NO159952B - HINGE. - Google Patents
HINGE. Download PDFInfo
- Publication number
- NO159952B NO159952B NO851610A NO851610A NO159952B NO 159952 B NO159952 B NO 159952B NO 851610 A NO851610 A NO 851610A NO 851610 A NO851610 A NO 851610A NO 159952 B NO159952 B NO 159952B
- Authority
- NO
- Norway
- Prior art keywords
- compounds
- mixture
- deoxy
- chloro
- hydroxybutazolidine
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 14
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 13
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 claims description 10
- -1 alkali metal salt Chemical class 0.000 claims description 7
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 6
- 229960004889 salicylic acid Drugs 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 150000008195 galaktosides Chemical class 0.000 claims description 5
- 229960001047 methyl salicylate Drugs 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical group OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229930182830 galactose Natural products 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000007858 starting material Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- OHVUCGNZTHLHRV-DUNLUGFTSA-N C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.ClC1(O)[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@H](O1)CO Chemical compound C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.ClC1(O)[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@H](O1)CO OHVUCGNZTHLHRV-DUNLUGFTSA-N 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- OHVUCGNZTHLHRV-HOHSTTGASA-N C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.ClC1(O)[C@H](NC(C)=O)[C@@H](O)[C@@H](O)[C@H](O1)CO Chemical compound C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.ClC1(O)[C@H](NC(C)=O)[C@@H](O)[C@@H](O)[C@H](O1)CO OHVUCGNZTHLHRV-HOHSTTGASA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- CBOJBBMQJBVCMW-BTVCFUMJSA-N (2r,3r,4s,5r)-2-amino-3,4,5,6-tetrahydroxyhexanal;hydrochloride Chemical compound Cl.O=C[C@H](N)[C@@H](O)[C@H](O)[C@H](O)CO CBOJBBMQJBVCMW-BTVCFUMJSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 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
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 2
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 2
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960001911 glucosamine hydrochloride Drugs 0.000 description 2
- 229930182478 glucoside Natural products 0.000 description 2
- 150000008131 glucosides Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 229950006780 n-acetylglucosamine Drugs 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- OMCPOTIMXFSZFU-UHFFFAOYSA-N (2-methoxycarbonylphenyl) 2-methoxybenzoate Chemical compound COC(=O)C1=CC=CC=C1OC(=O)C1=CC=CC=C1OC OMCPOTIMXFSZFU-UHFFFAOYSA-N 0.000 description 1
- CBOJBBMQJBVCMW-NQZVPSPJSA-N (2r,3r,4r,5r)-2-amino-3,4,5,6-tetrahydroxyhexanal;hydrochloride Chemical compound Cl.O=C[C@H](N)[C@@H](O)[C@@H](O)[C@H](O)CO CBOJBBMQJBVCMW-NQZVPSPJSA-N 0.000 description 1
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 102000011759 adducin Human genes 0.000 description 1
- 108010076723 adducin Proteins 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960003671 mercuric iodide Drugs 0.000 description 1
- YFDLHELOZYVNJE-UHFFFAOYSA-L mercury diiodide Chemical compound I[Hg]I YFDLHELOZYVNJE-UHFFFAOYSA-L 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical class O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- E—FIXED CONSTRUCTIONS
- E05—LOCKS; KEYS; WINDOW OR DOOR FITTINGS; SAFES
- E05D—HINGES OR SUSPENSION DEVICES FOR DOORS, WINDOWS OR WINGS
- E05D7/00—Hinges or pivots of special construction
- E05D7/12—Hinges or pivots of special construction to allow easy detachment of the hinge from the wing or the frame
Landscapes
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Hinges (AREA)
- Vehicle Step Arrangements And Article Storage (AREA)
Description
Fremgangsmåte ved fremstilling av terapeutisk virksomme 2'-alkanoylamido-2'-deoxy-glucosider og -galactosider av hydroxybutazolidin eller av salicylsyre. Process for the production of therapeutically effective 2'-alkanoylamido-2'-deoxy-glucosides and galactosides of hydroxybutazolidine or of salicylic acid.
