HK1153385A

HK1153385A - Pyridopyrazinones derivatives insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes

Info

Publication number: HK1153385A
Application number: HK11107433.7A
Authority: HK
Inventors: Gérard Botton; Eric Valeur; Micheline Kergoat; Christine Charon; Samer Elbawab
Original assignee: Merck Patent Gmbh
Priority date: 2008-03-05
Filing date: 2009-02-27
Publication date: 2012-03-30

Description

Pyridopyrazinone derivatives as insulin secretion stimulators, methods for obtaining them and their use in the treatment of diabetes

Technical Field

The present invention relates to pyridopyrazinone derivatives of formula (I) as insulin secretion stimulators. The invention also relates to a method for producing these pyridopyrazinone derivatives and to the use thereof for the prophylaxis and/or treatment of diabetes and related pathologies.

Background

Type II diabetes is one of the most common diseases worldwide. In 2007, its prevalence was estimated to be 5.9% (2.46 billion) of the adult population, and is continuously increasing. Diabetes, a major risk factor for the development of cardiovascular disease and stroke, can lead to serious microvascular and macrovascular complications (these diseases can cause disability or even death) and is therefore more severe.

Type II diabetes is characterized by fasting and postprandial hyperglycemia, which are the result of two major defects: insulin resistance is produced at the level of the target tissue and insulin secretion from the islet beta cells is altered. The latter abnormality appears to occur very early, as it occurs at the Impaired Glucose Tolerance (IGT) stage (Mitrakou et al, N.Engl. J.Med.326: 22-29, 1992). UK Pre-diabetic Productivity Studies (UKPDS) noted that 50% of beta cell function had been lost when Diabetes was diagnosed, suggesting that impairment of beta cell function may begin 10-12 years before Diabetes was diagnosed (Holman, Diabetes Res. Clin. practice.40: S21, 1998 or UKPDS Group, Diabetes 44: 1249-58, 1995).

Insulin secretion deficiency is due to a defect in both the quality and number of beta cells, i.e., a decrease in the number of beta cells and a specific defect in insulin release in response to changes in glucose concentration, particularly the first phase of its secretion, because the response to non-glucose secretagogues is preserved (Pfeifer et al, am.J. Med.70: 579-88, 1981). The importance of restoring the normal release pattern of insulin in response to glucose concentration to control blood glucose within the normal range is supported by studies in which non-diabetic volunteers were taken, and results suggest that delaying insulin secretion in response to phase 1 of glucose concentration results in glucose tolerance (Calles-Ecandon et al, Diabetes 36: 1167-72, 1987).

Oral hypoglycemic agents, such as sulfonylureas and glinides, known for the treatment of type II diabetes, can induce insulin secretion by binding to sulfonylurea receptors on the beta cell K-ATP channel, which leads to increased intracellular calcium and extracellular insulin secretion. Thus, this increased insulin release is completely independent of plasma glucose levels, and treatment with such molecules typically induces sustained hyperinsulinemia, which in turn may lead to several side effects, such as severe hypoglycemia, weight gain, and increased risk of cardiovascular disease. Furthermore, persistent hyperinsulinemia resulting from treatment with sulfonylureas (which do not have a retention effect on beta cell numbers) may lead to secondary decline due to beta cell depletion, another detrimental side effect of these compounds.

A new method for treating type II diabetes should in particular be able to restore the normal release of insulin in response to glucose concentrations, while being able to maintain or increase the number of beta cells. GLP-1 analogs, such as glucagon-like peptide-1 analogs (exenatide) or liraglutide (liraglutide), have the above-described effects, but such substances are peptides and must therefore be administered by parenteral routes.

For new oral small molecule drugs, these features are more advantageous over other antidiabetic drugs.

According to the invention, the compounds of formula (I) are insulin secretion stimulators and can be used for the treatment of diabetes and pathologies associated therewith. They can lower blood glucose levels by restoring defective glucose-induced insulin secretion in type II diabetic patients.

Patent application WO 2007020521 discloses pyridopyrazinone derivatives useful as PDE V inhibitors.

EP 770079 describes pyridopyrazinone derivatives as PDE IV and TNF inhibitors.

In patent application WO 2004031189 pyridopyrazinone derivatives are described as corticotropin releasing factor receptor antagonists, which are useful in the treatment of anxiety and depression.

US 4296114 describes pyridopyrazinone derivatives for use as anti-inflammatory agents.

No pyridopyrazinone derivatives having antidiabetic activity have been described in the prior art.

Disclosure of Invention

The present invention relates to pyridopyrazinone derivatives of formula (I) which are useful for the treatment of diabetes and pathologies associated therewith. The pyridopyrazinone derivatives according to the present invention have the following formula (I):

wherein:

x, Y, Z, W is a nitrogen atom and the others are carbon atoms substituted with substituents selected from:

-hydrogen, and (C) hydrogen,

-T；

x is preferably N;

a is as follows: aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, arylthioalkyl, arylalkylthioalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, heteroarylalkylthioalkyl, heterocycloalkylalkyl, heterocycloalkyloxyalkyl, heterocycloalkylalkoxyalkyl, heterocycloalkylthioalkyl, heterocycloalkylalkylthioalkyl, arylalkenyl, arylalkynyl; heteroaryl or heterocycloalkyl groups may include one or more heteroatoms selected from N, O and S;

each of these groups may be optionally substituted with one or more substituents selected from T;

preferably a is aryl, arylalkyl, heteroaryl which may include one or more heteroatoms selected from N, O and S; each of these groups may be optionally substituted with one or more substituents selected from T;

more preferably A is: phenyl, benzyl, each of which may be optionally substituted with one or more substituents selected from T;

a is preferably aryl, more preferably phenyl;

r1 is: alkyl, alkyloxyalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkyloxyalkyl, heterocycloalkylalkoxyalkyl, heterocycloalkylthioalkyl, heterocycloalkylthioalkylthioalkyl, R3R 4N-alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl;

preferably R1 is: alkyl, alkyloxyalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkyloxyalkyl, heterocycloalkylalkoxyalkyl, heterocycloalkylthioalkyl, heterocycloalkylthioalkylthioalkyl, each of which may be optionally substituted with one or more substituents selected from T;

more preferably R1 is: alkyl, alkyloxyalkyl, cycloalkyl, cycloalkylalkyl; each of these groups may be optionally substituted with one or more substituents selected from T;

it is also preferred that R1 is: ethyl, isopropyl, butyl, 2-difluoroethyl, 2-methoxyethyl, cyclopropyl, cyclopropylmethyl;

t is selected from: hydroxy, thio, halogen, cyano, trifluoromethoxy, trifluoromethyl, carboxy, carboxymethyl, carboxyethyl, alkyl, cycloalkyl, alkoxy, alkylamino, aryl, arylsulfonylalkyl, aryloxy, arylalkoxy, NR3R4, azido, nitro, guanidino, amidino, phosphono, oxo, carbamoyl, alkylsulfonyl, alkylsulfinyl, alkylthio, SF5, two T groups can form methylenedioxy;

preferably T is: hydroxy, thio, halogen, cyano, trifluoromethoxy, trifluoromethyl, carboxy, carboxymethyl, carboxyethyl, alkyl, cycloalkyl, alkoxy, aryl, arylsulfonylalkyl, aryloxy, arylalkoxy, NR3R4, azido, guanidino, amidino, phosphono, oxo, carbamoyl, alkylsulfonyl, alkylsulfinyl, alkylthio, SF5, two T groups can form methylenedioxy;

it is also preferred that T is: halogen, trifluoromethyl, alkyl, alkoxy;

it is also preferred that T is: alkyl, cycloalkyl, Cl, F;

r3 and R4 are independently selected from: hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;

r3 and R4 may also constitute heterocycloalkyl which may include one or more heteroatoms selected from N, O and S;

r3 and R4 may be independently optionally substituted with one or more substituents selected from T;

preferably R3 and R4 are independently selected from lower alkyl, cycloalkyl;

and racemic forms, tautomers, enantiomers, diastereomers, epimers, and polymorphs thereof, and mixtures thereof, and pharmaceutically acceptable salts thereof.

