WO2009109258A1 - Quinoxalinone derivatives as insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes - Google Patents

Quinoxalinone derivatives as insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes Download PDF

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Publication number
WO2009109258A1
WO2009109258A1 PCT/EP2009/000209 EP2009000209W WO2009109258A1 WO 2009109258 A1 WO2009109258 A1 WO 2009109258A1 EP 2009000209 W EP2009000209 W EP 2009000209W WO 2009109258 A1 WO2009109258 A1 WO 2009109258A1
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Prior art keywords
quinoxalin
ethyl
groups
compound
formula
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PCT/EP2009/000209
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French (fr)
Inventor
Gérard Botton
Eric Valeur
Micheline Kergoat
Christine Charon
Samer Elbawab
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Merck Patent Gmbh
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Priority to AU2009221327A priority Critical patent/AU2009221327B2/en
Priority to ES09718118.4T priority patent/ES2548583T3/en
Priority to CA2717718A priority patent/CA2717718C/en
Priority to CN200980105428.XA priority patent/CN101952258B/en
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to EA201001407A priority patent/EA021904B1/en
Priority to DK09718118.4T priority patent/DK2247580T3/en
Priority to JP2010549024A priority patent/JP5618837B2/en
Priority to MX2010009576A priority patent/MX2010009576A/en
Priority to BRPI0908406A priority patent/BRPI0908406B8/en
Priority to EP09718118.4A priority patent/EP2247580B1/en
Priority to US12/920,736 priority patent/US8415352B2/en
Publication of WO2009109258A1 publication Critical patent/WO2009109258A1/en
Priority to IL207720A priority patent/IL207720A/en
Priority to ZA2010/07059A priority patent/ZA201007059B/en
Priority to US13/734,288 priority patent/US8835634B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P3/06—Antihyperlipidemics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to quinoxalinone derivatives of formula (I) as insulin secretion stimulators.
  • the invention also relates to the preparation and use of these quinoxalinone derivatives for the prophylaxis and/or treatment of diabetes and pathologies associated.
  • Type 2 diabetes mellitus is one of the most common worldwide diseases. In 2007, its prevalence was estimated at 5.9 % (246 million people) of the adult population and is in continuous increase. This disease is even more serious since it could lead to severe micro- and macro-complications, which could become disabling or lethal, as diabetes is a major risk factor for cardiovascular disease and stroke.
  • Type 2 diabetes is characterized by a fasted and post-prandial hyperglycemia, consequence of two main defects: an insulin resistance at the level of target tissues and an altered insulin secretion from the pancreatic beta cells. This latter anomaly seems to appear very early as it is present at the Impaired Glucose Tolerance (IGT) stage (Mitrakou et al., N. Engl. J. Med. 326: 22-29, 1992). It has been observed in UK Prospective Diabetes Study (UKPDS) that 50% of the beta cell function is already lost when diabetes is diagnosed, suggesting that deterioration in beta cell function may begin 10- 12 years before diabetes diagnosis (Holman, Diabetes Res. CHn. Pract. 40 : S21, 1998 or UKPDS Group, Diabetes 44: 1249-58, 1995).
  • ITT Impaired Glucose Tolerance
  • UKPDS UK Prospective Diabetes Study
  • the defective insulin secretion is due to a quantitative and a qualitative defect of the beta cell, i.e. a decreased beta cell mass and a specific defect of insulin release in response to glucose, especially the first phase of secretion, since the response to non-glucose secretagogues is preserved (Pfeifer et al., Am. J. Med. 70: 579-88, 1981 ).
  • the importance of restoring a normal profile of insulin release in response to glucose to maintain the glycemic control within a normal range was supported by studies in non diabetic volunteers showing that delaying the first phase of insulin secretion in response to glucose led to glucose intolerance (Calles-Escandon et al.,
  • Oral antidiabetics available for treatment of type 2 diabetic patients such as sulfonylureas or glinides, are known to induce insulin secretion, by binding to sulfonyurea receptor on the K-ATP channels of the beta cell, leading to increase in intracellular calcium and insulin exocytosis.
  • This insulin release is thus totally independent of the plasma glucose level and treatment with these molecules usually induces sustained hyperinsulinemia, which could lead to several side-effects, such as severe hypoglycaemia, body weight gain, and aggravation of cardiovascular risk.
  • the prolonged hyperinsulinemia observed with sulfonylurea treatment with no preservative effect of the beta cell mass, could lead to secondary failure due to beta cell exhaustion, another deleterious side effect of these compounds.
  • New treatment of type 2 diabetes should restore a normal profile of insulin release specifically in response to glucose, while preserving or increasing the beta cell mass. This is observed with GLP-1 analogs, such as exenatide or liraglutide, but these molecules are peptides and must be administered by parenteral route. Such characteristics for a new oral small molecule would be a great advantage over the other antidiabetic drugs.
  • the compounds of the formula (I) are insulin secretion stimulators, useful for treatment of diabetes and pathologies associated. They lower blood glucose levels by restoring the defective glucose-induced insulin secretion in type 2 diabetics.
  • the patent application EP 995742 discloses cGMP-PDE inhibitors, characterized by the presence of a sulfonamide group -SO 2 NHCO-, useful as hypoglycemics, bronchodilating, vasodilating, smooth muscle cell inhibitory, and antiallergic effects.
  • EP 1068190 discloses quinoxalinones serine protease inhibitors for treatment of thrombotic disorders.
  • the present invention is directed towards quinoxalinone derivatives of formula (I). Said derivatives are useful for treating diabetes and pathologies associated therewith.
  • Quinoxalinone derivatives according to the invention have the following formula (I):
  • R1 is: hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyloxyalkyl, R7R8N-alkyl, alkylthioalkyl; heterocycloalkyl and heteroaryl groups can include one or more heteroatom selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z;
  • R1 is: alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkyloxyalkyl, R7R8N-alkyl, alkylthioalkyl; heterocycloalkyl groups can include one or more heteroatom selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z;
  • R1 is: alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkyloxyalkyl, R7R8N-alkyl; heterocycloalkyl groups can include one or more heteroatom selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z;
  • R1 is: methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, butyl, cyclopropyl, cyclopropylmethyl; each of these groups can be optionally substituted by one or more groups selected from Y or Z;
  • R1 is: hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyloxyalkyl, R7R8N-alkyl, alkylthioalkyl; heterocycloalkyl and heteroaryl groups can include one or more heteroatom selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z; wherein Y is thiazolidinyl, oxazolidinyl, tetrahydrothienyl, dihydrofuranyl, tetrahydrofuranyl, pyrazolidinyl, 1 ,3- dioxolanyl, pyranyl, dihydropyranyl, isoxazolidinyl, imidazolidinyl and the like;
  • R6 is: alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, arylalkylthioalkyl, arylalkylsulfinylalkyl, arylalkylsulfonylalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, heteroarylalkylthioalkyl, heteroarylalkylsulfinylalkyl, heteroarylalkylsulfonylalkyl, heteroarylalkylthioalkyl, heteroaryl
  • R6 is: alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylthioalkyl, arylsulfonylalkyl, aryloxyalkyl, arylalkyloxyalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heterocycloalkylalkyl, heterocycloalkyloxyalkyl; heteroaryl or heterocycloalkyl groups can include one or more heteroatoms selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z;
  • R6 is: alkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, arylthioalkyl, arylsulfonylalkyl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; heteroaryl or heterocycloalkyl groups can include one or more heteroatoms selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z;
  • R6 is: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, benzyl, furanyl, pyridinyl, pyrimidinyl, pyrazolyl, phenylthiomethyl, phenylsulphonylmethyl; each of these groups can be optionally substituted by one or more groups selected from Y or Z.
  • R2, R3, R4, R5 are independently selected from hydrogen, Y or Z; other preferred compounds are compounds of general formula (I), wherein R1 , R2, R3, R4, R5 and R6 can be optionally substituted by one or more groups selected from Z;
  • Y is: alkyl, cycloalkyl, heterocycloalkyl, alkoxy, heteroaryl, aryl, alkylsulfonyl, aryloxy, arylalkoxy, alkylsulfinyl, alkylthio; heteroaryl or heterocycloalkyl groups can include one or more heteroatom selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Z;
  • Y is: alkyl, cycloalkyl, alkoxy, aryl, alkylsulfonyl, aryloxy, arylalkoxy, alkylsulfinyl, alkylthio; each of these groups can be optionally substituted by one or more groups selected from Z;
  • Z is: hydroxy, thio, halogen, cyano, trifluoromethoxy, trifluoromethyl, carboxy, carboxy methyle, carboxyethyle, alkyle, cycloalkyl, alkoxy, NR7R8, azido, nitro, guanidino, amidino, phosphono, oxo, alkylthio, alkylsulfonyl, SF5, two Y groups can form a methylenedioxy;
  • Z is: halogen, trifluoromethyl, carboxy, alkoxy, alkylthio, alkylsulfonyl;
  • R7 and R8 are independently selected from: - hydrogen; - lower alkyl, cycloalkyl;
  • R7 and R8 can also constitute a heterocycloakyl group, which can include one or more heteroatoms selected from N, O and S; R7 and R8 independently can be optionally substituted by one or more substituents selected from Z;
  • the compounds of the formula (I) may be chosen from:
  • the compounds of the formula (I) according to the invention may be chosen from: 1-Butyl-3-ethyl-quinoxalin-2(1/-/)-one
  • the invention also relates to the racemic forms, tautomeric forms, enantiomers, diastereoisomers, epimers and organic or mineral salts of the compounds of the general formula (I), as well as their crystalline forms, including their polymorphic forms and the polymorphic forms of the compounds of formula (I).
  • the present invention is directed not only to racemic mixtures of these compounds, but also to individual stereoisomers and/or diastereoisomers thereof, as well or as mixtures of these in all proportions.
  • the compounds of the invention of the formula (I), as defined above, containing a sufficiently acidic function or a sufficiently basic function, or both, may include the corresponding pharmaceutically acceptable salts of an organic or mineral acid, or of an organic or mineral base.
  • pharmaceutically acceptable salts refers to the relatively non-toxic mineral and organic acid-addition salts, and the base-addition salts, of the compounds of the present invention. These salts may be prepared in situ during the final isolation and purification of the compounds.
  • the acid-addition salts may be prepared by separately reacting the purified compound in its purified form with an organic or mineral acid and isolating the salt thus formed.
  • the resulting salts are, for example, hydrochlorides, hydrobromides, sulfates, hydrogenosulfates, dihydrogenophosphates, citrates, maleates, fumarates, trifluoroacetates, 2- naphtalenesulfonates, para-toluenesulfonates.
  • the invention also relates to pharmaceutically acceptable salts with organic or inorganic bases.
  • the basic-addition salts may be prepared by separately reacting the purified compound in its purified form with an organic or inorganic base and isolating the salt thus formed.
  • the resulting salts are, for example, metal salts, particularly alkali metal salts, alkaline-earth metal salts and transition metal salts (such as sodium, potassium, calcium, magnesium, aluminum), or salts obtained with bases, such as ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine, morpholine), or with basic amino-acids, or with osamines (such as meglumine), or with aminoalcohols (such as 3-aminobutanol and 2- aminoethanol).
  • bases such as ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine, morpholine), or with basic amino-acids, or with osamines (such as meglumine), or with aminoalcohols (such as 3-aminobutanol and 2- aminoethanol).
  • bases such as ammonia or secondary or ter
  • the invention also relates to the salts used for chiral resolution of the racemates.
  • the following chiral acids can be used : (+)-D-di-O- benzoyltartaric acid, (-)-L-di-O-benzoyltartaric acid, (-)-L-di-O,O'-p-toluyl-L- tartaric acid, (+)-D-di-O,O'-p-toluyl-L-tartaric acid, (R)-(+)-malic acid, (S)-(-)- malic acid, (+)-camphoric acid, (-)-camphoric acid, R-(-)1 ,1'-binaphtalen-2,2'- diyl hydrogenophosphonic, (+)-camphanic acid, (-)-camphanic acid, (S)-(+)-2- phenylpropionic acid, (R)-(+)-2-phenylpropionic acid, D-(
  • the following chiral amines can be used: quinine, brucine, (S)- 1-(benzyloxymethyl)propylamine (III), (-)-ephedrine, (4S,5R)-(+)-1 , 2,2,3,4- tetramethyl-5-phenyl-1 ,3-oxazolidine, (R)-1-phenyl-2-p-tolylethylamine, (S)- phenylglycinol, (-)-N-methylephedrine, (+)-(2S,3R)-4-dimethylamino-3- methyl-1 ,2-diphenyl-2-butanol, (S)-phenylglycinol, (S)- ⁇ -methylbenzylamine or any mixture of them.
  • prodrugs of the compounds of formula (I) are also included in the scope of the present invention.
  • prodrug refers to any compound that when administered to a biological system generates the "drug” substance (a biologically active compound) as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s).
  • aryl refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi ( ⁇ ) electron system and includes biaryl groups, all of which may be optionally substituted. Suitable aryl groups include phenyl, naphthyl, biphenyl, anthryl, phenanthryl, indenyl and the like.
  • heteroaryl refers to 5-14 ring atom aromatic heterocycles containing 1 to 4 heteroatoms, as ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include O, S, N.
  • Suitable heteroaryl groups include furanyl, benzofuranyl, thienyl, pyridyl, pyridyl-N-oxide, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, isoxazolyl, quinolinyl, triazolyl, pyridazinyl, pyrrolyl, imidazolyl, indazolyl, isothiazolyl, indolyl, oxadiazolyl and the like.
  • cycloalkyl means saturated carbocyclic rings, optionally substituted, and includes mono-, bi- and tri-cyclic compounds with 3 to 10 carbon atoms. Suitable cycloalkyl groups are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, adamantyl and the like.
  • heterocycloalkyl refers to optionally substituted monocyclic, bicyclic or tricyclic radicals, comprising one or more heteroatoms, preferably chosen from among O, S and N 1 optionally in the oxidized state (for S and N), and optionally one or more double bonds. At least one of the rings preferably comprises from 1 to 4 endocyclic heteroatoms, more preferably from 1 to 3 heteroatoms. Most preferably, the heterocycloalkyl (or simply "heterocyclic") radical comprises one or more rings, each having from 5 to 8 nodes.
  • heterocyclic radicals are: morpholinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, tetrahydrothienyl, dihydrofuranyl, tetrahydrofuranyl, pyrazolidinyl, 1 ,3-dioxolanyl, pyrrolidinyl, pyranyl, dihydropyranyl, isoxazolidinyl, imidazolyl, imidazolidinyl and the like.
  • alkyl refers to a saturated aliphatic groups, including straight chain and branched chain groups. Suitable alkyl groups, having 1 to 20 carbon atoms, include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decanoyl, dodecanoyl, hexadecyl, octadecyl groups and the like.
  • alkenyl refers to unsaturated groups comprising at least one carbon-carbon double bond, and includes 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.
