US 8,158,623 B2Granted

Heptacyclic compounds and the pharmaceutical uses thereof for preventing and treating diabetes and metabolic syndrome

AssigneeShanghai Institute of Materia Medica, Chinese Academy of Sciences

InventorsJianhua Shen, Ying Leng, Hualiang Jiang, Junhua Chen

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Abstract

The invention discloses a new use of a class of heptacyclic compounds in the preparation of formulations for the prevention and treatment of diabetes and metabolic syndromes; the present invention also discloses a new class of heptacyclic compounds; the present invention also discloses a process for preparing the heptacyclic compounds and a composition containing the same. The heptacyclic compounds of the present invention can be used to effectively preventing or treating diseases such as diabetes and metabolic syndromes.

Claims11

Dependent claims

A method for the treatment of diabetes and metabolic syndromes in mammals, which comprises administering to mammals in need thereof a therapeutically effective amount of the compound of Formula (I), geometric isomers, enantiomers, diastereoisomers, racemates, pharmaceutically acceptable salts thereof or their mixtures;

wherein, Ar1 and Ar2 are selected from benzene or heterocycle;
X is O;
Y is selected from O, N, S or SO2;
R1, R2, R4, R5, R6 and R8 are independently selected from hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, —CONR′R″, ═O, —SR′, —SO3R′, —SO2NR′R″, —SO2R′, —NO2 or —CN;
R3 is independently selected from unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, —CONR′R″, ═O, —SR′, —SO3R′, —SO2NR′R″, —SOR′, —SO2R′, —NO2 or —CN;
when R4 is substituted C1-C10 alkyl, its substituent is selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halo, —COORa, —NRaRb, —ORa, —CORa, —CONRaRb, ═O, —SRa, —SO3Ra, —SO2NRaRb, —SORa, SO2Ra, —NO2, —CN;
wherein Ra and Rb are selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl;
R7 is independently selected from unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, ═O, —SR′, —SO3R′, —SO2NR′R″, —SOR′, —SO2R′, —NO2 or —CN
wherein R′ and R″ are independently selected from hydrogen, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, or R′ and R″ are taken together to form a 4- to 7-membered ring.

6 more elements

A compound of the structure of Formula (I):

or geometric isomers, enantiomers, diastereoisomers, racemates, pharmaceutically acceptable salts thereof,
wherein, Ar1 and Ar2 are selected from benzene or heterocycle;
X is O;
Y is selected from O, N, S or SO2;
R3 is —OR′;
R1 and R5 are independently selected from H, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, —CONR′R″, ═O, —SR′, —SO3R′, —SO2NR′R″, —SOR′, —SO2R′, —NO2 or —CN;
R2, R6 and R8 are independently selected from hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, —CONR′R″, ═O, —SR′, —SO3R′, —SO2NR′R″, —SOR′, —SO2R′, —NO2 or —CN;
R4 is independently selected from hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, —CONR′R″, ═O, —SR′, —SO3R′, —SO2NR′R″, —SOR′, —SO2R′, —NO2 or —CN;
wherein the substituents for the unsubstituted or substituted C1-C10 alkyl are 1-3 groups selected from the group consisting of:
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, —COORa, —NRaRb, —ORa, —CORa, —CONRaRb, ═O, —SRa, —SO3Ra, —SO2NRaRb, —SORa, —SO2Ra, —NO2 or —CN, wherein Ra and Rb are independently selected from hydrogen, C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl;
R7 is independently selected from unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, ═O, —SR′, —SO3R′, —SO2NR′R″, —SOR′, —SO2R′, —NO2 or —CN;
wherein R′ and R″ are independently selected from hydrogen, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, or R′ and R″ are taken together to form a 4- to 7-membered ring;
and when R3 is OH, R4 is
R9 and R10 are independently selected from H, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted amino, —CORc, —CONRcRd;
wherein Rc and Rd are independently selected from hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, or Rc and Rd are taken together to form a 4- to 7-membered ring.

