Synthetic retinoids (in cell modulation)

Patent metadata

Field	Value
Publication number	US-11324825-B2
Application number	US-201916357755-A
Country	US
Kind code	B2
Filing date	Mar 19, 2019
Priority date	Aug 9, 2016
Publication date	May 10, 2022
Grant date	May 10, 2022

Abstract

There are described novel compounds of formula I: (I) in which, in which A1, A2, A3, A4, R1 and R2 are each as herein defined, for use in the treatment or alleviation of an RAR mediated condition; and methods related thereto.

First claim

The invention claimed is:

1. A compound of formula I:

in which
A 1 is N or CR 3 ;
A 2 is N or CR 4 ;
A 3 is N or CR 5 ;
R 3 , R 4 and R 5 , which may be the same or different, are each hydrogen, alkyl C1-10 , alkene C2-12 , aryl, aralkyl, halogen, trifluoroalkyl, cyano, nitro, —NR a R b , —OR a , glycol, —C(O)R a , —C(O)OR a , —OC(O)R a , —S(O)R a R b , —C(O)NR a R b or a solubilising group;
R 7 is hydrogen, propynyl, —(CH 2 ) n C≡CH, —(CH 2 ) n SH, —(CH 2 ) n SO 2 F or —(CH 2 ) n C═CH 2 , alkyl C1-10 , said alkyl being optionally substituted by aryl or heteroaryl;
R 8 , R 9 , R 10 and R 11 , which may be the same or different, are each hydrogen or alkyl C1-4 , aryl, halogen, trifluoroalkyl, —OR c or glycol, or together one pair of R 8 and R 10 or R 9 and R 11 represent a bond;
R 12 and R 13 , which may be the same or different, are each hydrogen, alkyl C1-4 or together one pair of R 10 and R 12 or R 11 and R 13 represent a bond, or R 12 and R 13 together form a group:
═CR 14 R 15

provided that the pair of R 10 and R 12 or R 11 and R 13 does not represent a bond if a pair from R 8 , R 9 , R 10 and R 11 represents a bond;
R 14 and R 15 , which may be the same or different, are each hydrogen or alkyl C1-10 ; and
R a , R b and R c , which may be the same or different, are each hydrogen or alkyl C1-10 ;
n is an integer from 1 to 6;
R 2 is a group III:

in which
X a is —C≡C—, —CH═CH— or —N═CH—;
X b is —C≡C— or is absent;
A 5 is N or CR 17 ;
A 6 is N or CR 18 ;
A 7 is N or CR 19 ;
A 8 is N or CR 20 ;
R 17 , R 18 , R 19 and R 20 , which may be the same or different, are each hydrogen, alkyl C1-10 , alkene C2-12 , aryl, aralkyl, halogen, trifluoroalkyl, cyano, nitro, —NR d R e , —OR d , glycol, —C(O)R d , —C(O)OR d , —OC(O)R d , —S(O)R d R e , —C(O)NR d R e or a solubilising group;
R 16 is —CR 21 ═CR 22 Y, —C≡C—R 23 or together with R 18 forms a ring IV:

A 9 is N or CR 24 ;
A 10 is N or CR 25 ;
A 11 is N or CR 26 ;
R 23 is a group V:

in which
A 12 is N or CR 27 ;
A 13 is N or CR 28 ;
A 14 is N or CR 29 ;
A 15 is N or CR 30 ;
R 21 and R 22 , which may be the same or different, are each hydrogen, alkyl C1-10 , alkene C2-12 , aryl, halogen or trifluoroalkyl;
R 24 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 , which may be the same or different, are each hydrogen, alkyl C1-10 , alkene C2-12 , aryl, halogen, trifluoroalkyl, —OR f , glycol or a solubilising group;
R d , R e and R f , which may be the same or different, are each hydrogen or alkyl C1-10 ;
Y is —CO 2 R 31 , —COH, —CO 2 CH 2 C≡CH, —CN, —SF 5 , —SO 3 H, —SO 2 NH 2 , —SO 2 CF 3 , —CF 3 , —CO 2 (CH 2 ) m SH, —CO 2 (CH 2 ) m SO 2 F, —CO 2 (CH 2 ) m CH═CH 2 , —C═NR 32 or —C═N + R 33 R 34 ;
R 31 is hydrogen, alkyl C1-10 , alkene C2-12 , aryl or a photocleavable group;
R 32 , R 33 and R 34 , which may be the same or different, are each hydrogen, alkyl C1-10 , alkene C2-12 or aryl;
m is an integer from 1 to 9;
with the proviso that when R 1 together with R 6 forms a ring II in which R 7 is hydrogen or alkyl C 1-10 , X a is —C≡C— and X b is absent, then Y is not —CO 2 R 13 ;
and isomers thereof;
in free or in salt form.

