3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals

Patent metadata

Field	Value
Publication number	US-9353068-B2
Application number	US-201213559401-A
Country	US
Kind code	B2
Filing date	Jul 26, 2012
Priority date	Jul 26, 2011
Publication date	May 31, 2016
Grant date	May 31, 2016

Abstract

The present invention relates to compounds of the formula I,

wherein Ht, G, R 10 , R 30 , R 40 , R 50 and R 60 have the meanings indicated in the claims, which are valuable pharmaceutical active compounds. They are inhibitors of the protease cathepsin A, and are useful for the treatment of diseases such as atherosclerosis, heart failure, renal diseases, liver diseases or inflammatory diseases, for example. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use and pharmaceutical compositions comprising them.

First claim

The invention claimed is:

1. A compound of the formula I, in any of its stereoisomeric forms or a physiologically acceptable salt thereof, or a physiologically acceptable solvate thereof,

wherein Ht is

G is selected from the group consisting of R 71 —O—C(O)—, R 72 —N(R 73 )—C(O)—, NC— and tetrazol-5-yl;
R 3 is hydrogen or (C 1 -C 6 )-alkyl;
R 4 is selected from the group consisting of (C 1 -C 7 )-alkyl, (C 3 -C 7 )-cycloalkyl-C s H 2s — and Ar—C s H 2s —, wherein s is independently 0, 1, 2 or 3;
R 10 is selected from the group consisting of hydrogen, (C 3 -C 7 )-cycloalkyl, Ar, Het 3 , Het 2 —C(O)—, R 14 —C(O)— and (C 1 -C 4 )-alkyl-S(O) m —;
R 14 is (C 1 -C 10 )-alkyl which is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, HO—, R 16 —O—, oxo, (C 3 -C 7 )-cycloalkyl, Ar, Het 1 ,Het 3 , NC—, H 2 N—C(O)—, (C 1 -C 4 )-alkyl-NH—C(O)—, di((C 1 -C 4 )-alkyl)N—C(O)—, Het 1 , —C(O)—, (C 1 -C 4 )-alkyl-C(O)—NH— and (C 1 -C 4 )-alkyl-S(O) m —;
R 16 is (C 1 -C 6 )-alkyl which is optionally substituted by one or more identical or different substituents selected from the group consisting of HO—, (C 1 -C 4 )-alkyl-O— and NC—;
R 30 is selected from the group consisting of R 31 , (C 3 -C 7 )-cycloalkyl, R 32 —C u H 2u — and Het 3 -C u H 2u —, wherein u is independently 0, 1, 2 or 3;
R 31 is (C 1 -C 10 )-alkyl which is substituted by one or more identical or different substituents selected from the group consisting of halogen, (C 3 -C 7 )-cycloalkyl, HO—, (C 1 -C 6 )-alkyl-O—, (C 1 -C 6 )-alkyl-S(O) m — and NC—;
R 32 is selected from the group consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle containing one, two or three identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and bonded via a ring carbon atom, wherein the phenyl and the heterocycle are optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, HO—, (C 1 -C 6 )-alkyl-O—, R 33 —O—, R 33 —(C 1 -C 4 )-alkyl-O—, —O—CH 2 —O—, —O—CF 2 —O—, (C 1 -C 6 )-alkyl-S(O) m —, H 2 N—S(O) 2 —, (C 1 -C 4 )-alkyl-NH—S(O) 2 —, di((C 1 -C 4 )-alkyl)N—S(O) 2 —, H 2 N—, (C 1 -C 6 )-alkyl-NH—, di((C 1 -C 6 )-alkyl)N—, Het 1 ,(C 1 -C 4 )-alkyl-C(O)—NH—, Ar—C(O)—NH—, (C 1 -C 4 )-alkyl-S( 0 ) 2 —NH— and NC—;
R 33 is selected from the group consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycles containing one, two or three identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and bonded via a ring carbon atom, wherein the phenyl and the heterocycle are optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, HO—, (C 1 -C 6 )-alkyl-O—, (C 1 -C 6 )-alkyl-S(O) m —, H 2 N—S(O) 2 —, (C 1 -C 4 )-alkyl-NH—S(O) 2 —, di((C 1 -C 4 )-alkyl)N—S(O) 2 — and NC—;
R 40 is hydrogen or (C 1 -C 4 )-alkyl;
or R 30 and R 40 together are (CH 2 ) x , which is optionally substituted by one or more identical or different (C 1 -C 4 )-alkyl substituents, wherein x is independently 2, 3, 4 or 5;
R 50 is selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, HO— and (C 1 -C 6 )-alkyl-O—;