The compound of formula (I) may be selected from:

1-cyclopropyl-3- (4-fluorophenyl) pyrido [3, 4-b ] pyrazin-2 (1H) -one;

1-cyclopropyl-3- [4- (trifluoromethyl) phenyl ] pyrido [3, 4-b ] pyrazin-2 (1H) -one;

1-cyclopropyl-3-phenylpyrido [3, 4-b ] pyrazin-2 (1H) -one;

2- (3-chlorophenyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chloro-2-methylphenyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorobenzyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4- (2, 2-difluoroethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4- (2-methoxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-cyclopropyl-6-methylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-cyclopropyl-7-methylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-cyclopropyl-8-methylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-cyclopropylmethylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-ethylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-isopropyl-pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4- (2-methoxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4-ethylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4-isopropyl-pyrido [2, 3-b ] pyrazin-3 (4H) -one;

3- (4-chlorophenyl) -1-cyclopropylpyrido [3, 4-b ] pyrazin-2 (1H) -one;

4- (2, 2-difluoroethyl) -2- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4- (2, 2-difluoroethyl) -2- (4-trifluoromethylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4- (2, 2-difluoroethyl) -2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4- (2-methoxyethyl) -2- (4-trifluoromethylphenyl) -pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4- (2-methoxyethyl) -2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4- (cyclopropylmethyl) -2- (4-fluoro-2-methylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-butyl-2- (4-chlorophenyl) -pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclobutyl-2- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (3-fluorophenyl) -pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (3-methylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (4-fluoro-2-methylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (4-fluorophenyl) -6-methoxypyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (4-fluorophenyl) -6-methylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (4-fluorophenyl) -7-methylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (4-fluorophenyl) -8-methylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (4-methylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (4-trifluoromethylphenyl) -8-methylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (4-trifluoromethylphenyl) -pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- [3- (trifluoromethyl) phenyl ] pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropylmethyl-2- (4-fluoro-2-methylphenyl) -pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropylmethyl-2- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropylmethyl-2- (4-trifluoromethylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropylmethyl-2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-ethyl-2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-isopropyl-2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (2-chlorophenyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (2, 4-dichlorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (2, 4, 5-trifluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (2-methoxyphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (4-methoxyphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chloro-2-methylphenyl) -4-isopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (2, 4-dichlorophenyl) -4-isopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluoro-2-methylphenyl) -4-isopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (2-ethoxyphenyl) -4-isopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (6-methoxypyridin-3-yl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

4-cyclopropyl-2- (2-thienyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (2-furyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4- (2-hydroxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4- (2-hydroxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4- (2-hydroxyethyl) -2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4- (3-hydroxypropyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4- (3-hydroxypropyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4- (3-hydroxypropyl) -2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chloro-2-methylphenyl) -4- (2-hydroxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chloro-2-methylphenyl) -4- (2-methoxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluoro-2-methylphenyl) -4- (2-methoxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (2, 4-dimethylphenyl) pyrido [2, 3-b) ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4- [2- (diethylamino) ethyl ] pyrido [2, 3-b ] pyrazin-3 (4H) -one;

1-ethyl-3- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-2 (1H) -one;

More preferably, the compounds of formula (I) according to the invention are selected from:

2- (4-chlorobenzyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4- (cyclopropylmethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-cyclopropylmethylpyrido [2, 3-b) ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-ethylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-isopropyl-pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4- (2-methoxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4- (2-methoxyethylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4-ethylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4- (2-hydroxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2-ethylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropylmethyl-2- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-ethyl-2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

The invention also relates to racemic forms, tautomers, enantiomers, diastereomers, epimers of the compounds of formula (I) and organic or inorganic salts of the compounds of formula (I), as well as various crystalline forms thereof, including polymorphs thereof, and polymorphs of the compounds of formula (I).

The invention relates not only to racemic mixtures of these compounds, but also to their individual stereoisomers and/or diastereomers and to mixtures thereof in all ratios.

The compounds of formula (I) of the invention as defined above which contain either sufficient acidic functionality or sufficient basic functionality or both may include the corresponding pharmaceutically acceptable salts with organic or inorganic acids or with inorganic or organic bases.

The term "pharmaceutically acceptable salts" refers to the relatively non-toxic inorganic and organic acid addition salts and base addition salts of the compounds of the present invention. These salts may be formed in situ by the final isolation and purification stages of these compounds.

In particular, acid addition salts may be prepared by reacting the purified compound in pure form with an organic or inorganic acid and isolating the salt thus obtained. The salts thus produced are, for example, the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, citrate, maleate, fumarate, trifluoroacetate, 2-naphthalenesulfonate and p-toluenesulfonate salts.

The invention also relates to pharmaceutically acceptable salts formed with organic or inorganic bases. In particular, base addition salts may be prepared by reacting the purified compound in pure form with an organic or inorganic base and isolating the salt thus formed. Salts thus formed are, for example, metal salts, in particular alkali metal, alkaline earth metal and transition metal salts (for example sodium, potassium, calcium, magnesium, aluminium), or salts with bases such as ammonia or secondary and tertiary amines (for example diethylamine, triethylamine, piperidine, piperazine, morpholine), or salts with basic amino acids, or with sugar amines (for example meglumine) or amino alcohols (for example 3-aminobutanol and 2-aminoethanol).

The invention also relates to salts for chiral resolution of racemates.

For example, the following chiral acids may be employed: (+) -D-di-O-benzoyltartaric acid, (-) -L-di-O, O '-p-toluoyl-L-tartaric acid, (+) -D-di-O, O' -p-toluoyl-L-tartaric acid, (R) - (+) -malic acid, (S) - (-) -malic acid, (+) -camphoric acid, (-) -camphoric acid, R- (-) -1, 1 '-binaphthyl-2, 2' -dihydrogenphosphonic acid, (+) -camphoric acid, (-) -camphoric acid, (S) - (+) -2-phenylpropionic acid, dihydrogenphosphonic acid, and mixtures thereof, (R) - (+) -2-phenylpropionic acid, D- (-) -mandelic acid, L- (+) -mandelic acid, D-tartaric acid, L-tartaric acid, or mixtures thereof.

For example, the following chiral amines may be employed: quinine, strychnine, (S) -1- (benzyloxymethyl) propylamine (III), (-) -ephedrine, (4S, 5R) - (+) -1, 2, 2, 3, 4-tetramethyl-5-phenyl-1, 3-Oxazolidines, (R) -1-phenyl-2-p-tolylethylamine, (S) -phenylglycinol, (-) -N-methylephedrine, (+) - (2S, 3R) -4-dimethylamino-3-methyl-1, 2-diphenyl-2-butanol, (S) -phenylglycinol, (S) - α -methylbenzylamine, or mixtures thereof.

The invention also includes prodrugs of the compounds of formula (I).

The term "prodrug" refers to a compound that, when administered to a biological system, produces a "drug" (biologically active compound) through a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, and/or a metabolic chemical reaction.

In accordance with the present invention, the following terms used herein have the following definitions, unless explicitly stated otherwise.

The term "aryl" refers to aromatic groups, including biaryls, having 5 to 14 ring atoms and a conjugated pi-electron system in at least one ring, all of which are optionally substituted. Suitable aryl groups include phenyl, naphthyl, biphenyl, anthryl, phenanthryl, indenyl, and the like.

The term "heteroaryl" refers to an aromatic heterocyclic ring of 5 to 14 ring atoms containing 1 to 4 heteroatoms as ring atoms in the aromatic ring and the remaining ring atoms being carbon atoms. Suitable heteroatoms include O, S, N. Suitable heteroaryl groups include furyl, benzofuryl, thienyl, pyridyl-N-oxide, pyrimidinyl, pyrazinyl, and the like,Azolyl, thiazolyl, isoOxazolyl, quinolinyl, triazolyl, pyridazinyl, pyrrolyl, imidazolyl, indazolyl, isothiazolyl, indolyl,Oxadiazolyl, and the like.

