US 10,487,124 B2Granted

Lantipeptide

AssigneesNaicons S.R.L., Fondazione Istituto Italiano Di Tecnologia

InventorsMarianna Iorio, Sonia Maffioli, Paolo Monciardini, Margherita Sosio, Stefano Donadio, Rosalia Bertorelli, Oscar Sasso, Angelo Reggiani

Life of this patent

Estimating the term…

Abstract

The present invention concerns novel lantipeptide (lanthionine-containing peptide) compounds having general formula (I), a process for their preparation, the key intermediates in said processes, their pharmaceutical acceptable salts and pharmaceutical compositions containing them, as well as their use in the treatment of pain.

Claims18

Dependent claims

A peptide compound having general formula (I)

R1 and R2 are independently selected among H or a sugar moiety chosen among monosaccharides, disaccharides, trisaccharides, oligosaccharides and their corresponding deoxy derivatives;
R3 and R4 are independently selected among OH, NH2, NR6R7 wherein R6 and R7 independently represent:
hydrogen;
or
an alkyl of 1 to 20 carbon atoms wherein said alkyl being linear, branched, cyclic or combinations thereof;
or
an alkenyl of 2 to 20 carbon atoms wherein said alkenyl being linear, branched, cyclic or combinations thereof;
or
an alkynyl of 2 to 20 carbon atoms wherein said alkynyl being linear, branched, cyclic or combinations thereof;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a naphthyl radical optionally substituted by one or two substituents selected from halo, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nOR8
in which n represents an integer from 2 to 8 and R8 represents
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nNR9R10
in which n represents an integer from 2 to 8 and R9 and R10 independently represent
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
R9 and R10 taken together represent a —(CH2)3, —(CH2)4—, —(CH2)2—O—(CH2)2, —(CH2)2—S—(CH2)2;
or
R9 and R10 taken together with the adjacent nitrogen atom represent:
a piperazine moiety which may be substituted in position 4 with a substituent selected from (C1-C4) alkyl, (C3-C8) cycloalkyl, pyridyl, benzyl and substituted benzyl wherein the phenyl moiety bears 1 or 2 substituents selected from chloro, bromo, nitro, (C1-C4) alkyl and (C1-C4) alkoxy;
R5 is selected as NR11R12 wherein R11 and R12 independently represent:
hydrogen;
or
an alkyl of 1 to 20 carbon atoms wherein said alkyl being linear, branched, cyclic or combinations thereof;
or
an alkenyl of 2 to 20 carbon atoms wherein said alkenyl being linear, branched, cyclic or combinations thereof;
or
an alkynyl of 2 to 20 carbon atoms wherein said alkynyl being linear, branched, cyclic or combinations thereof;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a naphthyl radical optionally substituted by one or two substituents selected from halo, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nOR8
in which n represents an integer from 2 to 8 and R8 represent
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nNR9R10
in which n represents an integer from 2 to 8 and R9 and R10 independently represent
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
R9 and R10 taken together represent a —(CH2)3, —(CH2)4—, —(CH2)2—O—(CH2)2, —(CH2)2—S—(CH2)2;
or
R9 and R10 taken together with the adjacent nitrogen atom represent:
a piperazine moiety which may be substituted in position 4 with a substituent selected from (C1-C4) alkyl, (C3-C8) cycloalkyl, pyridyl, benzyl and substituted benzyl wherein the phenyl moiety bears 1 or 2 substituents selected from chloro, bromo, nitro, (C1-C4) alkyl and (C1-C4) alkoxy;
when R11 or R12 is hydrogen, R12 or R11 is —CO—R13 where R13 is selected among
NH2, or
an alkyl of 1 to 20 carbon atoms wherein said alkyl being linear, branched, cyclic or combinations thereof;
or
an alkenyl of 2 to 20 carbon atoms wherein said alkenyl being linear, branched, cyclic or combinations thereof;
or
an alkynyl of 2 to 20 carbon atoms wherein said alkynyl being linear, branched, cyclic or combinations thereof;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a naphthyl radical optionally substituted by one or two substituents selected from halo, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nOR8
in which n represents an integer from 2 to 8;
and R8 represents
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nNR9R10
in which n represents an integer from 2 to 8;
and R9 and R10 independently represent
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
R9 and R10 taken together represent a —(CH2)3, —(CH2)4—, —(CH2)2—O—(CH2)2, —(CH2)2—S—(CH2)2;
or
R9 and R10 taken together with the adjacent nitrogen atom represent:
a piperazine moiety which may be substituted in position 4 with a substituent selected from (C1-C4) alkyl, (C3-C8) cycloalkyl, pyridyl, benzyl and substituted benzyl wherein the phenyl moiety bears 1 or 2 substituents selected from chloro, bromo, nitro, (C1-C4) alkyl and (C1-C4) alkoxy;
X and Y each independently represents an amino acid respectively in positions 16 and 20 of the peptide chain, wherein the amino acid is independently selected between Dha (dehydroalanine) and Ser (Serine);
Z1 and Z2 are independently chosen between the groups S, S—O—, S═O, O—S═O, and O═S═O,
provided that when
R3 and R4 are both OH, or one of R3 and R4 is OH and the other is NH2
then
R11 and R12 are not both hydrogen.

