Cyclosporin derivatives wherein the mebmt sidechain has been cyclized

Patent metadata

Field	Value
Publication number	US-2016200767-A1
Application number	US-201614991009-A
Country	US
Kind code	A1
Filing date	Jan 8, 2016
Priority date	Jan 8, 2015
Publication date	Jul 14, 2016
Grant date	—

Abstract

The present invention relates to cyclosporin analogs that are potent inhibitors of cyclophilin D and have low immunosuppressive activity; processes for preparing them; pharmaceutical compositions containing them; and methods for using these analogs and compositions containing them for the treatment of medical conditions, including but not limited to ischemic conditions, such as ischemia-reperfusion (I/R) injury, including myocardial FR injury, cerebral I/R injury, and ocular or retinal I/R injury.

First claim

What is claimed is:

1 . A compound of Formula I:

wherein:
R 1 is

R 2 is —CH 3 , —CH 2 CH 3 , —CH(CH 3 )(OH), —CH(CH 3 ) 2 or —CH 2 CH 2 CH 3 ;
R 3 is —H, —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 haloalkyl, —SC 1-6 alkyl, —CH 2 OH, —CH 2 OCH 3 ,

R 4 is —CH 3 , —CH 2 CH 3 or —CH 2 CH 2 CH 3 ;
R 5 is —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 2 (OH), —CH(CH 3 )(CH 2 CH 3 ) or —CH 2 CH(R 7 )(CH 2 CH 3 );
R 6 is —CH 3 or —CH 2 OH;
R 7 is —OC 1-6 alkyl;
R 8 is —H or —C 1-6 alkyl;
R 9 is —H, —C 1-6 alkyl or —OH;
R 10 is —H, —C 1-6 alkyl or —OH;
R 11 is —H or —C 1-6 alkyl;
R 12 is —H or —C 1-6 alkyl;
R 13 is —H or —C 1-6 alkyl;
X is O or NR 8 ;
Y is CR 9 R 10 ; CR 11 or C═O;
Z is (CH 2 ) m , CR 12 , NR 13 or O;
W is (CH 2 ) n ;
m is 1, 2 or 3;
n is 0 or 1; and
the dashed line indicates that the bond joining Y and Z is a single or double bond;
provided that:
(a) when the bond joining Y and Z is a single bond, then Y is CR 9 R 10 or C═O, and

Z is (CH 2 ) m , NR 13 or O; and
(b) when the bond joining Y and Z is a double bond, then Y is CR 11 and Z is CR 12 ;

or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 , wherein X is O; Y is CR 9 R 10 ; Z is (CH 2 ) m ; each of R 9 and R 10 is H; m is 1; n is 0; and the bond joining Y and Z is a single bond.

3 . The compound of claim 1 , wherein X is O; Y is CR 9 R 10 ; Z is (CH 2 ) m ; R 10 is H; m is 1; n is 0; and the bond joining Y and Z is a single bond.

4 . The compound of claim 1 , wherein X is O; Y is CR 11 ; Z is CR 12 ; R 10 is H; R 11 is H; R 12 is H; m is 1; and n is 0, and the bond joining Y and Z is a double bond.

5 . The compound of claim 1 , wherein X is O; Y is CR 9 R 10 ; Z is (CH 2 ) m ; each of R 9 and R 10 is H; m is 2 or 3; n is 0; and the bond joining Y and Z is a single bond.

6 . The compound of claim 1 , wherein X is NR 8 ; Y is CR 9 R 10 ; Z is (CH 2 ) m ; each of R 9 and R 10 is H; m is 1; n is 0; and the bond joining Y and Z is a single bond.

7 . The compound of claim 1 , wherein X is O; Y is C═O or CR 9 R 10 ; Z is NR 13 ; each of R 9 and R 10 is H; R 13 is —C 1-6 alkyl; n is 1; and the bond joining Y and Z is a single bond.

8 . The compound of claim 1 , wherein X is O, m is 1 or 2, and n is 0.

9 . The compound of claim 1 , wherein R 1 is:

10 . The compound of claim 1 , wherein R 2 is —CH 3 , —CH 2 CH 3 , —CH(CH 3 )(OH) or —CH(CH 3 ) 2 .

11 . The compound of claim 1 , wherein R 3 is H, —C 1-3 alkyl or —C 1-3 haloalkyl.

12 . The compound of claim 1 , wherein R 4 is —CH 3 ; R 5 is —CH 2 CH(CH 3 ) 2 ; and R 6 is —CH 3 .

13 . The compound of claim 1 , wherein:
R 1 is

R 2 is —CH 3 , —CH 2 CH 3 , —CH(CH 3 )(OH) or —CH(CH 3 ) 2 ;
R 3 is H, —C 1-3 alkyl or —C 1-3 haloalkyl;
R 4 is —CH 3 ;
R 5 is —CH 2 CH(CH 3 ) 2 ;
R 6 is —CH 3 ;
R 8 is —H or —CH 3 ;
R 9 is —H, —CH 3 or —OH;
R 10 is —H;
R 11 is —H;
R 12 is —H;
R 13 —CH 3 ; and
Z is (CH 2 ) m , CR 12 or NR 13 .

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

and pharmaceutically acceptable salts thereof.

15 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

16 . A method of treating an ischemic condition in a subject, the method comprising administering a therapeutically effective amount of a compound of claim 1 to the subject, thereby treating the ischemic condition.

17 . The method of claim 16 , wherein the ischemic condition is an ischemia-reperfusion injury.

18 . The method of claim 17 , wherein the ischemia-reperfusion injury is a myocardial ischemia-reperfusion injury.

19 . The method of claim 18 , wherein the treatment comprises protecting the subject's myocardial cells or myocardial tissue from the myocardial ischemia-reperfusion injury.

20 . The method of claim 16 , wherein the ischemic condition is associated with a myocardial infarct.

21 . The method of claim 17 , wherein the ischemia-reperfusion injury is a cerebral ischemia-reperfusion injury.

22 . The method of claim 21 , wherein the treatment comprises protecting the subject's brain cells or brain tissue from the cerebral ischemia-reperfusion injury.

23 . The method of claim 16 , wherein the ischemic condition is associated with artery obstruction, artery constriction or rapid irregular heartbeat.

24 . The method of claim 17 , wherein the ischemia-reperfusion injury is an ocular ischemia-reperfusion injury.

25 . The method of claim 24 , wherein the treatment comprises protecting the subject's ocular cells or ocular tissue from the ocular ischemia-reperfusion injury.

26 . The method of claim 17 , wherein the ischemia-reperfusion injury is a retinal ischemia-reperfusion injury.

27 . The method of claim 26 , wherein the treatment comprises protecting the subject's retinal cells or retinal tissue from the retinal ischemia-reperfusion injury.

28 . The method of claim 27 , wherein the retinal cells are retinal ganglion cells.

29 . The method of claim 24 , wherein the treatment comprises protecting the subject from optic nerve degeneration.

30 . The method of claim 16 , wherein the ischemic condition is associated with increased intraocular pressure, central retinal vein or artery occlusion, macular degeneration, diabetes or glaucoma.

31 . The method of claim 16 , wherein the subject is a human.

Assignees

• Allergan Inc

Inventors

• Pettit Simon N
• Jones Andrew D
• Frydrych Catherine Simone V
• Thomas Alex J
• Garst Michael E

Classifications

• A61P39/06

  Free radical scavengers or antioxidants · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K7/645 Primary

  Cyclosporins; Related peptides · CPC title