2. The compound according to claim 1 wherein A 1 is CR 3 , A 2 is CR 4 , A 3 is CR 5 ; and
R 2 , R 3 , R 4 , and R 5 are each as defined in claim 1 .

3. The compound according to claim 1 wherein R 2 is a group III:

wherein X a is —C≡C— and X b is —C≡C—; and
A 5 , A 6 , A 7 , A 8 and R 16 are each as defined in claim 1 .

4. The compound according to claim 3 wherein X b is absent and X a is selected from a group consisting of: —C≡C—, —CH═CH—, and —N═CH—.

5. The compound according to claim 3 wherein A 5 is CR 17 , A 6 is CR 18 , A 7 is CR 19 and A 8 is CR 20 ; and
X a , X b , R 16 , R 17 , R 18 , R 19 and R 20 are each as defined in claim 1 .

6. The compound according to claim 3 wherein A 5 is CR 17 , A 6 is CR 18 , A 7 is CR 19 and A 8 is CR 20 ; and
R 17 , R 19 and R 20 are each as defined in claim 1 ;
R 16 together with R 18 forms a ring IV:

wherein A 9 , A 10 , A 11 and Y are each as defined in claim 1 .

7. The compound according to claim 3 wherein R 2 is a group III;

and R 16 is —C≡C—R 23
wherein R 23 is a group V:

in which
A 12 is CR 27 , A 13 is CR 28 , A 14 is CR 29 and A 15 is CR 30 ; and
R 27 , R 28 , R 29 , R 30 and Y are each as defined in claim 1 .

8. The compound according to claim 7 wherein R 16 is —C≡C—R 23 , R 23 is a group V and Y is —CO 2 R 31 , —COH, —CO 2 CH 2 C≡CH, —CN, —SF 5 , —SO 3 H, —SO 2 NH 2 , —SO 2 CF 3 , in which R 31 is hydrogen, alkyl C1-10 , alkene C2-12 , aryl or a photocleavable group.

9. The compound according to claim 7 wherein Y is —CO 2 R 31 in which R 31 is hydrogen, alkyl C1-10 , alkene C2-12 , aryl or a photocleavable group.

10. The compound according to claim 1 wherein R 7 is alkyl C1-10.

11. The compound according to claim 1 wherein R 8 , R 9 , R 10 and R 11 are each hydrogen.

12. The compound according to claim 1 wherein R 8 and R 10 or R 9 and R 11 represent a bond.

13. The compound according to claim 1 wherein R 12 and R 13 are the same or different; R 12 and R 13 may each represent alkyl C1-4.

14. The compound according to claim 1 wherein R 2 is selected from a group consisting of group VI:

wherein R 31 is as defined in claim 1 .

15. The compound of formula I according to claim 1 that is selected from the group consisting of:
(2E)-3-(4-2-[4,4-dimethyl-1-(propyn-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl] ethynylphenyl)prop-2-enoic acid; and
(2E)-3-(4-2-[4,4-dimethyl-1-(propyn-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl] ethynylphenyl)prop-2-enoic acid methyl ester;
and isomers thereof;
in free or in salt form.

16. A composition comprising the compound according to claim 1 in combination with one or more pharmaceutically acceptable excipients; said composition being for use in the generation of reactive oxygen species when said compound is activated by light.

17. The composition according to claim 16 for use in the treatment of one or more of a cancer selected from head and neck tumours, breast cancer, gynaecological tumours, brain tumours, colore

Assignees

• Univ Durham

Inventors

• Whiting Andrew
• Ambler Carrie
• Coles Mark
• Chisholm David

Classifications

• A61K31/435 Primary

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• A61P31/10

  Antimycotics · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61K31/07

  Retinol compounds, e.g. vitamin A (retinoic acids A61K31/203) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title