WO2000018732A2 - Disubstituted pyrrolidinones, medicaments containing these compounds, their use and the production thereof - Google Patents

Disubstituted pyrrolidinones, medicaments containing these compounds, their use and the production thereof 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
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general formula
methyl
oxymethyl
biphenylyl
pyrrolidinone
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PCT/EP1999/007141
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German (de)
French (fr)
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WO2000018732A3 (en
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Frank Himmelsbach
Brian Guth
Hans-Dieter Schubert
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Boehringer Ingelheim Pharma Kg
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Publication of WO2000018732A3 publication Critical patent/WO2000018732A3/en

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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
    • 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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Abstract

The invention relates to disubstituted pyrrolidinones of general formula (I) in which R1 and R2 are defined in Claim No. 1. The invention also relates to the tautomers thereof, stereoisomers thereof, including their mixtures and their salts, especially the physiologically compatible salts with inorganic or organic acids or bases which comprise valuable pharmacological properties, preferably antithrombotic effects. In addition, the invention relates to medicaments containing these compounds, to their use and to a method for the production thereof.

Description

Disubstituierte Pyrrolidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung sowie ihre Herstellung Disubstituted pyrrolidinones, medicaments containing these compounds and their use and their preparation
In der EP-A-0 483 667 und EP-A-0 567 966 werden bereits disubstituierte Pyrrolidinone beschrieben, welche wertvolle pharma- kologische Eigenschaften aufweisen, insbesondere antiaggrega- torische Wirkungen.EP-A-0 483 667 and EP-A-0 567 966 already describe disubstituted pyrrolidinones which have valuable pharmacological properties, in particular antiaggregatory effects.
Es wurde nun gefunden, daß die disubstituierten Pyrrolidinone der allgemeinen FormelIt has now been found that the disubstituted pyrrolidinones of the general formula
Figure imgf000003_0001
Figure imgf000003_0001
deren Tautomere, deren Stereoisomere und deren Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren oder Basen, noch wertvollere pharmakologische Eigenschaften aufweisen, vorzugsweise antithrombotische Wirkungen, wobei sich die obigen Verbindungen von denen der EP-A-0 483 667 und der EP-A-0 567 966 immer durch die Reste Rx oder R2 oder R und R2 unterscheiden.whose tautomers, their stereoisomers and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, have even more valuable pharmacological properties, preferably antithrombotic effects, the above compounds differing from those of EP-A-0 483 667 and EP Always distinguish -A-0 567 966 by the radicals R x or R 2 or R and R 2 .
Gegenstand der vorliegenden Erfindung sind die Verbindungen der obigen allgemeinen Formel I, deren Tautomere, deren Stereoisomere und deren Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren oder Basen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung. In der obigen allgemeinen Formel I bedeutenThe 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. In the above general formula I mean
R-L eine C6_18-Alkylgruppe undR L is a C 6 _ 18 alkyl group and
R2 ein Wasserstoffatom, eine
Figure imgf000004_0001
, C4_8-Cycloalkyl- , C3.7-Cycloalkyl-C1.3-alkyl-, R4-CO-0- (HCR3) - oder Phenyl-C^-al- kyl-Gruppe, in denenR 2 is a hydrogen atom, a
Figure imgf000004_0001
, 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
R3 ein Wasserstoffatom oder eine C^-Alkylgruppe undR 3 is a hydrogen atom or a C ^ alkyl group and
R4 eine C1.4-Alkyl- , C^-Alkoxy- oder C5_7-Cycloalkoxygruppe darstellen undR 4 is a C 1 . Represent 4 alkyl, C ^ alkoxy or C 5 _ 7 cycloalkoxy group and
der Phenylteil durch Fluor-, Chlor- oder Bromatome, durch Methyl-, Methoxy- oder Trifluormethylgruppen mono- oder di- substituiert sein kann, wobei die Substituenten gleich oder verschieden sein können.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.
Bevorzugte Verbindungen der obigen allgemeinen Formel I sind diejenigen, in denenPreferred compounds of the above general formula I are those in which
Rx eine C6_18-Alkylgruppe undR x is a C 6 _ 18 alkyl group and
R2 ein Wasserstoffatom, eine C^-Alkyl-, C5_7-Cycloalkyl- , C5-7-Cycloalkyl-C1.3-alkyl-/ R4-CO-0- (HCR3) - oder Phenyl- C^-alkyl-Gruppe, in denenR 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
R3 ein Wasserstoffatom oder eine Methylgruppe undR 3 is a hydrogen atom or a methyl group and
R4 eine C1-4-Alkyl-, C1_4-Alkoxy- oder C5_7-Cycloalkoxygruppe darstellen,R 4 represents a C 1-4 alkyl, C 1 _ 4 alkoxy or C 5 _ 7 cycloalkoxy group,
bedeuten, deren Tautomere, deren Stereoisomere und deren Salze.mean, their tautomers, their stereoisomers and their salts.
Besonders bevorzugte Verbindungen der obigen allgemeinen Formel I sind diejenigen, in denen R eine C6.18-Alkylgruppe undParticularly preferred compounds of the general formula I above are those in which R a C 6 . 18 alkyl group and
R2 eine C^g-Alkyl- oder C5_7-Cycloalkylgruppe bedeuten, insbesondere diejenigen, in denenR 2 is a C ^ g alkyl or C 5 _ 7 cycloalkyl group, in particular those in which
R_ eine C6.18-Alkylgruppe undR_ is a C 6.18 alkyl group and
R2 eine C1.4-Alkylgruppe bedeuten,R 2 represents a C 1.4 alkyl group,
deren Tautomere, deren Stereoisomere und deren Salze.their tautomers, their stereoisomers and their salts.
