WO1997025312A1 - NOUVEAUX DERIVES DE ROLIPRAM UTILISES COMME INHIBITEURS DE cAMP-PDE IV - Google Patents

NOUVEAUX DERIVES DE ROLIPRAM UTILISES COMME INHIBITEURS DE cAMP-PDE IV Download PDF

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Publication number
WO1997025312A1
WO1997025312A1 PCT/DE1997/000058 DE9700058W WO9725312A1 WO 1997025312 A1 WO1997025312 A1 WO 1997025312A1 DE 9700058 W DE9700058 W DE 9700058W WO 9725312 A1 WO9725312 A1 WO 9725312A1
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Prior art keywords
formula
alkyl
cyclopentyloxy
compound
methoxyphenyl
Prior art date
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PCT/DE1997/000058
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German (de)
English (en)
Inventor
Ralph Schmiechen
Henry Laurent
Peter Esperling
Kurt Hamp
Alfred Breitkopf
Carlo SKÖTSCH
Herbert Schneider
Helmut Wachtel
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Schering Aktiengesellschaft
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Priority to AU19229/97A priority Critical patent/AU1922997A/en
Publication of WO1997025312A1 publication Critical patent/WO1997025312A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/58—One oxygen atom, e.g. butenolide

Definitions

  • the invention relates to the compounds of formula I, the process for their preparation and their use in medicaments.
  • cAMP-PDE IV inhibitor selective inhibitors of cAMP-specific phosphodiesterase IV
  • cAMP-PDE IV inhibitor selective inhibitors of cAMP-specific phosphodiesterase IV
  • One of the best known compounds of the inhibitors of cAMP-PDE-IV is rolipram (4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone, USP 4,194,926. Numerous modifications have been made to the molecule to improve the effectiveness of rolipram without achieving the desired increase in effectiveness.
  • the compounds of the formula I are very potent selective cAMP-PDE IV inhibitors which are metabolically very stable. Since the new compounds which have properties known from inhibitors of PDE-IV, such as influencing the central neurotransmission, relaxation of the smooth muscle cells and inhibition of TNF production and at the same time have an extended duration of action, they are more advantageous as a medicament than rolipram.
  • the invention relates to the compounds of formula I.
  • R 1 C1..4 alkyl
  • R 2 C * _6 alkyl, C3_7 cycloalkyl, C3. 7- Cycloalkyl-C * .2-alkyl, C 2 -6-alkenyl, C ⁇ .g- bicycloalkyl, a heterocycle or C ⁇ . ⁇ -alkyl which is substituted by one or more halogens, hydroxy, carboxy, C 1-4 alkoxy, C 4 alkoxycarbonyl or an amino group which is optionally substituted by C 1.4 alkyl, R3
  • R 4 is hydrogen or Cj.5- alkyl
  • R 5 is hydrogen, C 6 alkyl, Ci.g alkanoyl, benzoyl, benzyl, mesyl, phenyl, benzethyl,
  • R ⁇ hydrogen, hydroxy and their isomers and mixtures thereof.
  • the compounds of formula I can contain one or more chiral centers and also include the racemic diastereomeric mixtures and the individual optical isomers.
  • Alkyl means in each case straight-chain or branched alkyl groups, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-methyl-butyl, 2,2-dimethylpropyl and hexyl .
  • Alkenyl means, for example, 1-propenyl, 2-propenyl or 3-methyl-2-propenyl.
  • Cycloalkyl means, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • heterocycle encompasses a 5- or 6-membered saturated heterocycle having an oxygen, sulfur or nitrogen atom, such as, for example, 2- and 3-tetrahydropyranyl, 2- and 3-tetrahydrofuranyl, dihydropyranyl, pyrrolidinyl, pyrrolinyl, Pipe ⁇ ridinyl and N-alkyl-pyrrolidinyl and N-alkyl-piperidinyl in which the alkyl radical contains 1-4 carbon atoms.
  • Heterocycles with more than one heteroatom such as morpholine, piperazine and N-alkyl-piperazine, are also included.
  • Halogen means chlorine, fluorine, bromine and iodine.
  • bicycloalkyls examples include bicyclo [2.2.1] hept-2-yl, bicyclo [2.2.2] oct-2-yl and bicyclo [3.2.1] oct-3-yl.
  • the new compounds of formula I and their isomers are inhibitors of phosphodiesterase IV and influence the signaling function of this important intracellular transmitter, which is the molecular substrate of the information transfer in a variety of biochemical reactions, through the targeted intervention in the cAMP metabolism.
  • the compounds of the formula I and their isomers are also TNF inhibitors and influence diseases which are triggered by stimulation of TNF and diseases in which other cytokines such as, for example, II-1 or U-6 are influenced by TNF.
  • diseases are, for example, inflammatory diseases, autoimmune diseases, bone resorption diseases and infection diseases.
  • TNF means both TNF-oc and TNF- ⁇ , both of which are antagonized by the compounds of the formula I. TNF- ⁇ is preferably inhibited.
  • the compounds of the formula I are therefore suitable for producing a pharmaceutical preparation which is used for the treatment and prophylaxis of diseases in living organisms which are triggered by suppression of cAMP or by stimulation of TNF.
