# US 7,745,443 B2 · Inhibitors of the GPIb-vWF interaction, their preparation and use

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- Number: US 7,745,443 B2
- Document ID: US7745443B2
- Status: Granted
- Kind: B2
- Application number: 11/731,978
- Filed: 2007-04-02
- Published: 2007-07-26
- Granted: 2010-06-29
- Earliest claimed: 2002-06-06
- Assignees: Sanofi-Aventis Deutschland GmbH; Ajinomoto Co., Inc.
- Inventors: Otmar Klingler; Melitta Just; Kuniya Sakurai; Naoyuki Fukuchi
- Web page: https://patentgrep.com/patent/US7745443B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 215/48: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 401/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to compounds of the formula I, in which R1, R2, A, B, D, E, n, m or o have the meanings indicated below. The compounds of the formula I are valuable pharmacologically active compounds. They are reversible inhibitors of the interaction between the plasma protein von Willebrand factor (vWF) and the blood platelet receptor glycoprotein Ib-IX-V complex (GPIb). They exhibit an antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of atherothrombotic diseases.

## Claims

### Claim 1

A compound of the formula I,
wherein
n is the integer zero, 1, 2, 3 or 4;
m is the integer zero, 1, 2, 3 or 4;
o is the integer zero, 1, 2, 3 or 4;
R1 is —(C1-C8)-alkyl;
R2 is —NR4R5, wherein
R4 and R5 are identical or different and are hydrogen atom or —(C1-C8)-alkyl;
A is —CO—NH—;
B is 1. a covalent bond,
2. a monocyclic or bicyclic 6- to 14-membered aryl, wherein aryl is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3,
3. (C3-C8)-cycloalkyl or
4. Het, wherein Het is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3,
D is —NH—;
E is Het, wherein Het is a saturated, partially unsaturated or aromatic monocyclic or bicyclic heterocyclic ring system containing 3 to 10 ring atoms of which 1, 2, 3 or 4 are identical or different heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur and wherein Het is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3;
with the proviso that, when B is a covalent bond and Het is a bicyclic heterocyclic ring system, the ring of Het to which D-(CH2)o— is attached contains at least one hetero atom;
R3 is 1. —(C1-C8)-alkyl,
2. (C1-C8)-alkoxy,
3. hydroxyl,
4. trifluoromethoxy,
5. trifluoromethyl,
6. halogen,
7. nitro,
8. —NR4R5, wherein R4 and R5 are as defined above,
9. —(C1-C8)-alkylcarbonyl,
10. —CN,
11. aminosulfonyl-,
12. amidino,
13. guanidino,
14. tri-((C1-C4)-alkyl)ammonio-,
15. di-((C1-C8)-alkyl)amino-,
16. (C1-C8)-alkylaminosulfonyl-,
17. di-((C1-C8)-alkyl)aminosulfonyl,
18. —O-Het, wherein Het is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3 and R3 is as defined above under 1. to 17., or
19. Het-, wherein Het is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3 and R3 is as defined above under 1. to 17.,
in all their stereoisomeric forms and their physiologically tolerable salts.

### Claim 2

A compound of the formula I,
wherein
n is the integer zero, 1, 2, 3 or 4;
m is the integer zero, 1, 2, 3 or 4;
o is the integer zero, 1, 2, 3 or 4;
R1 is —(C1-C8)-alkyl;
R2 is —NR4R5, wherein
R4 and R5 are identical or different and are hydrogen atom or —(C1-C8)-alkyl;
A is —CO—NH—;
B is 1. a monocyclic or bicyclic 6- to 14-membered aryl, wherein aryl is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3,
2. (C3-C8)-cycloalkyl or
3. Het, wherein Het is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3,
D is —NH—;
E is Het, wherein Het is a saturated, partially unsaturated or aromatic monocyclic or bicyclic heterocyclic ring system containing 3 to 10 ring atoms of which 1, 2, 3 or 4 are identical or different heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur and wherein Het is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3;
with the proviso that, when B is a covalent bond and Het is a bicyclic heterocyclic ring system, the ring of Het to which D-(CH2)o— is attached contains at least one hetero atom;
R3 is 1. —(C1-C8)-alkyl,
2. (C1-C8)-alkoxy,
3. hydroxyl,
4. trifluoromethoxy,
5. trifluoromethyl,
6. halogen,
7. nitro,
8. —NR4R5, wherein R4 and R5 are as defined above,
9. —(C1-C8)-alkylcarbonyl,
10. —CN,
11. aminosulfonyl-,
12. amidino,
13. guanidino,
14. tri-((C1-C4)-alkyl)ammonio-,
15. di-((C1-C8)-alkyl)amino-,
16. (C1-C8)-alkylaminosulfonyl-,
17. di-((C1-C8)-alkyl)aminosulfonyl,
18. —O-Het, wherein Het is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3 and R3 is as defined above under 1. to 17., or
19. Het-, wherein Het is unsubstituted or mono-, di-, tri- or tetrasubstituted independently of one another by R3 and R3 is as defined above under 1. to 17.,
in all their stereoisomeric forms and their physiologically tolerable salts.

