AU695301B2 - Bicyclic tetrahydro pyrazolopyridines - Google Patents

Description

I t WO 95/01980 I'CT/IB94/001S6 .1- 6 BICYCLIC TETRAHYDRO PYRAZOLOPYRIDINES Backqround of the Invention This invention relates to a series of bicycllc tetrahydro pyrazolopyridines which are selective inhibitors of phosphodiesterase (PDE) type IV or the production of tumor 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 treatment of the above diseases in mammals, especially humans and to pharmaceutical Icompositions useful therefor, I Since the recognition that cyclic AMP is an intracellular second messenger Sutherland, and T. W, Rail, Pharmacol. Rev,, 1960, 12, 265), inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized Beavo and D, H. Reifsnyder, TIPS, 1990, 1, 150), and their selective inhibition has led to improved drug therapy Nicholson, R, A. Chn liss and M. Shahid, TiPS, 1991, 2, 19), More particularly, it has been recognized that Inhibition of PDE type IV can lead to inhibition of inflammatory mediator release Verghese et al, J. Mol. Cell Cardiol,, 1989, 12 (Suppl. II), S 61) and airway smooth muscle relaxation J. Torphy in Directions for New Anti-Asthma Druqs, eds S. R. O'Donnel' 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 cardiovascular effects or antiplatelet effects.

TNF is recognized to be involved in many infectious and auto-immune diseases 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 Immunopathology, 1992, 62, S11), itt 4 4 III I itt I t 4 4144 ii 4 0 4 I I 4 it

I.

It I t t itt' 0 II *t t It I Ii lILt it It SUmnmary of the Invention The present invention relates to compounds of' the formula R1 R/N

N

R2~ I and pharmaccutically acceptable salts thercof; wherein R 1 is (CI-CG)alkyl, or

(C

2

.C

3 )alkenyl, wherein each alkyl or alkenyl group may be optionally substituted with up to two (CI-C 2 )alkyl or trifluoromethyt groups or tip to three halogens; X is oxygen or two hydrogen atoms; R 2 and R 3 are selected from thle group Consisting of (C 3

-C

14 )CyCloalkyl,

(C

4

-C

7 )hieterocyclic group contUining oxygen, sulphur, SO 2 or NR 5 wherein R 5 is hydrogen or (Cl-C 4 )aIlkyl, or a group of the Formula /0 (R)a wherein a is an integer from 1 to 5; b and c is 0 or 1; R 4 is hydrogen, hydroxy, (C 1

-C

5 )alkyl, (C 2

-C

5 )alkeny I, (C1 -C 5 )alkoxy, (C 3

-C

6 )cycloalkoxy, halogen, trifluoromethyl, C0 2

R

6

CONR

6

R

7 NR6.R 7

NO

2 or SO 2

NR

6

R

7 wherein R 6 and R 7 are each independently hydrogen or (C1_C 4 )alkyl; Wherein Z is Oxygen, Sulphur, SO 2 or NR 8 15 wherein R 8 is hydrogen or (C1_C 4 )alkyl; and y is (C 1

-C

5 )alkylene or (C 2

-C

6 )alkenyl optionally substituted with up to two (CI-C 7 )alkyl groups; or a group of the formula R9 w wherein p is an integer from 1 to 3, W is oxo or hydroxy, R 9 is (Cl-C 3 )alkyl; wherein each said alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic group may be optionally substituted with one to fourteen, preferably one to five, of the group consisting of

(C'-C

2 )alkyl, trifluoromethyl or halogen with the proviso that when R 2 is phenyl it is mono-substituted in the 2 or 3 position or di-substituted in thle 2 and 3 positions of the phenyl ring; and with the proviso that heterocycle excludes pyridinyl and wherein at each occurrence alkyl, alkenyl and alkoxy are as hereinibefore defined.

(N:ALISH100026RRB 1414 0601 3 In one embod ilentt, tile invention relates to a compound at' Formula I wherein RI is (CI-0 3 )alkyl and R* 2 and R 3 are cach Independently selected from the group consisting of

(C

3

-C

7 )uycloalkyl, (C 4

-C

7 )heterocyelie group containing S0 2 or at group of the Formula s wherein it is an integer from I to 5 and R 4 is hiydrogen, hiydroxy, (C 1

-C

5 )alkyl, (CI..

C

5 )a-lkoxy or halogen.

In anothier embodiment, the invention relates to a compound of for1mula 1 whlerein RJ is ethiyl or isopropyl; R 2 is phienyl, 2-metiylhenyl, 3-methiylhenyl, 2miethioxyphenyl, 3-tuethloxyphienyl or 3-trifluoromethiy Ipheny I and R 3 is cyclobutyl, l0 cyclopentyl, cyclohiexyl, 3-sulfolanyl, 4-111lu1Orphenyl or 3,4-dicihlorophienyl, Tille present invention further relates to at phiarmaceutical composition for thle inhibition of phlosphiodiesterase (PDE) type IV and thle production of tumior necrosis factor (TNF) comprising at pharmaceutically effective amiount of a compound according to formula I and the phiarmaceutically acceptable salts thereof, and at phiarmaceutically carrier,frte rlae toamto frth inbtono The present in vention frle eae oi elo o lciiiiino phosphodiesterase (PDE) type IV and the production o1' tumlor necrosis factor (TNF) comprising administering to a patient an effective amount of a compound according to formula l and thle phiarmaceutically acceptable salts thlereof, (N:AUBH1WOO26MRfB 1- I 4U- i WO 95/01980 PCT/IB94/00156 .4- The present invention further relates to a method of treating an inflammatory condition in mammals which comprises administering to said mammal an antlinflammatory amount of a compound of the formula I and the pharmaceutically acceptable salts thereof.

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 salts thereof together with a pharmaceutically acceptable carrier.