  • Diseases which are influenced by excessive or unregulated TNF stimulation or inhibition of PDE IV include allergic and inflammatory diseases, autoimmune diseases, cerebral diseases, pulmonary diseases, infectious diseases and bone resorption diseases such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and gout , Sepsis, septic shock, endotoxin shock, gram negative sepsis, toxic shock syndrome, ARDS (acute respiratory distress syndrome), pulmonary sarcoidosis, asthma, chronic bronchitis, allergic rhinitis, conjunctivitis, fibrosis including cystic fibrosis and atherosclerosis, silulonosis, glulosis, pyrulosis, glulosis, pyrulosis, athe
  • the compounds are suitable for the treatment of infectious diseases such as viral infections with, for example, HIV, Borna, Epstein, Barr, Masem, Arbovirus pathogens, especially of the central nervous system, parasitic infections such as cerebral malaria, fever, myalgia, HIV , AIDS, cachexia and mad cow disease.
  • infectious diseases such as viral infections with, for example, HIV, Borna, Epstein, Barr, Masem, Arbovirus pathogens, especially of the central nervous system, parasitic infections such as cerebral malaria, fever, myalgia, HIV , AIDS, cachexia and mad cow disease.
  • Other diseases that can be treated with the compounds of formula I are multiple sclerosis, leprosy, diabetes mellitus, diabetes insipidus, leukemia, panencephalitis, cerebral disorders such as depression, senile dementia, multi-infarction, dementia and stroke.
  • the compounds of the formula I can also be used for the treatment of inflammatory skin diseases, such as, for example, psoriasis, urticaria, atopic dermatitis, allergic rhinitis, contact dermatitis, rheumatic arthritis, lupus ery thematosus, sunburn, eczema.
  • inflammatory skin diseases such as, for example, psoriasis, urticaria, atopic dermatitis, allergic rhinitis, contact dermatitis, rheumatic arthritis, lupus ery thematosus, sunburn, eczema.
  • the effectiveness of the compounds of the formula I in the known indications can be shown by appropriate pharmacological tests.
  • the biological activity is often greater in one of the stereoisomers.
  • the agents are produced by customary processes by bringing the active ingredient into the form of a pharmaceutical preparation with suitable carriers, auxiliaries and / or additives which is suitable for enteral or parenteral administration.
  • suitable carriers auxiliaries and / or additives which is suitable for enteral or parenteral administration.
  • the application can take place orally or sublingually as a solid in the form of capsules or tablets or as liquid in the form of solutions, suspensions, elixirs, aerosols or emulsions or rectally in the form of suppositories or in the form of injection solutions which can optionally be used subcutaneously or topically or intrathecally.
  • the auxiliary organic and inorganic carrier materials known to the person skilled in the art are suitable as auxiliaries for the desired pharmaceutical formulation, such as, for. B.
  • osmotic pressure or buffer water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. If necessary, preservatives, stabilizers, wetting agents, emulsifiers or salts to change the osmotic pressure or buffer may also be included.
  • the pharmaceutical preparations can be in solid form, for example as tablets, dragees, suppositories, capsules or in liquid form, for. B. present as solutions, suspensions or emulsions.
  • Auxiliaries close to the surface such as salts, bile acids or animal or vegetable phosphohpides, but also mixtures thereof and liposomes or their constituents can also be used as carrier systems.
  • tablets, coated tablets or capsules with talc and / or hydrocarbon carrier or binder such as. B. lactose, corn or potato starch, suitable.
  • the application can also be in liquid form, such as. B. as juice to which sweetener may be added.
  • Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use, or implanted mini pumps with delayed release of active ingredient are also suitable.
  • the pharmaceutical product can be administered in a single dose or in multiple doses e.g. B. 2, 3 or 4 times a day or by an osmotic pump, which allow continuous application.
  • the active compounds can be administered simultaneously, for example alternately, in a single or separate dosage or at different times.
  • the active ingredients are processed in a conventional manner using conventional emulsifiers and auxiliaries.
  • the dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors.
  • the daily dose is 0.001-100 mg, preferably 0.01-40 mg, and the dose can be given as a single dose to be administered once or divided into 2 or more daily doses.
  • the compounds of the formula I are prepared by methods known per se, as are described in the literature (for example in standard works such as Houben-Weyl, methods of Org. Chemie, Georg Thieme Verlag Stuttgart), and under reaction conditions which are suitable for the implementations mentioned are known or suitable. It is also possible to use known variants which are not mentioned here.
  • the invention therefore relates to the process for the preparation of the compounds of the formula I and their isomers.
  • R 1 , R 2 and R 4 have the above meaning and R * - * 'is hydrogen or C ⁇ _6-alkyl, decarboxylated.
  • the decarboxylation is carried out thermally by heating to 180 ° C., optionally in an inert solvent such as hydrocarbons.