137 more elements

A method of treatment of a disease or disorder in a mammal comprising the administration of an effective amount of a peptide compound having general formula (I)

wherein
R1 and R2 are independently selected among H or a sugar moiety chosen among monosaccharides, disaccharides, trisaccharides, oligosaccharides and their corresponding deoxy derivatives;
R3 and R4 are independently selected among OH, NH2, NR6R7 wherein R6 and R7 independently represent:
hydrogen;
or
an alkyl of 1 to 20 carbon atoms wherein said alkyl being linear, branched, cyclic or combinations thereof;
or
an alkenyl of 2 to 20 carbon atoms wherein said alkenyl being linear, branched, cyclic or combinations thereof;
or
an alkynyl of 2 to 20 carbon atoms wherein said alkynyl being linear, branched, cyclic or combinations thereof);
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a naphthyl radical optionally substituted by one or two substituents selected from halo, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nOR8
in which n represents an integer from 2 to 8 and R8 represents
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nNR9R10
in which n represents an integer from 2 to 8 and R9 and R10 independently represent
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
R9 and R10 taken together represent a —(CH2)3, —(CH2)4—, —(CH2)2—O—(CH2)2, —(CH2)2—S—(CH2)2;
or
R9 and R10 taken together with the adjacent nitrogen atom represent:
a piperazine moiety which may be substituted in position 4 with a substituent selected from (C1-C4) alkyl, (C3-C8) cycloalkyl, pyridyl, benzyl and substituted benzyl wherein the phenyl moiety bears 1 or 2 substituents selected from chloro, bromo, nitro, (C1-C4) alkyl and (C1-C4) alkoxy;
R5 is selected as NR11R12 wherein R11 and R12 independently represent:
hydrogen;
or
an alkyl of 1 to 20 carbon atoms wherein said alkyl being linear, branched, cyclic or combinations thereof;
or
an alkenyl of 2 to 20 carbon atoms wherein said alkenyl being linear, branched, cyclic or combinations thereof;
or
an alkynyl of 2 to 20 carbon atoms wherein said alkynyl being linear, branched, cyclic or combinations thereof;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a naphthyl radical optionally substituted by one or two substituents selected from halo, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nOR8
in which n represents an integer from 2 to 8 and R8 represent
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nNR9R10
in which n represents an integer from 2 to 8 and R9 and R10 independently represent
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
R9 and R10 taken together represent a —(CH2)3, —(CH2)4—, —(CH2)2—O—(CH2)2, —(CH2)2—S—(CH2)2;
or
R9 and R10 taken together with the adjacent nitrogen atom represent:
a piperazine moiety which may be substituted in position 4 with a substituent selected from (C1-C4) alkyl, (C3-C8) cycloalkyl, pyridyl, benzyl and substituted benzyl wherein the phenyl moiety bears 1 or 2 substituents selected from chloro, bromo, nitro, (C1-C4) alkyl and (C1-C4) alkoxy;
when R11 or R12 is hydrogen, R12 or R11 is —CO—R13 where R13 is selected among
NH2, or
an alkyl of 1 to 20 carbon atoms wherein said alkyl being linear, branched, cyclic or combinations thereof;
or
an alkenyl of 2 to 20 carbon atoms wherein said alkenyl being linear, branched, cyclic or combinations thereof;
or
an alkynyl of 2 to 20 carbon atoms wherein said alkynyl being linear, branched, cyclic or combinations thereof;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a naphthyl radical optionally substituted by one or two substituents selected from halo, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nOR8
in which n represents an integer from 2 to 8;
and R8 represents
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nNR9R10
in which n represents an integer from 2 to 8;
and R9 and R10 independently represent
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
R9 and R10 taken together represent a —(CH2)3, —(CH2)4—, —(CH2)2—O—(CH2)2, —(CH2)2—S—(CH2)2;
or
R9 and R10 taken together with the adjacent nitrogen atom represent:
a piperazine moiety which may be substituted in position 4 with a substituent selected from (C1-C4) alkyl, (C3-C8) cycloalkyl, pyridyl, benzyl and substituted benzyl wherein the phenyl moiety bears 1 or 2 substituents selected from chloro, bromo, nitro, (C1-C4) alkyl and (C1-C4) alkoxy;
X and Y each independently represents an amino acid respectively in positions 16 and 20 of the peptide chain, wherein the amino acid is independently selected between Dha (dehydroalanine) and Ser (Serine);
Z1 and Z2 are independently chosen between the groups S, S—O—, S═O, O—S═O, and O═S═O;
wherein the disease or disorder is selected from the group consisting of
pain;
inflammatory pain;
neuropathic pain;
cancer pain;
pain induced by chemotherapy treatment;
migraine;
topical anaesthesia;
and
general anaesthesia.

144 more elements

Dependencies are inferred from the claim text.

