NO172981B - EICOSA-5,8,11-TRIYNOIC ACID COMPOUNDS, PROCEDURE FOR THEIR PREPARATION AND USE OF THE COMPOUNDS IN COSMETIC PREPARATIONS - Google Patents
EICOSA-5,8,11-TRIYNOIC ACID COMPOUNDS, PROCEDURE FOR THEIR PREPARATION AND USE OF THE COMPOUNDS IN COSMETIC PREPARATIONS Download PDFInfo
- Publication number
- NO172981B NO172981B NO921726A NO921726A NO172981B NO 172981 B NO172981 B NO 172981B NO 921726 A NO921726 A NO 921726A NO 921726 A NO921726 A NO 921726A NO 172981 B NO172981 B NO 172981B
- Authority
- NO
- Norway
- Prior art keywords
- compounds
- acid
- formula
- preparation
- eicosa
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 35
- 150000001875 compounds Chemical class 0.000 title claims description 24
- 239000002253 acid Substances 0.000 title claims description 19
- 238000000034 method Methods 0.000 title claims description 16
- 239000002537 cosmetic Substances 0.000 title claims description 8
- 150000002148 esters Chemical group 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 150000001408 amides Chemical class 0.000 claims description 14
- -1 alkyl radical Chemical class 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- 150000001412 amines Chemical group 0.000 claims description 6
- VWWMOACCGFHMEV-UHFFFAOYSA-N dicarbide(2-) Chemical compound [C-]#[C-] VWWMOACCGFHMEV-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 150000003254 radicals Chemical class 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- LWJZTSJJPDDJEB-UHFFFAOYSA-N 2-methylhex-5-ynoic acid Chemical compound OC(=O)C(C)CCC#C LWJZTSJJPDDJEB-UHFFFAOYSA-N 0.000 claims description 3
- 150000005840 aryl radicals Chemical class 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 claims description 2
- UNSRRHDPHVZAHH-UHFFFAOYSA-N 5,8,11-eicosatrienoic acid Chemical class CCCCCCCCC=CCC=CCC=CCCCC(O)=O UNSRRHDPHVZAHH-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 230000009435 amidation Effects 0.000 claims description 2
- 238000007112 amidation reaction Methods 0.000 claims description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 229960002442 glucosamine Drugs 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims 2
- 239000002202 Polyethylene glycol Substances 0.000 claims 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- 229920001223 polyethylene glycol Polymers 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 239000000203 mixture Substances 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 14
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OFCPMJGTZUVUSM-UHFFFAOYSA-N 6-heptynoic acid Chemical compound OC(=O)CCCCC#C OFCPMJGTZUVUSM-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 238000000921 elemental analysis Methods 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 7
- 239000012298 atmosphere Substances 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- ILLHQJIJCRNRCJ-UHFFFAOYSA-N dec-1-yne Chemical compound CCCCCCCCC#C ILLHQJIJCRNRCJ-UHFFFAOYSA-N 0.000 description 5
- 238000002329 infrared spectrum Methods 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 230000000699 topical effect Effects 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 235000021342 arachidonic acid Nutrition 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000013067 intermediate product Substances 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 102000003820 Lipoxygenases Human genes 0.000 description 3
- 108090000128 Lipoxygenases Proteins 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229940114079 arachidonic acid Drugs 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- JZYKFLLRVPPISG-UHFFFAOYSA-N hex-5-ynenitrile Chemical compound C#CCCCC#N JZYKFLLRVPPISG-UHFFFAOYSA-N 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 2
- GIAFURWZWWWBQT-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanol Chemical compound NCCOCCO GIAFURWZWWWBQT-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 150000002617 leukotrienes Chemical class 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 150000002901 organomagnesium compounds Chemical class 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- CBOJBBMQJBVCMW-BTVCFUMJSA-N (2r,3r,4s,5r)-2-amino-3,4,5,6-tetrahydroxyhexanal;hydrochloride Chemical compound Cl.O=C[C@H](N)[C@@H](O)[C@H](O)[C@H](O)CO CBOJBBMQJBVCMW-BTVCFUMJSA-N 0.000 description 1
- ABADUMLIAZCWJD-UHFFFAOYSA-N 1,3-dioxole Chemical compound C1OC=CO1 ABADUMLIAZCWJD-UHFFFAOYSA-N 0.000 description 1
- PWJZZTCBODZPBR-UHFFFAOYSA-N 1-chlorotetradeca-1,3-diyne Chemical compound CCCCCCCCCCC#CC#CCl PWJZZTCBODZPBR-UHFFFAOYSA-N 0.000 description 1
- VUGPATWMNVUEQK-UHFFFAOYSA-N 1-cyclohexyl-3-(2-methylphenyl)-1-[2-[(4,7,7-trimethyl-3-bicyclo[2.2.1]heptanyl)oxy]ethyl]urea Chemical compound CC1=CC=CC=C1NC(=O)N(C1CCCCC1)CCOC1C(C2(C)C)(C)CCC2C1 VUGPATWMNVUEQK-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- KQIGMPWTAHJUMN-UHFFFAOYSA-N 3-aminopropane-1,2-diol Chemical compound NCC(O)CO KQIGMPWTAHJUMN-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical class OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 102100037611 Lysophospholipase Human genes 0.000 description 1
- 229910017741 MH2O Inorganic materials 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000010022 Myron Substances 0.000 description 1
- 241001439614 Myron Species 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 108010058864 Phospholipases A2 Proteins 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- NUZWLKWWNNJHPT-UHFFFAOYSA-N anthralin Chemical compound C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O NUZWLKWWNNJHPT-UHFFFAOYSA-N 0.000 description 1
- 239000000058 anti acne agent Substances 0.000 description 1
- 229940031012 anti-acne preparations Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940124340 antiacne agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940030999 antipsoriatics Drugs 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000021466 carotenoid Nutrition 0.000 description 1
- 150000001747 carotenoids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 229960002311 dithranol Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960001911 glucosamine hydrochloride Drugs 0.000 description 1
- 230000003779 hair growth Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 150000002442 hydroxyeicosatetraenoic acids Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Chemical class 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002353 niosome Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical class OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011975 tartaric acid Chemical class 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003595 thromboxanes Chemical class 0.000 description 1
- SLYPOVJCSQHITR-UHFFFAOYSA-N tioxolone Chemical compound OC1=CC=C2SC(=O)OC2=C1 SLYPOVJCSQHITR-UHFFFAOYSA-N 0.000 description 1
- 229960003070 tioxolone Drugs 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cosmetics (AREA)
Description
Den foreliggende oppfinnelse vedrører eicosa-5,8,11-triyn-syreforbindelser, og det særegne ved forbindelsene i henhold til oppfinnelsen er at de har formelen: The present invention relates to eicosa-5,8,11-trienoic acid compounds, and the peculiarity of the compounds according to the invention is that they have the formula:
hvori R er en C]_-Cg-alkoksygruppe substituert med en eller flere hydroksylgrupper, eller en aminogruppe med struktur hvori Ri og R2 er like eller forskjellige og står for et hydrogenatom, Ci-Cg-alkyl hvor kjeden eventuelt er avbrudt med oksygen, idet alkylradikalet eventuelt er substituert med en eller flere hydroksylgrupper, idet R]_ og R2 ikke samtidig betegner hydrogen, eller at R]_ og R2 sammen med nitrogenatomet danner en heterocyklisk C5- eller Cg-ring valgt blant pyrrolidin, morfolin, piperazin og 2'-hydroksy-4-etylpiperazin, idet det ene av radikalene R]_ og R2, når det annet er et hydrogenatom, kan være et arylradikal med formel (II): in which R is a C1-C8 alkoxy group substituted with one or more hydroxyl groups, or an amino group with a structure in which R1 and R2 are the same or different and represent a hydrogen atom, C1-C8 alkyl where the chain is optionally interrupted by oxygen, in that the alkyl radical is optionally substituted with one or more hydroxyl groups, in that R]_ and R2 do not simultaneously denote hydrogen, or that R]_ and R2 together with the nitrogen atom form a heterocyclic C5 or Cg ring selected from pyrrolidine, morpholine, piperazine and 2 '-hydroxy-4-ethylpiperazine, one of the radicals R] and R2, when the other is a hydrogen atom, can be an aryl radical of formula (II):
hvori R3 og R4 uavhengig av hverandre står for et hydrogen- in which R3 and R4 independently represent a hydrogen
atom, eller hydroksyl, idet aminfunksjonen også kan skrive seg fra et sukkeramin, som glukosamin, såvel som forbindelsenes isomerer og deres kosmetisk tålbare salter. atom, or hydroxyl, as the amine function can also be written from a sugar amine, such as glucosamine, as well as the compounds' isomers and their cosmetically acceptable salts.
Oppfinnelsen vedrører også en fremgangsmåte for fremstilling av forbindelsene i henhold til oppfinnelsen, og det særegne ved fremgangsmåten i henhold til oppfinnelsen er at decyn-1 med formel: The invention also relates to a method for producing the compounds according to the invention, and the peculiarity of the method according to the invention is that decyn-1 with the formula:
behandles med en sterk base for fremstilling av det tilsvarende acetylid som omsettes med 1,4-dihalogenbutyn-2 for fremstilling av l-halogen-2,5-tetradekadiyn med formel: som omsettes med heksyn-5-karboksylsyre for fremstilling av eicosatriynsyren is treated with a strong base to produce the corresponding acetylide which is reacted with 1,4-dihalobutyne-2 to produce l-halo-2,5-tetradecadiyne of formula: which is reacted with hexyne-5-carboxylic acid to produce the eicosatriic acid
som deretter på kjent måte underkastes en forestring henholdsvis amidering for dannelse av de angitte estere eller amider (I) hvori R har den tidligere anførte betydning. which is then subjected in a known manner to an esterification or amidation to form the specified esters or amides (I) in which R has the previously stated meaning.
