US2018370905A1PendingUtilityA1
Compounds Useful for the Treatment of Metabolic Disorders and Synthesis of the Same
Assignee: NORTH CAROLINA CENTRAL UNIVPriority: Apr 5, 2013Filed: Jun 25, 2018Published: Dec 27, 2018
Est. expiryApr 5, 2033(~6.7 yrs left)· nominal 20-yr term from priority
C07D 271/06A61K 31/44C07D 249/08C07C 235/68C07C 45/46A61K 31/196A61K 31/167C07D 295/155C07C 2601/14A61K 31/5375C07D 213/82C07D 207/34A61K 31/245A61K 31/277C07C 233/66C07C 253/30C07C 231/02C07C 233/81A61K 45/06C07C 255/60C07D 257/04C07D 213/75C07C 235/64A61K 31/40C07C 67/39
44
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Claims
Abstract
The present invention provides compounds of Formula (I): wherein variables X, Y, Z and R1 are as described herein. Some of the compounds described herein are glutamate dehydrogenase activators. The invention is also directed to pharmaceutical compositions comprising these compounds, uses of these compounds and compositions in the treatment of metabolic disorders as well as synthesis of the compounds.
Claims
exact text as granted — not AI-modified1 - 44 . (canceled)
45 . A method of treating a diabetes-related disorder selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), dyslipidemia, hypertriglyceridemia, and insulin resistance, the method comprising the administration to a subject in need thereof an effective amount of a compound of Formula I:
wherein:
X is O or S;
R 1 is selected from:
(1) hydrogen, or
(2) C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) C 3-6 cycloalkyl,
(c) CF 3 ,
(d) OR a
(3) C 3-6 cycloalkyl,
(4) araalkyl, or
(5) phenyl;
wherein Y is aryl substituted with phenyl and cyclohexyl, Z is aryl substituted with tetrazolyl, oxadiazolyl, or triazine, each of which can be substituted with C 1-6 alkyl, and wherein Y and Z are each independently aryl or heterocycle;
wherein heterocycle is selected from the group consisting of: benzimidazolyl, benzopyranyl, benzofuranyl, benzothiazolyl, benzoxazolyl, chromanyl, 1,3-dioxolanyl, furanyl, imidazolinyl, imidazolyl, indazolyl, indolinyl, indolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, purinyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiazolinyl, thiazolyl, triazine and thienyl, which aryl or heterocycle is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) C 1-6 alkyl,
(c) OR a ,
(d) NO 2 ,
(e) CN,
(f) NR b R c ,
(g) OCO 2 R e ,
(h) CO 2 R a ,
(i) C(═O)R a ,
(j) C(═O)NR b R c ,
(k) S(O) d R e ,
(m) N(R b )SO 2 R e ,
(n) N(R b )CO 2 R a ,
(o) N(R b )C(═O)R a ,
(p) OCOR e ,
(q) CF 3
R a is independently selected from:
(1) hydrogen, or
(2) C 1-6 alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(c) hydroxyl,
(d) CN, or
(e) aryl or heterocycle wherein heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, triazine and pyrazinyl, which aryl or heterocycle is unsubstituted or substituted with 1-7 substituents each independently selected from:
(i) halo,
(ii) O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(iii) CN,
(iv) nitro,
(v) hydroxyl, or
(vi) C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo;
R b and R c are independently selected from:
(1) hydrogen, or
(2) C 1-6 alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) OR a ,
(c) CN,
(d) CO 2 R a ,
(e) aryl or heterocycle, wherein heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, triazine and pyrazinyl, which aryl or heterocycle is unsubstituted or substituted with 1-7 substituents each independently selected from:
(i) halo,
(ii) OR a ,
(iii) C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(iv) nitro;
R e is independently selected from:
(1) C 1-6 alkyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) OR a ,
(c) CO 2 R a ,
(d) CN, or
(e) aryl or heterocycle, wherein heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, triazine and pyrazinyl, which aryl or heterocycle is unsubstituted or substituted with 1-7 substituents each independently selected from:
(i) halo,
(ii) OR a ,
(iii) C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, or
(iv) nitro;
d is 0, 1, or 2; or
an individual enantiomer, diastereomer, pharmaceutically acceptable salt or prodrug thereof.
46 . The method of claim 45 , wherein Y and Z are each independently selected from the group consisting of:
wherein Y and Z are each independently unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(c) OR a ,
(d) NO 2 ,
(e) CN,
(f) NR b R c ,
(g) OCO 2 R
(h) CO 2 R a ,
(i) C(═O)R a ,
(j) C(═O)NR b R c ,
(k) S(O) d R e ,
(m) N(R b )SO 2 R e ,
(n) N(R b )CO 2 R a ,
(O) N(R b )C(═O)R a , or
(p) OCOR e .
47 . The method of claim 45 , wherein the compound of Formula I is selected from the group consisting of:
48 . The method of claim 45 , wherein the compound is selected from the group consisting of:
49 . The method of claim 45 , wherein the compound has the following structure:
50 . The method of claim 45 , wherein the compound has the following structure:
51 . The method of claim 45 , wherein the compound has the following structure:
52 . The method of claim 45 , wherein the compound has the following structure:
53 . The method of claim 45 , wherein the diabetes-related disorder is non-alcoholic steatohepatitis (NASH).
54 . A method of treating a diabetes-related disorder selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), dyslipidemia, hypertriglyceridemia, and insulin resistance, the method comprising the administration to a subject in need thereof an effective amount of a compound having the following structure:
55 . The method of claim 54 , wherein the diabetes-related disorder is non-alcoholic steatohepatitis (NASH).
56 . A method of treating non-alcoholic steatohepatitis (NASH), the method comprising the administration to a subject in need thereof an effective amount of a compound having the following structure:
57 . The method of claim 56 , wherein the compound is selected from the group consisting of:
58 . The method of claim 56 , wherein the compound has the following structure:
59 . The method of claim 56 , wherein the compound has the following structure:
60 . The method of claim 56 , wherein the compound has the following structure:
61 . The method of claim 56 , wherein the compound has the following structure:Join the waitlist — get patent alerts
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