Synthetic retinoids for use in RAR activation

Patent metadata

Field	Value
Publication number	US-12344587-B2
Application number	US-202017435939-A
Country	US
Kind code	B2
Filing date	Mar 11, 2020
Priority date	Mar 11, 2019
Publication date	Jul 1, 2025
Grant date	Jul 1, 2025

Abstract

The present invention relates to compounds of formula I: in which A 1 -A 7 and R 1 to R 5 are defined herein, for use in the treatment of a condition or disease which is alleviated by the activation of retinoic acid receptors (RAR). The invention also relates to pharmaceutical compounds comprising such compounds, and related methods of treatment. In an aspect, the invention relates to a method of screening compounds for therapeutic potential in the treatment of a condition or disease which is alleviated by the activation of retinoic acid receptors (RAR). Aspects of the invention relate to novel compounds of formula I in which at least one of A 1 to A 3 is N or at least one of A 4 is CR 12 or A 5 is CR 13 in which R 12 /R 13 is halogen.

First claim

The invention claimed is:

1. A compound of formula I:

in which:
A 1 is Nor CR 6 ;
A 2 is N or CR 7 ;
A 3 is N or CR 8 ;
R 6 and R 8 , are each independently hydrogen, C 1 -C 10 alkyl, F, Br or Cl;
R 9 is independently hydrogen, C 1 -C 10 alkyl, F, Br, Cl or —OCR 9 in which R 9 is H or C 3 -C 6 alkyl;
R 1 to R 4 are each independently C 1 -C 10 alkyl, or R 1 and R 2 and/or R 3 and R 4 join to form a 3-membered ring;
A 3 is N or CR 12 ;
A 5 is N or CR 13 ;
A 6 is N or CR 14 ;
A 7 is N or CR 15 ;
each R 13 to R 15 is independently H, halogen or haloalkyl C 1 -C 10 , and
R 5 is —C(═O)R 16 or —C(═O)OR 16 in which R 16 is H or C 1-10 alkyl;
with the proviso that at least one of A 1 to A 3 is N;
in free or in salt form.

2. The compound as claimed in claim 1 , wherein A 1 and A 3 are N.

3. The compound as claimed in claim 1 , wherein A 2 is CR 7 .

4. The compound as claimed in claim 3 , R 7 is hydrogen.

5. The compound as claimed in claim 1 , wherein R 5 is —COOH.

6. The compound as claimed in claim 1 , wherein at least one of A 4 , A 5 or A 6 is CF.

7. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

8. The compound according to claim 7 , wherein the compound is

9. The compound of formula I as defined in claim 1 , in a manufacture of a medicament for use in the treatment of a disease or condition which is alleviated by the activation of RAR.

10. A method of treatment of a patient with a disease or condition which is alleviated by the activation of RAR, the method comprising administering to a patient a therapeutically effective amount of the compound of formula I, wherein formula I is as defined in claim 1 .

11. A pharmaceutical composition comprising the compound of formula I as defined in claim 1 , optionally in conjunction with one or more pharmaceutically acceptable excipients, diluents or carriers, for use in the treatment of a disease or condition which is alleviated by the activation of RAR.

12. A method of screening the compounds as claimed in claim 1 for therapeutic potential in the treatment of conditions or diseases which are alleviated by the activation of RAR, the method comprising:
performing an assay to determine the efficacy (E max ) of the compound in activating a RAR as an indicator of genomic activity;
performing an assay to determine the efficacy (E max ) of the compound as an indicator of non-genomic activity;
for each assay, comparing the E max to a baseline value; and
selecting the compounds which has an E max above the baseline value in both assays for further investigation.

13. The method as claimed in claim 12 , wherein the assay to determine the efficacy (E max ) of the compound as an indicator of non-genomic activity is a kinase phosphorylation assay.

14. The method as claimed in claim 13 , wherein the kinase phosphorylation assay is an ERK1/2 phosphorylation assay.

Assignees

• Univ Durham

Inventors

• Whiting Andrew
• Chisholm David
• Greig Iain
• Khatib Thabat
• Mccaffery Peter

Classifications

• C07C2602/10

  the other ring being six-membered, e.g. tetraline · CPC title

• A61P19/00

  Drugs for skeletal disorders · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A61K31/4965

  Non-condensed pyrazines · CPC title