Als besonders bevorzugte Verbindungen der allgemeinen Formel I seien beispielsweise folgende erwähnt :The following may be mentioned as particularly preferred compounds of the general formula I:
(1) (3S, 5S) -5- [ [4 ' - (N-Hexyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon,(1) (3S, 5S) -5- [[4 '- (N-Hexyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone,
(2) (3S, 5S) -5- [ [4 ' - (N-Octyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon,(2) (3S, 5S) -5- [[4 '- (N-octyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone,
(3) (3S,5S) -5- [ [4 ' - (N-Decyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon,(3) (3S, 5S) -5- [[4 '- (N-decyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone,
(4) (3S, 5S) -5- [ [4 ' - (N-Dodecyloxycarbonylamidino) -4-biphe- nylyl] oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon,(4) (3S, 5S) -5- [[4 '- (N-dodecyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone,
(5) (3S, 5S) -5- [ [4 ' - (N-Tetradecyloxycarbonylamidino) -4-biphe- nylyl] oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon,(5) (3S, 5S) -5- [[4 '- (N-tetradecyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone,
(6) (3S, 5S) -5- [ [4 ' - (N-Hexadecyloxycarbonylamidino) -4-biphe- nylyl] oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon,(6) (3S, 5S) -5- [[4 '- (N-hexadecyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone,
(7) (3S,5S) -5- [ [4 ' - (N-Hexyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon,(7) (3S, 5S) -5- [[4 '- (N-Hexyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone,
(8) (3S, 5S) -5- [ [4 ' - (N-Octyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon, (9) (3S, 5S) -5- [ [4 ' - (N-Decyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon,(8) (3S, 5S) -5- [[4 '- (N-octyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone, (9) (3S, 5S) -5- [[4 '- (N-decyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone,
(10) (3S, 5S) -5- [ [4 ' - (N-Dodecyloxycarbonylamidino) -4-biphe- nylyl] oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon,(10) (3S, 5S) -5- [[4 '- (N-dodecyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone,
(11) (3S, 5S) -5- [ [4 ' - (N-Tetradecyloxycarbonylamidino) -4-biphe- nylyl] oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon und(11) (3S, 5S) -5- [[4 '- (N-tetradecyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone and
(12) (3S,5S)-5-[[4'- (N-Hexadecyloxycarbonylamidino) -4-biphe- nylyl] oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon(12) (3S, 5S) -5 - [[4'- (N-Hexadecyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone
sowie deren Tautomere und deren Salze.as well as their tautomers and their salts.
Erfindungsgemäß können die neuen Verbindungen beispielsweise nach folgenden an und für sich bekannten Verfahren hergestellt werden :According to the invention, the new compounds can be prepared, for example, by the following processes which are known per se:
a. Zur Herstellung einer Verbindung der allgemeinen Formel I, in der R2 eine C1.18-Alkyl- , C4.8-Cycloalkyl- , C3_7-Cycloalkyl- C^-alkyl-, R4-CO-0- (HCR3) - oder Phenyl-C1.3-alkyl-Gruppe darstellt :a. For the preparation of a compound of the general formula I in which R 2 is a C 1 . 18 alkyl, C 4 . 8- cycloalkyl-, C 3 _ 7 -cycloalkyl- C ^ -alkyl-, R 4 -CO-0- (HCR 3 ) - or phenyl-C 1 . 3 alkyl group represents:
Umsetzung einer Verbindung der allgemeinen FormelImplementation of a compound of the general formula
Figure imgf000006_0001
Figure imgf000006_0001
in derin the
Rx wie eingangs erwähnt definiert ist, mit einem Alkohol der allgemeinen FormelR x is defined as mentioned above, with an alcohol of the general formula
HO - R5 , (III)HO - R 5 , (III)
in der R5 eine
Figure imgf000007_0001
, C4_e-Cycloalkyl- , C3_7-Cycloalkyl-C1_3-alkyl- , R4-CO-0- (HCR3) - oder Phenyl-C^-alkyl-Gruppe darstellt, wobeiin the R 5 a
Figure imgf000007_0001
, C 4 _ e -cycloalkyl-, C 3 _ 7 -cycloalkyl-C 1 _ 3 -alkyl-, R 4 -CO-0- (HCR 3 ) - or phenyl-C ^ -alkyl group, where
R3 und R4 wie eingangs erwähnt definiert sind,R 3 and R 4 are defined as mentioned at the outset,
oder mit deren Formamidacetalen -or with their formamide acetals -
oder mit einer Verbindung der allgemeinen Formelor with a compound of the general formula
Zx - R6 , (IV)Z x - R 6 , (IV)
in derin the
R6 eine Cx.18-Alkyl- , C4.8-Cycloalkyl- , C3_7-Cycloalkyl-C1.3-alkyl- ,R 6 is a C x . 18 alkyl, C 4 . 8- cycloalkyl-, C 3 _ 7 -cycloalkyl-C 1 . 3 -alkyl-,
R4-CO-0- (HCR3) - oder Phenyl -C^-alkyJ -Gruppe undR 4 -CO-0- (HCR 3 ) - or phenyl -C ^ alkylJ group and
Zx eine Austrittsgruppe wie ein Halogenatom, z. B. ein Chlor-,Z x is a leaving group such as a halogen atom, e.g. B. a chlorine,
Brom- oder Iodatom, darstellen.Bromine or iodine atom.
