Compounds and methods for inducing UCP1 expression
View Patent ↗The compounds and methods of the present disclosure exhibit induce Ucp1 transcription, enhance of mitochondrial respiration, activate protein kinase A, increase lipolysis, and increase p38 MAPK phosphorylation in cells, particularly brown adipocytes and white adipocytes. They also protect primary cardiomyocytes against hypertrophy induced by adrenergic agonists. Such compounds and methods are useful in the treatment and prevention of conditions such as obesity and associated complex metabolic, endocrine, and hemodynamic changes, as well as related conditions as dyslipidemias, cardiovascular disease, and type 2 diabetes.
1 . A method of treating or preventing a condition, comprising administering to a subject in need thereof an effective amount of a compound of formula (Ia):
or a tautomer and/or salt thereof;
wherein:
X is S or CH 2 ;
R 1 is H, C 1-3 alkyl, or C 1-3 alkoxy;
R 2 is H or C 1-3 alkoxy;
R 3 is H, C 1-3 alkoxy, phenoxy, or benzyloxy;
R 4 is H, hydroxyl, C 1-3 alkoxy, or C 1-3 haloalkoxy;
or R 3 and R 4 combine to form a dioxane or dioxolane ring, including the atoms to which R 3 and R 4 are attached;
R 5 is H or C 1-3 alkyl;
R 6 is H;
R 7 is a quinazolin-4-on-2-yl group
wherein the phenyl ring of the quinazolin-4-on-2-yl group may be substituted or unsubstituted; and
R 8 is H, C 1-5 alkyl, C 1-5 alkenyl, or amino;
wherein the condition is selected from obesity and associated complex metabolic, endocrine, and hemodynamic changes, dyslipidemias, cardiovascular disease, and type 2 diabetes.
2 . The method of claim 1 , wherein:
R 1 is H, CH 3 , methoxy, or ethoxy;
R 2 is H or methoxy;
R 3 is H, methoxy, ethoxy, phenoxy, or benzyloxy;
R 4 is H, methoxy, ethoxy, tetrafluoroethoxy, or hydroxyl;
or R 3 and R 4 combine to form a dioxane or dioxolane ring, including the atoms to which R 3 and R 4 are attached; and
R 5 is H or methyl.
3 . The method of claim 2 , wherein:
R 2 is H;
R 3 is H, methoxy, ethoxy, or phenoxy; and
R 4 is H, methoxy, tetrafluoroethoxy, or hydroxyl;
or R 3 and R 4 combine to form a dioxane or dioxolane ring including the atoms to which R 3 and R 4 are attached.
4 . The method of claim 3 , wherein the compound of formula (Ia) is selected from:
or a tautomer and/or salt thereof.
5 . The method of claim 2 , wherein:
R 7 is
and
R 8 is H, CH 3 , ethyl, methoxypropyl, or amino.
6 . The method of claim 5 , wherein the compound of formula (Ia) is selected from:
or a tautomer and/or salt thereof.
7 . The method of claim 5 , wherein the compound of formula (Ia) is a compound of formula (Ib):
or a tautomer or salt thereof; wherein:
R 1 is H or methoxy;
R 3 is H or methoxy, and R 4 is H or methoxy,
or R 3 and R 4 combine to form a dioxane or dioxolane ring including the atoms to which R 3 and R 4 are attached;
and R 8 is H or C 1-3 alkyl.
8 . The method of claim 7 , wherein the compound of formula (Ib) is selected from:
or a tautomer and/or salt thereof.
9 . The method of claim 5 , wherein the compound of formula (Ia) is
or a tautomer and/or salt thereof.
10 . The method of claim 9 , wherein the compound of formula (Ia) is
or a tautomer and/or salt thereof.
11 . A method of administering a β-adrenergic agonist to a patient, comprising conjointly administering the β-adrenergic agonist with a compound of formula (Ia):
or a tautomer and/or salt thereof;
wherein:
X is S or CH 2 ;
R 1 is H, C 1-3 alkyl, or C 1-3 alkoxy;
R 2 is H or C 1-3 alkoxy;
R 3 is H, C 1-3 alkoxy, phenoxy, or benzyloxy;
R 4 is H, hydroxyl, C 1-3 alkoxy, or C 1-3 haloalkoxy;
or R 3 and R 4 combine to form a dioxane or dioxolane ring, including the atoms to which R 3 and R 4 are attached;
R 5 is H or C 1-3 alkyl;
R 6 is H;
R 7 is a quinazolin-4-on-2-yl group,
wherein the phenyl ring of the quinazolin-4-on-2-yl group may be substituted or unsubstituted; and
R 8 is H, C 1-5 alkyl, C 1-5 alkenyl, or amino.
12 . A method of reducing β-adrenergic agonist-induced cardiac hypertrophy, comprising administering, to a patient receiving a β-adrenergic agonist, a compound of formula (Ia):
or a tautomer and/or salt thereof;
wherein:
X is S or CH 2 ;
R 1 is H, C 1-3 alkyl, or C 1-3 alkoxy;
R 2 is H or C 1-3 alkoxy;
R 3 is H, C 1-3 alkoxy, phenoxy, or benzyloxy;
R 4 is H, hydroxyl, C 1-3 alkoxy, or C 1-3 haloalkoxy;
or R 3 and R 4 combine to form a dioxane or dioxolane ring, including the atoms to which R 3 and R 4 are attached;
R 5 is H or C 1-3 alkyl;
R 6 is H;
R 7 is a quinazolin-4-on-2-yl group,
wherein the phenyl ring of the quinazolin-4-on-2-yl group may be substituted or unsubstituted; and
R 8 is H, C 1-5 alkyl, C 1-5 alkenyl, or amino.
13 . The method of claim 11 , wherein the compound of formula (Ia) is selected from:
or a tautomer and/or salt thereof.
14 . The method of claim 11 , wherein the β-adrenergic agonist is selected from isoproterenol, phenylephrine, denopamine, dobutamine, dopexamine, epinephrine, prenalterol, xamoterol, Arformoterol, Buphenine, Clenbuterol, Dopexamine, Epinephrine, Fenoterol, Formoterol, Isoetarine, Isoprenaline, Levosalbutamol, levalbuterol, Orciprenaline, metaproterenol, Pirbuterol, Procaterol, Ritodrine, Salbutamol, albuterol, Salmeterol, Terbutaline, Arbutamine, Befunolol, Bromoacetylalprenololmenthane, Broxaterol, Cimaterol, Cirazoline, Etilefrine, Hexoprenaline, Higenamine, Isoxsuprine, Mabuterol, Methoxyphenamine, Oxyfedrine, Ractopamine, Reproterol, Rimiterol, Tretoquinol, Tulobuterol, Zilpaterol, Zinterol, CL316,243, Rafabegron, Mirabegron, Solabegron, Amibegron, Talibegron, and L-796568.
15 . The method of claim 14 , wherein the β-adrenergic agonist is selected from isoproterenol and phenylephrine.