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Claims for Patent: 6,087,380

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Claims for Patent: 6,087,380

Title: Disubstituted bicyclic heterocycles, the preparations and the use thereof as pharmaceutical compositions
Abstract:New disubstituted bicyclic heterocycles of general formula Compounds of the above general formula I, wherein E denotes an R.sub.b NH--C(.dbd.NH)-- group, have valuable pharmacological properties, particularly a thrombin-inhibiting effect and the effect of prolonging thrombin time, and those wherein E denotes a cyano group, are valuable intermediates for preparing the other compounds of general formula I. Exemplary compounds of formula I are: (a) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (b) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide, (c) 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl- carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide, and (d) 1-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]-benzimid azol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide.
Inventor(s): Hauel; Norbert (Schemmerhofen, DE), Priepke; Henning (Warthausen, DE), Ries; Uwe (Biberach, DE), Stassen; Jean Marie (Warthausen, DE), Wienen; Wolfgang (Biberach, DE)
Assignee: Boehringer Ingelheim Pharma KG (Ingelheim, DE)
Application Number:09/025,690
Patent Claims: 1. A compound of the formula 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-ca rboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide,

(f) 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-ca rboxylic 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)-aminomethy l]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethy l)-amide or a physiologically acceptable salt thereof.

8. 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomet hyl]-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.
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