The term "cycloalkyl" refers to a saturated carbocyclic ring, optionally substituted, which includes monocyclic, bicyclic, and tricyclic compounds having 3 to 10 carbon atoms. Suitable cycloalkyl groups are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, adamantyl and the like.

The term "heterocycloalkyl" refers to an optionally substituted monocyclic, bicyclic or tricyclic group, including one or more heteroatoms preferably selected from O, S and N, optionally present in an oxidized state (for S and N), and optionally having one or more double bonds. At least one ring preferably contains 1 to 4 ring heteroatoms, preferably 1 to 3 heteroatoms. More preferably, the heterocycloalkyl (or simply "heterocycle") group contains one or more rings, each ring having from 5 to 8 nodes. Examples of heterocycles include: morpholinyl, piperidinyl, piperazinyl, thiazolidinyl,Oxazolidinyl, tetrahydrothienyl, dihydrofuryl, tetrahydrofuranyl, pyrazolidinyl, 1, 3-dioxolanyl, pyrrolidinyl, pyranyl, dihydropyranyl, isovalerylOxazolidinyl, imidazolyl, imidazolidinyl, and the like.

The term "alkyl" refers to saturated aliphatic groups, including straight and branched chain groups. Suitable alkyl groups have 1 to 20 carbon atoms and include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl, dodecyl, hexadecyl, octadecyl, and the like.

The term "alkylene" refers to a divalent group obtained by removing one hydrogen atom from an alkyl group.

The term "alkenyl" refers to an unsaturated group that includes at least one carbon-carbon double bond, including straight chain, branched chain, and cyclic groups. Suitable alkenyl groups having 2 to 20 carbon atoms include ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl and the like.

The term "alkynyl" refers to an unsaturated group that includes at least one carbon-carbon triple bond, including straight, branched, and cyclic groups, and optionally has at least one carbon-carbon double bond. Suitable alkynyl groups having 2 to 20 carbon atoms include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, and the like.

The term "arylalkyl" refers to an alkyl group substituted with an aryl group, preferably an alkane having 1 to 20 carbon atoms. Suitable arylalkyl groups include benzyl, picolyl, and the like.

The term "alkoxy" refers to the group alk-O-, where "alk" is alkyl.

The term "aryloxy" refers to the group aryl-O-.

The term "aryloxyalkyl" refers to an alkyl group substituted with an aryloxy group.

The term "arylalkoxyalkyl" refers to an alkyl group substituted with an arylalkoxy group.

The term "arylalkoxy" refers to the group aryl-Alk-O-, wherein "Alk" is alkyl.

The term "arylthioalkyl" refers to an alkyl group substituted with an arylthio group.

The term "arylalkylthioalkyl" refers to an alkyl group substituted with an arylalkylthio group.

The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group.

The term "heteroaryloxyalkyl" refers to an alkyl group substituted with a heteroaryloxy group.

The term "heteroarylalkoxyalkyl" refers to an alkyl group substituted with a heteroarylalkoxy group.

The term "heteroarylthioalkyl" refers to an alkyl group substituted with a heteroarylthio group.

The term "heteroarylalkylthioalkyl" refers to an alkyl group substituted with a heteroarylalkylthio group.

The term "heterocycloalkylalkyl" refers to an alkyl group substituted with a heterocycloalkyl group.

The term "heterocycloalkyloxyalkyl" refers to an alkyl group substituted with a heterocycloalkyloxy group.

The term "heterocycloalkylalkoxyalkyl" refers to an alkyl group substituted with a heterocycloalkylalkoxy group.

The term "heterocycloalkylthioalkyl" refers to an alkyl group substituted with a heterocycloalkylthio group.

The term "heterocycloalkylalkylthioalkyl" refers to an alkyl group substituted with a heterocycloalkylalkylthio group.

The term "arylalkenyl" refers to an alkenyl group substituted with an aryl group.

The term "arylalkynyl" refers to an alkynyl group substituted with an aryl group.

The term "alkyloxyalkyl" refers to an alkyl group substituted with an alkyloxy group.

The term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group.

The term "lower" as used in describing organic groups or compounds means, for example, having up to and including 10, preferably up to and including 6, still preferably 1 to 4 carbon atoms. Such groups may be linear, branched or cyclic.

The term "arylsulfonylalkyl" refers to the group aryl-SO₂-Alk, wherein "Alk" is alkyl.

The term "alkylthio" refers to the group alk-S-, wherein "alk" is alkyl.

The term "halogen" refers to a fluorine, bromine or chlorine atom.

The term "amidino" refers to-C (NR3) -NR3R4, wherein R3R4 is as defined above, all groups other than hydrogen being optionally substituted.

The compounds of formula (I) of the present invention have hypoglycemic activity and are therefore useful in the treatment of pathologies associated with the insulin resistance syndrome.

Insulin resistance is characterized by a reduction in insulin action (see "pressure medicine", (1997), 26(14), 671-677) and is associated with a variety of pathologies such as diabetes, particularly non-insulin dependent diabetes mellitus (type II diabetes, also known as NIDDM), lipid metabolism disorders, obesity, arterial hypertension, and certain cardiac, microvascular and macrovascular complications such as atherosclerosis, retinopathy and neuropathy. In this regard, reference may be made to, for example, Diabetes, 37, (1988), 1595-; journal of Diabetes and its compositions, 12, (1998), 110-; horm. res., 38, (1992), 28-32.

The invention also relates to a pharmaceutical composition comprising as active ingredient at least one compound of formula (I) and/or a pharmaceutically acceptable salt thereof, as defined above, and one or more pharmaceutically acceptable carriers, adjuvants, diluents or excipients. The skilled person is well aware of various carriers, adjuvants, diluents or excipients which are suitable for formulating pharmaceutical compositions. The pharmaceutical compositions of the present invention may be administered by a variety of routes including oral, parenteral, intravenous, intramuscular, rectal, transmucosal or transdermal. Thus, these pharmaceutical compositions may be in the form of injection solutions or suspensions, in multi-dose form, as plain or coated tablets, as sugar-coated tablets, as glutinous rice capsules (wafer capsules), gel capsules, pills, sachets, powders, suppositories or rectal capsules, solutions or suspensions, for transdermal use in polar solvents, or for transmucosal use.

Excipients suitable for such administration are pharmaceutically acceptable excipients, for example cellulose or microcrystalline cellulose derivatives, alkaline earth metal carbonates, magnesium phosphate, starch, modified starch, lactose and the like in the case of solid dosage forms.

For rectal use, preferred excipients include cocoa butter or polyethylene glycol stearate.

For parenteral use, the most suitable carriers for use are water, aqueous solutions, physiological saline and isotonic solutions.

For example, for oral administration, in the case of granules, tablets or coated tablets, pills, capsules, gel capsules, gels, sachets or powders, a suitable dosage of the compound is from about 0.1mg/kg to about 100mg/kg, preferably from about 0.5mg/kg to about 50mg/kg, more preferably from about 1mg/kg to about 10mg/kg, most preferably from about 2mg/kg to about 5mg/kg of body weight per day.

Considering that the body weight is usually 10kg-100kg, for the purpose of illustrating the daily oral dosage range which can be used and is described above, a suitable dosage of the compound of formula (I) may be about 1-10 mg/day to 1000-10000 mg/day, preferably about 5-50 mg/day to 500-5000 mg/day, more preferably 10-100mg to 100-1000 mg/day, most preferably 20-200mg to 50-500 mg/day.

However, it will be understood that the specific dose for a particular patient will depend upon a variety of factors including the activity of the specific compound employed; the age, weight, general health, sex, and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs previously administered, as well as the severity of the particular disease being treated, will be understood by those skilled in the art.

As mentioned above, the formulations of the present invention suitable for oral administration may be in the form of discrete units such as capsules, sachets or tablets, each containing a predetermined amount of the active ingredient; can also be powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be administered as a bolus, electuary or paste.

