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WO1996012720A1 - Tetrahydropyrazolopyridines bicycliques et leur emploi comme medicaments - Google Patents

Tetrahydropyrazolopyridines bicycliques et leur emploi comme medicaments Download PDF

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Publication number
WO1996012720A1
WO1996012720A1 PCT/IB1995/000847 IB9500847W WO9612720A1 WO 1996012720 A1 WO1996012720 A1 WO 1996012720A1 IB 9500847 W IB9500847 W IB 9500847W WO 9612720 A1 WO9612720 A1 WO 9612720A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
group
formula
alkenyl
Prior art date
Application number
PCT/IB1995/000847
Other languages
English (en)
Inventor
Allen J. Duplantier
Original Assignee
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to AU35317/95A priority Critical patent/AU702105B2/en
Priority to CA 2201728 priority patent/CA2201728A1/fr
Priority to EP95932148A priority patent/EP0787132A1/fr
Priority to JP8513751A priority patent/JPH09511758A/ja
Priority to NZ292991A priority patent/NZ292991A/xx
Priority to PL95319758A priority patent/PL319758A1/xx
Priority to KR1019970702557A priority patent/KR970707124A/ko
Publication of WO1996012720A1 publication Critical patent/WO1996012720A1/fr
Priority to NO971811A priority patent/NO971811L/no

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to a series of bicyclic tetrahydro pyrazolopyridines which are selective inhibitors of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (hereinafter TNF) and as such are useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases; and AIDS, septic shock and other diseases involving the production of TNF.
  • PDE phosphodiesterase
  • TNF tumor necrosis factor
  • This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans and to pharmaceutical compositions useful therefor.
  • TNF is recognized to be involved in many infectious and auto-immune diseases (W. Friers, FEBS Letters. 1991 , 285, 199). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C.E. Spooner et al., Clinical Immunology and Immunopathology, 1992, 62, S11). Summary of the Invention
  • the present invention relates to compounds of the formula
  • R 1 is hydrogen, (C 1 -C 3 )alkyl, (C 2 -C 3 )alkenyl, (C 3 -C 5 )cycloalkyl or methylene (C 3 -C 5 )cycloalkyl wherein each alkyl or alkenyl group may be optionally substituted with up to two (C 1 -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; (C 1 -C 14 )alkyl optionally substituted with halogen or cyano; (C 1 -C 14 )alkyl sulfonyl; (C 1 -C 14 )alkoxy; naphthalyl; (C 2 -C 7 )alkenyl; (C 3 -C 7 )cycloalkyl; (C 1 -C 4 )alkyl(C 3 -C 7 )cycloalkyl; (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl; (C 4 -C 7 )heterocyclic group containing oxygen; sulphur; SO 2 or NR 5 wherein R 5 is hydrogen or (C 1 -C 4 )alkyl; (C 4 -C 7 )heterocycloalkyl-(W) d wherein the (C 4 -C 7 )heterocycl
  • each said alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic group may be optionally substituted with one to fourteen, preferably one to five, of the group consisting of (C 1 -C 2 )alkyl, trifluoromethyl or halogen; or the group of the formula
  • R 3 cannot be hydrogen, methyl, phenyl, 4-fluorophenyl or 2-pyridyl and with the proviso that when R 2 is 4-methylphenyl and R 3 is 4-fluorophenyl, R 1 cannot be phenyl, methyl or n-propyl and with the proviso that when R 1 is ethyl and R 2 is phenyl, R 3 cannot be 4-chlorophenyl, 4-fluorophenyl or 4-methylphenyl, with the proviso that when R 1 is ethyl and R 2 is 4-methoxyphenyl, R 3 cannot be 4-fluorophenyl and with the proviso that when W is CO or sulfonyl, d is 1 ;
  • R 2 and R 3 cannot both be independently selected from the group consisting of hydrogen, (C 1 -C 14 )alkyl, (C 1 -C 14 )alkoxy, (C 2 -C 7 )alkenyl, (C 4 -C 7 )heterocyclic group containing oxygen, sulphur, SO 2 or NR 5 wherein R 5 is hydrogen or (C 1 -C 4 )alkyl, or a group of the formula wherein a is an integer from 1 to 5; b and c is O or 1 ; R 4 is hydrogen, hydroxy, (C 1 -C 5 )alkyl, (C 2 -C 5 )alkenyl, (C 1 -C 5 )alkoxy, (C 3 -C 6 )cycloalkoxy, halogen, trifluoromethyl, CO 2 R 6 , CONR 8 R 7 , NR 6 R 7 , NO 2 or SO 2 NR 6 R 7 wherein R 6 and R 7 are
  • each said alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic group may be optionally substituted with one to fourteen, preferably one to five, of the group consisting of (C 1 -C 2 )alkyl, trifluoromethyl or halogen.
