Sulfonanilide analogs as selective aromatase modulators (SAMs)
View Patent ↗Compounds and methods suppressing aromatase activity expression in cancer cells. Provided are compounds are those of formula I: wherein R 1 may be alkyl, cycloalkyl, haloalkyl, aryl, substituted aryl, haloaryl, alkoxy, alkylaryl, and arylalkyl; R 2 is H, alkyl, aryl, alkylaryl, arylalkyl, and cycloalkyl; R 3 , with the base nitrogen, forms an amide or sulfonamide; R 4 is selected from nitro, amine, amide, and benzamide; or a pharmaceutically acceptable salts thereof. Also provided are small molecule selective aromatase inhibitors having a molecular weight of less 500 g/mol. In some embodiments, the small molecule selective aromatase inhibitors described herein have a molecular weight of less than 450 g/mol. Also provided are methods for suppressing aromatase activity expression in cancer cells comprising the step of administering a pharmaceutically effective amount of a small molecule aromatase inhibitor to a subject in need of such treatment. In one embodiment, the cancer cells are breast cancer cells.
1. A compound of formula I:
wherein R 1 is selected from the group consisting of cycloalkyl, haloalkyl, aryl, substituted aryl, haloaryl, alkoxy, alkylaryl, and arylalkyl,
R 2 is selected from the group consisting of alkyl, aryl, alkylaryl, arylalkyl, and cycloalkyl;
R 3 , with the base nitrogen, forms a sulfonamide;
R 4 is selected from the group consisting of nitro, amine, amide, and benzamide;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein R 1 is selected from the group consisting of cyclopentyl, cyclohexyl, methylcyclohexyl, benzyl, nitrobenzyl, alkylbenzyl, dialkylbenzyl, alkoxybenzyl, halobenzyl, phenylalkyl, phenylbenzyl, phenylbenzyloxy, naphthyl, and naphthylmethyl; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 wherein R 1 is selected from the group consisting of cyclopentyl, cyclohexyl, methylcyclohexyl, ethylcyclohexyl, 1-methoxypropyl, and 1-ethoxypropyl; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 2 wherein R 1 is selected from the group consisting of nitrobenzyl, phenylbenzyl, naphthyl, naphthylmethyl, methoxybenzyl, isopropylbenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, dimethylbenzyl, and phenylethyl; or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4 wherein R 1 is selected from 4-nitrobenzyl, 2-phenylbenzyl, naphthyl, α-naphthylmethyl, β-naphthylmethyl, 4-methoxybenzyl, 4-isopropylbenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 3,6-dimethylbenzyl, and phenylethyl; or a pharmaceutically acceptable salt thereof.
6. The compound of claim 5 wherein R 1 is selected from the group consisting of phenylbenzyl and methylnaphthyl; or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 wherein R 1 is substituted aryl, and wherein the aryl substituent is selected from the group consisting of alkyl, aryl, halo, alkylaryl, arylalkyl, and combinations thereof or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 wherein R 2 is selected from C 1 to C 10 alkyl, wherein the alkyl may be straight chain, branched, or cyclic, or a combination thereof or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 wherein R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, pentyl, hexyl or cyclohexyl; or a pharmaceutically acceptable salt thereof.
10. The compound of claim 9 wherein R 2 is methyl; or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 wherein R 2 is selected from the group consisting of alkylaryl, benzyl, alkoxybenzyl, alkylbenzyl, halobenzyl, biphenyl, and naphthyl; or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11 wherein R 2 is selected from the group consisting of benzyl, methoxybenzyl, methylbenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, isopropylbenzyl, dimethylbenzyl, phenylbenzyl, and naphthyl; or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12 wherein R 2 is selected from the group consisting of benzyl, 4-methoxybenzyl, 4-methylbenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-isopropylbenzyl, 2,5-dimethylbenzyl, 4-phenylbenzyl, and 2-naphthyl; or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 wherein R 4 is selected from the group consisting of benzyl, cyanobenzamide, halobenzamide, dihalobenzamide, nitrobenzamide, naphthylamide; or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 wherein R 4 is selected from the group consisting of 4-cyanobenzamide, 3,4-dichlorobenzamide, 3-nitrobenzamide, and 2-naphthylamide; or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 wherein R 4 is an alkylamide; or a pharmaceutically acceptable salt thereof.
17. The compound of claim 16 wherein R 4 is cyclohexylamide; or a pharmaceutically acceptable salt thereof.
18. A method for suppressing aromatase activity expression in cancer cells comprising the step of administering a pharmaceutically effective amount of an aromatase inhibitor of structure I:
wherein R 1 is selected from the group consisting of cycloalkyl, haloalkyl, aryl, substituted aryl, haloaryl, alkoxy, alkylaryl, and arylalkyl,
R 2 is selected from the group consisting of alkyl, aryl, alkylaryl, arylalkyl, and cycloalkyl;
R 3 , with the base nitrogen, forms a sulfonamide;
R 4 is selected from the group consisting of nitro, amine, amide, and benzamide;
or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.
19. The method of claim 18 wherein the cancer cells are breast cancer cells.