Method of treating or preventing Ras-mediated diseases
Disclosed are compounds, for example, a compound of formula I, wherein R, R 0 , R 1 -R 8 , n, X, Y, Y′, and E are as described herein, pharmaceutical compositions containing such compounds, and methods of treating or preventing a disease or condition for example, cancer, mediated by the ras gene.
1. A method of inhibiting growth of a tumor in a human patient, said tumor having been determined to contain a mutant ras gene encoding for expression of a hyperactive Ras, the method comprising administering to said patient a prodrug of formula II, (Z)- or (E)-isomer thereof, or pharmaceutically acceptable salt thereof, wherein said prodrug of formula II is:
wherein:
R and R 0 are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;
n is 0, 1, or 2;
Y and Y′ together is double-bonded oxygen;
R 1 , R 3 , and R 4 are hydrogen and R 2 is selected from halogen and alkoxy;
R 7 is hydrogen;
R 8 is alkyl;
R 12 and R 16 are hydrogen; R 13 , R 14 , and R 15 are alkoxy; and
X is NR′R″, where R′ is an unsubstituted group selected from phenyl and benzyl; and R″ is hydrogen;
wherein R 14 of said prodrug is converted in vivo in said patient to a Ras-inhibitory effective amount of a compound of formula II wherein R 14 is hydroxyl.
2. The method of claim 1 , wherein the prodrug is selected from:
(Z)-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-phenylacetamide,
(Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-phenylacetamide,
(Z)-N-benzyl-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)acetamide, and
(Z)-N-benzyl-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)acetamide,
or a pharmaceutically acceptable salt thereof.
3. The method of claim 2 , wherein the prodrug is:
(Z)-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-phenylacetamide.
4. The method of claim 2 , wherein the prodrug is:
(Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-phenylacetamide.
5. The method of claim 2 , wherein the prodrug is:
(Z)-N-benzyl-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)acetamide.
6. The method of claim 2 , wherein the prodrug is:
(Z)-N-benzyl-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)acetamide.