2,2′-tandem dithiazole compound, preparation method therefor, and use thereof

Patent metadata

Field	Value
Publication number	US-9643941-B2
Application number	US-201515301763-A
Country	US
Kind code	B2
Filing date	Mar 27, 2015
Priority date	Apr 4, 2014
Publication date	May 9, 2017
Grant date	May 9, 2017

Abstract

The present invention relates to a thiazole-based compound, a preparation method therefor, and a use thereof. More specifically, the present invention relates to a 2,2′-bis-thiazole-based compound, a preparation method therefor, and a use of 2,2′-bis-thiazole-based compound a histone deacetylase inhibitor in the preparation of an antitumor medicament, a medicament for treating autoimmune diseases, a medicament for treating type II diabetes mellitus and complication thereof, or a medicament for treating neurodegenerative diseases.

First claim

The invention claimed is:

1. A 2,2′-bis-thiazole-based compound represented by formula I:

wherein,
R 1 and R 2 are each independently selected from the group consisting of H, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl; or R 1 and R 2 together with the carbon atoms to which they are attached form a 5- to 7-membered cyclic structure;
X is

Y is

or C 2 -C 6 alkenylene, wherein n is 1, 2, 3 or 4;
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with C 6 -C 10 aryl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted with C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, and 5- to 7-membered heteroaryl; the 5- to 7-membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S; and
R 4 is R 4a , R 4b , R 4c , R 4d or R 4e :

wherein R 5 , R 6 , R 7 and R 8 are selected from the group consisting of H, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl (C 1 -C 6 ) alkylene, C 1 -C 6 alkyl substituted with C 6 -C 10 aryl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted with C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, and

the 5- to 7-membered heteroaryl contains 1 to 3 heteroatom(s) selected from N, O and S.

2. The 2,2′-bis-thiazole-based compound according to claim 1 , wherein,
R 1 and R 2 are each independently H or C 1 -C 6 alkyl; or R 1 and R 2 together with the carbon atoms to which they are attached form a 5-, 6- or 7-membered saturated cyclic structure;
Y is

R 3 is C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with C 6 -C 10 aryl, or C 3 -C 6 cycloalkyl;
R 5 is hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, or

R 6 is H or C 1 -C 6 alkyl;
R 7 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxyl (C 1 -C 6 ) alkylene, C 6 -C 10 aryl or 5- to 7-membered heteroaryl, the 5- to 7-membered heteroaryl contains 1 to 3 heteroatom(s) selected from N, O and S; and
R 8 is C 6 -C 10 aryl.

3. The 2,2′-bis-thiazole-based compound according to claim 2 , wherein,
R 3 is C 1 -C 4 alkyl, benzyl, or cyclopropyl;
R 5 is hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl, or

R 6 is H or methyl;
R 7 is C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 4 alkoxy, hydroxy C 1 -C 4 alkylene, C 6 -C 10 aryl or 5- to 7-membered heteroaryl, the 5- to 7-membered heteroaryl contains 1-2 heteroatom(s) selected from N, O and S; and
R 8 is phenyl.

4. The 2,2′-bis-thiazole-based compound according to claim 3 , wherein R 7 is methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethyloxy, hydroxymethyl, hydroxyethyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.

5. The 2,2′-bis-thiazole-based compound according to claim 1 , wherein the 2,2′-bis-thiazole-based compound is selected from the following compounds:

6. A process for preparing the 2,2′-bis-thiazole-based compound according to claim 1 , the process comprising,
obtaining compound I a by Route I,

wherein definitions of R 1 , R 2 , R 3 and n are the same as defined in the formula I in claim 1 ,
by converting compound 1 to acyl chloride using an acyl chloride reagent;
subjecting the acyl chloride to a substitution reaction with TFAA in the presence of a base at room temperature or under heating; and hydrolyzing a resultant of the substitution reaction to form the compound Ia;
preparing compound I b by Route IV:

wherein definitions of R 1 , R 2 , R 3 and n are the same as defined in the formula I in claim 1 ,
by subjecting compound 2 to a Curtius rearrangement reaction to form a Boc-protected amine 12;
removing a Boc-group from compound 12 to form a free amine 13;
oxidizing compound 7 by TEMPO and BAIB to form acid 14;
reacting the acid 14 with the amine 13 under a condensing agent to form compound 15; and
subjecting the compound 15 to a de-ethyleneglycol reaction under a Lewis acid to form the compound I b ; or
preparing compound I c by Route V:

wherein definitions of R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , X and Y are the same as defined in the formula I in claim 1 and R 9 is one selected from R 4b , R 4c and R 4d ,
subjecting compound I ab to a dehydration condensation reaction with

in a solvent at room temperature or under heating to form the compound I c .

7. A pharmaceutical composition comprising a therapeutically effective amount of one or more 2,2′-bis-thiazole-based compounds represented by the formula I according to claim 1 and a pharmaceutically acceptable excipient.

8. A process for preparing the 2,2′-bis-thiazole-based compound according to claim 1 , the process comprising,
obtaining compound I a by Route II,

wherein definitions of R 1 , R 2 , R 3 and n are the same as defined in the formula I in claim 1 ,
by converting compound 2 to acyl chloride using an acyl chloride reagent;
reacting the acyl chloride with concentrated ammonia water under an ice bath to form compound 3;
subjecting compound 4 to an additive reaction with TMS-CF 3 under a catalyst of TBAF in tetrahydrofuran to form compound 5;
hydrolyzing compound 5 with H + to form compound 6;
reacting the compound 6 with 2-chloroethanol in DMF in a presence of K 2 CO 3 to form compound 7;
sulfonylating compound 7 in DCM in a presence of TsCl and Et 3 N to form compound 8;
reacting the compound 8 with the compound 3 under sodium hydride in DMF to form compound 9; or
subjecting the compound 9 to a de-ethyleneglycol reaction under a Lewis acid to form the compound Ia;
preparing compound I b by Route IV:

wherein definitions of R 1 , R 2 , R 3 and n are the same as defined in the formula I in claim 1 ,
s

Assignees

• Shanghai Inst Materia Medica Cas

Inventors

• Nan Fajun
• Li Jia
• Xie Xin
• Gong Chaojun
• Zhou Yubo
• Chai Hui
• Zhang Yangming
• Su Mingbo

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title