This invention further relates to 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 administering to a patient an effective amount of a compound according to formula 1 and the pharmaceutically acceptable salts thereof, Specific preferred compounds of the invention are: 3-ethyl-i -(4-methoxyphenyl)-6-phenyl-7-oxo-4,5,6, 7-tetrahydro-iH-pyrazolo- [3,4-c]pyridine; .3-ethyl-i-cyclopentyl-6-phenyl-7-oxo-4,5,6,7-tetrahydro-i H-pyrazolo- [3,4-c]pyridine; 3-ethyl-i -(3,4-dichlorophenyl)-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-i

H-

pyrazolo[3,4-c]pyridine; 3-ethyl-i -cyclopentyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1

H-

pyrazolo[3,4-c]pyridine; 3-ethyl-i -(4-fluorophenyl)-6-(2-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-i

H-

pyrazolo[3,4-c]pyridine; 3-ethyl-i -cyclopentyl-6-(3-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4c]pyridine; 3-ethyl-1 -cyclopentyl-6-(3-trifluoromethylphenyl)-7-oxo-4 ,5,6,7-tetrahydro-1Hpyrazolo[3,4-cjpyridine; 3-ethyl-i -cyclohexyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1

H-

pyrazolo[3,4-c]pyridine; WO 95/01980 PCT/1394/0OA 56 3-isopropyl-i .cyclopentyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-i Hpyrazolo [3,4-clpyrldlne; 3-ethyl-i -cyclobutyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 Hpyrazolo pyridilne; 3-ethyl-i -cyclopentyl-6-phenyl-4,5,6,7-tetrahydro-1 H-pyrazolo [3,4-c]pyrldlne; 3-ethyl-i -cyclopentyl-6-(2-methyiphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4cjpyriciine; 3-ethyl-i -(3-sulfolanyl)-6-(3-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-I Hpyrazolo[3,4-c] pyridine; 3-ethyl-i -(3-sulfolanyl)-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 Hpyrazolo[3,4-cI pyridlne; 3-ethyl-i -cyclobutyl-6-(3-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4cipyridine; 3-ethyl-i (3-suIf olIan yl) (3-trlfl uo rom ethyl phen yl)-7-oxo-4,5,6,7-tetrahydro-i1 Hpyrazolo[3,4-cjpyridlne; 3-ethyl-i -cyclobutyl-6-(3-trlfluoromethylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 Hpyrazolo pyridine; 3-ethyl-i -cyclobutyl-6-(2-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-i H-pyrazolo[3,4c~pyrlne, 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 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,

R

1 R 2 and R 3 as used herein, unless otherwise indicated, are as defined above with reference to formula 1, The following reaction schemes illustrate, but are not limiting to the preparation of the compounds of the present invention.

wo 95101980 WO 9501980ICT/1B94/00I 56 SCHEME I 6H 1

IV

0 6NRa2

V

CH

3 SCHEME 2

KN.

OR 5 N

I

ORR

12 v II I R I WO 95/01980 PCT/IB94/00156 -7" In Reaction 1 of Scheme 1, the 2-pyrrolidlnone 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- 4methoxybenzene, 3-methoxybenzene, 2-methoxybenzene, 3-methylbenzene, 4methylbenzene, 2-methylbenzene, 3-trifluoromethylbenzene, 2-trifluoromethylbenzene, 3,4-dlmethoxybenzene or 3-cyclopentoxy-4-methoxybenzene. The reaction temperature will generally be in the range of about 110 0 C to about 1700C, preferably about 1500C, for a time period of about 14 hours to about 22 hours, preferably about 18 hours, under inert reaction conditions, In Reaction 2 of Scheme 1, R' 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 -150C to about 1500C, preferably about 000C The N-(aryl)-2-pyrrolidone compound of formula V is then added and the reaction mixture is warmed to room temperature while being 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, by first washing the combined organics with water and brine, then drying 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 1,2,5,6tetrahydropyridine 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 is added and the reaction mixture is heated to reflux for a time period between about 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 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- In 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-l-p-tolyltriazene in an aprotic solvent. The preferred aprotic solvent is 1,2-dichloroethane, The time period for the reaction is between about 30 minutes to about 120 minutes, preferably about 45 minutes, In Reaction 1 of Scheme 2, the 1,2,5,6-tetrahydropyridine compound of formula VIII, wherein R 5 is hydrogen or methyl, is converted to the corresponding 4,5,6,7tetrahydro-7-oxo-lH-pyrazolo[3,4-c]pyridine compound IX by reacting VIII with a hydrazine of the formula R 3

HNNH

2 Both derivatives of the compound of formula VIII, 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 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 compound VIII is converted to the corresponding compound of formula IX by reacting VIII 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 Hpyrazolo[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 pressure. The resulting dry solid is suspended in cold ether and treated with oxalyl 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

C

WO 95/01980 PCT/IB94/00156 -9" solution is added dropwise to stirred ammonium hydroxide at a temperature between about -100C to about 100C, preferably 0oC, 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 by reacting VIII with a hydrazine hydrochlorlde in a polar protic solvent, preferably methanol. The reaction mixture is heated to a temperature between about 70°C to about 1100C, preferably about 900C, under a gentle stream of nitrogen until all of the solvent is removed, The neat mixture is then heated to a temperature between about 12000C to about 1800C, preferably about 1500C, for a time period between about minutes to about 90 minutes, preferably 60 minutes.

The compounds so formed of formula IX may be converted to the corresponding 6-R 2 -4,5,6,7-tetrahydro-7-oxo-1H-pyrazolo [3,4-c]pyridine compound, wherein R 2 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) nitrete in water at a temperature between about -150C to about 150C, preferably about 00C, for a time period between about 20 minutes to about 50 minutes, preferably about 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 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 2000C to about 300C, preferably about 250C, and an alkyl halide of formula R 2 halide, wherein R 2 is as defined with reference to formula I other than a group of formula II, is 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[3,4c]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 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

A

7 Cr _I I. I r 1- WO 95/01980 PCT/IB94/00156 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 (PDE 4 and, consequently, demonstrate their effectiveness for treating inflammatory diseases is shown by the following in tro assay.

