C-22 ring stabilized rapamycin derivatives

Claim 2

A compound of the formula: ##STR33## wherein R 1 is C 1 -C 6 lower alkyl, C 1 -C 6 lower acyl, C 1 -C 6 alkylthio, C 6 -C 10 aryl, C 7 -C 16 arylalkyl, C 6 -C 10 arylthio, C 7 -C 16 arylalkylthio, cyano, C 1 -C 6 perfluorinated lower alkyl, or ##STR34## wherein R is a chain of 1-5 carbon atoms; and R 2 , R 3 and R 4 are each independently hydrogen or SiEt 3 ; or a pharmaceutically acceptable salt thereof.

Claim 3

A compound of claim 1 which is C-22-methyl-rapamycin or a pharmaceutically acceptable salt thereof.

Claim 4

A compound of claim 1 which is C-22-ethyl-rapamycin or a pharmaceutically acceptable salt thereof.

Claim 5

A compound of claim 1 which is C-22-methyl-C-27-hydroxy-rapamycin or a pharmaceutically acceptable salt thereof.

Claim 6

A compound of claim 1 which is C-22-ethyl-C-27-hydroxy-rapamycin or a pharmaceutically acceptable salt thereof.

Claim 7

A compound of the formula: ##STR35## wherein R 1 is C 1 -C 6 lower alkyl, C 1 -C 6 alkylthio, C 6 -C 10 aryl, C 7 -C 16 arylalkyl, C 6 -C 10 arylthio, C 7 -C 16 arylalkylthio, cyano, C 1 -C 6 perfluorinated lower alkyl, or ##STR36## wherein R is a chain of 1-5 carbon atoms; and R 2 , R 3 , and R 4 are each independently: a.) hydrogen; or b.) SiEt 3 ; or ##STR37## wherein R 5 is hydrogen, alkyl of 1-6 carbon atoms, aminoalkyl of 1-4 carbon atoms, aralkyl of 7-10 carbon atoms, --(CH 2 ) q CO 2 R 8 , --(CH 2 ) r NR 9 CO 2 R 10 , carbamylalkyl of 2-3 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, guanylalkyl of 2-4 carbon atoms, mercaptoalkyl of 1-4 carbon atoms, alkylthioalkyl of 2-6 carbon atoms, indolylmethyl, hydroxyphenylmethyl, imidazolylmethyl or phenyl which is optionally mono-, di- or tri-substituted with a substituent selected form alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or --CO 2 H; R 6 and R 9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms; R 7 , R 8 , and R 10 are each, independently, alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, fluorenylmethyl, or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or --CO 2 H; m is 0-4; n is 0-4; p is 1-2; q is 0-4; r is 0-4; wherein R 5 , R 6 , m, and n are independent in each of the ##STR38## subunits when p=2; or d.) --CONH(CR 11 R 12 ) n --X wherein R 11 and R 12 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, halogen, or trifluoromethyl; X is hydrogen, lower alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, trifluoromethyl, nitro, alkoxy of 1-6 carbon atoms, carboalkoxy of 2-7 carbon atoms, aralkyl of 7-10 carbon atoms, halo, dialkylamino of 1-6 carbon atoms per alkyl group, thioalkyl of 1-6 carbon atoms, or Y; Y is a phenyl group which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, or --CO 2 H; n=0-5; with the proviso that R 2 , R 3 and R 4 are not all hydrogen and when n=0, X is lower alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, aralkyl of 7-10 carbon atoms, or Y; or ##STR39## wherein R 13 is