US2020331828A1PendingUtilityA1
Novel compounds which activate estrogen receptors and compositions and methods of using the same
Est. expiryJan 6, 2036(~9.4 yrs left)· nominal 20-yr term from priority
Inventors:John A. KatzenellenbogenBenita KatzenellenbogenSung Hoon KimZeynep Madak-ErdoganPhilip Shaul
A61P 35/00C07C 39/17C07C 49/733C07C 39/42C07C 49/755C07C 2602/08A61P 25/00C07C 39/367C07C 39/06C07C 255/47C07C 235/34C07C 39/12C07C 2602/10C07C 39/23C07C 57/38C07C 2603/74C07C 43/196C07C 39/14C07C 2601/14
50
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Claims
Abstract
Provided are compounds of formulae provided herein. The compounds may include pathway-preferential estrogens (PaPEs) derivatives with tissue-selective activities. Also provided are pharmaceutical compositions comprising the compounds, as well as methods of treating a disease or condition including administering the compounds. The disease or condition may include postmenopausal symptoms, cardiovascular disease, stroke, vascular disease, bone disease, metabolic disease, arthritis, osteoporosis, obesity, vasomotor/hot flush, cognitive decline, cancer including breast cancer.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1 . A compound of formula (i):
and stereoisomers and pharmaceutically acceptable salts thereof;
wherein
n is an integer from 0 to 4;
m is an integer from 0 to 4;
X is H, hydroxy, or C 1-4 alkoxy;
R 1 and R 2 are independently H, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, amino, —S—C 1-4 alkyl, or halo;
R 3 is H, hydroxy, oxo, cyano, halo, C 1-4 alkyl, or C 1-4 alkoxy;
each R 4 is independently hydrogen, hydroxy, oxo, halo, C 1-4 alkyl, or C 1-4 alkoxy;
R 5 is H, C 1-4 alkynyl, or is absent if a double bond is present; and
- - - is an optional double bond.
2 . A compound according claim 1 , wherein C 1-4 alkyl or C 1-4 alkoxy is substituted with one or more of halo, cyano, amino, hydroxy, and C 1-4 alkoxy,
3 . A compound according to any one of claim 1 or 2 , wherein R 3 is hydroxyl.
4 . A compound according to any one of claims 1 - 3 , wherein at least one of R 1 and R 2 is C 1-4 alkyl.
5 . A compound according to claim 4 , wherein both R 1 and R 2 are C 1-4 alkyl.
6 . A compound according to claim 4 , wherein at least one of R 1 and R 2 is methyl.
7 . A compound according to claim 6 , wherein both R 1 and R 2 are methyl.
8 . A compound according to any one of claims 1 - 7 , wherein C 1-4 alkyl is substituted.
9 . A compound according to claim 8 , wherein the substituent is hydroxy.
10 . A compound according to any one of claims 1 - 9 , wherein R 1 and R 2 are independently selected from H, methyl, ethyl, chloro, —CH 2 OH, and —CH 2 OMe.
11 . A compound according to any one of claims 1 - 10 , wherein R 3 is selected from H, OH, oxo, chloro, cyano, or methoxy.
12 . A compound according to any one of claims 1 - 11 , wherein R 4 is selected from fluoro, chloro, bromo, methoxy, hydroxy, or oxo.
13 . A compound according to any one of claims 1 - 12 , wherein R 5 is H.
14 . A compound according to any one of claims 1 - 12 , wherein R 5 is —CCH.
15 . A compound according any one of claims 1 - 11 , 13 or 14 , wherein m is 0.
16 . A compound according to any one of claims 1 - 15 , wherein n is 1.
17 . A compound according to any one of claims 1 - 15 , wherein n is 2.
18 . A compound according to any one of claims 1 , 3 - 7 , 10 , 11 , 13 , 15 - 17 wherein the compound is selected from the group consisting of:
19 . A compound according to claim 1 of formula (ii):
and stereoisomers and salts thereof
wherein
R is H or methyl.
20 . A compound according to formula (iii):
and stereoisomers and salts thereof;
wherein
m is an integer from 0 to 3;
R 1 and R 2 are independently H, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, amino, —S—C 1-4 alkyl, or halo;
R 5 is H, hydroxy, or C 1-4 alkyl; and
each R 6 is independently H, hydroxy, halo, or C 1-4 alkyl.
21 . A compound according to claim 20 , wherein C 1-4 alkyl is substituted with one or more of halo, cyano, amino, hydroxy, and C 1-4 alkoxy.
