NO160133B - Analogifremgangsmaate ved fremstilling av terapeutisk aktive 2-amino-3-(halobenzoyl)-methylfenyleddiksyrer, estere og salter derav. - Google Patents
Analogifremgangsmaate ved fremstilling av terapeutisk aktive 2-amino-3-(halobenzoyl)-methylfenyleddiksyrer, estere og salter derav. Download PDFInfo
- Publication number
- NO160133B NO160133B NO820468A NO820468A NO160133B NO 160133 B NO160133 B NO 160133B NO 820468 A NO820468 A NO 820468A NO 820468 A NO820468 A NO 820468A NO 160133 B NO160133 B NO 160133B
- Authority
- NO
- Norway
- Prior art keywords
- amino
- preparation
- salts
- esters
- halobenzoyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 13
- 238000002360 preparation method Methods 0.000 title claims description 11
- 150000002148 esters Chemical class 0.000 title claims description 3
- 150000001243 acetic acids Chemical class 0.000 title 1
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 125000005907 alkyl ester group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- WNCLIUXXSKAOND-UHFFFAOYSA-M sodium;2-[2-amino-3-(4-chlorobenzoyl)-5-methylphenyl]acetate Chemical compound [Na+].CC1=CC(CC([O-])=O)=C(N)C(C(=O)C=2C=CC(Cl)=CC=2)=C1 WNCLIUXXSKAOND-UHFFFAOYSA-M 0.000 claims description 3
- UFZNNOHNAOYQQP-UHFFFAOYSA-N 7-phenacyl-1,3-dihydroindol-2-one Chemical compound C=1C=CC=2CC(=O)NC=2C=1CC(=O)C1=CC=CC=C1 UFZNNOHNAOYQQP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000203 mixture Substances 0.000 description 7
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 6
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- 241001465754 Metazoa Species 0.000 description 4
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- 238000012986 modification Methods 0.000 description 3
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 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 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- MJAQSCHBMPGJES-UHFFFAOYSA-M sodium (2-amino-3-benzoylphenyl)acetate Chemical compound [Na+].NC1=C(CC([O-])=O)C=CC=C1C(=O)C1=CC=CC=C1 MJAQSCHBMPGJES-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- YBNYPWAZNIKXNI-UHFFFAOYSA-N 1-(4-chlorobenzoyl)-6-methyl-3H-indol-2-one Chemical compound ClC1=CC=C(C(=O)N2C(CC3=CC=C(C=C23)C)=O)C=C1 YBNYPWAZNIKXNI-UHFFFAOYSA-N 0.000 description 1
- NDUYSRWSHUHRGD-UHFFFAOYSA-N 4-methyl-7-(2,3,5-trichlorobenzoyl)-1,3-dihydroindol-2-one Chemical compound ClC1=C(C(=O)C=2C=CC(=C3CC(NC23)=O)C)C=C(C=C1Cl)Cl NDUYSRWSHUHRGD-UHFFFAOYSA-N 0.000 description 1
- ROYCPOZLJYCXIZ-UHFFFAOYSA-N 7-(2,4-dichlorobenzoyl)-5-methyl-1,3-dihydroindol-2-one Chemical compound ClC1=C(C(=O)C=2C=C(C=C3CC(NC23)=O)C)C=CC(=C1)Cl ROYCPOZLJYCXIZ-UHFFFAOYSA-N 0.000 description 1
- GEVQCJAIVLZAMK-UHFFFAOYSA-N 7-(4-chlorobenzoyl)-5-methyl-1,3-dihydroindol-2-one Chemical compound ClC1=CC=C(C(=O)C=2C=C(C=C3CC(NC23)=O)C)C=C1 GEVQCJAIVLZAMK-UHFFFAOYSA-N 0.000 description 1
- WQRSNHWRHMQPLP-UHFFFAOYSA-N 7-(4-fluorobenzoyl)-5-methyl-1,3-dihydroindol-2-one Chemical compound C=1C(C)=CC=2CC(=O)NC=2C=1C(=O)C1=CC=C(F)C=C1 WQRSNHWRHMQPLP-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000295146 Gallionellaceae Species 0.000 description 1
- 206010017788 Gastric haemorrhage Diseases 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products 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 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- MKNIBNQJIMDODU-UHFFFAOYSA-M NC1=C(C(=CC=C1C(C1=C(C(=CC(=C1)Cl)Cl)Cl)=O)C)CC(=O)[O-].[Na+] Chemical compound NC1=C(C(=CC=C1C(C1=C(C(=CC(=C1)Cl)Cl)Cl)=O)C)CC(=O)[O-].[Na+] MKNIBNQJIMDODU-UHFFFAOYSA-M 0.000 description 1
