.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Details for Patent: 6,469,039

« Back to Dashboard

Details for Patent: 6,469,039

Title: Disubstituted bicyclic heterocycles, the preparation 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)
Filing Date:Apr 06, 2000
Application Number:09/544,931
Claims:1. A compound of the formula I

wherein: A is a carbonyl or sulfonyl group linked to the benzo moiety of the group Het; B is an ethylene group, wherein a methylene group, linked either to the group Het or Ar, is optionally replaced by an oxygen or sulfur atom or by a sulfinyl, sulfonyl, carbonyl, or --NR.sub.1 -- group, wherein R.sub.1 is a hydrogen atom or a C.sub.1-6 -alkyl group; E is a R.sub.b NH--C (.dbd.NH)-- group, wherein R.sub.b is a hydrogen atom or 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, wherein the ethoxy moiety in the 2-position of the abovementioned C.sub.1-9 -alkoxycarbonyl group is unsubstituted or additionally substituted by a C.sub.1-3 -alkylsulfonyl or 2-(C.sub.1-3 -alkoxy)-ethyl group; Ar is 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; Het is 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 is a R.sub.2 NR.sub.3 -- group, wherein R.sub.2 is a C.sub.1-4 -alkyl group optionally substituted by a carboxy, C.sub.1-6 -alkyloxycarbonyl, benzyloxycarbonyl, C.sub.1-3 -alkylsulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, trifluorosulfonylamino, trifluorosulfonylaminocarbonyl, or 1H-tetrazolyl group, a C.sub.2-4 -alkyl group substituted at a carbon which is other than 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, or a piperidinyl group optionally substituted by a C.sub.1-3 -alkyl group, and R.sub.3 is a hydrogen atom, a C.sub.1-6 -alkyl group, a C.sub.3-7 -cycloalkyl group optionally substituted by a C.sub.1-3 -alkyl group, a C.sub.3-6 -alkenyl or alkynyl group, wherein the unsaturated part is not linked directly to the nitrogen atom of the R.sub.2 NR.sub.3 -- group, a benzyl group, or phenyl group optionally substituted by a fluorine, chlorine, or bromine atom or by a C.sub.1-3 -alkyl or C.sub.1-3 -alkoxy group,

or a physiologically acceptable salt thereof.

2. The compound of the formula I according to claim 1, wherein: R.sub.b is a hydrogen atom or 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, wherein the ethoxy moiety in the 2-position of the abovementioned C.sub.1-9 -alkoxycarbonyl group is unsubstituted or additionally substituted by a C.sub.1-3 -alkylsulfonyl or 2-(C.sub.1-3 -alkoxy)-ethyl group,

or a physiologically acceptable salt thereof.

3. The compound of the formula I according to claim 2, wherein: B is an ethylene group in which the methylene group linked to the group Ar is optionally replaced by an oxygen or sulfur atom or by an --NR.sub.1 -- group, wherein R.sub.1 is a hydrogen atom or a C.sub.1-4 -alkyl group; Ar is a 1,4-phenylene group optionally substituted by a chlorine atom or by a methyl, ethyl, or methoxy group; Het is a 1-(C.sub.1-3 -alkyl)-2,5-benzimidazolylene or 1-cyclopropyl-2,5-benzimidazolylene group; and R.sub.a is 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 -alkylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group, or a C.sub.2-4 -alkyl group substituted at a carbon which is other than 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 is a phenyl group optionally substituted by a fluorine, chlorine, or bromine atom or by a C.sub.1-3 -alkyl or C.sub.1-3 -alkoxy group,

or a physiologically acceptable salt thereof.

4. The compound of the formula I according to claim 1, wherein B is an ethylene group in which the methylene group linked to the group Ar is optionally replaced by an oxygen or sulfur atom or by an --NR.sub.1 -- group, wherein R.sub.1 is a hydrogen atom or a methyl group; R.sub.a is an R.sub.2 NR.sub.3 -- group, wherein R.sub.2 is a C.sub.1-3 -alkyl group 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 than the one in the .alpha.-position relative to the adjacent nitrogen atom, by a hydroxy, benzyloxy, 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 is a phenyl group optionally substituted by a fluorine, chlorine, or bromine atom or by a C.sub.1-3 -alkyl or C.sub.1-3 -alkoxy group,

or a physiologically acceptable salt thereof.

5. A compound of the formula I according to claim 2, wherein A is a carbonyl group linked to the benzo moiety of the group Het; B is an ethylene group in which the methylene group attached to the group Ar is optionally replaced by an --NR.sub.1 -- group, wherein R.sub.1 is a hydrogen atom or a methyl group; Ar is a 1,4-phenylene group optionally substituted by a methoxy group, Het is a 1-methyl-2,5-benzimidazolylene group; and R.sub.a is a R.sub.2 NR.sub.3 -- group, wherein R.sub.2 is a C.sub.1-3 -alkyl group optionally substituted by a carboxy, C.sub.1-6 -alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl, or 1H-tetrazolyl group, or a C.sub.2-3 -alkyl group substituted at a carbon which is other than the one in the .alpha.-position relative to the adjacent nitrogen atom, by a hydroxy, benzyloxy, 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 is a phenyl group optionally substituted by a fluorine, chlorine, or bromine atom or by a C.sub.1-3 -alkyl or C.sub.1-3 -alkoxy 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-phenyl-N-(2-hydroxycarbonylethyl)-amide; (b) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)-amide; (c) 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide; (d) 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide, (e) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide; (f) 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-ca rboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide; (g) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-hydroxycarbonylethyl-N-methyl)-2-aminoethyl]-amide; (h) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide; (i) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-hydroxycarbonylethyl)-amide; (j) 1-Methyl-2-[N-(4-amidino-2-methoxyphenyl)-aminomethyl]-benzimidazol-5-yl-c arboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide; (k) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide; and (l) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-thieno[2. 3-d]imidazol-5-y-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide;

or a physiologically acceptable salt thereof.

7. 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, or a physiologically acceptable salt thereof.

8. A physiologically acceptable salt of a compound according to one of claims 1, 2, 3, 4, 5, 6, or 7.

9. A pharmaceutical composition containing a compound according to one of claims 1, 2, 3, 4, 5, 6, or 7, or a physiologically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.

10. A method for the prophylaxis or treatment of venous and arterial thrombotic disease in patient in need thereof, which comprises administering to the patient an antithrombotic amount of a compound according one of claims 1, 2, 3, 4, 5, 6, or 7, or a physiologically acceptable salt thereof.

11. The method of claim 10, wherein the 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.

12. A method for providing antithrombotic support in thrombolytic treatment utilizing rt-PA or streptokinase in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of a compound according to one of claims 1, 2, 3, 4, 5, 6, or 7, or a physiologically acceptable salt thereof.

13. A method for treating or preventing fibrin-dependent inflammatory processes in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of a compound according to one of claims 1, 2, 3, 4, 5, 6, or, 7, or a physiologically acceptable salt thereof.
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

How are People Using DrugPatentWatch?

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc