US2012309786A1PendingUtilityA1
3-amino-pyridine derivatives for the treatment of metabolic disorders
Est. expirySep 21, 2026(~0.2 yrs left)· nominal 20-yr term from priority
Inventors:Nabajyoti DekaKamlesh Jyotindra PadiyaSwapnil Ramesh BajareRhushikesh Arun KulkarniTaj Usman KhanSivaramakrishnan HariharanRosalind Adaikalasamy Marita
A61P 31/04A61P 31/00A61P 7/00A61P 3/10A61P 9/10A61P 35/00A61P 5/50A61P 9/00A61P 43/00A61P 3/08A61P 5/48A61P 3/06A61P 3/04A61P 9/12A61P 1/16A61P 15/00A61P 15/08C07D 401/12A61K 31/4709A61K 31/4725
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Claims
Abstract
Compounds represented by the general formula (I): pharmaceutically acceptable salts or solvates thereof, a process for their manufacture; pharmaceutical compositions containing them; and use of the compounds in the treatment of metabolic disorders related to insulin resistance or hyperglycemia are described.
Claims
exact text as granted — not AI-modified1 . A compound of general formula (I) or a pharmaceutically acceptable salt thereof, the general formula (I) being represented by:
wherein:
Ar is a quinoline moiety which is substituted or unsubstituted;
B is —O—;
R 1 is hydrogen or S(O) 2 R 4 ;
R 2 is S(O) 2 R 4 , C(O)R 5 , or C(O)(CH 2 ) n —C(O)OR 6 ;
R 3 is halogen, cyano, C(O)OR 7 , or C(O)NR 8 R 9 ;
R 4 is substituted or unsubstituted aryl;
R 5 is (C 1 -C 6 )alkyl or substituted or unsubstituted aryl;
R 6 is hydrogen, (C 1 -C 4 )alkyl, or substituted or unsubstituted aryl;
R 7 is hydrogen or (C 1 -C 4 )alkyl;
R 8 and R 9 are independently hydrogen or (C 1 -C 6 )alkyl; and
n is an integer from 1-3.
2 . The compound according to claim 1 ;
wherein:
Ar is a quinoline moiety which is substituted or unsubstituted;
B is —O—;
R 1 is H;
R 2 is S(O) 2 R 4 ;
R 3 is chlorine; and
R 4 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2-chloro-4-trifluoromethylphenyl, 3-fluoro-4-methylphenyl, 3-chloro-4-methylphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-4-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-chloro-4-trifluoromethylphenyl, 3-chloro-4-methylphenyl, 2-chloro-4-fluorophenyl), 4-cyanophenyl, phenyl-3-carboxylic acid [phenyl-3-COOH], or 4-acetamidophenyl [(CH 3 CONH-phenyl].
3 . The compound according to claim 2 ;
wherein:
Ar is quinolin-3-yl;
B is —O—;
R 1 is H;
R 2 is —S(O) 2 R 4 ;
R 3 is chlorine; and
R 4 is phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 3-fluoro-4-methylphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-chloro-4-trifluoromethylphenyl, or 2-fluoro-4-chlorophenyl.
4 . The compound according to claim 2 ;
wherein:
Ar is quinolin-6-yl;
B is —O—;
R 1 is H;
R 2 is —S(O) 2 R 4 ;
R 3 is chlorine; and
R 4 is 3,4 dimethoxyphenyl, 2,4-difluorophenyl, or 2,4-dichlorophenyl.
5 . The compound according to claim 1 ;
wherein:
Ar is a quinoline moiety which is substituted or unsubstituted;
B is —O—;
R 1 is S(O) 2 R 4 ;
R 2 is S(O) 2 R 4 ;
R 3 is halogen; and
R 4 is substituted aryl.
6 . The compound according to claim 5 ;
wherein:
Ar is quinolin-3-yl;
B is —O—;
R 1 is S(O) 2 R 4 ;
R 2 is S(O) 2 R 4 ;
R 3 is chlorine; and
R 4 is 2,4-dichlorophenyl.
7 . The compound according to claim 1 ;
wherein:
Ar is a quinoline moiety which is substituted or unsubstituted;
B is —O—;
R 1 is H;
R 2 is C(O)OR 5 ;
R 3 is halogen; and
R 5 is (C 1 -C 6 )alkyl or substituted or unsubstituted aryl.
8 . The compound according to claim 7 ;
wherein:
Ar is quinolin-3-yl;
B is —O—;
R 1 is H;
R 2 is C(O)OR 5 ;
R 3 is chlorine; and
R 5 is phenyl.
9 . The compound according to claim 1 ;
wherein:
Ar is a quinoline moiety which is substituted or unsubstituted;
B is —O—;
R 1 is H;
R 2 is C(O)(CH 2 ) n —C(O)OR 6 ;
R 3 is halogen;
R 6 is hydrogen, (C 1 -C 4 )alkyl, or substituted or unsubstituted aryl; and
n is an integer from 1-3.
