AU9240298A - Bicyclic tetrahydro pyrazolopyridines and their use as medicaments - Google Patents

Description

S

S F Ref: 322335D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPEI1FICATION FOR A STANDARD PATENT .4 Ca. *5.

ORIGINAL

Name and Address of Applicant: Actual Inventor(s): Address -for Service: Pfizer Inc.

235 East 42nd Street New York New York 10017 UNI TED STATES OF AMERICA Allen J. Duplantier Spruson &.Ferguson, Patent -Attorneys Level'33,St Martins Tower,A~l Market Street Sydney.- New South Wales, 2000, Australia Invention Title: Bicyclic Tetrahydro, Pyrazolopy-idines and Medicamnents their use as The following statement-is a full description o hsivnin nldn h best method of pefforming it known to me/us:o. thl s inventionj including the -1- Background of the Invention This invention relates to a series of bicyclic tetrahydro pyrazolopyridines whici 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;i arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitisi' 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 jo compositions useful therefor.

Since the recognition that cyclic AMP is an intracellular second messenger, Sutherland, and T. W. Rail, Pharmacol. Rev. 1960, 12, 265), inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized Beavo and D. H. Reifsnyder, TIPS, 1990, 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 2o relaxation J. Torphy in Directions for New Anti-Asthm Druns, 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 j 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 |ji 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 Immunopatholoy, 19962, S11).

2 Summary of the Invention The present invention relates to compounds of the formula

R'

NN

R R2 N and pharmaceutically acceptable salts thereof; wherein RI is hydrogen, (C'-C 6 )aikyl, (C- 3 aknl C-C 5 )cycloalkyi. or methylene-(C 3

-C

5 )cycloalkyl wherein each alkyl or alkenyl group may be optionally substituted with up to two (C'-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; 1o (Cl-C 14 )allcyl optionally substituted with halogen or cyano; (C,-C 14 )alkyl sulfonyl; 14 )alkoxy; naphthialyl; (C 2

-C

7 )alkenyl; (C 3

-C

14 )cycloalkyl; (CI-C 4 )alkyl-

(C

3

-C

7 )cycloalkyi; (C3-C 7 )cycloalkyl(C'-C 4 )alkyl; (C 4

-C

7 )heterocyclic group containing oxygen, sulphur, SO-) or NR 5 wherein R- 5 is hydrogen or (C t

-C

4 )alkyl or when R 2 is an aromatic heterocycle then R 5 is absent; (C 4

-C

7 )heterocycloalkyl-(W)d wherein the (C 4 1 C )heterocycloalkyl group contains one or more oxygen, sulphur, S0 2 or NR 1 groups wherein R1 5 is hydrogen or (C'-C 4 )alkyl optionally substituted with halogen or

C

4 )alkyl, d is 0 or 1 and W is (Cl-C 4 )alkyl, CO or sulfonyl; CONRIORI I wherein RIO and R1 1 are each independently hydrogen or (Cl-C )alkyl; (C 1

-C

5 )alkyl carbonyl;' (Clhydroen hyrony,; (Cl-C 5 )alky bny-Clkcy,( (IC)lC)lkoy (CIC 3 -C)cy caroyC S NRRweenR 6 adRareahindependently hydrogen or (C 1

-C

4 )alkyl, wherein fth frml hyroen Y s( hC)lydror (CI-C5)aikeyl optionalylubstituted wth up to two C 1

-C

7 )aikyl o

(C

3 -C.)cycloalk~yl groups; and Z is oxygen, sulphur, CO, SO 2 or NR 8 wherein R 8 is hydrogen or (Ct-C 4 )alkyl; or a group of the formula

W,

wherein p is an integer from t 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 m~ay be optionally substituted with one to fourteen,, pieferably one to five, of the group consisting of

(C

1

-C

2 )alkyl, trifluoromethyl or halogen; or the group of the formula whrinm n and pare Ior 2; or agroup of the formula S. a Q wherein Q ishdrx or a gopof thefoml with the proviso that is not an unsubstituted or 4-substituted phenyl group; and with, the provis3 that heterocycle excludes pyridinyl and wherein at each occurrence alkyl, I alkenyl and alkoxy are as hereinbefore defined.

In one embodiment, the invention relates to compounds of the formula I wherein Ri is (C lC 3 )alkyl and R3~ is (C 3

-C

7 )cycloalkyl, .(C 4

-C

7 )heterocyclic group containing SO,) or a group of the formula

/(R

1 2 wherein a is an integer from 1 to 5 and R 4 is independently selected from hydrogen, hydroxy, (C l-C 5 )alkyl, (Cl-C 5 )alkoxy or halogen.

Jn another embodiment, the invention relates to compounds of the formula I wherein RI is (C 1

-C

3 )alkyl and R 2 and R 3 are each independently selected from the group sconsisting of (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, (Cl-C 5 )alkyl, (C 1

-C

5 )alkoxy or halogen.

In another embodiment, the invention relates to compounds of the formula I wherein RI Is ethyl or isopropyl; R 2 is 2-mrethylphenyl, 3-methyiphenyl, 2-methoxyphenyl, 3methoxypherlyl, 2-hydroxyphenyl, 3I-hydroxyphenyl, cyclopropylmethyl, benzyl, isobutyl, isobutenyl, 2-ethylpheriyl, naphthalenyl, 2-chiorophenyl, 3-inethylbutyl, dimethylcarbamylt, 1-methylbenzyl, isopropyl, 1-picolyl, 2-picolyl, 3-picolyl,'[2-methyl-5- 1chlorophenyll 2-chlorothiophen--5-ylmethyl, [2-hydroxy-5-methylphenyll, 3 isoxazol-4-ylmethyl, 3-chforobenzyI, thiophen-2-ylmethyl, **,thio phene-2-carbonyl, tetrahydroflirfuiryl, 3-cyanobeolzyl, morpholine-4-carbonyl, or isopropylsulfonyl, 4-methoxyphenylsulfonyl or 3-trifluoromethyiphenyl and R 3 is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolanyl, 4-fluorophenyl or 3 ,4-dichlorophenyl.

Preferred compounds of te invention are: 3-ethyl.-1-(4-methoxyphenyl)-6-phenyl-7-oxo-4,5,6,7-tetrahydro- IH-pyrazolo- 3-ethyl.--cyclopentyl-6-phenyl 7-oxo-4,5,6,7-tetrahydro- tH-pyrazolo- [3,4-pyiie *25 3-ethl-1-(3,4-dichlorophenyl)-6-(3-methoxyphenyl)-7-oxo4,5 ,6 ,7-tetrahydro- 1Hpyrazolo[3.4-cjpycidine; 3-ethyl-1--cyclopentyl-6-(3-methoxyphenyl)-7-oxo-4,5 ,6,7-tetrahydro- 1Hpyrazolo[3,4-clpyridine; 3-ethyl-I-,(4-fluorophenyl)-6-(2-methoxyphenyi)-7-oxo-4,5,6,7-tetrahydro- IIpyrazolo[3,4_-pyridine;, 3-ethyvl-1-cyclopentyl-6-(3-methyiphenyl)-7-oxo-4,5,6,7-tetrahydro-l Hpyrazolo[3,4-c]P-yridine;,.

3-ethyl-1--cyclopentyl-6(3-trifluoromethylphenyl)7-oxo-4,5,6 ,7-tetrahydro-1H1pyrazolo[3,4-c]pyridine: 3-ethyl-1-cyclohexyl-6-(3-methoxyphenyl)-7-oxo-4, 5 ,6,7-tetrahydro-LHpyrazolo[3 ,4-c]pyridine; 3-isopropyl1-l-cyclopentyl-6-('-methoxyphenyl)- 7 -oxo- 4 5 ,6,7-tetrahydro-1Hpyrazolo[3 ,4-clpyridine; 3ethyl- 1-cyclopentyl-6-pheniyl-4,5 ,6,7-tetrahydro-1H-pyrazoIo[ 3 ,4-c]pyridine; 3-ethyl-I-cyclopentyl-6-(2-methylpheny-7-OXOA4, 5 ,6,7-tetrahydro-1Hpyrazoto[3 ,4-e]pyridine; 3-ethytl1-(3-sulfolanyl)-6-(3-methylphelyl)-7-OXO- 4 5 ,6,7-tetrahydro-1Hpyrazolo[3 ,4-c]pyridine; 3-ethyl-1-(3-sulfolanyl)-6-(3-methoxyphelyl)-7-oxo-, 5 ,6,7-tetrahydro-1Hpyrazolo[3 ,4-cilpyridine; 3.-ethyl-l-cyclobutyl-6-(3-metliypheyl)-7-oxo- 4 5 ,6 ,7-tetrahydro-1Hpyrazolo[3 ,4-cjpyridine; 3-ty* 3-uflny)--3tilormtyp yl--x-,,6,7-tetrahydro- 1H-pyrazolo[3,4-clpyridine; 3-ethyl-1-cyclobutyl-6-(3-trifluoromethylphefl)l>'0xo- 4 5 ,6,7-tetrahydro-IH- *pyrazolo[3,4-clpyridine; 3-ethyl-1-cyclobutyl-6-(2-mietiylphel> 7 -oxo-4, 5 ,6,7-tetrahydro-1I{ pyrazolo[3 ,4-c]pyridine.

