Patent CA-2124989-A1 (CA)
Title: Endothelin antagonistic peptide
Inventor: ISHIKAWA KIYOFUMI
IPC: A61K38/00
Filed: 1994-06-02
Abstract: ABSTRACT OF THE DISCLOSURE   A peptide derivative of the formula:                                           (I) wherein R2 is a hydrogen atom or a lower alkyl group; R3 is  a  lower  alkyl  group  which  is  unsubstituted  or substituted  with  a  lower  alkylthio  group,  a  lower alkenyl group, a cycloalkyl group or a cycloalkyl lower alkyl group wherein optional one to four hydrogen atoms on the ring may independently be replaced by a lower alkyl group, an aryl group, a heteroaryl group, an aryl lower alkyl group or a heteroaryl lower alkyl group; R4 is a hydrogen atom,  a  lower alkyl  group or an  acyl group; X and Y are mutually dependent; when X is a group of the formula R11-O-C(=O)  or a group of the formula R12R13N-C(=O), Y is a group of the formula:                                           (II) wherein R11 is a lower alkyl group or an aryl group, R12 is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a 1-adamantyl group, or an aryl group or  a  heteroaryl  group  wherein  optional  one  or  two hydrogen atoms on the ring may independently be replaced by an optional group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group and a formyl amino group, R13 is a hydrogen atom, a  lower  alkyl  group  which  is   unsubstituted  or substituted with a hydroxyl group, a cycloalkyl group or a cycloalkyl lower alkyl group,  or R12 and R13  form, together  with  the  adjacent  nitrogen  atom,  a  5-  to 9-membered  nitrogen-containing  saturated  heterocyclic ring having 4 to 8 carbon atoms (wherein among methylene groups forming the ring, optional one methylene group may be replaced by a thio group, optional one to four hydrogen atoms on the carbon atoms of the heterocyclic ring may independently be replaced by  a  lower  alkyl group or a hydroxy lower alkyl group, and further two adjacent carbon atoms in the heterocyclic ring may form a benzo-fused ring), R5 is a hydrogen atom, or a lower alkyl group or a lower alkenyl group which may have one to three substituents selected from the group consisting of  a  hydroxyl  group,  a lower  alkoxy  group,  a  lower alkylthio group, an aryl group and a heteroaryl group, n is 0 or 1, z is a hydroxymethyl group, a group of the formula CO2R61  (wherein R61  is  a  hydrogen  atom or  a lower alkyl group),  a group of the  formula CONR62R63 (wherein each of R62 and R63 is independently a hydrogen atom,  an aryl group,  a heteroaryl group,  or a  lower alkyl group which may have one to three substituents selected from the group consisting of a hydroxyl group, a carboxyl group and a sulfo group), a 1H-tetrazol-5-yl group, a sulfo group or a phosphono group, and when X is a group of the formula:                                    (III) Y is a group of the formula:                                           (IV) wherein R71 is a hydrogen atom,  R72 is a lower alkyl group which is unsubstituted or substituted with a lower alkylthio group, a cycloalkyl group, an aryl group or a heteroaryl  group,  or  R71  and  R72  together  form  an alkylene group having 2 to 5 carbon atoms, m is 0, 1 or 2, Q is a group of the formula COOR8  (wherein R8 is a hydrogen atom or a lower alkyl group), a sulfo group or a  1H-tetrazol-5-yl  group,  each  of  R91  and  R92  is independently a hydrogen atom, or a lower alkyl group or a  lower  alkenyl  group which  may  have  one  to  three substituents selected from the group consisting of a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group, a carboxyl group, a carbamoyl group, an amino group, a guanidino group, an aryl group and a heteroaryl group, or R91 and R92 together form an alkylene  group  having  2  to  4  carbon  atoms  wherein optional one hydrogen atom in the alkylene group may be replaced by a hydroxyl group, and one sulfur atom may be present, and U and W together form a single bond; or a pharmaceutically acceptable salt thereof.