Die Umsetzung mit einem Alkohol der allgemeinen Formel III wird zweckmäßigerweise in einem Lösungsmittel oder Lösungsmittelgemisch wie Methylenchlorid, Benzol, Toluol, Chlorbenzol, Tetrahydrofuran, Benzol/Tetrahydrofuran oder Dioxan, vorzugsweise jedoch in einem Alkohol der allgemeinen Formel III, gegebenenfalls in Gegenwart einer Säure wie Salzsäure oder in Gegenwart eines wasserentziehenden Mittels, z.B. in Gegenwart von Chlorameisensäureisobutylester, Thionylchlorid, Trimethyl- chlorsilan, Salzsäure, Schwefelsäure, Methansulfonsäure, p-Toluolsulfonsäure, Phosphortrichlorid, Phosphorpentoxid, N,N' -Dicyclohexylcarbodiimid, N,N' -Dicyclohexylcarbodi- imid/N-Hydroxysuccinimid, N,N' -Carbonyldiimidazol- oder N,N' -Thionyldiimidazol, Triphenylphosphin/Tetrachlorkohlen- stoff oder Triphenylphosphin/Azodicarbonsäurediethylester gegebenenfalls in Gegenwart einer Base wie Kaliumcarbonat , N-Ethyl-diisopropylamin oder N,N-Dimethylamino-pyridin zweckmäßigerweise bei Temperaturen zwischen 0 und 150°C, vorzugsweise bei Temperaturen zwischen 0 und 80°C, durchgeführt.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. in the presence of isobutyl chloroformate, thionyl chloride, trimethyl chlorosilane, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N '-dicyclohexylcarbodiimide, N, N' -Dicyclohexylcarbodi- imide / N-hydroxysuccinimide, N, N '- Carbonyldiimidazole or N, N'-thionyldiimidazole, triphenylphosphine / carbon tetrachloride or triphenylphosphine / diethyl azodicarboxylate, optionally in the presence of a base such as potassium carbonate, N-ethyl-diisopropylamine or N, N-dimethylamino-pyridine, advantageously at temperatures between 0 and 150 ° C. preferably carried out at temperatures between 0 and 80 ° C.
Mit einer Verbindung der allgemeinen Formel IV wird die Umsetzung zweckmäßigerweise in einem Lösungsmittel wie Methylen- chlorid, Tetrahydrofuran, Dioxan, Dimethylsulfoxid, Dimethyl- formamid oder Aceton gegebenenfalls in Gegenwart eines Reaktionsbeschleunigers wie Natrium- oder Kaliumiodid und vorzugsweise in Gegenwart einer Base wie Natriumcarbonat oder Kaliumcarbonat oder in Gegenwart einer tertiären organischen Base wie N-Ethyl-diisopropylamin oder N-Methyl-morpholin, welche gleichzeitig auch als Lösungsmittel dienen können, oder gegebenenfalls in Gegenwart von Silberkarbonat oder Silberoxid bei Temperaturen zwischen -30 und 100°C, vorzugsweise jedoch bei Temperaturen zwischen -10 und 80°C, durchgeführt.With a compound of general formula IV, 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.
b. Zur Herstellung einer Verbindung der allgemeinen Formel I, in der R1 eine C6.18-Alkylgruppe darstellt:b. For the preparation of a compound of the general formula I in which R 1 is a C 6 . 18 alkyl group:
Umsetzung einer Verbindung der allgemeinen FormelImplementation of a compound of the general formula
Figure imgf000008_0001
Figure imgf000008_0001
in derin the
R2 wie eingangs erwähnt definiert ist, mit einer Verbindung der allgemeinen FormelR 2 is defined as mentioned at the beginning, with a compound of the general formula
Z2-C0-0R! , (VI)Z 2 -C0-0R ! , (VI)
in derin the
R1 wie eingangs erwähnt definiert ist undR 1 is defined as mentioned at the beginning and
Z2 eine Austrittsgruppe wie ein Halogenatom, z.B. ein Chloratom, bedeutet.Z 2 represents a leaving group such as a halogen atom, for example a chlorine atom.
Die Umsetzung wird vorzugsweise in einem Lösungsmittel oder Lösungsmittelgemisch wie Aceton, Aceton/Wasser, Methylenchlorid, Tetrahydrofuran, Tetrahydrofuran/Wasser, Toluol oder Dioxan gegebenenfalls in Gegenwart einer anorganischen oder einer tertiären organischen Base wie Kaliumcarbonat oder N-Ethyl-di- isopropylamin, vorzugsweise bei Temperaturen zwischen 0 und 80°C, durchgeführt.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.
Die als Ausgangsstoffe verwendeten Verbindungen der allgemeinen Formeln II bis VI, welche teilweise literaturbekannt sind, erhält man nach literaturbekannten Verfahren, beispielsweise- nach den in den Europäischen Offenlegungsschriften 0 483 667 und 0 567 966 beschriebenen Verfahren.The compounds of general formulas II to VI used as starting materials, some of which are known from the literature, are obtained by processes known from the literature, for example by the processes described in European laid-open publications 0 483 667 and 0 567 966.
Ferner können die erhaltenen Verbindungen der allgemeinen Formel I in ihre Enantiomeren und/oder Diastereomeren aufgetrennt werden .Furthermore, the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
So lassen sich beispielsweise die erhaltenen Verbindungen der allgemeinen Formel I, welche in Racematen auftreten, nach an sich bekannten Methoden (siehe Allinger N. L. und Eliel E. L. in "Topics in Stereochemistry" , Vol. 6, Wiley Interscience, 1971) in ihre optischen Antipoden und Verbindungen der allgemeinen Formel I mit mindestes 2 asymmetrischen Kohlenstoffato- men auf Grund ihrer physikalisch-chemischen Unterschiede nach an sich bekannten Methoden, z.B. durch Chromatographie und/ oder fraktionierte Kristallisation, in ihre Diastereomeren auftrennen, die, falls sie in racemischer Form anfallen, anschließend wie oben erwähnt in die Enantiomeren getrennt werden können .For example, 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) Compounds of the general formula I with at least 2 asymmetric carbon atoms on the basis of their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.