BIOLOGICAL ASSAY (Human lung PDEV) 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 Tekmar Tissumizere (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 The supernatant is filtered twice through a 0.22 pm filter and applied to a Mono-Q FPLC column (Pharmacia LKB Biotechnology, 800 Centennial Avenue, Piscataway, New Jersey 08854) pre-equilibrated with pH 7.4 Tris/PMSF buffer. A flow rate of 1 ml/minute 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 PDEv activity, determined by 3 H]cAMP hydrolysis and the ability of a known PDEj inhibitor rolipram) to inhibit that hydrolysis. Appropriate 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 pM compound, 4% DMSO), Further serial dilutions are made in 4% DMSO to achieve desired concentrations. Final DMSO concentration in assay tube is 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 pl compound or DMSO for control and blank) ii) 25 pl pH 7,5 Tris buffer iii) 3 H]cAMP (1 pM) iv) 25 pl PDEv enzyme (for blank, enzyme is preincubated in boiling water for 5 minutes) The reaction tubes are shaken and placed in a water bath (370C) for minutes, at which time the reaction is stopped by placing the tubes in a boiling water WO 95/01980 PCT/IB94/00156 -11bath for 4 minutes, Washing buffer (0.5 ml, 0,1M 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES)/0.1M 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 ml bed volume) previously equilibrated with washing buffer. 3 H]cAMP is washed with 2 x 6 ml washing buffer, and 3 H]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 3

H],

inhibition 1 average cpm (test compound) average cpm (blank) average cpm (control) average cpm (blank) is defined as that concentration of compound which inhibits 50% of specific hydrolysis of 3 H]cAMP to 3

(TNF)

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 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 106 cells in 1.0 ml in 24-well plates, The cells are incubated at 37 0 C carbon dioxide) and allowed to adhere to the plates for 2 hours, after which time non-adherent cells are removed by gentle washing. Test compounds (10pl) are then added to the cells at 3-4 concentrations each and incubated for 1 hour. LPS (10pl) is added to appropriate wells. Plates are incubated overnight (18 hrs) at 370C. At the end of the incubation period TNF was analyzed by a sandwich ELISA (R&D Quantikine Kit). 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, HNO 3 H2SO 4

H

3

PO

4

CH

3

SO

3 H, p-CH 3

C

6

H

4

SO

3 H, CH 3

CO

2 H, gluconic acid, tartaric acid, maleic acid and succinic acid. Pharmaceutically-acceptable cationic salts of the compounds of this

:A

WO 95/01980 PCTIIB94/00156 -12- Invention of formula I wherein R 4 is CO, 2 R and R1 Is hydrogen Include, but are not limited to, those of sodium, potassium, calcium, magnesium, ammonium, N,N'dibenzylethylenedlamine, N-methylglucamlne (meglumine), ethanolamine and diethanolamine, 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 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% solution. In practice the physician will determine the actual dosage which will be 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 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 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 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 route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovales either alone or in 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.

~n WO 95/01980 PCT/lB94100156 i Iq 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 comprising a compound of the formula I and the pharmaceuticaily 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 3-Ethyl-1-(4-methoxvyph-en6-phenvl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo 3,4c]pyridine A mixture of 3-hydroxy-2-oxo-1-phenyl-4-propionyl-1,2,5,9-tetrahydro-pyridine 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 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 givl, 345 mg of the title compound as a red oil that crystallized upon standing at room temperature. The desired 1-(4methoxyphenyl) regioisomer is less polar than the 2-(4-methoxyphenyl) byproduct.

M.P. 43-450C, IR (chloroform) lactam C=0, 1665 cm'; 'H NMR (300 MHz, CDCI,) d 1.32 (t,J 7.6 Hz, 3H), 2.74 J 7.6 Hz, 2H), 2.96 J 6.6 Hz, 2H), 3.79 3H), 4.10 (t,J 6.6 Hz, 2H), 6.89 (d,J 9.0 Hz, 2H), 7.22-7.39 5H), 7.45 (d,J 9.0 Hz, 2H); Anal. calcd. for C 2

,H

21 C, 72.60; H, 6.09; N, 12.09. Found: C, 72.48; H, 6.08; N, 11.66; MS m/z 347.

Examples 2-15 Reaction of the appropriate hydrazine hydrochloride with the requisite 4alkanoyl-3-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine, analogous to the proceduar of Example 1, affords the following compounds Ex.# R' R 2

R

3 M.p.oC Mass Spectra or Mass Spectra or Analysis (calcd.) Analysis (found) %N %N 2 ethyl phenyl methyl 80-83 70.56, 6.71, 16.46 70.61, 6.77, 15.51 3 ethyl phenyl tert-butyl 120-121 72.70, 7,79, 14.13 72.50, 7.96, 14.16 if WO 95/01980 PCTIIB94OOIS6 .14- 4 ethyl 4-methoxy 4-methoxy 42-45 70.01, 6,14, 11.13 70.05, 6,07, 11.00 I phenyl phenyl ethyl 4-fluoro tert-butyl 92-94 315,1747 HRMS phenyl 315.1741 6 ethyl phenyl 3,4- (o1l) [Mi 386.26 MS mlz 386 dichiorophenyl 7 ethyl 4-fluoro 4-methoxy 129-130' 69.03, 5.52, 11.50 68.75, 5,37, 11.43 ____phenyl phenyl 8 methyl phenyl 4-fluoro 139.140' 321.3 MS m/z 322 phenyl 9 ethyl phenyl cyclopent 73-75 309.1841 HRMS 309,1823 methyl phenyl 4-methoxy 167-166 333.1477 HRMS phenyl 1333.1477 11 ethyl phenyl 5-phenyl (oil) 388.2389 HRMS pentyl 388.2395 12 methyl 4-methoxy 4-fluoro 1 4 0 14 2 68,36, 5,16, 11.96 67.92, 5.03, 11.72 phenyl phenyl 13 methyl 4-methoxy 3-fluoro 133-138 68.36, 5,16, 11.96 68.04, 5.04, 11.75 phenyl 14 ethyl 4-methoxy 3,4- 50-60 60.59, 4.60, 10.09 60.34, 4.56, 9,86 phenyl dichiorophenyl ethyl 3-methoxy methyl (oil) 285.35 MS m/z 286 ____phenyl

IIII

Recrystallizing solvents: "isopropyl ether, b 5 Ethyl acetate in petroleum ether, Example 16 3-Ethyl-i -(4-phenylcarboxylic acid)-6-phenyl-7-oxo-4,5,6,7-tetrahvdro-1 H- Pyrazolo [3,4-clhyridine A mixture of 3-hydroxy-2-oxo-1 -phenyl-4-propionyl-i 2,5,6-tetrahydro-pyridine grams, 4.08 mmole), 4-hydrazinobenzoic acid (0.68 grams, 4.49 mmole) and 30 ml of 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 concentrated under reduced pressure.

