Substituted chroman-6-yloxy-cycloalkanes and their use as pharmaceuticals

Patent metadata

Field	Value
Publication number	US-9440941-B2
Application number	US-201414772375-A
Country	US
Kind code	B2
Filing date	Mar 7, 2014
Priority date	Mar 8, 2013
Publication date	Sep 13, 2016
Grant date	Sep 13, 2016

Abstract

The present invention relates to substituted chroman-6-yloxy-cycloalkanes of the formula (I) in which Ar, R1 to R4, p and q are as defined in the claims. The compounds of the formula (I) are inhibitors of the sodium-calcium exchanger (NCX), especially of the sodium-calcium exchanger of subtype 1 (NCX1), and are suitable for the treatment of diverse disorders in which intracellular calcium homeostasis is disturbed, such as arrhythmias, heart failure and stroke. The invention furthermore relates to processes for the preparation of the compounds of the formula (I), their use as pharmaceuticals, and pharmaceutical compositions comprising them.

First claim

What is 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
Ar is phenyl which is unsubstituted or substituted by one or more identical or different substituents R0;
R0 is selected from the series consisting of halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-, HO—, (C 1 -C 6 )-alkyl-O—, (C 3 -C 7 )-cycloalkyl-O— and (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-O—, and two groups R0 bonded to adjacent ring carbon atoms in Ar, together with the carbon atoms carrying them, can form a 5-membered to 7-membered mono-unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which 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;
R1 is hydrogen or one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;
R2 is selected from the series consisting of hydrogen, (C 1 -C 6 )-alkyl, HO—, (C 1 -C 6 )-alkyl-O—, (C 1 -C 6 )-alkyl-C(O)—O—, phenyl-C(O)—O—, Het1-C(O)—O—, R5-N(R6)-, R7-C(O)—N(R8)-, R7-S(O) 2 —N(R8)-, R9-N(R10)-C(O)—N(R8)- and R5-N(R6)-C(O)—, wherein (C 1 -C 6 )-alkyl is unsubstituted or substituted by one or more identical or different substituents R20;
R3 is selected from the series consisting of hydrogen and (C 1 -C 6 )-alkyl, wherein (C 1 -C 6 )-alkyl is unsubstituted or substituted by one or two identical or different substituents selected from the series consisting of (C 3 -C 7 )-cycloalkyl, phenyl, HO— and (C 1 -C 4 )-alkyl-O—;
or the groups R2 and R3 together are oxo;
R4 is hydrogen or one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—;
R5 and R6 are independently of one another selected from the series consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 7 )-cycloalkyl, (C 6 -C 10 )-bicycloalkyl, phenyl, Het1 and Het2, wherein (C 1 -C 6 )-alkyl is unsubstituted or substituted by one or more identical or different substituents R20, and (C 3 -C 7 )-cycloalkyl, (C 6 -C 10 )-bicycloalkyl and Het2 all are unsubstituted or substituted by one or more identical or different substituents R21, and phenyl and Het1 all are unsubstituted or substituted by one or more identical or different substituents R22,
or the groups R5 and R6, together with the nitrogen atom carrying them, form a 4-membered to 7-membered, monocyclic, saturated or partially unsaturated heterocycle which, in addition to the nitrogen atom carrying R5 and R6, 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 R21;
R7 is selected from the series consisting of (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, phenyl, Het1 and Het2, wherein (C 1 -C 6 )-alkyl is unsubstituted or substituted by one or more identical or different substituents R20, and (C 3 -C 7 )-cycloalkyl and Het2 all are unsubstituted or substituted by one or more identical or different substituents R21, and phenyl and Het1 all are unsubstituted or substituted by one or more identical or different substituents R22;
