CA2201728A1 - Bicyclic tetrahydro pyrazolopyridines and their use as medicaments - Google Patents

Abstract

Compounds of formula (I) wherein R1, R2, R3 and X are as defined. The compounds of formula (I) and the pharmaceutically acceptable salts thereof are useful in inhibiting phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) and in 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.

Description

~WO 96/12720 ~ 2 ~ 1 7 2 8 PCT/I~95/00847 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 10 necrosis factor (hereinafter TNF) and as such are useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases; and AIDS, septic shock and other diseases involving the production of TNF.
This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans and to pharmaceutical oompositions useful therefor.
Since the recognition that cyclic AMP is an intracellular second messenger ~E.W. 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
l-ave been recognized (J.A. Beavo and D. H. Reifsnyder, TiPS, 1990, 11, 150), and their selective inhibition has led to improved drug therapy (C.D. Nicholson, R. A. Challiss and M. Shahid, TiPS, 1991, 12, 19). More particularly, it has been recognized that inhibition of PDE type IV can lead to inhibition of inflammatory mediator release (M.W. Verghese ~t al., J. Mol. Cell Cardiol., 1989, 12 (Suppl. Il), S 61) and airway smooth muscle relaxation (T. J. Torphy in Directions for New Anti-Asthma Druqs, eds S. R. O'Donnell and C. G. A. Persson, 1988, 37, Birkhauser-Verlag). Thus, compounds that inhibit PC)E
type IV, but which have poor activity against other PDE types, would inhibit the release of inflammatory mediators and relax airway smooth muscle without causing 30 ~ardiovascular effects or antiplatelet effects.
TNF is recognized to be involved in many infectious and auto-immune disease l~\N. Friers, FEBS Letters, 1991, 285, 199). Furthermore, it has been shown that TNF is lthe prime mediator of the inflammatory response seen in sepsis and septic shock (C.E.
Spooner et al., Clinical Immunology and Immunopathology, 1992, 62, S11).

2 2 ~ ~ 7 ~ ~ PCT/IB951~.317 ~

Summary of the Invention The present invention relates to compounds of the formula Rl , ~N~

10 and pharmaceutically acceptable salts thereof;
wherein R1 is hydrogen, (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C5)cycloalkyl or methylene (C3-C5)cycloalkyl wherein each alkyl or alkenyl group may be optionally substituted with up to two (C1-C2)alkyl ortrifluoromethyl groups or up to three halogens;
X is oxygen or two hydrogen atoms;
R2 and R3 are each independently selected from the group consisting of hydrogen; (Cl-Cl4)alkyl optionally substituted with halogen or cyano; (Cl-Cl4)alkyl sulfonyl; (C'-C14)alkoxy; naphthalyl; (C2-C7)alkenyl; (C3-C7)cycloalkyl; (C1-C4)alkyl(C3-C7)cycloalkyl; (C3-C7)cycloalkyl(Cl-C4)alkyl; (C4-C7)heterocyclic group containing oxygen; sulphur; SO2 or NR5 wherein R5 is hydrogen or (C1-C4)alkyl; (C4-20 C7)heterocycloalkyl-(W)d wherein the (C4-C7)heterocycloalkyl group contains one or more oxygen; sulphur; SO2 or NR5 groups wherein R5 is hydrogen or (C1-C4)alkyl optionally substituted with halogen or (Cl-C4)alkyl, d is 0 or 1 and W is (C'-C4)alkyl, CO
or sulfonyl; CONR'R" wherein R' and R" are each independently hydrogen or (C'-C4)alkyl; (Cl-C5)alkyl carbonyl; (C'-C5)alkoxy carbonyl; (Cl-C5)alkyl carbonyl (C1-25 C5)alkyl; (C1-C5)alkoxy carbonyl (C1-C5)alkyl; (C1-C5)alkoxy(C1-C5)alkyl; R12R13N(C1-C5)alkyl wherein R12 and R13 are each independently hydrogen or (C1-C5)alkyl; or a group of the formula ( R 4 ) a ~ ( Y ) b ~ ( Z ) c~ I I

wherein a is an integer from 0 to 5; b and c is O or 1; R4 is independently selected from hydrogen, hydroxy, (C1-C5)alkyl, (C2-C5)alkenyl, (C1-C5)alkoxy, (C3-C6)cycloalkoxy, ~1~ WO 96/12720 2 2 0 1 7 2 8 PCT1IB95/00847 halogen, trifluoromethyl, CO2R~, CONR6R7, NR6R7, CONHOH, CN, NO2 or SO2NR6R7 wherein R5 and R' are each independently hydrogen or (Cl-C4)alkyl; wherein Y is (C1-C4)alkyl, (C2-C5)aikylene or (C2-C6)alkenyl optionally substituted with up to two (Cl-C7)alkyl or (C3-C7)cycloalkyl groups; and Z is oxygen, sulphur, CO, SO2 or NR8 wherein 5 R8 is hydrogen or (Cl-C4)alkyl; or a group of the formula ~ ~p~

wherein p is an integer from 1 to 3, W is hydroxy, R9 is (C'-C3)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-C2)alkyl, trifluoromethyl or halogen; or the group of the formula ( C H2 ) n 1 ~
~-- (CH2)p wherein m, n and p are 1 or 2; or a group of the formula N

wherein Q is hydroxy or a group of the formula -WO 96/12720 2 ~ ~ 1 7 2 ~3 PCT/~B95/00847 ~

~0 ~; H2N

with the proviso that when R' is ethyl and R2 is 4-methylphenyl, R3 cannot be hydrogen, methyl, phenyl, 4-fluorophenyl or 2-pyridyl and with the proviso that when R2 is 4-methylphenyl and R3 is 4-fluorophenyl, Rl cannot be phenyl, methyl or n-propyl and 10 with the proviso that when R1 is ethyl and R2 is phenyl, R3 cannot be 4-chlorophenyl, 4-fluorophenyl or 4-methylphenyl, with the proviso that when R1 is ethyl and R2 is 4-methoxyphenyl, R3 cannot be 4-fluorophenyl and with the proviso that when W is CO
or sulfonyl, d is 1;
with the proviso that R2 and R3 cannot both be independently selected from the 15 group consisting of hydrogen, (C1-C14)alkyl, (C1-C14)alkoxy, (C2-C7)alkenyl, (C4-C')heterocyclic group containing oxygen, sulphur, SO2 or NR5 wherein R5 is hydrogen or (C1-C4)alkyl, or a group of the formula ( R 4 ) a ~ ( Y ) b ~ ( Z ) c~ I I

wherein a is an integer from 1 to 5; b and c is O or 1; R4 is hydrogen, hydroxy, (C1-C5)alkyl, (C2-C5)alkenyl, (C1-C5)alkoxy, (C3-C6)cycloalkoxy, halogen, trifluoromethyl, CO2R6, CoNR6R7, NR6R7, NO2 or SO2NR6R7 wherein R5 and R7 are each independently 2~ hydrogen or (C1-C4)alkyl; wherein Z is oxygen, sulphur, SO2 or NR8 wherein R8 is hydrogen or (C1-C4)alkyl; and Y is (C1-C5)alkylene or (C2-C5)alkenyl optionally substituted with up to two (C1-C')alkyl or (C3-C7)cycloalkyl groups; or a group of the formula 3~ ~
W

