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  • 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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  • 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
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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
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • 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
  • A61P3/08—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
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  • 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
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
  • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
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  • 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
  • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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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
  • C07D401/10—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 linked by a carbon chain containing aromatic rings
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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
  • C07D401/12—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 linked by a chain containing hetero atoms as chain links
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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
  • C07D401/14—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 three or more hetero rings
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  • 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
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  • 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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  • 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
  • C07D403/12—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 chain containing hetero atoms as chain links
• • 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
  • C07D405/04—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
  • C07D405/06—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 only aliphatic carbon atoms
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  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • 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
  • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
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  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems

Definitions

• the present invention relates to new compounds derived from thiohydantoin (or 2-thioxo-4-imidazolidinone), their manufacturing process and their use as active principles for the preparation of medicaments intended in particular for the treatment of diabetes.
• WO 98/33776 cites a library of compounds obtained by combinatorial chemistry and tested for their antimicrobial or analgesic properties.
• WO 93/18057 and EP 584694 describe acids or esters comprising a 2-thiohydantoin ring which are inhibitors of platelet aggregation. Preparations of compounds comprising the 2-thiohydantoin ring without indicating industrial utility have also been described for example in J. Prakt. Chem., Vol 333 (2), p 261-266, Indian J. Chem (1974), vol 12, n ° 6, p 577-579, Chem. Abstr 68 (1968), 87240d and Organic Magn. Resonnance, vol 19, (1) p 27-30. Subject of the invention
• the present invention relates to new compounds comprising in their structure the heterocycle 2-thiohydantoin (or 2-thioxo-4-imidazolidinone) as well as their preparation process and their use in therapy, in particular for the preparation of a medicament intended for the treatment diabetes, diseases due to hyperglycemia, hypertriglyceridemias, dyslipidemias or obesity. Description
• Ri represents an aromatic ring which is unsubstituted or substituted by one or more atoms or groups of atoms chosen from halogens, linear or branched C 1 -C 4 alkoxy groups, linear, branched or cyclic C 4 alkyl, C 1 -C 4 linear or branched, nitro, trifluoromethyl, trifluoromethoxy, methylenedioxy or
• R 2 represents a hydrogen atom, a linear, branched or cyclic C 1 -C 7 alkyl group, optionally interrupted by one or more oxygen atoms, a C 3 haloalkyl group, a C 3 alkenyl group - C 5 , linear or branched, a C 3 -C 4 alkynyl group, linear or branched, a C 2 -C 6 hydroxyalkyl group, a C 2 -C 4 aminoalkyl group, a C 2 -C 3 cyanoalkyl group , a linear or branched CpC 3 alkyl group, substituted by one or more substituents
• R or an aromatic ring unsubstituted or substituted by one or more atoms or groups of atoms chosen from halogens, alkoxy groups Cj-C 4 linear or branched, alkyl C 4 linear, branched or cyclic, alkylthio Cj-C 4 linear or branched, amino, cyano, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, methylenedioxy, ethylenedioxy, difluoromethylenedioxy, aminosulfonyl, dimethylamino, Cj-hydroxyalkyl, C 2 -C 3 -alkyl ester, methanesulfonylamino t- butoxycarbonylamino, or
• R 3 , R 5 and R ⁇ each independently represent a hydrogen atom or a C- alkyl group . -,
• R4 represents a hydrogen atom, a -G- * alkyl group or a hydroxy group, or,
• R 3 and R 4 together form a methylene group, or
• R 5 and R ⁇ together form an ethylene group -CH 2 -CH 2 -
• R 7 represents a carboxylic acid group which is free or esterified by a C * alkyl group .
• a phenyl ring which is unsubstituted or substituted by one or more methoxy, phenyl or methylenedioxy groups, a 2-furyl ring, a 2-, 3- or 4-pyridinyl ring or a 4-morpholinyl group
• m 2 or 3
• X represents an oxygen atom, a sulfur atom, a sulfoxide group, a sulfonyl group, a carbonyl group, a group
• R 8 represents a hydrogen atom, a hydroxy group, a C 2 -C hydroxyalkyl group, a benzoyl group or a CO 2 CH 3 group ,
• R 9 represents a hydrogen atom or forms, with Rg an ethylenedioxy group
• Rio represents a methyl group, a hydroxy C 2 -C 4, 1- oxoalkyl, C 2 -C, SO 2 N (CH 3) 2 group, a 2-pyridinyl or 2-pyrimidinyl group, provided that at least one of the substituents Ri and R 2 represents an aromatic ring substituted at least by a group
• the invention also includes, when the substituents R 3 and R 4 are different, the compounds of configuration R, the compounds of configuration S and their mixtures.
