AU702105B2

AU702105B2 - Bicyclic tetrahydro pyrazolopyridines and their use as medicaments

Info

Publication number: AU702105B2
Application number: AU35317/95A
Authority: AU
Inventors: Allen J Duplantier
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 1994-10-20
Filing date: 1995-10-06
Publication date: 1999-02-11
Anticipated expiration: 2015-10-06
Also published as: WO1996012720A1; PL319758A1; CN1050129C; JPH09511758A; NO971811L; IL115667A0; FI954991A; AU3531795A; KR970707124A; CZ120097A3; BR9504491A; FI954991A0; EP0787132A1; HUT77517A; NZ292991A; NO971811D0; ZA958839B; CN1161040A; MX9504422A

Description

WO 96/12720 PCT/IB95/00847 -1- BICYCLIC TETRAHYDRO PYRAZOLOPYRIDINES AND THEIR USE AS MEDICAMENTS 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 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 compositions useful therefor.

Since the recognition that cyclic AMP is an intracellular second messenger Sutherland, and T. W. Rall, 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, 11, 150), and their selective inhibition has led to improved drug therapy 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 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 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 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).

Summary of the Invention The present invention relates to a compound of the formula R2-' N N and pharmaceutically acceptable salts thereof; wherein RI is hydrogen, (Cl-C 3 )alkyl, (C 2

-C

3 )alkenyl, (C 3

-C

5 )cycloalkyl or methylene

(C

3

-C

5 )cycloalkyl wherein each alkyl or alkenyl group may be optionally substituted with up to two (Cl-C 2 )alkyl or trifluoromethyl groups or up to three halogens; X is oxygen or two hydrogen atoms;

R

2 and R 3 are each independently selected from the group consisting of hydrogen; (Cl-

C

14 )alkyl optionally substituted with halogen or cyano; 4 )alkyl sulfonyl;

(C

1 -C 14 )alkoxy; naphthalyl; (C 2

-C

7 )alkenyl; (C 3

-C

7 )cycloalkyl; (C 1

-C

4 )alkyl-

(C

3

-C

7 )cycloalkyl; (C 3

-C

7 )cycloalkyl(C 1

-C

4 )alkyl; (C 4

-C

7 )heterocyclic group containing oxygen, sulphur, SO 2 or NR 5 wherein R 5 is hydrogen or (Cl-C 4 )alkyl or when R 2 is an *S aromatic heterocycle then R 5 is absent; (C 4

-C

7 )heterocycloalkyl-(W)d wherein the (C 4

C

7 )heterocycloalkyl group contains one or more oxygen, sulphur, S0 2 or NR 15 groups wherein R 15 is hydrogen or (Cl-C 4 )alkyl optionally substituted with halogen or (Cl-C 4 )alkyl, d is 0 or 1 and W is (Cl-C 4 )alkyl, CO or sulfonyl; CONRIOR 11 wherein R 10 and R 11 are each :V independently hydrogen or (Cl-C 4 )alkyl; (CI-C 5 )alkyl carbonyl; (Cl-C 5 )alkoxy carbonyl; (C 1

C

5 )alkyl carbonyl (Cl-C 5 )alkyl; (Cl-C 5 )alkoxy carbonyl (Cl-C 5 )alkyl; (Cl-C 5 )alkoxy(Cl-

C

5 )alkyl; R1 2 Rl 3 N(Cl-C 5 )alkyl wherein R 12 and R 13 are each independently hydrogen or (C 1

C

5 )alkyl; or a group of the formula

(R

4 )a I wherein a is an integer from 0 to 5; b and c is 0 or 1; R 4 is independently selected from hydrogen, hydroxy, (Cl-C 5 )alkyl, (C 2

-C

5 )alkenyl, (C'-C 5 )alkoxy, (C 3

-C

6 )cycloalkoxy, halogen, trifluoromethyl, C0 2

R

6

CONR

6

R

7

NR

6

R

7 CONHOH, CN, NO 2 or SO 2

NR

6

R

7 wherein R 6 and R 7 are each independently hydrogen or (Cl-C 4 )alkyl, wherein Y is (Cl-C 5 )alkyl or (C 2

-C

6 )alkenyl optionally substituted with Up to two (C 1

-C

7 )alkyl or

(C

3

-C

7 )cycloalkyl groups; and Z is oxygen, sulphur, CO, SO 2 or NR 8 wherein R 8 is hydrogen ~r (C 1

-C

4 )alkyl; or a group of the formula IN:\LIBH]3731 29E:KBM wherein p is an integer from 1 to 3, W' is hydroxy or oxo, R 9 is (C 1

-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 (C1-C 2 )alkyl, trifluoromethyl or halogen; or the group of the formula CH2n

(CH

2 )m

(CH

2 wherein m, n and p are 1 or 2; or a group of the formula wherein Q is hydroxy or a group of the formula 0@ 0

O

0

V

S. H2

N

with the proviso that R 2 and R 3 cannot both be independently selected from the group consisting of hydrogen, (C1-C14)alkyl, (C1-C14)alkoxy, (C2-C7)alkenyl, (C3_C14)cycloalkyl, cycloalkylalkyl, pyridyl, alkylpyridyl, (C4-C7)heterocyclic group containing oxygen, sulphur,

SO

2 or NR 5 wherein R 5 is hydrogen or (C-C4)alkyl; or a group of the formula /ry [N:\LIBH373129E:KBM 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 )alkenyl, (C 1

-C

5 )alkoxy, (C 3

-C

6 )cycloalkoxy, halogen, dialkylamino, trifluoromethyl, C0 2

R

6

CONR

6

R

7

NR

6

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, S02 or NR 8 wherein RS is hydrogen or (C 1

-C

4 )alkyl; and Y is (C 1

-C

5 )alkyl or (C 2

-C

6 )alkenyl optionally substituted with up to two

(C

1

-C

7 )alkyl or (C 3

-C

7 )cycloalkyl groups; or a group of the formula R9 p IP1

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 1

-C

2 )alkyl, trifluoromethyl or halogen.