, ~WO 96/12720 ~ 2 0 ~ ~ 2 ~ PCT/IB95100847 wherein p is an integer from 1 to 3, W is oxo or hydroxy, R9 is (C1-C3)alkyl; wherein each said alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic group may be optionally ~ubstituted with one to fourteen, preferably one to five, of the group consisting of (C1-C~2)alkyl, trifluoromethyl or halogen.
The above proviso is added to exclude subject matter in prior filed PCT Patent ~pplication No. PCT/IB/94/00156.
In one embodiment, the invention relates to a compound of formula I wherei R1 is (C1-C3)alkyl and R3 is (C3-C7)cycloalkyl, (C4-C7)heterocyclic group containing SO2 or a group of the formula ( R4)a --~ I I I

wherein a is an integer from 1 to 5 and R4 is independently selected from hydrogen, 15 hydroxy, (Cl-C5)alkyl, (C1-C5)alkoxy or halogen.
In another embodiment, the invention relates to a compound of formula I
wherein R1 is ethyl or isopropyl; R2 is phenyl, 2-methylphenyl, 3-methylphenyl, 2-methoxyphenyl ,3-methoxyphenyl ,2-hydroxy-phenyl ,3-hydroxyphenyl ,4-hydroxyphenyl, cyclopropylmethyl, benzyl, isobutyl, isobutenyl, 2-ethylphenyl, naphthalenyl, 2-20 chlorophenyl, 3-methylbutyl, dimethylcarbamyl, 1-methylbenzyl, isopropyl, 1-picolyl, 2-picolyl, 3-picolyl, 2-methyl-5-chlorophenyl, 2-chlorothiophen-5-ylmethyl, 2-hydroxy-5-methylphenyl, 3,5-dimethyl-isox~sl-4-ylmethyl, 3-chlorobenzyl, thiophen-2-ylmethyl, 2-hydroxy-5-chlorophenyl, thiophene-2-carbonyl, tetrahydrofurfuryl, 3-cyanobenzyl,morpholine-4-carbonyl, isopropylsulfonyl, 4-methoxyphenylsulfonyl or 3-25 trifluoromethylphenyl, and R3 is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolanyl, 4-fluorophenyl or 3,4-dichlorophenyl.
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 30 airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory cliseases, ~IDS, septic shock and other ~ise~ses involving the production of TNF comprising a pharmaceutically effective amount of a compound accordir1g to claim 1 and a pharm~ceutic~lly acceptable carrier.

wo 96/12720 ~ 2 ~ ~ 7 ~ ~3 PCT/IB9 "'00~17 ~

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 conditionselected 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 comprisingadministering 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 Uhalogen~, 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.
Rl, R2 and R3, 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 96/12720 2 2 0 1 7 2 8 PCT/I:E~95/00847 O O
0 ~NH 1~NR2 2 IV V o Vl ~Rl o VI I

SCHEME Z

R~ ~oR5 z,N~Rl V I I I I X

f X

wo 96/12720 ~ 2 0 1 7 ~ 8 PCT/IB95/00847 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 Uaryl~ is a group of the formula ll by reacting IV with an aryl halide neat in the presence of copper power and potassium carbonate. Suitable aryl halides include 1-iodo- or 1-bromo- 4-5 methoxybenzene, 3-methoxybenzene, 2-methoxybenzene, 3-methylbenzene, 4-methylbenzene, 2-methylbenzene, 3-trifluoromethylbenzene, 2-trifluoromethylbenzene, 3,4-dimethoxybenzene or 3-cyclopentoxy4-methoxybenzene. The reaction temperaturewill generally be in the range of about 1 10C to about 170C, preferably about 150C, for a time period of about 14 hours to about 22 hours, preferably about 18 hours, under 10 inert reaction conditions.
In Reaction 2 of Scheme 1, R1 halide is added to a suspension of magnesium in an anhydrous aprotic solvent. The reaction mixture is heated to reflux until all the magnesium is consumed and thereafter cooled to a temperature between about -15 C
to about 1 5C, preferably about 0C. The N-(aryl)-2-pyrrolidone compound of formula 15 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, preferab!~ 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 20 manner, e.g., 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 1,2,5,6-tetrahydropyridine compound of formula Vl by dispersing the precirit~tP in a mixture 25 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 1.5 hours to about 4.5 hours, preferably about 3.0 hours. The preferred non-polar aprotic solvent is benzene and the preferred base is sodium hydroxide. The solvents are removed and the resulting residue is treated with a solution of sodium alkoxide in 30 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 ~ iified to pH=3 with hydrochloric acid.

