Patent EP-0632052-A1 (EP)
Title: Endothelin antagonistic peptides
Inventor: ISHIKAWA KIYOFUMI C O BANYU PH
IPC: C07D209/42
Filed: 1994-06-01
Abstract: A peptide derivative of the formula:
       
 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:
       
 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:
       
 , Y is a group of the formula:
       
 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.