US2017298033A1PendingUtilityA1
Bisphenol derivatives and their use as androgen receptor activity modulators
Est. expiryApr 15, 2036(~9.8 yrs left)· nominal 20-yr term from priority
Inventors:Raymond AndersenMarianne Dorothy SadarKunzhong JianNasrin R. MawjiJun WangCarmen Adriana BanuelosYu-Chi Yang
A61P 35/00A61P 43/00A61P 35/04A61P 27/02A61P 13/08A61P 21/00A61P 17/02A61P 15/00A61P 17/14A61P 17/00C07C 233/18A61K 31/5375C07C 43/23C07D 295/088C07C 317/28C07D 233/60C07C 311/04A61K 31/4164A61K 31/09C07C 317/18C07C 317/22A61K 45/06A61K 31/10C07C 311/51C07C 69/28A61K 31/145A61P 17/10C07C 69/63C07C 311/05C07C 217/36A61K 31/165C07C 317/16A61K 31/222C07C 69/02
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Claims
Abstract
Compounds having a structure of Formula I: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1 , R 2 , R 3 , R 11a , R 11b , R 11c , R 11d , and X, are as defined herein, are provided. Uses of such compounds for modulating androgen receptor activity, imaging diagnostics in cancer and therapeutics, and methods for treatment of subjects in need thereof, including prostate cancer are also provided.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having the following structure (I):
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
X is —S(O) n — or —C(R 8 R 9 )—;
R 1 is H, hydroxyl or —OC(═O)R 13 ;
R 2 is hydroxyl or —OC(═O)R 13 ;
R 3 is halo, —OH, —OR 4 ; —OC(═O)R 13 , —NH 2 , —NHC(═O)R 13 , —N(C(═O)R 13 ) 2 , —NHS(O) n R 5 , —N(C(═O)R 13 )(S(O) n R 5 ), —N(C 1 -C 6 alkyl)(S(O) n R 5 ), —S(O) n R 5 , —N 3 , aryl, carbocyclyl, heteroaryl or heterocyclyl which are optionally substituted with one or more R 6 ;
R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, carbocyclyl, heteroaryl or heterocyclyl which are optionally substituted with one or more R 6 ;
R 5 is each independently C 1 -C 6 alkyl or aryl which are optionally substituted with one or more R 6 ;
R 6 is each independently selected from the group consisting of H, F, Cl, Br, I, 123 I, hydroxyl, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 6 -C 12 aryl, wherein each R 6 is optionally substituted with one or more of halogen, 123 I, 18 F, hydroxyl, —OS(O) 2 -aryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 8 and R 9 are each independently H or C 1 -C 6 alkyl;
R 11a , R 11b , R 11c and R 11d are each independently H, methyl, F, Cl, Br, I, or 123 I;
R 13 is C 1 -C 6 alkyl; and
n is 0, 1, or 2;
wherein at least one of R 11a , R 11b , R 11c and R 11d is methyl F, Cl, Br, I, or 123 I.
2 . The compound of claim 1 , wherein at least two of R 11a , R 11b , R 11c and R 11d are methyl, F, Cl, Br, I, or 123 I.
3 . The compound of claim 1 , wherein any two of R 11a , R 11b , R 11c and R 11d are independently methyl, F, Cl, Br, I, or 123 I and the remaining two of R 11a , R 11b , R 11c and R 11d are each H.
4 . The compound of claim 1 , wherein R 11a and R 11b are each H; and R 11c and R 11d are each independently methyl, F, Cl, Br, I, or 123 I.
5 . The compound of claim 4 , wherein R 11c and R 11d are each independently methyl, Cl, or Br.
6 . The compound of claim 5 , wherein R 11c and R 11d are each Cl.
7 . The compound of claim 1 , wherein R 11a and R 11c are each H; and R 11b and R 11d are each independently methyl, F, Cl, Br, I, or 123 I.
8 . The compound of claim 7 , wherein R 11b and R 11d are each independently methyl, Cl, or Br.
9 . The compound of claim 8 , wherein R 11b and R 11d are each Cl.
10 . The compound of claim 1 , wherein X is —S(O) 2 —.
11 . The compound of claim 1 , wherein X is —C(R 8 R 9 )— and R 8 and R 9 are each independently C 1 -C 3 alkyl.
12 . The compound of claim 11 , wherein R 8 an R 9 are each methyl.
13 . The compound of claim 1 , wherein R 1 and R 2 are each independently hydroxyl or —OC(═O)R 13 .