Endelig vedrører oppfinnelsen anvendelse av forbindelsene i henhold til oppfinnelsen i kosmetiske preparater i en mengde på 0,01 til 10 vekt% av det hele preparat. Finally, the invention concerns the use of the compounds according to the invention in cosmetic preparations in an amount of 0.01 to 10% by weight of the entire preparation.
Disse og andre trekk ved oppfinnelsen fremgår av patentkravene. These and other features of the invention appear in the patent claims.
Det er kjent at et visst antall av substanser spiller en viktig rolle ved visse inflammatoriske prosesser i huden. Disse substanser, inklusive prostaglandinene, hydroksyeicosatetraen-syrer, tromboksaner, leukotriener, har en felles opprinnelse som er arachidonsyre. (Se "VOORHEES-Leukotrienes and other Lipoxygenase Products in the Pathogenesis and Therapy of Psoriasis and other Dermatoses", Arch Dermatol., bind 119, juli 1983, 541-547). It is known that a certain number of substances play an important role in certain inflammatory processes in the skin. These substances, including the prostaglandins, hydroxyeicosatetraenoic acids, thromboxanes, leukotrienes, have a common origin which is arachidonic acid. (See "VOORHEES-Leukotrienes and other Lipoxygenase Products in the Pathogenesis and Therapy of Psoriasis and other Dermatoses", Arch Dermatol., vol. 119, July 1983, 541-547).
Dannelsen av disse substanser skjer hovedsakelig ved frigivelse av arachidonsyrer knyttet med en esterbinding til lipider tilstede i epidermis (fosfolipider). The formation of these substances occurs mainly by the release of arachidonic acids linked by an ester bond to lipids present in the epidermis (phospholipids).
Det er i oppfinnelsens sammenheng overraskende påvist at spesielle estere eller amider av eicosatriynsyre-5,8,11 inhiberer den enzymatiske metabolisme av arachidonsyre frembragt av cyklooksygenase og lipoksygenaser. Dette resultat er fullstendig uventet på basis av blokkering av syrefunksjonen i form av de estere eller amider som er angitt i det etter-følgende, idet disse forbindelser har en annen biotilgjenge-lighet enn de tilsvarende syrer og meddeler dem forbedrede egenskaper. In the context of the invention, it has surprisingly been shown that special esters or amides of eicosatriic acid-5,8,11 inhibit the enzymatic metabolism of arachidonic acid produced by cyclooxygenase and lipoxygenases. This result is completely unexpected on the basis of blocking the acid function in the form of the esters or amides indicated below, these compounds having a different bioavailability than the corresponding acids and giving them improved properties.
Oppfinnelsen finner anvendelse på det kosmetiske område, som f.eks. i antiaknepreparater, solingsmidler eller ettersolings-midler eller ved kosmetisk behandling av seborrheiske der-matitter. The invention finds application in the cosmetic area, such as e.g. in anti-acne preparations, tanning agents or after-tanning agents or in the cosmetic treatment of seborrheic dermatitis.
Ytterligere formål for oppfinnelsen vil fremgå av den etter-følgende beskrivelse med eksempler. Further objects of the invention will be apparent from the following description with examples.
Som salter av forbindelsene I kan nevnes salter av saltsyre, melkesyre, vinsyre og sitronsyre. As salts of the compounds I, salts of hydrochloric acid, lactic acid, tartaric acid and citric acid can be mentioned.
De spesielt foretrukne forbindelser kan velges blant følgende: når R betegner en C^-Cg substituert alkoksygruppe betegner denne spesielt 2-hydroksyetoksy, 2-hydroksypropyloksy, 2,3-dihydroksypropyloksy eller også dens isomer, 1,3-dihydroksy-2-propyloksy. The particularly preferred compounds can be chosen from the following: when R denotes a C 1 -C 8 substituted alkoxy group, this denotes in particular 2-hydroxyethoxy, 2-hydroxypropyloxy, 2,3-dihydroxypropyloxy or also its isomer, 1,3-dihydroxy-2-propyloxy.
når R betegner en aminogruppe med struktur when R denotes an amino group with structure
er de foretrukne betydninger av R^ og R2 følgende: the preferred meanings of R 1 and R 2 are the following:
. for Ri og/eller R2 i form av lavere alkyl, henholdsvis metyl, etyl, isopropyl, . for Ri og/eller R2 i betydningen alkyl hvor kjeden eventuelt er avbrudt med oksygen, som . for R1 and/or R2 in the form of lower alkyl, respectively methyl, ethyl, isopropyl, . for Ri and/or R2 in the sense of alkyl where the chain is optionally interrupted by oxygen, which
-CH2-CH2-0-CH2CH2OH, -CH2-CH2-0-CH2CH2OH,
. for Ri og/eller R2 i form av Ci-Cg-alkyl substituert med en eller flere hydroksylgrupper, foretrekkes følgende betydninger: . for R1 and/or R2 in the form of C1-C8 alkyl substituted with one or more hydroxyl groups, the following meanings are preferred:
CH2CH20H, CH2CH0HCH3, CH2CH0HCH20H, CH2CH20H, CH2CH0HCH3, CH2CH0HCH20H,
. når Ri og R2 danner en ring er forbindelsene amider substituert med pyrrolidin, morfolin, piperazin og 2'-hydroksy-4-etylpiperazin, . når ett av radikalene eller R2 står for H og det annet et arylradikal, dreier det seg foretrukket om parahydroksyfenyl. . when R1 and R2 form a ring, the compounds are amides substituted with pyrrolidine, morpholine, piperazine and 2'-hydroxy-4-ethylpiperazine, . when one of the radicals or R2 stands for H and the other an aryl radical, it is preferably parahydroxyphenyl.
Blant forbindelsene med formel (I) kan nevnes: Among the compounds of formula (I) can be mentioned:
- 2',3'-dihydroksypropyl-eicosatriynoat-5,8,11 - 2',3'-dihydroxypropyl-eicosatriynoate-5,8,11
- N-(2-hydroksyetyloksyetyl)-eicosatriynamid-5,8,11 - N-(2-hydroxyethyloxyethyl)-eicosatriynamide-5,8,11
- N-etyleicosatriynamid-5,8,11 - N-ethyleicosatriynamide-5,8,11
- pyrrolidinoeicosatriynamid-5,8,11 - pyrrolidinoeicosatriynamide-5,8,11
- N,N-di(2-hydroksyetyl)-eicosatriynamid-5,8,11 - N,N-di(2-hydroxyethyl)-eicosatriynamide-5,8,11
- N-(2-hydroksyetyl)-eicosatriynamid-5,8,11 - N-(2-hydroxyethyl)-eicosatriynamide-5,8,11
- N-(2,3-dihydroksypropyl)-eicosatriynamid-5,8,11 - N-(2,3-dihydroxypropyl)-eicosatriynamide-5,8,11
- 4'-(2-hydroksyetyl)-piperazinoeicosatriynamid-5,8,11 - 4'-(2-hydroxyethyl)-piperazinoeicosatriynamide-5,8,11
- N-(parahydroksyfenyl)-eicosatriynamid-5,8,11. - N-(parahydroxyphenyl)-eicosatriynamide-5,8,11.
Blant disse foretrekkes spesielt: Among these, particular preference is given to:
- N-(2-hydroksyetyloksyetyl)-eicosatriynamid-5 ,8,11 - N-(2-hydroxyethyloxyethyl)-eicosatriynamide-5,8,11
- 2',3'-dihydroksypropyl-eicosatriynamid-5,8,11 - 2',3'-dihydroxypropyl-eicosatriynamide-5,8,11
- N-etyleicosatriynamid-5,8,11 - N-ethyleicosatriynamide-5,8,11
- pyrrolidinoeicosatriynamid-5,8,11 - pyrrolidinoeicosatriynamide-5,8,11
- 4'-(2-hydroksyetyl)-piperazinoeicosatriynamid-5,8,11. - 4'-(2-hydroxyethyl)-piperazinoeicosatriynamide-5,8,11.
Disse estere eller amider fremstilles fra eicosatriynsyre-5,8,11 som i seg selv er kjent fra tidligere (se A. VAN DORP og medarbeidere, Recueil 85, 1966, side 1233). Det etter-følgende skjema A beskriver en slik syntese. Syntesen av produktet merket med <14>C såvel som syntese av tallrike homologer av denne syre er beskrevet spesielt i arbeidet til ULLMAN MYRON, 1970, Ohio State University, Ph.D., Biochemistry. These esters or amides are prepared from eicosatriic acid-5,8,11 which itself is known from earlier (see A. VAN DORP et al., Recueil 85, 1966, page 1233). The following scheme A describes such a synthesis. The synthesis of the product labeled with <14>C as well as the synthesis of numerous homologues of this acid is described in particular in the work of ULLMAN MYRON, 1970, Ohio State University, Ph.D., Biochemistry.
Syren er også beskrevet i US-PS 3.033.884. The acid is also described in US-PS 3,033,884.
