US2010105654A1PendingUtilityA1
Substituted quinazolinone compounds
Est. expiryMay 23, 2023(expired)· nominal 20-yr term from priority
Inventors:Rustum BoyceNatalia AurrecoecheaDaniel ChuAaron SmithChristopher R. ConleeBrian D. ThompsonJudith De Armas KuntzDavid Lee MussoKevin BarvianStephen Andrew ThomsonWilliam R. SwainKien S. DuBrian A. ChauderJason D. SpeakeMichael J. Bishop
A61P 3/10A61P 43/00A61P 5/50C07D 417/14C07D 401/14C07D 239/95C07D 403/12C07D 487/04C07D 403/14C07D 471/04C07D 217/24C07D 401/06C07D 239/96C07D 403/06C07D 405/12C07D 401/12C07D 253/08C07D 239/91A61P 3/04C07D 401/04C07D 417/04
50
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Claims
Abstract
A variety of small molecule, guanidine-containing molecules capable of acting as MC4-R agonists are provided. The compounds are useful in treating MC4-R mediated diseases when administered to subjects. The compounds have the structures VA, VB, VIIA and VIIB where the values of the variables are defined herein.
Claims
exact text as granted — not AI-modified1 . A compound of formula VA, VB, mixtures thereof, or pharmaceutically acceptable salts of the compound,
wherein
R 1 is selected from substituted or unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups;
R 3 is selected from substituted or unsubstituted aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, or cycloalkylamino groups;
R 4 , R 5 , and R 6 are independently selected from H, Cl, I, F, Br, OH, NH 2 , CN, NO 2 , or substituted or unsubstituted alkoxy or alkyl groups;
R 1′ and R 2′ , together with the nitrogen to which they are bound, form a substituted or unsubstituted heterocyclyl group; and
R 3′ is selected from substituted or unsubstituted cycloalkyl groups.
2 . The compound of claim 1 , wherein R 4 , R 5 , and R 6 are all H.
3 . The compound of claim 1 , wherein R 3′ is a substituted or unsubstituted polycyclic cycloalkyl group.
4 . The compound of claim 3 , wherein R 3′ is a substituted or unsubstituted polycyclic cycloalkyl group of formula VIII
5 . The compound of claim 1 , wherein R 1 is a substituted or unsubstituted arylalkyl group.
6 . The compound of claim 5 , wherein R 1 is a substituted phenylethyl group.
7 . The compound of claim 6 , wherein R 1 is a 4-substituted phenylethyl group or is a 2,4-disubstituted phenylethyl group.
8 . The compound of claim 6 , wherein R 1 is selected from 2-fluoro-4-methoxyphenylethyl, 2-chloro-4-methoxyphenylethyl, 4-fluorophenylethyl, 4-chlorophenylethyl, 4-chloro-2-fluorophenylethyl, 2,4-dichlorophenylethyl, 4-bromophenylethyl, or 4-bromo-2-fluorophenylethyl groups.
9 . The compound of claim 1 , wherein R 1 is selected from phenylethyl, 2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-phenoxyphenylethyl, 4-bromophenylethyl, 4-methylphenylethyl, 4-chlorophenylethyl, 4-fluorophenylethyl, 4-ethylphenylethyl, cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl, 2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, indolylethyl, 4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl, 2-fluoro-4-methylphenylethyl, 4-chloro-2-fluorophenylethyl, 4-bromo-2-fluorophenylethyl, 2-fluoro-4-methoxyphenylethyl, 2-trifluoromethyl-4-fluorophenylethyl, 2,4-difluorophenylethyl, 2,4-dimethylphenylethyl, 2,4-dimethoxyphenylethyl, (2-pyridyl)ethyl, (3-pyridyl)ethyl, (4-pyridyl)ethyl, (pyridyl)(hydroxymethyl)ethyl, or (phenyl)(hydroxymethyl)ethyl groups.
10 . The compound of claim 1 , wherein R 3 is selected from substituted or unsubstituted heterocyclyl groups, or substituted or unsubstituted heteroaryl groups.
