US2018362500A1PendingUtilityA1
Vitamin d receptor-coregulator inhibitors
Est. expiryAug 26, 2031(~5.1 yrs left)· nominal 20-yr term from priority
A61K 45/06A61P 35/00C07D 209/14C07D 407/12C07D 209/16C07D 209/10C07D 401/12A61K 31/404A61K 2300/00
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Claims
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.
Claims
exact text as granted — not AI-modified1 . 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 R 1 , R 2 and R 3 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.
2 . The compound of claim 1 , wherein n is 0.
3 . The compound of any of claims 1 - 2 , wherein A is phenyl.
4 . The compound of claim 3 , wherein m is 0.
5 . The compound of claim 3 , wherein m is 1.
6 . The compound of claim 5 , wherein R 2 is selected from the group consisting of alkyl, alkoxy, amino, halo, haloalkyl and nitro.
7 . The compound of any of claims 1 - 2 , wherein B is phenyl.
8 . The compound of claim 7 , wherein p is 0.
9 . The compound of claim 7 , wherein p is 1.
10 . The compound of claim 9 , wherein R 3 is selected from the group consisting of alkyl, alkoxy, amino, halo, haloalkyl and nitro.
11 . The compound of claim 1 , wherein the compound is 4-chloro-N-((2-chlorophenyl)(2-methyl-1H-indol-3-yl)methyl)aniline.
12 . 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, SO 2 or NH;
R 1 and R 2 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 R 1 and R 2 are taken together with the atoms to which they are attached to form an optionally substituted ring;
R 3 and R 4 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 R 1 and R 2 are taken together with the atoms to which they are attached to form a phenyl ring, then R 3 is not methyl;
each R 5 and R 6 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.
13 . The compound of claim 12 , wherein R 3 is methyl.
14 . The compound of any of claims 12 - 13 , wherein R 4 is hydrogen.
15 . The compound of any of claims 12 - 14 , wherein A is phenyl.
16 . The compound of any of claims 12 - 15 , wherein B is phenyl.
17 . A pharmaceutical composition comprising a compound according to claim 12 and a pharmaceutically acceptable carrier.
18 . 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 R 1 , R 2 and R 3 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.
19 . The composition of claim 18 , wherein n is 0.
20 . The composition of any of claims 18 - 19 , wherein A is phenyl.
21 . The composition of claim 20 , wherein m is 0.
22 . The composition of claim 20 , wherein m is 1.
23 . The composition of claim 22 , wherein R 2 is selected from the group consisting of alkyl, alkoxy, amino, halo, haloalkyl and nitro.
24 . The composition of any of claims 18 - 23 , wherein B is phenyl.
25 . The composition of claim 24 , wherein p is 0.
26 . The composition of claim 24 , wherein p is 1.
27 . The composition of claim 26 , wherein R 3 is selected from the group consisting of alkyl, alkoxy, amino, halo, haloalkyl and nitro.
28 . The composition of claim 18 , wherein the compound is 4-chloro-N-((2-chlorophenyl)(2-methyl-1H-indol-3-yl)methyl)aniline
29 . 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, SO 2 or NH;
R 1 and R 2 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 R 1 and R 2 are taken together with the atoms to which they are attached to form an optionally substituted ring;
R 3 and R 4 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 R 5 and R 6 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.
30 . The method of claim 29 , wherein the compound has the following formula (V):
wherein:
n is 0, 1, 2, 3, or 4; and
each R 7 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.
31 . The method of any of claims 29 - 30 , wherein R 3 is methyl.
32 . The method of any of claims 29 - 31 , wherein R 4 is hydrogen.
33 . The method of claim 30 , wherein n is 0.
34 . The method of any of claims 29 - 33 , wherein A is phenyl.
35 . The method of claim 34 , wherein m is 0.
36 . The method of claim 34 , wherein m is 1.
37 . The method of claim 36 , wherein R 5 is selected from the group consisting of alkyl, alkoxy, amino, halo, haloalkyl and nitro.
38 . The method of any of claims 29 - 33 , wherein A is pyridyl.
39 . The method of any of claims 29 - 38 , wherein B is phenyl.
40 . The method of claim 39 , wherein p is 0.
41 . The method of claim 39 , wherein p is 1.
42 . The method of claim 41 , wherein R 6 is selected from the group consisting of alkyl, alkoxy, amino, halo, haloalkyl and nitro.
43 . The method of any of claims 29 - 42 , wherein X is NH.
44 . The method of claim 29 , wherein the compound is 4-chloro-N-((2-chlorophenyl)(2-methyl-1H-indol-3-yl)methyl)aniline.
45 . The method of any of claims 29 - 44 , wherein the target gene is TRPV6.
46 . 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, SO 2 or NH;
R 1 and R 2 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 R 1 and R 2 are taken together with the atoms to which they are attached to form an optionally substituted ring;
R 3 and R 2 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 R 5 and R 6 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.
47 . The method of claim 46 , wherein the compound has the following formula (V):
wherein:
n is 0, 1, 2, 3, or 4; and
each R 7 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.
48 . The method of any of claims 46 - 47 , wherein R 3 is methyl.
49 . The method of any of claims 46 - 48 , wherein R 4 is hydrogen.
50 . The method of claim 47 , wherein n is 0.
51 . The method of any of claims 46 - 50 , wherein A is phenyl.
52 . The method of claim 51 , wherein m is 0.
53 . The method of claim 51 , wherein m is 1.
54 . The method of claim 53 , wherein R 5 is selected from the group consisting of alkyl, alkoxy, amino, halo, haloalkyl and nitro.
