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WO1995001980A1 - Tetrahydro pyrazolopyridines bicycliques - Google Patents

Tetrahydro pyrazolopyridines bicycliques Download PDF

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Publication number
WO1995001980A1
WO1995001980A1 PCT/IB1994/000156 IB9400156W WO9501980A1 WO 1995001980 A1 WO1995001980 A1 WO 1995001980A1 IB 9400156 W IB9400156 W IB 9400156W WO 9501980 A1 WO9501980 A1 WO 9501980A1
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WO
WIPO (PCT)
Prior art keywords
ethyl
oxo
tetrahydro
pyrazolo
pyridine
Prior art date
Application number
PCT/IB1994/000156
Other languages
English (en)
Inventor
Allen Jacob 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 CA002166721A priority Critical patent/CA2166721C/fr
Priority to EP94916370A priority patent/EP0707585A1/fr
Priority to KR1019960700019A priority patent/KR100228949B1/ko
Priority to RU96103653A priority patent/RU2131876C1/ru
Priority to AU68057/94A priority patent/AU695301B2/en
Priority to BR9406946A priority patent/BR9406946A/pt
Priority to PL94312426A priority patent/PL312426A1/xx
Priority to NZ266525A priority patent/NZ266525A/en
Priority to JP7503938A priority patent/JP2944048B2/ja
Publication of WO1995001980A1 publication Critical patent/WO1995001980A1/fr
Priority to NO960056A priority patent/NO305029B1/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
    • A61P35/00—Antineoplastic agents
    • 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'-C 7 )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'-C ⁇ 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'-C' ⁇ alkyl, (C 1 - C ,4 )alkoxy, (C 2 -C 7 )alkenyl, a (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
  • 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'-C ⁇ alkoxy, (C 3 -C ⁇ )cycloalkoxy, halogen, trifluoromethyl, CO 2 R 6 , CONR 6 R 7 , NR 6 R 7 , NO 2 or SO 2 NR 6 R 7 wherein R ⁇ and R 7 are each independently hydrogen or (C 1 -C 4 )alkyl; wherein Z is oxygen, sulphur, SO 2 or NR 8 wherein R 8 is hydrogen or (C'-C ⁇ alkyl; and Y is (C'-C 5 )alkylene or (C 2 -C 6 )alkenyl optionally substituted with up to two (C'-C 7 )alkyl or (C 3 -C 7 )cycloalkyl groups; or a group of
  • R 9 is (C'-C ⁇ alkyl; wherein each said alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic group may be optionally substituted with one to fourteen, preferably one to five, of the group consisting of (C 1 - C 2 )alkyl, trifluoromethyl or halogen with the proviso that when R 1 is ethyl and R 2 is 4- methylphenyl, 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
  • R 1 is (C 1 -C 3 )alkyl and R 2 and R 3 are each independently selected from the group consisting of (C 3 -C )cycloalkyl, (C 4 -C 7 )heterocyclic group containing SO 2 or a group of the formula
  • a is an integer from 1 to 5 and R 4 is hydrogen, hydroxy, (C'-C ⁇ alkyl, (C 1 -
  • 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 or 3-trifluoromethylphenyl and R 3 is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolanyl, 4-fluorophenyl or 3,4-dichlorophenyl.
  • the present invention further relates to a pharmaceutical composition for the inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) comprising a pharmaceutically effective amount of a compound according to formula I and the pharmaceutically acceptable salts thereof, 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.
  • the present invention further relates to a pharmaceutical composition for the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF comprising a pharmaceutically effective amount of a compound according to formula I and the pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable carrier.
  • This invention further relates to a method of treating or preventing a condition selected from the group consisting of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF comprising administering to a patient an effective amount of a compound according to formula 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.
  • 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- 4- methoxybenzene, 3-methoxybenzene, 2-methoxybenzene, 3-methylbenzene, 4- methylbenzene, 2-methylbenzene, 3-trifluoromethylbenzene, 2-trifluoromethylbenzene, 3,4-dimethoxybenzeneor3-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 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 VII) 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 H- pyrazolo[3,4-c]pyridine compound by reacting IX with sodium methoxide in a polar protic solvent, preferably methanol, for a time period between about 15 minutes to about 45 minutes, preferably 30 minutes.
  • a polar protic solvent preferably methanol
  • 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 VIM 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-1 H-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.
