EP1425256A1 - Method for preparing unsaturated fatty hydroxy-acids and esters thereof, their use in pharmaceutical and/or cosmetic compositions - Google Patents
Method for preparing unsaturated fatty hydroxy-acids and esters thereof, their use in pharmaceutical and/or cosmetic compositionsInfo
- Publication number
- EP1425256A1 EP1425256A1 EP02798004A EP02798004A EP1425256A1 EP 1425256 A1 EP1425256 A1 EP 1425256A1 EP 02798004 A EP02798004 A EP 02798004A EP 02798004 A EP02798004 A EP 02798004A EP 1425256 A1 EP1425256 A1 EP 1425256A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- preparation
- formula
- product
- hydroxy
- collagen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 68
- 239000002537 cosmetic Substances 0.000 title claims abstract description 13
- 150000002148 esters Chemical class 0.000 title claims abstract description 8
- 239000000203 mixture Substances 0.000 title claims abstract description 6
- 150000001261 hydroxy acids Chemical class 0.000 title claims abstract description 5
- 229960002424 collagenase Drugs 0.000 claims abstract description 29
- 230000002366 lipolytic effect Effects 0.000 claims abstract description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 42
- 230000008569 process Effects 0.000 claims description 35
- 108010035532 Collagen Proteins 0.000 claims description 28
- 102000008186 Collagen Human genes 0.000 claims description 28
- 229920001436 collagen Polymers 0.000 claims description 28
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 26
- 102000029816 Collagenase Human genes 0.000 claims description 25
- 108060005980 Collagenase Proteins 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 23
- -1 alkynyl radical Chemical class 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- HVFSJXUIRWUHRG-UHFFFAOYSA-N oic acid Natural products C1CC2C3CC=C4CC(OC5C(C(O)C(O)C(CO)O5)O)CC(O)C4(C)C3CCC2(C)C1C(C)C(O)CC(C)=C(C)C(=O)OC1OC(COC(C)=O)C(O)C(O)C1OC(C(C1O)O)OC(COC(C)=O)C1OC1OC(CO)C(O)C(O)C1O HVFSJXUIRWUHRG-UHFFFAOYSA-N 0.000 claims description 14
- 238000010511 deprotection reaction Methods 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000003377 acid catalyst Substances 0.000 claims description 7
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 230000031709 bromination Effects 0.000 claims description 6
- 238000005893 bromination reaction Methods 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
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- 238000007254 oxidation reaction Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 238000006052 Horner reaction Methods 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 5
- 230000015556 catabolic process Effects 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 230000001580 bacterial effect Effects 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 238000007127 saponification reaction Methods 0.000 claims description 4
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 claims description 4
- 208000035143 Bacterial infection Diseases 0.000 claims description 3
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- 238000006731 degradation reaction Methods 0.000 claims description 3
- 150000002314 glycerols Chemical class 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 2
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 claims description 2
- 101100202428 Neopyropia yezoensis atps gene Proteins 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 230000003255 anti-acne Effects 0.000 claims description 2
- 150000005840 aryl radicals Chemical class 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 150000002009 diols Chemical class 0.000 claims description 2
- 150000002084 enol ethers Chemical class 0.000 claims description 2
- 210000003041 ligament Anatomy 0.000 claims description 2
- LFMTUFVYMCDPGY-UHFFFAOYSA-N n,n-diethylethanamine oxide Chemical compound CC[N+]([O-])(CC)CC LFMTUFVYMCDPGY-UHFFFAOYSA-N 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 230000008929 regeneration Effects 0.000 claims description 2
- 238000011069 regeneration method Methods 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- NZBUCABTIWJWAN-UHFFFAOYSA-N tetrabromomethane;triphenylphosphane Chemical compound BrC(Br)(Br)Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NZBUCABTIWJWAN-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 239000000058 anti acne agent Substances 0.000 abstract description 2
- 229940124340 antiacne agent Drugs 0.000 abstract description 2
- 238000009472 formulation Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000000047 product Substances 0.000 description 40
- 239000002609 medium Substances 0.000 description 19
- 239000000243 solution Substances 0.000 description 17
- 230000000694 effects Effects 0.000 description 15
- 238000012512 characterization method Methods 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 239000001963 growth medium Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
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- 150000001299 aldehydes Chemical class 0.000 description 8
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- 150000002632 lipids Chemical class 0.000 description 7
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- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
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- GMXIEASXPUEOTG-UHFFFAOYSA-N 8-bromooctan-1-ol Chemical compound OCCCCCCCCBr GMXIEASXPUEOTG-UHFFFAOYSA-N 0.000 description 4
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- 108010076503 Matrix Metalloproteinase 13 Proteins 0.000 description 4
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- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 229940055019 propionibacterium acne Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229940109850 royal jelly Drugs 0.000 description 1
- 210000002374 sebum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 150000005691 triesters Chemical class 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- 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
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
Definitions
- the present invention relates to the field of chemical processes and to the use of the products obtained by these chemical processes.
- the present invention relates more particularly to a process for the preparation of unsaturated hydroxy fatty acids and their esters corresponding to the following general formula (Id):
- R x OH, Cl, Br, OR 3 where R 3 represents an alkyl, alkenyl, alkynyl radical, linear or branched from 1 to 16 carbons or glycerol esters, optionally substituted by one or more carbon atoms, nitrogen, sulfur or halogens such as fluorine, chlorine, bromine and iodine,
- metal salts has a number of drawbacks.
- the latter can be contaminated by metal salts and therefore their cosmetic application and / or pharmacological is limited due to this contamination.
- the use of metal salts leads to contamination of the environment of the industries in which the synthesis is carried out.
- the preparation process therefore aims to solve the problems mentioned above by proposing a new original synthetic route allowing industrial transposition.
- the process of the invention is remarkable in that it makes it possible to obtain a faster method of synthesis with better yields than the processes already known from the prior art.
- the process of the invention makes it possible to avoid, in the first steps of said process, chromatographies which are not industrial purification techniques.
- R 17 R 2 , m and n have the same meaning as in formula (Id).
- the first step in this synthesis is bromination, the starting compound for the reaction is a diol of formula (II).
- This bromination requires the use of a solvent which can in particular be toluene, benzene, dimethylformamide, tetrahydrofuran, cyclohexane, heptane, petroleum ether, etc.
- the reagent used in this bromination step can be aqueous HBr or no, Ph 3 P, Br 2 , carbon tetrabromide triphenylphosphine, hydrobromic acid.
- the second step is an oxidation to aldehyde of formula (IV) in the presence of a cyclic or non-cyclic, anhydrous or non-anhydrous tertiary amine N-oxide in the presence of DMSO.
- the hydrobromide of the corresponding tertiary amine is removed by simple filtration.
- the cyclic or non-cyclic, anhydrous or non-anhydrous tertiary amine N-oxides present in the second step are chosen from N methyl morpholine oxide, trimethylamine oxide or triethylamine oxide or mixture thereof.
- the prior art knows other techniques for synthesizing aldehydes of general formula IV.
- step 2 of the method of the invention overcomes the drawbacks of the techniques already known in the state of the art.
- mention may be made of the oxidation reaction in the presence of manganese salts of the corresponding cyclic alkenes (Lee et al., 1993, J. Org. Chem., Vol. 10, pages 2918-2919).
- Step 2 of the process which is the subject of the invention therefore makes it possible to avoid a step in the presence of metal salts.
- the article by Guindon et al., Of 1984 J. Org. Chem., Vol.
- Step 3 of the process of the invention is a Witting-Horner reaction.
- This reaction is a reaction known to a person skilled in the art (Modem Synthetic Reaction, Second edition, Herbet O. House, Wittig Horner reaction pages 682 to 709) and any experimental condition described in the state of the art can be used in the part of the present invention.
- the Witting-Horner reaction can be carried out in the presence of triethylphosphonoacetate and potassium carbonate.
- Step 4 of the process of the invention is a saponification step. No particular experimental condition is implemented in the process of the invention. Those skilled in the art will be able to find the appropriate experimental conditions to use for this step.
- Step 5 of the process is a step of specific protection of the alcohol function of the compound of general formula Ib obtained in step 4.
- This reaction is carried out in any enol ether in the presence of an acid catalyst.
- the reaction is carried out in the dihydropyran in the presence of APTS (Para toluene sulfonic acid).
- APTS Par toluene sulfonic acid
- the product of general formula obtained after step 5 is purified by simple aqueous washing and drying over sulfate.
- Step 2 and step 5 of the process of the invention are not described in the state of the art. They make it possible to solve the technical problems described above while increasing the yield and the speed of the process for the synthesis of the compounds of general formula I.
- step 5 of the process of the invention can undergo a final deprotection in order to obtain the compound of general formula
- the product of formula (Id) obtained in step 5 of the process of the invention can be used in a glycerol esterification reaction.
- monoesters (2 possible isomers: in positions 1 and 2)
- diesters (2 possible isomers: diesters 1,1 and 1,2)
- triesters can be obtained.
- the compound obtained can undergo a final deprotection under experimental conditions identical to the deprotection conditions of the product of formula (Id) mentioned above.
- Collagen is the most abundant and important protein in the human body and the skin. This scleroprotein notably represents 75% of the proteins of the dermis to which it ensures solidity.
- the fibroblast manufactures from amino acids (hydroxyproline, lysine, proline) procollagen molecules which transform in the presence of vitamin C into collagen molecules. To form a network of fibrils, collagen must create bonds between these different molecules.
- the renewal of collagen changes with age.
- the soluble collagen which gives flexibility and resistance to the skin and mucous membranes degrades more and more quickly under the influence of a proteolytic enzyme that is collagenase, which leads, at the level of the dermis, to an aging of the structure fibrous proteins.
- the insoluble collagen which causes a loss of elasticity stiffens by polymerizing with glucose molecules thanks to multiple bonds that are difficult to reverse (glycation phenomenon). These bonds make collagen more resistant to attack by collagenases, which results in increasing rigidity of the collagen fibers. This hardening phenomenon, characteristic of aged skin tissue, must be combated as soon as possible because it increases the destruction of fibroblasts by free radicals but also the denaturation of proteins in the dermis.
- Collagenases are enzymes weakly expressed under normal physiological conditions. Their overexpression during aging and in particular during menopause in women leads to greater denaturation of the fibrous proteins of the dermis.
- the invention therefore relates to the use of the products capable of being obtained by the process of the invention as an anti-collagenase active agent.
- the work of the Applicant has more particularly made it possible to demonstrate the anti-collagenase activity of hydroxy-10-decene-2 (trans) oic acid (DHA) and of the glycerol ester of hydroxy-10-decene acid.
- -2 (trans) oic glycerol monoester in position 1).
- the invention also relates to the use of hydroxy-10-decene-2 (trans) oic acid (DHA) or of the glycerol ester of hydroxy-10-decene acid.
- 2 (trans) oic as an active anti-collagenase agent in a pharmaceutical and / or cosmetic preparation.
- the invention relates to the use of hydroxy-10-decene-2 (trans) oic acid (DHA) and / or the glycerol ester of hydroxy-10-decene-2 (trans) oic acid for the preparation of 'a medicine intended to prevent or cure the breakdown of collagen.
- This medication is especially intended to prevent or cure the breakdown of collagen by bacterial collagenases during a bacterial infection.
- the invention also relates to the use of hydroxy-10-decene acid.
- the invention also relates to the use of hydroxy-10-decene-2 (trans) oic acid (DHA) and / or of the glycerol ester of hydroxy-10-dececene acid.
- the invention also relates to the use of hydroxy-10-decene-2 (trans) oic acid (DHA) and / or the glycerol ester of hydroxy-10-decene-2 (trans) oic acid for the preparation. of a medicament intended to prevent or cure degenerative diseases presenting a fibrinoid degeneration of collagen and also called "collagen diseases".
- DHA hydroxy-10-decene-2
- trans oic acid
- a medicament intended to prevent or cure degenerative diseases presenting a fibrinoid degeneration of collagen and also called "collagen diseases”.
- the products obtained by the process which is the subject of the pending invention are, as indicated above, used in the cosmetic and / or pharmaceutical field.
- the work of the Applicant has made it possible to demonstrate that the products obtained by the process of the invention followed by a final deprotection step and, more particularly, hydroxy (10 - decene - 2 (trans) oic acid ( DHA) exhibit lipolytic activity. Consequently, the products obtained by the process of the invention followed by a final deprotection step and, more particularly, DHA can, in particular, be used in slimming treatments and in any treatment known to require lipolytic activity.
- the products obtained by the process which is the subject of the pending invention are, as indicated above, used in the cosmetic and / or pharmaceutical field.
- the work of the Applicant has made it possible to demonstrate that the products obtained by the process of the invention followed by a final deprotection step and, more particularly, hydroxy (10 - decene) 2 (trans) oic acid ( DHA) have anti-acne activity.
- the treatment of acne requires the treatment of two major problems which are, on the one hand, hyperseborrhea and, on the other hand, the bacterial proliferation responsible for skin inflammation.
