US2004266669A1PendingUtilityA1
Cyclosporin derivatives for the treatment of immune disorders
Priority: Jun 20, 2003Filed: Jun 20, 2003Published: Dec 30, 2004
Est. expiryJun 20, 2023(expired)· nominal 20-yr term from priority
A61P 43/00A61K 38/13C07K 7/645
50
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Claims
Abstract
The present invention relates to a cyclosporin analog of the following formula (I) or a pro-drug or pharmaceutically acceptable salt thereof: wherein A is of the formula: where Q, W, X, Y, and Z are defined herein. In a second embodiment, the present invention relates to pharmaceutical compositions comprising pro-drugs or pharmaceutically acceptable salts of the compounds of the present invention and the use thereof for treating autoimmune diseases or for the prevention of organ transplantation rejection in a subject. In a third embodiment, the present invention relates to processes for the production of novel cyclosporin analogs of the present invention.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A cyclosporin analog of formula I or a pro-drug or a pharmaceutically acceptable salt thereof:
and
A is of the formula:
wherein:
Q is
where
i) X is selected from hydrogen, halogen, C 1 -C 6 alkyl, or aryl;
ii) one of Y and Z is selected from: hydrogen, deuterium, halogen, or methyl and the other is independently selected from:
a) halogen;
b) R 1 , where R 1 is selected from:
1) hydrogen;
2) deuterium;
3) C 1 -C 6 alkyl, optionally substituted with halogen, TMS, aryl, heterocycloalkyl, or heteroaryl;
4) C 2 -C 6 alkenyl, optionally substituted with halogen, TMS, aryl, heterocycloalkyl, or heteroaryl;
5) C 2 -C 6 alkynyl, optionally substituted with halogen, TMS, aryl, heterocycloalkyl, or heteroaryl;
6) C 3 -C 12 cycloalkyl;
7) substituted C 3 -C 12 cycloalkyl;
8) aryl;
9) substituted aryl;
10)heterocycloalkyl;
11)substituted heterocycloalkyl;
12)heteroaryl; or
13)substituted heteroaryl;
c) —C(O)OR 1 , where R 1 is as previously defined;
d) —C(O)OCH 2 —V—R 1 , where R 1 is as previously defined and V is —O— or —S—;
e) —C(O)N(R 3 )(R 4 ), where R 3 and R 4 are independently selected from R 1 as previously defined;
f) —C(O)SR 1 , where R 1 is as previously defined;
g) —C(O)OCH 2 OC(O)R 1 , where R 1 is as previously defined;
h) —C(S)OR 1 , where R 1 is as previously defined;
i) —C(S)SR 1 , where R 1 is as previously defined;
j) R 2 , where R 2 is selected from:
1) C 1 -C 6 alkyl-M-R 1 , where R 1 is as previously defined and M is absent or selected from:
i. —NH—;
ii. —N(CH 3 )—;
iii. —S—;
iv. —S(O) n —, where n=0, 1, or 2; or
v. —O—;
2) C 2 -C 6 alkenyl-M-R 1 , where R 1 and M are as previously defined; or
3) C 2 -C 6 alkynyl-M-R 1 , where R 1 and M are as previously defined;
k) Or in the alternative, Y and Z are taken together with the carbon atom to which they are attached to form a C 3 -C 12 cycloalkyl moiety; and
iii) G is independently selected from halogen, TMS, R 1 or R 2 as previously defined;
B is selected from:
i) -αAbu-;
ii) -Val-;
iii) -Thr-; or
iv) -Nva-;
U is selected from:
i) -(D)Ala-;
ii) -(D)Ser-;
iii) —[O-(2-hydroxyethyl)(D)Ser]-;
iv) —[O-(acyl)(D)Ser]-; or
v) —[O-(2-acyloxyethyl)(D)Ser]-; and
W is selected from hydrogen or a hydroxy protecting group.
2 . A compound formula I according to claim 1 , wherein A is of the formula A1:
where W, X, Y, and Z are as previously defined.
3 . A compound of formula I according to claim 1 , wherein A is of the formula A2:
where X, Y, and Z are as previously defined.
4 . A compound of formula I according to claim 1 , wherein A is of the formula A3:
where Y and Z are as previously defined.
5 . A compound of formula I according to claim 1 , wherein A is of the formula A4:
where W and G are as previously defined.
6 . A compound of formula I according to claim 1 , wherein A is of the formula A5:
where G is as previously defined.
