Claims
- 1. A compound of the formula Ia ##STR2## wherein R.sub.1 represents a hydrogen atom,
- a phenyl group optionally substituted by a chlorine or bromine atom, by an C.sub.1-2 -alkyl, C.sub.1-2 -alkoxy or trifluoromethyl group, by a carboxy, alkoxycarbonyl, aminocarbonyl, aminosulphonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulphonylamino or alkanoylamino group,
- an allyl group,
- a C.sub.1-4 -alkyl group which may be substituted by two phenyl groups, by a C.sub.3-7 -cycloalkyl, naphthyl or phenyl group, whilst the latter may be substituted by a fluorine, chlorine or bromine atom, by a C.sub.1-4 -alkyl group, by a C.sub.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.sub.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,
- a carbonyl group substituted by an alkyl, phenyl, alkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, carboxy, alkoxycarbonyl or dialkylaminocarbonyl group, or
- a sulphonyl group substituted by an alkyl, dialkylamino, phenyl or alkoxyphenyl group;
- R.sub.2 represents a hydrogen atom or an optionally phenyl-substituted C.sub.1-4 -alkyl group,
- B represents an amidino group optionally substituted by one or two C.sub.1-4 -alkyl groups, by a cyano, hydroxy, methoxy, benzyl, benzoyl, methoxybenzoyl, benzyloxycarbonyl, phenyloxycarbonyl or an C.sub.1-4 -alkyloxycarbonyl group,
- a cyano, aminomethyl or guanidinomethyl group;
- Y represents a straight-chained or branched C.sub.1-5 -alkylene group;
- E represents a carbonyl group substituted by a hydroxy, C.sub.1-6 -alkoxy, amino, C.sub.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.sub.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
- R.sub.1 represents a hydrogen atom,
- a phenyl group optionally substituted by a chlorine or bromine atom, by an C.sub.1-2 -alkyl, C.sub.1-2 -alkoxy or trifluoromethyl group, by a carboxy, alkoxycarbonyl, aminocarbonyl, aminosulphonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulphonylamino or alkanoylamino group,
- a C.sub.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.sub.1-4 -alkyl group optionally substituted by a C.sub.3-7 -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 C.sub.1-4 -alkyl, C.sub.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,
- a carbonyl group substituted by an alkyl, phenyl, alkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, carboxy, alkoxycarbonyl or dialkylaminocarbonyl group, or
- a sulphonyl group substituted by an alkyl, dialkylamino, phenyl or alkoxyphenyl group;
- R.sub.2 represents a hydrogen atom or an optionally phenyl-substituted C.sub.1-4 -alkyl group,
- B represents an amidino group optionally substituted by one or two C.sub.1-4 -alkyl groups, by a benzyl, cyano, hydroxy, alkoxy, benzoyl, benzyloxycarbonyl, phenyloxycarbonyl or C.sub.1-4 -alkyloxycarbonyl group,
- a aminomethyl or guanidinomethyl group;
- Y represents a straight-chained or branched C.sub.1-5 -alkylene group;
- E represents a carbonyl group substituted by a hydroxy, C.sub.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
- R.sub.1 represents a hydrogen atom,
- a phenyl group optionally substituted by a chlorine or bromine atom, by an C.sub.1-2 -alkyl, C.sub.1-2 -alkoxy or trifluoromethyl group, by a carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl, methanesulphonylamino or acetylamino group,
- a C.sub.2-4 -alkyl group substituted in 2-, 3- or 4-position by a hydroxy, C.sub.1-2 -alkoxy, phenoxy, methylsulphenyl, methylsulphinyl, methylsulphonyl, phenylsulphenyl, phenylsulphinyl, phenylsulphonyl, amino, acetylamino, benzoylamino, N-methyl-acetylamino, methanesulphonylamino or benzenesulphonylamino group,
- a C.sub.1-4 -alkyl group which may by substituted by two phenyl groups, by a C.sub.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.sub.1-4 -alkyl group, by a C.sub.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.sub.1-2 -alkoxycarbonyl, aminocarbonyl, C.sub.1-2 -alkylaminocarbonyl, di-(C.sub.1-2 -alkyl)-aminocarbonyl or benzylaminocarbonyl group,
- a carbonyl group substituted by a C.sub.1-3 -alkyl, phenyl, C.sub.1-3 -alkoxy-C.sub.1-3 -alkyl, amino, C.sub.1-3 -alkylamino, di-C.sub.1-3 -alkylamino, amino-C.sub.1-3 -alkyl, carboxy, C.sub.1-3 -alkoxycarbonyl or di(C.sub.1-3 -alkyl)-aminocarbonyl group, or
- a sulphonyl group substituted by a C.sub.1-3 -alkyl, di-(C.sub.1-3 -alkyl)-amino, phenyl or C.sub.1-3 -alkoxyphenyl group;
- R.sub.2 represents a hydrogen atom or a C.sub.1-4 -alkyl group optionally substituted by a phenyl group,
- B represents an amidino group optionally substituted by one or two C.sub.1-4 -alkyl groups, by a benzyl, cyano, hydroxy, methoxy, C.sub.1-4 -alklyoxycarbonyl, benzyloxycarbonyl, phenyloxycarbonyl or benzoyl group,