  • 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 about 1.5 hours to about 2.5 hours, preferably 2 hours, and filtered.
  • the filtrate is concentrated to a white solid.
  • DMSO DMSO to achieve desired concentrations.
  • Final DMSO concentration in assay tube is 1 %.
  • the following are added, in order, to a 12 x 75 mm glass tube (all concentrations are given as final concentrations in assay tube).
  • iv) 25 ⁇ l PDE IV enzyme for blank, enzyme is preincubated in boiling water for 5 minutes
  • 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 NaCI, pH 8.5
  • each tube is applied to an Affi-Gel 601 column (Biorad Laboratories,
  • % inhibition 1 - average cpm (test compound) - average cpm (blank) average cpm (control) - average cpm (blank)
  • IC 50 is defined as that concentration of compound which inhibits 50% of specific hydrolysis of [ 3 H]cAMP to [ 3 H]5'AMP.
  • TNF TNF
  • EDTA ethylenediaminetetraacetic acid
  • Mononuclear cells are isolated by FicolF/Hypaque and washed three times in incomplete HBSS. Cells are resuspended in a final concentration of 1 x 10 6 cells per ml in pre-warmed RPMI (containing 5% FCS, glutamine, pen/step and nystatin). Monocytes are plated as 1 x 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 ⁇ l) is added to appropriate wells. Plates are incubated overnight (18 hrs) at 37°C.
  • TNF was analyzed by a sandwich ELISA (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 HCI, HBr, HN0 3 , H 2 S0 4 , H 3 P0 4 , CH 3 SO 3 H, p-CH 3 C 6 H 4 S0 3 H, CH 3 C0 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 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.
  • 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.
  • the resulting dry solid was suspended in cold ether (ice-bath) and treated with oxalyl chloride (31 ⁇ l, 0.35 mmole) and anhydrous N,N-dimethylformamide (1 drop). After stirring for 1 hour the valatiles are removed under reduced pressure, and the crude residue was dissolved in dry tetrahydrofuran. The resulting solution was added dropwise to briskly stirred ammonium hydroxide at 0°C. After warming to ambient temperature over 2 hours the reaction mixture was concentrated under reduced pressure until a yellow solid begins to precipitate. At this time the mixture was diluted with water to approximately 100 ml and filtered, and the precipitate was washed with water to give 81 mg of the title compound.
  • 26 iso- 4-methoxy 3,4- 145-147° 61.40, 4.92, 9.76 61.29, 4.81 , 9.53 propyl phenyl dichloro phenyl
  • Recrystallizing solvents a 5% Ethyl acetate/petroleum ether. b Isopropyl ether. c Ethyl acetate/hexane. d Ethyl ether. "5% Ethyl acetate/pentane. 'Pentane.
  • Example 65 1 -cvclopentyl-3-ethyl-6-cvclopropylmethyl-7-oxo-4.5.6.7-tetrahydro-1 H- pyrazolo[3,4-clpyridine
  • a solution of 1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4- c]pyridine (0.21 grams, 0.92 mmoles) in THF (5 ml) is treated with 60% sodium hydride in mineral oil (40 mg, 1.01 mmoles).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Composés de la formule (I) dans laquelle R?1, R2, R3¿ et X sont tels que définis dans le descriptif. Les composés de la formule (I) et leurs sels pharmaceutiquement acceptables conviennent à l'inhibition de la phosphodiestérase (PDE) de type IV et de la production du facteur de nécrose tumorale (TNF), ainsi qu'au traitement de l'asthme, de l'arthrite, de la bronchite, des affections chroniques et obstructives des voies aériennes, du psoriasis de la rhinite allergique, de la dermatite et d'autres maladies inflammatoires, du SIDA, du choc septique et d'autres maladies impliquant la production de TNF.
PCT/IB1994/000156 1993-07-06 1994-06-16 Tetrahydro pyrazolopyridines bicycliques WO1995001980A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
CA002166721A CA2166721C (fr) 1993-07-06 1994-06-16 Tetrahydropyrazolopyridines bicycliques
EP94916370A EP0707585A1 (fr) 1993-07-06 1994-06-16 Tetrahydro pyrazolopyridines bicycliques
KR1019960700019A KR100228949B1 (ko) 1993-07-06 1994-06-16 이환상 테트라하이드로 피라졸로피리딘
RU96103653A RU2131876C1 (ru) 1993-07-06 1994-06-16 Бициклические тетрагидропиразолпиридины или их фармацевтически приемлемые соли, фармацевтическая композиция, способ ингибирования фосфодиэстеразы, способ лечения
AU68057/94A AU695301B2 (en) 1993-07-06 1994-06-16 Bicyclic tetrahydro pyrazolopyridines
BR9406946A BR9406946A (pt) 1993-07-06 1994-06-16 Tetra-hidro-pirazolpiridinas bicíclicas
PL94312426A PL312426A1 (en) 1993-07-06 1994-06-16 Bicyclic tetrahydropyrazolepyridines
NZ266525A NZ266525A (en) 1993-07-06 1994-06-16 4,5,6,7-tetrahydro-1h-pyrazolo[3,4-c]pyridine derivatives and medicaments
JP7503938A JP2944048B2 (ja) 1993-07-06 1994-06-16 二環式テトラヒドロピラゾロピリジン
NO960056A NO305029B1 (no) 1993-07-06 1996-01-05 Bicykliske tetrahydropyrazolopyridiner

