NL192371C - Anti-inflammatory agents for external use, as well as compounds suitable for use in such a composition. - Google Patents
Anti-inflammatory agents for external use, as well as compounds suitable for use in such a composition. Download PDFInfo
- Publication number
- NL192371C NL192371C NL8102775A NL8102775A NL192371C NL 192371 C NL192371 C NL 192371C NL 8102775 A NL8102775 A NL 8102775A NL 8102775 A NL8102775 A NL 8102775A NL 192371 C NL192371 C NL 192371C
- Authority
- NL
- Netherlands
- Prior art keywords
- phenyl
- propionate
- pyridylmethyl
- ylmethyl
- group
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 47
- 150000001875 compounds Chemical class 0.000 title claims description 43
- 229940121363 anti-inflammatory agent Drugs 0.000 title description 5
- 239000002260 anti-inflammatory agent Substances 0.000 title description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 11
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 11
- -1 Polyoxyethylene monostearate Polymers 0.000 claims description 10
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical group OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 5
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 5
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- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 229940126062 Compound A Drugs 0.000 claims description 2
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- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012177 spermaceti Substances 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- LFQCEHFDDXELDD-UHFFFAOYSA-N tetramethyl orthosilicate Chemical compound CO[Si](OC)(OC)OC LFQCEHFDDXELDD-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/86—Unsaturated compounds containing keto groups containing six-membered aromatic rings and other rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Description
Ontstekingswerende samenstelling voor uitwendig gebruik, alsmede voor toepassing in zo'n samenstelling geschikte verbindingenAnti-inflammatory composition for external use, as well as compounds suitable for use in such a composition
De uitvinding heeft betrekking op een ontstekingswerende samenstelling voor uitwendig gebruik bij mens en 5 dier door plaatselijke toediening van farmaceutische samenstellingen die deze middelen bevatten, alsmede voor toepassing in zo’n samenstelling geschikte verbindingen.The invention relates to an anti-inflammatory composition for topical use in humans and animals by topical administration of pharmaceutical compositions containing these agents, as well as compounds suitable for use in such a composition.
De bekende ontstekingswerende middelen omvatten steroïde en niet-steroïde geneesmiddelen. Veel corticosteroïden bezitten een krachtige ontstekingswerende werking, zowel systemisch als plaatselijk, doch hun toepassing in plaatselijk aan te brengen samenstellingen wordt beperkt door het feit dat ze intradeimaal 10 kunnen worden geabsorbeerd en door de neveneffecten die bij langdurige toediening kunnen optreden.The known anti-inflammatory agents include steroid and non-steroidal drugs. Many corticosteroids have potent anti-inflammatory activity, both systemically and topically, but their use in topically applied compositions is limited by the fact that they can be absorbed intradeally and by the side effects that can occur with prolonged administration.
De bekende niet-steroïde ontstekingswerende geneesmiddelen omvatten een aantal verbindingen, bijvoorbeeld aspirine en andere salicylzuurverbindingen, aldofenac, bindazac, bufexamac, fenoprofen, flufenaminezuur, ibuprofen, indomethacin, ketoprofen, mefenaminezuur, naproxen en fenylbutazon. Met uitzondering van een gering aantal zijn deze niet-steroïde ontstekingswerende geneesmiddelen op 15 systemische of op plaatselijke wijze gebruikt, doch niet volgens beide toedieningswijzen. Aspirine en veel andere analgetische middelen kunnen bijvoorbeeld systemisch worden toegediend, gewoonlijk op orale wijze, voor de behandeling van artritis, reumatiek en andere met ontsteking gepaard gaande aandoeningen, doch zij worden niet toegepast voor plaatselijke toediening als uitwendige ontstekingswerende middelen. Anderzijds wordt methyisaiicyiaat, dat uitwendig wordt toegepast voor reumatische aandoeningen, te giftig 20 beschouwd voor inwendige toediening. Evenzo worden verbindingen zoals bindazac of bufexamac gewoonlijk uitsluitend uitwendig toegepast. In het algemeen wordt er derhalve ten aanzien van de niet-steroïde ontstekingswerende middelen een onderscheid aanwezig geacht tussen de middelen voor inwendig en die voor uitwendig gebruik.The known non-steroidal anti-inflammatory drugs include a number of compounds, for example, aspirin and other salicylic acid compounds, aldofenac, bindazac, bufexamac, phenoprofen, fluphenamic acid, ibuprofen, indomethacin, ketoprofen, mefenamic acid, naproxen and phenylbutazone. With the exception of a small number, these non-steroidal anti-inflammatory drugs have been used systemically or topically, but not by either route of administration. For example, aspirin and many other analgesics can be administered systemically, usually orally, for the treatment of arthritis, rheumatism and other inflammatory conditions, but they are not used for topical administration as external anti-inflammatory agents. On the other hand, methyl silicate, which is used externally for rheumatic diseases, is considered too toxic for internal administration. Likewise, compounds such as bindazac or bufexamac are usually used only externally. In general, therefore, as regards the non-steroidal anti-inflammatory agents, a distinction is considered to exist between the agents for internal use and those for external use.
Het Franse octrooischrift 2.395.256 beschrijft 4-(2-oxocycloalkaan-1-ylmethyl)fenylazijnzuurverbindingen 25 en het Franse octrooischrift 2.400.500 beschrijft 4-(2-oxocycloalkylideenmethyl)fenylazijnzuurverbindingen die een analgetische, antipyretische en ontstekingswerende werkzaamheid bezitten. Voorbeelden van de in deze octrooischriften beschreven fenylazijnzuurverfoindingen omvatten de hierna genoemde verbindingen 1 t/m 15. De voor deze verbindingen in deze octrooischriften beschreven werkzaamheden zijn gebleken na inwendige toediening van de verbindingen langs orale of intestinale weg, doch deze octrooischriften 30 bevatten geen aanwijzing dat deze verbindingen een werking bezitten, wanneer zij plaatselijk worden aangebracht op het menselijk of dierlijk lichaam, zoals bij uitwendige ontstekingswerende middelen. Verrassenderwijze is nu gevonden dat een aantal van deze bekende verbindingen en nauw verwante, niet als zodanig genoemde derivaten een bruikbare ontstekingswerende werking bezitten, wanneer zij uitwendig worden aangebracht.French Patent 2,395,256 discloses 4- (2-oxocycloalkan-1-ylmethyl) phenylacetic acid compounds and French Patent 2,400,500 discloses 4- (2-oxocycloalkylidenemethyl) phenylacetic acid compounds which have analgesic, antipyretic and anti-inflammatory activity. Examples of the phenylacetic acid compounds described in these patents include compounds 1 to 15 mentioned below. The activities described for these compounds in these patents have been found following internal administration of the compounds by oral or intestinal route, but these patents do not indicate that these compounds have an effect when applied topically to the human or animal body, such as with external anti-inflammatory agents. Surprisingly, it has now been found that some of these known compounds and closely related, unnamed derivatives have useful anti-inflammatory activity when applied externally.