~ WO 96/12720 2 2 0 1 7 2 ~3 PCT/II~95/00847 In Reaction 3 of Scheme 1, the compound of formula Vl is converted to the corresponding 3-methoxy-1 ,2,5,6-tetrahydropyridine compouncl Vll by heating to reflux a reaction mixture of Vl and 3-methyl-1-p-tolyltriazene in an aprotic solvent. The prefel,ed aprotic solvel1t is 1,2-dichloroethane. The time period for the reaction is 5 between about 30 minutes to about 120 minutes, preferably about 45 minutes.
In Reaction 1 of Scheme 2, the 1 ,2,5,6-tetrahydropyridine compound of formula '~III, wherein R5 is hydrogen or methyl, is converted to the corresponding 4,5,6,7-1:etrahydro-7-oxo-1 H-pyrazolo[3,4-c]pyridine compound IX by reacting Ylll with a hydrazine of the formula R3HNNH2. Both derivatives of the cornpound of formula Vlll, 10 3-hydroxy and 3-methoxy, may be used as starting materials under orle of three different sets of reaction conditions.
Under one set of reaction conditions, the 1,2,5,6-tetrahydropyridine compound l~f formula Vlll is converted to the corresponding compound of formula IX by reacting '~lll with a hydræine hydrochloride and sodium alkoxide in an anhydrous polar protic 15 solvent. The preferred sodium alkoxide is sodium methoxide and the preferred i3nhydrous 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-tetrahyalro-pyridine 20 compound Vlll is converted to the corresponding compound of formula IX by reacting 'Vlll 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 lFurther reacted to give the corresponding 1-(4-benzamide)-7-oxo-4,5,6,7-tetrahydro-1 H-25 Ipyrazolo[3,4-c]pyridine compound by reacting IX with sodium methoxide in a polar protic solvent, preferc.bly 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,Iperferably benzene, and thereafter, the non-polar solvent is removed under reduced 30 Ipressure. 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 2~ ' 3 WO 96/12720 ' . PCT/IB95/00847 solution is added dropwise to stirred ammonium hydroxide at a temperature between about -10C to about 10C, preferably 0C.
Under a third set of reaction conditions, the 1,2,5,6-tetrahydropyridine compound of formula Vlll is converted to the corresponding compound of formula IX
5 by reacting Vlll with a hydrazine hydrochloride in a polar protic solvent, prefe,tlbly methanol. The reaction mixture is heated to a temperature between about 70C to about 110C, preferably about 90C, under a gentle stream of nitrogen until all of the solvent is removed. The neat mixture is then heated to a temperature between about 120C to about 180C, preferably about 150C, for a time period between about 3010 minutes to about 90 minutes, preferably 60 minutes.
The compounds so formed of formula IX may be converted to the corresponding 6-R2-4,5,6,7-tetrahydro-7-oxo-1 H-pyrazolo [3,4-c]pyridine compound, wherein R2 is other than the group of formula ll, by reacting a solution of IX in a polar aprotic solvent, preferably acetonitrile, with a solution of ammonium cerium (IV) nitrate 15 in water at atemperature between about -15C to about 15C, preferably about 0C, for a time period between about 20 minutes to about 50 minutes, preferably about 35 minutes. Upon completion of the reaction, the mixture is diluted with water and extracted with ethyl acetate. The combined organics are then washed with saturated sodium bicarbonate followed by sodium sulfite. The compound so formed in a polar20 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 20C to about 30C, preferably about 25C, and an alkyl halide of formula R2 halide, wherein R2 is as defined with reference to formula I other than a group of formula ll, is 25 added. The reaction mixture is stirred and heated to reflux for a time period between about 12 hours to about 20 hours, preferably 16 hours.
In Reaction 2 of Scheme 2, the 2-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo~3,4-c]pyridine compound IX is converted to the corresponding compound of formula X by reacting IX with a reducing agent, preferably lithium aluminum hydride, in a non-polar 30 aprotic solvent, preferably ether. The reaction is stirred for a time period between about 12 hours to about 20 hours, preferably 16 hours. Water and base, preferably sodium hydroxide, is then added and the reaction mixture is stirred for a time period between ~ WO 96/12720 2 2 0 1 7 2 ~ PCT/IB95/00847 about 1.5 hours to about 2.5 hours, preferably 2 hours, and filtered. The filtrate is ooncentrated to a white solid.
The ability of the compounds or the pharmaceutically acceptable salts thereof 1o inhibit phosphodie~erase IV (PDE4) and, consequently, demonstrate their 5 effectiveness for treating inflammatory diseases is shown by the following in vitro assay.
BIOLOGICAL ASSAY
(Human lung PDE,V) Thirty to forty grams of human lung tissue is placed in 50 ml of pH 7.4 Tris/phenylmethylsulfonyl fluoride (PMSF)/sucrose buffer and homogenized using a10 Tekmar Tissumizer~ (Tekmar Co., 7143 Kemper Road, Cincinnati, Ohio 46249) at full speed for 30 seconds. The homogenate is centrifuged at 48,000 x 9 for 70 minutes at C. The supernatant is filtered twice through a 0.22,um filter and applied to a Mono-Q
I~PLC column (Pharmacia LKB Biotechnology,800 Centennial Avenue, PiscaLaway, NewJersey 08854) pre-equilibrated with pH 7.4 Tris/PMSF buffer. A flow rate of 1 ml/minute 15 is used to apply the sample to the column, followed by a 2 ml/minute flow rate for ~,ubsequent washing and elution. Sample is eluted using an increasing, step-wise NaCI
gradient in the pH 7.4 Tris/PMSF buffer. Eight ml fractions are collected. Fractions are assayed for specific PDEIv activity, determined by [3H]cAMP hydrolysis and the ability of a known PDE,v inhibitor (e.g. rolipram) to inhibit that hydrolysis. Appropriate 20 fractions are pooled, diluted with ethylene glycol (2 ml ethylene glycol/5 ml of enzyme prep) and stored at-20C until use.
Compounds are dissolved in DMSO at a concentration of 10 mM and diluted l :25 in water (400,uM compound, 4% DMSO). Further serial dilutions are made in 4%
DMSO to achieve desired concentrations. Final DMSO concentration in assay tube is 25 1%. In ~lurlic~te 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 ~I cornpound or DMSO (1 %, for control and blank) ii) 25 ~I pH 7.~ Tris buffer iii) [3H]cAMP (1 ~M) iv) 25 ~I PDE,v enzyme ffor blank, enzyme is preinc~ Ih~ted in boiling water for 5 minutes) The reaction tubes are shaken and placed in a water bath (37C) for 20 minutes, at which time the reaction is stopped by placing the tubes in a boiling water wo 96/12720 ~ 2 i~ PCT/IB9';/00847 bath for 4 minutes. Washing buffer (0.5 ml, 0.1M 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid (HEPES)/0.1 M NaCI, pH 8.5) is added to each tube on an ice bath.
The contents of each tube are applied to an Affi-Gel 601 column (Biorad Laboratories, P.O. Box 1229, 85A Marcus Drive, Melville, New York 11747) (boronate aflinity gel, 1 5 ml bed volume) previously equilibrated with washing buffer. [3H]cAMP is washed with 2 x 6 ml washing buffer, and [3H]5'AMP is then eluted with 4 ml of 0.25M acetic acid.
After vortexing, 1 ml of the elution is added to 3 ml scintillation fluid in a suitable vial, vortexed and counted for [3H].
% inhibition = 1 - averaqe cpm (test comPound) - averaqe cpm (blank) average cpm (control) - average cpm (blank) IC50 is defined as that concentration of compound which inhibits 50% of specifichydrolysis of [3H]cAMP to [3H]5'AMP.
(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 yitro assay:
Peripheral blood (100 mls) from human volunteers is collected in ~0 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 37C (5% carbon dioxide) and allowed to 25 adhere to the plates for 2 hours, after which time non-adherent cells are removed by gentle washing. Test compounds (101JI) are then added to the cells at 34 concentrations each and incuh~ted for 1 hour. LPS (10~1) is added to appropriatewells. Plates are inc~h~ted overnight (18 hrs) at 37C. At the end of the incubation period TNF was analyzed by a sandwich ELISA (R&D Quantikine Kit). IC50 30 determinations are made for each compound based on linear reylession analysis.
Pharmaceutically-acceptable acid addition salts of the compounds of this invention include, but are not limited to, those formed with HCI, HBr, HNO3, H2SO4, H3PO4, CH3SO3H, p-CH3C6H4SO3H, CH3COzH~ gluconic acid, tartaric acid, maleic acid and succinic acid. Pharmaceutically-acceptable cationic salts of the compounds of this ~ WO 96/12720 2 2 0 1 7 2 ~ PCT/IB95/00847 invention of formula I wherein R4 is C02R6 and R5 is hydrogen include, ~ut are not limited to, those of sodium, potassium, calcium, magnesium, ammonium, N,N'-clibenzylethylenediamine, N-methylglucamine (meglumine), ethanolamine and cliethanolamine.
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 claily 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 a~re typically within the range of 0.1 to 10 mg per single dose as required. Forintranasal or inhaler administration, the dosage is generally forrnulated as a 0.1 to 1%
(w/v) solution. In practice the physician will determine the actual dosage which will be most s~ ~it~hle 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 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg. However, some variation in dosage will necess~rily occur depending on the condition of the subject being treated. The person responsible for administration ~ill, 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 a.d",i,lial,t~lion and standard pharmaceutical practice. For example, they may be ad",i"islered 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 parenlelt-lly; for example, intravenously, intramuscularly or subcutaneously.