12 more elements

A compound of the structure of formula (II):

or geometric isomers, enantiomers, diastereoisomers, racemates, pharmaceutically acceptable salts thereof,
R3 is —OR′;
R1 and R5 are independently selected from H, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C1-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, —CONR′R″, ═O, —SR′, —SO3R′, —SO2NR′R″, —SOR′, —SO2R′, —NO2 or —CN;
R2, R6 and R8 are independently selected from hydrogen unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C1-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, —CONR′R″, ═O—SR′, —SO3R′, —SO2NR′R″, —SOR′, —SO2R′, —NO2 or —CN;
R4 is independently selected from hydrogen unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl halo, —COOR′, —NR′R″, —OR′, —COR′, —CONR′R″, ═O, —SR′, —SO3R′, —SO2NR′R″, —SOR′, —SO2R′, —NO2 or —CN;
wherein the substituents for the unsubstituted or substituted C1-C10 alkyl are 1-3 groups selected from the group consisting of:
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, —COORa, —NRaRb, —ORa, —CORa, —CONRaRb, ═O, —SRa, —SO3Ra, —SO2NRaRb, —SORa, —SO2Ra, —NO2 or —CN, wherein Ra and Rb are independently selected from hydrogen, C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl;
R7 is independently selected from unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, ═O—SR′, —SO3R′, —SO2NR′R″, —SOR′, —SO2R′, —NO2 or —CN;
wherein R′ and R″ are independently selected from hydrogen, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl unsubstituted or substituted C2-C10 alkynyl, or R′ and R″ are taken together to form a 4- to 7-membered ring;
and when R3 is OH, R4 is
R9 and R10 are independently selected from H, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkyl, unsubstituted or substituted amino, —CORc, —CONRcRd;
wherein Rc and Rd are independently selected from hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C1-C10 alkenyl, unsubstituted or substituted C2-C10 alkyl, or Rc and Rd are taken together to form a 4- to 7-membered ring.

9 more elements

A composition comprising:

(a) an effective amount of a compound of Formula (I), geometric isomers, enantiomers, diastereoisomers, racemates, pharmaceutically acceptable salts thereof or their mixtures;
wherein Ar1 and Ar2 are selected from benzene or heterocycle;
X is O;
Y is selected from O, N, S or SO2;
R3 is —OR′;
R1 and R5 are independently selected from H, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, —CONR′R″, ═O, —SR′, —SO3R′, —SO2NR′R″, —SO2R′, —NO2 or —CN;
R2, R6 and R8 are independently selected from hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, —CONR′R″, ═O, —SR′, —SO3R′, —SO2NR′R″, —SOR′, —SO2R′, —NO2 or —CN;
R4 is independently selected from hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, —CONR′R″, ═O, —SR′, —SO3R′, —SO2NR′R″, —SOR′, —SO2R′, —NO2 or —CN;
wherein the substituents for the unsubstituted or substituted C1-C10 alkyl are 1-3 groups selected from the group consisting of:
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, —COORa, —NRaRb, —ORa, —CORa, —CONRaRb, ═O, —SRa, —SO3Ra, —SO2NRaRb, —SORa, —SO2Ra, —NO2 or —CN, wherein Ra and Rb are independently selected from hydrogen, C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl;
R7 is independently selected from unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, ═O, —SR′, —SO3R′, —SO2NR′R″, —SOR′, —SO2R′, —NO2 or —CN;
wherein R′ and R″ are independently selected from hydrogen, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, or R′ and R″ are taken together to form a 4- to 7-membered ring;
and when R3 is OH, R4 is
R9 and R10 are independently selected from H, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted amino, —CORc, —CONRcRd:
wherein Rc and Rd are independently selected from hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, or Rc and Rd are taken together to form a 4- to 7-membered ring;
(b) a bromatologically or pharmaceutically acceptable carrier or excipient.

13 more elements

Dependencies are inferred from the claim text.

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Abstract

wherein, Ar1 and Ar2 are selected from benzene or heterocycle;
X is O;
Y is selected from O, N, S or SO2;
R1, R2, R4, R5, R6 and R8 are independently selected from hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, —CONR′R″, ═O, —SR′, —SO3R′, —SO2NR′R″, —SO2R′, —NO2 or —CN;
R3 is independently selected from unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, —CONR′R″, ═O, —SR′, —SO3R′, —SO2NR′R″, —SOR′, —SO2R′, —NO2 or —CN;
when R4 is substituted C1-C10 alkyl, its substituent is selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halo, —COORa, —NRaRb, —ORa, —CORa, —CONRaRb, ═O, —SRa, —SO3Ra, —SO2NRaRb, —SORa, SO2Ra, —NO2, —CN;
wherein Ra and Rb are selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl;
R7 is independently selected from unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, halo, —COOR′, —NR′R″, —OR′, —COR′, ═O, —SR′, —SO3R′, —SO2NR′R″, —SOR′, —SO2R′, —NO2 or —CN
wherein R′ and R″ are independently selected from hydrogen, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, or R′ and R″ are taken together to form a 4- to 7-membered ring.

6 more elements