NO133802B - - Google Patents
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- NO133802B NO133802B NO343/71*[A NO34371A NO133802B NO 133802 B NO133802 B NO 133802B NO 34371 A NO34371 A NO 34371A NO 133802 B NO133802 B NO 133802B
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- Norway
- Prior art keywords
- vitamin
- acid
- group
- approx
- general formula
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- 229930002330 retinoic acid Natural products 0.000 claims description 27
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 8
- 230000000699 topical effect Effects 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- -1 n-decyl Chemical group 0.000 description 6
- 206010020915 Hypervitaminosis Diseases 0.000 description 5
- 206010040880 Skin irritation Diseases 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 150000004508 retinoic acid derivatives Chemical class 0.000 description 5
- 230000036556 skin irritation Effects 0.000 description 5
- 231100000475 skin irritation Toxicity 0.000 description 5
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- 206010039509 Scab Diseases 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 201000006122 hypervitaminosis A Diseases 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 206010063409 Acarodermatitis Diseases 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 201000004384 Alopecia Diseases 0.000 description 2
- 208000010392 Bone Fractures Diseases 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 241000447727 Scabies Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- UZBQIPPOMKBLAS-UHFFFAOYSA-N diethylazanide Chemical compound CC[N-]CC UZBQIPPOMKBLAS-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000003676 hair loss Effects 0.000 description 2
- 208000020442 loss of weight Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- WKYDOCGICAMTKE-NBIQJRODSA-N n-ethyl retinamide Chemical compound CCNC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C WKYDOCGICAMTKE-NBIQJRODSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 208000005687 scabies Diseases 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000009121 systemic therapy Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- AZJQQNWSSLCLJN-UHFFFAOYSA-N 2-ethoxyquinoline Chemical compound C1=CC=CC2=NC(OCC)=CC=C21 AZJQQNWSSLCLJN-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- UYIFTLBWAOGQBI-BZDYCCQFSA-N Benzhormovarine Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4O)C)CC2=CC=3OC(=O)C1=CC=CC=C1 UYIFTLBWAOGQBI-BZDYCCQFSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 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
- 241000700199 Cavia porcellus Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000006670 Multiple fractures Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 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
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 210000003756 cervix mucus Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006003 cornification Effects 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 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 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Nærværende oppfinnelse vedrorer en analogifremgangsmåte for fremstilling av terapeutisk virksomme vitamin A-syreamider av den generelle formel hvor R og hver betyr en eventuelt med en lavere alkoksygruppe eller en di-laverealkylamino-gruppe substituert alkylgruppe med 1-10 karbonatomer, The present invention relates to an analogous method for the preparation of therapeutically effective vitamin A acid amides of the general formula where R and each means an alkyl group with 1-10 carbon atoms optionally substituted with a lower alkoxy group or a di-lower alkylamino group,
en hydroksy-laverealkylgruppe, eller en fenyl- eller benzylgruppe, a hydroxy-lower alkyl group, or a phenyl or benzyl group,
idet R i tillegg betyr hydrogen. where R additionally means hydrogen.
Uttrykket "alkylgruppe" betyr såvel rettkjedete som forgrenete hydrokarbongrupper med 1-10 karbonatqmer, som metyl, etyl, propyl, isopropyl, n-butyl, tert.butyl, pentyl, heksyl, heptyl, n-decyl o.l. uttrykket "hydroksy-laverealkylgruppe" betyr hydroksy-laverealkylgrupper med 1-4 karbonatomer, som f.eks. en hydroksyetylgruppe:. Uttrykket "lavere alkoksy-gruppe" betyr rettkjedete eller forgrenete alkoksygrupper med 1-4 karbonatomer, f.eks. metoksy, etoksy o.l. uttrykket "laverealkyl-aminogruppe" betyr alkylaminogrupper med 1-4 karbonatomer, f.eks. metylamino, etylamino o.l. The term "alkyl group" means both straight-chain and branched hydrocarbon groups with 1-10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert.butyl, pentyl, hexyl, heptyl, n-decyl and the like. the term "hydroxy-lower alkyl group" means hydroxy-lower alkyl groups with 1-4 carbon atoms, such as e.g. a hydroxyethyl group:. The term "lower alkoxy group" means straight-chain or branched alkoxy groups with 1-4 carbon atoms, e.g. methoxy, ethoxy etc. the term "lower alkylamino group" means alkylamino groups of 1-4 carbon atoms, e.g. methylamino, ethylamino, etc.