Die Enantiomerentrennung erfolgt vorzugsweise durch Säulentrennung an chiralen Phasen oder durch Umkristallisieren aus einem optisch aktiven Lösungsmittel oder durch Umsetzen mit einer, mit der racemischen Verbindung Salze oder Derivate wie z.B. Ester oder Amide bildenden optisch aktiven Substanz, insbesondere Säuren und ihre aktivierten Derivate oder Alkohole, und Trennen des auf diese Weise erhaltenen diastereomeren Salzgemisches oder Derivates, z.B. auf Grund von verschiedenen Löslichkeiten, wobei aus den reinen diastereomeren Salzen oder Derivaten die freien Antipoden durch Einwirkung geeigneter Mittel freigesetzt werden können. Besonders gebräuchliche, optisch aktive Säuren sind z.B. die D- und L-Formen von Weinsäu- re oder DibenzoylWeinsäure, Di-o-TolylWeinsäure, Apfelsäure, Mandelsäure, Camphersulfonsäure, Glutaminsäure, Asparaginsäure oder Chinasäure. Als optisch aktiver Alkohol kommt beispielsweise (+) - oder (-) -Menthol und als optisch aktiver Acylrest in Amiden beispielsweise der (+) - oder (- ) -Menthyloxycarbonyl- rest in Betracht.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. Particularly common, 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. Examples of suitable optically active alcohols are (+) or (-) menthol and optically active acyl radicals in amides are, for example, the (+) - or (-) menthyloxycarbonyl radicals.
Desweiteren können die erhaltenen Verbindungen der Formel I in ihre Salze, insbesondere für die pharmazeutische Anwendung in ihre physiologisch verträglichen Salze mit anorganischen oder organischen Säuren, übergeführt werden. Als Säuren kommen hierfür beispielsweise Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Methansulfonsäure, Phosphorsäure, Fumarsäure, Bernsteinsäure, Milchsäure, Zitronensäure, Weinsäure oder Maleinsäure in Betracht .Furthermore, 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. Examples of 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.
Außerdem lassen sich die so erhaltenen neuen Verbindungen der Formel I, falls diese eine Carboxygruppe enthalten, gewünsch- tenfalls anschließend in ihre Salze mit anorganischen oder organischen Basen, insbesondere für die pharmazeutische Anwendung in ihre physiologisch verträglichen Salze, überführen. Als Basen kommen hierbei beispielsweise Natriumhydroxid, Kaliumhydroxid, Cyclohexylamin, Ethanolamin, Diethanolamin und Triethanolamin in Betracht.In addition, 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 here are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
Wie bereits eingangs erwähnt, weisen die neuen disubstituier- ten Pyrrolidinone der allgemeinen Formel I und deren Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren oder Basen, wertvolle Eigenschaften auf. So werden mit den neuen Verbindungen der allgemeinen Formel I nach oraler Gabe hohe und langanhaltende Plasmaspiegel von Fradafiban (BIBU 52) erzielt. Somit weisen die neuen Verbindungen der allgemeinen Formel I und deren Salze wertvolle pharmakologische Eigenschaften auf, neben einer entzündungshemmenden und den Knochenabbau hemmenden Wirkung insbesondere antithrombotische, antiaggregatorische und tumor- bzw. metastasenhemmende Wirkungen. Die Plasmaspiegel von Fradifaban werden nach oraler Gabe der Verbindungen der vorliegenden Erfindung nach an sich bekannten Methoden bestimmt (siehe Circulation 1997; 96: 1130-1138).As already mentioned at the beginning, the new disubstituted pyrrolidinones of the general formula I and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, have valuable properties. With the new compounds of general formula I, high and long-lasting plasma levels of Fradafiban (BIBU 52) are achieved after oral administration. Thus, 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).
Auf Grund ihrer biologischen Eigenschaften eignen sich die neuen erfindungsgemäßen Verbindungen der allgemeinen Formel -I und ihre physiologisch verträglichen Salze zur Bekämpfung bzw. Verhütung von Krankheiten, bei denen kleinere oder größere Zeil-Aggregate auftreten oder Zeil-Matrixinteraktionen eine Rolle spielen, z.B. bei der Bekämpfung bzw. Verhütung von venösen und arteriellen Thrombosen, von zerebrovasculären Erkrankungen, von Lungenembolien, des Herzinfarktes, der Arte- riosklerose, der Osteoporose und der Metastasierung von Tumoren und der Therapie genetisch bedingter oder auch erworbener Störungen der Interaktionen von Zellen untereinander oder mit soliden Strukturen. Weiterhin eignen sich diese zur Begleittherapie bei der Thrombolyse mit Fibrinolytica oder Gefäßinterventionen wie transluminaler Angioplastie oder auch bei der Therapie von Schockzuständen, der Psoriasis, des Diabetes und von Entzündungen.Because of their biological properties, 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.