7 . A compound of formula I, according to claim 1 , selected from:
Example 1. A compound of formula I, wherin A is of the formula (1-2) and W is Ac; Example 2. A compound of formula I, wherein Q is W is Ac and X═Y=Z=hydrogen; Example 3. A compound of formula I, wherein Q is W is H and X═Y=Z=hydrogen; Example 4. A compound of formula I, wherein Q is Y is CH 3 , and W═X=Z=hydrogen; Example 5. A compound of formula I, wherein Q is Y=Z=CH 3 , and W═X=hydrogen; Example 6. A compound of formula I, wherein Q is Y is —(CH 2 ) 3 CH 3 , and W═X=Z=hydrogen; Example 7. A compound of formula I, wherein Q is Y is —(CH 2 ) 2 Br, and W═X=Z=hydrogen; Example 8. A compound of formula I, wherein Q is Y is ortho-Me-phenyl, and W═X=Z=hydrogen; Example 9. A compound of formula I, wherein Q is Y is ortho-Br-phenyl, and W═X=Z=hydrogen; Example 10. A compound of formula I, wherein Q is Y is —CO 2 Me, and W═X=Z=hydrogen; Example 11. A compound of formula I, wherein Q is Y is meta-CHO-phenyl, and W═X=Z=hydrogen; Example 12. A compound of formula I, wherein Q is Y is Et, and W═X=Z=hydrogen; Example 13. A compound of formula I, wherein Q is Y is —CH═CHCH 2 TMS, and W═X=Z=hydrogen; Example 14. A compound of formula I, wherein Q is G is H, and W is H; Example 15. A compound of formula I, wherein Q is Y is propyl, and W═X=Z=hydrogen; Example 16. A compound of formula I, wherein Q is Y is cyclopropyl, and W═X=Z=hydrogen; Example 17. A compound of formula I, wherein Q is Y is —CH═CHCH 3 , and W═X=Z=hydrogen; Example 18. A compound of formula I, wherein Q is X═Y═CH 3 , and W=Z=hydrogen; Example 19. A compound of formula I, wherein Q is W═X═Y=hydrogen, and Z=CH 3 ; Example 20. A compound of formula I, wherein Q is Y is p-bromophenyl, and W═X=Z=hydrogen; Example 21. A compound of formula I, wherein Q is W═X═Y=hydrogen, and Z=—CH 2 CH═CH 2 ; Example 22. A compound of formula I, wherein Q is W═X═Y=hydrogen, and Z is ethyl; Example 23. A compound of formula I, wherein Q is W═X═Y=hydrogen, and Z=—CH═CHCH 3 ; Example 24. A compound of formula I, wherein Q is W═X═Y=hydrogen, and Z=—CH 2 OCH 3 ; Example 25. A compound of formula I, wherein Q is G=—CH═CHCH 3 and W=hydrogen; Example 26. A compound of formula I, wherein Q is G=propyl and W=hydrogen; or Example 27. A compound of formula I, wherein Q is G=—CH 3 and W=hydrogen.
8 . A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula (I) in claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.
9 . A method of treating organ transplantation rejection in a subject, which comprises administering to said subject a therapeutically effective amount of the pharmaceutical composition of claim 8 .
10 . A method of treating an immune disorder in a subject, which comprises administering to said subject a therapeutically effective amount of the pharmaceutical composition of claim 1 .
11 . The method of claim 10 , wherein said immune disorder is selected from the group consisting of: rheumatoid arthritis, inflammatory bowel disease, psoriasis, asthma, atopic dermatitis, allergic rhinitis, and chronic obstructive pulmonary disease.
12 . A method of treating an immune disorder in a subject, which comprises topically administering to said subject a therapeutically effective amount of the pharmaceutical composition of claim 1 .
13 . The method of claim 12 , wherein said inflammatory or immune disorder is selected from the group consisting of psoriasis and eczema.
14 . The method of claim 12 , wherein said topically administering is achieved via inhalation.
15 . The method of claim 14 , wherein said inflammatory or immune disorder is an obstructive airways disease.
16 . The method of claim 15 , wherein said airways disease is selected from the group consisting of asthma, allergic rhinitis, bronchitis, cystic fibrosis, and chronic obstructive pulmonary disease.
17 . The method of claim 16 , wherein said chronic obstructive pulmonary disease is emphysema or chronic bronchitis.
18 . A process for the preparation of a compound of formula I, wherein Q is z
wherein X, Y, and Z are as defined in claim 1 , comprising
i) reacting cyclosporin A with a reagent capable of oxidative cleavage to form a compound of formula I, wherein A is represented by the formula:
where W is as defined in claim 1;
ii) reacting a compound formed in step i with a Grignard reagent of formula
where X, Y, and Z are as defined in claim 1 to form a compound of formula I, wherein A is represented by the formula:
wherein W, X, Y, and Z are as defined in claim 1;
iii) reacting a compound formed in step ii with an with an electrophile, such as, but not limited to, mesyl chloride, chloroformate, or triflate chloride to form a compound of formula I, wherein A is represented by the formula:
wherein EWG is an electron withdrawing group and W, X, Y, and Z are as defined in claim 1; and
iv) reacting a compound formed in step iii with a palladium catalyst.
19 . A process for the preparation of a compound of formula I, wherein Q is
comprising
i) reacting a compound formed in step i of claim 18 with a lithium acetylide represented by the formula
wherein G is as defined in claim 1 to form a compound of formula, wherein A is represented by the formula
wherein G and W are as defined in claim 1;
ii) reacting a compound formed in step i with an electrophile, such as, but not limited to, mesyl chloride, chloroformate, or triflate chloride to form a compound of formula I, wherein A is represented by the formula
wherein EWG is an electron-withdrawing group, and G and W are as defined in claim 1 , which then undergoes elimination.Join the waitlist — get patent alerts
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