Foreliggende oppfinnelse angår en fremgangsmåte ved fremstilling av anti-inflamma-torisk virksomme 2'-alkanoyl-amido-2'-deoxy-glucosider og de 4'-epimere derav, nemlig 2-alkanoylamido-2'-deoxy-galactosider, av salicylsyre og dens alkalimetallsalter eller av hydroxybutazolidin. Forbindelsene som fremstilles ved fremgangsmåten ifølge oppfinnelsen, har terapeutisk aktivitet som er karakteristisk for ut-gangsforbindelsene og er særlig interessante på The present invention relates to a method for the production of anti-inflammatory active 2'-alkanoyl-amido-2'-deoxy-glucosides and their 4'-epimers, namely 2-alkanoylamido-2'-deoxy-galactosides, of salicylic acid and its alkali metal salts or of hydroxybutazolidine. The compounds produced by the method according to the invention have therapeutic activity that is characteristic of the starting compounds and are particularly interesting for
grunn av deres forsinkede absorbsjon og derav due to their delayed absorption and hence
følgende forlengede virkning ved oral administrering. following prolonged effect by oral administration.
De nye forbindelser som fremstilles etter The new compounds that are produced after
fremgangsmåten ifølge oppfinnelsen, kan representeres ved formelen: the method according to the invention can be represented by the formula:
hvor R betegner en alkylgruppe inneholdende 1—4 carbonatomer, og Z betegner et radikal dannet ved å fjerne hydroxylgruppen fra salicylsyre eller et alkalimetallsalt av denne, for-trinsvis natriumsaltet, eller fra hydroxybutazo- where R denotes an alkyl group containing 1-4 carbon atoms, and Z denotes a radical formed by removing the hydroxyl group from salicylic acid or an alkali metal salt thereof, preferably the sodium salt, or from hydroxybutazo
lidin [4-butyl-l-(4-hydroxyfenyl)-2-fenyl-3,5-pyrazolidindion-1,2]. lidine [4-butyl-1-(4-hydroxyphenyl)-2-phenyl-3,5-pyrazolidinedione-1,2].
Fremgangsmåten ved fremstilling av de nye forbindelser utmerker seg ved at en 2-lavere-alkanoylamido-3,4,6-tri-0-acyl-l-klor-2-deoxy-a-D-glucose eller den tilsvarende galactose omsettes med hydroxybutazolidin eller med methylsalicylat, idet de tre acylgrupper i glucose-eller galactosedelen av den erholdte forbindelse deretter fjernes hydrolytisk, og — dersom methylsalicylat er anvendt — at den således erholdte forbindelse om ønskes overføres til et alkalimetallsalt. The procedure for the preparation of the new compounds is distinguished by the fact that a 2-lower-alkanoylamido-3,4,6-tri-0-acyl-1-chloro-2-deoxy-α-D-glucose or the corresponding galactose is reacted with hydroxybutazolidine or with methyl salicylate, the three acyl groups in the glucose or galactose part of the compound obtained are then hydrolytically removed, and — if methyl salicylate is used — that the compound thus obtained is, if desired, transferred to an alkali metal salt.
De mest hensiktsmessige trialcylforbindel-ser er O-triacetatene, og reaksjonen vil bli beskrevet for anvendelse av disse forbindelser som i det følgende vil bli referert til som 1-klor-N-acetylglucosamin-triacetat og 1-klor-N-acetyl-galactosamin-triacetat. Produktene som dannes ved denne reaksjon, er 3', 4', 6'-tri-0-acetyl-(3-D-2'-acetamido-2'-deoxy-glucosider og galactosider av den som utgangsmateriale anvendte hydroxyforbindelse. O-acetyl-gruppene fjernes deretter ved hydrolyse. The most suitable triacyl compounds are the O-triacetates, and the reaction will be described for the use of these compounds which will be referred to in the following as 1-chloro-N-acetylglucosamine-triacetate and 1-chloro-N-acetyl-galactosamine- triacetate. The products formed by this reaction are 3', 4', 6'-tri-0-acetyl-(3-D-2'-acetamido-2'-deoxy-glucosides and galactosides of the hydroxy compound used as starting material. O- the acetyl groups are then removed by hydrolysis.
