Cyclosporins for the treatment of immune disorders
View Patent ↗The present invention relates to a cyclosporin analog of the following formula (I) or its pro-drug or pharmaceutically acceptable salt: In formula I, the formula for residue A is: where X and Y are defined according to the claimed invention the present invention also relates to pharmaceutical compositions comprising pro-drugs or pharmaceutically acceptable salts of the compounds of the present invention and the use thereof for treating an inflammatory or immune disorder in a subject need of such treatment.
1. A cyclosporin analog of formula (1), or pharmaceutically acceptable salt:
wherein,
A is of the formula:
wherein
X is absent, —C 1 ,-C 6 alkyl-, or —C 3 -C 6 cycloalkyl-
Y is selected from the group consisting of:
(i) C(O)—O—R 1 , where R 1 -is C 1 -C 6 alkyl substituted with halogen, heterocyclic, aryl, C 1 -C 6 -alkoxy, C 1 -C 6 alkylthio, halogen-substituted C 1 -C 6 alkoxy, or halogen-substituted C 1 -C 6 alkylthio;
(ii) C(O)—S—R 1 ;
(iii) C(O)—OCH 2 —OC(O)R 2 , where R 2 is C 1 -C 6 alkyl optionally substituted with halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, heterocyclic or aryl;
(iv) C(S)—O—R 1 ; and
(v) C(S)—S—R 1 ;
B is -αAbu-, -Val-, -Thr- or -Nva-; and
U is —(D)Ala-, -(D)Ser-, —[O-(2-hydroxyethyl)(D)Ser]—, —[O-acyl(D)Ser]— or—[O-(2-acyloxyethyl)(D)Ser]-.
2. A cyclosporin analog according to claim 1 or pharmaceutically acceptable salt, wherein in formula (I), B is -αAbu-, and U is -(D)Ala-.
3. A cyclosporin analog according to claim 1 or pharmaceutically acceptable salt, wherein for formula I, X is absent.
4. A cyclosporin analog according to claim 1 or pharmaceutically acceptable salt, selected from the group consisting of:
Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCH 2 Ph;
Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCH 2 F;
Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCHF 2 ;
Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCF 3 ;
Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCH 2 CF 3 ;
Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCH 2 Cl;
Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCH 2 OCH 3 ;
Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCH 2 OCH 2 CH 2 O CH 3 ;
Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—C(=O)SCH 2 Ph; and
Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOFmoc.
5. A pharmaceutical composition, said composition comprising at least one cyclosporin analog of claim 1 , said cyclosporin analog being present alone or in combination with a pharmaceutically acceptable carrier or excipient.
6. A method of treating an inflammatory or immune disorder in a subject while eliminating or reducing the toxicity associated with the administration of cyclosporin A, comprising the step of systemically administering to said subject a pharmaceutical composition of claim 5 .
7. The method of claim 6 , wherein said inflammatory or immune disorder is organ transplant rejection.
8. The method of claim 6 , wherein said inflammatory or immune disorder is selected from the group consisting of: rheumatoid arthritis, inflammatory bowel disease, psoriasis, atopic dermatitis, asthma, allergic rhinitis, and chronic obstructive pulmonary disease.
9. The method of claim 6 , wherein said systemically administering is accomplished orally, intraperitoneally, intravenously, intramuscularly, intrasternally, subcutaneously, or through intravenous injection or infusion.