NO170023B - Analogifremgangsmaate for fremstilling av nye terapeutisk aktive alfa-glucosidaseinhibitorer - Google Patents
Analogifremgangsmaate for fremstilling av nye terapeutisk aktive alfa-glucosidaseinhibitorer Download PDFInfo
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- NO170023B NO170023B NO892230A NO892230A NO170023B NO 170023 B NO170023 B NO 170023B NO 892230 A NO892230 A NO 892230A NO 892230 A NO892230 A NO 892230A NO 170023 B NO170023 B NO 170023B
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- general formula
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- ether
- therapeutically active
- methyl
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- 238000000034 method Methods 0.000 title claims description 7
- 239000003112 inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000005171 halobenzenes Chemical class 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- 239000000243 solution Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000008961 swelling Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 210000002683 foot Anatomy 0.000 description 3
- QMBFJLTXYWWQIQ-UHFFFAOYSA-N 2-[2-(2,3-dimethylanilino)phenyl]acetic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)CC(O)=O)=C1C QMBFJLTXYWWQIQ-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 2
- 239000005751 Copper oxide Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000001741 anti-phlogistic effect Effects 0.000 description 2
- 239000002152 aqueous-organic solution Substances 0.000 description 2
- 229910000431 copper oxide Inorganic materials 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 210000000548 hind-foot Anatomy 0.000 description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000020477 pH reduction 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
- 239000002244 precipitate Substances 0.000 description 2
- GETTZEONDQJALK-UHFFFAOYSA-N trifluorotoluene Substances FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 2
- RWXUNIMBRXGNEP-UHFFFAOYSA-N 1-bromo-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1Br RWXUNIMBRXGNEP-UHFFFAOYSA-N 0.000 description 1
- NNMBNYHMJRJUBC-UHFFFAOYSA-N 1-bromo-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(Br)=C1 NNMBNYHMJRJUBC-UHFFFAOYSA-N 0.000 description 1
- UBWFVMBSAYFSAU-UHFFFAOYSA-N 2-[4-(2,6-dichloroanilino)phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1NC1=C(Cl)C=CC=C1Cl UBWFVMBSAYFSAU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- 206010061218 Inflammation Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- -1 phenyl- Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 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
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/12—Acyclic radicals, not substituted by cyclic structures attached to a nitrogen atom of the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/048—Pyridine radicals
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/06—Heterocyclic radicals
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Description
Fremgangsmåte for fremstilling av hittil ukjente substituerte fenyleddiksyrer med terapeutisk virkning.
Nærværende oppfinnelse vedrorer en fremgangsmåte for fremstilling av hittil ukjente, substituerte fenyleddiksyrer med den generelle formel (I),
hvor betyr "hydrogen, metyl- eller etylgruppen og R2 metyl- eller etylgruppen eller trifluormetyl-gruppen. Fremgangsmåten består i at man omsetter en forbindelse med den generelle formel (II), med et substituert halogenbenzen med den generelle formel (III),
hvor Hal betyr brom eller jod og
R1 og R2 har den under formel (I) angitte betydning, i nærvær av et syrebindende middel og eventuelt en katalysator som fremskynder utvekslingen av aromatisk bundet halogen. Reaksjonen ifolge oppfinnelsen inntrer i almindelighet forst ved hoyere temperaturer. Derfor gjennomfores omsetningen f.eks. i et hoyerekokende, inert organisk opplosningsmiddel. Den kan også gjennomfores ved koketemperaturen for forbindelsen med den generelle formel (III), som er anvendt i overskudd, og samtidig kan tjene som reaksjonsmedium. Som syrebindende mid-ler egner seg f.eks. uorganiske basiske stoffer som hydrok-sydene, karbonatene eller hydridene av natrium eller kalium, tertiære organiske baser, spesielt hoyerekokende, som f.eks. kinolin. Eventuelt fremskyndes reaksjonen gjennom katalysa-torer, som f.eks. kobberpulver.
Av utgangsstoffene med de generelle formler (II) og (III) er
et storre antall kjent og ytterligere er fremstillbare analogt de kjente.