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) comprising a pharmaceutically effective amount of a compound according to formula I and the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

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 of formula I and a pharmaceutically acceptable carrier.

The present invention further relates to a method for the inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) copiing, administering to a 'atient an effective amount of a compound .according to formula I and the pharmaceutically acceptable salts thereof.

The present invention further rlates to a- method of treating an inflammatory condition in mammirals which comprises admtnistering -to said mammal an antiinfiammatory amount of a compound of the formula I and the pharmaceutically acceptable salts thereof.- IThe invention further relates to a method for treating and preventing a condition selected from the group consisting of asthma, arthritis, bronchitis, chronic obstructive Sairways 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 of formula I and the pharmaceutically acceptable salts thereof.

Detailed Description of the invention The term "halogen", as used herein, unless otherwise indicated, includes chloro, tluoro and bromo.

To 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 s and arthritis.

R

1

R

2 and R 3 as used herein, unless otherwise indicated are as defined above with S reference to formula I.

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

I

0 I v SCHEMlE I 0 N R2 2 rttC 4J R 2 SC'4ENE 2

N

0

NN

R'-

0 Ro viii

RC

~alSi~3a c~ ~~ssr~ ~X 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 -dimethoxybenzeneorS-cyclopentoxy-4-methoxybenzene. The reaction temperature will generally be in the range of about 110 C to about 1700C, preferably about 1500C, for a time period of about 14 hours to about 22 hours, preferably about 18 hours, under inert reaction conditions.

In Reaction 2 of Scheme 1, R' halide is added to a suspension of magnesium in an anhydrous aprotic solvent. The reaction mixture is heated to reflux until all the magnesium is consumed and thereafter cooled to a temperature between about -15 0

C

to about 15 0 C, preferably about 0 0 C. The N-(aryl)-2-pyrrolidone compound of formula V is then added and the reaction mixture is warmed to room temperature while being S 20 stirred for a time period between about 1.5 hours to about 2.5 hours, preferably about 2 hours. Suitable alkyl halides include bromomethane, bromoethane or Sbromopropane. The preferred anhydrous aprotic solvent is anhydrous ether. Upon S 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.

i i ~p~~a i t i

"A

I i I'~e

B

ai i a. a.

54 a a 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 Vill, 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,. Both derivatives of the compound of formula VIII, 10 3-hydroxy and 3-methoxy, may be used as starting materials under one of three different sets of reaction conditions.

Under one set of reaction conditions, the 1,2,5,6-tetrahydropyridine compound of formula VIII is converted to the corresponding compound of formula IX by reacting VIII with a hydrazine hydrochloride and sodium alkoxide in an anhydrous polar protic 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 S 20 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 1 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 Schloride and NN-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 -=iigi 4iii .i l *.A jll~

I"'

Ir, ~el~p~ 1solution is added 1dropwise to stirred ammohifur'yrd at aeperature between about -100 to about 100C, Under aq third set -of reaction ,conditions-- the, 1 .2,5,6-tetrahydropyridine .compoid of formula-VIII is coirte to-the corresponding compound of formula IX 6y reacting V.III withi a hidrazine hydrochlond in a poa protic solvent, preferably methanol. Thb reaction mixture is heated to a temperature between 0 aoti1Cpirayabut 90Q; under a-gentle strLeam of nitrogen until all of the s'olvent is removed. The neat ;h'iixture is then heated to a temperature between about 1200~C to about 180 rteal -u 1 50C.fra time period b~tweenabout minutes to about 90 m rinutes, oreferably 60 minutes.

The compounds so formed 'of ormula IX.-mai be co Inverted to the corresponding 6-R 2 -4,5 b ,7 tetrahydro-7-oxo-1 ki-pyrazolo [3 4-cjpyridine comipound, wherein, R' is -other than'the group of formula 1I, by reacting a solution of.IX in a polar k aprotic solvent, preferably acetonitr-ile, with a scilution of amcnium cerium (IV) nitrate in water at a temperature between about wl150 C to about 150C, prefcrably about 0OC for a tine period between -about 20 miputes 1:6 about 50 minutes, preferably about mintes Upn cmpletion 'otereaction, the- mixture is diluted-~'th water and 4, s extracted with ethyl acetate. The combined organics are then washed with satckrated sodium bicarbonate followed'by sodium'sdlfte. The compound so formedin a polar aprotic solvent, preferably tetrahydrofuran, is treated with sodium hydride, heated to T eflux and stirred -for a time period between about 30 minutes to. about 60 minutes, o* preferably 45 minutes. The reaction mixture is cooled'to a temperature btenabout 200C to about 000C, preferably about 2500, and an alkyl Ih alide-of formula R' halide, wherein R 2 is as defined wth reference to formula I other than a group of formula 11, is added. 7b6 reaction mixture is stirred-and heated to reflu'x for a time period between about J2 hours to about 20:hou7,s, preferably 16 hours.

In -Reaction 2 of Scheme 21' the-.2-oxo-4,56,7.tetrajhydrol1 H-pyrazolo(3,4olpyridine 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 solvent, Preferably ether. The reaction is stirred for a time period between about _12 hours to about 20 hours, preferably 16.hours. Water and base, preferably sodium hydroxide, is then added. and the reaction mixture is stirred for a. time period between

'A

7 sI about 1.5 hours to about 2.5 hours, preferably 2 hours, and filtered. The filtrate is concentrated to a white solid.

The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit phosphodiesterase IV (PDE 4 and, consequently, demonstrate their effectiveness for treating inflammatory diseases is shown by the following in vitro assay.

BIOLOGICAL ASSAY (Human lung PDE,v) Thirty to forty grams of human lung tissue is placed in 50 ml of pH 7.4 Tris/phenylmethylsulfonyl fluoride (PMSF)/sucrose buffer and homogenized using a 10 Tekmar Tissumizer@ (Tekmar Co., 7143 Kemper Road, Cincinnati, Ohio 45249) at full speed for 30 seconds. The homogenate is centrifuged at 48,000 x g for 70 minutes at 40 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 S of a known PDE,, inhibitor rolipram) to inhibit that hydrolysis. Appropriate *o 20 fractions are pooled, diluted with ethylene glycol (2 ml ethylene glycol/5 ml of enzyme prep) and stored at -200C 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) 2 5 pl compound or DMSO for control and blank) ii) 25 pl pH 7.5 Tris buffer iii) ['H]cAMP (1 pM) iv) 25 pl PDE, enzyme (for blank, enzyme is preincubated in boiling water for 5 minutes) The reaction tubes are shaken and placed in a water bath (37 0 C) for :minutes, at which time the reaction is stopped by placing the tubes in a boiing water

I,

bath for 4 minutes. Washing buffer (0.5 ml, 0.1M 4 -(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES)/0.1 M NaCI, pH 8.5) is added to each tube on an ice bath.

The contents of each tube are applied to an Affi-Gel 601 column (Biorad Laboratories, P.O. Box 1229, 85A Marcus Drive, Melville, New York 11747) (boronate affinity gel, 1 ml bed volume) previously equilibrated with washing buffer. ['H]cAMP is washed with 2 x 6 ml washing buffer, and [H]5'AMP is then eluted with 4 ml of 0.25M acetic acid.

After vortexing, I mlof 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) averae cpm (blank) 0 average cpm (control) average cpm (blank) ICso is defined as that concentration of compound which inhibits 50% of specific hydrolysis of ['H]cAMP to *a a ae a. *a a *.at 1

(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 10 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 370 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 (10p1) are then added to the ,cells at 3-4 concentrations each and incubated for 1 hour. LPS (101l) 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 EUSA (R&D Quantikine Kit). ICSO 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,, HSO,

H

3 PO, CH 3

SO

3 H, p-CH 3

C

6

HSO

3 H, CHCOH, gluconic acid, tartaric acid, maleic acid and succinic acid. Pharmaceutialy-acceptable cationic salts of the compounds of this -i r j

;I

i-S; 1! 7; 13 invention 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 activej compounds of the. present invention) are generally in the range of from 0.1-100 mg daily for an average adult patient (70 kg). Thus for a typical adult patient, individual 10 tablets or capsules contain from 0.1 to 50 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration o 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 Sof the particular patient: The above dosages are exemplary of the average case but S- 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 S 20 routes may be used including orally, parenterally and topically. In general, the active S compound will be administered orally or parenterally at dosages between about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration 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, bul 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.

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 s comprising a compound of the formula I and the pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable diluent or carrier.

The following examples illustrate the present invention and related compounds, however, the invention is not to be construed as limited to the Examples.

