26 319 12 ethyl 3-cyclopentoxy-4-methoxyphenyl oil 373.45 373 13 ethyl 3-methylphenyl oil 273.33 273 14 ethyl 3-trifluoromethylphenyl oil 327.30 327 15 Preparation 15 3-Hvdroxv-1-(3-methvlphenvn-2-oxo-4-propionvl-1.2.5.6-tetrahvdropvridine To a stirred suspension of magnesium turnings (1.9 grams, 79 mmole) in 30 ml of anhydrous ether was added dropwise bromoethane (5.9 ml, 79 mmole). A mild 20 reflux was initiated after approximately 1 ml was added. After all of the magnesium was consumed, the reaction mixture was cooled to 0°C and N-(3-rnethylphenyl)-2-pyrrolidone (8.7 grams, 50 mmole) was added at once. After warming to room temperature and stirring for 2 hours the reaction mixture was poured over ice and extracted with ethyl acetate. The combined organics are washed with water and brine, 25 dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 8.8 grams of a white solid. The above solid is dispersed in a mixture of 40 ml benzene and 86 ml 1N sodium nydroxide, and with vigorous mechanical stirring ethyl oxalyl chloride (7.2 ml, 64 mmole) was added. After stirring at reflux over 1.5 hours the layers Eire separated 30 and the aqueous layer was extracted with ethyl acetate. The combined organics are WO 95/01980 PCT/IB94/00156 -24- washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an amber oil. GCMS [M+] 305. The above intermediate was dissolved in 20 ml anhydrous ethanol and treated with a solution of sodium methoxide in methanol (prepared from the careful addition of 5 sodium (1.0 grams) to 10 ml anhydrous methanol). After being stirred at reflux over 1.5 hours, the mixture was concentrated under reduced pressure and 100 ml of water was added. The mixture was acidified to pH 3 with 6N hydrochloric acid and the dull yellow precipitate was filtered and washed with water. Recrystallization from 75 ml isopropyl ether affords 6.8 grams of pale yellow crystals. MP. 115-116°; 'H NMR (300 MHz, 10 CDCI3) 1.16 (t,J = 7.2 Hz. 3H), 2.37 (s, 3H), 2.74-2.82 (m, 4H), 3.85 (t.J = 6.8 Hz, 2H), 7.08-7.14 (m, 3H), 7.30 (t.J = 7.7 Hz, 1H); MS m/z [M+] 259. Preparations 16-29 Reaction of the appropriate 2-pyrrolidinone with the requisite alkylmagnesium bromide, followed by treatment with ethyl oxalyl chloride and base, analogous to that 15 reported in Preparation 15, affords the following compounds of formula VI. Prep# R1 R2 m.p. °C M.W. Mass Spectra [M+] 16 methyl phenyl oil 231.25 231 17 ethyl phenyl 140-142 245.28 245 18 ethyl 4-fluorophenyl 133-135 263.27 263 19 methyl 4-methoxyphenyl oil 261.28 262 20 ethyl 4-methoxyphenyl 121-122 275.30 276 21 n-propyl 4-methoxyphenyl 125-126 289.33 289 22 ethyl 3-methoxyphenyl 129-130 275.30 275 23 ethyl 2-methoxyphenyl 119-120 275.30 275 24 ethyl 4-methylphenyl 110-112 259.30 260 25 ethyl 2-methylphenyl oil 259.30 259 26 ethyl 3-trifluoromethylphenyl 117-118 313.28 313 27 ethyl 2-trifluoromethylphenyl oil 313.28 313 28 ethyl 3,4-dimethoxyphenyl 179-180 305.33 306 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 95/01980 PCT/IB94/00156 -25- Prep# R1 R2 m.p. °C M.W. Mass Spectra [M+] 29 ethyl 3-cyclopentoxy-4-methoxyphenyl 133-134 359.42 360 Preparation 30 5 N-(2-MethoxvphenvlV2-pyrrolidone A mixture of 2-pyrrolidone (15.0 grams, 176 mmole), 2-iodoanisole (7.6 ml, 59 mmole), copper powder (7.5 grams, 117 mmole) and potassium carbonate (8.1 grams, 59 mmole) are stirred under nitrogen at 150°C. After 18 hours, the reaction mixture was filtered through a 6x15 cm pad of silica gel eiuting with 1:1 ethyl acetate/hexane 10 to give a pale yellow oil. ^The unreacted reagents are removed by vacuum distillation (0.6 mm, 80-100°C) leaving 9.2 grams of the title compound as a honey-like oil. 'H NMR (300 MHz, CDCI3) 2.20 (pentet, 2H), 2.55 (t, 2H), 3.75 (t, 2H), 3.82 (s, 3H), 6.93-7.02 (m, 2H), 7.25-7.30 (m, 2H); MS m/z [M+] 191. Preparations 31-39 15 Reactions of the appropriate iodo- or bromobenzene with 2-pyrrolidinone, analogous to that reported in Preparation 30, affords the following compounds of formula V. 20 25 Prep# R M.W. Mass Spectra [M+] 31 4-methoxyphenyl 191.22 191 32 3-methoxyphenyl 191.22 191 33 3-methylphenyl 175.23 175 34 4-methylphenyl 175.23 175 35 2-methylphenyl 175.23 175 36 3-trifluoromethylphenyl 229.20 229 37 2-trifluoromethylphenyl 229.20 229 38 3,4-dimethoxyphenyl 221.26 221 39 3-cyclopentoxy-4-methoxyphenyl 275.35 275 * WO 95/01980 O •26- CLA1MS O PCT/IB94/00156