- the work of the Applicant has made it possible to demonstrate that the products obtained by the process of the invention followed by a final deprotection step and, more particularly, DHA exhibit both a seboregulatory activity and an anti activity -bacterial.
- DHA is capable of inhibiting cutaneous 5-alpha reductase, the enzyme responsible for the production of di-hydro-testosterone.
- Treatment with 0.1% DHA and treatment with 0.5% DHA respectively reduced by approximately 70% and by approximately 90% the activity of 5-alpha-reductase compared to an untreated control. This inhibition leads to a considerable reduction in the level of sebum.
- DHA DHA exhibits, after 14 or 28 days of treatment, a bactericidal effect of approximately 95 to 100% tested on Propionibacterium acnes, Staphylococcus aureus and Malassezia furfur.
- .7 15.6 and 7Hz
- the product is purified by chromatography on silica CH 2 Cl 2 / acetone 9/1 to l / l and CH 2 Cl 2 / methanol 95/5.
- 27 g of product are obtained in the form of an oil which crystallizes in the form of an amorphous yellow white solid with a purity between 85-90%.
- Step 2 Oxidation to aldehyde.
- the product is purified by distillation at 81 ° C under P ⁇ lmbar (9g, 57%).
- Example 3 Evaluation of the anti-collagenase activity of products obtained by the process of the invention on frozen sections of human skin.
- the sections are covered with the solutions to be tested and then incubated for 2 hours at 37 ° C. in a humid chamber.
- the solutions are eliminated by repetitive rinsing and the sections are stained with picrosirius.
- the microscopic examination is carried out at the objective of 2.5 and the paper photographs are taken with a Kodak Gold 100 ASA film.
- Table 2 summarizes the results of the alteration of the collagen structure as a function of the solution tested. An absence of alteration of the collagen structure is indicated by 0 while a moderately or markedly to very strongly altered collagen structure is indicated by 1 or 2 respectively.
- the application of the Tris buffer control or of the excipient does not induce any alteration of the collagen structure.
- the 1% and 2% DHA product completely inhibits collagenase activity, so that ML40 and GM at 2% slightly inhibits the activity of collagenase.
- Example 4 Evaluation of the anti-collagenase activity of GM obtained by the method of the invention on explants of human skin maintained in survival.
- the study is carried out on a product at 5% GM in comparison with the excipient (hydrocerin), a positive control and a control in the presence of collagenase at 100 U / ml.
- Hydrocerin is used as an excipient for the preparation of the product to be applied. This study was carried out twice. In the first study, it was found that the action of collagenase on D2 remains very limited and not significant. In the second study, the application time is extended and the explants are removed on D2 and D4.
- the product is applied on D0 and D2 at a rate of 20 mg per explant and the collagenase is incorporated into the culture media of the last 24 batches.
- the histological study includes: paraffin impregnation, sections, staining with sirius red F3B colorimetric measurements of collagen by image analysis report with photos.
- the dermis has a normal structure, with regular collagen bundles in all the compartments, - for the controls with collagenase, the collagen bundles are very strongly degraded and the thickness of the dermis has halved, for the explants with excipient and collagenase, the collagen bundles are strongly degraded, the alteration being less than that observed on the controls with collagenase, and the thickness of the dermis decreased by almost half,
- the collagen bundles are very slightly degraded and the thickness of the dermis has slightly decreased
- the dermal structure is identical to that of controls without collagenase.
- the GM product shows a marked anti-collagenase activity.
- Example 5 Evaluation of the anti-lipolytic activity of DHA obtained by the method of the invention on explants of adipose tissues ex vivo.
- DHA is incorporated into the culture medium at the final concentration of 0.25 and 0.5%. After an 8-day contact, the activity is evaluated by assaying the lipids released into the culture medium.
- P202-AB31 are prepared and put to survival in BEM medium (BIO-EC's Explants Medium). The explants are divided into 4 batches of 3 explants: a control batch, a positive control batch (0.1% caffeine), two batches produced (DHA 0.25 and 0.5%).
- the explants are put into survival in 2 ml of culture medium, in which the product to be tested is incorporated.
- the culture medium is removed.
- the media taken on D2, D4, D6 and D8 are combined in the same tube and stored at -20 ° C for the determination of lipids.
- explants of fixed adipose tissue are dehydrated, impregnated with paraffin, placed in a block, cut and colored with Masson trichrome.
- the lipids are separated and assayed by TLC.
- the viability and the morphology of the adipocytes is controlled by the histological study. Lipolytic activity is evaluated by analyzing the proportions of monoglycerides, diglycerides, triglycerides and free fatty acids. at . Histology.
- control and treated explants show no visible alterations or cellular necrosis.
- results obtained are collated in Table 4 below.
- the results are expressed in mass ( ⁇ g) of each category of lipids released into the culture medium, during the 8 days of treatment.
- Table 5 represents the statistical analysis by the Student test of the results of the assay of fatty acids released in the culture medium, during the 8 days of treatment.
- the essential parameter in this study is the variation in the amount and percentage of fatty acids released into the culture medium after the treatment period.
- DHA at 0.25 and 0.50% leads to a significant increase of 1075 and 1087% respectively.
- the increase in the concentration used does not have any effects on efficacy. It seems that the maximum effective dose is around 0.25%.
- the DHA applied at 0.25 and 0.5% exhibits significant lipolytic activity in comparison with that of caffeine.
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- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
The invention concerns a method for preparing unsaturated fatty hydroxy-acids and esters thereof corresponding to general formula (Id) and their use in pharmaceutical and/or cosmetic formulations as active anti-collagenase, lipolytic and/or anti-acne agent.
Description
PROCEDE DE PREPARATION DES HYDROXY-ACIDES GRAS PROCESS FOR THE PREPARATION OF FATTY HYDROXY-ACIDS
INSATURÉS ET DE LEURS ESTERS, LEUR UTILISATION DANS DESUNSATURATED AND THEIR ESTERS, THEIR USE IN
PRÉPARATIONS PHARMACEUTIQUES E /OU COSMÉTIQUESPHARMACEUTICAL AND / OR COSMETIC PREPARATIONS
La présente invention se rapporte au domaine des procédés chimiques et à l ' utilisation des produits obtenus par ces procédés chimiques .The present invention relates to the field of chemical processes and to the use of the products obtained by these chemical processes.
La présente invention se rapporte plus particulièrement à un procédé de préparation des hydroxy-acides gras insaturés et de leurs esters répondant à la formule générale suivante (Id) :The present invention relates more particularly to a process for the preparation of unsaturated hydroxy fatty acids and their esters corresponding to the following general formula (Id):
avec n= 1 à 4 m = 2 à 16 with n = 1 to 4 m = 2 to 16
Rx= OH, Cl, Br, OR3 où R3 représente un radical alkyl, alcényl, alcynyl, linéaire ou ramifié de 1 à 16 carbones ou esters du glycérol, éventuellement substitué par un ou plusieurs atomes de carbone, d'azote, de soufre ou d'halogènes tels que fluor, chlore, brome et iode,R x = OH, Cl, Br, OR 3 where R 3 represents an alkyl, alkenyl, alkynyl radical, linear or branched from 1 to 16 carbons or glycerol esters, optionally substituted by one or more carbon atoms, nitrogen, sulfur or halogens such as fluorine, chlorine, bromine and iodine,
R2= H, SiR'1R, 2R'3 où R' l t R'2, R'3 identiques ou différents les uns des autres, représentent un radical alkyl, alcényl, alcynyl, linéaire ou ramifié de 1 à 16 carbones ou esters du glycérol, éventuellement substitué par un ou plusieurs atomes de carbone, d'azote, de soufre ou d'halogènes tels que fluor, chlore, brome et iode, ou R2= C-Ar3 avec Ar représentant un radical aryl éventuellement substitué par un ou plusieurs atomes de carbone, d'azote, de soufre ou d'halogènes tels que fluor, chlore, brome et iode,
ou R2= le tétrahydropyranyl de formuleR 2 = H, SiR ' 1 R , 2 R' 3 where R ' lt R' 2 , R ' 3 identical or different from each other, represent an alkyl, alkenyl, alkynyl radical, linear or branched from 1 to 16 carbons or glycerol esters, optionally substituted by one or more carbon, nitrogen, sulfur or halogen atoms such as fluorine, chlorine, bromine and iodine, or R 2 = C-Ar 3 with Ar representing an aryl radical optionally substituted by one or more carbon, nitrogen, sulfur or halogen atoms such as fluorine, chlorine, bromine and iodine, or R 2 = tetrahydropyranyl of formula
et à l'utilisation desdits produits comme agent anti-collagénase, agent lipolytique ou agent anti-acnéique dans une préparation médicamenteuse et/ou cosmétique . and the use of said products as an anti-collagenase agent, lipolytic agent or anti-acne agent in a medicinal and / or cosmetic preparation.
Les produits répondant à la formule générale (Id) sont connus et décrits dans la littérature pour leurs propriétés biologiques et plus particulièrement pour leurs propriétés cosmétiques et pharmacologiques . D'ailleurs, le principal constituant lipidique de la gelée royale des abeilles qui est l'acide hydroxy-10-décène-2 (trans) oique (ou DHA) répond à la formule générale (Id) dans laquelle Rx= OH, R2= H, n= 1 et m= 3.The products corresponding to the general formula (Id) are known and described in the literature for their biological properties and more particularly for their cosmetic and pharmacological properties. Moreover, the main lipid constituent of royal jelly of bees which is hydroxy-10-decene-2 (trans) oic acid (or DHA) corresponds to the general formula (Id) in which R x = OH, R 2 = H, n = 1 and m = 3.
Différents documents de l'état de la technique rapportent des procédés de préparation des hydroxy-acides gras insaturés et de leurs esters (Lee et al., 1993, J. Org. Chem. , vol. 58, pages 2918-2919 ; Hurd et Saunders, 1952, J. Am. Chem. Soc, vol. 74, pages 5324-5328 ; Krishnamurthy et al., 1989, Indian J. Chem. Sect. A, vol. 28, pages 288-291 ; Plettner et al., 1995, J. Chem. Ecol . , vol. 21, pages 1017-1030). Les procédés déjà connus dans l'état de la technique présentent une étape d'oxydation durant laquelle des sels métalliques comme les sels de chrome ou de manganèse sont employés. Or, l'utilisation de sels métalliques présente un certain nombre d'inconvénients. D'une part, au niveau des produits obtenus par lesdits procédés, ces derniers peuvent être contaminés par les sels métalliques et donc leur application cosmétique
et/ou pharmacologique est limitée du fait de cette contamination. D'autre part, l'utilisation de sels métalliques entraîne une contamination de l'environnement des industries dans lesquelles la synthèse est effectuée.Various documents of the state of the art report processes for the preparation of unsaturated hydroxy fatty acids and their esters (Lee et al., 1993, J. Org. Chem., Vol. 58, pages 2918-2919; Hurd and Saunders, 1952, J. Am. Chem. Soc, vol. 74, pages 5324-5328; Krishnamurthy et al., 1989, Indian J. Chem. Sect. A, vol. 28, pages 288-291; Plettner et al. , 1995, J. Chem. Ecol., Vol. 21, pages 1017-1030). The methods already known in the state of the art have an oxidation step during which metal salts such as chromium or manganese salts are used. However, the use of metal salts has a number of drawbacks. On the one hand, at the level of the products obtained by said processes, the latter can be contaminated by metal salts and therefore their cosmetic application and / or pharmacological is limited due to this contamination. On the other hand, the use of metal salts leads to contamination of the environment of the industries in which the synthesis is carried out.
Le procédé de préparation vise donc à résoudre les problèmes cités ci -dessus en proposant une nouvelle voie de synthèse originale permettant une transposition industrielle.The preparation process therefore aims to solve the problems mentioned above by proposing a new original synthetic route allowing industrial transposition.
De plus, le procédé de l'invention est remarquable en ce qu'il permet d'obtenir une méthode de synthèse plus rapide avec de meilleurs rendements que les procédés déjà connus de l'art antérieur. En effet, le procédé de l'invention permet d'éviter, dans les premières étapes dudit procédé, les chromatographies qui ne sont pas des techniques industrielles de purification.In addition, the process of the invention is remarkable in that it makes it possible to obtain a faster method of synthesis with better yields than the processes already known from the prior art. In fact, the process of the invention makes it possible to avoid, in the first steps of said process, chromatographies which are not industrial purification techniques.
Le schéma général de synthèse est le suivant The general summary scheme is as follows
Ib laIb la
où R17 R2, m et n ont la même signification que dans la formule (Id) .where R 17 R 2 , m and n have the same meaning as in formula (Id).
