Cyclosporin derivatives wherein the MeBmt sidechain has been cyclized

Patent metadata

Field	Value
Publication number	US-9914755-B2
Application number	US-201614991009-A
Country	US
Kind code	B2
Filing date	Jan 8, 2016
Priority date	Jan 8, 2015
Publication date	Mar 13, 2018
Grant date	Mar 13, 2018

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 9 is —H;
R 10 is —H;
X is O;
Y is CR 9 R 10 ;
Z is (CH 2 ) m ;
W is (CH 2 ) n ;
m is 1;
n is 0; and
the dashed line indicates that the bond joining Y and Z is a single bond;

or a pharmaceutically acceptable salt thereof.

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

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

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

5. 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 .

6. 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 ; and
R 6 is —CH 3 .

7. A compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or 7 , and a pharmaceutically acceptable carrier.

Assignees

• Allergan Inc

Inventors

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

Classifications

• 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

• A61P39/06

  Free radical scavengers or antioxidants · CPC title