Method of stimulating insulin secretion and/or modulating INS-1 kinase with substituted pyrazinones and/or substituted tetrahydroquinoxalinones

Patent metadata

Field	Value
Publication number	US-9233937-B2
Application number	US-201414337796-A
Country	US
Kind code	B2
Filing date	Jul 22, 2014
Priority date	Apr 29, 2008
Publication date	Jan 12, 2016
Grant date	Jan 12, 2016

Abstract

Arylpyrazinone derivatives of formula (I),

as insulin secretion stimulators, the preparation and use of these pyrazinone derivatives for the prophylaxis and/or treatment of diabetes and pathologies associated.

First claim

The invention claimed is:

1. A method of stimulating insulin secretion in a host and/or a method of modulating INS-1 kinase activity in a host, comprising administering to a host in need thereof an effective amount of a compound of formula (I)

wherein:
R1 is Z;
R2 is hydrogen, alkyl, or cycloalkyl;
R3 is hydrogen, halogen, alkyl, or cycloalkyl;
A is aryl, heteroaryl, or arylalkyl,
A is selected aryl, heteroaryl, or arylalkyl,
wherein alkyl, aryl and heteroaryl groups can be optionally substituted by one or more substituents Y;
Z is:
alkyl, alkenyl, alkynyl, alkoxyalkyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, arylthioalkyl, arylalkylthioalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, heteroarylalkylthioalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxyalkyl, heterocycloalkylalkoxyalkyl, heterocycloalkylthioalkyl, heterocycloalkylalkylthioalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, cycloalkylalkoxyalkyl, cycloalkylthioalkyl, or cycloalkylalkylthioalkyl,
each of these groups can be optionally substituted by one or more substituents Y;
Y is:
hydroxy, thio, halogen, cyano, trifluoromethoxy, trifluoromethyl, carboxy, carboxymethyl, carboxyethyl, alkyl, alkoxy, alkylamino, aryl, aryl sulfonylalkyl, aryloxy, arylalkoxy, NR5R6, azido, nitro, guanidino, amidino, phosphono, oxo, carbamoyle, alkylsulfonyl, alkylsulfinyl, alkylthio, or SF 5 and two Y groups can optionally form a methylenedioxy;
R5 and R6 are independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl,
wherein alkyl, aryl and heteroaryl groups can be independently optionally substituted by one or more substituents Y,or
R5 and R6 together can optionally constitute a heterocycle;
or R2 and R3 can constitute a cycle compound then corresponds to formula (II)

wherein:
n is 4;
R4 is one or more hydrogen, alkyl, alkoxy, cycloalkyl, or aryl,
wherein alkyl, cycloalkyl and aryl groups can be optionally substituted by one or more hydroxy, halogen, alkyl, alkoxy, trifluoromethoxy, trifluoromethyl, alkylsulfonyl, or NR7R8; and
R7 and R8 are independently hydrogen, alkyl, or cycloalkyl;
or racemic forms, tautomers, enantiomers, diastereomers, epimers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

2. The method according to claim 1 , wherein in the compound of formula (I):
R1 is alkyl, cycloalkyl, cycloalkylalkyl, or alkoxyalkyl;
wherein each of these groups can be, independently optionally substituted by one or more halogen, or hydroxy;
R2 is hydrogen, alkyl, or cycloalkyl;
R3 is hydrogen, alkyl, cycloalkyl, or halogen;
A is aryl, or heteroaryl;
wherein aryl and heteroaryl groups can be independently optionally substituted by one or more substituents Y;
Y is:
hydroxy, thio, halogen, cyano, trifluoromethoxy, trifluoromethyl, carboxy, carboxymethyl, carboxyethyl, alkyl, alkoxy, alkylamino, aryl, aryl sulfonylalkyl, aryloxy, arylalkoxy, NR5R6, azido, nitro, guanidino, amidino, phosphono, oxo, carbamoyl, alkylsulfonyl, alkylsulfinyl, alkylthio, or SF 5 , and two Y groups can optionally form methylenedioxy,
R5 and R6 are independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
wherein alkyl, aryl and heteroaryl groups can be independently optionally substituted by one or more substituents Y; or
R5 and R6 together can optionally constitute a heterocycle; or
R2 and R3 can constitute a cycle which compound then corresponds to formula (II),