La première étape de cette synthèse est une bromation, le composé de départ de la réaction est un diol de formule (II) . De nombreuses techniques permettant une bromation sont connues dans l'état de la technique et sont utilisables par l'homme du métier à cette étape. Cette bromation nécessite l'utilisation
d'un solvant qui peut notamment être le toluène, le benzène, le diméthylformamide, le tétrahydrofuran, le cyclohexane, l'heptane, 1 ' éther de pétrole, etc.. Le réactif utilisé dans cette étape de bromation peut être le HBr aqueux ou non, le Ph3P,Br2, le tétrabromide de carbone triphénylphosphine, l'acide hydrobromique. A titre d'exemple, on peut citer les conditions expérimentales de bromation utilisant du HBr aqueux décrites dans Geresh et al., Tetrahedron Asymmery, 1998, vol. 9, pages 89-96.The first step in this synthesis is bromination, the starting compound for the reaction is a diol of formula (II). Many techniques allowing bromination are known in the state of the art and can be used by a person skilled in the art at this stage. This bromination requires the use of a solvent which can in particular be toluene, benzene, dimethylformamide, tetrahydrofuran, cyclohexane, heptane, petroleum ether, etc. The reagent used in this bromination step can be aqueous HBr or no, Ph 3 P, Br 2 , carbon tetrabromide triphenylphosphine, hydrobromic acid. By way of example, mention may be made of the experimental bromination conditions using aqueous HBr described in Geresh et al., Tetrahedron Asymmery, 1998, vol. 9, pages 89-96.
La seconde étape est une oxydation en aldéhyde de formule (IV) en présence d'un N-oxyde d'aminé tertiaire cyclique ou non cyclique, anhydre ou non anhydre en présence de DMSO. En fin de réaction, le bromydrate de l'aminé tertiaire correspondante est éliminé par simple filtration. De façon avantageuse, les N-oxydes d'aminé tertiaire cycliques ou non cycliques, anhydres ou non anhydres présents à la seconde étape sont choisis parmi le N méthyl morpholine oxyde, le triméthylamine oxyde ou le triéthylamine oxyde ou mélange de ceux-ci. L'art antérieur connaît d'autres techniques permettant de synthétiser les aldéhydes de formule générale IV. Cependant, l'étape 2 du procédé de l'invention permet de résoudre les inconvénients des techniques déjà connues dans l'état de la technique. A titre d'exemple, on peut citer la réaction d'oxydation en présence de sels de manganèse des alcènes cycliques correspondant (Lee et al., 1993, J. Org. Chem., vol. 10, pages 2918-2919). L'étape 2 du procédé objet de l'invention permet donc d'éviter une étape en présence de sels métalliques. L'article de Guindon et al., de 1984 (J. Org. Chem., vol. 49, pages 3912-3920) décrit la synthèse de 8-hydroxy-octanal à partir de 1 , 1-diméthoxy- 8 -méthoxyméthoxy-octane .
Cependant le rendement de synthèse de 8-hydroxy-octanal est relativement faible (36%) alors que l'étape 2 de l'invention permet d'obtenir des rendements plus élevés. Les autres techniques connues dans l'art antérieur permettant de synthétiser les aldéhydes de formule générale IV sont des méthodes de synthèse longues présentant plus de 4 étapes .The second step is an oxidation to aldehyde of formula (IV) in the presence of a cyclic or non-cyclic, anhydrous or non-anhydrous tertiary amine N-oxide in the presence of DMSO. At the end of the reaction, the hydrobromide of the corresponding tertiary amine is removed by simple filtration. Advantageously, the cyclic or non-cyclic, anhydrous or non-anhydrous tertiary amine N-oxides present in the second step are chosen from N methyl morpholine oxide, trimethylamine oxide or triethylamine oxide or mixture thereof. The prior art knows other techniques for synthesizing aldehydes of general formula IV. However, step 2 of the method of the invention overcomes the drawbacks of the techniques already known in the state of the art. By way of example, mention may be made of the oxidation reaction in the presence of manganese salts of the corresponding cyclic alkenes (Lee et al., 1993, J. Org. Chem., Vol. 10, pages 2918-2919). Step 2 of the process which is the subject of the invention therefore makes it possible to avoid a step in the presence of metal salts. The article by Guindon et al., Of 1984 (J. Org. Chem., Vol. 49, pages 3912-3920) describes the synthesis of 8-hydroxy-octanal from 1,1-dimethoxy-8-methoxymethoxy- octane. However, the yield of synthesis of 8-hydroxy-octanal is relatively low (36%) while step 2 of the invention makes it possible to obtain higher yields. The other techniques known in the prior art making it possible to synthesize the aldehydes of general formula IV are long synthesis methods having more than 4 steps.
L'étape 3 du procédé de l'invention est une réaction de Witting-Horner . Cette réaction est une réaction connue de l'homme du métier (Modem Synthetic Reaction, Second édition, Herbet O. House, Wittig Horner reaction pages 682 à 709) et toute condition expérimentale décrite dans l'état de la technique peut être utilisée dans le cadre de la présente invention. A titre d'exemple, la réaction de Witting-Horner peut être réalisée en présence de triëthylphosphonoacétate et de carbonate de potassium.Step 3 of the process of the invention is a Witting-Horner reaction. This reaction is a reaction known to a person skilled in the art (Modem Synthetic Reaction, Second edition, Herbet O. House, Wittig Horner reaction pages 682 to 709) and any experimental condition described in the state of the art can be used in the part of the present invention. By way of example, the Witting-Horner reaction can be carried out in the presence of triethylphosphonoacetate and potassium carbonate.
L'étape 4 du procédé de l'invention est une étape de saponification. Aucune condition expérimentale particulière n'est mise en œuvre dans le procédé de l'invention. L'homme du métier sera à même de trouver les conditions expérimentales adéquates à utiliser pour cette étape.Step 4 of the process of the invention is a saponification step. No particular experimental condition is implemented in the process of the invention. Those skilled in the art will be able to find the appropriate experimental conditions to use for this step.
L'étape 5 du procédé est une étape de protection spécifique de la fonction alcool du composé de formule générale Ib obtenu à l'étape 4. Cette réaction s'effectue dans tout éther d'énol en présence d'un catalyseur acide. De façon avantageuse, la réaction s'effectue dans le dihydropyrane en présence d'APTS (Acide para toluène sulfonique) . Le produit de formule générale le obtenu après l'étape 5 est purifié par simple lavage aqueux et séchage sur sulfate.
L'étape 2 et l'étape 5 du procédé de l'invention sont non décrites dans l'état de la technique. Elles permettent de résoudre les problèmes techniques décrits ci -dessus tout en augmentant le rendement et la rapidité du procédé de synthèse des composés de formule générale I .Step 5 of the process is a step of specific protection of the alcohol function of the compound of general formula Ib obtained in step 4. This reaction is carried out in any enol ether in the presence of an acid catalyst. Advantageously, the reaction is carried out in the dihydropyran in the presence of APTS (Para toluene sulfonic acid). The product of general formula obtained after step 5 is purified by simple aqueous washing and drying over sulfate. Step 2 and step 5 of the process of the invention are not described in the state of the art. They make it possible to solve the technical problems described above while increasing the yield and the speed of the process for the synthesis of the compounds of general formula I.
Le produit de formule (Id) obtenu à l'étape 5 du procédé de l'invention peut subir une déprotection finale afin d'obtenir le composé de formule généraleThe product of formula (Id) obtained in step 5 of the process of the invention can undergo a final deprotection in order to obtain the compound of general formula
(le) . Cette déprotection est réalisée dans une solution de méthanol contenant un catalyseur acide. Tout catalyseur acide peut être utilisé dans l'invention. De façon avantageuse, le catalyseur acide utilisé est 1 ' ATPS .(the) . This deprotection is carried out in a methanol solution containing an acid catalyst. Any acid catalyst can be used in the invention. Advantageously, the acid catalyst used is 1 ATPS.
Le produit de formule (Id) obtenu à l'étape 5 du procédé de l'invention peut être utilisé dans une réaction d' estérification du glycérol. Suivant les quantités relatives de glycérol utilisées, peuvent être obtenus des monoesters (2 isomères possibles : en position 1 et 2) , des diesters (2 isomères possibles : diesters 1,1 et 1,2) et des triesters . Après l'étape d' estérification du glycérol, le composé obtenu peut subir une déprotection finale dans des conditions expérimentales identiques aux conditions de déprotection du produit de formule (Id) citées ci- dessus .The product of formula (Id) obtained in step 5 of the process of the invention can be used in a glycerol esterification reaction. Depending on the relative amounts of glycerol used, monoesters (2 possible isomers: in positions 1 and 2), diesters (2 possible isomers: diesters 1,1 and 1,2) and triesters can be obtained. After the glycerol esterification step, the compound obtained can undergo a final deprotection under experimental conditions identical to the deprotection conditions of the product of formula (Id) mentioned above.
Les produits obtenus par le procédé objet de l'invention en instance sont, comme indiqué précédemment, utilisés dans le domaine cosmetologique et/ou pharmaceutique. Cependant, les travaux de la Demanderesse ont permis de mettre en évidence que les produits obtenus par le procédé de l'invention suivi
d'une étape de déprotection finale présentent une activité anti-collagénase .The products obtained by the process which is the subject of the pending invention are, as indicated above, used in the cosmetic and / or pharmaceutical field. However, the work of the Applicant has made it possible to demonstrate that the products obtained by the process of the invention followed of a final deprotection step exhibit anti-collagenase activity.
Le collagene est la protéine la plus abondante et la plus importante du corps humain et de la peau. Cette scléroprotéine représente notamment 75% des protéines du derme auquel elle assure solidité. Le fibroblaste fabrique à partir des acides aminés (hydroxyproline, lysine, proline) des molécules de procollagene qui se transforment en présence de vitamine C en molécules de collagene. Pour former un réseau de fibrilles, le collagene doit créer des liaisons entre ces différentes molécules.Collagen is the most abundant and important protein in the human body and the skin. This scleroprotein notably represents 75% of the proteins of the dermis to which it ensures solidity. The fibroblast manufactures from amino acids (hydroxyproline, lysine, proline) procollagen molecules which transform in the presence of vitamin C into collagen molecules. To form a network of fibrils, collagen must create bonds between these different molecules.
Le renouvellement du collagene change avec l'âge. Le collagene soluble qui donne souplesse et résistance à la peau et aux muqueuses se dégrade de plus en plus rapidement sous l'influence d'une enzyme protéolytique qu'est la collagénase, ce qui entraîne, au niveau du derme, un vieillissement de la structure fibreuse des protéines. En outre, le collagene insoluble qui entraîne une perte d'élasticité se rigidifie en se polymérisant avec des molécules de glucose grâce à des liaisons multiples difficilement réversibles (phénomène de glycation) . Ces liaisons rendent le collagene plus résistant à l'attaque par les collagénases ce qui entraîne une rigidité croissante des fibres de collagene. Ce phénomène de durcissement, caractéristique des tissus cutanés âgés, doit être combattu le plus tôt possible car il augmente la destruction des fibroblastes par les radicaux libres mais aussi la dénaturation des protéines du derme.The renewal of collagen changes with age. The soluble collagen which gives flexibility and resistance to the skin and mucous membranes degrades more and more quickly under the influence of a proteolytic enzyme that is collagenase, which leads, at the level of the dermis, to an aging of the structure fibrous proteins. In addition, the insoluble collagen which causes a loss of elasticity stiffens by polymerizing with glucose molecules thanks to multiple bonds that are difficult to reverse (glycation phenomenon). These bonds make collagen more resistant to attack by collagenases, which results in increasing rigidity of the collagen fibers. This hardening phenomenon, characteristic of aged skin tissue, must be combated as soon as possible because it increases the destruction of fibroblasts by free radicals but also the denaturation of proteins in the dermis.
Les collagénases sont des enzymes faiblement exprimées dans les conditions physiologiques normales. Leur surexpression lors au vieillissement et en particulier lors de la ménopause chez la femme
entraîne une dénaturation plus importante des protéines fibreuses du derme.Collagenases are enzymes weakly expressed under normal physiological conditions. Their overexpression during aging and in particular during menopause in women leads to greater denaturation of the fibrous proteins of the dermis.
Cependant, la destruction des fibres de collagene peut survenir lors d' autres circonstances que le vieillissement. En effet, lors d'une infection bactérienne, les collagénases bactériennes peuvent détruire les fibres de collagene de l'hôte infecté.However, the destruction of collagen fibers can occur in circumstances other than aging. Indeed, during a bacterial infection, bacterial collagenases can destroy the collagen fibers of the infected host.
De plus, l'invasion tumorale nécessite une dégradation de la membrane basale et de la matrice extra-cellulaire et de toutes les protéines de structure de ces composants parmi lesquelles se trouve le collagene. Ainsi, il a été montré une très nette relation entre le pouvoir invasif des tumeurs et la présence d'activité collagénase dans les tumeurs humaines. On retrouve les collagénases au niveau des cellules tumorales, mais aussi dans les fibroblastes entourant la tumeur. Les cellules épithéliales normales sécrètent un taux très faible de collagénases, alors que ces protéines sont surexprimées par les cellules tumorales invasives ou métastatiques .In addition, tumor invasion requires degradation of the basement membrane and of the extracellular matrix and of all the structural proteins of these components, among which is collagen. Thus, a very clear relationship has been shown between the invasiveness of tumors and the presence of collagenase activity in human tumors. Collagenases are found in tumor cells, but also in the fibroblasts surrounding the tumor. Normal epithelial cells secrete very low levels of collagenases, while these proteins are overexpressed by invasive or metastatic tumor cells.
