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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
  • C07D409/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
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  • A61P3/00—Drugs for disorders of the metabolism
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  • 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
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  • A61P35/00—Antineoplastic agents
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  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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  • A61P9/00—Drugs for disorders of the cardiovascular system
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• • A—HUMAN NECESSITIES
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  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
  • C07D233/70—One oxygen atom
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems

Definitions

• the present invention relates to poly-substituted imidazolone derivatives, the pharmaceutical compositions comprising them and their therapeutic applications in the fields of human and animal health.
• the present invention also relates to a process for the preparation of these derivatives.
• the compounds according to the invention thus have activating properties of PPARs (Peroxisome Proliferator-Activated Receptor), in particular PPAR ⁇ , and antagonistic properties of the AT1 receptor of angiotensin II.
• PPARs Peroxisome Proliferator-Activated Receptor
• the molecules described in the invention are therefore of particular interest for treating pathologies related to lipid and carbohydrate disorders and / or hypertension.
• the compounds according to the invention are of particular interest for the treatment of pathologies related to disorders of lipid and / or carbohydrate metabolism, such as diabetes, obesity, dyslipidemia or inflammation, as well as to allow the reduction of the global cardiovascular risk.
• the PPARs ( ⁇ , ⁇ and ⁇ ) are indeed known to be involved in this type of pathology (Kota BP et al., 2005): ligands of these receptors, for example fibrates or thiazolidinediones, are therefore marketed to treat such pathologies (Lefebvre P et al., 2006) and many PPAR modulators, agonists or antagonists, selective or not, are currently in advanced development for the treatment of these pathologies.
• the family of PPARs comprises three distinct members, designated ⁇ , ⁇ and ⁇ (also called ⁇ ), each coded by a different gene. These receptors are part of the superfamily of nuclear receptors and transcription factors that are activated by the binding of certain fatty acids and / or their lipid metabolites.
• angiotensin II an octapeptide produced by the Renin- Angiotensin (SRA)
• SRA Renin- Angiotensin
• Angiotensin II is derived from Angiotensin I cleavage by Angiotensin Converting Enzyme (ACE).
• ACE Angiotensin Converting Enzyme
• Angiotensin II produces its effects by stimulating specific receptors called AT1 and AT2 (de Gasparo M et al., 2000).
• the AT1 receptor has a ubiquitous distribution and is involved in the main physiological actions of angiotensin II: Activation of the AT1 receptor stimulates vasoconstriction, growth and cell proliferation via activation of different tyrosine kinases.
• the present invention thus relates to new compounds whose mechanism of action "multimodal" PPAR / AT1 allows a major therapeutic advance.
• Diabetes, obesity, dyslipidemia (LDL cholesterol levels (for low density lipoproteins or LDL) and high triglycerides, low HDL cholesterol (for high density lipoproteins or high density lipoproteins), etc.) and hypertension are indeed clearly identified cardiovascular risk factors (Mensah M, 2004), which predispose an individual to develop a cardiovascular pathology.
• Hypertension characterized by a high blood pressure (greater than 140/90 mm Hg), is currently treated by 6 types of molecules: diuretics, beta-blockers, angiostensin converting enzyme inhibitors, calcium channel blockers, vasodilators or alpha-blockers.
• cardiovascular disease is the leading cause of death in industrialized countries and is becoming increasingly common in developing countries. These diseases include coronary heart disease, cerebral ischemia and peripheral arterial diseases.
• the current therapeutic strategies consist on the one hand to combine several drugs to reduce the different risk factors individually (Morphy R and Rankovic Z, 2005), which can sometimes cause serious side reactions (for example, the simultaneous administration of fibrates and statins increases the risk of myopathy (Denke MA, 2003)), and on the other hand to develop drugs whose mechanism of action "multimodal" has advantages related to the administration of a single active ingredient in terms of compliance, tolerance, pharmacokinetics and pharmacodynamics. Such products would reduce the risk of cardiovascular disease and treat each dysfunction and its consequences independently (dyslipidemia, diabetes, etc.).
• Benson et al. mentions the advantages of angiotensin II receptor antagonist molecules and PPAR ⁇ receptor agonists for the treatment of metabolic syndrome. It has recently been shown that angiotensin II antagonists selectively activate the PPAR ⁇ receptor (Benson SC, Pershadsingh HA, Ho Cl, Chittiboyina A, Desai P, Pravenec M, Qi N, Wang J, Avery MA and Kurtz TW, 2004). , Kurtz TW, 2005). This effect is specific for PPAR ⁇ , no activation of PPAR ⁇ and PPAR ⁇ has been shown.
• Thiazolidinediones also appear to regulate the signal of angiotensin II at multiple levels, significantly reducing AT1 receptor expression and repressing signal transduction through this receptor to suppress vascular remodeling, formation of atherosclerotic lesion and oxidative stress (Kintscher U et al., 2004).
• Patent applications WO2004060399 and WO2004014308 disclose compounds having a PPAR agonist character and angiotensin II receptor antagonist of interest for weight loss and treatment of cardiovascular diseases and insulin resistance syndromes.
• the molecules described in the invention are therefore of particular interest for treating pathologies related to lipid and carbohydrate disorders and / or hypertension such as the complications associated with the metabolic syndrome. , diabetes, dyslipidemias, atherosclerosis, cardiovascular diseases, obesity, hypertension, inflammatory diseases (asthma, etc.), insulin resistance, neurodegenerative diseases, cancers, etc., as well as than to allow the reduction of the overall cardio-vascular risk.
• the compounds according to the invention are of particular interest for treating dyslipidemias and / or hypertension (especially hypertension associated or not with dyslipidemias and / or hypertension associated or not with diabetes). ⁇
• R1 represents a hydrogen atom or an alkyl, cycloalkyl, alkyloxy, alkylthio, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl or heterocycle group;
• R2 and R3 which may be identical or different, independently represent a hydrogen atom or an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl or a heterocycle group, or R2 and R3 may together form with the carbon to which they are attached a ring or a heterocycle;
• Z represents an oxygen atom or a sulfur atom
• X is an alkyl group having a main chain of 1 to 6 carbon atoms, or X is an alkenyl or alkynyl group having a main chain of 2 to 6 carbon atoms;
• X'1, X'2, X'3, X'4 and X'5 identical or different, independently representing a hydrogen or halogen atom, an NO2 group, nitrile, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, -OR4, -SR4, -NR4R5, -SOR6, -SO 2 R6, a heterocycle, one of X'1, X'2, X'3, X'4 and X'5 being L2;
• L1 and L2 can not simultaneously represent a covalent bond if X has only 1 carbon atom;
• X1, X2, X3, X4 and X5 which may be identical or different, independently represent a hydrogen or halogen atom, an NO2, nitrile, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, -OR4, -SR4 group, -NR4R5, -SOR6, -SO 2 R6, a heterocycle or a group of type -YE, at least one of the groups X1, X2, X3, X4 and X5 being a group of type -YE;
• R4 and R5 which may be identical or different, independently represent a hydrogen atom or an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl or a heterocycle group, or R4 and R5 may together form with the nitrogen atom to which they are bound a heterocycle;
• R6 substituted or unsubstituted, independently represents an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl or heterocycle group;
• Y represents a substituted or unsubstituted methylene group, an oxygen, sulfur or selenium atom, a group SO, SO2, SeO, SeO2 or NR in which R represents a hydrogen atom or an alkyl, cycloalkyl or alkenyl group; alkynyl, aryl, arylalkyl or a heterocycle; E represents an alkyl, cycloalkyl, alkenyl or alkynyl chain, optionally comprising one or more Y1 groups and substituted by one or more W groups,
• Y1 represents an oxygen atom, sulfur atom or a group of NR type, R representing a hydrogen atom or an alkyl, cycloalkyl, alkenyl, alkynyl, aryl or arylalkyl group, in particular a hydrogen atom or an alkyl radical; ;
• W represents:
• R4, R5 and R6 being as previously defined;
• alkyl denotes a saturated hydrocarbon radical, linear, branched or cyclic, substituted or unsubstituted, having from 1 to 24, preferably 1 to 10 carbon atoms. Mention may be made, for example, of the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl, n-hexyl or cyclohexyl radicals. ⁇
• alkenyl refers to an unsaturated hydrocarbon radical
• linear, branched or cyclic, substituted or unsubstituted having from 2 to 24, preferably 2 to 10 carbon atoms.
• alkynyl refers to an unsaturated hydrocarbon radical
• linear, branched or cyclic, substituted or unsubstituted having from 2 to 24, preferably 2 to 10 carbon atoms.
• the ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl or 2-pentynyl radicals may be mentioned.
• alkyloxy refers to an alkyl chain attached to the molecule through an oxygen atom (ether linkage).
• alkyl meets the previously stated definition. By way of example, mention may be made of methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, sec-butyloxy or hexyloxy radicals.
• alkylthio refers to an alkyl chain bonded to the molecule via a sulfur atom (thioether bond).
• alkyl meets the previously stated definition. By way of example, mention may be made of methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, sec-butylthio or hexylthio radicals.
• aryl refers to an aromatic hydrocarbon radical, substituted or unsubstituted, preferably having 6 to 14 carbon atoms. It may in particular be substituted by at least one halogen atom, an alkyl, hydroxyl, thiol, alkyloxy or alkylthio radical or a nitro (NO 2) function.