  • alkynyl refers to unsaturated groups comprising at least one carbon-carbon triple bond and includes straight chain, branched chain and cyclic groups; and optionally includes 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.
  • arylalkyl refers to an alkyl group, preferably an alkyl group having 1 to 20 carbon atoms, substituted with an aryl group. Suitable arylalkyl groups include benzyl, picolyl, and the like.
  • alkoxy refers to the group alk-O- wherein “alk” is an alkyl group.
  • aryloxy refers to the group aryl-O-.
  • aryloxyalkyl refers to an alkyl group substituted with an aryloxy group.
  • arylalkyloxyalkyl refers to an alkyl group substituted with an arylalkyloxy group.
  • arylalkoxy refers to the group aryl-Alk-O-, wherein "AIk” is an alkyl group.
  • alkylthioalkyl refers to an alkyl group substituted with an alkylthio.
  • arylthioalkyl refers to an alkyl group substituted with an arylthio group.
  • alkylsulfinyl refers to an alkyl-SO- group.
  • alkylsulfonyl refers to an alkyl-SO 2 - group.
  • arylsulfinylalkyl refers to an alkyl group substituted with an arylsulfinyl (aryl-SO-) group.
  • arylalkylsulfinylalkyl refers to an alkyl group substituted with an arylalkylsulfinyl group.
  • arylsulfonylalkyl refers to an alkyl group substituted with an arylsulfonyl (aryl-SO 2 -) group.
  • arylalkylsulfonylalkyl refers to an alkyl group substituted with an arylalkylsulfonyl group.
  • arylalkylthioalkyl refers to an alkyl group substituted with an arylalkylthio.
  • heteroarylalkyl refers to an alkyl group substituted with a heteroaryl group.
  • heteroaryloxyalkyl refers to an alkyl group substituted with a heteroaryloxy group.
  • heteroarylalkoxyalkyl refers to an alkyl group substituted with a heteroarylalkoxy group.
  • heteroarylthioalkyl refers to an alkyl group substituted with a heteroarylthio group.
  • heteroarylsulfinylalkyl refers to an alkyl group substituted with a heteroarylsulfinyl group.
  • heteroarylsulfonylalkyl refers to an alkyl group substituted with a heteroarylsulfonyl group.
  • heteroarylalkylthioalkyl refers to an alkyl group substituted with a heteroarylalkylthio group.
  • heteroarylalkylsulfinylalkyl refers to an alkyl group substituted with a heteroarylalkylsulfinyl group.
  • heteroarylalkylsulfonylalkyl refers to an alkyl group substituted with a heteroarylalkylsulfonyl group.
  • heterocycloalkylalkyl refers to an alkyl group substituted with a heterocycloalkyl group.
  • heterocycloalkyloxyalkyl refers to an alkyl group substituted with a heterocycloalkyloxy group.
  • heterocycloalkylalkoxyalkyl refers to an alkyl group substituted with a heterocycloalkylalkoxy group.
  • heterocycloalkylthioalkyl refers to an alkyl group substituted with a heterocycloalkylthio group.
  • heterocycloalkylsulfinylalkyl refers to an alkyl group substituted with a heterocycloalkylsulfinyl group.
  • heterocycloalkylsulfonylalkyl refers to an alkyl group substituted with a heterocycloalkylsulfonyl group.
  • heterocycloalkylalkylthioalkyl refers to an alkyl group substituted with a heterocycloalkylalkylthio group.
  • heterocycloalkylalkylsulfinylalkyl refers to an alkyl group substituted with a heterocycloalkylalkylsulfinyl group.
  • heterocycloalkylalkylsulfonylalkyl refers to an alkyl group substituted with a heterocycloalkylalkylsulfonyl group.
  • alkyloxyalkyl refers to an alkyl group substituted with an alkyloxy group.
  • cycloalkylalkyl refers to an alkyl group substituted with a cycloalkyl group.
  • lower referred to herein in connection with organic radicals or compounds respectively defines such as with up to and including 10, preferably up to and including 6, and advantageously 1 to 4 carbon atoms.
  • Such groups may be straight, branched, or cyclic chain.
  • alkylthio refers to the group alkyl-S-, wherein “alk” is an alkyl group.
  • halogen refers to a fluorine, bromine or chlorine atom.
  • amino refers to -C(NR7)-NR7R8 where R7R8 are as defined above, all, except hydrogen, are optionally substituted.
  • the invention's compounds according to formula (I) exhibit an hypoglycemic activity, and are useful in the treatment of pathologies associated with the syndrome of insulin resistance.
  • Insulin resistance is characterised by a reduction in the action of insulin (cf. "Presse Medicale”, (1997), 26(14), 671-677) and is involved in many pathological conditions, such as diabetes and more particularly non-insulin- dependent diabetes (type Il diabetes or NIDDM), dyslipidaemia, obesity, arterial hypertension, and also certain cardiac, microvascular and macrovascular complications, for instance atherosclerosis, retinopathy and neuropathy.
  • type Il diabetes or NIDDM non-insulin- dependent diabetes
  • dyslipidaemia for instance atherosclerosis, retinopathy and neuropathy.
  • atherosclerosis retinopathy and neuropathy
  • the invention also relates to pharmaceutical composition containing as active ingredient at least one compound of formula (I), as defined above, and/or a pharmaceutically acceptable salt thereof, in combination with one or several pharmaceutically acceptable carrier, adjuvant, diluent or excipient.
  • a pharmaceutically acceptable carrier for example, a pharmaceutically acceptable sulfate, a pharmaceutically acceptable sulfate, a pharmaceutically acceptable sulfate, a pharmaceutically acceptable sulfate, as defined above, and/or a pharmaceutically acceptable salt thereof, in combination with one or several pharmaceutically acceptable carrier, adjuvant, diluent or excipient.
  • carrier, adjuvant, diluent or excipient compounds suitable to formulate a pharmaceutical composition.
  • the pharmaceutical compositions of the present invention can be administered by a variety of routes including oral, parenteral, intravenous, intramuscular, rectal, permucous or percutaneous.
  • excipients that are suitable for such administrations are pharmaceutically acceptable excipients, such as cellulose or microcrystalline cellulose derivatives, alkaline-earth metal carbonates, magnesium phosphate, starches, modified starches, lactose and the like for solid forms.
  • cocoa butter or polyethylene glycol stearates are the preferred excipients.
  • water, aqueous solutions, physiological saline and isotonic solutions are the vehicles most appropriately used.
  • a suitable posology of the compounds is between about 0.1 mg/kg and about 100 mg/kg, preferably between about 0.5 mg/kg and about 50 mg/kg, more preferably between about 1 mg/kg and about 10 mg/kg and most preferably between about 2 mg/kg and about 5 mg/kg of body weight per day.
  • suitable dosages of the compounds of the formula (I) will be between about 1-10 mg/per day and 1000-10000 mg/per day, preferably between about 5-50 mg/per day and 500-5000 mg/per day, more preferably between 10-100 mg and 100-1000 mg/per day and most preferably between 20-200 mg and 50-500 mg/per day.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.
  • formulations of the present invention suitable for oral administration may be presented as discrete units, such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • the hyperglycemia is the results of two main defects: an alteration of the insulin secretion and a reduction in the effectiveness of insulin at level of three sites to knowing the liver, the muscles and adipose tissue.
  • the present invention also relates to compound of general formula (I) as well as its racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and the pharmaceutically acceptable salts thereof, for the preparation of a medicament for the prevention and/or treatment of pathologies associated with hyperglycaemia; for the preparation of a medicament that induces insulin secretion in response of glucose concentration, preferably for the treatment of diabetes, more preferably for the prevention and/or treatment of type Il diabetes and pathologies associated to metabolic disorders, hypercholesteremia, hyperlipidemia, which are increased by hyperinsulinemia and hyperglycemia; for the treatment of diseases chosen from diabetes related microvascular and macrovascular complications, such as arterial hypertension, inflammatory processes, microangiopathy, macroangiopathy, retinopathy and neuropathy; for reducing hyperglycaemia, for the treatment of dyslipidaemia and obesity; or diseases such as cardiovascular diseases, comprising atherosclerosis, myocardial ischemia.
  • the present invention also relates to the use of at least a compound of the general formula (I), as well as its racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and the pharmaceutically acceptable salts, and pro-drugs thereof, for the prevention and/or treatment of pathologies associated with hyperglycaemia, preferably for the treatment of diabetes, more preferably for the prevention and/or treatment of type Il diabetes and pathologies associated to metabolic disorders, hypercholesteremia, hyperlipidemia, which are increased by hyperinsulinemia and hyperglycemia; for the treatment of diseases chosen from diabetes related microvascular and macrovascular complications, such as arterial hypertension, inflammatory processes, microangiopathy, macroangiopathy, retinopathy and neuropathy; for reducing hyperglycaemia, for the treatment of dyslipidaemia and obesity; or diseases such as cardiovascular diseases, comprising atherosclerosis, myocardial ischemia.
  • pathologies associated with hyperglycaemia preferably for the treatment of diabetes
  • the present invention also relates to manufacturing process of compounds of formula (I), as defined above, according to the following representative methods shown in Scheme 1 (Preparation of the Intermediates diaminophenyl derivatives); Scheme 2 (Method A) or Scheme 3 (Method B), in which R1 , R2, R3, R4, R5 and R6 are as above defined in formula (I) and Hal is a halogen atom, preferably Cl, Br.
  • Scheme 1 Preparation of the Intermediates diaminophenyl derivatives
  • Scheme 2 Method 3
  • R1 , R2, R3, R4, R5 and R6 are as above defined in formula (I)
  • Hal is a halogen atom, preferably Cl, Br.
  • Hal is a halogen atom, preferably Cl, Br;
  • R1 , R2, R3, R4 and R5 are as above defined in formula (I).
  • Phenyl nitro amino derivatives (2) are prepared by reacting an halo- nitrophenyl derivative (1) with an amine, in the presence of at least one equivalent of a base, such as sodium or potassium carbonate, cesium carbonate, or in the presence of at least two equivalents of the considered amine, in an inert solvent, such as tetrahydrofurane, acetonitrile or toluene, at a temperature between 20 0 C and the reflux for 1 to 24h.
  • Diamino phenyl derivatives (3) may be prepared from compounds of formula (2) by reduction of the nitro to the corresponding primary aromatic amine.
  • Preferred methods use metal, such as Zn, Sn or Fe, in acids, such as aqueous HCI.
  • metal in lower state of oxidation such as Sn(ll)chloride in HCI.
  • metal catalysts from metals such as Pd, Pt or Ni, preferably Pd on charcoal or Raney Nickel in solvents, such as methanol, ethanol, tetrahydrofurane.
  • Rx is Hal, ORe (wherein Re is hydrogen, lower alky!);
  • Hal is a halogen atom, preferably Cl, Br;
  • R1 is as above defined in formula (I);
  • R6 is as above defined in formula (I);
  • R2, R3, R4 and R5 are as above defined in formula (I).
  • Quinoxalinones (I) are prepared by cyclization of (3) with a an ⁇ - keto acid derivative in a solvent, such as, for example, methanol, acetonitrile, dimethylformamide (DMF) or toluene, at a temperature between 20°C and the reflux, more preferably reflux, for 1 to 36 h.
  • a solvent such as, for example, methanol, acetonitrile, dimethylformamide (DMF) or toluene
  • Rx is Hal, ORe (wherein Re is hydrogen, lower alkyl); Hal is a halogen atom, preferably Cl, Br;
  • R1 is as above defined in formula (I);
  • R6 is as above defined in formula (I);
  • R2, R3, R4 and R5 are as above defined in formula (I).
  • Hydroxyquinoxalinones (5) are obtained by cyclization of (3) with, for example, chloro(oxo)acetate derivatives in the presence of at least one equivalent of a base, an inorganic base, such as sodium or potassium carbonate, cesium carbonate, or an organic base, such as triethylamine or diisopropylethylamine, in a inert solvent, such as, for example, dichloromethane, acetonitrile, DMF, at a temperature between 20 0 C and the reflux, for 1 to 24h.
  • a base such as sodium or potassium carbonate, cesium carbonate
  • an organic base such as triethylamine or diisopropylethylamine
  • Bromo derivatives (6) are prepared by bromination of (5) using a brominating agent, such as POBr 3 , in an inert solvent, such as 1 ,2-dichloroethane, at a temperature between 20 0 C and the reflux, more preferably reflux for 1 to 24h.
  • a brominating agent such as POBr 3
  • an inert solvent such as 1 ,2-dichloroethane
  • Quinoxalinones (I) are prepared by reacting the bromo compounds (6) with boronic acid derivatives or their esters, in the presence of a base, such as sodium carbonate or potassium carbonate, and a catalyst, such as bis(triphenylphosphine) palladium(ll)chloride, in an inert solvent, such as dimethylformamide or toluene, at a temperature between 20 0 C and the reflux, more preferably reflux, for 1 to 24h.
  • a base such as sodium carbonate or potassium carbonate
  • a catalyst such as bis(triphenylphosphine) palladium(ll)chloride
  • the starting materials used are known products or products prepared according to known procedures. The percentages are expressed on a weight basis, unless otherwise mentioned.
  • the compounds were characterised especially via the following analytical techniques.
  • the NMR spectra were acquired using a Bruker Avance DPX 300 MHz NMR spectrometer.
  • the masses were determined by HPLC coupled to an Agilent Series 1100 mass detector.
  • the melting points (m.p.) were measured on a Stuart Scientific block.
  • Example 2-7 /V 1 -ethyl-3-fluorobenzene-1 ,2-diamine
  • Example 3-7 1 -ethyl-7-methyl-3-propyl-quinoxalin-2(1 H)-one
  • Example 3-10 1 -ethyl-6,7-difluoro-3-(4-chlorophenyl)quinoxalin-2(1 H)- one
  • Example 3-12 1 -ethyl-3-furan-2-yl-quinoxalin-2(1 H)-one
  • Example 3-13 1-ethyl-5-fluoro-3-(4-fluorophenyl)quinoxalin-2(1W)-one
  • Example 3-18 3-(4-chlorophenyl)-1 -(2,2,2-trifluoroethyl)quinoxalin- 2(1H)-one
  • Example 6-3 1-ethyl-3-(4-fluorophenyl)quinoxalin-2(1//)-one
  • Example 6-4 1 -ethyl-3-(4-methylphenyl)quinoxal in-2(1 H)-one
  • Example 6-5 1 -ethyl-3-(4-fluoro-2-methylphenyl)quinoxalin-2(1 H)-one
  • Example 6-8 1-ethyl-3-(4-methanesulfonyl-phenyl)quinoxalin-2(1/-/)-one
  • Example 6-13 4-(4-ethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-benzoic acid
  • Example 6-16 1-ethvl-3-pvridin-3-vl-quinoxalin-2(1ffl-one
  • Example 10-2 3- ⁇ [(4-chlorophenyl)sulfonyl]methyl ⁇ -1 -methyl- quinoxalin-2(1 H)-one
  • Example 10-3 1 -ethyl-3- ⁇ [(4-methoxyphenyl)sulfonyl]methyl ⁇ quinoxalin-
  • Example 10-4 1 -methyl-3-[(phenylsulfonyl)methyl]quinoxalin-2(1 H)-one
  • Example 10-5 1 -ethyl-3-[(phenylsulfonyl)methyl]quinoxalin-2(1 H)-one
  • the INS-1 cells were selected to evaluate compounds of the present invention for their superior response to glucose and other physiological and pharmacological insulin secretagogues.
