Sulfamides and their use as endothelin receptor antagonists

A compound of formula II

• or an optically pure enantiomer or diastereomer, a mixture of enantiomers or diastereomers, a diastereomeric racemate, a mixture of diastereomeric racemates or a meso-form or a pharmaceutically acceptable salt thereof;
• wherein
• R1 represents aryl;
• aryl-lower alkyl;
• heteroaryl;
• heteroaryl-lower alkyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• heterocyclyl;
• heterocyclyl-lower alkyl;
• lower alkyl;
• or hydrogen;
• R2 represents —CH3;
• —(CH2)n—Y—Ra;
• —(CH2)m—C≡C—(CH2)p-Z-Ra;
• —(CH2)k—C(Rb)═CRcRd;
• or —CH2-tetrahydrofuran-2-yl;
• Y represents a bond, —O—;
• —NH—;
• —NH—SO2—;
• —NH—SO2—NH—;
• O—CO—;
• —CO—O—;
• —O—CO—NH—;
• —NH—CO—O—;
• or —NH—CO—NH—;
• Ra represents aryl;
• heteroaryl;
• lower alkyl;
• cycloalkyl;
• or hydrogen;
• Z represents oxygen or a bond;
• k represents 1, 2, 3, 4, 5 or 6;
• Rb and Rc independently represent hydrogen or lower alkyl;
• and
• Rd represents hydrogen;
• lower alkyl;
• aryl;
• or heteroaryl;
• n represents 2, 3, 4, 5 or 6;
• m represents 1, 2, 3, 4 or 5;
• p represents 0 (zero), 1, 2 or 3 and if p represents 0 (zero), Z cannot represent oxygen;
• R3 represents aryl;
• or heteroaryl;
• and
• R4 represents hydrogen;
• trifluoromethyl;
• lower alkyl;
• lower alkyl-amino;
• lower alkyloxy;
• lower alkyloxy-lower alkyloxy;
• hydroxy-lower alkoxy;
• lower alkyl-sulfinyl;
• lower alkylthio;
• lower alkylthio-lower alkyl;
• hydroxy-lower alkyl;
• lower alkyl-oxylower alkyl;
• hydroxy-lower alkyl-oxy-lower alkyl;
• hydroxy-lower alkyl-amino;
• lower alkyl-amino-lower alkyl;
• amino;
• di-lower alkyl-amino;
• [N-(hydroxy-lower alkyl)-N(lower alkyl)]-amino;
• aryl;
• aryl-amino;
• aryl-lower alkyl-amino;
• aryl-thio;
• aryl-lower alkyl-thio;
• aryloxy;
• aryl-lower alkyl-oxy;
• aryl-lower alkyl;
• aryl-sulfinyl;
• heteroaryl;
• heteroaryl-oxy;
• heteroaryl-lower alkyl-oxy;
• heteroaryl-amino;
• heteroaryl-lower alkyl-amino;
• heteroaryl-thio;
• heteroaryl-lower alkyl-thio;
• heteroaryl-lower alkyl;
• heteroaryl-sulfinyl;
• heterocyclyl;
• heterocyclyl-lower alkyl-oxy;
• heterocyclyl-oxy;
• heterocyclyl-amino;
• heterocyclyl-lower alkyl-amino;
• heterocyclyl-thio;
• heterocyclyl-lower alkyl-thio;
• heterocyclyl-lower alkyl;
• heterocyclyl-sulfinyl;
• cycloalkyl;
• cycloalkyl-oxy;
• cycloalkyl-lower alkyl-oxy;
• cycloalkyl-amino;
• cycloalkyl-lower alkyl-amino;
• cycloalkyl-thio;
• cycloalkyl-lower alkyl-thio;
• cycloalkyl-lower alkyl;
• or cycloalkylsulfinyl.