0: t The above proviso is added to exclude subject matter in prior filed PCT Patent Application No. PCT/IB/94/00156.

SIn one embodiment, the invention relates to a compound of formula I wherein R 1 is (Cl-

C

3 )alkyl and R 3 is (C 3

-C

7 )cycloalkyl, (C 4

-C

7 )heterocyclic group containing SO2 or a group of the formula 4 )a

III

wherein a is an integer from 1 to 5 and R 4 is independently selected from hydrogen, hydroxy, (Cl-C 6 )alkyl (Cl-C 5 )alkoxy or halogen.

In another embodiment, the invention relates to a compound of formula I wherein R 1 is ethyl or isopropyl; R 2 is naphthalenyl, dimethylcarbamyl, 1-picolyl, 2-picolyl, 3-picolyl, dimethyl-isoxazol-4-ylmethyl, thiophen-2-ylmethyl, thiophene-2-carbonyl, tetrahydrofurfuryl, 3-cyanobenzyl, morpholine-4-carbonyl or isopropylsulfonyl and R 3 is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolanyl, 4-fluorophenyl or 3,4-dichlorophenyl.

[N:\LIBH373129E:KBM The present invention further relates to a pharmaceutical composition for the inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) and 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 claim 1 and a pharmaceutically acceptable carrier.

o IN:\LIBH]373129E:KWW WO 96/12720 PCT/IB95/00847 -6- The present invention further relates to a method for the inhibition of 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.

The present invention further relates to 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.

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 I and the pharmaceutically acceptable salts thereof.

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 I.

The following reaction schemes illustrate, but are not limiting to the preparation of the compounds of the present invention.

WO 96/12720 WO 9612720PCTIB95/00847 -7- SCHEME I 0 NH 1 1 v 0 N

R

2 2 v

OCH

3 SCHEME 2 I1 'OR 5 N IN 0 R3

VIII

WO 96/12720 PCT/IB95/00847 -8- 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- 4methoxybenzene, 3-methoxybenzene, 2-methoxybenzene, 3-methylbenzene, 4methylbenzene, 2-methylbenzene, 3-trifluoromethylbenzene, 2-trifluoromethylbenzene, 3,4-dimethoxybenzene or 3-cyclopentoxy-4-methoxybenzene. The reaction temperature wilt generally be in the range of about 110 0 C to about 1700C, preferably about 150°C, 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 -15 C to about 150C, preferably about 00C. 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 96/12720 PCT/IB95/00847 -9- 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-1H-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 WO 96/12720 PCT/IB95/00847 solution is added dropwise to stirred ammonium hydroxide at a temperature between about -100C to about 100C, preferably OOC.

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 hydrochloride in a polar protic solvent, preferably methanol. The reaction mixture is heated to a temperature between about 70 0 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 1200C 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-lH-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) nitrate in water at a temperature between about -150C to about 150C, preferably about OOC, 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 to about 30°C, 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 WO 96/12720 PCT/IB95/00847 -11about 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 vitro assay.

BIOLOGICAL ASSAY (Human lung PDE,,) 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 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 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 PDE,, activity, determined by 3 H]cAMP hydrolysis and the ability of a known PDEv 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 0 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 96/12720 PCT/IB95/00847 -12bath 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)

IC

5 0 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). IC 5 0 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

H

2

SO

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 WO 96/12720 PCT/IB95/00847 -13invention of formula I wherein R 4 is C0 2

R

6 and R 6 is hydrogen include, but are not limited to, those of sodium, potassium, calcium, magnesium, ammonium, N,N'dibenzylethylenediamine, N-methylglucamine (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.

WO 96/12720 PCT/IB95/00847 -14- 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 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 1-Cyclohexyl-3-ethyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahvdro-1Hpyrazolo[3,4-c]pyridine A solution of 3-methoxy-1 -(3-methoxyphenyl)-2-oxo-4-propionyl-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 900C 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, 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. 'H NMR (250 MHz, CDCI 3 1.20-1.52 (m, 6H, including t at 1.23, J 7.6 Hz, 3H), 1.64-1.74 1H), 1.80-2.06 6H), 2.67 (q, J 7.6 Hz, 2H), 2.87 J 6.7 Hz, 2H), 3.82 3H), 3.97 J 6.7 Hz, 2H), 5.13 (tt, J 4.3 and 11.3 Hz, 1H), 6.79-6.93 3H), 7.31 J 8.1 Hz, 1H); HRMS calculated for C 2 1

H

2 7 353.2103. Found: 353.2094.

Examples 2-16 Reaction of the appropriate hydrazine hydrochloride with the requisite 4alkanoyl-3-methoxy-2-oxo-1,2,5,6-tetrahydropyridine, analogous to the procedure of Example 1, affords the following compounds of formula IX.

WO 96/12720 WO 9612720PCT/JB95/00847 Mass Spectra or Mass Spectra or Analysis (calcd.) Analysis (found) Ex.# R 1 R R 3 M.p.