Für die Bekämpfung bzw. Verhütung der vorstehend erwähnten Krankheiten liegt die Dosis zwischen 0,1 μg und 30 mg/kg Körpergewicht, vorzugsweise bei 1 μg bis 15 mg/kg Körpergewicht, bei bis zu 4 Gaben pro Tag. Hierzu lassen sich die erfindungsgemäß hergestellten Verbindungen der Formel I, gegebenenfalls in Kombination mit anderen Wirksubstanzen wie Thromboxan-Re- zeptor-Antagonisten und Thromboxansynthesehemmer oder deren Kombinationen, ADP-Rezeptorantagonisten, Clopidogrel, Ticlo- pidine, Serotonin-Antagonisten, α-Rezeptorantagonisten, Al- kylniträte wie Glycerintrinitrat , Phosphodiesterasehemmer, Prostacyclin und deren Analoga, Fibrinolytica wie tPA, Prouro- kinase, Urokinase, Streptokinase, oder Antikoagulantien wie Heparin, Dermatansulfat , aktiviertes Protein C, Vitamin K-An- tagonisten, Hirudin, Inhibitoren des Thrombins oder anderer aktivierter Gerinnungsfaktoren, zusammen mit einem oder mehreren inerten üblichen Trägerstoffen und/oder Verdünnungsmitteln, z.B. mit Maisstärke, Milchzucker, Rohrzucker, mikro- kristalliner Zellulose, Magnesiumstearat, Polyvinylpyrrolidon, Zitronensäure, Weinsäure, Wasser, Wasser/Ethanol, Wasser/Gly- cerin, Wasser/Sorbit, Wasser/Polyethylenglykol, Propylengly- kol, Stearylalkohol, Carboxymethylcellulose oder fetthaltigen Substanze wie Hartfett oder deren geeigneten Gemischen, in übliche galenische Zubereitungen wie Tabletten, Dragees, Kapseln, Pulver, Suspensionen, Lösungen, Sprays oder Zäpfchen einarbeiten.For the control or prevention of the aforementioned diseases, the dose is between 0.1 μg and 30 mg / kg body weight, preferably 1 μg to 15 mg / kg body weight, with up to 4 doses per day. For this purpose, 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, α 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 desirin, inhibitors Coagulation factors, together with one or more inert customary carriers and / or diluents, for example with corn starch, milk sugar, cane sugar, micro- crystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures, in customary Work in galenical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.
Die nachfolgenden Beispiele sollen die Erfindung näher erläutern: The following examples are intended to explain the invention in more detail:
Beispie] 1Example] 1
(3S, 5S) -5- [ [4 ' - (N-Octyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon(3S, 5S) -5- [[4 '- (N-Octyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone
Zu 3 g (3S, 5S) -5- [ ( ' -Amidino-4-biphenylyl) oxymethyl] - 3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon-toluolsulfonat in 29 ml Aceton und 16 ml Wasser werden 2.06 g Kaliumcarbonat zugegeben. Nach Abkühlung auf 15°C werden 1.75 ml Chlorameisen- säureoctylester in 3 ml Aceton zugetropft . Nach 2 Stunden bei Raumtemperatur werden 20 ml Wasser zugesetzt und 30 Minuten gerührt. Der Niederschlag wird abgesaugt, mit wäßrigem Aceton nachgewaschen und getrocknet . Ausbeute: 2.9 g (100 % der Theorie), Schmelzpunkt: 136-138 °C Massenspektrum: (M+H) + = 538To 3 g (3S, 5S) -5- [('-amidino-4-biphenylyl) oxymethyl] - 3- [(methoxycarbonyl) methyl] -2-pyrrolidinone toluenesulfonate in 29 ml acetone and 16 ml water are 2.06 g potassium carbonate admitted. After cooling to 15 ° C., 1.75 ml of octyl chloroformate in 3 ml of acetone are added dropwise. After 2 hours at room temperature, 20 ml of water are added and the mixture is stirred for 30 minutes. The precipitate is filtered off, washed with aqueous acetone and dried. Yield: 2.9 g (100% of theory), melting point: 136-138 ° C mass spectrum: (M + H) + = 538
Analog werden folgende Verbindungen erhalten:The following connections are obtained analogously:
(3S, 5S) -5- [ [4 ' - (N-Hexyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon(3S, 5S) -5- [[4 '- (N-Hexyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone
(3S, 5S) -5- [ [4 ' - (N-Decyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- t (methoxycarbonyl) methyl] -2-pyrrolidinon(3S, 5S) -5- [[4 '- (N-decyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- t (methoxycarbonyl) methyl] -2-pyrrolidinone
(3S, 5S) -5- [ [4 ' - (N-Dodecyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon(3S, 5S) -5- [[4 '- (N-Dodecyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone
(3S, 5S) -5- [ [4 ' - (N-Tetradecyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon(3S, 5S) -5- [[4 '- (N-tetradecyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone
(3S, 5S) -5- [ [4 ' - (N-Hexadecyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon(3S, 5S) -5- [[4 '- (N-Hexadecyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone
(3S, 5S) -5- [ [4 ' - (N-Hexyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon (3S, 5S) -5- [ [4 ' - (N-Octyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon(3S, 5S) -5- [[4 '- (N-Hexyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone (3S, 5S) -5- [[4 '- (N-Octyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone
(3S, 5S) -5- [ [4 ' - (N-Decyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon(3S, 5S) -5- [[4 '- (N-decyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone
(3S, 5S) -5- [ [4 ' - (N-Dodecyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon(3S, 5S) -5- [[4 '- (N-Dodecyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone
(3S, 5S) -5- [ [4 ' - (N-Tetradecyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon(3S, 5S) -5- [[4 '- (N-tetradecyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone
(3S, 5S) -5- [ [4 ' - (N-Hexadecyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon(3S, 5S) -5- [[4 '- (N-Hexadecyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone
Bei spi l 2.At game 2.
