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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
  • C07D213/46—Oxygen atoms
  • C07D213/50—Ketonic radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/12—Ketones
  • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
  • C07C45/28—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of CHx-moieties
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C46/00—Preparation of quinones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C50/00—Quinones
  • C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
  • C07C50/28—Quinones containing groups having oxygen atoms singly bound to carbon atoms with monocyclic quinoid structure

Definitions

• the present invention relates to new derivatives of 3-aryl-2,5-dihydroxy-1,4-benzoquinones, their preparation process, the pharmaceutical compositions which contain them as well as their use as anti-diabetics.
• the derivatives of the present invention exhibit insulinomimetic properties such as an increase in the autophosphorylation of the insulin receptor and of protein kinase B.
• Insulin resistance is a very complex syndrome with defects at different levels of the intracellular signaling cascade of insulin.
• insulin receptors Kahn et al., Mechanism of action of hormones that act at the cell surface, 8 th edition, WB 91-134, Saunders, Philadelphia, 1992
• This post-receptor defect is located on the one hand on the tyrosine phosphorylation of 1TRS1 and on the other hand on the IRS1 / PI3 kinase interaction (Y. Le Marchand-Brustel, Exp. Clin. Endocrinol. Diabetes, 1999, 107, 126-132), thereby limiting the activation of protein kinase
• the properties of the compounds of the present invention on the insulin receptor and protein kinase B therefore make them extremely advantageous for the treatment of diseases associated with deregulation of glycemia. They may in particular be used in the treatment of diabetes (type I or type II diabetes).
• VR ⁇ and R 2 identical or different, each represent a hydrogen atom or a linear or branched (Ci-C 6 ) acyl group, or linear or branched (CrC 6 ) alkyl, Ar represents an aryl or heteroaryl group, A represents a group chosen from:
• R 4 substitutes the carbon atom linked to the benzoquinone ring and represents a hydrogen atom or a linear or branched (CrC 6 ) alkyl group
• R 5 substitutes the carbon atom linked to the residue R 3 and represents a hydrogen atom or a group chosen from linear or branched (-C 6 ) alkyl, aryl and heteroaryl,
• VR 3 represents an aryl, heteroaryl, dicyclopropylmethyl or benzhydryl group, or AR 3 represents an optionally substituted naphthyl group, and in this case Ar represents an aryl group,
• aryl group is understood to mean phenyl, biphenylyl, naphthyl or tetrahydronaphthyl, each of these groups being optionally substituted by one or more atoms or groups, identical or different, chosen from halogen atoms and alkyl groups (C ⁇ -C 6 ) linear or branched, hydroxy, alkoxy (dC 6) linear or branched polyhaloalkyl (C i -C 6) linear or branched, amino (optionally substituted by one or more alkyl (Ci-Ce) linear or branched), nitro, linear or branched (Ci-C 6 ) acyl, alkylenedioxy (Ci-C 2 ) or phenyloxy.
• halogen atoms and alkyl groups C ⁇ -C 6 ) linear or branched, hydroxy, alkoxy (dC 6) linear or branched polyhaloalkyl (C i -C 6) linear or branched
• optionally substituted naphthyl group means a naphthyl group which is unsubstituted or substituted by one or more atoms or groups, identical or different, chosen from halogen atoms and linear or branched (C 1 -C 6 ) alkyl groups, hydroxy, linear or branched alkoxy (Ci-Ce), linear or branched polyhaloalkyl (Ci-C 6 ), amino (optionally substituted by one or more alkyl groups (Ci-C 6 ) linear or branched), nitro, acyl (Ci-C 6 ) linear or branched, alkylenedioxy (Ci-C 2 ) or phenyloxy.
• heteroaryl group is meant a 5 to 12-membered mono- or bicyclic aromatic group containing one, two or three heteroatoms chosen from oxygen, nitrogen or sulfur, it being understood that the heteroaryl may be optionally substituted by one or more atoms or groups , identical or different, chosen from halogen atoms and linear or branched (Ci-Ce) alkyl, hydroxy, linear or branched (Ci-C 6 ) alkoxy, linear or branched polyhaloalkyl (CrC 6 ), amino (substituted optionally with one or more alkyl (Ci -This) linear or branched), nitro, acyl (Q-Ce) linear or branched alkylenedioxy (Ci-C 2), or phenyloxy.
• heteroaryl groups non-limiting mention may be made of thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl and pyrimidinyl groups.
• stereoisomer is meant a geometric double bond isomer or an optical isomer.
• V Ri and R 2 identical or different, each represents a hydrogen atom or an acyl group (Ci-C 6) linear or branched alkyl or (Ci-C 6) linear or branched,
• VR 3 represents an aryl, heteroaryl, dicyclopropylmethyl or benzhydryl group
• V Ar represents an aryl or heteroaryl group
• V A represents a group chosen from:
• R substitutes the carbon atom linked to the benzoquinone ring and represents a hydrogen atom or a linear or branched (Ci-C 6 ) alkyl group
• R 5 substitutes the carbon atom linked to the residue R 3 and represents a hydrogen atom or a group chosen from linear or branched (Ci-C 6 ) alkyl, aryl and heteroaryl,
• V Ri and R identical or different, each represent a hydrogen atom or an acyl group (C ⁇ -C 6 ) linear or branched, or alkyl (Ci-C 6 ) linear or branched, Ar represents an aryl group, AR 3 represents an optionally substituted naphthyl group,
• the preferred Ri and R groups are the hydrogen atom.