• the aryl radicals according to the present invention are chosen from phenyl, naphthyl (for example 1-naphthyl or 2-naphthyl), biphenyl (for example, 2-, 3- or 4-biphenyl), anthryl or fluorenyl. Phenyl groups, substituted or unsubstituted, are very particularly preferred.
• heteroaryl refers to an aromatic hydrocarbon radical having one or more heteroatoms such as nitrogen, sulfur and oxygen, substituted or unsubstituted. It may in particular be substituted with at least one halogen atom, an alkyl radical (as defined above), hydroxyl, thiol, alkyloxy (as defined above), alkylthio (as defined above). or a nitro function (NO2).
• pyridinyl pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1, 2, 3) - and (1,2,4) -triazolyl, pyrazinyl and pyrimidinyl groups.
• tetrazolyl furyl, thienyl, isoxazolyl, thiazolyl, isoxazolyl or oxazolyl, etc.
• arylalkyl refers to an alkyl group radical substituted with an aryl group.
• alkyl and aryl are as previously defined.
• the optionally substituted phenethyl groups are particularly preferred.
• heterocycle refers to a mono- or poly-cyclic radical, saturated, unsaturated or aromatic, substituted or unsubstituted, comprising one or more heteroatoms such as nitrogen, sulfur and oxygen. They may be advantageously substituted with at least one alkyl, alkenyl, aryl, alkyloxy or alkylthio group as defined above or with a halogen atom.
• cycloalkyl more particularly denotes a saturated hydrocarbon ring, substituted or unsubstituted, generally having from 3 to 24, preferably 3 to 10 carbon atoms. Cycloalkyls include especially cyclohexyl, cyclopentyl, cyclopropyl, cyclobutyl, cycloheptyl or norbornyl.
• ring is meant more particularly a hydrocarbon ring, substituted or unsubstituted, optionally having at least one heteroatom (such as in particular a nitrogen, sulfur or oxygen atom), saturated, unsaturated or aromatic.
• the rings include especially cycloalkyl, aryl or heterocycle groups as defined above.
• halogen is meant the chlorine, bromine, fluorine and iodine atoms.
• the sulfur atoms may, in the context of the present invention, be oxidized or not.
• the radicals thus defined may be substituted, in particular by at least one halogen atom, an alkyl, cycloalkyl, aryl, hydroxyl, thiol, alkyloxy, alkylthio, hydroxyl or heterocycle radical or a nitro (NO 2) function.
• the alkyl group may be a perhaloalkyl radical, in particular perfluoroalkyl, such as -CF 3 .
• X represents an alkyl group whose main chain comprises 1, 2, 3, 4, 5 or 6 carbon atoms or X represents an alkenyl or alkynyl group whose main chain comprises 2, 3, 4, 5 or 6 carbon atoms.
• a particular aspect of the invention relates to the compounds of general formula (I) in which L1 represents a group of formula (II) as defined below:
• the compounds of formula (I) have an L1 group of formula (II) as defined below:
• the compounds of formula (I) have an L1 group of formula (II) as defined below:
• X'1, X'2, X'4 and X'5 represent a hydrogen atom, a nitro function (-NO 2 ), a trifluoromethyl radical (-CF3), an alkoxy group, preferably methoxy, or an alkyl group, preferably methyl, ethyl or propyl and X'3 represents the L2 group.
• the compounds of formula (I) have an L1 group of formula (II) as defined below:
• X'1, X'2, X'4 and X'5 represent a hydrogen atom and X'3 represents the L2 group.
• Another aspect of the invention relates to compounds of general formula (I) wherein L2 is a covalent bond.
• a preferred aspect of the invention relates to the compounds of the general formula (I) wherein I 2 is a covalent bond and L 1 is a group of the formula (II) as defined above.
• L 1 represents a group of formula (II) as defined above and 1 represents a covalent bond located in the para position relative to X.
• the invention relates to compounds of general formula
• R1, R2, R3, Z, X, X1, X2, X3, X4, X5, X'1, X'2, X'4 and X'5 are as previously defined.
• Another aspect of the invention relates to the compounds of general formula (I) wherein L 2 represents a carbonyl group (CO).
• the invention relates to the compounds of general formula (I) in which L1 represents a group of formula (II) as defined above and L2 represents a carbonyl group (CO).
• L1 represents a group of formula (II) as defined above and L2 represents a carbonyl group (CO) located in position para to X.
• the invention relates to compounds of general formula (IV ):
• Another preferred aspect of the invention relates to the compounds of the general formula (I) in which L 2 represents an oxygen atom. More preferentially, the invention relates to the compounds of general formula (I) in which L 1 represents a group of formula (II) as defined above and
• L2 represents an oxygen atom
• L1 represents a group of formula (II) as defined above and L2 represents an oxygen atom located in the para position relative to X.
• the invention relates to compounds of general formula (V) :
• Another preferred aspect of the invention relates to the compounds of general formula (I) in which L 2 represents a sulfur atom. More preferentially, the invention relates to the compounds of general formula (I) in which L 1 represents a group of formula (II) as defined above and
• L2 represents a sulfur atom (oxidized or not).
• L1 represents a group of formula (II) as defined above and L2 represents a sulfur atom (oxidized or not) located in the para position relative to X.
• Vl General
• Another preferred aspect of the invention relates to the compounds of general formula (I) in which I-2 represents a methylene group (-CH 2 -). More preferentially, the invention relates to the compounds of general formula (I) in which L 1 represents a group of formula (II) as defined above and L 2 represents a methylene group.
• L1 represents a group of formula (II) as defined above and L2 represents a methylene group situated in the para position relative to X.
• the invention relates to the compounds of general formula (VII):
• Another particular aspect of the invention relates to the compounds of general formula (I) in which L1 represents a covalent bond and L2 is as defined above.
• the invention relates to compounds of general formula (I) in which L1 and I2 simultaneously represent a covalent bond and wherein X has more than one carbon atom.
• the invention relates to the compounds of general formula (VIII):
• R1, R2, R3, Z, X, X1, X2, X3, X4 and X5 are as defined above and wherein X is as previously defined and has more than one carbon atom.
• Another particular aspect of the invention relates to the compounds of general formula (I) in which L1 represents a group of formula (II) as defined below:
• the compounds of formula (I) have an L1 group of formula (II) as defined below:
• Another aspect of the invention relates to compounds of the general formula (I) in which I-2 is a covalent bond.
• a preferred aspect of the invention relates to the compounds of general formula (I) in which L2 represents a covalent bond and L1 represents a group of formula (II) as defined above.
• L1 represents a group of formula (II) as defined above and L2 represents a covalent bond located in position meta with respect to X.
• the invention relates to the compounds of general formula (IX):
• Another particular aspect of the invention relates to the compounds of general formula (I) in which L1 represents a group of formula (X) as defined below.
• the compounds of formula (I) have an L1 group of formula (X) as defined below:
• the compounds of formula (I) have an L1 group of formula (X) as defined below:
• Another aspect of the invention relates to compounds of general formula (I) wherein L2 is a covalent bond.
• a preferred aspect of the invention relates to the compounds of general formula (I) in which L2 represents a covalent bond and L1 represents a group of formula (X) as defined above.
• L1 represents a group of formula (X) as defined above and X'1 represents the group L2, the group L2 being a covalent bond.
• XI general formula
• a particular object of the invention relates to the compounds of general formula (I), advantageously (III), (IV), (V), (VI), (VII), (VIII), (IX) or (Xl) wherein R 1 is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, or a heterocycle, preferably an alkyl group.
• R 1 represents a substituted or unsubstituted alkyl group comprising in its main chain preferably 1, 2, 3, 4, 5 or 6 carbon atoms.
• R1 may be substituted with an aryl or cycloalkyl group, optionally comprising a heteroatom.
• R 1 may for example represent a butyl, isobutyl, propyl, ethyl, methyl, cyclopropyl or methyl group substituted by a phenyl group or by a thiophenyl group. Even more preferentially, R 1 represents a butyl group.
• a particular object of the invention relates to the compounds of general formula (I), advantageously (III), (IV), (V), (VI), (VII), (VIII), (IX) or (Xl) in which R2 and R3, which may be identical or different, independently represent an alkyl group preferably comprising 1, 2, 3, 4, 5 or 6 carbon atoms or an arylalkyl group, or in which R2 and R3 form with the carbon to which they are bonded a ring, preferably a ring having 3 to 8 carbon atoms.
• the ring formed by R2, R3 and the carbon to which they are bonded can thus comprise 3, 4, 5, 6, 7 or 8 carbon atoms.
• R2 and R3 which are identical or different, independently represent a hydrogen atom, a methyl, ethyl or a phenyl group, or R2 and R3 form, with the carbon to which they are bonded, a ring comprising 5 or 6 carbon atoms. preferably cyclopentyl or cyclohexyl.
• a particular object of the invention relates to the compounds of general formula (I), advantageously (III), (IV), (V), (VI), (VII), (VIII), (IX) or (Xl) wherein Z represents an oxygen atom.
• a particular object of the invention relates to the compounds of general formula (I), advantageously (III), (IV), (V), (VI), (VII), (VIII), (IX) or (Xl) in which X represents an alkyl group whose main chain comprises 1 or 2 carbon atoms, preferably unsubstituted.