0 C %N %N 2 ethyl 2-methoxy- cyclobutyl 123-4 70.13, 7.12, 12.91 69.93, 7.09, 12.81 phenyl 3 ethyl 2-methyl- 3-methyl oil 337.46 MS (mlz) 338 phenyl cyclo- 4 ethyl 2-ethyl- cyclobutyl oil 323.44 MS 324 phenyl ethyl 2-ethyl- cyclo- 106-7 337.46 MS 337 ____phenyl pentyl 6 ethyl 1-naphth- cyclo- 188-90 359.47 MS 360 alene pentyl 7 ethyl 1 -naphth- cyclohexyl 199-201 373.5 MS 372 alene 8 ethyl 2-chloro- cyclo- 100-3 66.37, 6.45, 12.22 66.65, 6.61, 11.92 ____phenyl pentyl 9 ethyl 2-chloro- cyclohexyl oil 357.88 MS 358 ____phenyl ethyl 2-methyl- bicyclo[2. 141-2 75.61, 7.79, 12.02 75.74, 7.84, 11.85 phenyl 2.1]hept- 2-yl 11 ethyl 2-methoxy-5- cyclo- 94-6 71.36, 7.70, 11.89 71.86, 7.71, 11.43 methyl- pentyl phenyl 12 ethyl 5-chloro-2- cyclo- 109-11 67.12, 6.76, 11.74 67.30, 7.02, 11.21 methyl- pentyl phenyl 13 ethyl 5-chloro-2- 4-fluoro- 90-2 [M+j 383.85 MS 384 methyl- phenyl ____phenyl 14 ethyl 5-chloro-2- cyclobutyl 135-7 66.37, 6.45, 12.22 67.17, 6.81, 11.78 methyl- ____phenyl ethyl 5-chloro-2- 4-fluoro- 129-30 63.08, 4.79, 10.51 63.08, 4.86, 10.41 methoxy- phenyl 16 ethyl 2-chloro- 4-tetra- oil 359.85 MS (mlz) 360 phenyl hydro- I pyranyl WO 96/12720 PCT/IB95/00847 -16- Recrystallization solvents: "Ethyl acetate/pentane. bEthyl ether/pentane.

"Isopropyl ether/pentane. dEthyl/acetate/petroleum ether. "Ethyl acetate. 'Ethyl acetate/hexane.

Example 17 3-Ethyl-6-(4-fluorophenyl)-1-(4-methoxyphenyl)-4,5.6,7-tetrahydro-1 Hpyrazolo[3,4-c]pyridine To a stirred solution of 3-Ethyl-6-(4-fluorophenyl)-1-(4-methoxyphenyl)-7-oxo- 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 acetate/hexane as eluent gives 0.12 grams of the title compound as a pale yellow paste. 'H NMR (250 MHz, CDCI 3 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 3H), 4.23 2H), 6.84-6.99 6H), 7.36 (d,J 9.0 Hz, 2H); MS m/z 352.

Examples 18 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 17, affords the following compounds of formula IX.

Mass Spectra Ex.# R 1

R

2

R

3 M.p.OC Mol. Weight (found) 18 ethyl isobutyl cyclopentyl oil 275.44 MS 276 Example 19 1-Cyclopentvl-3-ethyl-6-benzyl-7-oxo-4,5,6,7-tetrahydro-1 H--pyrazolo 3,4c]pyridine A solution of 1 -cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1 Hpyrazolo[3,4,c]pyridine (0.12 grams, 0.51 mmoles) in DMF (5 ml) is treated with sodium hydride in mineral oil (32 mgrams, 0.77 mmoles). After stirring at ambient temperature over 1 hour benzylbromide (0.22 grams, 1.29 mmoles) is added. After 4 hours the mixture is diluted with water (50 ml) and extracted with ethyl acetate. The combined organic layers are washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel eluting with WO 96/12720 WO 9612720PCTJIB95/00847 -17- 1:4 ethyl acetate/hexane gives 0.13 grams of the title compound as a colorless oil. MS m/z 324.

Examl~ies 20-68 Reaction of 1 -cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo [3,4c]pyridine with sodium hydride in DMF followed by addition of the requisite electrophile analogous to the procedure of Example 19, affords the following compounds of formula IX where R' =ethyl and R 3 =cyclopentyl.

Mass Mass Spectra or Spectra/Analysis 0 Analysis (Calcd) (found) %H, Ex. electrophile R 2 Mp 0 C %N %N cyclopropyl cyclopropyl oil 287.41 MS (mlz) 288 methyl methyl bromide 21 cyclopentyl cyclopentyl oil 301.43 MS 302 bromide 22 isobutyl isobutyl oil 289.42 MS 290 bromide 23 methallyl methallyl oil 287.41 MS 288 bromide 24 isoamyl- 3-methyl oil 303.45 MS 304 bromide ethyl 2- 1 -ethoxy- oil 347.46 MS 348 bromo- carbonyl butyrate 26 dimethyl- dimethyl- oil 304.39 MS 305 carbamyl 27 neopentyl neopentyl oil [M+J 303.45 MS 304 bromide ?0 28 ethyl 4- 3-ethoxy- oil 347.46 MS 348 bromo- carbonylbutyrate propyl 29 1-bromo-2- 2-phenyl oil 337.47 MS (mlz) 338 phenyl ethyl ethane 1-bromo-1- 1-phenyl 70-1 74.74, 8.06, 74.66, 8.22, 12.47 phenyl ethyl 12.45 Iethane II

