Cyclic dodecapeptide and intermediates therefor

Claim 2

A compound selected from the group consisting of ##STR18## and ##STR19## and pharmaceutically acceptable salts thereof, wherein: R 2 and R 3 are, independently, protecting groups for the side chain amino substituent of lysine selected from benzyloxycarbonyl, tosyl, t-amyloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl and substituted benzyloxycarbonyl where in said substituent is selected from halo and nitro; R 4 , r 5 and R 6 are selected from the group consisting of hydrogen and a protecting group for the alcoholic hydroxyl group of threonine and serine selected from acetyl, benzoyl, tert-butyl, trityl, benzyl, 2,6 dichlorobenzyl and benzyloxycarbonyl; R 11 is selected from the group consisting of hydrogen and an α-carboxyl protecting group selected from C 1 -C 6 alkyl, benzyl, substituted benzyl, phenacyl, phthalimidomethyl, benzhydryl, trichloroethyl, 4-picolyl, β-methylthioethyl, 4-(methylthio)phenyl, said substituent on benzyl being selected from nitro, methyl and methoxy; and each of m and n is an integer of from 1 through 5, inclusive; and all chiral amino acids other than D-Trp are of the L-configuration.

Claim 3

A compound of claim 1 wherein R 2 and R 3 are 2-chlorobenzyloxycarbonyl, R 4 , R 5 and R 6 are benzyl, R 11 is benzyl, m is 2 and n is 1.

Claim 4

A compound of the formula: ##STR20## and pharmaceutically acceptable salts thereof, wherein each of m and n is a whole number from 1 through 5; and all chiral amino acids other than D-Trp are in the L-configuration.

Claim 5

A compound of the formula: ##STR20## and pharmaceutically acceptable salts thereof, wherein each of m and n is a whole number from 1 through 5; and all chiral amino acids other than D-Trp are in the L-configuration.

Claim 6

A compound according to claim 3 which is selected from 4-aminobutyryl-L-lysyl-L-asparaginyl-L-phenylalanyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L aspartic acid cyclic (12β→1) peptide and the pharmaceutically acceptable salts thereof.

Claim 7

A compound of the formula: ##STR21## wherein: R 1 is an acid labile or photolytic labile protecting group that is cleavable under conditions that will not remove the R 2 and R 3 protecting groups; R 2 and R 3 are, independently, protecting groups for the side chain amino substituent of lysine selected from the class consisting of benzyloxycarbonyl, tosyl, t-amyloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl and substituted benzyloxycarbonyl, said substituent selected from halo and nitro and said R 2 and R 3 groups being stable to cleavage under conditions that result in cleavage of said R 1 group; R 4 , r 5 and R 6 are, independently, selected from the group consisting of hydrogen and a protecting group for the alcoholic hydroxyl group of threonine and serine selected from acetyl, benzoyl, tert-butyl, trityl, benzyl, 2,6 dichlorobenzyl and benzyloxycarbonyl; and R 7 is selected from the group consisting of OH, NHNH 2 , N 3 , OCH 3 and --O--CH 2 --; m is a whole number from 1 through 5; and all chiral amino acids in said compound other than D-Trp are in the L-configuration.

Claim 8

A compound of the formula: ##STR21## wherein: R 1 is an acid labile or photolytic labile protecting group that is cleavable under conditions that will not remove the R 2 and R 3 protecting groups; R 2 and R 3 are, independently, protecting groups for the side chain amino substituent of lysine selected from the class consisting of benzyloxycarbonyl, tosyl, t-amyloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl and substituted benzyloxycarbonyl, said substituent selected from halo and nitro and said R 2 and R 3 groups being stable to cleavage under conditions that result in cleavage of said R 1 group; R 4 , r 5 and R 6 are, independently, selected from the group consisting of hydrogen and a protecting group for the alcoholic hydroxyl group of threonine and serine selected from acetyl, benzoyl, tert-butyl, trityl, benzyl, 2,6 dichlorobenzyl and benzyloxycarbonyl; and R 7 is selected from the group consisting of OH, NHNH 2 , N 3 , OCH 3 and --O--CH 2 --; m is a whole number from 1 through 5; and all chiral amino acids in said compound other than D-Trp are in the L-configuration.

Claim 9

A compound according to claim 5 wherein R 1 is t-butyloxycarbonyl, R 2 and R 3 are 2-chlorobenzyloxycarbonyl and R 4 , R 5 and R 6 are benzyl.

Claim 10

A compound according to claim 6 wherein R 7 is NHNH 2 .

Claim 11

A compound according to claim 6 wherein R 7 is --O--CH 2 --.

Claim 12

A compound selected from those of the formula: ##STR22## wherein: R 2 and R 3 are protecting groups for the side chain amino substituent of lysine selected from the class consisting of benzyloxycarbonyl, tosyl, t-amyloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl and substituted benzyloxycarbonyl, said substituent being selected from halo and nitro, said R 2 and R 3 groups being stable to cleavage under conditions that result in cleavage of said R 10 group; R 4 , r 5 and R 6 are selected from the group consisting of hydrogen and a protecting group for the alcoholic hydroxyl group of threonine and serine selected from acetyl, benzoyl, tert-butyl, trityl, benzyl, 2,6-dichlorobenzyl and benzyloxycarbonyl; R 8 is hydrogen or a side chain carboxyl protecting group which is removable under conditions that will not remove the R 9 carboxyl protecting group; R 9 is an α-carboxyl protecting group which is stable under reaction conditions which cleave said R 10 and R 8 protecting groups, said α-carboxyl protecting group being selected from the class consisting of C 1 -C 6 alkyl, benzyl, phenacyl, phthalimidomethyl, benzhydryl, trichloroethyl, 4-picolyl, β-methylthioethyl, 4-(methylthio)phenyl and substituted benzyl, said substituent being selected from the group consisting of nitro, methoxy and methyl; R 10 is hydrogen or an acid labile or photolytic labile protecting group that is cleavable under conditions that will not remove said R 2 and R 3 protecting groups; each of m and n is a whole number from 1 through 5; all chiral amino acids in said compounds other than D-Trp being of the L-configuration.

