# US 10,246,449 B2 · 1,2,3 triazole-thiazole compounds, process for preparation and use thereof

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- Number: US 10,246,449 B2
- Document ID: US10246449B2
- Status: Granted
- Kind: B2
- Application number: 16/064,415
- Filed: 2016-12-20
- Published: 2018-12-27
- Granted: 2019-04-02
- Earliest claimed: 2015-12-21
- Assignees: Council of Scientific and Industrial Research
- Applicants: Council of Scientific & Industrial Research
- Inventors: Rajesh Sudhir Gokhale; Dumbala Srinivasa Reddy; Balamkundu Seetharamsingh; Parul Ganju; Vivek Tirunelveli Natarajan
- Web page: https://patentgrep.com/patent/US10246449B2

## CPC

- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61P 17/00: Drugs for dermatological disorders
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

A 1,2,3 triazole-thiazole compound of formula (I) or pharmaceutically acceptable salt thereof, process for its preparation, its pharmaceutical composition and method for the treatment for stalling vitiligo spread or provide prophylactic benefit to individuals with vitiligo predisposition.

## Claims

### Claim 1

A 1,2,3 triazole-thiazole compound of formula (I);
wherein;
R is independently selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl and alkoxyalkyl;
n is 1, 2 or 3; and
X is a halogen;
or pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound as claimed in claim 1, wherein said compound of formula (I) is selected from the group consisting of 2-(4-Chlorophenyl)-4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)thiazole (NDS-100971), 2-(4-Chlorophenyl)-4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)thiazole (NDS-100972), 4-((4-Butyl-1H-1,2,3-triazol-1-yl)methyl)-2-(4-chlorophenyl)thiazole (NDS-100973) 2-(4-Chlorophenyl)-4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)thiazole (NDS-100971), 2-(4-Chlorophenyl)-4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)thiazole (NDS-100972), 4-((4-Butyl-1H-1,2,3-triazol-1-yl)methyl)-2-(4-chlorophenyl)thiazole (NDS-100973), 2-(4-Bromophenyl)-4-((4-butyl-1H-1,2,3-triazol-1-yl)methyl)thiazole, 2-(4-Fluorophenyl)-4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)thiazole, 4-((4-Benzyl-1H-1,2,3-triazol-1-yl)methyl)-2-(4-fluorophenyl)thiazole, 4-((4-Cyclohexyl-1H-1,2,3-triazol-1-yl)methyl)-2-(4-fluorophenyl)thiazole, 4-((4-Cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)-2-(4-fluorophenyl)thiazole, 2-(4-Fluorophenyl)-4-((4-propyl-1H-1,2,3-triazol-1-yl)methyl) thiazole, 2-(4-Bromophenyl)-4-((4-propyl-1H-1,2,3-triazol-1-yl)methyl)thiazole, 2-(4-Chlorophenyl)-4-((4-propyl-1H-1,2,3-triazol-1-yl)methyl)thiazole, 4-((4-Benzyl-1H-1,2,3-triazol-1-yl)methyl)-2-(4-chlorophenyl)thiazole, 2-(4-Bromophenyl)-4-((4-cyclohexyl-1H-1,2,3-triazol-1-yl)methyl)thiazole, 2-(4-Chlorophenyl)-4-((4-cyclohexyl-1H-1,2,3-triazol-1-yl)methyl)thiazole, 2-(4-Bromo phenyl)-4-((4-cyclopentyl-1H-1,2,3-triazol-1-yl) methyl)thiazole, 2-(4-Chloro phenyl)-4-((4-cyclopentyl-1H-1,2,3-triazol-1-yl) methyl) thiazole, 4-((4-Cyclopentyl-1H-1,2,3-triazol-1-yl)methyl)-2-(4-fluorophenyl)thiazole, (1-((2-(4-Fluorophenyl)thiazol-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol, (1-((2-(4-Chlorophenyl)thiazol-4-yl)methyl)-1H-1,2,3-triazol-4-yl) methanol, (1-((2-(4-Bromophenyl)thiazol-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol, 2-(4-Bromophenyl)-4-((4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)methyl) thiazole, 2-(4-Chlorophenyl)-4-((4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)methyl) thiazole, 2-(4-Fluorophenyl)-4-((4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)methyl) thiazole, 2-(4-Fluorophenyl)-4-((4-(p-tolyl)-1H-1,2,3-triazol-1-yl)methyl)thiazole, 2-(4-Bromophenyl)-4-((4-(p-tolyl)-1H-1,2,3-triazol-1-yl)methyl) thiazole, 2-(4-Chlorophenyl)-4-((4-(p-tolyl)-1H-1,2,3-triazol-1-yl)methyl)thiazole, 2-(4-Chlorophenyl)-4-(2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl)thiazole, 2-(4-Bromophenyl)-4-(2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl)thiazole, 2-(4-Fluorophenyl)-4-(2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl)thiazole, 2-(4-Chlorophenyl)-4-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)ethyl)thiazole, 2-(4-Bromophenyl)-4-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)ethyl)thiazole, 4-(2-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)ethyl)-2-(4-fluorophenyl) thiazole, (1-(2-(2-(4-Fluorophenyl)thiazol-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)methanol, (1-(2-(2-(4-Bromophenyl)thiazol-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)methanol, (1-(2-(2-(4-Chlorophenyl)thiazol-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)methanol, 2-(4-Fluorophenyl)-4-(2-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)ethyl)thiazole, 2-(4-Chlorophenyl)-4-(2-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)ethyl)thiazole, 2-(4-Bromophenyl)-4-(2-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)ethyl)thiazole, 2-(4-Bromophenyl)-4-(2-(5-(p-tolyl)-1H-1,2,3-triazol-1-yl)ethyl)thiazole, 2-(4-Fluorophenyl)-4-(2-(5-phenyl-1H-1,2,3-triazol-1-yl)ethyl)thiazole, 2-(4-Chlorophenyl)-4-(2-(5-phenyl-1H-1,2,3-triazol-1-yl)ethyl)thiazole, 2-(4-Bromophenyl)-4-(2-(5-phenyl-1H-1,2,3-triazol-1-yl)ethyl) thiazole, 2-(4-Bromophenyl)-4-(2-(5-propyl-1H-1,2,3-triazol-1-yl)ethyl)thiazole, 2-(4-Fluorophenyl)-4-(2-(5-propyl-1H-1,2,3-triazol-1-yl)ethyl)thiazole, 2-(4-Chlorophenyl)-4-(2-(5-propyl-1H-1,2,3-triazol-1-yl)ethyl)thiazole, 4-(2-(5-Cyclopropyl-1H-1,2,3-triazol-1-yl)ethyl)-2-(4-fluorophenyl)thiazole, 2-(4-Chlorophenyl)-4-(2-(5-cyclopropyl-1H-1,2,3-triazol-1-yl)ethyl)thiazole, 2-(4-Bromophenyl)-4-(2-(5-cyclopropyl-1H-1,2,3-triazol-1-yl)ethyl)thiazole, (1-(2-(2-(4-Fluorophenyl)thiazol-4-yl)ethyl)-1H-1,2,3-triazol-5-yl) methanol, (1-(2-(2-(4-Chlorophenyl)thiazol-4-yl)ethyl)-1H-1,2,3-triazol-5-yl) methanol and (1-(2-(2-(4-Bromophenyl)thiazol-4-yl)ethyl)-1H-1,2,3-triazol-5-yl)methanol.