The invention also relates to the compounds of general formula (I), their racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and their pharmaceutically acceptable salts, for the preparation of a medicament for the prevention and/or treatment of pathologies associated with hyperglycemia; for the preparation of a medicament for inducing insulin secretion in response to glucose concentrations, preferably for the treatment of diabetes, more preferably for the prevention and/or treatment of type II diabetes and pathologies associated with metabolic diseases, hypercholesterolemia, hyperlipidemia, which are caused by hyperinsulinemia and hyperglycemia; for treating a disease selected from: microvascular and macrovascular complications associated with diabetes, such as arterial hypertension, inflammation, microangiopathy, macroangiopathy, retinopathy and neuropathy; for lowering hyperglycemia, for treating dyslipidemia and obesity; or diseases such as cardiovascular diseases including atherosclerosis, myocardial ischemia.

The invention also relates to the use of at least one compound of the general formula (I), its racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and the pharmaceutically acceptable salts and prodrugs thereof, for the manufacture of a medicament for the treatment of: medicaments for the prevention and/or treatment of pathologies associated with hyperglycemia, preferably for the treatment of diabetes, more preferably for the prevention and/or treatment of type II diabetes and pathologies associated with metabolic diseases, hypercholesterolemia, hyperlipidemia, which are caused by hyperinsulinemia and hyperglycemia; for treating a disease selected from: microvascular and macrovascular complications associated with diabetes, such as arterial hypertension, inflammation, microangiopathy, macroangiopathy, retinopathy and neuropathy; for lowering hyperglycemia, for treating dyslipidemia and obesity; or diseases such as cardiovascular diseases including atherosclerosis, myocardial ischemia.

The present invention also relates to a process for the preparation of a compound of formula (I) as defined above, according to the representative process shown in the following scheme: scheme 1 (preparation of diaminopyridine derivative intermediates); scheme 2 (method a) or scheme 3 (method B), wherein X, Y, Z, W, R1, a are as defined above for formula (I) and Hal is a halogen atom, preferably Cl or Br.

The following flow is given for illustrative purposes and is merely to aid in the description of the invention. Needless to say, the person skilled in the art can, depending on the desired properties of the compound of formula (I), select suitable starting materials in which the nature of the substituents R1 and a, in particular the nature and length of the desired chain, can be varied, and make appropriate modifications to the given process.

The compounds used in the present invention can be prepared by employing or modifying known methods known in the art or methods described in the literature, patents or patent applications, Chemical Abstracts (Chemical Abstracts) and the internet, unless otherwise specified.

Preparation of intermediate diaminopyridine derivative:

scheme 1:

wherein:

hal is a halogen atom, preferably Cl or Br;

r1 is as defined for formula (I);

x, Y, Z and W are as defined for formula (I).

The pyridine nitroamino derivative of formula (2) can be prepared by the following method: the halo-nitropyridine derivative of formula (1) is reacted with an amine in the presence of at least one equivalent of a base (e.g., sodium or potassium carbonate, cesium carbonate), or in the presence of at least two equivalents of an amine, in an inert solvent such as tetrahydrofuran, acetonitrile or toluene, at a temperature of 20 ℃ to reflux for 1 to 24 hours. Diaminopyridine derivatives of formula (3) may be prepared from compounds of formula (2) by reduction of the nitro group to the corresponding primary aromatic amine. Preferred processes employ metals such as Zn, Sn or Fe in an acid, such as aqueous HCl. Other preferred methods employ metals in a low oxidation state, such as tin chloride (ll) in HCl. Particular preference is given to carrying out the reduction by catalytic hydrogenation using a metal catalyst of a metal such as Pd, Pt or Ni, preferably Pd on charcoal or Raney nickel, in a solvent such as methanol, ethanol, tetrahydrofuran.

Preparation of pyridopyrazinone derivatives:

scheme 2-method A

The process is particularly suitable for the preparation of compounds of formula (I) as defined below, wherein:

rx is Hal, ORe (where Re is hydrogen, lower alkyl);

hal is a halogen atom, preferably Cl or Br;

r1 is as defined above for formula (I);

a is as defined above for formula (I);

x, Y, Z and W are as defined above for formula (I).

Pyridopyrazinones of formula (I) are prepared as follows: the cyclization is carried out by reacting the compound of formula (3) with an α -keto acid derivative in a solvent such as methanol, acetonitrile, Dimethylformamide (DMF) or toluene at 20 ℃ to reflux, more preferably at reflux, for 1 to 36 hours.

Scheme 3-method B

This process is particularly applicable to compounds of formula (I) wherein:

rx is Hal, ORe (where Re is hydrogen, lower alkyl);

hal is a halogen atom, preferably Cl or Br;

r1 is as defined above for formula (I);

a is as defined above for formula (I);

x, Y, Z and W are as defined above for formula (I).

The hydroxypyridopyrazinone compound of formula (5) is obtained as follows: the cyclisation is carried out by reacting the compound of formula (3) with, for example, a chloro (oxo) acetate derivative in the presence of at least one equivalent of a base (inorganic base, such as sodium or potassium carbonate, cesium carbonate, or an organic base, such as triethylamine or diisopropylethylamine) in an inert solvent (such as dichloromethane, acetonitrile, DMF) at 20 ℃ under reflux for 1 to 24 hours.

The bromo derivative of formula (6) is prepared as follows: in an inert solvent (e.g. 1, 2-dichloroethane) at 20 deg.C to reflux, more preferably at reflux, with a brominating agent such as POBr₃Brominating the compound of formula (5) for 1-24 h.

Pyridopyrazinones of formula (I) are prepared as follows: the bromo compound of formula (6) is reacted with a boronic acid derivative or ester thereof in the presence of a base (e.g. sodium or potassium carbonate) and a catalyst (e.g. bis (triphenylphosphine) palladium (II) chloride) in an inert solvent (e.g. dimethylformamide or toluene) at 20 ℃ to reflux, more preferably reflux, for 1 to 24 h.

The following examples are intended to illustrate, but not to limit, the present invention. The starting materials used are known products or can be prepared by known methods. Percentages are by weight unless otherwise indicated.

The compounds can be identified in particular by the following analytical techniques.

NMR spectra were obtained using a Bruker Avance DPX 300MHz NMR spectrophotometer.

The mass was determined using HPLC coupled to an Agilent Series 1100 mass detector. Melting points (m.p.) were determined using a Stuart Scientific block.

Example (b):

example 1: n- (cyclopropylmethyl) -3-nitropyridin-2-amine

3g (18.9mM) 2-chloro-3-nitropyridine and 5g (70.3mM) cyclopropylmethylamine in 12ml tetrahydrofuran are refluxed for 1h with stirring. Water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give 3.5g N- (cyclopropylmethyl) -3-nitropyridin-2-amine as a yellow oil. Yield: 95.7 percent.

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：0.06(m，2H)，0.24(m，2H)，0.95(m，1H)，3.22(t，1H)，6.53(m，1H)，8.18(m，1H)，8.25(m，1H)，8.31(m，1H)。

In the same manner as in example 1, the following compounds were obtained.

Examples 1 to 2: n- (2, 2-difluoroethyl) -3-nitropyridin-2-amine

C₇H₁F₂N₃O₂203.15 mass M +1 204

Examples 1 to 3: n-cyclopropyl-3-nitropyridin-2-amines

C₈H₉N₃O₂179.18 mass M +1 180.0

Examples 1 to 4: n- (cyclopropyl) -3-nitropyridin-4-amine

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：0.46(m，2H)，0.67(m，2H)，2.45(m，1H)，7.05(d，1H)，8.05(s，1H)，8.14(d，1H)，8.79(s，1H)

Examples 1 to 5: n- (cyclopropylmethyl) -3-nitropyridin-4-amine

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：0.20(m，2H)，0.39(m，2H)，1.05(m，1H)，3.17(t，2H)，6.94(d，1H)，8.15(d，1H)，8.33(s，1H)，8.91(s，1H)

Example 2: n is a radical of²- (cyclopropylmethyl) pyridine-2, 3-diamine

To a solution of 3.5g (18.1mM) N- (cyclopropylmethyl) -3-nitropyridin-2-amine in 36ml of methanol was added 700mg of 5% palladium on charcoal and the reaction mixture was stirred at room temperature under atmospheric pressure under hydrogen for 3 h. The catalyst was removed by filtration over Celite and the filtrate evaporated in vacuo to give 3.1g N²- (cyclopropylmethyl) pyridine-2, 3-diamine, as a solid. Yield: 99.5 percent.

