Rapamycin analogues and the uses thereof in the treatment of neurological, proliferative, and inflammatory disorders
View Patent ↗The present invention provides for methods of treating neurological disorders or complications due to stroke or head injury; benign or malignant neoplastic disease, carcinomas and adenocarcinomas; proliferative disorders; and inflammatory disorders using compounds of the following structure: The compounds are therefore useful as neuroprotective and neuroregenerative, anti-proliferative, and anti-inflammatory agents.
1. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and a compound of the formula I:
wherein:
R 1 and R 2 are different, independent groups and are selected from the group consisting of OR 3 and N(R 3′ )(R 3″ ); or
R 1 and R 2 are different, are connected through a single bond, and are selected from the group consisting of O and NR 3 ;
R 3 , R 3′ , and R 3″ are independently selected from the group consisting of H, C 1 to C 6 alkyl, C 1 to C 6 substituted alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R 4 and R 4′ are:
(a) independently selected from the group consisting of H, OH, O(C 1 to C 6 alkyl), O(substituted C 1 to C 6 alkyl), O(acyl), O(aryl), O(substituted aryl), and halogen; or
(b) taken together to form a double bond to O;
R 5 , R 6 , and R 7 are independently selected from the group consisting of H, OH, and OCH 3 ;
R 8 and R 9 are connected through a double bond and are CH;
R 15 is selected from the group consisting of C═O, CHOH, and CH 2 ;
n is 1 or 2;
wherein the acyl group is HC(O)— or a —C(O)R′″— group, wherein R′″ is selected from C 1 to C 6 alkyl, substituted alkyl, and alkoxy;
wherein the heteroaryl group is a monocyclic, aromatic 4- to 7-membered ring having one to four heteroatoms independently selected from N, S and O;
wherein the aryl group is an aromatic system of 6-20 carbon atoms in a single or multiple ring fused or linked ring system wherein at least one part of the fused or linked rings forms the conjugated system;
wherein the substituents for the substituted alkyl, aryl, heteroaryl, or acyl are one or more substituents independently selected from halogen, CN, OH, NO 2 , amino, aryl, a heterocyclic ring consisting of a monocyclic, saturated, partially unsaturated, or wholly unsaturated 4- to 7-membered ring having 1 to 4 heteroatoms independently selected from N, S, O, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, and arylthio; or a pharmaceutically acceptable salt thereof.
2. The composition according to claim 1 , wherein said R 1 and R 2 are connected through a single bond.
3. The composition according to claim 1 , wherein R 1 is O, R 2 is NR 3 .
4. The composition according to claim 1 , wherein R 1 is OR 3 and R 2 is N(R 3′ )(NR 3″ ).
5. The composition according to claim 1 , wherein R 3 , R 3′ or R 3″ is an aryl or substituted aryl.
6. The composition according to claim 5 , wherein said substituted aryl is a substituted benzene ring.
7. The composition according to claim 6 , wherein said aryl or substituted aryl is of the structure:
wherein:
R 10 , R 11 , R 12 , R 13 , and R 14 are independently selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halogen, acyl, OH, O(alkyl), O(substituted alkyl), O(aryl), O(substituted aryl), O(acyl), NH 2 , NH(alkyl), NH(substituted alkyl), NH(aryl), NH(substituted aryl), and NH(acyl).
8. The composition according to claim 1 , wherein R 4 or R 4′ is OH.
9. The composition according to claim 1 , wherein R 4 or R 4′ is O(acyl).
10. The composition according to claim 9 , wherein said acyl is:
11. The composition according to claim 1 , wherein R 5 , R 6 , and R 7 are OCH 3 .
12. The composition according to claim 1 , wherein n is 2.
13. The composition according to claim 1 , wherein R 15 is C═O.
14. The composition according to claim 1 , wherein R 1 is OR 3 ; R 2 is N(R 3′ )(R 3″ ); R 3 is H; R 3′ is H; R 3″ is phenyl; R 4 is OH; R 5 -R 7 are OCH 3 .
15. The composition according to claim 1 , wherein R 1 and R 2 are connected through a single bond; R 1 is O; R 2 is NR 3 ; R 3 is phenyl; R 4 is OH; R 5 -R 7 are OCH 3 .
16. The composition according to claim 1 , wherein R 1 and R 2 are connected through a single bond; R 1 is O; R 2 is NR 3 ; R 4 is OH; R 5 -R 7 are OCH 3 ; and R 3 is
17. The composition according to claim 1 , wherein R 1 and R 2 are connected through a single bond; R 1 is O; R 2 is NR 3 ; R 4 is OH; R 5 -R 7 are OCH 3 ; and R 3 is
18. The composition according to claim 1 , wherein R 1 and R 2 are connected through a single bond; R 1 is O; R 2 is NR 3 ; R 3 is phenyl; R 5 -R 7 are OCH 3 ; and R 4 is