wherein:
n is 4; and
R4 is one or more hydrogen, alkyl, alkoxy, cycloalkyl, or aryl;
wherein alkyl, cycloalkyl and aryl groups can be optionally substituted by one or more hydroxy, halogen, alkyl, alkoxy, trifluoromethoxy, trifluoromethyl, or alkylsulfonyl;
or racemic forms, tautomers, enantiomers, diastereomers, epimers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

3. The method according to claim 2 , wherein R1 is ethyl, propyl, isopropyl, butyl, cyclopropyl, or cyclopropylmethyl.

4. The method according to claim 2 , wherein R2 and R3 are independently hydrogen, alkyl or constitute a cycle, which corresponds to tetrahydroquinoxalin-2(1H)-one.

5. The method according to claim 2 , wherein R2 and R3 are hydrogen, or constitute a cycle, which corresponds to tetrahydroquinoxalin-2(1H)-one.

6. The method according to claim 2 , wherein A is phenyl, indolyl, or quinolinyl, wherein each of these groups can be optionally substituted by one or more groups Y.

7. The method according to claim 2 , wherein Y is halogen, trifluoromethoxy, trifluoromethyl, carboxy, alkyl, alkoxy, alkylsulfonyl, and two Y groups can optionally form a methylenedioxy.

8. The method according to claim 1 , wherein in the compound of formula (I):
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, or alkoxyalkyl,
wherein each of these groups can be independently optionally substituted by one or more substituents Y;
R2 is hydrogen, alkyl, or cycloalkyl;
R3 is hydrogen, halogen, alkyl, or cycloalkyl;
A is aryl, or heteroaryl,
wherein aryl and heteroaryl groups can be optionally substituted by one or more substituents Y;
Y is:
hydroxy, thio, halogen, cyano, trifluoromethoxy, trifluoromethyl, carboxy, carboxymethyl, carboxyethyl, alkyl, alkoxy, alkylamino, aryl, aryl sulfonylalkyl, aryloxy, arylalkoxy, NR5R6, azido, nitro, guanidino, amidino, phosphono, oxo, carbamoyl, alkylsulfonyl, alkylsulfinyl, alkylthio, or SF 5 , and two Y groups can optionally form a methylenedioxy;
R5 and R6 are independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
wherein alkyl, aryl and heteroaryl groups can be independently optionally substituted by one or more substituents Y; or
R5 and R6 together can optionally constitute a heterocycle; or
R2 and R3 can constitute a cycle which compound then corresponds to formula (II),

wherein:
n is 4; and
R4 is one or more hydrogen, alkyl, alkoxy, cycloalkyl, or aryl;
wherein alkyl, cycloalkyl and aryl groups can be optionally substituted by one or more of hydroxy, halogen, alkyl, alkoxy, trifluoromethoxy, trifluoromethyl, or alkylsulfonyl;
or racemic forms, tautomers, enantiomers, diastereomers, epimers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

9. The method according to claim 1 , wherein said host suffers from diabetes.

10. The method according to claim 9 , wherein said diabetes is type II diabetes.

11. The method according to claim 1 , wherein said host suffers from dyslipidemia or obesity.

12. The method according to claim 1 , wherein said host suffers from diabetes related microvascular or macrovascular complications.

13. The method according to claim 1 , wherein hyperglycemia is reduced in said host.

14. The method according to claim 1 , wherein the compound is
1-cyclopropyl-3-phenylpyrazin-2(1H)-one;
1-(cyclopropylmethyl)-3-phenylpyrazin-2(1H)-one;
1-ethyl-3-

Assignees

• Merck Patent Gmbh

Inventors

• Botton Gerard
• Valeur Eric
• Charon Christine
• Kergoat Micheline
• Elbawab Samer

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title