Macrocyclic urea derivatives as inhibitors of TAFIa, their preparation and their use as pharmaceuticals

Patent metadata

Field	Value
Publication number	US-9834527-B2
Application number	US-201414895695-A
Country	US
Kind code	B2
Filing date	Jun 5, 2014
Priority date	Jun 10, 2013
Publication date	Dec 5, 2017
Grant date	Dec 5, 2017

Abstract

The present invention relates to macrocydic urea derivatives of the formula I (I) in which R1, R2, R3, V and Y are as defined below. The compounds of the formula I are inhibitors of the enzyme TAFIa (activated thrombin-activatable fibrinolysis inhibitor). The invention further relates to the process for the preparation of the compounds of formula I and to the use thereof as medicaments.

First claim

What is claimed:

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
V is —(CH 2 ) 4 ;
Y is a covalent bond or phenyl, optionally substituted by one, two or three R15 groups;
R1 is —(C 1 -C 6 )-alkyl
R2 is methyl;
R3 is Het substituted by —NH 2 , or (C 4 -C 8 )-cycloalkyl substituted by —NH 2 ,
wherein Het is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl and thiophenyl, bonded via a ring carbon atom to the methylene group to which R3 is attached, and
wherein Het and —(C 4 -C 8 )-cycloalkyl are optionally substituted by one, two or three R15 groups; and

each R15 group is independently —(C 1 -C 4 )-alkyl, —O—CF 3 , —NH 2 , —OH, —CF 3 or halogen.

2. The compound of claim 1 , in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, wherein
V is —(CH 2 ) 4 ;
Y is a covalent bond or phenyl;
R1 is isopropyl;
R2 is methyl; and
R3 is Het substituted by —NH 2 , or —(C 4 -C 8 )-cycloalkyl substituted by —NH 2 ,
wherein Het is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl and thiophenyl, bonded via a ring carbon atom to the methylene group to which R3 is attached.

3. The compound of claim 1 , in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, wherein
V is —(CH 2 ) 4 —;
Y is a covalent bond or phenyl;
R1 is isopropyl;
R2 is methyl; and
R3 is pyridinyl substituted by —NH 2 , cyclobutyl substituted by —NH 2 , or cyclopentyl substituted by —NH 2 .

4. The compound of claim 1 having the structure of formula II,

in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
(S)-3-(6-Amino-pyridin-3-yl)-2-[3-((9 S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid;
(S)-3-(3-Amino-cyclobutyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid;
(S)-3-((1R,3R)-3-Amino-cyclopentyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid; or
(S)-3-(6-Amino-pyridin-3-yl)-2-[3-((3 S,6R)-3-isopropyl-5-oxo-1,8-dioxa-4-aza-cyclododec-6-yl)-ureido]-2-methyl-propionic acid.

6. A pharmaceutical composition, comprising a compound of claim 1 , in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. A method for preparing a compound of claim 1 , the method comprising:
reacting a compound of formula XVI:

with a compound of formula VII:

to provide a compound of claim 1 ,
wherein
V is —(CH 2 ) 4 —;
Y is a covalent bond or phenyl, optionally substituted by one, two or three R15 groups;
R1 is —(C 1 -C 6 )-alkyl;
R2 is methyl;
R3 is Het substituted by —NH 2 , or —(C 4 -C 8 )-cycloalkyl substituted by —NH 2 ,
wherein Het is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl and thiophenyl, wherein each group is bonded via a ring carbon atom to the methylene group to which R3 is attached, and
wherein Het and —(C 4 -C 8 )-cycloalkyl are optionally substituted by one, two or three R15 groups;
each R15 group is independently —(C 1 -C 4 )alkyl, —OCF 3 , —NH 2 , —OH, —CF 3 or halogen; and

PG is an ester protective group.

8. The method of claim 7 , further comprising preparing the compound of formula XVI:

the method comprising:
reacting a compound of formula XV:

with an azide source to provide a compound of formula XVI,
wherein
R2 is methyl;
R3 is Het substituted by —NH 2 , or —(C 4 -C 8 )-cycloalkyl substituted by —NH 2 ,
wherein Het is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl and thiophenyl, wherein each group is bonded via a ring carbon atom to the methylene group to which R3 is attached, and
wherein Het and —(C 4 -C 8 )-cycloalkyl are optionally substituted by one, two or three R15 groups;
each R15 group is independently —(C 1 -C 4 )alkyl, —OCF 3 , —NH 2 , —OH, —CF 3 or halogen; and
PG is an ester protective group.

9. A pharmaceutical composition comprising a compound of claim 1 and an antithrombotic, thrombolytic or other substance having profibrinolytic activity.

Assignees

• Sanofi Sa

Inventors

• Evers Andreas
• Kallus Christopher
• Wagner Michael
• Wehlan Hermut

Classifications

• 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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P35/04

  specific for metastasis · CPC title