• the invention also relates to the compounds of formula I or their addition salts with a pharmaceutically acceptable acid for their use as an active pharmacological substance.
• the invention relates to the use of at least one compound according to formula I above as an active principle for the preparation of a medicament intended for use in therapy, in particular for combating diseases due to hyperglycemia, diabetes, hypertriglyceridemia, dyslipidemia or obesity.
• C 1 -C 4 alkyl group includes a saturated hydrocarbon chain having from 1 to 4 carbon atoms, linear, branched or alternatively cyclic.
• Examples of C ⁇ -C 4 alkyl groups include methyl, ethyl, propyl, butyl, 1-methylethyl, cyclopropyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl groups.
• the term “C” alkyl group is understood to mean .
• -C optionally interrupted by one or more oxygen atoms, a saturated hydrocarbon chain, linear, branched or comprising a ring, having from 1 to 7 carbon atoms, said chain being capable of comprising one or more non-consecutive oxygen atoms between 2 carbon atoms.
• CrC alkyl groups optionally interrupted by one or more oxygen atoms include the groups mentioned above as well as, in particular, the pentyl, hexyl, heptyl, 1-methylethyl, cyclohexyl, cyclohexylmethyl, methylcyclohexyl, methoxyethyl, ethoxyethyl, ethoxyethoxyethyl groups or tetrahydropyranyleoxyalkyle.
• C * * haloalkyl group means a C 1 -C 3 alkyl group carrying at least one halogen atom chosen from fluorine, chlorine or bromine, preferably fluorine, for example a trifluoromethyl group. or 2,2,2-trifluoroethyl.
• linear or branched C r C 4 alkoxy group is meant the methoxy, ethoxy, propoxy, butoxy or 1-methylethoxy groups.
• C 3 -C 5 alkenyl group is meant a chain, linear or branched, comprising in its structure a double bond between 2 carbons.
• C 3 -C 4 alkynyl group means a chain, linear or branched, comprising in its structure a triple bond between 2 carbons.
• C 2 -C 6 hydroxyalkyl group is meant an alkyl group having 2 to 6 carbon atoms substituted by a hydroxyl group.
• Examples of C 2 -C 6 hydroxyalkyl groups include 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, or 6-hydroxyhexyl.
• C 2 -C 4 aminoalkyl group is meant an alkyl group having 2 to 4 carbon atoms, substituted by an amino group NH 2 , said amino group being capable of being protected by a group of atoms known from l a person skilled in the art, for example an alkylsulfonyl group or a t-butoxycarbonyl group (Boc).
• C 2 -C 3 cyanoalkyl group is meant an alkyl group comprising one or two carbon atoms, substituted by a cyano group.
• aromatic rings are phenyl, 2- or 3-thienyl, 2- or 3-furyl 2-, 3- or 4-pyridinyl, 1- or 2-naphthyl, indolyl, 1-H-imidazolyl, 1- H- benzimidazolyl, benzotriazolyl, 1,3-dihydro-2-oxo-benzimidazolyl, 1,3-dihydro-2-oxo indolyl, 2H-2-oxo-benzopyranyl, 2H-4H-3-oxo-l, 4- benzoxazinyl.
• Halogen includes fluorine, chlorine or bromine, the preferred halogen atoms in the compounds of formula I according to the invention being fluorine and chlorine.
• the compounds of formula I carrying an amine function by the presence of a nitrogenous heterocycle or by the presence of an amino substituent can be salified by reaction with a non-toxic and therapeutically acceptable acid.
• these acids one can choose mineral acids such as hydrochloric, hydrobromic, phosphoric and sulfuric acids, or organic acids such as methanesulfonic, benzenesulfonic, citric, maleic, fumaric, oxalic, lactic, tartaric or trifluoroacetic acids.
• a preferred family of the compounds of formula (I) of the invention comprises: a) the compounds of formula
• R ! represents a phenyl ring optionally substituted by one or more atoms or groups of atoms chosen from halogens, linear -C 4 alkyl groups or
• R 2 represents a Cj alkyl group . -C 7 linear, branched or cyclic, a linear C 3 -C 5 alkenyl group, or a phenyl, 2-thienyl or 3-pyridinyl ring optionally substituted by one or more atoms or groups of atoms chosen from halogens, alkoxy groups -C 4 linear or branched alkyl linear CpC 4 alkylthio, C1-C4 linear, amino, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, methylenedioxy or
• R 4 represents a hydrogen atom, a linear alkyl group or a hydroxy group
• R 3 , R 5 , and R ⁇ each independently represent a hydrogen atom or a linear C 1 -C alkyl group
• X represents an oxygen atom, a sulfoxide group or a carbon atom substituted by a hydroxyalkyl group.
