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Claims for Patent: 7,666,901

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Summary for Patent: 7,666,901
Title:Analogs of 17-hydroxywortmannin as PI3K inhibitors
Abstract: The present invention relates to compounds of formula I: ##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.8 are defined herein.
Inventor(s): Zask; Arie (New York, NY), Cai; Ping (New City, NY), Gu; Jianxin (River Edge, NJ), Kaplan; Joshua (Nyack, NY), Yu; Ker (Pine Brook, NJ), Zhu; Tianmin (Monroe, NY)
Assignee: Wyeth (Madison, NJ)
Application Number:11/248,510
Patent Claims:1. A compound selected from the group consisting of: (1E,4S,4aR,5R,6aS,7S,9aR)-1-[(diethylamino)methylene]-7,11-dihydroxy-4-(m- ethoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodeca- hydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S,9aR)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl- -2,10-dioxo-1-(Pyrrolidin-1-ylmethylene)-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodec- ahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S,9aR)-1-(anilinomethylene)-7,11-dihydroxy-4-(methoxym- ethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodecahydroin- deno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-{[tert-butyl(2-hydroxyethyl)amino]methylene}-7,11- -dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8- ,9,9a,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-{[[3-(dimethylamino)propyl](methyl)amino]methylen- e}-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6- ,6a,7,8,9,9a,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-1-{- [methyl(1-methylpyrrolidin-3-yl)amino]methylene}-2,10-dioxo-1,2,4,4a,5,6,6- a,7,8,9,9a,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-[(4-cyclohexylpiperazin-1-yl)methylene]-7,11-dihy- droxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a- ,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-{([butyl(methyl)amino]methylene}-7,11-dihydroxy-4- -(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-dod- ecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-{[cyclohexyl(methyl)amino]methylene}-7,11-dihydro- xy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10- -dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-[(4-benzylpiperazin-1-yl)methylene]-7,11-dihydrox- y-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-- dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,1- 0-dioxo-1-(piperidin-1-ylmethylene)-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodecahydr- oindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-(3,4-dihydroisoquinolin-2(1H)-ylmethylene)-7,11-d- ihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9- ,9a,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,1- 0-dioxo-1-[(4-phenylpiperazin-1-yl)methylene]-1,2,4,4a,5,6,6a,7,8,9,9a,10-- dodecahydroindeno [4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-1-[- (4-methylpiperazin-1-yl)methylene]-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-- dodecahydroindeno [4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,1- 0-dioxo-1-[(4-phenylpiperidin-1-yl)methylene]-1,2,4,4a,5,6,6a,7,8,9,9a,10-- dodecahydroindeno [4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-7-(formyloxy)-11-hydroxy-4-(methoxymethyl)-4a,6a -dimethyl-2,10-dioxo-1-(pyrrolidin-1-ylmethylene)-1,2,4,4a,5,6,6a,7,8,9,9- a,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-[(diethylamino)methylene]-7-(formyloxy)-11-hydrox- y-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-- dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-[(diethylamino)methylene]-7-(formyloxy)-11-hydrox- y-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-- dodecahydroindeno[4,5-h]isochromen-5-yl acetate; Acetic acid 4-{[bis-(2-hydroxy-ethyl)-amino]-methylene}-6,17-dihydroxy-1-methoxymethy- l-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-o- xa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-[(tert-butyl-methyl-amino)-methylene]-6,17-dihydroxy-1-methoxymethyl-10- ,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-c- yclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[bis-(3-dimethylamino-propyl)-amino]-methylene}-6,17-dihydroxy-1-metho- xymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahy- dro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; 