N-substituted indenoisoquinolines and syntheses thereof
N-Substituted indenoisoquinoline compounds, and pharmaceutical formulations of N-substituted indenoisoquinoline compounds are described. Also described are processes for preparing N-substituted indenoisoquinoline compounds. Also described are methods for treating cancer in mammals using the described N-substituted indenoisoquinoline compounds or pharmaceutical formulations thereof.
1. A compound of the formula
or a pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein:
m is an integer from 0 to about 6;
R 6 is selected from the group consisting of haloalkyl, halocycloalkyl, hydroxy, alkoxy, cycloalkoxy, haloalkoxy, halocycloalkoxy, optionally substituted heteroaryl, aryloxy, heteroaryloxy, and heteroarylamino, acyloxy, haloacyloxy, amino, alkyl and dialkylamino, trialkylammonium, hydroxyalkylamino, bis(hydroxyalkyl)amino, hydroxyalkylaminoalkylamino, heteroarylalkylaminoalkylamino, acylamino, hydroxylamino, alkoxylamino, acyloxylamino, cycloalkyl, heterocyclyl, heterocyclylamino, alkynyl, acyl, urethanyl, cyano, nitro, thio, alkylsulfonyl, sulfonic acid, carboxylic acid, and phosphonic acid; provided that when R 6 is hydroxy, alkylamino, or hydroxyalkylamino, m is the integer 0;
R a represents 1-4 substituents each of which is independently selected from the group consisting of hydrogen, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, cyano, nitro, optionally substituted alkylthio, optionally substituted alkylsulfonyl, carboxylic acid, and sulfonic acid; or R a represents 2-4 substituents where 2 of said substituents are adjacent substituents and are taken together with the attached carbons to form an optionally substituted heterocycle, and where any remaining substituents are each independently selected from the group consisting of hydrogen, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, cyano, nitro, optionally substituted alkylthio, optionally substituted alkylsulfonyl, carboxylic acid, and sulfonic acid;
R d represents 1-4 substituents each of which is independently selected from the group consisting of hydrogen, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, cyano, nitro, optionally substituted alkylthio, optionally substituted alkylsulfonyl, carboxylic acid, and sulfonic acid; or R d represents 2-4 substituents where 2 of said substituents are adjacent substituents and are taken together with the attached carbons to form an optionally substituted heterocycle, and where any remaining substituents are each independently selected from the group consisting of hydrogen, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, cyano, nitro, optionally substituted alkylthio, optionally substituted alkylsulfonyl, carboxylic acid, and sulfonic acid, and
wherein at least one of R a or R d is not hydrogen.
2. The compound of claim 1 , wherein R 6 is selected from the group consisting of amino, alkyl and dialkylamino, trialkylammonium, hydroxyalkylamino, bis(hydroxyalkyl)amino, and hydroxyalkylaminoalkylamino.
3. The compound of claim 1 , wherein R 6 is selected from the group consisting of heteroaryl, heteroaryloxy, and heteroarylamino, heteroarylalkylaminoalkylamino, heterocyclyl, heterocyclylamino, each of which is optionally substituted.
4. The compound of claim 1 , wherein R 6 is optionally substituted heterocyclyl or optionally substituted heterocyclylamino.
5. The compound of claim 1 , wherein R 6 is morpholin-4-yl.
6. The compound of claim 1 , wherein R 6 is optionally substituted heteroaryl or optionally substituted heteroarylamino.
7. The compound of claim 1 , wherein R 6 is imidazole-1-yl.
8. The compound of claim 1 , wherein R d includes an alkylenedioxy group.
9. The compound of claim 1 , wherein R d includes one or more optionally substituted alkoxy.
10. The compound of claim 1 , wherein R a includes one or more alkoxy optionally substituted with alkenyl, alkynyl, halo, nitro, cyano, azido, amino, alkylamino, dialkylamino, hydroxyalkylamino, bis(hydroxyalkyl)amino, cycloalkyl, aryl, hetereocyclyl, heteroaryl, alkylcarbonyl, alkoxycarbonyl, or hydrazinecarbonyl.
11. The compound of claim 10 , wherein said alkoxy is optionally substituted with amino, alkylamino, or dialkylamino.
12. The compound of claim 10 , wherein said alkoxy is optionally substituted with heterocyclyl.
13. The compound of claim 12 , wherein said heterocyclyl is morpholino, 4-methylpiperazinyl, piperidinyl, or pyrrodinyl.
14. The compound of claim 10 , wherein said alkoxy is optionally substituted with alkylcarbonyl, alkoxycarbonyl, or hydrazinecarbonyl.