De reaksjoner som utnyttes ved fremstillingen av glucosider, kan representeres som føl-ger: The reactions used in the production of glucosides can be represented as follows:
I disse formler betegner Y acyl, og Z har de ovenfor angitte betydninger. In these formulas, Y denotes acyl, and Z has the meanings given above.
O-triacetat-derivatene fremstilles på hensiktsmessig måte ved å omsette utgangsforbindelsen med 1-klor-N-acetylglucosamin-triacetat eller 1-klor-N-acetyl-galactosamin-triacetat i et inert organisk oppløsningsmiddel eller en oppløs-ningsmiddelblanding i nærvær av et dehydro-halogenerings-fremmende middel såsom mercu-ricyanid, mercurijodid eller sølvkarbonat og oppvarme ved forhøyet temperatur, fortrinnsvis i en inert atmosfære. Produktet separeres fra reaksjonsblandingen og kan renses ved kromatografering på aluminiumoxyd. The O-triacetate derivatives are conveniently prepared by reacting the starting compound with 1-chloro-N-acetylglucosamine-triacetate or 1-chloro-N-acetyl-galactosamine-triacetate in an inert organic solvent or a solvent mixture in the presence of a dehydro -halogenation-promoting agent such as mercuricyanide, mercuric iodide or silver carbonate and heating at an elevated temperature, preferably in an inert atmosphere. The product is separated from the reaction mixture and can be purified by chromatography on aluminum oxide.
Hydrolysereaksjonen, som fortrinnsvis full-føres i en inert atmosfære, utføres på hensiktsmessig måte ved at man tar opp O-triacetat-derivatene i en lavere alkohol såsom methanol inneholdende et metallalkoholat såsom natrium-methoxyd og holder blandingen ved romtemperatur i et tidsrom fra 10 minutter til 1 time. Produktet isoleres etter en hvilken som helst hensiktsmessig metode. Eksempelvis kan blandingen gjøres nøytral med en lavere al-kansyre og deretter tilsettes vann. og kjøles. Produktet som utskilles ved kjøling, er vanlig-vis krystallinsk og separeres ved filtrering. The hydrolysis reaction, which is preferably carried out in an inert atmosphere, is conveniently carried out by taking up the O-triacetate derivatives in a lower alcohol such as methanol containing a metal alcoholate such as sodium methoxide and keeping the mixture at room temperature for a period of 10 minutes to 1 hour. The product is isolated by any suitable method. For example, the mixture can be made neutral with a lower alkanoic acid and then water is added. and cooled. The product that separates on cooling is usually crystalline and is separated by filtration.
For fremstillingen av derivatet av salicylsyre eller dens natriumsalt er den foretruk-ne utgangsforbindelse o-carbomethoxy-fenol (methylsalicylat). Ved hydrolyse med natrium-methoxyd dannes natriumsaltet av gluco-sidet. Saltene overføres til syrer ved behand-ling med fortynnet syre, hensiktsmessig en mi-neralsyre såsom saltsyre. For the preparation of the derivative of salicylic acid or its sodium salt, the preferred starting compound is o-carbomethoxy-phenol (methyl salicylate). On hydrolysis with sodium methoxide, the sodium salt of the glucoside is formed. The salts are transferred to acids by treatment with dilute acid, suitably a mineral acid such as hydrochloric acid.
