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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
  • C07C69/734—Ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/35—Ketones, e.g. benzophenone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/37—Esters of carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q5/00—Preparations for care of the hair
  • A61Q5/008—Preparations for oily hair
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C21/00—Acyclic unsaturated compounds containing halogen atoms
  • C07C21/02—Acyclic unsaturated compounds containing halogen atoms containing carbon-to-carbon double bonds
  • C07C21/14—Acyclic unsaturated compounds containing halogen atoms containing carbon-to-carbon double bonds containing bromine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
  • C07C403/02—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains containing only carbon and hydrogen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/008—Preparations for oily skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/08—Anti-ageing preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q7/00—Preparations for affecting hair growth
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the invention relates, as new and useful industrial products, to new fumagalone derivatives. It also relates to their method of preparation and their use in pharmaceutical compositions intended for use in human or veterinary medicine, or in cosmetic compositions.
• angiogenesis is the formation of new blood microvessels from already existing vessels. Angiogenesis plays an important role in the development of embryonic tissues but almost never occurs in healthy adult tissues.
• Angiogenesis is also associated with the pathological process of various inflammatory diseases. As such, the inhibition of angiogenesis may have an implication in the treatment and prevention of these diseases. Abnormal angiogenesis is thus involved in various inflammatory diseases. Many groups of researchers have tried to discover new molecules capable of inhibiting angiogenesis, as for example Taylor by application of Protamine (Taylor, S. et al., Nature, 1982, 297, 307) or the use heparin in the presence of cortisone by Folkman (Folkman, J. et al., Science, 1983, 221, 719).
• dysregulation of angiogenesis control is associated with multiple disorders: tumors, hemangiomas (exaggerated angiogenesis) (Creamer, D. et al., Br. J. Dermatol, 1997, 136). (6), 859-865, Jackson, JR et al., FASEB.J, 1997, 11 (6), 457-465), ulcers (deficient angiogenesis).
• steroids have been used for the treatment of hemangiomas, the effectiveness of which is probably due to their antiangiogenic activity.
• TNP-470 AGM 1470 described in patent EP 0 357 061 and its successor, FR-118847 described in patent EP 0 386 667 , are active in many models of angiogenesis and have recognized antitumor activity (Logothetis,
• fumagillin derivatives such as the 6-epifumagillols described in patent EP 0 387 650, also have applications in the inhibition of angiogenesis, the suppression of cell proliferation and immunosuppression. In this case again, their synthesis is done by a semisynthetic process.
• Fumagalone has an inhibitory activity of the enzyme MetAP-2, in vitro, reversibly, by the reaction of the aldehyde group with the histidine 231 of the enzyme MetAP-2, forming an aminal. Fumagalone also exhibits inhibitory activity of endothelial cell proliferation in vivo.
• the applicant has thus invented new compounds of formula (I), derived from fumagalone by developing a synthesis process that provides access to analogs difficult to obtain.
• This synthetic process involves a step of chiral deprotonation.
• the advantage of chiral deprotonation is to obtain an enantiopure product from a compound having a planar element of symmetry.
• the action of a commercial chiral base on a prochiral cyclohexanone allows an asymmetric deprotonation leading to the formation mainly of a chiral enolate.
• the enolate formed is now asymmetrical.
• R 1 represents a radical of structure (a) or of structure (b)
• R 5 , R 6 and R 7 being as defined below;
• R 2 represents a lower alkyl radical of 1 to 5 carbon atoms
• R 3 represents a lower alkyl radical of 1 to 5 carbon atoms
• R 4 represents a radical of structure (c), linked by a single bond to cyclohexane which carries it:
• R 4 represents an oxygen atom bound by a double bond to cyclohexane which carries it;
• R 5 represents a hydrogen atom or a methyl radical or a trifluoromethyl radical
• R 6 and R ⁇ represent, independently of one another, a hydrogen atom or trifluoromethyl radical.
• the invention also relates to optical and geometric isomers, salts and mixtures of said compounds of formula (I).
• lower alkyl radical is understood to mean an alkyl radical containing from 1 to 5 carbon atoms, branched or unbranched, and in particular a methyl, ethyl, propyl, isopropyl, n-propyl, butyl or isobutyl radical. butyl, pentyl, isopentyl or n-pentyl.
• the compounds of formula (I) more particularly preferred are those for which at least one, and preferably all the conditions below are met:
• R 2 represents an isopentyl radical, and more preferably a 3-methylbutyl radical
• R 3 represents a methyl radical
• the subject of the present invention is also the processes for preparing the compounds of formula (I), or possible isomers, optical and / or geometric, pure or mixed, in all proportions, of said compounds of formula (I), any forms tautomers, or salts of said compounds of formula (I), in particular according to the reaction schemes given in Figures 2 to 4.
• Compound 3 can be converted to 4: 4-hydroxymethylcyclohexanone ketone by deprotection of the acetal in acidic medium, using a Dowex acid resin in H + form, for example.
