Peri-carbinols

Patent metadata

Field	Value
Publication number	US-9604997-B2
Application number	US-201314653771-A
Country	US
Kind code	B2
Filing date	Dec 19, 2013
Priority date	Dec 20, 2012
Publication date	Mar 28, 2017
Grant date	Mar 28, 2017

Abstract

The present invention is directed to compounds of formula (I):

pharmaceutical compositions, and methods of use for treating, reducing a symptom of or reducing the risk of macular degeneration.

First claim

The invention claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
each D is independently H, NH 2 or A, wherein one D is NH 2 and the other D is H or A;
U, V, Z, Y and X are each independently CH, CA or N, wherein one of U, V, Z, Y and X is N and the other of U, V, Z, Y and X is CH or CA;
each A is independently selected from F, Cl, and Br,
each Q is independently straight chain C 1-6 -alkyl or branched chain C 3-6 -alkyl, wherein the alkyl is optionally substituted with 1-6 F, or
both Q, together with the carbon atom to which they are attached, form a C 3-6 -carbocycle or a saturated heterocycle selected from

wherein “*” denotes the position of the carbon atom to which both Q are attached, wherein the carbocycle or the heterocycle is optionally substituted with one or more R Q , wherein each R Q is independently H, straight chain C 1-6 -alkyl, branched chain C 3-6 -alkyl or halogen; and
n is 0, 1, 2, or 3.

2. The compound of claim 1 , wherein one D is NH 2 and the other D is H, F or Cl.

3. The compound of claim 1 , wherein U is N.

4. The compound of claim 1 , wherein Y is N.

5. The compound of claim 1 , wherein n is 0, 1 or 2.

6. The compound of claim 1 , wherein each A is independently F or Cl.

7. The compound of claim 5 , wherein at least one Q is straight chain C 1-6 -alkyl.

8. The compound of claim 7 , wherein at least one Q is methyl, ethyl or propyl.

9. The compound of claim 8 , wherein each Q is methyl.

10. The compound of claim 1 , wherein at least one Q is straight chain C 1-6 -alkyl substituted with 1-6 F.

11. The compound of claim 10 , wherein at least one Q is methyl, ethyl or propyl substituted with 1-6 F.

12. The compound of claim 11 , wherein at least one Q is CH 2 F, CHF 2 , or CF 3 .

13. The compound of claim 1 , wherein both Q, together with the carbon atom to which they are attached, form a ring selected from

wherein “*” denotes the position of the carbon atom to which both Q are attached.

14. The compound of claim 1 , selected from the group consisting of:

and a pharmaceutically acceptable salt thereof.

15. The compound of claim 14 , wherein n is 0, 1 or 2.

16. The compound of claim 15 , selected from the group consisting of:

and a pharmaceutically acceptable salt thereof.

17. The compound of claim 16 , which is

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17 , wherein each A is independently F or Cl.

19. The compound of claim 18 , wherein each Q is independently selected from straight chain C 1-6 alkyl or branched C 3-6 alkyl.

20. The compound of claim 18 , wherein both Q, together with the carbon atom to which they are attached, form a ring selected from

wherein “*” denotes the position of the carbon atom to which both Q are attached.

21. The compound of claim 17 , selected from the group consisting of:

and a pharmaceutically acceptable salt thereof.

22. The compound of claim 21 , selected from the group consisting of:

and a pharmaceutically acceptable salt thereof.

23. The compound of claim 14 , which is

or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

25. The pharmaceutical composition of claim 24 , wherein the compound is selected from the group consisting of:

and a pharmaceutically acceptable salt thereof.

26. A method of treating macular degeneration or a retinal disease or disorder characterized by accumulation of A2E and/or lipofuscin in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
each D is independently H, NH 2 or A, wherein one D is NH 2 and the other D is H or A;
U, V, Z, Y and X are each independently CH, CA or N, wherein one of U, V, Z, Y and X is N and the other of U, V, Z, Y and X is CH or CA;
each A is independently selected from F, Cl, Br, CF 2 H, CF 3 , R′, OR, COOR, CON(R) 2 , N(R′) 2 , NRCOR, NRCOOR′, NRCON(R) 2 , NRSO 2 R′, SO 2 R′, SO 2 N(R) 2 , unsubstituted phenyl, and phenyl substituted with 1-3 substituents, wherein each substituent is independently selected from F, Cl, CF 2 H, CF 3 , OR and R′, or two such substituents, together with the carbon atoms of the phenyl ring to which they are attached, form a five- or six-membered ring having a structure selected from

wherein “*” denotes the positions of the carbon atoms to which the substituents are attached on the phenyl ring,
alternatively, when attached to adjacent atoms in formula (I), any two A, together with the atoms to which they are attached, form a five- or six-membered ring having a structure selected from

wherein “*” denotes the positions of the atoms to which the two A are attached on formula (I);
each R is independently H, straight C 1-6 -alkyl, branched chain C 3-6 -alkyl or cyclic C 3-6 -alkyl;
each R′ is independently straight C 1-6 -alkyl, branched chain C 3-6 -alkyl or cyclic C 3-6 -alkyl;
each R Q is independently H, straight C 1-6 -alkyl, branched chain C 3-6 -alkyl or halogen;
each Q is independently H, straight C 1-6 -alkyl or branched chain C 3-6 -alkyl, wherein the alkyl is optionally substituted with 1-6 F, or
both Q, together with the carbon atom to which they are attached, form a C 3-6 -carbocycle or a saturated heterocycle selected from

wherein “*” denotes the position of the carbon atom to which both Q are attached, wherein the carbocycle or the heterocycle is optionally substituted with one or more R Q ; and
n is 0, 1, 2, or 3.

27. The method of claim 26 , wherein the macular

Assignees

• Aldexa Therapeutics Inc
• Aldeyra Therapeutics Inc

Inventors

• Jordan Thomas A
• Chabala John Clifford
• Ling Ke-Qing
• Kinney William A

Classifications

• A61P27/00

  Drugs for disorders of the senses · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• C07D217/22

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring · CPC title

• C07D215/38 Primary

  Nitrogen atoms (nitro radicals C07D215/18) · CPC title