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：0.00(m，2H)，0.24(m，2H)，0.89(m，1H)，2.96(t，2H)，4.5(s，2H)，5.37(t，1H)，6.15(m，1H)，6.44(d，1H)，7.13(1d，1H)

In the same manner as in example 2, the following compounds were obtained.

Example 2-2: n is a radical of²- (2, 2-difluoroethyl) pyridine-2, 3-diamine

C₇H₉F₂N₃173.16, Mass Spectrum M +1 174.1

Examples 2 to 3: n is a radical of²-cyclopropylpyridine-2, 3-diamine

(C₈H₁₁N₃149.19, Mass Spectrum M +1 150.1

Examples 2 to 4: n is a radical of⁴-cyclopropylpyridine-3, 4-diamine

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：0.29(m，2H)，0.61(m，2H)，2.23(m，1H)，4.40(s，2H)，5.65(s，1H)，6.50(d，1H)，7.49(m，2H)

Examples 2 to 5: n is a radical of⁴- (cyclopropylmethylpyridine) -3, 4-diamine

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：0.02(m，2H)，0.28(m，2H)，0.84(m，1H)，2.74(t，2H)，4.41(s，2H)，5.19(m，1H)，6.14(d，1H)，7.35(d，1H)，7.41(s，1H)

Method A

Example 3: 2- (4-chlorophenyl) -4-cyclopropylmethylpyrido [2, 3-b ] pyrazin-3 (4H) -one

430mg (2.63mM) N²- (cyclopropylmethyl) pyridine-2, 3-diamine and 485.4mg (2.63mM) (4-chlorophenyl) (oxo) acetic acid were refluxed in 6ml methanol for 16 h. The solid crystallized, the compound filtered and washed with methanol to give 300mg of 2- (4-chlorophenyl) -4- (cyclopropylmethyl) pyrido [2, 3-b]Pyrazin-3 (4H) -one, as a beige solid. Yield: 36.5 percent.

NMR ¹H(300MHz/CF₃COOD)δ(ppm)：0.59(m，4H)，1，23(m，1H)，4.44(d，2H)，7.44(d，2H)，7.83(m，1H)，8.11(d，2H)，8.66(d，1H)，8.89(d，1H)

In the same manner as in example 3, the following compounds were obtained.

Example 3-2: 2- (4-chlorophenyl) -4-ethylpyrido [2, 3-b ] pyrazin-3 (4H) -one

NMR ¹H(300MHz/CF₃COOD)δ(ppm)：0.18(t，3H)，3.30(q，2H)，6.16(d，2H)，6.55(m，1H)，6.84(d，2H)，7.37(d，1H)，7.63(d，1H)

Examples 3 to 3: 2- (4-fluorophenyl) -4-ethylpyrido [2, 3-b ] pyrazin-3 (4H) -one

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：1.30(t，3H)，4.47(q，2H)，7.36(t，2H)，7.51(m，1H)，8.33(m，3H)，8.69(d，1H)

Examples 3 to 4: 4-Ethyl-2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：1.30(t，3H)，4.47(q，2H)，7.54(m，4H)，8.24(m，3H)，8.67(d，1H)

Examples 3 to 5: 2- (4-chlorophenyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one

NMR ¹H(300MHz/CF₃COOD)δ(ppm)：1.15(m，2H)，1.60(m，2H)，3.27(m，1H)，7.40(d，2H)，7.83(m，1H)，8.13(d，2H)，8.64(d，1H)，8.86(d，1H)

C₁₆H₁₂ClN₃297.74 mass M +1 298.0

Examples 3 to 6: 4-cyclopropyl-2- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

NMR ¹H(300MHz/CF₃COOD)δ(ppm)：1.10(m，2H)，1.57(m，2H)，3.23(m，1H)，7.06(m，2H)，7.79(m，1H)，8.15(m，2H)，8.59(d，1H)，8.83(d，1H)

C₁₆H₁₂FN₃281,28 mass M +1 282.1 mass M

Examples 3 to 7: 4-cyclopropylmethyl-2- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：0.46(m，4H)，1.33(m，1H)，4.34(d，2H)，7.34(t，2H)，7.49(m，1H)，8.30(m，3H)，8.65(d，1H)

Examples 3 to 8: 2- (4-chlorophenyl) -4- (2, 2-difluoroethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：4.88(td，2H)，6.41(tt，1H)，7.59(m，3H)，8.28(m，3H)，8.66(d，1H)

Examples 3 to 9: 3- (4-chlorophenyl) -1-cyclopropylpyrido [3, 4-b ] pyrazin-2 (1H) -one

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：0.97(m，2H)，1.36(m，2H)，3.12(m，1H)，7.63(d，2H)，7.82(d，1H)，8.29(d，2H)，8.66(d，1H)，9.04(s，1H)

C₁₆H₁₂ClN₃297.74 mass M +1 298.0

Examples 3 to 10: 1-cyclopropyl-3- (4-fluorophenyl) pyrido [3, 4-b ] pyrazin-2 (1H) -one

C₁₆H₁₂FN₃281.28 mass M +1 282.0

Examples 3 to 11: 1-cyclopropyl-3-phenylpyrido [3, 4-b ] pyrazin-2 (1H) -one

C₁₆H₁₃N₃263.29 mass M +1 264.1

Examples 3 to 12: 1-cyclopropyl-3- [4- (trifluoromethyl) phenyl ] pyrido [3, 4-b ] pyrazin-2 (1H) -one

C₁₇H₁₂F₃N₃331.29 mass M +1 332.0

Examples 3 to 13: 2- (4-chlorophenyl) -4-cyclopropyl-8-methylpyrido [2, 3-b ] pyrazin-3 (4H) -one

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：0.92(m.2H)，1.25(m，2H)，2.69(s，3H)，3.08(m，1H)，7.36(d，1H)，7.61(d，2H)，8.34(d，2H)，8.52(d，1H)

C₁₇H₁₄ClN₃311.77 mass M +1 312.0

m.p.：159-163℃

Examples 3 to 14: 4-cyclopropyl-2- (4-fluorophenyl) -6-methylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₄FN₃295.31 mass M +1 296.0

Examples 3 to 15: 2- (4-chlorobenzyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one

NMR ¹H(300MHz/CDCl₃)δ(ppm)：0.86(q，2H)，1.28(q，2H)，3.00(m，1H)，4.12(s，2H)，7.19(m，3H)，7.30(d，2H)，8.02(d，1H)，8.50(m，1H)

Examples 3 to 16: 2- (4-fluorophenyl) -4- (2-methoxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₄FN₃O₂299.3, mass M +1 300.0

m.p.：124-127℃

Examples 3 to 17: 4-butyl-2- (4-chlorophenyl) -pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₆ClN₃313.79 mass M +1 314.0

Examples 3 to 18: 2- (4-chlorophenyl) -4-isopropyl-pyrido [2, 3-b ] pyrazin-3 (4H) -one

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：1.55(d，6H)，5.86(m，1H)，7.40(m，1H)，7.50(d，2H)，8.15(d，2H)，8.20(d，1H)，8.60(d，1H)

C₁₆H₁₄ClN₃299.76 mass M +1 299.7

Examples 3 to 19: 4-cyclopropyl-2- (4-trifluoromethylphenyl) -pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₂F₃N₃331.29 mass M +1 332.1