Fremgangsmåten ifolge oppfinnelsen karakteriseres ved at man omsetter vitamin A-syren eller et funksjonelt derivat av denne med et amin med den generelle formel, The method according to the invention is characterized by reacting the vitamin A acid or a functional derivative thereof with an amine of the general formula,
hvor R og R^ har. de oven angitte betydninger. where R and R^ have. the above meanings.
Som amin med formel II foretrekkes anvendelsen av etyDamin, As the amine of formula II, the use of ethylamine is preferred,
Som funksjonelle derivater av vitamin A-syre kan spesielt As functional derivatives of vitamin A acid can especially
nevnes vitamin A-syrehalogenidene, fortrinnsvis klorid, såvel som vitamin A-syreester. mention is made of the vitamin A acid halides, preferably chloride, as well as vitamin A acid esters.
Det er hensiktsmessig å foreta reaksjonen i et inert organisk opplosningsmiddel, som f.eks. eter, og ved en temperatur fra ca. romtemperatur til reaksjonsblandingens tilbakelopstemperatur. Det er også hensiktsmessig å gjennomfore reaksjonen i inert-gassatmosfære, f.eks. i nitrogenatmosfære. It is appropriate to carry out the reaction in an inert organic solvent, such as e.g. ether, and at a temperature from approx. room temperature to the reflux temperature of the reaction mixture. It is also appropriate to carry out the reaction in an inert gas atmosphere, e.g. in a nitrogen atmosphere.
De nye vitamin A-syreamidene kan anvendes The new vitamin A acid amides can be used
for topisk og systemisk terapi av precancerose og carcinoma, såvel som for systemisk og topisk profylaxe av carcinoma. for topical and systemic therapy of precancer and carcinoma, as well as for systemic and topical prophylaxis of carcinoma.
De kan anvendes som sådanne eller i kombinasjon med cysto-statiske midler såvel som med strålings-terapi. Dessuten kan de anvendes for topisk og systemisk terapi av acne, psoriasis og andre ledsagende dermatologiske affeksjoner med forsterket eller patologisk foranderlig forhorning såvel som ved eksem. De kan også anvendes ved affeksjoner av slimhud som skyldes inflammatoriske eller degenerative hhv. metaplastiske for-andringer. Som foretrukket vitamin A-syreamid kan vitamin A-syreetylamid nevnes. They can be used as such or in combination with cystostatic agents as well as with radiation therapy. In addition, they can be used for topical and systemic therapy of acne, psoriasis and other accompanying dermatological conditions with increased or pathologically variable cornification as well as eczema. They can also be used for affections of the mucous membrane which are caused by inflammatory or degenerative or metaplastic pre-changes. Vitamin A acid ethylamide can be mentioned as preferred vitamin A acid amide.
De på mus og rotter gjennomførte toksisitetsundersokninger ga folgende resultater med hensyn til akutt toksisitet: The toxicity studies carried out on mice and rats gave the following results with regard to acute toxicity:
De med fremgangsmåten ifolge oppfinnelsen erholdte substituerte vitamin A-syreamider innehar en utpreget epithel-beskyttelses-virkning (vist ifolge Boguth et al. Int. Z. Vitaminf. 1960, 31, 6), og forårsaker i motsetning til fri vitamin A-syre og det usubstituerte amidet ingen hudirritasjon og ingen såkalt A- hy per vi t ami nose-. The substituted vitamin A acid amides obtained with the method according to the invention have a pronounced epithelial protective effect (shown according to Boguth et al. Int. Z. Vitaminf. 1960, 31, 6), and in contrast to free vitamin A acid and the unsubstituted amide no skin irritation and no so-called A- hy per vi t ami nose-.