35 De uitvinding heeft derhalve betrekking op een ontstekingswerende samenstelling voor uitwendig gebruik bij mens en dier, die gekenmerkt is, doordat deze een fenylazijnzuurderivaat met formule 1 van het formuleblad, waarin: n = 1 of 2; R1 een waterstofatoom of een alkylgroep met 1-4 koolstofatomen, 40 R2 een waterstofatoom, een alkylgroep met 1-6 koolstofatomen, een aralkylgroep of een pyridylmethylgroep en 'y A-B-een CH-CHa-of C = CH-groep voorstelt, of een farmaceutisch aanvaardbaar zout van een dergelijke veibinding, opgenomen in een 45 geschikt farmaceutisch middel, bevat, en de vorm bezit van een crème, zalf, lotion, smeersel of pleister.The invention therefore relates to an anti-inflammatory composition for external use in humans and animals, characterized in that it comprises a phenylacetic acid derivative of formula 1 of the formula sheet, wherein: n = 1 or 2; R 1 represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R 2 represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, an aralkyl group or a pyridylmethyl group and 'y AB-a CH-CHa or C = CH group, or a pharmaceutically acceptable salt of such fiber binding, incorporated into a suitable pharmaceutical agent, and in the form of a cream, ointment, lotion, spread or plaster.
Wanneer R2 een aralkylgroep is, bijvoorbeeld een benzyl- of fenethylgroep, kan deze desgewenst aan de aromatische ring gesubstitueerd zijn door één of meer lagere alkylgroepen, lagere alkoxygroepen, halogeenatomen of trifluormethylgroepen. Wanneer R2 een pyridylmethylgroep is, kan dit de 2-, 3- of 4-pyridylmethylgroep zijn.When R2 is an aralkyl group, for example a benzyl or phenethyl group, it may optionally be substituted on the aromatic ring by one or more lower alkyl groups, lower alkoxy groups, halogen atoms or trifluoromethyl groups. When R2 is a pyridylmethyl group it can be the 2-, 3- or 4-pyridylmethyl group.
50 Bijzondere voorkeur verdienen samenstellingen, die een van de volgende verbindingen met formule 1 bevatten: 2- pyridylmethyl-2-[4-(2-oxocyclopentaan-1-ylmethyl)fenyl]propionaat, 3- pyridylmethyl-2-[4-(2-oxocyclopentaan-1-ylmethyl)fenyl]propionaat, 4- pyridylmethyl-2-[4-(2-oxocyclopentaan-1-ylmethyl)fenyl]propionaat, 55 2-pyridylmethyl-2-[4-(2-oxo-1 -cyclohexylideenmethyl)fenyl]propionaat of methyl-2-[4-(2-oxocyclopentaan-1-ylmethyl)fenyl]propionaat.Particular preference is given to compositions containing one of the following compounds of formula 1: 2-pyridylmethyl-2- [4- (2-oxocyclopentan-1-ylmethyl) phenyl] propionate, 3-pyridylmethyl-2- [4- (2 -oxocyclopentan-1-ylmethyl) phenyl] propionate, 4-pyridylmethyl-2- [4- (2-oxocyclopentan-1-ylmethyl) phenyl] propionate, 55 2-pyridylmethyl-2- [4- (2-oxo-1 - cyclohexylidenemethyl) phenyl] propionate or methyl 2- [4- (2-oxocyclopentan-1-ylmethyl) phenyl] propionate.
De fenyiazijnzuurderivaten met formule 1, die worden toegepast in de samenstellingen volgens de onderhavige uitvinding omvatten zowel bekende als nieuwe verbindingen. De bekende veibindingen en hun bereiding zijn beschreven in de Franse octrooischriften 2.395.256 en 2.400.500 en voorbeelden hiervan zijn: 1) 2-[4-(2-oxocyclopentaan-1 •ylmethyl)fenyl]propionzuur 2) 4-(2-oxocyciopentaan-1 -ylmethyl)fenylazijnzuur 5 3) 2-[4-(2-oxocydohexaan-1-ylmethyl)fenyl]propionzuur 4) Arginine-2-[4-{2-oxocydopentaan-1 -ylmethyi)fenyl]propionaat 5) Lysine-2-[4-(2-oxocyclopentaan-1 -ylmethyl)fenyljpropionaat 6) Natrium-2-[4-(2-oxocyck>pentaan-1 -ylmethyl)fenyl]propionaat 7) 2-[4-(2-oxocydopentylideenmethyl)fenyllpropionzuur 10 8) Ethyl-2-[4-(2-oxocydopentylideenmethyl)fenyl]propionaat 9) 2-[4-(2-oxocydohexylideenmethyl)fenyl]propionzuur 10) Methyl-2-[4-(2-oxo-1 -cydohexylideenmethyl)fenyi]propionaat 11) Ethyl-2-[4-(2-oxo-1 -cydohexylideenmethyl)fenyl]propionaat 12) Butyl-2-[4-(2-oxo-1-cydohexylideenmethyl)fenyl]propionaat 15 13) Arginine-2-[4-(2-oxo-1-cydohexylideenmethyl)fenyl]propionaat 14) Lysino-2-[4-(2-oxo-1 -cydohexylideenmethyl)fenyl]propionaat 15) Natrium-2-[4-(2-oxo-1 -cydohexylideenmethyl)fenyl]propionaatThe phenylacetic acid derivatives of formula 1 used in the compositions of the present invention include both known and new compounds. The known fiber bonds and their preparation are described in French Pat. Nos. 2,395,256 and 2,400,500 and examples thereof are: 1) 2- [4- (2-oxocyclopentan-1-ylmethyl) phenyl] propionic acid 2) 4- (2- oxocyciopentan-1-ylmethyl) phenylacetic acid 5 3) 2- [4- (2-oxocydohexan-1-ylmethyl) phenyl] propionic acid 4) Arginine-2- [4- {2-oxocydopentan-1-ylmethyl) phenyl] propionate 5) Lysine-2- [4- (2-oxocyclopentane-1-ylmethyl) phenyl propionate 6) Sodium 2- [4- (2-oxocyck> pentane-1-ylmethyl) phenyl] propionate 7) 2- [4- (2- oxocydopentylidenemethyl) phenylpropionic acid 10 8) Ethyl 2- [4- (2-oxocydopentylidenemethyl) phenyl] propionate 9) 2- [4- (2-oxocydohexylidenemethyl) phenyl] propionic acid 10) Methyl-2- [4- (2-oxo- 1 -cydohexylidenemethyl) phenyl] propionate 11) Ethyl 2- [4- (2-oxo-1 -cydohexylidenemethyl) phenyl] propionate 12) Butyl-2- [4- (2-oxo-1-cydohexylidenemethyl) phenyl] propionate 15 13) Arginine-2- [4- (2-oxo-1-cydohexylidenemethyl) phenyl] propionate 14) Lysino-2- [4- (2-oxo-1 -cydohexylidenemethyl) phenyl] propionate 15) Sodium-2- [4- (2-oxo-1-cydohexylidenemethyl) phenyl] propionate
Voorbeelden van de toegepaste nieuwe verbindingen zijn weergegeven in de hierna volgende tabel A, waarin hun structuur met betrekking tot dezelfde symbden als in formule 1, hun elementaire analyse en hun 20 massaspedrum zijn weergegeven.Examples of the new compounds used are shown in Table A below, showing their structure with respect to the same symbos as in Formula 1, their elemental analysis, and their mass pedal.