A compound of formula III

• or an optically pure enantiomer or diastereomer, a mixture of enantiomers or diastereomers, a diastereomeric racemate, a mixture of diastereomeric racemates or a meso-form or a pharmaceutically acceptable salt thereof;
• wherein
• R1 represents aryl;
• aryl-lower alkyl;
• heteroaryl;
• heteroaryl-lower alkyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• heterocyclyl;
• heterocydyl-lower alkyl;
• lower alkyl;
• or hydrogen;
• R2 represents —CH3;
• —(CH2)n—Y—Ra;
• —(CH2)m—C≡C—(CH2)p-Z-Ra;
• —(CH2)k—C(Rb)═CRcRd;
• —CH2-tetrahydrofuran-2-yl;
• k represents 1, 2, 3, 4, 5 or 6;
• p represents 0 (zero), 1, 2 or 3 and if p represents 0 (zero), Z cannot represent oxygen;
• m represents 1, 2, 3, 4 or 5;
• n represents 2, 3, 4, 5 or 6;
• Y represents a bond, —O—;
• —NH—;
• —NH—SO2—;
• —NH—SO2—NH—;
• O—CO—;
• —CO—O—;
• —O—CO—NH—;
• —NH—CO—O—;
• or —NH—CO—NH—;
• Ra represents aryl;
• heteroaryl;
• lower alkyl;
• cycloalkyl;
• or hydrogen;
• Z represents oxygen or a bond;
• Rb and Rc independently represent hydrogen or lower alkyl;
• Rd represents hydrogen;
• lower alkyl;
• aryl;
• or heteroaryl;
• R4 represents hydrogen;
• trifluoromethyl;
• lower alkyl;
• lower alkyl-amino;
• lower alkyloxy;
• lower alkyloxy-lower alkyloxy;
• hydroxy-lower alkoxy;
• lower alkyl-sulfinyl;
• lower alkylthio;
• lower alkylthio-lower alkyl;
• hydroxy-lower alkyl;
• lower alkyl-oxylower alkyl;
• hydroxy-lower alkyl-oxy-lower alkyl;
• hydroxy-lower alkyl-amino;
• lower alkyl-amino-lower alkyl;
• amino;
• di-lower alkyl-amino;
• [N-(hydroxy-lower alkyl)-N(lower alkyl)]-amino;
• aryl;
• aryl-amino;
• aryl-lower alkyl-amino;
• aryl-thio;
• aryl-lower alkyl-thio;
• aryloxy;
• aryl-lower alkyl-oxy;
• aryl-lower alkyl;
• aryl-sulfinyl;
• heteroaryl;
• heteroaryl-oxy;
• heteroaryl-lower alkyl-oxy;
• heteroaryl-amino;
• heteroaryl-lower alkyl-amino;
• heteroaryl-thio;
• heteroaryl-lower alkyl-thio;
• heteroaryl-lower alkyl;
• heteroaryl-sulfinyl;
• heterocyclyl;
• heterocyclyl-lower alkyl-oxy;
• heterocyclyl-oxy;
• heterocyclyl-amino;
• heterocyclyl-lower alkyl-amino;
• heterocyclyl-thio;
• heterocyclyl-lower alkyl-thio;
• heterocyclyl-lower alkyl;
• heterocyclyl-sulfinyl;
• cycloalkyl;
• cycloalkyl-oxy;
• cycloalkyl-lower alkyl-oxy;
• cycloalkyl-amino;
• cycloalkyl-lower alkyl-amino;
• cycloalkyl-thio;
• cycloalkyl-lower alkyl-thio;
• cycloalkyl-lower alkyl;
• or cycloalkylsulfinyl;
• and
• A represents hydrogen, methyl, ethyl, chlorine, bromine, fluorine, trifluoromethyl or methoxy.

A compound of formula IV

• or an optically pure enantiomer or diastereomer, a mixture of enantiomers or diastereomers, a diastereomeric racemate, a mixture of diastereomeric racemates or a meso-form or a pharmaceutically acceptable salt thereof;
• wherein
• R1 represents aryl;
• aryl-lower alkyl;
• heteroaryl;
• heteroaryl-lower alkyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• heterocyclyl;
• heterocyclyl-lower alkyl;
• lower alkyl;
• or hydrogen;
• R4 represents hydrogen;
• trifluoromethyl;
• lower alkyl;
• lower alkyl-amino;
• lower alkyloxy;
• lower alkyloxy-lower alkyloxy;
• hydroxy-lower alkoxy;
• lower alkyl-sulfinyl;
• lower alkylthio;
• lower alkylthio-lower alkyl;
• hydroxy-lower alkyl;
• lower alkyl-oxylower alkyl;
• hydroxy-lower alkyl-oxy-lower alkyl;
• hydroxy-lower alkyl-amino;
• lower alkyl-amino-lower alkyl;
• amino;
• di-lower alkyl-amino;
• [N-(hydroxy-lower alkyl)-N(lower alkyl)]-amino;
• aryl;
• aryl-amino;
• aryl-lower alkyl-amino;
• aryl-thio;
• aryl-lower alkyl-thio;
• aryloxy;
• aryl-lower alkyl-oxy;
• aryl-lower alkyl;
• aryl-sulfinyl;
• heteroaryl;
• heteroaryl-oxy;
• heteroaryl-lower alkyl-oxy;
• heteroaryl-amino;
• heteroaryl-lower alkyl-amino;
• heteroaryl-thio;
• heteroaryl-lower alkyl-thio;
• heteroaryl-lower alkyl;
• heteroaryl-sulfinyl;
• heterocyclyl;
• heterocyclyl-lower alkyl-oxy;
• heterocyclyl-oxy;
• heterocyclyl-amino;
• heterocyclyl-lower alkyl-amino;
• heterocyclyl-thio;
• heterocyclyl-lower alkyl-thio;
• heterocyclyl-lower alkyl;
• heterocyclyl-sulfinyl;
• cycloalkyl;
• cycloalkyl-oxy;
• cycloalkyl-lower alkyl-oxy;
• cycloalkyl-amino;
• cycloalkyl-lower alkyl-amino;
• cycloalkyl-thio;
• cycloalkyl-lower alkyl-thio;
• cycloalkyl-lower alkyl;
• or cycloalkylsulfinyl
• n represents 2, 3, 4, 5 or 6;
• A represents hydrogen, methyl, ethyl, chlorine, bromine, fluorine, trifluoromethyl or methoxy;
• and
• R5 represents hydrogen, lower alkyl, aryl, heteroaryl or cycloalkyl.

A compound of formula V

• or an optically pure enantiomer or diastereomer, a mixture of enantiomers or diastereomers, a diastereomeric racemate, a mixture of diastereomeric racemates or a meso-form or a pharmaceutically acceptable salt thereof;
• wherein
• R1 represents aryl;
• aryl-lower alkyl;
• heteroaryl;
• heteroaryl-lower alkyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• heterocyclyl;
• heterocyclyl-lower alkyl;
• lower alkyl;
• or hydrogen;
• A represents hydrogen, methyl, ethyl, chlorine, bromine, fluorine, trifluoromethyl or methoxy;
• and
• R5 represents hydrogen, lower alkyl, aryl, heteroaryl or cycloalkyl.