1. A compound of the formula 10 15 20 N.Z. PATENT OFFICE - 4 SEP 1997 1 7 and pharmaceutically acceptable salts thereof; wherein R1 is (C -C )alkyl, (C5-C3)alkenyl, (C3-C5)cycloalkyl or methylene (C3-C5)cycloalkyl wherein each alkyl or alkenyl group may be optionally substituted with up to two (C'-C2)alkyl or trifluoromethyl 3 groups or up to three halogens; X is oxygen or two hydrogen atoms; R is selected from the group consisting of hydrogen, (C'-C14)alkyl, (C'-C7)alkenyl, (C^-C'Jheterocyclic group containing oxygen, sulphur, SO, or NR5 wherein R5 is hydrogen or (C'-C^alkyl, or a group of the formula /—\ (R*>« -<Y)b-<Z>c " wherein a is an integer fran 1 to 5; b and c are each independently 0 or 1; 4 1 R is hydrogen, hydroxy, (C - , C5)alkyl, (C'-C5)alkenyl, (C'-C'Jalkoxy, (C3-C")cycloalkoxy, halogen, trifluoromethyl, COjR8, CONR'R7, NR6R7, NOa or S02NR°R7 wherein R6 and R7 are each independently 25 hydrogen or (C'-C4)alkyl; wherein Z is oxygen, sulphur, S02 or NR8 wherein Re is hydrogen or (C'-C4)alkyl; and Y is (C'-C^alkylene or (C2-C°)alkenyl optionally substituted with up to two (C'-C7)alkyl or (C3-C7)cycloalkyl groups; or R3 is a group of the formula L\ 30 WO 55/01980 PCT /IB94/00156 -27- wherein p is an integer from 1 to 3, W is oxo or hydroxy, and R9 is (c1-C3)alkyl; wherein each said alkyl, alkenyl, cycioalkyl, alkoxyalkyl or heterocyclic group may be optionally substituted with one or more _ _ of theigroup consisting of (C1- 2 C2)alkyl, trifluoromethyl or halogen* and R is either mono-substituted phenyl, 2 substituted in the 2 or 3 positions of the phenyl ring, or R is disubstituted phenyl, disubstituted in the 2 and 3 positions of the phenyl ring, wherein the substituents for R^ are selected from the group consisting of hydroxy, (C*- Cs)alkyl, (C*-C6)alkenyl, (C'-C6)alkoxy, (C3-C8)cycIoaIkoxy, halogen, trifluoromethyl, COjR8, CONR8R\ NRaR7, NOa or SO,NR8R7 wherein Re and R7 are each independently hydrogen or (C'-C4)alkyl.