11 . The compound of claim 10 , wherein R 3 is selected from substituted or unsubstituted pyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, thiophenyl, tetrahydrothiophenyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrazinyl, thiazolyl, pyrimidinyl, quinuclidinyl, indolyl, imidazolyl, triazolyl, tetrazolyl, or pyridazinyl groups.
12 . The compound of claim 1 , wherein R 3 is selected from heteroaryl or heterocyclyl groups of formula
which may be additionally substituted or may be unsubstituted.
13 . The compound of claim 1 , wherein R 3 is selected from aryl or cycloalkyl groups of formula
which may be additionally substituted or may be unsubstituted.
14 . The compound of claim 1 , wherein R 1′ and R 2′ , together with the nitrogen to which they are bound, form a substituted or unsubstituted piperazinyl group.
15 . The compound of claim 14 , wherein R 1′ and R 2′ , together with the nitrogen to which they are bound, form a piperazinyl group that is substituted with at least one group selected from, fluoromethyl, difluoromethyl, or trifluoromethyl groups.
16 . The compound of claim 14 , wherein R 1′ and R 2′ , together with the nitrogen to which they are bound, form a piperazinyl group comprising at least one carbonyl group such that the piperazinyl group is a piperazinone that may be additionally substituted.
17 . The compound of claim 16 , wherein R 1′ and R 2′ , together with the nitrogen to which they are bound form a piperazinone of formula
which may be additionally substituted.
18 . The compound of claim 17 , wherein R 1′ and R 2′ , together with the nitrogen to which they are bound form a piperazinone of formula
19 . The compound of claim 18 , wherein R 1′ and R 2′ , together with the nitrogen to which they are bound form a piperazinone of formula
20 . The compound of claim 14 , wherein R 1′ and R 2′ , together with the nitrogen to which they are bound, form a piperazinyl group of formula
21 . The compound of claim 1 , wherein the compound is a compound of formula
22 . The compound of claim 1 , wherein the compound is a compound of formula
23 . The compound of claim 1 , wherein the compound is a compound of formula
24 . The compound of claim 1 , wherein the compound is a compound of formula
25 . The compound of claim 1 , wherein the compound is a compound of formula
26 . The compound of claim 1 , wherein the compound is a compound of formula
27 . The compound of claim 1 , wherein the compound is a compound of formula
28 . The compound of claim 1 , wherein the compound is a compound of formula
29 . The compound of claim 1 , wherein the compound is a compound of formula
30 . The compound of claim 1 , wherein the compound is a compound of formula
31 . The compound of claim 1 , wherein the compound is a compound of formula
32 . The compound of claim 1 , wherein the compound is a compound of formula
33 . The compound of claim 1 , wherein the compound is a compound of formula
34 . The compound of claim 1 , wherein the compound is a compound of formula
35 . The compound of claim 1 , wherein the compound is a compound of formula
36 . The compound of claim 1 , wherein the compound is a compound of formula
37 . The compound of claim 1 , wherein the compound is a compound of formula
38 . A pharmaceutical formulation comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
39 . A method of treating an MC4-R mediated disease, comprising administering to a subject in need thereof, the compound of claim 1 .
40 . The method according to claim 39 , wherein the disease is obesity or type II diabetes.
41 . The method according to claim 39 , wherein the compound exhibits a t 1/2 value of less than 35 hours in a tissue with high blood perfusion.
42 . The method according to claim 41 , wherein the tissue with high blood perfusion is selected from a brain, a liver, a kidney or a heart.
43 . A compound of formula VIIA, VIIB, mixtures thereof, or pharmaceutically acceptable salts of the compound,
wherein
R 1 is selected from substituted or unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups;
R 3 is selected from H or substituted or unsubstituted arylalkyl, heteroarylalkyl, alkoxy, alkylamino, dialkylamino, aryl, heteroaryl, heterocyclyl, cycloalkyl, aminocycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups;
R 4 , R 5 , and R 6 are independently selected from H, Cl, I, F, Br, OH, NH 2 , CN, NO 2 , or substituted or unsubstituted alkoxy or alkyl groups;
R 3′ is selected from H or substituted or unsubstituted aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, or cycloalkylalkyl groups; and
Y is selected from a moiety of formula
wherein
R 1′ is selected from substituted or unsubstituted alkyl groups;
R 2′ , R 4′ , and R 5′ are independently selected from H or substituted or unsubstituted alkyl groups;
R 6′ is selected from substituted or unsubstituted alkyl groups; or R 5′ and R 6′ , together with the nitrogen to which they are bound, form a heterocyclyl or heteroaryl group; and
R 7′ is selected from CN, or substituted or unsubstituted alkyl, aryl, or arylalkyl groups.