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US8829293A 1993-07-06 1993-07-06
US08/088,292 1993-07-06

Publications (1)

Publication Number Publication Date
WO1995001980A1 true WO1995001980A1 (fr) 1995-01-19

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EP (1) EP0707585A1 (fr)
JP (1) JP2944048B2 (fr)
KR (1) KR100228949B1 (fr)
CN (1) CN1048015C (fr)
AU (1) AU695301B2 (fr)
BR (1) BR9406946A (fr)
CA (1) CA2166721C (fr)
CZ (1) CZ3696A3 (fr)
EG (1) EG20513A (fr)
FI (1) FI943208L (fr)
HU (1) HUT74170A (fr)
IL (1) IL110175A (fr)
MX (1) MX9405132A (fr)
NO (1) NO305029B1 (fr)
NZ (1) NZ266525A (fr)
PL (1) PL312426A1 (fr)
RU (1) RU2131876C1 (fr)
TW (1) TW316904B (fr)
WO (1) WO1995001980A1 (fr)
ZA (1) ZA944844B (fr)

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996012720A1 (fr) * 1994-10-20 1996-05-02 Pfizer Inc. Tetrahydropyrazolopyridines bicycliques et leur emploi comme medicaments
WO1996039408A1 (fr) * 1995-06-06 1996-12-12 Pfizer Inc. 5,6-DIHYDRO-9H-PYRAZOLO[3,4-c]-1,2-4-TRIAZOLO[4,3-α]PYRIDINES TRICYCLIQUES
WO1998009961A1 (fr) * 1996-09-04 1998-03-12 Pfizer Inc. Derives d'indazole et leur utilisation en tant qu'inhibiteurs de phosphodiesterase (pde) de type iv et de la production du facteur de necrose des tumeurs (tnf)
WO2000039131A1 (fr) * 1998-12-23 2000-07-06 Du Pont Pharmaceuticals Company Heterobicycliques contenant de l'azote utilises comme inhibiteurs du facteur xa
AP932A (en) * 1996-08-26 2001-02-02 Pfizer Tricyclic 5,6-dihydro-9H-pyrazolo (3,4c)-1,2,4,-triazolo (4,3-a) pyridines.
EP1145716A2 (fr) * 2000-04-13 2001-10-17 Nippon Zoki Pharmaceutical Co., Ltd. Agent thérapeutique pour traitement de la dermatite
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
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
US6858616B2 (en) 1998-12-23 2005-02-22 Bristol-Myers Squibb Pharma Company Nitrogen containing heterobicycles as factor Xa inhibitors
US6960595B2 (en) * 2001-03-23 2005-11-01 Bristol-Myers Squibb Pharma Company 5-6 to 5-7 Heterobicycles as factor Xa inhibitors
US7135469B2 (en) * 2003-03-18 2006-11-14 Bristol Myers Squibb, Co. Linear chain substituted monocyclic and bicyclic derivatives as factor Xa inhibitors
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7153824B2 (en) 2003-04-01 2006-12-26 Applied Research Systems Ars Holding N.V. Inhibitors of phosphodiesterases in infertility
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US7468376B2 (en) 2003-02-27 2008-12-23 Palau Pharma, S.A. Pyrazolopyridine derivates
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2012118972A2 (fr) 2011-03-01 2012-09-07 Synegy Pharmaceuticals Inc. Procédé de préparation d'agonistes du guanylate cyclase c
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014131024A2 (fr) 2013-02-25 2014-08-28 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et applications associées
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
WO2015021358A2 (fr) 2013-08-09 2015-02-12 Dominique Charmot Composés et procédés d'inhibition du transport de phosphate
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2020237096A1 (fr) 2019-05-21 2020-11-26 Ardelyx, Inc. Combinaison pour baisser le phosphate sérique chez un patient