A

WO 95101980 PCT/IB94/00156 -16.

Recrystallization from methanol gives 0,64 grams of the title compound as an orange solid, M.P. 261-26300, 'H NMR (300 MHz, DMSO-d) 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 7.65 (d,J 8.6 Hz, 2H), 7.96 (d,J 8.6 Hz, 2H), 13.05 1H); MS m/z 362.

Example 17 1 -(4-Benzamide)-3-ethyl-6-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahdro-1 Hpyrazolo[3,4-clpvridine To a stirred solution of sodium methoxide in methanol (prepared from 6.6 mg Na) is added 3-ethyl-6-(4-methoxyphenyl)-1-(4-phenylcarboxyllc acld)-7-oxo-4,5,6,7tetrahydro-1 H-pyrazolo[3,4-c]pyrldine (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 pl, 0,35 mmole) and anhydrous N,N-dimethylformamide (1 drop). After stirring for 1 hour the valatiles 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 00C. 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 and filtered, and the precipitate was washed with water to give 81 mg of the title compound. Decomposition point 243-245C0; 'H NMR (DMSO-d 6 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 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 1H), 7.59 (d,J 8.5 Hz, 2H), 7,90 (d,J 8,6 Hz, 2H), 8.04 1H); Anal. calcd. for C 22

H

22

N

4 0 3 C, 67.68; H, 5,68; N, 14.35. Found: C, 67.19; H, 5.31; N, 13.55. HRMS calcd. for C 22

H

22

N

4 0 3

[M]

391.1770. Found 391.1781.

The starting 3-ethyl-6-(4-methoxyphenyl)-1-(4-phenylcarboxylic acid)-7-oxo- 4,5,6,7-tetrahydro-lH-pyrazolo pyridine was prepared using the appropriate reagents according to the procedure of example 16.

WO 95101980 WO 95/1980 CT111194/0O 156

OF

-16- Example 18 1 -(3,4..dchloroRhenyl)-3-ethvl-6-(3-methoxylhenvl -7-oxo-4,56,67-tetrahvdro-I Hpyrazolo !3,4-cl vrldlne A stirred mixture of 3-methoxy-1 -(3-methoxyphenyl)-2-oxo-4-proponyl-1 ,2,5,6tetrahydro-pyridlne (0.49 grams, 1,7 mmole), 3,4-dichlorophenylhydrazine hydrochloride (0,40 grams, 1.87 mmole) and sodium methoxlde (46 mg, 0.85 mmole) in anhydrous ethanol was heated to reflux. After 16 hours, the mixture was concentrated under reduced pressure and chrornatographed on a silica gel column using 1:4 ethyl acetate/hexane as eluent to give a white solid. Recrystallization from ether gave 0,46 grams of white needles, M,P. 97-990C, IH NMR (250 MHz, CDCI 3 1,31 (t,J 7,5 Hz, 3H), 2,73 (q,J 7,T6 Hz, 2H), 2,96 (t,J 6,6 Hz, 2H), 3.79 3H), 4.09 (t,J 6.6 Hz, 2H), 6,78-6,91 (in, 3H), 7,29-7.49 (in, 3H), 7,73 (d,J 1.8 Hz, MS m/z 416.

.Examples 19-42 Reaction of the appropriate hydrazine hydrochloride with the requisite 4alkanoyl-3-inethoxy-2-oxo-1,2,5,6-tetrahydropyridine, analogous to the procedure of Example 18, affords the following compounds.