14 . The compound of claim 13 , wherein R 1 and R 2 are both hydroxyl.
15 . The compound of claim 13 , wherein R 1 and R 2 are both —OC(═O)R 13 .
16 . The compound of claim 13 , wherein R 1 and R 2 are both —OC(═O)R 13 , wherein R 13 is methyl.
17 . The compound of claim 1 , wherein R 1 is H.
18 . The compound of claim 1 , wherein R 3 is —OH.
19 . The compound of claim 1 , wherein R 3 is —OC(═O)R 13 .
20 . The compound of claim 1 , wherein R 3 is —OC(═O)R 13 , wherein R 13 is methyl.
21 . The compound of claim 1 , wherein R 3 is —OR 4 and R 4 is C 1 -C 6 alkyl.
22 . The compound of claim 21 , wherein R 4 is a methyl, ethyl, n-propyl, or i-propyl.
23 . The compound of claim 1 , wherein R 3 is F.
24 . The compound of claim 1 , wherein R 3 is an optionally substituted 5 or 6 membered heteroaryl or an optionally substituted 3 to 7 membered heterocylyl, wherein said heteroaryl or said heterocyclyl respectively comprise at least one N atom.
25 . The compound of claim 1 , wherein R 3 is selected from a group consisting of pyrrole, furan, thiophene, pyrazole, pyridine, pyridazine, pyrimidine, imidazole, thiazole, isoxazole, oxadiazole, thiadiazole, oxazole, triazole, isothiazole, oxazine, triazine, azepine, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine, and tetrazine.
26 . The compound of claim 1 , wherein R 3 is —NH 2 , —NHC(═O)R 13 , —N(C(═O)R 13 ) 2 , —NHS(O) n R 5 , —N(C(═O)R 13 )(S(O) n R 5 ), —N(C 1 -C 6 alkyl)(S(O) n R 5 ) or —S(O) n R 5 .
27 . The compound of claim 26 , wherein R 3 is —NH 2 , —NHC(═O)(C1-C4 alkyl), —N[(C(═O)(C1-C4 alkyl)] 2 , —NHS(O) n (C1-C3 alkyl), —N[C(═O)(C1-C4 alkyl)][(S(O) n (C1-C3 alkyl)], —N[C1-C6 alkyl][S(O) n (C1-C3 alkyl)], or —S(O) n (C1-C3 alkyl).
28 . The compound of claim 1 , wherein each R 13 is C 1 -C 4 alkyl.
29 . The compound of claim 28 , wherein each R 13 is methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, i-butyl, or sec-butyl.
30 . The compound of claim 1 , wherein R 1 and R 2 are each independently —OH or —OC(═O)R 13 , wherein R 13 is methyl.
31 . The compound of claim 1 , wherein at least one of R 1 , R 2 and R 3 is —OC(═O)R 13 , wherein R 13 is methyl.
32 . The compound of claim 1 , wherein any two of R 1 , R 2 and R 3 are each —OC(═O)R 13 , wherein R 13 is methyl.
33 . The compound of claim 32 , wherein R 1 and R 2 are each —OC(═O)R 13 , wherein R 13 is methyl.
34 . The compound of claim 1 , wherein R 1 , R 2 and R 3 are each —OC(═O)R 13 , wherein R 13 is methyl.
35 . The compound of claim 1 , wherein the compound has one of the following structures:
or pharmaceutically acceptable salt thereof.
36 . The compound of claim 1 , wherein the compound has one of the following structures:
or a pharmaceutically acceptable salt thereof.
37 . A compound having the following structure (II):
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
R 1 is H, —OH or —OC(═O)R;
R 2 is —OH or —OC(═O)R 13 ;
R 3 is halo, —OH, —OR, —OC(═O)R 13 , —NH 2 , NHC(═O)R 13 , —N(C(═O)R 13 ) 2 , —NHS(O) n R 5 , —N(C 1 -C 6 alkyl)S(O) n R 5 , —N(C(═O)R 13 )(S(O) n R 5 ), —S(O) n R 5 , —N 3 , aryl, carbocyclyl, heteroaryl or heterocyclyl which are optionally substituted with one or more R 6 ;
R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, carbocyclyl, heteroaryl or heterocyclyl which are optionally substituted with one or more R 6 ;
R 5 is each independently C 1 -C 6 alkyl or aryl which are optionally substituted with one or more R 6 ;
R 6 is each independently selected from the group consisting of H, F, Cl, Br, I, 123 I, hydroxyl, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 6 -C 12 aryl, wherein each R 6 is optionally substituted with one or more of halogen, 123 I, 18 F, hydroxyl, —OS(O) 2 -aryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; and
n is 0, 1, or 2.