15. The compound of claim 10 , wherein R a includes one methoxy and one alkoxy substituted with alkenyl, alkynyl, halo, nitro, cyano, azido, amino, alkylamino, dialkylamino, cycloalkyl, aryl, hetereocyclyl, heteroaryl, alkylcarbonyl, alkoxycarbonyl, or hydrazinecarbonyl.
16. The compound of claim 10 , wherein R a includes one optionally substituted alkoxy and one hydroxy.
17. The compound of claim 1 , wherein m is 3.
18. The compound of claim 1 , wherein the compound is
2-(3-bromopropoxy)-3-methoxy-6-(3-morpholinopropyl)-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione;
2-(allyloxy)-3-methoxy-6-(3-morpholinopropyl)-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione;
2-(3-azidopropoxy)-3-methoxy-6-(3-morpholinopropyl)-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione;
2-(3-Aminopropoxy)-3-methoxy-6-(3-morpholinopropyl)-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione;
2-(3-(dimethylamino)propoxy)-3-methoxy-6-(3-morpholinopropyl)-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione;
2-(3-(ethylamino)propoxy)-3-methoxy-6-(3-morpholinopropyl)-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione;
3-Methoxy-2-(3-morpholinopropoxy)-6-(3-morpholinopropyl)-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione;
3-methoxy-2-(3-(4-methylpiperazin-1-yl)propoxy)-6-(3-morpholinopropyl)-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione;
3-methoxy-6-(3-morpholinopropyl)-2-(3-(piperidin-1-yl)propoxy)-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione;
3-methoxy-6-(3-morpholinopropyl)-2-(3-(pyrrolidin-1-yl)propoxy)-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione;
Methyl 2-((3-Methoxy-6-(3-morpholinopropyl)-5,12-dioxo-6,12-dihydro-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinolin-2-yl)oxy)acetate; or
2-((12-hydroxy-3-methoxy-6-(3-morpholinopropyl)-5-oxo-6,12-dihydro-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinolin-2-yl)oxy)acetohydrazide.
19. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and one or more pharmaceutically acceptable carriers, diluents, and excipients.
20. A method for treating cancer, the method comprising the step of administering to a patient in need of relief from said cancer a therapeutically effective amount of a compound of the formula
or a pharmaceutically acceptable salt, hydrate, or solvate thereof,
wherein:
m is an integer from 0 to about 6;
R 6 is selected from the group consisting of haloalkyl, halocycloalkyl, hydroxy, alkoxy, cycloalkoxy, haloalkoxy, halocycloalkoxy, optionally substituted heteroaryl, aryloxy, heteroaryloxy, and heteroarylamino, acyloxy, haloacyloxy, amino, alkyl and dialkylamino, trialkylammonium, hydroxyalkylamino, bis(hydroxyalkyl)amino, hydroxyalkylaminoalkylamino, heteroarylalkylaminoalkylamino, acylamino, hydroxylamino, alkoxylamino, acyloxylamino, cycloalkyl, heterocyclyl, heterocyclylamino, alkynyl, acyl, urethanyl, cyano, nitro, thio, alkylsulfonyl, sulfonic acid, carboxylic acid, and phosphonic acid; provided that when R 6 is hydroxy, alkylamino, or hydroxyalkylamino, m is the integer 0;
R a represents 1-4 substituents each of which is independently selected from the group consisting of hydrogen, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, cyano, nitro, optionally substituted alkylthio, optionally substituted alkylsulfonyl, carboxylic acid, and sulfonic acid; or R a represents 2-4 substituents where 2 of said substituents are adjacent substituents and are taken together with the attached carbons to form an optionally substituted heterocycle, and where any remaining substituents are each independently selected from the group consisting of hydrogen, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, cyano, nitro, optionally substituted alkylthio, optionally substituted alkylsulfonyl, carboxylic acid, and sulfonic acid;
R d represents 1-4 substituents each of which is independently selected from the group consisting of hydrogen, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, cyano, nitro, optionally substituted alkylthio, optionally substituted alkylsulfonyl, carboxylic acid, and sulfonic acid; or R d represents 2-4 substituents where 2 of said substituents are adjacent substituents and are taken together with the attached carbons to form an optionally substituted heterocycle, and where any remaining substituents are each independently selected from the group consisting of hydrogen, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, cyano, nitro, optionally substituted alkylthio, optionally substituted alkylsulfonyl, carboxylic acid, and sulfonic acid, and
wherein at least one of R a or R d is not hydrogen.