Ex.# RI R 2

R

3 M.p.AC Mass Spectra or Mass Spectra or Analysis (calcd.) Analysis (found), %N %N 19 methyl 4-methoxy 3-4- 143-144a 59,71, 4.26, 10.45 56.13, 4.02, 9.65 phenyl dichioro- 20 ethyl 3-methoxy cyclo- 64-65 340.2025 HRMS [MI] phenyl pentyl 340.2046 21 ethyl 4-methoxy cyclo- 96-98 70.77, 7.42, 12.38 70,44, 7,68, 11.69 phenyl pentyl 22 methyl 4-methoxy cyclo- 121-122 70.13, 7.12, 12.91 69,48, 7.10, 12.70 phenyl pentyl 23 iso- phenyl 3,4- oil (M 400.0983 HRMS propyl dichioro 400.0966 24 ethyl 3,4-dimeth- cyclo- 107-108 [M 369,46 MS m/z [M]I 369 _____oxyphenyl 25 ethyl 3,4-dimeth- 3,4- 1 9 0 19 1 59.20, 4.74, 9.41 59.41, 4.46, 9,71 oxyphenyl dichlorophenyl______ If WO 95/01980 PICT/B94/OO1 56 Ex.# RI R 2 R3M~p.C Mass Spectra or Mass Spectra or Analysis (calcd.) Analysis (found) %N %N 26 iso- 4-methoxy 3,4- 145-147c 61,40, 4,92, 9.76 61,29, 4,81, 9,53 propyl phenyl dichloro 27 propyl 4-methoxy cyclo- 102-103r, 71.36, 7.70, 11.69 70.98, 7.66, 11.73 ____phenyl 28 iso- 3-methoxy 3,4- 1 2 6 1 2 7 61.40, 4.92, 9.76 61.55, 5,10, 9.97 propyl phenyl dichiorophenyl 29 ethyl 4-methoxy- 3,4- 54-56 62.40, 5.44, 8.40 62,15, 5,50, 3-cyclo- dichioropentoxy- phenyl phenyl ethyl 4-methoxy- cyclo- 88-89 423.55 MS mlz 423 3-cyclo- pentyl pentoxy- 31 ethyl 3-methoxy 4-fluoro- 139-14011 69.03, 5.79, 11.50 69.05, 5.42, 11.57 phenyl 32 ethyl 2-methoxy cyclo- 119-120 70.77, 7.42, 12.38 70.63, 7.16, 12,01 phenyl 33 ethyl 2-methoxy 4-fluoro- 103-104' 365.41 MS m/z 366 phenyl phenyl 34 jethyl 3-methyl cyclo- oil 74.27, 7.79, 12.99 74.54, 7.89, 12.63 ____phenyl pentyl ethyl 3-methyl 4-fluoro- oil 72.19,5.77, 12.02 72.06, 5,55, 11.52 ____phenyl phenyl 36 ethyl 3-trifluoro- cyclo- oil 63.65, 5,87, 11.13 63.95, 5.73, 10.97 methyl- pentyl phenyl 37 ethyl 3-trifluoro- 4-fluoro- 139-140f 4.25, 10.42 62.60, 4.08, 10.41 methyl- phenyl 38 ethyl 4-methyl- cycle- 93-94 74.27, 7.79, 12,99 74.10, 7.52, 12.59 phenyl pentyl 39 ethyl 2-methyl- 4-fluoro- 14 1 14 2 72.19, 5.77, 12.03 72.36, 5.52, 12.09 ____phenyl phenyl thyl 2-methyl- cycl- 130-1 31 MW 323.44 MVS m/z 323 phenyl pentyl I WO 95101980 PCT/11394/0OI 56 Ex,# RI R 2 R3 M~p, 0 C Mass Spectra or Mass Spectra or Analysis (calod.) Analysis (found) %N %N 41 ethyl 2-trifluoro- 4-fluoro- 48-50 MW 403.38 MS m/z 404 methyl- phenyl 1_ phenyl A I 42 ethyl 3-methyl- 3-sulfo- oil MW 373.47 MS mn/z 374 phenyl Ilanyl I Recrystallizing solvents: 15% Ethyl acetate/petroleum ether, b Isopropyl ether.

Ethyl acetate/hexane. dEthyl ether, Ethyl acetate/pentane, 'Pentane.

Example 43 1 -Cvclohexyl-3-ethyl-6-(3-methoxvohenyl)-7-oxo-4.5.6,7-tetrahvdro-1 Hpyrazolo [3,4-cl pyridine A solution of 3-methoxy-1 -(3-methoxyphenyl)-2-oxo-4-proponyl-1 .2,5,6-pyridine (0.80 grams, 2,8 mmole) and cyclohexylhydrazine hydrochloride (0.54 grams, 3.6 mmole) in methanol (15 ml) was warmed to 9000 under a gentle stream of nitrogen until all of the solvent was removed. The neat mixture was then heated to approximately 15000C under nitrogen for 1 hour. After cooling to room temperature, the mixture was dissolved in ether and washed with 1 N hydrochloric acid followed by brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, Chrorhatography on silica gel using 1:1 ethyl acetate/hexane as eluent gives 0.47 grams of the title compound as a yellow oil. IH NMVR (250 MHz, CDCl,) 1.20-1.52 (in, 6H, including t at 1.23, J =7.6 Hz, 3H), 1 .64-1.74 (in, 1 1.80-2.06 (in, 6H), 2.67 (q,J =7.6 Hz, 2H), 2.87 (t,J =6.7 Hz, 2H), 3.82 3H), 3.97 (t,J 6.7 Hz, 2H), 5.13 (tt, J 4,3 and 11.3 Hz, 1 6.79-6.93 (mn, 3H), 7.31 (t,J 8.1 Hz, 1 HRMVS calculated for C 2

,H

27

N

3

O

2 353.2103. Found: 353.2094.

Examples 44-57 Reaction of the appropriate hydrazine hydrochloride with the requisite 4alkanoyl-3-inethoxy-2-oxo-1 .2,5.6-tetrahydropyridine, analogous to the procedure of Example 43, affords the following compounds.

Ex.# R' R 2 R3 M.p.OC Mass Spectra or Mass Spectra or Analysis (calcd.) Analysis (found)

%N

44 iso- 4-methoxy cyclo- 102-103- 354 MS [M-1 354 L- .propyl ,phenyl pentyl WO 95101980 PCT/1B94/001 56 -19- Ex.# R' R 3 M~p.

0 C Mass Spectra or Mass Spectra or Analysis (calod.) Analysis (found) %N %N Iso- 3-methoxy cyclo. 9 9 1 0 0 b 71.36, 7.70, 11,89 71.10, 7,56, 11.73 propyl phenyl pentyl 46 ethyl 3-methoxy cyclobutyl 73-740 70.13, 7,12, 12.91 70.10, 7.22, 12.93 phenyl 47 ethyl phenyl methylene 60-620 73,19, 7,17, 14.23 73,34, 7.08, 13.95 cyclopropyl 48 ethyl 3-methoxy methylene oil IM-] 326 MS [MW] 326 phenyl cyclo.