22 . A compound according to any one of claim 20 or 21 , wherein at least one of R 1 and R 2 is C 1-4 alkyl.
23 . A compound according to claim 22 , wherein both R 1 and R 2 are C 1-4 alkyl.
24 . A compound according to claim 22 , wherein at least one of R 1 and R 2 is methyl.
25 . A compound according to claim 22 , wherein both R 1 and R 2 are methyl.
26 . A compound according to any one of claims 20 - 25 , wherein C 1-4 alkyl is substituted.
27 . A compound according to claim 26 , wherein the substituent is hydroxy.
28 . A compound according to any one of claims 20 - 27 , wherein R 5 is hydroxy.
29 . A compound according to any one of claims 20 - 27 , wherein R 5 is C 1-4 alkyl.
30 . A compound according to claim 29 , wherein R 5 is substituted C 1-4 alkyl.
31 . A compound according to claim 30 , wherein R 5 is —CH(OH)(CH 3 ).
32 . A compound according to any one of claims 20 - 31 , wherein R 6 is C 1-4 alkyl.
33 . A compound according to claim 32 , wherein R 6 is substituted C 1-4 alkyl.
34 . A compound according to claim 33 , wherein R 6 is —CH 2 OH.
35 . A compound according to any one of claims 18 - 32 , wherein m is 1.
36 . A compound according to any one of claims 20 - 35 selected from the group consisting of:
37 . A compound having the formula (iv):
wherein R 1 and R 2 is selected from H, C 1-4 alkyl group, haloalkyl, hydroxyalkyl, alkyloxyalkyl, cycloalkyloxyalkyl, alkylthio, alkylthioalkyl, cycloalkylthioalkyl, R′R″N-alkyl where R′ and R″ are independently alkyl, alkylcarbonyl, or cyclic alkyl, and the parenthesis represents the presence or absence of hydroxyl, and
wherein R 3 and R 4 are independently selected from H, hydroxy, C 1-4 alkyl, hydroxy-C 1-4 alkyl, cyano, cyanoalkyl, nitro, nitroalkyl, —C(O)-aryl, —C(O)H, alkyl aldehyde, carboxyl, and carboxyalkyl, or wherein
R 3 and R 4 form a ring of from 4 to 8 member atoms, wherein the ring is substituted with cyano or hydroxy.
38 . A compound according to claim 37 , of formula (v):
wherein R 5 and R 6 are independently selected from hydroxyl, cyano, hydroxylalkyl, cyanoalkyl, halogenated hydroxylalkyl, and halogenated cyanoalkyl.
39 . A compound according to formula (vi):
and stereoisomers and pharmaceutically acceptable salts thereof;
wherein
n is an integer from 0 to 4;
m is an integer from 0 to 4;
X is H, hydroxy, or C 1-4 alkoxy;
R 1 and R 2 are independently H, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, amino, —S—C 1-4 alkyl, or halo;
R 3 is H, hydroxy, oxo, cyano, halo, C 1-4 alkyl, or C 1-4 alkoxy;
each R 4 is independently hydrogen, hydroxy, oxo, halo, C 1-4 alkyl, or C 1-4 alkoxy;
R 5 is H, alkynyl, or is absent if a double bond is present;
R 6 and R 7 are independently selected from C 1-4 alkyl and H; and
- - - is an optional double bond.
40 . A compound according claim 39 , wherein C 1-4 alkyl or C 1-4 alkoxy is substituted with one or more of halo, cyano, amino, hydroxy, and C 1-4 alkoxy,
41 . A compound according to any one of claim 39 or 40 , wherein R 3 is hydroxyl.
42 . A compound according to any one of claims 39 - 41 , wherein at least one of R 1 and R 2 is C 1-4 alkyl.
43 . A compound according to claim 42 , wherein both R 1 and R 2 are C 1-4 alkyl.
44 . A compound according to claim 42 , wherein at least one of R 1 and R 2 is methyl.
45 . A compound according to claim 44 , wherein both R 1 and R 2 are methyl.
46 . A compound according to any one of claims 39 - 45 , wherein C 1-4 alkyl is substituted.
47 . A compound according to claim 46 , wherein the substituent is hydroxy.
48 . A compound according to any one of claims 39 - 47 , wherein R 1 and R 2 are independently selected from H, methyl, ethyl, chloro, —CH 2 OH, and —CH 2 OMe.
