Substituted 1,2,3,4-tetrahydroisoquinolines with angiotensin II receptor antagonist properties

Claim 1

A method for treating cognitive decline in a mammal suffering therefrom comprising administering to said mammal a therapeutically effective amount of a compound of Formula I ##STR58## or a pharmaceutically acceptable salt thereof wherein: R 1 and R 2 are each indepdendently hydrogen, lower alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, acylamino, CF 3 , carboxy, carboalkoxy, hydroxyalkyl, aminoalkyl, and nitro; n is an integer from zero to 4; X is absent, O, S, NH, N-alkyl, and is attached to the tetrahydroisoquinoline at the 5 to 6 position; R 3 is hydrogen, alkoxy, aralkoxy, alkylthio, or halogen; R 4 is hydrogen, alkyl, hydroxyalkyl, CO 2 R 6 , CON(R 6 ) 2 wherein R 6 is hydrogen or lower alkyl; and R 5 is alkyl, aryl, aralkyl which can be unsubstituted or substituted on the alkyl and/or on the aryl portion, diaralkyl, the aryl portion can be unsubstituted or substituted, COR 7 , SO 2 R 7 wherein R 7 is aralkyl, alkyl, diaralkyl, OR 8 , NR 8 R 9 wherein R 8 and R 9 are each independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl wherein aryl is phenyl or naphthyl and the substituents are one or more selected from: alkyl, alkoxy, hydroxy, halogen, NO 2 , NH 2 , NHalkyl, N(alkyl) 2 , SCH, and SH.

Claim 2

A method for treating cognitive decline in a mammal suffering therefrom comprising administering to said mammal a therapeutically effective amount of a compound of Formula I ##STR58## or a pharmaceutically acceptable salt thereof wherein: R 1 and R 2 are each indepdendently hydrogen, lower alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, acylamino, CF 3 , carboxy, carboalkoxy, hydroxyalkyl, aminoalkyl, and nitro; n is an integer from zero to 4; X is absent, O, S, NH, N-alkyl, and is attached to the tetrahydroisoquinoline at the 5 to 6 position; R 3 is hydrogen, alkoxy, aralkoxy, alkylthio, or halogen; R 4 is hydrogen, alkyl, hydroxyalkyl, CO 2 R 6 , CON(R 6 ) 2 wherein R 6 is hydrogen or lower alkyl; and R 5 is alkyl, aryl, aralkyl which can be unsubstituted or substituted on the alkyl and/or on the aryl portion, diaralkyl, the aryl portion can be unsubstituted or substituted, COR 7 , SO 2 R 7 wherein R 7 is aralkyl, alkyl, diaralkyl, OR 8 , NR 8 R 9 wherein R 8 and R 9 are each independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl wherein aryl is phenyl or naphthyl and the substituents are one or more selected from: alkyl, alkoxy, hydroxy, halogen, NO 2 , NH 2 , NHalkyl, N(alkyl) 2 , SCH, and SH.

Claim 3

A method for treating atherosclerosis in a mammal suffering therefrom which comprises administering a therapeutically effective amount of a compound of Formula I ##STR59## or a pharmeceutically acceptable salt thereof wherein: R 1 and R 2 are each independently hydrogen, lower alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, acylamino, CF 3 , carboxy, carboalkoxy, hydroxyalkyl, aminoalkyl, and nitro; n is an integer from zero to 4; X is absent, O, S, NH, N-alkyl, and is attached to the tetrahydroisoquinoline at the 5 or 6 position; R 3 is hydrogen, alkoxy, aralkoxy, alkylthio, or halogen; R 4 is hydrogen, alkyl, hydroxyalkyl, CO 2 R 6 , CON(R 6 ) 2 wherein R 6 is hydrogen or lower alkyl; and R 5 is alkyl, aryl, aralkyl which can be unsubstituted or substituted on the alkyl and/or on the aryl portion, diaralkyl, the aryl portion can be unsubstituted or substituted, COR 7 , SO 2 R 7 wherein R 7 is aralkyl, alkyl, diaralkyl, OR 8 , NR 8 R 9 wherein R 8 and R 9 are each independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl wherein aryl is phenyl or naphthyl and the substituents are one or more selected from: alkyl, alkoxy, hydroxy, halogen, NO 2 , NH 2 , NHalkyl, N(alkyl) 2 , SCH, and SH.

