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US 2014/0194472 A1Published application
Vitamin d receptor-coregulator inhibitors
AssigneesWomen & Infants Hospital of Rhode Island, UWM Research Foundation, Inc.
InventorsAlexander E. Arnold, Preetpal Singh Sidhu, Premchendar Nandhikonda, Rakesh K. Singh
Life of this patent
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Abstract
Described herein are compounds, pharmaceutical compositions and methods for inhibiting the expression of a vitamin D receptor target gene, inhibiting interactions between the vitamin D receptor and at least one vitamin D receptor coactivator, for treating cancer in a subject, and for inhibiting angiogenesis in a subject.
Claims96
A compound of formula (I):
- wherein:
- m is 0, 1, 2, 3, 4 or 5;
- n is 0, 1, 2, 3, or 4;
- p is 0, 1, 2, 3, 4 or 5;
- each R1, R2 and R3 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido;
- A is selected from the group consisting of aryl, heteroaryl and heterocyclyl;
- and
- B is selected from the group consisting of aryl, heteroaryl and heterocyclyl;
- wherein the compound is not N-((2-methyl-1H-indol-3-yl)(phenyl)methyl)aniline, N-((2-methyl-1H-indol-3-yl)(2-nitrophenyl)methyl)aniline, N-((4-methoxyphenyl)(2-methyl-1H-indol-3-yl)methyl)-4-methylaniline, 4-methyl-N-((2-methyl-1H-indol-3-yl)(phenyl)methyl)aniline or N-((2-methyl-1H-indol-3-yl)(phenyl)methyl)naphthalen-2-amine;
- wherein A is not pyridyl or tetrahydropyranyl;
- wherein B is not
- and
- wherein when B is pyridyl, A is not isoxazolyl or thiazolyl.
10 more elements
A compound of formula (II):
- wherein:
- m is 0, 1, 2, 3, 4 or 5;
- p is 0, 1, 2, 3, 4 or 5;
- X is O, S, SO, SO2 or NH;
- R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido, or R1 and R2 are taken together with the atoms to which they are attached to form an optionally substituted ring;
- R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido;
- wherein if R1 and R2 are taken together with the atoms to which they are attached to form a phenyl ring, then R3 is not methyl;
- each R5 and R6 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido;
- A is selected from the group consisting of aryl, heteroaryl and heterocyclyl;
- and
- B is selected from the group consisting of aryl, heteroaryl and heterocyclyl.
8 more elements
A pharmaceutical composition comprising a compound of formula (III):
- wherein:
- m is 0, 1, 2, 3, 4 or 5;
- n is 0, 1, 2, 3, or 4;
- p is 0, 1, 2, 3, 4 or 5;
- each R1, R2 and R3 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido;
- A is selected from the group consisting of aryl, heteroaryl and heterocyclyl;
- and
- B is selected from the group consisting of aryl, heteroaryl and heterocyclyl;
- wherein A is not pyridyl
- wherein when B is pyridyl, A is not isoxazolyl or thiazolyl;
- and a pharmaceutically acceptable carrier.
8 more elements
A method of inhibiting the expression of a vitamin D receptor target gene in a sample, comprising contacting the sample with an effective amount of a compound of formula (IV):
- wherein:
- m is 0, 1, 2, 3, 4 or 5;
- p is 0, 1, 2, 3, 4 or 5;
- X is O, S, SO, SO2 or NH;
- R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido, or R1 and R2 are taken together with the atoms to which they are attached to form an optionally substituted ring;
- R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido;
- each R5 and R6 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido;
- A is selected from the group consisting of aryl, heteroaryl and heterocyclyl;
- and
- B is selected from the group consisting of aryl, heteroaryl and heterocyclyl.
7 more elements
A method of inhibiting an interaction between a vitamin D receptor and at least one vitamin D receptor coactivator in a sample, comprising contacting the sample with an effective amount of a compound of formula (IV):
- wherein:
- m is 0, 1, 2, 3, 4 or 5;
- p is 0, 1, 2, 3, 4 or 5;
- X is O, S, SO, SO2 or NH;
- R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido, or R1 and R2 are taken together with the atoms to which they are attached to form an optionally substituted ring;
- R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido;
- each R5 and R6 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido;
- A is selected from the group consisting of aryl, heteroaryl and heterocyclyl;
- and
- B is selected from the group consisting of aryl, heteroaryl and heterocyclyl.
7 more elements
A method of treating cancer in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula (IV):
- wherein:
- m is 0, 1, 2, 3, 4 or 5;
- p is 0, 1, 2, 3, 4 or 5;
- X is O, S, SO, SO2 or NH;
- R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido, or R1 and R2 are taken together with the atoms to which they are attached to form an optionally substituted ring;
- R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido;
- each R5 and R6 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido;
- A is selected from the group consisting of aryl, heteroaryl and heterocyclyl;
- and
- B is selected from the group consisting of aryl, heteroaryl and heterocyclyl.
7 more elements
A method of inhibiting angiogenesis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (IV):
- wherein:
- m is 0, 1, 2, 3, 4 or 5;
- p is 0, 1, 2, 3, 4 or 5;
- X is O, S, SO, SO2 or NH;
- R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido, or R1 and R2 are taken together with the atoms to which they are attached to form an optionally substituted ring;
- R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido;
- each R5 and R6 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, acylamido, acyloxy, alkoxy, amido, amino, carboxy, cyano, ester, halo, haloalkyl, hydroxy, imino, nitro, phosphonate, sulfinyl, sulfonyl, sulfonate, sulfonamino, sulfonamido, thioamido, thiol, and ureido;
- A is selected from the group consisting of aryl, heteroaryl and heterocyclyl;
- and
- B is selected from the group consisting of aryl, heteroaryl and heterocyclyl.
7 more elements
Dependencies are inferred from the claim text.