49 . A compound according to any one of claims 39 - 48 , wherein R 3 is selected from H, OH, oxo, chloro, cyano, or methoxy.
50 . A compound according to any one of claims 39 - 49 , wherein R 4 is selected from fluoro, chloro, bromo, methoxy, hydroxy, or oxo.
51 . A compound according to any one of claims 39 - 50 , wherein R 5 is H.
52 . A compound according to any one of claims 39 - 50 , wherein R 5 is —CCH.
53 . A compound according any one of claims 39 - 49 , 51 , or 52 , wherein m is 0.
54 . A compound according to any one of claims 39 - 53 , wherein n is 1.
55 . A compound according to any one of claims 39 - 54 , wherein n is 2.
56 . A compound according to any one of claims 39 - 55 , wherein R 6 is methyl.
57 . A compound according to any one of claims 39 - 56 , wherein R 7 is H.
58 . A compound according to formula (vii):
and stereoisomers and salts thereof;
wherein
R 7 and R 8 are independently H, C 1-5 alkyl, amino, hydroxyl, cyano, amido, cyclic C 3-8 alkyl, or heterocyclyl.
59 . A compound according to claim 58 , wherein R 7 and R 8 are selected from C 1-4 alkylaminocarboxy-C 1-4 alkyl, C 1-4 alkylamino-C 1-4 alkyl, C 1-4 alkylamino-C 1-4 alkyl-amino-carboxy-C 1-4 alkyl, C 1-4 alkyloxy-C 1-4 alkylamino-carboxy-C 1-4 alkyl, C 1-4 alkylthio-C 1-4 alkylamino-carboxy-C 1-4 alkyl, or C 1-4 alkylthio-C 1-4 alkyl.
60 . A compound according to claim 58 or 59 , wherein R 7 is methyl.
61 . A compound according to any one of claims 58 - 60 , wherein R 8 is substituted C 1-5 alkyl.
62 . A compound according to claim 61 , wherein R 8 is substituted with —C(O)—R, —C(O)NR N1 R N2 , —C(O)OR, —NR N1 C(O)R, or —OC(O)R, wherein R N1 , R N2 and R are independently selected from H or C 1-4 alkyl.
63 . A compound according to claim 62 , wherein at least one of R N1 , R N2 , or R is —(CH 2 ) n —R 10 , wherein n is an integer of from 2 to 5, and wherein R 10 is —C(O)—R, —C(O)NR N1 R N2 , —C(O)OR, —NR N1 C(O)R, or —OC(O)R, wherein R N1 , R N2 and R are independently selected from H, aryl, cycloalkyl, or C 1-4 alkyl optionally substituted with OH or amino.
64 . A compound according to any one of claims 58 - 63 , wherein the compound is
65 . A compound selected from the group consisting of
and stereoisomers and pharmaceutically acceptable salts thereof.
66 . A compound according to claim 65 , selected from the group consisting of
and pharmaceutically acceptable salts thereof.
67 . A pharmaceutical composition comprising a compound of any one of claims 1 - 66 and a pharmaceutically acceptable excipient.
68 . A method of treating a disease or condition in a subject, the method comprising administering a therapeutically effective amount of a compound or composition according to any one of claims 1 - 67 .
69 . The method of claim 68 wherein the disease or condition is affected by the extranuclear-initiated pathway of the estrogen receptor.
70 . The method of any one of claim 68 or 69 , wherein the disease or condition is selected from postmenopausal symptoms, cardiovascular disease, stroke, vascular disease, bone disease, metabolic disease, arthritis, osteoporosis, obesity, vasomotor/hot flush, cognitive decline, and cancer.
71 . The method of any one of claims 68 - 70 , wherein the disease is stroke.
72 . The method of any one of claims 68 - 70 , wherein the disease is metabolic disease.
73 . The method of any one of claims 68 - 70 , wherein the cancer is breast cancer.
74 . The method of claim 73 , wherein the disease is obesity-related breast cancer.
75 . The method of claim 73 , wherein the disease is estrogen-responsive breast cancer.
76 . The method of any one of claims 68 - 70 , wherein the disease is vascular disease.
77 . The method of any one of claims 68 - 70 , wherein the disease is osteoporosis.
78 . The method of any one of claims 68 - 77 , wherein the subject is human.
79 . A kit comprising a compound or composition of any one of claims 1 - 67 and instructions for use.Join the waitlist — get patent alerts
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