De onderhavige uitvinding heeft voorts betrekking op nieuwe verbindingen, die weliswaar binnen algemene formuleringen uit de stand der techniek vallen, maar niet als zodanig genoemd zijn. Deze nieuwe verbindingen zijn de verbindingen met de formule 1, waarin n = 1 of 2, R1 een waterstofatoom of een alkylgroep met 1-4 koolstofatomen en ofwel R2 een aralkylgroep of een pyridylmethylgroep en 25 y A-B-een CH-CH2-of C-CH-groep voorstelt, ofwel R2 een alkylgroep met 1-6 koolstofatomen voorstelt en y A-B-een y CH-CH2-groep voorstelt.The present invention further relates to new compounds which, although within general formulations of the prior art, are not identified as such. These new compounds are the compounds of formula 1, wherein n = 1 or 2, R 1 is a hydrogen atom or an alkyl group of 1 to 4 carbon atoms and either R 2 is an aralkyl group or a pyridylmethyl group and 25 y AB-a CH-CH 2 or C- CH group, or R2 represents an alkyl group of 1-6 carbon atoms and y AB-represents y CH-CH2 group.
3030
TABEL ATABLE A
No. R, R2 y A — B — n Elementair Analyse % M.S.(M+)No. R, R2 y A - B - n Elemental Analysis% M.S. (M +)
C Η NC Η N
35 - 16 H CH3 ")CH —CH2— 1 Ber. 73,14; 7,37 24635 - 16 H CH 3 ") CH - CH 2 - 1 Calc. 73.14; 7.37 246
Gev. 73,08; 7,36 17 CH3 C2Hs yCH — CH2— 1 Ber. 74,42; 8,08 274 40 Gev. 74,75; 8,11 18 CH3 C4H9 y CH — CH2 — 1 Ber. 75,46; 8,67 302Gev. 73.08; 7.36 17 CH 3 C 2 H 5 y CH - CH 2 - 1 Ber. 74.42; 8.08 274 40 Found. 74.75; 8.11 18 CH3 C4H9 y CH - CH2 - 1 Ber. 75.46; 8.67 302
Gev. 75,19; 8,66 45 19 CH3 groep met formule 5 y CH — CH2— 1 Ber. 78,54; 7,19 336Gev. 75.19; 8.66 45 19 CH 3 group of formula 5 y CH - CH 2 - 1 Ber. 78.54; 7.19 336
Gev. 78,46; 7,21 20 CH3 groep met formule 6 y CH — CH2— 1 Ber. 74,75; 6,87 4,15 337Gev. 78.46; 7.21 CH3 group of formula 6 y CH - CH2 - 1 Ber. 74.75; 6.87 4.15 337
Gev. 74,63; 6,91; 4,11 5Ö --- 21 CH3 groep met formule 8 y CH — CH2 — 1 Ber. 74,75; 6,87; 4,15 337Gev. 74.63; 6.91; 4.11 5Ö --- 21 CH3 group of formula 8 y CH - CH2 - 1 Ber. 74.75; 6.87; 4.15 337
Gev. 74,59; 6,81; 4,06 22 CH3 groep met formule 7 yCH-CH2— 1 Ber. 74,75; 6,87; 4,15 337 55 Gev. 74,55; 6,80; 4,23 TABEL A (vervolg)Gev. 74.59; 6.81; 4.06 22 CH 3 group of formula 7 yCH-CH 2 - 1 Ber. 74.75; 6.87; 4.15 337 55 Found. 74.55; 6.80; 4.23 TABLE A (continued)
No. R., R2 / A — B — n Elementair Analyse % M.S.(M+)No. R., R2 / A - B - n Elemental Analysis% M.S. (M +)
C Η NC Η N
5 -\- 23 H groep met formule 5 y C = CH — 2 Ber. 79,01; 6,63 3345-23 H group of formula 5 y C = CH-2 Ber. 79.01; 6.63 334
Gev. 79,00; 6,47 24 CH3 groep met formule 6 C = CH — 2 Ber. 75,62; 6,63; 4,01 349 10 Gev. 75,57; 6,75; 4,20 25 CH3 groep met formule 8 \ C = CH — 2 Ber. 75,62; 6,63; 4,01 349Gev. 79.00; 6.47 24 CH 3 group of formula 6 C = CH-2 Ber. 75.62; 6.63; 4.01 349 10 Gev. 75.57; 6.75; 4.20 25 CH3 group with formula 8 \ C = CH-2 Ber. 75.62; 6.63; 4.01 349
Gev. 75,68; 6,45; 4,38 15 26 CH3 groep met formule 7 C = CH — 2 Ber. 75,62; 6,63; 4,01 349Gev. 75.68; 6.45; 4.38 15 26 CH 3 group of formula 7 C = CH-2 Ber. 75.62; 6.63; 4.01 349
Gev. 75,49; 6,63; 3,98Gev. 75.49; 6.63; 3.98
Van de nieuwe verbindingen wordt in verband met hun goede werkzaamheid in ontstekingswerende 20 samenstellingen voor uitwendig gebruik de voorkeur gegeven aan de volgende verbindingen: 2- pyridylmethyl-2-[4-(2-oxocyclopentaan-1-ylmethyl)fenyl]propionaat, 3- pyridylmethyl-2-[4-(2-oxocyclopentaan-1-ylmethyl)fenyl]propionaat, 4- pyridylmethyl-2-[4-(2-oxocyclopentaan-1-ylmethyl)fenyl]propionaat, 2-pyridylmethyl-2-[4-(2-oxo-1-cyclohexylideenmethyl)fenyl]propionaat en 25 methyl-2-[4-(2-oxocyclopentaan-1 -ylmethyl)fenyl]propionaat.Among the new compounds, due to their good activity in anti-inflammatory compositions for external use, the following compounds are preferred: 2-pyridylmethyl-2- [4- (2-oxocyclopentan-1-ylmethyl) phenyl] propionate, 3- pyridylmethyl-2- [4- (2-oxocyclopentan-1-ylmethyl) phenyl] propionate, 4-pyridylmethyl-2- [4- (2-oxocyclopentan-1-ylmethyl) phenyl] propionate, 2-pyridylmethyl-2- [4 - (2-oxo-1-cyclohexylidenemethyl) phenyl] propionate and methyl 2- [4- (2-oxocyclopentane-1-methylmethyl) phenyl] propionate.
De nieuwe verbindingen met formule 1, volgens de onderhavige uitvinding kunnen bereid worden door een zuur met formule 1, waarin R2 een waterstofatoom voorstelt (of een reactief derivaat van een dergelijk zuur, zoals zuurhalogenide) te laten reageren met een alkanol met formule R2OH, waarin R2 een aralkyl- of pyridylmethylgroep is. Deze reactie kan uitgevoerd worden volgens verschillende werkwijzen, A, B en C, 30 zoals weergegeven op het formuleblad, waarin alle symbolen de bovengenoemde betekenissen bezitten, behalve dat X een halogeenatoom zoals chloor of broom voorstelt.The new compounds of formula 1 of the present invention can be prepared by reacting an acid of formula 1, wherein R2 represents a hydrogen atom (or a reactive derivative of such an acid, such as acid halide) with an alkanol of formula R2OH, wherein R2 is an aralkyl or pyridylmethyl group. This reaction can be carried out by various methods, A, B and C, as shown on the formula sheet, in which all symbols have the above meanings, except that X represents a halogen atom such as chlorine or bromine.