• the primary alcohol of compound 4 can be protected with a silyl group by using terbutyldimethylsilyl chloride for example, which leads to 5: 4- (tert-butyl-dimethyl-silanyloxymethyl) -cyclohexanone ketone
• the asymmetric deprotonation of 5 provides, after oxidation of the intermediate silyl enol ether, cyclohexenone 6: 4 (S) -4- (tert-butyl-dimethyl-silanyloxymethyl) -cyclohex-2-enone BS
• the present invention relates to a method for the total synthesis of the fumagalone derivatives 10 to 14, 17 and 18 given in FIG. 1, according to the reaction schemes given in FIGS. 3 and 4.
• compound 9 provides the compound 10 2 (S) -3 (S) -4 (S) -3- (1,5-dimethyl-hex-1-enyl) -4-hydroxymethyl -2-methoxy-cyclohexanone by treatment with tetrabutyl ammonium fluoride, for example:
• Oxidation of the alcohol by treatment with an oxidant provides the aldehyde 11: 1 (S) -2 (S) -3 (S) -2- (1,5-Dimethyl).
• an oxidant such as Dess Martin Periodinane
• the compounds according to the invention find an application in the fields of dermatology, in particular, they find applications in the topical and systemic treatment of disorders related to a disorder of angiogenesis, they also find applications outside of dermatology .
• the compounds of general formula (I) exhibit anti-angiogenic biological properties. This activity can be demonstrated in vitro by a method using a commonly accepted biological target of fumagillin and analogous molecules, a methionine aminopeptidase (MetAP-2) identified by Griffith et al. (Griffith, E.C. et al., Chem Biol, 1997, 4 (6), 461-471). The inhibitory activity of various fumagillin derivatives with respect to this enzyme has a good correlation with the antiangiogenic effect.
• MethodAP-2 methionine aminopeptidase
• the biological activity of the compounds is evaluated by measuring their methionine aminopeptidase MetAP-2 inhibitory activity (Li, X., Chang, YH, Biochem Biophys Res Comm 1996, 227, 152 ).
• the biological activity is characterized in this system, by determining the concentration of compound required inhibitor to inhibit 50% of the enzyme activity (IC 50 ).
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising at least one compound of formula (I) as defined above in a pharmaceutically acceptable carrier.
• the present invention therefore also relates to such a pharmaceutical composition as a medicament intended in particular for the treatment of the aforementioned conditions.
• compositions according to the invention may be carried out orally, parenterally, topically or ocularly.
• the pharmaceutical compositions can be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, suspensions of microspheres or nanospheres or lipid vesicles or polymers for controlled release.
• compositions may be in the form of solutions or suspensions for infusion or injection.
• the compounds according to the invention are generally administered at a daily dose of about 0.001 mg / kg to 500 mg / kg and preferably from about 0.01 mg / kg to 50 mg / kg body weight in 1 to 3 doses. .
• compositions based on compounds according to the invention are intended for the treatment of the skin and the mucous membranes and are in the form of ointments, creams, milks, ointments, powders, soaked swabs, solutions, gels, sprays, lotions or suspensions. They may also be in the form of suspensions of microspheres or nanospheres or lipid or polymeric vesicles or polymeric patches and hydrogels allowing controlled release. These compositions topically can be presented in anhydrous form or in aqueous form according to the clinical indication.
• Eyes are mainly eye drops.
• compositions of the present invention in particular for the topical or ocular route, contain at least one compound of formula (I) as defined above at a concentration preferably of between 0.0001% and 20% and preferably of 0.001%. at 5% relative to the total weight of the composition.
• the subject of the present invention is also, as a medicament, the pharmaceutical compositions as defined above.
• the pharmaceutical compositions of the present invention are particularly suitable for the treatment of conditions related to a disorder of angiogenesis, such as rosacea.
• the compounds of formula (I) according to the invention also find application in the cosmetics field, in particular in the care of the skin or the scalp and in particular for the treatment of acne-prone skin, for the regrowth of hair, the anti-fall, to fight against the greasiness of the skin or the hair, in the protection against the harmful effects of the sun or in the treatment of the physiologically dry skins, to prevent and / or fight against the photo-induced aging or chronological.
• the present invention therefore also relates to a cosmetic composition containing, in a cosmetically acceptable carrier, at least one compound of formula (I) as defined above.
• This cosmetic composition may in particular be in the form of a cream, a milk, a lotion, a gel, suspensions of microspheres or nanospheres or lipid or polymeric vesicles, a soap or a shampoo .
• the concentration of compound of formula (I) in the cosmetic compositions may be between 0.0001 and 3% by weight relative to the total weight of the composition.
• the compounds according to the invention can also be used in cosmetic compositions for body and hair hygiene.
• the compounds according to the invention can be advantageously used in combination with retinoids, with corticosteroids or estrogens, in combination with anti-free radicals, with ⁇ -hydroxy or ⁇ -keto acids or derivatives, with salicylic acid derivatives, or with ion channel blockers such as potassium channels or, more particularly for pharmaceutical compositions, in combination with drugs known to interfere with the immune system.
• the pharmaceutical and cosmetic compositions according to the invention may, in addition, contain inert or even pharmacodynamically or cosmetically active additives or combinations of these additives and, in particular:
• antifungal agents agents promoting the regrowth of hair
• compositions according to the invention may also contain flavor enhancers, preservatives, stabilizing agents, moisture regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifiers, UV-A and UV-B filters, anti-oxidants.