R8 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;
R9 is selected from the series consisting of (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-, phenyl-(C 1 -C 4 )-alkyl- and Het1-(C 1 -C 4 )-alkyl-;
R10 is selected from the series consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-, phenyl-(C 1 -C 4 )-alkyl- and Het1-(C 1 -C 4 )-alkyl-;
R20 is selected from the series consisting of R24, fluorine, HO—, oxo, (C 1 -C 6 )-alkyl-O—, (C 3 -C 7 )-cycloalkyl-O—, R30-C(O)—O—, R30-NH—C(O)—O—, HO—S(O) 2 —O—, (HO) 2 P(O)—O—, (HO) 2 P(O)—O—CH 2 —O—C(O)—O—, (C 1 -C 6 )-alkyl-S(O) n , (C 3 -C 7 )-cycloalkyl-S(O) n —, R31-N(R32)-, R33-C(O)—N(R32)-, (C 1 -C 6 )-alkyl-S(O) 2 —N(R32)-, R31-N(R32)-C(O)—, R34-O—C(O)— and R31-N(R32)-S(O) 2 —;
R21 is selected from the series consisting of (C 1 -C 4 )-alkyl, HO—(C 1 -C 4 )-alkyl-, R31-N(R32)-(C 1 -C 4 )-alkyl-, R34-O—C(O)—(C 1 -C 4 )-alkyl-, R24, fluorine, HO—, oxo, (C 1 -C 6 )-alkyl-O—, (C 3 -C 7 )-cycloalkyl-O—, R30-C(O)—O—, R30-NH—C(O)—O—, HO—S(O) 2 —O—, (HO) 2 P(O)—O—, (HO) 2 P(O)—O—CH 2 —O—C(O)—O—, (C 1 -C 6 )-alkyl-S(O) n —, (C 3 -C 7 )-cycloalkyl-S(O) n —, R31-N(R32)-, R33-C(O)—N(R32)-, (C 1 -C 6 )-alkyl-S(O) 2 —N(R32)-, R31-N(R32)-C(O)—, R34-O—C(O)— and R31-N(R32)-S(O) 2 —;
R22 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, HO—(C 1 -C 4 )-alkyl-, (C 3 -C 7 )-cycloalkyl, HO—, oxo, (C 1 -C 6 )-alkyl-O—, (C 3 -C 7 )-cycloalkyl-O—, HO—S(O) 2 —O—, (HO) 2 P(O)—O—, (HO) 2 P(O)—O—CH 2 —O—C(O)—O—, (C 1 -C 6 )-alkyl-S(O) n —, (C 3 -C 7 )-cycloalkyl-S(O) n —, R31-N(R32)-, R33-C(O)—N(R32)-, R33-O—C(O)—N(R32)-, (C 1 -C 6 )-alkyl-S(O) 2 —N(R32)-, NC—, R33-C(O)—, R31-N(R32)-C(O)—, R34-O—C(O)— and R31-N(R32)-S(O) 2 —;
R24 is a 3-membered to 10-membered, monocyclic or bicyclic ring which is saturated, partially unsaturated or aromatic and comprises 0, 1, 2, 3 or 4 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents R22;
R30 and R33 are independently of one another selected from the series consisting of (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-, phenyl-(C 1 -C 4 )-alkyl- and Het1-(C 1 -C 4 )-alkyl-;
R31 and R32 are independently of one another selected from the series consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-, phenyl-(C 1 -C 4 )-alkyl- and Het1-(C 1 -C 4 )-alkyl-,
or the groups R31 and R32, together with the nitrogen atom carrying them, form a 4-membered to 7-membered, monocyclic saturated heterocycle which, in addition to the nitrogen atom carrying R31 and R32, 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 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, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-, phenyl-(C 1 -C 4 )-alkyl- and Het1-(C 1 -C 4 )-alkyl-;
Het1 is a 5-membered or 6-membered, monocyclic, aromatic heterocycle which comprises 1, 2 or 3 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, 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 and (C 1 -C 4 )-alkyl-O—, unless specified otherwise;
Het2 is a 4-membered to 10-membered, monocyclic or bicyclic, saturated or partially unsaturated heterocycle which comprises 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur;
n is selected from the series consisting of 0, 1 and 2, wherein all numbers n are independent of one another;
p and q are independently of one another selected from the series consisting of 0 and 1;

Assignees

• Sanofi Sa

Inventors

• Czechtizky Werngard
• Weston John
• Rackelmann Nils
• Kraft Volker
• Arndt Petra
• Wirth Klaus
• Goegelein Heinz
• Ritzeler Olaf

Classifications

• A61P43/00

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

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/12

  Antihypertensives · 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