  • INS-1 cells were cultured in complete medium, RPM11640 containing 1mM sodium pyruvate, 50 ⁇ M 2-mercaptoethanol, 2mM glutamine, 1OmM HEPES, 100IU/ml_ penicillin, and 100 ⁇ g/mL streptomycin (CM), supplemented with 1OmM glucose, and 10% (vol/vol) heat-inactivated fetal calf serum (FCS), as described by Asfari et al. (Endocrinology 130: 167-178, 1992).
  • FCS heat-inactivated fetal calf serum
  • INS-1 cells were plated and cultured in 48-well plates. After 2 days of culture, the medium was removed and cells were cultured for 24h with a medium change to 5mM glucose, 1 % FCS. The cells were then washed with Krebs- Ringer Bicarbonate HEPES buffer (KRBH; 135mM NaCI; 3,6mM KCI; 5mM NaHCO3; 0,5mM NaH2PO4; 0,5mM MgCI2; 1 ,5mM CaCI2 and 1OmM HEPES; pH 7,4) 0,1 % BSA containing 2,8mM glucose and preincubated for 30 min at 37°C in the same buffer.
  • Krebs- Ringer Bicarbonate HEPES buffer KRBH; 135mM NaCI; 3,6mM KCI; 5mM NaHCO3; 0,5mM NaH2PO4; 0,5mM MgCI2; 1 ,5mM CaCI2 and 1OmM HEPES; pH 7,4
  • the cells were then washed twice and incubated for 1h in KRBH 0,1 % BSA containing 4,2mM glucose and different concentrations of the tested molecule. Insulin concentration in the collected supematants was measured with ELISA using rat insulin antibody (Insulin Rat Elit PLUS, cat. ref 10-1145-01). Insulin secretion results are expressed in % of control (glucose 4,2mM).
  • Insulin secretion in INS-1 cells insulin at 4,2 mM
  • Insulin secretion in diabetic NOSTZ rat islets Insulin secretion in diabetic NOSTZ rat islets.
  • Rat pancreatic islets of Langerhans were isolated from the pancreas of 8 rats by collagenase P (Boehringer, Meylan, France) digestion. Islets were purified by sedimentation in Hanks balanced salt solution [NaCI (137mM) ; KCI (5.36 mM) ; MgSO 4 , 7 H 2 O (0.81 mM) ; Na 2 HPO 4 , 12 H 2 O (0.34 mM) ; KH 2 PO 4 (0.44 mM) ; CaCI 2 , 2 H 2 O (1.26 mM) ; NaHCO 3 (4.17 mM)] followed by Ficoll gradient separation.
  • Hanks balanced salt solution NaCI (137mM) ; KCI (5.36 mM) ; MgSO 4 , 7 H 2 O (0.81 mM) ; Na 2 HPO 4 , 12 H 2 O (0.34 mM) ; KH 2 PO 4 (0.44 mM) ; CaCI
  • Islets were then hand-picked under stereoscopic microscope and batches of 3 islets were incubated for 90 minutes at 37°C with continuous shaking under a humidified condition (95% O 2 , 5% CO 2 ) in 1 ml of Krebs/Hepes pH 7 solution [NaCI (115 mM), NaHCO 3 (24 mM), KCI (5 mM), MgCI 2 (1 mM), CaCI 2 , 2 H 2 O (1mM), 0.2 % of Bovine serum albumin (Fraction V, fatty acid free, Boehringer, Mannheim), 10 mM Hepes] containing the required glucose or compound concentration. Compounds were dissolved in DMSO at 2.10- 2M stock solutions. They were then diluted at the required concentration in Krebs/Hepes buffer containing the required glucose concentration. At the end of incubation, media was collected and insulin levels were measured using ELISA (EUROBIO, Courtaboeuf, France).
  • ELISA ELISA
  • Islets were hand-picked and incubated in the presence of increasing concentrations of compounds in the presence of glucose at 2.8 or 8 mM. At the end of incubation, media was collected and insulin levels were measured using ELISA method. Results are expressed as % of glucose control (2.8 or 8 mM) and represent Means ⁇ SEM.

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Abstract

The present invention relates to quinoxalinone derivatives of formula (I), wherein R1, R2, R3, R4, R5 and R6 are as defined in claim 1, as insulin secretion stimulators. The invention also relates to the preparation and use of these quinoxalinone derivatives for the prophylaxis and/or treatment of diabetes and pathologies associated. Other preferred compounds are compounds of general formula (I), wherein R1, R2, R3, R4, R5 and R6 can be optionally substituted by one or more groups selected from Z.

Description

Quinoxalinone derivatives as insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes
Field of the invention The present invention relates to quinoxalinone derivatives of formula (I) as insulin secretion stimulators. The invention also relates to the preparation and use of these quinoxalinone derivatives for the prophylaxis and/or treatment of diabetes and pathologies associated.
Background of the invention
Type 2 diabetes mellitus is one of the most common worldwide diseases. In 2007, its prevalence was estimated at 5.9 % (246 million people) of the adult population and is in continuous increase. This disease is even more serious since it could lead to severe micro- and macro-complications, which could become disabling or lethal, as diabetes is a major risk factor for cardiovascular disease and stroke.
Type 2 diabetes is characterized by a fasted and post-prandial hyperglycemia, consequence of two main defects: an insulin resistance at the level of target tissues and an altered insulin secretion from the pancreatic beta cells. This latter anomaly seems to appear very early as it is present at the Impaired Glucose Tolerance (IGT) stage (Mitrakou et al., N. Engl. J. Med. 326: 22-29, 1992). It has been observed in UK Prospective Diabetes Study (UKPDS) that 50% of the beta cell function is already lost when diabetes is diagnosed, suggesting that deterioration in beta cell function may begin 10- 12 years before diabetes diagnosis (Holman, Diabetes Res. CHn. Pract. 40 : S21, 1998 or UKPDS Group, Diabetes 44: 1249-58, 1995).
The defective insulin secretion is due to a quantitative and a qualitative defect of the beta cell, i.e. a decreased beta cell mass and a specific defect of insulin release in response to glucose, especially the first phase of secretion, since the response to non-glucose secretagogues is preserved (Pfeifer et al., Am. J. Med. 70: 579-88, 1981 ). The importance of restoring a normal profile of insulin release in response to glucose to maintain the glycemic control within a normal range was supported by studies in non diabetic volunteers showing that delaying the first phase of insulin secretion in response to glucose led to glucose intolerance (Calles-Escandon et al.,
Diabetes 36: 1167-72,1987).
Oral antidiabetics available for treatment of type 2 diabetic patients, such as sulfonylureas or glinides, are known to induce insulin secretion, by binding to sulfonyurea receptor on the K-ATP channels of the beta cell, leading to increase in intracellular calcium and insulin exocytosis. This insulin release is thus totally independent of the plasma glucose level and treatment with these molecules usually induces sustained hyperinsulinemia, which could lead to several side-effects, such as severe hypoglycaemia, body weight gain, and aggravation of cardiovascular risk. In addition, the prolonged hyperinsulinemia observed with sulfonylurea treatment, with no preservative effect of the beta cell mass, could lead to secondary failure due to beta cell exhaustion, another deleterious side effect of these compounds.
New treatment of type 2 diabetes should restore a normal profile of insulin release specifically in response to glucose, while preserving or increasing the beta cell mass. This is observed with GLP-1 analogs, such as exenatide or liraglutide, but these molecules are peptides and must be administered by parenteral route. Such characteristics for a new oral small molecule would be a great advantage over the other antidiabetic drugs.
According to the present invention, the compounds of the formula (I) are insulin secretion stimulators, useful for treatment of diabetes and pathologies associated. They lower blood glucose levels by restoring the defective glucose-induced insulin secretion in type 2 diabetics. The patent application EP 995742 discloses cGMP-PDE inhibitors, characterized by the presence of a sulfonamide group -SO2NHCO-, useful as hypoglycemics, bronchodilating, vasodilating, smooth muscle cell inhibitory, and antiallergic effects. EP 1068190 discloses quinoxalinones serine protease inhibitors for treatment of thrombotic disorders.
Summary of the invention
The present invention is directed towards quinoxalinone derivatives of formula (I). Said derivatives are useful for treating diabetes and pathologies associated therewith. Quinoxalinone derivatives according to the invention have the following formula (I):
Figure imgf000004_0001
(I) wherein:
R1 is: hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyloxyalkyl, R7R8N-alkyl, alkylthioalkyl; heterocycloalkyl and heteroaryl groups can include one or more heteroatom selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z;
preferably, R1 is: alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkyloxyalkyl, R7R8N-alkyl, alkylthioalkyl; heterocycloalkyl groups can include one or more heteroatom selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z;
more preferably, R1 is: alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkyloxyalkyl, R7R8N-alkyl; heterocycloalkyl groups can include one or more heteroatom selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z;
still more preferably R1 is: methyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, butyl, cyclopropyl, cyclopropylmethyl; each of these groups can be optionally substituted by one or more groups selected from Y or Z;
other preferred compounds, are compounds wherein R1 is: hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyloxyalkyl, R7R8N-alkyl, alkylthioalkyl; heterocycloalkyl and heteroaryl groups can include one or more heteroatom selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z; wherein Y is thiazolidinyl, oxazolidinyl, tetrahydrothienyl, dihydrofuranyl, tetrahydrofuranyl, pyrazolidinyl, 1 ,3- dioxolanyl, pyranyl, dihydropyranyl, isoxazolidinyl, imidazolidinyl and the like;
R6 is: alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, arylalkylthioalkyl, arylalkylsulfinylalkyl, arylalkylsulfonylalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, heteroarylalkylthioalkyl, heteroarylalkylsulfinylalkyl, heteroarylalkylsulfonylalkyl, heterocycloalkylalkyl, heterocycloalkyloxyalkyl, heterocycloalkylalkyloxyalkyl, heterocycloalkylthioalkyl, heterocycloalkylsulfinylalkyl, heterocycloalkylsulfonylalkyl, heterocycloalkylalkylthioalkyl, heterocycloalkylalkylsulfinylalkyl, heterocycloalkylalkylsulfonylalkyl; heteroaryl or heterocycloalkyl groups can include one or more heteroatoms selected from N1 O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z;
preferably, R6 is: alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylthioalkyl, arylsulfonylalkyl, aryloxyalkyl, arylalkyloxyalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heterocycloalkylalkyl, heterocycloalkyloxyalkyl; heteroaryl or heterocycloalkyl groups can include one or more heteroatoms selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z;
more preferably, R6 is: alkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, arylthioalkyl, arylsulfonylalkyl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; heteroaryl or heterocycloalkyl groups can include one or more heteroatoms selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z;
still, more preferably, R6 is: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, benzyl, furanyl, pyridinyl, pyrimidinyl, pyrazolyl, phenylthiomethyl, phenylsulphonylmethyl; each of these groups can be optionally substituted by one or more groups selected from Y or Z.
R2, R3, R4, R5 are independently selected from hydrogen, Y or Z; other preferred compounds are compounds of general formula (I), wherein R1 , R2, R3, R4, R5 and R6 can be optionally substituted by one or more groups selected from Z;
Y is: alkyl, cycloalkyl, heterocycloalkyl, alkoxy, heteroaryl, aryl, alkylsulfonyl, aryloxy, arylalkoxy, alkylsulfinyl, alkylthio; heteroaryl or heterocycloalkyl groups can include one or more heteroatom selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Z;
preferably, Y is: alkyl, cycloalkyl, alkoxy, aryl, alkylsulfonyl, aryloxy, arylalkoxy, alkylsulfinyl, alkylthio; each of these groups can be optionally substituted by one or more groups selected from Z;
Z is: hydroxy, thio, halogen, cyano, trifluoromethoxy, trifluoromethyl, carboxy, carboxy methyle, carboxyethyle, alkyle, cycloalkyl, alkoxy, NR7R8, azido, nitro, guanidino, amidino, phosphono, oxo, alkylthio, alkylsulfonyl, SF5, two Y groups can form a methylenedioxy;
preferably, Z is: halogen, trifluoromethyl, carboxy, alkoxy, alkylthio, alkylsulfonyl;
R7 and R8 are independently selected from: - hydrogen; - lower alkyl, cycloalkyl;
R7 and R8 can also constitute a heterocycloakyl group, which can include one or more heteroatoms selected from N, O and S; R7 and R8 independently can be optionally substituted by one or more substituents selected from Z;
as well as its racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and the pharmaceutically acceptable salts thereof.
