Cyclosporins Modified on the MeBmt Sidechain by Heterocyclic Rings

摘要

The present invention relates to novel cyclosporin analogs, processes for preparing them, pharmaceutical compositions containing them, and methods for using these analogs and the compositions containing them for the treatment of medical conditions, including but not limited to ocular conditions such as dry eye.

主权项

1. A compound of Formula I: wherein: R1 is Het1,
wherein Het1 is a heterocyclyl substituted with 0, 1, 2, 3 or 4 Ra;wherein each Ra is independently selected from the group consisting of halogen, —C1-6 alkyl, —OC1-6 alkyl and —(CH2)nRb;wherein each Rb is independently selected from Het2, —C1-6 haloalkyl, —OH, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)2 wherein each C1-6 alkyl is the same or different; andwherein each Het2 is independently a heterocyclyl optionally substituted with one or more halogen, —C1-6 alkyl, —C1-6 haloalkyl, —(CH2)1-6OH, —(CH2)1-6NH2, —(CH2)1-6NH(C1-6 alkyl) or —(CH2)1-6N(C1-6 alkyl)2 wherein each C1-6 alkyl is the same or different; R2 is —CH3, —CH2CH3, —CH(CH3)2, —CH2CH2CH3 or —CH(CH3)(OH); R3 is —H, —C1-6alkyl, —OC1-6alkyl, —SC1-6alkyl, —CH2OH, —CH2OCH3, R4 is —CH3 or —CH2CH3; R5 is —CH(CH3)2, —CH2CH(CH3)2, —CH2C(CH3)2(OH), —CH(CH3)(CH2CH3) or —CH2CH(Rc)(CH2CH3), wherein Rc is OC1-6 alkyl; R6 is —CH3 or —CH2OH; L is absent or —O—(CH2)p—, wherein the oxygen atom is directly joined to the carbon atom of the (CH2)m; m is 1, 2, 3 or 4; n is 1, 2 or 3; and p is 0 or 1; or a pharmaceutically acceptable salt thereof.