• reaction mixture is then stirred overnight at ambient temperature (RT) and then filtered through Celite. The solid is rinsed with pentane. After evaporation of the solvents, the residue is chromatographed on silica gel (eluent CyH / AcOEt 95/5). 2.7 g (92%) of olefin 2 are thus obtained (colorless oil).
• Ref 2 and 3 Nicolaou, K.C .; Magolda, R.L .; Claremon, D. A. J. Am. Chem. Soc. 1980, 102, 1404-1409.
• the aldehyde 11 (50 mg, 188 ⁇ mol) dissolved in THF (1 ml) is treated with CF 3 SiMe 3 (30 ⁇ l, 197 ⁇ mol, 1.05 eq) and TBAF (10 ⁇ l, 0.05 eq) at 0 ° C. After 1 hour at this temperature, the mixture is hydrolyzed by adding a saturated solution of NH 4 Cl. After extraction with ethyl acetate, the organic phases are combined, dried over anhydrous magnesium sulfate and the solvents are evaporated. The residue obtained is dissolved in THF (1 mL) and then TBAF (200 ⁇ L, 1 eq) is added.
• reaction medium is hydrolyzed by adding a saturated solution of NH 4 Cl.
• organic phases are combined, dried over anhydrous magnesium sulfate and the solvents are evaporated.
• the residue obtained is dissolved in CH 2 Cl 2 (1 mL) and then Dess Martin periodinane (1.6 mL, 770 ⁇ mol, 4 eq) is added.
• the mixture is stirred overnight at 0 ° C. and then hydrolyzed by adding a saturated solution of NaHCO 3 as well as a saturated solution of Na 2 S 2 O 3 .
• the mixture obtained is stirred for 1 h at 0 ° C. and then extracted with CH 2 Cl 2 .
• Dess Martin periodinane (220 ⁇ L, 0.105 mmol, 15% solution, 1.5 eq) is added to a solution of alcohol 16 (30 mg, 0.070 mmol) in CH 2 CI 2 (1 mL). The solution is stirred overnight, and then the reaction is stopped by the successive addition of a saturated aqueous solution of NaHCO 3 (1 mL) and then a saturated aqueous solution of Na 2 S 2 O 3 (1 mL). After extraction with CH 2 Cl 2 and evaporation of the solvents under reduced pressure, the residue is purified on preparative TLC (eluent Hexane / AcOEt 9/1). The aldehyde 17 is obtained in the form of a colorless oil (26 mg, 87%).
• Diketone 12 (10 mg, 30 ⁇ mol) dissolved in THF (0.3 mL) is treated with CF 3 SiMe 3 (5 ⁇ L, 33 ⁇ mol, 1.1 eq) and TBAF (3 ⁇ L, 0.1 eq) at 0 ° C. After 1 h at this temperature, the mixture is hydrolyzed by addition of a 1N solution of HCl. After extraction with ethyl acetate, the organic phases are combined, dried over anhydrous magnesium sulphate and the solvents are evaporated. The residue obtained is purified on preparative TLC (CyH / AcOEt: 8/2). Compound 18 is obtained as a colorless oil (3 mg, 25%).
• Cyclohexenone 6 (12 mg, 50 ⁇ mol) dissolved in THF is treated with TBAF (50 ⁇ L, 1 M in THF, 1 eq) for 1 hour at RT. The reaction is stopped by hydrolysis (NH 4 Cl) and extracted with AcOEt. The organic phases are dried (MgSO 4 ) and then the solvents are evaporated under reduced pressure. The residue obtained is dissolved in CH 2 Cl 2 (0.5 mL) then Et 3 N (8 ⁇ L, 60 ⁇ mol) and the DMAP (8 mg, 60 ⁇ mol) are added, together with a solution of the (S) -chloride.
• the hydrazine (5 ml, 103.1 mmol, 2 eq) is added dropwise to the chloride of 2,4,6-triisopropylbenzenesulfonyl (15 g, 53.7 mmol) in 30 ml of THF at -10 ° C.
• the reaction is stirred at 0 ° C. for 3 h and then hydrolysed.
• the organic phase is washed 3 times with 10 ml of a saturated solution of sodium chloride and then dried over Na 2 SO 4 . After evaporation of the solvent, the solid obtained is dried for 1 h under vacuum (10 mm Hg) over P 2 O 5 .
• the composition is injected into an adult individual at a frequency of 1 to 7 times per week for 1 to 12 months.
• the composition is injected to an adult individual at a frequency of 1 to 7 times per week for 1 to 12 months.
• the composition is injected into an adult individual at a frequency of 1 to 7 times per week for 1 to 12 months.
• the composition is injected to an adult individual at a frequency of 1 to 7 times per week for 1 to 12 months.

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• 2004
  • 2004-06-30 FR FR0407235A patent/FR2872511B1/fr not_active Expired - Fee Related
• 2005
  • 2005-06-29 WO PCT/FR2005/001656 patent/WO2006010859A1/fr not_active Application Discontinuation
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