1-(11-Acetoxy-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,7- ,10,11,12,13,14,15,16,17-decahydro-2-oxa-cyclopenta[a]phenanthren-4-yliden- emethyl)-piperidine-4-carboxylic acid methyl ester; 1-(11-Acetoxy-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,7- ,10,11,12,13,14,15,16,17-decahydro-2-oxa-cyclopenta[a]phenanthren-4-yliden- emethyl)-piperidine-4-carboxylic acid; 4-[(11-Acetoxy-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,- 7,10,11,12,13,14,15,16,17-decahydro-2-oxa-cyclopenta[a]phenanthren-4-ylide- nemethyl)-methyl-amino]-2,5-dimethyl-hex-2-enoic acid methyl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-4-[({3-[4-(4-methoxy-phenyl)-piperazi- n-1-yl]-propyl}-methyl-amino)-methylene]-10,13-dimethyl-3,7-dioxo-1,3,4,7,- 10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-4-({methyl-[3-(4-methyl-pip- erazin-1-yl)-propyl]-amino}-methylene)-3,7-dioxo-1,3,4,7,10,11,12,13,14,15- ,16,17-dodecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-4-{[methyl-(3-morpholin-4-y- l-propyl)-amino]-methylene}-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dode- cahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[(2-benzenesulfonyl-ethyl)-(3-diethylamino-propyl)-amino]-methylene}-6- ,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13- ,14,15,16,17-dodecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[(1-aza-bicyclo[3,3,1]non-5-ylmethyl)-benzyl-amino]-methylene}-6,17-di- hydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15- ,16,17-dodecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-4-[4-(3-morpholin-4-yl-prop- yl)-piperazin-1-ylmethylene]-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dod- ecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[(2-dimethylamino-ethyl)-methyl-amino]-methylene}-6,17-dihydroxy-1-met- hoxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodeca- hydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-[4-(3-dimethylamino-propyl)-piperazin-1-ylmethylene]-6,17-dihydroxy-1-m- ethoxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dode- cahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-4-[4-(2-morpholin-4-yl-ethy- l)-piperazin-1-ylmethylene]-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dode- cahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-4[4-(1-methyl-piperidin-4-y- l)-piperazin-1-ylmethylene]-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dode- cahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; [(11-Acetoxy-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,7,- 10,11,12,13,14,15,16,17-decahydro-2-oxa-cyclopenta[a]phenanthren-4-ylidene- methyl)-methyl-amino]-acetic acid tert-butyl ester; Acetic acid 4{[(2,3-dihydroxy-propyl)-methyl-amino]-methylene}-6,17-dihydroxy-1-metho- xymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahy- dro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; 4-[(11-Acetoxy-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,- 7,10,11,12,13,14,15,16,17-decahydro-2-oxa-cyclopenta[a]phenanthren-4-ylide- nemethyl)-methyl-amino]-butyric acid; 1-(11-Acetoxy-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,7- ,10,11,12,13,14,15,16,17-decahydro-2-oxa-cyclopenta[a]phenanthren-4-yliden- emethyl)-azetidine-2-carboxylic acid; 1-(11-Acetoxy-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,7- ,10,11,12,13,14,15,16,17-decahydro-2-oxa-cyclopenta[a]phenanthren-4-yliden- emethyl)-pyrrolidine-2-carboxylic acid methyl ester; Acetic acid 4-{[benzyl-(2-cyano-ethyl)-amino]-methylene}-6,17-dihydroxy-1-methoxymeth- yl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-- oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[(2-diethylamino-ethyl)-methyl-amino]-methylene}-6,17-dihydroxy-1-meth- oxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecah- ydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[(2-diethylamino-ethyl)-ethyl-amino]-methylene}-6,17-dihydroxy-1-metho- xymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahy- dro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[benzyl-(2-dimethylamino-ethyl)-amino]-methylene}-6,17-dihydroxy-1-met- hoxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodeca- hydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-4-(4-oxo-piperidi- n-1-ylmethylene)-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclope- nta[a]phenanthren-11-yl