• C- . -C 2 provided that at least one of the substituents Ri and R 2 represents an aromatic ring substituted at least by one group b) the addition salts of compounds of formula I with an acid, in particular the pharmaceutically acceptable salts.
• Rj represents a phenyl group substituted at least in the para position by a group
• the compounds of formula I can be prepared according to a first general process A consisting in:
• Ri represents an unsubstituted aromatic ring or substituted by one or more atoms or groups of atoms selected from halogen, alkoxy C 1 -C 4 linear or branched C 1 -C 4 linear, branched or cyclic alkylthio in linear or branched -C 4 , nitro, trifiuoromethyl, trifluoromethoxy, methylenedioxy or
• n 2 or 3
• X represents an oxygen atom, a sulfur atom, a sulfoxide group, a sulfonyl group, a carbonyl group, a group or a group
• R 3 , R4, R 5 and R ⁇ each independently represent a hydrogen atom or an alkyl group at -,
• Rg represents a hydrogen atom, a hydroxy group, a C ⁇ -C 2 hydroxyalkyl group, a benzoyl group or a CO 2 CH 3 group ,
• R 9 represents a hydrogen atom or forms, with R ethylenedioxy, Rio represents a methyl group, a hydroxy C 2 -C 4 1-oxoalkyl, C 2 -C 4 alkyl, SO 2 N (CH 3 ) 2 , a 2-pyridinyl group or a 2-pyrimidinyl group,
• R 2 represents: a linear, branched or cyclic C ⁇ -C 7 alkyl group, optionally interrupted by one or more oxygen atoms, a haloalkyl group -C 3 , a C 3 -C 5 alkenyl group, linear or branched, a C 3 -C alkynyl group, linear or branched, a C -C 6 hydroxyalkyl group, a C 2 -C protected aminoalkyl group 4, a cyanoalkyl group, C 2 -C 3 alkyl, C 1 -C 3, linear or branched, optionally substituted by one or more substituents R 7, or an unsubstituted aromatic ring or substituted by one or more atoms or groups atoms chosen from halogens, linear or branched C1-C 4 alkoxy groups, linear, branched or cyclic C ⁇ -C 4 alkyl,
• Ri, R 2 , R 3 , R 4 retain the same meaning as above, it being understood that at least one of the groups Ri and R 2 contains in its structure an aromatic ring substituted at least by the group
• Ri, R 2 , R 3 , R 4 retain the same meaning as above, it being understood that at least one of the groups Ri and R 2 contains in its structure an aromatic ring substituted at least by the group
• stage 1) of process E described above the compounds of formula Ha can be reacted according to a process F consisting in intimately mixing the 2 compounds 11a and in, without solvent, and in bringing the mixture to a temperature of about 110 to 130 ° C, for 0.5 to 3 hours, to obtain the compound of formula I in which Ri, R 2 , R 3 and R 4 retain the same meaning as in the starting materials.
• the compounds of formula Ha and m can be reacted according to a method consisting in intimately mixing the compounds Ha and m in a tube or a reactor in PTFE in the presence of a small amount of acetic acid and heat the mixture for 1 to 15 minutes by means of microwave radiation, to obtain the compound of formula I in which Ri, R 2 , R 3 and ⁇ retain the same meaning as in the starting materials.
• the compounds of formula U can be obtained by reaction of an amine of formula
• the compounds of formula I in which R4 represents a hydroxy group can be obtained from the compounds of formula (I) in which R 4 is a hydrogen atom, by controlled oxidation by means of air oxygen in a solvent such as, for example, dimethyl sulfoxide (DMSO).
• DMSO dimethyl sulfoxide
• the compounds of formula I in which one of the groups R 1 or R 2 comprises a primary or secondary amino substituent can be obtained according to a process analogous to the processes A and E described above, using starting compounds carrying the amino group protected by an amino-protecting group such as for example the Boc group (t-butyloxycarbonyl), said protecting group being eliminated by means known to those skilled in the art after obtaining the cyclized compound of central structure 2-thioxo-4 - imidazolidinone.
• an amino-protecting group such as for example the Boc group (t-butyloxycarbonyl)
• the compounds according to the invention contain one or more carbon atoms having an asymmetry.
• the compound is a racemic compound, that is to say containing the R and S isomers in substantially equal amounts.
• the R or S configuration is indicated in correspondence with the position of the introducing substituent of the asymmetric center.