38 . The compound of claim 37 , wherein R 1 is —OH or —OC(═O)R 13 .
39 . The compound of claim 37 , wherein R 1 is H.
40 . The compound of claim 37 , wherein R 3 is —OH.
41 . The compound of claim 37 , wherein R 3 is —OC(═O)R 13 , wherein R 13 is methyl.
42 . The compound of claim 37 , wherein R 3 is —OR 4 , wherein R 4 is C 1 -C 6 alkyl.
43 . The compound of claim 37 , wherein R 4 is methyl.
44 . The compound of claim 37 , wherein R 3 is optionally substituted 5 or 6 membered heteroaryl or optionally substituted 3 to 7 membered heterocylyl, wherein said heteroaryl or said heterocyclyl respectively comprise at least one N atom.
45 . The compound of claim 37 , wherein R 3 is selected from a group consisting of pyrrole, furan, thiophene, pyrazole, pyridine, pyridazine, pyrimidine, imidazole, thiazole, isoxazole, oxadiazole, thiadiazole, oxazole, triazole, isothiazole, oxazine, triazine, azepine, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine, and tetrazine.
46 . The compound of claim 1 , wherein R 3 is —NH 2 , —NHC(═O)R 13 , —N(C(═O)R 13 ) 2 , —NHS(O) n R 5 , —N(C(═O)R 13 )(S(O) n R 5 ), —N(C 1 -C 6 alkyl)(S(O) n R 5 ) or —S(O) n R 5 .
47 . The compound of claim 46 , wherein R 3 is —NH 2 , —NHC(═O)(C1-C4 alkyl), —N[(C(═O)(C1-C4 alkyl)] 2 , —NH[S(O) n (C1-C3 alkyl)], —N[C(═O)(C1-C4 alkyl)][(S(O) n (C1-C3 alkyl)], —N[C1-C6 alkyl][S(O) n (C1-C3 alkyl)], or —S(O) n (C1-C3 alkyl).
48 . The compound of claim 37 , wherein each R 13 is C 1 -C 4 alkyl.
49 . The compound of claim 37 , wherein R 1 and R 2 are each independently OH or —OC(═O)R 13 , wherein R 13 is methyl.
50 . The compound of claim 37 , wherein at least one of R 1 , R 2 and R 3 is —OC(═O)R 13 , wherein R 13 is methyl.
51 . The compound of claim 37 , wherein any two of R 1 , R 2 and R 3 are each —OC(═O)R 13 , wherein R 13 is methyl.
52 . The compound of claim 37 , wherein R 1 , R 2 and R 3 are each —OC(═O)R 13 , wherein R 13 is methyl.
53 . The compound of claim 37 , wherein R 1 , R 2 and R 3 are each —OH.
54 . The compound of claim 37 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
55 . A pharmaceutical composition comprising a compound of any one of claims 1 - 54 and a pharmaceutically acceptable carrier.
56 . The pharmaceutical composition of claim 55 , further comprising an additional therapeutic agent.
57 . The pharmaceutical composition of claim 56 , wherein the additional therapeutic agent is for treating prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration.
59 . The pharmaceutical composition of claim 56 , wherein the additional therapeutic agent is enzalutamide, galeterone, abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, bevacizumab (Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX 011, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111, ODM-201, ODM-204, niclosamide, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10-AR441bsAb, sintokamide, radium 233, or related compounds thereof.
60 . A method for modulating androgen receptor activity, comprising: administering a pharmaceutical composition according to claim 55 to a subject in need thereof.
61 . The method of claim 60 , wherein the modulating androgen receptor (AR) is inhibiting androgen receptor.
62 . The method of claim 61 , wherein the modulating AR is inhibiting transactivation of androgen receptor N-terminal domain (NTD).
63 . The method of claim 60 , wherein the subject is human.
64 . The method of any one of claims 60 - 63 , wherein the modulating AR is for treating a condition or disease selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration.
65 . The method of claim 64 , wherein the condition or disease is prostate cancer.
66 . The method of claim 65 , wherein the prostate cancer is primary or localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, advanced prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer
67 . The method of claim 65 , wherein the prostate cancer is CRPC.
68 . The method of claim 65 , wherein the prostate cancer express full-length androgen receptor (AR) or truncated AR splice variant.Cited by (0)
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