  • the compounds of the formula Ia are not prepared via the starting materials Ua according to the syntheses known from USP 4,193,626 and USP 4,153,713 but according to the following scheme:
  • the ketone is reacted with nitromethane in inert solvents such as halogenated hydrocarbons, cyclic or acyclic ethers or hydrocarbons such as dichloromethane, tetrahydrofuran, toluene in the presence of organic bases such as triethylamine.
  • inert solvents such as halogenated hydrocarbons, cyclic or acyclic ethers or hydrocarbons such as dichloromethane, tetrahydrofuran, toluene
  • organic bases such as triethylamine.
  • the condensation is carried out under pressure.
  • the 2-nitroethanol derivative thus obtained is dehydrated in the usual manner in the presence of p-toluenesulfonic acid.
  • the subsequent reaction of the nitrostyrene derivative with a di- (C ⁇ _5) -alkyl-malonic ester is carried out in the presence of bases such as alkali metal alcoholates either at room temperature or under pressure.
  • REPLACEMENT BUTT (RULE 26)
  • the cyclization to the corresponding lactam is achieved reductively with Raney nickel in inert solvents such as cyclic ethers, alcohols and mixtures thereof. Increased H2 pressure and elevated temperature are advantageous for the implementation.
  • the saponification of the ester group is carried out basic by hydrolyzing at elevated temperature up to the boiling point of the reaction mixture with alkali metal hydroxides in aqueous solvents such as alcohols or cyclic ethers.
  • R * and R 2 have the meaning given above, R denotes C 5 alkyl and shark halogen, cyclized with ammonia to give a compound of the formula I-c '
  • the compounds of formula III are cyclized by reacting the halogen derivative, in particular the bromide or iodide, with ammonia in protic solvents such as alcohols.
  • the reaction is generally carried out at temperatures from 0 ° C. to room temperature.
  • the hydroxylation can be carried out in the presence of Cu (I) and Cu (II) halides, such as bromides, in aqueous solvent mixtures, such as, for example, dimethylformamide / water, by introducing air.
  • aqueous solvent mixtures such as, for example, dimethylformamide / water
  • Rl and R 2 have the above meaning and R is in each case C 1-4 alkyl, intramolecularly condensed to a compound of formula Id.
  • the condensation to the lactone of the formula I-d is achieved by heating the compound of the formula IV in inert solvents such as high-boiling hydrocarbons with p-toluenesulfonic acid.
  • R- and R 2 have the above meaning, rearranged with hydroxylamines to a compound of the formula Ie and, if desired, then hydrogenated to a compound of the formula If.
  • the intermediate oxime formed can be obtained, for example, with O-mesitylene-sulfonyl-hydroxylamine in inert solvents such as halogenated or aromatic hydrocarbons at room temperature.
  • inert solvents such as halogenated or aromatic hydrocarbons at room temperature.
  • the rearrangement occurs in the presence of bases such as basic alumina.
  • the double bond can be reduced in a customary manner, for example in the presence of noble metal catalysts such as palladium or platinum, if appropriate on supports, in polar solvents at room temperature or elevated temperature. If desired, the compounds of the formula I obtained in this way can subsequently be alkylated, acylated or arylated or separated into the isomers.
  • noble metal catalysts such as palladium or platinum
  • the R- ⁇ substituent can be introduced by customary methods, for example by reacting the reactive derivative R 5 X, where X is halogen or tosylate, in the presence of a base such as alkali metal hydroxide, carbonate or alcoholate or alkali metal hydride.
  • a base such as alkali metal hydroxide, carbonate or alcoholate or alkali metal hydride.
  • the isomer mixtures can be separated into the enantiomers by customary methods such as chromatography, crystallization or conversion into diastereomers such as salt formation.
  • the enantiomers can be separated in the final stage or in the intermediate stages; if appropriate, the enantiomers can also be synthesized from chiral intermediates or with chiral auxiliaries.
  • the compounds of formula V are by the method of M.J. Bestmann et al. Chem. Ber.118, 2640-2658 [1985].
  • Sodium hydride (4.0 g, 166 mmol) is added to dimethoxyethane (160 ml) with stirring. At 0 ° C., ethyl phosphonoacetate (33 ml, 166 mmol) is then dissolved in dimethoxyethane (50 ml), slowly added dropwise and the mixture is stirred at room temperature for 1 hour. A solution of (3-cyclopentyloxy-4-methoxyacetophenone (15 g, 64 mmol) in dimethoxymethane (50 ml) is then added and the mixture is heated to 80 ° C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule (I), leur production et leur utilisation dans des médicaments.
PCT/DE1997/000058 1996-01-12 1997-01-10 NOUVEAUX DERIVES DE ROLIPRAM UTILISES COMME INHIBITEURS DE cAMP-PDE IV WO1997025312A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU19229/97A AU1922997A (en) 1996-01-12 1997-01-10 New rolipram derivatives as camp-pde iv inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE1996101938 DE19601938A1 (de) 1996-01-12 1996-01-12 Neue Phosphodiesteraseinhibitoren
DE19601938.9 1996-01-12

