# US 9,040,544 B2 · 2,5-substituted oxazolopyrimidine derivatives

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- Number: US 9,040,544 B2
- Document ID: US9040544B2
- Status: Granted
- Kind: B2
- Application number: 13/521,825
- Filed: 2011-01-14
- Published: 2013-03-21
- Granted: 2015-05-26
- Earliest claimed: 2010-01-14
- Assignees: Sanofi
- Applicants: Dieter Kadereit; Matthias Schaefer; Stephanie Hachtel; Axel Dietrich; Thomas Huebschle; Katrin Hiss
- Inventors: Dieter Kadereit; Matthias Schaefer; Stephanie Hachtel; Axel Dietrich; Thomas Huebschle; Katrin Hiss
- Web page: https://patentgrep.com/patent/US9040544B2

## CPC

- C07D 498/04: Ortho-condensed systems
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- C07D 498/22: in which the condensed system contains four or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The invention relates to oxazolopyrimidine compounds of formula I, where A, R1 and R2 are defined as stated in the claims. The compounds of formula I are suitable, for example, for wound healing.

## Claims

### Claim 1

A compound of the formula I, in any of its stereoisomeric forms, or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof,
wherein
A is chosen from NH, O or S;
R1 is chosen from C3-C7)-cycloalkyl-CuH2u— or Het-CvH2v—, wherein u and v are chosen from 1 or 2, or R1 is a residue of a saturated or unsaturated, 3-membered to 10-membered, monocyclic or bicyclic ring which comprises 0, 1, 2, 3 or 4 identical or different ring heteroatoms chosen from N, O or S, wherein one or two of the ring nitrogen atoms may carry a hydrogen atom or a (C1-C4)-alkyl substituent and one or two of the ring sulfur atoms may carry one or two oxo groups, and wherein the residue of a ring is optionally substituted on one or more ring carbon atoms by identical or different substituents R11;
R2 is chosen from phenyl or pyridinyl, wherein the ring nitrogen atom of the pyridinyl may carry an oxy substituent, and wherein the phenyl and the pyridinyl are optionally substituted on one or more ring carbon atoms by identical or different substituents R22
R11 is chosen from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, oxo, (C1-C4)-alkyl-S(O)m—, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, (C1-C4)-alkylcarbonylamino, (C1-C4)-alkylsulfonylamino, nitro, cyano, (C1-C4)-alkylcarbonyl, aminosulfonyl, (C1-C4)-alkylaminosulfonyl or di((C1-C4)-alkyl)aminosulfonyl;
R22 is chosen from halogen, hydroxy, (C1-C4)-alkyl-, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m—, amino, nitro, cyano, hydroxycarbonyl, (C1-C4)-alkyloxycarbonyl, aminocarbonyl, aminosulfonyl, R23 or R23—O—;
R23 is a residue of a saturated 3-membered to 7-membered, monocyclic or bicyclic ring which comprises 0, 1, 2, 3 or 4 identical or different ring heteroatoms chosen from N, O or S, wherein one or two of the ring nitrogen atoms may carry a hydrogen atom or a (C1-C4)-alkyl substituent and one of the ring sulfur atoms may carry one or two oxo groups, and wherein the residue of a ring is optionally substituted on one or more ring carbon atoms by identical or different substituents R24;
R24 is chosen from halogen, (C1-C4)-alkyl, hydroxy or oxo;
Het is a residue of a saturated, 4-membered to 7-membered, monocyclic heterocycle which comprises 1 or 2 identical or different ring heteroatoms chosen from N, O or S and which is bonded via a ring carbon atom, wherein the residue of a heterocycle is optionally substituted by one or more identical or different substituents chosen from fluorine or (C1-C4)-alkyl; and
m is chosen from 0, 1 or 2, wherein all numbers m are independent of each other;
wherein all cycloalkyl groups, independently of each other and independently of any other substituents, are optionally substituted by one or more identical or different substituents chosen from fluorine or (C1-C4)-alkyl;
wherein all alkyl, CuH2u, CvH2v, alkenyl and alkynyl groups, independently of each other and independently of any other substituents, are optionally substituted by one or more fluorine substituents.

### Claim 2 (depends on 1)

A compound of the formula I, in any of its stereoisomeric forms, or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, as claimed in claim 1, wherein A is chosen from O or S.