• a particular object of the invention relates to the compounds of general formula (I), advantageously (III), (IV), (V), (VI), (VII), (VIII), (IX) or (Xl) in which X1, X2, X3, X4 and X5, which are identical or different, independently represent a hydrogen atom, a halogen atom, preferably bromine or fluorine, an alkyl group, preferably a propyl, ethyl or isobutyl, an alkyloxy group, preferably methoxy, a nitrile group (CN), a nitro group (NO2) or a group of the type -YE as defined above, at least one of the groups X1, X2, X3, X4 and X5 being a group of type -YE.
• X1, X2, X3, X4 and X5 being a group of type -YE.
• only one of the groups X1, X2, X3, X4 and X5 represents a group of type -YE.
• X 2 or X 4 represents the group YE (the group YE is then in the meta position of the aromatic ring to which it is attached), X 1, X 3, X 5 and X 4 or X 2, respectively, optionally representing a hydrogen atom, a halogen atom, an alkyl, alkoxy, nitrile group or a nitro group (NO2).
• a particular object of the invention relates to the compounds of general formula (I), advantageously (III), (IV), (V), (VI), (VII), (VIII), (IX) or (Xl) wherein at least 3 of X1, X2, X3, X4 and X5 are hydrogen.
• a particular object of the invention relates to the compounds of general formula (I), advantageously (III), (IV), (V), (VI), (VII), (VIII), (IX) or (Xl) wherein at least one of X1, X2, X3, X4 and X5 is a halogen atom, preferably bromine or fluorine.
• a particular object of the invention relates to the compounds of general formula (I), advantageously (III), (IV), (V), (VI), (VII), (VIII), (IX) or (Xl) in wherein at least one of X1, X2, X3, X4 and X5 represents an alkyl chain, preferably ethyl, propyl or isobutyl.
• a particular object of the invention relates to the compounds of general formula (I), advantageously (III), (IV), (V), (VI), (VII), (VIII), (IX) or (Xl) in wherein at least one of X1, X2, X3, X4 and X5 is alkoxy, preferably methoxy.
• a particular object of the invention relates to the compounds of general formula (I), advantageously (III), (IV), (V), (VI), (VII), (VIII), (IX) or (Xl) in which at least one of the groups X1, X2, X3, X4 and X5 represents a nitrile group.
• a particular object of the invention relates to the compounds of general formula (I), advantageously (III), (IV), (V), (VI), (VII), (VIII), (IX) or (Xl) in which at least one of the groups X1, X2, X3, X4 and X5 represents a nitro group (NO 2 ).
• a particular object of the invention relates to the compounds of general formula (I), advantageously (III), (IV), (V), (VI), (VII), (VIII), (IX) or (Xl) in which Y represents an oxygen atom.
• a particular object of the invention relates to the compounds of general formula (I), advantageously (III), (IV), (V), (VI), (VII), (VIII), (IX) or (Xl) in which E represents an alkyl main chain, branched or unbranched, preferably containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, substituted with one or more groups W as defined above preferably by a single group W.
• a particular object of the invention relates to the compounds of general formula (I), advantageously (III), (IV), (V), (VI), (VII), (VIII), (IX) or (Xl) wherein the group W represents a carboxylic acid -COOH or a derivative of ester type -COOR4, thioester -COSR4, amide -CONR4R5, thioamide-CSNR4R5, nitrile -CN, acylsulfonamide -CONHSO 2 R6, hydrazide -CONHNR4R5, or tetrazole; R4, R5 and R6 being as defined above.
• W represents a carboxylic acid -COOH or a derivative of the ester -COOR4, nitrile -CN or tetrazole type.
• a particular object of the invention relates to the compounds of general formula (I), advantageously (III), (IV), (V), (VI), (VII), (VIII), (IX) or (Xl) wherein YE is -O-C (CH 3 ) -COOH, -O- (CH 2 ) 3 -C (CH 3 ) 2 -COOH, -O-CH 2 -CN, -O-CH 2 -C (CH 2 ) 2 -COOH, -O- (CH 2 ) 6 -C (CH 3 ) 2 -COOH, -O-CH 2 -COOH, -O-CH (CH 3 ) -COOH, -O-CH (CH 3 ) 2 CH 3 ) -COOH, -O-CH (CH (CH 3 ) 2 ) -COOH, -O-CH 2 -tetrazole, -O-CH (CH 2 CH 3 ) -tetrazole, -OC (spiro
• the subject of the invention is the compounds of general formula (I) in which at least one of the following conditions, preferably all the conditions, is fulfilled:
• R 1 represents an alkyl group, substituted or unsubstituted, preferably containing 1, 2, 3, 4, 5 or 6 carbon atoms; and or
• R 2 and R 3 which may be identical or different, independently represent an alkyl group, preferably containing 1, 2, 3, 4, 5 or 6 carbon atoms or an arylalkyl group, or R 2 and R 3 form, with the carbon to which they are bonded, a ring comprising 3 to 8 carbon atoms; and or
• Z represents an oxygen atom
• X is an alkyl group, the main chain of which has 1 or 2 carbon atoms;
• L1 represents: (i) a covalent bond, or
• X'3 representing L2; or alternatively X'1, X'3, X'4 and X'5, which may be identical or different, independently represent a hydrogen atom, a halogen atom or an alkyl chain; X'2 representing L2; and or
• L1 and I2 can not simultaneously represent a covalent bond if X has only 1 carbon atom;
• X1, X2, X3, X4 and X5 which may be identical or different, independently represent a hydrogen atom, a halogen atom, an alkyl chain, an alkoxy group, a nitrile group, a nitro group (NO 2 ) or a group of the type -YE, at least one, preferably only one, X1, X2, X3, X4 and X5 groups being a -YE type group; and or
• Y represents an oxygen atom
• E represents an alkyl chain, branched or unbranched, preferably comprising 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, substituted with one or more W groups; and or
• W represents a carboxylic acid -COOH or a derivative of ester type -COOR4, nitrile -CN or tetrazole;
• the compounds according to the invention are:
• the compounds of the present invention include their stereoisomers
• the compounds according to the invention may contain one or more asymmetric centers.
• the present invention includes stereoisomers (diastereoisomers, enantiomers), pure or in mixture, as well as racemic mixtures.
• the present invention also includes the geometric isomers of the compounds according to the invention.
• an enantiomerically pure (or enriched) mixture is desired, it can be obtained either by purification of the final product or of chiral intermediates, or by asymmetric synthesis according to methods known to those skilled in the art (using, for example, reagents and catalysts chiral).
• Some compounds according to the invention may have different stable tautomeric forms and all such forms and mixtures thereof are included in the invention.
• the present invention also relates to the pharmaceutically acceptable salts of the compounds according to the invention.
• this term refers to the low or non-toxic salts obtained from bases or acids, organic or inorganic. These salts can be obtained during the final purification step of the compound according to the invention or by incorporation of the salt on the already purified compound. Certain compounds according to the invention and their salts could be stable in several solid forms.
• the present invention includes all solid forms of the compounds according to the invention which includes amorphous, polymorphic, mono- and polycrystalline forms.
• the compounds according to the invention may exist in free form or in solvated form, for example with pharmaceutically acceptable solvents such as water (hydrates) or ethanol.
• the present invention also includes the prodrugs of the compounds according to the invention which, after administration in a subject, are transformed into compounds as described in the invention or their metabolites which have therapeutic activities comparable to the compounds according to the invention.
• the expected metabolites are metabolites resulting from the oxidation of the compounds leading to mono- or polyhydroxylated compounds or metabolites resulting from the oxidation of these hydroxylated metabolites (ketone, hydroxy-keto or carboxylic derivatives).
• Expected metabolites are also those resulting from glucuronidations or the metabolites resulting from the opening of the imidazolone ring or derivatives or the metabolites derived from N-dealkylation as shown in scheme A below:
• the compounds according to the invention labeled with one or more isotopes are also included in the invention: these compounds are structurally identical but differ in that at least one atom of the structure is replaced by one isotope (radioactive or not).
• isotopes that can be included in the structure of the compounds of the invention may be selected from hydrogen, carbon, nitrogen, oxygen, sulfur such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, respectively.
• the 3 H and 14 C radioactive isotopes are particularly preferred because they are easy to prepare and detect in vivo in vivo bioavailability studies.
• the heavy isotopes (such as H 2) are preferred because they are used as internal standards in analytical studies.
• the subject of the present invention is also the compounds as described above, as medicaments.
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising, in a pharmaceutically acceptable carrier, at least one compound as described above, optionally in combination with another therapeutic and / or cosmetic active ingredient.
• a pharmaceutical composition for the treatment of pathologies related to lipid and carbohydrate disorders and / or hypertension such as complications associated with the metabolic syndrome, diabetes, dyslipidemias, atherosclerosis, diseases cardiovascular, obesity, hypertension, inflammatory diseases (asthma, etc.), insulin resistance, neurodegenerative diseases, cancers, etc., and / or to reduce the overall cardiovascular risk.
• the pharmaceutical composition according to the invention is preferentially used to treat dyslipidemias and / or hypertension (notably hypertension associated or not with dyslipidemias and / or hypertension associated or not with diabetes).