Etter disse fremgangsmåter fåes 2'-alkano-yl-amido-2'-deoxy-glucosider og -galactosider, f. eks. 2'-acetamido-2'-deoxy-glucosider og -galactosider av salicylsyre og hydroxybutazolidin. Following these procedures, 2'-alkano-yl-amido-2'-deoxy-glucosides and -galactosides are obtained, e.g. 2'-acetamido-2'-deoxy-glucosides and -galactosides of salicylic acid and hydroxybutazolidine.
De nye forbindelser som fremstilles etter fremgangsmåten ifølge oppfinnelsen, er sta-bile og har antiinflammatorisk virkning som er karakteristisk for de som utgangsmaterialer anvendte forbindelser, men oppveier sterkt min-skede uønskede bivirkninger. De administreres normalt i opprettholdte, daglige doser som kan sammenlignes med de doser som anvendes av utgangsforbindelsen. Eksempelvis er den daglige dose for butazolidin-derivatenes ved-kommende omtrent 300—600 mg, mens den for aspirin er omtrent 1—3 g pr. dag. På grunn av deres forsinkede absorpsjon kan de administreres i vesentlig høyere doser uten at der opp-står risiko for bivirkninger. The new compounds produced according to the method according to the invention are stable and have an anti-inflammatory effect which is characteristic of the compounds used as starting materials, but outweighs the greatly reduced unwanted side effects. They are normally administered in sustained, daily doses comparable to the doses used by the parent compound. For example, the daily dose for the butazolidine derivatives is approximately 300-600 mg, while for aspirin it is approximately 1-3 g per day. Due to their delayed absorption, they can be administered in significantly higher doses without the risk of side effects arising.
Forbindelsene fremstilt etter fremgangsmåten ifølge oppfinnelsen kan administreres alene eller sammen med en i farmasøytisk henseende aksepterbar bærer. Valget av bærer vil avhenge av den valgte administreringsmåte og vanlig farmasøytisk praksis. For oral administrering kan forbindelsene gis i form av tabletter som inneholder fyllstoffer såsom stivelse eller melke-sukker. Vandige oppløsninger såsom eliksirer som kan tilsettes smaksstoffer, kan også anvendes. For parenteral anvendelse kan der benyttes iso-toniske blandinger i pyrogenfritt vann. The compounds prepared according to the method according to the invention can be administered alone or together with a pharmaceutically acceptable carrier. The choice of carrier will depend on the chosen mode of administration and usual pharmaceutical practice. For oral administration, the compounds can be given in the form of tablets containing fillers such as starch or milk sugar. Aqueous solutions such as elixirs to which flavoring substances can be added can also be used. For parenteral use, isotonic mixtures in pyrogen-free water can be used.
1-klor-N-acetylglucosamin-triacetat som anvendes som utgangsmateriale ved fremstillingen av de nye forbindelser, fremstilles etter den følgende fremgangsmåte. 1-Chloro-N-acetylglucosamine triacetate, which is used as starting material in the preparation of the new compounds, is prepared according to the following procedure.