D'autres maladies dégénérâtives présentent une dégénérescence fibrinoide du collagene et sont également appelées « maladies du collagene ».Other degenerative diseases have fibrinoid collagen degeneration and are also called "collagen diseases".
L'invention concerne donc l'utilisation des produits susceptibles d'être obtenus par le procédé de l'invention comme agent actif anti-collagénase. Les travaux de la Demanderesse ont plus particulièrement permis de mettre en évidence l'activité anti- collagénase de l'acide hydroxy-10-décène-2 (trans) oïque (DHA) et du glycérol ester de l'acide hydroxy-10- décène-2 (trans) oique (monoester du glycérol en position 1). L'invention concerne également l'utilisation de l'acide hydroxy-10-décène-2 (trans) oïque (DHA) ou du glycérol ester de l'acide hydroxy- 10 -décène-
2 (trans) oïque comme agent actif anti-collagénase dans une préparation pharmaceutique et/ou cosmétique.The invention therefore relates to the use of the products capable of being obtained by the process of the invention as an anti-collagenase active agent. The work of the Applicant has more particularly made it possible to demonstrate the anti-collagenase activity of hydroxy-10-decene-2 (trans) oic acid (DHA) and of the glycerol ester of hydroxy-10-decene acid. -2 (trans) oic (glycerol monoester in position 1). The invention also relates to the use of hydroxy-10-decene-2 (trans) oic acid (DHA) or of the glycerol ester of hydroxy-10-decene acid. 2 (trans) oic as an active anti-collagenase agent in a pharmaceutical and / or cosmetic preparation.
L'invention concerne l'utilisation de l'acide hydroxy-10-décène-2 (trans) oïque (DHA) et/ou du glycérol ester de l'acide hydroxy- 10 -dëcène- 2 (trans) oïque pour la préparation d'un médicament destiné à prévenir ou à guérir la dégradation du collagene. Ce médicament est tout particulièrement destiné à prévenir ou à guérir la dégradation du collagene par les collagénases bactériennes lors d'une infection bactérienne.The invention relates to the use of hydroxy-10-decene-2 (trans) oic acid (DHA) and / or the glycerol ester of hydroxy-10-decene-2 (trans) oic acid for the preparation of 'a medicine intended to prevent or cure the breakdown of collagen. This medication is especially intended to prevent or cure the breakdown of collagen by bacterial collagenases during a bacterial infection.
L' invention concerne également l'utilisation de l'acide hydroxy- 10 -décène -The invention also relates to the use of hydroxy-10-decene acid.
2 (trans) oïque (DHA) et/ou du glycérol ester de l'acide hydroxy-10-décène-2 (trans) oïque pour la préparation d'un médicament destiné à la régénérescence de la peau et des ligaments.2 (trans) oic (DHA) and / or glycerol ester of hydroxy-10-decene-2 (trans) oic acid for the preparation of a medicament intended for the regeneration of the skin and ligaments.
L'invention concerne aussi l'utilisation de l'acide hydroxy- 10 -décène- 2 (trans) oïque (DHA) et/ou du glycérol ester de l'acide hydroxy- 10 -décène-The invention also relates to the use of hydroxy-10-decene-2 (trans) oic acid (DHA) and / or of the glycerol ester of hydroxy-10-dececene acid.
2 (trans) oïque pour la préparation d'un médicament destiné à prévenir ou à guérir l'invasion tumorale.2 (trans) oic for the preparation of a medicament for preventing or curing tumor invasion.
L'invention concerne aussi l'utilisation de l'acide hydroxy- 10 -décène-2 (trans) oïque (DHA) et/ou du glycérol ester de l'acide hydroxy- 10-décêne- 2 (trans) oïque pour la préparation d'un médicament destiné à prévenir ou à guérir des maladies dégénératives présentant une dégénérescence fibrinoïde du collagene et également appelées « maladies du collagene » .
Les produits obtenus par le procédé objet de l'invention en instance sont, comme indiqué précédemment, utilisés dans le domaine cosmetologique et/ou pharmaceutique. Les travaux de la Demanderesse ont permis de mettre en évidence que les produits obtenus par le procédé de l'invention suivi d'une étape de déprotection finale et, plus particulièrement, l'acide hydroxy- 10 - décène - 2 ( trans ) oïque (DHA) présentent une activité lipolytique. Par conséquent, les produits obtenus par le procédé de l'invention suivi d'une étape de déprotection finale et, plus particulièrement, le DHA peuvent, notamment, être utilisés dans les traitements amincissants et dans tout traitement connu pour nécessiter une activité lipolytique.The invention also relates to the use of hydroxy-10-decene-2 (trans) oic acid (DHA) and / or the glycerol ester of hydroxy-10-decene-2 (trans) oic acid for the preparation. of a medicament intended to prevent or cure degenerative diseases presenting a fibrinoid degeneration of collagen and also called "collagen diseases". The products obtained by the process which is the subject of the pending invention are, as indicated above, used in the cosmetic and / or pharmaceutical field. The work of the Applicant has made it possible to demonstrate that the products obtained by the process of the invention followed by a final deprotection step and, more particularly, hydroxy (10 - decene - 2 (trans) oic acid ( DHA) exhibit lipolytic activity. Consequently, the products obtained by the process of the invention followed by a final deprotection step and, more particularly, DHA can, in particular, be used in slimming treatments and in any treatment known to require lipolytic activity.
Les produits obtenus par le procédé objet de l'invention en instance sont, comme indiqué précédemment, utilisés dans le domaine cosmetologique et/ou pharmaceutique. Les travaux de la Demanderesse ont permis de mettre en évidence que les produits obtenus par le procédé de l'invention suivi d'une étape de déprotection finale et, plus particulièrement, l'acide hydroxy- 10 - décène- 2 ( trans ) oïque (DHA) présentent une activité anti-acnéique.The products obtained by the process which is the subject of the pending invention are, as indicated above, used in the cosmetic and / or pharmaceutical field. The work of the Applicant has made it possible to demonstrate that the products obtained by the process of the invention followed by a final deprotection step and, more particularly, hydroxy (10 - decene) 2 (trans) oic acid ( DHA) have anti-acne activity.
Le traitement de l'acné nécessite le traitement de deux problèmes majeurs que sont, d'une part, 1 ' hyperséborrhée et, d'autre part, la prolifération bactérienne responsable de l'inflammation cutanée. Les travaux de la Demanderesse ont permis de mettre en évidence que les produits obtenus par le procédé de l'invention suivi d'une étape de déprotection finale et, plus particulièrement, le DHA présentent à la fois une activité sébo-régulatrice et une activité anti-bactérienne .
En effet, le DHA est capable d'inhiber la 5 -alpha reductase cutanée, enzyme responsable de la production de la di-hydro-testosterone . Un traitement avec 0,1% de DHA et un traitement avec 0,5% de DHA réduisent respectivement d'environ 70% et d'environ 90% l'activité de la 5-alpha-rëductase par rapport à un contrôle non traité. Cette inhibition entraîne une réduction considérable du taux de sébum.The treatment of acne requires the treatment of two major problems which are, on the one hand, hyperseborrhea and, on the other hand, the bacterial proliferation responsible for skin inflammation. The work of the Applicant has made it possible to demonstrate that the products obtained by the process of the invention followed by a final deprotection step and, more particularly, DHA exhibit both a seboregulatory activity and an anti activity -bacterial. Indeed, DHA is capable of inhibiting cutaneous 5-alpha reductase, the enzyme responsible for the production of di-hydro-testosterone. Treatment with 0.1% DHA and treatment with 0.5% DHA respectively reduced by approximately 70% and by approximately 90% the activity of 5-alpha-reductase compared to an untreated control. This inhibition leads to a considerable reduction in the level of sebum.
De plus, 0,5% de DHA présentent, après 14 ou 28 jours de traitement, un effet bactéricide d'environ 95 à 100% testé sur Propionibacterium acnés, Staphylococcus aureus et Malassezia furfur.In addition, 0.5% of DHA exhibits, after 14 or 28 days of treatment, a bactericidal effect of approximately 95 to 100% tested on Propionibacterium acnes, Staphylococcus aureus and Malassezia furfur.
D'autres avantages et caractéristiques de 1 ' invention apparaîtront des exemples qui suivent concernant, d'une part, des procédés de synthèse de l'invention, et d'autre part, des propriétés anti- collagénase et lipolytique des produits susceptibles d'être obtenus par les procédés de synthèse de 1 ' invention .Other advantages and characteristics of the invention will appear from the following examples relating, on the one hand, to methods of synthesis of the invention, and on the other hand, to the anti-collagenase and lipolytic properties of the products capable of being obtained by the synthetic methods of the invention.
Exemple 1 : Mode opératoire pour la synthèse de la (n=l, m=6, Rl=OEt) et le (triester de glycérol) .Example 1: Procedure for the synthesis of (n = l, m = 6, Rl = OEt) and the (glycerol triester).
1. Etape 1 de Bromation.1. Stage 1 of Bromation.
438g (3mol) de 1, 8-octanediol sont mis en solution dans 31 de toluène. 375ml (3.3mol) d'HBr aqueux 48% sont ensuite ajoutés. Le milieu est ensuite chauffé pour éliminer l'eau présente et l'eau formée lors de la réaction par distillation azéotropique .
Après 13.5h de contact, le milieu est refroidi et repris par une solution saturée de NaHC03. La phase organique est séparée et lavée par une solution saturée de NaCl . Après séchage sur MgS04, le milieu est concentré pour donner un brut de 672g.438g (3mol) of 1.8-octanediol are dissolved in 31 of toluene. 375ml (3.3mol) of 48% aqueous HBr are then added. The medium is then heated to remove the water present and the water formed during the reaction by azeotropic distillation. After 13.5 h of contact, the medium is cooled and taken up in a saturated NaHCO 3 solution . The organic phase is separated and washed with a saturated NaCl solution. After drying over MgSO 4 , the medium is concentrated to give a crude of 672g.
Le 8 -bromooctanol est purifié par distillation sous pression réduite, à 96°C sous P<lmbar, m=575g (92%) .The 8-bromooctanol is purified by distillation under reduced pressure, at 96 ° C under P <lmbar, m = 575g (92%).
Caractérisât ion :Characterization :
- CCM : Rf = 0,8 (heptane/éther iso 8/2)- TLC: Rf = 0.8 (heptane / 8/2 iso ether)
- RMN XH (200Mhz, CDC13) : 3.65 (t, 2H, J=6.4Hz) ; 3.43 (t, 2H, ιJ=6.8Hz) ; 1.87 (m, 2H) ; 1.36-- X H NMR (200MHz, CDC1 3): 3.65 (t, 2H, J = 6.4Hz); 3.43 (t, 2H, ιJ = 6.8Hz); 1.87 (m, 2H); 1.36-
1.69 (m, 10H) .1.69 (m, 10H).
2. Etape d'oxydation en aldéhyde.2. Aldehyde oxidation step.
M=209.13 M= 144.22M = 209.13 M = 144.22
708 g (5.87, 3éq) de N- Oxyde de N- Methylmorpholine anhydre sont mis en solution, sous N2, dans 31 de DMSO. 410g (1,96 mol) de 8 -bromooctanol dissous dans 11 de DMSO sont ensuite additionnés en 30min. Le milieu devient limpide. Le bromure d'ammonium de la N-Methylmorpholine précipite. Après 65h d'agitation à température ambiante, ce sel est filtré et le milieu est repris par 4 1 d'une solution saturée de NaCl . Après extraction par 4 x 11 d'acétate d'éthyle et séchage, 320 g de brut, constitués à 74% d'aldéhyde (R=83%) et 26% de 1.8-octanediol .
Caractérisât ion :708 g (5.87, 3 eq) of anhydrous N-oxide of N-methylmorpholine are dissolved, under N 2 , in 31 of DMSO. 410 g (1.96 mol) of 8-bromooctanol dissolved in 11 of DMSO are then added over 30 min. The environment becomes clear. The ammonium bromide of N-Methylmorpholine precipitates. After 65 hours of stirring at room temperature, this salt is filtered and the medium is taken up in 4 1 of a saturated NaCl solution. After extraction with 4 x 11 of ethyl acetate and drying, 320 g of crude, consisting of 74% aldehyde (R = 83%) and 26% of 1.8-octanediol. Characterization :
- CCM : Rf = 0,6 (heptane/acétate d'éthyle 8/2)- TLC: Rf = 0.6 (heptane / ethyl acetate 8/2)
- RMN 1H (400Mhz, CDCl3) : 9.74 (t, 1H, <J=1.7Hz) ; 3.61 (t, 2H, J=6.6Hz) ; 2.41 (dt, 2H, .7=1.7 et 7.3Hz) ; 1.51-1.65 (m, 4H) ; 1.24 -1.37 (m, 6H) .- 1 H NMR (400Mhz, CDCl 3 ): 9.74 (t, 1H, <J = 1.7Hz); 3.61 (t, 2H, J = 6.6Hz); 2.41 (dt, 2H, .7 = 1.7 and 7.3Hz); 1.51-1.65 (m, 4H); 1.24 -1.37 (m, 6H).
