BICYCLIC HETEROCYCLES, MEDICAMENTS CONTAINING SAID COMPOUNDS, USE THEREOF, AND METHOD FOR PRODUCTION OF SAME

• US 20110136805A1
• Filed: 11/03/2007
• Published: 06/09/2011
• Est. Priority Date: 11/10/2006
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Himmelsbach, Frank, Jung, Birgit
• Granted Patent: US 8,399,461 B2
• Time in Patent Office: Days
• US Class Current: 514/234.5
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 239/94 Nitrogen atoms

Abstract

The present invention relates to bicyclic heterocycles of general formula

the tautomers, the stereoisomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases, as well as benign prostatic hyperplasia (BPH), diseases of the lungs and respiratory tract, and the preparation thereof.

Claims

1. Bicyclic heterocycles of general formula (I)

2. Compounds according to claim 1,

R denotes a group selected from among

cis-4-(methoxycarbonylamino)-cyclohexyl, trans-4-(methoxycarbonylamino)-cyclohexyl,

cis-4-(N-methoxycarbonyl-N-methyl-amino)-cyclohexyl, trans-4-(N-methoxycarbonyl-N-methyl-amino)-cyclohexyl,

cis-4-(ethyloxycarbonylamino)-cyclohexyl, trans-4-(ethyloxycarbonylamino)-cyclohexyl,

cis-4-(N-ethyloxycarbonyl-N-methyl-amino)-cyclohexyl, trans-4-(N-ethyloxycarbonyl-N-methyl-amino)-cyclohexyl,

cis-4-(tert.-butoxycarbonylamino)-cyclohexyl, trans-4-(tert.-butoxycarbonylamino)-cyclohexyl,

cis-4-(N-tert.-butoxycarbonyl-N-methyl-amino)-cyclohexyl, trans-4-(N-tert.-butoxycarbonyl-N-methyl-amino)-cyclohexyl,

cis-4-(methoxyacetyl-amino)-cyclohexyl, trans-4-(methoxyacetyl-amino)-cyclohexyl,

cis-4-(N-methoxyacetyl-N-methyl-amino)-cyclohexyl, trans-4-(N-methoxyacetyl-N-methyl-amino)-cyclohexyl,

cis-4-(dimethylaminocarbonyl-amino)-cyclohexyl, trans-4-(dimethylaminocarbonyl-amino)-cyclohexyl,

cis-4-(N-dimethylaminocarbonyl-N-methyl-amino)-cyclohexyl, trans-4-(N-dimethylaminocarbonyl-N-methyl-amino)-cyclohexyl,

cis-4-(morpholinocarbonyl-amino)-cyclohexyl, trans-4-(morpholinocarbonyl-amino)-cyclohexyl,

cis-4-(N-morpholinocarbonyl-N-methyl-amino)-cyclohexyl, trans-4-(N-morpholinocarbonyl-N-methyl-amino)-cyclohexyl,

cis-4-(piperazin-1-ylcarbonyl-amino)-cyclohexyl, trans-4-(piperazin-1-ylcarbonyl-amino)-cyclohexyl,

cis-4-(N-piperazin-1-ylcarbonyl-N-methyl-amino)-cyclohexyl, trans-4-(N-piperazin-1-ylcarbonyl-N-methyl-amino)-cyclohexyl,

cis-4-[(4-methyl-piperazin-1-ylcarbonyl)-amino]-cyclohexyl, trans-4-[(4-methyl-piperazin-1-ylcarbonyl)-amino]-cyclohexyl,

cis-4-[N-(4-methyl-piperazin-1-ylcarbonyl)-N-methyl-amino]-cyclohexyl, trans-4-[N-(4-methyl-piperazin-1-ylcarbonyl)-N-methyl-amino]-cyclohexyl,

cis-4-(methanesulphonylamino)-cyclohexyl, trans-4-(methanesulphonylamino)-cyclohexyl,

cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexyl, trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexyl, cis-4-phthalimido-cyclohexyl and trans-4-phthalimido-cyclohexyl,

optionally in the form of the tautomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts, solvates and hydrates thereof.

3. Physiologically acceptable salts of the compounds according to claim 1 with inorganic or organic acids.

4. Pharmaceutical compositions, containing a compound according to claim 1 or a physiologically acceptable salt according to claim 2 optionally together with one or more inert carriers and/or diluents.

