Macrocyclic urea and sulfamide derivatives as inhibitors of TAFIa

Patent metadata

Field	Value
Publication number	US-9309207-B2
Application number	US-201514811364-A
Country	US
Kind code	B2
Filing date	Jul 28, 2015
Priority date	Jun 6, 2008
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

The invention relates to compounds of the formula (I) which are inhibitors of activated thrombin-activable fibrinolysis inhibitor. The compounds of the formula I are suitable for producing medicaments for prophylaxis, secondary prevention and treatment of one or more disorders associated with thromboses, embolisms, hypercoagulability or fibrotic changes.

First claim

The invention claimed is:

1. A compound of the formula (I)

or a stereoisomer thereof or a physiologically tolerated salt of any of the foregoing, wherein
X is —C(O)— or —SO 2 —;
U is an oxygen atom;
A is an oxygen atom, or —(C 0 -C 4 )-alkylene-;
V is
1) —(C 5 -C 9 )-alkylene-, wherein said alkylene is unsubstituted or substituted independently of one another once, twice or three times by —OH, NH 2 or halogen, or
2) —(C 3 -C 9 )-alkenylene-;
D is —(C 1 -C 2 )-alkylene-;
Y is
—(C 6 -C 14 )-aryl, wherein said aryl is unsubstituted or substituted independently of one another once, twice or three times by R15;
R1 is
1) a hydrogen atom,
2) —(C 1 -C 6 )-alkyl,
3) —(C 1 -C 6 )-alkyl-OH,
4) —(C 0 -C 4 )-alkyl-(C 3 -C 6 )-cycloalkyl,
5) —(C 1 -C 10 )-alkyl-O—C(O)—O—R2,
6) —(CH 2 ) r —(C 6 -C 14 )-aryl, wherein said aryl is unsubstituted or substituted independently of one another once, twice or three times by R15, and r is the integer zero, 1, 2 or 3, or
7) —(CH 2 ) s -Het, wherein Het is a 4- to 15-membered heterocyclic ring system having 4 to 15 ring atoms which are present in one, two or three ring systems which are connected together, and which comprise, depending on the ring size, one, two, three or four identical or different heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and in which Het is unsubstituted or substituted independently of one another once, twice or three times by R15, and s is the integer zero, 1, 2 or 3;
R2 is
1) —(C 1 -C 6 )-alkyl,
2) —(CH 2 ) r —(C 6 -C 14 )-aryl, wherein said aryl is unsubstituted or substituted independently of one another once, twice or three times by R15, and r is the integer zero, 1, 2 or 3, or
3) —(C 0 -C 4 )-alkyl-(C 3 -C 6 )-cycloalkyl;
R3 is
1) —(C 2 -C 6 )-alkylene-NH 2 , wherein said alkylene is unsubstituted or substituted once, twice, three or four times by halogen,
2) —(C 1 -C 4 )-alkylene-O—(C 1 -C 4 )-alkylene-NH 2 ,
3) —(C 1 -C 4 )-alkylene-SO 2 —(C 1 -C 4 )-alkylene-NH 2 ,
4) —(C 0 -C 4 )-alkylene-Het, wherein said Het is as defined above and is substituted by —NH 2 and once, twice or three times by R15,
5) —(C 0 -C 4 )-alkylene-(C 3 -C 8 )-cycloalkyl-NH 2 , or
6) —(C 0 -C 6 )-alkylene-cyclic amine, wherein the cyclic amine is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, morpholinyl, and thiomorpholinyl;
R6 is
1) a hydrogen atom,
2) —(C 1 -C 6 )-alkyl, wherein said alkyl is unsubstituted or substituted independently of one another once, twice or three times by R16,
3) —O—(C 1 -C 6 )-alkyl, wherein said alkyl is unsubstituted or substituted independently of one another once, twice or three times by R16,
4) —(C 0 -C 4 )-alkylene-Het, wherein said Het is as defined above, wherein said alkylene and Het are unsubstituted or substituted independently of one another once, twice or three times by R16,
5) —(C 0 -C 4 )-alkylene-aryl, wherein said alkylene and aryl are unsubstituted or substituted independently of one another once, twice or three times by R16, or
6) —(C 0 -C 4 )-alkylene-(C 3 -C 8 )-cycloalkyl, wherein said alkylene and cycloalkyl are unsubstituted or substituted independently of one another once, twice or three times by R16;
R7 is a hydrogen atom, halogen or —(C 1 -C 6 )-alkyl;
R8 is a hydrogen atom, halogen or —(C 1 -C 6 )-alkyl;
R9 is a hydrogen atom, halogen or —(C 1 -C 6 )-alkyl;
R15 is a hydrogen atom, —(C 1 -C 4 )-alkyl, —O—CF 3 , —NH 2 , —OH, —CF 3 or halogen; and
R16 is —O—CF 3 , —NH 2 , —OH, —CF 3 or halogen.