The compounds of the formula (I) may be chosen from:
1 -(2,2-difluoroethy!)-3-phenyl-quinoxalin-2( 1 H)-one 3-(4-chlorophenyl)-1 -(2,2-difluoroethyl)quinoxalin-2(1 H)-one
3-(4-chlorophenyl)-1 -cyclopropyl-quinoxalin-2( 1 H)-one
1 -butyl-3-(4-fluorophenyl)quinoxalin-2(1 H)-one
3-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)quinoxalin-2(1H)-one
1 ,3-diethyl-5-fluoro-quinoxalin-2(1 H)-one 1 -ethyl-7-methyl-3-propyl-quinoxalin-2(1 H)-one
1 -ethyl-3-butyl-quinoxalin-2(1 /V)-one
1-ethyl-6,7-difluoro-3-(4-fluorophenyl)quinoxalin-2(1/-/)-one
1 -ethyl-6,7-difluoro-3-(4-chlorophenyl)quinoxalin-2(1 H)-one
1-cyclopropyl-3-phenylquinoxalin-2(1H)-one 1 -ethyl-3-furan-2-yl-quinoxalin-2(1 H)-one
1 -ethyl-5-fluoro-3-(4-fluorophenyl)quinoxalin-2(1 H)-one
1 -cyclopropyl-3-(4-fluorophenyl)quinoxalin-2( 1 H)-one
1 -butyl-3-(4-chlorophenyl)quinoxalin-2(1 H)-one
1-butyl-3-phenyl-quinoxalin-2(1H)-one 3-(4-chlorobenzyl)-1-ethyl-quinoxalin-2(1H)-one
3-(4-chlorophenyl)-1-(2,2,2-trifluoroethyl)quinoxalin-2(1/^)-one
3-phenyl-1-(2,2,2-trifluoroethyl)quinoxalin-2(1H)-one
1-(2,2,2-trifluoroethyl)-3-(4-trifluoromethylphenyl)quinoxalin-2(1H)-one
1 -cyclopropylmethyl-3-ethyl-quinoxalin-2( 1 H)-one 1 -ethyl-3-isopropyl-7-methyl-quinoxalin-2( 1 H)-one
1 -ethyl-5-fluoro-3-isobutyl-quinoxalin-2(1 H)-one
1 ,3-diethyl-6,7-difluoro-quinoxalin-2(1 H)-one 1 -(2,2-difluoroethyl)-3-ethylquinoxalin-2( 1 H)-one
1 ,3-diethyl-5-fluoroquinoxalin-2(1 H)-one
1 ,3-diethyl-7-methylquinoxalin-2(1 /-/)-one
1 -ethyl-5-fluoro-3-propylquinoxalin-2( 1 H)-one 1 -butyl-3-ethylquinoxalin-2(1 H)-one
3-butyl-1-ethylquinoxalin-2(1H)-one
1 -ethyl-3-isobutyl-7-methylquinoxalin-2( 1 H)-one
1 -cyclopropyl-S-propylquinoxalin^CI /-/)-one
1-cyclopropyl-3-ethylquinoxalin-2(1H)-one 1 ,3-diethyl-quinoxalin-2(1 H)-one
1-(2,2-difluoroethyl)-3-(4-fluorophenyl)quinoxalin-2(1/-/)-one
3-(4-chlorophenyl)-1 -ethyl-5-fluoroquinoxalin-2(1 H)-one
3-(4-chlorophenyl)-1 -ethyl-quinoxalin-2(1 H)-one
3-(2-chlorophenyl)-1-ethyl-quinoxalin-2(1H)-one 1 -ethyl-3-(4-fluorophenyl)quinoxalin-2(1 H)-one
1-ethyl-3-(4-methylphenyl)quinoxalin-2(1H)-one
1-ethyl-3-(4-fluoro-2-methylphenyl)quinoxalin-2(1H)-one
1 -ethyl-3-(4-chloro-2-methylphenyl)quinoxalin-2(1 H)-one
1-ethyl-3-(4-trifluoromethylphenyl)quinoxalin-2(1H)-one 1 -ethyl-3-(4-methanesulfonyl-phenyl)quinoxalin-2( 1 H)-one
3-(2,4-dimethoxy-pyrimidin-5-yl)-1-ethyl-quinoxalin-2(1 W)-one
1-ethyl-3-(4-ethylphenyl)quinoxalin-2(1 H)-one
1 -ethyl-3-furan-3-yl-quinoxalin-2(1 H)-one
3-(3,4-dimethoxyphenyl)-1-ethyl-quinoxalin-2(1/-/)-one 4-(4-ethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-benzoic acid
1-ethyl-3-(1-methyl-1 H-pyrazol-4-yi)quinoxalin-2(1H)-one
3-(3-chlorophenyl)-1-ethyl-quinoxalin-2(1H)-one
1-ethyl-3-pyridin-3-yl-quinoxalin-2(1H)-one 3-(2,5-difluorophenyl)-1-ethyl-quinoxalin-2(1 H)-one 1-ethyl-3-(1 H-indol-6-yl)quinoxalin-2(1H)-one 1-ethyl-3-(1 H-indol-5-yl)quinoxalin-2(1H)-one 1 -ethyl-3-(4-methylbenzyl)quinoxalin-2(1 H)-one
1 -ethyl-3-(4-morpholin-4-ylphenyl)quinoxalin-2(1 /-/)-one
3-(2,3-dihydro-1 ,4-benzodioxin-6-yl)-1-ethylquinoxalin-2(1/-/)-one
3-(1 ,3-benzodioxol-5-yl)-1-ethylquinoxalin-2(1H)-one 1 -ethyl-3-benzylquinoxalin-2(1 H)-one
1-ethyl-3-{[(4-methylphenyl)thio]methyl}quinoxalin-2(1H)-one 1 -ethyl-3-{[(4-methylphenyl)sulfonyl]methyl}quinoxalin-2( 1 H)-one 3-{[(4-chlorophenyl)sulfonyl]methyl}-1-methyl-quinoxalin-2(1/-/)-one 1 -ethyl-3-{[(4-methoxyphenyl)sulfonyl]methyl}quinoxalin-2( 1 /-/)-one 1 -methyl-3-[(phenylsulfonyl)methyl]quinoxalin-2(1 H)-one 1 -ethyl-3-[(phenylsulfonyl)methyl]quinoxalin-2(1 H)-one 3-{[(4-chlorobenzyl)sulfonyl]methyl}-1-ethylquinoxalin-2(1H)-one 3-[(benzylsulfonyl)methyl]-1 -ethylquinoxalin-2(1 H)-one as well as its racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and the pharmaceutically acceptable salts thereof.
More preferably, the compounds of the formula (I) according to the invention may be chosen from: 1-Butyl-3-ethyl-quinoxalin-2(1/-/)-one
1 -Cyclopropyl-3-phenylquinoxalin-2(1 H)-one
1 -Ethyl-3-(4-fluoro-2-methylphenyl)quinoxalin-2( 1 H)-one
1 -Ethyl-3-(4-fluorophenyl)quinoxalin-2(1 H)-one
1-Ethyl-3-(4-methylphenyl)quinoxalin-2(1H)-one 1-Ethyl-3-(4-trifluoromethylphenyl)quinoxalin-2(1H)-one
3-(4-Chlorophenyl)-1-(2,2-difluoroethyl)quinoxalin-2(1H)-one
3-(4-Chlorophenyl)-1-ethyl-quinoxalin-2(1H)-one
1-ethyl-3-(4-chloro-2-methylphenyl)quinoxalin-2(1H)-one as well as its racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and the pharmaceutically acceptable salts thereof. The invention also relates to the racemic forms, tautomeric forms, enantiomers, diastereoisomers, epimers and organic or mineral salts of the compounds of the general formula (I), as well as their crystalline forms, including their polymorphic forms and the polymorphic forms of the compounds of formula (I).
The present invention is directed not only to racemic mixtures of these compounds, but also to individual stereoisomers and/or diastereoisomers thereof, as well or as mixtures of these in all proportions. The compounds of the invention of the formula (I), as defined above, containing a sufficiently acidic function or a sufficiently basic function, or both, may include the corresponding pharmaceutically acceptable salts of an organic or mineral acid, or of an organic or mineral base. The expression "pharmaceutically acceptable salts" refers to the relatively non-toxic mineral and organic acid-addition salts, and the base-addition salts, of the compounds of the present invention. These salts may be prepared in situ during the final isolation and purification of the compounds. In particular, the acid-addition salts may be prepared by separately reacting the purified compound in its purified form with an organic or mineral acid and isolating the salt thus formed. The resulting salts are, for example, hydrochlorides, hydrobromides, sulfates, hydrogenosulfates, dihydrogenophosphates, citrates, maleates, fumarates, trifluoroacetates, 2- naphtalenesulfonates, para-toluenesulfonates.
The invention also relates to pharmaceutically acceptable salts with organic or inorganic bases. In particular, the basic-addition salts may be prepared by separately reacting the purified compound in its purified form with an organic or inorganic base and isolating the salt thus formed. The resulting salts are, for example, metal salts, particularly alkali metal salts, alkaline-earth metal salts and transition metal salts (such as sodium, potassium, calcium, magnesium, aluminum), or salts obtained with bases, such as ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine, morpholine), or with basic amino-acids, or with osamines (such as meglumine), or with aminoalcohols (such as 3-aminobutanol and 2- aminoethanol).
The invention also relates to the salts used for chiral resolution of the racemates. As examples, the following chiral acids can be used : (+)-D-di-O- benzoyltartaric acid, (-)-L-di-O-benzoyltartaric acid, (-)-L-di-O,O'-p-toluyl-L- tartaric acid, (+)-D-di-O,O'-p-toluyl-L-tartaric acid, (R)-(+)-malic acid, (S)-(-)- malic acid, (+)-camphoric acid, (-)-camphoric acid, R-(-)1 ,1'-binaphtalen-2,2'- diyl hydrogenophosphonic, (+)-camphanic acid, (-)-camphanic acid, (S)-(+)-2- phenylpropionic acid, (R)-(+)-2-phenylpropionic acid, D-(-)-mandelic acid, L- (+)-mandelic acid, D-tartaric acid, L-tartaric acid, or any mixture of them. As examples, the following chiral amines can be used: quinine, brucine, (S)- 1-(benzyloxymethyl)propylamine (III), (-)-ephedrine, (4S,5R)-(+)-1 , 2,2,3,4- tetramethyl-5-phenyl-1 ,3-oxazolidine, (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 any mixture of them.
Also included in the scope of the present invention are prodrugs of the compounds of formula (I). The term "prodrug" as used herein refers to any compound that when administered to a biological system generates the "drug" substance (a biologically active compound) as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s).
In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The term "aryl" refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi (π) electron system and includes biaryl groups, all of which may be optionally substituted. Suitable aryl groups include phenyl, naphthyl, biphenyl, anthryl, phenanthryl, indenyl and the like.
The term "heteroaryl" refers to 5-14 ring atom aromatic heterocycles containing 1 to 4 heteroatoms, as ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include O, S, N. Suitable heteroaryl groups include furanyl, benzofuranyl, thienyl, pyridyl, pyridyl-N-oxide, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, isoxazolyl, quinolinyl, triazolyl, pyridazinyl, pyrrolyl, imidazolyl, indazolyl, isothiazolyl, indolyl, oxadiazolyl and the like.
The term "cycloalkyl" means saturated carbocyclic rings, optionally substituted, and includes mono-, bi- and tri-cyclic compounds with 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 optionally substituted monocyclic, bicyclic or tricyclic radicals, comprising one or more heteroatoms, preferably chosen from among O, S and N1 optionally in the oxidized state (for S and N), and optionally one or more double bonds. At least one of the rings preferably comprises from 1 to 4 endocyclic heteroatoms, more preferably from 1 to 3 heteroatoms. Most preferably, the heterocycloalkyl (or simply "heterocyclic") radical comprises one or more rings, each having from 5 to 8 nodes. Examples of heterocyclic radicals are: morpholinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, tetrahydrothienyl, dihydrofuranyl, tetrahydrofuranyl, pyrazolidinyl, 1 ,3-dioxolanyl, pyrrolidinyl, pyranyl, dihydropyranyl, isoxazolidinyl, imidazolyl, imidazolidinyl and the like.
The term "alkyl" refers to a saturated aliphatic groups, including straight chain and branched chain groups. Suitable alkyl groups, having 1 to 20 carbon atoms, include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decanoyl, dodecanoyl, hexadecyl, octadecyl groups and the like.
The term "alkenyl" refers to unsaturated groups comprising at least one carbon-carbon double bond, and includes 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 unsaturated groups comprising at least one carbon-carbon triple bond and includes straight chain, branched chain and cyclic groups; and optionally includes 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, preferably an alkyl group having 1 to 20 carbon atoms, substituted with an aryl group. Suitable arylalkyl groups include benzyl, picolyl, and the like.
The term "alkoxy" refers to the group alk-O- wherein "alk" is an alkyl group.
The term "aryloxy" refers to the group aryl-O-.
The term "aryloxyalkyl" refers to an alkyl group substituted with an aryloxy group.
The term "arylalkyloxyalkyl" refers to an alkyl group substituted with an arylalkyloxy group.
The term "arylalkoxy" refers to the group aryl-Alk-O-, wherein "AIk" is an alkyl group. The term "alkylthioalkyl" refers to an alkyl group substituted with an alkylthio.
The term "arylthioalkyl" refers to an alkyl group substituted with an arylthio group.
The term "alkylsulfinyl" refers to an alkyl-SO- group.
The term "alkylsulfonyl" refers to an alkyl-SO2- group.
The term "arylsulfinylalkyl" refers to an alkyl group substituted with an arylsulfinyl (aryl-SO-) group.
The term "arylalkylsulfinylalkyl" refers to an alkyl group substituted with an arylalkylsulfinyl group.
The term "arylsulfonylalkyl" refers to an alkyl group substituted with an arylsulfonyl (aryl-SO2-) group.
The term "arylalkylsulfonylalkyl" refers to an alkyl group substituted with an arylalkylsulfonyl group.
The term "arylalkylthioalkyl" refers to an alkyl group substituted with an arylalkylthio.
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 "heteroarylsulfinylalkyl" refers to an alkyl group substituted with a heteroarylsulfinyl group.
The term "heteroarylsulfonylalkyl" refers to an alkyl group substituted with a heteroarylsulfonyl group.
The term "heteroarylalkylthioalkyl" refers to an alkyl group substituted with a heteroarylalkylthio group.
The term "heteroarylalkylsulfinylalkyl" refers to an alkyl group substituted with a heteroarylalkylsulfinyl group.
The term "heteroarylalkylsulfonylalkyl" refers to an alkyl group substituted with a heteroarylalkylsulfonyl 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 "heterocycloalkylsulfinylalkyl" refers to an alkyl group substituted with a heterocycloalkylsulfinyl group.
The term "heterocycloalkylsulfonylalkyl" refers to an alkyl group substituted with a heterocycloalkylsulfonyl group.
The term "heterocycloalkylalkylthioalkyl" refers to an alkyl group substituted with a heterocycloalkylalkylthio group.
The term "heterocycloalkylalkylsulfinylalkyl" refers to an alkyl group substituted with a heterocycloalkylalkylsulfinyl group.
The term "heterocycloalkylalkylsulfonylalkyl" refers to an alkyl group substituted with a heterocycloalkylalkylsulfonyl 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" referred to herein in connection with organic radicals or compounds respectively defines such as with up to and including 10, preferably up to and including 6, and advantageously 1 to 4 carbon atoms. Such groups may be straight, branched, or cyclic chain.
The terms "alkylthio" refers to the group alkyl-S-, wherein "alk" is an alkyl group.
The term "halogen" refers to a fluorine, bromine or chlorine atom. The term "amidino" refers to -C(NR7)-NR7R8 where R7R8 are as defined above, all, except hydrogen, are optionally substituted.
The invention's compounds according to formula (I) exhibit an hypoglycemic activity, and are useful in the treatment of pathologies associated with the syndrome of insulin resistance.
Insulin resistance is characterised by a reduction in the action of insulin (cf. "Presse Medicale", (1997), 26(14), 671-677) and is involved in many pathological conditions, such as diabetes and more particularly non-insulin- dependent diabetes (type Il diabetes or NIDDM), dyslipidaemia, obesity, arterial hypertension, and also certain cardiac, microvascular and macrovascular complications, for instance atherosclerosis, retinopathy and neuropathy. In this respect, reference will be made, for Example, to Diabetes, 37, (1988), 1595-1607; Journal of Diabetes and its complications, 12, (1998), 110-119; Horm. Res., 38, (1992), 28-32.