  • the invention relates to a compound of formula I wherein R 1 is (C 1 -C 3 )alkyl and R 3 is (C 3 -C 7 )cycloalkyl, (C 4 -C 7 )heterocyclic group containing SO 2 or a group of the formula wherein a is an integer from 1 to 5 and R 4 is independently selected from hydrogen, hydroxy, (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy or halogen.
  • the invention relates to a compound of formula I wherein R 1 is ethyl or isopropyl; R 2 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
  • the present invention further relates to a pharmaceutical composition for the inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) and for the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF comprising a pharmaceutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
  • PDE phosphodiesterase
  • TNF tumor necrosis factor
  • 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.
  • PDE phosphodiesterase
  • TNF tumor necrosis factor
  • the present invention further relates to a method of treating an inflammatory condition in mammals which comprises administering to said mammal an antiinflammatory amount of a compound of the formula I and the pharmaceutically acceptable salts thereof.
  • This invention further relates to a method of treating or preventing a condition selected from the group consisting of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF comprising administering to a patient an effective amount of a compound according to formula I and the pharmaceutically acceptable salts thereof.
  • halogen as used herein, unless otherwise indicated, includes chloro, fluoro and bromo.
  • alkyl, alkoxy and alkenyl groups referred to herein may be straight chained or if comprising three or more carbons may be straight chained, branched, cyclic or a combination of cyclic and branched or straight chained moieties.
  • the "inflammatory diseases” which can be treated according to this invention include, but are not limited to asthma, chronic obstructive pulmonary disease, bronchitis and arthritis.
  • R 1 , R 2 and R 3 as used herein, unless otherwise indicated, are as defined above with reference to formula I.
  • Suitable aryl halides include 1-iodo- or 1-bromo- 4-methoxybenzene, 3-methoxybenzene, 2-methoxybenzene, 3-m ethyl benzene, 4-methylbenzene, 2-methylbenzene, 3-trifluoromethylbenzene, 2-trifluoromethylbenzene, 3,4-dimethoxybenzene or 3-cyclopentoxy-4-methoxybenzene.
  • the reaction temperature will generally be in the range of about 110°C to about 170°C, preferably about 150°C, for a time period of about 14 hours to about 22 hours, preferably about 18 hours, under inert reaction conditions.
  • R 1 halide is added to a suspension of magnesium in an anhydrous aprotic solvent.
  • the reaction mixture is heated to reflux until all the magnesium is consumed and thereafter cooled to a temperature between about -15°C to about 15°C, preferably about 0°C.
  • the N-(aryl)-2-pyrrolidone compound of formula V is then added and the reaction mixture is warmed to room temperature while being stirred for a time period between about 1.5 hours to about 2.5 hours, preferably about 2 hours.
  • Suitable alkyl halides include bromomethane, bromoethane or bromopropane.
  • the preferred anhydrous aprotic solvent is anhydrous ether.
  • the desired intermediate may be isolated in a conventional 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 VI by dispersing the precipitate in a mixture of a non-polar aprotic solvent and base.
  • 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 ethanol.
  • the compound of formula VI is converted to the corresponding 3-methoxy-1 ,2,5,6-tetrahydropyridine compound VII by heating to reflux a reaction mixture of VI and 3-methyl-1-p-tolyltriazene in an aprotic solvent.
  • the preferred aprotic solvent is 1 ,2-dichloroethane.
