Cyclic imino derivatives and pharmaceutical compositions containing them

• US 5,541,343 A
• Filed: 12/28/1994
• Issued: 07/30/1996
• Est. Priority Date: 11/02/1990
• Status: Expired due to Term

• Current Assignee: Dr. Karl Thomae GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Karl Thomae GmbH
• Inventors: Himmelsbach, Frank, Mueller, Thomas, Linz, Guenter, Pieper, Helmut, Austel, Volkhard, Eisert, Wolfgang, Weisenberger, Johannes, Krueger, Gerd
• Primary Examiner(s): Springer, David B.
• Application Number:
  US08/365,336
• Time in Patent Office: 580 Days
• Field of Search: 548/550, 514/424
• US Class Current: 514/424
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 207/26 2-Pyrrolidones
• CPC Class Codes: C07D 207/273 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 other ring carbon atoms
• CPC Class Codes: C07D 207/277 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07F 9/572 Five-membered rings

Abstract

The invention relates to cyclic imino compounds which have, inter alia, valuable pharmacological properties, especially inhibitory effects on cell aggregation, pharmaceutical compositions which contain these compounds and processes for preparing them.

Claims

1. A compound of the formula Ia ##STR2## wherein R₁ represents a hydrogen atom,

a phenyl group optionally substituted by a chlorine or bromine atom, by an C_1-2 -alkyl, C_1-2 -alkoxy or trifluoromethyl group, by a carboxy, alkoxycarbonyl, aminocarbonyl, aminosulphonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulphonylamino or alkanoylamino group,

an allyl group,

a C_1-4 -alkyl group which may be substituted by two phenyl groups, by a C_3-7 -cycloalkyl, naphthyl or phenyl group, whilst the latter may be substituted by a fluorine, chlorine or bromine atom, by a C_1-4 -alkyl group, by a C_1-6 -alkoxy group, by an alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, phenyl, phenylalkyl, phenylalkoxy, hydroxy or trifluoromethyl group, by two alkoxy groups or by two chlorine or bromine atoms,

a C_2-4 -alkyl group substituted in 2-, 3- or 4-position by an alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, phenylsulphenyl, phenylsulphinyl, phenylsulphonyl, amino, alkanoylamino, benzoylamino, N-alkyl-alkanoylamino, alkanesulphonylamino, phenylsulphonylamino, hydroxy, alkoxy or phenoxy group,

a methyl group substituted by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, benzylaminocarbonyl, bis(2-methoxyethyl)aminocarbonyl or biphenylyl group,

R₂ represents a hydrogen atom or an optionally phenyl-substituted C_1-4 -alkyl group,

B represents an amidino group optionally substituted by one or two C_1-4 -alkyl groups, by a cyano, hydroxy, methoxy, benzyl, benzoyl, methoxybenzoyl, benzyloxycarbonyl, phenyloxycarbonyl or an C_1-4 -alkyloxycarbonyl group,

a cyano, aminomethyl or guanidinomethyl group;

Y represents a straight-chained or branched C_1-5 -alkylene group;

E represents a carbonyl group substituted by a hydroxy, C_1-6 -alkoxy, amino, C_1-4 -alkylamino, dialkylaminocarbonyl-alkoxy or phenylalkoxy group wherein the phenyl nucleus may additionally be substituted by one or two methoxy groups, and

X represents biphenylyloxy-C_1-2 -alkylene group attached via the alkylene moiety to the pyrrolidinone ring in 4- or 5-position, wherein each phenylene moiety may be substituted by a fluorine, chlorine or bromine atom or by an alkyl, alkoxy, trifluoromethyl, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, nitro, alkanoylamino or alkanesulphonylamino group or by another alkyl group,

wherein, unless otherwise stated, the above-mentioned alkyl, alkoxy and alkanoyl moieties may each contain from 1 to 3 carbon atoms,

or a pharmaceutically acceptable salt thereof.