Claim 4

A method for treating atherosclerosis in a mammal suffering therefrom which comprises administering a therapeutically effective amount of a compound of Formula I ##STR59## or a pharmeceutically acceptable salt thereof wherein: R 1 and R 2 are each independently hydrogen, lower alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, acylamino, CF 3 , carboxy, carboalkoxy, hydroxyalkyl, aminoalkyl, and nitro; n is an integer from zero to 4; X is absent, O, S, NH, N-alkyl, and is attached to the tetrahydroisoquinoline at the 5 or 6 position; R 3 is hydrogen, alkoxy, aralkoxy, alkylthio, or halogen; R 4 is hydrogen, alkyl, hydroxyalkyl, CO 2 R 6 , CON(R 6 ) 2 wherein R 6 is hydrogen or lower alkyl; and R 5 is alkyl, aryl, aralkyl which can be unsubstituted or substituted on the alkyl and/or on the aryl portion, diaralkyl, the aryl portion can be unsubstituted or substituted, COR 7 , SO 2 R 7 wherein R 7 is aralkyl, alkyl, diaralkyl, OR 8 , NR 8 R 9 wherein R 8 and R 9 are each independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl wherein aryl is phenyl or naphthyl and the substituents are one or more selected from: alkyl, alkoxy, hydroxy, halogen, NO 2 , NH 2 , NHalkyl, N(alkyl) 2 , SCH, and SH.

Claim 5

A method for treating female reproductive disorders is a mammal suffering therefrom which comprises administering a therapeutically effective amount of a compound of Formula I ##STR60## or a pharmaceutically acceptable salt thereof wherein: R 1 and R 2 are each independently hydrogen, lower alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, acylamino, CF 3 , carboxy, carboalkoxy, hydroxyalkyl, aminoalkyl, and nitro; n is an integer from zero to 4; X is absent, O, S, NH, N-alkyl, and is attached to the tetrahydroisoquinoline at the 5 to 6 position; R 3 is hydrogen, alkoxy, aralkoxy, alkylthio, or halogen; R 4 is hydrogen, alkyl, hydroxyalkyl, CO 2 R 6 , CON(R 6 ) 2 wherein R 6 is hydrogen or lower alkyl; and R 5 is alkyl, aryl, aralkyl which can be unsubstituted or substituted on the alkyl and/or on the aryl position, diaralkyl, the aryl portion can be unsubstituted or substituted, COR 7 , SO 2 R 7 wherein R 7 is aralkyl, alkyl, diaralkyl, OR 8 , NR 8 R 9 wherein R 8 and R 9 are each independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl wherein aryl is phenyl or naphthyl and the substituents are one or more selected from: alkyl, alkoxy, hydroxy, halogen, NO 2 , NH 2 , NHalkyl, N(alkyl) 2 , SCH, and SH.

Claim 6

A method for treating female reproductive disorders is a mammal suffering therefrom which comprises administering a therapeutically effective amount of a compound of Formula I ##STR60## or a pharmaceutically acceptable salt thereof wherein: R 1 and R 2 are each independently hydrogen, lower alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, acylamino, CF 3 , carboxy, carboalkoxy, hydroxyalkyl, aminoalkyl, and nitro; n is an integer from zero to 4; X is absent, O, S, NH, N-alkyl, and is attached to the tetrahydroisoquinoline at the 5 to 6 position; R 3 is hydrogen, alkoxy, aralkoxy, alkylthio, or halogen; R 4 is hydrogen, alkyl, hydroxyalkyl, CO 2 R 6 , CON(R 6 ) 2 wherein R 6 is hydrogen or lower alkyl; and R 5 is alkyl, aryl, aralkyl which can be unsubstituted or substituted on the alkyl and/or on the aryl position, diaralkyl, the aryl portion can be unsubstituted or substituted, COR 7 , SO 2 R 7 wherein R 7 is aralkyl, alkyl, diaralkyl, OR 8 , NR 8 R 9 wherein R 8 and R 9 are each independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl wherein aryl is phenyl or naphthyl and the substituents are one or more selected from: alkyl, alkoxy, hydroxy, halogen, NO 2 , NH 2 , NHalkyl, N(alkyl) 2 , SCH, and SH.

Claim 7

A method for treating depression in a mammal suffering therefrom which comprises administering a therapeutically effective amount of a compound of Formula I ##STR61## or a pharmaceutically acceptable salt thereof wherein: R 1 and R 2 are each independently hydrogen, lower alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, acylamino, CF 3 , carboxy, carboalkoxy, hydroxyalkyl, aminoalkyl, and nitro; n is an integer from zero to 4; X is absent, O, S, NH, N-alkyl, and is attached to the tetrahydroisoquinoline at the 5 or 6 position; R 3 is hydrogen, alkoxy, aralkoxy, alkylthio, or halogen; R 4 is hydrogen, alkyl, hydroxyalkyl, CO 2 R 6 , CON(R 6 ) 2 wherein R 6 is hydrogen or lower alkyl; and R 5 is alkyl, aryl, aralkyl which can be unsubstituted or substituted on the alkyl and/or on the aryl portion, diaralkyl, the aryl portion can be unsubstituted or substituted, COR 7 , SO 2 R 7 wherein R 7 is aralkyl, alkyl, diaralkyl, OR 8 , NR 8 R 9 wherein R 8 and R 9 are each independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl wherein aryl is phenyl or naphthyl and the substituents are one or more selected from: alkyl, alkoxy, hydroxy, halogen, NO 2 , NH 2 , NHalkyl, N(alkyl) 2 , SCH, and SH.