wo 96/12720 2 2 0 1 7 ~ ~ PCT/IB~5/00847 ~

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 saltsthereof 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-Cvclohexvl-3-ethvl-6-(3-methoxvphenvl)-7-oxo-4,5,6,7-tetrahvdro-1 H-Pvrazolo r3.4-cl 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 90C under a gentle stream of nitrogen 15 until all of the solvent was removed. The neat mixture was then heated to approximately 150C 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.
Chromatography on silica gel using 1:1 ethyl acetate/hexane as eluent gives 0.4720 grams of the title compound as a yellow oil. lH NMR (250 MHz, CDCI3) 1.20-1.52 (m, 6H, including t at 1.23, J = 7.6 Hz, 3H), 1.64-1.74 (m, 1 H), 1.80-2.06 (m, 6H), 2.67 (q, J = 7.6 Hz, 2H), 2.87 (t, J = 6.7 Hz, 2H), 3.82 (s, 3H), 3.97 (t, J = 6.7 Hz, 2H), 5.13 (tt, J = 4.3 and 11.3 Hz, 1 H), 6.79-6.93 (m, 3H), 7.31 (t, J = 8.1 Hz, 1 H); HRMS calculated for C2,H27N3O2[M+]: 353.2103. Found: 353.2094.
~5 ExamPles 2-16 Reaction of the appropriate hydrazine hydrochloride with the requisite 4-alkanoyl-3-methoxy-2-oxo-1,2,5,6-tetrahydropyridine, analogous to the procedure of Example 1, affords the following compounds of formula IX.

~ WO96112720 2 2 0 1 7 2 8 PCT/IB95/0~47 Mass Spectra or Mass Spectra or Analysis (caicd.) Analysis (found) Ex.# R1 R2 R3 M.p.C %C, %H~ %N %C~ %H, %N
:2 ethyi 2-methoxy- cyclobutyl 123-4 70.13, 7.12, 12.91 69.93, 7.Q9, 12.81 phenyl :3 ethyl 2-methyl- 3-methyl oil [M+] 337.46 MS (m/z) 338 phenyl cyclo-pentyl 4 ethyl 2-ethyl- cyclobutyl oil [M+] 323.44 MS (m/z) 324 phenyl 'j ethyl 2-ethyl- cyclo- 106-7 [M+] 337.46 MS (m/z) 337 phenyl pentyl 6 ethyl 1-naphth- cyclo- 188-90 [M+] 359.47 MS (m/z) 360 alene pentyl 7 ethyl 1-naphth- cyclohexyl 199-201 [M+] 373.5 MS (m/z) 372 alene 8 ethyl 2-chloro- cyclo- 100-3 66.37, 6.45, 12.22 66.65, 6.61, 11.92 phenyl pentyl '3 ethyl 2-chloro- cyclohexyl oil [M+] 357.88 MS (m/z) 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 71.88, 7.71, 11.43 methyl- pentyl phenyl J2 ethyl 5-chloro-2- cyclo- 109-11 67.12, 6.76, 11.74 67.30, 7.02, 11.21 methyl- pentyl phenyl 113 ethyl 5-chloro-2- 4-fluoro- 90-2 [M+] 383.85 MS (m/z) 384 methyl- phenyl phenyl 114 ethyl 5-chloro-2- cyclobutyl 135-7 66.37, 6.45, 12.22 67.17, 6.81, 11.78 methyl-phenyl 115 ethyl 5-chloro-2- 4-fluoro- 129-30 63.08, 4.79, 10.51 63.08, 4.86, 10.41 methoxy- phenyl phenyl 116 ethyl 2-chloro- 4-tetra- oil [M+] 359.85 MS (m/z) 360 phenyl hydro-pyranyl WO 96/12720 ~ ~ U 1 7 2 8 PCT/~95/00847 ~

Recrystallization solvents: ~Ethyl acetate/pentane. bEthyl ether/pentane.
Clsopropyl ether/pentane. dEthyll~cet~t~lpetroleum ether. Ethyl acetate. fEthyl~et~te/hexane .
Example 17 3-Ethvl-6-(4-fluorophenvl)-1-(4-methoxvphenyl)-4,5,6,7-tetrahydro-1 H-Pvrazolo r3,4-cl pyridine To a stirred solution of 3-Ethyl-6-(4-fluorophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-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 ~cet~te/hexane as eluent gives 0.12 grams of the title compound as a pale yellowpaste. lH NMR (250 MHz, CDC13) 1.28 (t,J = 7.6 Hz,3H),2.66 (q,J = 7.6 Hz, 2H), 2.71 (t,J = 5.7 Hz,2H), 3.49 (t,J = 5.7 Hz, 2H), 3.84 (s, 3H),4.23 (s, 2H), 6.84-6.99 (m, 6H), 7.36 (d,J = 9.0 Hz, 2H); MS m/z [M+] 352.
ExamPles 18 Reaction of the appropriate 7-oxo-2,5,6,7-tetrahydro-1 H-pyrazolo~3,4-c]pyridinewith lithium aluminum hydride, analogous to the procedure of Example 17, affords the following compounds of formula IX.
Mass Spectra Ex.# Rl R2 R3 M.p.C Mol. Weight [M+] ffound) 18 ethyl isobutyl cyclopentyl oil 275.44 MS (m/z) 276 Example 19 1-Cvclopentyl-3-ethYI-6-benzyl-7-oxo-4.5.6.7-tetrahydro-1 H--pyrazolor3.4-clpvridine A solution of 1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1 H-30 pyrazolo[3,4,c]pyridine (0.12 grams, 0.51 mmoles) in DMF (5 ml) is treated with 60%
sodium hydride in mineral oil (32 mgrams, 0.77 mmoles). After stirring at ambienttemperature over 1 hour benzylbromide (0.22 grams, 1.29 mmoles) is added. A~ter 4 hours the mixture is diluted with water (50 ml) and extracted with ethyl ~cet~te The combined organic layers are washed with water and brine, dried over sodium sulfate 35 and concer,l,aled under reduced pressure. Chromatography on silica gel eluting with ~ W O 96/12720 2 2 3 1 7 2 8 PCT/LB9S/00847 1 :4 ethyl ~et~te/hexane gives 0.1 3 grams of the title compound as a colorless oil. MS
m/z [M+] 324.
Examples 20-68 Reaction of 1 -cyclopentyl-3-ethyl-7-oxo~,5,6,7-tetrahydro-1 H-pyrazolo[3,4-5 c]pyridine with sodium hydride in DMF followed by addition of the requisite electrophile analogous to the procedure of Example 1 9, affords the following compounds of formula lX where R1 =ethyl and R3=cyclopentyl.
Mass Mass Spectra or Spectra/Analysis 1 0 Analysis (Calcd) (found) %C, %H, -x. # electrophile R2 MpC %C, %H, %N %N
cyclopropyl cyclopropyl oil [M+] 287.41 MS (m/z) 288 methyl methyl bromide 21 cyclopentyl cyclopentyl oil [M+l 301.43 MS (m/z) 302 bromide 22 isobutyl isobutyl oil [M+] 289.42MS (m/z) 290 bromide 15 23 methallyl methallyl oil [M+] 287.41MS (m/z) 288 bru,,.ide 24 isoamyl- 3-methyl oil [M+] 303.4sMS (m/z) 304 bromide butyl ethyl 2- 1-ethoxy- oil [M+] 347.46MS (m/z) 348 bromo- carbonyl butyrate propyl 26 dimethyl- dimethyl- oil [M+] 304.39MS (m/z) 305 carbamyl carbamyl 27 neoper,lyl neopenlyl oil [M+] 303.45MS (m/z) 304 bromide 20 28 ethyl 4- 3-ethoxy- oil [M+l 347.46MS (m/z) 348 bromo- carbonyl-butyrate propyl 29 1-bromo-2- 2-phenyl oil [M+] 337.47MS (m/z) 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 ethane WO 96/12720 2 2 0 1 7 ~ 8 : PCT/IB95/00847 /~

