Fused pyrroledicarboxamides and their use as pharmaceuticals

Patent metadata

Field	Value
Publication number	US-9284333-B2
Application number	US-201314375273-A
Country	US
Kind code	B2
Filing date	Feb 1, 2013
Priority date	Feb 3, 2012
Publication date	Mar 15, 2016
Grant date	Mar 15, 2016

Abstract

The present invention relates to fused pyrroledicarboxamides of the formula (I), in which R1 to R9, X, m and n are as defined in the claims. The compounds of the formula (I) are inhibitors of the acid-sensitive potassium channel TASK-1 and suitable for the treatment of TASK-1 channel-mediated diseases such as arrhythmias, in particular atrial arrhythmias like atrial fibrillation or atrial flutter, and respiratory disorders, in particular sleep-related respiratory disorders like sleep apnea, for example.

First claim

The invention claimed is:

1. A compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof,

wherein
n is selected from the series consisting of 0 and 1;
m is selected from the series consisting of 0, 1 and 2, with the proviso that m and n cannot simultaneously be 0;
X is selected from the series consisting of oxygen, sulfur and (R10)(R11)C;
one of the groups R1 and R2 is the group R20-NH— and the other of the groups R1 and R2 is the group (R30)(R31)N—;
R3 is selected from the series consisting of hydrogen, halogen and (C 1 -C 4 )-alkyl;
R4, R5, R6, R7, R8, R9, R10 and R11 are independently of one another selected from the series consisting of hydrogen, fluorine and (C 1 -C 4 )-alkyl;
R20 is selected from the series consisting of (C 5 -C 7 )-cycloalkyl to which a benzene ring or a Het1 ring is fused, and (R21)(R22)(R23)C—, wherein the (C 5 -C 7 )-cycloalkyl is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—, and the fused benzene ring and Het1 ring is unsubstituted or substituted by one or more identical or different substituents R24;
R21 is selected from the series consisting of phenyl and Het1, which are all unsubstituted or substituted by one or more identical or different substituents R24;
R22 is selected from the series consisting of hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, R25-(C 1 -C 4 )-alkyl- and phenyl;
R23 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;
R24 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, HO—, (C 1 -C 4 )-alkyl-O—, (C 1 -C 4 )-alkyl-S(O) p —, F 5 S—, NC—, (C 1 -C 4 )-alkyl-O—C(O)—, —(C 3 -C 5 )-alkanediyl-, —O—(C 1 -C 4 )-alkanediyl-O— and —(C 1 -C 4 )-alkanediyl-O—C(O)—;
R25 is selected from the series consisting of (C 3 -C 7 )-cycloalkyl, (C 1 -C 4 )-alkyl-O— and (C 1 -C 4 )-alkyl-S—;
R30 is selected from the series consisting of hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-, HO—(C 1 -C 4 )-alkyl- and (C 1 -C 4 )-alkyl-O—(C 1 -C 4 )-alkyl-;
R31 is selected from the series consisting of (C 3 -C 7 )-cycloalkyl, (C 5 -C 7 )-cycloalkyl to which a benzene ring is fused, phenyl, Het2 and (R32)(R33)(R34)C—, wherein the (C 3 -C 7 )-cycloalkyl and (C 5 -C 7 )-cycloalkyl are unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine, (C 1 -C 4 )-alkyl, HO— and (C 1 -C 4 )-alkyl-O— and the fused benzene ring is unsubstituted or substituted by one or more identical or different substituents R35;
or the groups R30 and R31, together with the nitrogen atom carrying them, form a 4-membered to 10-membered, monocyclic or bicyclic, saturated or partially unsaturated heterocycle which, in addition to the nitrogen atom carrying R30 and R31, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents R36;
R32 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;
R33 is selected from the series consisting of hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, R37-(C 1 -C 4 )-alkyl- and (C 1 -C 4 )-alkyl-O—C(O)—;