3. Etape 3 : Réaction de Witting-Horner,3. Step 3: Witting-Horner reaction,
Le brut précédent (320g) est placé en solution dans 31 d'eau. 800ml (4.2mol, 2.1éq) de triethylphosphonoacetate sont ensuite ajoutés suivis de 830g (6mol) de carbonate de potassium. Après 20h d'agitation, la réaction est terminée. Le milieu est extrait par 4 x 11 d' éther isopropylique. Après séchage sur MgS04, les phases organiques sont évaporées pour conduire à 650g de brut.The previous crude (320g) is placed in solution in 31 of water. 800ml (4.2mol, 2.1éq) of triethylphosphonoacetate are then added followed by 830g (6mol) of potassium carbonate. After 20 hours of stirring, the reaction is finished. The medium is extracted with 4 x 11 isopropyl ether. After drying over MgSO 4 , the organic phases are evaporated to yield 650 g of crude.
Le produit est purifié soit par distillation E=120°C sous P<lmbar.The product is purified either by distillation E = 120 ° C under P <lmbar.
Dans ce cas, on récupère 280g d'un liquide incolore conforme par RMN (R=80% à partir de l'aldéhyde ou 66% à partir du dérivé brome) soit par chromatographie avec une élution heptane/acétate d'éthyle 8/2 dans ce cas 119.6g de produits sont obtenus (28% à partir du dérivé brome) .
Caractérisât ion :In this case, 280 g of a colorless, conforming liquid are recovered by NMR (R = 80% from the aldehyde or 66% from the bromine derivative) or by chromatography with a heptane / ethyl acetate 8/2 elution. in this case 119.6 g of products are obtained (28% from the bromine derivative). Characterization :
- CCM : Rf = 0,8 (heptane/acétate d'éthyle- TLC: Rf = 0.8 (heptane / ethyl acetate
8/2)8/2)
- RMN XH (400Mhz, CDC13) : 6.91-6.99 (m,- X H NMR (400MHz, CDC1 3): 6.91-6.99 (m,
1H) ; 5.78-5.82 (dt, 1H, «7=1.4 et 15.6Hz) ; 4.17 (q,1H); 5.78-5.82 (dt, 1H, "7 = 1.4 and 15.6Hz); 4.17 (q,
2H, «7=7.1Hz ) ; 3.63 (t, 2H, =6.6Hz) ; 2.18 (dq, 2H, J=1.2 et 7.3Hz) ; 1.22 -1.65 (m, 11H) .2H, "7 = 7.1Hz); 3.63 (t, 2H, = 6.6Hz); 2.18 (dq, 2H, J = 1.2 and 7.3Hz); 1.22 -1.65 (m, 11H).
4. Etape 4 : Réaction de saponification.4. Step 4: Saponification reaction.
EtOH/HzOEtOH / H z O
M =214.31 M =186.25M = 214.31 M = 186.25
119.6g (0.56mol) d' hydroxyester est dissous dans 600ml d'éthanol et 400ml d'une solution 4.6N de KOH sont additionnés. Le milieu est agité 8h. Le milieu est extrait par de l' éther isopropylique. La phase aqueuse est acidifiée à pH=l et extraite à l'acétate d'éthyle. Après séchage et évaporation , 99.6g de solide rose sont obtenus. Recristallisé dans un mélange éther isopropylique / éther de pétrole, le produit est obtenu sous forme d'un solide blanc (86g, 83%) .119.6g (0.56mol) of hydroxyester is dissolved in 600ml of ethanol and 400ml of a 4.6N KOH solution are added. The medium is agitated for 8 hours. The medium is extracted with isopropyl ether. The aqueous phase is acidified to pH = 1 and extracted with ethyl acetate. After drying and evaporation, 99.6 g of pink solid are obtained. Recrystallized from an isopropyl ether / petroleum ether mixture, the product is obtained in the form of a white solid (86g, 83%).
Caractérisât ion : CCM : Rf = 0,2 (heptane/acétate d'éthyleCharacterization: TLC: Rf = 0.2 (heptane / ethyl acetate
7/3)7/3)
Point de fusion : F=61.3°CMelting point: F = 61.3 ° C
RMN 1H (400Mhz, CDC13) : 7.06 (dt, 1H, 1 H NMR (400Mhz, CDC1 3 ): 7.06 (dt, 1H,
.7=15.6 et 7Hz) ; 5.81 (dt, 1H, .7=1.5 et 15.6Hz) ; 3.64 (t, 2H, «7=6.6Hz) ; 2.22 (dq, 2H, «7=1.2 et 7.3Hz) ;.7 = 15.6 and 7Hz); 5.81 (dt, 1H, .7 = 1.5 and 15.6Hz); 3.64 (t, 2H, "7 = 6.6Hz); 2.22 (dq, 2H, "7 = 1.2 and 7.3Hz);
1.52-1.58 (m, 2H) ; 1.45 -1.48 (m, 2H) ; 1.33 -1.37651.52-1.58 (m, 2H); 1.45 -1.48 (m, 2H); 1.33 -1.3765
(m, 6H) .
5. Etape 5 : Réaction de protection.(m, 6H). 5. Step 5: Protective reaction.
86g (0.46mol) d' hydroxyacide sont placés en solution avec 45ml (0.48mol) de 3 , 4-dihydro-2H-pyranne dans 500ml de THF. 1ml d'HCl concentré est ajouté et le milieu est agité 24h.86g (0.46mol) of hydroxy acid are placed in solution with 45ml (0.48mol) of 3, 4-dihydro-2H-pyranne in 500ml of THF. 1 ml of concentrated HCl is added and the medium is stirred for 24 hours.
Le THF est ensuite concentré, le brut est repris dans de l'acétate d'éthyle et lavé avec une solution de NaCl saturée jusqu'à pH neutre. Après séchage sur MgS04, 132g de produit brut sont obtenus (>100%) .The THF is then concentrated, the crude is taken up in ethyl acetate and washed with a saturated NaCl solution until neutral pH. After drying over MgSO 4 , 132 g of crude product are obtained (> 100%).
Caractérisât ionCharacterization
CCM : Rf = 0,4 (heptane/acétate d'éthyleTLC: Rf = 0.4 (heptane / ethyl acetate
7/3)7/3)
RMN XH (400Mhz, CDCl3) : 7.06 (dt, 1H, «7=15.6 et 7Hz) ; 5.81 (dd, 1H, «7=1.6 et 15.6Hz) ; 4.58 (t, 1H, «7=2.8Hz) ; 3.82-3.91 (m, 1H) ; 3.71-3.73 (m, 1H) ; 3.51 -3.52 (m, 1H) ; 3.36 -3.39 (m, 1H) ; 2.20 (m, 2H) ; 1.33 -1.89 (m, 16H) . X H NMR (400Mhz, CDCl 3): 7.06 (dt, 1H, "7 = 15.6 and 7 Hz); 5.81 (dd, 1H, "7 = 1.6 and 15.6Hz); 4.58 (t, 1H, "7 = 2.8Hz); 3.82-3.91 (m, 1H); 3.71-3.73 (m, 1H); 3.51 -3.52 (m, 1H); 3.36 -3.39 (m, 1H); 2.20 (m, 2H); 1.33 -1.89 (m, 16H).
6. Etape 6 : réaction d' estérif ication du glycérol6. Step 6: Glycerol Esterification Reaction
8.4g (0.091mol) de glycérol sont placés en solution dans 500ml de dichlorométhane . Le brut précédent (0.46mol) , après élimination des traces d'eau par distillation azéotropique, est dissous dans 500ml
de dichloro éthane et ajouté au milieu. 56.8g (0.46mol) de diméthylaminopyridine sont ensuite ajouté suivis de 97g (0.46mol) de dicyclohexylcarbodiimide . Le milieu est agité 78h. Un précipité apparaît qui est filtré. Le milieu est concentré et repris dans de l'éther isopropylique. Après filtration et concentration, 156g de brut sont obtenus et purifiés par chromatographie et avec une élution heptane/acétate d λéthyle 7/3. 99g d'une fraction contenant 2/3 de produit et 1/3 d' acylurée sont obtenus.8.4g (0.091mol) of glycerol are placed in solution in 500ml of dichloromethane. The preceding crude (0.46 mol), after elimination of the traces of water by azeotropic distillation, is dissolved in 500 ml of dichloroethane and added to the medium. 56.8g (0.46mol) of dimethylaminopyridine are then added followed by 97g (0.46mol) of dicyclohexylcarbodiimide. The medium is stirred for 78 hours. A precipitate appears which is filtered. The medium is concentrated and taken up in isopropyl ether. After filtration and concentration, 156 g of crude is obtained and purified by chromatography and elution with a heptane / ethyl acetate 7/3 λ. 99g of a fraction containing 2/3 of product and 1/3 of acylurea are obtained.
Caractérisât ion :Characterization :
CCM : Rf = 0.7 (heptane/acétate d'éthyle 7/3)TLC: Rf = 0.7 (heptane / ethyl acetate 7/3)
RMN *H (400Mhz, CDC13) : 6.96 (m, 3H) ; 5.80NMR * H (400Mhz, CDC1 3 ): 6.96 (m, 3H); 5.80
(dd, 3H, «7=1.6 et 15.6Hz) ; 5.29-5.31 (m, 1H) ; 4.54-(dd, 3H, "7 = 1.6 and 15.6Hz); 5.29-5.31 (m, 1H); 4.54-
4.57 (m, 3H) ; 4.20-4.39 (m, 4H) ; 3.81-3.89 (m, 3H) ;4.57 (m, 3H); 4.20-4.39 (m, 4H); 3.81-3.89 (m, 3H);
3.68 -3.72 (m, 3H) ; 3.41-3.49 (m, 3H) ; 3.34-3.39 (m, 3H) ; 2.25-2.18 (m, 6H) ; 1.33 -1.99 (m, 48H) .3.68 -3.72 (m, 3H); 3.41-3.49 (m, 3H); 3.34-3.39 (m, 3H); 2.25-2.18 (m, 6H); 1.33 -1.99 (m, 48H).
7. Etape 7 : Déprotection finale.7. Step 7: Final deprotection.
99g (0.136mol) du mélange précédent est solubilisé dans 11 de méthanol avec 9.9g d'APTS. Le milieu est agité 14h. La réaction est terminée, le milieu est alors concentré. L'huile obtenue est alors reprise dans H20 et amenée à pH=6 avec une solution saturée de NaHC03. La phase aqueuse est extraite avec
du dichlorométhane . Après séchage de la phase organique et évaporation, 77g d'une huile jaune sont obtenus. 99g (0.136mol) of the above mixture is dissolved in 11 of methanol with 9.9g of APTS. The medium is agitated at 2 p.m. The reaction is complete, the medium is then concentrated. The oil obtained is then taken up in H 2 0 and brought to pH = 6 with a saturated NaHCO 3 solution . The aqueous phase is extracted with dichloromethane. After drying the organic phase and evaporation, 77 g of a yellow oil are obtained.
Le produit est purifié par chromatographie sur silice CH2Cl2/acétone 9/1 à l/l et CH2Cl2/méthanol 95/5.The product is purified by chromatography on silica CH 2 Cl 2 / acetone 9/1 to l / l and CH 2 Cl 2 / methanol 95/5.
27 g de produit sont obtenus sous forme d'une huile qui cristallise sous forme d'un solide blanc jaune amorphe de pureté entre 85-90%.27 g of product are obtained in the form of an oil which crystallizes in the form of an amorphous yellow white solid with a purity between 85-90%.
Caractérisât ion :Characterization :
CCM : Rf = 0.2 (CH2Cl2/acétone 9/1) RMN ^Η (400Mhz, CDCl3) : 6.94-7.01 (m, 3H) ; 5.78-5.84 (m,3H) ; 5.29-5.31 (m, 1H) ; 4.20-4.34 (m, 4H) ; 3.60 -3.65 (m, 6H) ; 2.16 -2.22 (m, 6H) ; 1.33 - 1.99 (m, 30H) .TLC: Rf = 0.2 (CH 2 Cl 2 / acetone 9/1) 1 H NMR (400Mhz, CDCl 3 ): 6.94-7.01 (m, 3H); 5.78-5.84 (m, 3H); 5.29-5.31 (m, 1H); 4.20-4.34 (m, 4H); 3.60 -3.65 (m, 6H); 2.16 -2.22 (m, 6H); 1.33 - 1.99 (m, 30H).