Mass Spectra or Spectra/Analysis Analysis (Calcd) (found) %C, %H, Ex. # electrophile R2 MpC %C, %H, %N %N
31 N,N- N,N- oil [M+] 290.41 MS (m/z) 291 dimethyl dimethyl methylene amino ammonium methyl chloride .32 isopropyl isopropyl oil [M+] 275.40 MS (m/z) 276 bromide 33 acetyl- acetyl oil [M+] 275.35 MS (m/z) 276 chloride 34 2-bromo- 1,3- 52-3 [M+] 319.41 MS (m/z) 320 methyl-1,3- dioxolan-2-dioxolane yl-methyl 6 35 3-picolyl 3-picolyl oil [M+] 324.43 MS (m/z) 325 chloride 36 2-picolyl 2-picolyl oil [M+] 324.43 MS (m/z) 325 chloride 37 4-picolyl 4-picolyl oil [M+] 324.43 MS (m/z) 325 chloride 38 benzene- benzene- oil [M+] 373.48 MS (m/z) 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-chloro- oil [M+] 363.91 MS (m/z) 364 (chloro- thiophen-methyl) 5ylmethyl thiophene 41 3-chloro- 3-methoxy oil [M+] 353.47 MS (m/z) 354 methyl benzyl anisole 42 4-chloro 3,5- 98-9 66.64, 7.65, 66.46, 7.79, 16.33 methyl-3,5- dimethyl- 16.36 dimethyl- isoxazol-4-iso.--- 'e ylmethyl 43 3-chloro- 3-chloro- oil [M+] 357.89 MS (m/z) 358 benzyl benzyl brol...de ~WO ~16/12720 2 2 0 1 ~ 3 PCT/IB95100847 Mass Mass Spectra or Spectra/Analysis Analysis (Calcd) (found) %C, %H, Ex. # electrophile R2 MpC %C, %H, %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 lM+] 379.50 MS (m/z) 380 sulfonyl sulfonyl chloride 46 4-chloro- 4-chloro- oil [M+] 407.92 MS (m/z) 408 benzene benzene sulfonyl sulfonyl chloride 47 methane- methane 55-60 [M+] 311.40 MS (m/z) 312 sulfonyl sulfonyl chloride 548 4-methoxy 4-methoxy 118- [M+] 403.50 MS (mlz) 404 benzene benzene 126 sulfonyl sulfonyl chloride 49 3-chloro- 3-chloro- 89-94 [M+] 407.92 MS (m/z) 408 benzene benzene sulfonyl sulfonyl chloride 2-chloro- thiophen-2- oil [M+] 329.47 MS (m/z) 330 methyl ylmethyl thiophene 51 2,5-dichloro- 2,5-dichloro oil [M+] 442.37 MS (m/z) 442 benzene benzene sulfonyl sulfonyl chloride 52 II ophene-2- thiophene-2- 77-8 62.95, 6.16, 62.87, 6.25, 12.35 carbonyl carbonyl 12.23 chloride 1053 isobutyryl isobutyryl oil [M+] 303.40 MS (m/z) 303 chloride 54 tetrahydro- tetrahydro oil [M+] 317.43 MS (m/z) 318 furfuryl furfuryl chloride benzoyl benzoyl 72-4 [M+] 337.42 MS (m/z) 338 chloride W O 96/12720 ~ 2 ~ ~ 7 ~ ~ PCTAnB95/00847 Mass Mass Spectra or Spectra/Analysis Analysis (Calcd) tfound) %C, %H, Ex. # electrophile RZ MpC %C, %H, %N %N
56 isonico- isonico- oil [M+] 338.41 MS (m/z) 339 tinoyl tinoyl chloride 57 nicotinoyl nicotinoyl 103-5 [M+] 338.41 MS (m/z) 339 chloride 58 2-bromo- 2-methoxy oil [M+] 291.39 MS (m/z) 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 6 60 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 1065 morpholine- morpholine- 153-4 [M+] 346.43 MS (m/z) 347 4-carbonyl 4-carbonyl chloride 66 ethylchloro ethoxy oil [M+] 306.38 MS (m/z) 306 formate carbonyl 67 2-(2-bromo- 2-(1,3-dioxo- oil [M+l 333.43 MS (m/z) 334 ethyl)-1,3- lan-2-yl) dioxolane ethyl 68 2-(chloro tetrahydro- oil [M+] 331.46 MS (m/z) 332 methyl) pyran-2-yl tetrahydro- methyl pyran -~Wo ~6/12720 2 2 ~ 1 7 2 8 ~ PCTAnB~5/00847 Example 69 6-(2-ChlorothioPhen-5-vl) methyl-S-ethyl-1-(4-fluoroPhenvl)-7-oxo-4-4,5.6.7-tetrahvdro-1 H-pyr~olo r3 ,4-Cl pyridine Reaction of 3-ethyl-1 -(4-fluorophenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyræolo [3,4-5 c~pyridine with 2-chloro-6-(chloromethyl)thiophene, analogous to the procedure of Example 19, affords the title compound. MS (m/z) 390.
Example 70 3-Ethvl-1-(4-fluorophenvl~-7-oxo-6-(thiophen-2-vl)-4,5,6,7-tetrahydro-1 H-p~razolor3,4-clPvridine Reaction of 3-ethyl-1-(4-fluorophenyl)-7-oxo~,5,6,7-tetrahydro-1 H-pyra7O1O[3,4-c]pyridine with 2-chloromethyl thiophene, analogous to the procedure of Example 19, affords the title compound. mp 106-7C; MS (m/z) 356.
ExamPle 71 1-CycloPentvl-~ethyl~-(2-hydroxv-5-methvlphenyl)-7-oxo~,5,6,7-tetrahydro-1 H-1 5 p~/razolor3,4-clpyridine A solution of 1-cyclopentyl-3-ethyl-6-(2-methoxy-5-methylphenyl)-7-oxo4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine (0.32 grams, 0.91 mmoles) in a 30% solution of H13r in acetic acid (10 ml) is stirred at 95C. 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. Recryst~ tion from isopropylether gives 0.15 grams of the title compound.
MP 181-2; MS (m/z) 340; Analysis calcd. for C20H25N302: C(70.77), H(7.42), N(12.38).
Found C(71.03), H(7.49) N(12.60).
ExamPle 72-78 Reaction of the requisite methoxyphenyl substituted 4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-clpyridine 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/
Analysis (Calcd.)Analysis ~formed) Ex.# R1 R2 R3 MpC%C, %H, %N %C, %H, %N
72 ethyl 2-hydroxy- cyclo- 164-5[M+]325.41 MS (m/z)326 phenyl pentyl 73 ethyl 3-hydroxy- cyclo- 178-9[M+]339.44 MS (m/z) 340 phenyl hexyl =