  • the time period for the reaction is between about 30 minutes to about 120 minutes, preferably about 45 minutes.
  • 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.
  • the 1 ,2,5,6-tetrahydro-pyridine compound VIII is converted to the corresponding compound of formula IX by reacting VIII with hydrazinobenzoic acid in an anhydrous polar protic solvent, preferably ethanol.
  • the reaction mixture is heated to reflux for a time period between about 16 hours to about 24 hours, preferably about 20 hours.
  • the compound IX so formed may be further reacted to give the corresponding 1-(4-benzamide)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine compound by reacting IX with sodium methoxide in a polar protic solvent, preferably m ethanol, for a time period between about 15 minutes to about 45 minutes, preferably 30 minutes.
  • a polar protic solvent preferably m ethanol
  • the polar protic solvent is removed under reduced pressure, the solid residue is suspended in a non-polar aprotic solvent, perferably benzene, and thereafter, the non-polar solvent is removed under reduced pressure.
  • the resulting dry solid is suspended in cold ether and treated with oxalyl chloride and N,N-dimethylformamide and allowed to stir for a time period between about 30 minutes to about 90 minutes, preferably 60 minutes.
  • the solvent is then removed and the crude residue is dissolved in dry tetrahydrofuran.
  • the resulting solution is added dropwise to stirred ammonium hydroxide at a temperature between about -10°C to about 10°C, preferably 0°C.
  • the 1 ,2,5,6-tetrahydropyridine compound of formula VIII is converted to the corresponding compound of formula IX by reacting VIII with a hydrazine hydrochloride in a polar protic solvent, preferably methanol.
  • a polar protic solvent preferably methanol.
  • the reaction mixture is heated to a temperature between about 70° C to about 110°C, preferably about 90°C, under a gentle stream of nitrogen until all of the solvent is removed.
  • the neat mixture is then heated to a temperature between about 120°C to about 180°C, preferably about 150°C, for a time period between about 30 minutes to about 90 minutes, preferably 60 minutes.
  • the compounds so formed of formula IX may be converted to the corresponding 6-R 2 -4,5,6,7-tetrahydro-7-oxo-1H-pyrazolo [3,4-c]pyridine compound, wherein R 2 is other than the group of formula II, by reacting a solution of IX in a polar aprotic solvent, preferably acetonitrile, with a solution of ammonium cerium (IV) nitrate in water at a temperature between about -15°C to about 15°C, preferably about 0°C, 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.
  • a polar aprotic solvent preferably acetonitrile
  • the combined organics are then washed with saturated sodium bicarbonate followed by sodium sulfite.
  • the compound so formed in a polar aprotic solvent, preferably tetrahydrofuran, is treated with sodium hydride, heated to reflux and stirred for a time period between about 30 minutes to about 60 minutes, preferably 45 minutes.
  • the reaction mixture is cooled to a temperature between about 20 °C to about 30 °C, preferably about 25 °C, and an alkyl halide of formula R 2 halide, wherein R 2 is as defined with reference to formula I other than a group of formula II, is added.
  • the reaction mixture is stirred and heated to reflux for a time period between about 12 hours to about 20 hours, preferably 16 hours.
  • 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 aprotic solvent, preferably ether.
  • a reducing agent preferably lithium aluminum hydride
  • a non-polar aprotic solvent preferably ether
  • DMSO DMSO to achieve desired concentrations.
  • Final DMSO concentration in assay tube is 1%.
  • the following are added, in order, to a 12 ⁇ 75 mm glass tube (all concentrations are given as final concentrations in assay tube).
  • the reaction tubes are shaken and placed in a water bath (37° C) for 20 minutes, at which time the reaction is stopped by placing the tubes in a boiling water bath for 4 minutes.
  • Washing buffer 0.5 ml, 0.1 M 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid (HEPES)/0.1 M NaCl, pH 8.5
  • HEPES 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid
  • each tube is applied to an Affi-Gel 601 column (Biorad Laboratories,
  • IC 50 is defined as that concentration of compound which inhibits 50% of specific hydrolysis of [ 3 H]cAMP to [ 3 H]5'AMP.