De folgende forsok ble utfort:The following experiments were carried out:
Forsok 1 er rettet på en sammenligning av den epitel-beskyttende virkning for de substituerte amider av vitamin A-syren, som fremstilles ifolge nærværende oppfinnelse, vitamin A-syre og vitamin A-syreamid, og Experiment 1 is aimed at a comparison of the epithelial-protective effect of the substituted amides of the vitamin A acid, which are produced according to the present invention, vitamin A acid and vitamin A acid amide, and
forsok 2 er rettet på en sammenligning av hudirritasjonseffek-ten og A-hypervitaminose bieffektene for de substituerte amider av vitamin A-syre som fremstilles ifolge nærværende oppfinnelse, vitamin A-syre og viatamin A-syreamid. experiment 2 is aimed at a comparison of the skin irritation effect and the A hypervitaminosis side effects for the substituted amides of vitamin A acid which are produced according to the present invention, vitamin A acid and vitamin A acid amide.
For sok 1 For sock 1
Her ble den foran angitte metode av Boguth et al., Int. Z. Vitaminf. _31, 6 (1960) anvendt og kastrerte hunrotter ble for-behandlet med en blanding av 1 meg oestradiol-benzoat og 250 meg testosteron-propionat i 0,1 ml sesamolje, inntil rene, dcjell-lignende celler opptråtte i vagina-sekretet. Deretter ble dosene av vitamin A-aktive forbindelser administrert i logaritmiske trinn med en faktor på 1,2. Verdien for den epitel-beskyttende virkning ble bestemt for hver forbindelse Here, the aforementioned method of Boguth et al., Int. Z. Vitaminf. _31, 6 (1960) used and castrated female rats were pre-treated with a mixture of 1 meg oestradiol benzoate and 250 meg testosterone propionate in 0.1 ml sesame oil, until clean, cell-like cells appeared in the vaginal secretion. Then, the doses of vitamin A active compounds were administered in logarithmic steps by a factor of 1.2. The value for the epithelial protective effect was determined for each compound
som dosen som er nodvendig for å gi bare ca. 50 % skjell-lignende celler i sekretet. as the dose required to give only approx. 50% scale-like cells in the secretion.
Resultatene av dette forsok er gjengitt i tabell 1. The results of this trial are reproduced in table 1.
Som det fremgår av resultatene av dette forsok har de substituerte amider av vitamin A-syre, som fremstilles ifolge nærværende oppfinnelse, epitel-beskyttende virkninger som er sammen-lignbare med virkningene av vitamin A-syre og vitamin A-syreamid. As can be seen from the results of this experiment, the substituted amides of vitamin A acid, which are prepared according to the present invention, have epithelial protective effects which are comparable to the effects of vitamin A acid and vitamin A acid amide.
Forsok 2 Attempt 2
Hudirritasjons- og A-hypervitaminoseprover ble utfort. Skin irritation and A-hypervitaminosis tests were carried out.
Hudirritasjonsprovene ble utfort på folgende måte: The skin irritation tests were carried out as follows:
Halvparten av skinnet på ryggen av et marsvin ble barbert bort. En 1%'s opplosning av provepreparatet opplost i aceton ble påfort 8 ganger i lopet av IO dager til 3en utsatte hud. Half the skin on the back of a guinea pig was shaved off. A 1% solution of the sample preparation dissolved in acetone was applied 8 times over the course of 10 days to 3 exposed skin.