Examples 3 to 20: 4-Cyclopropylmethyl-2- (4-trifluoromethylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₈H₁₄F₃N₃345.32 mass M +1 346.1

Examples 3 to 21: 4- (2, 2-difluoroethyl) -2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₅H₁₄F₂N₃287.27 mass spec 288.0

Examples 3 to 22: 4- (2, 2-difluoroethyl) -2- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₅H₁₀F₃N₃305.27 mass M +1 306.0

Examples 3 to 23: 4- (2, 2-difluoroethyl) -2- (4-trifluoromethylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₀F₅N₃355.27 mass M +1 356.0

Examples 3 to 24: 4- (2-methoxyethyl) -2- (4-trifluoromethylphenyl) -pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₄F₃N₃O₂349.31 mass M +1 350.1

Examples 3 to 25: 2- (4-chlorophenyl) -4- (2-methoxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₄ClN₃O₂315.76 mass M +1 316.0

Examples 3 to 26: 4- (2-methoxyethyl) -2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₅N₃O₂281.31 mass M +1 282.1

Examples 3 to 27: 4-cyclopropyl-2- (4-trifluoromethylphenyl) -8-methylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₈H₁₄F₃N₃345.32 mass M +1 346.3

Examples 3 to 28: 4-cyclopropyl-2- (4-fluorophenyl) -8-methylpyrido [2, 3-b ] pyrazin-3- (4H) -one

C₁₇H₁₄FN₃295.32 mass M +1 296.1

Examples 3 to 29: 4-cyclopropylmethyl-2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₅N₃277.33 mass M +1 278.1 mass M +1

Examples 3 to 30: 2- (4-chlorophenyl) -4-cyclopropyl-7-methylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₄ClN₃311.77 mass M +1 312.0

Examples 3 to 31: 4-cyclopropyl-2- (4-fluorophenyl) -7-methylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₄FN₃295.32 mass M +1 296.1

Examples 3 to 32: 2- (4-fluoro-phenyl) -4-isopropyl-pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₄FN₃283.30 mass M +1 284.1

Examples 3 to 33: 4-isopropyl-2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₅N₃265.31 mass M +1 266.1

Examples 3 to 34: 2- (4-chlorophenyl) -4-cyclopropyl-6-methylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₇H₁₄ClN₃311.77 mass M +1 312.0

Examples 3 to 35: 4-cyclopropyl-2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₃N₃263.29 mass M +1 264.1

Examples 3 to 36: 4-cyclopropyl-2- (4-fluorophenyl) -6-methoxypyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₄FN₃O₂311.31, mass M +1 312.1

Examples 3 to 37: 4-cyclobutyl-2- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₄FN₃295.31 mass M +1 296.1

Examples 3 to 38: 2- (4-chlorophenyl) -4- (2-hydroxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₅H₁₂ClN₃O₂301.73 mass M +1 302.0

Examples 3 to 39: 2- (4-fluorophenyl) -4- (2-hydroxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₅H₁₂FN₃O₂285.28 mass M +1 286.1

Examples 3 to 40: 4- (2-hydroxyethyl) -2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₅H₁₃N₃O₂267.29, Mass Spectrum M +1 268.1

Examples 3 to 41: 2- (4-chlorophenyl) -4- (3-hydroxypropyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₄ClN₃O₂315.76, mass M +1 316.1

Examples 3 to 42: 2- (4-fluorophenyl) -4- (3-hydroxypropyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₄FN₃O₂299.30, Mass Spectrum M +1 300.1

Examples 3 to 43: 4- (3-hydroxypropyl) -2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₅N₃O₂281.31 mass M +1 282.1

Examples 3 to 44: 1-ethyl-3- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-2 (1H) -one

C₁₅H₁₂FN₃269.27 mass M +1 270.0

Examples 3 to 45: 2- (4-fluorophenyl) -4- [2- (diethylamino) ethyl ] pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₉H₂₁FN₄340.39 mass M +1 341.1

Examples 3 to 46: 2- (4-chlorophenyl) -4- [2- (diethylamino) ethyl ] pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₉H₂₁ClN₄356.85 mass M +1 357.1

Method B

Example 4: 4- (cyclopropylmethyl) -2-hydroxypyrido [2, 3-b ] pyrazin-3 (4H) -one

1.6g (9.8mM) N in 20ml dichloromethane were added with stirring at room temperature²- (Cyclopropylmethyl) pyridine-2, 3-diamine and 1.7ml (9.8mM) diisopropylamine 1.1ml (9.8mM) ethyl chloro (oxo) acetate were added dropwise. The reaction mixture was stirred at room temperature for 16h, and water was added. Separating the organic layer, extracting the aqueous layer twice with dichloromethane, washing the combined organic layers with water, drying over anhydrous sodium sulfate, evaporating the solvent in vacuo, and purifying the compound by silica gel column chromatography using dichloromethane/methanol (95/5) as eluent to yield 700mg of 4- (cyclopropylmethyl) -2-hydroxypyrido [2, 3-b ] after evaporation]Pyrazin-3 (4H) -one, as a solid. Yield: 33 percent.

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：0.19(m，4H)，1.03(m，1H)，3.90(d，2H)，6.98(m，1H)，7.29(d，1H)，7.96(d，1H)，11.94(s，1H)

In the same manner as in example 4, the following compounds were obtained.

Example 4-2: 4- (cyclopropyl) -2-hydroxypyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₀H₉N₃O₂203.2, mass M +1 204.0

Example 5: 2-bromo-4- (cyclopropylmethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

700mg (3.22mM)4- (cyclopropylmethyl) -2-hydroxypyrido [2, 3-b ] pyrazin-3 (4H) -one and 972.3mg (3.22mM) tribromooxyphosphorus are refluxed for 16H in 95% 10ml dichloroethane with stirring. The reaction mixture was then basified with aqueous sodium carbonate, the aqueous layer was extracted with dichloromethane, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, the solvent was removed in vacuo, and the compound was further purified by silica gel column chromatography using dichloromethane as eluent to give, after evaporation, 650mg of 2-bromo-4- (cyclopropylmethyl) pyrido [2)3-b ] pyrazin-3 (4H) -one as a white solid. Yield: 66.5 percent.

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：0.46(m，4H)，1.31(m，1H)，4.26(d，2H)，7.49(m，1H)，8.22(d，1H)，8.68(d，1H)

In the same manner as in example 5, the following compounds were obtained.

Example 5-2: 2-bromo-4- (cyclopropyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₀H₈BrN₃266.1 for O and 267.0 for mass M + 1.

m.p.144-146℃

Example 6: 4- (cyclopropylmethyl) -2- (4-fluoro-2-methylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

To a solution of 200mg (0.71mM) 2-bromo-4- (cyclopropylmethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one and 25.3mg (0.036mM) bis (triphenylphosphine) palladium (II) chloride in 1ml dimethylformamide was added 142.9mg (0.93mM) (4-fluoro-2-methylphenyl) boronic acid, 0.1ml ethanol and 715. mu.l of 2M aqueous sodium carbonate solution. The reaction mixture was then refluxed for 20h with stirring, water and ethyl acetate were added, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate and the solvent was removed in vacuo. The compound was purified by column chromatography on silica gel using dichloromethane as eluent to give 100mg of 4- (cyclopropylmethyl) -2- (4-fluoro-2-methylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one as a white solid after evaporation. (yield: 45.3%)

NMR ¹H(300MHz/DMSO-d6)δ(ppm)：0.27(m.4H)，1.15(m，1H)，4.10(d，2H)，6.96(171，2H)，7.31(m，2H)，8.08(d，1H)，8.48(d，1H)

C₁₈H₁₆FN₃309.34 mass M +1 310.1

In the same manner as in example 6, the following compounds were obtained.