### Claim 3 (depends on 1)

A compound of the formula I, in any of its stereoisomeric forms, or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, as claimed in claim 1, wherein R2 is chosen from phenyl or pyridinyl, wherein the ring nitrogen atom of the pyridinyl may carry an oxy substituent, and wherein the phenyl and the pyridinyl are optionally substituted on one or more ring carbon atoms by identical or different substituents R22.

### Claim 4 (depends on 1)

A compound of the formula I, in any of its stereoisomeric forms, or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, as claimed in claim 1, wherein
A is chosen from O or S;
R1 is chosen from (C3-C7)-cycloalkyl-CuH2u— or Het-CvH2v—, wherein u and v are chosen from 1 or 2, or R1 is a residue of a saturated or unsaturated, 3-membered to 10-membered, monocyclic or bicyclic ring which comprises 0, 1, 2, 3 or 4 identical or different ring heteroatoms chosen from N, O or S, wherein one or two of the ring nitrogen atoms may carry a hydrogen atom or a (C1-C4)-alkyl substituent and one or two of the ring sulfur atoms may carry one or two oxo groups, and wherein the residue of a ring is optionally substituted on one or more ring carbon atoms by identical or different substituents R11; and
R2 is chosen from phenyl and pyridinyl, wherein the ring nitrogen atom of the pyridinyl can carry an oxy substituent, and wherein the phenyl and the pyridinyl are optionally substituted on one or more ring carbon atoms by identical or different substituents R22.

### Claim 5 (depends on 1)

A compound of the formula I, in any of its stereoisomeric forms, or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, as claimed in claim 1, wherein A is O.

### Claim 6 (depends on 1)

A compound of the formula I, in any of its stereoisomeric forms, or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, as claimed in claim 1, wherein
A is O;
R1 is chosen from (C3-C7)-cycloalkyl-CuH2u— or Het-CvH2v—, wherein u and v are chosen from 1 and 2, or R1 is a residue of a saturated or unsaturated, 3-membered to 7-membered, monocyclic ring which comprises 0, 1 or 2 identical or different ring heteroatoms chosen from N, O or S, wherein one or two of the ring nitrogen atoms may carry a hydrogen atom or a (C1-C4)-alkyl substituent and one or two of the ring sulfur atoms may carry one or two oxo groups, and wherein the residue of a ring is optionally substituted on one or more ring carbon atoms by identical or different substituents R11;
R2 is chosen from phenyl or pyridinyl, wherein the ring nitrogen atom of the pyridinyl may carry an oxy substituent, and wherein the phenyl and the pyridinyl are optionally substituted on one or more ring carbon atoms by identical or different substituents R22;
R11 is chosen from halogen, (C1-C4)-alkyl, (C1-C4)-alkyloxy or cyano;
R22 is chosen from halogen, hydroxy, (C1-C4)-alkyl-, (C1-C4)-alkyloxy, cyano, R23 or R23—O—;
R23 is a residue of a saturated 3-membered to 6-membered, monocyclic ring which comprises 0 or 1 ring heteroatom chosen from N, O or S, wherein one or two of the ring nitrogen atoms may carry a hydrogen atom or a (C1-C4)-alkyl substituent and one of the ring sulfur atoms may carry one or two oxo groups, and wherein the residue of a ring is optionally substituted on one or more ring carbon atoms by identical or different substituents R24;
R24 is chosen from fluorine, (C1-C4)-alkyl or hydroxy; and
Het is a residue of a saturated, 4-membered to 7-membered, monocyclic heterocycle which comprises 1 ring heteroatom chosen from N, O or S and which is bonded via a ring carbon atom, wherein the residue of a heterocycle is optionally substituted by one or more identical or different substituents chosen from fluorine or (C1-C4)-alkyl;
wherein all cycloalkyl groups, independently of each other and independently of any other substituents, are optionally substituted by one or more identical or different substituents chosen from fluorine or (C1-C4)-alkyl;
wherein all alkyl, CuH2u and CvH2v groups, independently of each other and independently of any other substituents, are optionally substituted by one or more fluorine substituents.