Werkwijze A omvat dat men een zuur (formule 2) laat reageren met de alkanol met formule 3, door koken onder temgvloeikoeling, in tegenwoordigheid van een dehydratatiemiddel zoals zwavelzuur, een polyfosforzuur of p-tolueensulfonzuur. Ongeveer 2 tot 3 mol van de alkanol, (formule 3) kan worden 35 toegepast per mol zuur (formule 2) in tegenwoordigheid van een reactieoplosmiddel, zoals benzeen, tolueen of xyleen, of men kan anderzijds een grotere overmaat van alkanol (formule 2) toepassen, zodat die tevens dient als het reactieoplosmiddel. Men kan de twee verbindingen eveneens met elkaar laten reageren in tegenwoordigheid van een dehydratatiemiddel, zoals dicyclohexylcarbodiimide.Method A comprises reacting an acid (Formula 2) with the alkanol of Formula 3 by refluxing in the presence of a dehydrating agent such as sulfuric acid, a polyphosphoric acid or p-toluenesulfonic acid. About 2 to 3 moles of the alkanol (Formula 3) may be used per mole of acid (Formula 2) in the presence of a reaction solvent, such as benzene, toluene or xylene, or alternatively, a larger excess of alkanol (Formula 2) may be used. so that it also serves as the reaction solvent. The two compounds can also be reacted with one another in the presence of a dehydrating agent such as dicyclohexylcarbodiimide.
Werkwijze B omvat dat men eerst het zuur (formule 2) laat reageren met een halogenerend middel (zoals 40 thionylchloride, fosforoxychloride of fosforpentachloride), ter vorming van een zuurhalogenide (formule 4), en daarna het zuurhalogenide (formule 4) laat reageren met 1 of 2 mol van een alkanol (foimule 3) in een inert organisch oplosmiddel (zoals tetrahydrofuran, dioxan, benzeen of tolueen), in tegenwoordigheid van een zuurbindend middel.Method B comprises first reacting the acid (Formula 2) with a halogenating agent (such as 40 thionyl chloride, phosphorus oxychloride or phosphorus pentachloride) to form an acid halide (Formula 4) and then reacting the acid halide (Formula 4) with 1 or 2 moles of an alkanol (formula 3) in an inert organic solvent (such as tetrahydrofuran, dioxane, benzene or toluene), in the presence of an acid binding agent.
Werkwijze C omvat dat men eerst onder koelen met ijs een alkanol (formule 3) mengt met een oplossing 45 van het zuur (formule 2) in een inert organisch oplosmiddel (zoals tetrahydrofuran, dioxan, benzeen of tolueen), trifenylfosfine en pyridinedisulfide, en daarna het mengsel door koken onder terugvloeikoeling laat reageren.Method C comprises first mixing an alkanol (Formula 3) with a solution of the acid (Formula 2) in an inert organic solvent (such as tetrahydrofuran, dioxane, benzene or toluene), triphenylphosphine and pyridine disulfide under ice-cooling, then react the mixture by refluxing.
Onafhankelijk van de toegepaste werkwijze kan het product uit het reactiemengsel worden afgescheiden en op bekende wijze worden gezuiverd, zoals extractie met een geschikt organisch oplosmiddel en 50 vacuümdestillatie.Irrespective of the method used, the product can be separated from the reaction mixture and purified in known manner, such as extraction with a suitable organic solvent and vacuum distillation.
De verbindingen volgens de uitvinding worden gemakkelijk percutaan geabsorbeerd en bezitten een grote ontstekingswerende werking, wanneer zij plaatselijk op het menselijke of dierlijke lichaam worden aangebracht, opgelost of gedispergeerd in een geschikte farmaceutische drager. Deze werking blijkt uit de resultaten van de hierna volgende farmacologische proeven, onder toepassing van de werkwijze van Jonelli 55 et al (G. Jonelli, L. Thibault, I. Ringler, Endrocrino!., 77, 625 (1965) gewijzigd door Misaka et al (Eiichi Misaka, Yoshio lizuka, Hiroyoshi Horikoshi, Takeshi Yamaguchi, Takayoshi Kojima, Yoko Endo, Yumiko Misawa, Hiroka Tsunoda, Yoshihiko Baba, Kiichiro Tanaka, Pharmacometrics, 19, 75 (1980)).The compounds of the invention are readily absorbed percutaneously and have a high anti-inflammatory effect when applied topically to the human or animal body, dissolved or dispersed in a suitable pharmaceutical carrier. This activity is evidenced by the results of the following pharmacological tests, using the method of Jonelli 55 et al (G. Jonelli, L. Thibault, I. Ringler, Endrocrino!., 77, 625 (1965) modified by Misaka et al. al (Eiichi Misaka, Yoshio lizuka, Hiroyoshi Horikoshi, Takeshi Yamaguchi, Takayoshi Kojima, Yoko Endo, Yumiko Misawa, Hiroka Tsunoda, Yoshihiko Baba, Kiichiro Tanaka, 19, 75 (1980)).
BepmevingsmethodeMethod of determination
Men past 3-4 weken oude vrouwelijke SD ratten met een lichaamsgewicht van 60-70 g toe alsmede een 4%’s crotonolie-oplossing in diethylether die men verder verdunt met een oplosmiddel (pyridine : water: diethylether = 4:1:5) om uiteindelijk een 2%’s oplossing te vetkrijgen.3-4 week old female SD rats with a body weight of 60-70 g are used, as well as a 4% croton oil solution in diethyl ether which is further diluted with a solvent (pyridine: water: diethyl ether = 4: 1: 5) to eventually get a 2% solution.
5 Men verdooft elke rat enigszins met diethylether. Men bestrijkt de binnenzijde van elke rechter oorschelp met met diethylether bevochtigde watten, laat de ether verdampen, en brengt daarna druppelsgewijze met een spuit 0,1 ml van de 2%’s crotonolie-oplossing aan, en droogt met een haardroger. Een kunststofkraag met een diameter van 16-19 mm is aangebracht om het hoofd van de rat, die in een kooi is geplaatst en op kamertemperatuur wordt gehouden (23-25°C).Each rat is slightly anesthetized with diethyl ether. The inside of each right auricle is covered with cotton wool moistened with diethyl ether, the ether is evaporated, then 0.1 ml of the 2% croton oil solution is applied dropwise with a syringe and dried with a hair dryer. A plastic collar with a diameter of 16-19 mm is fitted around the head of the rat, which is placed in a cage and kept at room temperature (23-25 ° C).
10 Elke proefverbinding wordt opgelost in crotonolie en aangebracht op het oor van de rat. Daarnaast is de proefverbinding samengesteld tot een zalf (onder toepassing van een lipofiele plastische base omvattende 95% vloeibare paraffine en 5% polyetheen), en de zalf wordt na het aanbrengen van de crotonolie, grondig uitgesmeerd op het oor van de rat met een microspatel.10 Each test compound is dissolved in croton oil and applied to the rat's ear. In addition, the test compound is formulated into an ointment (using a lipophilic plastic base comprising 95% liquid paraffin and 5% polyethylene), and the ointment is thoroughly spread on the rat's ear with a microspatula after application of the croton oil.
Zes uren na de behandeling veegt men de zalf van het oor af, verdooft de rat licht met diethylether, en 15 doorboort de oorschelp van beide oren met een leertang met een diameter van 7 mm. Men weegt elk uitgeboorde gedeelte van het oor en leidt het gewicht van het uitgeboorde gedeelte van het niet behandelde linkeroor af uit het gewicht van het uitgeboorde gedeelte van het rechter oor, dat behandeld is met de crotonolie en de zalf, om het percentage van de gewichtstoename van het rechteroor te berekenen. Evenzo wordt een percentage van de onderdrukkingssnelheid berekend voor elke proefverbinding bij de toegepaste 20 concentraties, ten opzichte van een controlegroep ratten waaraan alleen crotonolie is toegediend.Six hours after the treatment, the ointment is wiped off the ear, the rat is lightly anaesthetized with diethyl ether, and pierces the auricle of both ears with 7 mm diameter leather tongs. Each drilled portion of the ear is weighed and the weight of the drilled portion of the untreated left ear is derived from the weight of the drilled portion of the right ear treated with the croton oil and ointment to determine the percentage of weight gain of the right ear. Likewise, a percentage of the suppression rate is calculated for each test compound at the concentrations used, relative to a control group of rats administered only croton oil.