Reaksjonen ble avlest på den lo. dag under bruk av en skala fra 0 til 4 for å bestemme graden som folger: 4 = sterkest reaksjon med skurv, rodhet og sterk krustdannelse 3 = sterk reaksjon med skurv, rodhet og noen krustdannelse 2 = moderat skurvdannelse, ingen rodhet, ingen krustdannelse The reaction was read on it. day using a scale from 0 to 4 to determine the degree as follows: 4 = strongest reaction with scabbing, redness and severe crusting 3 = strong reaction with scabbing, redness and some crusting 2 = moderate scabbing, no redness, no crusting
1 = svak skurv 1 = weak scab
0 = ingen reaksjon . 0 = no reaction.
Hypervitaminose-provene ble utfort med mus som veidde 25-27 g som mottok 10 i.p. administrasjoner av provesubstansen suspen-dert i arachis-olje i lopet av 14 dager. De folgende symptomer ble vurdert: tap av vekt, hudskurv, tap av hår og benbrudd. De ble vurdert etter en skala fra O til 4 som folger: The hypervitaminosis tests were performed with mice weighing 25-27 g receiving 10 i.p. administrations of the test substance suspended in arachis oil over the course of 14 days. The following symptoms were assessed: loss of weight, scabies, loss of hair and broken bones. They were assessed on a scale from 0 to 4 as follows:
1. Tap av vekt: >10 g = 4 1. Loss of weight: >10 g = 4
7-9 g = 3 7-9 g = 3
4-6 g = 2 4-6 g = 2
1-3 g = 1 1-3 g = 1
< 1 g = 0- < 1 g = 0-
2. Hudskurv: meget sterk = 4_ 2. Scabies: very strong = 4_
sterk = 3 strong = 3
moderat = 2 moderate = 2
svak =«1 weak =«1
ingen = 0 none = 0
3. Tap av hår: meget sterkt = 4 3. Loss of hair: very severe = 4
sterkt = 3 strong = 3
moderat = 2 moderate = 2
svakt = 1 weak = 1
intet =0 nothing =0
4. Benbrudd: Antall ekstremiteter med frakturerte ben: 0 til 4 4. Bone fractures: Number of extremities with fractured bones: 0 to 4
Den laveste daglige dose som gir hypervitaminose ved 14 dagers proven med mus ble angitt i tabellene. Betingelsen for dyrene som resulterer i et total på minst 3 poeng ble betraktet som hypervitaminose. Angivelsen >400 ble innfort i tabellen hvis 400 mg/kg ikke ga noen hypervitaminose. Det er mulig at meget hoyere doser av disse preparater kan anvendes uten å gi noen hypervitaminose. The lowest daily dose that produces hypervitaminosis in the 14-day test with mice was indicated in the tables. The condition of the animals resulting in a total of at least 3 points was considered as hypervitaminosis. The indication >400 was entered in the table if 400 mg/kg did not cause any hypervitaminosis. It is possible that much higher doses of these preparations can be used without causing any hypervitaminosis.
Resultatene av dette forsok er satt opp i tabell 2. The results of this trial are set out in table 2.
Som det fremgår av resultatene fra dette forsok har de substituerte amider av vitamin A-syre, som fremstilles ifolge nærværende oppfinnelse, nesten ingen hudirritasjon og nesten ingen A-hypervitaminose i sammenligning med vitamin A-syre og vitamin A-syreamid. As can be seen from the results of this experiment, the substituted amides of vitamin A acid, which are produced according to the present invention, have almost no skin irritation and almost no A hypervitaminosis in comparison with vitamin A acid and vitamin A acid amide.
Forbindelsene, som fremstilles ifolge fremgangsmåten, kan anvendes som legemidler, f.eks. i form av farmasøytiske preparater. The compounds, which are produced according to the method, can be used as pharmaceuticals, e.g. in the form of pharmaceutical preparations.