I

WO 96/12720 WO 9612720PCTIIB95/00847 Mass Mass Spectra or Spectra/Analysis Analysis (Calcd) (found) %H, Ex. electrophile R 2 Mp 0 C %N %N 31 N,N- N,N- oil 290.41 MS 291 dimethyl dimethyl methylene amino ammonium methyl chloride 32 isopropyl isopropyl oil [M+I 275.40 MS 276 bromide 33 acetyl- acetyl oil 275.35 MS 276 chloride 34 2-bromo- 1,3- 52-3 319.41 MS 320 methyl-i dioxolan-2dioxolane yl-methyl 3-picolyl 3-picolyl oil 324.43 MS 325 chloride 36 2-picolyl 2-picolyl oil 324.43 MS (mlz) 325 chloride 37 4-picolyl 4-picolyl oil 324.43 MS 325 chloride 38 benzene- benzene- oil IM+] 373.48 MS (mlz) 374 sulfonyl sulfonyl chloride 39 isopropyl isopropyl 117-9 56.61, 7.42, 56.78, 7.43, 12.33 sulfonyl sulfonyl 12.38 chloride 2-chloro-5- 2-chioro- oil IM+J 363.91 MS 364 (chloro- thiophenmethyl) Sylmethyl thiophene 41 3-chloro- 3-methoxy oil 353.47 MS (mlz) 354 methyl benzyl anisole 42 4-chloro 3,5- 98-9 66.64, 7.65, 66.46, 7.79, 16.33 dimethyl- 16.36 dimethyl- isoxazol-4isoxazole ylmethyl 43 3-chloro- 3-chloro- oil 357.89 MS 358 benzyl benzyl bromide WO 96112720 WO 9612720PCTJLB95/00847 -19- Mass Mass Spectra or Spectra/Analysis Analysis (Calcd) (found) %H, Ex. electrophile R 2 Mp 0 C %N %N 44 2-chloro- 2-chloro- 68-9 67.12, 6.76, 67.13, 7.03, 11.90 benzyl benzyl 11.74 bromide thiophene-2- thiophene-2- oil 379.50 MS 380 sulfonyl sulfonyl chloride 46 4-chloro- 4-chloro- oil 407.92 MS 408 benzene benzene sulfonyl sulfonyl chloride 47 methane- methane 55-60 311.40 MS (mlz) 312 sulfonyl sulfonyl chloride 48 4-methoxy 4-methoxy 118- 403.50 MS 404 benzene benzene 126 sulfonyl sulfonyl chloride 49 3-chloro- 3-chloro- 89-94 407.92 MS 408 benzene benzene sulfonyl sulfonyl chloride 2-chloro- thiophen-2- oil 329.47 MS 330 methyl ylmethyl thiophene_________ 51 2,5-dichloro- 2,5-dichioro, oil 442.37 MS (mlz) 442 benzene benzene sulfonyl sulfonyl chloride 52 thiophene-2- thiophene-2- 77-8 62.95, 6.16, 62.87, 6.25, 12.35 carbonyl carbonyl 12.23 chloride 1 53 isobutyryl isobutyryl oil 303.40 MS 303 chloride 54 tetrahydro- tetrahydro oil 317.43 MS 318 furfuryl furfuryl chloride benzoyl benzoyl 72-4 337.42 MS (mlz) 338 chloride IIIII WO 96/12720 WO 9612720PCTJLB95/00847 Mass Mass Spectra or Spectra/Analysis Analysis (Calcd) (found) %H, Ex. electrophile R 2 Mp 0 C %N %N 56 isonico- isonico- oil IM+] 338.41 MS 339 tinoyl tinoyl chloride 57 nicotinoyl nicotinoyl 103-5 338.41 MS 339 chloride 58 2-bromo- 2-methoxy oil 291.39 MS 292 ethylmethyl ethyl ether 59 3-(bromo- 3-cyano oil 72.39, 6.94, 72.19, 6.98, 15.75 methyl) benzyl 16.08 benzonitrile methyl methoxy oil 61.84, 7.26, 61.34, 7.47, 14.23 chloro carbonyl 14.42 formate 61 2-(bromo- 2-cyano oil 72.3, 6.9, 16.1 72.5, 7.2, 15.3 methyl) benzyl benzonitrile 62 4-(bromo- 4-cyano oil 72.3, 6.9, 16.1 70.6, 6.9, 15.5 methyl benzyl benzonitrile 63 3-bromo- 2-cyano- oil 67.09, 7.74, 66.82, 7.55, 18.92 propio- ethyl 19.56 nitrile 64 3-bromo-2- 2-butan-3- 59-61 67.3, 8.31, 13.85 67.1, 8.21, 13.50 butanone onyl morpholine- morpholine- 153-4 346.43 MS 347 4-carbonyl 4-carbonyl chloride 66 ethylchloro ethoxy oil 306.38 MS 306 formate 67 2-(2-bromo- 2-(1,3-dio®ro- oil 333.43 MS (mlz) 334 ethyl)-1 lan-2-yl) dioxolane ethyl 68 2-(chloro tetrahydro- oil 331.46 MS 332 methyl) pyran-2-yl tetrahydro- methyl pyran I WO 96/12720 WO 9612720PCTIB95/00847 -21- Example 69 6-(2-Chlorothiophen-5-yI) methyl-3-ethyl-1 -(4-fluorophenvl)-7-oxo-4-4,5,6 .7tetrahvdro-I H-ovrazolo [3,4-Cl pyridine Reaction of 3-ethyl-i luorophenyl)-7-oxo-4, 5,6,7-tetrahydro-1 H-pyrazolo [3,4c~pyridine with 2-chloro-5-(chloromethyl)thiophene, analogous to the procedure of Example 19, affords the title compound. MVS 390.

Examp~le 3-Ethyl-i -(4-fluorophenvl)-7-oxo-6-(thiophen-2-yl)-4,5,6,7-tetrahvdro-1 Hpyrazolo [3.4-cl pvridine Reaction of 3-ethyl-i -(4-fluorophenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo [3,4cipyridine with 2-chioromethyl thiophene, analogous to the procedure of Example 19, affords the title compound. mp 106-70C; MVS 356.

Example 71 1 -Cvclopentvl-3-ethyl-6-(2-hvdroxy-5-methylphenvi)-7-oxo-4,5,6,7-tetrahvdro-1 H- Pvrazolo [3,4-cl Pyridine A solution of 1 -cyclopentyl-3-ethyl-6-(2-methoxy-5-methylphenyl)-7-oxo-4,5,6,7tetrahydro-1 H-pyrazolo[3,4-c]pyridine (0.32 grams, 0.91 mmoles) in a 30% solution of HBr in acetic acid (10 ml) is stirred at 95 0 C. After 24 hours the mixture is concentrated under reduced pressure; dissolved in ethylacetate; washed with saturated sodium bicarbonate and brine; dried over magnesium sulfate and concentrated under reduced pressure. Recrystallization from isopropylether gives 0.15 grams of the title compound.

