(4E)-4-(4-substituted benzylideneamino)-2,3-dihydro-3-substituted-2-thioxothiazole-5-carbonitriles as A2AR antagonist and process for preparation thereof

Patent metadata

Field	Value
Publication number	US-9518033-B2
Application number	US-201414758994-A
Country	US
Kind code	B2
Filing date	Jan 3, 2014
Priority date	Jan 3, 2013
Publication date	Dec 13, 2016
Grant date	Dec 13, 2016

Abstract

The present invention provides (4E)-4-(4-substituted benzylideneamino)-2,3-dihydro-3-substituted-2-thioxothiazole-5-carbonitriles of general formula A, below, and a process for the preparation thereof.

The compounds of present invention are useful in the treatment of central nervous disorders including, Parkinson disease, Huntington's disease, attention disorder, cognition, Alzheimer disease, depression and hypertension.

First claim

The invention claimed is:

1. A compound of formula A and pharmaceutically acceptable salts thereof,

wherein R is selected from the group consisting of hydrogen, alkyl having carbon numbers up to 10, cycloalkyl, aromatic, aromatics having substituents selected from the group consisting of halogen, OH, COOH, OCH 3 , and alkyl, and substituted heterocyclics including heteroaromatics compounds having up to seven members; R 1 is selected from nucleophiles selected from the group consisting of halides, O along with a substituent selected from the group consisting of hydrogen, alkyl having carbon numbers up to 10, cycloalkyl, aromatic, aromatics having substituents selected from the group consisting of halogen, OH, COOH, OCH 3 , and alkyl, and substituted heterocyclics including heteroaromatics compounds having up to seven members, S along with a substituent selected from the group consisting of hydrogen, alkyl having carbon numbers up to 10, cycloalkyl, aromatic, aromatics having substituents selected from the group consisting of halogen, OH, COOH, OCH 3 , and alkyl, and substituted heterocyclics including heteroaromatics compounds having up to seven members, COO along with a substituent selected from the group consisting of hydrogen, alkyl having carbon numbers up to 10, cycloalkyl, aromatic, aromatics having substituents selected from the group consisting of halogen, OH, COOH, OCH 3 , and alkyl, and substituted heterocyclics including heteroaromatics compounds having up to seven members, NR2R3 wherein R2 and R3 are selected from the group consisting of hydrogen, alkyl having carbon numbers up to 10, cycloalkyl, aromatic, aromatics having substituents selected from the group consisting of halogen, OH, COOH, OCH 3 , and alkyl, substituted heterocyclics including heteroaromatics compounds having up to seven members and substituted amino, and alkyl having up to five carbon chain.

2. A pharmaceutical compound selected from the group consisting of:
a. 4E)-4-(4-fluorobenzylideneamino)-3-ethyl-2,3-dihydro-2-thioxothiazole-5-carbonitrile,
b. (4E)4-(4-fluorobenzylideneamino)-3-propyl-2,3-dihydro-2-thioxothiazole-5-carbonitrile,
c. (4E)-4-fluorobenzylideneamino)-3-butyl-2,3-dihydro-2-thioxothiazole-5-carbonitrile,
d. (4E)-4-(4-fluorobenzylideneamino)-3-phenylethyl-2,3-dihydro-2-thioxothiazole-5-carbonitrile,
e. (4E)-4-(4-fluorobenzylideneamino)-3-phenyl-2,3-dihydro-2-thioxothiazole-5-carbonitrile,
f (4E)-4-(4-chlorobenzylideneamino)-3-ethyl-2,3-dihydro-2-thioxothiazole-5-carbonitrile,
g. (4E)4-(4-chlorobenzylideneamino)-3-propyl-2,3-dihydro-2-thioxothiazole-5-carbonitrile,
h. (4E)-4-(chlorobenzylideneamino)-3-butyl-2,3-dihydro-2-thioxothiazole-5-carbonitrile,
i. (4E)4-(4-chlorobenzylideneamino)-3-phenyl-2,3-dihydro-2-thioxothiazole-5-carbonitrile
j. (4E)-4-(4-Bromobenzylideneamino)-3-ethyl-2,3-dihydro-2-thioxothiazole-5-carbonitrile,
k. (4E)4-(4-bromobenzylideneamino)-3-propyl-2,3-dihydro-2-thioxothiazole-5-carbonitrile,
l. (4E)-4-(4-bromobenzylideneamino)-3-butyl-2,3-dihydro-2-thioxothiazole-5-carbonitrile,
m. (4E)4-(4-bromobenzylideneamino)-3-phenylethyl-2,3-dihydro-2-thioxothiazole-5-carbonitrile, and
n. (4E)4-(4-bromobenzylideneamino)-3-phenyl-2,3-dihydro-2-thioxothiazole-5-carbonitrile.

3. The pharmaceutical compound of claim 2 , wherein the compound exhibits adenosine A 2A receptor affinity (KiA 2A ) in the range of 0.004 to 10.98 nm.

4. The pharmaceutical compound of claim 2 , wherein the compound is:
n. (4E)4-(4-bromobenzylideneamino)-3-phenyl-2,3-dihydro-2-thioxothiazole-5-carbonitrile and exhibits Adenosine A 2A receptor antagonistic ability 0.56 pmol/ml cAMP concentration.

5. The pharmaceutical compound of claim 2 , wherein the compound exhibits the significant attenuation of catalepsy score in haloperidol-induced mice at the dose of 10 mg/kg (0.75±0.144).

6. A process for preparation of the compound of claim 1 , wherein said process comprises the step of
reacting a compound of formula 1,

with p-substituted benzaldehyde of the formula,

wherein R is selected from a group consisting of ethyl, propyl, butyl, and phenyl and the reaction is carried out in polar solvents selected from the group consisting of chloroform, dichloromethane, ethanol and acetic acid in the presence of Lewis acid catalyst selected from the group consisting of AlCl 3 BF 3 , ZnCl 2 , and FeCl 3 (2-3 mole %) at a temperature ranging between 20 to 30° C. for a period ranging between 6-12 hr.

7. The process as claimed in claim 6 , wherein p-substituted benzaldehyde is selected from a group consisting of fluorobenzaldehyde, chlorobenzaldehyde and bromo benzaldehyde.

Assignees

• Council Scient Ind Res

Inventors

• Luthra Pratibha Mehta
• Mishra Chandrabhushan

Classifications

• C07D277/54 Primary

  Nitrogen and either oxygen or sulfur atoms · CPC title

• C07D277/56

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title