55 . The method of any of claims 46 - 50 , wherein A is pyridyl.
56 . The method of any of claims 46 - 55 , wherein B is phenyl.
57 . The method of claim 56 , wherein p is 0.
58 . The method of claim 56 , wherein p is 1.
59 . The method of claim 58 , wherein R 6 is selected from the group consisting of alkyl, alkoxy, amino, halo, haloalkyl and nitro.
60 . The method of any of claims 46 - 59 , wherein X is NH.
61 . The method of claim 46 , wherein the compound is 4-chloro-N-((2-chlorophenyl)(2-methyl-1H-indol-3-yl)methyl)aniline.
62 . The method of any of claims 46 - 61 , wherein the at least one vitamin D receptor coactivator is selected from the group consisting of Akt, ARA55, ARA70, β-catenin, BRCA1, BRCA2, BRG1, Calreticulin, CARM1, CAV1, CBP, CDC-25B, CDK7, CFL1, CITED1, CoAA, Cyclin A1, Cyclin A2, Cyclin 1, Cyclin D3, Cyclin E1, DAP3, Daxx, DJ-1, DNAJB1, DRIP130, E6-AP, ELL, FKHR, Fli-1, FLNa, Gelsolin, HDAC3, HDAC4, HMG-1, HMG-2, JAB1, Ku80, LATS2/KPM, MGMT, MLL2, MN1, MTA1, MTA2, MUC1, N-CoR, NSD1, p-TEFb, p53, p54nrb, p57, p68, p300, PAD4, PARP-1, PCAF, PDEF, PDK1, PGC-1a, PGC-1β, PELP1, PIAS1, PIAS3, PIAS4, PIN1, PPM1D, PRAME, PUS1, RACK1, RAF1, RANBP2, Rb, REA, REG, SAF-A, SAP30, SENP1, Six3, SNURF, SRA, SRC-1, SRC-2, SRC-3, SRY, STAT3, SUMO-1, SYT, TBL1, TBP, TDG, TGIF, TLS, TRAP100, TRAP220, TRRAP, TSG101, UBC9, VAV3, and WSTF.
63 . 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, SO 2 or NH;
R 1 and R 2 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 R 1 and R 2 are taken together with the atoms to which they are attached to form an optionally substituted ring;
R 3 and R 4 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 R 5 and R 6 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.
64 . The method of claim 63 , wherein the compound has the following formula (V):
wherein:
n is 0, 1, 2, 3, or 4; and
each R 7 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.
65 . The method of any of claims 63 - 64 , wherein R 3 is methyl.
66 . The method of any of claims 63 - 65 , wherein R 4 is hydrogen.
67 . The method of claim 64 , wherein n is 0.
68 . The method of any of claims 63 - 67 , wherein A is phenyl.
69 . The method of claim 68 , wherein m is 0.
70 . The method of claim 68 , wherein m is 1.
71 . The method of claim 70 , wherein R 5 is selected from the group consisting of alkyl, alkoxy, amino, halo, haloalkyl and nitro.
72 . The method of any of claims 63 - 67 , wherein A is pyridyl.
73 . The method of any of claims 63 - 72 , wherein B is phenyl.
74 . The method of claim 73 , wherein p is 0.
75 . The method of claim 73 , wherein p is 1.
76 . The method of claim 75 , wherein R 6 is selected from the group consisting of alkyl, alkoxy, amino, halo, haloalkyl and nitro.
77 . The method of any of claims 63 - 76 , wherein X is NH.
78 . The method of claim 63 , wherein the compound is 4-chloro-N-((2-chlorophenyl)(2-methyl-1H-indol-3-yl)methyl)aniline.
79 . The method of any of claims 63 - 78 , wherein the cancer is selected from the group consisting of prostate cancer, ovarian cancer, endometrial cancer, breast cancer and colorectal cancer.
80 . The method of claim 79 , wherein the cancer is epithelial ovarian cancer.
81 . 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, SO 2 or NH;
R 1 and R 2 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 R 1 and R 2 are taken together with the atoms to which they are attached to form an optionally substituted ring;
R 3 and R 4 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 R 5 and R 6 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.
82 . The method of claim 81 , wherein the compound has the following formula (V):
wherein:
n is 0, 1, 2, 3, or 4; and
each R 7 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.
83 . The method of any of claims 81 - 82 , wherein R 3 is methyl.
84 . The method of any of claims 81 - 83 , wherein R 4 is hydrogen.
85 . The method of claim 82 , wherein n is 0.
86 . The method of any of claims 81 - 85 , wherein A is phenyl.
87 . The method of claim 86 , wherein m is 0.
88 . The method of claim 86 , wherein m is 1.
89 . The method of claim 88 , wherein R 5 is selected from the group consisting of alkyl, alkoxy, amino, halo, haloalkyl and nitro.
90 . The method of any of claims 81 - 85 , wherein A is pyridyl.
91 . The method of any of claims 81 - 90 , wherein B is phenyl.
92 . The method of claim 91 , wherein p is 0.
93 . The method of claim 91 , wherein p is 1.
94 . The method of claim 93 , wherein R 6 is selected from the group consisting of alkyl, alkoxy, amino, halo, haloalkyl and nitro.
95 . The method of any of claims 81 - 94 , wherein X is NH.
96 . The method of claim 81 , wherein the compound is 4-chloro-N-((2-chlorophenyl)(2-methyl-1H-indol-3-yl)methyl)aniline.Cited by (0)
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