ester; 4-{[(2-Dimethylamino-ethyl)-ethyl-amino]-methylene}-6,17-dihydroxy-1-meth- oxymethyl-10,13-dimethyl-10,11,12,13,14,15,16,17-octahydro-1H,4H-2-oxa-cyc- lopenta[a]phenanthrene-3,7-dione; Acetic acid 4-{[(2-dimethylamino-ethyl)-ethyl-amino]methylene}-6,17-dihydroxy-1-metho- xymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahy- dro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-[1,4']bipiperidinyl-1'-ylmethylene-6,17-dihydroxy-1-methoxymethyl-10,13- -dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cycl- openta[a]phenanthren-11-yl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-4-morpholin-4-ylmethylene-3- ,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclopenta[a]ph- enanthren-11-yl ester; Propionic acid 4-{[(2-dimethylamino-ethyl)-methyl-amino]-methylene}-6,17-dihydroxy-1-met- hoxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodeca- hydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; (1E,4S,4aR,5R,6aS,7S,9aR)-1-[(diethylamino)methylene]-5,7,11-trihydroxy-4- -(methoxymethyl)-4a,6a-dimethyl-4a,5,6,6a,7,8,9,9a-octahydroindeno[4,5-h]i- sochromene-2,10(1H,4H)-dione; Acetic acid 4-butylsulfanylmethylene-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,- 7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclopenta[a]phe- nanthren-11-yl ester; 7-Pegylated di-(1E,4S,4aR,5R,6aS,7S)-1-{[[3-(dimethylamino)propyl](methyl)amino]methy- lene}-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,- 5,6,6a,7,8,9,9a,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-{[[3-(dimethylamino)propyl](methyl)amino]methylen- e}-5,7,11-trihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-4a,5,6,6a,7,8,9,9a-o- ctahydroindeno[4,5-h]isochromene-2,10(1H,4H)-dione; (1E,4S,4.alpha.R,5R,6.alpha.S,7S,9.alpha.R)-1-({tert-butyl[2-(dimethylami- no)ethyl]amino}methylene)-7,11-dihydroxy-4-(methoxymethyl)-4, .alpha.6.alpha.-dimethyl-2,10-dioxo-1,2,4,4.alpha.,5,6,6.alpha.,7,8,9,9.a- lpha.,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate; Butanoic acid 4-{[(2-dimethylamino-propyl)-methyl-amino]-methylene}-6,17-dihydroxy-1-me- thoxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodec- ahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[(2-dimethylamino-propyl)-ethyl-amino]methylene}-6,17-dihydroxy-1-meth- oxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecah- ydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester (1E,4S,4aR,5R,6aS,7S,9aR)-1-({4-[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)- ethyl]piperazin-1-yl}methylene)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dim- ethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodecahydroindeno[4,5-h]isoch- romen-5-yl acetate; (1Z,4S,4aR,5R,6aS,7S)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,1- 0-dioxo-1{12-oxo-16-[(3aR,4R,6aS)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-- 4-yl]-5,8-dioxa-2,11-diazahexadec-1-ylidene}-1,2,4,4a,5,6,6a,7,8,9,9a,10-d- odecahydroindeno[4,5-h]isochromen-5-yl acetate; 7-Pegylated (1E,4S,4aR,5R,6aS,7S,9aR)-1-[(diethylamino)methylene]-7,11-dihydroxy-4-(m- ethoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodeca- hydroindeno[4,5-h]isochromen-5-yl acetate; (1Z,4S,4aR,5R,6aS,7S)-1-{[t-butylamino]methylene}-7,11-dihydroxy-4-(metho- xymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodecahydr- oindeno[4,5-h]isochromen-5-yl acetate; (1Z,4S,4aR,5R,6aS,7S)-7,11-dihydroxy-1-{[(2-mercaptoethyl)amino]methylene- }-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-- dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1Z,4S,4aR,5R,6aS,7S,9aR)-1-[(ethylamino)methylene]-7,11-dihydroxy-4-in-(- methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodec- ahydroindeno[4,5-h]isochromen-5-yl acetate; and salts, solvates, and hydrates thereof.