or R32 and R33, together with the carbon atom carrying them, form a (C 3 -C 7 )-cycloalkane ring which, irrespective of the group R34, is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;
R34 is selected from the series consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, R38-(C 3 -C 7 )-cycloalkyl-, (C 1 -C 4 )-alkyl-O—C(O)—, (R39)(R40)N—C(O)—, phenyl and Het2, wherein the (C 1 -C 6 )-alkyl is unsubstituted or substituted by one or more identical or different substituents R41, and the phenyl is unsubstituted or substituted by one or more identical or different substituents R35;
R35 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, HO—(C 1 -C 4 )-alkyl-, (C 1 -C 4 )-alkyl-O—(C 1 -C 4 )-alkyl-, (C 1 -C 4 )-alkyl-O—C(O)—(C 1 -C 4 )-alkyl-, NC—, HO—, (C 1 -C 4 )-alkyl-O—, (C 1 -C 4 )-alkyl-S(O) p —, (C 1 -C 4 )-alkyl-S(O) 2 —NH—, R42-O—C(O)—, (R43)(R44)N—C(O)— and (R45)(R46)N—S(O) 2 —;
R36 is selected from the series consisting of fluorine, (C 1 -C 6 )-alkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl, (C 3 -C 7 )-cycloalkyl, phenyl, Het3, HO—, (C 1 -C 4 )-alkyl-O—, (C 3 -C 7 )-cycloalkyl-O—, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-O—, phenyl-O—, (C 1 -C 4 )-alkyl-S(O) p —, NC— and R47-O—C(O)—, wherein the (C 1 -C 6 )-alkyl is unsubstituted or substituted by one or more identical or different substituents R48;
R37 is selected from the series consisting of (C 3 -C 7 )-cycloalkyl, (C 1 -C 4 )-alkyl-O— and (C 1 -C 4 )-alkyl-S—;
R38 is selected from the series consisting of phenyl, HO— and (C 1 -C 4 )-alkyl-O—;
R39, R40, R42, R47, R49, R50 and R51 are independently of one another selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;
R41 is selected from the series consisting of (C 3 -C 7 )-cycloalkyl, phenyl, Het1, HO—, (C 1 -C 4 )-alkyl-O— and (C 1 -C 4 )-alkyl-S—;
R43, R44, R45 and R46 are independently of one another selected from the series consisting of hydrogen, (C 1 -C 4 )-alkyl, HO—(C 1 -C 4 )-alkyl- and (C 1 -C 4 )-alkyl-O—(C 1 -C 4 )-alkyl-;
R48 is selected from the series consisting of (C 3 -C 7 )-cycloalkyl, phenyl, Het3, HO—, (C 1 -C 4 )-alkyl-O—, (C 1 -C 4 )-alkyl-C(O)—O—, (C 1 -C 4 )-alkyl-S(O) p —, (C 1 -C 4 )-alkyl-C(O)—(R49)N—, (R50)(R51)N—C(O)— and (C 1 -C 4 )-alkyl-O—C(O)—;
p is selected from the series consisting of 0, 1 and 2, wherein all numbers p are independent of one another;
Het1 is a 5-membered or 6-membered, monocyclic, aromatic heterocycle comprising 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, which is bonded via a ring carbon atom and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, NC—, HO—, (C 1 -C 4 )-alkyl-O— and (C 1 -C 4 )-alkyl-S(O) p —, unless specified otherwise;
Het2 is a 4-membered to 10-membered, monocyclic or bicyclic, saturated, partially unsaturated or aromatic heterocycle comprising 1, 2, 3 or 4 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, which is bonded via a ring carbon atom and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C 1 —C)-alkyl, NC—, HO— and (C 1 -C 4 )-alkyl-O—;
Het3 is a 4-membered to 7-membered, monocyclic, saturated, partially unsaturated or aromatic heterocycle comprising 1, 2 or 3 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, NC—, HO—, (C 1 -C 4 )-alkyl-O— and (C 1 -C 4 )-alkyl-S(O) p —;
wherein all phenyl groups are unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, NC—, HO— and (C 1 -C 4 )-alkyl-O—, unless specified otherwise;
wherein all cycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group, can be substituted by one or more identical or different substitue

Assignees

• Sanofi Sa

Inventors

• Bialy Laurent
• Lorenz Katrin
• Wirth Klaus
• Steinmeyer Klaus
• Hessler Gerhard

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/06

  Antiarrhythmics · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title