a mono-, di-, poly-, or per-fluorinated alkyl group of 1-10 carbon atoms, with the proviso that R 2 , R 3 and R 4 are not all hydrogen, alkyl of 1-10 carbon atoms, arylalkyl of 7-10 carbon atoms, or aryl wherein the aryl group may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, and --CO 2 H; or ##STR40## wherein X is --(CH 2 ) m -- or --Ar--; R 14 and R 15 are each, independently, hydrogen, alkyl of 1-12 carbon atoms, --(CH 2 ) n --Ar, --(CH 2 ) p --NR 16 R 17 , or --(CH 2 ) p --N+R 16 R 17 R 18 Y--; R 16 and R 17 are each, independently, hydrogen, alkyl of 1-12 carbon atoms, or --(CH 2 ) n --Ar; Ar is an optionally mono- or di-substituted group selected from ##STR41## in which the optional substituents are selected from the group consisting of alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, or perfluoroalkyl of 1-6 carbon atoms; R 8 is alkyl of 1-6 carbon atoms; Y is a halide, sulfate, phosphate, or p-toluenesulfonate anion; m=1-6; n=1-6; p=1-6; or g.) --CONHSO 2 --Ar wherein Ar is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benxoxazolyl, benzoisoxazolyl, or benzodioxolyl; wherein the Ar group may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, or --CO 2 H; with the proviso that R 2 , R 3 and R 4 are not all hydrogen; or a pharmaceutically acceptable salt thereof when the Ar group contains a basic nitrogen or when the Ar group is substituted by dialkylamino of 1-6 carbon atoms per alkyl group, --SO 3 H, --PO 3 H, or --CO 2 H; h) --SO 2 R 19 wherein R 19 is alkyl, alkenyl, or alkynyl containing 1 to 6 carbon atoms; or an aromatic moiety selected from the group consisting of phenyl and naphthyl or a heterocyclic moiety selected from the group consisting of thiophenyl and quinolinyl or NHCO 2 R 20 wherein R 20 is lower alkyl containing 1 to 6 carbon atoms; or ##STR42## wherein R 21 and R 22 are each, independently, hydrogen or alkyl of 1-3 carbon atoms or, if R 21 and R 22 are alkyl of 1-3 carbon atoms, R 21 and R 22 together with the nitrogen to which they are attached form a saturated heterocyclic ring having 4-5 carbon atoms; and m=1-3: or ##STR43## wherein R 24 is hydrogen, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, (CH 2 ) s NR 25 R 26 , aminoalkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, guanylalkyl of 2-4 carbon atoms, mercaptoalkyl of 1-4 carbon atoms, alkylthioalkyl of 2-6 carbon atoms, indolmethyl, hydroxyphenylmethyl, imidazolylmethyl, or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or --CO 2 H; R 25 is hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms; R 23 and R 26 are each independently hydrogen, formyl, alkanoyl of 2-7 carbon atoms, arylalkanoyl of 8-11 carbon atoms, aryloyl, or CO 2 R 27 ; R 27 is alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, allyl, fluorenylmethyl, or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino or --CO 2 H; m is 0-4; n is 0-4; p is 0-1; q is 0-4; r is 0-4; and s is 0-4 or a pharmaceutically acceptable salt thereof.