Example 1 to 3-Ethyl-l-(4-methoxyphenyl)-6-phenyl-7-oxo-4,5,6,7-tetrahydro-IHpyrazolo[3,4-c]pyridine SA mixture of :3-hydroxy-2-oxo-l-phenyl-4-propionyl-1,2,5,6-tetrahydro-pyridine (1.0 g, 4.1 mmole), 4-methoxyphenylhydrazine hydrochloride (0.8 g, 4.6 mmole) and sodium methoxide (0.11 grams, 2 mmole) in 35 ml anhydrous ethanol (distilled from Mg) 15 was heated at reflux. After 12 hours, the solvent was removed by rotory evaporation under reduced pressure, and the crude residue was chromatographed on a 4x20 cm silica column using 1:1 ether/hexane as eluent to give 345 mg of the title compound as a red oil S that crystallized upon standing at room temperature. The desired 1-(4-methoxyphenyl) regioisomer is less polar than the 2-(4-methoxyphenyl) byproduct. M.P. 43-45°C, IR (chloroform) lactam C=O, 1665 cm- 1 tH NMR (300 MHz, CDC13) d 1.32 J 7.6 Hz, 3H), 2.74 J 7.6 Hz, 2H), 2.96 J 6.6 Hz, 2H), 3.79 3H), 4.10 J S 6.6 Hz, 2H), 6.89 J 9.0 Hz, 2H), 7.22-7.39 5H), 7.45 J 9.0 Hz, 2H); S Anal. calcd, for C 2 1

H

21

N

3 02: C, 72.60; H, 6.09; N, 12.09. Found: C, 72.48; H, 6.08; S N, 11.66; MS m!z (M 347.

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

Ex. R 1

R

2

R

3 M.p.°C Mass Spectra or Mass Spectra or Analysis (calcd.) Analysis (found) %C, %N %N 2 ethyl phenyl methyl 80-83 70.56, 6.71, 16.46 70.61, 6.77, 15.51 3 ethyl phenyl tert-butyl 120-121 72.70, 7.79, 14.13 72.50, 7.96, 14.16 1

B

;1 i 3 -4 i 9i 4 ethyl ethyl 4-methoxy I 4-methoxy 142-45 phenyl phenyl 70.01, 6.14, 11.13 170.05, 6.07, 11.00A 1 ethyl 7 ethyl 8 mnethyl 4-fluoro phenyl phenyl 4-fluoro phenyl phenyl tert-butyl 3,4dichiorophenyl 4-methoxy phenyl 4-fl uoro phanyl cyclopenit yl 92-94 315.1747 HRMS 315.1741 IMS Mlz 386 (oil) [*1386.26 12_-1,10 T69.03, 5.52, 11.50 68.75, 5.37, 11.43 139-.40b fiMi 321.3 MS ml~z jM*] 322 4* S S.

S

S S

S

S

S

9 ethyl phenyl 10 methyl phenyl 11 Tethyl pey 737 309.1841 4-methoxy 1167-168 333.1477< phenyl 5-phenyl pentyl 4-fl uoro phenyl HRMS 309.1823 HRMS 333.1477 HRMS (M+l) 388.2395 67.92,-5.03,11.72 (oil) 388.2389 14 0 14 2 b 168.36, 5.16. 11.96 m7 iethyl 13 methyll 14 ethyl ethyl 4-methoxy phenyl 4-methoxy I 3-fluo-o 133-13's 68.36, 5.16, 11.96 168.04, 5.04, 11.75 phenyl 4-methoxy phenyl 3-methoxy phenyl phenyl 3,4dichlorophenyl methyl 0-60 j60-.59.4.60 1009 ~60.34, 4.56, 9.86 MS MfZ[M'1286 (oil) [M'J 285.35

I

Recrystallizing solvents: Oisopropyl ether b 5 Ethyl acetate in petroleum ether.

Example 16 3-Ethyl- 1 -(4-ohenvlcarboxylic acid)- 6 -oh nVl.7oxo..45,6,7tetrahydro1

H-

Dyrazolof3,4-ciPyridine, A mixture of 3-hydroxy-2-oxo-1 -phenyl-4-propony.1 2 ,5.6-tetrahydr-pyidine grams, 4.08 mmole), 4-hydrazinobenzoic acid (0.68 grams, 4.49 mmole) and 30 ml of anhydrous ethanol was heated at reflux. After 20 hours, the-mixture was concentrated by rotary evaporation under reduced pressure, and the solid residue was suspended in a mixture of ethyl acetate (500 ml) and pH 4 buffer (200 ml). The organic layer was s eparated (leaving behind most of the 2-(4-phenylcarboxylic acid) byproduct), washed with brine, dried over sodium sulfatie, filtered and concentrated under reduced pressure.

A.,

ebb 4 Cl *O

SOPS

Recrystallization from methanol gives 0.64 grams of the title compound as an orange solid. M.P. 261-2630C. 'H NMR (300 MHz, DMSO-d 6 I d 1.23 ft,J 7.6 Hz, 3H), 2.68 (q,J 7.6 Hz, 2H), 2.94 (t,J =6.5 Hz, 2H), 4.05 (t,J 6.5 Hz, 2H), 7.20-7.41 (in, 7.65 (d:J 8.6 Hz. 7.96 (d,J 8.6 Hz, 2H), 13.05 1 MS m/z 362.

Example 17 1 -(4-Benzamid e)- 3 -ethvl- 6 -(4-methoxyrphenv)7oxo4.56,7tetrahVdro.1

H-

pyrazolo[3,4-clpyridine To a stirred solution of sodium methoxide in methanol (prepared from 6.6 mg Na) is added 3 -ethyl-6-(4-methoxyphenyl)-l-(4..phenylcarboxylic acid)-7-oxo-4,5,6,7tetrahydro-1 H-pyrazolo[3,4-c~pyridine (96 mg, 0.25 mmole). After30 minutes, methanol was removed under reduced pressure, the solid residue was suspended in benzene, and the benzene was removed under reduced pressure. The resulting dry solid was suspended in cold ether (ice-bath) and treated with oxalyl chloride (31 Pl, 0.35 inmole) and anhydrous N.N-dimethylformamide (1 drop). After stirring for 1 hour the valatiles are remov ed under reduced pressure, and the crude residue was dissolved in dry tetrahydrofuran. The resulting solution was added dropwise to briskly stirred amnmonium hydroxide at 0 0 G. After, warming to ambient temperature over 2 hours the reaction mixture was concentrated under reduced pressure'until a yellow solid begins to precipitate. At this time the mixture was diluted with water to approximately 100 ml 20 and filtered, and the precipitate was washed with water to give 81 mg of the title compound- Decomposition point 243-245OC; 'H NMR (DMSO-I) 1.24 (t,J 7.6 Hz, 3H), 2.68 (q,J =7.6 Hz, 2H), 2.93 (t,J 6.5 Hz, 2H), 3.75 3H), 3.99 (t,J =6.5 Hz, 2H), 6.94 (d,J =9.1 Hz, 2H), 7.27 (d,J =9.0 Hz, 2H), 7.43 1 7.59 (d,J 8.5 Hz, 2H), 7.90 (d.J =8.6 Hz, 2H), 8.04 1 Anal. calcd. for C 22 H,2, 4 0: C, 67.68; H, 5.68; N, 14.35. Found: C, 67.19; H, 5.31; N, 13.55. HRMS calcd. for C 22

H

22 N,0 3 391.1770. Found 391.1781.

The starting 3-ty--4mtoyhnl--4peycroyi acid)-7-oxo- 4,5,6,7-tetrahydro-1 H-pyrazolo pyridine was .prepared using the appropriate reagents according to the procedure of example 16.

'41; SO bOb S. *b S. S SSSOS S Example 18 1 -(3.4-dichlorophenV)-3-ethVI-6-(3-methoxvohenvn7-oxo 5 6 7-erahvd 1 .H- 5*5

*C

5 0 pyrazoio r3,4-clpyridine A stirred mixture of 3 -melhoxy-l-(3.methoxyphenyl)-2..oxo-4-propionyl-1,2,5,6teirahydro-pyridine (0.49 grams, 1.7 mmole), 3.4-dichlorophenylhydrazine hydrochloride (0.40 grams, 1.87 mmole) and sodium methoxide (46 mg, 0.85 mmole) in anhydrous ethanol was heated to reflux. After 16 hours, the mixture was concentrated under reduced pressure and chromatographed on a silica gel column using 1:4 ethyl acetate/hexane as e,:uent to give a white solid. Recrystallization from ether gave 0.46 grams of white needles. M.P. 97-990C, 'H NMR (250 MHz, CDCI,) 1.31 (t,J =7.5 HZ, 3H), 2.73 (q,J 7.6 Hz. 2.96 (t.J 8.6 Hz, 2H), 3.79 3H),,4.09 (t,J 6.6 Hz, 6.78-6.91 (in. 3H), 7-29-7.49 (in, 3H), 7.73 (d,J =1.8 Hz, 1 MS m/z 416.

Examples 19-42 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 18, affords the following compounds.

Ex.# R' R 2 R3 M-p.