Exemple 2 ; Mode opératoire pour la synthèse de;Example 2; Procedure for the synthesis of;
1. Etape 1 : Protection du 8-bromooctanol1. Step 1: Protection of 8-bromooctanol
M =209.13 M =323.39M = 209.13 M = 323.39
21 g (0,1 mol) de 8 -bromooctanol sont dissous dans 200ml de dichlorométhane. 16 g (0,104 mol) de chlorure de terbutyldimethylsilyle sont ensuite ajouté à 0°C, suivis de 7,5 g (0,11 mol) d'imidazole. Un précipité se forme instantanément. Après 3h d'agitation, le milieu est filtré, concentré et le brut est distillé.21 g (0.1 mol) of 8-bromooctanol are dissolved in 200 ml of dichloromethane. 16 g (0.104 mol) of terbutyldimethylsilyl chloride are then added at 0 ° C., followed by 7.5 g (0.11 mol) of imidazole. A precipitate is formed instantly. After 3 hours of stirring, the medium is filtered, concentrated and the crude is distilled.
25,8 g de produit sont ainsi isolés à 99- 104°C sous P <1 mbar (82%) .
Caractérisât ion :25.8 g of product are thus isolated at 99-104 ° C under P <1 mbar (82%). Characterization :
RMN XH (400Mhz, CDC13) 3.59 (t, 2H, «J= X H NMR (400MHz, CDC1 3) 3.59 (t, 2H, "J =
6.6Hz) ; 3.39 (t, 2H, «7= 6.9Hz) ; 1.82-1.89 (m, 2H) ; 1.30-1.50 (m, 10H) ; 0.88 (t, 9H, «7= 2.7Hz) ; 0.04 (s, 6H) .6.6Hz); 3.39 (t, 2H, "7 = 6.9 Hz); 1.82-1.89 (m, 2H); 1.30-1.50 (m, 10H); 0.88 (t, 9H, "7 = 2.7Hz); 0.04 (s, 6H).
2. Etape 2 : Oxydation en aldéhyde .2. Step 2: Oxidation to aldehyde.
M =323.39 M = 258.48M = 323.39 M = 258.48
20 g (61 mmol) de dérivé silylé sont mis en solution dans 200ml de DMSO. 21,7 g (0,18 mol) de N- oxyde de jV-methylmorpholine sont ensuite ajoutés. Le milieu est agité 72h. Un précipité apparaît. Le milieu est dilué avec NaCl saturé puis extrait avec de l' éther isopropylique. Après séchage et évaporation, 15,3 g de brut sont obtenus .20 g (61 mmol) of silylated derivative are dissolved in 200 ml of DMSO. 21.7 g (0.18 mol) of jV-methylmorpholine N-oxide are then added. The medium is stirred for 72 hours. A precipitate appears. The medium is diluted with saturated NaCl and then extracted with isopropyl ether. After drying and evaporation, 15.3 g of crude oil are obtained.
Le produit est purifié par distillation à 81°C sous P<lmbar ( 9g, 57%) .The product is purified by distillation at 81 ° C under P <lmbar (9g, 57%).
Caractérisât ion :Characterization :
RMN αH (400Mhz, CDCl3) : 9.76 (t, 1H, «J= 1.9Hz) ; 3.59 (t, 2H, «J= 6.6Hz) ; 2.42 (dt, 2H, «7= 1.8 et 7.2Hz) ; 1.49-1.68 (m, 4H) ; 1.30-1.32 (m, 6H) ; 0.88 (t, 9H, «7= 2.7Hz) ; 0.04 (t, 6H, «7= 2.9Hz). Α H NMR (400Mhz, CDCl 3 ): 9.76 (t, 1H, "J = 1.9Hz); 3.59 (t, 2H, "J = 6.6 Hz); 2.42 (dt, 2H, "7 = 1.8 and 7.2Hz); 1.49-1.68 (m, 4H); 1.30-1.32 (m, 6H); 0.88 (t, 9H, "7 = 2.7Hz); 0.04 (t, 6H, "7 = 2.9Hz).
3. Etape 3 : Réaction de Wittinq.3. Step 3: Wittinq reaction.
TBDMSO^ -2U°~ . TBDMSO^ COOEtTBDMSO ^ -2U ° ~. TBDMSO ^ COOEt
NaHNaH
M =258.48
835 mg (21 mmol) de NaH sont mis en solution avec 5 ml de THF et refroidis à T<°C. 4,2 ml (22 mmol) de triethylphosphonoacetate sont ajoutés goutte à goutte. Après 3h d'agitation à température ambiante, 5 g (19 mmol) d'aldéhyde sont ajoutés à froid et l'agitation est maintenue 17 h. Après hydrolyse avec H20, extraction à l'acétate d'éthyle, séchage et évaporation, 6,7 g de brut sont obtenus.M = 258.48 835 mg (21 mmol) of NaH are dissolved in 5 ml of THF and cooled to T <° C. 4.2 ml (22 mmol) of triethylphosphonoacetate are added dropwise. After 3 hours of stirring at room temperature, 5 g (19 mmol) of aldehyde are added cold and stirring is continued for 17 hours. After hydrolysis with H 2 0, extraction with ethyl acetate, drying and evaporation, 6.7 g of crude are obtained.
3,7 g de produits sont obtenus par purification sur gel de silice (élution heptane/acétate d'éthyle 8/2) (60%) .3.7 g of products are obtained by purification on silica gel (elution heptane / ethyl acetate 8/2) (60%).
Caractérisât ion :Characterization :
CCM : Rf= 0.6 (heptane /acétate d'éthyle 8/2)TLC: Rf = 0.6 (heptane / ethyl acetate 8/2)
RMN ^Η (400Mhz, CDCl3) : 6.95 (dt, 1H, «7=NMR ^ Η (400Mhz, CDCl 3 ): 6.95 (dt, 1H, "7 =
8.6 et 15.6Hz) ; 5.79 (dt, 1H, «7= 1.4 et 15.6Hz) ; 4.178.6 and 15.6Hz); 5.79 (dt, 1H, "7 = 1.4 and 15.6Hz); 4.17
(q, 2H, «7= 7.1Hz ) ; 3.58 ( dt, 2H, J= 6.6 et 9.8Hz) ;(q, 2H, "7 = 7.1Hz); 3.58 (dt, 2H, J = 6.6 and 9.8Hz);
2.15-2.21 (m, 2H) ; 1.46 -1.51 (m, 4H) ; 1.24 -1.42 (m, 9H) ; 0.88 (t, 9H, «7= 2.7Hz) ; 0.04 (t, 6H, «7= 2.9Hz).2.15-2.21 (m, 2H); 1.46 -1.51 (m, 4H); 1.24 -1.42 (m, 9H); 0.88 (t, 9H, "7 = 2.7Hz); 0.04 (t, 6H, "7 = 2.9Hz).
4. Etape 4 : Saponification.4. Step 4: Saponification.
TBDMSO v/\ /\^\/-*ï5i^COOEt KOH ,COθH EtθH/H,0TBDMSO v / \ / \ ^ \ / - * ï 5i ^ COOEt KOH, COθH EtθH / H, 0
2 g (6 mmol) d'ester sont dissous dans 10 ml d'éthanol et 5 ml d'une solution de NaOH 3,8 N sont ajoutés. La réaction est terminée en 4h. Le milieu est acidifié à pH=l et extrait à l'acétate d'éthyle. Le produit est ainsi obtenu sans autre purification (1,5 g, 83%) .
Caractérisât ion :2 g (6 mmol) of ester are dissolved in 10 ml of ethanol and 5 ml of a 3.8 N NaOH solution are added. The reaction is finished in 4 hours. The medium is acidified to pH = 1 and extracted with ethyl acetate. The product is thus obtained without further purification (1.5 g, 83%). Characterization :
CCM : 0.2 (heptane/acétate d'éthyle 7/3)TLC: 0.2 (heptane / ethyl acetate 7/3)
RMN XH (400Mhz, CDCl3) : 7.07 (dt, 1H, «7= X H NMR (400Mhz, CDCl 3): 7.07 (dt, 1H, "7 =
8.6 et 15.6Hz) ; 5.81 (dt, 1H, «7= 1.4 et 15.6Hz) ; 3.598.6 and 15.6Hz); 5.81 (dt, 1H, "7 = 1.4 and 15.6Hz); 3.59
( dt, 2H, «7= 6.6 et 9.8Hz) ; 2.21 -2.27 (m, 2H) ; 1.46(dt, 2H, "7 = 6.6 and 9.8 Hz); 2.21 -2.27 (m, 2H); 1.46
-1.51 (m, 4H) ; 1.24 -1.42 (m, 6H) ; 0.89 (t, 9H, «J= 2.7Hz) ; 0.04 (t, 6H, J= 2.9Hz).-1.51 (m, 4H); 1.24 -1.42 (m, 6H); 0.89 (t, 9H, "J = 2.7 Hz); 0.04 (t, 6H, J = 2.9Hz).
Exemple 3 : Evaluation de l'activité anti- collagénase de produits obtenus par le procédé de l'invention sur coupes congelées de peau humaine.Example 3: Evaluation of the anti-collagenase activity of products obtained by the process of the invention on frozen sections of human skin.
1. Mode opératoire.1. Procedure.
Cette étude est réalisée sur différentes solutions à la concentration de 1 % et 2 % de principes actifs en comparaison avec l'excipient seul, les témoins tampon et collagénase. Les principes actifs utilisés sont le DHA, le 2-diméthylamino éthyl ester de l'acide hydroxy-10 -décène-2 (trans) oïque (ML40) et le glycérol ester de l'acide hydroxy- 10 -décène- 2 (trans) oïque (GM) . Le tableau 1 résume les différentes solutions testées.This study is carried out on different solutions at the concentration of 1% and 2% of active principles in comparison with the excipient alone, the buffer and collagenase controls. The active ingredients used are DHA, 2-dimethylamino ethyl ester of hydroxy-10-decene-2 (trans) oic acid (ML40) and glycerol ester of hydroxy-10-decene-2 (trans) acid oic (GM). Table 1 summarizes the different solutions tested.
Tableau 1Table 1
Des coupes congelées de 5 μm, provenant d'une plastie mammaire d'une femme de 54 ans, sont
placées sur des lames histologiques (4 coupes par lame) . Chaque solution est testée sur une lame.5 μm frozen sections from a breast plasty of a 54 year old woman are placed on histological slides (4 sections per slide). Each solution is tested on a slide.
Les coupes sont recouvertes des solutions à tester puis mises à incuber pendant 2 heures à 37°C en chambre humide. Les solutions sont éliminées par rinçages répétitifs et les coupes sont colorées au picrosirius. L'examen microscopique est réalisé à l'objectif de 2,5 et les photographies papier sont prises avec un film Kodak Gold 100 ASA.The sections are covered with the solutions to be tested and then incubated for 2 hours at 37 ° C. in a humid chamber. The solutions are eliminated by repetitive rinsing and the sections are stained with picrosirius. The microscopic examination is carried out at the objective of 2.5 and the paper photographs are taken with a Kodak Gold 100 ASA film.
2. Résultats .2. Results.
Le tableau 2 résume les résultats de l'altération de la structure collagenique en fonction de la solution testée. Une absence d'altération de la structure collagenique est indiquée par 0 alors qu'une structure collagenique moyennement ou nettement à très fortement altérée est indiquée respectivement par 1 ou 2.Table 2 summarizes the results of the alteration of the collagen structure as a function of the solution tested. An absence of alteration of the collagen structure is indicated by 0 while a moderately or markedly to very strongly altered collagen structure is indicated by 1 or 2 respectively.
Tableau 2Table 2
De plus, l'application du témoin tampon Tris ou de l'excipient n'induit aucune altération de la structure collagenique.In addition, the application of the Tris buffer control or of the excipient does not induce any alteration of the collagen structure.
Par conséquent, le produit DHA à 1 et à 2 % inhibe totalement l'activité de la collagénase, alors
que les produits ML40 et GM à 2% inhibe légèrement l'activité de la collagénase.Therefore, the 1% and 2% DHA product completely inhibits collagenase activity, so that ML40 and GM at 2% slightly inhibits the activity of collagenase.
Exemple 4 : Evaluation de l'activité anti- collagénase du GM obtenu par le procédé de l'invention sur explants de peau humaine maintenue en survie.Example 4: Evaluation of the anti-collagenase activity of GM obtained by the method of the invention on explants of human skin maintained in survival.
1. Mode opératoire.1. Procedure.
L'étude est faite sur un produit à 5% de GM en comparaison avec de l'excipient (hydrocérine) , un contrôle positif et un témoin en présence de la collagénase à 100 U/ml.The study is carried out on a product at 5% GM in comparison with the excipient (hydrocerin), a positive control and a control in the presence of collagenase at 100 U / ml.