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PE20081889A1 (es) * 2007-03-23 2009-03-05 Smithkline Beecham Corp Indol carboxamidas como inhibidores de ikk2
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WO1998009961A1 (fr) * 1996-09-04 1998-03-12 Pfizer Inc. Derives d'indazole et leur utilisation en tant qu'inhibiteurs de phosphodiesterase (pde) de type iv et de la production du facteur de necrose des tumeurs (tnf)
US6673810B2 (en) 1998-12-23 2004-01-06 Bristol-Myers Squibb Pharma Company Imidazo-heterobicycles as factor Xa inhibitors
US6413980B1 (en) 1998-12-23 2002-07-02 Bristol-Myers Squibb Pharma Company Nitrogen containing heterobicycles as factor Xa inhibitors
WO2000039131A1 (fr) * 1998-12-23 2000-07-06 Du Pont Pharmaceuticals Company Heterobicycliques contenant de l'azote utilises comme inhibiteurs du facteur xa
US6858616B2 (en) 1998-12-23 2005-02-22 Bristol-Myers Squibb Pharma Company Nitrogen containing heterobicycles as factor Xa inhibitors
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
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
EP1145716A2 (fr) * 2000-04-13 2001-10-17 Nippon Zoki Pharmaceutical Co., Ltd. Agent thérapeutique pour traitement de la dermatite
EP1145716A3 (fr) * 2000-04-13 2002-06-12 Nippon Zoki Pharmaceutical Co., Ltd. Agent thérapeutique pour traitement de la dermatite
US6960595B2 (en) * 2001-03-23 2005-11-01 Bristol-Myers Squibb Pharma Company 5-6 to 5-7 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
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
WO2002088122A1 (fr) * 2001-04-26 2002-11-07 Ajinomoto Co., Inc. Composes heterocycliques
US7902179B2 (en) 2001-04-26 2011-03-08 Ajinomoto Co., Inc. Heterocyclic compounds
US7468376B2 (en) 2003-02-27 2008-12-23 Palau Pharma, S.A. Pyrazolopyridine derivates
US8536194B2 (en) 2003-02-27 2013-09-17 Palau Pharma, S.A. Pyrazolopyridine derivates
US7135469B2 (en) * 2003-03-18 2006-11-14 Bristol Myers Squibb, Co. Linear chain substituted monocyclic and bicyclic derivatives as factor Xa inhibitors
US7153824B2 (en) 2003-04-01 2006-12-26 Applied Research Systems Ars Holding N.V. Inhibitors of phosphodiesterases in infertility
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7230024B2 (en) 2003-04-23 2007-06-12 Pfizer Inc Cannabinoid receptor ligands and uses thereof
US7241788B2 (en) 2003-04-23 2007-07-10 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
WO2007003389A3 (fr) * 2005-07-06 2007-04-19 Aicuris Gmbh & Co Kg Sulfolanylpyrazols substitues et leur utilisation
WO2007003389A2 (fr) * 2005-07-06 2007-01-11 Aicuris Gmbh & Co. Kg Sulfolanylpyrazols substitues et leur utilisation
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
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WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
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NO960056L (no) 1996-01-05
KR960703852A (ko) 1996-08-31
TW316904B (fr) 1997-10-01
CZ3696A3 (en) 1997-06-11
EP0707585A1 (fr) 1996-04-24
CA2166721C (fr) 1999-07-27
CN1129940A (zh) 1996-08-28
NO960056D0 (no) 1996-01-05
JPH08507084A (ja) 1996-07-30
AU695301B2 (en) 1998-08-13
PL312426A1 (en) 1996-04-29
NO305029B1 (no) 1999-03-22
KR100228949B1 (ko) 1999-11-01
FI943208L (fi) 1995-01-07
CA2166721A1 (fr) 1995-01-19
JP2944048B2 (ja) 1999-08-30
IL110175A (en) 2000-01-31
CN1048015C (zh) 2000-01-05
IL110175A0 (en) 1994-10-07
MX9405132A (es) 1995-01-31
ZA944844B (en) 1996-01-05
BR9406946A (pt) 1996-08-06
RU2131876C1 (ru) 1999-06-20
EG20513A (en) 1999-06-30
FI943208A0 (fi) 1994-07-05
NZ266525A (en) 1997-10-24
HUT74170A (en) 1996-11-28
HU9503934D0 (en) 1996-03-28
AU6805794A (en) 1995-02-06

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