• a solution of 100 g (0.56 M) of 4- (4-morpholinyl) aniline in 3 l of absolute ethanol is prepared and 69 g (0.84 M) of sodium acetate are added, then 109 ml ( 0.84 M) of ethyl 2-bromopropionate.
• the reaction mixture is then stirred for 16 hours at reflux of the solvent. After cooling, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in 1.5 l of ethyl acetate and the solution obtained is washed with an aqueous solution of sodium chloride. The organic phase is dried over magnesium sulfate, then concentrated under reduced pressure.
• a solution of 3.46 g (19.5 mM) of 3- (trifluoromethoxy) aniline in 150 ml of dimethylformamide is prepared and the mixture is cooled to 0 ° C.
• a solution of 3.83 g (21.45 mM) of thiocarbonyldiimidazole dissolved in 60 ml of dimethylformamide is then added dropwise.
• the reaction mixture is stirred at ordinary temperature for 1 hour 30 minutes, then poured into 300 ml of water, extracted with twice 100 ml of ethyl ether. These organic phases are washed with twice 50 ml of water, dried over magnesium sulfate and then concentrated under reduced pressure.
• N- [3,5-dichloro-4- (4-morpholinyl) phenyl] alanine A mixture of 1.66 g (6J2 mM) of 3,5-dichloro-4- (4- mo holinyl) aniline is prepared, 2 g (23.5 mM) sodium bicarbonate and 1.25 ml (13.44 mM) 2-bromopropanoic acid and the reaction mixture is stirred at 100 ° C for 4 hours.
• the mixture is then cooled and then taken up in 60 ml of ethyl acetate and 40 ml of water, then brought to slightly acidic pH using a solution N of hydrochloric acid.
• the separated aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with a solution of sodium chloride then dried over magnesium sulfate and concentrated under reduced pressure.
• the crude product thus obtained is used without additional purification for the following syntheses.
• a solution of 0.13 g (1.36 mM) of the urea / hydrogen peroxide addition compound in 4 ml of methanol is prepared and 0.05 g (0.34 mM) of phthalic anhydride is added, then 0.2 g (0.68 mM) of the ester obtained according to the XIN preparation.
• the reaction mixture is stirred for 1 hour 30 minutes at room temperature, then poured into 50 ml of water.
• the mixture is extracted with 2 times 50 ml of ethyl acetate then the combined organic phases are washed with water and then dried over magnesium sulfate and concentrated under reduced pressure.
• Example 7 3- (4-chlorophenyl) -5-methyl-1- [4- (4-morpholinyl) phenyl] -2-thioxo-4-imidazolidinone 0.6 g (2 mM) of the acid obtained is dissolved according to preparation II in 5 ml of dichloromethane and 0.1 g of triethylamine and 0.68 g (4 mM) of isothiocyanate are added
• Example 8 3- (3-chlorophenyl) -5-methyl-1- [4- (4-morpholinyl) phenyl] -2-thioxo-4-imidazolidinone
• Example 12 3- (2-fluorophenyl) -5-methyl-1- [4- (4-morpholinyl) phenyl] -2-thioxo-4-imidazolidinone
• isothiocyanate of 2-fluorophenyl the expected product is obtained in the form of yellow crystals (yield***** 58%).
• Example 35 1- [4- (2S, 6S-dimethyl-4-morpholinyl) phenyl] -5-methyl-3-phenyl-2-thioxo-4-imidazolidinone
• the expected product is obtained in the form of a white powder
• a solution of 1.7 g (4.3 mM) of the compound obtained according to Example 2 in 85 ml of dimethyl sulfoxide is prepared and 8.5 ml of water is added.
• the reaction mixture is kept for 22 hours at 100 ° C., with the introduction of compressed air.
• the solution is then cooled, poured into 850 ml of water and the mixture obtained is extracted several times with ethyl acetate.
• the combined organic phases are washed with a sodium chloride solution and then dried over magnesium sulfate and concentrated under reduced pressure.
• the residue is purified by chromatography on silica gel, eluting with the aid of a dichloromethane / ethyl ether mixture (90/10; v / v).
• HC1 means hydrochloride
• HBr means hydrobromide
• Ms means methanesulfonate
• Tfa means trifluoroacetate.
• a solution of 0.3 g (1.27 mM) of 2,6-dimethyl-4- (4-morpholinyl) nitrobenzene in 15 ml of ethanol is prepared in a Parr flask.
• 0.217 g (1.27 mM) of sodium sulfate, 0.56 ml (1.27 mM) of ethyl pyruvate and finally 30 mg of 10% palladium on carbon are added successively and under a nitrogen atmosphere.