2. A compound of the formula Ia, according to claim 1, wherein

R₁ represents a hydrogen atom,

a phenyl group optionally substituted by a chlorine or bromine atom, by an C_1-2 -alkyl, C_1-2 -alkoxy or trifluoromethyl group, by a carboxy, alkoxycarbonyl, aminocarbonyl,

aminosulphonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulphonylamino or alkanoylamino group,

a C_2-4 -alkyl group substituted in 2-, 3- or 4-position by a hydroxy, alkoxy, phenoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, phenylsulphenyl, phenylsulphinyl, phenylsulphonyl, amino, alkanoylamino, benzoylamino, N-alkyl-alkanoylamino, alkanesulphonylamino or benzenesulphonylamino group,

a C_1-4 -alkyl group optionally substituted by a C₃,7 -cycloalkyl group, by two phenyl groups or by a phenyl group, whilst the latter may be substituted by a fluorine, chlorine or bromine atom, by a C₁,4 -alkyl, C_1-6 -alkoxy, phenyl, phenylalkyl, phenylalkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, hydroxy or trifluoromethyl group, by two alkoxy groups or by two chlorine or bromine atoms,

a methyl group which is substituted by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl or phenylalkylaminocarbonyl group,

R₂ represents a hydrogen atom or an optionally phenyl-substituted C_1-4 -alkyl group,

B represents an amidino group optionally substituted by one or two C_1-4 -alkyl groups, by a benzyl, cyano, hydroxy, alkoxy, benzoyl, benzyloxycarbonyl, phenyloxycarbonyl or C_1-4 -alkyloxycarbonyl group,

a aminomethyl or guanidinomethyl group;

Y represents a straight-chained or branched C_1-5 -alkylene group;

E represents a carbonyl group substituted by a hydroxy, C_1-6 -alkoxy, dialkylaminocarbonylalkoxy or phenylalkoxy group in which the phenyl nucleus may be substituted by one or two alkoxy groups; and

X represents a biphenylyloxymethylene or biphenylyloxyethylene attached via the alkylene moiety to the pyrrolidinone ring in 4- or 5-position, wherein each phenylene moiety may be substituted by a fluorine, chlorine or bromine atom, by one or two alkyl groups, by an alkoxy, trifluoromethyl, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, nitro, alkanoylamino or alkanesulphonylamino group;

wherein, unless otherwise mentioned, the above-mentioned alkyl, alkoxy and alkanoyl moieties may each contain from 1 to 3 carbon atoms.

or a pharmaceutically acceptable salt thereof.

3. A compound of the formula Ia, according to claim 1, wherein

R₁ represents a hydrogen atom,

a phenyl group optionally substituted by a chlorine or bromine atom, by an C_1-2 -alkyl, C_1-2 -alkoxy or trifluoromethyl group, by a carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl, methanesulphonylamino or acetylamino group,

a C_2-4 -alkyl group substituted in 2-, 3- or 4-position by a hydroxy, C_1-2 '"'"'alkoxy, phenoxy, methylsulphenyl, methylsulphinyl, methylsulphonyl, phenylsulphenyl, phenylsulphinyl, phenylsulphonyl, amino, acetylamino, benzoylamino, N-methyl-acetylamino, methanesulphonylamino or benzenesulphonylamino group,

a C_1-4 -alkyl group which may by substituted by two phenyl groups, by a C_5-7 -cycloalkyl group or by a phenyl group, whilst the latter may be substituted by a fluorine, chlorine or bromine atom, by a C_1-4 -alkyl group, by a C_1-6 -alkoxy group, by a phenyl, phenylmethyl, hydroxy, benzyloxy, methylsulphenyl, methylsulphinyl, methylsulphonyl or trifluoromethyl group, by two methoxy groups or by two chlorine atoms,

a methyl group substituted by a carboxy, C_1-2 -alkoxycarbonyl, aminocarbonyl, C_1-2 -alkylaminocarbonyl, di-(C₁.2 -alkyl)-aminocarbonyl or benzylaminocarbonyl group,

R₂ represents a hydrogen atom or a C_1-4 -alkyl group optionally substituted by a phenyl group,