• Another subject of the invention resides in the use of at least one compound as described above for the preparation of pharmaceutical compositions intended for the treatment of various pathologies, in particular linked to disorders of the metabolism and / or to the hypertension, including complications associated with metabolic syndrome, diabetes, dyslipidemia, atherosclerosis, cardiovascular disease, obesity, hypertension, inflammatory diseases (including asthma, etc.), insulin resistance, neurodegenerative diseases, cancers, etc., as well as to reduce the overall cardiovascular risk.
• the subject of the invention is the use of at least one compound as described above for the preparation of pharmaceutical compositions intended to treat the risk factors for cardiovascular diseases linked to disorders of lipid metabolism and / or or hypertension and intended to reduce the overall risk.
• the molecules according to the invention may advantageously be administered in combination with other therapeutic and / or cosmetic agents, commercialized or in development, such as: diabetics: insulin-secreting agents (sulfonylureas (glibenclamide, glimepiride, gliclazide, etc.) and glinides (repaglinide, nateglinide, etc.)), alpha-glucosidase inhibitors, PPAR ⁇ agonists (thiazolidinediones such as rosiglitazone, pioglitazone), mixed agonists PPAR ⁇ / PPAR ⁇ (tesaglitazar, muraglitazar), pan-PPAR (compounds simultaneously activating the 3 PPAR isoforms), biguanides (metformin), inhibitors of Dipeptidyl Peptidase IV (MK-431, vildagliptin), Glucagon agonists -Like Peptide-1
• hypolipidemic and / or hypocholesterolemic molecules fibrates (fenofibrate, gemfibrozil), HMG CoA reductase inhibitors or hydroxylmethylglutaryl Coenzyme A reductase inhibitors (statins such as atorvastatin, simvastatin, fluvastatin), cholesterol absorption inhibitors ( ezetimibe, phytosterols), CETP inhibitors or
• angiotensin-converting enzyme (ACE) inhibitors captopril, enalapril, ramipril or quinapril
• angiotensin II receptor antagonists leukin, renin, renin, renin, renin, renin, renin, renin, renin, renin, renin, renin, renin, renin, renin, renin, renin II receptor antagonists (losartan, valsartan, telmisartan, eposartan, irbesartan, etc.), beta-blockers (atenolol, metoprolol, labetalol, propranolol), thiazide and non-thiazide diuretics (furosemide, indapamide, hydrochlorothiazide, anti-aldosterone), vasodilators, calcium channel blockers (nifedipine, felodipine or aml
• anti-platelet agents Aspirin, Ticlopidine, Dipyridamol, Clopidogrel, Flurbiprofen, etc.
• anti-obesity agents Sibutramine, lipase inhibitors (orlistat), PPAR ⁇ agonists and antagonists, cannabinoid CB1 receptor antagonists (especially rimonabant), etc.
• anti-inflammatory agents for example, corticosteroids (prednisone, betamethasone, dexamethasone, prednisolone, methylprednisolone, hydrocortisone, etc.), NSAIDs or non-steroidal anti-inflammatory drugs derived from indole (indomethacin, sulindac), NSAIDs from the arylcarboxylic group (tiaprofenic acid, diclofenac, etodolac, flurbiprofen, ibuprofen, ketoprofen, naproxen, nabumetone, alminoprofen), NSAIDs derived from oxicam (meloxicam, piroxicam, tenoxicam), NSAIDs from the fenamate group, selective inhibitors COX2 (celecoxib, rofecoxib), etc. anti-oxidizing agents: for example probucol, etc.
• corticosteroids prednisone, betamet
• thiazide or non-thiazide diuretics for example, thiazide or non-thiazide diuretics (furosemide, indapamide, hydrochlorothiazide, anti-aldosterone), ACE inhibitors (captopril, enalapril, ramipril or quinapril), digitalis ( digoxin, digitoxin), beta blockers (atenolol, metoprolol, labetalol, propranolol),
• Phosphodiesterases (enoximone, milrinone), etc.
• beta-blockers atenolol, metoprolol, labetalol, propranolol
• blockers of calcium channel nifedipine, felodipine or amlodipine, bepridil, diltiazem or verapamil
• NO donor agents trinitrin, isosorbide dinitrate, molsidomine
• Amiodarone etc.
• anticancer agents cytotoxic agents (agents interacting with DNA, alkylating agents, cisplatin and derivatives), cytostatic agents (GnRH analogs (gonadotropin-releasing hormone) or somatostatin analogues) , progestins, anti-estrogens, aromatase inhibitors, etc.), modulators of the immune response (interferons, IL2, etc.), etc. anti-asthmatics such as bronchodilators (especially beta2-receptor agonists), corticosteroids, cromoglycate, leukotriene receptor antagonists (notably montelukast), etc.
• bronchodilators especially beta2-receptor agonists
• corticosteroids especially cromoglycate
• leukotriene receptor antagonists notably montelukast
• corticosteroids used in the treatment of skin pathologies such as psoriasis and dermatitis, vasodilators and / or anti-ischemic agents (in particular buflomedil, Ginkgo Biloba extract, naftidrofuryl, pentoxifylline, piribedil), etc.
• the invention also relates to a method for treating pathologies related to lipid metabolism and / or hypertension comprising administering to a subject, in particular a human subject, an effective amount of a compound or a pharmaceutical composition such as as defined above.
• an effective amount refers to an amount of the compound sufficient to produce the desired biological result.
• subject means a mammal and more particularly a human.
• treatment refers to curative, symptomatic or preventive treatment.
• the compounds of the present invention can thus be used in subjects (such as mammals, in particular humans) with a declared disease.
• the compounds of the present invention can also be used to delay or slow progression or prevent further progression of the disease, thereby improving the condition of the subjects.
• the compounds of this can be administered to non-diseased subjects who may develop the disease normally or who have a significant risk of developing the disease.
• compositions according to the invention advantageously comprise one or more excipients or vehicles, which are pharmaceutically acceptable.
• excipients or vehicles for example, saline, physiological, isotonic, buffered, etc., solutions compatible with a pharmaceutical use and known to those skilled in the art may be mentioned.
• the compositions may contain one or more agents or vehicles selected from dispersants, solubilizers, stabilizers, preservatives, etc.
• Agents or vehicles that can be used in formulations include methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, and the like. acacia, liposomes, etc.
• compositions may be formulated as injectable suspensions, gels, oils, tablets, suppositories, powders, capsules, aerosols, etc., optionally using dosage forms or devices providing sustained and / or delayed release.
• an agent such as cellulose, carbonates or starches is advantageously used.
• the compounds or compositions according to the invention can be administered in different ways and in different forms. Thus, they may be, for example, administered systemically, orally, parenterally, by inhalation or by injection, for example intravenously, intramuscularly, subcutaneously, trans-dermally, intra-arterially, etc.
• the compounds are generally packaged as liquid suspensions, which can be injected by means of syringes or infusions, for example.
• the flow rate and / or the injected dose can be adapted by those skilled in the art depending on the patient, the pathology, the mode of administration, etc.
• the compounds are administered in doses which can vary between 1 ⁇ g and 2 g per administration, preferably from 0.1 mg to 1 g per administration. Administrations may be daily or repeated several times a day.
• the compositions according to the invention may comprise, in addition, other agents or active principles.
• the invention also relates to processes for the preparation of compounds derived from poly-substituted imidazolones according to the invention.
• the compounds of the invention may be prepared from commercial products, using a combination of chemical reactions known to those skilled in the art.
• the subject of the present invention is a process for the preparation of the compounds according to the invention as described above comprising: (i) a step of condensation of a halogen derivative or of a derivative carrying a sulfonate-type leaving group, preferentially mesylate or tosylate, on a mono- or polysubstituted imidazolone heterocycle or a cyclization step of an aminoamide suitably substituted with an ortho-ester, and optionally, before and / or after step (i), (ii) a or several steps of insertion and / or transformation of functional groups.
• the compounds of general formula (I) are obtained by hydrolysis, thermolysis or hydrogenolysis (A) of an intermediate of general formula (Ia):
• R1, R2, R3, Z, X, L1, L2, X1, X2, X3, X4 and X5 are as previously defined, with at least one of X1, X2, X3, X4 and X5 representing group of type -Y-E ', the group E' being by definition a group which by hydrolysis, thermolysis or hydrogenolysis makes it possible to generate the group E.
• This strategy is preferably applied if E contains at least one carboxylic acid function.
• E ' is in this case a group comprising a chemical function that can be converted into a carboxylic derivative by hydrolysis, thermolysis or hydrogenolysis.
• carboxylic acid-hydrolyzable chemical functions are acid derivatives (esters, thioesters, orthoesters, etc.) and nitrile, tetrazolyl, 1,3-oxazol-2-yl, 1,3-oxazolin-2- functions. yle, etc.
• the hydrolysis reactions may advantageously be carried out in the presence of an organic acid (eg trifluoroacetic acid) or an inorganic acid (eg hydrochloric acid) or in the presence of a base (eg sodium hydroxide) in water or a solvent mixture containing water (water / methanol, water / ethanol, water / THF (tetrahydrofuran), water / dioxane, etc.). They are conducted at temperatures between -10 0 C and 120 0 C, preferably between 20 ° C and the reflux temperature of the solvent used.
• an organic acid eg trifluoroacetic acid
• an inorganic acid eg hydrochloric acid
• a base eg sodium hydroxide
• thermolysis generates an acid function
• tertiary alkyl esters preferably tert-butyl esters.