10 . The compound according to claim 9 ;
wherein:
Ar is quinolin-3-yl;
B is —O—;
R 1 is H:
R 2 is C(O)(CH 2 ) 2 —C(O)OR 6 ;
R 3 is chlorine; and
R 6 is hydrogen.
11 . The compound according to claim 1 ;
wherein the compound is selected from:
N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methoxybenzenesulfonamide;
2,4-Dichloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide;
N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide;
3,4-Dichloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide;
N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide;
N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,4-dimethoxybenzenesulfonamide;
N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide;
2-Chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethyl) benzenesulfonamide;
N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-2,4-difluorobenzenesulfonamide;
N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide;
4-Chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide;
N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-difluorobenzenesulfonamide;
N-(5-(Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,6-difluorobenzenesulfonamide;
3,5-Dichloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide;
N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3-fluoro-4-methylbenzenesulfonamide:
N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,5-dimethylbenzenesulfonamide;
N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-1)-2,4,6-trimethylbenzenesulfonamide;
4-chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2-fluorobenzenesulfonamide;
N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide;
2,4-Dichloro-N-(5-chloro-6-(quinolin-6-yloxy)pyridin-3-yl)benzenesulfonamide;
N-(5-Chloro-6-(quinolin-6-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide;
N-(5-Chloro-6-(quinolin-6-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide;
2,4-Dichloro-N-[(2,4-dichlorophenyl)sulfonyl]-N-[5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl]-benzenesulfonamide;
Phenyl 5-chloro-6-(quinolin-3-yloxy)pyridin-3-ylcarbamate; and
4-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-ylamino)-4-oxobutanoic acid.
12 . The compound according to claim 1 ;
wherein the compound is selected from:
N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methoxybenzenesulfonamide,
N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide; and
N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.
13 . A process for the preparation of a compound of general formula (I) according to claim 1 , the general formula (I) being represented by:
wherein:
Ar is a quinoline moiety which is substituted or unsubstituted;
B is —O—;
R 3 is halogen, cyano, C(O)OR 7 or C(O)NR 8 R 9 ;
R 7 is hydrogen or (C 1 -C 4 )alkyl;
R 8 and R 9 are independently hydrogen or (C 1 -C 6 )alkyl;
R 1 is H;
R 2 is S(O) 2 R 4 ; and
R 4 is substituted or unsubstituted aryl;
wherein the process comprises:
a) reacting a compound of general formula (II) with a compound of formula (III), in presence of a base, to obtain a compound of general formula (IV);
wherein the general formula (II)is represented by:
wherein:
Hal is fluorine, chlorine, bromine, or iodine; and
R 3 is as defined above;
wherein the formula (III) is represented by:
Ar—BH;
wherein Ar and B are as defined above; and
wherein the general formula (IV) is represented by:
wherein Ar, B, and R 3 are as defined above;
b) subjecting the nitro compound of formula (IV) above to reduction to obtain a corresponding amino compound of general formula (V):
wherein Ar, B, and R 3 are as defined above; and
c) reacting the amino compound of general formula (V) with one equivalent of Hal-SO 2 R 4 , in the presence of a base, to obtain the compound of formula (I);
wherein:
Hal is fluorine, chlorine, bromine, or iodine; and
R 4 is as defined above; and
d) optionally, converting the resulting compound into a pharmaceutically acceptable salt.
14 . A process for the preparation of a compound of general formula (I) according to claim 1 , the general formula (I) being represented by:
wherein:
Ar is a quinoline moiety which is substituted or unsubstituted;
B is —O—;
R 3 is halogen, cyano, C(O)OR 7 , or C(O)NR 8 R 9 ;
R 7 is hydrogen or (C 1 -C 4 )alkyl;
R 8 and R 9 are independently hydrogen or (C 1 -C 6 )alkyl;
R 1 and R 2 are S(O) 2 R 4 ; and
R 4 is substituted or unsubstituted aryl;
wherein the process comprises:
a) reacting a compound of general formula (II) with a compound of formula (III), in presence of a base, to obtain a compound of general formula (IV);
wherein the general formula (II) is represented by:
wherein:
Hal is F, Cl, Br, or I; and
R 3 is as defined above;
wherein the formula (III) is represented by:
Ar—BH
wherein Ar and B are as defined above;
wherein the general formula (IV) is represented by:
wherein Ar, B, and R 3 are as defined above;
b) subjecting the nitro compound of formula (IV) above to reduction to obtain a corresponding amino compound of general formula (V):
wherein Ar, B, and R 3 are as defined above; and
c) reacting the amino compound of general formula (V) with two equivalents of Hal-SO 2 R 4 at 45° C., in the presence of triethyl amine as a base, to obtain the compound of formula (I);
wherein:
Hal is fluorine, chlorine, bromine, or iodine; and
R 4 is as defined above; and
d) optionally, converting the resulting compound into a pharmaceutically acceptable salt.