The invention also relates to pharmaceutical composition containing as active ingredient at least one compound of formula (I), as defined above, and/or a pharmaceutically acceptable salt thereof, in combination with one or several pharmaceutically acceptable carrier, adjuvant, diluent or excipient. A person skilled in the art is aware of a whole variety of such carrier, adjuvant, diluent or excipient compounds suitable to formulate a pharmaceutical composition. The pharmaceutical compositions of the present invention can be administered by a variety of routes including oral, parenteral, intravenous, intramuscular, rectal, permucous or percutaneous.
They will thus be presented in the form of injectable solutions or suspensions or multi-dose bottles, in the form of plain or coated tablets, sugar-coated tablets, wafer capsules, gel capsules, pills, sachets, powders, suppositories or rectal capsules, solutions or suspensions, for percutaneous use in a polar solvent, or for permucous use.
The excipients that are suitable for such administrations are pharmaceutically acceptable excipients, such as cellulose or microcrystalline cellulose derivatives, alkaline-earth metal carbonates, magnesium phosphate, starches, modified starches, lactose and the like for solid forms.
For rectal use, cocoa butter or polyethylene glycol stearates are the preferred excipients. For parenteral use, water, aqueous solutions, physiological saline and isotonic solutions are the vehicles most appropriately used. For example, in the case of an oral administration, for example in the form of granules, tablets or coated tablets, pills, capsules, gel capsules, gels, cachets or powders, a suitable posology of the compounds is between about 0.1 mg/kg and about 100 mg/kg, preferably between about 0.5 mg/kg and about 50 mg/kg, more preferably between about 1 mg/kg and about 10 mg/kg and most preferably between about 2 mg/kg and about 5 mg/kg of body weight per day. If representative body weights of 10 kg and 100 kg are considered, in order to illustrate the daily oral dosage range that can be used and as described above, suitable dosages of the compounds of the formula (I) will be between about 1-10 mg/per day and 1000-10000 mg/per day, preferably between about 5-50 mg/per day and 500-5000 mg/per day, more preferably between 10-100 mg and 100-1000 mg/per day and most preferably between 20-200 mg and 50-500 mg/per day.
It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.
As noted above, formulations of the present invention suitable for oral administration may be presented as discrete units, such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.
In the non-insulin-dependent diabetes, for the man, the hyperglycemia is the results of two main defects: an alteration of the insulin secretion and a reduction in the effectiveness of insulin at level of three sites to knowing the liver, the muscles and adipose tissue.
The present invention also relates to compound of general formula (I) as well as its racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and the pharmaceutically acceptable salts thereof, for the preparation of a medicament for the prevention and/or treatment of pathologies associated with hyperglycaemia; for the preparation of a medicament that induces insulin secretion in response of glucose concentration, preferably for the treatment of diabetes, more preferably for the prevention and/or treatment of type Il diabetes and pathologies associated to metabolic disorders, hypercholesteremia, hyperlipidemia, which are increased by hyperinsulinemia and hyperglycemia; for the treatment of diseases chosen from diabetes related microvascular and macrovascular complications, such as arterial hypertension, inflammatory processes, microangiopathy, macroangiopathy, retinopathy and neuropathy; for reducing hyperglycaemia, for the treatment of dyslipidaemia and obesity; or diseases such as cardiovascular diseases, comprising atherosclerosis, myocardial ischemia.
The present invention also relates to the use of at least a compound of the general formula (I), as well as its racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and the pharmaceutically acceptable salts, and pro-drugs thereof, for the prevention and/or treatment of pathologies associated with hyperglycaemia, preferably for the treatment of diabetes, more preferably for the prevention and/or treatment of type Il diabetes and pathologies associated to metabolic disorders, hypercholesteremia, hyperlipidemia, which are increased by hyperinsulinemia and hyperglycemia; for the treatment of diseases chosen from diabetes related microvascular and macrovascular complications, such as arterial hypertension, inflammatory processes, microangiopathy, macroangiopathy, retinopathy and neuropathy; for reducing hyperglycaemia, for the treatment of dyslipidaemia and obesity; or diseases such as cardiovascular diseases, comprising atherosclerosis, myocardial ischemia.
The present invention also relates to manufacturing process of compounds of formula (I), as defined above, according to the following representative methods shown in Scheme 1 (Preparation of the Intermediates diaminophenyl derivatives); Scheme 2 (Method A) or Scheme 3 (Method B), in which R1 , R2, R3, R4, R5 and R6 are as above defined in formula (I) and Hal is a halogen atom, preferably Cl, Br. The following schemes are given for representative purposes, and solely for the purpose of facilitating the representation. Needless to say, depending on the nature of the compounds of the formula (I) to be obtained, the methodologies presented may be adapted by a person skilled in the art by selecting the appropriate starting materials, in which the nature of the substituents R1 , R6 may be modified, especially as a function of the nature and length of the desired chain.
The compounds useful according to the invention may be prepared, unless specifically specified, by the application or adaptation of known methods, by which are meant methods used heretofore or described in the literature, patents or patent applications, the Chemical Abstracts and on the Internet.
Preparation of the intermediates diaminophenyl derivatives: Scheme 1:
Figure imgf000022_0001
(3)
(1 ) (2)
wherein:
Hal is a halogen atom, preferably Cl, Br;
R1 , R2, R3, R4 and R5 are as above defined in formula (I).
Phenyl nitro amino derivatives (2) are prepared by reacting an halo- nitrophenyl derivative (1) with an amine, in the presence of at least one equivalent of a base, such as sodium or potassium carbonate, cesium carbonate, or in the presence of at least two equivalents of the considered amine, in an inert solvent, such as tetrahydrofurane, acetonitrile or toluene, at a temperature between 200C and the reflux for 1 to 24h. Diamino phenyl derivatives (3) may be prepared from compounds of formula (2) by reduction of the nitro to the corresponding primary aromatic amine. Preferred methods use metal, such as Zn, Sn or Fe, in acids, such as aqueous HCI. Other preferred method, use metal in lower state of oxidation, such as Sn(ll)chloride in HCI. Particularly preferred is the reduction by catalytic hydrogenation, which uses metal catalysts from metals such as Pd, Pt or Ni, preferably Pd on charcoal or Raney Nickel in solvents, such as methanol, ethanol, tetrahydrofurane.
Preparation of the quinoxalinone derivatives: Scheme 2 - Method A
Figure imgf000023_0001
This method is particularly suitable for compounds of formula (I), wherein:
Rx is Hal, ORe (wherein Re is hydrogen, lower alky!);
Hal is a halogen atom, preferably Cl, Br;
R1 is as above defined in formula (I);
R6 is as above defined in formula (I);
R2, R3, R4 and R5 are as above defined in formula (I).
Quinoxalinones (I) are prepared by cyclization of (3) with a an α- keto acid derivative in a solvent, such as, for example, methanol, acetonitrile, dimethylformamide (DMF) or toluene, at a temperature between 20°C and the reflux, more preferably reflux, for 1 to 36 h.
Scheme 3 - Method B
Figure imgf000023_0002
This method is particularly suitable for compounds of formula (I), wherein: Rx is Hal, ORe (wherein Re is hydrogen, lower alkyl); Hal is a halogen atom, preferably Cl, Br;
R1 is as above defined in formula (I);
R6 is as above defined in formula (I);
R2, R3, R4 and R5 are as above defined in formula (I).
Hydroxyquinoxalinones (5) are obtained by cyclization of (3) with, for example, chloro(oxo)acetate derivatives in the presence of at least one equivalent of a base, an inorganic base, such as sodium or potassium carbonate, cesium carbonate, or an organic base, such as triethylamine or diisopropylethylamine, in a inert solvent, such as, for example, dichloromethane, acetonitrile, DMF, at a temperature between 200C and the reflux, for 1 to 24h.
Bromo derivatives (6) are prepared by bromination of (5) using a brominating agent, such as POBr3, in an inert solvent, such as 1 ,2-dichloroethane, at a temperature between 200C and the reflux, more preferably reflux for 1 to 24h. Quinoxalinones (I) are prepared by reacting the bromo compounds (6) with boronic acid derivatives or their esters, in the presence of a base, such as sodium carbonate or potassium carbonate, and a catalyst, such as bis(triphenylphosphine) palladium(ll)chloride, in an inert solvent, such as dimethylformamide or toluene, at a temperature between 200C and the reflux, more preferably reflux, for 1 to 24h.
The examples that follow illustrate the invention without, however, limiting it.
The starting materials used are known products or products prepared according to known procedures. The percentages are expressed on a weight basis, unless otherwise mentioned.
The compounds were characterised especially via the following analytical techniques.
The NMR spectra were acquired using a Bruker Avance DPX 300 MHz NMR spectrometer. The masses were determined by HPLC coupled to an Agilent Series 1100 mass detector. The melting points (m.p.) were measured on a Stuart Scientific block.
Examples:
Example 1 : Λ/-(2,2-difluoroethyl)-2-nitroaniline
Figure imgf000025_0001
2 ml (19 mM) of 2-Chloronitrobenzene and 2,7 ml (36 mM) of 2,2- difluoroethyl amine in 2 ml of acetonitrile were refluxed under stirring for 24 h. 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 under vacuum to give 3,65 g of Λ/-(2,2- difluoroethyl)-2-nitroaniline as an orange solid. Yield: 95%.
NMR 1H (300 MHz / DMSO-d6) δ (ppm): 3,96(m,2H), 6,30(tt,1 H), 6,82(t,1 H), 7,29(d,1H), 7,62(UH)1 8,13(d,1H), 8,27(t,1 H)
The following compounds were obtained using the same procedure as in Example 1
Example 1-2: /V-ethyl-2-nitroaniline
Figure imgf000025_0002
C8HI0N2O2 = 166,18 Mass spectrometry M+1 = 167,1 Example 1-3: Λ/-cyclopropyl-2-nitroaniline
Figure imgf000026_0001
C9Hi0N2O2 = 178,19 Mass spectrometry M+1 = 179,0
Example 1.4: /V-butyl-2-nitroaniline
CH0
Figure imgf000026_0002
NMR 1H (300 MHz / DMSO-d6) δ (ppm): 0,94(t,3H), 1 ,41(m,2H), 1 ,63(m,2H), 3,35 (m,2H), 6,69(t,1 H), 7,08(d,1H), 7,55(t,1H), 8,06(d,1H), 8,13(m,1 H)
Example 1.5: /V-ethyl-4,5-difluoro-2-nitroaniline
H1
Figure imgf000026_0003
NMR 1H (300 MHz / CDCy δ (ppm): 1 ,31(t,3H), 3,23(m,2H), 6,54(m,1 H), 7,94(m,2H)
Example 1.6: Λ/-ethyl-5-methyl-2-nitroaniline
Figure imgf000027_0001
C9H12N2O2 = 180,20 Mass spectrometry M+1 = 181 ,1 m.p.: 45°C
Example 1.7: Λ/-ethyl-3-fluoro-2-nitroaniline
Figure imgf000027_0002
NMR 1H (300 MHz / DMSO-d6) δ (ppm) : 1 ,19(t,3H), 3,29(q,2H), 6,56(m,1 H), 6,78(d,1 H), 7,19(m,1H), 7,43(m,1 H)
Example 2: Λ/-(2,2-difluoroethyl)benzene-1 ,2-diamine
Figure imgf000027_0003
To a solution of 3,6 g (18 mM) of Λ/-(2,2-difluoroethyl)-2-nitroaniline in 25 ml of methanol, were added 470 mg of palladium on carbon at 5%. The reaction mixture was stirred for 3 h at room temperature under hydrogen atmosphere, at room pressure and room temperature. The catalyst was filtrated on Celite and the filtrate was evaporated under vacuum to give 3 g of Λ/-(2,2-difluoro ethyl)benzene-1 ,2-diamine as an oil. Yield: 97,5%. NMR 1H (300 MHz / DMSO-d6) δ (ppm): 3,48(m,2H), 4,56(s,2H), 4,80(t,1 H), 6,15(tt,1H), 6,56(m,4H)
The following compounds were obtained using the same procedure as in Example 2.
Example 2-2: Λ/-ethylbenzene-1,2-diamine H,
Figure imgf000028_0001
C8Hi2N2 = 136,19 Mass spectrometry M+1 = 137,2
Example 2-3: Λ/-cyclopropylbenzene-1,2-diamine
Figure imgf000028_0002
NMR 1H (300 MHz / DMSO-d6) δ (ppm): 0,27(m,2H), 0,59(m,2H), 2,21(m,1 H), 4,33(s,2H), 4,88(s,1H), 6,39(m,3H), 6,68(d,1 H)
Example 2-4: Λ/-butvlbenzene-1.2-diamine
Figure imgf000028_0003
NMR 1H (300 MHz / DMSO-d6) δ (ppm): 0,94(t,3H), 1 ,44(m,2H), 1 ,60(m,2H), 3,02 (m,2H), 4,31 (m,1 H)1 4,49(s,2H), 6,43(m,2H), 6,53(m,2H
Example 2-5: Λ/-ethyl-4,5-difluorobenzene-1 ,2-diamine
Figure imgf000029_0001
NMR 1H (300 MHz / CDCh) δ (ppm): 1 ,22(t,3H), 2,98(q,2H), 3,13(m,2H) 6,37(m,1 H), 6,49(m,1 H), 7,19(s,1 H)
Example 2-6: Λ^-ethyl^-methylbenzene-i ,2-diamine
Figure imgf000029_0002
C9Hi4N2 = 150,22 Mass spectrometry M+1 = 151 ,1
Example 2-7: /V1-ethyl-3-fluorobenzene-1 ,2-diamine
H,
Figure imgf000029_0003
NMR 1H (300 MHz / DMSO-d6) δ (ppm): 1 ,22(t,3H), 3,07(m,2H), 4,45(s,2H), 4,72(m,1 H), 6,28(1 H), 6,50(m,2H) Method A
Example 3: 1-(2,2-difluoroethyl)-3-phenyl-quinoxalin-2(1H)-one
Figure imgf000030_0001
To a solution of 400 mg (2,32 mM) of Λ/-(2,2-difluoroethyl)benzene-1 ,2- diamine in 7 ml of methanol were added 349 mg (2,32 mM) of 2-Oxo-2- phenylacetic acid. The mixture was refluxed for 3 h and the solvent was then removed under vacuum. The residue was further purified by silica gel column chromatography using dichloromethane/cyclohexane as eluant, to give 231 ,8 mg of 1-(2,2-difluoroethyl)-3-phenyl-quinoxalin-2(1H)-one as a pale beige solid. Yield: 35%.
NMR 1H (300 MHz / DMSO-d6) δ (ppm): 4,87(td,2H), 6,44(tt,1 H), 7,46(m,1 H)
7,55(m,3H), 7,68(t,1 H), 7,76(d,1 H), 7,92(d,1 H), 8,25(m,2H) m.p.: 85-880C
Ci6Hi2F2N2O = 286,28 Mass spectrometry M+1 = 287,1
Example 3-2: 3-(4-chlorophenyl)-1 -(2,2-difluoroethyl)quinoxalin-2(1 H)- one
Figure imgf000030_0002
To a solution of 400 mg (2,32 mM) of Λ/-(2,2-difluoroethyl)benzene-1 ,2- diamine in 7 ml of methanol were added 428 mg (2,32 mM) of 4-chloro-α- oxo-benzeneacetic acid. The mixture was refluxed for 3 h. A solid was filtered, washed and dried under vacuum to give 236 mg of 3-(4- chlorophenyl)-1-(2,2-difluoroethyl) quinoxalin-2(1 H)-one Yield: 32%.