• Ar advantageously represents an aryl group and more particularly the phenyl or naphthyl groups, unsubstituted or substituted.
• Ar represents a phenyl or naphthyl group, these groups being unsubstituted or substituted by a halogen atom such as chlorine or bromine for example.
• the preferred AR 3 groups are the unsubstituted or substituted naphthyl group and the arylethenyl group and more particularly the non-phenylethenyl group. substituted or substituted.
• the substitutions of these naphthyl and phenylethenyl groups are preferably halogen atoms such as chlorine, bromine or fluorine.
• stereoisomers as well as the addition salts with a pharmaceutically acceptable acid or base of the preferred compounds of the invention form an integral part of the invention.
• hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulfonic, camphoric acids. , oxalic.
• the invention also relates to a novel derivative of 3-aryl-2,5-dihydroxy-1,4-benzoquinone which is 2- (4-bromophenyl) -3,6-dihydroxy-5-phenyl-1,4-benzoquinone , as well as its addition salts with a pharmaceutically acceptable base.
• the invention also extends to a process for preparing the compounds of formula (I), characterized in that a compound of formula (II) is reacted:
• R represents a linear or branched (Ci-C 6 ) alkyl group
• the compounds of the present invention in addition to the fact that they are new, exhibit advantageous pharmacological properties. They have insulin-like properties that make them useful in the treatment of diseases associated with blood sugar dysregulation, such as type I or IL diabetes
• the invention also extends to pharmaceutical compositions containing as active principle at least one compound of formula (I) with one or more inert, non-toxic and suitable excipients.
• pharmaceutical compositions according to the invention mention may be made more particularly of those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), nasal administration, simple or coated tablets, sublingual tablets, capsules, tablets, suppositories, creams, ointments, dermal gels, injections, oral suspensions, etc.
• the useful dosage is adaptable according to the nature and severity of the condition, the route of administration as well as the age and weight of the patient and any associated treatments. This dosage varies from 0.5 mg to 2 g per 24 hours in one or more doses.
• the expected product is obtained according to the process described in Example 1, replacing, in stage D, the cinnamaldehyde with 4-chloro-cinnamaldehyde.
• the expected product is obtained according to the process described in Example 1, replacing, in stage D, cinnamaldehyde with 4-bromo-cinnamaldehyde.
• the expected product is obtained according to the process described in Example 1, replacing, in stage D, cinnamaldehyde with 3-phenyl-2-propynal.
• the expected product is obtained according to the process described in Example 1 by replacing, in stage D, the cinnamaldehyde with 3,3-diphenylacrylaldehyde.
• the expected product is obtained according to the process described in Example 1 by replacing, in stage D, the cinnamaldehyde with (2E) -3- (2-naphthyl) -2-propenal.
• the expected product is obtained according to the process described in Example 1, replacing, in Stage D, cinnamaldehyde with 2-phenylcyclopropane carbaldehyde.
• the expected product is obtained according to the process described in Example 1, replacing, in stage D, cinnamaldehyde with (2Z) -3-phenyl-2-propenal.
• the expected product is obtained according to the process described in Example 1, replacing, in Stage D, cinnamaldehyde with (2 £) -2-methyl-3-phenyl-2-propenal. Melting point: 205-206 ° C
• the expected product is obtained according to the process described in Example 1 by replacing, in stage D, the cinnamaldehyde with (2E) -3-phenyl-2-butenal.
• the expected product is obtained according to the process described in stages B to D of Example 1, from the compound obtained in the preceding stage.
• the expected product is obtained according to the process described in Example 13 by replacing, in stage A, (4-chlorophenyl) -acetyl chloride with (4-phenoxyphenyl) -acetyl chloride.
• the expected product is obtained according to the process described in Example 13 by replacing, in Stage A, (4-chlorophenyl) -acetyl chloride with 2-pyridylacetyl chloride.
• Stage B 4- (4-Chlorophenyl) -3-hydroxy-6- (2-naphthylmethylene) -pyran-2,5-dione
• the flask After cooling to room temperature, the flask is immersed in an ice bath and 10 ml of a mixture of diethyl ether and hexane (1/1) are added.
• the title product is obtained in the form of a yellow powder after filtration.
• the title compound is obtained in the form of a yellow powder after recrystallization from a CH 2 C1 2 / Hexane mixture.
• Example 13 The procedure is as in Example 13 starting from (4-fluorophenyl) acetyl chloride and naphthaldehyde.
• Example 13 The procedure is as in Example 13 starting from (4-bromophenyl) acetyl chloride and naphthaldehyde.