0 C Mass Spectra or Mass Spectra or Analysis (caicd.) Analysis (found).

%N %N 19 methyl 4-methoxy 3-4- 143-144' 59.71, 4.26, 10.45 56.13. 4.02, 9.65 phenyl dichlorophenyl 20 ethyl 3-methoxy cyclo- 641-65 [MJ -340.2025 HRMS [M-1 ____phenyl pentyl 1 340.2046 21 ethyl 4-methoxy cycle- 96-98 70.77, 7.42, 12.38 70.44, 7.68, 11.69 phenyl pentyl 22 miethyl 4-methoxy cycle- 121-122 70.13, 7.12, 12.91 69.148, 7.10, 12.70 -phenyl pentyl 23 iso- phenyl 3.4- ,*oil [Mij 400.0983 HRMS [M-1 propyl dichloro 400.096 phenyl 24 ethyl 3.4-dimreth- cycle- 107-108 Ii369.48 Mmz[M36 oxyphenyl pentyl Z[M 319 ethyl j3.4- dimneth- _,?xyphenyf 3.4dichiorophenyl 190-191b 59.20. 4-74, 9.41 59.41, 4.46: 9.71 I- S L I S. 0 0s* Ex.# R' R2R 3 M.p.OC Mass Spectra or Mass Spectra Or Analysis (calod.) Analysis (found) %N %N 26 iso- 4-methoxy 3,4- 145-147r 61.40, 4.92, 9.76 61.29, 4.81, 9.53 propyl phenyl dichioro henyl 27 propyl 4-methoxy cyclo- 102-103- 71.36. 7.70. 11.89 70.98, 7.66.,11.73 phenyl pentyl 28 iso- 3-methoxy 3.4- 126-127d 61.40. 4.92. 9.76 61.55, 5.10, 9.97 propyl phenyl dichlorophenyl 29 ethyl 4-methoxy- 3.4- 54-56 62.40, 5.44, 8.40 62.15, 5.50, 7.97 3-cyclo- dichioropentoxy- phenyl phenyl 30 ethyl 4-methoxy- cyclo- 88-89 [M-1 423. 55 MS mfz *423 3-cyclo- pentyl pentoxyphenylI 31 ethyl 3-methoxy 4-fluoro- 139-140e 69.03, 5.79. 11.50 69.05, 6.42, 11.57 ____phenyl phenyl 32 ethyl 2-methoxy cyclo- 119-120 70.77. 7.42, 12.38 70.63, 7.16, 12.01 phenyl pentyl 33 ethyl 2-methoxy 4-fluoro- 103-104' 365.41 MS mlz [M~J 366 _____phenyl phony] 34 ethyl 3-methyl cyclo- oil 74.27. 7.79, 12.99 74.54, 7.89, 12.63 ____phenyl pentyl 100 15 3-methyl phenyl 4-fluorophenyl 72.19,5.77..12.02 72.06, 36 ethyl 3-trifluoro- cyclo- oil 63.65. 5.87, 11.1 3 63.95, methyl- pentyl phenyl 37 ethyl 3-trifluoro- 4-fluoro- 139-140t 62.53, 4.25, 10.42 62.60, methyl- phenyl phenyl 38 ethyl 4-methyl- cyclo- 93-94 174.2 17, 7.79, 12.99 74.10, ____phenyl pentyl 39. ethyl 2-methyl- 4-fluoro- 141-14k 7219. 5.77, 12-03 72.36,'i ____phenyl phenyl 5.55, 11.62 5.73, 10.97 t.08, 10.41 r-52, 12.59 .62, 12.09 323 2-methylphenyt Cyclopentyl 130-131 MY323.44 MS rrhz 19 Ex.#R' R R 3 M.p.OC Mass Spectra or Mass Spectra or Analysis (calcd.) Analysis (found) %N 41 ethyl 2-trifluoro- 4-fluoro- 48-50 MW 403.38 MS m/z 404 methyl- phenyl ____phenyl 42 ehl 3-methyl- 3 sulfa- oil MW 373.47 M S mz 3:S74 phenyl lanyl Recrystallizing solvents: Ethyl acetate/petroleum ether. Isopropyl ether.

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

Example 43 1 -Cyclohexvl-3-ethyl-6-(3-methoxyphenyl)-7-oxo-4.5,6.7-tetrahVdro-1 Hpyrazolo[3,4-cipyridine solution of 3-methoxy-1 -(3-methoxy heny)-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 9011C under a gentle stream of nitrogen e* until all of the solvent was removed. The neat mixture was then heated to *0 approximately 1500 C 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, 15 dried over sodium sulfate, filtered and concentrated under reduced pressure.

Chromatography on silica gel using 1:1 ethyl acetate/hexane as eluent gives 0.47 grams of the title compound as a yellow oil. 'H NMR (250 MHz, CDCI,) 1.20-1.52 (in, 6H, including t at 1.23, J 7.6 Hz, 3H), 1.64-1.74 (in, 1 1.80-2.06 6H). 2.67 (qJ 0 =7.6 Hz, 2H), 2.87 (t,J 6.7 Hz, 2H), 3.82 3H), 3.97 (t,J 6.7 Hz, 2H), 5.13 (tt, J 4.3 and 11.3 Hz, 1H), 6.79-6.93 (in, 3H), 7.31 (t.J =8.1 Hz, 1H); HRMS calculated far 0 21

H,,N

3 0 2 [M 353.2103. Found: 353.2094.

Examples 44-57 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 43, affords the following compounds.

Ex.# R R 2

R

3 M-p- 0 C Mass Spectra or Mass Spectra or Analysis (calcd.) Analysis (found) 44 iso- 4-methoxy cyclo- 102-1031 [MIJ 354 MS [M-1 3S4 propyl. phenyl pentyl 1.

C CC *4* 4

C.

4 C

S

*4.i.4.

4 4 *4 44 4 4 a 4 Ex.# R' R R M.p.OC Mass Spectra or Mass Spectra or Analysis (cajod.) Analysis (found) %N %N iso- 3-methoxy cyclo- 99-1W0 71.35, 7.70. 11.89 71.10, 7.56.,11.73 ___propyl phenyl Ipentyl 46 ethyl 3-methoxyI cyclobutyl 73-74b 70.13, 7.12. 12.91 70.10, 7.22.,12.93 phenyl1 47 ethyl phenyl methylene 60-62' 73.19. 7.17, 14.23 73.34, 7.08. 13.95 cyclopropyl 48 ethyl 3-methoxy methylene oil [M J 1326 MS [M-1 326 phenyl cyclopropyl 49 ethyl 4-methoxy- phenyl 1 5 6 1 5 7 b 72.60, 6.09, 12.10 172.35. 5.91, 12.02 phenyl ethyl, 3-methoxy- 3-sulto- oil 58.59. 5.95. 10.79 58-46. 6.03. 9.82 phenyl lanylI S1 ethyl 13-methoxy- 4-trihluoro- 124-125" 63.61. 4.85, 10.12 63.40. 4.51, 1009 phenyl methyl- 52 ethyl 3-methyl- cyclobutyl oil 7375, 7.49. 13.58 73.22, 7.56, 13.03 phenyl 5S3 ethyl 3-trifluoro- 3-sullfa- oil MW 427.44 NIS mlz 428 methyl- lanyl ____phenyl 54 ethyl 31-trifluoro- cyclobutyl 'oil 52.80, 5.55, 11.56 63.01. 5.54, 11.19 methyl- ____phenyl ethyl phenyl 2-indanyt 155-156- 77.28, 6.49. 11.76 1 i I eth yl 2-methylphenyl cyclobutyl 100-102 1MW 309.41 77.35, 6.48. 11.08 MS mlz 310 MS,.m/z 388, 389, 390 57, ethyl 3-methoxyphenyl 2-indanyl 160-62 MW 387.48 -t to a arse 10~v00 I 1Mass Spectra or Mass Spectra or 2 3 Analysis (calcd.) Analysis (found) Ex# R' R R M-p.

0 C

%N

58 ethyl 2-methoxy- cyclobutyl 123-4 70.13, 7.12, 12.91 69.93, 7.09, 12.81 phenyl ethyl 2-methyl- 3-methyl oil 337.46 MVS (Mfz) 338 59 phenyl cyclepentyl 60 ethyl 2-ethyl- cyclobutyl oil [M 1 323.44 MS 324 pheniyl 61 ethyl 2-ethyl- 1Cycle- 106-7 337.46 MS (mlz) 33 ____phenyl pentyl 62 ethyl 1-naphth- cycle- 188-90 359.47 MS (mfz) 360 alene pentyl 63 ethyl 1-naphth- cyclohexyl 199-201i 373.5. MS 372 alene 64 ethyl 2-chloro- cyclo- 100-3 66.37, 6.45, 12.22 66.65, 6.61, 11.92 ____phenyl pentyl ethyl 2-chloro- cyclohexyl oil f M+1 357.8 MS (mlz) 358 ethyl 2-methyl- bicycle 141-2 j75.61. 7.79. 1 2.02 75.74, 7.84, 11.85 66 phenyl 2.1]hept- 2-yl ethyl 12-rnethoxy-5- cycle- 94-6 71.36, 7.70. 11.89 71.8., 7.71. 11.43 67 methyl- pentyl ____phenyl ethyl 5-chlo-2- cyclo- 109-11 67.12, 6.76 I 1.74 67.30, 7.02, 11.21 68 methyl- pentyl ____phenyl ethyl 5-chloro-2- 4-fluoro- 90-2 tM+I 3B3.85 MIS 384 69 methyl- phenyl phenyl ethyl 6-chloro-2- cyclobutyl' 135-7 66.37, 6.45, 12.22 67.17, 6.81. 11.78 methylphenyl ethyl 5-chloro-2- 4-fluoro- 129-30 63.08. 4.79, 10.51 63.08, 4.86. 10.411 methoxy- phenyl phenyl 72ethyl 2-chloro- 4-tetra- oil [M+j 359.85 MVS (rn/Z) 3 72 phenyl hydropyranyl 22 Recrystalization solvents: aEthyl acetate/pentane. bEthyl ether/pentafle. Cisopropyl etherlpentafle. dEthylacetate/petroleum ether. eEthyl acetate. fEthyl acetate/hexane.