• thermolysis reactions are preferably carried out in the absence of solvent (molten mixture) or in an inert solvent such as dichloromethane, chloroform, toluene, tetrahydrofuran or dioxane.
• solvent molten mixture
• inert solvent such as dichloromethane, chloroform, toluene, tetrahydrofuran or dioxane.
• strong acids such as para-toluenesulfonic acid is generally necessary for thermolysis.
• Examples of chemical functions whose hydrogenolysis generates an acid function are the arylalkyl esters, preferably the benzyl esters.
• the hydrogenolysis reactions are carried out in the presence of a metal catalyst (Pd / C, Pt, etc.) in a suitable solvent such as methanol, ethanol, tetrahydrofuran (THF), acetic acid, ethyl acetate, etc. They are carried out at temperatures of between 0 ° C. and 60 ° C., preferably at room temperature, under a hydrogen pressure of between 1 and 6 bars.
• a metal catalyst Pd / C, Pt, etc.
• suitable solvent such as methanol, ethanol, tetrahydrofuran (THF), acetic acid, ethyl acetate, etc.
• THF tetrahydrofuran
• An alternative is to release hydrogen in situ using ammonium formate.
• the compounds (Ia) correspond to the esterified form of the compounds (I).
• E may in this case be a group containing a chemical function, for example a nitrile function, which may be converted into tetrazole by methods known to those skilled in the art, or a protected tetrazole group by a protective group, preferably a benzyloxymethylether or trityl group which may be hydrolyzed according to methods known to those skilled in the art.
• a chemical function for example a nitrile function
• a protective group preferably a benzyloxymethylether or trityl group which may be hydrolyzed according to methods known to those skilled in the art.
• E contains at least one amide function
• E ' is in this case a group containing a chemical function that can be converted, by methods known to those skilled in the art, into an amide, for example a carboxylic acid function.
• E contains at least one acylsulfonamide function E 'is in this case a group containing a chemical function that can be converted, by methods known to those skilled in the art, into acylsulfonamide, for example a carboxylic acid function.
• E contains at least one hydrazide function
• E ' is in this case a group containing a chemical function that can be converted, by methods known to those skilled in the hydrazide art, for example a carboxylic acid function.
• the compounds of general formula (I) according to the invention in which Z represents a sulfur atom can be obtained from compounds of general formula (Ia) according to the invention in which Z represents an oxygen atom by reaction with conventional agents known to those skilled in the art such as Lawesson's reagent.
• LG representing a reactive group chosen for example from halogens (iodine, bromine, chlorine) or a leaving group of sulphonate type such as mesylate or tosylate in the presence of any activators known to those skilled in the art.
• the condensation reaction can be carried out by multiple routes, known to those skilled in the art.
• a preferred route is to work in a solvent such as dichloromethane, chloroform, diethyl ether, tetrahydrofuran, acetonitrile or dimethylformamide.
• Such reactions are carried out in the presence of bases such as sodium hydride or carbonates (such as potassium or sodium carbonate).
• bases such as sodium hydride or carbonates (such as potassium or sodium carbonate).
• These reactions can be carried out at temperatures of between -25 ° C. and 250 ° C., preferably between -10 ° C. and the boiling point of the envisaged solvent.
• X4 and X5 are as defined above, at least one of groups X1, X2, X3, X4 or X5 being a group of type Y-E 'can be obtained preferably and advantageously according to the following method (see diagram 3) by reaction of a compound of formula LG-E 'with a compound of formula (Ib) in which X, L1, L2, X1, X2, X3, X4 and X5 are as defined above, at least one of the groups X1, X2, X3, X4 or X5 being a Y-H group, Y being an oxygen or sulfur atom (scheme 3).
• E ' is by definition a group which by hydrolysis, thermolysis or hydrogenolysis makes it possible to generate the group E and LG represents a reactive group chosen for example from - o4 -
• halogens iodine, bromine, chlorine
• a leaving group of sulphonate type such as mesylate or tosylate in the presence of any activators known to those skilled in the art.
• the condensation reaction of group LG-E ' can be carried out by multiple routes known to those skilled in the art.
• a preferred route is to work in a solvent such as dichloromethane, chloroform, diethyl ether, tetrahydrofuran, acetonitrile or dimethylformamide.
• Such reactions are carried out in the presence of bases such as sodium hydride or carbonates (such as potassium carbonate, sodium).
• bases such as sodium hydride or carbonates (such as potassium carbonate, sodium).
• These reactions can be carried out at temperatures between -25 and 250 ° C., preferably between -10 ° C. and the boiling point of the envisaged solvent.
• the compounds of general formula (XVI) in which R 1, R 2, R 3 are as defined above and Z represents an oxygen atom are prepared from an amino acid ester of general formula (XVIII) and a imidate of general formula (XIX) in which R1, R2 and R3 are as defined above and RO represents an alkyl group, preferably methyl or ethyl, according to a procedure described by (Bernhart C et al., 1993) (scheme 4) .
• the compounds of general formula (XVIII) are known compounds, commercial or can be prepared according to methods known to those skilled in the art such as, for example, from compounds of formula (XVIII) in which R2 and R3 are as defined previously and RO represents a hydrogen atom according to the Fischer esterification method (Tsang JW et al., 1984). These compounds can also be obtained optically pure using asymmetric synthesis methods or chiral purification methods known to those skilled in the art.
• the compounds of general formula (XIX) are prepared from a nitrile of formula (XX) in ethanol in the presence of acid such as hydrochloric acid, R1 being as defined previously (Bernhart C et al., 1993, Black SL et al., 2003, McEwain S and Nelson J, 1942) (Scheme 5).
• the compounds of general formula (XVI) in which R 1, R 2, R 3 are as defined above and Z represents an oxygen atom are prepared from an aminoamide of general formula (XXI) and from an alkyl orthoester of general formula (XXII) in which R1, R2 and R3 are as defined above and R'O represents a short alkyl chain
• R2 and R3 are as previously defined are known compounds, commercial or can be prepared according to methods known to those skilled in the art.
• the compounds of general formula (XVI) in which R 1, R 2, R 3 are as defined above and Z represents an oxygen atom are prepared by reacting an acid halide of general formula (XXIII) in which R 1 is as defined above and Hal represents a halogen, preferably a chlorine atom, on an aminoamide of general formula (XXI) in which R 2 and R 3 are as defined above (Scheme 7).
• halogens iodine, bromine, chlorine
• a leaving group of sulfonate type such as mesylate or tosylate
• the condensation reaction of group LG-E ' can be carried out by multiple routes known to those skilled in the art.
• a preferred route is to work in a solvent such as dichloromethane, chloroform, diethyl ether, tetrahydrofuran, acetonitrile or dimethylformamide.
• Such reactions are carried out in the presence of bases such as sodium hydride or carbonates (such as potassium carbonate, sodium).
• bases such as sodium hydride or carbonates (such as potassium carbonate, sodium).
• These reactions can be carried out at temperatures between -25 and 250 ° C., preferably between -10 ° C. and the boiling point of the envisaged solvent.
• Preferred synthesis routes include, in particular, the use of a selective reduction reaction of compounds of formula (XVII) in which L 2 represents a carbonyl group and L 1 represents a group of formula (II) in which X '1, X' 2, X'3, X'4 and X'5 are as defined above for obtaining compounds of formula (XVII) in which L2 represents a methylene group and L1 represents a group of formula (II) in which X'1, X'2, X'3, X'4 and X'5 are as defined above.
• XXV a derivative of general formula (XXV) in which X6, X7, X8, X9 and X10, which are identical or different, independently represent an atom of hydrogen or halogen, an acidic or boronic ester group, an NO2 group, nitrile, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, -OR4, -SR4, -NR4R5, -SOR6, -SO 2 R6, or a heterocycle, one of the X6, X7, X8, X9 and X10 being -, O -
• a reactive group such as a halogen, a boronic acid or a boronic ester and an aromatic derivative of general formula (XXVI) in which X1, X2, X3, X4 and X5 are as defined above, L2 being a covalent bond and RG being a reactive group such as a halogen or a boronic acid in the presence of metal catalysts known to those skilled in the art.
• the compounds of general formula (Ib) in which L1, L2, X, X1, X2, X3, X4 and X5 are as defined above, at least one of groups X1, X2, X3, X4 or X5 being a group OR4 of the hydroxy type may be obtained preferably and advantageously by a demethylation reaction of the compounds of general formula (Ib) in which L1, L2, X, X1, X2, X3, X4 and X5 are as defined above, one at least groups X1, X2, X3, X4 or X5 being a group OR4 of methoxy type under conditions known to those skilled in the art for example in the presence of boron tribromide.
• X6, X7, X8, X9 and X10 which may be identical or different, independently represent a hydrogen or halogen atom, an acid or boronic ester group, an NO2 group, a nitrile or an alkyl group.
• the condensation reaction can be carried out by multiple routes, known to those skilled in the art.
• a preferred route is to work in a solvent such as dichloromethane, chloroform, diethyl ether, tetrahydrofuran, acetonitrile or dimethylformamide.
• Such reactions are carried out in the presence of bases such as sodium hydride or carbonates (such as potassium or sodium carbonate).
• bases such as sodium hydride or carbonates (such as potassium or sodium carbonate).
• These reactions can be carried out at temperatures of between -25 ° C. and 250 ° C., preferably between -10 ° C. and the boiling point of the envisaged solvent.