2. A compound according to claim 1 wherein R1 is (C'-C3)alkyl, 3 R is selected from the group consisting of (C3-C7)cycloalkyl, (C4-C7)heterocyclic group containing SOs and a group of the formula (R">a /r~^\ [ i ] wherein a is an integer from 1 to 5 and R* is hydrogen, hydroxy, (C'-C'jalkyi, (C1- 2 C5)alkoxy or halogen, and the substituents for R are selected from the gro consisting of hydroxy, (C^C5) alkyl, (C^-C^alkoxy and halogen.

3. A compound according to claim 1 wherein R' is ethyl or isopropyi; R2 is 2-methylphenyl, 3-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl or 3-trifluoromethylphenyl and R3 is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolanyl, 4-fluorophenyl or 3,4-dichlorophenyl. "p'/Fr: " ^•—l A compound according to claim 1 selected from the group consisting of: -

4 SEP 1997 3-ethyl-1-(3,4-dichloropheny!)-6-(3-methoxyphenyl)-7-oxo-4,5,6l7-tetrahydro-1H- pyrazolo[3,4-c]pyridine; 3-ethyl-1 -cyclopentyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine; 3-ethyl-1-(4-fluorophenyl)-6-(2-methoxyphenyI)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine; S-ethyl-l-cyclopentyl-EHS-trifluoromethylphenyO^-oxo^.S.ej-tetrahydro-IH-pyrazolo [3,4-c] pyridine; 5 3-ethyl-1 -cyclohexyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H- pyrazolo [3,4-c] pyridine; 3-isopropyl-1-cyclopentyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo [3,4-c] pyridine; 3-ethyl-1-cyclobutyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-10 pyrazolo [3,4-c] pyridine; 3-ethyl-1-cyclopentyl-6-(2-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine; 3-ethyl-1-(3-sulfolanyl)-6-(3-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-15 pyrazolo[3,4-c]pyridine; 3-ethyl-1-(3-sulfolanyl)-6-(3-methoxypheny!)-7-oxo-4,5t6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine; 3-ethyl-1 -cyclobutyl-6-(3-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine; 20 3-ethyl-1 -(3-sulfolanyl)-6-(3-trifluoromethylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H- pyrazolo [3,4-c]pyridine; 3-ethyl-1-cyclobutyl-6-(3-trifluoromethylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine; and 3-ethyl-1 -cyclobutyl-6-(2-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-25 c]pyridine.

5. A pharmaceutical composition for the inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) comprising a pharmaceutically effective amount of a compound of formula I according to claim 1 and a pharmaceutically acceptable carrier. 30

6. The use, in the preparation of a medicament for the inhibition of phosphodiesterase (PDE) type IV, of a compound of formula I according to/ claim 1.

7. The use, in the preparation of a medicament for inhibiting the production of tumor necrosis factor, of a ccnpound of formula I according to claim 1. WO 95/01980 ) PCT/IB94/00156 -29-

8. A pharmaceutical composition for the treatment of inflammatory diseases and diseases involving the production of TNF comprising a pharmaceutically effective amount of a compound 5 of formula I according to claim 1 and a pharmaceutically acceptable carrier.

9. The use, in the preparation of a medicament for treatina or preventing a condition selected from the group consisting of inflammatory diseases and diseases involving the production of TNF, of a compound of formula I according to claim 1. 0

10. A compound of the formula I as defined in claim 1 or a pharmaceutically acceptable salts thereof substantially as herein described with reference to any example thereof. 11 • A pharmaceutical composition for the inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) as defined in claim 5 substantially as herein described with reference to any example thereof.

12. The use of any one of claims 6, 7 and 9 substantially as herein described with reference to any example thereof.

13. A pharmaceutical composition for the treatment of inflammatory diseases, and diseases involving the production of TNF as defined in claim 8 substantially as herein described with reference to any example thereof. end OF claims r T """*" - 4 SEP 1997 </div>