B represents an amidino group optionally substituted by one or two C_1-4 -alkyl groups, by a benzyl, cyano, hydroxy, methoxy, C_1-4 -alkyloxycarbonyl, benzyloxycarbonyl, phenyloxycarbonyl or benzoyl group,

a aminomethyl or guanidinomethyl group;

Y represents a straight-chained C_1-5 -alkylene group; and

E represents a carbonyl group substituted by a hydroxy or C_1-6 -alkoxy group or by dialkylaminocarbonylmethoxy group in which each alkyl moiety may contain 1 to 3 carbon atoms or by a phenylalkoxy group having 1 to 3 carbon atoms in the alkoxy moiety whilst the phenyl nucleus may be substituted by one or two methoxy groups, and

X represents a 4-biphenylyloxymethylene group attached via the methylene moiety to the pyrrolidinone ring in 4- or 5-position, wherein the biphenyl moiety may be substituted by one or two methyl groups, by a fluorine, chlorine or bromine atom, by a methoxy, ethoxy, trifluoromethyl, methylsulphenyl, methylsulphinyl, methylsulphonyl, nitro, acetylamino or methanesulphonylamino group;

or a pharmaceutically acceptable salt thereof.

4. A compound of the formula Ia, according to claim 1 wherein

R₁ represents a hydrogen atom,

a phenyl group optionally substituted by a chlorine or bromine atom, by an C_1-2 -alkyl, C_1-2 -alkoxy or trifluoromethyl group,

an C_1-4 -alkyl group optionally substituted by two phenyl groups or by a C_5-7 -cycloalkyl group,

a phenyl-C_1-4 -alkyl group wherein the phenyl nucleus is optionally substituted by an C_1-4 -alkyl or C_2-6 -alkoxy group, by one or two methoxy groups, by one or two chlorine atoms, by a bromine atom, by a trifluoromethyl, methylsulphenyl, methylsulphinyl, methylsulphonyl, phenyl or benzyl group,

an C₂,4 -alkyl group substituted in 2-, 3- or 4-position by a hydroxy, methoxy, ethoxy or phenoxy group, or

a methyl group substituted by a carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, C_1-2 -alkylaminocarbonyl, benzylaminocarbonyl or di-(C_1-2 -alkyl)-aminocarbonyl group;

R₂ represents a hydrogen atom, an C_1-4 -alkyl or phenyl-C_1-3 -alkyl group;

X represents a 4-biphenylyloxymethylene group attached via the methylene moiety to the pyrrolidinone ring in 4- or 5-position, whereby the biphenyl moiety is optionally substituted by one or two methyl groups, by a fluorine, chlorine or bromine atom, by a trifluoromethyl, methylsulphenyl, methylsulphinyl, methylsulphonyl, nitro, acetylamino or methanesulphonylamino group;

B represents an amidino group optionally substituted by one or two methyl groups, by an C_2-4 -alkyl, benzyl, benzyloxycarbonyl, benzoyl, phenoxycarbonyl, C_1-4 -alkoxycarbonyl, hydroxy, methoxy or cyano group,

a aminomethyl or guanidinomethyl group;

Y represents an n-C_1-5 -alkylene group; and

E represents a carbonyl group substituted by a hydroxy, C_1-6 -alkoxy, phenyl-C_1-3 -alkoxy, methoxyphenyl-C-_1-3 -alkoxy, dimethoxyphenyl-C_1-3 -alkoxy or dimethylaminocarbonylmethoxy group;

or a pharmaceutically acceptable salt thereof.

