Claims
- 1. A compound of the formula I
- R.sub.a --A--Het--B--Ar--E (I)
- wherein
- A denotes a carbonyl or sulphonyl group linked to the benzo moiety of the group Het,
- B denotes an ethylene group, wherein a methylene group, linked either to the group Het or Ar, is optionally replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl, carbonyl or --NR.sub.1 group, wherein
- R.sub.1 denotes a hydrogen atom or a C.sub.1-6 -alkyl group,
- E denotes a cyano or R.sub.b NH--C(.dbd.NH)-- group wherein
- R.sub.b denotes a hydrogen atom, a hydroxy group, C.sub.1-9 -alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C.sub.1-3 -alkoxycarbonyl, benzoyl, p-C.sub.1-3 -alkyl-benzoyl or pyridinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C.sub.1-9 -alkoxycarbonyl group is optionally, additionally, substituted by a C.sub.1-3 -alkylsulfonyl or 2-(C.sub.1-3 -alkoxy)-ethyl group,
- Ar denotes a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom or by a trifluoromethyl, C.sub.1-3 -alkyl or C.sub.1-3 -alkoxy group, or a thienylene group optionally substituted in the carbon skeleton by a C.sub.1-3 -alkyl group,
- Het denotes a bicyclic heterocycle of formula ##STR9## wherein, X is a nitrogen atom and
- Y is an imino group optionally substituted by a C.sub.1-6 -alkyl or C.sub.3-7 -cycloalkyl group
- and R.sub.a denotes an R.sub.2 NR.sub.3 -- group wherein
- R.sub.2 denotes a C.sub.1-4 -alkyl group, which is optionally substituted by a carboxy, C.sub.1-6 -alkyloxycarbonyl, benzyloxycarbonyl, C.sub.1-3 -alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, trifluorosulphonylamino, trifluorosulphonylaminocarbonyl or 1H-tetrazolyl group, or
- a C.sub.2-4 -alkyl group substituted, at a carbon which is other the one in the .alpha.-position relative to the adjacent nitrogen atom, by a hydroxy, phenyl-C.sub.1-3 -alkoxy, carboxy-C.sub.1-3 -alkylamino, C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino, N-(C.sub.1-3 -alkyl)-carboxy-C.sub.1-3 -alkylamino or N-(C.sub.1-3 -alkyl)-C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino group, and
- R.sub.3 denotes a pyridinyl group optionally substituted by a methyl group,
- or, if E is a group of the formula R.sub.b NH--C--(.dbd.NH)--, a physiologically acceptable salt thereof or, if E is a cyano group, a salt thereof.
- 2. A compound of the formula I according to claim 1, wherein
- A denotes a carbonyl or sulphonyl group linked to the benzo moiety of the group Het,
- B denotes an ethylene group, in which a methylene group, linked either to the group Het or Ar, is optionally replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl, carbonyl or --NR.sub.1 -- group, wherein
- R.sub.1 denotes a hydrogen atom or a C.sub.1-5 -alkyl group,
- E denotes an R.sub.b NH--C(.dbd.NH)-- group wherein
- R.sub.b denotes a hydrogen atom, a hydroxy group, C.sub.1-9 -alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C.sub.1-3 -alkoxycarbonyl, benzoyl, p-C.sub.1-3 -alkyl-benzoyl or pyridinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C.sub.1-9 -alkoxycarbonyl group is optionally, additionally, substituted by a C.sub.1-3 -alkylsulfonyl or 2-(C.sub.1-3 -alkoxy)-ethyl group,
- Ar denotes a phenylene group optionally substituted by a fluorine, chlorine or bromine atom or by a trifluoromethyl, C.sub.1-3 -alkyl or C.sub.1-3 -alkoxy group,
- or a thienylene group optionally substituted in the carbon skeleton by a C.sub.1-3 -alkyl group,
- Het denotes a bicyclic heterocycle of formula ##STR10## wherein, X is a nitrogen atom and
- Y is an imino group optionally substituted by a C.sub.1-6 -alkyl or C.sub.3-7 -cycloalkyl group
- and R.sub.a denotes a R.sub.2 NR.sub.3 -- group wherein
- R.sub.2 denotes a C.sub.1-4 -alkyl group, which is optionally substituted by a carboxy, C.sub.1-6 -alkyloxycarbonyl, benzyloxycarbonyl, C.sub.1-3 -alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, trifluorosulphonylamino, trifluorosulphonylaminocarbonyl or 1H-tetrazolyl group, or
- a C.sub.2-4 -alkyl group substituted, at a carbon which is other the one in the .alpha.-position relative to the adjacent nitrogen atom, by a hydroxy, phenyl-C.sub.1-3 -alkoxy, carboxy-C.sub.1-3 -alkylamino, C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino, N-(C.sub.1-3 -alkyl)-carboxy-C.sub.1-3 -alkylamino or N-(C.sub.1-3 -alkyl)-C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino group, and
- R.sub.3 denotes pyridinyl group optionally substituted by a methyl group,
- or a physiologically acceptable salt thereof.
