# US 7,612,080 B2 · GTPase inhibitors and use thereof for controlling platelet hyperactivity

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- Number: US 7,612,080 B2
- Document ID: US7612080B2
- Status: Granted
- Kind: B2
- Application number: 11/283,556
- Filed: 2005-11-18
- Published: 2006-06-22
- Granted: 2009-11-03
- Earliest claimed: 2004-11-19
- Assignees: Cincinnati Children's Hospital Medical Center
- Inventors: Yi Zheng; Huzoor Akbar; David A. Williams; Wieslaw Adam Mazur
- Web page: https://patentgrep.com/patent/US7612080B2

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The preferred embodiments generally relate to methods and compositions that affect the GTP-binding activity of members of the Rho family GTPases, preferably Rac (Rac1, Rac2 and/or Rac3), such compositions include compounds that modulate the GTP/GDP exchange activity, along with uses for the compounds including screening for compounds which recognize Rac GTPase, and methods of treating pathological conditions associated or related to a Rho family GTPase, including Rac. The preferred embodiments also relate to methods of using such compounds, or derivatives thereof, e.g., in therapeutics, diagnostics, and as research tools.

## Claims

### Claim 1

A method for treating platelet hyperreactivity in a subject, comprising administering to the subject in need thereof an effective amount of at least one compound having the formula (IIa):
wherein:
R1 to R2 are independently selected from the group consisting of H, —X-Alk, —X-Alk-X′, and —X—Y—X′; wherein
X is —CR7R8;
X′ is —CHR7R8;
Alk is a C2-C18 substituted or unsubstituted hydrocarbon chain;
Y is a C2-C8 substituted or unsubstituted alkylene chain;
R6 is H or (C1-C4) alkyl; and
R7 and R8 are independently selected from the group consisting of H and (C1-C4) alkyl;
or a salt of a compound of formula (IIa), wherein the platelet hyperreactivity is a condition selected from the group consisting of arterial thrombosis, stroke, atherosclerosis, Kawasaki syndrome, and moyamoya.

### Claim 2 (depends on 1)

The method of claim 1, wherein Alk is substituted with halo, halo (C1-C4) alkoxy, (C3-C8) cycloalkyl, hydroxy, or acetyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein Y is substituted with an NR6 group.

### Claim 4

A method for treating platelet hyperreactivity in a subject, comprising administering to the subject in need thereof an effective amount of at least one compound having the formula (III):
wherein:
R10 to R12 are independently selected from the group consisting of H, halo, (C1-C4) alkyl, branched (C3-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxy, NO2, and NH2;
or a salt of a compound of formula (III), wherein the platelet hyperreactivity is a condition selected from the group consisting of arterial thrombosis, stroke, atherosclerosis, Kawasaki syndrome, and moyamoya.

### Claim 5 (depends on 4)

The method of claim 4, wherein R10 to R12 are independently selected from the group consisting of H, (C1-C4) alkyl, and branched (C3-C4) alkyl.

### Claim 6

A method for treating platelet hyperreactivity in a subject, comprising administering to the subject in need thereof an effective amount of at least one compound having the formula (IV):
or pharmaceutically acceptable salts thereof, wherein the platelet hyperreactivity is a condition selected from the group consisting of arterial thrombosis, stroke, atherosclerosis, Kawasaki syndrome, and moyamoya.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the compound is N6-(2-((4-(diethylamino) 1-methylbutyl)amino)-6-methyl-4-pyrimidinyl)-2-methyl-4,6-quinolinediamine.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the platelet hyperreactivity is mediated by a Rho GTPase selected from the group consisting of Rac1, Rac2, and combinations thereof.

### Claim 9 (depends on 8)

The method according to claim 8, wherein the Rho GTPase is Rac1.