NMR 1H (300 MHz / DMSO-d6) δ (ppm): 4,85(td,2H), 6,43(tt,1 H)1 7,46(t,1 H),
7,59(d,2H), 7,70(t,1H), 7,77(d,1H), 7,92(d,1H), β,31(d,2H) m.p.: 133-136°C
The following compounds were obtained using the same or a similar procedure as in Example 3 or 3-2
Example 3-3: 3-(4-chlorophenyl)-1-cyclopropyl-quinoxalin-2(1H)-one
Figure imgf000031_0001
NMR 1H (300 MHz / DMSO-d6) δ (ppm): 0,91(m,3H), 1 ,35(m,2H), 3,09(m,1H), 7,41(t,1 H), 7,57(d,2H), 7,67(t,1 H), 7,87(m,2H), 8,27(d,2H) m.p.: 102-1050C
Example 3-4: 1-butyl-3-(4-fluorophenyl)quinoxalin-2(1W)-one
Figure imgf000031_0002
NMR 1H (300 MHz / DMSO-d6) δ (ppm) : 0,96(t,3H), 1 ,46(m,2H),
1 ,68(m,2H), 4,31(t,2H), 7,34(m,3H), 7,66(m,2H), 7,92(d,1H), 8,39(t,2H) Example 3-5: 3-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)quinoxalin-2(1tf)- one
Figure imgf000032_0001
NMR 1H (300 MHz / DMSO-d6) δ (ppm): 4,94(q,2H), 7,10(t,2H), 7,29(d,1 H), 7,36(t,1 h), 7,53(t,1 h), 7,88(d,1 H), 8,35(m,2H)
C16H10F4N2O = 322,26 Mass spectrometry M+1 = 324,0
Example 3-6: 1,3-diethyl-5-fluoro-qulnoxalin-2(1A/)-one
Figure imgf000032_0002
Ci2H13FN2O = 220,24 Mass spectrometry M+1 = 221 ,1
Example 3-7: 1 -ethyl-7-methyl-3-propyl-quinoxalin-2(1 H)-one
Figure imgf000032_0003
C14H18N2O = 230,31 Mass spectrometry M+1 = 231 ,0
Example 3-8: 1-ethyl-3-butyl-quinoxalin-2(1W)-one
Figure imgf000033_0001
Ci4Hi8N2O = 230,31 Mass spectrometry M+1 = 231 ,1
Example 3-9: 1-ethyl-6,7-difluoro-3-(4-fluorophenyl)quinoxalin-2(1W)-one
Figure imgf000033_0002
NMR 1H (300 MHz / CDCh) δ (ppm): 1 ,34(t,3H), 4,23(q,2H), 7,08(m,3H), 7,66(U H)1 8,34(m,2H) m.p.: 116-1180C
Example 3-10: 1 -ethyl-6,7-difluoro-3-(4-chlorophenyl)quinoxalin-2(1 H)- one
Figure imgf000033_0003
NMR 1H (300 MHz / CDCh) δ (ppm): 1 ,34(t,3H,) 4,25(q,2H), 7,04(m,1 H), 7,36(d,2H), 7,70(U H)1 8,27(d,2H) m.p.: 135-1370C
Example 3-11 : 1-cyclopropyl-3-phenylquinoxalin-2(1W)-one
Figure imgf000034_0001
NMR 1H (300 MHz / DMSO-d6) δ (ppm) : 0,97(m,2H), 1 ,40(m,2H), 3,17(ITi1I H), 7,45(tf1 H), 7,57(m,3H), 7,70(UH)1 7,92(t,2H), 8,24(m,2H) m.p.: 102-1050C
Example 3-12: 1 -ethyl-3-furan-2-yl-quinoxalin-2(1 H)-one
Figure imgf000034_0002
Ci4H12N2O2 = 240,26 Mass spectrometry M+1 = 241 ,1
Example 3-13: 1-ethyl-5-fluoro-3-(4-fluorophenyl)quinoxalin-2(1W)-one
Figure imgf000034_0003
NMR 1H (300 MHz / DMSO-d6) δ (ppm) : 1 ,28(t,3H), 4,31 (q,2H), 7,25(t,1 H), 7,33(t,2H), 7,48(Cl1I H), 7,65(m,1 H), 8,38(m,2H)
Example 3-14 1-cyclopropyl-3-(4-fluorophenyl)quinoxalin-2(1H)-one
Figure imgf000035_0001
C17H13FN2O = 280,30 Mass spectrometry M+1 = 281 ,1 m.p.: 179-1820C
Example 3-15: 1-butyl-3-(4-chlorophenyl)quinoxalin-2(1H)-one
Figure imgf000035_0002
C18H17CIN2O = 312,80 Mass spectrometry M+1 = 313,0 m.p.: 99-1020C
Example 3-16: 1-butyl-3-phenyl-quinoxalin-2(1H)-one
Figure imgf000035_0003
C18H18N2O = 278,35 Mass spectrometry M+1 = 279,0 m.p.: 40-43-0C
Example 3-17: 3-(4-chlorobenzvl)-1-ethyl-quinoxalin-2(1/-fl-one
Figure imgf000036_0001
Ci7Hi5CIN2O = 298,77 Mass spectrometry M+1 = 299,1
Example 3-18: 3-(4-chlorophenyl)-1 -(2,2,2-trifluoroethyl)quinoxalin- 2(1H)-one
Figure imgf000036_0002
Ci6HioCIF3N2O = 338,72 Mass spectrometry M+1 = 339,0
Example 3-19: 3-phenyl-1-(2,2,2-triftuoroethyl)quinoxalin-2(1W)-one
Figure imgf000036_0003
C16HnF3N2O = 304,27 Mass spectrometry M+1 = 305,1
Example 3-20: 1-(2,2,2-trifluoroethyl)-3-(4- trifluoromethylphenyl)quinoxalin-2(1H)-one
Figure imgf000037_0001
Ci7H10F6N2O = 372,27 Mass spectrometry M+1 = 373,0
Example 3-21: 1-cyclopropylmethyl-3-ethyl-quinoxalin-2(1W)-one
Figure imgf000037_0002
C14H16N2O = 228,29 Mass spectrometry M+1 = 229,0
Example 3-22: 1-ethyl-3-isopropyl-7-methyl-quinoxalin-2(1H)-one
Figure imgf000037_0003
C14H18N2O = 230,31 Mass spectrometry M+1 = 231 ,0 Example 3-23: 1-ethyl-5-fluoro-3-isobutyl-quinoxalin-2(1W)-one
Figure imgf000037_0004
C14H17FN2O = 248,30 Mass spectrometry M+1 = 249,1 Example 3-24: 1.3-diethvl-6.7-difluoro-αuinoxalin-2MA/)-one
Figure imgf000038_0001
Ci2H12F2N2O = 238,23 Mass spectrometry M+1 = 239,1 m.p.: 117-119°C
Example 3-25: 1-(2,2-difluoroethyl)-3-ethylquinoxalin-2(1W)-one
Figure imgf000038_0002
C12H12F2N2O = 238,23 Mass spectrometry M+1 = 239,1
Example 3-26: 1,3-diethyl-5-fluoroquinoxalin-2(1W)-one
Figure imgf000038_0003
Ci2H13FN2O = 220,24 Mass spectrometry M+1 = 221 ,1
Example 3-27: 1 ,3-diethyl-7-methylquinoxalin-2(1 H)-one
Figure imgf000039_0001
Ci3H16N2O = 216,28 Mass spectrometry M+1 = 217,1
Example 3-28: 1-ethyl-5-fluoro-3-propylquinoxalin-2(1W)-one
Figure imgf000039_0002
Ci3H15FN2O = 234,27 Mass spectrometry M+1 = 235,1
Example 3-29: 1-butyl-3-ethylquinoxalin-2(1H)-one
Figure imgf000039_0003
CuH18N2O = 230,31 Mass spectrometry M+1 = 231 ,1 m.p: 48-510C
Example 3-30: 3-butyl-1 -ethylquinoxalin-2(1 H)-one
Figure imgf000039_0004
C14H18N2O = 230,31 Mass spectrometry M+1 = 231 ,1
Example 3-31 : 1 -ethyl-3-isobutyl-7-methylquinoxalin-2(1 H)-one
Figure imgf000040_0001
Ci5H20N2O = 244,33 Mass spectrometry M+1 = 245,1
Example 3-32: 1 -cyclopropyl-S-propylquinoxalin^i H)-one
Figure imgf000040_0002
CuHi6N2O = 228,29 Mass spectrometry M+1 = 229,1 m.p: 72-75°C
Example 3-33: 1-cyclopropyl-3-ethylquinoxalin-2(1W)-one
Figure imgf000040_0003
Ci3Hi4N2O = 214,26 Mass spectrometry M+1 = 215,1 m.p: 77-800C
Example 3-34: 1-(2,2-difluoroethyl)-3-(4-fluorophenyl)quinoxalin-2(1H)-one
Figure imgf000040_0004
Ci6Hi1F3N2O = 304,27 Mass spectrometry M+1 = 305,1 m.p: 151-154°C Example 3-35: 3-(4-chlorophenyl)-1-ethyl-5-fluoroquinoxalin-2(1W)-one
Figure imgf000041_0001
NMR 1H (300 MHz / DMSO-d6) δ (ppm) : 1 ,29(t,3H), 4,35(s,2H), 7,29(t,1H), 7,48(d,1 H), 7,61(s,1 H), 7,69(m,1 H), 8,33(d,2H)
Method B
Example 4: 1 -ethyl-1 ,4-dihydroquinoxaline-2,3-dione
Figure imgf000041_0002
To 12 g (88.1 mmol) of N-ethylbenzene-1 ,2-diamine in 150 ml of methanol were added dropwise 8.1 g (92.5 mM) of oxalyl chloride. The exothermic mixture reached 55°C and solidified. The mixture was heated at 1300C for 2h. The purple solid formed was filtered and washed with isopropanol to give 1 -ethyl-1 ,4-dihydroquinoxaline-2,3-dione as a solid (7.2g). Yield: 43%.
C10H10N2O2 = 190,20 Mass spectrometry M-1 = 189,1
Example 5: 3-bromo-1-ethyl-qtiinoxaHn-2(1H)-one
To 2 g (10.5 mM) of 1 -ethyl-1 ,4-dihydroquinoxaline-2,3-dione in 20 ml of dichloroethane were added dropwise 3.16 g (11.0 mM) of POBr3. The reaction mixture was refluxed under stirring for 2h and then treated with ice cold and an aqueous sodium carbonate solution. The mixture was filtered and the filtrate was extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated to give 1 ,4 g of 3-bromo-1-ethyl-quinoxalin- 2(1H)-one as a yellow solid. Yield:53%.
Ci0H9BrN2O = 253,1 Mass spectrometry M-1 = 252,9
Example 6: 3-(4-chlorophenyl)-1 -ethyl-quinoxalin-2(1 H)-one
Figure imgf000042_0001
To 200 mg (0.79 mM) of 3-bromo-1-ethyl-quinoxalin-2(1 /-/)-one and 27.7 mg (0.04 mM) of bis(triphenylphosphine)palladium (II) chloride in 1 ml of dimethylformamide were added under nitrogen 185,3 mg (1 ,185 mM) of 4- chlorophenylboronic acid and 0,8 ml (1 ,6 mM) of a 2M sodium carbonate aqueous solution. The reaction mixture was heated to 9O0C and stirred for 30 min under nitrogen atmosphere. Water was added and the mixture was extracted with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The compound was purified through a silica plug eluting with dichloromethane, which afforded after evaporation 132 mg of 3-(4-chlorophenyl)-1-ethyl-quinoxaline-2(1H)-one as a solid. Yield: 59%.