Tablette mit 50 mg WirkstoffTablet with 50 mg of active ingredient
Zusammensetzung :Composition:
(1) Wirkstoff 50,0 mg(1) Active ingredient 50.0 mg
(2) Milchzucker 98,0 mg(2) milk sugar 98.0 mg
(3) Maisstärke 50,0 mg(3) corn starch 50.0 mg
(4) Polyvinylpyrrolidon 15,0 mg(4) Polyvinylpyrrolidone 15.0 mg
(5) Magnesiumstearat 2,0 mg(5) Magnesium stearate 2.0 mg
215,0 mg215.0 mg
Herstellung:Manufacturing:
(1), (2) und (3) werden gemischt und mit einer wäßrigen Lösung von (4) granuliert. Dem getrockneten Granulat wird (5) zugemischt. Aus dieser Mischung werden Tabletten gepreßt, biplan mit beidseitiger Facette und einseitiger Teilkerbe. Durchmesser der Tabletten: 9 mm. Beiapieil 1(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with a facet on both sides and a partial notch on one side. Tablet diameter: 9 mm. Beiapieil 1
Tablette mit 350 mg WirkstoffTablet with 350 mg of active ingredient
Zusammensetzung :Composition:
(1) Wirkstoff 350,0 mg(1) Active ingredient 350.0 mg
(2) Milchzucker 136,0 mg(2) milk sugar 136.0 mg
(3) Maisstärke 80,0 mg(3) corn starch 80.0 mg
(4) Polyvinylpyrrolidon 30,0 mg(4) polyvinyl pyrrolidone 30.0 mg
(5) Magnesiumstearat 4 , 0 mg(5) Magnesium stearate 4.0 mg
600,0 mg600.0 mg
Herstellung:Manufacturing:
(1) , (2) und (3) werden gemischt und mit einer wäßrigen Lösung von (4) granuliert. Dem getrockneten Granulat wird (5) zugemischt. Aus dieser Mischung werden Tabletten gepreßt, biplan mit beidseitiger Facette und einseitiger Teilkerbe. Durchmesser der Tabletten: 12 mm.(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with facets on both sides and partial notch on one side. Tablet diameter: 12 mm.
Beispiel 4Example 4
Kapseln mit 50 mg WirkstoffCapsules with 50 mg of active ingredient
Zusammensetzung :Composition:
(1) Wirkstoff 50,0 mg(1) Active ingredient 50.0 mg
(2) Maisstärke getrocknet 58,0 mg(2) Corn starch dried 58.0 mg
(3) Milchzucker pulverisiert 50,0 mg(3) Milk sugar powdered 50.0 mg
(4) Magnesiumstearat 2 , o mg(4) Magnesium stearate 2.0 mg
160,0 mg160.0 mg
Herstellung:Manufacturing:
(1) wird mit (3) verrieben. Diese Verreibung wird der Mischung aus (2) und (4) unter intensiver Mischung zugegeben. Diese Pulvermischung wird auf einer Kapselabfüllmaschine in Hartgelatine-Steckkapseln Größe 3 abgefüllt .(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.
Bei sp el 5.At sp el 5.
Kapseln mit 350 mg WirkstoffCapsules with 350 mg of active ingredient
Zusammensetzung:Composition:
(1) Wirkstoff 350,0 mg(1) Active ingredient 350.0 mg
(2) Maisstärke getrocknet 46,0 mg(2) Corn starch dried 46.0 mg
(3) Milchzucker pulverisiert 30,0 mg(3) Milk sugar powdered 30.0 mg
(4) Magnesiumstearat 4,0 mg(4) Magnesium stearate 4.0 mg
430,0 mg430.0 mg
Herstellung:Manufacturing:
(1) wird mit (3) verrieben. Diese Verreibung wird der Mischung aus (2) und (4) unter intensiver Mischung zugegeben.(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
Diese Pulvermischung wird auf einer Kapselabfüllmaschine in Hartgelatine-Steckkapseln Größe 0 abgefüllt. This powder mixture is filled in a size 0 hard gelatin capsule on a capsule filling machine.

Claims

Patentansprüche claims
1. Disubstituierten Pyrrolidinone der allgemeinen Formel1. Disubstituted pyrrolidinones of the general formula
Figure imgf000017_0001
Figure imgf000017_0001
in derin the
R eine C6.18-Alkylgruppe undR a C 6 . 18 alkyl group and
R2 ein Wasserstoffatom, eine
Figure imgf000017_0002
, C4.8-Cycloalkyl- , C3.7-Cycloalkyl-C1_3-alkyl-, R4-C0-0- (HCR3) - oder Phenyl- C^-alkyl-Gruppe, in denenR 2 is a hydrogen atom, a
Figure imgf000017_0002
, C 4 . 8- cycloalkyl-, C 3 . 7- Cycloalkyl-C 1 _ 3 -alkyl-, R 4 -C0-0- (HCR 3 ) - or phenyl-C ^ -alkyl group, in which
R3 ein Wasserstoffatom oder eine C1_4-Alkylgruppe undR 3 is a hydrogen atom or a C 1 _ 4 alkyl group and
R4 eine C1.4-Alkyl-, C1.4-Alkoxy- oder C5.7-Cycloalkoxygruppe darstellen undR 4 is a C 1 . 4 -alkyl-, C 1 . 4 -alkoxy- or C 5 . Represent 7 -cycloalkoxy group and
der Phenylteil durch Fluor-, Chlor- oder Bromatome, durch Methyl-, Methoxy- oder Trifluormethylgruppen mono- oder di- substituiert sein kann, wobei die Substituenten gleich oder verschieden sein können,the phenyl part can be mono- or di-substituted by fluorine, chlorine or bromine atoms, by methyl, methoxy or trifluoromethyl groups, where the substituents can be identical or different,
bedeuten, deren Tautomere, deren Stereoisomere und deren Salze .mean, their tautomers, their stereoisomers and their salts.
2. Disubstituierten Pyrrolidinone der allgemeinen Formel I gemäß Anspruch 1 , in denen2. Disubstituted pyrrolidinones of the general formula I according to claim 1, in which
Rx eine C6.1B-Alkylgruppe und R2 ein Wasserstoffatom, eine
Figure imgf000018_0001
, Cs.7-Cycloalkyl- , Cg^-Cycloalkyl-C^-alkyl-, R4-CO-0- (HCR3) - oder Phenyl- C^-alkyl-Gruppe, in denenR x a C 6 . 1B alkyl group and R 2 is a hydrogen atom, a
Figure imgf000018_0001
, C s . 7- Cycloalkyl-, C g ^ -Cycloalkyl-C ^ -alkyl-, R 4 -CO-0- (HCR 3 ) - or phenyl- C ^ alkyl group, in which
R3 ein Wasserstoffatom oder eine Methylgruppe undR 3 is a hydrogen atom or a methyl group and
R4 eine C^-Alkyl- , C-^-Alkoxy- oder C5.7-Cycloalkoxygruppe darstellen,R 4 is a C ^ alkyl, C - ^ alkoxy or C 5 . 7 -cycloalkoxy group,
bedeuten, deren Tautomere, deren Stereoisomere und deren Salze .mean, their tautomers, their stereoisomers and their salts.
