Aryl-2,2′-tandem bisthiazole compound and preparation method and use thereof

Patent metadata

Field	Value
Publication number	US-10766889-B2
Application number	US-201716329336-A
Country	US
Kind code	B2
Filing date	Aug 24, 2017
Priority date	Aug 31, 2016
Publication date	Sep 8, 2020
Grant date	Sep 8, 2020

Abstract

The invention describes an aryl-2,2′-tandem bisthiazole compound and a preparation method and the use thereof. In particular, disclosed in the present invention are an aryl-2,2′-tandem bisthiazole compound with the structure as shown in general formula I and the preparation method thereof and use thereof as a histone deacetylase inhibitor in the preparation of antitumor drugs.

First claim

The invention claimed is:

1. A compound of formula I or an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

wherein,
R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 5 -C 10 aryl; and R 2 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 5 -C 10 aryl; or
R 1 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 5 -C 10 aryl; and R 2 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 5 -C 10 aryl;
or R 1 and R 2 together with the carbon atom to which they are attached form a 5-7 membered saturated or partially saturated ring;
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 5 -C 10 aryl; and
R 4 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl;
wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 5 -C 10 aryl is unsubstituted or substituted with one or more groups selected from the group consisting of halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 5 -C 10 aryl.

2. The compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof of claim 1 , wherein, R 1 is H, C 1 -C 6 alkyl, or C 6 -C 10 aryl, and R 2 is C 1 -C 6 alkyl or C 6 -C 10 aryl; or R 1 is C 1 -C 6 alkyl or C 6 -C 10 aryl, and R 2 is H, C 1 -C 6 alkyl, or C 6 -C 10 aryl; or R 1 and R 2 together with the carbon atom to which they are attached form a 5, 6 or 7 membered partially saturated ring.

3. The compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof of claim 1 , wherein, R 3 is C 1 -C 4 alkyl, C 6 -C 10 aryl substituted C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl.

4. The compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof of claim 1 , wherein, R 4 is C 1 -C 6 alkyl.

5. A compound selected from the group consisting of:

or an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

6. A method for preparing the compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of formula II-1, R 1 , R 2 , and R 3 are defined as in claim 1 , and R 4 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl,

the method comprising:
(1) condensing methyl 4-acetylbenzoate with tert-butyl sulfenamide to form tert-butyl sulfoximine 1;
(2) reacting tert-butyl sulfinimide 1 with a Grignard reagent to form tert-butyl sulfenamide 2;
(3) deprotecting tert-butyl sulfinamide 2 to form amine 3;
(4) condensing amine 3 with acid 4 to form methyl ester 5; and
(5) reacting methyl ester 5 with alkali to form a hydrolysis product, reacting the hydrolysis product with a hydroxylamine protected by a protecting group to form a condensation product protected by the protecting group, and removing the protecting group to form the compound of formula II-1; or
wherein the compound is of formula II-2, R 1 , R 2 , and R 3 are defined as in claim 1 ,

or the method comprising:
(i) reacting acid 4 with methyl 4-aminomethylbenzoate to form methyl ester 8;
(ii) reacting methyl ester 8 with alkali to form a hydrolysis product, reacting the hydrolysis product with a hydroxylamine protected by a protecting group to form a condensation product, and removing the protecting group to form the compound of formula II-2.

7. A pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof of claim 1 , and pharmaceutically acceptable carriers.

8. A method of inhibiting a histone deacetylase in a subject in need thereof comprising administering to the subject an effective amount of the compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1 .

9. A method of inhibiting tumor cells or a tumor in a subject in need thereof comprising administering to the subject an effective amount of the compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1 .

10. A method of claim 9 , wherein the tumor cells are multiple myeloma cells, colon cancer cells, lung cancer cells, embryo lung cells, liver cancer cells, breast cancer cells, ovarian cancer cells, pancreatic cancer cells, rectal cancer cells, gastric cancer cells, lymphoma cells or leukemia cells; and the tumor is multiple myeloma, colon cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, pancreatic cancer, rectal cancer, gastric cancer, lymphoma, or leukemia.

11. A pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof of claim 5 , and pharmaceutically acceptable carriers.

12. A method of inhibiting a histone deacetylase in a subject in need thereof comprising administering to the subject an effective amount of the compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to claim 5 .

13. A method of inhibiting tumor cells or a tumor in a subject in need thereof comprising administering to the subject an effective amount of the compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to claim 5 .

14. A method of claim 13 , wherein the tumor cells are multiple myeloma cells, colon cancer cells, lung cancer cells, embryo lung cells, liver cancer cells, breast cancer cells, ovarian cancer cells, pancreatic cancer cells, rectal cancer cells, gastric cancer cells, lymphoma cells or leukemia cells; and the tumor is multiple myeloma, colon cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, pancreatic cancer, rectal cancer, gastric cancer, lymphoma, or leukemia.

15. A compound selected from the group consisting of:

and

an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising an effective amount of the compound, the optical isomer, or the pharmaceutically acceptable salt thereof of claim 15 , and a pharmaceutically acceptable carrier.

Assignees

• Shanghai Inst Materia Medica Cas

Inventors

• Nan Fajun
• Li Jia
• Ding Jian
• Geng Meiyu
• Zhang Yangming
• Chen Yi
• Zhou Yubo
• Gong Chaojun
• Su Mingbo
• Gao Anhui

Classifications

• C07D277/56 Primary

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07D417/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title