Synthetic retinoids (in cell modulation)

Patent metadata

Field	Value
Publication number	US-11833203-B2
Application number	US-201716323924-A
Country	US
Kind code	B2
Filing date	Aug 9, 2017
Priority date	Aug 9, 2016
Publication date	Dec 5, 2023
Grant date	Dec 5, 2023

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 method of treating a patient with photodynamic therapy (PDT), the method comprising the administration of a highly conjugated retinoid compound that generates reactive oxygen species when said compound is activated by light.

2. The method according to claim 1 wherein the highly conjugated retinoid compound possesses a retinoid structure that includes at least six conjugated double or triple bonds.

3. The method according to claim 2 wherein the highly conjugated retinoid compound is 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 ;
A 4 is N or CR 6 ;
R 3 , R 4 , R 5 and R 6 , 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 1 is —NR 7a R 7b or together with R 6 forms a ring II:

R 7 and R 7a are each hydrogen, propynyl, —(CH 2 ) n C≡CH, —(CH 2 ) n SH, —(CH 2 )SO 2 F or —(CH 2 ) n C═CH 2 , alkyl C1-10 , said alkyl being optionally substituted by aryl or heteroaryl;
R 7b is hydrogen, propynyl, 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;
and isomers thereof;
in free or in salt form.

4. The method according to claim 3 wherein A 1 is CR 3 , A 2 is CR 4 , A 3 is CR 5 and A 4 is CR 6 ; and
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each as defined in claim 3 .

5. The method according to claim 3 wherein A 1 , A 2 , A 3 , A 4 and R 2 are each as defined in claim 3 ; and
R 1 together with R 6 forms a ring II:

wherein R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each as defined in claim 3 .

6. The method according to claim 5 wherein A 1 is CR 3 , A 2 is CR 4 , A 3 is CR 5 and A 4 is CR 6 .

7. The method according to claim 3 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 3 .

8. The method 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—.

9. The method according to claim 3 wherein A 5 is CR 17 , A 6 is CR 18 ,
A 7 is CR 19 and A 18 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 3 .

10. The method 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 3 ;
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 3 .

11. The method 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 3 .

12. The method according to claim 11 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.

13. The method according to claim 11 wherein Y is —CO 2 R 31 in which R 31 is hydrogen, alkyl C1-10 , alkene C2-12 , aryl or a photocleavable group.

14. The method according to claim 3 wherein R 7 or R 7a is alkyl C1-10.

15. The method according to claim 3 wherein R 8 , R 9 , R 10 and R 11 are each hydrogen.

16. The method according to claim 3 wherein R 8 and R 10 or R 9 and R 11 represent a bond.

17. The method according to claim 3 wherein R 12 and R 13 each represent alkyl C1-4.

18. The method according to claim 3 wherein R 2 is selected from a group consisting of: group VI:

Assignees

• Univ Durham

Inventors

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

Classifications

• A61K41/0057 Primary

  Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent · CPC title

• A61K31/07

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

• A61K31/435 Primary

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

• A61K31/47

  Quinolines; Isoquinolines · CPC title

• A61K47/551

  one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid · CPC title