De resultaten zijn weergegeven in de hierna volgende tabellen B en C, waarin ”n" het aantal ratten in elke testgroep weergeeft. De ID^, is de dosis, die 50% onderdrukking levert. (Bepaald aan de hand van een lijn, die verkregen is volgens de methode van de kleinste kwadraten.)The results are shown in Tables B and C below, in which "n" represents the number of rats in each test group. The ID 1, is the dose, which provides 50% suppression. (Determined by a line, obtained is by the least squares method.)
25 TABEL B25 TABLE B
Proeven met in crotonolie opgeloste proefverbindingenTests with test compounds dissolved in croton oil
Proefverbinding pg/oor n Gewichtstoename Onderdrukkings- ID^, pg/oor van het uitgeboorde snelheid (%) 30 gedeelte (%) 0 13 130,9 ±8,0 250 10 91,9 ±12,1 29,0 A 500 10 66,8 ±11,8 49,0 35 1.000 8 16,5 ±3,5 87,4 0 10 151,6 ±15,4 B 250 10 107,8 ±14,4 28,9 500 10 96,2 ±12,7 36,5 40 1.000 10 67,5 ±10,5 55,5 0 10 130,4 ±11,1 c 250 10 76,2 ±10,2 41,6 500 10 67,7 ± 24,0 48,1 45 1.000 10 38,9 ±14,2 70,2 0 10 130,4 ± 11,1 D 250 10 96,3 ±17,9 26,2 94? U 500 10 70,2 ± 24,1 46,2 50 1.000 10 68,4 ±10,6 47,5 0 12 111,1 ±8,7Test connection pg / ear n Weight gain Suppression ID ^, pg / ear of the cored speed (%) 30 part (%) 0 13 130.9 ± 8.0 250 10 91.9 ± 12.1 29.0 A 500 10 66.8 ± 11.8 49.0 35 1,000 8 16.5 ± 3.5 87.4 0 10 151.6 ± 15.4 B 250 10 107.8 ± 14.4 28.9 500 10 96.2 ± 12.7 36.5 40 1,000 10 67.5 ± 10.5 55.5 0 10 130.4 ± 11.1 c 250 10 76.2 ± 10.2 41.6 500 10 67.7 ± 24, 0 48.1 45 1,000 10 38.9 ± 14.2 70.2 0 10 130.4 ± 11.1 D 250 10 96.3 ± 17.9 26.2 94? U 500 10 70.2 ± 24.1 46.2 50 1,000 10 68.4 ± 10.6 47.5 0 12 111.1 ± 8.7
Indomethacin 250 10 88,4 ± 13,2 20,4 1 2Q8 (controle) 500 10 61,0 ±10,5 45,1 55 1.000 10 37,3 ± 5,6 66,4Indomethacin 250 10 88.4 ± 13.2 20.4 1 2Q8 (control) 500 10 61.0 ± 10.5 45.1 55 1,000 10 37.3 ± 5.6 66.4
TABEL CTABLE C
Proeven met tot zalf geformuleerde proefverbindingen (zalf op basis van plastibase 50W met 1% of 5% proefverbinding.) 5 Proefverbinding (n) Gewichtstoename van het Onderdrukkingssnelheid t.o.v. de uitgeboorde gedeelte (%) controleverbinding (%)Tests with ointment-formulated test compounds (plastibase 50W ointment with 1% or 5% test compound.) 5 Test Compound (s) Weight increase in Suppression Rate over the bored portion (%) control compound (%)
Crotonolie 15 129,0 ±13,8 E (1%) 15 43,8 ± 9,8 66,0 10 (5%) 15 49,4 ±7,6 61,7 B (1%) 15 58,4 ±7,2 52,1Croton oil 15 129.0 ± 13.8 E (1%) 15 43.8 ± 9.8 66.0 10 (5%) 15 49.4 ± 7.6 61.7 B (1%) 15 58.4 ± 7.2 52.1
In deze tabellen is: 15 A: 2-[4-(2-oxocyclopentaan-1-ylmethyl)fenyl]propionzuur B: 2-[4-(2-oxo-1 -cyclohexylideenmethyl)fenyl]propionzuur C: 2-pyridylmethyl-2-[4-(2-oxocyclopentaan-1 -ylmethyl)fenyl]propionaat D: 3-pyridylmethyl-2-[4-(2-oxocyclopentaan-1 -ylmethyl)fenyl]propionaat E: Natrium 2-[4-(2-oxocyclopentaan-1-ylmethyl)fenyl]propionaat 20 De bovenstaande proeven tonen duidelijk dat de in de onderhavige uitvinding toegepaste verbindingen, weergegeven door de proefverbindingen A-E, een krachtige ontstekingswerende werking vertonen, wanneer zij uitwendig worden toegediend. De verbindingen met formule 1 en hun farmaceutisch aanvaardbare zouten zijn derhalve bruikbaar als uitwendige ontstekingswerende middelen voor traumata, brandwonden, acute of chronische excemen, contact-dermatitis, zoster en andere ontstekingsziekten van de huid, veroorzaakt door 25 verschillende factoren.In these tables: 15 A: 2- [4- (2-oxocyclopentan-1-ylmethyl) phenyl] propionic acid B: 2- [4- (2-oxo-1-cyclohexylidenemethyl) phenyl] propionic acid C: 2-pyridylmethyl- 2- [4- (2-oxocyclopentane-1-ylmethyl) phenyl] propionate D: 3-pyridylmethyl-2- [4- (2-oxocyclopentane-1-ylmethyl) phenyl] propionate E: Sodium 2- [4- (2 -oxocyclopentan-1-ylmethyl) phenyl] propionate The above tests clearly show that the compounds used in the present invention, represented by the test compounds AE, exhibit potent anti-inflammatory activity when administered externally. The compounds of formula 1 and their pharmaceutically acceptable salts are therefore useful as external anti-inflammatory agents for trauma, burns, acute or chronic extremes, contact dermatitis, zoster and other inflammatory skin diseases caused by various factors.
De ontstekingswerende samenstellingen voor uitwendig gebruik volgens de uitvinding kunnen tevens één of meer farmaceutische toevoegsels bevatten die voor die bijzondere samenstelling geschikt zijn zoals verzachtende middelen, bevochtigingsmiddelen, dispergeermiddelen, emulgeermiddelen, emulsie-stabilisatoren, gelee rmiddelen, suspendeermiddelen, conserveringsmiddelen en percutane absorptie 30 bevorderende middelen. De samenstelling kan in het bijzonder bestanddelen bevatten zoals natuurlijke of synthetische oliën, wassen, vetten, paraffinen, een mengsel van zachte paraffine en zware oliën, hogere vetzuuralcoholen, wolalcoholen, hogere vetzuren, glyceriden, zepen, sorbitanesters, polysorbaten, macrogol-esters en celluloseëthers.The anti-inflammatory compositions for external use according to the invention may also contain one or more pharmaceutical additives suitable for that particular composition, such as emollients, wetting agents, dispersing agents, emulsifying agents, emulsion stabilizers, gelling agents, suspending agents, preservatives and percutaneous absorption promoting agents. . In particular, the composition may contain ingredients such as natural or synthetic oils, waxes, fats, paraffins, a mixture of soft paraffin and heavy oils, higher fatty alcohols, wool alcohols, higher fatty acids, glycerides, soaps, sorbitan esters, polysorbates, macrogol esters and cellulose ethers .
De samenstellingen volgens de uitvinding bezitten de vorm van crèmes, zalven, lotions, smeersels of 35 pleisters. Kenmerkende bestanddelen voor dergelijke formuleringen worden hierna gegeven. In elk geval kan de formulering op geschikte wijze 0,1-10% , bij vootkeur 1-5% van het werkzame bestanddeel met formule 1 of het famnaceutisch aanvaardbare zout daarvan (berekend op een gewicht/gewicht of gewicht/ volume-basis) bevatten. Water in olie-emulsies vormen de samenstelling die verreweg de voorkeur verdient, en die bij voorkeur het natriumzout of een organisch amine (bijvoorbeeld triethanolamine of benzylamine)-40 zout van de verbinding met formule 1 bevat.The compositions of the invention are in the form of creams, ointments, lotions, spreads or patches. Typical ingredients for such formulations are given below. In any case, the formulation may suitably contain 0.1-10%, preferably 1-5% of the active ingredient of Formula 1 or its pharmaceutically acceptable salt (calculated on a weight / weight or weight / volume basis) . Water in oil emulsions form the most preferred composition, which preferably contains the sodium salt or an organic amine (e.g. triethanolamine or benzylamine) -40 salt of the compound of formula 1.
Bestanddelen voor olieachtige zalvenIngredients for oily ointments
Oliën en wassen: olijfolie, amandelolie, ricinusolie, sesamolie, katoenzaadolie, palmolie, arachideolie, pindaolie, lanoline, ceresien, bijenwas, camaubawas, spermaceti, miciokristallijne was, paraffine (vast en 45 vloeibaar), squalaan, squaleen, mengsel van zachte paraffine en zware oliën.Oils and waxes: olive oil, almond oil, castor oil, sesame oil, cottonseed oil, palm oil, peanut oil, peanut oil, lanolin, ceresien, beeswax, camauba wax, spermaceti, microcrystalline wax, paraffin (solid and 45 liquid), squalane, squalene, soft paraffin mixture heavy oils.
Vetzuren: stearinezuur, palmitinezuur, myristinezuur.Fatty acids: stearic acid, palmitic acid, myristic acid.
Alcoholen: stearylalcohol, cetylalcohol, oleyalcohol.Alcohols: stearyl alcohol, cetyl alcohol, oley alcohol.
Andere verbindingen: ’’Plastibase” (polyetheen gedispergeerd in vloeibare paraffine).Other compounds: "Plastibase" (polyethylene dispersed in liquid paraffin).
Olie-in-water lotion 50 Minerale olie 20%Oil-in-water lotion 50 Mineral oil 20%
Cetylalcohol 2%Cetyl alcohol 2%
Mengsel van zachte paraffine en zware oliën 5%Mixture of soft paraffin and heavy oils 5%
Glycerylmonostearaat 3%Glyceryl monostearate 3%
Polysorbaat 60 7% 55 Water 63%Polysorbate 60 7% 55 Water 63%
Conserveringsmiddelen q.s.Preservatives q.s.
Bestanddelen voor in water oplosbare preparaten voor lotions a) op basis van macrogolIngredients for water-soluble lotions a) based on macrogol
Macrogol 4,000 55%Macrogol 4,000 55%
Macrogol 400 35% 5 Glycerol 10% b) Op basis van een gel 1. "Carbopol 940” (carboxylvinyl polymeer) 1,0%Macrogol 400 35% 5 Glycerol 10% b) Based on a gel 1. "Carbopol 940" (carboxyl vinyl polymer) 1.0%
Hydroxethylcellulose 1,0%Hydroxethyl cellulose 1.0%
Macrogol 300 10% 10 Ethanol 30%Macrogol 300 10% 10 Ethanol 30%
Diisopropyladipaat 20%Diisopropyladipate 20%
Diisopropanolamine 1,1%Diisopropanolamine 1.1%
Water tot 100% 2. ’’Carbopol 940” (carboxyvinyl polymeer) 0,4% 15 Ethyleenoxide oleylalcohol ether 2,5% ’’Polyox” hars WSR N-3000 (methylcellulose en ethyleenoxide copoly- 0,2% meer) ”Ucon 50H B660” vloeistof 10% PVP 1,5% 20 Glycerol 5%Water up to 100% 2. "Carbopol 940" (carboxyvinyl polymer) 0.4% 15 Ethylene oxide oleyl alcohol ether 2.5% "Polyox" resin WSR N-3000 (methyl cellulose and ethylene oxide copoly- 0.2% more) "Ucon 50H B660 ”liquid 10% PVP 1.5% 20 Glycerol 5%
Diisopropanolamine (10%) 3%Diisopropanolamine (10%) 3%
Water tot 100%Water up to 100%
De bovengenoemde samenstellingen kunnen eveneens percutane absorptie bevorderende middelen 25 bevatten, zoals dimethylsulfoxide, propylgallaat, diisopropyladipaat, diethylsebacaat en ethylcaproaat.The above compositions may also contain percutaneous absorption enhancers such as dimethyl sulfoxide, propyl gallate, diisopropyl adipate, diethyl sebacate and ethyl caproate.
De uitvinding wordt nader toegelicht door de hierna volgende niet beperkende voorbeelden. De voorbeelden l-V beschrijven de bereiding van verbindingen met formule 1. De voorbeelden VI-IX tonen enkele kenmerkende farmaceutische samenstellingen volgens de uitvinding die de kenmerkende verbindingen met formule 1 bevatten. De in deze voorbeelden toegepaste verbindingen A, B en D zijn aangeduid met 30 dezelfde letters die zijn toegepast bij de hierboven beschreven farmacologische proeven.The invention is further illustrated by the following non-limiting examples. Examples 1-V describe the preparation of compounds of formula 1. Examples VI-IX show some typical pharmaceutical compositions of the invention containing the typical compounds of formula 1. The compounds A, B and D used in these examples are designated by the same letters used in the pharmacological tests described above.
Voorbeeld IExample I
2-Pyridylmethyl 2-[4-(2-oxocyclopentaan-1 -ylmethyl)fenyl]propionaat2-Pyridylmethyl 2- [4- (2-oxocyclopentane-1-ylmethyl) phenyl] propionate
Men laat een mengsel van 4,93 g (2-[4-(2-oxycyclopentaan-1-ylmethyl)fenyl]propionzuur, 4,8 g thionyl-35 chloride en 40 ml benzeen reageren door 2 uren koken onder terugvloeikoeling. Na afloop van de reactie verwijdert men het oplosmiddel en de thionylchloride door destillatie onder verminderde druk. Aan het verkregen residu voegt men 40 ml tetrahydrofuran én 3,3 g 2-pyridinemethanol toe en daarna, onder koelen met ijs, 3,0 g triethylamine, en roert het mengsel 2 uren bij kamertemperatuur. Na afloop van de reactie verwijdert men het oplosmiddel door destillatie onder verminderde druk. Aan het verkregen residu voegt 40 men water toe en extraheert het mengsel met ethylacetaat. De ethylacetaatlaag wast men met achtereenvolgens een 5%’s waterige natriumcarbonaatoplossing en water en droogt boven natriumsulfaat.A mixture of 4.93 g of 2- (4- (2-oxycyclopentan-1-ylmethyl) phenyl] propionic acid, 4.8 g of thionyl-35 chloride and 40 ml of benzene is reacted by refluxing for 2 hours. from the reaction, the solvent and thionyl chloride are removed by distillation under reduced pressure: 40 ml of tetrahydrofuran and 3.3 g of 2-pyridine methanol are added to the residue obtained, then 3.0 g of triethylamine, while cooling with ice, are stirred the mixture at room temperature for 2 hours After the reaction is complete, the solvent is removed by distillation under reduced pressure, 40 are added to the residue obtained and water is extracted, and the mixture is extracted with ethyl acetate, the ethyl acetate layer is washed successively with a 5% aqueous sodium carbonate solution and water and dries over sodium sulfate.