NMR 1H (300 MHz / DMSO-d6) δ (ppm) : 1 ,35(t,3H), 4,42(q,2H), 7,49(m,1 H), 7,62(d,2H), 7,73(d,2H), 7,99(d,1 H), 8,37(d,2H) Ci6Hi3CIN2O = 284,74 Mass spectrometry M+1 = 285,0 m.p.: 138-14O0C
This compound was also prepared using method A
The following compounds were obtained using the same procedure as in Example 6
Example 6-2: 3-(2-chlorophenyl)-1 -ethyl-quinoxalin-2(1 H)-one
Figure imgf000043_0001
Ci6H13CIN2O = 284,74 Mass spectrometry M+1 = 285,1
Example 6-3: 1-ethyl-3-(4-fluorophenyl)quinoxalin-2(1//)-one
Figure imgf000043_0002
Ci6Hi3FN2O = 268,29 Mass spectrometry M+1 = 269,1 m.p.: 110-1150C
Example 6-4: 1 -ethyl-3-(4-methylphenyl)quinoxal in-2(1 H)-one
Figure imgf000043_0003
C17Hi6N2O = 264,32 Mass spectrometry M+1 = 265,1
Example 6-5: 1 -ethyl-3-(4-fluoro-2-methylphenyl)quinoxalin-2(1 H)-one
Figure imgf000044_0001
Ci7H15FN2O = 282,31 Mass spectrometry M+1 = 283,1
Example 6-6: 1-ethyl-3-(4-chloro-2-methylphenyl)quinoxalin-2(1H)-one
Figure imgf000044_0002
Ci7H15CIN2O = 298,77 Mass spectrometry M+1 = 299,1
Example 6-7: 1-ethyl-3-(4-trifluoromethylphenyl)quinoxalin-2(1fl)-one
Figure imgf000044_0003
C17H13F3N2O = 318,29 Mass spectrometry M+1 = 319,1
Example 6-8: 1-ethyl-3-(4-methanesulfonyl-phenyl)quinoxalin-2(1/-/)-one
Figure imgf000045_0001
Ci7Hi6N2O3S = 328,39 Mass spectrometry M+1 = 329,1
Example 6-9: 3-(2,4-dimethoxy-pyrimidin-5-yl)-1 -ethyl-quinoxalin-2(1 H)- one
Figure imgf000045_0002
Ci6H16N4O3 = 312,33 Mass spectrometry M+1 = 313,0
Example 6-10: 1-ethyl-3-(4-ethylphenyl)quinoxalin-2(1H)-one
Figure imgf000045_0003
Ci8Hi8N2O = 278,35 Mass spectrometry M+1 = 279,1
Example 6-11: 1-ethyl-3-furan-3-yl-quinoxalin-2(1W)-one
Figure imgf000045_0004
Ci4Hi2N2O2 = 240,26 Mass spectrometry M+1 = 241 ,1
Example 6-12: 3-(3,4-dimethoxyphenyl)-1 -ethyl-quinoxalin-2(1 H)-one
Figure imgf000046_0001
Ci8Hi8N2O3 = 310,35 Mass spectrometry M+1 = 311 ,1
Example 6-13: 4-(4-ethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-benzoic acid
Figure imgf000046_0002
Ci7H14N2O3 = 294,3 Mass spectrometry M+1 = 295,1
Example 6-14: 1-ethyI-3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-2(1H)-one
Figure imgf000046_0003
C14Hi4N4O= 254,29 Mass spectrometry M+1 = 255,1 Example 6-15: 3-(3-chlorophenyl)-1 -ethyl-quinoxalin-2(1 W)-one
Figure imgf000047_0001
Ci4Hi3CIN2O= 284,74 Mass spectrometry M+1 = 285,0
Example 6-16: 1-ethvl-3-pvridin-3-vl-quinoxalin-2(1ffl-one
Figure imgf000047_0002
C15H13N3O= 251 ,29 Mass spectrometry M+1 = 252,1
Example 6-17: 3-(2,5-difluorophenyl)-1-ethyl-quinoxalin-2(1/Y)-one
Figure imgf000047_0003
Ci6Hi2F2N2O= 286,28 Mass spectrometry M+1 = 287,1 Example 6-18: 1-ethyl-3-(1H-indol-6-yl)quinoxalin-2(1W)-one
Figure imgf000047_0004
Ci8Hi5N3O = 289,33 Mass spectrometry M+1 = 290,1 Example 6-19: 1-ethyl-3-(1H-indol-5-yl)quinoxalin-2(1H)-one
Figure imgf000048_0001
C18H15N3O = 289,33 Mass spectrometry M+1 = 290,1
Example 6-20: 1 -ethyl-3-(4-methylbenzyl)quinoxalin-2(1 H)-one
Figure imgf000048_0002
Ci8H18N2O = 278,35 Mass spectrometry M+1 = 279,1
Example 6-21 : 1-ethyl-3-(4-morpholin-4-ylphenyl)quinoxalin-2(1H)-one
Figure imgf000048_0003
NMR 1H (300 MHz / DMSO-d6) δ (ppm) : 1 ,30(t,3H) 2,40(s,2H) 3,55(s,4H) 3,67(t,2H) 4,37(q,2H) 7,46(m,3H) 7,68(d,2H) 7,90(d,1 H) 8,24(d,2H)
Example 6-22: 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-ethylquinoxalin- 2(1H)-one
Figure imgf000048_0004
Ci8Hi6N2O3 = 308,33 Mass spectrometry M+1 = 309,1
Example 6-23: 3-(1,3-benzodioxol-5-yl)-1-ethylquinoxalin-2(1H)-one
Figure imgf000049_0001
Ci7Hi4N2O3 = 294,30 Mass spectrometry M+1 = 295,1
Example 6-24: 1-ethyl-3-benzylquinoxalin-2(1 H)-one
Figure imgf000049_0002
NMR 1H (300 MHz / DMSO-d6) δ (ppm) : 1 ,23(t,3H), 4,18(s,2H), 4,27(q,2H), 7,15-7,40(m,6H), 7,60(d,2H), 7,80(d,1 H)
Example 7: 1-ethyl-3-methyl-quinoxalin-2(1W)-one
5,4 g (39,6 mM) of N-ethylbenzene-1 ,2-diamine and 2,76 ml (39,6 mM) of 2- oxopropanoic acid in 200 ml of methanol were refluxed for 8h. The solvent was removed under vacuum. The residue was further purified by silica gel column chromatography, using dichloromethane, followed by dichloromethane/dimethylketone (95/5) as eluant to give 4,2 g of 1-ethyl-3- methyl-quinoxalin-2(1H)-one as a yellow solid. Yield: 56,7%. NMR 1H (300 MHz / DMSO-d6) δ (ppm) : 1 ,24(t,3H), 2,45(s,3H), 4,25(q,2H), 7,34(Hi1I H)1 7,59(0,2H), 7,75(d,1 H)
Example 8: 3-(bromomethyl)-1 -ethyl-quinoxalin-2(1 W)-one
Figure imgf000050_0001
4,2 g (22,3 mM) of 1-ethyl-3-methyl-quinoxalin-2(1 H)-one, 3,97 g (22,3 mM) of N-bromosuccinimide and 53,3 mg of benzoylperoxide in 220 ml of carbon tetrachloride were refluxed for 4h. The reaction mixture was filtered and the solvent was removed under vacuum. The residue was further purified by silica gel column chromatography, using dichloromethane/cyclohexane (70/30) as eluant to give a solid, which was taken up in methylterbutyloxide. After filtration, 2,4 g of 3-(bromomethyl)-1-ethyl-quinoxalin-2(1 H)-one were obtained as a tan solid. Yield: 40,3%.
NMR 1H (300 MHz / DMSO-d6) δ (ppm) : 1 ,26(t,3H), 4,29(q,2H), 4,67(s,2H),
7,42(m,1 H), 7,67(m,2H), 7,85(d,1 H)
Example 9: 1-ethyl-3-{[(4-methylphenyl)thio]methyl}quinoxalin-2(1H)- one
Figure imgf000050_0002
162,7 mg (1 ,3 mM) of 4-methylthiophenol were added to 480,6 μl (1 ,3 mM) of sodium ethylate at 21% in ethanol. The reaction mixture was stirred for 30 min at room temperature, the solvent was then removed under vacuum. 350 mg (1 ,3 mM) of 3-(bromomethyl)-1-ethyl-quinoxalin-2(1 H)-one in 3 ml of acetonitrile were then added and the reaction mixture was maintained under stirring for 2Oh at room temperature. Water was poured and the precipitate was filtered and washed with water to give 370 mg of 1 -ethyl-3-{[(4- methylphenyl)thio]methyl}quinoxalin-2(1H)-one. Yield: 91 %.
NMR 1H (300 MHz / DMSO-d6) δ (ppm) : 1 ,25(t,3H), 2,26(s,3H), 4,29(m,4H), 7,14(171,2H), 7,36(m,3H), 7,β2(m,2H), 7,76(m,1 H) Ci8H18N2OS = 310,41 Mass spectrometry M+1 = 311 ,1
Example 10: 1-ethyl-3-{[(4-methylphenyl)sulfonyl]methyl}quinoxalin- 2(1H)-one
Figure imgf000051_0001
To 280 mg (0,90 mM) of 1-ethyl-3-{[(4-methylphenyl)thio]methyl}quinoxalin- 2(1H)-one and 75,8 mg (0,9OmM) in a mixture of 6 ml of THF/water (50/50) were added portion wise 1 ,1 g (1 ,8 mM) of oxone. The reaction mixture was maintained under stirring for 30 min and water was added. A precipitate was filtrated and washed thoroughly with water, to give, after drying, 154 mg of 1- ethyl-3-{[(4-methylphenyl)sulfonyl]methyl}quinoxalin-2(1 H)-one as a solid. Yield: 50%.
Figure imgf000051_0002
Mass spectrometry M+1 = 343,1
The following compounds were obtained using the same procedure as in Example 10.
Example 10-2: 3-{[(4-chlorophenyl)sulfonyl]methyl}-1 -methyl- quinoxalin-2(1 H)-one
Figure imgf000052_0001
NMR 1H (300 MHz / DMSO-d6) δ (ppm) : 3,62(s,3H), 4,98(s,2H), 7,43(t,1 H), 7,56-7,69(m,3H), 7,72-7,74(clcl,2H), 7,83-7,86(dd,2H) C16H13CIN2O3S = 348,80 Mass spectrometry M+1 = 349,1
Example 10-3: 1 -ethyl-3-{[(4-methoxyphenyl)sulfonyl]methyl}quinoxalin-
2(1H)-one
Figure imgf000052_0002
C18H18N2O4S = 358,41 Mass spectrometry M+1 = 359,0
Example 10-4: 1 -methyl-3-[(phenylsulfonyl)methyl]quinoxalin-2(1 H)-one
Figure imgf000052_0003
C16H14N2O3S = S^1SB Mass spectrometry M+1 = 315,1
Example 10-5: 1 -ethyl-3-[(phenylsulfonyl)methyl]quinoxalin-2(1 H)-one
Figure imgf000053_0001
Ci8H16N2O3S = 328,39 Mass spectrometry M+1 = 329,1
Example 10-6: 3-{[(4-chlorobenzyl)sulfonyl]methyl}-1-ethylquinoxalin- 2(1H)-one
Figure imgf000053_0002
Ci8Hi7CIN2O3S = 376,86 Mass spectrometry M+1 = 377,0
Example 10-7: 3-[(benzylsulfonyl)methyl]-1-ethylquinoxalin-2(1H)-one
Figure imgf000053_0003
Ci8Hi8N2O3S = 342,41 Mass spectrometry M+1 = 343,1
BIOLOGICAL ASSAYS
The INS-1 cells were selected to evaluate compounds of the present invention for their superior response to glucose and other physiological and pharmacological insulin secretagogues.
Culture of pancreatic INS-1 cells INS-1 cells were cultured in complete medium, RPM11640 containing 1mM sodium pyruvate, 50μM 2-mercaptoethanol, 2mM glutamine, 1OmM HEPES, 100IU/ml_ penicillin, and 100μg/mL streptomycin (CM), supplemented with 1OmM 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 and cultured in 48-well plates. After 2 days of culture, the medium was removed and cells were cultured for 24h with a medium change to 5mM glucose, 1 % FCS. The cells were then washed with Krebs- Ringer Bicarbonate HEPES buffer (KRBH; 135mM NaCI; 3,6mM KCI; 5mM NaHCO3; 0,5mM NaH2PO4; 0,5mM MgCI2; 1 ,5mM CaCI2 and 1OmM HEPES; pH 7,4) 0,1 % BSA containing 2,8mM glucose and preincubated for 30 min at 37°C in the same buffer. The cells were then washed twice and incubated for 1h in KRBH 0,1 % BSA containing 4,2mM glucose and different concentrations of the tested molecule. Insulin concentration in the collected supematants was measured with ELISA using rat insulin antibody (Insulin Rat Elit PLUS, cat. ref 10-1145-01). Insulin secretion results are expressed in % of control (glucose 4,2mM).
Insulin secretion in INS-1 cells (glucose at 4,2 mM)
Figure imgf000054_0001
Figure imgf000055_0001
Insulin secretion in diabetic NOSTZ rat islets.
Materials and Methods. Islets isolation and treatments.
14 ± 3 weeks non-fasted NOSTZ (PORTHA et al., 1974) male rats (Charles Rivers-Domaine des Oncins, I'Arbresle, France) were anesthetised with sodium pentobarbital (Nembutal® : 45 mg/kg in 5 ml/kg administered intra peritoneally) and body temperature was maintained with a heat lamp.
Rat pancreatic islets of Langerhans were isolated from the pancreas of 8 rats by collagenase P (Boehringer, Meylan, France) digestion. Islets were purified by sedimentation in Hanks balanced salt solution [NaCI (137mM) ; KCI (5.36 mM) ; MgSO4, 7 H2O (0.81 mM) ; Na2HPO4, 12 H2O (0.34 mM) ; KH2PO4 (0.44 mM) ; CaCI2, 2 H2O (1.26 mM) ; NaHCO3 (4.17 mM)] followed by Ficoll gradient separation. Islets were then hand-picked under stereoscopic microscope and batches of 3 islets were incubated for 90 minutes at 37°C with continuous shaking under a humidified condition (95% O2, 5% CO2) in 1 ml of Krebs/Hepes pH 7 solution [NaCI (115 mM), NaHCO3 (24 mM), KCI (5 mM), MgCI2 (1 mM), CaCI2, 2 H2O (1mM), 0.2 % of Bovine serum albumin (Fraction V, fatty acid free, Boehringer, Mannheim), 10 mM Hepes] containing the required glucose or compound concentration. Compounds were dissolved in DMSO at 2.10- 2M stock solutions. They were then diluted at the required concentration in Krebs/Hepes buffer containing the required glucose concentration. At the end of incubation, media was collected and insulin levels were measured using ELISA (EUROBIO, Courtaboeuf, France).
GLUCOSE 2.8 MM GLUCOSE 8 MM
EXAMPLE (M) 0 10-4 0 10-7 10-6 10-5 10-4
6 100 ± 13 94 ± 17 100 ± 9 126 ± 9 124± 8 226 ± 12 413 ±7 6-3 100 ± 13 114 + 17 100 ±9 133 ± 8 135 ± 11 168 ± 9 440 ± 8
Table - Dose response effect of compounds on insulin secretion in diabetic NOSTZ rat islets.
Islets were hand-picked and incubated in the presence of increasing concentrations of compounds in the presence of glucose at 2.8 or 8 mM. At the end of incubation, media was collected and insulin levels were measured using ELISA method. Results are expressed as % of glucose control (2.8 or 8 mM) and represent Means ± SEM.
In islets isolated from NOSTZ diabetic rats, the compounds showed no effect in the presence of a low, non-stimulatory, glucose concentration (2.8 mM), even at high concentration (10"4 M), while they potentiated insulin secretion in response to 8 mM glucose, a stimulatory glucose concentration. These results show that the effect of the compounds on the insulin secretion is dependent on the glucose level and suggest that a treatment with these compounds should avoid hypoglycemic risk

Claims

Claims
1. A compound of the general formula (I)
Figure imgf000057_0001
10 O wherein: R1 is: hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyloxyalkyl, R7R8N-alkyl, -J5 alkylthioalkyl; heterocycloalkyl and heteroaryl groups can include one or more heteroatom selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z; 0 R6 is: alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, arylalkylthioalkyl, arylalkylsulfinylalkyl, arylalkylsulfonylalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, 5 heteroarylsulfinylalkyl, heteroaryisulfonylalkyl, heteroarylalkylthioalkyl, heteroarylalkylsulfinylalkyl, heteroarylalkylsulfonylalkyl, heterocycloalkylalkyl, heterocycloalkyloxyalkyl, heterocycloalkylalkyloxyalkyl, heterocycloalkylthioalkyl, heterocycloalkylsulfinylalkyl, heterocycloalkylsulfonylalkyl, heterocycloalkylalkylthioalkyl, 0 heterocycloalkylalkylsulfinylalkyl, heterocycloalkylalkylsulfonylalkyl; heteroaryl or heterocycloalkyl groups can include one or more heteroatoms selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z;
R2, R3, R4, R5 are independently selected from hydrogen, Y or Z;
Y is: alkyl, cycloalkyl, heterocycloalkyl, alkoxy, heteroaryl, aryl, alkylsulfonyl, aryloxy, arylalkoxy, alkylsulfinyl, alkylthio; heteroaryl or heterocycloalkyl groups can include one or more heteroatom selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Z;
Z is: hydroxy, thio, halogen, cyano, trifluoromethoxy, trifluoromethyl, carboxy, carboxy methyle, carboxyethyle, alkyle, cycloalkyl, alkoxy, NR7R8, azido, nitro, guanidino, amidino, phosphono, oxo, alkylthio, alkylsulfonyl, SF5, two Y groups can form a methylenedioxy;
R7 and R8 are independently selected from:
- hydrogen;
- lower alkyl, cycloalkyl;
R7 and R8 can also constitute a heterocycloakyl group, which can include one or more heteroatoms selected from N1 O and S; R7 and R8 independently can be optionally substituted by one or more substituents selected from Z;
as well as its racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and the pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 , wherein R1 is: alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkyloxyalkyl, R7R8N- alkyl, alkylthioalkyl; heterocycloalkyl groups can include one or more heteroatom selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z1 as defined in claim
1.
