Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for production of same

• US 8,399,461 B2
• Filed: 11/03/2007
• Issued: 03/19/2013
• 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
• Primary Examiner(s): BARKER, MICHAEL P
• Application Number:
  US12/513,731
• Publication Number:
  US 20110136805A1
• Time in Patent Office: 1,963 Days
• Field of Search: None
• 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. A bicyclic heterocycle of formula (I)

2. The compound according to claim 1, wherein

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,

or a tautomer or pharmacologically acceptable acid addition salt thereof.

3. A physiologically acceptable salt of the compound according to claim 1 with an inorganic or organic acid.

4. A pharmaceutical composition containing a compound according to claim 1 or a pharmacologically acceptable acid addition salt thereof, optionally together with one or more inert carriers and/or diluents.

5. A process for preparing the compound of formula I according to claim 1, comprising

a) reacting a compound of formula (II)

6. A process for preparing the compound of formula (I) according to claim 1, wherein

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,

comprising reacting a compound of formula (VI)

7. A process for preparing the compound of formula (I) according to claim 1, wherein

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

comprising reacting a compound of formula (VII)

8. A medicament combination which contains in addition to one or more compounds of formula I according to claim 1 or a pharmaceutically acceptable acid addition salt thereof and, 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.