- 208000002151 Pleural effusion Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- SOYCMDCMZDHQFP-UHFFFAOYSA-N amfenac Chemical class NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=CC=C1 SOYCMDCMZDHQFP-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
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- 238000003556 assay Methods 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
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- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
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- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
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- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
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- 235000001727 glucose Nutrition 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical class OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 238000002844 melting Methods 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLECYLUMRPAYIA-UHFFFAOYSA-M sodium 2-[2-amino-3-(4-chlorobenzoyl)-4-methylphenyl]acetate Chemical compound NC1=C(C=CC(=C1C(C1=CC=C(C=C1)Cl)=O)C)CC(=O)[O-].[Na+] ZLECYLUMRPAYIA-UHFFFAOYSA-M 0.000 description 1
- WFSVKMGPJMLIQS-UHFFFAOYSA-M sodium 2-[2-amino-3-(4-fluorobenzoyl)-5-methylphenyl]acetate hydrate Chemical compound O.NC1=C(C=C(C=C1C(C1=CC=C(C=C1)F)=O)C)CC(=O)[O-].[Na+] WFSVKMGPJMLIQS-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- JKKFZJKBJQWGQB-UHFFFAOYSA-M sodium;2-[2-amino-3-(2,4-dichlorobenzoyl)-5-methylphenyl]acetate Chemical compound [Na+].CC1=CC(CC([O-])=O)=C(N)C(C(=O)C=2C(=CC(Cl)=CC=2)Cl)=C1 JKKFZJKBJQWGQB-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Description
Foreliggende oppfinnelse angår fremstilling av nye, terapeutisk aktive 2-amino-3-(halobenzoyl)-methylfenyleddiksyrer, deres alkylestere og metallsalter.
Visse 2-amino-3-(5 og 6)-benzoylfenyleddiksyrer med forskjellige substituenter på benzoyl- og fenylgruppene og fremgangsmåter for fremstilling og bruk av disse er beskrevet i US patentskrift 4 045 576. Forbindelsene kjent fra denne publikasjon, er ikke methylfenyleddiksyrer eller derivater derav.
US patentskrift 4 221 716 beskriver en fremgangsmåte for fremstilling av 7-acylindolin-2-oner som er mellom-produkter ved fremstilling av foreliggende nye forbindelser.
Oppfinnelsen angår således en analogifremgangsmåte for fremstilling av terapeutisk aktive forbindelser av formelen:
hvori R betegner hydrogen, laverealkyl eller et farmasøytisk akseptabelt kation,
Y er halogen, og
n er et helt tall fra 1 til 3.
De nye forbindelser utviser verdifulle farmakologiske egenskaper og er anvendbare som farmasøytiske midler. Forbindelsene utviser glimrende antiinflammatorisk og analgetisk aktivitet i varmblodige dyr med minimal gastro-intestinal toksisitet.
I definisjonen av symboler i de foregående formler og hvor de ellers fremkommer i foreliggende beskrivelse, har uttrykkene følgende betydning.
Uttrykket "laverealkyl" som anvendt her, innbefatter rettkjedede og forgrenede radikaler med opptil 6 carbonatomer, fortrinnsvis ikke mere enn 4 carbonatomer, f.eks. _ grupper som methyl, ethyl, propyl, isopropyl, butyl, sek-butyl, t-butyl, amyl, isoamyl og hexyl.