Publications (1)

Publication Number Publication Date
WO1997025312A1 true WO1997025312A1 (fr) 1997-07-17

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DE (1) DE19601938A1 (fr)
WO (1) WO1997025312A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047905A1 (fr) * 1999-12-23 2001-07-05 Icos Corporation Derives de pyrrolidine convenant comme inhibiteurs de la phpsphodiesterase a specificite amp cyclique
WO2001047879A1 (fr) * 1999-12-23 2001-07-05 Icos Corporation Pyrrolidines inhibitrices de la phosphodiesterase specifique d'amp cyclique
JP2002265441A (ja) * 2001-03-13 2002-09-18 Japan Science & Technology Corp ピロリノン誘導体及びその製造方法
US6680336B2 (en) 1999-12-15 2004-01-20 Icos Corporation Cyclic AMP-specific phosphodiesterase inhibitors
US7226930B2 (en) 2003-04-18 2007-06-05 Memory Pharmaceutical Corporation Phosphodiesterase 4 inhibitors
US7235579B2 (en) 2001-10-16 2007-06-26 Memory Pharmaceuticals Corp. Phosphodiesterase 4 inhibitors
US7432266B2 (en) 2004-10-15 2008-10-07 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors
US7585882B2 (en) 2004-10-20 2009-09-08 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors
US7696198B2 (en) 2003-04-16 2010-04-13 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
JP2016510759A (ja) * 2013-03-13 2016-04-11 イーライ リリー アンド カンパニー アゼチジニルオキシフェニルピロリジン化合物

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US6316472B1 (en) * 1999-05-13 2001-11-13 Merck Frosst Canada & Co. Heterosubstituted pyridine derivatives as PDE 4 inhibitors

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US5459151A (en) * 1993-04-30 1995-10-17 American Home Products Corporation N-acyl substituted phenyl piperidines as bronchodilators and antiinflammatory agents

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
US6680336B2 (en) 1999-12-15 2004-01-20 Icos Corporation Cyclic AMP-specific phosphodiesterase inhibitors
WO2001047905A1 (fr) * 1999-12-23 2001-07-05 Icos Corporation Derives de pyrrolidine convenant comme inhibiteurs de la phpsphodiesterase a specificite amp cyclique
WO2001047879A1 (fr) * 1999-12-23 2001-07-05 Icos Corporation Pyrrolidines inhibitrices de la phosphodiesterase specifique d'amp cyclique
US6376489B1 (en) 1999-12-23 2002-04-23 Icos Corporation Cyclic AMP-specific phosphodiesterase inhibitors
JP2003519135A (ja) * 1999-12-23 2003-06-17 アイコス コーポレイション 環状ａｍｐ特異性ホスホジエステラーゼ阻害剤としてのピロリジン誘導体
EA007589B1 (ru) * 1999-12-23 2006-12-29 Айкос Корпорейшен ПИРРОЛИДИНЫ, КОТОРЫЕ ИНГИБИРУЮТ цАМФ-СПЕЦИФИЧНУЮ PDE
JP2002265441A (ja) * 2001-03-13 2002-09-18 Japan Science & Technology Corp ピロリノン誘導体及びその製造方法
US7235579B2 (en) 2001-10-16 2007-06-26 Memory Pharmaceuticals Corp. Phosphodiesterase 4 inhibitors
US7696198B2 (en) 2003-04-16 2010-04-13 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors
US7495017B2 (en) 2003-04-18 2009-02-24 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors
US7226930B2 (en) 2003-04-18 2007-06-05 Memory Pharmaceutical Corporation Phosphodiesterase 4 inhibitors
US7432266B2 (en) 2004-10-15 2008-10-07 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors
US7723348B2 (en) 2004-10-15 2010-05-25 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors
US7585882B2 (en) 2004-10-20 2009-09-08 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors
JP2016510759A (ja) * 2013-03-13 2016-04-11 イーライ リリー アンド カンパニー アゼチジニルオキシフェニルピロリジン化合物

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Publication number Publication date
AU1922997A (en) 1997-08-01
DE19601938A1 (de) 1997-07-17

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