44 . The compound of claim 43 , wherein R 4 , R 5 , and R 6 are all H.
45 . The compound of claim 43 , wherein R 3′ is a substituted or unsubstituted polycyclic cycloalkyl group.
46 . The compound of claim 45 , wherein R 3′ is a substituted or unsubstituted polycyclic cycloalkyl group of formula VIII
47 . The compound of claim 43 , wherein R 1 is a substituted or unsubstituted arylalkyl group.
48 . The compound of claim 47 , wherein R 1 is a substituted phenylethyl group.
49 . The compound of claim 48 , wherein R 1 is a 4-substituted phenylethyl group or is a 2,4-disubstituted phenylethyl group.
50 . The compound of claim 47 , wherein R 1 is selected from 2-fluoro-4-methoxyphenylethyl, 2-chloro-4-methoxyphenylethyl, 4-fluorophenylethyl, 4-chlorophenylethyl, 4-chloro-2-fluorophenylethyl, 2,4-dichlorophenylethyl, 4-bromophenylethyl, or 4-bromo-2-fluorophenylethyl groups.
51 . The compound of claim 50 , wherein R 3 is selected from substituted or unsubstituted heterocyclyl groups or substituted or unsubstituted heteroaryl groups.
52 . The compound of claim 51 , wherein R 3 is selected from substituted or unsubstituted pyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, thiophenyl, tetrahydrothiophenyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrazinyl, thiazolyl, pyrimidinyl, quinuclidinyl, indolyl, imidazolyl, triazolyl, tetrazolyl, or pyridazinyl groups.
53 . The compound of claim 43 , wherein R 1 is selected from phenylethyl, 2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-phenoxyphenylethyl, 4-bromophenylethyl, 4-methylphenylethyl, 4-chlorophenylethyl, 4-fluorophenylethyl, 4-ethylphenylethyl, cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl, 2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, indolylethyl, 4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl, 2-fluoro-4-methylphenylethyl, 4-chloro-2-fluorophenylethyl, 4-bromo-2-fluorophenylethyl, 2-fluoro-4-methoxyphenylethyl, 2-trifluoromethyl-4-fluorophenylethyl, 2,4-difluorophenylethyl, 2,4-dimethylphenylethyl, 2,4-dimethoxyphenylethyl, (2-pyridyl)ethyl, (3-pyridyl)ethyl, (4-pyridyl)ethyl, (pyridyl)(hydroxymethyl)ethyl, or (phenyl)(hydroxymethyl)ethyl groups.
54 . The compound of claim 43 , wherein R 3 is selected from heteroaryl or heterocyclyl groups of formula
which may be additionally substituted or may be unsubstituted.
55 . The compound of claim 43 , wherein R 3 is selected from aryl, cycloalkyl, or aminocycloalkyl groups of formula
which may be additionally substituted or may be unsubstituted.
56 . The compound of claim 43 , wherein Y is selected from
57 . The compound of claim 57 , wherein Y is selected from
58 . A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and the compound of claim 43 .
59 . A method of treating an MC4-R mediated disease, comprising administering to a subject in need thereof, the compound of claim 43 .
60 . The method according to claim 59 , wherein the disease is obesity or type II diabetes.
61 . The method according to claim 59 , wherein the compound exhibits a t 1/2 value of less than 35 hours in a tissue with high blood perfusion.
62 . The method according to claim 61 , wherein the tissue with high blood perfusion is selected from a brain, a liver, a kidney or a heart.Cited by (0)
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