Rapamycin derivatives

Claim 2

A compound of the formula ##STR26## wherein: X is selected from the group consisting of H, --OR 10 , --S(O) n R 10 , --NR 10 R 11 , C 1 -C 6 alkyl and aryl; Y is selected from the group consisting of H, --OR 10 , --S(O) n R 10 , --NR 10 R 11 , C 1 -C 6 alkyl and aryl; or X and Y taken together are ═O ; n is selected from the group consisting of 0, 1 and 2; R 1 is selected from the group consisting of ═O, (--OR 6 ,H) and (H,H); R 2 is selected from the group consisting of ═O, (H,H), and (H,OH); R 3 and R 6 are independently selected from the group consisting of --H, C 1 -C 4 alkyl, C(═O)R 7 , --C(═O)OR 7 , --C(═O)NHR 7 , and --C(═S)OR 7 ; R 4 is selected from the group consisting of ═O and (H,OR 6 ); or R 3 and R 4 can be taken together to form a bridge of the formula A--C(R 8 )(R 9 )--O--B, where A is a bond to the oxygen bonded to the carbon at the 28-position and B is a bond to the carbon at the 30-position; R 5 is selected from the group consisting of --H and C 1 -C 4 alkyl; R 7 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl groups, and heterocyclic groups; R 8 and R 9 are independently selected from the group consisting of H, C 1 to C 6 alkyl, or R 8 and R 9 taken together are ═O ; R 10 and R 11 are independently selected from the group consisting of H, C 1 -C 6 alkyl and aryl; provided that, (a) at least one of X and Y is H; and (b) when Y is --OR 10 then R 10 is other than CH 3 ; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Claim 3

A compound of claim 1 where R 1 is (H,OH).

Claim 4

A compound of claim 1 where R 2 is ═O.

Claim 5

A compound of claim 1 where R 3 is H.

Claim 6

A compound of claim 1 where R 4 is ═O.

Claim 7

A compound of claim 1 where R 5 is H.

Claim 8

A compound of claim 1 where R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H.

Claim 9

A compound of claim 1 where one of X and Y is selected from the group consisting of OR 10 and SR 10 or where X and Y are taken together as ═O.

Claim 10

A compound of claim 8 where X and Y are taken together as ═O.

Claim 11

A compound of claim 8 where one of X and Y is selected from the group consisting of --OR 10 and --SR 10 where R 10 is selected from the group consisting of optionally substituted C 1 -C 3 alkyl, optionally substituted benzyl, and optionally substituted phenyl.

Claim 12

A compound of claim 1 where, when one of X and Y is an C 1 -C 6 alkyl group or when one of R 10 and R 11 is an C 1 -C 6 alkyl group, said C 1 -C 6 alkyl group is selected from the group consisting of branched, straight-chain, cyclic, polycyclic, saturated and unsaturated alkyl groups which may be substituted with 0, 1 or more substituents selected from the group consisting of aryl, keto, hydroxyl, alkoxyl, acyloxy, amino, N-acylamino, halogen, cyano and carboxyl substituents, and in which at least one carbon atom may be replaced with a heteroatom selected from the group consisting of O, S and N.

Claim 13

A compound of claim 8 where, when one of X and Y is an aryl group or when one of R 10 or R 11 is an aryl group, said aryl group is selected from the group consisting of cyclic, heterocyclic, polycyclic and heteropolycyclic C 2 to C 14 aryl groups, which may be substituted by one to five members selected from the group consisting of C 1 -C 6 alkyl, hydroxyl, alkoxyl, acyloxy, amino, N-acylamino, halogen, cyano, carboxyl and nitro groups.

Claim 14

A compound of claim 7 where one of X and Y is selected from the group consisting of OR 10 and SR 10 or where X and Y are taken together as ═O.

Claim 15

A compound of claim 13 where X and Y are taken together as ═O.

Claim 16

A compound of claim 7 where one of X and Y is selected from the group consisting of --OR 10 and --SR 10 where R 10 is selected from the group consisting of optionally substituted C 1 -C 3 alkyl, optionally substituted benzyl, and optionally substituted phenyl.