49 ethyl 4-methoxy- phenyl 1 6 6- 1 5 7 b 72,60, 6.09, 12.10 72.35, 5,9 1, 12.02 phenyl ethyl 3-methoxy- 3-sulfo- oil 58.59, 5.95, 10.79 58.46, 6.03, 9,82 _____phenyl lanyl 51 ethyl 3-methoxy- 4-trifluoro- 12 4 1 2 5 d 63.61, 4,85, 10.12 63,40, 4.51, 10.09 phenyl methyl.

phenyl 52 ethyl 3-methyl- cyclobutyl oil 73.75, 7.49, 13,58 73,22, 7,56, 13.03 phenyl 53 ethyl 3-trifluoro- 3-sulfo- oil MW 427.44 MS m/z 428 methyl- lanyl ____phenyl 54 ethyl 3-trifluoro- cyclobutyl oil 62,80, 5,55, 11,.56 63.01, 5,54, 11.19 methylphenyl ethyl phenyl 2-Indanyl 155-1566 77.28, 6.49, 11.76 77.35, 6.48, 11.08 56 ethyl 2-methyl- cyclobutyl 100-102 MW 309.41 MS m/z 310 phenyl 57 ethyl 3-methoxy- 2-indanyl 60-62( MW 387.48 MS m/z 388, 389, phenyl 390 Recrystallization solvents: 8Ethyl acetate/pentane. 'Ethyl ether/pentane.

'Isopropyl ether/pentane. 'Ethyl/acetate/petroleum ether. 'Ethyl acetate, 'Ethyl acetate/hexane.

a

C

WO 95(01980 PCT/1B94/00I 56 Example 58 3-Ethyl-6.(4-fluoroehenl)-l .(4.methoxvlhenvl)-4,5,6,7-tetrah vdro-I H.

pyrazoloMO cl oyridine To a stirred solution of 3-Ethyl.6-(4.fluorophenyl).1.(4-methoxyphenyl)7-oxo.

4,5,67-tetrahydro-1 H-pyrazoio[3,4-c]pyridine (0.3 grams, 0.82 mmole) In 50 ml ether was added lithium aluminum hydride (33 mg, 0.86 mmoie). 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 acetate/hexane as eluent gives 0.12 grams of the title compound as a pale yellow paste, I H NMR (250 MHz, CDCI 3 1.28 (tJ 7.6 Hz, 3H), 2.66 (qJ 7.6 Hz, 2H), 2.71 (tJ =5.7 Hz, 2H), 3.49 (tJ =5.7 Hz, 2H), 3,84 3H), 4.23 6,84-6.99 (in, 6H-), 7.36 (d,J 9,0 Hz, 2H); MS m/z 352, Examples 59-63 Reaction of the appropriate 7-oxo*2,567-tetrahydro-1 H-pyraizolo (3 1 4-cjpyridine with lithium aluminum hydride 1 analogous to the procedure of Example 58, affords the following compounds.

0 Ex.# R' R 2 R3M.p.O0 Mot. Weight Mass Spectra [M'11 (found) 59 ethyl 4-methoxy-3- cyclopentyl oil 409.57 409 cyciopentoxy phenyl 60 ethyl phenyl 3,4-dichloro- oil 372.30 371 .373 61 ethyl phenyl cyclopentyl oil 295,43 296 62 ethyl 3-methoxy cyclobutyl oil 311.43 312 phenyl 63 ethyl 3-methoxy cyclohexyl oil 339.48 340 phenyl Example 64 1 -cVclopentvl-3-ethyl-7-oXo-4,5,6,7-tetrahydro-1 H-Dvrazolo [3,-cipyridine A stirred solution of 1 -cyclopentyi-3-ethyl-6-(4-methoxyphenyl)-7-oxo-4,5,67tetrahydro-1 H-pyrazoo [3,4-c~pyridine (2.58 grams, 7.60 mmoles) in acetonitrile (90 ml) at 0OC is treated with a solution of ceric ammonium nitrate (12.5 grams, 22.8 mmoles) WO 95/01980 PCT/IB94/00156 -21in water (110 ml). After stirring for 35 minutes the mixture is diluted with water (550 ml) and extracted with ethyl acetate (100 ml x The combined organics are washed with 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 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 recrystallized from ether to give .814 grams of a tan solid. M.P. 143-1450C; MS 234; 'H NMR (250 MHz,

CDCI

3 1.21 J 7.6 Hz, 3H), 1.62-2.13 8H), 2,62 J 7.6 Hz, 2H), 2.73 J 6.8 Hz, 2H), 3.51 (dt, J 2.7 and 6,8 Hz, 2H), 5,47 1 5.61 (pentet, J 7.7 Hz, 1 i Example 1 -cvclopentvl-3-ethyl-6-cyclopropylmethyl-7-oxo-4,5,6,7-tetrahydr-1 Hpyrazolo(3,4-c]pyridine A solution of 1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4c]pyridine (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 250C and (bromomethyl) cyclopropane (0.31 grams, 2.29 mmoles) is added. The mixture is stirred at reflux for 16 hours and then cooled to 2500C before 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 288; 'H NMR (300 MHz, CDCI 3 0.26-0.31 2H), 0.50-0.56 2H), 0.85-1.06 1H), 1.20 J 7.6 Hz, 3H), 1.62-2.08 8H), 2.61 J 7.6 Hz, 2H), 2.74 (t, i J 6.8 Hz, 2H), 3.39 J 6.9 Hz, 2H), 3.63 J 6.8 Hz, 2H), 5.67 (pentet, J 7.8 Hz, 1H).

Preparation 1 4-lsobutyrvl-3-methoxy-1-phenyl-2-oxo-1,2,5,6-tetrahydropyridine 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 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-1,2,5,6tetrahydropyridine (0.52 grams, 2.0 mmole) in tetrahydrofuran (4 ml) was added dropwise via cannula. After approximately 20 minutes methyl iodide (0.20 ml, WO 95/01980 PCT/IB94/00156 -22mmole) 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.

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, CDCI 3 1,15 6H), 2.72 2H), 3.47 (heptet, 1H), 3.82 2H), 3,97 3H), 7,21-7,45 5H); MS m/z 274.