wo 96/12720 2 2 0 1 7 2 ~ - pcTlIBs~loo847 ~

Mass Spectra/ Mass Spectra/
Analysis (Calcd.) Analysis (formed) Ex.# R1 R2 R3 MpC%C, %H, %N %C, %H, %N
74 ethyl 4-hydroxy- cyclo- 228-970.13, 7.12, 12.91 69.02, 7.05, 12.79 phenyl pentyl ethyl s-chloro- cyclo- 124-563.41, 6.16, 11.68 63.60, 6.24, 11.56 2-hydroxy- pentyl phenyl 76 ethyl 5-chloro- 4- 173-462.26, 4.44, 10.89 62.41, 4.61, 10.86 2-hydroxy- fluoro-phenyl phenyl 77 ethyl 3-hydroxy- cyclo- 161-270.13, 7.12, 12.91 70.18, 7.25, 12.86 phenyl pentyl 78 ethyl 3-hydroxy- cyclo- 134-9[M+]339.44 MS (m/z) 340 benzyl pentyl Example 79 6-Acetonvl-1 -cvclo~entvl-3-ethyl-7-oxo-4.5~6,7-tetrahydro-1 H-Pyrazolor3.4-clPvridine A solution of 1-cyclopentyl-3-ethyl-6-methallyl-7-oxo4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine (0.12 grams, 0.41 mmoles) indioxane (25 ml) and water (60 ml) is treated with potassium carbonate (0.035 grams) followed by 33m) of a solution of NalO4 (2.19) and KmnO4 (0.026 grams) in water (100 ml). After 1 hourthe mixture is extracted with ether. The combined ether layers are washed with brine; dried over 1 5 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. MS (m/z) 290.
ExamPle 80 1-cycloPentvl-3-ethyl-6-(2-hydroxvpropyl)-7-oxo-4l5l6l7-tetrahydro-l H-pyrazolor3,4-clPvridine A solution of 6-acetonyl-1 -cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-t H-pyrazolo[3,4-c]pyridine (30 m grams, 0.1 0 mmoles) in anhydrous methanol (2ml) at 0 C
is treated with sodium borohydride (38 mgrams). After 15 minutes aqueous saturated ammonium chloride is added and the mixture is extracted with ether. The combinedether layers are washed with brine, dried over sodium sulfate and concer,LIated under reduced pressure. Chromatography on a silica gel column using 1 :2 ethyl ~WO !~6/12720 2 ~ O 1 7 2 g PCT/IB~5/00847 ~cetz~te/hexane as eluent gives 20 mgrams of the title compound as a colorless oil. MS
(nn/z) 292.
Example 81 6-(Aceton-1-vloxime)-1-cvclopentvl-3-ethvl-7-oxo-4 5,6,7-tetrahydro-1H-6 pyrazolo r3,4-cl Pvridine A solution of 6-Acetonyl-1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine (o.15 gramsO in anhydrous pyridine (5ml) is treated withhydroxylamine hydrochloride (0.040 grams) at ambient temperature. After 20 hours the mixture is concentrated under reduced pressure and then suspended in ethyl acetate.
10 The suspension is washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. Recrystallization from isopropyl ether gives 0.10 grams of the title compound as a white solid. MP 147-9C; MS (m/z) 305; Analysis calcd. for C,6H24N402; C(63.13), H(7.94, N(18.41). Found C(62.80), H (8.20), N (18.55).
Example 82 6-(0-Aminocarbonyloximeacelonvl)-1 -cvcloPentvl-3-ethyl-7-oxo4.6.6 7-tetrahydro-1 H-Pvræolor3,4-clPyridine A solution of 6-(oximeacetonyl)-1-cyclopentyl-3-ethyl-7-oxo4,~,6,7-tetrahydro-1H-p~rrazolo[3,4-c]pyridine (0.10 grams) in THF (sml) at 0C is treated with chlorosulfonly isocyanate (70 mgrams). After stirring for 1 hours at 25C the mixture is concentrated under reduced pressure, dissolved in ethyl acetate; washed with water and brine; dried ô~er MgSO4 and concentrated under reduced pressure. Chrornatography on a silica gel column eluting with 1:3 ethyl~cet~t~/hexane gives the title compound as a pale yellow oil. MS (m/z) 348.
Examples 83-86 Reaction of 1-cyclopentyl-3-4,5,6,7-tetrahydro-lH-pyræolo[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 R1=ethyl and R3=cyclopentyl.
Mass SpectraMass Spectra or Analysisor Analysis (calcd.) (found) Ex. # Electrophile R2 MPC %C, %H, %N %C, %H, %N
83 isopropyl- isopropyl-108-11359.05, 8.37,58.79, 8.38, sulfonyl- sulfonyl 112.91 12.51 chloride WO 96/12720 PCT/Ill95/OQ847 ~ 22Q~ 72~