### Claim 7 (depends on 1)

A compound of the formula I, in any of its stereoisomeric forms, or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, as claimed in claim 1, wherein
A is O;
R1 is a residue of a saturated or unsaturated, 3-membered to 7-membered, monocyclic ring which comprises 0 or 1 ring heteroatom chosen from N, O or S, wherein a ring nitrogen atom may carry a hydrogen atom or a (C1-C4)-alkyl substituent and a ring sulfur atom may carry one or two oxo groups, and wherein the residue of a ring is optionally substituted on one or more ring carbon atoms by identical or different substituents R11;
R2 is chosen from phenyl or pyridinyl, wherein the ring nitrogen atom of the pyridinyl may carry an oxy substituent, and wherein the phenyl and the pyridinyl are optionally substituted on one or more ring carbon atoms by identical or different substituents R22;
R11 is chosen from halogen, (C1-C4)-alkyl or (C1-C4)-alkyloxy;
R22 is chosen from halogen, hydroxy, (C1-C4)-alkyl-, (C1-C4)-alkyloxy, R23 or R23—O—;
R23 is a residue of a saturated 3-membered to 6-membered, monocyclic ring which comprises 0 or 1 ring heteroatom chosen from N, O or S, wherein one or two of the ring nitrogen atoms may carry a hydrogen atom or a (C1-C4)-alkyl substituent and one of the ring sulfur atoms may carry one or two oxo groups, and wherein the residue of a ring is optionally substituted on one or more ring carbon atoms by identical or different substituents R24; and
R24 is chosen from fluorine, (C1-C4)-alkyl or hydroxy;
wherein all cycloalkyl groups, independently of each other and independently of any other substituents, are optionally substituted by one or more identical or different substituents chosen from fluorine or (C1-C4)-alkyl;
wherein all alkyl groups, independently of each other and independently of any other substituents, are optionally substituted by one or more fluorine substituents.

### Claim 8 (depends on 1)

A compound of the formula I, in any of its stereoisomeric forms, or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, as claimed in claim 1, wherein A is O.

### Claim 9 (depends on 1)

A compound of the formula I, or a physiologically acceptable salt thereof, as claimed in claim 1, chosen from
5-(2-fluoro-phenoxy)-2-(4-methoxy-3,5-dimethyl-phenyl)-oxazolo[5,4-d]pyrimidine,
4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenol,
5-(2-fluoro-phenoxy)-2-(3-methoxy-phenyl)-oxazolo[5,4-d]pyrimidine,
4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-phenol,
5-(2-fluoro-phenoxy)-2-(4-methoxy-3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine,
5-(2-fluoro-phenoxy)-2-(4-methoxy-3-trifluoromethyl-phenyl)-oxazolo[5,4-d]pyrimidine,
4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2-methyl-phenol,
2-(4-methoxy-3,5-dimethyl-phenyl)-5-phenoxy-oxazolo[5,4-d]pyrimidine,
2-(4-methoxy-3,5-dimethyl-phenyl)-5-(pyridin-3-yloxy)-oxazolo[5,4-d]pyrimidine, or
4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2-trifluoromethyl-phenol.

### Claim 10 (depends on 1)

A compound of the formula I, or a physiologically acceptable salt thereof, as claimed in claim 1, chosen from
2,6-dimethyl-4-[5-(pyridin-3-yloxy)-oxazolo[5,4-d]pyrimidin-2-yl]-phenol,
4-[5-(3-fluorophenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2-isopropyl-6-methyl-phenol,
5-(2-fluorophenoxy)-2-(4-methanesulfonyl-3-methylphenyl)-oxazolo[5,4-d]pyrimidine, or
5-(2-fluorophenoxy)-2-(4-methanesulfonyl-2-methylphenyl)-oxazolo[5,4-d]pyrimidine.

### Claim 11 (depends on 1)

A pharmaceutical composition, comprising at least one compound of the formula I as claimed in claim 1 or a physiologically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 12 (depends on 1)

A process for the preparation of a compound of the formula I as claimed in claim 1, comprising reacting a compound of the formula II with a compound of the formula III,
wherein the groups A, R1 and R2 in the compounds of the formulae II and III are defined as in the compounds of the formula I and additionally functional groups can be present in protected form or in the form of a precursor group, and the group L1 is a halogen atom or a group of the formula —S(O)-Alk or —S(O)2-Alk wherein Alk is (C1-C4)-alkyl.

### Claim 13 (depends on 11)

A method of treating diabetic foot syndrome in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 11.