S1PR2 antagonists and uses therefor

Patent metadata

Field	Value
Publication number	US-10858358-B2
Application number	US-201916586498-A
Country	US
Kind code	B2
Filing date	Sep 27, 2019
Priority date	Jun 1, 2015
Publication date	Dec 8, 2020
Grant date	Dec 8, 2020

Abstract

Methods and compositions are provided for the treatment of familial exudative vitreoretinopathy (FEVR) through the administration of a therapeutically effective amount of a sphingosine-1-phosphate receptor type 2 (S1PR2) antagonist. Also provided herein are (Z)-2-cyano-1-(2,6-dichloropyridin-4-yl)-3-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)guanidine and analogs thereof, and their use in treating retinopathies and diseases characterized by insufficient angiogenesis.

First claim

The invention claimed is:

1. A compound of formula (XII):

or a pharmaceutically acceptable salt thereof,
wherein:
G 1 is CR 12 or NR 13 , wherein R 12 and R 13 are each independently selected from the group consisting of H, C 1 -C 4 alkyl, and benzyl;
R c and R d are independently selected from the group consisting of H, C 1 -C 4 alkyl, and benzyl; or R c and R d are joined to form a 5- or 6-membered heterocycloalkyl ring; and,
the cyano group is in the (Z) or (E) configuration.

2. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein:
G 1 is CR 12 and R 12 is H; and,
R d is H.

3. The compound of claim 2 , selected from the group consisting of:
(E)-2-cyano-3-(2,6-dichloropyridin-4-yl)-1-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)-1-methylguanidine;
(E)-2-cyano-3-(2,6-dichloropyridin-4-yl)-1-ethyl-1-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)guanidine;
(E)-2-cyano-3-(2,6-dichloropyridin-4-yl)-1-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)-1-propylguanidine;
(E)-1-butyl-2-cyano-3-(2,6-dichloropyridin-4-yl)-1-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)guanidine;
(E)-2-cyano-3-(2,6-dichloropyridin-4-yl)-1-isopropyl-1-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)guanidine;
(E)-1-benzyl-2-cyano-3-(2,6-dichloropyridin-4-yl)-1-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)guanidine; and,
a diastereomer of the foregoing, wherein the cyano group is in the (Z) form; or the pharmaceutically acceptable salt of any of the foregoing.

4. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein:
G 1 is CR 12 and R 12 is H; and,
R c is H.

5. The compound of claim 4 , selected from the group consisting of:
(Z)-2-cyano-1-(2,6-dichloropyridin-4-yl)-3-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)-1-methylguanidine;
(Z)-2-cyano-1-(2,6-dichloropyridin-4-yl)-1-ethyl-3-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)guanidine;
(Z)-2-cyano-1-(2,6-dichloropyridin-4-yl)-3-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)-1-propylguanidine;
(Z)-1-butyl-2-cyano-1-(2,6-dichloropyridin-4-yl)-3-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)guanidine;
(Z)-2-cyano-1-(2,6-dichloropyridin-4-yl)-1-isopropyl-3-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)guanidine;
(Z)-1-benzyl-2-cyano-1-(2,6-dichloropyridin-4-yl)-3-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)guanidine; and,
a diastereomer of the foregoing, wherein the cyano group is in the (E) form; or the pharmaceutically acceptable salt of any of the foregoing.

6. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein:
G 1 is CR 12 ; and,
R c and R d are each H.

7. The compound of claim 6 , selected from the group consisting of:
(Z)-2-cyano-1-(2,6-dichloropyridin-4-yl)-3-(1-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)ethyl)guanidine;
(Z)-2-cyano-1-(2,6-dichloropyridin-4-yl)-3-(1-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)propyl)guanidine;
(Z)-2-cyano-1-(2,6-dichloropyridin-4-yl)-3-(1-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-methylpropyl)guanidine;
(Z)-2-cyano-1-(2,6-dichloropyridin-4-yl)-3-(1-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-phenylethyl)guanidine; and,
a diastereomer of the foregoing, wherein the cyano group is in the (E) form; or the pharmaceutically acceptable salt of any of the foregoing.

8. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein:
G 1 is NR 13 ; and,
R c and R d are each H.

9. The compound of claim 8 , selected from the group consisting of:
(E)-N′-cyano-N-(2,6-dichloropyridin-4-yl)-2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)hydrazinecarboximidamide;
(E)-N′-cyano-N-(2,6-dichloropyridin-4-yl)-2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-methylhydrazinecarboximidamide;
(E)-N′-cyano-N-(2,6-dichloropyridin-4-yl)-2-ethyl-2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)hydrazinecarboximidamide;
(E)-N′-cyano-N-(2,6-dichloropyridin-4-yl)-2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-propylhydrazinecarboximidamide;
(E)-2-butyl-N′-cyano-N-(2,6-dichloropyridin-4-yl)-2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)hydrazinecarboximidamide;
(E)-N′-cyano-N-(2,6-dichloropyridin-4-yl)-2-isopropyl-2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)hydrazinecarboximidamide;
(E)-2-b enzyl-N′-cyano-N-(2,6-dichloropyridin-4-yl)-2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)hydrazinecarboximidamide; and,
a diastereomer of the foregoing, wherein the cyano group is in the (Z) form; or the pharmaceutically acceptable salt of any of the foregoing.

10. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein:
G 1 is CR 12 and R 12 is H.

11. The compound of claim 10 , selected from the group consisting of:
(Z)-2-cyano-1-(2,6-dichloropyridin-4-yl)-3-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)-1,3-dimethylguanidine;
(Z)-2-cyano-1-(2,6-dichloropyridin-4-yl)-3-isopropyl-3-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)-1-methylguanidine;
(Z)-2-cyano-1-(2,6-dichloropyridin-4-yl)-1-isopropyl-3-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)-3-methylguanidine;
(Z)-1-benzyl-2-cyano-3-(2,6-dichloropyridin-4-yl)-1-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)-3-methylguanidine;
(Z)-1-benzyl-2-cyano-1-(2,6-dichloropyridin-4-yl)-3-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)-3-methylguanidine; and,
a diastereomer of the foregoing, wherein the cyano group is in the (E) form; or the pharmaceutically acceptable salt of any of the foregoing.

12. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein:
G 1 is CR 12 and CR 12 is H; and,
R c and R d are joined to form a 5- or 6-membered heterocycloalkyl ring.

13. The compound of claim 12 , selected from the group consisting of:
(Z)—N-(1-(2,6-dichloropyridin-4-yl)-3-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)tetrahydropyrimidin-2(1H)-ylidene)cyanamide;
(Z)—N-(1-(2,6-dichloropyridin-4-yl)-3-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)imidazolidin-2-ylidene)cyanamide; and,
a diastereomer of the foregoing, wherein the cyano group is in the (E) form; or the pharmaceutically acceptable salt of any of the foregoing.

14. A method of treating an eye condition in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of the compound of claim 1 , or a pharmaceutically-acceptable salt thereof.

15. The method of claim 14 , wherein the eye condition is caused by a primary defect in retinal vascularization followed by secondary aberrant neovascularization that can result in retina detachment.

16. The method of claim 14 , wherein the eye condition is a retinopathy.

17. The method of claim 16 , wherein the retinopathy is selected from the group consisting of diabetic retinopathy, macular degeneration, hypertensive retinopathy, radiation retinopathy, solar retinopathy, retinopathy of prematurity (ROP), Norrie disease (ND), familial exudative vitreoretinopathy (FEVR), Coats' disease, sickle cell retinopathy, and re

Assignees

• Univ Dalhousie

Inventors

• Mcmaster Christopher
• Simms Gordon

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07C317/48

  the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups · 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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title