15 . A process for the preparation of a compound of general formula (I) according to claim 1 , the general formula (I) being represented by:
wherein:
Ar is a quinoline moiety which is substituted or unsubstituted;
B is —O—;
R 3 is halogen, cyano, C(O)OR 7 , or C(O)NR 8 R 9 ;
R 7 is hydrogen or (C 1 -C 4 )alkyl;
R 8 and R 9 are independently hydrogen or (C 1 -C 6 )alkyl;
R 1 is H;
R 2 is C(O)(CH 2 ) n —C(O)OR 6 ;
n is an integer from 1-3; and
R 6 is hydrogen, (C 1 -C 4 )alkyl, or substituted or unsubstituted aryl,
wherein the process comprises:
a) reacting a compound of general formula (II) with a compound of formula (III) in presence of cesium carbonate as a base, to obtain a compound of general formula (IV);
wherein the general formula (II) is represented by:
wherein:
Hal is fluorine, chlorine, bromine, or iodine; and
R 3 is as defined above,
wherein the formula (III) is represented by:
Ar—BH;
wherein Ar and B are as defined above;
wherein the general formula (IV) is represented by:
wherein Ar, B, and R 3 are as defined above;
b) subjecting the nitro compound of formula (IV) above to reduction to obtain a corresponding amino compound of general formula (V):
wherein Ar, B, and R 3 are as defined above; and
c) refluxing the amino compound of the general formula (V) above with an anhydride [(CH 2 ) n (CO) 2 O] to obtain an acid of formula (I); and
d) optionally, converting the acid of formula (I) to an ester of formula (I);
wherein:
R 2 is C(O)(CH 2 ) n —C(O)OR 6 ;
n is an integer from 1-3; and
R 6 is (C 1 -C 4 )alkyl or substituted or unsubstituted aryl; and
e) optionally, converting the resulting acid or ester into a pharmaceutically acceptable salt.
16 . A process for the preparation of a compound of general formula (I) according to claim 1 , the general formula (I) being represented by:
wherein:
Ar is a quinoline moiety which is substituted or unsubstituted;
B is —O—;
R 3 is halogen, cyano, C(O)OR 7 or C(O)NR 8 R 9 ;
R 7 is hydrogen or (C 1 -C 4 )alkyl;
R 8 and R 9 are independently hydrogen or (C 1 -C 6 )alkyl;
R 1 is H;
R 2 is C(O)OR 5 ; and
R 5 is (C 1 -C 6 )alkyl or substituted or unsubstituted aryl;
wherein the process comprises:
a) reacting a compound of general formula (II) with a compound of formula (III), in presence of cesium carbonate as a base, to obtain a compound of general formula (IV);
wherein the general formula (II) is represented by:
wherein:
Hal is fluorine, chlorine, bromine, or iodine; and
R 3 is as defined above;
wherein the formula (III) is represented by:
Ar—BH;
wherein Ar and B are as defined above;
wherein the general formula (IV) is represented by:
wherein Ar, B, and R 3 are as defined above;
b) subjecting the nitro compound of formula (IV) to reduction to obtain a corresponding amino compound of general formula (V):
wherein Ar, B, and R 3 are as defined above; and
c) refluxing the amino compound of general formula (V) with R 5 -carbonochloridate, in the presence of pyridine or triethyl amine as a base, to obtain the compound of formula (I):
wherein R 5 is as defined above; and
d) optionally, converting the resulting compound into a pharmaceutically acceptable salt.
17 . A pharmaceutical composition, comprising:
a therapeutically effective amount of a compound of general formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.
18 . A pharmaceutical composition, comprising:
a therapeutically effective amount of a compound of general formula (I) according to claim 1 , or a pharmaceutically acceptable salt or thereof; at least one further pharmaceutically active compound; and a pharmaceutically acceptable carrier or diluent.
19 . A method for the treatment of a metabolic disorder related to insulin resistance or hyperglycemia, comprising:
administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof.
20 . The method according to claim 19 ;
wherein the metabolic disorder related to insulin resistance or hyperglycemia is selected from:
type 2 diabetes, obesity, glucose intolerance, dyslipidemia, hyperinsulinemia, atherosclerotic disease, polycystic ovary syndrome, coronary artery disease, hypertension, and non alcoholic fatty liver disease.
21 . The method according to claim 20 ;
wherein the metabolic disorder related to insulin resistance or hyperglycemia is type 2 diabetes.
22 . The method according to claim 20 ;
wherein the metabolic disorder related to insulin resistance or hyperglycemia is dyslipidemia.Join the waitlist — get patent alerts
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