De for systemisk anvendelse benyttede preparater kan fremstilles ved at man til en forbindelse med den generelle formel I som aktiv bestanddel tilsetter en ikke-toksisk, inert og i slike preparater vanlige faste eller flytende bærestoffer. The preparations used for systemic use can be prepared by adding to a compound of the general formula I as active ingredient a non-toxic, inert solid or liquid carrier that is common in such preparations.
Midlene kan administreres enteralt eller parenteralt. For den enterale administrasjon egner seg f.eks. midler i form av The agents can be administered enterally or parenterally. For enteral administration, e.g. funds in the form of
tabletter, kapsler, dragéer, sirup, suspensjoner, losninger og suppositorier. For den parenterale administrasjonen egner seg midler i form av infusjons- eller injeksjonslosninger. tablets, capsules, dragees, syrups, suspensions, solutions and suppositories. Agents in the form of infusion or injection solutions are suitable for parenteral administration.
Doseringen ved administrasjonen av forbindelsen kan variere alt efter anvendelsesområdet og den enkelte pasients behov. The dosage when administering the compound can vary according to the area of application and the needs of the individual patient.
Foitaiitielsene ifolge fremgangsmåten kan administreres i mengder opptil 1000 mg daglig i en eller flere doser. The foitaiitiels according to the method can be administered in amounts up to 1000 mg daily in one or more doses.
En foretrukket administråsjonsform er kapsler med et innhold A preferred form of administration is capsules with a content
fra ca. 20 mg til ca. 200 mg aktivstoff. Egnede former er kapsler av hård- eller mykgelatin, metylcellulose eller av et annet egnet materiale, som loses lett i fordoyelsessystemet. from approx. 20 mg to approx. 200 mg of active substance. Suitable forms are capsules of hard or soft gelatin, methylcellulose or of another suitable material, which are easily dissolved in the digestive system.
Preparatene kan inneholde inerte eller også medisinsk aktive tilsetningsstoffer. Tabletter eller granulater kan f.eks. inneholde en rekke bindemidler, fyllstoffer, bærestoffer eller fortynningsmidler. Flytende stoffer kan f.eks. foreligge i form av en steril og med vann blandbar losning. Kapsler kan foruten aktivstoff i tillegg inneholde et fyllmateriale eller fortykningsmiddel. Dessuten kan de inneholde smaksforbedrende tilsetninger, såvel som de vanlige konserverings-, stabiliserings-, fuktholdende- eller emulgeringsmidler. Videre kan de inneholde salter for å forandre det osmotiske trykket, puffer eller andre tilsetninger. The preparations may contain inert or medically active additives. Tablets or granules can e.g. contain a number of binders, fillers, carriers or diluents. Liquid substances can e.g. available in the form of a sterile and water-miscible solution. In addition to the active substance, capsules may also contain a filler or thickener. In addition, they may contain flavor-enhancing additives, as well as the usual preservatives, stabilizers, humectants or emulsifiers. Furthermore, they may contain salts to change the osmotic pressure, buffers or other additives.
De foran nevnte bærestoffene og fortynningsmidlene kan være organiske eller uorganiske stoffer, f.eks. vann, gelatin, melkesukker, stivelse, magnesiumstearat, talkum, gummi arabicum, polyalkylenglykoler og lignende. En forutsetning er at de ved fremstilling av preparatene anvendte hjelpestoffene er ikke-toksiske. The carriers and diluents mentioned above can be organic or inorganic substances, e.g. water, gelatin, milk sugar, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like. A prerequisite is that the excipients used in the preparation of the preparations are non-toxic.