Som det videre ble funnet, har de nye syrer med den generelle formel (I) verdifulle terapeutiske egenskaper, spesielt anti-flogistisk (anti-inflammatorisk), analgetisk og antipyretisk virkning med gunstig terapeutisk indeks. De kan anvendes oralt eller rektalt for behandling av revmatiske, arthritiske og andre inflammatoriske sykdommer. Den antiflogistiske virkning lar seg påvise i dyreforsok, f.eks. ved UV-Erythem hos marsvin og ved Bolus alba-bdem hos rotter.
De fblgende forbindelser [o-(a,a,a-trifluor-m-toluidino)-fenyl]-eddiksyre og [o-(2,3-xylidino)-fenyl]-eddiksyre fremstilt
:ifølge oppfinnelsen er sammenlignet med [p-(2,6-diklor-anilino)-fenyl]-eddiksyre ifblge det franske medisinske patent nr. 4244 M.
Den nedenstående undersbkelsesmetode og fblgende resultater
ble oppnådd:
Bolus alba- bdem hos rotter
(Wilhelmi, G., Japanese J. Pharmacol. 15, (1965) 187 - 198).
Som forsbksdyr ble anvendt hvite hanrotter med vekt 110 - 130 g, og 6 dyr pr. dose. Forsbkssubstansen administreres oralt som suspensjon med tragant. 1 time senere utlbses ved subkutan injeksjon av 0,1 ml av en 10 %'ig suspensjon av Bolus alba et bdem i fotsålen på den hbyre bakpote. 5 timer senere drepes rottene og bakpoten amputeres. Svelningen måles ved bestemmelse av vektsdifferansen mellom den venste, normal pote og den hbyre, svellede pote. Middelvekten av svelningen for med forsbkssubstansen behandlede rotter sammenlignes med den for ubehandlede kontrolldyr. Den med prbvesubstansen oppnådde midlere svelningsreduksjon uttrykkes i prosent.
Som det fremgår av foranstående tabell bevirker de nevnte forbindelser 1 og 2 i den angitte mengde etter oral administrasjon en svelningsreduksjon hos rotter innen et område på 25 - 34 % ved en ved Bolus alba fremkalt betennelse. Den provede forbindelse etter fransk medisinsk patent nr. 4244 M viser derimot ingen farmakologisk virkning.
I syrene med den generelle formel (I) og de tilsvarende, nedenfor nevnte utgangsstoffer er R, og R2 uavhengig av hver-andre lavere alkylgrupper f.eks. metyl- eller etylgrupper.
De etterfølgende eksempler redegjor nærmere for gjennomfbringen av fremgangsmåten ifblge oppfinnelsen. Temperaturene er angitt i Celsiusgrader.
EKSEMPEL 1
En blanding av 13,3 g 2-indolinon, 50 ml m-brom-a,a,a-trifluor-toluen, 1,0 g kobberstbv og 10,0 g kaliumkarbonat kokes i 24 timer, hvorved noe bromtrifluortoluen destilleres langsomt fra for azeotropt å fjerne det dannede vann. Etter avkjbling fil-treres reaksjonsblandingen, og nutsjegodset oppkokes kort med benzen og nutsjes fra. De to filtrater forenes og inndampes forst under vannstrålevakuum og så under hbyvakuum. Resten opptas i eter og vaskes tre ganger med kald l-n natronlut. Den basiske opplbsning innstilles svakt sur med 5-n saltsyre, mettes med natriumklorid og ekstraheres med eter. Ved inndampning av den eteriske opplbsning blir en rod olje tilbake, som kromato-graferes på den 60-dobbelte menge silikagel. Eluering med en blanding av benzen/etylacetat/iseddik 94/5/1 gir i fraksjonene 2-7 den rå [o-(a,a,a-trifluor-m-toluLlino)-fenyl]-eddiksyre, som renses ved fornyet kromatografi og deretter krystallisasjon fra eter/petroleter, smeltepunkt 113 - 115°.