Uttrykket "halogen" innbefatter klor, fluor, brom og jod.
Eksempler på farmasøytisk akseptable metallkationer er natrium, kalium, calcium, magnesium, sink, aluminium, kobber og hydrater derav.
Analogifremgangsmåten ifølge oppfinnelsen er kjenne-tegnet ved at et 7-benzoylmethylindolin-2-on av formelen:
hvori Y og n er som ovenfor angitt, hydrolyseres i vandig basisk løsning under dannelse av salter derav som deretter surgjøres under dannelse av syren, og for fremstilling av laverealkylestere derav omdannes syren til et metallsalt som deretter omsettes i et egnet løsningsmiddel med et alkyl-halogenid under dannelse av den ønskede ester.
Utgangsforbindelsene kan fremstilles etter konven-sjonelle metoder, slik som beskrevet i US patentskrifter 4 045 576 og 4 221 716.
Fremstilling av forbindelsene illustreres i de etter-følgende eksempler.
Eksempel 1
Fremstilling av n3trium-2-amino-3-(4-fluorbenzoyl)-5-methyl-fenylacetat- monohydrat
En blanding av 8,0 g (0,03 mol) 7-(4-fluorbenzoyl)-5-methylindolin-2-on i 120 ml 3N natriumhydroxyd ble oppvarmet til tilbakeløpskokning i 16 timer. Etter fortynning med vann til 300 ml ble løsningen ved 50°C titrert med konsen-trert saltsyre til pH 8,2. Den resulterende orange løsning ble filtrert, og filtratet ble avkjølt til 5°C og surgjort til pH 4,5 med iseddik. Det resulterende gule, faste materiale ble oppsamlet og vasket med vann, deretter løst i methylenklorid. Vann ble tilsatt, og blandingen ble titrert med fortynnet natriumbicarbonatløsning inntil en pH på 7,0 ble opprettholdt. Det vandige lag ble fraskilt og konsen-trert ved azeotrop destillasjon av vannet med absolutt ethylalkohol. Det erholdte gule pulver ble oppløst i isopropyl-alkohol, og 1 ml vann ble tilsatt. Etter at blandingen hadde stått i 3 dager, ble det resulterende gule, faste materiale oppsamlet og tørket ved 25°C under høyvakuum i 2 dager under dannelse av 1,6 g (16,5% utbytte) av tittelforbindelsen som et gult pulver med et smeltepunkt på 140-160°C.
Analyse:
Beregnet for C16H13<F>N03Na-H20: C 58,72; H 4,62; N 4,28 Funnet; C 58,71; H 4,68; N 4,26
Eksempel 2
Fremstilling av natrium-2-amino-3-(4-klorbenzoyl)-5-methyl-fenylacetat
Ved å følge prosedyren beskrevet i eksempel 1 ga en blanding av 11,5 g (0,04 mol) 7-(4-klorbenzoyl)-5-methyl-indolin-2-on og 160 ml 3 N natriumhydroxyd etter omkrystal-lisering fra vann, 2,5 g (18%) av tittelforbindelsen som orange nåler med smeltepunkt 262 oC.
Analyse:
Beregnet for C16H13ClN03Na: C 59,00; H 4,02; N 4,30
Funnet: C 58,82; H 4,09; N 4,32
Eksempel 3
Fremstilling av natrium-2-amino-3-(2,4-diklorbenzoyl)-5~ methylf enylacetat
Ved å følge prosedyren beskrevet i eksempel 1 ga en blanding av 7-(2,4-diklorbenzoyl)-5-methyllndolin-2-on og 3 N natriumhydroxyd tittelforbindelsen.
Eksempel 4
Fremstilling av natrium-2-amino-3-(2,3,5-triklorbenzoyl)-6-methylf enylacetat
Ved å følge prosedyren beskrevet i eksempel 1, ble det ut fra en blanding av 7-(2,3,5-triklorbenzoyl)-4-methylindolin-2-on og 3 N natriumhydroxyd fremstilt tittelforbindelsen.
