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WO2000018732A2 - Pyrrolidinones disubstituees, medicaments contenant ces composes, leur utilisation et leur production - Google Patents

Pyrrolidinones disubstituees, medicaments contenant ces composes, leur utilisation et leur production Download PDF

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Publication number
WO2000018732A2
WO2000018732A2 PCT/EP1999/007141 EP9907141W WO0018732A2 WO 2000018732 A2 WO2000018732 A2 WO 2000018732A2 EP 9907141 W EP9907141 W EP 9907141W WO 0018732 A2 WO0018732 A2 WO 0018732A2
Authority
WO
WIPO (PCT)
Prior art keywords
general formula
methyl
oxymethyl
biphenylyl
pyrrolidinone
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP1999/007141
Other languages
German (de)
English (en)
Other versions
WO2000018732A3 (fr
Inventor
Frank Himmelsbach
Brian Guth
Hans-Dieter Schubert
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals 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 Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Priority to AU60875/99A priority Critical patent/AU6087599A/en
Publication of WO2000018732A2 publication Critical patent/WO2000018732A2/fr
Publication of WO2000018732A3 publication Critical patent/WO2000018732A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • EP-A-0 483 667 and EP-A-0 567 966 already describe disubstituted pyrrolidinones which have valuable pharmacological properties, in particular antiaggregatory effects.
  • the present invention relates to the compounds of the general formula I above, their tautomers, their stereoisomers and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, medicaments containing these compounds, their use and process for their preparation.
  • general formula I mean
  • R L is a C 6 _ 18 alkyl group
  • R 2 is a hydrogen atom, a , C 4 _ 8 -cycloalkyl-, C 3 . 7- cycloalkyl-C 1 . 3 -alkyl-, R 4 -CO-0- (HCR 3 ) - or phenyl-C ⁇ -alkyl- group, in which
  • R 3 is a hydrogen atom or a C ⁇ alkyl group
  • R 4 is a C 1 . Represent 4 alkyl, C ⁇ alkoxy or C 5 _ 7 cycloalkoxy group and
  • the phenyl moiety can be mono- or di-substituted by fluorine, chlorine or bromine atoms, by methyl, methoxy or trifluoromethyl groups, it being possible for the substituents to be identical or different.
  • R x is a C 6 _ 18 alkyl group
  • R 2 is a hydrogen atom, a C 1-4 alkyl, C 5 _ 7 cycloalkyl, C 5-7 cycloalkyl C 1 . 3 -alkyl- / R 4 -CO-0- (HCR 3 ) - or phenyl- C ⁇ alkyl group, in which
  • R 3 is a hydrogen atom or a methyl group
  • R 4 represents a C 1-4 alkyl, C 1 _ 4 alkoxy or C 5 _ 7 cycloalkoxy group
  • Particularly preferred compounds of the general formula I above are those in which R a C 6 . 18 alkyl group and
  • R 2 is a C ⁇ g alkyl or C 5 _ 7 cycloalkyl group, in particular those in which
  • R_ is a C 6.18 alkyl group
  • R 2 represents a C 1.4 alkyl group
  • the new compounds can be prepared, for example, by the following processes which are known per se:
  • R x is defined as mentioned above, with an alcohol of the general formula
  • R 3 and R 4 are defined as mentioned at the outset
  • R 6 is a C x . 18 alkyl, C 4 . 8- cycloalkyl-, C 3 _ 7 -cycloalkyl-C 1 . 3 -alkyl-,
  • Z x is a leaving group such as a halogen atom, e.g. B. a chlorine,
  • the reaction with an alcohol of the general formula III is advantageously carried out in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, but preferably in an alcohol of the general formula III, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, e.g.
  • the reaction is conveniently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide or acetone optionally in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl -morpholine, which can also serve as a solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 ° C, but preferably at temperatures between -10 and 80 ° C.
  • a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide or acetone
  • a reaction accelerator such as sodium or potassium iodide
  • a base such as sodium carbonate or potassium carbonate
  • R 2 is defined as mentioned at the beginning, with a compound of the general formula
  • R 1 is defined as mentioned at the beginning and
  • Z 2 represents a leaving group such as a halogen atom, for example a chlorine atom.
  • the reaction is preferably carried out in a solvent or solvent mixture such as acetone, acetone / water, methylene chloride, tetrahydrofuran, tetrahydrofuran / water, toluene or dioxane, optionally in the presence of an inorganic or a tertiary organic base such as potassium carbonate or N-ethyl-di- Isopropylamine, preferably carried out at temperatures between 0 and 80 ° C.
  • a solvent or solvent mixture such as acetone, acetone / water, methylene chloride, tetrahydrofuran, tetrahydrofuran / water, toluene or dioxane
  • an inorganic or a tertiary organic base such as potassium carbonate or N-ethyl-di- Isopropylamine, preferably carried out at temperatures between 0 and 80 ° C.
  • the compounds of general formula I obtained which occur in racemates can be converted into their optical antipodes and by known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)
  • the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as, for example, esters or amides, with the racemic compound, in particular acids and their activated derivatives or alcohols, and Separation of the diastereomeric salt mixture or derivative obtained in this way, for example on the basis of different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • an optically active substance which forms salts or derivatives, such as, for example, esters or amides