Claim 8

A method for treating depression in a mammal suffering therefrom which comprises administering a therapeutically effective amount of a compound of Formula I ##STR61## or a pharmaceutically acceptable salt thereof wherein: R 1 and R 2 are each independently hydrogen, lower alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, acylamino, CF 3 , carboxy, carboalkoxy, hydroxyalkyl, aminoalkyl, and nitro; n is an integer from zero to 4; X is absent, O, S, NH, N-alkyl, and is attached to the tetrahydroisoquinoline at the 5 or 6 position; R 3 is hydrogen, alkoxy, aralkoxy, alkylthio, or halogen; R 4 is hydrogen, alkyl, hydroxyalkyl, CO 2 R 6 , CON(R 6 ) 2 wherein R 6 is hydrogen or lower alkyl; and R 5 is alkyl, aryl, aralkyl which can be unsubstituted or substituted on the alkyl and/or on the aryl portion, diaralkyl, the aryl portion can be unsubstituted or substituted, COR 7 , SO 2 R 7 wherein R 7 is aralkyl, alkyl, diaralkyl, OR 8 , NR 8 R 9 wherein R 8 and R 9 are each independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl wherein aryl is phenyl or naphthyl and the substituents are one or more selected from: alkyl, alkoxy, hydroxy, halogen, NO 2 , NH 2 , NHalkyl, N(alkyl) 2 , SCH, and SH.

Claim 9

A method for treating vascular and cardiac hypertrophy in a mammal suffering therefrom which comprises administering a therapeutically effective amount of a compound of Formula I ##STR62## or a pharmaceutically acceptable salt thereof wherein: R 1 and R 2 are each independently hydrogen, lower alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, acylamino, CF 3 , carboxy, carboalkoxy, hydroxyalkyl, aminoalkyl, and nitro; n is an integer from zero to 4; X is absent, O, S, NH, N-alkyl, and is attached to the tetrahydroisoquinoline at the 5 to 6 position; R 3 is hydrogen, alkoxy, aralkoxy, alkylthio, or halogen; R 4 is hydrogen, alkyl, hydroxyalkyl, CO 2 R 6 , CON(R 6 ) 2 wherein R 6 is hydrogen or lower alkyl; and R 5 is alkyl, aryl, aralkyl which can be unsubstituted or substituted on the alkyl and/or on the aryl portion, diaralkyl, the aryl portion can be unsubstituted or substituted, COR 7 , SO 2 R 7 wherein R 7 is aralkyl, alkyl, diaralkyl, OR 8 , NR 8 R 9 wherein R 8 and R 9 are each independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl wherein aryl is phenyl or naphthyl and the substituents are one or more selected from: alkyl, alkoxy, hydroxy, halogen, NO 2 , NH 2 , NHalkyl, N(alkyl) 2 , SCH, and SH.

Claim 10

A method for treating vascular and cardiac hypertrophy in a mammal suffering therefrom which comprises administering a therapeutically effective amount of a compound of Formula I ##STR62## or a pharmaceutically acceptable salt thereof wherein: R 1 and R 2 are each independently hydrogen, lower alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, acylamino, CF 3 , carboxy, carboalkoxy, hydroxyalkyl, aminoalkyl, and nitro; n is an integer from zero to 4; X is absent, O, S, NH, N-alkyl, and is attached to the tetrahydroisoquinoline at the 5 to 6 position; R 3 is hydrogen, alkoxy, aralkoxy, alkylthio, or halogen; R 4 is hydrogen, alkyl, hydroxyalkyl, CO 2 R 6 , CON(R 6 ) 2 wherein R 6 is hydrogen or lower alkyl; and R 5 is alkyl, aryl, aralkyl which can be unsubstituted or substituted on the alkyl and/or on the aryl portion, diaralkyl, the aryl portion can be unsubstituted or substituted, COR 7 , SO 2 R 7 wherein R 7 is aralkyl, alkyl, diaralkyl, OR 8 , NR 8 R 9 wherein R 8 and R 9 are each independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl wherein aryl is phenyl or naphthyl and the substituents are one or more selected from: alkyl, alkoxy, hydroxy, halogen, NO 2 , NH 2 , NHalkyl, N(alkyl) 2 , SCH, and SH.