5. Use of a compound according to at least one of claims 1 to 2 for preparing a pharmaceutical composition that is suitable for the treatment of benign or malignant tumours, for the prevention and treatment of diseases of the airways and lung as well as for the treatment of diseases of the gastro-intestinal tract and the bile duct and gall bladder.

6. Process for preparing the compounds of general formula I according to claim 1, characterised in that

a) a compound of formula (II)

7. Process for preparing the compounds of general formula (I) according to claim 1, characterised in that

R denotes a group selected from among cis-4-(methoxycarbonylamino)-cyclohexyl, trans-4-(methoxycarbonylamino)-cyclohexyl, cis-4-(N-methoxycarbonyl-N-methyl-amino)-cyclohexyl, trans-4-(N-methoxycarbonyl-N-methyl-amino)-cyclohexyl, cis-4-(ethyloxycarbonylamino)-cyclohexyl, trans-4-(ethyloxycarbonylamino)-cyclohexyl, cis-4-(N-ethyloxycarbonyl-N-methyl-amino)-cyclohexyl, trans-4-(N-ethyloxycarbonyl-N-methyl-amino)-cyclohexyl, cis-4-(tert.-butoxycarbonylamino)-cyclohexyl, trans-4-(tert.-butoxycarbonylamino)-cyclohexyl, cis-4-(N-tert.-butoxycarbonyl-N-methyl-amino)-cyclohexyl, trans-4-(N-tert.-butoxycarbonyl-N-methyl-amino)-cyclohexyl, cis-4-(acetylamino)-cyclohexyl, trans-4-(acetylamino)-cyclohexyl, cis-4-(N-acetyl-N-methyl-amino)-cyclohexyl, trans-4-(N-acetyl-N-methyl-amino)-cyclohexyl, cis-4-(methoxyacetyl-amino)-cyclohexyl, trans-4-(methoxyacetyl-amino)-cyclohexyl, cis-4-(N-methoxyacetyl-N-methyl-amino)-cyclohexyl, trans-4-(N-methoxyacetyl-N-methyl-amino)-cyclohexyl, cis-4-(dimethylaminocarbonyl-amino)-cyclohexyl, trans-4-(dimethylaminocarbonyl-amino)-cyclohexyl, cis-4-(N-dimethylaminocarbonyl-N-methyl-amino)-cyclohexyl, trans-4-(N-dimethylaminocarbonyl-N-methyl-amino)-cyclohexyl, cis-4-(morpholinocarbonyl-amino)-cyclohexyl, trans-4-(morpholinocarbonyl-amino)-cyclohexyl, cis-4-(N-morpholinocarbonyl-N-methyl-amino)-cyclohexyl, trans-4-(N-morpholinocarbonyl-N-methyl-amino)-cyclohexyl, cis-4-(piperazin-1-ylcarbonyl-amino)-cyclohexyl, trans-4-(piperazin-1-ylcarbonyl-amino)-cyclohexyl, cis-4-(N-piperazin-1-ylcarbonyl-N-methyl-amino)-cyclohexyl, trans-4-(N-piperazin-1-ylcarbonyl-N-methyl-amino)-cyclohexyl, cis-4-[(4-methyl-piperazin-1-ylcarbonyl)-amino]-cyclohexyl, trans-4-[(4-methyl-piperazin-1-ylcarbonyl)-amino]-cyclohexyl, cis-4-[N-(4-methyl-piperazin-1-ylcarbonyl)-N-methyl-amino]-cyclohexyl, trans-4-[N-(4-methyl-piperazin-1-ylcarbonyl)-N-methyl-amino]-cyclohexyl, cis-4-(methanesulphonylamino)-cyclohexyl, trans-4-(methanesulphonylamino)-cyclohexyl, cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexyl and trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexyl,

a compound of general formula (VI)

8. Process for preparing the compounds of general formula (I) according to claim 1, characterised in that

R denotes a cis-4-phthalimido-cyclohex-1-yl or trans-4-phthalimido-cyclohex-1-yl group, and

a compound of general formula (VII)

9. Medicament combinations which contain in addition to one or more compounds of formula 1 according to one of claim 1 or 2, as a further active substance, one or more compounds selected from among the categories of the betamimetics, anticholinergics, corticosteroids, other PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists, H1-antihistamines, PAF-antagonists, PI3-kinase inhibitors, MPR4-inhibitors, iNOS-inhibitors and SYK-inhibitors or double or triple combinations thereof.