Nadat het oplosmiddel door destillatie is verwijderd zuivert men het verkregen residu door destillatie onder verminderde druk bij 230-235°C/0,3 mm kwik (badtemperatuur), ter verkrijging van 2,0 g van de gewenste verbinding.After the solvent is removed by distillation, the resulting residue is purified by distillation under reduced pressure at 230-235 ° C / 0.3 mm mercury (bath temperature), to obtain 2.0 g of the desired compound.
45 Massa spectrum: M+ = 337 Elementair analyse:45 Mass spectrum: M + = 337 Elemental analysis:
Berekend voor C21H2303N: C, 74,75; H, 6,87, N, 4,15%Calculated for C21 H2303N: C, 74.75; H, 6.87, N, 4.15%
Gevonden: C, 74,63; H, 6,91; N, 4,11%Found: C, 74.63; H, 6.91; N, 4.11%
50 Voorbeeld II50 Example II
3‘Pyridylmethyl 2-[4-(2-oxocyclopentaan-1 -ylmethyl)fenyl]propionaat3 "Pyridylmethyl 2- [4- (2-oxocyclopentane-1-ylmethyl) phenyl] propionate
Men kookt een mengsel van 4,93 g 2-[4-(2-oxocydopentaan-1-ylmethyl)-fenyl]propionzuur, 4,8 g thionylchloride en 40 ml benzeen 2 uren onder terugvloeikoeling.A mixture of 4.93 g of 2- [4- (2-oxocydopentan-1-ylmethyl) -phenyl] propionic acid, 4.8 g of thionyl chloride and 40 ml of benzene is refluxed for 2 hours.
Na afkoeling verwijdert men het oplosmiddel en het thionylchloride door destillatie. Aan het verkregen 55 residu voegt men 40 ml tetrahydrofuran en 3,3 g 3-pyridinemethanol toe en daarna, onder koelen met ijs, 3,0 g triethylamine, en roert het mengsel 2 uren bij kamertemperatuur. Na afloop van de reactie verwijdert men het oplosmiddel door destillatie onder verminderde druk. Men voegt aan het verkregen residu water toe en extraheert het mengsel daarna met ethylacetaat. De ethylacetaatlaag wast men met achtereenvolgens een 5%’s waterige natriumcarbonaatoplossing en water en droogt daarna boven natriumsulfaat.After cooling, the solvent and thionyl chloride are removed by distillation. To the resulting 55 residue, 40 ml of tetrahydrofuran and 3.3 g of 3-pyridine methanol are added and then, under ice-cooling, 3.0 g of triethylamine, and the mixture is stirred at room temperature for 2 hours. After the reaction is complete, the solvent is removed by distillation under reduced pressure. Water is added to the resulting residue and the mixture is then extracted with ethyl acetate. The ethyl acetate layer is washed successively with 5% aqueous sodium carbonate solution and water and then dried over sodium sulfate.
Men verwijdert het oplosmiddel door destillatie en zuivert het verkregen residu door destillatie onder verminderde druk bij 215-220°C/0,3 mm kwik (badtemperatuur) ter vorming van 1,8 g van de gewenste 5 veifoinding.The solvent is removed by distillation and the resulting residue is purified by distillation under reduced pressure at 215-220 ° C / 0.3 mm Hg (bath temperature) to give 1.8 g of the desired vein.
Massa spectrum: M+ = 337 Elementair analyse:Mass spectrum: M + = 337 Elemental analysis:
Berekend voor C21H2303N: C, 74,75; H, 6,87; N, 4,15%Calculated for C21 H2303N: C, 74.75; H, 6.87; N, 4.15%
Gevonden: C, 74,59; H, 6,81; N, 4,06% 10Found: C, 74.59; H, 6.81; N, 4.06% 10
Voorbeeld IIIExample III
4-Pyridylmethyl 2-[4-(2-oxocyclopentaan- 1-ylmethyl)fenyl]propionaat . Aan een oplossing van 4,93 g 2-[4-(2-oxocydopentaan-1 -ylmethyl)-fenyl]propionzuur en 3,3 g 4-pyridinemethanol in 50 ml tetrahydrofuran voegt men 4,3 g dicyclohexylcaibodiimide toe. Na 5 uren roeren 15 bij kamertemperatuur voegt men aan het mengsel een kleine hoeveelheid azijnzuur toe en verwijdert het onoplosbare ureum door filtratie. Men voegt ethylacetaat toe aan het fikraat en wast het mengsel met water en droogt boven natriumsulfaat. Na verwijderen van het oplosmiddel verkrijgt men een olieachtige stof, cüe men zuivert door destillatie onder verminderde druk bij 225-233°C/0,2 mm kwik (badtemperatuur), ter vorming van 1,8 g van de gewenste verbinding.4-Pyridylmethyl 2- [4- (2-oxocyclopentan-1-ylmethyl) phenyl] propionate. 4.3 g of dicyclohexyl caibodiimide are added to a solution of 4.93 g of 2- [4- (2-oxocydopentane-1-ylmethyl) -phenyl] propionic acid and 3.3 g of 4-pyridine methanol in 50 ml of tetrahydrofuran. After stirring for 5 hours at room temperature, a small amount of acetic acid is added to the mixture and the insoluble urea is removed by filtration. Ethyl acetate is added to the filtrate and the mixture is washed with water and dried over sodium sulfate. After removal of the solvent, an oily substance is obtained, purified by distillation under reduced pressure at 225-233 ° C / 0.2 mm mercury (bath temperature), to form 1.8 g of the desired compound.
20 Massa spectrum: M+ = 337 Elementair analyse:20 Mass spectrum: M + = 337 Elemental analysis:
Berekend voor C21H2303N: C, 74,75; H, 6,87; N, 4,15%Calculated for C21 H2303N: C, 74.75; H, 6.87; N, 4.15%
Gevonden C, 74,55; H, 6,80; N, 4,23%Found C, 74.55; H, 6.80; N, 4.23%
25 Voorbeeld IVExample IV
2-Pyridylmethyl 2-[4-(2-oxo-1-cyclohexylideenmethyl)fenyl]propionaat2-Pyridylmethyl 2- [4- (2-oxo-1-cyclohexylidenemethyl) phenyl] propionate
Aan een oplossing van 2,58 g 2-[4-(2-oxo-1-cyclohexylideenmethyl)-fenyl]propionzuur in 50 ml tetrahydrofuran voegt men, onder koelen met ijs, 2,62 g trifenylfosfine en 2,2 g pyridinesulfide toe en roert het mengsel 30 minuten bij kamertemperatuur. Aan het mengsel voegt men een oplossing van 2,73 g 30 2-pyridinemethanol in 5 ml tetrahydrofuran toe en kookt het verkregen mengsel 3 uren onder terugvloei-koeling.To a solution of 2.58 g of 2- [4- (2-oxo-1-cyclohexylidenemethyl) -phenyl] propionic acid in 50 ml of tetrahydrofuran, 2.62 g of triphenylphosphine and 2.2 g of pyridine sulfide are added, while cooling with ice. and stir the mixture at room temperature for 30 minutes. A solution of 2.73 g of 2-pyridine methanol in 5 ml of tetrahydrofuran is added to the mixture and the resulting mixture is refluxed for 3 hours.