Oppfinnelsen vedrører som tidligere nevnt en ny fremgangsmåte for fremstilling av eicosatriynsyre-5,8,11 som tillater at estere og amider i samsvar med oppfinnelsen kan fremstilles med fordelaktige utbytter og omkostninger (skjema B). As previously mentioned, the invention relates to a new method for the production of eicosatriic acid-5,8,11 which allows esters and amides in accordance with the invention to be produced with advantageous yields and costs (scheme B).
Den nye fremgangsmåte er hovedsakelig karakterisert ved at man syntetiserer et halogentetradekadiyn-2,5 (3) i et eneste trinn ved å omsette decyn-1 (1) med 1,4-dihalogenbutyn-2 (2) i nærvær av en sterk base som en organomagnesiumforbindelse. Under The new method is mainly characterized by synthesizing a halotetradecadiyne-2,5 (3) in a single step by reacting decyne-1 (1) with 1,4-dihalobutyne-2 (2) in the presence of a strong base which an organomagnesium compound. Under
denne reaksjon dannes acetylidet av decyn (1) ved ombytting med this reaction forms the acetylide of decyne (1) by exchange with
denne sterke base, acetylidet omsettes med dihalogenidet (2) i overskudd og man oppnår på overraskende måte forbindelsen (3) med et meget godt utbytte. Dette resultat er spesielt overraskende når man vet at syntesen av dette halogenid hittil har vært gjennomført ved omstendelige sammenkjedingsreaksjoner ved hjelp av et propargylalkoholderivat med forholdsvis dårlige utbytter. this strong base, the acetylide is reacted with the dihalide (2) in excess and the compound (3) is surprisingly obtained in a very good yield. This result is particularly surprising when one knows that the synthesis of this halide has so far been carried out by complicated chain reactions using a propargyl alcohol derivative with relatively poor yields.
REAKSJONSSKJEMA A REACTION FORM A
a) Syntese av l-bromtetradekadiyn-2,5 a) Synthesis of l-bromotetradecadiyne-2,5
b) Syntese av 5-heksynkarboksylsyre c) Koblingsreaksj on b) Synthesis of 5-hexynecarboxylic acid c) Coupling reaction
REAKSJONSSKJEMA B REACTION FORM B
a) Syntese av l-halogentetradekadiyn-2,5 a) Synthesis of l-halo-tetradecadiyne-2,5
b) Syntese av 5-heksynkarboksylsyre c) Koblingsreaksj on b) Synthesis of 5-hexynecarboxylic acid c) Coupling reaction
Syntesen av 5-heksynkarboksylsyre (6) som omsettes med 1-halogentetradekadiyn-2,5 (3) er kjent i seg selv og består i et første trinn i å omsette kaliumcyanid med 1-halogenpentyn (4). 5-heksynnitril (5) omdannes så til tilsvarende syre (6) ved innvirkning av kalilut etterfulgt av en surgjøring av reaksj onsblandingen. The synthesis of 5-hexynecarboxylic acid (6) which is reacted with 1-halogentetradecadiyne-2,5 (3) is known in itself and consists in a first step in reacting potassium cyanide with 1-halopentyne (4). 5-hexynenitrile (5) is then converted to the corresponding acid (6) by the action of potassium hydroxide followed by an acidification of the reaction mixture.
Acetylidet av syren (6) dannes ved omsetning med to ekvivalenter organo-magnesiumforbindelser. Dianionet kobles til 1-halogentetradekadiyn i en eter som tetrahydrofuran. Denne reaksjon kan eventuelt gjennomføres i nærvær av et aprotisk løsningsmiddel som heksametylfosforamid (HMPA). Man oppnår da et godt utbytte av eicosatriynsyre-5,8,11 (7). The acetylide of the acid (6) is formed by reaction with two equivalents of organo-magnesium compounds. The dianion is coupled to 1-halotetradecadiyne in an ether such as tetrahydrofuran. This reaction can optionally be carried out in the presence of an aprotic solvent such as hexamethylphosphoramide (HMPA). A good yield of eicosatriic acid-5,8,11 is then achieved (7).
Estere oppnås i samsvar med oppfinnelsen ved hjelp av i og for seg kjente reaksjoner og fremstilles spesielt ved hjelp av en første metode ved omsetning med syren med formel (7) og fosforpentaklorid etterfulgt av omsetning av det tilsvarende syreklorid (8) med en alkohol (9) (R'-OH), hvori R' er en lavere Ci-Cg-alkylgruppe eventuelt substituert med en eller flere hydroksylgrupper og/eller med kjeden avbrudt med oksygen. Denne reaksjon tilsvarer følgende reaksjonsskjema: Esters are obtained in accordance with the invention by means of reactions known per se and are produced in particular by means of a first method by reaction with the acid of formula (7) and phosphorus pentachloride followed by reaction of the corresponding acid chloride (8) with an alcohol (9 ) (R'-OH), in which R' is a lower Ci-Cg alkyl group optionally substituted with one or more hydroxyl groups and/or with the chain interrupted by oxygen. This reaction corresponds to the following reaction scheme:
Den annen metode anvender prosessen beskrevet i H. NORMANT og medarbeidere, Synthesis 197 5, side 805, bestående i å tildanne kaliumsaltet av syren i DMF ved omsetning med kaliumbikarbonat i nærvær av et diamin (N,N,N<*>,N'-tetrametylpropylendiamin-1,3). Man omsetter deretter kaliumkarboksylatet med et halogenid med formel (R<*->X) hvori R' er som tidligere angitt og X betegner et halogen som Br eller Cl: Når den første metode anvendes og radikalet R' er substituert med minst to hydroksylfunksjoner, som f.eks. glyserolesteren, er det fordelaktig å beskytte to av de tre hydroksylfunksjoner i form av dioksolan (11) i henhold til følgende reaksjons-skjerna: The second method uses the process described in H. NORMANT et al., Synthesis 1975, page 805, consisting of forming the potassium salt of the acid in DMF by reaction with potassium bicarbonate in the presence of a diamine (N,N,N<*>,N' -tetramethylpropylenediamine-1,3). The potassium carboxylate is then reacted with a halide of formula (R<*->X) in which R' is as previously indicated and X denotes a halogen such as Br or Cl: When the first method is used and the radical R' is substituted with at least two hydroxyl functions, like for example. the glycerol ester, it is advantageous to protect two of the three hydroxyl functions in the form of dioxolane (11) according to the following reaction core:
Dioksolanet (11) omsettes så med syrekloridet (8). Esteren (12) oppnådd på denne måte behandles under milde betingelser i metanol i nærvær av en sur katalysator for å fjerne den beskyttende gruppe for de to alkoholfunksjoner i henhold til følgende reaksjonsskjema: The dioxolane (11) is then reacted with the acid chloride (8). The ester (12) thus obtained is treated under mild conditions in methanol in the presence of an acidic catalyst to remove the protecting group for the two alcohol functions according to the following reaction scheme:
Amidene i samsvar med oppfinnelsen kan oppnås ved hjelp av to metoder. The amides according to the invention can be obtained by means of two methods.
Den første metode består i å omsette syrekloridet (8) med The first method consists in reacting the acid chloride (8) with
aminet the amine
i nærvær av et tertiært amin i henhold til følgende reaksjons-skjerna: Den annen metode som anvendes er en kjent metode beskrevet i HEINZ A. STAAB, Liebigs Ann. Chem., 1957, 609, 75. Ved denne metode omsettes syren (7) i DMF ved 80°C med karbonyldiimidazol (CDI)) i to til tre timer og man tilsetter deretter ved vanlig temperatur et overskudd av amin med formel til mellomproduktet dannet i henhold til følgende reaksjons-skjerna: in the presence of a tertiary amine according to the following reaction core: The second method used is a known method described in HEINZ A. STAAB, Liebigs Ann. Chem., 1957, 609, 75. In this method, the acid (7) is reacted in DMF at 80°C with carbonyldiimidazole (CDI)) for two to three hours and an excess of amine with the formula is then added at room temperature to the intermediate product formed according to the following reaction core:
hvori R]_ og R2 har de tidligere angitte betydninger. wherein R]_ and R 2 have the previously indicated meanings.
Forbindelsene med formel (I) har en spesiell virkning ved inhibering av metabolismen av arachidonsyre og særlig med hensyn til lipoksygenaser som er en kilde til dannelse av leukotriener og hydroksylerte syrer som spiller en viktig rolle ved inflammatoriske prosesser. The compounds of formula (I) have a particular effect by inhibiting the metabolism of arachidonic acid and particularly with respect to lipoxygenases which are a source of formation of leukotrienes and hydroxylated acids which play an important role in inflammatory processes.
Forbindelsene kan tilføres mennesker eller dyr i form av preparater inneholdende en eller flere kosmetisk tålbare bærere eller fortynningsmidler. Preparatene kan også inneholde andre aktive substanser som ikke virker antagonistisk overfor forbindelsene i samsvar med oppfinnelsen. Preparatene tilføres lokalt/topisk. The compounds can be administered to humans or animals in the form of preparations containing one or more cosmetically acceptable carriers or diluents. The preparations may also contain other active substances which do not act antagonistically to the compounds according to the invention. The preparations are administered locally/topically.
For topisk/lokal tilførsel anvendes preparater i form av salver, tinkturer, kremer, pomader, pulvere, plastere, impregnerte tamponger, oppløsninger, vann, geler, spraymidler eller også suspensjoner. For topical/local application, preparations in the form of ointments, tinctures, creams, pomades, powders, plasters, impregnated tampons, solutions, water, gels, sprays or also suspensions are used.