L' hydrocérine est utilisé comme excipient pour la préparation du produit à appliquer. Cette étude a été réalisée deux fois. Dans la première étude, il a été constaté que l'action de la collagénase à J2 reste très limitée et non significative. Dans la deuxième étude, le temps d'application est prolongé et le prélèvement des explants est effectué à J2 et à J4.Hydrocerin is used as an excipient for the preparation of the product to be applied. This study was carried out twice. In the first study, it was found that the action of collagenase on D2 remains very limited and not significant. In the second study, the application time is extended and the explants are removed on D2 and D4.
a. Préparation des explants.at. Explant preparation.
Des explants de peau humaine préparés et répartis en 16 lots de trois explants chacun sont mis en survie selon le tableau 3.Human skin explants prepared and divided into 16 lots of three explants each are put to survival according to Table 3.
Tableau 3Table 3
J2 J4D2 D4
Témoin 3 explants 3 explantsWitness 3 explants 3 explants
Excipient 3 explants 3 explantsExcipient 3 explants 3 explants
Produit à 5% GM 3 explants 3 explants5% GM product 3 explants 3 explants
Contrôle positif 3 explants 3 explantsPositive control 3 explants 3 explants
Témoin + collagénase 3 explants 3 explantsControl + collagenase 3 explants 3 explants
Excipient + collagénase 3 explants 3 explantsExcipient + collagenase 3 explants 3 explants
Produit à 5% GM + collagénase 3 explants 3 explantsProduct at 5% GM + collagenase 3 explants 3 explants
Contrôle positif + collagénase 3 explants 3 explants
b . Application du produit à 5% de GM .Positive control + collagenase 3 explants 3 explants b. Application of the product at 5% GM.
Le produit est appl iqué à J0 et à J2 à raison de 20 mg par explant et la collagénase est incorporée dans les milieux de culture des 24 derniers lots .The product is applied on D0 and D2 at a rate of 20 mg per explant and the collagenase is incorporated into the culture media of the last 24 batches.
c. Histologie. Trois explants de chaque lot sont prélevés à J2 et à J4 fixés au Bouin ordinaire et traités en histologie .vs. Histology. Three explants from each batch are taken on D2 and D4 fixed at the ordinary Bouin and treated in histology.
L'étude histologique comprend : imprégnation en paraffine, coupes, coloration au rouge sirius F3B mesures colorimétriques du collagene par analyse d'images rapport avec photos .The histological study includes: paraffin impregnation, sections, staining with sirius red F3B colorimetric measurements of collagen by image analysis report with photos.
2. Résultats.2. Results.
Les prélèvements réalisés à J2 ne montrent aucune activité significative de la collagénase quelque soit le lot examiné. Pour cette raison, la survie, le contact et l'application sont prolongés jusqu'à J4. L'action de la collagénase est notée de 2 manières : intensité de la coloration du réseau de collagene et épaisseur de la structure dermique. Avec cette étude, sont corrélées la pénétration du principe actif et son activité inhibitrice vis-à-vis de la collagénase. Les résultats obtenus sont les suivants :The samples taken on D2 show no significant activity of the collagenase whatever the batch examined. For this reason, survival, contact and application are extended until D4. The action of collagenase is noted in 2 ways: intensity of coloration of the collagen network and thickness of the dermal structure. With this study, the penetration of the active ingredient and its inhibitory activity vis-à-vis collagenase are correlated. The results obtained are as follows:
- pour les témoins sans collagénase, le derme présente une structure normale, avec des faisceaux de collagene réguliers dans tous les compartiments,
- pour les témoins avec collagénase, les faisceaux de collagene sont très fortement dégradés et l'épaisseur du derme a diminué de moitié, pour les explants avec excipient et collagénase, les faisceaux de collagene sont fortement dégradés, l'altération étant inférieure à celle observée sur les témoins avec collagénase, et l'épaisseur du derme a diminué de presque moitié,- for controls without collagenase, the dermis has a normal structure, with regular collagen bundles in all the compartments, - for the controls with collagenase, the collagen bundles are very strongly degraded and the thickness of the dermis has halved, for the explants with excipient and collagenase, the collagen bundles are strongly degraded, the alteration being less than that observed on the controls with collagenase, and the thickness of the dermis decreased by almost half,
- pour les explants avec produit à 5% de GM et collagénase, les faisceaux de collagene sont très légèrement dégradés et l'épaisseur du derme a légèrement diminué,- for explants with product containing 5% GM and collagenase, the collagen bundles are very slightly degraded and the thickness of the dermis has slightly decreased,
- pour les explants avec contrôle positif (phénanthroline) et collagénase, la structure dermique est identique à celle des témoins sans collagénase.- for explants with positive control (phenanthroline) and collagenase, the dermal structure is identical to that of controls without collagenase.
Dans ces conditions expérimentales, le produit GM montre une nette activité anti-collagénase.Under these experimental conditions, the GM product shows a marked anti-collagenase activity.
Exemple 5 : Evaluation de l'activité anti- lipolytique du DHA obtenu par le procédé de l'invention sur des explants de tissus adipeux ex vivo.Example 5: Evaluation of the anti-lipolytic activity of DHA obtained by the method of the invention on explants of adipose tissues ex vivo.
1 . Mode opératoire.1. Procedure.
Le DHA est incorporé dans le milieu de culture à la concentration finale de 0,25 et de 0,5 %. Après un contact de 8 jours, l'activité est évaluée par dosage des lipides relargués dans le milieu de culture.DHA is incorporated into the culture medium at the final concentration of 0.25 and 0.5%. After an 8-day contact, the activity is evaluated by assaying the lipids released into the culture medium.
a. Préparation des explants. Douze explants de tissus adipeux (plastieat. Explant preparation. Twelve explants of adipose tissue (plasty
P202-AB31) sont préparés et mis en survie en milieu BEM (BIO-EC's Explants Médium). Les explants sont répartis en 4 lots de 3 explants : un lot Témoin, un lot Témoin Positif (caféine à 0,1%),
deux lots produit (DHA à 0,25 et 0,5%) .P202-AB31) are prepared and put to survival in BEM medium (BIO-EC's Explants Medium). The explants are divided into 4 batches of 3 explants: a control batch, a positive control batch (0.1% caffeine), two batches produced (DHA 0.25 and 0.5%).
b. Application des produits.b. Application of products.
A J0, les explants sont mis en survie dans 2 ml de milieu de culture, dans lequel le produit à tester est incorporé.At D0, the explants are put into survival in 2 ml of culture medium, in which the product to be tested is incorporated.
Ce traitement est renouvelé à J2 , J4 et Jβ .This treatment is repeated on D2, D4 and Dβ.
c . Prélèvements . A J2 , J4 , J6 et J8 , le milieu de culture est prélevé. Pour chaque explant, les milieux prélevés à J2 , J4 , J6 et J8 sont regroupés dans un même tube et conservé à -20°C en vue du dosage des lipides.vs . Specimens . At D2, D4, D6 and D8, the culture medium is removed. For each explant, the media taken on D2, D4, D6 and D8 are combined in the same tube and stored at -20 ° C for the determination of lipids.
A J8 , les explants de tissus adipeux sont prélevés et fixés dans du Bouin ordinaire en vue de l'étude histologique.On D8, the explants of adipose tissues are removed and fixed in ordinary Bouin for the histological study.
d. Histologie.d. Histology.
Les explants de tissus adipeux fixés sont déshydratés, imprégnés en paraffine, mis en bloc, coupés et colorés au trichrome de Masson.The explants of fixed adipose tissue are dehydrated, impregnated with paraffin, placed in a block, cut and colored with Masson trichrome.
e. Dosage des Lipides.e. Dosage of Lipids.
Après extraction du milieu de culture, les lipides sont séparés et dosés par CCM.After extraction from the culture medium, the lipids are separated and assayed by TLC.
2. Résultats .2. Results.
La viabi l ité et la morphologie des adipocytes est contrôlée par l ' étude histologique . L ' activité lipolytique est évaluée par l ' analyse des proport i ons de monoglycéri de s , diglycérides , triglycérides et acides gras libres .
a . Histologie .The viability and the morphology of the adipocytes is controlled by the histological study. Lipolytic activity is evaluated by analyzing the proportions of monoglycerides, diglycerides, triglycerides and free fatty acids. at . Histology.
Après 8 jours de maintien en survie, les explants témoins et traités ne présentent pas d'altérations visibles, ni de nécroses cellulaires.After 8 days of survival, the control and treated explants show no visible alterations or cellular necrosis.
b. Dosage des lipides.b. Determination of lipids.
Les résultats obtenus sont regroupés dans le tableau 4 ci-dessous. Les résultats sont exprimés en masse (μg) de chaque catégorie de lipides libérés dans le milieu de culture, pendant les 8 jours de traitemen .The results obtained are collated in Table 4 below. The results are expressed in mass (μg) of each category of lipids released into the culture medium, during the 8 days of treatment.
Tableau 4Table 4
Le tableau 5 c i - de ssous représ ente l ' analyse statistique par le test de Student des résultats du dosage des acides gras libérés dans le milieu de culture , pendant les 8 j ours de traitement .
Tableau 5Table 5 below represents the statistical analysis by the Student test of the results of the assay of fatty acids released in the culture medium, during the 8 days of treatment. Table 5
Le paramètre essentiel dans cette étude est la variation de la quantité et le pourcentage des acides gras libérés dans le milieu de culture après la période de traitement .The essential parameter in this study is the variation in the amount and percentage of fatty acids released into the culture medium after the treatment period.
Par rapport au Témoin non traité, une augmentation d'un facteur d'environ 29 (2780%) pour le témoin positif (caféine à 0,1%) est observée.Compared to the untreated control, an increase of a factor of about 29 (2780%) for the positive control (0.1% caffeine) is observed.
Le DHA à 0,25 et 0,50% entraîne une augmentation significative respectivement de 1075 et 1087%. L'augmentation de la concentration utilisée n'engendre pas des effets sur l'efficacité. Il semble que la dose maximale efficace soit de l'ordre de 0,25%.DHA at 0.25 and 0.50% leads to a significant increase of 1075 and 1087% respectively. The increase in the concentration used does not have any effects on efficacy. It seems that the maximum effective dose is around 0.25%.
Dans les conditions opératoires décrites ci-dessus et selon le test de Student, le DHA appliqué à 0,25 et à 0,5% présente une activité lipolytique significative en comparaison avec celle de la caféine.
Under the operating conditions described above and according to the Student test, the DHA applied at 0.25 and 0.5% exhibits significant lipolytic activity in comparison with that of caffeine.
Claims
REVENDICATIONS
1) Procédé de préparation des hydroxy- acides gras insaturés et de leurs esters répondant à la formule générale suivante ( Id) :1) Process for the preparation of unsaturated fatty hydroxy acids and their esters corresponding to the following general formula (Id):
Formule ( Id)Formula (Id)
avec n= 1 à 4 m = 2 à 16 with n = 1 to 4 m = 2 to 16
R = OH, Cl, Br, OR3 où R3 représente un radical alkyl, alcényl, alcynyl, linéaire ou ramifié de 1 à 16 carbones ou esters du glycérol, éventuellement substitué par un ou plusieurs atomes de carbone, d'azote, de soufre ou d'halogènes tels que fluor, chlore, brome et iode,R = OH, Cl, Br, OR 3 where R 3 represents an alkyl, alkenyl, alkynyl radical, linear or branched from 1 to 16 carbons or esters of glycerol, optionally substituted by one or more carbon, nitrogen, sulfur or halogens such as fluorine, chlorine, bromine and iodine,
R2= H,
R'2, R'3 identiques ou différents les uns des autres, représentent un radical alkyl, alcényl, alcynyl, linéaire ou ramifié de 1 à 16 carbones ou esters du glycérol, éventuellement substitué par un ou plusieurs atomes de carbone, d'azote, de soufre ou d'halogènes tels que fluor, chlore, brome et iode, ou R2= C-Ar3 avec Ar représentant un radical aryl éventuellement substitué par un ou plusieurs atomes de carbone, d'azote, de soufre ou d'halogènes tels que fluor, chlore, brome et iode, ou R2= le tétrahydropyranyl de formule :R 2 = H, R ' 2 , R' 3 identical or different from each other, represent an alkyl, alkenyl, alkynyl radical, linear or branched from 1 to 16 carbons or glycerol esters, optionally substituted by one or more carbon atoms, nitrogen , sulfur or halogens such as fluorine, chlorine, bromine and iodine, or R 2 = C-Ar 3 with Ar representing an aryl radical optionally substituted by one or more carbon, nitrogen, sulfur or halogens such as fluorine, chlorine, bromine and iodine, or R 2 = tetrahydropyranyl of formula:
caractérisé en ce que le schéma réactionnel est le suivant :
characterized in that the reaction scheme is as follows:
III IVIII IV
Ib laIb la
le the
où Rl t R2, m et n ont la même signification que dans la formule Id.where R lt R 2 , m and n have the same meaning as in the formula Id.
2) Procédé selon la revendication 1, caractérisé en ce que la première étape est une bromation, le composé de départ étant un diol de formule (II) .2) Method according to claim 1, characterized in that the first step is a bromination, the starting compound being a diol of formula (II).