Claim 13

A compound selected from those of the formula: ##STR22## wherein: R 2 and R 3 are protecting groups for the side chain amino substituent of lysine selected from the class consisting of benzyloxycarbonyl, tosyl, t-amyloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl and substituted benzyloxycarbonyl, said substituent being selected from halo and nitro, said R 2 and R 3 groups being stable to cleavage under conditions that result in cleavage of said R 10 group; R 4 , r 5 and R 6 are selected from the group consisting of hydrogen and a protecting group for the alcoholic hydroxyl group of threonine and serine selected from acetyl, benzoyl, tert-butyl, trityl, benzyl, 2,6-dichlorobenzyl and benzyloxycarbonyl; R 8 is hydrogen or a side chain carboxyl protecting group which is removable under conditions that will not remove the R 9 carboxyl protecting group; R 9 is an α-carboxyl protecting group which is stable under reaction conditions which cleave said R 10 and R 8 protecting groups, said α-carboxyl protecting group being selected from the class consisting of C 1 -C 6 alkyl, benzyl, phenacyl, phthalimidomethyl, benzhydryl, trichloroethyl, 4-picolyl, β-methylthioethyl, 4-(methylthio)phenyl and substituted benzyl, said substituent being selected from the group consisting of nitro, methoxy and methyl; R 10 is hydrogen or an acid labile or photolytic labile protecting group that is cleavable under conditions that will not remove said R 2 and R 3 protecting groups; each of m and n is a whole number from 1 through 5; all chiral amino acids in said compounds other than D-Trp being of the L-configuration.

Claim 14

A compound according to claim 9 wherein R 2 and R 3 are 2-chlorobenzyloxycarbonyl, R 4 , R 5 and R 6 are benzyl, R 8 is t-butyl, R 9 is benzyl and R 10 is t-butyloxycarbonyl.

Claim 15

A compound according to claim 9, wherein R 2 and R 3 are 2-chlorobenzyloxycarbonyl, R 4 , R 5 and R 6 are benzyl, R 8 is hydrogen, R 9 is benzyl and R 10 is hydrogen.

Claim 16

A compound of the formula: ##STR23## wherein: R 1 is an acid labile or photolytic labile protecting group that is cleavable under conditions that will not remove the R 2 and R 3 protecting groups; R 2 and R 3 are protecting groups for the side chain amino substituent of lysine selected from the class consisting of benzyloxycarbonyl, tosyl, t-amyloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl and substituted benzyloxycarbonyl, said substituent being selected from halo and nitro, said R 2 and R 3 groups being stable to cleavage under conditions that result in cleavage of said R 1 group; R 4 , r 5 and R 6 are selected from the group consisting of hydrogen and a protecting group for the alcoholic hydroxyl group of threonine and serine selected from acetyl, benzoyl, tert-butyl, trityl, benzyl, 2,6-dichlorobenzyl and benzyloxycarbonyl; R 12 is selected from the class consisting of hydrogen and an α-carboxyl protecting group selected from the group consisting of C 1 -C 6 alkyl, benzyl, phenacyl, phthalimidomethyl, benzhydryl, trichloroethyl, 4-picolyl, β-methylthioethyl, 4-(methylthio)phenyl and substituted benzyl, said substituent being selected from the group consisting of nitro, methoxy and methyl; each of m and n is a whole number from 1 through 5; all chiral amino acids in said compound other than D-Trp being of the L-configuration.

Claim 17

A compound of the formula: ##STR23## wherein: R 1 is an acid labile or photolytic labile protecting group that is cleavable under conditions that will not remove the R 2 and R 3 protecting groups; R 2 and R 3 are protecting groups for the side chain amino substituent of lysine selected from the class consisting of benzyloxycarbonyl, tosyl, t-amyloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl and substituted benzyloxycarbonyl, said substituent being selected from halo and nitro, said R 2 and R 3 groups being stable to cleavage under conditions that result in cleavage of said R 1 group; R 4 , r 5 and R 6 are selected from the group consisting of hydrogen and a protecting group for the alcoholic hydroxyl group of threonine and serine selected from acetyl, benzoyl, tert-butyl, trityl, benzyl, 2,6-dichlorobenzyl and benzyloxycarbonyl; R 12 is selected from the class consisting of hydrogen and an α-carboxyl protecting group selected from the group consisting of C 1 -C 6 alkyl, benzyl, phenacyl, phthalimidomethyl, benzhydryl, trichloroethyl, 4-picolyl, β-methylthioethyl, 4-(methylthio)phenyl and substituted benzyl, said substituent being selected from the group consisting of nitro, methoxy and methyl; each of m and n is a whole number from 1 through 5; all chiral amino acids in said compound other than D-Trp being of the L-configuration.