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Abstract

A peptide compound having general formula (I)

R1 and R2 are independently selected among H or a sugar moiety chosen among monosaccharides, disaccharides, trisaccharides, oligosaccharides and their corresponding deoxy derivatives;
R3 and R4 are independently selected among OH, NH2, NR6R7 wherein R6 and R7 independently represent:
hydrogen;
or
an alkyl of 1 to 20 carbon atoms wherein said alkyl being linear, branched, cyclic or combinations thereof;
or
an alkenyl of 2 to 20 carbon atoms wherein said alkenyl being linear, branched, cyclic or combinations thereof;
or
an alkynyl of 2 to 20 carbon atoms wherein said alkynyl being linear, branched, cyclic or combinations thereof;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a naphthyl radical optionally substituted by one or two substituents selected from halo, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nOR8
in which n represents an integer from 2 to 8 and R8 represents
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nNR9R10
in which n represents an integer from 2 to 8 and R9 and R10 independently represent
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
R9 and R10 taken together represent a —(CH2)3, —(CH2)4—, —(CH2)2—O—(CH2)2, —(CH2)2—S—(CH2)2;
or
R9 and R10 taken together with the adjacent nitrogen atom represent:
a piperazine moiety which may be substituted in position 4 with a substituent selected from (C1-C4) alkyl, (C3-C8) cycloalkyl, pyridyl, benzyl and substituted benzyl wherein the phenyl moiety bears 1 or 2 substituents selected from chloro, bromo, nitro, (C1-C4) alkyl and (C1-C4) alkoxy;
R5 is selected as NR11R12 wherein R11 and R12 independently represent:
hydrogen;
or
an alkyl of 1 to 20 carbon atoms wherein said alkyl being linear, branched, cyclic or combinations thereof;
or
an alkenyl of 2 to 20 carbon atoms wherein said alkenyl being linear, branched, cyclic or combinations thereof;
or
an alkynyl of 2 to 20 carbon atoms wherein said alkynyl being linear, branched, cyclic or combinations thereof;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a naphthyl radical optionally substituted by one or two substituents selected from halo, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nOR8
in which n represents an integer from 2 to 8 and R8 represent
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nNR9R10
in which n represents an integer from 2 to 8 and R9 and R10 independently represent
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
R9 and R10 taken together represent a —(CH2)3, —(CH2)4—, —(CH2)2—O—(CH2)2, —(CH2)2—S—(CH2)2;
or
R9 and R10 taken together with the adjacent nitrogen atom represent:
a piperazine moiety which may be substituted in position 4 with a substituent selected from (C1-C4) alkyl, (C3-C8) cycloalkyl, pyridyl, benzyl and substituted benzyl wherein the phenyl moiety bears 1 or 2 substituents selected from chloro, bromo, nitro, (C1-C4) alkyl and (C1-C4) alkoxy;
when R11 or R12 is hydrogen, R12 or R11 is —CO—R13 where R13 is selected among
NH2, or
an alkyl of 1 to 20 carbon atoms wherein said alkyl being linear, branched, cyclic or combinations thereof;
or
an alkenyl of 2 to 20 carbon atoms wherein said alkenyl being linear, branched, cyclic or combinations thereof;
or
an alkynyl of 2 to 20 carbon atoms wherein said alkynyl being linear, branched, cyclic or combinations thereof;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a naphthyl radical optionally substituted by one or two substituents selected from halo, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nOR8
in which n represents an integer from 2 to 8;
and R8 represents
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a group of formula
—(CH2)nNR9R10
in which n represents an integer from 2 to 8;
and R9 and R10 independently represent
hydrogen;
or
(C1-C4) alkyl;
or
a cycloalkyl of 3 to 8 carbon atom optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a phenyl radical optionally substituted by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
or
a benzyl radical optionally substituted on the phenyl ring by one or two substituents independently selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, phenyl, phenyl-lower alkyl of 1 to 4 carbon atoms, phenoxy, phenoxy-lower alkyl of 1 to 4 carbon atoms wherein the phenyl and the phenyl portion of the phenyl lower-alkyl, phenoxy and phenoxy-lower alkyl group is optionally substituted by one or two substituents selected from halo, cyano, lower alkyl of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms, and lower alkoxy of 1 to 4 carbon atoms optionally substituted by 1 to 3 halogen atoms;
R9 and R10 taken together represent a —(CH2)3, —(CH2)4—, —(CH2)2—O—(CH2)2, —(CH2)2—S—(CH2)2;
or
R9 and R10 taken together with the adjacent nitrogen atom represent:
a piperazine moiety which may be substituted in position 4 with a substituent selected from (C1-C4) alkyl, (C3-C8) cycloalkyl, pyridyl, benzyl and substituted benzyl wherein the phenyl moiety bears 1 or 2 substituents selected from chloro, bromo, nitro, (C1-C4) alkyl and (C1-C4) alkoxy;
X and Y each independently represents an amino acid respectively in positions 16 and 20 of the peptide chain, wherein the amino acid is independently selected between Dha (dehydroalanine) and Ser (Serine);
Z1 and Z2 are independently chosen between the groups S, S—O—, S═O, O—S═O, and O═S═O,
provided that when
R3 and R4 are both OH, or one of R3 and R4 is OH and the other is NH2
then
R11 and R12 are not both hydrogen.

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