• the mixture obtained is hydrogenated with stirring and under a pressure of 3400 hPa at room temperature for 5 h.
• the reaction mixture is then filtered and the filtrate is concentrated under reduced pressure.
• the evaporation residue is purified by chromatography on silica gel, eluting with the aid of a hexane mixture (ethyl acetate (80/20; v / v).
• the expected product is obtained in the form of an oil yellow (yield: 57%).
• a solution of 1 g (5.6 mM) of thiocarbonyldiimidazole in 20 ml of dichloromethane is prepared and a solution of 1 g (5.6 mM) of 4- (4-morpholinyl) aniline in 10 ml is added dropwise. dichloromethane. The reaction mixture is then stirred for 1 hour at room temperature. 1.09 g (5.6 mM) of N- (4-methoxyphenyl) alanine in 10 ml of dichloromethane are then added and then 0.18 ml (5.6 mM) of triethylamine. The reaction mixture is stirred for 4 h and then concentrated under reduced pressure.
• the evaporation residue is purified by chromatography on silica gel, eluting with the aid of a dichloromethane / ethyl acetate mixture (90/10; v / v).
• the expected product is obtained in the form of white crystals (yield: 54%).
• the animals are housed in cages with a filter cover and have free access to irradiated standard food as well as filtered drinking water. All the equipment used (cages, bottles, pipettes and shavings) is sterilized by autoclaving, irradiation or soaking in a disinfectant. The room temperature is maintained at 23 ⁇ 2 ° C. The light and dark cycle is 12 hours.
• each animal is marked using an electronic chip, the implantation of which is carried out under anesthesia by inhalation of a CO 2 / O 2 mixture.
• mice Groups of 10 mice are formed and the treatments begin when the animals are 10 to 11 weeks old.
• the products are suspended in 3% gum arabic and administered to the animals using a gavage cannula, for 10 days at the rate of two administrations per day, as well as in the morning of the eleventh day.
• the products are tested in doses below 200 mg / kg.
• the animals in the control group receive the administration vehicle only.
• a blood sample is taken before treatment, then three hours after the last administration of the product.
• the animals are anesthetized by inhalation of a CO 2 / O 2 mixture, the blood is taken from the retro-orbital sinus, collected in a dry tube and kept cold.
• the serum is separated by centrifugation at 2800 g (15 minutes,
• the serum glucose and triglyceride levels are determined on a Konélab 30 analyzer, using Konélab kits. Animals with a pre-treatment blood glucose lower than 3 g / 1 are systematically excluded from the study.
• the average glucose and triglyceride levels before and after treatment are calculated and the results are expressed as a percentage change in these means over time.
• the results expressed as a percentage change in the blood sugar level and the triglyceride level show that the compounds of formula I according to the invention or their addition salts with a non-toxic acid make it possible to lower the blood sugar level up to values of - 73% and the triglyceride level up to values of - 56%. It was also observed that the treatment with the compounds according to the invention was accompanied by a favorable modification of the lipid parameters.
• the compounds according to the invention can be used as active principle of a medicament intended for the treatment of diabetes in mammals and, more particularly, in humans. They can be used to fight hypertriglyceridemia and diseases caused by an excess of triglycerides in the blood, such as for example atherosclerosis.
• they can be useful for the prevention or treatment of diseases associated with hyperglycemia or hypertriglyceridemia such as for example type II diabetes, hypertension, dyslipidemia, cardiovascular disease, and obesity; they are also useful for the treatment of diseases due to microvascular or macrovascular complications in diabetics, in particular in the renal or central nervous system, said complications being generally associated with metabolic syndrome X.
• the compounds according to the invention are also useful for treating cerebral ischemia or stroke.
• compositions incorporating the compounds according to the invention can be formulated in particular by association of these compounds with usual non-toxic excipients according to methods well known to those skilled in the art, preferably so as to obtain drugs administered orally, for example capsules or tablets.
• the daily dosage in humans will preferably be between 5 and 500 mg.
• formulations in the form of capsules or tablets are preferred for reasons of patient comfort, the compounds according to the invention can also be prescribed in other galenical forms, for example if the patient does not accept or does not accept is unable to accept solid oral formulations or if the treatment requires very rapid bioavailability of the active ingredient.
• the medicament can thus be presented in the form of an oral syrup, or in an injectable form, preferably subcutaneous or intramuscular.

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Diabetes (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Obesity (AREA)
• Hematology (AREA)
• Vascular Medicine (AREA)
• Endocrinology (AREA)
• Child & Adolescent Psychology (AREA)
• Urology & Nephrology (AREA)
• Emergency Medicine (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Plural Heterocyclic Compounds (AREA)

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