2. A compound of the formula (I), a stereoisomer thereof, or a physiologically tolerated salt of any of the foregoing, as claimed in claim 1 , wherein
V is —(C 5 -C 8 )-alkylene- or —(C 3 -C 6 )-alkenylene-;
Y is
—(C 6 -C 14 )-aryl, wherein said aryl is selected from the group consisting of phenyl, naphthyl, anthryl and fluorenyl, and wherein said aryl is unsubstituted or substituted independently of one another once, twice or three times by R15;
R1 is
1) a hydrogen atom, or
2) —(C 1 -C 4 )-alkyl;
R3 is
1) —(C 2 -C 6 )-alkylene-NH 2 , wherein said alkylene is unsubstituted or substituted once, twice, three or four times by halogen,
2) —(C 1 -C 4 )-alkylene-SO 2 —(C 1 -C 4 )-alkylene-NH 2 , or
3) —(C 0 -C 4 )-alkylene-Het, wherein said Het is as defined above and is substituted by —NH 2 and once, twice or three times by R15;
R6 is
1) a hydrogen atom,
2) —(C 1 -C 6 )-alkyl, wherein said alkyl is unsubstituted or substituted independently of one another once, twice or three times by R16,
3) —O—(C 1 -C 6 )-alkyl, wherein said alkyl is unsubstituted or substituted independently of one another once, twice or three times by R16,
4) —(C 0 -C 4 )-alkylene-Het, wherein said Het is as defined above, wherein said alkylene and Het are unsubstituted or substituted independently of one another once, twice or three times by R16,
5) —(C 0 -C 4 )-alkylene-aryl, wherein said alkylene and aryl are unsubstituted or substituted independently of one another once, twice or three times by R16, or
6) —(C 0 -C 4 )-alkylene-(C 3 -C 6 )-cycloalkyl, wherein said alkylene and cycloalkyl are unsubstituted or substituted independently of one another once, twice or three times by R16;
R7 is a hydrogen atom, F or —(C 1 -C 4 )-alkyl;
R8 is a hydrogen atom, F or —(C 1 -C 4 )-alkyl;
R9 is a hydrogen atom, F or —(C 1 -C 4 )-alkyl;
R15 is a hydrogen atom, —(C 1 -C 4 )-alkyl, —O—CF 3 , —NH 2 , —OH, —CF 3 , or halogen; and
R16 is —O—CF 3 , —OH, —CF 3 or F.

3. A compound of the formula (I), a stereoisomer thereof, or a physiologically tolerated salt of any of the foregoing, as claimed in claim 1 , wherein
X is —C(O)—;
U is an oxygen atom;
A is an oxygen atom or —(C 0 -C 4 )-alkylene-;
V is
1) —(C 5 -C 8 )-alkylene-, wherein said alkylene is unsubstituted or substituted independently of one another once or twice by —OH, F or Cl, or
—(C 3 -C 6 )-alkenylene-;
D is —(C 1 -C 2 )-alkylene-;
Y is
phenyl, wherein said phenyl is unsubstituted or substituted independently of one another once, twice or three times by R15;
R1 is
1) a hydrogen atom, or
2) —(C 1 -C 4 )-alkyl;
R3 is
1) —(C 2 -C 6 )-alkylene-NH 2 ,
2) —(C 1 -C 4 )-alkylene-SO 2 —(C 1 -C 4 )-alkylene-NH 2 , or
3) —(C 0 -C 4 )-alkylene-pyridyl, wherein said pyridyl is substituted by —NH 2 and once, twice or three times by R15;
R6 is
1) a hydrogen atom,
2) —(C 1 -C 6 )-alkyl,
3) —CF 3 ,
4) —(C 0 -C 4 )-alkylene-phenyl, or
5) —(C 0 -C 4 )-alkylene-(C 3 -C 6 )-cycloalkyl;
R7, R8 and R9 are each a hydrogen atom; and
R15 is a hydrogen atom, —(C 1 -C 4 )-alkyl, —CF 3 , or halogen.

4. A compound of the formula (I), a stereoisomer thereof, or a physiologically tolerated salt of any of the foregoing, as claimed in claim 1 , wherein
X is —C(O)—;
U is an oxygen atom
A is an oxygen atom or —(C 0 -C 4 )-alkylene-;
V is —(C 5 -C 8 )-alkylene- or —(C 3 -C 6 )-alkenylene-;
D is —(C 1 -C 2 )-alkylene-;
Y is
phenyl, wherein said phenyl is unsubstituted or substituted independently of one another once, twice or three times by R15;
R1 is
1) a hydrogen atom, or
2) —(C 1 -C 4 )-alkyl;
R3 is
1) —(C 2 -C 6 )-alkylene-NH 2 ,
2) —(C 1 -C 4 )-alkylene-SO 2 —(C 1 -C 4 )-alkylene-NH 2 , or
3) —(C 0 -C 4 )-alkylene-pyridyl, wherein said pyridyl is substituted by —NH 2 or once, twice or three times by R15;
R6

Assignees

• Sanofi Sa

Inventors

• Kallus Christopher
• Broenstrup Mark
• Evers Andreas
• Globisch Anja
• Schreuder Herman
• Wagner Michael

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · 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

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P7/00

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