For topisk anvendelse kan de fremstilte produktene hensiktsmessig anvendes i form av salver, tinkturer, krem, losninger, "lotions", spray, suspensjoner og lignende. Foretrukket er salver, krem og losninger. Disse for topisk anvendelse benyttede preparater kan fremstilles ved at man til de fremstilte produkter, hvilke tjener som aktive bestanddeler, For topical application, the manufactured products can be suitably used in the form of ointments, tinctures, creams, solutions, "lotions", sprays, suspensions and the like. Ointments, creams and solutions are preferred. These preparations used for topical application can be prepared by adding to the manufactured products, which serve as active ingredients,
tilsetter ikke-toksiske inerte, for den topiske behandling adds non-toxic inerts, for the topical treatment
egnede og i slike preparater vanlige faste eller flytende bærestoffer. suitable solid or liquid carriers common in such preparations.
Det er hensiktsmessig ved topisk anvendelse å benytte 1 til ca. 10%'ige, fortrinnsvis ca. 2 til ca. 5%'ige losninger, It is appropriate for topical application to use 1 to approx. 10%, preferably approx. 2 to approx. 5% solutions,
og ca. 1 til ca. 10%'ig, fortrinnsvis ca. 2 til ca. 5%'ig salve eller krem. and approx. 1 to approx. 10%, preferably approx. 2 to approx. 5% ointment or cream.
De fremstilte produkter kan også anvendes sammen med et antioksydasjonsmiddel. Av disse kommer særlig tocoferol, N-metyl-Y-tocoferamin, såvel som butylert hydroksyanisol, butylert hydroksytoluen eller etoksykinolin, i betraktning. The manufactured products can also be used together with an antioxidant. Of these, in particular tocopherol, N-methyl-Y-tocopheramine, as well as butylated hydroxyanisole, butylated hydroxytoluene or ethoxyquinoline, come into consideration.
EKSEMPEL 1 EXAMPLE 1
60 vektsdeler etylamin og 300 volumdeler absolutt eter omrores under iskjoling i nitrogenatmosfære, og til dette tildryppes 30 minutter syrekloridet av 30 vektsdeler vitamin A-syre i lOO volumdeler absolutt eter. Man rorer 4 timer ved romtemperatur, og derefter rorer man 2 timer under tilbakelop. Man avkjoler blandingen, fortynner med lOOO volumdeler eter 60 parts by weight of ethylamine and 300 parts by volume of absolute ether are stirred under ice-cooling in a nitrogen atmosphere, and to this the acid chloride of 30 parts by weight of vitamin A acid in 100 parts by volume of absolute ether is added dropwise for 30 minutes. You stir for 4 hours at room temperature, and then you stir for 2 hours under reflux. The mixture is cooled, diluted with 100 parts by volume of ether
og vasker 4 ganger med hver gang lOO volumdeler vann. Eter-losningen torkes over natriumsulfat, opplosningsmidlet avdampes og resten krystalliseres i en benzen-heksan-blanding. Man erholder vitamin A-syreetylamidet med et smp. på 137 - 138°C; X . = 347 mn, E }% 1540. and wash 4 times with lOO parts by volume of water each time. The ether solution is dried over sodium sulphate, the solvent is evaporated and the residue is crystallized in a benzene-hexane mixture. The vitamin A acid ethylamide is obtained with a m.p. at 137 - 138°C; X . = 347 mn, E }% 1540.
maks ~' lem max ~' limb
EKSEMPEL 2 EXAMPLE 2
Analogt eksempel 1 kan folgende substituerte vitamin A-syreamider fremstilles: Analogously to example 1, the following substituted vitamin A acid amides can be prepared:
EKSEMPEL 3 EXAMPLE 3
Analogt eksempel 1 fremstilles vitamin A-syredietylamidet. Analogous to example 1, the vitamin A acid diethylamide is prepared.
For å rense dette stoffet, blir det kromatografert ved hjelp av 600 g aluminiumoksyd (aktivitet III noytral) og ved hjelp av heksan, hvorved man efter å ha isolert en forfraksjon erholder det rene amidet sammen med heksan. Efter å ha fjernet opplosningsmidlet erholder man vitamin A-syredietylamidet i form av en olje. Ama:k.s 340 mp E lcm 1300. In order to purify this substance, it is chromatographed using 600 g of aluminum oxide (activity III neutral) and using hexane, whereby, after isolating a preliminary fraction, the pure amide is obtained together with hexane. After removing the solvent, the vitamin A acid diethylamide is obtained in the form of an oil. Ama:k.s 340 mp E lcm 1300.