  • EDTA ethylenediaminetetraacetic acid
  • Mononuclear cells are isolated by Ficoll/Hypaque and washed three times in incomplete HBSS. Cells are resuspended in a final concentration of 1 ⁇ 10 6 cells per ml in pre-warmed RPMI (containing 5% FCS, glutamine, pen/step and nystatin). Monocytes are plated as 1 ⁇ 10 6 cells in 1.0 ml in 24-well plates. The cells are incubated at 37°C (5% carbon dioxide) and allowed to adhere to the plates for 2 hours, after which time non-adherent cells are removed by gentle washing.
  • 37°C 5% carbon dioxide
  • Test compounds (10 ⁇ l) are then added to the cells at 3-4 concentrations each and incubated for 1 hour.
  • LPS (10/sl) is added to appropriate wells. Plates are incubated overnight (18 hrs) at 37 °C.
  • TNF was analyzed by a sandwich EUSA (R&D Quantikine Kit). IC 50 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 HCl, HBr, HNO 3 , H 2 SO 4 , H 3 PO 4 , CH 3 SO 3 H, p-CH 3 C 6 H 4 SO 3 H, CH 3 CO 2 H, gluconic acid, tartaric acid, maleic acid and succinic acid.
  • Pharmaceutically-acceptable cationic salts of the compounds of this invention of formula I wherein R 4 is CO 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.
  • oral dosages of the compounds of formula I and the pharmaceutically acceptable salts thereof are generally in the range of from 0.1-100 mg daily for an average adult patient (70 kg).
  • individual tablets or capsules contain from 0.1 to 50 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier.
  • Dosages for intravenous administration are typically within the range of 0.1 to 10 mg per single dose as required.
  • the dosage is generally formulated as a 0.1 to 1% (w/v) solution.
  • the active compound will be administered orally or parenterally at dosages between about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • the active compounds of the present invention can be administered alone, but will generally be administered in an admixture with a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • 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.
  • 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.
  • compositions comprising a compound of the formula I and the pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable diluent or carrier.
  • methyl iodide (0.20 ml, 3.0 mmole) was added to the bright orange-red solution and the mixture was allowed to come to room temperature over 2.5 hours.
  • the reaction mixture is poured into saturated aqueous ammonium chloride and the organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des composés de formule (I) où R?1, R2, R3¿ et X sont tels que définis. Les composés de cette formule (I) ainsi que leurs sels acceptables du point de vue pharmaceutique s'avèrent efficaces comme inhibiteurs de la phosphodiestérase (PDE) de type IV et de la production du facteur de nécrose des tumeurs (TNF) ainsi que dans le traitement de l'asthme, de l'arthrite, de la bronchite, des maladies chroniques obstructives des voies respiratoires, du psoriasis, des rhinites allergiques, des dermatites et autres maladies inflammatoires, du syndrome d'immuno-déficience acquise, du choc septique et d'autres affections donnant lieu à une production de TNF.
