Method of treating or preventing ras-mediated diseases

Abstract

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 - 33 . (canceled) 
     
     
         34 . A method of selectively inhibiting in a mammal the growth of cancer cells harboring activated Ras relative to cells lacking activated Ras, which method comprising administering in vivo a Ras-inhibitory amount of at least one compound of formula II having a selectivity index greater than one, a pharmaceutically acceptable salt or prodrug thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R and R 0  are hydrogen; n is 0, 1 or 2; 
 Y and Y′ together is oxygen or sulfur; 
 R 1 , R 2 , R 3 , and R 4  are independently selected from hydrogen, hydroxyl, halogen, alkyl, trifluoromethyl, alkoxy, and alkylmercapto; 
 R 7  and R 8  are independently selected from hydrogen, alkyl, trifluoromethyl and alkoxy; 
 R 12  and R 16  are hydrogen; 
 R 13  and R 15  are selected from hydrogen, halogen, hydroxy, and alkoxy; 
 R 14  is selected from hydroxy, formyloxy, alkylcarbonyloxy, hydroxyalkyl, aldehydo, amino, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto, alkylmercapto, azido, and substituted or unsubstituted groups selected from alkylsulfonyl, alkylsulfinyl, alkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, and sulfonamido; 
 or R 13  and R 14  together form an alkylenedioxy group; and 
 X is NR′R″, where R′ is selected from the group consisting of arylalkyl, aryl, heterocyclyl, and heterocycloalkyl, and the aryl of the aryl and arylalkyl structure or the heterocyclyl or the heterocycloalkyl structure may optionally be substituted with one or more of halo, alkyl, trifluoromethyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano, oxo, alkylcarbonyloxy, and sulfonamido; and R″ is hydrogen; 
 wherein said selectivity index is the numerical ratio of the concentration of said compound to cause in vitro 50% growth inhibition of a cell, selected from COLO 205, Caco-2, and HT-29, lacking activated Ras to the concentration of said compound to cause in vitro 50% growth inhibition of a cell, selected from A549, HCT116, and SW480, harboring activated Ras; 
 wherein at least one compound of formula II or a pharmaceutically acceptable salt or prodrug thereof is administered alone or in combination with at least one additional therapeutic agent other than a compound or pharmaceutically acceptable salt or prodrug of formula II. 
 
     
     
         35 . The method of  claim 34 , wherein Y and Y′ together is oxygen. 
     
     
         36 . The method of  claim 35 , wherein R 1 , R 3 , and R 4  are hydrogen and R 2  is selected from hydroxyl, halogen, alkyl, trifluoromethyl, alkoxy, and alkylmercapto. 
     
     
         37 . The method of  claim 36 , wherein R 2  is selected from halogen and alkoxy. 
     
     
         38 . The method of  claim 37 , wherein R 2  is selected from fluorine and methoxy. 
     
     
         39 . The method of  claim 34 , wherein R 7  is hydrogen and R 8  is independently selected from alkyl, trifluoromethyl, and alkoxy. 
     
     
         40 . The method of  claim 39 , wherein R 8  is alkyl. 
     
     
         41 . The method of  claim 34 , wherein R 14  is selected from hydroxy, formyloxy, alkylcarbonyloxy, hydroxyalkyl, aldehydo, amino, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, alkylsulfonyl, alkylsulfinyl, alkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, and sulfonamido. 
     
     
         42 . The method of  claim 41 , wherein R 14  is selected from hydroxy and methylsulfonyloxy. 
     
     
         43 . The method of  claim 34 , wherein the heterocycle of the heterocyclyl and heterocycloalkyl is selected from furanyl, pyrrolyl, N-methyl pyrrolyl, pyridyl, diazolyl, pyrrolidinyl, and N-methyl pyrrolidinyl. 
     
     
         44 . The method of  claim 34 , wherein R 14  is aryl or arylalkyl, optionally substituted on the aryl by one or more halogen atoms. 
     
     
         45 . The method of  claim 34 , wherein the activated Ras is encoded in the tumor cell by a Ras-activating mutation in a ras gene. 
     
     
         46 . The method of  claim 34 , wherein said selectivity index is at least ten. 
     
     
         47 . The method of  claim 46 , wherein said selectivity index is at least one hundred. 
     
     
         48 . The method of  claim 34 , wherein said compound is selected from:
 (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethylbenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide (001),   (Z)-2-(5-fluoro-1-(4-formoxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide (002),   (Z)—N-(2-(dimethylamino)ethyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide (003),   (Z)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(pyridin-3-yl)acetamide (004),   (Z)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide (005),   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide (006),   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide (007),   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5,6-dimethoxy-2-methyl-1H-inden-3-yl)acetamide (008),   (Z)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(pyridin-3-ylmethyl)acetamide (009),   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(pyridin-2-ylmethyl)acetamide (010),   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(pyridin-3-ylmethyl)acetamide (011),   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide (012),   (Z)-2-(1-(3-bromo-4-hydroxy-5-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide (013),   (Z)-2-(1-(3-chloro-4-hydroxy-5-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide (014),   (Z)—N-benzyl-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)acetamide (015),   (Z)-2-(1-(3-fluoro-4-hydroxy-5-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide (016),   (Z)-2-(5-fluoro-1-((7-hydroxybenzo[d][1,3]dioxol-5-yl)methylene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide (017),   (Z)—N-((1H-pyrrol-2-yl)methyl)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)acetamide (018),   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide (019),   (Z)—N-(furan-2-ylmethyl)-2-(1-(3-hydroxy-4-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide (020),   (Z)-2-(5-fluoro-1-(4-(hydroxymethyl)-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide (021),   (Z)—N-((1H-pyrrol-2-yl)methyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide (022),   (Z)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(pyridin-2-ylmethyl)acetamide (028),   (Z)-2-(5-fluoro-1-(4-mesyloxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide (029),   (Z)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-phenylacetamide (034),   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-phenylacetamide (035),   (Z)-2-(1-(4-aminocarbonyl-3,5-dimethoxybenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide (065),   (Z)-2-(1-(3,5-dimethoxy-4-sulfamoylbenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide (067),   (Z)-2-(1-(3,5-dimethoxy-4-sulfamoylbenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-(pyridin-2-ylmethyl)acetamide (068), and   (Z)-2-(1-(3,5-dimethoxy-4-ureidobenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-((4-methylpyridin-3-yl)methyl)acetamide (069),   or the corresponding Z- or E-isomer thereof, prodrug, or salt thereof.   
     
     
         49 . The method of  claim 34 , wherein the cancer cells are metastatic, drug resistant, or radiation resistant. 
     
     
         50 . The method of  claim 34 , wherein the Ras-inhibitory amount is less than or equal to about 10 mg/kg (compound/body weight). 
     
     
         51 . The method of  claim 34 , wherein the Ras-inhibitory amount is the amount required to cause at least a 10% reduction in cancer cell growth in vivo.