Example 6-2: 4-cyclopropyl-2- (4-fluoro-2-methylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₄FN₃295.31 mass M +1 296.1

m.p.：165-167℃

Examples 6 to 3: 2- (4-chloro-2-methylphenyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₄ClN₃311.76 mass M +1 312.0

Examples 6 to 4: 4-cyclopropyl-2- (3-fluorophenyl) -pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₂FN₃281.29 mass M +1 282.1

Examples 6 to 5: 2- (3-chlorophenyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₂ClN₃297.74 mass M +1 298.0

Examples 6 to 6: 4-cyclopropyl-2- (3-methylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₅N₃277.32 mass M +1 278.1 mass M +1

Examples 6 to 7: 4-cyclopropylmethyl-2- (4-fluoro-2-methylphenyl) -pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₈H₁₆FN₃309.34 mass M +1 310.1

Examples 6 to 8: 4-cyclopropyl-2- (4-methylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₅N₃277.32 mass M +1 278.1 mass M +1

Examples 6 to 9: 4-cyclopropyl-2- [3- (trifluoromethyl) phenyl ] pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₂F₃N₃331.29 mass M +1 332.1

Examples 6 to 10: 2- (2-chlorophenyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₂ClN₃297.74 mass M +1 298.0

Examples 6 to 11: 4-cyclopropyl-2- (2, 4-dichlorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₁Cl₂N₃332.18 mass M +1 333.2

Examples 6 to 12: 4-cyclopropyl-2- (2, 4, 5-trifluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₀F₃N₃317.27 mass M +1 318.0

Examples 6 to 13: 4-cyclopropyl-2- (2-methoxyphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₅N₃O₂293.32, Mass Spectrum M +1 294.1

Examples 6 to 14: 4-cyclopropyl-2- (4-methoxyphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₅N₃O₂293.32, Mass Spectrum M +1 294.1

Examples 6 to 15: 2- (4-chloro-2-methylphenyl) -4-isopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₆ClN₃313.78 mass M +1 314.0

Examples 6 to 16: 2- (2, 4-dichlorophenyl) -4-isopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₃Cl₂N₃334.20 mass spectrumM+1＝334.0

Examples 6 to 17: 2- (4-fluoro-2-methylphenyl) -4-isopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₆FN₃297.33 mass M +1 298.1

Examples 6 to 18: 2- (2-ethoxyphenyl) -4-isopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₈H₁₉N₃O₂309.36 mass M +1 310.1

Examples 6 to 19: 4-cyclopropyl-2- (6-methoxypyridin-3-yl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₄N₄O₂294.31 mass M +1 295.1

Examples 6 to 20: 4-cyclopropyl-2- (2-thienyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₄H₁₁N₃269.32 mass M +1 270.0 OS

Examples 6 to 21: 4-cyclopropyl-2- (2-furyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₄H₁₁N₃O₂253.26 mass M +1 254.0

Examples 6 to 22: 2- (4-chloro-2-methylphenyl) -4- (2-hydroxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₄ClN₃O₂315.75 mass M +1 316.0

Examples 6 to 23: 2- (4-fluoro-2-methylphenyl) -4- (2-hydroxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₆H₁₄FN₃O₂299.3, mass M +1 300.1

Examples 6 to 24: 2- (4-chloro-2-methylphenyl) -4- (2-methoxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₆ClN₃O₂329.78 mass M +1 330.0

Examples 6 to 25: 2- (4-fluoro-2-methylphenyl) -4- (2-methoxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₇H₁₆FN₃O₂313.33 mass M +1 314.1

Examples 6 to 26: 4-cyclopropyl-2- (2, 4-dimethylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one

C₁₈H₁₇N₃291.35 mass M +1 292.1

Biological assay

INS-1 cells were selected for evaluation of superior responses of the compounds of the invention to glucose and other physiological and pharmacological insulin secretagogue concentrations.

Culture of islet INS-1 cells

INS-1 cells were cultured in complete medium PRMI 1640 containing 1mM sodium pyruvate, 50. mu.M 2-mercaptoethanol, 2mM glutamine, 10mM HEPES, 100IU/mL penicillin and 100. mu.g/mL streptomycin (CM), supplemented with 10mM glucose, and 10% (vol/vol) heat-inactivated Fetal Calf Serum (FCS), as described by Asfari et al (Endocrinology 130: 167-178, 1992).

Insulin secretion assay

INS-1 cells were plated in 48-well plates and cultured. After 2 days of culture, the medium was removed and replaced with 5mM glucose and 1% FCS for 24 h. The cells were then washed with Krebs-Ringer bicarbonate HEPES buffer (KRBH; 135mM NaCl; 3.6mM KCl)；5mM NaHCO₃；0.5mM NaH₂PO₄；0.5mM MgCl₂；1.5mM CaCl₂And 10mM HEPES; pH 7.4), 0.1% BSA with 2.8mM glucose, in the same buffer at 37 ℃ for 30 min. The cells were then washed twice and incubated for 1h in KRBH 0.1% BSA (containing 4.2mM glucose and varying concentrations of test compound). The concentration of Insulin in the collected supernatants was determined by ELISA using Rat Insulin antibody (Insulin Rat Elit PLUS, cat. ref 10-1145-01).

Insulin secretion results are expressed as% relative to control (glucose concentration 4.2 mM).

Insulin secretion in INS-1 cells (glucose concentration 4.2mM)

Insulin secretion in diabetic N0STZ rat islets

Materials and methods

Isolation and processing of islets

Nembutal sodium anesthetized 14 + -3 week old non-fasting N0STZ (PORTHA et al, 1974) male rats (Charles Rivers-Domain des incins, I' Arbresle, France) (Nembutal): 45mg/kg was administered intraperitoneally at 5 ml/kg), and body temperature was maintained using a heat lamp.

Langerhans rat islets were isolated from 8 rat islets by collagenase P (Boehringer, Meylan, france). Islets were passed through a balanced salt solution [ NaCl (137mM) in Hanks; KCl (5.36 mM); MgSO (MgSO)₄，7H₂O(0.81mM)；Na₂HPO₄，12H₂O(0.34mM)；KH₂PO₄(0.44mM)；CaCl₂，2H₂O(1.26mM)；NaHCO₃(4.17mM)]And then separating and purifying the pancreatic islets by a Ficoll gradient. The islets were then manually picked under a stereomicroscope and placed in a humid environment (95% O) at 37 deg.C₂，5％CO₂)3 islets were incubated in batches of 1ml Krebs/Hepes pH 7 solution containing NaCl (115mM), NaHCO for 90 minutes with medium and constant shaking₃(24mM)、KCl(5mM)、MgCl₂(1mM)、CaCl₂，、2H₂O (1mM), 0.2% bovine serum albumin (fraction V, fatty acid free, Boehringer, Mannheim), 10mM Hepes), containing glucose or compound at the desired concentration. Compounds were dissolved in DMSO as stock solutions at a concentration of 2.10-2M. Then diluted in Krebs/Hepes buffer containing glucose at the desired concentration.

After incubation, the medium was collected and the insulin concentration was determined by ELISA (EUROBIO, Courtaboeuf, France).

TABLE-dose response of Compounds to insulin secretion from the islets of diabetic N0STZ rats

Islets were manually selected and incubated in the presence of 2.8 or 8mM glucose and compounds at elevated concentrations. After incubation, the medium was collected and insulin levels were measured by ELISA. Results are expressed as% relative to glucose control (2.8 or 8mM) as mean ± SEM.

In islets isolated from N0STZ diabetic rats, glucose was present at low, non-irritating concentrations (2.8mM) and even at high concentrations (10 mM)^-4M) shows no effect in the presence of glucose, whereas at glucose concentrations of 8mM glucose, which have a stimulating effect, the compounds enhance insulin secretion. These results show that the effect of the compounds on insulin secretion is glucose level dependent, indicating that treatment with these compounds avoids the risk of hypoglycemia.