Example 73 pyrazoIo[3,4-c]pyridine.

To a stirred solution of 3-ty--4furpey 4mtoyhnl-,,6 ,7tetrahydro-lH-pyrazolo[3,A-1pyridine (0.3 gramns, 0.82 mmole) in 50 ml ether was added lithium aluminum hydride (33 mg, 0.86 mmnole). After stirring for 16 hours water ml) was added followed by 3N sodium hydroxide (1 ml). After stirring for 2 hours the lo 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. 1Hl NMR (250 MHz, CDCl 3 12(,3=7.6 Hz, 3H), 2.66 J 7.6 Hz, 2H), 2.71 J 5.7 Hz, 2H), 3.49 J 5.7 Hz, 2H1), 3.84 3H), 4.23 211), 6.84-6.99 (in, 611), 7.3 6 J 9.0 Hz, 2H); MS nilz 352.

C

08** C C C. C C

U*@

Examples 74-79 Reaction of the appropriate 7-oxo-2,5 ,6,7-tetrahydro-H-pyrazolo[ 3 ,4-cjpyridine with lithium aluminum hydride, analogous to the procedure of Example 73, affords the Ex. R 1

R

2 R3 M.p.

0 C Mol. Weight Mass Spectra (found) 74 ety Sobuy cyclopentyl oil 275.44 MIS (mfz) 276 ethyl 4-methoxy- cyclontyl oil 409.57 409 3cyclopentoxy phenyl -4 76 ethyl phenyl 3,4- oil dichiorophenyl 77 ethyl phenyl cyclopentyl oil 78 ethyl 3etxy cyclobutyloi phenyl 79q ethyl 3-methoxy cyclohexyl oil phenyl 37 .2.30 371.373 295.43 296 311.43 312 339.48- 340 Example 1-cyclopentyl- 3 ethy7oxo45,6,7-tetrahydroIH-pyrazolo[ 3 4 cI~pyridine A stirred solution of, 1-ylpny--~hl6(-ehxphn -7x- ,6,7terb oI-yao 34cprdn (2.58 grams, 7.60 mmole6) in. acetonitrile (90 ml) aL0 0 C s treted with a solution of ceric ammoniiumnirt(15gam,2.mnos)n water (110, After stirring for 35 minutes the-mixture is diluted withf water (550 ml)'

V

V.

n:Iiiih]O24K'W"

I

and extracted with ethyl acetate (100 ml x The combined organics are washed with saturated sodium bicarbonate (250 ml) followed by 10% sodium sulfite until the aqueous wash beco mes pale yellow. The organic layer is then washed fuirther with saturated bicarbonate and brine, and treated with decolorizing charcoal. After stirring for minutes the mixture is dried over sodium sulfate, filtered through celite and concentrated under reduced pressure. The brown residue is recrystallized from ether to give .814 grams of a tan solid. M.P. 143-145'C; MIS 234; ill NMR (250 MHz,

CDCI

3 1.21 J I 7.6 Hz, 3H), 1.62-2.13 (mn, 8H), 2.62 J 7.6 Hz, 211), 2.73 (t, J 6.8 Hz, 2H), 3.51 (dt, J 2.7 and 6.8 Hz, 2H), 5.47 IH), 5.61 (pentet, J 7.7 Hz, 111).

*1 Example 81 1-ylpny--ty--ylpoymehl7oo4567ttayr-H pyrazolo[3,4-clpyridifle A solution of 1-cyclopentyl-3-ethyl-7-oxo- 4 ,S ,6,7-tetrahydro-1lH-pyrazolo[ 3 ,4clpyridine (0.21 grams, 0.92 mmoles) in THF (5 ml) is treated with 60% sodium hydride in mineral oil (40 mng, 1.01 mimoles). After stirring at reflux over 45 minutes the reaction mixture is cooled to 251C and (bromemethyl)cyclopropaiie (0.31 grams, 2.29 inmoles) is added. The mixture is stirred at reflux for 16 hours and then cooled to 25'C before concentrating under reduced pressure. Chromatography on. silica gel eluting with 1: 1 0 626 ethylacetate/hexane gives, 0. 19 grams of the title compound as- a colorless oil. MIS ml/z IM+1 288; IH NMR (300 MHz, CDCI 3 0.26-0.31 (in, 2H)" 0.50-0.56 (in, 2H), 0.85- 1-06 (in, 1H), 1.20 J 7.6 Hz, 31H), 1.62-2.08 (in 811), 2.61 J 7.6 Hz, 2H), 2.74 J 6.8 Hz, 211), 3.39 =6.9 Hz, 2H), 3.63 6.8H1-z, 2H), 5.67 (pentet, 1 7.8 Hz, III).

.Example 82 1-ylpny--ty--ezl7oo-,,, erhdol-yaoo34 O:cpyridine A solution of 1-cylopefltyl-3--ethyl-7-oxOa-, 5 ,6,7-tetrahydro-11-piYrazolo[ 3 ,4c]pyidine (0.12 grams, 0.51 minoles) in DMF (5 ml) is treated with .60% sodium hydride h- 0i mineral oil (32 ingrains, 0.77 mmoles). After stirring at-ambient temperature over 1 hour benzylbroinide (0.22 grams, 1.29 mingles) 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 a nd c oncent rated under reduced pressure. Chromatography on silica-gel eluting with .1 1

-I

I I ~1 -1 I p' In:%ibhI0214:KWW: 'F 24 1:4 ethyl acetate/hexane gives 0.13 grams of the title compound as a colorless oil. MVS m/z 324.

Examples 83-1 31 Reaction of 1 -cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazclc [3,4c~pyridine with sodium hydride in DMVF followed by addition of the requisite electrophile analogous'to the procedure of Example 82, affords the following compounds of formula IX where R'=ethyl and R 3 =cyclopentyl.

Mass Mass Spectra or Spectra/Analysis Analysis (Calod) (found) %H, x. electrophiie R 2 Mp-C %N cyclopropyl cyclopropyl oil 287.41 MS (mfz) 288 83 methyl methyl bromide 84 cyclopentyl cyclopentyl oil 301.43 MS (mfz) 302 84 bromide 85 isobutyl isobutyl oil 28.42 MS 290 85 bromide 86 -methallyl methallyl oil 287.41 MS 288 87 isoamyl- 3-methyl oil 303.45 MS 304 bromide butyl 88 ethyl 2- 1 -ethoxy- oil JIM+) 347.46 MS (mlz) 348 bromo- carbonyl butyrate propyl *89. dimethyl- dimnethyl- oil 304.39 MS (milz) 305 carbamyl carbamyl neopentyl neopentyl oil 303.45 MS (miz) 304 OWa020- ethyl.4- 3-ethoxy- oil 347.46 MS (mhz) 348 bromo- carbonyl- ____butyrate propyl 9 2 1-bromo-2- 2-phenyl- oil. 337.47 MS (mhz) 338 phenyl ethyl ethane I1-bromo-l- 1-phenyl 70-1 74.74, 8.06, 74.66, 8.22, 12.47 9 3 p her- yl .ethyl 12.45 'ethane, SI

C.

0 0t CC. 0.

.C iG

C

C* S~o C. C Mass Mass Spectra or Spectra/Analysis Analysis (Calcd) (found) %H, Ex. elRtopi2 Mp 0 C %N %N oil 290.41 MS (mlz) 291 -9 dimethyl dimnethyl methylene amino ammonium methyl chloride isopropyl isopropyl oil 275.40 MS (mfz) 276 bromide 96. acetyl- acetyl oil 275.35 MS (mlz) 276 chloride 2-bromd- 1,3- 52-3 319.41 MS 320 97 methyl-i dioxolan-2dioxolane yl-methyl 98 3-picolyl 3-picolyl oil 324.43 MS (mfz) 325 chloride 99 2-picolyl 2-picolyl oil [M 324.43 MS 325 chloride 100 4-picolyl .4-picolyl oil 324.43 MS (mlz) 325 chloride benzene- benzene- oil 373.48 MS (mfz) 3l74 01 sulfonyl sulfonyl chloride 12 isopropyl isopro -pyl 117-9 56.61. 7.42, 56.78, 7.43, 12.33 1(2 suironyl sulfonyl 12.38 chloride 2-chloro-5- 2-chloro- oil 363.91 MS (mlz) 364 *13 (chloro- thlophenthiophene 3-chloro- 3-methoxy oil 353.47 MS (mlz) 354 14 methyl benzyl.

arusole: 4-chloror -3,5 98_9 r 66.64, 7.65, 66.46, 7.79, 16.33 105 methyl-3 5-.dmth. 16.36 dimethyl ixazol-4 isoXazole :ylmetl 3-chioro-' 3-chloro-, oil 357.89 MS 358 106 benzy4 benzyl bro-mide.

4

I

I.