En oppløsning av 23 g rent natrium i 1000 ml methanol anvendes 10 like porsjoner som beskrevet nedenfor: 21,5 g glucosamin-hydroklorid og en 100 ml's porsjon av den ovennevnte oppløsning, hvirvles rundt i en 250 ml Erlenmeyer-kolbe i nøyaktig 70 sekunder. Natriumkloridet som utskilles, fjernes ved filtrering under trykk gjen-nom en trakt av sintret glass stukket ned i en 2 liters rundkolbe. Denne operasjon utføres ytterligere ni ganger, og den totale filterkake vaskes med 100 ml methanol. Det totale filtrat i kolben behandles under nitrogenatmosfære med 153 g eddiksyreanhydrid og oppvarmes en kort tid. Oppløsningen omrøres deretter i omtrent 15 timer, hvorunder N-acetyl-glucosami-net utfelles i omtrent 70 pst. utbytte. Det separeres ved filtrering, vaskes grundig med methanol og tørres til konstant vekt. Smeltepunkt 202—204°C. A solution of 23 g of pure sodium in 1000 ml of methanol is used in 10 equal portions as described below: 21.5 g of glucosamine hydrochloride and a 100 ml portion of the above solution are swirled around in a 250 ml Erlenmeyer flask for exactly 70 seconds. The sodium chloride that is secreted is removed by filtration under pressure through a sintered glass funnel inserted into a 2 liter round flask. This operation is carried out a further nine times, and the total filter cake is washed with 100 ml of methanol. The total filtrate in the flask is treated under a nitrogen atmosphere with 153 g of acetic anhydride and heated for a short time. The solution is then stirred for approximately 15 hours, during which the N-acetyl-glucosamine is precipitated in approximately 70 percent yield. It is separated by filtration, washed thoroughly with methanol and dried to constant weight. Melting point 202-204°C.
Dette produkt overføres til 1-klor-O-tri-acetatderivatet etter den følgende fremgangsmåte. This product is transferred to the 1-chloro-O-tri-acetate derivative according to the following procedure.
En suspensjon av 25 g N-acetylglucosamin og 70 ml acetylklorid omrøres under nitrogenatmosfære i 10 minutter. På dette tidspunkt tilsettes der 1 ml eddiksyre mettet med HCl-gass (ved 0°C). Etter 15 minutter begynner blandingen å koke, og den får stå å koke forsiktig med tilbakeløpskjøling. Etter 2 timer er alt mate-riale oppløst og der er dannet en gulbrun opp-løsning. Blandingen omrøres deretter i omtrent 15 timer. Det tilsettes 500 ml kloroform, og blandingen helles over på et kilo is og omrøres i 3 minutter. (Resten av denne fremgangsmåte bør utføres så raskt som mulig for å oppnå størt mulig utbytte). Blandingen separeres, og kloroformskiktet tilsettes raskt til en iskald, mettet natriumbikarbonatoppløsning under kraftig omrøring. Den svakt basiske blanding separeres påny, og kloroformskiktet vaskes én gang med vann, tørres over vannfritt natrium-sulfat og filtreres, og filtratet inndampes til tørrhet i vakuum ved omtrent 35°C. Residuet taes opp i ethylacetat ved 55—60°C, filtreres og tilsettes kim, og blandingen får stå og krystal-lisere natten over ved lav temperatur. Det er-holdes 26,8 g produkt, som beskyttes mot lys og oppbevares i en tett tillukket beholder i et kjø-leskap. A suspension of 25 g of N-acetylglucosamine and 70 ml of acetyl chloride is stirred under a nitrogen atmosphere for 10 minutes. At this point, 1 ml of acetic acid saturated with HCl gas (at 0°C) is added. After 15 minutes, the mixture begins to boil, and it is left to boil gently with reflux cooling. After 2 hours, all the material has dissolved and a yellowish-brown solution has formed. The mixture is then stirred for about 15 hours. 500 ml of chloroform is added, and the mixture is poured over a kilogram of ice and stirred for 3 minutes. (The rest of this procedure should be carried out as quickly as possible to achieve the greatest possible yield). The mixture is separated and the chloroform layer is added rapidly to an ice-cold saturated sodium bicarbonate solution with vigorous stirring. The slightly basic mixture is separated again, and the chloroform layer is washed once with water, dried over anhydrous sodium sulfate and filtered, and the filtrate is evaporated to dryness in vacuo at about 35°C. The residue is taken up in ethyl acetate at 55-60°C, filtered and germ is added, and the mixture is allowed to stand and crystallize overnight at a low temperature. There is 26.8 g of product, which is protected from light and stored in a tightly closed container in a refrigerator.