MVP 181-2; MVS 340; Analysis calcd. for C 20

H-

25

N

3 0 2 C(70.77), H(7.42), N(12.38).

Found C(71 H(7.49) N(1 2.60).

Example 72-78 Reaction of the requisite methoxyphenyl substituted 4,5,6,7-tetrahydro-1 Hpyrazolo[3,4-c]pyridine with 30% HBr in glacial acetic acid, analogous to the procedure of Example 71, affords the following compounds of formula IX Mass Spectra/ Mass Spectra/ 2 Analysis (Calcd.) Analysis (formed) Ex.# R 1

R

2

R

3 Mp 0 C %N %N 72 ethyl 2-hydroxy- cyclo- 164-5 [M+]325.41 MS (m/z)326 phenyl pentyl 73 1ethyl I3-hydroxy- cyclo- 178-9 [M+]339.44 MS 340 ____phenyl hexyl WO 96/12720 WO 9612720PCTIIB95/00847 Mass Spectral Mass Spectra/ Analysis (Calcd.) Analysis (formed) Ex.# R' R 2 R 3

MP

0 C %N %N 74 ethyl 4-hydroxy- cyclo- 228-9 70.13, 7.12, 12.91 69.02, 7.05, 12.79 ______phenyl pentyl ethyl 5-chioro- cyclo- 124-5 63.41, 6.16, 11.68 63.60, 6.24, 11.56 2-hydroxy- pentyl phenyl 76 ethyl 5-chloro- 4- 173-4 62.26, 4.44, 10.69 62.41, 4.61, 10.86 2-hydroxy- fluorophenyl phenyl____ 77 ethyl 3-hydroxy- cyclo- 161-2 70.13, 7.12, 12.91 70.18, 7.25, 12.86 phenyl pentyl 78 ethyl 3-hydroxy- cyclo- 134-9 [M+]339.44 MS 340 benzyl pentyl I_ Example 79 6-Aceto nyl- 1 -cycl opentvl-3-ethvl-7-oxo-4, 5.6,7-tetrahvdro-1 H-Dyrazolo f3.4cipyridine A solution of 1 -cyclopentyl-3-ethyl-6-methallyl-7-oxo-4, 5,6,7-tetrahydro-1 Hpyrazolo[3,4-c]pyridine (0.12 grams, 0.41 rnmoles) indioxane (25 ml) and water (60 ml) is treated with potassium carbonate (0.035 grams) followed by 33m) of a solution of NalO 4 (2.1lg) and KmnO 4 (0.026 grams) in water (100 ml). After 1 hour the mixture is extracted with ether. The combined ether layers are washed with brine; dried over sodium sulfate and concentrated under reduced pressure. Chromatography on a silica gel column using 1:3 ethylacetate/hexane as eluent gives 0.042 grams of the title compound as a colorless oil. MVS 290.

Example 1 -cvclopentvl-3-ethl-6-(2-hvdroxvpropl)-7-oxo-4,5,6,7-tetrahvdro-1 H- Pvrazolo [3.4-cl Pyridine A solution of 6-acetonyl-1 -cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1 Hpyrazolo[3,4-c]pyridine (30 m grams, 0.10 mmoles) in anhydrous methanol (2ml) at 0OC is treated with sodium borohydride (38 ingrains). After 15 minutes aqueous saturated ammioniumn chloride is added and the mixture is extracted with ether. The combined ether layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on a silica gel column using 1:2 ethyl WO 96/12720 PCT/IB95/00847 -23acetate/hexane as eluent gives 20 mgrams of the title compound as a colorless oil. MS 292.

Example 81 6-(Aceton-1 -yloxime)-l -cyclopentvl-3-ethvl-7-oxo-4,5,6,7-tetrahydro-1 HyDvrazolo[3,4-clpyridine A solution of 6-Acetonyl-1 -cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1

H-

pyrazolo[3,4-c]pyridine (0.15 grams0 in anhydrous pyridine (5ml) is treated with hydroxylamine hydrochloride (0.040 grams) at ambient temperature. After 20 hours the mixture is concentrated under reduced pressure and then suspended in ethyl acetate.

The suspension is washed with water and brine, dried over MgSO 4 and concentrated under reduced pressure. Recrystallization from isopropyl ether gives 0.10 grams of the title compound as a white solid. MP 147-90C; MS 305; Analysis calcd. for C,,H244N,2; C(63.13), H(7.94, N(18.41). Found C(62.80), H N (18.55).

Example 82 6-(O-Aminocarbonyloximeacetonvyl)-1 -cVyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro- 1 H-pyrazolof3,4-clpvridine A solution of 6-(oximeacetonyl)-1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1

H-

pyrazolo[3,4-c]pyridine (0.10 grams) in THF (5ml) at OOC is treated with chlorosulfonly isocyanate (70 mgrams). After stirring for 1 hours at 25 0 C the mixture is concentrated under reduced pressure, dissolved in ethyl acetate; washed with water and brine; dried over MgSO 4 and concentrated under reduced pressure. Chromatography on a silica gel column eluting with 1:3 ethylacetate/hexane gives the title compound as a pale yellow oil. MS 348.

Examples 83-86 Reaction of 1-cyclopentyl-3-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine with sodium hydride in DMF followed by the addition of the requisite electrophile, analogous to the procedure of Example 19, affords the following compounds of formula X where R'=ethyl and R 3 =cyclopentyl.