84 thiophene-2- ll,iophene-2- oil 65.62, 7.04, 62.60, 6.74, carbonyl- carbonyl 12.75 11.84 chloride dimethyl- dimethyl- oil [M+] 290.41 MS (m/z) 291 carbamyl carbamyl 86 2-chloro-5- 2-chloro- oil [M~] 349.93 MS (m/z) 350 (chloro- thiophen-methyl) 5-yl methyl thiophene Preparation 1 4-lsobutyrvl-3-methoxy-1 -phenvl-2-oxo-1,2,5,6-tetrahvdropyridine A stirred solution of freshly distilled diisopropylamine (0.16 ml, 2.21 mmole) in anhydrous tetrahydrofuran (4 ml) was cooled to 0C and treated with 2.5 M n-butyl lithium (0.85 ml, 2.11 mmole). After 15 minutes the mixture was cooled to -78C and a pre-cooled solution of 4-propionyl-3-methoxy-1 -phenyl-2-oxo-1,2,5,6-tetrahydropyridine (0.52 grams, 2.0 mmole) in tetrahydrofuran (4 ml) was added dropwise via cannula. After approximately 20 minutes methyl iodide (0.20 ml, 3.0mmole) 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 ~cet~ta/hexane as eluent gives 0.12 grams of the title compound as a yellow oil and 0.1 grams of recovered starting material. 1H NMR (250 MHz, CDCI3) 1.15 (d, 6H), 2.72 (t, 2H), 3.47 (heptet, lH), 3.82 (t, 2H), 3.97 (s, 3H), 7.21-7.45 (m, 5H); MS m/z [M+] 274.
Preparations 2-3 Reaction of the appropriate 3-methoxy-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine with lithium diisopropylamine and methyl iodide, analogous to the procedure of preparation 1, affords the following compounds of formula Vll.
25 Prep~ R2 m-p- C M.W. Mass Spectra [M+]
2 4-methoxyphenyl oil 303.36 304 3 3-methoxyphenyl oil 303.36 304 ~wo ~6/12720 2 2 0 1 7 2 ~ PCTIIB95/00847 Preparation 4 3-Methoxy-1 -(4-methvlphenvl)-2-oxo4-~ropionvl-1.2,5,6-tetrahvdro~yridine A solution of 3-hydroxy-1-(4-methylphenyl)-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine (5.9 grams, 23 mmole) and 3-methyl-1-p-tolyltriazine (5.1 grams, 34 5 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, a~nd the combined organics are washed with 1 N hydrochloric acid followed by water and brine, dried over magnesium sulfate, filtered and concentrated under reduced10 pressure. The resulting quantitative brown oil was clean by thin layer chromatography and 1H NMR and was used without purification. lH NMR (300 MHz, CDC13) 1.12 (t,J =
7.2 Hz, 3H), 2.34 (s, 3H), 2.71 (t,J = 6.7 Hz, 2H), 2.93 (q,J = 7.2 Hz, 2H), 3.77 (t,J =
6.8 Hz, 2H), 3.94 (s, 3H), 7.20 (s, 4H); MS [M+] 273.

Preparations 5-14 Reaction of the appropriate 3-hydroxy-1-aryl-2-oxo-4-alkanoyl-1,2,5,6-tetrahydropyridine with 3-methyl-1-p-tolyltriazine, analogous to the procedure of Preparation 4, affords the following compounds of formula Vl.
20 Prep~ R1 R2 m-p- C M.W. Mass Spectra [M~]
ethyl phenyl oil 269.31 260 6 methyl4-methoxyphenyl oil 275.30 275 7 ethyl4-methoxyphenyl 81-82 289.33 289 8 n-propyl4-methoxyphenyl oil 303.36 303 9 ethyl3-methoxyphenyl 59-60 289.33289, 290 ethyl2-methoxyphenyl oil 289.33 289 11 ethyl3,4-dimethoxyphenyl oil 319.26 319 12 ethyl3-cyclopentoxy4- oil 373.45 373 methoxyphenyl 13 ethyl 3-methylphenyl oil 273.33 273 14 ethyl3-trifluoromethylphenyl oil 327.30 327 WO 96/12720 PCT/lDg.,lOO~q7 ~
~2~1 7~&

Preparation 15 3-Hydroxv-1 -(3-methvlPhenvl)-2-oxo4-propionvl-1,2,5,6-tetrahydropvridine 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 5 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)-2-pyrrolidone (8.7 grams, 50 mmole) was added at once. After warming to room temperature and stirring for 2 hours the reaction mixture was poured over ice and extracted with ethyl acetate. The combined organics are washed with water and brine, 10 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 lN
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 15 and the aqueous layer was extracted with ethyl acetate. The combined organics are washed with water and brine, dried over magnesium sulfate, filtered and concer,l,~ted under reduced pressure to give an amber oil. GCMS [M+] 305.
The above intermediate was dissolved in 20 ml anhydrous ethanol and treated with a solution of sodium methoxide in methanol (prepared from the careful addition of 20 sodium (1.0 grams) to 10 ml anhydrous methanol). After being stirred at reflux over 1.5 hours, the mixture was concentrated under reduced pressure and 100 ml of water was added. The mixture was acidified to pH 3 with 6N hydrochloric acid and the dull yellow precipit~te was filtered and washed with water. Recryst~ tion from 75 ml isopropyl ether affords 6.8 grams of pale yellow crystals. M.P. 115-116; lH NMR (300 MHz,25 CDCI3) 1.16 (t,J = 7.2 Hz, 3H), 2.37 (s, 3H), 2.74-2.82 (m, 4H), 3.85 (t,J = 6.8 Hz, 2H), 7.08-7.14 (m, 3H), 7.30 (t,J = 7.7 Hz, lH); MS m/z [M+] 259.
Preparations 16-29 Reaction of the appropriate 2-pyrrolidinone with the recluisite alkylmagnesium bromide, followed by treatment with ethyl oxalyl chloride and base, analogous to that 30 reported in Preparation 15, affords the following compounds of formula Vl.
Mass Spectra Prep~ Rl R2 m-p- C M.W. [M+]

~ wc~ 96~12720 ~ 2 0 1 7 2 ~3 PCT/~B9_/008~7 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 methyl4-methoxyphenyl oil 261.28 262 ethyl4-methoxyphenyl 121-122 275.30 276 21 n-propyl4-methoxyphenyl 126-126 289.33 289 22 ethyl3-methoxyphenyl 129-130 275.30 275 23 ethyl2-methoxyphenyl 119-120 275.30 275 24 ethyl 4-methylphenyl 110-112 259.30 260 ethyl 2-methylphenyl oil 259.30 259 26 ethyl3-trifluoromethylphenyl 117-118 313.28 313 27 ethyl2-trifluoromethylphenyl oil 313.28 313 28 ethyl3,4-dimethoxyphenyl 179-180 305.33 306 29 ethyl3-cyclopentoxy4- 133-134 359.42 360 methoxyphenyl Preparation 30 N-(2-MethoxvPhenvl)-2-pvrrolidone A mixture of 2-pyrrolidone (15.0 grams,176 mmole), 2-iodoanisole (7.6 ml, 59 20 rnmole), copper powder (7.5 grams,117 mmole) and potassium carbonate (8.1 grams, ';9 mmole) are stirred under nitrogen at 150C. After 18 hours, the reaction mixture was filtered through a 6x15 cm pad of silica gel eluting with 1:1 ethyl ~cet~t~/hexane to give a pale yellow oil. The unreacted reagents are removedl by vacuum ~listill~tion (0.6 mm, 80-100C) leaving 9.2 grams of the title compound as a honey-like oil. lH
25 ~IMR (300 MHz, CDCI3) 2.20 (pentet, 2H), 2.55 (t, 2H), 3.75 (t, 2H), 3.82 (s, 3H), 6.93-J~.02 (m, 2H), 7.25-7.30 (m, 2H); MS m/z [M+] 191.
PreParations 31-39 Reactions of the applupri~e iodo- or bromobenzene with 2-pyrrolidinone, ~malogous to that reported in Preparation 30, affords the following compounds of 30 formula V.