EKSEMPEL 2
13,3 g (0,10 mol) 2-indolinon opploses i 50 ml 1-metyl-2-pyrro-lidinon og tilsettes under nitrogen 4,8 g (0,10 mol) natrium-hydrid-dispersjon (50 %). Etter 1 time tilsettes 22,5 g (0,10 mol) m-brom-a, o,a-trifluortoluen i 20 ml 1-metyl-2-pyrro-lidinon og 2,0 g kobberstov. Blandingen rores i 22 timer ved 150 og helles så på vann. Den vandig-organiske opplbsning surgjores til pH 4, ekstraheres med eter, og eteropplosningen ekstraheres grundig med 2-n natriumkarbonatopplosning.. Forsiktig surgjbring av natriumkarbonatopplbsningen gir et gult bunnfall. Den erholdte suspensjon ekstraheres med eter, og eteropplosningen avfarges ved tilsetning av litt aktivt kull ved værelsetemperatur. Etter konsentrering av den eteriske opplbsning i rotasjonsfordamperen ved 0 - 20° og tilsetning av petroleter utfelles fargelbse krystaller av Lo- (a ,or ,a-tri-fluor-m-toluidino)-fenyl]-eddiksyren. Utbyttet 2,9 g (10 %), smeltepunkt 113 - 115° (fra eter-petroleter).
EKSEMPEL _3
13,3 g (0,10 mol) 2-indolinon opploses i 50 ml l-metyl-2-pyrrolidinon og tilsettes under nitrogen 12,0 g (0,214 mol) kaliumhydroksyd. Etter 1 time tilsettes 22,5 g (0,10 mol) m-brom-a ,or ,a-trifluor-toluen i 20 ml 1-metyl-2-pyrrolidinon og 3,0 g kobberstov. Blandingen rbres i 18 timer ved 160° og helles så på vann. Den vandig-organiske opplbsning surgjores til pH 4, ekstraheres med eter, og eteropplosningen ekstraheres grundig med 2-n natriumkarbonatopplosning. Forsiktig surgjbring av natriumkarbonatopplbsningen gir et gult bunnfall. Den erholdte suspensjon ekstraheres med eter, og eteropplosningen avfarges ved tilsetning av litt aktivt kull ved værelsetemperatur. Etter konsentrering av den eteriske opplbsning i rotasjonsfordamperen ved 0 - 20° og tilsetning av petroleter
utfelles fargelose krystaller av [o-(or,a,a-trifluor-m-toluidino)-fenyl]-eddiksyre. Utbytte 4,2 g (14,5 %), smeltepunkt 113 - 115°
(fra eter-petroleter).
På analog måte til disse eksempler kan også fblgende fenyl-
eddiksyre fremstilles:
[o-( 2, 3-xylidino)-fenyl]-eddiksyre, smp. 112°,
Claims (1)
- Fremgangsmåte for fremstilling av hittil ukjente,substituerte fenyleddiksyrer med terapeutisk virkning og med den generelle formel (I),hvor betyr hydrogen, metyl- eller etylgruppen,og R2 metyl- eller etylgruppen eller trifluormetyl- gruppen, karakterisert ved at man omsetter en forbindelse med den generelle formel (II), med et substituert halogenbenzen med den generelle formel (III), hvor Hal betyr brom eller jod,og og R_ har den under formel (I) angitte betydning, i nærvær av et syrebindende middel og eventuelt en katalysator som fremskynder utvekslingen av aromatisk bundet halogen.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP88401340A EP0344383A1 (en) | 1988-06-02 | 1988-06-02 | Novel alpha-Glucosidase inhibitors |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO892230D0 NO892230D0 (no) | 1989-06-01 |
| NO892230L NO892230L (no) | 1989-12-04 |
| NO170023B true NO170023B (no) | 1992-05-25 |
| NO170023C NO170023C (no) | 1992-09-02 |
Family
ID=8200392