Preparations 2-3 Reaction of the appropriate 3-methoxy-2-oxo-4-propionyl-1,2,5,6tetrahydropyridine with lithium diisopropylamine and methyl iodide, analogous to the procedure of preparation 1, affords the following compounds of formula VII, Prep# R 2 m.p. OC M.W. Mass Spectra [M 2 4-methoxyphenyl oil 303.36 304 3 3-methoxyphenyl oil 303.36 304 Preparation 4 3-Methoxy-1-(4-methylphenvl)-2-oxo-4-propionvl-1,2,5,6-tetrahvdropyridine A solution of 3-hydroxy-1 -(4-methylphenyl)-2-oxo-4-propionyl-1,2,5,6tetrahydropyridine (5,9 grams, 23 mmole) and 3-methyl-i-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, 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, CDCI,) 1.12 (t,J 7.2 Hz, 3H), 2.34 3H), 2.71 (t,J 6.7 Hz, 2H), 2.93 (q,J 7.2 Hz, 2H), 3.77 (t,J 6.8 Hz, 2H), 3.94 3H), 7.20 4H); MS [M 273.

Preparations 5-14

'I

WO 95/01980 rCT/194/0015G Reaction of the appropriate 3-hydroxy-1-aryl-2-oxo-4-alkanoyl-1,2,5,6tetrahydropyrldine with 3-methyl-l-p-tolyltriazine, analogous to the procedure of Preparation 4, affords the following compounds of formula VII.

Prep# R' R 2 m.p. °C M.W. Mass Spectra 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- oil 373.45 373 methoxyphenyl 13 ethyl 3-methylphenyl oil 273.33 273 14 ethyl 3-trifluoromethylphenyl oil 327.30 327 Preparation 3-Hydroxv-1-(3-methylphenyl)-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine 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 reflux was initiated after approximately 1 ml was added. After all of the magnesium was consumed, the reaction mixture was cooled to 00C and N-(3-methylphenyl)-2pyrrolidone (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, 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 hydroxide, 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 are separated and the aqueous layer was extracted with ethyl acetate. The combined organics are I I ii 'I vii I-e WO 95/01980 PCT/IB94/00156 -24washed 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 adcition of sodium (1,0 grams) to 10 ml anhydrous methanol), After being stirred at reflux over 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. M.P. 115-1160; 'H NMR (300 MHz,

CDCI

3 1.16 (t,J 7.2 Hz, 3H), 2.37 3H), 2.74-2.82 4H), 3.85 (t,J 6,8 Hz, 2H), 7.08-7.14 3H), 7.30 (t,J 7,7 Hz, 1H); MS m/z 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 reported in Preparation 15, affords the following compounds of formula VI.

Prep# R' R 2 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 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 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 WO 95/01980 WO 9501980PCT/1B94/001 56 Prep# R R 2 m.p, 0 C M.W. Mass Spectra [M+1 29 ethyl 3-cyclopentoxy-4- 133-1 34 359.42 360 meth oxyph enyl Preparation N-(2-Methoxvphenyl)-2-pyrrolidone A mixture of 2-pyrrolidone (15.0 grams, 176 mmole), 2-lodoanisole (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 15000, After 18 hours, the reaction mixture was filtered through a 6x1 5 cm pad of silica gel eluting with 1:1 ethyl acetate/hexane to give a pale yellow oil. The unreacted reagents are removed by vacuum distillation (0.6 mm, 80-1 0000C) leaving 9,2 grams of the title compound as a honey-like oil. 1

H

NMVR (300 MHz, CDCI,) 2.20 (pentet, 2H), 2.55 2H), 3.75 2H), 3,82 3H), 6.93- 7,02 (in, 2H), 7.25-7.30 (in, 2H); MS m/z 191.

Preparations 31-39 Reactions of the appropriate iodo- or broinobenzene with 2-pyrrolidinone, analogous to that reported in Preparation 30, affords the following compounds of formula V.

Prep# Ra M.W Mass Spectra [M+1 31 4-methoxyphenyl 191.22 191 32 3-methoxyphenyl 191.22 191 33 3-methylphenyl 175.23 175 34 4-methylphenyl 175.23 175 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- 275.35 275 methoxyphenyl_______ I

Claims (4)

