발생일자 2015.01.21 

사건번호 1:15-cv-00010 

법원국가 UNITED STATES OF AMERICA 

관할법원명 D.C.N.D.WestVirginia(지방법원) 

침해권리 특허 

원고명 Boehringer Ingelheim Pharma GMBH & CO. KG / Boehringer Ingelheim International GMBH/ BOEHRINGER INGELHEIM PHARMACEUTICALS, Inc ( 독일 / 외국기업 )  

피고명 Mylan Pharmaceuticals, Inc. ( 미국 / 외국기업 )  

소송유형 침해금지 

[Boehringer Ingelheim Pharma GMBH & CO. KG v. Mylan Pharmaceuticals, Inc.] 사건번호 1:15-cv-00010에 따르면 원고 Boehringer Ingelheim Pharma GMBH & CO. KG / Boehringer Ingelheim International GMBH/ BOEHRINGER INGELHEIM PHARMACEUTICALS, Inc는 피고 Mylan Pharmaceuticals, Inc.을 상대로 특허 US6087380을 침해하였다는 이유로 미국 웨스트버지니아 북부 지방법원에 소를 제기하였다. 

분쟁결과 분쟁중 

산업분류 화학∙바이오 > 유기화학기술 

계쟁제품

75mg and 150mg dabigatran etexilate mesylate capsules, generic version of PRADAXA 

지재권번호/명칭

US6087380   Disubstituted bicyclic heterocycles, the preparations and the use thereof as pharmaceutical compositions 

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. 

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.