• X1, X2, X3, X4 and X5 are as defined above and X6, X7, X8, X9 and X10, which may be identical or different, independently represent a hydrogen or halogen atom, an acid or boronic ester group, a group NO2, nitrile, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, -OR4, -SR4, -NR4R5, -SOR6, -SO 2 R6, a heterocycle, one of X6, X7, X8, X9 and X10 being a reactive group RG such as a halogen, a boronic acid or a boronic ester are known compounds, commercial or can be prepared according to methods known to those skilled in the art. LEGENDS OF FIGURES
• LDL-Cholesterol Low Density Lipoprotein Cholesterol
• HDL-Cholesterol High Density Lipoprotein Cholesterol
• VLDL-cholesterol Very Low Density Lipoprotein Cholesterol
• FIG. 1 In Vitro Evaluation of the Activating Properties of the Compounds According to the Invention on PPARs
• PPARs The activation of PPARs is evaluated in vitro on a monkey kidney fibroblast (COS-7) line, by measuring the transcriptional activity of chimeras consisting of the DNA binding domain of the Gal4 transcription factor of the yeast and the ligand binding domain of the different PPARs.
• the compounds are tested at doses of between 0.01 and 100 ⁇ M on GaW-PPAR ⁇ , ⁇ and ⁇ chimeras.
• the induction factor i.e., the ratio of the luminescence induced by the compound to the luminescence induced by the control, is measured for each condition. It is then normalized with respect to an internal reference and the results are expressed in percentages: the higher the percentage of activation, the more the compound has a PPAR activator character.
• FIG. 1a The compounds according to the invention are tested at doses of between 0.01 and 100 ⁇ M on the GaW-PPAR ⁇ and Gal4-
• EC50 ( ⁇ M) for PPAR alpha and PPAR gamma (human isoforms) compounds according to the invention L ⁇ C50 corresponds to the concentration of compound according to the invention which is reached 50% of the maximum response. The lower I ⁇ C50 is, the higher the affinity of the compound according to the invention for the receptor.
• FIG. 2 In Vitro Evaluation of the Binding of the Compounds According to the Invention to the Human AT1 Receptor of Angiotensin II
• the results presented reflect the specific binding of the compounds according to the invention on the human AT1 receptor of angiotensin II.
• Specific binding is the difference between total binding and non-specific binding determined in the presence of an excess of unlabeled reference ligand (saralasin).
• the displacement of the radiolabeled molecule is measured for each dose of compound according to the invention.
• the IC50 corresponds to the concentration of compound according to the invention necessary to obtain 50% inhibition of the binding of the reference molecule (saralasin). The lower the NC50, the stronger the affinity of the compound according to the invention for the AT1 receptor.
• FIGS. 3a and 3b Ex Vivo Evaluation of the Antagonist Effect of the Compounds According to the Invention on the AT1 Receptor of Angiotensin II
• the invention has been tested as an agonist or antagonist of human AT1 receptor angiotensin II on rabbit thoracic aorta.
• the parameter measured is the maximum change in the voltage induced by each concentration of compound.
• the results are expressed as a percentage of the control response to angiotensin II.
• FIG. 3a Agonist activity of the compounds according to the invention at 0.3, 3 and 30 ⁇ M.
• FIG. 3b antagonistic activity of the compounds according to the invention at 0.3, 3 and 30 ⁇ M.
• FIGS. 4a to 4f In vivo evaluation, in ApoE2 / E2 mice, of the lipid-lowering properties of the compounds according to the invention
• the effect of the compounds according to the invention is evaluated in vivo in the humanized mouse for the E2 isoform of apolipoprotein E (E2 / E2).
• the total cholesterol and plasma triglyceride levels are measured in the E2 / E2 dyslipidemic mouse after 7 days of oral treatment with the compounds according to the invention.
• These parameters are compared with those obtained with control animals (not treated with the compounds according to the invention): the measured difference reflects the effect on body weight and the lipid-lowering effect of the compounds according to the invention.
• FIG. 4a Plasma cholesterol level after 7 days of treatment with compound 1, administered at 25, 50, 100 and 200 mpk.
• FIG. 4b Plasma triglyceride levels after 8 days of treatment with compound 1, administered at 25, 50, 100 and 200 mpk.
• the effectiveness of the compounds according to the invention is also evaluated by measuring, in liver tissue and epididymal adipose tissue, the expression of genes involved in lipid and / or carbohydrate metabolism. Expression levels of each gene are normalized to the level of expression of a reference gene (36B4 in liver tissue and 18S in adipose tissue).
• the induction factor that is to say the ratio between the relative signal (induced by the compound according to the invention) and the average of the relative values of the control group, is then calculated. The higher this factor, the more the compound has an activating character of gene expression. The final result is represented as the average of the induction values in each experimental group.
• FIG. 4d Expression of ACO (acyl-CoA oxidase) in hepatic tissue, in E2 / E2 mice, after 7 days of treatment with compound 1, administered at 4 doses (25, 50, 100 and 200 mpk)
• FIG. 4e Expression of Apo CIII (Apolipoprotein C3) in liver tissue, in E2 / E2 mice, after 7 days of treatment with compound 1, administered at 4 doses (25, 50, 100 and 200 mpk)
• FIG. 4f Expression of PEPCK (PhosphoEnoIPyruvate CarboxyKinase) in Epididymal Adipose Tissue, in the E2 / E2 Mouse, After 7 Days of Treatment with Compound 1, Administered at Four Doses (25, 50, 100 and 200 mpk)
• PEPCK PhosphoEnoIPyruvate CarboxyKinase
• FIGS. 5a to 5e In vivo evaluation, in the ApoE2 / E2 mouse, of the lipid-lowering properties of the compounds according to the invention
• the effect of the compounds according to the invention is evaluated in vivo in the humanized mouse for the E2 isoform of apolipoprotein E (E2 / E2).
• the total cholesterol and plasma triglyceride levels are measured in the E2 / E2 dyslipidemic mouse after 7 days of oral treatment with the compounds according to the invention. These parameters are compared with those obtained with control animals (not treated with the compounds according to the invention): the measured difference reflects the effect on body weight and the lipid-lowering effect of the compounds according to the invention
• FIG. 5a Plasma cholesterol level after 7 days of treatment with compound 21, administered at 10, 30 and 100 mpk.
• the effectiveness of the compounds according to the invention is also evaluated by measuring, in liver tissue, the expression of genes involved in lipid and / or carbohydrate metabolism.
• the expression levels of each gene are normalized to the level of expression of the reference gene 36B4.
• the induction factor that is the ratio between the relative signal (induced by the compound according to the invention) and the average of the relative values of the control group, is then calculated. The higher this factor, the more the compound has an activating character of gene expression. The final result is represented as the average of the induction values in each experimental group.
• FIG. 5d Expression of PDK4 (Pyruvate Dehydrogenase Kinase, Isoform 4) in liver tissue, in E2 / E2 mice, after 7 days of treatment with compound 21, administered at 10, 30 and 100 mpk.
• Figure 5e Expression of ACO (acyl-CoA oxidase) in liver tissue, in E2 / E2 mice, after 7 days of treatment with compound 21, administered at 10, 30 and 100 mpk.
• ACO acyl-CoA oxidase
• FIGS. 6a to 6h In vivo evaluation, in the db / db mouse, of the antidiabetic and anti-lipid properties of the compounds according to the invention.
• the effect of the compounds according to the invention is evaluated in vivo in db / db mice by measuring total cholesterol, triglycerides, plasma glucose and insulin levels after 28 days of oral treatment with the compounds according to the invention. the invention. These parameters are compared with those obtained with control animals (not treated with the compounds according to the invention): the measured difference reflects the lipid-lowering effect and the effect on the insulin resistance of the compounds according to the invention. .
• FIG. 6a Plasma triglyceride levels after 28 days of treatment with compound 1, administered at 10, 30 and 100 mpk
• FIG. 6b Plasma free fatty acid levels after 28 days of treatment with compound 1, administered at 10, 30 and 100 mpk
• the effectiveness of the compounds according to the invention is also evaluated by measuring, in liver tissues, the expression of genes involved in metabolism. carbohydrate and lipid, energy dissipation and anti-inflammatory response.
• the expression levels of each gene are normalized to the level of expression of the 36B4 reference genes.
• the induction factor that is to say the ratio between the relative signal (induced by the compound according to the invention) and the average of the relative values of the control group, is then calculated. The higher this factor, the more the compound has an activating character of gene expression. The final result is represented as the average of the induction values in each experimental group.
• FIG. 6g Expression of ApoCIII (Apolipoprotein C3) in the liver tissue, in db / db mice, after 28 days of treatment with compound 1, administered at 10, 30 and 100 mpk.
• ApoCIII Apolipoprotein C3
• FIG. 6h Expression of FGb (fibrinogen beta chain) in liver tissue, in db / db mice, after 28 days of treatment with compound
• FIGS. 7a to 7i In vivo evaluation, in the db / db mouse, of the antidiabetic and anti-lipid properties of the compounds according to the invention.
• the effect of the compounds according to the invention is evaluated in vivo in db / db mice by measuring total cholesterol, triglycerides, plasma glucose and insulin levels after 28 days of oral treatment with the compounds according to the invention. the invention. These parameters are compared with those obtained with control animals (not treated with the compounds according to the invention): the measured difference reflects the lipid-lowering effect and the effect on the insulin resistance of the compounds according to the invention.
