US2023202983A1PendingUtilityA1
Cannabinoid receptor mediating compounds
Assignee: THE USA AS REPRESENTED BY THE SEC DEP OF HEALTH AND HUMAN SERVICESPriority: Nov 13, 2012Filed: Sep 29, 2022Published: Jun 29, 2023
Est. expiryNov 13, 2032(~6.3 yrs left)· nominal 20-yr term from priority
C07D 401/12C07D 231/06C07D 417/12C07D 409/12C07D 403/12A61P 3/04A61P 35/00A61P 3/10
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Claims
Abstract
A compound, or a pharmaceutically acceptable salt or ester thereof, comprising (i) a CB1 receptor mediating scaffold conjugated to (ii) a second therapeutic scaffold.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:
wherein A is an amidino-containing moiety, a hydrazino-containing moiety,
R 1 , R 2 , and R 3 are each independently selected from optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, optionally-substituted boronate, optionally-substituted silyl, or imino;
X is SO 2 or C═O;
R 10 , R 11 , R 12 , R 13 and R 20 are each independently selected from H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, optionally-substituted boronate, optionally-substituted silyl, or imino;
R 21 is optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, optionally-substituted boronate, optionally-substituted silyl, or imino;
M is S or Se;
a, b, and c are each independently 0, 1, 2, 3, 4 or 5;
m, x, and y are each independently 0, 1, 2, 3, 4, 5 or 6;
d is 0 or 1; and
z is 1 or 2.
2 . The compound of claim 1 , wherein A is an amidino-containing moiety having a structure of
wherein R 4 is selected from H, optionally-substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, optionally-substituted boronate, optionally-substituted silyl, or imino; and R 5 is selected from optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, optionally-substituted boronate, optionally-substituted silyl, or imino
3 . The compound of claim 2 , wherein R 4 is H, hydroxy, C 1 -C 6 alkyl, or acyl.
4 . The compound of claim 2 or 3 , wherein R 5 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, amino, phenyl, heteroaryl, acyl or heterocycloalkyl.
5 . The compound of claim 2 or 4 , wherein R 4 is H.
6 . The compound of claim 1 , wherein the amidino-containing moiety of A is a biguanidino-containing moiety having a structure of
wherein R 4 , R 6 , R 7 , and R 8 are each independently selected from H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, optionally-substituted boronate, optionally-substituted silyl, or imino.
7 . The compound of claim 6 , wherein R 4 and R 6 are each H.
8 . The compound of claim 6 or 7 , wherein R 7 and R 8 are each independently selected from H or C 1 -C 6 alkyl.
9 . The compound of claim 1 , wherein A is a hydrazino-containing moiety having a structure of
wherein R 9 is H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, optionally-substituted boronate, optionally-substituted silyl, or imino
10 . The compound of claim 9 , wherein R 9 is H or C 1 -C 6 alkyl.
11 . The compound of any one of claims 1 to 10 , wherein a and c are each one, R 1 is halogen, and R 3 is halogen.
12 . The compound of any one of claims 1 to 11 , wherein b is zero.
13 . The compound of any one of claims 1 to 12 , wherein X is SO 2 .
14 . The compound of claim 1 , wherein A is
wherein R 4 is H; R 5 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —N(alkyl) 2 , —NH(alkyl), phenyl, N-heteroaryl, N-heterocycloalkyl; and X is SO 2 .
15 . The compound of claim 1 , wherein the compound has a structure of:
16 . The compound of claim 15 , wherein A is —NH—NH 2 .
17 . The compound of claim 2 , wherein the compound has a structure of:
18 . The compound of claim 17 , wherein R 5 is methyl, phenyl, —NHBoc, pyridinyl, cyclopropyl, tert-butyl, morpholinyl, pyrrolidinyl, or —N(methyl) 2 .
19 . The compound of claim 1 , wherein the compound has a structure of:
wherein R 14 is H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, optionally-substituted boronate, optionally-substituted silyl, or imino
20 . The compound of claim 19 , wherein R 14 is H, acyl, or C 1 -C 6 alkyl.
21 . The compound of claim 1 , wherein the compound has a structure of:
22 . The compound of claim 1 , wherein the compound has a structure of:
wherein R 15 is H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, optionally-substituted boronate, optionally-substituted silyl, or imino
23 . The compound of claim 22 , wherein R 15 is H, C 1 -C 6 alkyl, or amino
24 . The compound of any one of claims 1 to 23 , wherein the compound is an S-enantiomer:
25 . The compound of claim 1 , wherein A constitutes at least a portion of a therapeutic scaffold.
26 . The compound of claim 25 , wherein the therapeutic scaffold comprises an antidiabetic agent, an anticancer agent, or an antiobesity agent.
27 . A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:
28 . A compound, or a pharmaceutically acceptable salt or ester thereof, comprising (i) a CB 1 receptor mediating scaffold and (ii) a second therapeutic scaffold.
29 . The compound of claim 28 , wherein the second therapeutic scaffold comprises an antidiabetic agent, an anticancer agent, or an antiobesity agent.
30 . The compound of claim 28 or 29 , wherein the compound is a 3-phenyl-N′-phenyl-N-imino-1H-pyrazole-1-carboximidiamide compound.
31 . The compound of claim 28 or 29 , wherein the CB 1 receptor mediating scaffold comprises a 3-phenyl-N′-phenyl-1H-pyrazole-1-carboximidiamide scaffold.
32 . The compound of any one of claims 1 to 31 , wherein the compound has a plasma half-life of 4 to 8 hours.
33 . The compound of any one of claims 1 to 32 , wherein the compound preferentially target CB 1 receptors in peripheral tissue, while not interacting with CB 1 receptors in brain tissue.
34 . A pharmaceutical composition comprising a compound of any one of claims 1 to 33 , and at least one pharmaceutically acceptable additive.
35 . A method for treating obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, a co-morbidity of obesity, dyslipidemias that predispose to arteriosclerotic heart disease, diabetic nephropathy, or gout, in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 33 .
36 . The method of claim 35 , comprising treating obesity in the subject.
37 . The method of claim 35 , comprising treating diabetes in the subject.
38 . A method of preventing or reversing the deposition of adipose tissue in a subject, comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1 to 33 .
39 . The method of any one of claims 35 to 38 , wherein administering of the compound causes substantially no adverse neuropsychiatric effects.
40 . The method of any one of claims 35 to 39 , wherein administering of the compound results in a ratio of maximum concentration in the brain to maximum concentration in plasma which is less than 0.1Cited by (0)
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