Na afkoeling giet men het mengsel uit in ijswater en extraheert met ethylacetaat. Het extract wast men met water en droogt boven natriumsulfaat. Men verwijdert het oplosmiddel door destillatie en zuivert het residu door silicagel kolomchromatografie waarbij men 1,71 g van een lichtgele olie verkrijgt.After cooling, the mixture is poured into ice water and extracted with ethyl acetate. The extract is washed with water and dried over sodium sulfate. The solvent is removed by distillation and the residue is purified by silica gel column chromatography to obtain 1.71 g of a pale yellow oil.
35 Massa spectrum: M+ = 349 Elementair analyse:35 Mass spectrum: M + = 349 Elemental analysis:
Berekend voor C^H^OgN: C, 75,62; H, 6,63; N, 4,01%Calcd for C 1 H 21 OgN: C, 75.62; H, 6.63; N, 4.01%
Gevonden: C, 75,57; H, 6,75; N, 4,20%Found: C, 75.57; H, 6.75; N, 4.20%
40 Voorbeeld V40 Example V
Methyl 2-[4-(2-oxocyclopentaan-1 -ylmethyl)fenyl]propionaatMethyl 2- [4- (2-oxocyclopentane-1-ylmethyl) phenyl] propionate
Men laat een mengsel van 5,0 g 2-[4-(2-oxocydopentaan-1 -ylmethyl)-fenyl)propionzuur, 50 ml methanol en 1,0 g geconcentreerd zwavelzuur 6 uren reageren door koken onder terugvloeikoeling. Na afloop van de reactie verwijdert men de overmaat methanol door destillatie onder verminderde druk. Men voegt aan het 45 residu water toe en extraheert het mengsel met diethylether. De diethyletheriaag wast men achtereenvolgens met water, een 5%’s waterige natriumcarbonaatoplossing en water. Na drogen verwijdert men de diethylether door afdampen. Men zuivert het verkregen residu door destillatie onder verminderde druk bij 195-200°C/0,1 mm kwik (badtemperatuur) waarbij men 4,8 g van de gewenste verbinding verkrijgt in de vorm van een kleurloze olie.A mixture of 5.0 g of 2- [4- (2-oxocydopentane-1-ylmethyl) -phenyl) propionic acid, 50 ml of methanol and 1.0 g of concentrated sulfuric acid is reacted for 6 hours under reflux. At the end of the reaction, the excess methanol is removed by distillation under reduced pressure. Water is added to the 45 residue and the mixture is extracted with diethyl ether. The diethyl ether layer is washed successively with water, a 5% aqueous sodium carbonate solution and water. After drying, the diethyl ether is removed by evaporation. The residue obtained is purified by distillation under reduced pressure at 195-200 ° C / 0.1 mm mercury (bath temperature), whereby 4.8 g of the desired compound are obtained in the form of a colorless oil.
50 Massa spectrum: M+ = 26050 Mass spectrum: M + = 260
Voorbeeld VI 1% ZalfExample VI 1% Ointment
Verbinding A 0,3 g 55 ’’Plastibase 50 W” (5% polyethyleen gedispergeerd in 95% vloeibare paraffine) 29,7 gCompound A 0.3 g 55 "Plastibase 50 W" (5% polyethylene dispersed in 95% liquid paraffin) 29.7 g
Claims (9)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7732180 | 1980-06-09 | ||
| JP7732180A JPS574919A (en) | 1980-06-09 | 1980-06-09 | Anti-inflammatory for external use |
| JP14525180 | 1980-10-17 | ||
| JP14525180A JPS5770867A (en) | 1980-10-17 | 1980-10-17 | Phenylacetic ester derivative |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NL8102775A NL8102775A (en) | 1982-01-04 |
| NL192371B NL192371B (en) | 1997-03-03 |
| NL192371C true NL192371C (en) | 1997-07-04 |
Family
ID=26418416
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8102775A NL192371C (en) | 1980-06-09 | 1981-06-09 | Anti-inflammatory agents for external use, as well as compounds suitable for use in such a composition. |
Country Status (8)
| Country | Link |
|---|---|
| CA (1) | CA1169776A (en) |
| CH (1) | CH645539A5 (en) |
| DE (1) | DE3122791A1 (en) |
| FR (1) | FR2483918B1 (en) |
| GB (1) | GB2078732B (en) |
| IT (1) | IT1193734B (en) |
| NL (1) | NL192371C (en) |
| SE (1) | SE8103598L (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6038323A (en) * | 1983-08-10 | 1985-02-27 | Sankyo Co Ltd | Ophthalmic anti-inflammatory agent |
| US5620980A (en) * | 1995-02-22 | 1997-04-15 | Macrochem Corporation | Method for treating hair loss |
| CN109020808B (en) * | 2017-06-12 | 2021-07-06 | 浙江九洲药业股份有限公司 | Preparation method of substituted phenylacetic acid derivative |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4161538A (en) * | 1977-04-05 | 1979-07-17 | Sankyo Company Limited | Substituted phenylacetic acid derivatives and process for the preparation thereof |
| JPS5432460A (en) * | 1977-08-16 | 1979-03-09 | Sankyo Co Ltd | Cycloalkylidenemethylphenylacetic acid derivative and their preparation |
| DE2804051A1 (en) * | 1978-01-27 | 1979-08-09 | Schering Ag | 4-Cycloalkyl:methyl-phenyl-acetic acid derivs. - useful as antiinflammatories e.g. for treating arthritis |
| DD141422A5 (en) * | 1978-01-27 | 1980-04-30 | Schering Ag | PROCESS FOR THE PREPARATION OF PHENYL ACID DERIVATIVES |
-
1981
- 1981-06-03 CH CH364581A patent/CH645539A5/en not_active IP Right Cessation
- 1981-06-08 CA CA000379199A patent/CA1169776A/en not_active Expired
- 1981-06-08 IT IT67784/81A patent/IT1193734B/en active
- 1981-06-09 DE DE19813122791 patent/DE3122791A1/en active Granted
- 1981-06-09 GB GB8117684A patent/GB2078732B/en not_active Expired
- 1981-06-09 FR FR8111293A patent/FR2483918B1/en not_active Expired
- 1981-06-09 NL NL8102775A patent/NL192371C/en not_active IP Right Cessation
- 1981-06-09 SE SE8103598A patent/SE8103598L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DE3122791C2 (en) | 1992-08-13 |
| GB2078732A (en) | 1982-01-13 |
| CA1169776A (en) | 1984-06-26 |
| SE8103598L (en) | 1981-12-10 |
| CH645539A5 (en) | 1984-10-15 |
| GB2078732B (en) | 1984-02-15 |
| NL192371B (en) | 1997-03-03 |
| FR2483918A1 (en) | 1981-12-11 |
| DE3122791A1 (en) | 1982-05-06 |
| FR2483918B1 (en) | 1988-05-27 |
| NL8102775A (en) | 1982-01-04 |
| IT8167784A0 (en) | 1981-06-08 |
| IT1193734B (en) | 1988-08-24 |
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