26 Mass Mass Spectra or Spectra/Analysis Analysis (Calcd) (found) %H, Ex. electrophile R2 Mp 0 C %N 2 -chioro- 2-chloro- 68-9 67.12, 6.76, 67.13, 7.03, 11.90 107 benzyl benzyl 11.74 bromide thiophene-2- thiophene-2- oil 379.50 MS (mn/z) 380 1 08 sulfonyl sultonyl chloride 4-chloro- 4-chloro- oil 407.92 MS 408 benzene benzene 109 sulfonyl sulfonyl c-hloride methane- methane 55-60 311.40 MVS 312 sulfonyl sulfonyl chloride 5 *3 9 20 a .99.9.

*9 aS a a~ 4-methoxy ben zene sulfonyl chloride 4-methoxy benzene sulfonyl 403.50 MVS (mfz) 404 3-chlorobenzene sulfa nyl chloride: 3-chlorobenzene sulfonyl 139-94 407.92

I

2-chloromethyl thiophene thiophen-2ylmethyl 329.47 MS 2.5-dichloro- 2,5-dichioro oil 442.37 II 1 14 benzene benzene sulfonyl sulfonyl chloride lhioptiene-2- thiophene-2- 77-8 62.95, 6.16, 62.

115 .carbonyl. carbonyl 12.23 chloride 1 16 isobutyryl .isobutyryll oil [M+I 303.40 .MS chloride tetrahydro- tetrahydro oil [M+I1317.43 MS -17, Iufry furfuryl -chloride 330 442 87, 6.25, 12.35 (mIz) 303 318

J

benzoylchloridebenzoyl 72-4 337.42 MS (mfz)335 -9 L I I 27 I C C C S Mass Mass Spectra or Spectra/Analysis Analysis (Calcd) (found) %H, Ex. electrophile Mp 0 C %N -isonico- isonico- oil 338.41 MS 339 chloride 120 nicotinoyl nicotinoyl 13S 338.41 MS 339 chloride 2-bromo- 2-methoxy i 291.39 MS 292 '2 1 Iethylmethyl ethyl etherT 3-(bromo., 3-cyano oil .72.39. 6.94. 72.19. 6.98, 15.75 122 methyl) benzyl 16.08 benzonitrile methyl methoxy oil 6184 726, 61-34, 7.47. 14.23 1 23 chloro carbonyl 14.42 formate 2-(bromo- 2-cyano oil 72.3, 6.9, 16.1 72.5, 7.2, 15.3 1 24 methyl) benzyl benzonitrile 4-(bromo-. 4-cyano. oil 72.3. 6.9, 16.1 70.6, 6.9, 15.5 1 25 methyl benzyl benzonitrile 3-bromo- 2-cyano- oil. 57.09, 7.74. 66.82. 7.55. 18.92 126 propia- ethyl 19.56 127 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 (mfz) 347 1 8 -carb6nyl 4-carbonyl chloride* 19Iethylchloro- ethoxy oil jM+] 305.38 MS 306 formate carbonyl bromno- 2-(1 .3-dioxo- oil 3313.43 MS (mfz) 334 1 0 ethyl)-1 Ian-2-yl) dioxolane,- ethyl 2-(chloro tetrahydro- Oil [M+1 331.46 MS (mlz) 332 methyl) pyran-2-yi 1 3 1. tetrahydro-' methyl pyran

J

.4,4- 28 Examiolel 32 6-(2,Chlorothioohen-5-yl) mnethyl -3-ethvl-l Iu aroph enyl) -7-oxo-4-4,5,6,7tetrahvdro-l H-pyrazolo r3.4-Cl pyridine Reaction of 3-ethyl-i -(4-fluorophenyl)-7-oxo-4,5,6,7-tetrahydro-l H-pyrazolo [3,4cjpyridine with 2 -chloro.5-(chloromethyl)thiophene, analogous to the procedure of Example 82, affords the title compound. MVS 390.

Examplel 33 3- EthylI- 1 4 -f Iu oro ph enyl) -7-oxo-6- t h io Ph en.2 y 4.5,67tetrah yd ro 1 H pVrazolo [3.4-cl pyridine ~Reaction of 3-ethyl-i 4 -fluropheyl)-7oxo4567erhdo -przl 34 olpyridine with 2-chioromethyl thiophene, analogous to the procedure of Example 82.

affords the title compound. mp 106-70C; MVS 356.

bxamle 134 *0.1 -Cyclooentyl-3-ethyl-6-(2-hyd rox--methVI henyl-7oxo45,6,7tetrahvdro-1

H-

5 pyrazolo 13,4-ci pyridine *0 A solution of l-cyclopentyl-3-ethyl6(2methoxy5methylphenyl)7oxo 4 7tetrahydro-IlH-pyraz-olo[s,4-cjpyridine (0.32 grams, 0.91 mmoles) in a'30% solution of H Br in aceti c acid -(10 ml1) is stirred at 9500 C. After 24 ho urs t he m ixtdure i s co n cen trate d under reduced pressure: dissolved in ethylacetate; washed with saturated sodium bicarbonate arid brine; dried ocver magnesium sulfate and concentrated under reduced pressure. Recrystallization from isopropylether gives 0.15 grams of the title compound.

IVMP 181-2; MVS 340; Analysis' calod. for C 20 H 2 5

NO

2 0C(70.77), H Nd (2.38).

2 Found C(71,03), H(7.49) N(12.60).

Expe35-141 .25 Reaction of the requisite methoxyphenyl substituted 4,5,6,7-tetrahydro-1

H-

pyrazolo 13,4-clpyridine with 30% HBr in glacial acetic acid, analogous to the procedure of Example 134, affords the following compounds of formula.

Mass Spectra/ Mass Spectra/ (Calcd.) Analysis (formed) E# AR 3 MpoC %N 1 35 ethyl 2-hydrox.y-. cyclo- 164-5 [M+1325-41 MS (m/zj 326 phenyl pentyl. 13 thyl 3-hydroxy- cyclo- .178-9 [M+J339.44 MS-%(Mfz) 340 I jH phenyl hexyl 29 IMass Spectral Mass Spectral Ex# RI 3 ma Analysis (Calcd.) Analysis (formed) 1 3

M

0 C %N

%N

13 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, 11.688 63.60, 6.24. 11.56 1 38 2-hydroxy- pentyl phenyl ethyl 5-chloro- 4- 173-4 62.26. 4.44* 10.89 62.41, 4.61, 10.86 139 2-hydroxy- fluorophony[ phenyl j 140 ethyl 3-hydroxy- cyclo- 161-2 70.13, 7.12, 12.91 70.18, 7,25, 12.86 5 141ethyl 3-hydroxy- cyclo- 134-9 [M+1339.44 MS 340 Example 142 *0 6 -Acetonl1 cclope tvl3ethloxo4556.

7 tthcrc-1H-przl 3 clpvridine A solution of l-cyclopentyl3ethyl .6.methall-7-ooo6,7thd1Hpyrazolo[3.4-cipyridine (0.12 grams, 0-41 nmoles) indioxane (25 ml) and water (60 ml) is treated. with potassium carbonate (0.035 grams) followed by 33m) of a solution of o ~Nab 4 2 .1g) and Kmn 4 (0.026 grams) in water (100 ml)_ After 1hour the mixture is *extracted with ether. The combined ether layers are washed with brine; dried oversodium sulfate and concentrated under reduced pressure. Chromatography on a silica 6 gel column using 1 :3 ethylacetate/hexane as eluent gives 0.042 grams of the title :*see compound as a colorless oil. MVS (in/z) 290.

Example 143 POO*: 1-c Vloentyl-3hyet(2hVld6(2.hroxvl-7oxo-4, 4 6 7 tthvdo1H ir--olo3.4cjpyridine A solution of 6-acetonyl-- cycbopenty3ethyl-7 o x ,5 ,7t ra y o- A 5pyrazolo[3,4-cjpyridine (30 mn grams, 0.10 mmoles) in anhydrous methanol (2mb) at QOO is treated with sodium borohydride (38 ingrains). After 15 minutes aqueous Saturated amnmonium chloride is added and the mixture is extracted with ether. The combined- 2 ether layers are.'washed with brine, dried over sodium sulfate and ponicentrated under reduced pressure. ,Chromatography.. on a silica gel 'Column using 1:2 ethyl acet ate! hexane as eluent gives 20 ingrains of ti-fe title compound as a colorless oil. MVS (mlz) 292.

Example1 4 4 6-(Acaton-1 -Vioxim 0-1 -cyclopentvl-3-ethyl-7-oxo-4667teirahvdro-1

H-

5 pvrazolor3.4-clpVridine A solution of 6-Acetonyl-1 -CYclopentyl-3-ethyl-7-oxo-45,6,7-tetrahydro. 1 Hpyrazolo[3,4-c]pyridine (0.15 gramsO in anihydrous 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, and concentrated under reduced pressure. Recrystallization from isopropyl ether gives 0.10 grams of the jtitle compound as a white solid. MP 147-90C; MS 305; Analysis caled. for' C63.3) H7.94, N(18.41). Found C(62.80), H N (18.55).