Eksempel 5
Fremstilling av natrium-2-amino-3-(4-klorbenzoyl)-4-methylf enylacetat
Ved å følge prosedyren beskrevet i eksempel 1, ble det ut fra en blanding av 4-klorbenzoyl-6-methylindolin-2-on og 3 N natriumhydroxyd fremstilt tittelforbindelsen.
I den siste tid har sterke antiinflammatoriske lege-midler generelt blitt funnet å gi alvorlige bivirkninger slik som mageblødning og sårdannelse når de administreres oralt til dyr i det effektive område. De nye forbindelser ble funnet å medføre den fordel at nedsatt hyppighet av mage-irritasjon er blitt observert når disse administreres innen det effektive område for å redusere inflammasjon sammen-lignet med indomethacin og 2-amino-3-benzoylfenyleddiksyrer og deres derivater som beskrevet i US patentskrift 4 045 576. Eksempelvis viste forbindelsen fremstilt ifølge eksempel 2, natrium-2-amino-3-(4-klorbenzoyl)-5-methylfenylacetat, seg å være ca. to ganger så kraftig som indomethacin og natrium-2-amino-3-benzoylfenylacetat, men utviste bare fjerdeparten av indomethacins irritasjon på magen og halvparten av den irritasjon på 'magen som utvises av natrium-2-amino-3-benzoyl-fenylacetat. Forbindelsen ifølge eksempel 2 ble funnet å
ha tilnærmet den halve styrke av natrium-2-amino-3-(4-klor-
benzoyl)-5-fluorfenylacetat, men utviste overraskende bare en fjerdepart av den irritasjon som utvises på magen av denne forbindelse.
Den antiinflammatoriske aktivitet ble demonstrert på laboratoriedyr under anvendelse av en modifikasjon av Evans Blue-Carrageenan Pleural Effusion Assay of Sancilio, L. F., J. Pharmacol. Exp. Ther. 168: 199-204 (1969) .
Magetoksisitet ble bestemt ved en modifikasjon av metoden beskrevet av Tsukada et al., Arzneim. Forsch. 28: 428-438 (1978) .
Forbindelsene virker også som analgetiske midler som bestemt ved en modifikasjon av metoden beskrevet av Collier, et al., Brit. J. Pharmacol. Chemother. '32: 295-310 (1968).
Effektive mengder av hvilke som helst av de foregående farmakologisk aktive forbindelser kan administreres til et levende dyr på hvilke som helst av forskjellige måter, slik som f.eks. oralt som i kapsler eller tabletter, parenteralt i form av sterile løsninger eller suspensjoner, og i enkelte tilfeller intra-venøst i form av sterile løsninger. Ved formulering av de nye preparater innarbeides den aktive bestanddel i en egnet bærer, illustrativt en farmasøytisk bærer. Egnede farma-søytiske bærere som er anvendbare ved formulering av pre-paratene, innbefatter stivelse, gelatin, glucose, magnesium-carbonat, lactose, malt .og lignende. Egnede væskeformige farmasøytiske bærere innbefatter ethylalkohol, propylen-glycol, glycerol, glucosesirup og lignende.
De farmakologisk aktive forbindelser kan med fordel anvendes innen en enhetsdose på fra 0,1 til 150 mg. Enhets-dosen kan administreres en gang daglig eller i multiple eller oppdelte daglige doser. Den daglige dose kan variere fra 0,3 til 450 mg. 5 til 25 mg synes å være optimale pr. enhetsdose.
Claims (2)
1. Analogifremgangsmåte for fremstilling av terapeutisk aktive forbindelser av formelen:
hvori R betegner hydrogen, laverealkyl eller et farmasøytisk akseptabelt kation,
Y er halogen, og
n er et helt tall fra 1 til 3,
karakterisert ved at et 7-benzoylmethyl-indolin-2-on av formelen:
hvori Y og n er som ovenfor angitt, hydrolyseres i vandig basisk løsning under dannelse av salter derav som deretter surgjøres under dannelse av syren, og for fremstilling av laverealkylestere derav omdannes syren til et metallsalt som deretter omsettes i et egnet løsningsmiddel med et alkyl-halogenid under dannelse av den ønskede ester.