Preparater for topisk tilførsel kan anvendes i vannfri form eller i vannholdig form alt etter klinisk indikasjon. Preparations for topical administration can be used in anhydrous form or in aqueous form depending on clinical indication.
Forbindelsene anvendes på det kosmetiske område særlig i form av kremer, hudvann, solingsprodukter, ettersolingsdempere, antiseborrhemiske eller antiaknemidler, og de kan inneholde inerte eller kosmetisk aktive hjelpestoffer og særlig: Hydratiserende midler som tiamorfolinon og dets derivater eller urea, antiseborrhemidler, tioksolon, midler som begunstiger fornyet hårvekst, andre antiinflammatoriske steroidholdige eller ikke-steroidholdige midler, karotenoider og særlig fJ-karoten, antipsoriasismidler som antralin og dets derivater, og inhibitorer for fosfolipase A2. The compounds are used in the cosmetic area, particularly in the form of creams, lotions, tanning products, after-sun conditioners, antiseborrheic or antiacne agents, and they may contain inert or cosmetically active excipients and in particular: Hydrating agents such as thiamorpholinone and its derivatives or urea, antiseborrheic agents, thioxolone, agents such as favors renewed hair growth, other anti-inflammatory steroidal or non-steroidal agents, carotenoids and especially fJ-carotene, antipsoriasis agents such as anthralin and its derivatives, and inhibitors of phospholipase A2.
Disse preparater kan likeledes inneholde midler for bedring av smaken, konserveringsmidler, stabiliseringsmidler, fuktighets-regulerende midler, pH-regulerende midler, osmotisk trykk-modifiserende midler, emulgeringsmidler, filtere UV-A og UV-B, antioksydasjonsmidler som a-tokoferol, butylhydroksyanisol eller butylhydroksytoluen, lokalbedøvelsesmidler, buffere, etc. These preparations may also contain agents for improving the taste, preservatives, stabilizers, moisture-regulating agents, pH-regulating agents, osmotic pressure-modifying agents, emulsifiers, filters UV-A and UV-B, antioxidants such as α-tocopherol, butylhydroxyanisole or butyl hydroxytoluene, local anesthetics, buffers, etc.
De kan likeledes kondisjoneres i form av i og for seg kjente preparater med retardert eller progressiv frigivelse og kan innføres i vandige faser av liposomer eller niosomer. Forbindelsene i samsvar med oppfinnelsen foreligger i preparatene i mengdeforhold mellom 0,01 og 10 vekt% i forhold til den totale vekt av blandingen og foretrukket mellom 0,1 og 5 %. They can likewise be conditioned in the form of per se known preparations with delayed or progressive release and can be introduced into aqueous phases of liposomes or niosomes. The compounds according to the invention are present in the preparations in quantities between 0.01 and 10% by weight in relation to the total weight of the mixture and preferably between 0.1 and 5%.
Ved kosmetisk anvendelse anvendes preparatene hovedsakelig som solingspreparater, ettersolingsbehandlingsmidler og for behandling av seborrheiske og/eller aknedermatitter. For cosmetic use, the preparations are mainly used as tanning preparations, after-sun treatment agents and for the treatment of seborrheic and/or acne dermatitis.
De etterfølgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.
FREMSTILLING AV EICOSATRIYNSYRE-5,8,11 PRODUCTION OF EICOSATRINIC ACID-5,8,11
a) Fremstilling av l-klortetradekadiyn-2,5 a) Preparation of l-chlorotetradecadiyne-2,5
I en 2 liters kolbe, utstyrt med røreverk, argontilførsel, In a 2 liter flask, equipped with a stirrer, argon supply,
anbringes 19,35 g magnesium (0,79 gramatom) og deretter 750 cm<5 >vannfritt tetrahydrofuran (THF). Man innfører så dråpevis 90,25 g etylbromid (1,15 ekvivalent) slik at THF holdes under tilbakeløp. Ved avsluttet tilsetning opprettholdes tilbake-løpet til total omdannelse av magnesium. Deretter tilsettes ved denne temperatur dråpevis 100 g 1-decyn (0,72 mol) i løpet av omtrent en halv time og blandingen holdes under tilbakeløp i ytterligere VA time etter avsluttet tilsetning. Man innfører så 5,20 g kobbercyanid og kokingen opprettholdes i en time. Til det derved dannede decyn-l-acetylid tilsettes ved en temperatur som holdes mellom 40 og 50°C 250 g 1,4-diklorbutyn-2, dvs 2,8 ekvivalenter i forhold til decyn. Kokingen opprettholdes i fem timer. Løsningsmiddelet fjernes på rotasjonsfordamper og den oppnådde oljeaktive masse avkjøles og omrøres i nærvær av 350 cm<5> vann mettet med ammoniumklorid og ekstraheres tre ganger med eter. Eterfasen vaskes to ganger med vann, tørkes over magnesiumsulfat og konsentreres ved vanlig trykk og deretter fjernes resten av eteren ved et redusert trykk på 6,6 x IO<2> Pa. Det rå l-klortetradekadiyn-2,5 destilleres ved en temperatur mellom 118 og 125°C under 2,6 Pa. I de siste fraksjoner mellom 125 og 130°C under 4 Pa destilleres resten av det ønskede produkt i blanding med 1-bromtetradekadiyn-2,5 som dannes i løpet av reaksjonen ved utbytting av klor med brom. 19.35 g of magnesium (0.79 gram atom) and then 750 cm<5> of anhydrous tetrahydrofuran (THF) are placed. 90.25 g of ethyl bromide (1.15 equivalent) is then introduced dropwise so that THF is kept under reflux. At the end of the addition, the return flow is maintained until total conversion of magnesium. Then, at this temperature, 100 g of 1-decyne (0.72 mol) are added dropwise over the course of approximately half an hour and the mixture is kept under reflux for a further 10 hours after the addition has been completed. 5.20 g of copper cyanide are then introduced and the boiling is maintained for one hour. To the decyn-1-acetylide thus formed, 250 g of 1,4-dichlorobutyne-2, i.e. 2.8 equivalents in relation to decyn, are added at a temperature maintained between 40 and 50°C. Boiling is maintained for five hours. The solvent is removed on a rotary evaporator and the oil-active mass obtained is cooled and stirred in the presence of 350 cm<5> of water saturated with ammonium chloride and extracted three times with ether. The ether phase is washed twice with water, dried over magnesium sulfate and concentrated at ordinary pressure and then the rest of the ether is removed at a reduced pressure of 6.6 x 10<2> Pa. The crude 1-chlorotetradecadiyne-2,5 is distilled at a temperature between 118 and 125°C under 2.6 Pa. In the last fractions between 125 and 130°C under 4 Pa, the rest of the desired product is distilled in a mixture with 1-bromotetradecadiyne-2,5 which is formed during the reaction by replacing chlorine with bromine.
Man oppnår 100 g l-klortetradekadiyn-2,5 inneholdende omtrent 3 til 5 % l-bromtetradekadiyn-2,5 bestemt ved hjelp av proton-NMR og som anvendes i det siste koblingstrinn. One obtains 100 g of 1-chlorotetradecadiyne-2,5 containing approximately 3 to 5% of 1-bromotetradecadiyne-2,5 determined by means of proton NMR and which is used in the last coupling step.
b) Fremstilling av heksyn-5-karboksylsyre b) Preparation of hexyne-5-carboxylic acid
Til en oppløsning, anbragt under inert atmosfære, anbringes To a solution, placed under an inert atmosphere, is placed
60,4 g natriumcyanid (1,23 mol) i et 200 cm<5> vannfritt dimetylsulfoksyd (DMSO) hvoretter man dråpevis ved en temperatur mellom 40 og 50°C innfører en oppløsning av 115 g 1-klorpentyn-4 (1,12 mol) i 100 cm<5> vannfritt DMSO. Reaksjonen er eksotermisk og det er nødvendig å avkjøle reaksjonsblandingen for å holde temperaturen under 70°C. Ved avsluttet tilsetning holdes blandingen i fem timer mellom 60 og 70°C og settes så bort over natten ved 20°C. Den helles så ut på 60.4 g of sodium cyanide (1.23 mol) in a 200 cm<5> of anhydrous dimethyl sulfoxide (DMSO), after which a solution of 115 g of 1-chloropentyne-4 (1.12 mol) in 100 cm<5> anhydrous DMSO. The reaction is exothermic and it is necessary to cool the reaction mixture to keep the temperature below 70°C. At the end of the addition, the mixture is kept for five hours between 60 and 70°C and then put away overnight at 20°C. It is then poured onto
1,5 liter vann. Den oppnådde blanding ekstraheres fire ganger med 200 cm<5> eter. Eterfåsene samles, vaskes to ganger med 60 cm<5> vann, tørkes over natriumsulfat og eteren avdrives under redusert trykk. Man oppnår 101 g 5-heksynnitril-l som er en gul væske som anvendes direkte i det følgende trinn. Spektra ^H NMR og IR tilsvarer den forventede struktur. 1.5 liters of water. The mixture obtained is extracted four times with 200 cm<5> of ether. The ether fractions are collected, washed twice with 60 cm<5> of water, dried over sodium sulfate and the ether is driven off under reduced pressure. 101 g of 5-hexynenitrile-1 is obtained, which is a yellow liquid which is used directly in the following step. The ^H NMR and IR spectra correspond to the expected structure.