Claim 8

A compound of the formula: ##STR35## wherein R 1 is C 1 -C 6 lower alkyl, C 1 -C 6 alkylthio, C 6 -C 10 aryl, C 7 -C 16 arylalkyl, C 6 -C 10 arylthio, C 7 -C 16 arylalkylthio, cyano, C 1 -C 6 perfluorinated lower alkyl, or ##STR36## wherein R is a chain of 1-5 carbon atoms; and R 2 , R 3 , and R 4 are each independently: a.) hydrogen; or b.) SiEt 3 ; or ##STR37## wherein R 5 is hydrogen, alkyl of 1-6 carbon atoms, aminoalkyl of 1-4 carbon atoms, aralkyl of 7-10 carbon atoms, --(CH 2 ) q CO 2 R 8 , --(CH 2 ) r NR 9 CO 2 R 10 , carbamylalkyl of 2-3 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, guanylalkyl of 2-4 carbon atoms, mercaptoalkyl of 1-4 carbon atoms, alkylthioalkyl of 2-6 carbon atoms, indolylmethyl, hydroxyphenylmethyl, imidazolylmethyl or phenyl which is optionally mono-, di- or tri-substituted with a substituent selected form alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or --CO 2 H; R 6 and R 9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms; R 7 , R 8 , and R 10 are each, independently, alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, fluorenylmethyl, or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or --CO 2 H; m is 0-4; n is 0-4; p is 1-2; q is 0-4; r is 0-4; wherein R 5 , R 6 , m, and n are independent in each of the ##STR38## subunits when p=2; or d.) --CONH(CR 11 R 12 ) n --X wherein R 11 and R 12 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, halogen, or trifluoromethyl; X is hydrogen, lower alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, trifluoromethyl, nitro, alkoxy of 1-6 carbon atoms, carboalkoxy of 2-7 carbon atoms, aralkyl of 7-10 carbon atoms, halo, dialkylamino of 1-6 carbon atoms per alkyl group, thioalkyl of 1-6 carbon atoms, or Y; Y is a phenyl group which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, or --CO 2 H; n=0-5; with the proviso that R 2 , R 3 and R 4 are not all hydrogen and when n=0, X is lower alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, aralkyl of 7-10 carbon atoms, or Y; or ##STR39## wherein R 13 is a mono-, di-, poly-, or per-fluorinated alkyl group of 1-10 carbon atoms, with the proviso that R 2 , R 3 and R 4 are not all hydrogen, alkyl of 1-10 carbon atoms, arylalkyl of 7-10 carbon atoms, or aryl wherein the aryl group may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, and --CO 2 H; or ##STR40## wherein X is --(CH 2 ) m -- or --Ar--; R 14 and R 15 are each, independently, hydrogen, alkyl of 1-12 carbon atoms, --(CH 2 ) n --Ar, --(CH 2 ) p --NR 16 R 17 , or --(CH 2 ) p --N+R 16 R 17 R 18 Y--; R 16 and R 17 are each, independently, hydrogen, alkyl of 1-12 carbon atoms, or --(CH 2 ) n --Ar; Ar is an optionally mono- or di-substituted group selected from ##STR41## in which the optional substituents are selected from the group consisting of alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, or perfluoroalkyl of 1-6 carbon atoms; R 8 is alkyl of 1-6 carbon atoms; Y is a halide, sulfate, phosphate, or p-toluenesulfonate anion; m=1-6; n=1-6; p=1-6; or g.) --CONHSO 2 --Ar wherein Ar is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benxoxazolyl, benzoisoxazolyl, or benzodioxolyl; wherein the Ar group may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO 3 H, --PO 3 H, or --CO 2 H; with the proviso that R 2 , R 3 and R 4 are not all hydrogen; or a pharmaceutically acceptable salt thereof when the Ar group contains a basic nitrogen or when the Ar group is substituted by dialkylamino of 1-6 carbon atoms per alkyl group, --SO 3 H, --PO 3 H, or --CO 2 H; h) --SO 2 R 19 wherein R 19 is alkyl, alkenyl, or alkynyl containing 1 to 6 carbon atoms; or an aromatic moiety selected from the group consisting of phenyl and naphthyl or a heterocyclic moiety selected from the group consisting of thiophenyl and quinolinyl or NHCO 2 R 20 wherein R 20 is lower alkyl containing 1 to 6 carbon atoms; or ##STR42## wherein R 21 and R 22 are each, independently, hydrogen or alkyl of 1-3 carbon atoms or, if R 21 and R 22 are alkyl of 1-3 carbon atoms, R 21 and R 22 together with the nitrogen to which they are attached form a saturated heterocyclic ring having 4-5 carbon atoms; and m=1-3: or ##STR43## wherein R 24 is hydrogen, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, (CH 2 ) s NR 25 R 26 , aminoalkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, guanylalkyl of 2-4 carbon atoms, mercaptoalkyl of 1-4 carbon atoms, alkylthioalkyl of 2-6 carbon atoms, indolmethyl, hydroxyphenylmethyl, imidazolylmethyl, or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or --CO 2 H; R 25 is hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms; R 23 and R 26 are each independently hydrogen, formyl, alkanoyl of 2-7 carbon atoms, arylalkanoyl of 8-11 carbon atoms, aryloyl, or CO 2 R 27 ; R 27 is alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, allyl, fluorenylmethyl, or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino or --CO 2 H; m is 0-4; n is 0-4; p is 0-1; q is 0-4; r is 0-4; and s is 0-4 or a pharmaceutically acceptable salt thereof.

Claim 9

A compound of claim 6 which is C-22-methyl-42-dimethylglycine rapamycin.