EKSEMPEL 4 EXAMPLE 4
Analogt eksemplene 1 og 3 kan folgende substituerte vitamin A-syreamider fremstilles: vitamin A-syre-di-n-butylamid Analogous to examples 1 and 3, the following substituted vitamin A acid amides can be prepared: vitamin A acid di-n-butylamide
A 337 mt E*% 985 A 337 mt E*% 985
maks r 1 cm max r 1 cm
- vitamin A-syre-di-n-decylamid - vitamin A-acid-di-n-decylamide
A . 337 mu e}% 775 A. 337 mu e}% 775
maks n 1 cm max n 1 cm
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH142870A CH529742A (en) | 1970-02-02 | 1970-02-02 | Process for the production of vitamin A acid amides |
Publications (2)
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NO133802B true NO133802B (en) | 1976-03-22 |
NO133802C NO133802C (en) | 1976-06-30 |
Family
ID=4210229
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NO343/71*[A NO133802C (en) | 1970-02-02 | 1971-02-01 |
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JP (1) | JPS544948B1 (en) |
AT (1) | AT303274B (en) |
BE (1) | BE762345A (en) |
CA (1) | CA963910A (en) |
CH (1) | CH529742A (en) |
DE (1) | DE2102586C2 (en) |
DK (1) | DK136311B (en) |
ES (1) | ES387834A1 (en) |
FI (1) | FI52715C (en) |
FR (1) | FR2081477B1 (en) |
GB (1) | GB1283887A (en) |
IE (1) | IE35133B1 (en) |
IL (1) | IL35987A (en) |
NL (1) | NL168415C (en) |
NO (1) | NO133802C (en) |
SE (1) | SE373133B (en) |
YU (1) | YU34355B (en) |
ZA (1) | ZA71142B (en) |
Families Citing this family (11)
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DE2300107C2 (en) * | 1973-01-03 | 1982-03-11 | Basf Ag, 6700 Ludwigshafen | Vitamin A acid anilide-4-carboxylic acid ethyl ester, process for its production and preparations containing it |
US4310546A (en) * | 1978-07-31 | 1982-01-12 | Johnson & Johnson | Novel retinoids and their use in preventing carcinogenesis |
DE2843870A1 (en) * | 1978-10-07 | 1980-04-24 | Basf Ag | N-HYDROXYPROPYLAMIDES OF ALL-E AND 13-Z RETINIC ACID |
DE2843915A1 (en) * | 1978-10-07 | 1980-04-24 | Basf Ag | N-BENZOYL RETINYLAMINE |
DE3002545A1 (en) * | 1980-01-25 | 1981-07-30 | Basf Ag, 6700 Ludwigshafen | 5-AMINO-TETRAZOLE DERIVATIVES OF RETINIC ACIDS, THEIR PRODUCTION AND THE PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
CH651007A5 (en) * | 1982-06-24 | 1985-08-30 | Hoffmann La Roche | POLYEN CONNECTIONS. |
KR100556682B1 (en) * | 1995-09-01 | 2006-06-21 | 코스모페름 베.파우 | Retinoylamide based derivatives of sphingoid bases |
US7566808B2 (en) * | 2004-02-17 | 2009-07-28 | President And Fellows Of Harvard College | Management of ophthalmologic disorders, including macular degeneration |
US20070270472A1 (en) * | 2004-07-09 | 2007-11-22 | Raphael Beumer | Amino, Amino Acid or Peptide Conjugates of Retinoic Acid |
KR100837186B1 (en) * | 2006-09-29 | 2008-06-13 | (주)아모레퍼시픽 | Retinoic acid derivative having anti-aging activity and preparation method thereof |