1-klor-N-acetylgalactosamin-triacetat fremstilles som ovenfor beskrevet, bortsett fra at der som utgangsmateriale anvendes galactosamin-hydroklorid i stedet for glucosamin-hydroklorid. 1-Chloro-N-acetylgalactosamine triacetate is prepared as described above, except that galactosamine hydrochloride is used as starting material instead of glucosamine hydrochloride.
De nedenstående eksempler vil ytterligere illustrere oppfinnelsen. The following examples will further illustrate the invention.
Eksempel 1. Example 1.
Ortho-carboxyfenyl-D-2'-acetamido-2'-deoxy-glucosid. Ortho-carboxyphenyl-D-2'-acetamido-2'-deoxy-glucoside.
Til en blanding av 62,3 g vannfritt kalium-karbonat, 34,7 ml methylsalicylat og 1380 ml aceton tilsettes 57 g 1-klor-N-acetylglucosamin-triacetat. Blandingen omrøres ved romtemperatur i 21 timer og filtreres. Oppløsningsmidlet fjernes ved lavt trykk, og residuet tritureres med ether for å utkrystallisere O-carbonmeth-oxyfenyl-tri-0-acetyl-p-D-2'-acetamido-2'-glucosid. 57 g of 1-chloro-N-acetylglucosamine triacetate is added to a mixture of 62.3 g of anhydrous potassium carbonate, 34.7 ml of methyl salicylate and 1380 ml of acetone. The mixture is stirred at room temperature for 21 hours and filtered. The solvent is removed under low pressure, and the residue is triturated with ether to crystallize O-carbonmethoxyphenyl-tri-O-acetyl-p-D-2'-acetamido-2'-glucoside.
Det således fremstilte produkt taes opp i 500 ml methanol som inneholder en ekviva-lent mengde frisk fremstilt natrium-methoxyd og holdes ved romtemperatur i en nitrogenatmosfære i 10 minutter. Oppløsningen gjøres nøytral med eddiksyre, og blandingen filtreres. Der tilsettes omtrent 60 ml vann, og opp-løsningen sentrifugeres. Produktet tar til å utfelles i løpet av omtrent 10 minutter. Blandingen holdes kald natten over, og produktet fra-skilles ved filtrering. The thus prepared product is taken up in 500 ml of methanol containing an equivalent amount of freshly prepared sodium methoxide and kept at room temperature in a nitrogen atmosphere for 10 minutes. The solution is made neutral with acetic acid, and the mixture is filtered. Approximately 60 ml of water is added, and the solution is centrifuged. The product takes about 10 minutes to precipitate. The mixture is kept cold overnight, and the product is separated by filtration.
Til en suspensjon av 30,1 g av den som ovenfor beskrevet fremstilte forbindelse i 1 liter To a suspension of 30.1 g of the compound prepared as described above in 1 liter
vann tilsettes 87 ml IN natriumhydroxydopp-løsning. Blandingen omrøres i 3 timer, og der tilsettes tilstrekkelig meget tørris (ca. 5 g) for å klarne oppløsningen. Ved tørrisens forsvinnen water, add 87 ml IN sodium hydroxide solution. The mixture is stirred for 3 hours, and a sufficient amount of dry ice (approx. 5 g) is added to clarify the solution. When the dry ice disappears
frysetørres blandingen, og det ønskede produkt fåes i form av natriumsaltet. Det kan renses ved omkrystallisering fra ethanol eller blandinger av methanol og isopropanol. Kaliumsal-tet fremstilles på tilsvarende måte ved at man erstatter natriumhydroxydet med kaliumhydr-oxyd. the mixture is freeze-dried, and the desired product is obtained in the form of the sodium salt. It can be purified by recrystallization from ethanol or mixtures of methanol and isopropanol. The potassium salt is prepared in a similar way by replacing the sodium hydroxide with potassium hydroxide.