2. The compound of claim 1 selected from the group consisting of: (1E,4S,4aR,5R,6aS,7S,9aR)-1-[(diethylamino)methylene]-7,11-dihydroxy-4-(m- ethoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodeca- hydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S,9aR)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl- -2,10-dioxo-1-(Pyrrolidin-1-ylmethylene)-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodec- ahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S,9aR)-1-(anilinomethylene)-7,11-dihydroxy-4-(methoxym- ethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodecahydroin- deno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-{[tert-butyl(2-hydroxyethyl)amino]methylene}-7,11- -dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8- ,9,9a,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-{[[3-(dimethylamino)propyl](methyl)amino]methylen- e}-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6- ,6a,7,8,9,9a,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,43,4aR,5R,6aS,7S)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-1-{- [methyl(1-methylpyrrolidin-3-yl)amino]methylene}-2,10-dioxo-1,2,4,4a,5,6,6- a,7,8,9,9a,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-[(4-cyclohexylpiperazin-1-yl)methylene]-7,11-dihy- droxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a- ,10-dodecahydroindeno[4,5-h]isochromen--5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-{[butyl(methyl)amino]methylene}-7,11-dihydroxy-4-- (methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-dode- cahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-{[cyclohexyl(methyl)amino]methylene}-7,11-dihydro- xy-4-(methoxymethyl)-4a6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-- dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-[(4-benzylpiperazin-1-yl)methylene]-7,11-dihydrox- y-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,6,9,9a,10-- dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,1- 0-dioxo-1-(piperidin-1-ylmethylene)-1,2,4,4a,5,6,6a,7,8,9,9a,10dodecahydro- indeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-(3,4-dihydroisoquinolin-2(1H)-ylmethylene)-7,11-d- ihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9- ,9a,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,1- 0-dioxo-1-[(4-phenylpiperazin-1-yl)methylene]-1,2,4,4a,5,6,6a,7,8,9,9a,10-- dodecahydroindeno [4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-1-[- (4-methylpiperazin-1-yl)methylene]-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-- dodecahydroindeno [4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,1- 0-dioxo-1-[(4-phenylpiperidin-1-yl)methylene]-1,2,4,4a,5,6,6a,7,8,9,9a,10-- dodecahydroindeno [4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-7-(formyloxy)-11-hydroxy-4-(methoxymethyl)-4a,6a-di- methyl-2,10-dioxo-1-(pyrrolidin-1-ylmethylene)-1,2,4,4a,5,6,6a,7,8,9,9a,10- -dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-[(diallylamino)methylene]-7-(formyloxy)-11-hydrox- y-4-(methoxymethyl)-4a,6a-dimethyl-2,10dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-d- odecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-[(diethylamino)methylene]-7-(formyloxy)-11-hydrox- y-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-- dodecahydroindeno[4,5-h]isochromen-5-yl acetate; Acetic acid 4-{[bis-(2-hydroxy-ethyl)-amino]-methylene}-6,17-dihydroxy-1-methoxymethy- l-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-o- xa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-[(tert-butyl-methyl-amino)-methylene]-6,17-dihydroxy-1-methoxymethyl-10- ,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-c- yclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[bis-(3-dimethylamino-propyl)-amino]-methylene}-6,17-dihydroxy-1-metho- xymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahy- dro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; 1-(11-Acetoxy-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,7- ,10,11,12,13,14,15,16,17-decahydro-2-oxa-cyclopenta[a]phenanthren-4-yliden- emethyl)-piperidine-4-carboxylic acid methyl ester; 1-(11-Acetoxy-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,7- ,10,11,12,13,14,15,16,17-decahydro-2-oxa-cyclopenta[a]phenanthren-4-yliden- emethyl)-piperidine-4-carboxylic acid; 4-[(11-Acetoxy-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,- 7,10,11,12,13,14,15,16,17-decahydro-2-oxa-cyclopenta[a]phenanthren-4-ylide- nemethyl)-methyl-amino]-2,5-dimethyl-hex-2-enoic acid methyl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-4-[({3-[4-(4-methoxy-phenyl)-piperazi- n-1-yl]-propyl}-methyl-amino)-methylene]-10,13-dimethyl-3,7-dioxo-1,3,4,7,- 10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-4-({methyl-[3-(4-methyl-pip- erazin-1-yl)-propyl]-amino}-methylene)-3,7-dioxo-1,3,4,7,10,11,12,13,14,15- ,16,17-dodecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-4-{[methyl-(3-morpholin-4-y- l-propyl)-amino]-methylene}-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,18,17-dode- cahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[(2-benzenesulfonyl-ethyl)-(3-diethylamino-propyl)-amino]-methylene}-6- ,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13- ,14,15,16,17-dodecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[(1-aza-bicyclo[3.3.1]non-5-ylmethyl)-benzyl-amino]-methylene}-6,17-di- hydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15- ,16,17-dodecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-4-[4-(3-morpholin-4-yl-prop- yl)-piperazin-1-ylmethylene]-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