R 60 is selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl;
or R 50 and R 60 together are (CH 2 ) y , which is optionally substituted by one or more identical or different (C 1 -C 4 )-alkyl substituents, wherein y is independently 2, 3, 4 or 5;
or R 30 and R 50 together are (CH 2 ) z , which is optionally substituted by one or more identical or different (C 1 -C 4 )-alkyl substituents, wherein z is independently 2, 3, 4 or 5;
R 71 is hydrogen or (C 1 -C 8 )-alkyl, which is optionally substituted by one or more identical or different substituents selected from the group consisting of (C 1 -C 6 )-alkyl-O— and (C 1 -C 6 )-alkyl-C(O)—O—;
R 72 is selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, —CH 2 —(CH 2 ) b —(C 3 -C 6 )-cycloalkyl, Het 4 and —(CH 2 ) b -Het 4 , wherein alkyl or cycloalkyl is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, HO—, HOOC—, (C 1 -C 6 )-alkyl-O— and (C 1 -C 6 )-alkyl-C(O)—O—, NC—, —N((C 1 -C 4 )-alkyl) 2 , and b is 0, 1 or 2;
R 73 is selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl;
or
R 72 and R 73 together with the nitrogen atom to which they are bonded form a saturated 4-membered to 7-membered monocyclic heterocycle, which optionally contains one further ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and which is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, HO— and (C 1 -C 4 )-alkyl-O—;
Ar, independently of each other group Ar, is selected from the group consisting of phenyl and aromatic 5-membered or 6-membered monocyclic heterocycles containing one, two or three identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and bonded via a ring carbon atom, wherein the phenyl and the heterocycle are optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-O—, —O—CH 2 —O—, O—CH 2 —CH 2 —O—, —O—CF 2 —O—, (C 1 -C 6 )-alkyl-S(O) m —, H 2 N—S(O) 2 —, CF 3 and NC—;
Het 1 , independently of each other group Het 1 , is a saturated or unsaturated 4-membered to 8-membered monocyclic heterocycle containing a ring nitrogen atom via which Het 1 is bonded, and optionally, one or two identical or different further ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and which is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, HO—, (C 1 -C 4 )-alkyl-O—, oxo and NC—;
Het 2 is a saturated 4-membered to 7-membered monocyclic heterocycle containing a ring nitrogen atom via which Het 2 is bonded, and optionally, one further ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and which is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, HO—, oxo and (C 1 -C 4 )-alkyl-O—;
Het 3 , independently of each other group Het 3 , is a saturated 4-membered to 7-membered monocyclic heterocycle containing one or two identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom, and which is optionally substituted by one or more identical or different substituents selected from the group consisting of fluorine, (C 1 -C 4 )-alkyl and oxo;
Het 4 , independently of each other group Het 4 , is a saturated or unsaturated 4-membered to 8-membered monocyclic heterocycle containing one to four ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and which is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, HO—, (C 1 -C 4 )-alkyl-O—, oxo and NC—;
m, indep

Assignees

• Ruf Sven
• Pernerstorfer Josef
• Sadowski Thorsten
• Horstick Georg
• Schreuder Herman
• Buning Christian
• Wirth Klaus
• Sanofi Sa

Inventors

• Ruf Sven
• Pernerstorfer Josef
• Sadowski Thorsten
• Horstick Georg
• Schreuder Herman
• Buning Christian
• Wirth Klaus

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/04

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

• A61P37/02

  Immunomodulators · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P7/08

  Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock (artificial tears A61P27/04) · CPC title