5. A compound of the formula Ia, according to claim 1, wherein

R₁ represents a hydrogen atom,

a phenyl group optionally substituted by a chlorine or bromine atom, by an C_1-2 -alkyl, C_1-2 -alkoxy or trifluoromethyl group,

an C_1-4 -alkyl group optionally substituted by two phenyl groups or by a C_5-7 -cycloalkyl group,

a phenyl-C_1-4 -alkyl group wherein the phenyl nucleus is optionally substituted by an C_1-4 -alkyl or C_2-6 -alkoxy group, by one or two methoxy groups, by one or two chlorine atoms, by a bromine atom, by a trifluoromethyl, methylsulphenyl, methylsulphinyl, methylsulphonyl, phenyl or benzyl group,

an C_2-4 -alkyl group substituted in 2-, 3- or 4-position by a hydroxy, methoxy, ethoxy or phenoxy group, or

a methyl group substituted by a carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, C_1-2 -alkylaminocarbonyl, benzylaminocarbonyl or di-(C_1-2 -alkyl)-aminocarbonyl group;

R₂ represents a hydrogen atom, an C_1-4 -alkyl or phenyl-C_1-3 -alkyl group;

X represents a 4-biphenylyloxymethylene group attached via the methylene moiety to the pyrrolidinone ring in 4- or 5-position, whereby the biphenyl moiety is optionally substituted by one or two methyl groups, by a fluorine, chlorine or bromine atom, by a trifluoromethyl, methylsulphenyl, methylsulphinyl, methylsulphonyl, nitro, acetylamino or methanesulphonylamino group;

B represents an amidino group in 4'"'"'-position optionally substituted by one or two methyl groups, by an C_2-4 -alkyl, benzyl, benzyloxycarbonyl, benzoyl, phenoxycarbonyl, C_1-4 -alkoxycarbonyl, hydroxy, methoxy or cyano group;

Y represents an n-C_1-5 -alkylene group; and

E represents a carbonyl group substituted by a hydroxy, C_1-6 -alkoxy, phenyl-C_1-3 -alkoxy, methoxyphenyl-C-_1-3 -alkoxy, dimethoxyphenyl-C_1-3 -alkoxy or dimethylaminocarbonylmethoxy group;

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound according to claim 2 and 6, 4, 5, 7 or 8 together with one or more inert carriers and/or diluents.

10. A method for treating or preventing diseases in which smaller or larger clumps of cells occur or in which cell-matrix interactions are involved, which method comprises administering a compound of formula I, according to claim 2, 3, 4, 5, 6, 7, or 8.

6. A compound selected from the group consisting of:

(3S,5S)-5-[(4'"'"'-amidino-4-biphenylyl)oxymethyl]-3-[(methoxycarbonyl)methyl]-2-pyrrolidinone,

(3S,5S)-5-[(4'"'"'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-(3-phenylpropyl)-2-pyrrolidinone.

(3S,5S)-5-[(4'"'"'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-2-pyrrolidinone,

(3S,5S)-5-[(4'"'"'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-phenyl-2-pyrrolidinone,

(3S,5S)-5-[(4'"'"'-amidino-2,3-dimethyl-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-(3-phenylpropyl)-2-pyrrolidinone,

(3S,5S)-5-[(4'"'"'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-[(dimethylaminocarbonyl)methyl]-2-pyrrolidinone,

(3S,5S)-5-[(4'"'"'-amidino-3'"'"'-fluoro-4-biphenylyl)oxymethyl]-3-carboxymethyl-2-pyrrolidinone,

(3R,S;

4R,S)-4-[(4'"'"'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-3-methyl-2-pyrrolidinone, (3S,5S)-5-[(4'"'"'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-methyl-2-pyrrolidinone and

(3S,5S)-5-[[4'"'"'-(N-methoxycarbonylamidino)-4-biphenylyl]oxymethyl]-3-[(methoxycarbonyl)methyl]-2-pyrrolidinone

and the pharmaceutically acceptable salts thereof.

7. (3S,5S)-5-[(4'"'"'-amidino-4-biphenylyl)oxymethyl]-3-(carboxymethyl)-2-pyrrolidinone or a pharmaceutically acceptable salt thereof.

8. (3S,5S)-5-[[4'"'"'-(N-methoxycarbonylamidino)-4-biphenylyl]oxymethyl]-3-[(methoxycarbonyl)methyl]-2-pyrrolidinone or a pharmaceutically acceptable salt thereof.