  • optically active acids are, for example, the D and L forms of tartar re or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
  • suitable optically active alcohols are (+) or (-) menthol and optically active acyl radicals in amides are, for example, the (+) - or (-) menthyloxycarbonyl radicals.
  • the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
  • suitable acids for this are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of the formula I obtained in this way if they contain a carboxy group, can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
  • Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the new disubstituted pyrrolidinones of the general formula I and their salts have valuable properties.
  • high and long-lasting plasma levels of Fradafiban (BIBU 52) are achieved after oral administration.
  • the new compounds of general formula I and their salts have valuable pharmacological properties, in addition to an anti-inflammatory and bone-depleting action, in particular antithrombotic, antiaggregatory and anti-tumor or metastatic effects.
  • the plasma levels of fradifaban are determined after oral administration of the compounds of the present invention by methods known per se (see Circulation 1997; 96: 1130-1138).
  • the new compounds of the general formula -I and their physiologically tolerable salts according to the invention are suitable for combating or preventing diseases in which smaller or larger cell aggregates occur or cell matrix interactions play a role, e.g. in combating or preventing venous and arterial thrombosis, cerebrovascular diseases, pulmonary embolism, myocardial infarction, arteriosclerosis, osteoporosis and the metastasis of tumors and the therapy of genetically determined or acquired disorders of the interactions of cells with or with one another solid structures.
  • These are also suitable for accompanying therapy in thrombolysis with fibrinolytics or vascular interventions such as transluminal angioplasty or in the therapy of shock conditions, psoriasis, diabetes and inflammation.
  • the dose is between 0.1 ⁇ g and 30 mg / kg body weight, preferably 1 ⁇ g to 15 mg / kg body weight, with up to 4 doses per day.
  • the compounds of the formula I prepared according to the invention optionally in combination with other active substances such as thromboxane receptor antagonists and thromboxane synthesis inhibitors or combinations thereof, ADP receptor antagonists, clopidogrel, ticlo pidines, serotonin antagonists, ⁇ receptor antagonists, Al - Kylnitrate such as glycerol trinitrate, phosphodiesterase inhibitors, prostacyclin and their analogs, fibrinolytics such as tPA, prourokinase, urokinase, streptokinase, or anticoagulants such as heparin, dermatan sulfate, activated protein C, vitamin K antagonists, hirudin, or inhibitors of other activated desir
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing. This powder mixture is filled into size 3 hard gelatin capsules on a capsule filling machine.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
  • This powder mixture is filled in a size 0 hard gelatin capsule on a capsule filling machine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des pyrrolidinones disubstituées de la formule générale (I), dans laquelle R1 et R2 correspondent à la définition donnée dans la revendication 1, les tautomères de ces composés, les stéréoisomères de ces composés, y compris leurs mélanges et leurs sels, en particulier leurs sels physiologiquement tolérés avec des acides ou des bases inorganiques ou organiques, lesquels présentent de précieuses caractéristiques pharmacologiques, de préférence des effets antithrombotiques, ainsi que des médicaments contenant ces composés, leur utilisation et leur procédé de production.
PCT/EP1999/007141 1998-09-30 1999-09-25 Pyrrolidinones disubstituees, medicaments contenant ces composes, leur utilisation et leur production Ceased WO2000018732A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU60875/99A AU6087599A (en) 1998-09-30 1999-09-25 Disubstituted pyrrolidinones, medicaments containing these compounds, their use and the production thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19844787A DE19844787A1 (de) 1998-09-30 1998-09-30 Disubstituierte Pyrrolidinone, diese Verbindung enthaltende Arzneimittel und deren Verwendung sowie ihre Herstellung
DE19844787.6 1998-09-30

Publications (2)

Publication Number Publication Date
WO2000018732A2 true WO2000018732A2 (fr) 2000-04-06
WO2000018732A3 WO2000018732A3 (fr) 2000-05-25

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/007141 Ceased WO2000018732A2 (fr) 1998-09-30 1999-09-25 Pyrrolidinones disubstituees, medicaments contenant ces composes, leur utilisation et leur production

Country Status (3)

Country Link
AU (1) AU6087599A (fr)
DE (1) DE19844787A1 (fr)
WO (1) WO2000018732A2 (fr)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4035961A1 (de) * 1990-11-02 1992-05-07 Thomae Gmbh Dr K Cyclische iminoderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung
DE4213919A1 (de) * 1992-04-28 1993-11-04 Thomae Gmbh Dr K Cyclische iminoderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel

Also Published As

Publication number Publication date
WO2000018732A3 (fr) 2000-05-25
DE19844787A1 (de) 2000-04-13
AU6087599A (en) 2000-04-17

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