PCT/IB1995/000847 1994-10-20 1995-10-06 Tetrahydropyrazolopyridines bicycliques et leur emploi comme medicaments WO1996012720A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
AU35317/95A AU702105B2 (en) 1994-10-20 1995-10-06 Bicyclic tetrahydro pyrazolopyridines and their use as medicaments
CA 2201728 CA2201728A1 (fr) 1994-10-20 1995-10-06 Tetrahydropyrazolopyridines bicycliques et leur emploi comme medicaments
EP95932148A EP0787132A1 (fr) 1994-10-20 1995-10-06 Tetrahydropyrazolopyridines bicycliques et leur emploi comme medicaments
JP8513751A JPH09511758A (ja) 1994-10-20 1995-10-06 二環式テトラヒドロピラゾロピリジンおよび医薬としてのその使用
NZ292991A NZ292991A (en) 1994-10-20 1995-10-06 Bicyclic tetrahydropyrazolopyridines that are selective inhibitors of phosphodiesterase (pde) type iv or the production of tnf and pharmaceutical compositions containing them
PL95319758A PL319758A1 (en) 1994-10-20 1995-10-06 Bicyclic tetrahydropyrasole pyridines and their application as medicines
KR1019970702557A KR970707124A (ko) 1994-10-20 1995-10-06 비사이클릭 테트라하이드로 피라졸로피리딘 및 약제로서 이의 용도(bicyclic tetrahydro pyrazolopyridines and their use as medicaments)
NO971811A NO971811L (no) 1994-10-20 1997-04-18 Bicykliske tetrahydropyrazolopyridiner og deres anvendelse som legemidler

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US32643494A 1994-10-20 1994-10-20
US08/326,434 1994-10-20

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WO1996012720A1 true WO1996012720A1 (fr) 1996-05-02

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EP (1) EP0787132A1 (fr)
JP (1) JPH09511758A (fr)
KR (1) KR970707124A (fr)
CN (1) CN1050129C (fr)
AU (1) AU702105B2 (fr)
BR (1) BR9504491A (fr)
CZ (1) CZ120097A3 (fr)
FI (1) FI954991A7 (fr)
HU (1) HUT77517A (fr)
IL (1) IL115667A0 (fr)
MX (1) MX9504422A (fr)
NO (1) NO971811L (fr)
NZ (1) NZ292991A (fr)
PL (1) PL319758A1 (fr)
WO (1) WO1996012720A1 (fr)
ZA (1) ZA958839B (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997042174A1 (fr) * 1996-05-03 1997-11-13 Pfizer Inc. Derives indazoles substitues, leur emploi pour inhiber la phosphodiesterase (pde) de type iv, et production du facteur de necrose tumorale
WO1997048697A1 (fr) * 1996-06-19 1997-12-24 Rhone-Poulenc Rorer Limited Composes azabicycliques substitues et leur utilisation en tant qu'inhibiteurs de la production de tnf et de la photodiesterase cyclique d'amp
WO1997049702A1 (fr) * 1996-06-25 1997-12-31 Pfizer Inc. Derives d'indazole substitues et leur utilisation en tant qu'inhibiteurs de phosphodiesterase (pde) type iv et du facteur de necrose tumorale (tnf)
WO1998050367A1 (fr) * 1997-05-08 1998-11-12 Pfizer Products Inc. Procedes et produits intermediaires pour la preparation de derives d'indazole substitues
WO2000039131A1 (fr) * 1998-12-23 2000-07-06 Du Pont Pharmaceuticals Company Heterobicycliques contenant de l'azote utilises comme inhibiteurs du facteur xa
US6326495B2 (en) 1999-04-30 2001-12-04 Pfizer Inc. Process for preparing 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3a,7,8-pentaaza-as-indacenes and intermediates useful therein
WO2002088122A1 (fr) * 2001-04-26 2002-11-07 Ajinomoto Co., Inc. Composes heterocycliques
CN1109673C (zh) * 1997-11-04 2003-05-28 辉瑞产品公司 制备用作iv型磷酸二酯酶抑制剂的4－氰基－4－(取代吲唑)环己烷羧酸的改良方法
WO2004014374A1 (fr) * 2002-07-25 2004-02-19 Pharmacia Italia S.P.A. Bicyclo-pyrazoles actifs utiles comme inhibiteurs de kinase, leur procede de preparation et compositions pharmaceutiques les comprenant
US6706730B2 (en) 2001-04-18 2004-03-16 Bristol-Myers Squibb Pharma Company 1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-ones as factor Xa inhibitors
US6750225B2 (en) 2001-04-18 2004-06-15 Bristol-Myers Squibb Pharms Company 1,4,5,6-tetrahydropyrazolo-[3,4,-c]-pyridin-7-ones useful as factor Xa inhibitors
FR2857363A1 (fr) * 2003-07-10 2005-01-14 Aventis Pharma Sa 4,5,6,7-tetrahydro-1h-pyrazolo[3,4-c] pyridines substituees compositions les contenant et utilisation