dod- ecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[(2-dimethylamino-ethyl)-methyl-amino]-methylene}-6,17-dihydroxy-1-met- hoxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodeca- hydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-[4-(3-dimethylamino-propyl)-piperazin-1-ylmethylene]-6,17-dihydroxy-1-m- ethoxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dode- cahydro-2-oxa-cyclopenta[a]phenanthren-11yl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-4-[4-(2-morpholin-4-yl-ethy- l)-piperazin-1-ylmethylene]-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dode- cahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-4-[4-(1-methyl-piperidin-4-- yl)-piperazin-1-ylmethylene]-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dod- ecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; [(11-Acetoxy-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,7,- 10,11,12,13,14,15,16,17-decahydro-2-oxa-cyclopenta[a]phenanthren-4-ylidene- methyl)-methyl-amino]-acetic acid tert-butyl ester; Acetic acid 4-{[(2,3-dihydroxy-propyl)-methyl-amino]-methylene}-6,17-dihydroxy-1-meth- oxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecah- ydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; 4[(11-Acetoxy-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,7- ,10,11,12,13,14,15,16,17-decahydro-2-oxa-cyclopenta[a]phenanthren-4-yliden- emethyl)-methyl-amino]-butyric acid; 1-(11-Acetoxy-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,7- ,10,11,12,13,14,15,16,17-decahydro-2-oxa-cyclopenta[a]phenanthren-4-yliden- emethyl)-azetidine-2-carboxylic acid; 1-(11-Acetoxy-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,7- ,10,11,12,13,14,15,16,17-decahydro-2-oxa-cyclopenta[a]phenanthren-4-yliden- emethyl)-pyrrolidine-2-carboxylic acid methyl ester; Acetic acid 4-{[benzyl-(2-cyano-ethyl)-amino]-methylene}-6,17-dihydroxy-1-methoxymeth- yl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-- oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[(2-diethylamino-ethyl)-methyl-amino]-methylene}-6,17-dihydroxy-1-meth- oxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecah- ydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[(2-diethylamino-ethyl)-ethyl-amino]-methylene}-6,17-dihydroxy-1-metho- xymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahy- dro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[benzyl-(2-dimethylamino-ethyl)-amino]-methylene}-6,17-dihydroxy-1-met- hoxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodeca- hydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-4-(4-oxo-piperidi- n-1-ylmethylene)-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclope- nta[a]phenanthren-11-yl ester; 4-{[(2-Dimethylamino-ethyl)-ethyl-amino]-methylene}-6,17-dihydroxy-1-meth- oxymethyl-10,13-dimethyl-10,11,12,13,14,15,16,17-octahydro-1H,4H-2-oxa-cyc- lopenta[a]phenanthrene-3,7-dione; Acetic acid 4-{[(2-dimethylamino-ethyl)-ethyl-amino]-methylene}-6,17-dihydroxy-1-meth- oxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecah- ydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-[1,4']bipiperidinyl-1'-ylmethylene-6,17-dihydroxy-1-methoxymethyl-10,13- -dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cycl- openta[a]phenanthren-11-yl ester; Acetic acid 6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-4-morpholin-4-ylmethylene-3- ,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclopenta[a]ph- enanthren-11-yl ester; Propionic acid 4-{[(2-dimethylamino-ethyl)-methyl-amino]-methylene}-6,17-dihydroxy-1-met- hoxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodeca- hydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; (1E,4S,4aR,5R,6aS,7S,9aR)-1-[(diethylamino)methylene]-5,7,11-trihydroxy-4- -(methoxymethyl)-4a,6a-dimethyl-4a,5,6,6a,7,8,9,9a-octahydroindeno[4,5-h]i- sochromene-2,10(1H,4H)-dione; Acetic acid 4-butylsulfanylmethylene-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,- 7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclopenta[a]phe- nanthren-11-yl ester; 7-Pegylated di-(1E,4S,4aR,5R,6aS,7S)-1-{[[3-(dimethylamino)propyl](methyl)amino]methy- lene}-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,- 5,6,6a,7,8,9,9a,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate; (1E,4S,4aR,5R,6aS,7S)-1-{[[3-(dimethylamino)propyl](methyl)amino]methylen- e}-5,7,11-trihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-4a,5,6,6a,7,8,9,9a-o- ctahydroindeno[4,5-h]isochromene-2,10(1H,4H)-dione; (1E,4S,4.alpha.R,5R,6.alpha.,7S,9.alpha.-1-({tert-butyl[2-(dimethylamino)- ethyl]amino}methylene)-7,11-dihydroxy-4-(methoxymethyl)-4.alpha.,6.alpha.-- dimethyl-2,10-dioxo-1,2,4,4.alpha.,5,6,6.alpha.,7,8,9,9a,10-dodecahydroind- eno[4,5-h]isochromen-5-yl acetate; Butanoic acid 4-{[(2-dimethylamino-propyl)-methyl-amino]-methylene}-6,17-dihydroxy-1-me- thoxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodec- ahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester; Acetic acid 4-{[(2-dimethylamino-propyl)-ethyl-amino]-methylene}-6,17-dihydroxy-1-met- hoxymethyl-10,13-dimethyl-3,7-dioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodeca- hydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester (1E,4S,4aR,5R,6aS,7S,9aR)-1-({4-[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl}- ethyl]piperazin-1-yl)methylene)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dim- ethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodecahydroindeno[4,5-h]isoch- romen-5-yl acetate; and salts, solvates, and hydrates thereof.

