Cyclic undecapeptide analogs of somatostatin and intermediates

Claim 2

A compound selected from the class consisting of and the non-toxic acid salts thereof, wherein Trp represents either D- or L- tryptophyl and all the other amino acids are of the L-configuration; R 2 is selected from the class consisting of a protecting group for the side chain amino substituent selected from benzyloxycarbonyl, tosyl, t-amyloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl and substituted benzyloxycarbonyl wherein said substituent is selected from halo and nitro; R 3 , r 4 and R 5 are selected from the class 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 10 is selected from the class consisting of hydrogen and a protecting group for the amino function selected from those defined by R 2 ; R 11 is selected from the class 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 n is a whole number from 1 through 5; and wherein at least one of R 2 , R 3 , R 4 , R 5 , R 10 and R 11 is other than hydrogen.

Claim 3

A compound according to claim 1 where n is two.

Claim 4

A compound according to claim 1 wherein Trp is D-tryptophyl.

Claim 5

A compound according to claim 1 wherein Trp is L-tryptophyl.

Claim 6

A compound according to claim 1 wherein R 2 and R 10 are 2-chlorobenzyloxycarbonyl, R 3 , R 4 and R 5 are benzyl, and R 11 is benzyl.

Claim 7

A compound of the formula ##STR14## and its non-toxic salts, wherein n is a whole number from 1 through 5; and all chiral amino acids in said compound being of the L-configuration, except for Trp, which is of the D- or L-configuration.

Claim 8

A compound of the formula ##STR14## and its non-toxic salts, wherein n is a whole number from 1 through 5; and all chiral amino acids in said compound being of the L-configuration, except for Trp, which is of the D- or L-configuration.

Claim 9

A compound according to claim 6 which is selected from L-lysyl-L-asparaginyl-L-phenylalanyl-L-phenylalanyl-L-tryptophyl-L-lysyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-glutamyl (cyclo-α-lysyl to γ-glutamyl)peptide and a non-toxic salt thereof.

Claim 10

A compound according to claim 6 which is selected from L-lysyl-L-asparaginyl-L-phenylalanyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-glutamyl (cyclo α-lysyl to γ-glutamyl)peptide and a non-toxic salt thereof.

Claim 11

A compound of the formula R-Lys(R 1 )-Asn-Phe-Phe-Trp-Lys(R 2 )-Thr(R 3 )-Phe-Thr(R 4 )-Ser(R 5 )-R 6 III wherein Trp represents either D- or L-tryptophyl and all other chiral amino acids are of the L-configuration; R is an α-amino protecting group that is cleavable under conditions that will not cleave the R 1 and R 2 protecting group; R 1 and R 2 is a protecting group 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 1 and R 2 group not being the same as said R group; R 3 , r 4 and R 5 are selected from the class 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 6 is selected from the class consisting of OH, NHNH 2 , N 3 , OCH 3 and ##STR15##

Claim 12

A compound of the formula R-Lys(R 1 )-Asn-Phe-Phe-Trp-Lys(R 2 )-Thr(R 3 )-Phe-Thr(R 4 )-Ser(R 5 )-R 6 III wherein Trp represents either D- or L-tryptophyl and all other chiral amino acids are of the L-configuration; R is an α-amino protecting group that is cleavable under conditions that will not cleave the R 1 and R 2 protecting group; R 1 and R 2 is a protecting group 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 1 and R 2 group not being the same as said R group; R 3 , r 4 and R 5 are selected from the class 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 6 is selected from the class consisting of OH, NHNH 2 , N 3 , OCH 3 and ##STR15##

Claim 13

A compound according to claim 9 wherein R is tert-butyloxycarbonyl, R 1 and R 2 are 2-chlorobenzyloxycarbonyl and R 3 , R 4 and R 5 are benzyl.

Claim 14

A compound according to claim 10 wherein R 6 is NHNH 2 .

Claim 15

A compound according to claim 10 wherein R 6 is ##STR16##

Claim 16

A compound selected from those of the formula ##STR17## wherein Trp represents either D- or L-tryptophyl and all other chiral amino acids are of the L-configuration; R 1 and R 2 is a protecting group 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; R 3 , r 4 and R 5 are selected from the class 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 7 is selected from the class consisting of hydrogen and an α-amino protecting group, said α-amino protecting group being different from said R 1 and R 2 protecting group and said α-amino protecting group being cleavable under conditions that will not cleave said R 1 and R 2 protecting group; R 8 is selected from the class consisting of hydrogen and 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 7 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 class consisting of nitro, methoxy and methyl; R 13 is selected from the class consisting of hydrogen and a protecting group selected from those defined by R 9 ; and n is a whole number from 1 through 5.

Claim 17

A compound selected from those of the formula ##STR17## wherein Trp represents either D- or L-tryptophyl and all other chiral amino acids are of the L-configuration; R 1 and R 2 is a protecting group 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; R 3 , r 4 and R 5 are selected from the class 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 7 is selected from the class consisting of hydrogen and an α-amino protecting group, said α-amino protecting group being different from said R 1 and R 2 protecting group and said α-amino protecting group being cleavable under conditions that will not cleave said R 1 and R 2 protecting group; R 8 is selected from the class consisting of hydrogen and 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 7 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 class consisting of nitro, methoxy and methyl; R 13 is selected from the class consisting of hydrogen and a protecting group selected from those defined by R 9 ; and n is a whole number from 1 through 5.

Claim 18

A compound according to claim 13 represented by formula A wherein R 1 and R 2 are 2-chlorobenzyloxycarbonyl, R 3 , R 4 and R 5 are benzyl, R 7 is t-butyloxycarbonyl, R 8 is t-butyl and R 9 is benzyl.

Claim 19

A compound according to claim 13 represented by formula A wherein R 1 and R 2 are 2-chlorobenzyloxycarbonyl, R 3 , R 4 and R 5 are benzyl, R 7 is hydrogen, R 8 is hydrogen and R 9 is benzyl.