Mass Spectra Mass Spectra or Analysis or Analysis (calcd.) (found) Ex. Electrophile R2MPC %N %N 83 isopropyl- isopropyl- 108-113 59.05, 8.37, 58.79, 8.38, sulfonyl- sulfonyl 112.91 12.51 Schloride WO 96/12720 PCT/IB95/00847 84 thiophene-2- thiophene-2- oil 65.62, 7.04, 62.60, 6.74, carbonyl- carbonyl 12.75 11.84 chloride dimethyl- dimethyl- oil 290.41 MS 291 carbamyl carbamyl 86 2-chloro-5- 2-chloro- oil 349.93 MS 350 (chloro- thiophenmethyl) 5-yl methyl thiophene Preparation 1 4-lsobutyrvl-3-methoxv-1-phenyl-2-oxo-1,2,5,6-tetrahydropvridine 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 -780C 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, 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.

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. °C M.W. Mass Spectra 2 4-methoxyphenyl oil 303.36 304 3 3-methoxyphenyl oil 303.36 304 WO 96/12720 PCT/IB95/00847 Preparation 4 3-Methoxy-1-(4-methylphenyl)-2-oxo-4-propionvl-1,2,5,6-tetrahydropyridine A solution of 3-hydroxy-1-(4-methylphenyl)-2-oxo-4-propionyl-1,2,5,6tetrahydropyridine (5.9 grams, 23 mmole) and 3-methyl- -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 3 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 273.

Preparations 5-14 Reaction of the appropriate 3-hydroxy-l-aryl-2-oxo-4-alkanoyl-1,2,5,6tetrahydropyridine with 3-methyl-l -p-tolyltriazine, analogous Preparation 4, affords the following compounds of formula VI.

to the procedure of Prep# R' R 2 m.p. OC M.W. Mass Spectra 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 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 WO 96/12720 PCT/IB95/00847 -26- Preparation 3-Hydroxv-1-(3-methylphenyl)-2-oxo-4-propionyl-1 ,2,56-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 0°C 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 washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an amber oil. GCMS 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 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; 1 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.

WO 96/12720 PCT/IB95/00847 -27- 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 29 ethyl 3-cyclopentoxy-4- 133-134 359.42 360 methoxyphenyl Preparation N-(2-Methoxvphenvl)-2-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 1500C. After 18 hours, the reaction mixture was filtered through a 6x15 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, 80-1000C) leaving 9.2 grams of the title compound as a honey-like oil. 'H NMR (300 MHz, CDCI 3 2.20 (pentet, 2H), 2.55 2H), 3.75 2H), 3.82 3H), 6.93- 7.02 2H), 7.25-7.30 2H); MS m/z 191.

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

Mass Spectra Prep# R M.W. WO 96/12720 WO 9612720PCTJLB95/00847 -28- 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

Claims

1. A compound of the formula R2-- N N and pharmaceutically acceptable salts thereof; wherein RI is hydrogen, (Cl-C 3 )alkyl, (C 2 -C 3 )alkenyl, (C 3 -C 5 )cycloalkyl or methylene (C 3 -C 5 )cycloalkyl wherein each alkyl or alkenyl group may be optionally substituted with up to two (CI-C 2 )alkyl or trifluoromethyl groups or up to three halogens; X is oxygen or two hydrogen atoms; R 2 and R 3 are each independently selected from the group consisting of hydrogen; (CI- .C 14 )alkyl optionally substituted with halogen or cyano; (CI- 1 )ly ufnl O (Cl-C 14 )alkoxy; naphthalyl; (C 2 -C 7 )alkenyl; (C 3 -C 7 )cycloalkyl; (Cl-C 4 )alkyl- (C 3 -C 7 )cycloalkyl; (C 3 -C 7 )cycloalkyl(Cl-C4)alkyl; (C 4 -C 7 )heterocyclic group containing oxygen, sulphur, SO 2 or NR 5 wherein R 5 is hydrogen or (CI-C 4 )alkyl or when R 2 is an aromatic heterocycle then R 5 is absent; (C4-C 7 )heterocycloalkyI-(W)d wherein the (C 4 C 7 )heterocycloalkyl group contains one or more oxygen, sulphur, SO 2 or NR 15 groups 0 wherein R 15 is hydrogen or (C 1 -C 4 )alkyl optionally substituted with halogen or (CI-C 4 )alkyl, d is 0 or 1 and W is (CI-C 4 )alkyl, CO or sulfonyl; CONRlOR 11 wherein RIO and R 11 are each independently hydrogen or (C'-C 4 )alkyl; (CI-C 5 )alkyl carbonyl; (C 1 -C 5 )alkoxy carbonyl; (CL- :C 5 )alkyl carbonyl (Cl-C 5 )alkyl; (CI-C 5 )alkoxy carbonyl (Cl-C 5 )alkyl; (Cl-C 5 )alkoxy(Cl- C 5 )alkyl; R 12 Rl 3 N(C 1 -C 5 )alkyl wherein R 12 and R 13 are each independently hydrogen or (CL- C 5 )alkyl; or a group of the formula (R 4 )a wherein a is an integer from 0 to 5; b and c is 0 or 1; R 4 is independently selected from hydrogen, hydroxy, (C 1 -C 5 )alkyl, (C 2 -C 5 )alkenyl, (C 1 -C 5 )alkoxy, (C 3 -C 6 )cycloalkoxy, halogen, trifluoromethyl, C0 2 R 6 CONR 6 R 7 NR 6 R 7 CONHOH, CN, NO 2 or SO 2 NR 6 R 7 wherein R 6 and R 7 are each independently hydrogen or (CI-C 4 )alkyl, wherein Y is (CI-C 5 )alkyl or (C 2 -C 6 )alkenyl optionally substituted with up to two (Cl-C 7 )alkyl or (C 3 -C 7 )cycloalkyl groups; and Z is oxygen, sulphur, CO, SO 2 or NR 8 wherein R 8 is hydrogen or (Cl-C 4 )alkyl; or a group of the formula IN:\LIBH]3731 29E:KWW R 9 P W' wherein p is an integer from 1 to 3, W' is hydroxy or oxo, 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 (C1-C 2 )alkyl, trifluoromethyl or halogen; or the group of the formula H2)n (CH 2 )m (CH 2 wherein m, n and p are 1 or 2; or a group of the formula aN :wherein Q is hydroxy or a group of the formula p *p >1 p.* 0 0 H 2 N with the proviso that R 2 and R 3 cannot both be independently selected from the group consisting of hydrogen, (C 1 -C 14 )alkyl, (C 1 -C 1 4 )alkoxy, (C 2 -C 7 )alkenyl, (C 3 -C 14 )cycloalkyl, cycloalkylalkyl, pyridyl, alkylpyridyl, (C 4 -C 7 )heterocyclic group containing oxygen, sulphur, SO 2 or NR 5 wherein R 5 is hydrogen or (C 1 -C 4 )alkyl; or a group of the formula (R4)a c 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 )alkenyl, (C 1 -C 5 )alkoxy, (C 3 -C 6 )cycloalkoxy, halogen, dialkylamino, trifluoromethyl, CO 2 R 6 CONR 6 R 7 NR 6 R 7 NO 2 or SO 2 NR 6 R 7 wherein R 6 and R 7 are each independently I jRA4 drogen or (Cl-C 4 )alkyl; wherein Z is oxygen, sulphur, SO 2 or NR 8 wherein RS is hydrogen [N:\LIBH]373129E:KBM 31 or (C'-C 4 )alkyl; and Y is (Cl-C 5 )alkyl or (C 2 -C 6 )alkenyl optionally substituted with up to two (C 1 -C 7 )alkyl or (C 3 -C 7 )cycloalkyl groups; or a group of the formula R 9 W1 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 (Cl-C 2 )alkyl, trifluoromethyl or halogen.