### Claim 3 (depends on 1)

A process for the preparation of 1,2,3 triazole-thiazole compound of formula (I) as claimed in claim 1, said process comprising the steps of:
(a) adding sodium azide to a solution of chloro compound in solvent followed by stirring the reaction mixture at temperature in the range of 50 to 60° C. for a period of 5 to 6 hours to afford a corresponding azido compound;
(b) adding the azido compound of step (a) to a solution of copper (II) sulfate pentahydrate, reducing agent and alkyne in a suitable solvent, followed by stirring the reaction mixture at temperature of 25 to 32° C. for a period of 5 to 6 hours.

### Claim 4 (depends on 3)

The process as claimed in claim 3, wherein said chloro compound is selected from the group consisting of 4-(chloromethyl)-2-(4-chlorophenyl)thiazole, 4-(chloromethyl)-2-(4-bromophenyl)thiazole, 4-(chloromethyl)-2-(4-fluorophenyl)thiazole and 4-(chloromethyl)-2-(4-iodophenyl)thiazole.

### Claim 5 (depends on 3)

The process as claimed in claim 3, wherein said azido compound is selected from the group consisting of 4-(Azidomethyl)-2-(4-chlorophenyl)thiazole, 4-(Azidomethyl)-2-(4-bromophenyl)thiazole, 4-(azidomethyl)-2-(4-fluorophenyl)thiazole and 4-(azidomethyl)-2-(4-iodophenyl)thiazole.

### Claim 6 (depends on 3)

The process as claimed in claim 3, wherein said solvent is selected from the group consisting of a polar aprotic solvent, t-butanol, water or mixture thereof.

### Claim 7 (depends on 3)

The process as claimed in claim 3, wherein said additive is selected from the group consisting of sodium ascorbate, 2-ethynylpyridine and triethyl amine.

### Claim 8 (depends on 3)

The process as claimed in claim 3, wherein said alkyne is R—C≡CH wherein ‘R’ is independently selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, hydroxyalky and alkoxyalkyl.

### Claim 9 (depends on 3)

The process as claimed in claim 3, wherein said alkyne is selected from the group consisting of phenylacetylene, cyclopropylacetylene, 1-hexyne, 1-heptyne, 5-hexyn-1-ol and ethylpropiolate.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

### Claim 11

A method for treating spread of depigmentation in vitiligo by suppressing immunogenic cell death of melanocytes and suppressing localization of calreticulin to the cell surface of melanocytes, wherein said method comprises administering to the subject a therapeutically effective amount of 1,2,3 triazole-thiazole compound of formula (I) or pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 11)

The method as claimed in claim 11, wherein said subject is human.

### Claim 13 (depends on 6)

The process according to claim 6, wherein the polar aprotic solvent is DMF or DMPU.