Natriumsaltet overføres til syren ved sur-gj øring av en kald, konsentrert oppløsning av saltet med fortynnet saltsyre, rask filtrering og vaskning med en liten mengde kaldt vann. The sodium salt is transferred to the acid by acidifying a cold, concentrated solution of the salt with dilute hydrochloric acid, rapid filtration and washing with a small amount of cold water.
Saltene og syren fremstilt i henhold til dette eksempel er alle verdifulle som anti-inflammatoriske midler på samme måte som aspirin. De er spesielt nyttige fordi de virker på lignende måte som enterisk-belagte kaps-ler. Ved oral administrering er der et opphold før der absorberes noen større mengder. Dess-uten varer frigjøringen av den aktive bestand-del i et forlenget tidsrom. The salts and acid prepared according to this example are all valuable as anti-inflammatory agents similar to aspirin. They are particularly useful because they work in a similar way to enteric-coated capsules. With oral administration, there is a delay before any larger amounts are absorbed. In addition, the release of the active ingredient lasts for an extended period of time.
Galactosider av disse forbindelser, som på tilsvarende måte er nyttige, fremstilles på samme vis. Galactosides of these compounds, which are similarly useful, are prepared in the same way.
Eksempel 2. Example 2.
Hydroxybutazolidin-|3-D-2'-acetamido-2'-deoxy-glucosid. Hydroxybutazolidine-|3-D-2'-acetamido-2'-deoxy-glucoside.
En blanding inneholdende 500 mg hydroxybutazolidin og 1,6 ml natriumhydroxyd og en ek-vivalent mengde 1-klor-N-acetylglucosamin-triacetat i 500 ml aceton omrøres under nitrogenatmosfære ved romtemperatur i 3 timer. Deretter A mixture containing 500 mg of hydroxybutazolidine and 1.6 ml of sodium hydroxide and an equivalent amount of 1-chloro-N-acetylglucosamine triacetate in 500 ml of acetone is stirred under a nitrogen atmosphere at room temperature for 3 hours. Then
fjernes oppløsningsmidlet og en liten mengde remove the solvent and a small amount
vann ved destillasjon ved lavt trykk. Residuet water by distillation at low pressure. The residue
vaskes med vann og taes opp i methylenklorid. washed with water and taken up in methylene chloride.
Den uoppløselige andel fjernes ved filtrering, og The insoluble portion is removed by filtration, and
filtratet destilleres ved lavt trykk, hvorved man the filtrate is distilled at low pressure, whereby one
får det ønskede produkt som et residuum. obtains the desired product as a residue.
O-acetyl-gruppene fjernes under anvendelse av methanol og natrium-methoxyd etter The O-acetyl groups are removed using methanol and sodium methoxide after
fremgangsmåten ifølge eksempel 1. the method according to example 1.
Det tilsvarende galactosid fremstilles på The corresponding galactoside is prepared on
tilsvarende måte. corresponding way.
Forbindelsene fremstilt i henhold til dette The compounds prepared according to this
eksempel er nyttige på samme måte som forbindelsene fremstilt i henhold til eksempel 1. Example are useful in the same way as the compounds prepared according to Example 1.