• FIG. 7a Plasma triglyceride levels after 28 days of treatment with compound 21, administered at 100 mpk.
• FIG. 7b Plasma free fatty acid levels after 28 days of treatment with compound 21, administered at 100 mpk
• FIG. 7c glycemia after 28 days of treatment with compound 21, administered at 100 mpk
• the effectiveness of the compounds according to the invention is also evaluated by measuring, in liver tissues and adipose epididymal tissues, the expression of genes involved in carbohydrate and lipid metabolism, energy dissipation and the anti-inflammatory response. Expression levels of each gene are normalized to the level of expression of the reference genes (36B4 in liver tissue and 18S in adipose tissue).
• the induction factor that is to say the ratio between the relative signal (induced by the compound according to the invention) and the average of the relative values of the control group, is then calculated. The higher this factor, the more the compound has an activating character of gene expression. The final result is represented as the average of the induction values in each experimental group.
• Figure 7e Expression of PDK4 (Pyruvate Dehydrogenase Kinase, Isoform 4) in liver tissue, in db / db mice, after 28 days of treatment with compound 21, administered at 100 mpk.
• PDK4 Poruvate Dehydrogenase Kinase, Isoform 4
• CPTIb Carnitine PalmitoyITransferase 1b
• FIG. 7g Expression of ApoCIII (Apolipoprotein C3) in the liver tissue, in db / db mice, after 28 days of treatment with compound 21, administered at 100 mpk.
• ApoCIII Apolipoprotein C3
• FIG. 7h Expression of FGb (fibrinogen beta chain) in liver tissue, in db / db mice, after 28 days of treatment with compound 21, administered at 100 mpk.
• FIG. 7i Expression of PEPCK (PhosphoEnoIPyruvate CarboxyKinase) in epididymal adipose tissue, in db / db mice, after 28 days of treatment with compound 21, administered at 100 mpk.
• PEPCK PhosphoEnoIPyruvate CarboxyKinase
• FIGS. 8a and 8b In vivo evaluation of the angiotensin II antagonist properties of the compounds according to the invention in rats
• FIG. 8a Measurement of the arterial pressure (P) in the Wistar rat under perfusion of angiotensin II and treated with compound 1 (1, 3, 10 and 30 mpk) intravenously. The results, expressed in mmHg, express the arterial pressure measured after administration of the compounds according to the invention at the indicated dose.
• FIG. 8b Measurement of the arterial pressure (P) in the Wistar rat under perfusion of angiotensin II and treated with compound 21 (1, 3, 10 and 30 mpk) intravenously.
• results express the arterial pressure measured after administration of the compounds according to the invention at the indicated dose.
• FIG. 8c Measurement of the difference in arterial pressure ( ⁇ P) in the Wistar rat under repeated administrations of angiotensin II (at 50, 100 and 200 ng / kg) and treated with compound 1 (20 mpk) intravenously .
• the results, expressed in mmHg, express the difference in arterial pressure measured between the basal pressure and the pressure measured after intravenous administration of angiotensin II (transient hypertension) and after intravenous administration of the compounds according to the invention to 20 mpk.
• Figures 9, 10 and 11 In vivo evaluation of the cardio-protective properties of the compounds according to the invention - Figure 9: Plasma triglyceride levels after 14 days of treatment with compound 1, administered at 150 mpk. The measured levels are compared with those obtained with control animals (not treated with the compounds according to the invention): the measured difference reflects the lipid-lowering effect of the compounds according to the invention.
• FIG. 10a Measurement of arterial pressure (P) in SHR rats treated for 14 days with compound 1 (150 mpk), before repeated administration of angiotensin II (50 ng / kg)
• the results express the arterial pressure measured after 14 days of treatment.
• FIG. 10b Measurement of the difference in arterial pressure ( ⁇ P) in SHR rats treated for 14 days with compound 1 (150 mpk), after 3 successive intravenous administrations of angiotensin II (50 ng / kg). The results , expressed in mm of Hg, express the difference in arterial pressure measured between the basal pressure and the pressure measured after administration of angiotensin II (transient hypertension).
• Figure 10c Measurement of the difference in arterial pressure ( ⁇ P) in the rat
• FIG. 11b Expression of PDK4 in hepatic tissue, in SHR rats, after 14 days of treatment with compound 1, administered at 150 mpk.
• the expression levels of each gene are determined and then normalized with respect to the level of expression of the reference gene 36B4.
• the induction factor that is to say the ratio between the relative signal (induced by the compound according to the invention) and the average of the relative values of the control group, is then calculated. The higher this factor, the more the compound has an activating character of gene expression. The final result is represented as the average of the induction values in each experimental group. ⁇ !
• FIG. 12 In vitro evaluation of the anti-inflammatory properties of the compounds according to the invention by measuring the secretion of MCP1 by monocytes treated with the compounds according to the invention and stimulated with PMA
• the anti-inflammatory effects of the compounds according to the invention were evaluated by measuring the secretion of MCP1 (monocyte chemotactic protein-1) by THP1 monocytes treated for 24 hours with the compounds according to the invention and stimulated simultaneously with PMA. (Phorbol 12-myristate 13-acetate, causes an inflammatory response of cells and their differentiation into macrophages). The more the amount of MCP-1 expressed is decreased, the more the compound according to the invention inhibits the inflammatory reaction.
• MCP1 monocyte chemotactic protein-1
• FIG. 13 In vitro evaluation of the anti-inflammatory properties of the compounds according to the invention by measuring the secretion of MCP1, IL8, VCAM and ICAM by HUVECs (Hiiman Umbilical Vein Endothelial CeIIs) treated with the compounds according to the invention and stimulated with LPS.
• HUVECs Hiiman Umbilical Vein Endothelial CeIIs
• MCP1 Monocyte chemotactic protein-1
• IL5 Interleukin 8
• VCAM Vascular CeII adhesion molecule
• ICAM Intercellular CeII Adhesion Molecule
• HUVEC after 24 hours of treatment with the compounds according to the invention at 10 and 50 ⁇ M 13b: Secretion of IL8 (Interleukin 8) in the HUVECs, after 24 hours of treatment with the compounds according to the invention at 10 and 50 ⁇ M
• VCAM Vascular CeII Adhesion Molecule
• TLC thin layer chromatography
• HPLC high performance liquid chromatography
• IR infra-red spectra
• the mass spectra are produced by ESI-MS (Electrospray Ionization - mass spectroscopy) or MALDI-TOF (Matrix Assisted Laser Desorption / lonization - Time of Flight).
• the NMR spectra are recorded at 200 or 300 MHz in a deuterated solvent which is specified for each analysis: DMSO- ⁇ k, CDCl3 or Methanol-d4.
• s for singlet if for singlet wide, d for doublet, dd for doublet split, ddd for double doublet split, t for triplet, td for doublet triplet, q for quadruplet, quintuplet, sext for sextuplet, m for multiplet or massive.
• Method 1A The nitrile chosen (1eq) is added at 0 ° C. to a solution of anhydrous ethanol saturated with gaseous hydrochloric acid. The reaction mixture is stirred at 0 ° C. for 96 h. The medium is then diluted in anhydrous diethyl ether and placed at -80 ° C. The ethyl imidate precipitates in the hydrochloride form. The precipitate is filtered and washed with diethyl ether at -20 ° C. The crystals are dried under vacuum in the presence of P2O5.
• Method 1 B The nitrile chosen (1eq) is added at 0 ° C. to a solution of anhydrous ethanol saturated with gaseous hydrochloric acid (6.3eq). The reaction mixture is stirred at room temperature for 18 hours. The reaction medium is concentrated to dryness under reduced pressure and then dried under high vacuum.
• Example 1.8 2- (thiophen-3-yl) ethylacetimidate hydrochloride Obtained as a white powder according to the general procedure described above (method 1B) from 2- (thiophen-3-yl) acetonitrile.
• the aminocarboxylic acid (1eq) is added at 0 ° C. to the chosen alcohol (methanol or ethanol) and then this mixture is saturated with gaseous hydrochloric acid in an anhydrous manner.
• Thionyl chloride is added dropwise.
• the reaction mixture is refluxed for 12 hours. After disappearance of raw materials, the reaction medium is brought to dryness under vacuum. The residue obtained after evaporation of the solvents is taken up in diethyl ether. The powder obtained is filtered and washed with diethyl ether.
• the product is obtained in the form of an oil.
• alkyl ester iodides are obtained by reacting methyl 2-methylpropanoate and alkyl diodide chosen in the presence of butyllithium and diisopropylamine according to the method described below:
• N, N-diisopropylamine (1, 1eq) is dissolved in tetrahydrofuran (10eq).
• the solution is cooled to 0 ° C. before adding dropwise n-butyllithium (1.1 eq).
• the solution is then cooled to -70 ° C. before adding 2-methylpropanoic acid (1eq).
• the solution is stirred at -70 ° C. for 15 minutes.
• the chosen diiodinated derivative (2eq) is added dropwise at -70 ° C. and the reaction mixture is gradually brought back to ambient temperature and left stirring for 20 hours.
• the solution is then hydrolysed by addition of 2N HCl to acidic pH.
• the aqueous phase is extracted with ethyl acetate.
• the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and taken to dryness.
• the residue is purified by chromatography on silica gel.
