Rapamycin analogues and the uses thereof in the treatment of neurological, proliferative,and inflammatory disorders
AssigneeWyeth
InventorsEdmund Graziani, Kevin Pong, Jerauld Skotnicki
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Abstract
The present invention provides compounds of the following structure, wherein R1, R2, R4, R4′, R6, R7, and R15 are defined above: These compounds are useful in treating neurological disorders or complications due to stroke or head injury; benign or malignant neoplastic disease, carcinomas and adenocarcinomas; proliferative disorders; and inflammatory disorders. The compounds are therefore useful as neuroprotective and neuroregenerative, anti-proliferative, and anti-inflammatory agents.
Claims44
A compound of the formula I:
- wherein:
- R1 and R2 are different, independent groups and are selected from the group consisting of OR3 and N(R3′)(R3″);
- or
- R1 and R2 are different, are connected through a single bond, and are selected from the group consisting of O and NR3;
- R3, R3′, and R3″ are independently selected from the group consisting of H, C1 to C6 alkyl, C1 to C6 substituted alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroalkyl;
- R4 and R4′ are:
- (a) independently selected from the group consisting of H, OH, O(C1 to C6 alkyl), O(substituted C1 to C6 alkyl), O(acyl), O(aryl), O(substituted aryl), and halogen;
- or
- (b) taken together to form a double bond to O;
- R5, R6, and R7 are independently selected from the group consisting of H, OH, and OCH3;
- R8 and R9 are connected through a (i) single bond and are CH2 or (ii) double bond and are CH;
- R15 is selected from the group consisting of C═O, CHOH, and CH2;
- n is 1 or 2;
- or a pharmaceutically acceptable salt thereof.
A compound of the formula Ia:
- wherein:
- R1 and R2 are different, independent groups and are selected from the group consisting of OH and N(R3′)(R3″);
- or
- R1 and R2 are different, are connected through a single bond, and are selected from the group consisting of O and NR3;
- R3′ and R3″ are independently selected from the group consisting of H, C1 to C6 alkyl, C1 to C6 substituted alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
- R8 and R9 are connected through a (i) single bond and are CH2 or (ii) a double bond and are CH;
- or a pharmaceutically acceptable salt thereof.
A compound of the formula Ib:
- wherein:
- R is independently selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halogen, acyl, OH, O(alkyl), O(substituted alkyl), O(aryl), O(substituted aryl), O(acyl), NH2, NH(alkyl), NH(substituted alkyl), NH(aryl), NH(substituted aryl), and NH(acyl);
- and
- m is 1 to 5.
A method of treating benign or malignant neoplastic disease comprising administering to a subject in need thereof a compound selected from (i) 9,27-dihydroxy-3-{2-[4-hydroxy-3-methoxycyclohexyl]-1-methylethyl}-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-37-phenyl-4,9,10,12,13,14,15,18,21,22,23,24,25,26,27,382,33,34,34a-nonadecahydro-3H-23,27-epoxy-18,15-(epoxyimino)pyrido[2,1-c][1,4]oxazacyclohentriacontine-1,5,11,28,29(6H,31H)-pentone and (ii) 37-(4-chloro-3-methylphenyl)-9,27-dihydroxy-3-{-2-[4-hydroxy-3-methoxycyclohexyl]-1-methylethyl}-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-4,9,10,12,13,14,15,18,21,22,23,24,25,26,27,32,33,34,34a-nonadecahydro-3H-23,27-epoxy-18,15-(epoxyimino)pyrido[2,1-c][1,4]oxazacyclohentriacontine-1,5,11,28,29(6H,31H)-pentone;
- and a pharmaceutically acceptable carrier.
A method of treating carcinomas and adenocarcinomas comprising administering to a subject in need thereof a compound selected from (i) 9,27-dihydroxy-3-{2-[4-hydroxy-3-methoxycyclohexyl]-1-methylethyl}-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-37-phenyl-4,9,10,12,13,14,15,18,21,22,23,24,25,26,27,32,33,34,34a-nonadecahydro-3H-23,27-epoxy-18,15-(epoxyimino)pyrido[2,1-c][1,4]oxazacyclohentriacontine-1,5,11,28,29(6H,31H)-pentone and (ii) 37-(4-chloro-3-methylphenyl)-9,27-dihydroxy-3-{-2-[4-hydroxy-3-methoxycyclohexyl]-1-methylethyl}-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-4,9,10,12,13,14,15,18,21,22,23,24,25,26,27,32,33,34,34a-nonadecahydro-3H-23,27-epoxy-18,15-(epoxyimino)pyrido[2,1-c][1,4]oxazacyclohentriacontine-1,5,11,28,29(6H,31H)-pentone;
- and a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.