3. The compound of claim 2 wherein the compound is (1E,4S,4aR,5R,6aS,7S)-1-{[[3-(dimethylamino)propyl](methyl)amino]methylen- e}-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6- ,8a,7,8,9,9a,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate.

4. The compound of claim 1 wherein the compound is PEGylated.

5. The compound of claim 2 wherein the compound is PEGylated.

6. The compound of claim 3 wherein the compound is PEGylated.

7. A method of treating a PI3K-dependent condition, said condition selected from the group consisting of tumor cell proliferation, tumor cell growth, and tumorigenesis, comprising administering to a subject a PI3K-inhibiting amount of a compound according to claim 1.

8. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

9. A method of treating tumor cell proliferation, tumor cell growth, or tumorigenesis comprising administering to a subject a pharmaceutical composition according to claim 8.

10. The method of claim 9 further comprising administering one or more agents that modulate growth factor signaling, cytokine response, and cell cycle control.

11. A method of treating tumor cell proliferation, tumor cell growth, or tumorigenesis comprising administering to a subject a pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

12. The compound 7-Pegylated di-(1E,4S,4aR,5R,6aS,7S)-1-{[[3-(dimethylamino)propyl](methyl)amino]methy- lene}-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,- 5,6,6a,7,8,9,9a,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate.

13. The method of claim 9, further comprising administering taxol.

14. The method of claim 13 further administering one or more agents that modulate growth factor signaling, cytokine response, and cell cycle control.

15. The method of claim 14, wherein the agent is selected from the group consisting of cytokines, interferon, rapamycin, pegylated rapamycin, HER2/EGFR inhibitors, MEK inhibitors, interferon-.alpha.(Intron-A), and Src kinase inhibitors.

Details for Patent 7,666,901

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Merck Sharp & Dohme Corp. INTRON A interferon alfa-2b For Injection 103132 1986-06-04 ⤷  Sign up for a Free Trial 2024-10-13
Merck Sharp & Dohme Corp. INTRON A interferon alfa-2b For Injection 103132 ⤷  Sign up for a Free Trial 2024-10-13
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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