Claims

1. A compound of the general formula (I):

wherein:

-hydrogen, and (C) hydrogen,

-T；

t is: hydroxy, thio, halogen, cyano, trifluoromethoxy, trifluoromethyl, carboxy, carboxymethyl, carboxyethyl, alkyl, cycloalkyl, alkoxy, alkylamino, aryl, arylsulfonylalkyl, aryloxy, arylalkoxy, NR3R4, azido, nitro, guanidino, amidino, phosphono, oxo, carbamoyl, alkylsulfonyl, alkylsulfinyl, alkylthio, SF5, two T groups can form methylenedioxy;

r3 and R4 independently may be optionally substituted with one or more substituents selected from T;

2. The compound of claim 1, wherein a is aryl, arylalkyl, heteroaryl which may include one or more heteroatoms selected from N, O and S; each of these groups may be optionally substituted by one or more substituents selected from T, as defined in claim 1.

3. A compound according to claim 2, wherein a is phenyl, benzyl, each of which may be optionally substituted by one or more substituents selected from T, T being as defined in claim 1.

4. The compound of claim 1, wherein R1 is alkyl, alkyloxyalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkyloxyalkyl, heterocycloalkylalkoxyalkyl, heterocycloalkylthioalkyl, heterocycloalkylthioalkylthioalkyl, each of which may optionally be substituted with one or more substituents selected from T, T being as defined in claim 1.

5. The compound of claim 4, wherein R1 is alkyl, alkyloxyalkyl, cycloalkyl, cycloalkylalkyl; each of these groups may be optionally substituted by one or more substituents selected from T, as defined in claim 1.

6. The compound of claim 5, wherein R1 is ethyl, isopropyl, butyl, 2-difluoroethyl, 2-methoxyethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl.

7. The compound of claim 1, wherein T is hydroxy, thio, halogen, cyano, trifluoromethoxy, trifluoromethyl, carboxy, carboxymethyl, carboxyethyl, alkyl, cycloalkyl, alkoxy, aryl, arylsulfonylalkyl, aryloxy, arylalkoxy, NR3R4, azido, guanidino, amidino, phosphono, oxo, carbamoyl, alkylsulfonyl, alkylsulfinyl, alkylthio, SF5, and two T groups can form methylenedioxy.

8. The compound of claim 1, wherein T is halo, trifluoromethyl, alkyl, cycloalkyl, alkoxy.

9. The compound of claim 1, wherein T is methyl, cycloalkyl, Cl, F.

10. The compound of claim 1 wherein R3 and R4 are independently selected from the group consisting of lower alkyl, cycloalkyl.

11. A compound according to any preceding claim, selected from the following compounds:

1-cyclopropyl-3- (4-fluorophenyl) pyrido [3, 4-b ] pyrazin-2 (1H) -one;

1-cyclopropyl-3-phenylpyrido [3, 4-b ] pyrazin-2 (1H) -one;

2- (3-chlorophenyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorobenzyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4- (2-methoxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-cyclopropylmethylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-ethylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-isopropyl-pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4- (2-methoxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4-ethylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4-isopropyl-pyrido [2, 3-b ] pyrazin-3 (4H) -one;

3- (4-chlorophenyl) -1-cyclopropylpyrido [3, 4-b ] pyrazin-2 (1H) -one;

4- (2, 2-difluoroethyl) -2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4- (2-methoxyethyl) -2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-butyl-2- (4-chlorophenyl) -pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclobutyl-2- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (3-fluorophenyl) -pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (3-methylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (4-methylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropylmethyl-2- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropylmethyl-2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-ethyl-2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-isopropyl-2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (2-chlorophenyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (2, 4-dichlorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (2-methoxyphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (4-methoxyphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chloro-2-methylphenyl) -4-isopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (2, 4-dichlorophenyl) -4-isopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluoro-2-methylphenyl) -4-isopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (2-ethoxyphenyl) -4-isopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (6-methoxypyridin-3-yl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (2-thienyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (2-furyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4- (2-hydroxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4- (2-hydroxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4- (2-hydroxyethyl) -2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4- (3-hydroxypropyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4- (3-hydroxypropyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4- (3-hydroxypropyl) -2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (2, 4-dimethylphenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

1-ethyl-3- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-2 (1H) -one;

12. The compound of claim 11 selected from the following:

2- (4-chlorobenzyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-cyclopropylmethylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-cyclopropylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-ethylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-chlorophenyl) -4-isopropyl-pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4- (2-methoxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4- (2-methoxyethylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4-ethylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

2- (4-fluorophenyl) -4- (2-hydroxyethyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropyl-2-ethylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-cyclopropylmethyl-2- (4-fluorophenyl) pyrido [2, 3-b ] pyrazin-3 (4H) -one;

4-ethyl-2-phenylpyrido [2, 3-b ] pyrazin-3 (4H) -one;

13. A process for the preparation of a compound of general formula (I) according to any one of the preceding claims, which process comprises:

a) reacting a compound of formula (1):

wherein:

x, Y, Z, W is as defined in claim 1;

hal is a halogen atom, preferably Cl or Br;

with amines R1-NH in an inert solvent in the presence of a base₂Reaction, wherein R1 is as defined in claim 1, to give a compound of formula (2):

b) reducing the compound of formula (2) with a metal such as Zn, Sn or Fe, or a metal in a low oxidation state such as tin (II) chloride in an acid; or catalytic hydrogenation with a metal catalyst such as Pd, Pt, Ni, preferably on Pd on charcoal or Raney nickel in a solvent to give a compound of formula (3):

c) reacting a compound of formula (3) in a solvent with an α -keto acid derivative of the formula:

wherein:

a is as defined in claim 1;

rx is Hal as defined above; or ORe, wherein Re is hydrogen, lower alkyl; to obtain the compound of formula (I).

14. A process for the preparation of a compound of general formula (I) according to any one of claims 1 to 12, which process comprises:

a) reacting a compound of formula (1):

wherein:

x, Y, Z, W is as defined in claim 1;

hal is a halogen atom, preferably Cl or Br;

d) reducing the compound of formula (2) with a metal such as Zn, Sn or Fe, or a metal in a low oxidation state such as tin (II) chloride in an acid; or catalytic hydrogenation with a metal catalyst such as Pd, Pt, Ni, preferably on Pd on charcoal or Raney nickel in a solvent to give a compound of formula (3):

e) reacting a compound of formula (3) in an inert solvent in the presence of a base with a compound of the formula:

wherein:

rx is as defined above;

to give a compound of formula (5):

f) reacting a compound of formula (5) with a brominating agent such as POBr in an inert solvent₃Reacting to obtain a compound of formula (6):

g) the compound of formula (6) is reacted with a boronic acid derivative or ester thereof in the presence of a base and a catalyst such as bis (triphenylphosphine) palladium (II) chloride in an inert solvent to give the compound of formula (I).

15. Compounds of general formula (I) wherein X, Y, Z, W, A and R1 are as defined in claim 1, and their racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the prevention and/or treatment of pathologies associated with hyperglycemia.

16. A compound of claim 15 for use in the manufacture of a medicament for inducing insulin secretion in response to glucose concentration.

17. A compound according to claim 15 or 16 for use in the manufacture of a medicament for the treatment of diabetes.

18. A compound according to claim 17 for use in the manufacture of a medicament for the treatment of type II diabetes.

19. A compound according to claim 15 or 16 for the manufacture of a medicament for the treatment of a disease selected from dyslipidemia and obesity.

20. A compound according to claims 15-18 for the preparation of a medicament for the treatment of a complication selected from the group consisting of microvascular and macrovascular complications associated with diabetes.

21. The compound of claim 20, wherein the complications include arterial hypertension, atherosclerosis, inflammation, microangiopathy, macroangiopathy, retinopathy and neuropathy.

22. A compound according to claim 15 for use in the manufacture of a medicament for reducing hyperglycemia.

23. Use of a compound of general formula (I) according to any one of claims 1 to 12, wherein X, Y, Z, W, A and R1 are as defined in claim 1, and its racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and pharmaceutically acceptable salts, for the manufacture of a medicament for the prevention and/or treatment of pathologies associated with hyperglycemia.

24. A pharmaceutical composition comprising at least one compound of general formula (I) according to any one of claims 1 to 12 and pharmaceutically acceptable excipients.