2. A compound according to claim 1 wherein RI is (C 1 -C 3 )alkyl and R 3 is (C 3 -C 7 )Cycloalkyl, (C 4 -C 7 )heterocyclic group containing S0 2 or a group of the formula (R 4 /a wherein a is an integer from 1 to 5 and R 4 is independently selected from hydrogen, hydroxy, I-C 5 )alkyl, (C 1 -C 5 )alkoxy or halogen.

3. A compound according to claim 1 wherein R 1 is ethyl or isopropyl; R 2 is naphthalenyl, dimethylcarbamyl, 1-picolyl, 2-picolyl, 3-picolyl, 3,5 -dimethyl-isoxazol-4-ylmethyl, thiophen-2-ylmethyl, thiophene-2-carbonyl, tetrahydrofurfuryl, 3-cyanobenzyl, morpholine-4-carbonyl, or isopropylsulfonyl, and R 3 is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolanyl, 4-fluorophenyl or 3,4-dichlorophenyl. A compound selected from the group 1 -cyclobutyl-3-ethyl-6-(2-methoxyphenyl)-7-oxo-4,5,6,

7-tetrahydro- 1H- pyrazoloL3 ,4c]pyridine, 3 -ethyl-i1 -mtyccoetl--2-ehlhnl 7-tetrahydro- 1 H- pyrazolo[3 ,4c]pyridine, 1 -cyclobutyl-3-ethyl-6-(2-ethylphenyl)-7-oxo-4,5,6, 7-tetrahydro-l1H- pyrazolo[13 ,4c]pyridine, 1 -cyclopentyl-3 -ethyl-6-(2-ethylphenyl)-7-oxo-4,5,6, 7-tetrahydro-l1H- pyrazolo[3 ,4c]pyridine, 6-(2-chlorophenyl)-l1-cyclopentyl-3 -ethyl-7-oxo-4 7-tetrahydro-l1H- pyrazolo[3 ,4c]pyridine, 6-(2-chlorophenyl)-l1-cyclohexyl-3-ethyl-7-oxo-4 ,5 7-tetrahydro- 1H- pyrazolo[3 ,4c]pyridine, [N:\LIBH]3731 29E:KWW 32 1 -cyclopentyl-3-ethyl-6-(2-methoxy-5-methylphenyl)-7-oxo-4 7-tetrahydro- 1H- pyrazolo [3 ,4c]pyridine, 6-(5-chloro-2-methylphenyl)- 1 -cyclopentyl-3-ethyl-7-oxo-4 7-tetrahydro- 1 H- pyrazolo [3 ,4clpyridihe, 6-(5-chloro-2-methylphenyl)-3 -ethyl-i -(4-fluorophenyl)-7-oxo-4 7-tetrahydro- 1 H- pyrazolo[3 ,4c]pyridine, -chloro-2-methylphenyl)- 1 -cyclobutyl-3 -ethyl-7-oxo-4 7-tetrahydro- 1 H- pyrazolo[3 ,4c]pyridine, -chloro-2-methoxyphenyl)-3 -ethyl- 1 -(4fluorophenyl)-7-oxo-4 ,5,6 ,7-tetrahydro- 1 H- pyrazolo[3 ,4c]pyridine, 6-(2-chlorophenyl)-3 -ethyl-i1 -(4-tetrahydropyranyl)-7-oxo-4 7-tetrahydro- 1 H- pyrazolo [3 ,4c]pyridine, 1 -cyclopentyl-3-ethyl-6-isobutyl-7-oxo-4 7-tetrahydro- 1 H-pyrazolo [3 ,4c]pyridine, 6-benzyl- 1 -cyclopentyl-3-ethyl-7-oxo-4 ,5,6 ,7-tetrahydro- 1 H-pyrazolo[3 ,4c]pyridine, :4 1 -cyclopentyl-6-cyclopentyl-3-ethyl-7-oxo-4 7-tetrahydro- 1H1-pyrazolo [3 ,4c]pyridine, 1 -cyclopentyl-'3-ethyl-6-isobutyl-7-oxo-4, 5,6,7-erhdo 1 H-pyrazolo [3 ,4c]pyridine, 1 -cyclopentyl-3 -ethyl-6-methallyl-7-oxo-4,5,6, 7-tetrahydro-l1H-pyrazolo [3 ,4c]pyridine, 1 -cyclopentyl-3 -ethyl-6-(3-methylbutyl)-7-oxo-4 7-tetrahydro-l1H- pyrazolo[3,4c]pyridine, 1 -cyclopentyl-3-ethyl-6-( 1 -ethoxycarbonylpropyl)-7-oxo-4 7-tetrahydro- 1 H- pyrazolo[3 ,4c]pyridine, 1~ -cyclopentyl-3 -ethyl-6-neopentyl-7-oxo-4 7-tetrahydro- 1 H-pyrazolo [3 ,4c]pyridine, 1 -cyclopentyl -3 -ethyl-6-benzyl--7-oxo-4 7-tetrahydro- 1 H-pyrazolo [3 ,4c] pyridine, 1-cyclopentyl-3-ethyl-6-(2-phenylethyl)-7-oxo-4 7-tetrahydro- 1H- pyrazolo[3 ,4c]pyridine, 1 -cyclopentyl-3-ethyl-6-( 1-phenylethyl)-7-oxo-4 7-tetrahydro-l1H- pyrazolo[3 ,4c]pyridine, 1 -cyclopentyl-3 -ethyl-6-isopropyl-7-oxo-4 7-tetrahydro- 1H-pyrazolo [3 ,4c]pyridine, 6-benzenesulfonyl-l1-cyclopentyl-3-ethyl-7-oxo-4 7-tetrahydro-l1H- pyrazolo[3 ,4c]pyridine, 1 -cyclopentyl-3 -ethyl-6-(3-methoxybenzyl)-7-oxo-4 7-tetrahydro- 1H- pyrazolo[3 ,4c]pyridine, 6-(3-chlorobenzyl)-l1-cyclopentyl-3 -ethyl-7-oxo-4 7-tetrahydro- 1li- pyrazolo[3 ,4c]pyridine, 6-(2-chlorobenzyl)-l1-cyclopentyl-3-ethyl-7-oxo-4 ,5,6 ,7-tetrahydro-l1H- pyrazolo [3 ,4c]pyridine, 6-(4-chlorobenzenesulfonyl)-l1-cyclopentyl-3-ethyl-7-oxo-4 7-tetrahydro-l1H- pyrazolo[3 ,4c]pyridine, 1 -cyclopentyl- 3 -ethyl- 6 -(4-methoxybenzenesulfonyl>7-oxo-4,5,6, 7-tetrahydro-l1H- ~---.pyrazolo [3 ,4c]pyridine, [N;\LIBH]3731 29E:KWW 33 6-(3-chlorobenzenesufonyl)- 1 -cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro- 1H- pyrazolo[3,4c]pyridine, 1 -cyclopentyl-6-(2,5-dichlorobenzenesulfonyl)-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H- pyrazolo[3,4c]pyridine, 3-ethyl-1 4 -fluorophenyl)-7-oxo-6-(thiophen-2-yl)-7-oxo-4,5,6,7-tetrahydro-1H- pyrazolo[3,4c]pyridine, I -cyclopentyl-3-ethyl-6-(2-hydroxy-5-methylphenyl)-7-oxo-4,5,6,7-tetrahydro- 1 H- pyrazolo[3,4c]pyridine, 1 -cyclopentyl-3-ethyl-6-(2-hydroxyphenyl)-7oxo-4,5,6,7-tetrahydro-1H- pyrazolo[3,4c]pyridine, 1 -cyclohexyl-3-ethyl-6-(3-hydroxyphenyl)-7-oxo-4,5,6,7-tetrahydro- 1 H- pyrazolo[3,4c]pyridine, 1 -cyclopentyl-3-ethyl-6-(4-hydroxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H- pyrazolo[3,4c]pyridine, 6-(5-chloro-2-hydroxyphenyl)- 1 -cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro- 1 H- pyrazolo[3,4c]pyridine, 6 -(5-chloro-2-hydroxyphenyl)-3-ethyl- 1 -(4-fluorophenyl)-7-oxo-4,5,6,7-tetrahydro- 1 H- pyrazolo[3,4c]pyridine, 1 -cyclopentyl-3-ethyl-6-(3-hydroxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H- pyrazolo[3,4c]pyridine, 1-cyclopentyl-3-ethyl-6-(3-hydroxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H- pyrazolo[3,4c]pyridine, 6-acetonyl-1 -cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4c]pyridine, pyrazolo[3,4c]pyridine. A tetrahydropyrazolopyridine derivative, substantially as hereinbefore described with reference to the examples, excluding examples 1, 17 and 6. A pharmaceutical composition for the inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) and 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 any one of claims 1 to 5 and a pharmaceutically acceptable carrier. 7. A method of treating or preventing a condition selected from the group consisting of asthuna, 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 any one of claims 1 to 5 or a pharmaceutical composition of claim 6.

8. A compound according to any one of claims 1 to 5 or a pharmaceutical ,,composition of claim 6 when used for treating or preventing a condition selected from the [N:\LIBH]373129E:KWW 34 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.

9. The use of a compound of any one of claims 1 to 5 for the manufacture of a medicament for 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. Dated 14 December, 1998 Pfizer Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON S C e [N:\LIBH1373129E:KWW