2. Fremgangsmåte ifølge krav 1 ved fremstilling av natrium-2-amino-3-(4-klorbenzoyl)-5-methylfenylacetat, karakterisert ved at tilsvarende utgangs-materialer anvendes.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23453181A | 1981-02-17 | 1981-02-17 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO820468L NO820468L (no) | 1982-08-18 |
| NO160133B true NO160133B (no) | 1988-12-05 |
| NO160133C NO160133C (no) | 1989-03-15 |
Family
ID=22881752
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO820468A NO160133C (no) | 1981-02-17 | 1982-02-16 | Analogifremgangsmaate ved fremstilling av terapeutisk aktive 2-amino-3-(halobenzoyl)-methylfenyleddiksyrer, estere og salter derav. |
Country Status (32)
| Country | Link |
|---|---|
| JP (1) | JPS57149256A (no) |
| KR (1) | KR880002289B1 (no) |
| AT (1) | AT387213B (no) |
| AU (1) | AU7950382A (no) |
| BE (1) | BE892156A (no) |
| CA (1) | CA1173852A (no) |
| CH (1) | CH651294A5 (no) |
| DE (1) | DE3204854C2 (no) |
| DK (1) | DK155936C (no) |
| EG (1) | EG15798A (no) |
| ES (1) | ES8301895A1 (no) |
| FI (1) | FI73970C (no) |
| FR (1) | FR2499981B1 (no) |
| GB (1) | GB2093027B (no) |
| GR (1) | GR76516B (no) |
| HK (1) | HK90384A (no) |
| HU (1) | HU187644B (no) |
| IE (1) | IE52289B1 (no) |
| IL (1) | IL64724A0 (no) |
| IT (1) | IT1157001B (no) |
| KE (1) | KE3454A (no) |
| LU (1) | LU83928A1 (no) |
| MY (1) | MY8500908A (no) |
| NL (1) | NL8200607A (no) |
| NO (1) | NO160133C (no) |
| NZ (1) | NZ199745A (no) |
| PL (1) | PL139815B1 (no) |
| PT (1) | PT74441B (no) |
| SE (1) | SE453387B (no) |
| SG (1) | SG68584G (no) |
| YU (1) | YU44333B (no) |
| ZA (1) | ZA82697B (no) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4683242A (en) * | 1985-10-28 | 1987-07-28 | A. H. Robins Company, Incorporated | Transdermal treatment for pain and inflammation with 2-amino-3-aroylbenzeneacetic acids, salts and esters |
| US5475034A (en) * | 1994-06-06 | 1995-12-12 | Alcon Laboratories, Inc. | Topically administrable compositions containing 3-benzoylphenylacetic acid derivatives for treatment of ophthalmic inflammatory disorders |
| BR9600975A (pt) * | 1996-03-11 | 1997-12-30 | Fundacao Oswaldo Cruz | Derivados do ácido gem-difluorfenilacético e de gem-difluorfenilacetamida processo de sua preparação e suas aplicações farmacêuticas |
| US6034266A (en) * | 1996-03-11 | 2000-03-07 | Fundacao Oswaldo Cruz-Fiocruz | Gem-difluoro derivative of phenylacetamide and phenylacetic acid and their pharmaceutical uses |
| AR030346A1 (es) * | 2000-08-14 | 2003-08-20 | Alcon Inc | Metodo de tratamiento de desordenes neurodegenerativos de la retina y cabeza de nervio optico |
| AR030345A1 (es) * | 2000-08-14 | 2003-08-20 | Alcon Inc | Metodo de tratamiento de desordenes relacionados con angiogenesis |
| AU2002247284A1 (en) | 2001-04-02 | 2002-10-15 | Alcon, Inc. | Method of treating ocular inflammatory and angiogenesis-related disorders using an amide derivative of flubiprofen or ketorolac |