US6858616B2 (en) 1998-12-23 2005-02-22 Bristol-Myers Squibb Pharma Company Nitrogen containing heterobicycles as factor Xa inhibitors
WO2005007653A3 (fr) * 2003-07-10 2005-03-24 Aventis Pharma Sa Tetrahydro-1h-pyrazolo[3,4-c]pyridines substituees, compositions les contenant et utilisation
US6967208B2 (en) 2001-09-21 2005-11-22 Bristol-Myers Squibb Pharma Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US6998408B2 (en) 2001-03-23 2006-02-14 Bristol-Myers Squibb Pharma Company 6-5, 6-6, or 6-7 Heterobicycles as factor Xa inhibitors
US7153824B2 (en) 2003-04-01 2006-12-26 Applied Research Systems Ars Holding N.V. Inhibitors of phosphodiesterases in infertility
WO2007064914A3 (fr) * 2005-12-01 2007-12-27 Elan Pharm Inc 5-(arylsulfonyl)-pyrazolopiperidines
US7338963B2 (en) 2001-09-21 2008-03-04 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
WO2009134203A1 (fr) * 2008-04-30 2009-11-05 Fredrik Almqvist Nouveaux composés peptidomimétiques
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
US7741350B1 (en) 2009-01-28 2010-06-22 Cara Therapeutics, Inc. Bicyclic pyrazolo-heterocycles
US8653127B2 (en) 2009-01-28 2014-02-18 Cara Therapeutics, Inc. Bicyclic pyrazolo-heterocycles
WO2015188051A1 (fr) * 2014-06-06 2015-12-10 Biogen Ma Inc. Agents de modulation d'atx

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CN115043768A (zh) * 2022-06-20 2022-09-13 新乡市润宇新材料科技有限公司 一种酸促进环丙基开环合成n-芳基吡咯烷-2-酮的方法

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WO2000039131A1 (fr) * 1998-12-23 2000-07-06 Du Pont Pharmaceuticals Company Heterobicycliques contenant de l'azote utilises comme inhibiteurs du facteur xa
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EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
US6998408B2 (en) 2001-03-23 2006-02-14 Bristol-Myers Squibb Pharma Company 6-5, 6-6, or 6-7 Heterobicycles as factor Xa inhibitors
US6706730B2 (en) 2001-04-18 2004-03-16 Bristol-Myers Squibb Pharma Company 1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-ones as factor Xa inhibitors
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US7902179B2 (en) 2001-04-26 2011-03-08 Ajinomoto Co., Inc. Heterocyclic compounds
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WO2005007653A3 (fr) * 2003-07-10 2005-03-24 Aventis Pharma Sa Tetrahydro-1h-pyrazolo[3,4-c]pyridines substituees, compositions les contenant et utilisation
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US7732609B2 (en) 2005-12-01 2010-06-08 Elan Pharmaceuticals, Inc. 5-(arylsulfonyl)-pyrazolopiperidines
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WO2009134203A1 (fr) * 2008-04-30 2009-11-05 Fredrik Almqvist Nouveaux composés peptidomimétiques
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US8211926B2 (en) 2009-01-28 2012-07-03 Cara Therapeutics, Inc. Bicyclic pyrazolo-heterocycles
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US7741350B1 (en) 2009-01-28 2010-06-22 Cara Therapeutics, Inc. Bicyclic pyrazolo-heterocycles
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US10144732B2 (en) 2014-06-06 2018-12-04 Biogen Ma Inc. ATX modulating agents

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AU702105B2 (en) 1999-02-11
JPH09511758A (ja) 1997-11-25
CZ120097A3 (cs) 1998-01-14
MX9504422A (es) 1997-04-30
NO971811D0 (no) 1997-04-18
NZ292991A (en) 1999-02-25
AU3531795A (en) 1996-05-15
IL115667A0 (en) 1996-01-19
FI954991A0 (fi) 1995-10-19
KR970707124A (ko) 1997-12-01
EP0787132A1 (fr) 1997-08-06
PL319758A1 (en) 1997-08-18
HUT77517A (hu) 1998-05-28
NO971811L (no) 1997-06-18
BR9504491A (pt) 1997-05-20
ZA958839B (en) 1997-04-21
CN1161040A (zh) 1997-10-01
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FI954991A7 (fi) 1996-04-21

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