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO892230A NO170023C (no) | 1988-06-02 | 1989-06-01 | Analogifremgangsmaate for fremstilling av nye terapeutisk aktive alfa-glucosidaseinhibitorer |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US5157116A (no) |
| EP (1) | EP0344383A1 (no) |
| JP (1) | JP2791419B2 (no) |
| KR (1) | KR0155541B1 (no) |
| CN (1) | CN1023803C (no) |
| AR (1) | AR247890A1 (no) |
| AT (1) | ATE129716T1 (no) |
| AU (1) | AU608711B2 (no) |
| CA (1) | CA1339740C (no) |
| DE (1) | DE68924670T2 (no) |
| DK (1) | DK267489A (no) |
| ES (1) | ES2081857T3 (no) |
| FI (1) | FI92934C (no) |
| GR (1) | GR3018354T3 (no) |
| HU (1) | HU203559B (no) |
| IE (1) | IE68455B1 (no) |
| IL (1) | IL90463A0 (no) |
| NO (1) | NO170023C (no) |
| NZ (1) | NZ229337A (no) |
| PH (1) | PH25908A (no) |
| PT (1) | PT90713B (no) |
| ZA (1) | ZA894068B (no) |
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| US5504078A (en) * | 1990-06-08 | 1996-04-02 | Merrell Dow Pharmaceuticals Inc. | α-glucosidase inhibitors |
| US5844102A (en) * | 1994-07-07 | 1998-12-01 | University Of Maryland Baltimore County | Glycohydrolase inhibitors, their preparation and use thereof |
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| AU4335997A (en) * | 1996-09-09 | 1998-03-26 | Wisconsin Alumni Research Foundation | Human salivary proteins and fragments thereof having alpha-glucosidase inhibitory activity |
| NZ525021A (en) * | 1997-04-15 | 2004-05-28 | Csir | Pharmaceutical compositions having appetite suppressant activity |
| EP0983239A1 (en) * | 1997-05-06 | 2000-03-08 | Novo Nordisk A/S | Novel heterocyclic compounds |
| GB2396815B (en) * | 1999-10-27 | 2004-09-08 | Phytopharm Plc | A composition comprising a pregnenone derivative and an NSAID |
| GB2363985B (en) * | 2000-06-30 | 2004-09-29 | Phytopharm Plc | Extracts,compounds & pharmaceutical compositions having anti-diabetic activity and their use |
| JP4486792B2 (ja) * | 2003-06-12 | 2010-06-23 | 学校法人近畿大学 | 環状オニウム化合物およびグルコシダーゼ阻害剤 |
| US7262318B2 (en) * | 2004-03-10 | 2007-08-28 | Pfizer, Inc. | Substituted heteroaryl- and phenylsulfamoyl compounds |
| WO2005092334A2 (en) * | 2004-03-25 | 2005-10-06 | David Priestman | Use of n-substituted imino sugars for appetite suppression |
| US20050288340A1 (en) * | 2004-06-29 | 2005-12-29 | Pfizer Inc | Substituted heteroaryl- and phenylsulfamoyl compounds |
| KR20070084455A (ko) * | 2004-11-23 | 2007-08-24 | 워너-램버트 캄파니 엘엘씨 | 지질혈증 치료용 ｈｍｇ ｃｏ-ａ 환원효소 억제제로서의7-(2ｈ-피라졸-3-일)-3,5-디히드록시-헵탄산 유도체 |
| EP2027137B1 (en) * | 2005-06-08 | 2015-02-18 | Amicus Therapeutics, Inc. | Imino and amino sugar purification |
| BRPI0613224A2 (pt) * | 2005-06-08 | 2010-12-28 | Amicus Therapeutics Inc | método para estabilizar um açúcar triflatado, método para aumentar o rendimento da reação de um produto de açúcar e composição de açúcar triflatado estabilizada |
| JP2008543784A (ja) * | 2005-06-08 | 2008-12-04 | アミカス セラピューティックス インコーポレイテッド | 結晶性糖組成物および作製方法 |
| US7741317B2 (en) | 2005-10-21 | 2010-06-22 | Bristol-Myers Squibb Company | LXR modulators |
| US7888376B2 (en) | 2005-11-23 | 2011-02-15 | Bristol-Myers Squibb Company | Heterocyclic CETP inhibitors |
| GB0614947D0 (en) * | 2006-07-27 | 2006-09-06 | Isis Innovation | Epitope reduction therapy |