Man innfører 200 g av det foregående nitril (2,15 mol) i 200 g of the preceding nitrile (2.15 mol) are introduced into
2,5 liter 2N kalilut. Blandingen omrøres i to timer ved 90°C og avkjøles deretter til 0°C hvoretter man tilsetter 5N saltsyre til pH omtrent 4 i blandingen. Blandingen ekstraheres fire ganger med 300 cm<5> eter og eterfåsene samles, vaskes to ganger med en vandig oppløsning av ammoniumklorid og tørkes deretter over magnesiumsulfat og konsentreres under redusert trykk. 2.5 liters of 2N potash. The mixture is stirred for two hours at 90°C and then cooled to 0°C, after which 5N hydrochloric acid is added to a pH of approximately 4 in the mixture. The mixture is extracted four times with 300 cm<5> of ether and the ether fractions are collected, washed twice with an aqueous solution of ammonium chloride and then dried over magnesium sulfate and concentrated under reduced pressure.
Man oppnår 23 0 g 5-heksynkarboksylsyre som er en væske ved vanlig temperatur, men krystalliserer ved 0°C. Spektra NMR og IR tilsvarer den forventede struktur. 230 g of 5-hexynecarboxylic acid is obtained, which is a liquid at ordinary temperature, but crystallizes at 0°C. The NMR and IR spectra correspond to the expected structure.
Elementæranalyse: C5H8O2Elemental analysis: C5H8O2
c) Fremstilling av eicosatriynsyre-5,8,11 c) Preparation of eicosatriic acid-5,8,11
I 200 cm<»> THF omdannes som i det foregående 20,05 g magnesium In 200 cm<»> THF, 20.05 g of magnesium are converted as in the previous case
(0,835 gramatom) til etylmagnesiumbromid ved tilsetning av 91 g etylbromid (0,835 mol). Til en separat fremstilt oppløsning som inneholder 46,64 g 5-heksynkarboksylsyre (0,417 mol) i 200 cm<»> vannfritt THF, omrørt ved 0°C under inert atmosfære, tilsettes oppløsningen av etylmagnesiumbromid fremstilt i det foregående. (0.835 gram atom) to ethylmagnesium bromide by adding 91 g of ethyl bromide (0.835 mol). To a separately prepared solution containing 46.64 g of 5-hexynecarboxylic acid (0.417 mol) in 200 cm<»> of anhydrous THF, stirred at 0°C under an inert atmosphere, is added the solution of ethylmagnesium bromide prepared previously.
Ved avsluttet tilsetning tilsettes 25 cm<5> heksametylfosforamid, deretter 2,5 g kuprocyanid. Den derved oppnådde blanding holdes deretter i omtrent en time ved en temperatur på 50°C for å sikre total omdannelse av 5-heksynkarboksylsyren til det tilsvarende acetylid i form av magnesiumkarboksylatet. At the end of the addition, add 25 cm<5> of hexamethylphosphoramide, then 2.5 g of cuprocyanide. The resulting mixture is then kept for approximately one hour at a temperature of 50°C to ensure total conversion of the 5-hexynecarboxylic acid to the corresponding acetylide in the form of the magnesium carboxylate.
Til denne blanding tilsettes dråpevis ved en temperatur på mellom 40 og 50°C en oppløsning inneholdende 0,32 mol 1-klortetradekadiyn i 100 cm<5> THF. To this mixture is added dropwise at a temperature of between 40 and 50°C a solution containing 0.32 mol of 1-chlorotetradecadiyne in 100 cm<5> THF.
Reaksjonsblandingen holdes under tilbakeløp av THF i 21 timer og ved dette tidspunkt tilsettes ytterligere 1,3 g kuprocyanid og tilbakeløpet opprettholdes i ytterligere åtte timer. Løsningsmiddelet avdampes. Den oppnådde viskøse væske surgjøres ved tilsetning av 100 cm<5> 4N svovelsyre og deretter 100 cm<5> 2N svovelsyre. Den oppnådde heterogene blanding ekstraheres tre ganger med 250 cm<5> eter. Eterfåsene samles og vaskes to ganger med tilsetning av 10 0 cm<5> av en mettet vandig oppløsning av ammoniumklorid, dekanteres, tørkes over natriumsulfat og konsentreres. Det oppnådde produkt opptas i 100 cm<5 >heksan og avkjøles til 0°C. The reaction mixture is kept under reflux of THF for 21 hours and at this point a further 1.3 g of cuprocyanide is added and the reflux is maintained for a further eight hours. The solvent is evaporated. The resulting viscous liquid is acidified by adding 100 cm<5> 4N sulfuric acid and then 100 cm<5> 2N sulfuric acid. The heterogeneous mixture obtained is extracted three times with 250 cm<5> of ether. The ether fractions are collected and washed twice with the addition of 100 cm<5> of a saturated aqueous solution of ammonium chloride, decanted, dried over sodium sulfate and concentrated. The product obtained is taken up in 100 cm<5 >hexane and cooled to 0°C.
Krystallene isoleres, vaskes med isblandet heksan og tørkes. Man oppnår 48 g av eicosatriynsyre-5,8,11 med smp. 69 - 7 0°C. The crystals are isolated, washed with ice-cold hexane and dried. 48 g of eicosatriic acid-5,8,11 with m.p. 69 - 70°C.
Spektra <*>H NMR og IR tilsvarer den forventede struktur. The <*>H NMR and IR spectra correspond to the expected structure.
FREMSTILLINGSEKSEMPEL 1 PRODUCTION EXAMPLE 1
Fremstilling av 2',3'-dihydroksypropyl-eicosatriynoat-5,8,11 Preparation of 2',3'-dihydroxypropyl-eicosatriynoate-5,8,11
a) Fremstilling av eicosatriynsyre-5,8,11-klorid Til en oppløsning av 4 g eicosatriynsyre-5,8,11 i 50 ml a) Preparation of eicosatriic acid-5,8,11-chloride For a solution of 4 g of eicosatriic acid-5,8,11 in 50 ml
vannfritt metylenklorid, omrørt ved 0°C, tilsettes sakte 4,1 g fosforpentaklorid. Et kvarter senere bringes oppløsningen under tilbakeløp i to timer hvor hele syremengden er omdannet. Løsningsmiddel og fosforoksykloridet avdampes under redusert trykk og man oppnår syrekloridet som anvendes som det er for de etterfølgende reaksjoner. anhydrous methylene chloride, stirred at 0°C, slowly add 4.1 g of phosphorus pentachloride. A quarter of an hour later, the solution is refluxed for two hours, where the entire amount of acid has been converted. The solvent and the phosphorus oxychloride are evaporated under reduced pressure and the acid chloride is obtained which is used as is for the subsequent reactions.
b) Fremstilling av esteren av 2,2-dimetyl-4-hydroksy-dioksolan-1,3-alkohol b) Preparation of the ester of 2,2-dimethyl-4-hydroxy-dioxolane-1,3-alcohol
Syrekloridet oppnådd i trinn a) oppløseliggjort i 30 cm<5 >vannfritt metylenklorid, tilsettes til en blanding av 2,5 cm<5 >pyridin, 5 cm<5> 2,2-dimetyl-4-hydroksymetyldioksolan-l,3 i 50 cm<5> metylenklorid omrørt ved 0°C under inert atmosfære. Den oppnådde oppløsning settes deretter bort over natten ved vanlig temperatur. The acid chloride obtained in step a) dissolved in 30 cm<5 >anhydrous methylene chloride, is added to a mixture of 2.5 cm<5 >pyridine, 5 cm<5> 2,2-dimethyl-4-hydroxymethyldioxolane-1,3 in 50 cm<5> methylene chloride stirred at 0°C under an inert atmosphere. The solution obtained is then set aside overnight at room temperature.
Reaksjonsblandingen vaskes med vann, den organiske fase tørkes over magnesiumsulfat og anbringes deretter i en kromatografe-ringskolonne med silikagel. Den forventede ester elueres med en blanding av etylacetat/heksan (1/9). Etter konsentrering av elueringsfåsene isoleres 2,7 g ester i form av en viskøs væske med spektra % NMR og IR tilsvarende den forventede struktur. The reaction mixture is washed with water, the organic phase is dried over magnesium sulphate and then placed in a chromatography column with silica gel. The expected ester is eluted with a mixture of ethyl acetate/hexane (1/9). After concentration of the elution phases, 2.7 g of ester are isolated in the form of a viscous liquid with % NMR and IR spectra corresponding to the expected structure.
c) Frigivelse av beskyttende gruppe for 2 *,3'-dihydroksy-propylgruppen c) Release of protecting group for the 2*,3'-dihydroxy-propyl group
En oppløsning av 2 g av den foregående beskyttede ester omrøres ved vanlig temperatur i 30 cm<5> metanol i nærvær av 2,2 g "Amberlite" (sulfonsyreharpiks é) i tre døgn. A solution of 2 g of the preceding protected ester is stirred at ordinary temperature in 30 cm<5> of methanol in the presence of 2.2 g of "Amberlite" (sulfonic acid resin é) for three days.
Ved dette stadium konstateres ved bekreftelse med tynnsjiktkromatografering at 1,3-dioksolandelen er omdannet til tilsvarende diol. Harpiksen fjernes så ved filtrering. Metanol avdampes under redusert trykk, den oppnådde væske oppløseliggjøres i minimum av metylenklorid og den oppnådde oppløsning innføres i en kolonne med silikagel. Esteren elueres med blanding av etylacetat/heksan (75/25). At this stage, confirmation with thin-layer chromatography confirms that the 1,3-dioxole portion has been converted to the corresponding diol. The resin is then removed by filtration. Methanol is evaporated under reduced pressure, the resulting liquid is dissolved in a minimum of methylene chloride and the resulting solution is introduced into a column of silica gel. The ester is eluted with a mixture of ethyl acetate/hexane (75/25).