Claim 17

A compound of claim 7 where, when one of X and Y is an C 1 -C 6 alkyl group or when one of R 10 and R 11 is an C 1 -C 6 alkyl group, said C 1 -C 6 alkyl group is selected from the group consisting of branched, straight-chain, cyclic, polycyclic, saturated and unsaturated alkyl groups which may be substituted with 0, 1 or more substituents selected from the group consisting of aryl, keto, hydroxyl, alkoxyl, acyloxy, amino, N-acylamino, halogen, cyano and carboxyl substituents, and in which at least one carbon atom may be replaced with a heteroatom selected from the group consisting of O, S and N.

Claim 18

A compound of claim 7 where, when one of X and Y is an aryl group or when one of R 10 or R 11 is an aryl group, said aryl group is selected from the group consisting of cyclic, heterocyclic, polycyclic and heteropolycyclic C 2 to C 14 aryl groups, which may be substituted by one to five members selected from the group consisting of C 1 -C 6 alkyl, hydroxyl, alkoxyl, acyloxy, amino, N-acylamino, halogen, cyano, carboxyl and nitro groups.

Claim 19

The compound of claim 1 selected from the group consisting of: (1) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is --OCH 3 ; (2) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is --OC 2 H 5 ; (3) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is --OC 2 H 5 ; (4) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is --OCH 2 CH 2 OH; (5) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is --OCH 2 CH 2 OH; (6) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is 3,4-dimethoxybenzyloxy; (7) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is 3,4-dimethoxybenzyloxy; (8) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is --SCH 3 ; (9) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is --SCH 3 ; (10) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is --SPh where Ph is phenyl; (11) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is --SPh where Ph is phenyl; (12) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is 2-furanyl; (13) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is 2-furanyl; (14) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is O-acetyl; (15) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, and each of X and Y is H; (16) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, and X and Y are taken together as ═O ; (17) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is allyl; (18) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is OH; (19) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is 2,4-dimethoxyphenyl; (20) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is 2,4-dimethoxyphenyl; or (21) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is --OH.

Claim 20

A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent, and an effective therapeutic or prophylactic amount of one or more compounds of the formula ##STR27## wherein: X is selected from the group consisting of H, --OR 10 , --S(O) n R 10 , --NR 10 R 11 , C 1 -C 6 alkyl and aryl; Y is selected from the group consisting of H, --OR 10 , --S(O) n R 10 , --NR 10 R 11 , C 1 -C 6 alkyl and aryl; or X and Y taken together are ═O ; n is selected from the group consisting of 0, 1 and 2; R 1 is selected from the group consisting of ═O, (--OR 6 ,H) and (H,H); R 2 is selected from the group consisting of ═O, (H,H), and (H,OH); R 3 and R 6 are independently selected from the group consisting of --H, C 1 -C 4 alkyl, --C(═O)R 7 , --C(═O )OR 7 , --C(═O )NHR 7 , and --C(═S)OR 7 ; R 4 is selected from the group consisting of ═O and (H,OR 6 ); or R 3 and R 4 can be taken together to form a bridge of the formula A--C(R 8 )(R 9 )--O--B, where A is a bond to the oxygen bonded to the carbon at the 28-position and B is a bond to the carbon at the 30-position; R 5 is selected from the group consisting of --H and C 1 -C 4 alkyl; R 7 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl groups, and heterocyclic groups; R 8 and R 9 are independently selected from the group consisting of H, C 1 to C 6 alkyl, or R 8 and R 9 taken together are ═O; R 10 , and R 11 are independently selected from the group consisting of H, C 1 -C 6 alkyl and aryl; provided that, (a) at least one of X and Y is H; and (b) when Y is --OR 10 , then R 10 is other than CH 3 ; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Claim 21