• Example 13 The procedure is as in Example 13 starting from (2-chlorophenyl) acetyl chloride and naphthaldehyde. Brown powder.
• Example 13 The procedure is as in Example 13 starting from (3-trifluoromethylphenyl) acetyl chloride and naphthaldehyde.
• Example 13 The procedure is as in Example 13 starting from (4-nitrophenyl) acetyl chloride and naphthaldehyde.
• Example 13 The procedure is as in Example 13 starting from (4-bromophenyl) acetyl chloride and (6-methoxy) -2-naphthaldehyde.
• Example 13 The procedure is as in Example 13 starting from (3-chlorophenyl) acetyl chloride and naphthaldehyde.
• Example 13 The procedure is as in Example 13, taking as starting material (4-bromophenyl) acetyl chloride.
• Example 13 The procedure is as in Example 13, taking as starting material (2-chlorophenyl) acetyl chloride.
• Example 13 The procedure is as in Example 13, taking as starting material (3-chlorophenyl) acetyl chloride.
• Example 13 The procedure is as in Example 13 starting from (4-chlorophenyl) acetyl chloride and 3,3-diphenylacrylaldehyde.
• Example 13 The procedure is as in Example 13, taking as starting material (4-fluorophenyl) acetyl chloride.
• Example 13 The procedure is as in Example 13, taking as starting material (3-methylphenyl) acetyl chloride.
• Example 13 The procedure is as in Example 13 starting from (4-ethylphenyl) acetyl chloride and 4-fluoro-cinnamaldehyde.
• the pharmacological effect of the compounds of the invention on cell signaling is evaluated in vitro on hamster ovary cells transfected with human insulin receptors (CHO-HIR).
• the techniques used come from TA V ARE and DENTON (1988, BIOCHEM. J., 250, 509-519) and TAVARE et al. (1988, Biochem. J.,
• the products are studied at 10 "5 M in incubation for two hours at 37 ° C on CHO-HIR in culture.
• a negative control (solvent) and positive control (50 nM insulin, 5 min incubation) were introduced in parallel in the same test.
• the enzymatic reactions are immediately stopped by a mixture of protease inhibitors (aprotinin, pepstatin, antipain, leuleptin, AEBSF) and the samples are immersed in ice at 4 ° C.
• protease inhibitors aprotinin, pepstatin, antipain, leuleptin, AEBSF
• the insulin receptor (IR) and protein kinase B phosphorylations are evaluated by immunoblotting as follows.
• the IRs are extracted from wheat germ lectin; the samples are then deposited by electrophoresis on 7.5% polyacrylamide gel and undergo an electrotransfer on a PDVF membrane in a semi-dry system. After blocking, the membranes are incubated with an antiphosphotyrosine antibody (p-tyr (PY99), ref SC7020, Santa Cruz) and the chemiluminescence associated with a conjugated antibody is detected by a LAS 1000 camera (Fujifilm).
• PY99 antiphosphotyrosine antibody
• ref SC7020 ref SC7020
• the amount of total IR deposited on blot is evaluated by chemiluminescence and the rate of phosphorylation of the receptors is reduced. to the amount of total receptor deposited.
• the determination of the protein kinase B phosphorylation state following an electrophoresis of the samples on 10% polyacrylamide gel is carried out by chemiluminescence after immunoblotting with anti-phospho protein kinase B (phospho Akt (Ser473) antibody) antibodies. , ref 9271, Cell Signaling) then related to the amount of total protein kinase B (AKT antibody, ref 9272, Cell signaling).
• anti-phospho protein kinase B phospho Akt (Ser473) antibody
• the phosphorylation induced by the compounds of the invention is expressed as a percentage relative to the insulin at 50 nM, fixed at 100% activation.
• the compounds of the invention activate either predominantly insulin receptors, predominantly protein kinase B, or both, which demonstrates their potential activity as insulinomimetic compounds.
• the compound of Example 27 to 10 "5 M has an activation percentage
• the compound of Example 30, at 10 " 5 M, has a activation percentage of
• mice 11-week-old female C57BL / 6 ob / ob mice, randomized to basal glycemia in fed animals, are treated for 9 days with the test compound at 10 or 20 mg / kg ⁇ o and compared to a control group receiving HEC 1%.
• Laboratory tests blood glucose, insulin, triglycerides
• the results are expressed in the form of percentages of variation compared to D0 (glycemia, body weight) compared to the control group.
• D0 glycemia, body weight
• the results obtained show that the body weight is significantly reduced after treatment with the compounds of the invention.
• the compound of Example 16 shows a decrease of -26.9% while the result obtained for the control group is
• the glycemia as well as the insulinemia are also greatly reduced during the treatment with the compounds of the invention.
• a result of -60.7% was recorded, compared to + 4.5% for the controls for glycemia, and -84.2% compared to the controls for insulinemia.
• the results obtained also show a decrease in triglycerides during treatment with the compounds of the invention: by way of example, the compound of Example 1 shows a reduction of -37.8% compared to the control.

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