3. Disubstituierten Pyrrolidinone der allgemeinen Formel I gemäß Anspruch 1 , in denen3. disubstituted pyrrolidinones of general formula I according to claim 1, in which
Rx eine C6.18-Alkylgruppe undR x a C 6 . 18 alkyl group and
R2 eine
Figure imgf000018_0002
oder C5.7-Cycloalkylgruppe bedeuten,R 2 a
Figure imgf000018_0002
or C 5 . 7 -cycloalkyl group,
deren Tautomere, deren Stereoisomere und deren Salze.their tautomers, their stereoisomers and their salts.
4. Disubstituierten Pyrrolidinone der allgemeinen Formel I gemäß Anspruch 1, in denen4. disubstituted pyrrolidinones of general formula I according to claim 1, in which
Rx eine C6_18-Alkylgruppe undR x is a C 6 _ 18 alkyl group and
R2 eine C^-Alkylgruppe bedeuten,R 2 represents a C 1-4 alkyl group,
deren Tautomere, deren Stereoisomere und deren Salze.their tautomers, their stereoisomers and their salts.
5. Folgende disubstituierte Pyrrolidinone der allgemeinen Formel I gemäß Anspruch 1:5. The following disubstituted pyrrolidinones of the general formula I according to claim 1:
(1) (3S, 5S) -5- [ [4 ' - (N-Hexyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon,(1) (3S, 5S) -5- [[4 '- (N-Hexyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone,
(2) (3S, 5S) -5- [ [4 ' - (N-Octyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon, (3) (3S, 5S) -5- [ [4 ' - (N-Decyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon,(2) (3S, 5S) -5- [[4 '- (N-octyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone, (3) (3S, 5S) -5- [[4 '- (N-decyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone,
(4) (3S, 5S) -5- [ [4 ' - (N-Dodecyloxycarbonylamidino) -4-biphe- nylyl] oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon,-(4) (3S, 5S) -5- [[4 '- (N-dodecyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone, -
(5) (3S,5S) -5- [ [4 ' - (N-Tetradecyloxycarbonylamidino) -4-biphe- nylyl] oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon,(5) (3S, 5S) -5- [[4 '- (N-tetradecyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone,
(6) (3S, 5S) -5- [ [4 ' - (N-Hexadecyloxycarbonylamidino) -4-biphe- nylyl] oxymethyl] -3- [ (methoxycarbonyl) methyl] -2-pyrrolidinon,(6) (3S, 5S) -5- [[4 '- (N-hexadecyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(methoxycarbonyl) methyl] -2-pyrrolidinone,
(7) (3S, 5S) -5- [ [4 ' - (N-Hexyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon,(7) (3S, 5S) -5- [[4 '- (N-Hexyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone,
(8) (3S, 5S) -5- [ [4 ' - (N-Octyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon,(8) (3S, 5S) -5- [[4 '- (N-octyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone,
(9) (3S, 5S) -5- [ [4 ' - (N-Decyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon,(9) (3S, 5S) -5- [[4 '- (N-decyloxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone,
(10) (3S, 5S) -5- [ [4 ' - (N-Dodecyloxycarbonylamidino) -4-biphe- nylyl] oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon,(10) (3S, 5S) -5- [[4 '- (N-dodecyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone,
(11) (3S, 5S) -5- [ [4 ' - (N-Tetradecyloxycarbonylamidino) -4-biphe- nylyl] oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon und(11) (3S, 5S) -5- [[4 '- (N-tetradecyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone and
(12) (3S, 5S) -5- [ [4 ' - (N-Hexadecyloxycarbonylamidino) -4-biphe- nylyl] oxymethyl] -3- [ (ethoxycarbonyl) methyl] -2-pyrrolidinon(12) (3S, 5S) -5- [[4 '- (N-Hexadecyloxycarbonylamidino) -4-biphenylyl] oxymethyl] -3- [(ethoxycarbonyl) methyl] -2-pyrrolidinone
sowie deren Tautomere und deren Salze.as well as their tautomers and their salts.
6. Physiologisch verträgliche Salze der Verbindungen nach mindestens einem der Ansprüche 1 bis 5 mit anorganischen oder organischen Säuren oder Basen. 6. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 5 with inorganic or organic acids or bases.
7. Arzneimittel, enthaltend eine Verbindung nach mindestens einem der Ansprüche 1 bis 5 oder ein physiologisch verträgliches Salz gemäß Anspruch 6 neben gegebenenfalls einem oder mehreren inerten Trägerstoffen und/oder Verdünnungsmitteln.7. Medicament containing a compound according to at least one of claims 1 to 5 or a physiologically acceptable salt according to claim 6 in addition to optionally one or more inert carriers and / or diluents.
8. Verwendung einer Verbindung nach mindestens einem der Ansprüche 1 bis 6 zur Herstellung eines Arzneimittels, das zur Bekämpfung bzw. Verhütung von Krankheiten, bei denen kleinere oder größere Zeil-Aggregate auftreten oder Zeil-Matrixinteraktionen eine Rolle spielen, geeignet ist.8. Use of a compound according to at least one of claims 1 to 6 for the manufacture of a medicament which is suitable for combating or preventing diseases in which smaller or larger cell aggregates occur or cell matrix interactions play a role.