- 3. A compound of the formula I according to claim 1, wherein
- A denotes a carbonyl or sulphonyl group linked to the benzo moiety of the group Het,
- B denotes an ethylene group in which the methylene group linked to the group Ar is optionally replaced by an oxygen or sulphur atom or by an --NR.sub.1 -- group, wherein
- R.sub.1 denotes a hydrogen atom or a C.sub.1-4 -alkyl group,
- E denotes an R.sub.b NH--C(.dbd.NH)-- group wherein
- R.sub.b denotes a hydrogen atom, a hydroxy, C.sub.1-9 -alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C.sub.1-3 -alkoxycarbonyl, benzoyl, p-C.sub.1-3 -alkyl-benzoyl or pyridinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C.sub.1-9 -alkoxycarbonyl group is optionally, additionally, substituted by a C.sub.1-3 -alkyl-sulfonyl or 2-(C.sub.1-3 -alkoxy)-ethyl group,
- Ar denotes a 1,4-phenylene group optionally substituted by a chlorine atom or by a methyl, ethyl or methoxy group or it denotes a 2,5-thienylene group,
- Het denotes a 1-(C.sub.1-3 -alkyl)-2,5-benzimidazolylene or 1-cyclopropyl-2,5-benzimidazolylene group and
- R.sub.a denotes an R.sub.2 NR.sub.3 -- group wherein
- R.sub.2 is a C.sub.1-4 -alkyl group substituted by a carboxy, C.sub.1-6 -alkyloxycarbonyl, benzyloxycarbonyl, C.sub.1-3 -alkylsulphonylaminocarbonyl or 1H-tetrazol-5-yl group, or
- a C.sub.2-4 -alkyl group substituted, at a carbon which is other the one in the .alpha.-position relative to the adjacent nitrogen atom, by a hydroxy, benzyloxy, carboxy-C.sub.1-3 -alkyl-amino, C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino, N-(C.sub.1-3 -alkyl)-carboxy-C.sub.1-3 -alkylamino or N-(C.sub.1-3 -alkyl)-C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino group, and
- R.sub.3 denotes a pyridinyl group optionally substituted by a methyl group,
- or a physiologically acceptable salt thereof.
- 4. A compound of the formula I according to claim 1, wherein
- A denotes a carbonyl or sulphonyl group linked to the benzo moiety of the group Het,
- B denotes an ethylene group in which the methylene group linked to the group Ar is optionally replaced by an oxygen or sulphur atom or by an --NR.sub.1 -- group, wherein
- R.sub.1 denotes a hydrogen atom or a methyl group,
- E denotes an R.sub.b NH--C(.dbd.NH)-- group, wherein
- R.sub.b denotes a hydrogen atom or a hydroxy, C.sub.1-9 -alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C.sub.1-3 -alkylbenzoyl or nicotinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C.sub.1-9 -alkoxycarbonyl group is optionally, additionally, substituted by a C.sub.1-3 -alkylsulphonyl or 2-(C.sub.1-3 -alkoxy)-ethyl group,
- Ar denotes a 1,4-phenylene group optionally substituted by a chlorine atom or by a methyl, ethyl or methoxy group, or it denotes a 2,5-thienylene group,
- Het denotes a 1-methyl-2,5-benzimidazolylene or 1-cyclopropyl-2,5-benzimidazolylene group and
- R.sub.a denotes a R.sub.2 NR.sub.3 -- group wherein
- R.sub.2 denotes a C.sub.1-3 -alkyl group which is optionally substituted by a carboxy, C.sub.1-6 -alkyloxycarbonyl, benzyloxycarbonyl, methylsulphonylaminocarbonyl or 1H-tetrazol-5-yl group, or
- a C.sub.2-3 -alkyl group substituted, at a carbon which is other the one in the .alpha.-position relative to the adjacent nitrogen atom, by a hydroxy, benzyloxy, carboxy-C.sub.1-3 -alkyl-amino, C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino, N-(C.sub.1-3 -alkyl)-carboxy-C.sub.1-3 -alkylamino or N-(C.sub.1-3 -alkyl)-C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino group, and
- R.sub.3 denotes a pyridinyl group,
- or a physiologically acceptable salt thereof.