3) Procédé selon l'une quelconque des revendications 1 ou 2 , caractérisé en ce que la première étape nécessite l'utilisation d'un solvant.
4) Procédé selon la revendication 3, caractérisé en ce que le solvant est choisi parmi le toluène, le benzène, le diméthylformamide , le tétrahydrofuran, le cyclohexane, l'heptane, 1 'éther de pétrole.3) Method according to any one of claims 1 or 2, characterized in that the first step requires the use of a solvent. 4) Process according to claim 3, characterized in that the solvent is chosen from toluene, benzene, dimethylformamide, tetrahydrofuran, cyclohexane, heptane, petroleum ether.
5) Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que le réactif utilisé dans la première étape est choisi parmi le HBr aqueux ou non, le Ph3P,Br2, le tétrabromide de carbone triphénylphosphine et l'acide hydrobromique.5) Method according to any one of the preceding claims, characterized in that the reagent used in the first step is chosen from aqueous HBr or not, Ph 3 P, Br 2 , carbon tetrabromide triphenylphosphine and hydrobromic acid .
6) Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que la seconde étape est une oxydation en aldéhyde de formule (IV) en présence d'un N-oxyde d'aminé tertiaire cyclique ou non cyclique, anhydre ou non anhydre et en présence de DMSO.6) Method according to any one of the preceding claims, characterized in that the second step is an aldehyde oxidation of formula (IV) in the presence of a cyclic or non-cyclic tertiary amine N-oxide, anhydrous or non-anhydrous and in the presence of DMSO.
7) Procédé selon la revendication 6, caractérisé en ce que le N-oxyde d'aminé tertiaire cyclique ou non cyclique, anhydre ou non anhydre est choisi parmi le N méthyl morpholine oxyde, le triméthylamine oxyde ou le triéthylamine oxyde ou un mélange de ceux-ci.7) Method according to claim 6, characterized in that the cyclic or non-cyclic, anhydrous or non-anhydrous tertiary amine N-oxide is chosen from N methyl morpholine oxide, trimethylamine oxide or triethylamine oxide or a mixture of those -this.
8) Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que l'étape 3 dudit procédé est une réaction de Witting- Horner et que l'étape 4 dudit procédé est une réaction de saponification.8) Method according to any one of the preceding claims, characterized in that step 3 of said method is a Witting-Horner reaction and that step 4 of said method is a saponification reaction.
9) Procédé selon la revendication 8, caractérisé en ce que ladite réaction de Witting-Horner
est réalisée en présence de triethylphosphonoacetate et de carbonate de potassium.9) Method according to claim 8, characterized in that said Witting-Horner reaction is carried out in the presence of triethylphosphonoacetate and potassium carbonate.
10) Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que l'étape 5 dudit procédé est une étape de protection spécifique de la fonction alcool du composé de formule générale (Ib) obtenu à l'étape 4.10) Method according to any one of the preceding claims, characterized in that step 5 of said method is a step of specific protection of the alcohol function of the compound of general formula (Ib) obtained in step 4.
11) Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que l'étape 5 s'effectue dans tout éther d'énol en présence d'un catalyseur acide.11) Method according to any one of the preceding claims, characterized in that step 5 is carried out in any enol ether in the presence of an acid catalyst.
12) Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que l'étape 5 s'effectue dans le dihydropyrane en présence d'APTS (Acide para toluène sulfonique) .12) Method according to any one of the preceding claims, characterized in that step 5 is carried out in the dihydropyran in the presence of APTS (Para toluene sulfonic acid).
13) Procédé selon l'une quelconque des revendications précédentes, caractérisé en ce que le produit de formule (Id) obtenu à l'étape 5 du procédé de l'invention subit une déprotection finale afin d'obtenir le composé de formule générale (le) .13) Process according to any one of the preceding claims, characterized in that the product of formula (Id) obtained in step 5 of the process of the invention undergoes a final deprotection in order to obtain the compound of general formula (the ).
14) Procédé selon l'une quelconque des revendications 1 à 12, caractérisé en ce que le produit de formule (Id) obtenu à l'étape 5 dudit procédé est utilisé dans une réaction d' estérification du glycérol avant de subir une déprotection finale.14) Method according to any one of claims 1 to 12, characterized in that the product of formula (Id) obtained in step 5 of said method is used in a glycerol esterification reaction before undergoing a final deprotection.
15) Procédé selon l'une des revendications revendication 13 ou 14, caractérisé en ce que ladite déprotection est réalisée dans une solution de méthanol contenant un catalyseur acide .
16) Procédé selon la revendication 15, caractérisé en ce le catalyseur acide utilisé est 1 ' ATPS .15) Method according to one of claims 13 or 14, characterized in that said deprotection is carried out in a methanol solution containing an acid catalyst. 16) Process according to claim 15, characterized in that the acid catalyst used is 1 ATPS.
17) Utilisation d'un produit susceptible d'être obtenu par un procédé selon l'une quelconque des revendications précédentes, comme agent actif anti- collagénase dans une préparation pharmaceutique et/ou cosmétique.17) Use of a product capable of being obtained by a process according to any one of the preceding claims, as an anti-collagenase active agent in a pharmaceutical and / or cosmetic preparation.
18) Utilisation selon la revendication 17, caractérisé en ce que ledit produit est l'acide hydroxy- 10 -décène-2 (trans) oïque (DHA) ou du glycérol ester de l'acide hydroxy-10 -décène-2 (trans) oïque .18) Use according to claim 17, characterized in that said product is hydroxy-10-decec-2 (trans) oic acid (DHA) or glycerol ester of hydroxy-10-decec-2 (trans) acid oic.
19) Utilisation selon la revendication 18, pour la préparation d'un médicament destiné à prévenir ou à guérir la dégradation du collagene.19) Use according to claim 18, for the preparation of a medicament intended to prevent or to cure the degradation of collagen.
20) Utilisation selon la revendication 19, pour la préparation d'un médicament destiné à prévenir ou à guérir la dégradation du collagene par les collagénases bactériennes lors d'une infection bactérienne .20) Use according to claim 19, for the preparation of a medicament intended to prevent or to cure the degradation of collagen by bacterial collagenases during a bacterial infection.
21) Utilisation selon la revendication 18, pour la préparation d'un médicament destiné à la régénérescence de la peau et des ligaments.21) Use according to claim 18, for the preparation of a medicament intended for the regeneration of the skin and ligaments.
22) Utilisation selon la revendication 18, pour préparation d'un médicament destiné à prévenir ou à guérir l'invasion tumorale.
23) Utilisation selon la revendication 18, pour la préparation d'un médicament destiné à prévenir ou à guérir des maladies dégénérâtives présentant une dégénérescence fibrinoïde du collagene et également appelées « maladies du collagene » .22) Use according to claim 18, for the preparation of a medicament intended to prevent or cure tumor invasion. 23) Use according to claim 18, for the preparation of a medicament for preventing or curing degenerative diseases having fibrinoid collagen degeneration and also called "collagen diseases".
24) Utilisation d'un produit susceptible d'être obtenu par un procédé selon l'une quelconque des revendications 1 à 16, comme agent actif lipolytique dans une préparation pharmaceutique et/ou cosmétique.24) Use of a product capable of being obtained by a process according to any one of claims 1 to 16, as lipolytic active agent in a pharmaceutical and / or cosmetic preparation.
25) Utilisation d'un produit susceptible d'être obtenu par un procédé selon l'une quelconque des revendications 1 à 16, comme agent actif anti-acnéique dans une préparation pharmaceutique et/ou cosmétique.25) Use of a product capable of being obtained by a process according to any one of claims 1 to 16, as anti-acne active agent in a pharmaceutical and / or cosmetic preparation.
26) Utilisation selon l'une quelconque des revendications 24 à 25, caractérisée en ce que ledit produit est l'acide hydroxy- 10 -décène-2 (trans) oïque (DHA) .
26) Use according to any one of claims 24 to 25, characterized in that said product is hydroxy-10-decen-2 (trans) oic acid (DHA).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0111815 | 2001-09-12 | ||
| FR0111815A FR2829491B1 (en) | 2001-09-12 | 2001-09-12 | PROCESS FOR THE PREPARATION OF UNSATURATED FATTY HYDROXY ACIDS AND THEIR ESTERS, THEIR USE AS ANTI-COLLAGENASE AGENT |
| PCT/FR2002/003094 WO2003022787A1 (en) | 2001-09-12 | 2002-09-11 | Method for preparing unsaturated fatty hydroxy-acids and esters thereof, their use in pharmaceutical and/or cosmetic compositions |
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| EP1425256A1 true EP1425256A1 (en) | 2004-06-09 |
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| EP (1) | EP1425256A1 (en) |
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| FR2892411B1 (en) * | 2005-10-21 | 2009-03-20 | Diverchim Sa | NOVEL PROCESS FOR PREPARING UNSATURATED HYDROXY FATTY ACIDS |
| FR2892410B1 (en) * | 2005-10-21 | 2010-10-15 | Fabre Pierre Dermo Cosmetique | NOVEL UNSATURATED FATTY HYDRO ACIDS AND THEIR DERMO COSMETOLOGICAL USE |
| US7951232B2 (en) * | 2006-02-09 | 2011-05-31 | Elevance Renewable Sciences, Inc. | Surface coating compositions and methods |
| WO2007092633A2 (en) * | 2006-02-09 | 2007-08-16 | Elevance Renewable Sciences, Inc. | Antimicrobial compositions, methods and systems |
| FR2911135B1 (en) * | 2007-01-09 | 2009-03-20 | Diverchim Sa | NOVEL PROCESS FOR PREPARING UNSATURATED HYDROXY FATTY ACIDS |
| FR2911134B1 (en) * | 2007-01-09 | 2009-03-06 | Diverchim Sa | NOVEL PROCESS FOR PREPARING UNSATURATED HYDROXY FATTY ACIDS |
| US20100240754A1 (en) * | 2007-01-16 | 2010-09-23 | Pierre Fabre Demo-Cosmetique | Unsaturated fatty amino acid derivatives and use thereof in dermal cosmetology |
| FR2911338B1 (en) * | 2007-01-16 | 2014-06-13 | Diverchim | NOVEL PROCESS FOR THE PREPARATION OF UNSATURATED AMINO ACID DERIVATIVES |
| CN101570482B (en) * | 2009-06-09 | 2012-12-26 | 李应阳 | Method for synthesizing jelly acid by omega-chlorine octanol |
| CN102603517A (en) * | 2012-02-15 | 2012-07-25 | 武汉工程大学 | Synthesis process of 10-HDA (10-hydroxy-2-decenoic acid) |
| CN103159617B (en) * | 2013-03-12 | 2014-12-10 | 南京师范大学 | Method for synthesis of 10-hydroxy-2-decenoic acid |
| KR102399290B1 (en) | 2014-05-08 | 2022-05-17 | 디에스엠 아이피 어셋츠 비.브이. | Methods and compositions comprising 10-hydroxy-2-decenoic acid |
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| JPH0215044A (en) * | 1988-07-01 | 1990-01-18 | Shin Etsu Chem Co Ltd | Production of royal jelly acid |
| FR2684988B1 (en) * | 1991-12-12 | 1995-07-13 | Fabre Pierre Cosmetique | INDUSTRIAL PROCESS FOR THE SYNTHESIS OF HYDROXY-10-DECENE-E-OUIQUE ACID AND OXO-9-DECENE-2-OUIQUE ACID, ACTIVE INGREDIENTS OF ROYAL JELLY. |
| FR2783517B1 (en) * | 1998-09-22 | 2001-02-09 | Oreal | NOVEL 10-HYROXY-2-DECENOIC ACID DERIVATIVES AND USE IN A COMPOSITION FOR PROMOTING SKIN DEQUAMATION, AND COMPOSITION COMPRISING THE SAME |
-
2001
- 2001-09-12 FR FR0111815A patent/FR2829491B1/en not_active Expired - Fee Related
-
2002
- 2002-09-11 CA CA002459760A patent/CA2459760A1/en not_active Abandoned
- 2002-09-11 BR BR0212467-0A patent/BR0212467A/en not_active IP Right Cessation
- 2002-09-11 JP JP2003526866A patent/JP2005502692A/en active Pending
- 2002-09-11 EP EP02798004A patent/EP1425256A1/en not_active Withdrawn
- 2002-09-11 CN CNA028179439A patent/CN1555351A/en active Pending
- 2002-09-11 WO PCT/FR2002/003094 patent/WO2003022787A1/en not_active Application Discontinuation
-
2004
- 2004-03-12 US US10/799,532 patent/US20040204596A1/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| See references of WO03022787A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003022787A1 (en) | 2003-03-20 |
| FR2829491B1 (en) | 2005-09-30 |
| FR2829491A1 (en) | 2003-03-14 |
| CA2459760A1 (en) | 2003-03-20 |
| US20040204596A1 (en) | 2004-10-14 |
| JP2005502692A (en) | 2005-01-27 |
| BR0212467A (en) | 2004-10-19 |
| CN1555351A (en) | 2004-12-15 |
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