Cyclosporin analogs

Patent metadata

Field	Value
Publication number	US-10065992-B2
Application number	US-201615290171-A
Country	US
Kind code	B2
Filing date	Oct 11, 2016
Priority date	Oct 12, 2010
Publication date	Sep 4, 2018
Grant date	Sep 4, 2018

Abstract

Disclosed herein are novel analogs of cyclosporin, pharmaceutical compositions containing them, and methods for their use in the treatment of dry eye and other conditions.

First claim

We claim:

1. A compound of Formula (I):

wherein:
A is —CH═CHR, —CH═CH—CH═CHR or —CH 2 CH 2 R,
wherein R is —CH 3 ; —CH 2 SH; —CH 2 -carboxyl; carboxyl;

wherein R 10 is C 1 -C 6 alkyl; or

wherein R 11 is C 1 -C 6 alkyl;
B is —CH 2 CH 3 , 1-hydroxyethyl, isopropyl, or n-propyl;
C is isobutyl, 2-hydroxyisobutyl, or 1-methylpropyl;
D is —CH 3 or —CH 2 OH;
R 1 and R 2 , which are identical or different, each represents hydrogen or C 1 -C 4 alkyl, or together represent C 3 -C 7 cycloalkyl;
X is S or —S(O) n , wherein n is 1 or 2;
R 3 is straight or branched C 1 -C 6 alkyl; straight or branched C 2 -C 6 alkenyl; straight or branched C 2 -C 6 alkynyl;
wherein R 3 is substituted with one or more groups, which are identical or different, selected from the group consisting of amino; monoalkylamino; dialkylamino; —NHC(═NH)NH 2 ; urea; imidazolyl; and saturated or partially unsaturated 5- or 6-member heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of N, O and S, and containing at least one N, and wherein said heterocyclyl is optionally substituted by one or more C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 selected from the group consisting of:
[(S)-2-diethylaminoethylthiomethyl-Sar] 3 cyclosporin A;
[(S)-2-aminoethylthiomethyl-Sar] 3 cyclosporin A;
[(S)-2-dimethylaminoethylthiomethyl-Sar] 3 cyclosporin A;
[(S)-(4-methylpiperidinyl)thiomethyl-Sar] 3 cyclosporin A;
[(S)-2-(morpholino)ethylthiomethyl-Sar] 3 cyclosporin A;
[(S)-2-isopropylaminoethylthiomethyl-Sar] 3 cyclosporin A;
[(S)-2-guanidinoethylthiomethyl-Sar] 3 cyclosporin A;
[(S)-2-diethylaminoethylthiomethyl-Sar] 3 cyclosporin D;
[(S)-2-(N-imidazolyl)ethylthiomethyl-Sar] 3 cyclosporin A;
[(S)-2-diethylamino-1,1-dimethyl-ethylthiomethyl-Sar] 3 cyclosporin A;
[(S)-2-morpholino-1,1-dimethyl-ethylthiomethyl-Sar] 3 cyclosporin A;
[(S)-3-diethylaminopropylthiomethyl-Sar] 3 cyclosporin A;
[(S)-3-(morpholino)-propylthiomethyl-Sar] 3 cyclosporin A;
[(S)-2-diethylaminoethyl-1-sulfinylmethyl-Sar] 3 cyclosporin A;
[dihydro-MeBmt] 1 [(S)-2-diethylaminoethyl-1-sulfinylmethyl-Sar] 3 cyclosporin A;
[(S)-3-Diethylaminopropyl-1-sulfonylmethyl-Sar] 3 cyclosporin A;
[(S)-3-(Morpholino)propyl-1-sulfonylmethyl-Sar] 3 cyclosporin A;
[(S)-(2-Diethylamino-1,1-dimethyl)-ethyl-1-sulfonylmethyl-Sar] 3 cyclosporin A;
and
[(S)-(2-Morpholino-1,1-dimethyl)-ethyl-1-sulfonylmethyl-Sar] 3 cyclosporin A;
and pharmaceutically acceptable salts thereof.

3. The compound according to claim 1 , wherein A is —CH═CHCH 3 , B is —CH 2 CH 3 , C is isobutyl, and D is —CH 3 .

4. The compound according to claim 1 , wherein A is —CH═CHCH 3 , B is 1-hydroxyethyl, C is isobutyl, and D is —CH 3 .

5. The compound according to claim 1 , wherein A is —CH═CHCH 3 , B is isopropyl, C is isobutyl, and D is —CH 3 .

6. The compound according to claim 1 , wherein A is —CH═CHCH 3 , B is n-propyl, C is isobutyl, and D is —CH 3 .

7. The compound according to claim 1 , wherein A is —CH═CHCH 3 , B is —CH 2 CH 3 , C is 1-methylpropyl, and D is —CH 3 .

8. The compound according to claim 1 , wherein A is —CH═CHCH 3 , B is —CH 2 CH 3 , C is isobutyl, and D is —CH 2 OH.

9. The compound according to claim 1 , wherein A is —CH═CHCH 3 , B is —CH 2 CH 3 , C is 2-hydroxyisobutyl, and D is —CH 3 .

10. The compound of claim 1 , wherein R 3 is straight or branched C 1 -C 6 alkyl substituted with amino; monoalkylamino; dialkylamino; imidazolyl; or heterocyclyl, wherein said heterocyclyl is selected from the group consisting of morpholinyl, piperidinyl, pyrrolidinyl, and pyrazolinyl, each of which is optionally substituted with one or more C 1 -C 6 alkyl.

11. A pharmaceutical composition comprising at least one compound of claim 1 , the compound being present alone or in combination with one or more pharmaceutically acceptable excipients.

12. The pharmaceutical composition according to claim 11 , wherein the concentration of the compound in the composition is about 0.01 to about 0.05 weight percent.

13. A method for treating dry eye associated with keratoconjunctivitis sicca in a mammal in need thereof, the method comprising administering to an eye of the mammal an effective amount of [(S)-2-diethylaminoethylthiomethyl-Sar] 3 cyclosporin A, or a pharmaceutically acceptable salt thereof.

14. The method according to claim 13 , wherein the mammal is a human.

Assignees

• Allergan Inc

Inventors

• Frydrych Catherine Simone Victoire
• Carling William Robert
• Garst Michael E
• Stern Michael E
• Schaumburg Christopher S

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P31/22

  for herpes viruses · CPC title

• A61P27/14

  Decongestants or antiallergics · CPC title

• A61P27/04

  Artificial tears; Irrigation solutions · CPC title