- 5. A compound of the formula I according to claim 1, wherein
- A denotes a carbonyl group linked to the benzo moiety of the group Het,
- B denotes an ethylene group wherein the methylene group attached to the group Ar is optionally replaced by an --NR.sub.1 group, whilst
- R.sub.1 denotes a hydrogen atom or a methyl group,
- E denotes an R.sub.b NH--C(.dbd.NH)-- group wherein
- R.sub.b is a hydrogen atom, a hydroxy, C.sub.1-9 -alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C.sub.1-3 -alkyl-benzoyl or nicotinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C.sub.1-9 -alkoxycarbonyl group is optionally, additionally, substituted by a methylsulfonyl or 2-ethoxy-ethyl group,
- Ar denotes a 1,4-phenylene group optionally substituted by a methoxy group or it denotes a 2,5-thienylene group,
- Het denotes a 1-methyl-2,5-benzimidazolylene group and
- R.sub.a denotes an R.sub.2 NR.sub.3 -- group wherein R.sub.2 denotes a C.sub.1-3 -alkyl group which is optionally substituted by a carboxy, C.sub.1-6 -alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group, or
- a C.sub.2-3 -alkyl group substituted, at a carbon which is other the one in the .alpha.-position relative to the adjacent nitrogen atom, by a hydroxy, benzyloxy, carboxy-C.sub.1-3 -alkyl-amino, C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino, N-(C.sub.1-3 -alkyl)-carboxy-C.sub.1-3 -alkylamino or N-(C.sub.1-3 -alkyl)-C.sub.1-3 -alkoxycarbonyl-C.sub.1-3 -alkylamino group, and
- R.sub.3 denotes a 2-pyridinyl group,
- or a physiologically acceptable salt thereof.
- 6. A compound selected from the group consisting of:
- (a) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide,
- (b) 1-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide,
- (c) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide,
- (d) 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide,
- (e) 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide,
- (f) 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-hydroxycarbonylethyl)-amide and
- (g) 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide,
- or a physiologically acceptable salt thereof.
- 7. 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide or a physiologically acceptable salt thereof.
- 8. 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide or a physiologically acceptable salt thereof.
- 9. 1-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide or a physiologically acceptable salt thereof.
- 10. A pharmaceutical composition containing a compound according to claim 1, wherein E denotes an R.sub.b NH--C(.dbd.NH)-- group, or a compound according to claim 2, 3, 4, 5, 6, 7, 8 or 9, or a physiologically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.
- 11. A method for the prophylaxis or treatment of venous and arterial thrombotic disease which comprises administering an antithrombotic amount of a compound according claim 1, wherein E denotes an R.sub.b NH--C(.dbd.NH)-- group, or a compound according to claim 2, 3, 4, 5, 6, 7, 8 or 9, or a physiogically acceptable salt thereof.
- 12. The method of claim 11 wherein said thrombotic disease is selected from the group consisting of deep leg vein thrombosis, reocclusion after a bypass operation or angioplasty (PT(C)A), occlusion in peripheral arterial disease, pulmonary embolism, disseminated intravascular coagulation, coronary thrombosis, stroke, and the occlusion of a shunt or stent.
- 13. A method for providing antithrombotic support in thrombolytic treatment utilizing rt-PA or streptokinase, which comprises administering a therapeutically effective amount of a compound according claim 1, wherein E denotes an R.sub.b NH--C(.dbd.NH)-- group, or a compound according to claim 2, 3, 4, 5, 6, 7, 8 or 9, or a physiologically acceptable salt thereof.
Priority Claims (2)
Number |
Date |
Country |
Kind |
197 51 939 |
Nov 1949 |
DEX |
|
197 06 229 |
Feb 1997 |
DEX |
|
REFERENCE TO PRIOR PROVISIONAL APPLICATION
Benefit of prior filed and copending U.S. provisional application Ser. No. 60/044,421, filed on Apr. 29, 1997, is hereby claimed.
US Referenced Citations (2)
Number |
Name |
Date |
Kind |
4675405 |
Musser et al. |
Jun 1987 |
|
5416099 |
Hartman et al. |
May 1995 |
|
Foreign Referenced Citations (4)
Number |
Date |
Country |
0 540 051 A1 |
May 1993 |
EPX |
0 623 596 A1 |
Nov 1994 |
EPX |
0 655 439 A2 |
May 1995 |
EPX |
41 29 603 A1 |
Mar 1993 |
DEX |
Non-Patent Literature Citations (1)
Entry |
Takayasu Nagahara; Dibasic (amidinoaryl) propanoic Acid Derivatives as Novel Blood Coagulation Factor Xa Inhibitors, J. Med. Chem. 1994, 37, 1200-1207-XP000608128. |