- a aminomethyl or guanidinomethyl group;
- Y represents a straight-chained C.sub.1-5 -alkylene group; and
- E represents a carbonyl group substituted by a hydroxy or C.sub.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
- R.sub.1 represents a hydrogen atom,
- a phenyl group optionally substituted by a chlorine or bromine atom, by an C.sub.1-2 -alkyl, C.sub.1-2 -alkoxy or trifluoromethyl group,
- an C.sub.1-4 -alkyl group optionally substituted by two phenyl groups or by a C.sub.5-7 -cycloalkyl group,
- a phenyl-C.sub.1-4 -alkyl group wherein the phenyl nucleus is optionally substituted by an C.sub.1-4 -alkyl or C.sub.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.sub.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.sub.1-2 -alkylaminocarbonyl, benzylaminocarbonyl or di-(C.sub.1-2 -alkyl)-aminocarbonyl group;
- a carbonyl group substituted by a methyl, phenyl, methoxymethyl, amino, methylamino, ethylamino, dimethylamino, aminomethyl, carboxy, methoxycarbonyl or dimethylaminocarbonyl group, or
- a sulphonyl group substituted by a methyl, dimethylamino, phenyl or methoxyphenyl group;
- R.sub.2 represents a hydrogen atom, an C.sub.1-4 -alkyl or phenyl-C.sub.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.sub.2-4 -alkyl, benzyl, benzyloxycarbonyl, benzoyl, phenoxycarbonyl, C.sub.1-4 -alkoxycarbonyl, hydroxy, methoxy or cyano group,
- a aminomethyl or guanidinomethyl group;
- Y represents an n-C.sub.1-5 -alkylene group; and
- E represents a carbonyl group substituted by a hydroxy, C.sub.1-6 -alkoxy, phenyl-C.sub.1-3 -alkoxy, methoxyphenyl-C-.sub.1-3 -alkoxy, dimethoxyphenyl-C.sub.1-3 -alkoxy or dimethylaminocarbonylmethoxy group;
- or a pharmaceutically acceptable salt thereof.
- 5. A compound of the formula Ia, according to claim 1, wherein
- R.sub.1 represents a hydrogen atom,
- a phenyl group optionally substituted by a chlorine or bromine atom, by an C.sub.1-2 -alkyl, C.sub.1-2 -alkoxy or trifluoromethyl group,
- an C.sub.1-4 -alkyl group optionally substituted by two phenyl groups or by a C.sub.5-7 -cycloalkyl group,
- a phenyl-C.sub.1-4 -alkyl group wherein the phenyl nucleus is optionally substituted by an C.sub.1-4 -alkyl or C.sub.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.sub.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.sub.1-2 -alkylaminocarbonyl, benzylaminocarbonyl or di-(C.sub.1-2 -alkyl)-aminocarbonyl group;
- a carbonyl group substituted by a methyl, phenyl, ethylamino, dimethylamino, methoxymethyl or aminomethyl group, or
- a sulphonyl group substituted by a methyl, dimethylamino, phenyl or methoxyphenyl group;
- R.sub.2 represents a hydrogen atom, an C.sub.1-4 -alkyl or phenyl-C.sub.1-3 -alkyl group;
- X represents a 4-biphenylyloxymethylene group attached via the methylene moiety to the pyryolidinone 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.sub.2-4 -alkyl, benzyl, benzyloxycarbonyl, benzoyl, phenoxycarbonyl, C.sub.1-4 -alkoxycarbonyl, hydroxy, methoxy or cyano group;
- Y represents an n-C.sub.1-5 -alkylene group; and
- E represents a carbonyl group substituted by a hydroxy, C.sub.1-6 -alkoxy, phenyl-C.sub.1-3 -alkoxy, methoxyphenyl-C-.sub.1-3 -alkoxy, dimethoxyphenyl-C.sub.1-3 -alkoxy or dimethylaminocarbonylmethoxy group; or a pharmaceutically acceptable salt thereof.
- 6. A compound selected from the group consisting of:
- (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-pyrrolidine;
- (3s,5S)-1-acetyl-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-pyrrolidine;
- (3S,5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-1-(dimethylaminosulphonyl)-pyrrolidine;
- and the pharmaceutically acceptable salts thereof.
- 7. (3S,5S)-1-Acetyl-5-[(4'-amidino-4-biphenylyl)oxymethyl]-3-carboxymethyl-pyrrolidine.
- 8. A pharmaceutical composition comprising a compound in accordance with claims 1, 2, 3, 4, 5, 6 or 7.
- 9. A method for treating or preventing thrombus formation which comprises administering to a subject an anti-thrombotic amount of a compound in accordance with claime 1, 2, 3, 4, 5, 6 or 7.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 40 35 961.1 |
Nov 1990 |
DEX |
|
Parent Case Info
This is a division of application Ser. No. 08/365,336, filed Dec. 28, 1994, now U.S. Pat. No. 5,541,343 which is a continuation of application Ser. No. 07/783,065, filed Oct. 25, 1991, now abandoned.
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
|
4247466 |
Chiccarelli |
Jan 1981 |
|
Foreign Referenced Citations (3)
| Number |
Date |
Country |
| 0194548 |
Sep 1986 |
EPX |
| 0196184 |
Oct 1986 |
EPX |
| 0350437 |
Jan 1990 |
EPX |
Divisions (1)
|
Number |
Date |
Country |
| Parent |
365336 |
Dec 1994 |
|
Continuations (1)
|
Number |
Date |
Country |
| Parent |
783065 |
Oct 1991 |
|
Patent Grant
5591769
