# US 8,541,428 B2 · Heterocyclic derivatives, pharmaceutical compositions and methods of use thereof

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- Number: US 8,541,428 B2
- Document ID: US8541428B2
- Status: Granted
- Kind: B2
- Application number: 12/438,291
- Filed: 2006-08-22
- Published: 2010-02-04
- Granted: 2013-09-24
- Earliest claimed: 2006-08-22
- Assignees: Technion Research & Development Foundation Limited
- Applicants: Moshe Gavish; Jehuda Arieh Veenman; Alex Shterenberg; Ilan Marek
- Inventors: Moshe Gavish; Jehuda Arieh Veenman; Alex Shterenberg; Ilan Marek
- Web page: https://patentgrep.com/patent/US8541428B2

## CPC

- C07D 239/91: with aryl or aralkyl radicals attached in position 2 or 3
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07D 239/90: with acyclic radicals attached in position 2 or 3
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to novel quinoxaline, quinazoline and phthalazine derivatives as well as multimeric derivatives, methods for their preparation, pharmaceutical compositions including such compounds, and methods of using these compounds for the treatment and prevention of brain damage resulting from brain injury, especially secondary brain damage due to traumatic brain injury (TBI). The compounds of the invention are also useful in treating and preventing neurodegenerative diseases.

## Claims

### Claim 1

A compound represented by the structure of Formula II:
wherein
R1 is oxo, R2 is a group of the formula A and is a single bond; or R1 is a group of the formula A, R2 is absent and is a double bond;
A is represented by the structure:
R3 and R4 are each independently selected from the group consisting of a linear or branched C1-C6 alkyl, a linear or branched C2-C6 alkenyl, a C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, hydroxy, alkoxy, aryloxy, amino, cyano and nitro;
R5 and R6 are each independently selected from the group consisting of hydrogen, a linear or branched C1-C6 alkyl, a linear or branched C2-C6 alkenyl, a C3-C8 cycloalkyl, heterocyclyl, aryl and heteroaryl;
X is selected from the group consisting of a bond, —O—, —S—, and —CR8R9, wherein R8 and R9 are independently selected from the group consisting of hydrogen and a linear or branched C1-C6 alkyl;
m is 0, 1, 2, 3 or 4; and
n is 0, 1, 2, 3, 4 or 5;
including salts, optical isomers, geometrical isomers, enantiomers, diastereomers, and mixtures thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein:
R5 and R6 are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; or
m and n are each 0; or
X is CH2, a bond or O; or
combinations thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound is represented by the structure of formula IIA or IIB

### Claim 4 (depends on 3)

The compound of claim 3, wherein the compound is selected from the group consisting of:

### Claim 5 (depends on 3)

The compound of claim 3 wherein the compound is selected from the group consisting of:

### Claim 6 (depends on 3)

The compound of claim 3, represented by the structure of formula IIB wherein X is O.

### Claim 7 (depends on 6)

The compound of claim 6, wherein R4 is halo and n is 0, 1 or 2.

### Claim 8 (depends on 6)

The compound of claim 6, wherein R5 is and R6 are each a C1-C6 alkyl.

### Claim 9 (depends on 8)

The compound of claim 8, wherein R5 is and R6 are each selected from methyl, ethyl, propyl and isopropyl.

### Claim 10 (depends on 5)

The compound of claim 5, which is represented by the structure:

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as an active ingredient a compound according to claim 1.

### Claim 12 (depends on 1)

A method for preventing neurodegeneration by cell apoptosis in subject with a neurodegenerative disease, comprising the step of administering to a subject in need thereof an effective amount of a compound according to claim 1.

### Claim 13 (depends on 1)

A method for treating or preventing progression of brain damage resulting from traumatic brain injury (TBI) or secondary brain damage resulting from TBI, comprising the step of administering to a subject in need thereof an effective amount of a compound according to claim 1.