1. 2. A compound according to claim 1 wherein R 1 is (C-C 3 )alkyl and R 2 and R 3 are each indcpendently selected from tlic group consisting of (C 3 -C 7 )cycloalkyl, (C 4 -C 7 )hcterocyclic group containing S0 2 0o' a group of the formula (R 4 )a wherein a is an integer from I to 5 and R 4 is hydrogen, hydroxy, (CI-C 5 )alkyl, (Cl-C 5 )alkoxy or halogen.
2. 3. A compound according to claim 1 wherein RI is ethyl or isopropyl; R 2 is phenyl, 2-methyiphenyl, 3-niethylphenyl, 2-niethoxyphenyl, 3-methoxyphenyl or 3-trifluoromethyphienyl and R 3 is cyclobutyl, cyclopentyl, cyclohlexyl, 3-sulfolanyl,
3. 4-fluorophenyl or 3,4-dichiorophienyl, 4. A compound selected from the group consisting of: 3 -ethyl- I-(4-methoxyphlenyl)-6-phenyl-7-oxo-4,5 ,6 ,7-tetrahydro- 1H-pyrazolo- [3 ,4-c]pyridine; 3-ethyl-i -cyclopentyl-6-phenyl-7-oxo-4 ,5,6 ,7-tetrahiydro- 11--pyrazolo- 16 (3,4-c]pyridine; V '433-ethyl-i ,4-dichlorophenyl)-6-(3 -methioxyphienyl)-7-oxo-4 ,5 ,6,7-tetrahydro-1H- pyrazolo pyridine; 3 -ethyl-i1 -cyclopentyl-6-(3 -methoxyphenyl)-7-oxo-4,5 7-tetrahydro-i1ll- 20pyrazolo[3 ,4-c]pyridine;
4. 203-ethyl-i1 -(4-fluorophenyl)-6-(2-rnethioxyphenyl)-7-oxo-4 6,7-tetrahiydro-iIJ- pyrazolo[3 ,4-c]pyridine; k 4 X [N:WStHJ00026:RRB 28 V b 3-ethyl-i -cyclopentyl-6-(3-mehylphenyl)-7-oxo-4,5 1 6,7-tetrahydro-I H-pyrazolo[3 1 4. olpyrldlne; 3-ethyl-I -cyclopentyl-6(3-trlfluoromethiylphenyl)7-oxo-4,5,6,7-tetrahlydro- H- pyrazolo[3,4-clpyrldlne; 6 3-ethyl-I -cyclohexyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-I H-pyrazolo[3 4. cipyrldine; 3-lsopropyl-i -cyclopentyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-i H- pyrazolo[3,4-c]pyrldine; 3-ethyl-i -cyclopentyl-6-phenyl-4,5,6,7-tetrahydro-I H-pyrazolo[3,4-cjpyridlne;' 3-ethyl-I -cyclopentyl-6-(2-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-I H-pyrazolo[3,4- c]pyrldlne; 3-ethyl-I -(3-sulfolanyl)-6-(3-methylphenyl)-7-oxo-4,5,6,7-tetrahydro- H-pyrazolo[3,4- c]pyrl dIne; 3-ethyl-i -(3-sulfolanyi)-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-I H- pyrazolo[3,4-c]pyrldine; 3-ethyl-I -cyclob utyl-6-(3-meth ylph enyl)-7-oxo-4 ,5,6,7-tetrahydro-i H -pyrazolo[3,4- c]pyridine; 3-ethyl-i -(3-sulfolanyl)-6-(3-trifluoromethylphenyl)-7-oxo-4,5,6,7-tetrahydro-I H- pyrazolo[3,4-clpyridine; 3-ethyl-I -cyclobutyl-6-(3-trifluoromethylphenyl)-7-oxo-4,5,6,7-tetrahydro-I H- pyrazolo[3,4-c]pyridine; 3-ethyl-I -cyclobutyl-6-(2-methylphenyl)-7-oxo-4 ,5,6,7-tetrahydro- I H-pyrazolo[3,4- c 5yidn. A 4,5,6,7-tetrahydro- H-pyrazolo[3,4-c]pyridine derivative, substantially as hereinbefore described with reference to Examples 18, 20, 28, 31 to 37, 39 to 43, 45, 46, 50 to 54, 56, 62 and 63. 6. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of any one of claims i to 5 and a pharmaceutically acceptable carrier, of 7. A method for the inhibition of phosphodiesterease (PDE) type IV and the production 3 oftumor necrosis factor (TNF) comprising administering to a patient an effective amount ofa compound of any one of claims i to 5 or a composition of claim 6. 8. 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 P'i [and other inflammatory diseases], AIDS, septic shock and other diseases involving the production of TNF comprising administering to a patient in need of such treatment, an effective amount of a compound of any one of claims I to 5 or a composition of claim 6. Dated 16 June, 1998 Pfizer Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 4 I I I IEItEN AINAL hu2ARLAA Ku±ruaV Intcmau ApplicAtion No I PCT/id 94/00156 1 A CLSIIAIN OFl SUllUKMlMA'rI1111 IPC 6 C070471/04 A61K31/435 //(C07D471/040231:00,221:00) According to International I'atcit ctaiifieation (111C) or to both national classification and IIIC Minimum documentation searched (clalliflCAtion system followcd by classification symbols) IPC 6 C07D A61K D~ocumentation searched other than minimumn documenttation to thc extent that such documcnW arc included in the fields searched lilectronic data baec consulted during the international search (name of data base and, where practical, search terms uscd) C. I)OCUMIINI'S COIJSID11IIII)T 1IC1II RIU.IIYANT Catecgory' Citation of document, with indication, wherc appropriate, of the relevant passages Relcvant to claim No, A EP,A,0 531 901 (FUJISAWA) 17 March 1993 see claims 1,9 X FR,A,1 463 883 (CIBA) 30 December 1966 1 see exaitiple 3 X CHEMICAL ABSTRACTS, vol. 86, no. 5, 1 1977, Columbus, Ohio, US; abstract no. 29733c, T. KAMETANI ET AL. 'Studies on the syntheses of heterocyclic compounds. DCLXIII. The reaction of pyridone derivatives with diazoalkane' page 362; see counipoud III CHEM. PHARM. BULL. 1976, 24(8), 1870 8 Vurther documents arc listed In the continuation of box C. [Mj Patent family members arc listed in annex. *Special categories of cited documents later document published alter the international filing date or priority date and not in conflict with the application hut document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular reicvance invention R' earlier document but publisihed on or after the international W document of particular relevance,, the claimed invention filing date cannot he considered novel or cannot be considered to Ut document which may throw doubts on priority claimn(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of patclar relevance,, the claimed invention citation or other special reason (as specified) cannot be consdrd to involve an inventive step when the document referring to an oral disclosure, usec, exhibition or document is combined with one or more other such docu. other means nicnt5., such combination being obvious to a person skilled document published prior to the international filing date but in the art. later than the priority date claimed W document member of the same patent family lDatc of the actual completion of the international scarch D~ate of mailing of the international search report 24 August 1994 09. 9 Name and mailing address of the ISA Authorizecd officer I-uropean Patent Office, PALI3 5818 I'atcntlaan 2 NI, 2280 1IIV Rtilswilk rel. (131.70) 340.204i,Tlx. 31 651 epu ni,Alfr Fus I V:x 31-70) 340-3016 A fr a s Form PCTIISA/21O (second shet)t (July 1992) iA~ WJ~L$LL1A%.AU1a nembu, Applicatlon No InsormAtion onl pAltn rAmily membcrm PCT/ 1 94/00156 rPavnL documcnL Publicaion Patent family Puliatio cIhvd In wuarch report. dittoa mmbr(s) dt EP-A-0531901 17-03-93 AU-A- 2280592 11-03-93 HU-A 65204 02-05-94 FR-A-1463883 BE-A- 669298 07-03-66 FR-M- 5155 12-06-67 FR-M- 4903 NL-A- 6511645 09-03-66 US-A- 3340269 US-A- 3365459 OA-A- 1821 14-01-70 Form PCTIISA/210 (patent family annex) (July 1992) K