Exainole145 -fe 15 6-(C-Aminocarbonyloximeacetony)-1 -cyclooentvl-3-ethyl7oxo456.7tetrahydro- 1 H-Dyrazolo [3.4-cl pyridine A oluion f 6(oximeacetony)-lcyclopentyl-3-ethyl.7-oxoA,5,s,7tetrahydro1 pyrazolo[3,4-clpyridine (0.10 grams) in THF (5m1) at 000 is treated with chicrosulfonly *isocyanate (70 ingrains). After stirring for 1 hours at 25 0 C the mixture is concentrated :20 under reduced pressure, dissolved in ethyl acetate; washed with water and brine; dried ovc-r MgSO, and concentrated uinder reduced 'pressure. Chromatography on a silica gel column eluting with 1:3 ethylacetate/hexane gives the title compound as a pale yellow'oil. MIS (in/z) 348.

Examples 146-149 2 5 Reaction of 1 -cyclopeintyl-3-4,5,6,7tetrahydrol H-pyrazolo [3,4-clpyridine with sodium hydride in DMF followed by the addition of the requisite electrophile, analogous to the procedure of Example 82Z affords the following compounds o1 formula X where R'=.ethyl and R 3 =ccoet Mass Spectra Mass Spectra or Analysis or Analysis (calcd.) (found) ElectrophileMP-C %N Isopropyt- isopropyl- 108-113 59.05. 8.37, 58.79, 8.38, -4 6- sulfbnyl-, sulfonyl 112.91: 12.51 chloride

I

'I

Jr 31 thiophene-2- thiophene-2- oil 65.62. 7.04, 62.60, 6.74, 147 carboniyl- carbonyl j12.75 11.84 148 dimethyl- dimethyl- oil [M]l 290.41 MS 291 carbamyl carbamyl 2-chioro- oil [M-1 349.93 MVS (mlz) 350 149 (chloro- thiophenmethyl) 5-yl methyl _____thiophene 1 4-lsobutyrvl-3-methoxy1 -ph enVl-2-oxo-1 .2-5.6-tetrahvdropyridin e A stirred solution of freshly distilled diisopropyiamine (0.15 ml, 2.21 mmole) in anhydrous tetrahydrofuran (4 ml) was cooled to 0 0 1C and treated with 2.5 M n-butyl lithium (0.85 ml. 2.11 mmole). After 15 minutes the mixture was cooled to -781C and :10 a pre-cooled solution of 4-propionyl-3-methoxy.-phenyl2-oxo1256 tetrahydropyridine (0.52 grams, 2.0 mrnole) in tetrahydrofuran (4 ml): was added dropwise via cannula. After appr oximately 20 minutes methyl iodide (0.20 ml, mmole) was added to the bright orange-red solution and the mixture was, allowed to to room temperature over 2.5 hours. The reaction mixture is poured into 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 1.15j(d, 6H), 2.72 2H), 3.47 (heptet, 1H), 3.82 Preparations 2-3 Reaction ofthe appropriate 3 -rnethoxy-2.oxo-4-propiony[.1 ,2,5.6tetrahydropyridine with lithium diisopropylamine and methyl iodide, analogous tot1he procedure of preparation 1, affords the following compounds of formula Vill.

Prep#j M. I p. OC M.W. Mass SpectraEM*] 2 4-m-et hoxyphenyl, o il 303.36 804, 3. 3-methoxyphenyl oil 303.36 304 6~ :1 a a a 6*.

6*6*56

C

.2

S.

S

S..

a a 6~Vta

S

I

PreParation 4 3-MethoxV-1 4 -methvlphenv)2oxo-4-Dopionvyl1 2 ,56-tetrahydroPyrjdine A solution of 3-hydroxy-l -(4-methylphenyl)-2-o6xo.4propionyl-1,2,5,6tetrahydropyridine (5.9 grams, 23 mmole) and 3 -miethyl-1.p-tolyltriazine (5.1 grams, 34 mmole) in 1,2-dichloroethane was heated to reflux for 45 minutes. The mixture was allowed to cool to room temperature and was poured into water and acidified with 6N hydrochloric acid. The aqueous layer was extracted 3 times with methylene chloride, and the combined organics are washed with 1 N hydrochloric acid followed by water -and brine, dried over magnesium sulfate, filtered and concentrated under reduced o pressure. The resulting qu antitative brown oil was, clean, by thin layer chromatography and 'H NMR and was used without purification. 'H NMFI (300 MHz, CDCI,) 1.12 (t,J= 7.2 Hz, 3H). 2.34 3H). 2.71 (t,J 6.7 Hz, 2H), 2.93 (q,J =7.2 Hz, 2H), 3.77 (tJ 6.8 Hz, 2H), 3.94 3H), 7.20 4H); MS [M'I 273.

Preparations 5-14 Reaction -of the appropriate 3 -hydroxy-l-aryI-2oxo-4-alkanoyl-1 2,5.5tetrahydropyridine with 3-methyl-i -p-tolyltriazine, analogous to the procedure of Preparation 4, affords the following compounds of formula VI.

0 Prep# .5 6 7 -8

AO

7777= Prep# RR ethyl -methyl ethyl n-propyl jethyl ethyl ethyl i ethyl:ethyl, phenyl 4 -methoxyph enyl 8 4-mnethoxyphenyl 9 ~3-methoxyphenyl 10 2-methoxyphenyl 11 3.4-climethox(yphenyl 12 3-cyclopentoxy.4 mnethoxyphenyl 'T I 3-methylphenyl M.P. OC oil oil 81-82 oil 5oil oil oil Oil

M.W.

259.31 275.30 303.36 289.33 289.33 319.26 373.45 Mass Spectra [M]1 260 275 289 303 289, 290 289 -319 373 273 327 I ~14j ethyl J 3 1-trifluorometh~ylphenylI 33 Preparation 3-Hydroxv-1-(3-methylphenvl)-2-oxo-4-Drooionvl-1,2,5.6-tetrahydropyridine To a stirred suspension of magnesium turnings (1.9 grams, 79 mmole) in 30 ml of anhydrous ether was added dropwise bromoethane (5.9 ml, 79 mmole). A mild reflux was initiated after approximately 1 ml was added. After all of the magnesium was consumed, the reaction mixture was cooled to 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, c 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 1N sodium hydroxide, and with vigorous mechanical stirring ethyl oxalyl chloride (7.2 ml, S 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 20 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. 115-116o; '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.

Mass p Spectra Pre# R' R rri.p. OC.. M.W. [M] *0s 16 methyl pheniyl 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-methyiphenyl oil 259.30 259 26 ethyl 3-trifluoromnethylphenyl 117-118 313.28 313 27 ethyl 2-trifluoromethylphenyl oil 313.28 313 28 ethyl 3,4-dimethoxyphenyl 179-180 305.33 306 29etyl 3-cycloperitoxy-4- 133-134 '359.42 29 ethyl methoxyphenyl 1I6 Preoaration N-(2-Methoxyphenvl'l-2-Dvrrolidone It St I I. *4 A mixture of 2-pyrrolidone (15.0 grams, 176 mmole), 2-iod oanisole (7.6 ml.. 59 mmole). co pper powder (7.5 grams, 117 mmole) and potassium carbonate (8.1 gramns,.

59 mmol e) are stirred under nitrogen at 1500 C. After 18 h ours, the reaction mixture was filtered through a Ux15. 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 compouind as a honey-like oil. YH 215 NMR (300 Ml-z, CDC[,) 2.20 (pentet, 2H)1, 2.55 2H), 3.82 3H), 6.93- 7.02 (in, 2H), 7.25-7.30 (in. 2H}; MS m/z [M1j 191.

Preoarations 31-39; Reactions of the appropriate iodo- o brorobenzene with 2-pyrrolidinone, analogous to that reported in- Preparation 30, affords the following compounds of formhula V.

I -I I Mass Specr Prep# I RMW M 4 1 .t.

I- A-> C C tl~O CECt I. C C. S

C

he 31 4-methoxyphenyl 191.22 191 32 3-methoxypheriyl 191.22 191 33 3-methylphenyl 175.23 175 34 4-methylphenyl 175.23 175 35 2-methylphenyl 175.23 175 36 3-trifluoromethylphenyl 229.20 229 37 2-trifluoromethylphenyl 229.20 229 38 3,4-dimethoxyphenyl 221.26 221 39 3-cyclopentoxy4. 275.35 275 methoxyphenyl

-L

I

1~

I:

Claims (8)