De ovenstående eksempler illustrerer fremstillingen av 2'-acetamid-forbindelser. Andre The above examples illustrate the preparation of 2'-acetamide compounds. Second
alkanoyiamidoforbindelser, såsom f. eks. pro-pionamido- eller butyramidoforbindelser fremstilles på tilsvarende måte. alkanoyiamido compounds, such as e.g. propionamido or butyramido compounds are prepared in a similar manner.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FI841751A FI73496C (en) | 1984-05-03 | 1984-05-03 | Hinge. |
Publications (3)
Publication Number | Publication Date |
---|---|
NO851610L NO851610L (en) | 1985-11-04 |
NO159952B true NO159952B (en) | 1988-11-14 |
NO159952C NO159952C (en) | 1989-02-22 |
Family
ID=8519001
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO851610A NO159952C (en) | 1984-05-03 | 1985-04-23 | HINGE. |
Country Status (4)
Country | Link |
---|---|
DK (1) | DK159504C (en) |
FI (1) | FI73496C (en) |
NO (1) | NO159952C (en) |
SE (1) | SE8502079L (en) |
-
1984
- 1984-05-03 FI FI841751A patent/FI73496C/en not_active IP Right Cessation
-
1985
- 1985-04-23 NO NO851610A patent/NO159952C/en unknown
- 1985-04-26 DK DK188085A patent/DK159504C/en not_active IP Right Cessation
- 1985-04-29 SE SE8502079A patent/SE8502079L/en unknown
Also Published As
Publication number | Publication date |
---|---|
FI841751A (en) | 1985-11-04 |
FI73496B (en) | 1987-06-30 |
DK159504B (en) | 1990-10-22 |
DK159504C (en) | 1991-03-25 |
NO159952C (en) | 1989-02-22 |
SE8502079D0 (en) | 1985-04-29 |
NO851610L (en) | 1985-11-04 |
SE8502079L (en) | 1985-11-04 |
DK188085D0 (en) | 1985-04-26 |
FI841751A0 (en) | 1984-05-03 |
DK188085A (en) | 1985-11-04 |
FI73496C (en) | 1987-10-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR900005607B1 (en) | Preparing process for homono-zirimycin glcosides | |
US5863903A (en) | Use of hydroxy alkyl piperidine and pyrrolidine compounds to treat diabetes | |
EP0051023B1 (en) | Derivatives of the benzoyl and alpha hydroxybenzyl-phenyl osides family, method for their preparation and their therapeutic application | |
Baker et al. | Puromycin. Synthetic studies. IX. Total synthesis | |
CA1085390A (en) | 5'-deoxy-pyrimidine nucleosides and process for the preparation thereof | |
WO1995024391A1 (en) | Piperidines and pyrrolidines | |
CA1234107A (en) | Retinoid acylates of sugars and amino sugars | |
US2552547A (en) | Derivatives of alkyl dihydrostreptobiosaminides | |
US4312872A (en) | 1-Alka-2,4-dienyl-2-hydroxymethyl-3,4,5-trihydroxypiperidines as inhibitors of α-glucoside hydrolases | |
FI77461B (en) | FOERFARANDE FOER FRAMSTAELLNING AV NYA (8S) -8-FLUORIERYTROMYCINDERIVAT. | |
NO173239B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF A THERAPEUTIC ACTIVE ETHOPODOPHYLLOTOXINGLUCOSIDACYL DERIVATIVE | |
DK171053B1 (en) | Castanospermine Esters and Glycosides ([1S- (1alpha, 6beta, 7alpha, 8beta, 8alphabeta)] - octahydro-1,6,7,8-indolizintetrol), processes for their preparation and drugs containing them | |
NO115023B (en) | ||
JPH03118390A (en) | Derivative of epypodophyllotoxin altroside | |
SU1240363A3 (en) | Method of producing (e)-5-(2-vinyl bromide)uridine | |
NO159952B (en) | HINGE. | |
US3956277A (en) | Purine sugar derivatives | |
KR880001565B1 (en) | Process for preparation aminocyclitol derivatives | |
CA2104476A1 (en) | New and improved solvent-free synthesis of ethereally substituted blocked monosaccharides and the selective hydrolysis_thereof | |
JPH0560478B2 (en) | ||
US4358441A (en) | Nicotinic derivatives of glucosamine and related pharmaceutical compositions | |
US6242425B1 (en) | Quinolinone glycoside, production process, and anti-allergic agent | |
Wolfrom et al. | Crystalline Phenylurethans (Carbanilates) of Sugar Glycosides | |
US3049551A (en) | Novobiocin intermediate and process therefor | |
JPS62155291A (en) | 3-amino-4, 5-dihydroxypiperidines and production and use thereof |