CN110831586B (en) * | 2017-05-23 | 2023-06-13 | 密执安大学评议会 | Dimethyl-nonyltetraalkenyl-trimethyl-cyclohexyl compounds and uses thereof |
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CH195065A (en) * | 1936-11-23 | 1938-01-15 | Int Suiker En Alcohol Compagni | Installation on vacuum apparatus to facilitate the replacement of individual tubes. |
NL257621A (en) * | 1959-11-23 | |||
FR1297730A (en) * | 1960-11-04 | 1962-07-06 | Hoffmann La Roche | Cosmetic preparation |
FR1320153A (en) * | 1962-01-22 | 1963-03-08 | Sumitomo Chemical Co | Process for the production of compounds derived from vitamin a 2-trans acid |
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1970
- 1970-02-02 CH CH142870A patent/CH529742A/en not_active IP Right Cessation
- 1970-12-09 FI FI703317A patent/FI52715C/en active
- 1970-12-15 NL NLAANVRAGE7018260,A patent/NL168415C/en not_active IP Right Cessation
- 1970-12-28 YU YU3184/70A patent/YU34355B/en unknown
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1971
- 1971-01-11 ZA ZA710142A patent/ZA71142B/en unknown
- 1971-01-12 IL IL35987A patent/IL35987A/en unknown
- 1971-01-20 DE DE2102586A patent/DE2102586C2/en not_active Expired
- 1971-01-29 FR FR7103020A patent/FR2081477B1/fr not_active Expired
- 1971-01-29 CA CA103,975A patent/CA963910A/en not_active Expired
- 1971-01-29 DK DK40571AA patent/DK136311B/en not_active Application Discontinuation
- 1971-02-01 ES ES387834A patent/ES387834A1/en not_active Expired
- 1971-02-01 BE BE762345A patent/BE762345A/en not_active IP Right Cessation
- 1971-02-01 JP JP356271A patent/JPS544948B1/ja active Pending
- 1971-02-01 AT AT79971A patent/AT303274B/en not_active IP Right Cessation
- 1971-02-01 NO NO343/71*[A patent/NO133802C/no unknown
- 1971-02-02 IE IE118/71A patent/IE35133B1/en unknown
- 1971-02-02 SE SE7101274A patent/SE373133B/xx unknown
- 1971-04-19 GB GB20880/71A patent/GB1283887A/en not_active Expired
Also Published As
Publication number | Publication date |
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ES387834A1 (en) | 1973-06-01 |
NO133802C (en) | 1976-06-30 |
FI52715B (en) | 1977-08-01 |
NL168415B (en) | 1981-11-16 |
DK136311B (en) | 1977-09-26 |
IE35133B1 (en) | 1975-11-26 |
DK136311C (en) | 1978-02-20 |
GB1283887A (en) | 1972-08-02 |
YU318470A (en) | 1978-12-31 |
YU34355B (en) | 1979-07-10 |
FR2081477B1 (en) | 1974-03-22 |
AT303274B (en) | 1972-11-27 |
ZA71142B (en) | 1971-10-27 |
DE2102586C2 (en) | 1985-03-14 |
BE762345A (en) | 1971-08-02 |
CA963910A (en) | 1975-03-04 |
IE35133L (en) | 1971-08-02 |
DE2102586A1 (en) | 1971-08-12 |
JPS544948B1 (en) | 1979-03-12 |
IL35987A0 (en) | 1971-03-24 |
CH529742A (en) | 1972-10-31 |
NL7018260A (en) | 1971-08-04 |
IL35987A (en) | 1974-01-14 |
FR2081477A1 (en) | 1971-12-03 |
SE373133B (en) | 1975-01-27 |
NL168415C (en) | 1982-04-16 |
FI52715C (en) | 1977-11-10 |
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