### Claim 3 (depends on 1)

A compound of the formula I, as claimed in claim 1, wherein
n is the integer zero or 1,
m is the integer zero or 1,
o is the integer zero or 1,
R1 is —(C1-C4)-alkyl;
R2 is —NR4R5, wherein
R4 and R5 are identical or different and are hydrogen atom or —(C1-C4)-alkyl;
A is —CO—NH—;
B is 1. a covalent bond,
2. a monocyclic or bicyclic 6- to 14-membered aryl, wherein aryl is unsubstituted or mono-, di- or trisubstituted independently of one another by R3, or
3. (C3-C7)-cycloalkyl,
D is —NH—;
E is Het selected from the group aziridine, oxirane, azetidine, pyrrole, furan, thiophene, dioxole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine, 1,4-dioxine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, indole, isoindole, benzofuran, benzothiophene, 1,3-benzodioxole, benzo[1,4]dioxine, 4H-benzo[1,4]oxazine, indazole, benzimidazole, benzoxazole, benzothiazole, quinoline, isoquinoline, chromane, isochromane, cinnoline, quinazoline, quinoxaline, phthalazine, pyridoimidazoles, pyridopyridines, pyridopyrimidines or ring systems which result from the listed heterocycles by fusion or condensation of a carbocyclic ring, for example benzo-fused, cyclopenta-fused, cyclohexa-fused or cyclohepta-fused derivatives of these heterocycles, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, piperidine, 1,3-dioxolane, 2-imidazoline, imidazolidine, 4,5-dihydro-1,3-oxazol, 1,3-oxazolidine, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine, perhydro-1,4-dioxane, piperazine, perhydro-1,4-oxazine morpholine), 2,3-dihydrobenzo[1,4]dioxine, indoline, isoindoline, 3,4-dihydro-2H-benzo[1,4]oxazine, perhydro-1,4-thiazine, perhydroazepine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline and wherein Het is unsubstituted or mono-, di- or trisubstituted independently of one another by R3;
R3 is 1. —(C1-C4)-alkyl,
2. hydroxyl,
3. halogen,
4. —NR4R5, wherein R4 and R5 are as defined above,
5. aminosulfonyl-,
6. (C1-C8)-alkylaminosulfonyl-,
7. di-((C1-C8)-alkyl)aminosulfonyl,
8. —(C1-C8)-alkoxy,
9. —O-Het, wherein Het is as defined above and is unsubstituted or mono-, di- or trisubstituted independently of one another by R3 and R3 is as defined above under 1. to 8., or
10. Het-, wherein Het is as defined above and is unsubstituted or mono-, di- or trisubstituted independently of one another by R3 and R3 is as defined above under 1. to 8.

### Claim 4 (depends on 1, 2)

A compound of the formula I as claimed in claim 1 or 2, wherein
n is the integer zero or 1,
m is the integer zero or 1,
o is the integer zero or 1,
R1 is methyl;
R2 is amino;
A is —CO—NH—;
B is phenyl, wherein phenyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R3,
D is —NH—;
E is Het, which is selected from the group pyridine, pyrimidine, pyrazine, quinoline, benzimidazole, benzothiazole, isoquinoline, chromane, isochromane, cinnoline, quinazoline, quinoxaline, phthalazine, pyridoimidazoles, pyrroline, pyrrolidine, tetrahydropyridine, indazole, piperidine, imidazolidine, 1,3-oxazolidine, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine, piperazine, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline and wherein Het is unsubstituted or mono-, di- or trisubstituted independently of one another by R3;
R3 is 1. methyl,
2. hydroxyl,
3. halogen,
4. —NH2,
5. aminosulfonyl-,
6. methoxyl,
7. —O-Het, wherein Het is as defined above and is unsubstituted or mono-, di- or trisubstituted independently of one another by R3 and R3 is as defined above under 1. to 6., or
8. Het-, wherein Het is as defined above and is unsubstituted or mono-, di- or trisubstituted independently of one another by R3 and R3 is as defined above under 1. to 6.

### Claim 5 (depends on 1)

A compound of the formula I as claimed in claim 1, wherein the compound of the formula I is
2-Amino-4-[(4-{[(4-amino-2-methyl-6-quinolinyl)carbonyl]amino}phenyl)amino]-1,6-dimethylpyrimidin-1-ium,
2-Amino-4-[(3-{[(4-amino-2-methyl-6-quinolinyl)carbonyl]amino}phenyl)amino]-1,6-dimethylpyrimidin-1-ium,
2-Amino-4-[(4-{[(4-amino-2-methyl-6-quinolinyl)carbonyl]amino}benzyl)amino]-1,6-dimethylpyrimidin-1-ium,
2-Amino-4-[(4-{[(4-amino-2-methyl-6-quinolinyl)carbonyl]amino}benzyl)amino]-6-methylpyrimidine, or
4-Amino-N-{4-[(1H-indazol-6-ylamino)methyl]phenyl}-2-methyl-6-quinolinecarboxamide.

### Claim 6 (depends on 1, 2)

A process for the preparation of a compound of the formula I as claimed in claim 1 or 2, which comprises linking the building blocks of the formulae II, III, and IV
by means of forming in a manner known per se an amide bond between the carboxylic acid group G1 depicted in formula II and the NH2 group G2 depicted in formula III or between the carboxylic acid group G2 depicted in formula III and the NH2 group G1 depicted in formula II and
by means of forming a bonding between building block of the formula III and building block of the formula IV by nucleophilic substitution of an halogen atom G4 depicted in formula IV by an amino group G3 depicted in formula III or
by means of forming a bonding between building block of the formula III and building block of the formula IV by nucleophilic substitution of an halogen atom G3 depicted in formula III by an amino group G4 depicted in formula IV.

### Claim 7 (depends on 1, 2)

A pharmaceutical preparation, comprising at least one compound of the formula I as claimed in claim 1 or 2 in all its stereoisomeric forms and mixtures thereof in any ratio and/or its physiologically tolerable salts and a pharmaceutically acceptable carrier.