Mass Spectra Prep# R M.W. [M+]

wo 96/12720 ~ 2 0 1 7 2 & PcT~Isg5/00847 31 4-methoxyphenyl 191.22 191 323-methoxyphenyl 191.22 191 333-methylphenyl 175.23 175 344-methylphenyl 175.23 175 6 352-methylphenyl 175.23 175 363-trifluoromethylphenyl 229.20 229 372-trifluoromethylphenyl 229.20 229 383,4-dimethoxyphenyl 221.26 221 393-cyclopentoxy4- 275.35 275 methoxyphenyl

Claims (6)

1. A compound of the formula and pharmaceutically acceptable salts thereof;
wherein R1 is hydrogen, (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C5)cycloalkyl or methylene (C3-C5)cycloalkyl wherein each alkyl or alkenyl group may be optionally substituted with up to two (C1-C2)alkyl or trifluoromethyl groups or up to three halogens;
X is oxygen or two hydrogen atoms;
R2 and R3 are each independently selected from the group consisting of hydrogen; (C1-C14)alkyl optionally substituted with halogen or cyano; (C1-C14)alkyl sulfonyl; (C1-C14)alkoxy; naphthalyl; (C2-C7)alkenyl; (C3-C7)cycloalkyl; (C1-C4)alkyl (C3-C7)cycloalkyl; (C3-C7)cycloalkyl(C1-C4)alkyl; (C4-C7)heterocyclic group containing oxygen; sulphur; SO2 or NR5 wherein R5 is hydrogen or (C1-C4)alkyl;
(C4-C7)heterocycloalkyl-(W)d wherein the (C4-C7)heterocycloalkyl group contains one or more oxygen; sulphur; SO2 or NR5 groups wherein R5 is hydrogen or (C1-C4)alkyl optionally substituted with halogen or (C1-C4)alkyl, d is 0 or 1 and W is (Cl-C4)alkyl, CO
or sulfonyl; CONR10R11 wherein R10 and R11 are each independently hydrogen or (C1-C4)alkyl; (C1-C5)alkyl carbonyl; (C1-C5)alkoxy carbonyl; (C1-C5)alkyl carbonyl (C1-C5)alkyl; (C1-C5)alkoxy carbonyl (C1-C5)alkyl; (C1-C5)alkoxy(C1-C5)alkyl; R12R13N
(C1-C5)alkyl wherein R12 and R13 are each independently hydrogen or (C1-C5)alkyl; or a group of the formula II

wherein a is an integer from 0 to 5; b and c is 0 or 1; R4 is independently selected from hydrogen, hydroxy, (C1-C5)alkyl, (C2-C5)alkenyl, (C1-C5)alkoxy, (C3-C5)cycloalkoxy, halogen, trifluoromethyl, CO2R6, CONR6R7, NR6R7, CONHOH, CN, NO2 or SO2NR6R7 wherein R6 and R7 are each independently hydrogen or (C1-C4)alkyl; wherein Y is (C1-C4)alkyl, (C2-C5)alkylene or (C2-C6)alkenyl optionally substituted with up to two (C1-C7)alkyl or (C3-C7)cycloalkyl groups; and Z is oxygen, sulphur, CO, SO2 or NR8 wherein R8 is hydrogen or (C1-C4)alkyl; or a group of the formula wherein p is an integer from 1 to 3, W is hydroxy, R9 is (C1-C3)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-C2)alkyl, trifluoromethyl or halogen; or the group of the formula 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 with the proviso that when R1 is ethyl and R is 4-methylphenyl, R3 cannot be hydrogen, methyl, phenyl, 4-fluorophenyl or 2-pyridyl and with the proviso that when R is4-methylphenyl and R3 is 4-fluorophenyl, R1 cannot be phenyl, methyl or n propyl and with the proviso that when R1 is ethyl and R is phenyl, R3 cannot be 4-chlorophenyl, 4-fluorophenyl or 4-methylphenyl, with the proviso that when R1 is ethyl and R is 4-methoxyphenyl, R3 cannot be 4-fluorophenyl and with the proviso that when W is CO
or sulfonyl, d is 1;
with the proviso that R and R3 cannot both be independently selected from the group consisting of hydrogen, (C1-C14)alkyl, (C1-C14)alkoxy, (C2-C7)alkenyl, (C4-C7)heterocyclic group containing oxygen, sulphur, SO2 or NR5 wherein R5 is hydrogen or (C1-C4)alkyl, or a group of the formula II

wherein a is an integer from 1 to 5; b and c is O or 1; R4 is hydrogen, hydroxy,(C1-C5)alkyl, (C2-C5)alkenyl, (C1-C5)alkoxy, (C3-C5)cycloalkoxy, halogen, trifluoromethyl, CO2R6, CONR6R7, NR6R7, NO2 or SO2NR6R7 wherein R6 and R7 are each independently hydrogen or (C1-C4)alkyl; wherein Z is oxygen, sulphur, SO2 or NR8 wherein R8 ishydrogen or (C1-C4)alkyl; and Y is (C1-C5)alkylene or (C2-C6)alkenyl optionally substituted with up to two (C1-C7)alkyl or (C3-C7)cycloalkyl groups; or a group of the formula wherein p is an integer from 1 to 3, W is oxo or hydroxy, R9 is (C1-C3)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-C2)alkyl, trifluoromethyl or halogen.

2. A compound according to claim 1 wherein R1 is (C1-C3)alkyl and R3 is (C3-C7)cycloalkyl, (C4-C7)heterocyclic group containing SO2 or a group of the formula III

wherein a is an integer from 1 to 5 and R4 is independently selected from hydrogen, hydroxy, (C1-C5)alkyl, (C1-C5)alkoxy or halogen.

3. A compound according to claim 1 wherein R1 is ethyl or isopropyl; R2 is phenyl,2-methylphenyl,3-methylphenyl,2-methoxyphenyl,3-methoxyphenyl,2-hydroxy-phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, cyclopropylmethyl, benzyl, isobutyl, isobutenyl, 2-ethylphenyl, naphthalenyl, 2-chlorophenyl, 3-methylbutyl, dimethylcarbamyl, 1-methylbenzyl, isopropyl, 1-picolyl, 2-picolyl, 3-picolyl, 2-methyl-5-chlorophenyl, 2-chlorothiophen-5-ylmethyl, 2-hydroxy-5-methylphenyl, 3,5-dimethyl-isoxazol-4-ylmethyl, 3-chlorobenzyl, thiophen-2-ylmethyl, 2-hydroxy-5-chlorophenyl, thiophene-2-carbonyl, tetrahydrofurfuryl, 3-cyanobenzyl, morpholine4-carbonyl, isopropylsulfonyl, 4-methoxyphenylsulfonyl or 3-trifluoromethylphenyl, and R3 iscyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolanyl, 4-fluorophenyl or 3,4-dichlorophenyl.

4. 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 effectiveamount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

5. 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 claim 1.

6. 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 claim 1.