| TWI358290B (en) | 2004-12-02 | 2012-02-21 | Alcon Inc | Topical nepafenac formulations |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1226344A (no) * | 1967-07-31 | 1971-03-24 | ||
| US3997368A (en) * | 1975-06-24 | 1976-12-14 | Bell Telephone Laboratories, Incorporated | Elimination of stacking faults in silicon devices: a gettering process |
| CH577461A5 (no) * | 1975-08-13 | 1976-07-15 | Robins Co Inc A H | |
| FR2366015A1 (fr) * | 1975-11-05 | 1978-04-28 | Robins Co Inc A H | Nouveaux acides amino-2 benzoyl-3 (5 et 6) phenylacetiques et leurs esters et sels de metaux alcalins, utiles notamment comme anti-inflammatoires, et leur procede de preparation |
| IL61945A (en) * | 1980-02-19 | 1984-09-30 | Robins Co Inc A H | 2-amino-3-(hydroxy(phenyl)methyl)phenylacetic acids,esters and amides and pharmaceutical compositions containing them |
-
1982
- 1982-01-07 IL IL64724A patent/IL64724A0/xx not_active IP Right Cessation
- 1982-01-14 AU AU79503/82A patent/AU7950382A/en not_active Abandoned
- 1982-01-24 EG EG8228A patent/EG15798A/xx active
- 1982-02-01 JP JP57014710A patent/JPS57149256A/ja active Granted
- 1982-02-03 ZA ZA82697A patent/ZA82697B/xx unknown
- 1982-02-05 AT AT0043382A patent/AT387213B/de not_active IP Right Cessation
- 1982-02-08 FI FI820392A patent/FI73970C/fi not_active IP Right Cessation
- 1982-02-09 CH CH791/82A patent/CH651294A5/fr not_active IP Right Cessation
- 1982-02-09 LU LU83928A patent/LU83928A1/fr unknown
- 1982-02-10 IT IT67152/82A patent/IT1157001B/it active
- 1982-02-11 DE DE3204854A patent/DE3204854C2/de not_active Expired - Fee Related
- 1982-02-12 GB GB8204137A patent/GB2093027B/en not_active Expired
- 1982-02-15 IE IE310/82A patent/IE52289B1/en not_active IP Right Cessation
- 1982-02-15 GR GR67320A patent/GR76516B/el unknown
- 1982-02-15 YU YU325/82A patent/YU44333B/xx unknown
- 1982-02-15 SE SE8200891A patent/SE453387B/sv unknown
- 1982-02-16 PT PT74441A patent/PT74441B/pt not_active IP Right Cessation
- 1982-02-16 BE BE0/207327A patent/BE892156A/fr not_active IP Right Cessation
- 1982-02-16 NZ NZ199745A patent/NZ199745A/en unknown
- 1982-02-16 NL NL8200607A patent/NL8200607A/nl not_active Application Discontinuation
- 1982-02-16 ES ES509622A patent/ES8301895A1/es not_active Expired
- 1982-02-16 DK DK067382A patent/DK155936C/da not_active IP Right Cessation
- 1982-02-16 CA CA000396392A patent/CA1173852A/en not_active Expired
- 1982-02-16 HU HU82464A patent/HU187644B/hu unknown
- 1982-02-16 KR KR8200673A patent/KR880002289B1/ko not_active Expired
- 1982-02-16 FR FR8202507A patent/FR2499981B1/fr not_active Expired
- 1982-02-16 PL PL1982235095A patent/PL139815B1/pl unknown
- 1982-02-16 NO NO820468A patent/NO160133C/no unknown
-
1984
- 1984-09-17 KE KE3454A patent/KE3454A/xx unknown
- 1984-09-21 SG SG68584A patent/SG68584G/en unknown
- 1984-11-15 HK HK903/84A patent/HK90384A/xx unknown
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1985
- 1985-12-30 MY MY908/85A patent/MY8500908A/xx unknown
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