3. A compound according to claim 2, wherein R1 is: alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkyloxyalkyl, R7R8N- alkyl; heterocycloalkyl groups can include one or more heteroatom selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z, as defined in claim 1.
4. A compound according to claim 3, wherein R1 is: methyl, ethyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl, butyl, cyclopropyl, cyclopropylmethyl; each of these groups can be optionally substituted by one or more groups selected from Y or Z, as defined in claim 1.
5. A compound according to claim 1 , wherein R6 is: alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylthioalkyl, arylsulfonylalkyl, aryloxyalkyl, arylalkyloxyalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heterocycloalkylalkyl, heterocycloalkyloxyalkyl; heteroaryl or heterocycloalkyl groups can include one or more heteroatoms selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z;
6. A compound according to claim 5, wherein R6 is: alkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, arylthioalkyl, arylsulfonylalkyl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; heteroaryl or heterocycloalkyl groups can include one or more heteroatoms selected from N, O and S; each of these groups can be optionally substituted by one or more groups selected from Y or Z, as defined in claim 1.
7. A compound according to claim 6, wherein R6 is: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, benzyl, furanyl, pyridinyl, pyrimidinyl, pyrazolyl, phenylthiomethyl, phenylsulphonylmethyl; each of these groups can be optionally substituted by one or more groups selected from Y or Z, as defined in claim 1.
8. A compound according to claims 1 to 7, wherein Y is: alkyl, cycloalkyl, alkoxy, aryl, alkylsulfonyl, aryloxy, arylalkoxy, alkylsulfinyl, alkylthio; each of these groups can be optionally substituted by one or more groups selected from Z, as defined in claim 1.
9. A compound according to claims 1 to 7, wherein R1 , R2, R3, R4, R5 and R6 can be optionally substituted by one or more groups selected from Z.
10. A compound according to claim 1 , wherein Z is: halogen, trifluoromethyl, carboxy, alkoxy, alkylthio, alkylsulfonyl.
11. A compound according to any of the preceding claims, selected from the following compounds:
1-(2,2-difluoroethyl)-3-phenyl-quinoxalin-2(1/-/)-one
3-(4-chlorophenyl)-1-(2,2-difluoroethyl)quinoxalin-2(1H)-one
3-(4-chlorophenyl)-1 -cyclopropyl-quinoxalin-2( 1 H)-one
1-butyl-3-(4-fluorophenyl)quinoxalin-2(1H)-one 3-(4-fluorophenyl)-1 -(2,2,2-trifluoroethyl)quinoxalin-2(1 H)-one
1 ,3-diethyl-5-fluoro-quinoxalin-2(1 H)-one
1-ethyl-7-methyl-3-propyl-quinoxalin-2(1H)-one
1-ethyl-3-butyl-quinoxalin-2(1H)-one
1-ethyl-6,7-difluoro-3-(4-fluorophenyl)quinoxalin-2(1H)-one 1-ethyl-6,7-difluoro-3-(4-chlorophenyl)quinoxalin-2(1/-/)-one
1-cyclopropyl-3-phenylquinoxalin-2(1/-/)-one
1-ethyl-3-furan-2-yl-quinoxalin-2(1H)-one 1 -ethyl-5-fluoro-3-(4-fluorophenyl)quinoxalin-2(1 H)-one
1 -cyclopropyl-3-(4-fluorophenyl)quinoxalin-2(1 H)-one
1-butyl-3-(4-chlorophenyl)quinoxalin-2(1H)-one
1-butyl-3-phenyl-quinoxalin-2(1/-/)-one 3-(4-chlorobenzyl)-1 -ethyl-quinoxalin-2(1 H)-one
3-(4-chlorophenyl)-1-(2,2,2-trifluoroethyl)quinoxalin-2(1H)-one
3-phenyl-1 -(2,2,2-trifluoroethyl)quinoxalin-2(1 H)-one
1-(2,2,2-trifluoroethyl)-3-(4-trifluoronnethylphenyl)quinoxalin-2(1/-/)-one
1-cyclopropylmethyl-3-ethyl-quinoxalin-2(1H)-one 1 -ethyl-3-isopropyl-7-methyl-quinoxalin-2(1 H)-one
1 -ethyl-5-fluoro-3-isobutyl-quinoxalin-2( 1 H)-one
1 ,3-diethyl-6,7-difluoro-quinoxalin-2(1 /-/)-one
1 -(2,2-difiuoroethyl)-3-ethylquinoxalin-2(1 H)-one
1 ,3-diethyl-5-fluoroquinoxalin-2(1 H)-one 1 ,3-diethyl-7-methylquinoxalin-2(1 H)-one
1 -ethyl-5-f luoro-3-propylquinoxalin-2( 1 H)-one
1-butyl-3-ethylquinoxalin-2(1H)-one
3-butyl-1 -ethylquinoxalin-2(1 H)-one
1-ethyl-3-isobutyl-7-methylquinoxalin-2(1H)-one 1 -cyclopropyl-3-propylquinoxalin-2(1 H)-one
1-cyclopropyl-3-ethylquinoxalin-2(1H)-one
1 ,3-diethyl-quinoxalin-2(1H)-one
1 -(2,2-difluoroethyl)-3-(4-fluorophenyl)quinoxalin-2(1 H)-one
3-(4-chlorophenyl)-1 -ethyl-5-f luoroquinoxalin-2( 1 H)-one 3-(4-chlorophenyl)-1 -ethyl-quinoxalin-2(1 H)-one
3-(2-chlorophenyl)-1-ethyl-quinoxalin-2(1H)-one
1 -ethyl-3-(4-f luorophenyl)quinoxalin-2( 1 H)-one
1 -ethyl-3-(4-methylphenyl)quinoxalin-2(1 H)-one
1-ethyl-3-(4-fluoro-2-methylphenyl)quinoxalin-2(1H)-one 1-ethyl-3-(4-chloro-2-methylphenyl)quinoxalin-2(1 H)-one
1 -ethyl-3-(4-trifluoromethylphenyl)quinoxalin-2( 1 H)-one
1 -ethyl-3-(4-methanesulfonyl-phenyl)quinoxalin-2( 1 H)-one 3-(2,4-dimethoxy-pyrimidin-5-yl)-1-ethyl-quinoxalin-2(1H)-one 1-ethyl-3-(4-ethylphenyl)quinoxalin-2(1H)-one 1-ethyl-3-furan-3-yl-quinoxalin-2(1H)-one 3-(3,4-dimethoxyphenyl)-1 -ethyl-quinoxalin-2( 1 H)-one 4-(4-ethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-benzoic acid
1-ethyl-3-(1 -methyl- 1 H-pyrazol-4-yl)quinoxalin-2(1 H)-one 3-(3-chlorophenyl)-1-ethyl-quinoxalin-2(1/-/)-one
1 -ethyl-3-pyridin-3-yl-quinoxalin-2( 1 H)-one 3-(2,5-difluorophenyl)-1 -ethyl-quinoxalin-2(1 H)-one
1 -ethyl-3-( 1 H-indol-6-yl)quinoxalin-2( 1 H)-one
1 -ethyl-3-( 1 H-indol-5-yl)quinoxalin-2( 1 H)-one
1-ethyl-3-(4-methylbenzyl)quinoxalin-2(1/-/)-one
1-ethyl-3-(4-morpholin-4-ylphenyl)quinoxalin-2(1H)-one 3-(2,3-dihydro-1 ,4-benzodioxin-6-yl)-1-ethylquinoxalin-2(1 H)-one
3-(1 ,3-benzodioxol-5-yl)-1-ethylquinoxalin-2(1/-/)-one
1 -ethyl-3-benzylquinoxalin-2(1 H)-one
1 -ethyl-3-{[(4-methylphenyl)thio]methyl}quinoxalin-2(1 H)-one
1 -ethyl-3-{[(4-methylphenyl)sulfonyl]methyl}quinoxalin-2( 1 H)-one 3-{[(4-chlorophenyl)sulfonyl]methyl}-1 -methyl-quinoxalin-2(1 H)-one
1-ethyl-3-{[(4-methoxyphenyl)sulfonyl]methyl}quinoxalin-2(1H)-one
1 -methyl-3-[(phenylsulfonyl)methyl]quinoxalin-2(1 H)-one
1 -ethyl-3-[(phenylsulfonyl)methyl]quinoxalin-2(1 H)-one
3-{[(4-chlorobenzyl)sulfonyl]methyl}-1-ethylquinoxalin-2(1H)-one 3-[(benzylsulfonyl)methyl]-1-ethylquinoxalin-2(1H)-one as well as its racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and the pharmaceutically acceptable salts thereof.
12. A compound according to claim 11 , selected from the following compounds: 1-Butyl-3-ethyl-quinoxalin-2(1H)-one 1-Cyclopropyl-3-phenylquinoxalin-2(1/-/)-one
1-Ethyl-3-(4-fluoro-2-methylphenyl)quinoxalin-2(1H)-one
1 -Ethyl-3-(4-f luorophenyl)quinoxalin-2( 1 /-/)-one
1 -Ethyl-3-(4-methylphenyl)quinoxalin-2( 1 /-/)-one
1 -Ethyl-3-(4-trifluoromethylphenyl)quinoxalin-2(1 /-/)-one
3-(4-Chlorophenyl)-1 -(2,2-difluoroethyl)quinoxalin-2( 1 H)-one
3-(4-Chlorophenyl)-1-ethyl-quinoxalin-2(1H)-one
1-ethyl-3-(4-chloro-2-methylphenyl)quinoxalin-2(1/-/)-one as well as its racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and the pharmaceutically acceptable salts thereof.
13. Process for the preparation of the compounds of general formula (I) according to any one of the preceding claims, the process comprising: a)reacting a compound of formula (1 )
Figure imgf000063_0001
R5
(1 ) wherein:
R2, R3, R4, R5 are as defined in claim 1 ;
Hal is a halogen atom, preferably Cl, Br; with an amine RI-NH2, wherein R1 is as defined in claim 1 , in the presence of of a base, in an inert solvent, to give a compound of formula (2)
R2 Rl
Figure imgf000063_0002
(2) b)reducing the compound of formula (2) with a metal, such as Zn, Sn or Fe, or metal in lower state of oxidation, such as Sn(ll)chloride, in acids; or by catalytic hydrogenation with metal catalysts, such as Pd, Pt, Ni, preferably Pd on charcoal or Raney Nickel, in solvents, to obtain a compound of formula (3)
Figure imgf000064_0001
R5 <3> wherein: R1 , R2, R3, R4 and R5 are as above defined; c) reacting the compound of formula (3) with an α- keto acid derivative of the following formula
Figure imgf000064_0002
wherein:
R6 is as defined in claim 1 ;
Rx is Hal, as above defined, or ORe, wherein Re is hydrogen, lower alkyl; in a solvent, to obtain a compound of formula (I).
14. Process for the preparation of the compounds of general formula (I) according to any one of the preceding claims, the process comprising: a)reacting a compound of formula (1 )
Figure imgf000064_0003
R5
(D wherein:
R2, R3, R4, R5 are as defined in claim 1 ; Hal is a halogen atom, preferably Cl, Br; with an amine RI-NH2, wherein R1 is as defined in claim 1 , in the presence of of a base, in an inert solvent, to give a compound of formula (2)
R2 Rl
Figure imgf000065_0001
(2) d)reducing the compound of formula (2) with a metal, such as Zn, Sn or Fe, or metal in lower state of oxidation, such as Sn(ll)chloride, in acids; or by catalytic hydrogenation with metal catalysts, such as Pd, Pt, Ni, preferably Pd on charcoal or Raney Nickel, in solvents, to obtain a compound of formula (3)
Figure imgf000065_0002
(3) wherein: R1 , R2, R3, R4 and R5 are as above defined; e)reacting the compound of formula (3) with a compound of the following formula
Figure imgf000065_0003
wherein Rx is defined as above, in the presence of a base, in a inert solvent to obtain the compound of formula (5);
Figure imgf000066_0001
R5
(5) wherein: R1 , R2, R3, R4 and R5 are as above, defined; f) reacting the compound of formula (5) with a brominating agent, such as
P0Br3, in an inert solvent, to give the compound of formula (6)
Figure imgf000066_0002
(6) wherein: R1 , R2, R3, R4 and R5 are as above defined; g) reacting the compound of formula (6) with boronic acid derivatives or their esters, in the presence of a base and a catalyst, such as bis(triphenylphosphine) palladium(ll)chloride, in an inert solvent, to obtain a compound of formula (I).
15. A compound of general formula (I) wherein R1 , R2, R3, R4, R5 and R6 are as defined in claim 1 , as well as its racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and the pharmaceutically acceptable salts thereof, for the preparation of a medicament for the prevention and/or treatment of pathologies associated with hyperglycaemia.
16. A compound according to claim 15, for the preparation of a medicament that induces insulin secretion in response of glucose concentration.
17. A compound according to claims 15 or 16, for the preparation of a medicament suitable for the treatment of diabetes.
18. A compound according to claim 17, for the preparation of a medicament suitable for the treatment of type Il diabetes.
19. A compound according to claims 15 or 16, for the preparation of a medicament suitable for the treatment of diseases chosen from dyslipidaemia and obesity
20. A compound according to claims 15 to 18, for the preparation of a medicament suitable for the treatment of diseases chosen from diabetes related microvascular and macrovascular complications.
21. A compound according to claim 20, for which the said complications include arterial hypertension, atherosclerosis, inflammatory processes, microangiopathy, macroangiopathy, retinopathy and neuropathy.
22. A compound according to claim 15, for the preparation of a medicament suitable for reducing hyperglycaemia.
23. Use of a compound of general formula (I) according to any one of claims 1 to 12, wherein R1 , R2, R3, R4, R5 and R6 are as defined in claim 1 , as well as its racemic forms, tautomers, enantiomers, diastereomers, epimers and polymorphs, and mixtures thereof, and the pharmaceutically acceptable salts thereof, for the preparation of a medicament, for the prevention and/or treatment of pathologies associated with hyperglycaemia.
24. A pharmaceutical composition containing at least a compound of general formula (I) according to claims 1 to 12 and a pharmaceutically acceptable excipient.
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