• Phenethyl bromides are obtained in 2 steps from the selected 2- (hydroxyphenyl) ethanol: the phenol function is alkylated and then the hydroxyl function carried on the alkyl chain is substituted by bromine. Substitution of the phenol function.
• the selected phenol (1eq) and bromo derivative (1eq) are solubilized in acetonitrile before adding potassium carbonate in suspension.
• the reaction mixture is refluxed for 12 hours.
• the medium is then brought back to room temperature, acidified with a 1N hydrochloric acid solution and then extracted with ethyl acetate.
• the organic phases are combined, dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel. bromination
• the product is purified by chromatography on silica gel (eluent cyclohexane / ethyl acetate 95/5). The product is obtained in the form of a colorless oil.
• the product is purified by chromatography on silica gel (eluent cyclohexane / ethyl acetate 98/2 then cyclohexane / ethyl acetate 95/5).
• the product is obtained in the form of a colorless oil.
• the product is purified by chromatography on silica gel (eluent cyclohexane / ethyl acetate 95/5). The product is obtained in the form of a colorless oil.
• biarylmethyl bromides are obtained in several stages according to different methods:
• Method 6A from the selected bromophenol, whose phenol function is alkylated. O-alkylation is followed by a Suzuki reaction. The aromatic methyl finally undergoes radical bromination. Substitution of bromophenol The bromophenol (1eq) and the halogenated derivative (3eq) chosen are solubilized in acetonitrile before adding the potassium carbonate (3eq) in suspension. The reaction mixture is refluxed for 12 hours. The medium is then brought back to ambient temperature and then acidified with a 1N hydrochloric acid solution and then extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel.
• N-bromosuccinimide (1, 2eq), benzoyl peroxide (0.08eq) and the biphenylmethyl derivative (1eq) obtained above are dissolved in chloroform.
• the reaction mixture is refluxed under a light source (500 W).
• the medium turns brown after 15 minutes of agitation at reflux and then fades gradually.
• the medium is brought back to ambient temperature and washed with water.
• the aqueous phase is extracted with dichloromethane.
• the organic phases are combined, dried over magnesium sulphate and evaporated under vacuum.
• the residue is purified by chromatography on silica gel. Analyzes of the purified product may show the presence of a portion of a derivative also bearing a bromine atom on the aromatic ring.
• Method 6B from the selected bromophenol.
• the Suzuki reaction is followed by O-alkylation.
• the aromatic methyl finally undergoes radical bromination.
• Reaction of Suzuki The boronic acid (1, 25eq) and the bromophenol (1eq) chosen are dissolved in 1,2-dimethoxyethane (100eq) under nitrogen before adding the palladium derivative tetrakis (triphenylphosphine) palladium (Pd [ P (Ph) 3 ] 4 ) (0.034eq).
• the reaction medium is refluxed for 12 hours. Water is added and the medium is extracted 3 times with ethyl acetate.
• the organic phases are combined, dried over sodium sulphate and brought to dryness.
• the residue is purified by chromatography on silica gel. Substitution of phenol
• the phenylphenol obtained (1eq) is dissolved in dimethylformamide.
• the brominated derivative chosen (4eq) is added at 80 ° C. before adding the potassium carbonate (3eq).
• the reaction mixture is stirred at 80 ° C. for 12 hours before adding bromine derivative (4eq) and potassium carbonate (4eq) again.
• the heating is maintained for 20 hours.
• Dimethylformamide is evaporated under vacuum.
• the residue is dissolved in ethyl acetate and washed with water.
• the aqueous phase is washed with ethyl acetate.
• the organic phases are combined, dried over sodium sulphate, filtered and evaporated to dryness.
• the residue is purified by chromatography on silica gel. Bromation of methyl
• the previously obtained biphenylmethyl derivative (1eq) is dissolved in carbon tetrachloride (80eq) before adding N-bromosuccinimide (1, 2eq) and 2,2'-azo-bis-isobutyronitrile (AIBN) (0.015eq) .
• the reaction mixture is heated at 80 ° C for 15 min before adding (0.016 eq) AIBN.
• the mixture is stirred under reflux for 12 hours.
• the reaction mixture is cooled to room temperature.
• the solid formed is filtered and the filtrate is evaporated to dryness.
• the residue is taken up in dichloromethane and washed with a saturated aqueous solution of sodium thiosulphate and then with a saturated aqueous solution of sodium chloride.
• Bromotoluene (1eq) is dissolved in dioxane (30eq) before successively adding hydroxyphenylboronic acid (1, 1 eq), the palladium derivative tetrakis (triphenylphosphine) palladium (Pd [P (Ph) 3 ] 4 ) (0 , 03eq) and potassium carbonate (3eq).
• the reaction medium is heated at 100 ° C. for 16 hours. After cooling, the solvent is evaporated under vacuum.
• the residue is taken up in ethyl acetate and washed with a saturated aqueous solution of sodium chloride.
• the organic phase is dried over sodium sulphate, filtered and brought to dryness.
• the residue is purified by chromatography on silica gel.
• Method 6D From the selected 1,2,4-triazole-3-thiol, thiazolotriazole bearing the ester function is prepared. Cyclization is followed by a reduction of the ester function to alcohol. The hydroxyl group finally reacts with N-bromosuccinimide and triphenylphosphine to give the brominated derivative. Cyclization of 1,2,4-triazole-3-thiol to thiazolotriazole
• 1,2,4-Triazole-3-thiol (1eq) is solubilized in absolute ethanol. 2-chloroacetoacetate ethyl (1eq) is added dropwise at room temperature and the reaction is continued at reflux for 12 hours. The precipitate formed is filtered, washed with ethanol and dried in an oven. Ester reduction
• ester (1eq) is dissolved in anhydrous THF.
• the medium is cooled in an ice bath to which sodium chloride has been added and the lithium tetrahydroaluminate (1eq) is added portionwise.
• the reaction medium is stirred for 2 hours.
• the filtrate is evaporated and the residue is recrystallized from acetonitrile.
• Preparation of the brominated derivative The alcohol previously obtained (1eq) is suspended in acetonitrile and then cooled to 0 ° C.
• the triphenylphosphine (3eq) is added portionwise.
• N-bromosuccinimide (3eq) is added in small portions at 0 ° C.
• the reaction mixture is stirred at room temperature for 12 hours.
• the medium is evaporated at room temperature.
• the residue is then taken up in a minimum of dichloromethane and purified by filtration on silica gel.
• Example 6.1 Ethyl 2 - ((4'-bromomethylbiphenyl-2-yl) oxy) -2-methylpropanoate and ethyl 2 - ((5-bromo-4'-bromomethylbiphenyl-2-yl) oxy) -2-methylpropanoate - UU -
• Example 6.2 Ethyl 2 - ((4'-bromomethylbiphenyl-3-yl) oxy) -2-methylpropanoate and ethyl 2 - ((6-bromo-4'-bromomethylbiphenyl-3-yl) oxy) -2-methylpropanoate
• Method 6A from 3-bromophenol and ethyl 2-bromoisobutyrate.
• the product is purified by chromatography on silica gel (eluent cyclohexane / ethyl acetate 9/1).
• the product is obtained in the form of a colorless oil.
• the product is purified by chromatography on silica gel (eluent cyclohexane / acetone 97/3). The product is obtained in the form of a colorless oil (mixture of the two compounds).
• Method 6A from 4-bromophenol and ethyl 2-bromoisobutyrate.
• the product is purified by chromatography on silica gel (eluent cyclohexane / ethyl acetate 95/5).
• the product is obtained in the form of a colorless oil.
• the product is purified by chromatography on silica gel (eluent cyclohexane / ethyl acetate 95/5). The product is obtained in the form of a colorless oil.
• the product is purified by chromatography on silica gel (eluent cyclohexane / ethyl acetate 98/2 then 99/1).
• the product is obtained in the form of a colorless oil.
• the product is obtained in the form of a colorless oil.
• the product is obtained in the form of a white solid.
• Example 6.8.2 The product is purified by chromatography on silica gel (eluent cyclohexane / ethyl acetate 100/0 to 96/4). The product is obtained in the form of a yellow oil.
• the benzoylbenzyl bromides are obtained in 3 or 4 stages from toluene and methoxybenzoyl chloride chosen. Friedel-Crafts acylation is followed by the demethylation of the methoxy function followed by O-alkylation. The aromatic methyl finally undergoes radical bromination. Friedel-Crafts acylation
• the aluminum chloride (1, 1eq) is added to toluene (10eq) at 0 0 C.
• the acid chloride chosen (1eq) is added dropwise.
• the reaction mixture is cooled to room temperature and stirred for 12 hours.
• the reaction medium is hydrolyzed slowly by adding water and then extracted with ethyl acetate.
• the organic phases are combined, dried over magnesium sulphate and brought to dryness.
• the residue is purified by chromatography on silica gel.
• N-bromosuccinimide (1, 2eq), benzoyl peroxide (0.08eq) and the phenyltolylmethanone derivative (1eq) obtained above are dissolved in chloroform.
• the reaction mixture is refluxed under a light source
• the medium turns brown after 15 minutes of agitation at reflux and then fades gradually.
• the medium is brought back to ambient temperature and washed with water.
• the aqueous phase is extracted with dichloromethane.
• the organic phases are combined, dried over magnesium sulphate and evaporated under vacuum. The residue is purified by chromatography on silica gel.

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