Sweetness receptor antagonist

Patent metadata

Field	Value
Publication number	US-9907766-B2
Application number	US-201615389639-A
Country	US
Kind code	B2
Filing date	Dec 23, 2016
Priority date	Jun 27, 2014
Publication date	Mar 6, 2018
Grant date	Mar 6, 2018

Abstract

Sweetness receptor antagonists represented by formula (I):

wherein each symbol is described herein, are useful for the prophylaxis or treatment of metabolic syndrome, diabetes, obesity and the like.

First claim

The invention claimed is:

1. 1-(4-Cyanophenyl)-3-(cyclohexylmethyl)thiourea or a salt thereof.

2. A method for the treatment of a disease selected from the group consisting of metabolic syndrome, diabetes, and obesity, which comprises administering to a subject in need thereof a compound represented by formula (I):

wherein
R 1 , R 2 , R 3 , R 4 , and R 5 are each independently a hydrogen atom or an electron-withdrawing group, provided at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is an electron-withdrawing group;
R 6 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
R a and R b are each independently a hydrogen atom or a C 1-6 alkyl group; and
X is S,

or a salt thereof.

3. The method according to claim 2 , wherein any one of R 1 , R 2 , R 3 , R 4 , and R 5 is an electron-withdrawing group.

4. The method according to claim 3 , wherein R 3 or R 4 is an electron-withdrawing group.

5. The method according to claim 2 , wherein said electron-withdrawing group is a halogen atom, a halo C 1-6 alkyl group, or a cyano group.

6. The method according to claim 2 , wherein R 6 is an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-10 cycloalkyl group.

7. The method according to claim 2 , wherein R 6 is a C 1-6 alkyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkyl-C 1-6 alkyl group, or a mono- or di-C 6-10 aryl-C 1-6 alkyl group.

8. The method according to claim 2 , wherein both R a and R b are hydrogen atoms.

9. The method according to claim 2 , wherein said compound represented by the formula (I) or a salt thereof is a compound selected from the group consisting of
1-benzyl-3-(3-cyanophenyl)thiourea;
1-benzyl-3-[4-(trifluoromethyl)phenyl]thiourea;
1-benzyl-3-(4-bromophenyl)thiourea;
1-(4-cyanophenyl)-3-cyclooctyl-thiourea;
1-(4-cyanophenyl)-3-cyclohexyl-thiourea;
1-(4-cyanophenyl)-3-(cyclohexylmethyl)thiourea;
1-benzhydryl-3-(4-cyanophenyl)thiourea; and
1-butyl-3-(4-cyanophenyl)thiourea,

or a salt of said compound.

10. A method for antagonizing a sweetness receptor, which comprises administering to a subject in need thereof a compound represented by formula (I):

wherein
R 1 , R 2 , R 3 , R 4 , and R 5 are each independently a hydrogen atom or an electron-withdrawing group, provided at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is an electron-withdrawing group;
R 6 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
R a and R b are each independently a hydrogen atom or a C 1-6 alkyl group; and
X is S,

or a salt thereof.

11. A method for sensitizing insulin, which comprises administering to a subject in need thereof a compound represented by formula (I):

wherein
R 1 , R 2 , R 3 , R 4 , and R 5 are each independently a hydrogen atom or an electron-withdrawing group, provided at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is an electron-withdrawing group;
R 6 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
R a and R b are each independently a hydrogen atom or a C 1-6 alkyl group; and
X is S,

or a salt thereof.

12. The method according to claim 10 , wherein R 6 is a C 1-6 alkyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkyl-C 1-6 alkyl group, or a mono- or di-C 6-10 aryl-C 1-6 alkyl group.

13. The method according to claim 10 , wherein both R a and R b are hydrogen atoms.

14. The method according to claim 10 , wherein said compound represented by the formula (I) or a salt thereof is a compound selected from the group consisting of
1-benzyl-3-(3-cyanophenyl)thiourea;
1-benzyl-3-[4-(trifluoromethyl)phenyl]thiourea;
1-benzyl-3-(4-bromophenyl)thiourea;
1-(4-cyanophenyl)-3-cyclooctyl-thiourea;
1-(4-cyanophenyl)-3-cyclohexyl-thiourea;
1-(4-cyanophenyl)-3-(cyclohexylmethyl)thiourea;
1-benzhydryl-3-(4-cyanophenyl)thiourea; and
1-butyl-3-(4-cyanophenyl)thiourea,
or a salt of said compound.

15. The method according to claim 11 , wherein R 6 is a C 1-6 alkyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkyl-C 1-6 alkyl group, or a mono- or di-C 6-10 aryl-C 1-6 alkyl group.

16. The method according to claim 11 , wherein both R a and R b are hydrogen atoms.

17. The method according to claim 11 , wherein said compound represented by the formula (I) or a salt thereof is a compound selected from the group consisting of
1-benzyl-3-(3-cyanophenyl)thiourea;
1-benzyl-3-[4-(trifluoromethyl)phenyl]thiourea;
1-benzyl-3-(4-bromophenyl)thiourea;
1-(4-cyanophenyl)-3-cyclooctyl-thiourea;
1-(4-cyanophenyl)-3-cyclohexyl-thiourea;
1-(4-cyanophenyl)-3-(cyclohexylmethyl)thiourea;
1-benzhydryl-3-(4-cyanophenyl)thiourea; and
1-butyl-3-(4-cyanophenyl)thiourea,

or a salt of said compound.

Assignees

• Ajinomoto Kk

Inventors

• Kitahara Yoshiro
• Ohsumi Koji
• Kitajima Seiji
• Ogawa Shimpei

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07C335/20

  being further substituted by nitrogen atoms, not being part of nitro or nitroso groups · CPC title

• C07C335/16

  having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton · CPC title

• A61K31/17 Primary

  having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64) · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title