| ES2382009T3 (es) | 2006-12-01 | 2012-06-04 | Bristol-Myers Squibb Company | Derivados de N-((3-bencil)-2,2-(bis-fenil-)-propan-1-amina como inhibidores de CETP para el tratamiento de aterosclerosis y enfermedades cardiovasculares |
| ATE518544T1 (de) | 2007-03-12 | 2011-08-15 | Zadec Aps | Rotbusch-extrakt gegen diabetes |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| EP2170930B3 (en) | 2007-06-04 | 2013-10-02 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| JP2011522828A (ja) | 2008-06-04 | 2011-08-04 | シナジー ファーマシューティカルズ インコーポレイテッド | 胃腸障害、炎症、癌、およびその他の障害の治療のために有用なグアニル酸シクラーゼのアゴニスト |
| AU2009270833B2 (en) | 2008-07-16 | 2015-02-19 | Bausch Health Ireland Limited | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
| JP2013528172A (ja) | 2010-05-21 | 2013-07-08 | ファイザー・インク | ２−フェニルベンゾイルアミド |
| US20130156720A1 (en) | 2010-08-27 | 2013-06-20 | Ironwood Pharmaceuticals, Inc. | Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| WO2012120414A2 (en) | 2011-03-04 | 2012-09-13 | Pfizer Inc. | Edn3-like peptides and uses thereof |
| US20150050371A1 (en) | 2012-03-09 | 2015-02-19 | Biotropics Malaysia Berhad | Extract Formulations of Rhodamnia Cinerea And Uses Thereof |
| WO2014151206A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| CA2905435A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
| JP2016516804A (ja) | 2013-04-17 | 2016-06-09 | ファイザー・インク | 心血管疾患を治療するためのｎ−ピペリジン−３−イルベンズアミド誘導体 |
| EP3004138B1 (en) | 2013-06-05 | 2024-03-13 | Bausch Health Ireland Limited | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
| AU2015308350B2 (en) | 2014-08-29 | 2020-03-05 | Tes Pharma S.R.L. | Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase |
| WO2016055901A1 (en) | 2014-10-08 | 2016-04-14 | Pfizer Inc. | Substituted amide compounds |
| WO2018069532A1 (en) | 2016-10-14 | 2018-04-19 | Tes Pharma S.R.L. | Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase |
| CN113302189A (zh) | 2018-11-20 | 2021-08-24 | Tes制药有限责任公司 | α-氨基-β-羧基己二烯二酸半醛去羧酶的抑制剂 |
| EP3911648A4 (en) | 2019-01-18 | 2022-10-26 | Astrazeneca AB | PCSK9 INHIBITORS AND METHODS OF USE THEREOF |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1555654A (en) * | 1977-06-25 | 1979-11-14 | Exxon Research Engineering Co | Agricultural burner apparatus |
| NO154918C (no) * | 1977-08-27 | 1987-01-14 | Bayer Ag | Analogifremgangsmaate til fremstilling av terapeutisk aktive derivater av 3,4,5-trihydroksypiperidin. |
| DE2830469A1 (de) * | 1978-07-11 | 1980-01-24 | Bayer Ag | Herstellung von l-desoxy-nojirimycin und n-substituierten derivaten |
| DE2922760A1 (de) * | 1979-06-05 | 1980-12-11 | Bayer Ag | Neue derivate von 3,4,5-trihydroxypiperidin, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel sowie in der tierernaehrung |
| GB2064527B (en) * | 1979-12-08 | 1984-05-02 | Nippon Shinyaku Co Ltd | Moranoline derivatives and process for preparation thereof |
| DE3038901A1 (de) * | 1980-10-15 | 1982-05-06 | Bayer Ag, 5090 Leverkusen | Verfahren zur herstellung von n-substituierten derivaten des 1-desoxynojirimycins |
| JPS61115093A (ja) * | 1984-11-09 | 1986-06-02 | Nippon Shinyaku Co Ltd | モラノリン誘導体の製法 |
| US4634765A (en) * | 1984-12-18 | 1987-01-06 | Merrell Dow Pharmaceuticals Inc. | Homodisaccharide hypoglycemic agents |