9. Verfahren zur Herstellung eines Arzneimittels gemäß Anspruch 7, dadurch gekennzeichnet, daß auf nichtchemischem Wege eine Verbindung nach mindestens einem der Ansprüche 1 bis 6 in einen oder mehrere inerte Trägerstoffe und/oder Verdünnungsmittel eingearbeitet wird.9. A method for producing a medicament according to claim 7, characterized in that a compound according to at least one of claims 1 to 6 is incorporated in one or more inert carriers and / or diluents by a non-chemical route.
10. Verfahren zur Herstellung der Verbindungen der allgemeinen Formel I gemäß den Ansprüchen 1 bis 6, dadurch gekennzeichnet, daß10. A process for the preparation of the compounds of general formula I according to claims 1 to 6, characterized in that
a. zur Herstellung einer Verbindung der allgemeinen Formel I, in der R2 eine
Figure imgf000020_0001
, C4.8-Cycloalkyl- , C3.7-Cycloalkyl- C^-alkyl-, R4-CO-0- (HCR3) - oder Phenyl-C^-alkyl-Gruppe darstellt, eine Verbindung der allgemeinen Formela. for the preparation of a compound of general formula I in which R 2 is a
Figure imgf000020_0001
, C 4 . 8- cycloalkyl-, C 3 . 7- Cycloalkyl- C ^ alkyl, R 4 -CO-0- (HCR 3 ) - or phenyl-C ^ alkyl group, a compound of the general formula
Figure imgf000020_0002
Figure imgf000020_0002
in derin the
Rx wie in den Ansprüchen 1 bis 5 erwähnt definiert ist, mit einem Alkohol der allgemeinen FormelR x is as defined in claims 1 to 5, with an alcohol of the general formula
HO - R5 , (III) in derHO - R 5 , (III) in the
R5 eine C^jj-Alkyl- , C4.8-Cycloalkyl- , C3.7-Cycloalkyl-C1.3-alkyl- ,R 5 is a C ^ jj alkyl, C 4 . 8- cycloalkyl-, C 3 . 7- cycloalkyl-C 1 . 3 -alkyl-,
R4-CO-0- (HCR3) - oder Phenyl-C^-alkyl-Gruppe darstellt, wobeiR 4 represents -CO-0- (HCR 3 ) - or phenyl-C ^ alkyl group, wherein
R3 und R4 wie in den Ansprüchen 1 bis 5 erwähnt definiert sind,R 3 and R 4 are as defined in claims 1 to 5,
oder mit deren Formamidacetalenor with their formamide acetals
oder mit einer Verbindung der allgemeinen Formelor with a compound of the general formula
Z, - R6 , (IV)Z, - R 6 , (IV)
in derin the
R6 eine
Figure imgf000021_0001
, C4.8-Cycloalkyl- , C3.7-Cycloalkyl-C1.3-alkyl- ,R 6 a
Figure imgf000021_0001
, C 4 . 8- cycloalkyl-, C 3 . 7- cycloalkyl-C 1 . 3 -alkyl-,
R4-CO-0- (HCR3) - oder Phenyl-C^-alkyl-Gruppe undR 4 -CO-0- (HCR 3 ) - or phenyl-C ^ alkyl group and
Zx eine Austrittsgruppe darstellen, umgesetzt wird oderZ x represents a leaving group, is implemented or
b. zur Herstellung einer Verbindung der allgemeinen Formel I, in der Rx eine C6.18-Alkylgruppe darstellt, eine Verbindung der allgemeinen Formelb. for the preparation of a compound of the general formula I in which R x is a C 6 . 18 alkyl group, a compound of the general formula
Figure imgf000021_0002
Figure imgf000021_0002
in derin the
R2 wie in den Ansprüchen 1 bis 5 erwähnt definiert ist, mit einer Verbindung der allgemeinen FormelR 2 is as defined in claims 1 to 5, with a compound of the general formula
Zjj-CO-OR! , (VI)Z yy -CO-OR ! , (VI)
in derin the
Rλ wie in den Ansprüchen 1 bis 5 erwähnt definiert ist undR λ is as defined in claims 1 to 5 and
Z2 eine Austrittsgruppe bedeutet, umgesetzt wird und gewünschtenfalls anschließend eine so erhaltene Verbindung der allgemeinen Formel I in ihre Stereoisomere aufgetrennt wird und/oderZ 2 represents a leaving group, is implemented and if desired, a compound of the general formula I thus obtained is then separated into its stereoisomers and / or
eine so erhaltene Verbindung der allgemeinen Formel I in ihre Salze, insbesondere für die pharmazeutische Anwendung in ihre physiologisch verträgliche Salze übergeführt wird. a compound of the general formula I thus obtained is converted into its salts, in particular for its pharmaceutical use into its physiologically tolerable salts.
PCT/EP1999/007141 1998-09-30 1999-09-25 Disubstituted pyrrolidinones, medicaments containing these compounds, their use and the production thereof WO2000018732A2 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0483667A2 (en) * 1990-11-02 1992-05-06 Dr. Karl Thomae GmbH Cyclic imino derivatives, process for their preparation and drugs containing them
EP0567966A1 (en) * 1992-04-28 1993-11-03 Dr. Karl Thomae GmbH Cyclic imino derivatives, medicaments containing these compounds and processes for the production thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0483667A2 (en) * 1990-11-02 1992-05-06 Dr. Karl Thomae GmbH Cyclic imino derivatives, process for their preparation and drugs containing them
EP0567966A1 (en) * 1992-04-28 1993-11-03 Dr. Karl Thomae GmbH Cyclic imino derivatives, medicaments containing these compounds and processes for the production thereof

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