Macrocyclic Urea Derivatives as Inhibitors of TAFIa, Their Preparation and Their Use as Pharmaceuticals

Patent metadata

Field	Value
Publication number	US-2016137618-A1
Application number	US-201414895695-A
Country	US
Kind code	A1
Filing date	Jun 5, 2014
Priority date	Jun 10, 2013
Publication date	May 19, 2016
Grant date	—

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

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 —(C2-C9)-alkylene-;
Y is a covalent bond or —(C6-C14)-aryl-,
wherein —(C6-C14)-aryl- is unsubstituted or substituted by one, two or three R15 groups;

R1 is —(C1-C6)-alkyl, —(C0-C4)-alkylene-aryl or —(C0-C4)-alkylene-(C3-C8)-cycloalkyl,
wherein alkyl, —(C0-C4)-alkylene, aryl and —(C3-C8)-cycloalkyl are unsubstituted or substituted by one, two or three R16 groups;

R2 is —(C1-C3)-alkyl;
R3 is Het substituted by —NH2, or —(C3-C8)-cycloalky substituted by —NH2,
wherein Het 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, and
wherein Het and —(C4-C8)-cycloalkyl are unsubstituted or substituted by one two or three R15 groups;

each R15 group is independently hydrogen, —(C1-C4)-alkyl, —O—CF3, —NH2, —OH, —CF3 or halogen; and
each R16 group is independently —O—CF3, —NH2, —OH, —CF3 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 —(CH2)4-; Y is a covalent bond or phenyl,
wherein phenyl is unsubstituted or substituted by one, two or three R15 groups;
R1 is isopropyl; R2 is methyl; R3 is Het substituted by —NH2, or —(C4-C8)-cycloalkyl substituted by —NH2,
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 —(C4-C8)-cycloalkyl are unsubstituted or substituted by one two or three R15 groups; and
each R15 group is independently hydrogen, —(C1-C4)-alkyl, —O—CF3, —NH2, —OH, —CF3 or halogen.

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 —(CH2)4-; Y is a covalent bond or phenyl; R1 is isopropyl; R2 is methyl; and R3 is pyridinyl substituted by —NH2, cyclobutyl substituted by —NH2, or cyclopentyl substituted by —NH2.

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-((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-(3-Amino-cyclobutyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[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-((3S,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 . (canceled)

8 . A method for treating a disorder associated with thromboses, embolisms, hypercoagulability or fibrotic changes, the method comprising administering to a patient in need of treatment, a compound of claim 1 , or a stereoisomeric form or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof.

9 . The method of claim 8 , wherein the disorder is myocardial infarction, angina pectoris, stroke, peripheral vascular disorder, deep vein thrombosis, pulmonary embolism, embolic or thrombotic event caused by cardiac arrhythmias, thrombosis following surgical procedure, disseminated intravascular coagulation, sepsis, intravascular event associated with fibrin formation, atherosclerosis, diabetes, the metabolic syndrome, tumor growth, tumor metastasis, inflammatory and degenerative articular disorder, impairment of the hemostatic system, fibrotic changes of the lung or scarring of the lung.

10 . A method for preparing a 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 —(C1-C3)-alkyl;
R3 is Het substituted by —NH2, or —(C3-C8)-cycloalky substituted by —NH2,
wherein Het 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, and
wherein Het and —(C4-C8)-cycloalkyl are unsubstituted or substituted by one, two or three R15 groups;

each R15 group is independently hydrogen, —(C1-C4)-alkyl, —O—CF3, —NH2, —OH, —CF3 or halogen.

11 . A method for preparing a compound of formula XII:

the method comprising:
reacting a compound of formula XVI:

with a compound of formula VII:

to provide a compound of formula XII,
wherein
V is —(C2-C9)-alkylene-;
Y is a covalent bond or —(C6-C14)-aryl-,
wherein —(C6-C14)-aryl- is unsubstituted or substituted by one, two or three R15 groups;

R1 is —(C1-C6)-alkyl, —(C0-C4)-alkylene-aryl or —(C0-C4)-alkylene-(C3-C8)-cycloalkyl,
wherein alkyl, —(C0-C4)-alkylene, aryl and —(C3-C8)-cycloalkyl are unsubstituted or substituted by one, two or three R16 groups;

R2 is —(C1-C3)-alkyl;
R3 is Het substituted by —NH2, or —(C3-C8)-cycloalky substituted by —NH2,
wherein Het 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, and
wherein Het and —(C4-C8)-cycloalkyl are unsubstituted or substituted by one, two or three R15 groups;

each R15 group is independently hydrogen, —(C1-C4)-alkyl, —O—CF3, —NH2, —OH, —CF3 or halogen;
each R16 group is independently —O—CF3, —NH2, —OH, —CF3 or halogen; and
PG is an ester or amino protective group.

12 . 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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · 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

• A61P35/04

  specific for metastasis · CPC title