Retinoid compound, preparation method therefor, intermediates thereof and application thereof

Patent metadata

Field	Value
Publication number	US-10556879-B2
Application number	US-201716083879-A
Country	US
Kind code	B2
Filing date	Jan 20, 2017
Priority date	Mar 11, 2016
Publication date	Feb 11, 2020
Grant date	Feb 11, 2020

Abstract

Disclosed are a retinoid compound, a preparation method therefor, intermediates thereof and an application thereof. The retinoid compound I of the present invention has a good tumor growth inhibition rate.

First claim

What is claimed is:

1. A compound represented by formula I, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof,

wherein:
(i) U is N, V is CR 9b , X is N, W is CR 9d , and the compound is represented by:

(ii) U is CR 9a , V is N, X is CR 9c , W is N, and the compound is represented by:

(iii) U is N, V is CR 9b , X is CR 9c , W is N, and the compound is represented by:

(iv) U is CR 9a , V is CR 9b , X is CR 9c , W is N, and the compound is represented by:

(v) U is CR 9a , V is CR 9b , X is CR 9c , W is CR 9d , and the compound is represented by:

in the definition of compound F, one, two, three, or four of R 9a , R 9b , R 9c and R 9d is not hydrogen;
in the definition of U, V, X and W, each of R 9a , R 9b , R 9c and R 9d is independently hydrogen, hydroxy, nitro, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with halogen, C 1 -C 6 alkoxy, —NR 10 R 11 ,

or —COOR 14 ;
each of R 10 , R 11 , R 12 , R 13 and R 14 is independently hydrogen or C 1 -C 6 alkyl;
the bond connecting AE, EG or GZ is independently a single bond;
Z is —O—, —S—, —S(═O)— or —SO 2 —;
E is —CH 2 —;
G is —CH 2 —;
A is —(CR 2 R 3 )—;
each of R 2 and R 3 is independently hydrogen, hydroxy, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkyl substituted with halogen, C 1 -C 6 alkoxy, C 1 -C 6 acyl, C 6 -C 10 aryl or “C 3 -C 6 heteroaryl having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen”;
m is 0, 1, 2 or 3;
when there are more than one substituents of R 1 , the substituents are identical or different; R 1 is hydrogen, hydroxy, nitro, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with halogen, C 1 -C 6 alkoxy, —NR 6 R 7 or —COOR 8 ;
each of R 6 , R 7 and R 8 is independently hydrogen or C 1 -C 6 alkyl;
Y is —CN, —COOR 15 or —CO 2 NHR 16 ;
each of R 15 and R 16 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkylacyl;