Etter konsentrering av de eluerte faser oppnås 1,1 g 2',3'-dihydroksypropyl-eicosatriynoat-5,8,11. Hovedtoppen (m/e:374) ved massespektrografering tilsvarer meget godt den forventede molekylvekt (M=374). Spektra NMR 250 MHz <1>H og <13>C indikerer at produktet inneholder omtrent 8 % av 11,31-dihydroksy-21 - propyleicosatriynoat-5,8,11-isomeren. After concentration of the eluted phases, 1.1 g of 2',3'-dihydroxypropyl-eicosatriynoate-5,8,11 is obtained. The main peak (m/e:374) by mass spectrography corresponds very well to the expected molecular weight (M=374). Spectra NMR 250 MHz <1>H and <13>C indicate that the product contains approximately 8% of the 11,31-dihydroxy-21-propyleicosatriynoate-5,8,11-isomer.
FREMSTILLINGSEKSEMPEL 2 PRODUCTION EXAMPLE 2
Fremstilling av N-(2-hydroksyetyloksyetyl)eicosatriynamid-5,8,11 (første syntesemåte) Preparation of N-(2-hydroxyethyloxyethyl)eicosatriynamide-5,8,11 (first method of synthesis)
Til en blanding av 0,36 g diglykolamin, 0,23 cm<5> trietylamin i 20 cm<5> metylenklorid, avkjølt til 0°C under inert atmosfære, tilsettes sakte en oppløsning av 1 g eicosatriynsyreklorid. Omdannelsen av syrekloridet, fulgt ved tynnsjiktkromatografering, er meget hurtig. Når den er fullstendig helles reaksjonsblandingen ut i 100 cm<5> isblandet vann. Den organiske fase dekanteres. Den vandige fase ekstraheres på nytt tre ganger med metylenklorid. Metylenkloridfåsene samles, vaskes med vann mettet med ammoniumklorid og tørkes over magnesiumsulfat og konsentreres. Man isolerer da 0,6 g amid som renses ved å føres gjennom en kolonne med silikagel. Amidet elueres med etylacetat. Etter avdamping av elueringsmiddelet oppnås 0,4 g N-(2-hydroksyetyloksyetyl)eicosatriynamid-5,8,11 i form av lysebrune krystaller med smp. 60°C. To a mixture of 0.36 g of diglycolamine, 0.23 cm<5> of triethylamine in 20 cm<5> of methylene chloride, cooled to 0°C under an inert atmosphere, a solution of 1 g of eicosatriic acid chloride is slowly added. The conversion of the acid chloride, followed by thin layer chromatography, is very rapid. When complete, the reaction mixture is poured into 100 cm<5> ice-mixed water. The organic phase is decanted. The aqueous phase is re-extracted three times with methylene chloride. The methylene chloride phases are collected, washed with water saturated with ammonium chloride and dried over magnesium sulfate and concentrated. 0.6 g of amide is then isolated, which is purified by passing it through a column of silica gel. The amide is eluted with ethyl acetate. After evaporation of the eluent, 0.4 g of N-(2-hydroxyethyloxyethyl)eicosatriynamide-5,8,11 is obtained in the form of light brown crystals with m.p. 60°C.
Spektra <13>c 250 MHz, IR og massespektrum tilsvarer den forventede struktur. Spectra <13>c 250 MHz, IR and mass spectrum correspond to the expected structure.
FREMSTILLINGSEKSEMPEL 3 PRODUCTION EXAMPLE 3
Fremstilling av N-(2-hydroksyetyloksyetyl)eicosatriynamid-5,8,11 (annen syntesemåte) Preparation of N-(2-hydroxyethyloxyethyl)eicosatriynamide-5,8,11 (another method of synthesis)
Man fremstiller en oppløsning av 15 g eicosatriynsyre-5,8,11 i 150 cm<5> vannfritt dimetylformamid omrørt under argonatmosfære hvortil man ved vanlig temperatur tilsetter 10,5 g karbonyldiimidazol. Blandingen holdes så i tre timer ved en temperatur mellom 70 og 80°C. Etter avkjøling til 0°C tilsettes dråpevis 10,5 g diglykolamin. A solution of 15 g of eicosatriic acid-5,8,11 in 150 cm<5> of anhydrous dimethylformamide is prepared, stirred under an argon atmosphere, to which 10.5 g of carbonyldiimidazole is added at ordinary temperature. The mixture is then kept for three hours at a temperature between 70 and 80°C. After cooling to 0°C, 10.5 g diglycolamine is added dropwise.
Blandingen omrøres ytterligere i et kvarter etter avsluttet tilsetning og settes så bort over natten ved vanlig temperatur og helles så ut over 300 g is. Produktet felles ut, filtreres, vaskes med vann og tørkes. 18 g amid omkrystalliseres så fra 150 cm<»> acetonitril og man oppnår 17 g N-(2-hydroksyetyloksy-etyl) eicosatriyanamid-5 , 8 , 11 i form av hvite krystaller med smp. 63°C. The mixture is stirred further for a quarter of an hour after the addition has been completed and is then set aside overnight at normal temperature and then poured over 300 g of ice. The product is precipitated, filtered, washed with water and dried. 18 g of amide are then recrystallized from 150 cm<»> of acetonitrile and 17 g of N-(2-hydroxyethyloxy-ethyl)eicosatriyanamid-5, 8, 11 are obtained in the form of white crystals with m.p. 63°C.
Elementæranlyse: C24H37NO3Elemental analysis: C24H37NO3
FREMSTILLINGSEKSEMPEL 4 PRODUCTION EXAMPLE 4
Fremstilling av N-etyleicosatriynamid-5,8,11 Preparation of N-ethyleicosatriynamide-5,8,11
En blanding omrørt under argonatmosfære av 1 g eicosatriynsyre-5,8,11, 0,7 g karbonyldiimidazol i 10 cm<5> vannfritt DMF holdes i tre timer ved temperatur 80°C. A mixture stirred under an argon atmosphere of 1 g of eicosatriic acid-5,8,11, 0.7 g of carbonyldiimidazole in 10 cm<5> of anhydrous DMF is kept for three hours at a temperature of 80°C.
Deretter tilsettes ved 0°C på en gang en 33 % vandig oppløsning av N-etylamin. En time senere konstateres at utgangssyren fullstendig er omdannet til tilsvarende amid. Reaksjonsblandingen helles ut i 100 cm<5> isblandet vann og det utfelte produkt samles på filter, vaskes med vann og tørkes. Man oppnår 1,1 g faststoff som omkrystalliseres fra 10 cm<5 >isblandet acetonitril. A 33% aqueous solution of N-ethylamine is then added all at once at 0°C. One hour later, it is established that the starting acid has been completely converted to the corresponding amide. The reaction mixture is poured into 100 cm<5> ice-mixed water and the precipitated product is collected on a filter, washed with water and dried. 1.1 g of solid is obtained, which is recrystallized from 10 cm<5> ice-mixed acetonitrile.
Man isolerer da 0,85 g N-etyleicosatriynamid-5,8,11 i form av hvite krystaller med smp. 68°C. 0.85 g of N-ethyleicosatriynamide-5,8,11 is then isolated in the form of white crystals with m.p. 68°C.
Elementæranalyse: C22H33NO Elemental analysis: C22H33NO
FREMSTILLINGSEKSEMPEL 5 PRODUCTION EXAMPLE 5
Fremstilling av pyrrolidino-eicosatriynamid-5,8,11 Preparation of pyrrolidino-eicosatriynamide-5,8,11
Til en oppløsning av 1 g eicosatriynsyre-5,8,11 i 10 cm<5 >vannfritt DMF, omrørt under argonatomosfære, tilsettes på en gang 0,7 g karbonyldiimidazol. Oppløsningen holdes så i tre timer ved 80°C og deretter innføres ved 0°C 0,5 g pyrrolidin. To timer senere er reaksjonen avsluttet. Reaksjonsblandingen helles ut i 100 cm<5> isblandet vann og ekstraheres med metylenklorid. Den organiske fase vaskes ved hjelp av en saltsyreopp-løsning og deretter med vann til pH nøytral, tørkes over natriumsulfat og konsentreres. Man oppnår 1,1 g pyrrolidino-eicosatriynamid-5 , 8 , 11 i form av en gul væske. Spektra IR og NMR <1>H 250 MHz er i samsvar med forventet struktur. To a solution of 1 g of eicosatriic acid-5,8,11 in 10 cm<5> of anhydrous DMF, stirred under an argon atmosphere, 0.7 g of carbonyldiimidazole is added at once. The solution is then kept for three hours at 80°C and then 0.5 g of pyrrolidine is introduced at 0°C. Two hours later, the reaction is complete. The reaction mixture is poured into 100 cm<5> ice-mixed water and extracted with methylene chloride. The organic phase is washed using a hydrochloric acid solution and then with water until the pH is neutral, dried over sodium sulphate and concentrated. 1.1 g of pyrrolidino-eicosatriynamide-5, 8, 11 is obtained in the form of a yellow liquid. Spectra IR and NMR <1>H 250 MHz are consistent with the expected structure.