A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent, and an effective therapeutic or prophylactic amount of one or more compounds of the formula ##STR27## wherein: X is selected from the group consisting of H, --OR 10 , --S(O) n R 10 , --NR 10 R 11 , C 1 -C 6 alkyl and aryl; Y is selected from the group consisting of H, --OR 10 , --S(O) n R 10 , --NR 10 R 11 , C 1 -C 6 alkyl and aryl; or X and Y taken together are ═O ; n is selected from the group consisting of 0, 1 and 2; R 1 is selected from the group consisting of ═O, (--OR 6 ,H) and (H,H); R 2 is selected from the group consisting of ═O, (H,H), and (H,OH); R 3 and R 6 are independently selected from the group consisting of --H, C 1 -C 4 alkyl, --C(═O)R 7 , --C(═O )OR 7 , --C(═O )NHR 7 , and --C(═S)OR 7 ; R 4 is selected from the group consisting of ═O and (H,OR 6 ); or R 3 and R 4 can be taken together to form a bridge of the formula A--C(R 8 )(R 9 )--O--B, where A is a bond to the oxygen bonded to the carbon at the 28-position and B is a bond to the carbon at the 30-position; R 5 is selected from the group consisting of --H and C 1 -C 4 alkyl; R 7 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl groups, and heterocyclic groups; R 8 and R 9 are independently selected from the group consisting of H, C 1 to C 6 alkyl, or R 8 and R 9 taken together are ═O; R 10 , and R 11 are independently selected from the group consisting of H, C 1 -C 6 alkyl and aryl; provided that, (a) at least one of X and Y is H; and (b) when Y is --OR 10 , then R 10 is other than CH 3 ; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Claim 22

The related pharmaceutical composition of claim 19 wherein the compound is from the group consisting of: (1) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is --OCH 3 ; (2) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is --OC 2 H 5 ; (3) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is --OC 2 H 5 ; (4) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is --OCH 2 CH 2 OH; (5) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is --OCH 2 CH 2 OH; (6) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is 3,4-dimethoxybenzyloxy; (7) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is 3, 4-dimethoxybenzyloxy; (8) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is --SCH 3 ; (9) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is --SCH 3 ; (10) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is --SPh where Ph is phenyl; (11) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is --SPh where Ph is phenyl; (12) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is 2-furanyl; (13) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is 2-furanyl; (14) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is O-acetyl; (15) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, and each of X and Y is H; (16) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, and X and Y are taken together as ═O ; (17) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is allyl; (18) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is OH; (19) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, Y is H and X is 2,4-dimethoxyphenyl; (20) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is 2,4-dimethoxyphenyl; or (21) R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, R 5 is H, X is H and Y is --OH.

Claim 23

A method of inhibiting the growth of pathogenic fungi in a human or other animal in need thereof which comprises administering to such human or other animal an effective, non-toxic amount of a composition of claim 19.

Claim 24

A method of inducing immunosuppression in a human or other animal in need thereof which comprises administering to such human or other animal an effective, non-toxic amount of a composition of claim 19.

Claim 25

A process for preparing compounds of claim 1 comprising contacting a compound of the formula: ##STR28## where R 1 is selected from the group consisting of ═O, (--OR 6 ,H) and (H,H); R 2 is selected from the group consisting of ═O, (H,H), and (H,OH); R 3 and R 6 are independently selected from the group consisting of --H, C 1 -C 4 alkyl, --C(═O)R 7 , --C(═O)OR 7 , --C(═O)NHR 7 , and --C(═S)OR 7 ; R 4 is selected from the group consisting of ═O and (H,OR 6 ); or R 3 and R 4 can be taken together to form a bridge of the formula A--C(R 8 )(R 9 )--O--B, where A is a bond to the oxygen bonded to the carbon at the 28-position and B is a bond to the carbon at the 30-position; R 5 is selected from the group consisting of --H and C 1 -C 4 alkyl; R 7 is selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, aryl groups, and heterocyclic groups; R 8 and R 9 are independently selected from the group consisting of H, C 1 to C 6 alkyl, or R 8 and R 9 taken together are ═O ; with an acid selected from the group consisting of protic acids and Lewis acids, and with an appropriate nucleophile.

Claim 26

The process of claim 23 where said acid is selected from the group consisting of trifluoroacetic acid and titanium tetrachloride.

Claim 27

The process of claim 24 where said acid is trifluoroacetic acid.

Claim 28

The process of claim 24 where R 1 is (H,OH), R 2 is ═O, R 3 is H, R 4 is ═O, and R 5 is H.

Claim 29

The process of claim 26 where said acid is trifluoroacetic acid.