with a proviso that the compound represented by formula I is not

2. The compound represented by formula I as defined in claim 1 , wherein,
when each of R 2 and R 3 is independently halogen, the “halogen” is fluorine, chlorine, bromine or iodine;
when each of R 2 and R 3 is independently “C 1 -C 6 alkyl”, the “C 1 -C 6 alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;
when each of R 2 and R 3 is independently “C 2 -C 6 alkenyl”, the “C 2 -C 6 alkenyl” is vinyl or propenyl;
when each of R 2 and R 3 is independently “C 1 -C 6 alkyl substituted with halogen”, the “C 1 -C 6 alkyl substituted with halogen” is trifluoromethyl;
when each of R 2 and R 3 is independently “C 1 -C 6 alkoxy”, the “C 1 -C 6 alkoxy” is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy or hexoxy;
when each of R 2 and R 3 is independently “C 1 -C 6 acyl”, the “C 1 -C 6 acyl” is acetyl or formyl;
when each of R 2 and R 3 is independently “C 6 -C 10 aryl”, the “C 6 -C 10 aryl” is phenyl;
when each of R 2 and R 3 is independently “C 3 -C 6 heteroaryl having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen”, the “C 3 -C 6 heteroaryl having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen” is pyridinyl or pyrimidinyl;
when R 1 is “halogen”, the “halogen” is fluorine, chlorine, bromine or iodine;
when R 1 is “C 1 -C 6 alkyl”, the “C 1 -C 6 alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;
when R 1 is “C 1 -C 6 alkyl substituted with halogen”, the “C 1 -C 6 alkyl substituted with halogen” is trifluoromethyl;
when R 1 is “C 1 -C 6 alkoxy”, the “C 1 -C 6 alkoxy” is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy or hexoxy;
when each of R 6 , R 7 and R 8 is independently “C 1 -C 6 alkyl”, the “C 1 -C 6 alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;
when each of R 9a , R 9b , R 9c and R 9d is independently “halogen”, the “halogen” is fluorine, chlorine, bromine or iodine;
when each of R 9a , R 9b , R 9c and R 9d is independently “C 1 -C 6 alkyl”, the “C 1 -C 6 alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;
when each of R 9a , R 9b , R 9c and R 9d is independently “C 1 -C 6 alkyl substituted with halogen”, the “C 1 -C 6 alkyl substituted with halogen” is trifluoromethyl;
when each of R 9a , R 9b , R 9c and R 9d is independently “C 1 -C 6 alkoxy”, the “C 1 -C 6 alkoxy” is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy or hexoxy;
when each of R 10 , R 1 , R 12 , R 13 and R 14 is independently “C 1 -C 6 alkyl”, the “C 1 -C 6 alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;
when each of R 15 and R 16 is independently “C 1 -C 6 alkyl”, the “C 1 -C 6 alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;
when each of R 15 and R 16 is independently “C 2 -C 6 alkenyl”, the “C 2 -C 6 alkenyl” is vinyl or propenyl;
when each of R 15 and R 16 is independently “C 1 -C 6 acyl”, the “C 1 -C 6 acyl” is formyl or acetyl.

3. The compound represented by formula I as defined in claim 1 , wherein,
A, E, G together with Z form the ring selected from the group consisting of

4. The compound represented by formula I as defined in claim 3 , wherein,
in compound A, when Y is —COOR 15 , R 15 is hydrogen or ethyl;
and/or, in compound A, Z is —S—, —S(═O)— or —SO 2 —;
and/or, in compound B, when Y is —COOR 15 , R 15 is methyl or ethyl;
and/or, in compound B, Z is —S— or —S(═O)—;
and/or, in compound C, when Y is —COOR 15 , R 15 is hydrogen or ethyl;
and/or, in compound C, Z is —S— or —S(═O)—;
and/or, in compound D, when Y is —COOR 15 , R 15 is hydrogen or ethyl;
and/or, in compound F, when Y is —COOR 15 , R 15 is hydrogen, methyl or ethyl;
and/or, in compound F, Z is —S—, —S(═O)— or —SO 2 —.

5. The compound represented by formula I as defined in claim 4 , wherein,
in compound A, when Y is COOH, Z is —S—;
and/or, in compound A, when Y is COOEt, Z is —S(═O)— or —SO 2 —;
and/or, in compound B, when Y is COOEt, Z is —S—;
and/or, in compound B, when Y is CNOEt, Z is —S— or —S—;
and/or, in compound B, when Y is CN, Z is —S— or;
and/or, in compound C, when Y is COOEtH, Z is —S—;
and/or, in compound C, when Y is COOEt, Z is —S— or —S(═O)—.

6. The compound represented by formula I as defined in claim 1 , wherein, the compound represented by formula I is selected from the group consisting of

Assignees

• Shanghai Inst Organic Chemistry Cas
• Univ Huazhong Science Tech
• Shanghai Inst Of Organic Chemistry Chinese Acadmeny Of Sciences

Inventors

• Cao Xin
• Yu Biao
• Wang Ning
• Chen Junwei

Classifications

• C07C229/56

  with amino and carboxyl groups bound in ortho-position · CPC title

• C07C63/70

  Monocarboxylic acids · CPC title

• C07C65/19

  having unsaturation outside the aromatic ring · CPC title

• C07C69/76

  Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring · CPC title

• A61P35/00

  Antineoplastic agents · CPC title