1. A compound of the formula N N and pharmaceutically acceptable salts thereof; wherein RI is hydrogen, (C'-C 6 )alkyl, (C 2 -C 3 )alkenyl, (C 3 -C 5 )cycloalkyl or methylene-(C 3 -G 5 )cycloalkyl wherein each alkyl or alkenyl group may be optionally substituted with up to two (C I-C 2 )alkyl or trifluoromethyl groups or up to three halogens; X is oxygen or two hydrogen atoms; R 2 an~d R 3 are each independently selected from the group consisting of hydrogen; (CtCl 4 )aI~yl optionally substituted with halogen or cyano; (C'-C 1 4 )allcyl sulfonyl; A._ (Cl-C' 4 )alkoxy; naphthalyl; (C 2 r-C 7 )alkenyl; (C 3 -Cl 4 )cycloalkyl; (Cl-C 4 )alkyl- .(C 3 C 7 )cycloalkcyl; (C 3 -C 7 )Celoalkyl(C 1 -C 4 )alkyl; (C 4 -C 7 )heterocycic group, containing oxygen, sulphur, S0 Or NR 5 wherein R 5 is hydrogen or (C 4 )alkyl or whenH R 2 is an aromatic heterocycle. then R 5 is absent; (C 4 -C 7 )heterocycloalkyl-(W)d wherein the (C 4 5 C 7 )heterocycloalkyl group contains one or more oxygen, sulphur, SO 2 ,or NR' 5 groups, whri R 1 5 is -hydrogen or (Cl-C 4 )alkyl optionally substituted with halogen or (CL C 4 )alkyl, d is 0 or. I and W is (C I-C 4 )alkyl, CO or sulfonyl; CONRIORI I wherein RIO and RI are each independently hydrogen or (CI-C 4 )alkyl; (C'-C 5 )alkyl carbonyl; (CL- CakoycArbonyl; (C 1 -C 5 )alkyl carbonyl (Cl-C 5 )alkyl; (C'-C 5 )alkoxy carbonyl (CL-- io C 5 )alkcyl; (C 1 -C 5 )alkoxy(C 1 -C 5 )alkyl; R 12 R 13 N(Cl-C 5 )alkyl wherein R 12 and R 1 3 'are each independently hydrogen or (IQ-C 5 )alkyl; or a group of the formula (R 4 )a CC'b(k /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, (C'-.)alkyl, (C 2 -C 5 )alkenyl, (C'-C)alkoxy, (-C)yoakxy, halogen, trifluoromnethyl, C021; 6 CON], 6 NR0R 7 CONHOH,. CN, :NO 2 or S0 2 NR R 7 .Wherein R 6 and R 7 are each independently hydrogen or (C 1 -C 4 )alkyl, wherein -Y s (I-C)akylor G 2 C0)alkenyl optionaly substituted with up to two (L-C 7 )aklo (C 3 C 7 )cycloalkyl groups an0 soyen upuG, S0? or NR 8 wherein. R 8 is hydrogen or*,,C -C4)Alkyl; Or a- group of thieformnula -9 MW wherein p is an integer from. 1 to 3, 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 (CI-C 2 )alkyi, trifluoromethyl or halogen; or the group of the formula B S S. S 0**t *Sea a. S C ta C 5 a S S. S

5. C wherein mn, n and p are 1 or 2;or a group of the f ormula wherein Q is hydroxy or a group of the formula H 2 N St 55 0. C 10 4 S~ 6 with the proviso that R 2 is not an unsubstituted, or 4-subst ituted-phenyl group; and with the proviso that heterocycle excludes pyridinyl and wherein at each occurrence alkyl, alkenyl and alkoxy are, as hereinibefore defined. 2. A compound according to claim 1 wherein R 1 is* (Cl-C 3 )alkyl and R 3 is (C-7ccoiy,(C4C 7 )heterocyqlic group containing.S0 2 or a group of the formula. 4 (R 4 a wherein: a is an-titeger fro i t6-5 and R 4 is independently slcedfo hydrogen, hydroxy, (C I-C 5 )alkyl' (C t -G 5 )alkoxy or halogen: 38 3. A compound according to claim 1 or claim 2 wherein RI is (C 1 C 3 )alkyl and R 2 and R 3 are each independently selected from the group consisting of (C 3 -C 7 )cycloalkyl, (C 4 -C 7 )heterocyclic group containing 502 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, (CI-C 5 )alkyl, (C 1 -C 5 )alkoxy or. halogen. A compound according to claim 1 wherein RI is ethyl or isopropyl; R 2 is 2- methyiphenyl, 3-methyiphenyl, 2-methoxyphenyl, 3-meflioxyphenyl, 2-hydroxyphenyl, 3- hydr oxyphenyl, cyclopropylmethyl, benzyl, .isobutyl, isobutenyl, 2-ethyip henyl, naphthalenyl, 2clrpey,3mtlby ldmetycardmyl, 1-hiethylbenzyl, isopropyl, 1-picolyl, 2-picolyl, 3-picolyl, [2-methyl-5-chlorophenyl],-2-chlorothiophen- 5-ylmethyl, [2-hydroxy-5-methylphenyl. 3,5-dimnethlyl-isoxazol-4-ylmethyl, 3- I choroenyl, thiophen-2-ylmethyl, [2-hydroxy-5-chlorophenyl], thiophene-2-carbonyl, tetrahydrofurfuryl, 3-cyanobeozyl, morpholine-4-carbonyl, or isopropylsulfonyl, 4" methoxyphenylsulfonyl or 3-trifluoromethylphenyl and R 3 is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolanyl; 4-fluorophenyl or 3 ,4-dichloropheniyl. A compound selected from the group consisting of: 3-ethyl4l-(4-mnethoxyplenyl)-6-phenly-7-oxo- 4 5 ,6,7-tetrahydro-IH-pyrazoIo- 9 [3,4-cjpyridine; 3-ethyl-1-cyclopettyl-6-phenyI- 7 -oxo- 4 5 ,6,7-tetrahydro-IH-pyrazolo- [3,4-clpyridine; 03--ethyl-l-(3 ,4.-dichlorophenyL)-6-(3-methoxypheflyl)- 7 -0xo- 4 ,S ,6,7-tetrahydro- LH- pyrazolo[3 ,4-c]pyridine; 3..ethyl-1.-cyclopefltyl-6-(3-methoxyphflyl)- 7 -Oxo- 4 ,S ,6,7-tetrAhydro-l H- pyrazolo[3 4-clpyridine- 3.-ethyl-i.-(4.-fluorophenyl)-6.-(2.-methoxyphenyl)- 7 -oxa- 4 ,S ,6,7-tetrahydro-1H- pyrazoIo[3,"--cjpyriiii 3.-thl.-.-ycopetyl-6-(3-methylphenyl)- 7 0xo- 4 ,S,6,7-tetrahydro-lH4- pyrazo[L,47c] 1yriuine, W0 3.-ethiyl--cyclopentyl-6(3.trifluoromethylpheflyl) 7 -0xo- 4 ,S ,6,7-tetrahydro-1H- pyrazolo[3 ,47clpyridine; ethyl.-ylod!hexyl-6-(3-methoxypheflyl)-70oxo4,5, 6 ,7-tetrahydro-1H- pyrazolo[3,4-:clpyridine;, 3isopopl-qyclopptyl.-6 3methoXyphenyl)- 7 -ox0A 5,6,7-tetrahydro-1 H-4 pyrazoloII3_4-c]pyrime .ety[1cycopentyl-6-pheflyt-4,5,6,74tetr todr0H ya~O34Cpyridine; 39 3-ethyl-I cyclopentyl-6-(2-methylphenyl)-7-oxo-4,5,6,7-tetraliydro-1H- pyrazolo[3,4-c]pyridine; 3-ehyl--(3-sulfolnyl)-6-(3-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-lH- pyrazolo[3 ,4 cpyrdie 3-ethyl-l-(3-sulfolanyl)-6-(3-methoxyphenyl)-7-oxo-4,5 ,6,7-tetrahydro-1H- pyrazo~o[3.4-clpyridine; 3-ethyl-l-cyclobutyl-6-(3-methylphenyl)-7-oxo-4,5 ,6,7-tetrahydro-lH- pyrazolo[3 ,4-c]pyridine; la iH-pyrazolo; -ne 3-ethyl-1-cyclobutyl-6-(3-trifluoromiethylphenyl)-7-oxo-4,5 ,6,7-tetrahydro -1H- O yrazolo[3,4-clip me; -pyrazolo[3,4-c]pyridine.

6. -A 4,5 ,6,7-tetrahydro-1H-pyrazolo[3,4-clpyridine derivative, substantially as hereinbefore described with reference to Examples .15, 18, 20, 24, 25, 28 to 3 7, 39 to 43, 45, 46, 48, 50 to 54, 56 to -72, 74, 75, 78 to 136, and 138 to 149.

7. A pharmaceutilcal composition comprising a pharmaceutically efci6amount of a compound of any one of claims -1 to 6 and a pharmaceutically acceptable carrier.

8. A method for the inhibition -of phosphodiesterase (P)DE) type IV and- the production of tumor necrosis factor (TNF) comprising administering to a patient an effective amount of a compound of any one of claims 1 to 6 or a composition of claim 7.

9. -A compound of any one of claims 1 to 6 or a composition of-cam7we *used for the inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) in a patient. 4 The use of a compound of any one of claims 1 to 6 for the manufacture of a medicament for the inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) in a patient. I1.. A method of treating or preventing a condition selected from the group consistinig 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 in need of such treatment,' an effective amount of a -compound of any one of claims 1 to 6 or a composition of claim.

12. A comipound. of any one of claims I to 6 or a composition of claim 7 when used for treating;o pentin- condition selected from the group consisting of asthma, arhriisbrochiischroni obstructive airways disease, psraialiergic rhinitis, involriing thbrouctin ofTFi aptet.[. demtii ado heriflamatry diseases AIIDS,' septic shock and other. diseases invovin theprouctin o TNF'ina paini

13. The use of a compound-of any one of claims 1 to 6 for the manufacture of a mnedicamnent 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 involving the production of TNF in a patient. Dated 11 November, 1998 Pfizer Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON &,FERGUSON 8 I *06e 19 6 4: @96 .4 S 4 6 e6 me.. .4 I. .1 aese. S .0 @0441 6 6 .6 '.4 4 4 A SSS6S I 3 J V I'; 3:V1 .'NW