Elementæranalysen tilsvarende et hemihydrat: C24H35NO, MH2O The elemental analysis corresponding to a hemihydrate: C24H35NO, MH2O
FREMSTILLINGSEKSEMPEL 6 PRODUCTION EXAMPLE 6
Fremstilling av N,N-di(2-hydroksyetyl)eicosatriynamid-5,8,11 Man behandler mellomproduktet dannet fra 1 g syre og 0,7 g karbonyldiimidazol i 10 cm<5> vannfritt DMF med 1 g dietanolamin. Preparation of N,N-di(2-hydroxyethyl)eicosatriynamide-5,8,11 The intermediate product formed from 1 g of acid and 0.7 g of carbonyldiimidazole in 10 cm<5> of anhydrous DMF is treated with 1 g of diethanolamine.
Når syren er omdannet avdampes dimetylformamidet under redusert trykk. Den oppnådde væske oppløseliggjøres i metylenklorid, vaskes i surt miljø og den organiske fase tørkes over natrium-sulf at og omrøres deretter i nærvær av 15 g silikagel. Gelen hvorpå amidet er fiksert filtreres og amidet frigis så ved ekstraksjon av silikagelen med etylacetat. When the acid has been converted, the dimethylformamide is evaporated under reduced pressure. The obtained liquid is made soluble in methylene chloride, washed in an acidic environment and the organic phase is dried over sodium sulphate and then stirred in the presence of 15 g of silica gel. The gel on which the amide is fixed is filtered and the amide is then released by extraction of the silica gel with ethyl acetate.
Etter avdamping av løsningsmiddelet oppnås 0,8 g N,N-di(2-hydroksyetyl)eicosatriynamid-5,8-11. Ved vanlig temperatur er dette en gul væske med spektra IR og NMR <1>H 250 MHz i samsvar med den forventede struktur. After evaporation of the solvent, 0.8 g of N,N-di(2-hydroxyethyl)eicosatriynamide-5,8-11 is obtained. At normal temperature, this is a yellow liquid with spectra IR and NMR <1>H 250 MHz in accordance with the expected structure.
FREMSTILLINGSEKSEMPEL 7 PRODUCTION EXAMPLE 7
Fremstilling av N-(2-hydroksyetyl)eicosatriynamid-5,8,11 Preparation of N-(2-hydroxyethyl)eicosatriynamide-5,8,11
En oppløsning av 8 g eicosatriynsyre-5,8,11, 5,62 g karbonyldiimidazol i 40 cm' vannfritt DMF holdes ved 80°C i tre timer under inert atmosfære. Deretter tilsettes ved 0°C 3,25 g etanolamin. Ved tynnsjiktkromatografering to timer senere konstateres at utgangssyren er fullstendig omdannet. A solution of 8 g of eicosatriic acid-5,8,11, 5.62 g of carbonyldiimidazole in 40 cm' of anhydrous DMF is kept at 80°C for three hours under an inert atmosphere. 3.25 g of ethanolamine are then added at 0°C. By thin-layer chromatography two hours later, it is established that the starting acid has been completely converted.
Reaksjonsblandingen konsentreres deretter ved inndamping under vakuum, oppløses så i 100 cm<5> metylenklorid og oppløsningen vaskes med vann, tørkes over natriumsulfat og metylenkloridet fjernes ved inndamping under vakuum. Man oppnår 9,1 g faststoff og etter omkrystallisering av dette isoleres 8 g N-(2-hydroksyetyl)eicosatriynamid-5,8,11 i form av hvite krystaller med smp. 87°c. The reaction mixture is then concentrated by evaporation under vacuum, then dissolved in 100 cm<5> of methylene chloride and the solution is washed with water, dried over sodium sulfate and the methylene chloride is removed by evaporation under vacuum. 9.1 g of solid is obtained and after recrystallization of this, 8 g of N-(2-hydroxyethyl)eicosatriynamide-5,8,11 are isolated in the form of white crystals with m.p. 87°c.
Spektra IR og NMR <1>H 250 MHz tilsvarer forventet struktur. Spectra IR and NMR <1>H 250 MHz correspond to the expected structure.
Analyse: C22<H>33N02Analysis: C22<H>33N02
FREMSTILLINGSEKSEMPEL 8 PRODUCTION EXAMPLE 8
Fremstilling av N-(2,3-dihydroksypropyl)eicosatriynamid-5, 8,11 På samme måte som i det foregående eksempel behandles 8 g eicosatriynsyre-5,8,11 i 40 cm<5> vannfritt DMF først med 5,62 g karbonyldiimidazol og deretter tilsettes ved 0°C 4,1 cm<5> 2,3-dihydroksypropylamin. Ved slutten av reaksjonen uthelles reaksjonsblandingen i isblandet vann. Det utfelte produkt samles på filter, oppløses i 3 00 cm<5> metylenklorid og opp-løsningen tørkes over natriumsulfat og konsentreres under redusert trykk. Det oppnådde faststoff omkrystalliseres direkte fra acetonitril. Man oppnår da 9 g N-(2,3-dihydroksypropyl) eicosatriynamid-5,8,11 i form av meget klare lysebrune krystaller med smp. 87°C. Preparation of N-(2,3-dihydroxypropyl)eicosatriynamide-5,8,11 In the same way as in the previous example, 8 g of eicosatriic acid-5,8,11 in 40 cm<5> of anhydrous DMF are first treated with 5.62 g carbonyldiimidazole and then added at 0°C 4.1 cm<5> 2,3-dihydroxypropylamine. At the end of the reaction, the reaction mixture is poured into ice-cold water. The precipitated product is collected on a filter, dissolved in 300 cm<5> of methylene chloride and the solution is dried over sodium sulphate and concentrated under reduced pressure. The solid obtained is recrystallized directly from acetonitrile. 9 g of N-(2,3-dihydroxypropyl)eicosatriynamide-5,8,11 are then obtained in the form of very clear light brown crystals with m.p. 87°C.
Spektra IR og NMR <1>H 250 MHz er i samsvar med forventet struktur. Spectra IR and NMR <1>H 250 MHz are consistent with the expected structure.
Elementæranalyse: C23H35NO3Elemental analysis: C23H35NO3
FREMSTILLINGSEKSEMPEL 9 PRODUCTION EXAMPLE 9
Fremstilling av 4-(2-hydroksyetyl)piperazinoeicosatriynamid-5,8,11 Preparation of 4-(2-hydroxyethyl)piperazinoeicosatriynamide-5,8,11
En blanding av 1 g eicosatriynsyre-5,8,11, 0,7 g karbonyldiimidazol (CDI) i 5 cm<*> vannfritt DMF, omrøres under inert atmosfære i tre timer ved temperatur mellom 70 og 80°C. Oppløsningen avkjøles så til 0°C hvoretter det tilsettes en oppløsning av 0,8 g 1-(2'-hydroksyetyl)piperazin i 5 cm' DMF. Omrøringen opprettholdes i to timer og reaksjonsblandingen settes bort over natten. Løsningsmiddelet avdampes under redusert trykk. Den oppnådde væske opptas i metylenklorid og oppløsningen vaskes flere ganger med vann, tørkes over natriumsulfat og konsentreres under redusert trykk. Man oppnår 0,8 g 4'-(2-hydroksyetyl)piperazinoeicosatriynamid-5,8,11 i form av en gul væske. A mixture of 1 g of eicosatriic acid-5,8,11, 0.7 g of carbonyldiimidazole (CDI) in 5 cm<*> anhydrous DMF, is stirred under an inert atmosphere for three hours at a temperature between 70 and 80°C. The solution is then cooled to 0°C, after which a solution of 0.8 g of 1-(2'-hydroxyethyl)piperazine in 5 cm' of DMF is added. Stirring is maintained for two hours and the reaction mixture is set aside overnight. The solvent is evaporated under reduced pressure. The liquid obtained is taken up in methylene chloride and the solution is washed several times with water, dried over sodium sulphate and concentrated under reduced pressure. 0.8 g of 4'-(2-hydroxyethyl)piperazinoeicosatriynamide-5,8,11 is obtained in the form of a yellow liquid.
Spektra IR og <*>H 25 0 MHz tilsvarer forventet struktur. Elementæranalysen tilsvarer et delvis hydratisert produkt. Spectra IR and <*>H 25 0 MHz correspond to the expected structure. The elemental analysis corresponds to a partially hydrated product.
Elementæranalyse: C26H40N2O2, 1/4 H2O Elemental analysis: C26H40N2O2, 1/4 H2O
FREMSTILLINGSEKSEMPEL 10 PRODUCTION EXAMPLE 10
Fremstilling av N- (parahydroksyfenyl)eicosatriynamid-5,8,11 Preparation of N-(parahydroxyphenyl)eicosatriynamide-5,8,11
På samme måte som i det foregående eksempel behandles mellomproduktet dannet fra 1 g eicosatriynsyre-5,8,11 og 0,7 g CDI med 0,727 g parahydroksyanilin. Deretter omrøres blandingen i 24 timer ved vanlig temperatur og deretter tilsettes gradvis vann til blandingen inntil alt dannet produkt utfelles. Det samles på filter og tørkes og omkrystalliseres fra isopropyl-eter og man oppnår 0,85 g N-(parahydroksyfenyl)eicosatriynamid-5,8,11 i form av meget lysebrune krystaller med smp. 121°C. Spektra IR og -^H NMR 250 MHz er i samsvar med forventet struktur. In the same way as in the previous example, the intermediate product formed from 1 g of eicosatriic acid-5,8,11 and 0.7 g of CDI is treated with 0.727 g of parahydroxyaniline. The mixture is then stirred for 24 hours at normal temperature and then water is gradually added to the mixture until all the product formed is precipitated. It is collected on a filter and dried and recrystallized from isopropyl ether and 0.85 g of N-(parahydroxyphenyl)eicosatriynamide-5,8,11 is obtained in the form of very light brown crystals with m.p. 121°C. Spectra IR and -^H NMR 250 MHz are consistent with the expected structure.
Elementæranalyse: C25H33NO2Elemental analysis: C25H33NO2
FREMSTILLINGSEKSEMPEL 11 PRODUCTION EXAMPLE 11
Fremstilling av N-(glukosyl)eicosatriynamid-5,8,11 Preparation of N-(glucosyl)eicosatriynamide-5,8,11
På samme måte som i eksempel 9 behandles mellomproduktet tildannet fra 0,9 g eicosatriynsyre-5,8,11 og 0,62 g karbonyldiimidazol (CDI) med 1,29 g glukosaminhydroklorid som på forhånd er behandlet med 0,6 g trietylamin. In the same way as in example 9, the intermediate product formed from 0.9 g of eicosatriic acid-5,8,11 and 0.62 g of carbonyldiimidazole (CDI) is treated with 1.29 g of glucosamine hydrochloride which has previously been treated with 0.6 g of triethylamine.
Ved slutten av reaksjonen avdampes karbonyldiimidazolet under redusert trykk. Det oppnådde pastaformede faststoff omrøres i 10 cm<5> metylenklorid og filtreres deretter. Det oppnådde produkt oppløses så i en minimumsmengde metanol og utfelles ved tilsetning av metylenklorid. Bunnfallet avsuges på filter og tørkes. Man oppnår 0,5 g N-(glukosyl)eicosatriynamid-5,8,11 i form av hvit-beige krystaller med smelte-spaltningspunkt ved 210°C. At the end of the reaction, the carbonyldiimidazole is evaporated under reduced pressure. The resulting pasty solid is stirred in 10 cm<5> of methylene chloride and then filtered. The product obtained is then dissolved in a minimum amount of methanol and precipitated by the addition of methylene chloride. The precipitate is sucked off on a filter and dried. 0.5 g of N-(glucosyl)eicosatriynamide-5,8,11 is obtained in the form of white-beige crystals with a melting point at 210°C.
Infrarød og 250 MHz <13>C NMR-spektra svarer til den forventede struktur. Infrared and 250 MHz <13>C NMR spectra correspond to the expected structure.
I det etterfølgende anføres noen eksempelvise sammensetninger av kosmetiske preparater med et innhold av forbindelsene i samsvar med oppfinnelsen. In the following, some exemplary compositions of cosmetic preparations with a content of the compounds in accordance with the invention are given.
Denne blanding foreligger i form av en gel som kan påføres topisk. Man oppnår likeledes gode resultater ved at man i blandingen erstatter 2<1>,3<1->dihydroksypropyleicosatriynoat-5,8,11 med N-(2-hydroksyetyl)eicosatriynamid-5,8,11. This mixture is in the form of a gel that can be applied topically. Good results are also obtained by replacing 2<1>,3<1->dihydroxypropyleicosatriynoate-5,8,11 with N-(2-hydroxyethyl)eicosatriynamide-5,8,11 in the mixture.
B Man fremstiller følgende blanding: B The following mixture is prepared:
Denne blanding foreligger i form av en hydrofob salve for topisk påføring. Man oppnår likeledes gode resultater ved at man i denne salve erstatter N-(2-hydroksyetyl)eicosatriynamid-5,8,11 med N-(2,3-dihydroksypropyl)eicosatriynamid-5,8,11 eller også med N-(2-hydroksyetyloksyetyl)eicosatriynamid-5,8,11. This mixture is available in the form of a hydrophobic ointment for topical application. Good results are also achieved by replacing N-(2-hydroxyethyl)eicosatriynamide-5,8,11 with N-(2,3-dihydroxypropyl)eicosatriynamide-5,8,11 or also with N-(2 -hydroxyethyloxyethyl)eicosatriynamide-5,8,11.
Denne blanding foreligger i form av en hydrofob salve for topisk påføring. This mixture is available in the form of a hydrophobic ointment for topical application.
Det er mulig i denne salve å erstatte N-etyleicosatriynamidet-5,8,11 med pyrrolidinoeicosatriynamidet-5,8,11. It is possible in this ointment to replace N-ethyleicosatriynamide-5,8,11 with pyrrolidinoeicosatriynamide-5,8,11.
D Man fremstiller følgende blanding: D The following mixture is prepared:
Denne blanding foreligger i form av en krem for topisk påføring. This mixture is available in the form of a cream for topical application.
E Man fremstiller følgende hudvann: E The following skin water is produced:
Dette hudvann anvendes for topisk påføring. This skin lotion is used for topical application.
Blaningene A til E fremstilles alle og lagres i inert atmosfære under utelukkelse av lys. The blends A to E are all prepared and stored in an inert atmosphere under the exclusion of light.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO921726A NO172981C (en) | 1985-07-05 | 1992-04-30 | EICOSA-5,8,11-TRIYNOIC ACID COMPOUNDS, PROCEDURE FOR THEIR PREPARATION AND USE OF THE COMPOUNDS IN COSMETIC PREPARATIONS |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8510363A FR2584400B1 (en) | 1985-07-05 | 1985-07-05 | ESTERS AND AMIDES OF EICOSATRIYNOIC ACID AND THEIR APPLICATION IN PHARMACY AND COSMETICS |
| NO862692A NO171905C (en) | 1985-07-05 | 1986-07-03 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE EICOSATHYRIC ACID-5,8,11-COMPOUNDS |
| NO921726A NO172981C (en) | 1985-07-05 | 1992-04-30 | EICOSA-5,8,11-TRIYNOIC ACID COMPOUNDS, PROCEDURE FOR THEIR PREPARATION AND USE OF THE COMPOUNDS IN COSMETIC PREPARATIONS |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO921726L NO921726L (en) | 1987-01-06 |
| NO921726D0 NO921726D0 (en) | 1992-04-30 |
| NO172981B true NO172981B (en) | 1993-06-28 |
| NO172981C NO172981C (en) | 1993-10-06 |
Family
ID=27251296
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO921726A NO172981C (en) | 1985-07-05 | 1992-04-30 | EICOSA-5,8,11-TRIYNOIC ACID COMPOUNDS, PROCEDURE FOR THEIR PREPARATION AND USE OF THE COMPOUNDS IN COSMETIC PREPARATIONS |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO172981C (en) |
-
1992
- 1992-04-30 NO NO921726A patent/NO172981C/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO172981C (en) | 1993-10-06 |
| NO921726L (en) | 1987-01-06 |
| NO921726D0 (en) | 1992-04-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK172070B1 (en) | Benzonaphthalene derivatives, processes for their preparation and use, and their pharmaceutical and cosmetic preparations | |
| US6043284A (en) | Anti-atherosclerotic diaryl compounds | |
| JP3233451B2 (en) | Aromatic compounds derived from imine, process for producing the same, and cosmetic compositions containing the same | |
| US4876381A (en) | Naphthalene derivatives possessing a retinoid-type action, processes for their preparation, and medicinal and cosmetic compositions containing these derivatives | |
| US5399577A (en) | Isoxazole derivatives and salts thereof | |
| EP0176033A2 (en) | Isoxazolecarboxylic-acid derivatives, their preparation and use | |
| FI91394B (en) | Esters and amides of eicosatriynoic acid and their use in cosmetology | |
| EP0386451B1 (en) | Oxygen-bearing diphenyl heteroalkanes, process for their preparation and use | |
| AU745699B2 (en) | (Poly) thiaalkynoic compounds and their derivatives, compositions comprising them and their use | |
| HU193817B (en) | Process for preparing 1-substituted tetraline-derivatives and pharmaceutic preparations containing them | |
| US5151534A (en) | Sulphur-containing eicosanoides and their application in pharmacy and in cosmetics | |
| US5075331A (en) | Benzofuran compounds, compositions containing them and processes for using the compositions | |
| NO172981B (en) | EICOSA-5,8,11-TRIYNOIC ACID COMPOUNDS, PROCEDURE FOR THEIR PREPARATION AND USE OF THE COMPOUNDS IN COSMETIC PREPARATIONS | |
| JPH02306947A (en) | Preparation of chiral bata-amino acid | |
| US4216312A (en) | Furyl substituted polyenes | |
| FR2550785A1 (en) | NOVEL COMPOSITIONS WITH ANTIMICROBIAL ACTIVITY CONTAINING BENZOIC ACID DERIVATIVES, PROCESS FOR THEIR PREPARATION, THEIR USE AS DISINFECTANT OR PRESERVATIVE DRUGS | |
| US4916136A (en) | Eicosatetraynoic acid amides and their application in pharmacy | |
| US5268494A (en) | Sulphur-containing eicosanoides and their application in pharmacy and in cosmetics | |
| DK170399B1 (en) | Naphthalene derivatives of the benzonorborn, process for their preparation and pharmaceuticals and cosmetics containing such compounds | |
| WO1994021591A1 (en) | Dermatologic preparation and novel benzoic acid derivative | |
| JP6826333B2 (en) | Narsgen optical resolution method | |
| JPH10130191A (en) | 2-acetyl carboxylic acid ester derivative and production of 2-ketone compounds from the same | |
| JPS62909B2 (en) |