| GB2181729B (en) * | 1985-10-12 | 1990-04-04 | Nippon Shinyaku Co Ltd | Glucosylmoranoline derivatives and production thereof |
| DE3737523A1 (de) * | 1987-11-05 | 1989-05-18 | Bayer Ag | Verwendung von substituierten hydroxypiperidinen als antivirale mittel |
-
1988
- 1988-06-02 EP EP88401340A patent/EP0344383A1/en not_active Withdrawn
-
1989
- 1989-04-28 ES ES89401227T patent/ES2081857T3/es not_active Expired - Lifetime
- 1989-04-28 AT AT89401227T patent/ATE129716T1/de not_active IP Right Cessation
- 1989-04-28 DE DE68924670T patent/DE68924670T2/de not_active Expired - Fee Related
- 1989-05-29 AR AR89314032A patent/AR247890A1/es active
- 1989-05-29 ZA ZA894068A patent/ZA894068B/xx unknown
- 1989-05-30 CA CA000601196A patent/CA1339740C/en not_active Expired - Fee Related
- 1989-05-30 NZ NZ229337A patent/NZ229337A/en unknown
- 1989-05-30 AU AU35801/89A patent/AU608711B2/en not_active Ceased
- 1989-05-30 IL IL90463A patent/IL90463A0/xx not_active IP Right Cessation
- 1989-05-31 HU HU892791A patent/HU203559B/hu not_active IP Right Cessation
- 1989-06-01 DK DK267489A patent/DK267489A/da not_active Application Discontinuation
- 1989-06-01 FI FI892682A patent/FI92934C/fi not_active IP Right Cessation
- 1989-06-01 CN CN89103723A patent/CN1023803C/zh not_active Expired - Fee Related
- 1989-06-01 PT PT90713A patent/PT90713B/pt not_active IP Right Cessation
- 1989-06-01 NO NO892230A patent/NO170023C/no not_active IP Right Cessation
- 1989-06-01 KR KR1019890007498A patent/KR0155541B1/ko not_active IP Right Cessation
- 1989-06-01 PH PH38729A patent/PH25908A/en unknown
- 1989-06-02 JP JP1139401A patent/JP2791419B2/ja not_active Expired - Fee Related
- 1989-06-12 IE IE179889A patent/IE68455B1/en not_active IP Right Cessation
-
1992
- 1992-02-18 US US07/839,014 patent/US5157116A/en not_active Expired - Fee Related
-
1995
- 1995-12-08 GR GR950403473T patent/GR3018354T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU3580189A (en) | 1990-02-01 |
| EP0344383A1 (en) | 1989-12-06 |
| DK267489D0 (da) | 1989-06-01 |
| DK267489A (da) | 1989-12-03 |
| DE68924670T2 (de) | 1996-05-23 |
| JP2791419B2 (ja) | 1998-08-27 |
| IL90463A0 (en) | 1990-01-18 |
| JPH0225498A (ja) | 1990-01-26 |
| GR3018354T3 (en) | 1996-03-31 |
| CA1339740C (en) | 1998-03-17 |
| NZ229337A (en) | 1990-12-21 |
| KR910000776A (ko) | 1991-01-30 |
| AR247890A1 (es) | 1995-04-28 |
| KR0155541B1 (ko) | 1998-10-15 |
| NO892230L (no) | 1989-12-04 |
| PH25908A (en) | 1991-12-19 |
| ZA894068B (en) | 1990-09-26 |
| ATE129716T1 (de) | 1995-11-15 |
| HUT50191A (en) | 1989-12-28 |
| FI92934B (fi) | 1994-10-14 |
| CN1040032A (zh) | 1990-02-28 |
| IE68455B1 (en) | 1996-06-26 |
| DE68924670D1 (de) | 1995-12-07 |
| HU203559B (en) | 1991-08-28 |
| AU608711B2 (en) | 1991-04-11 |
| IE891798L (en) | 1989-12-02 |
| FI92934C (fi) | 1995-01-25 |
| CN1023803C (zh) | 1994-02-16 |
| FI892682A0 (fi) | 1989-06-01 |
| ES2081857T3 (es) | 1996-03-16 |
| US5157116A (en) | 1992-10-20 |
| NO170023C (no) | 1992-09-02 |
| FI892682A (fi) | 1989-12-03 |
| NO892230D0 (no) | 1989-06-01 |
| PT90713B (pt) | 1993-09-30 |
| PT90713A (pt) | 1989-12-29 |
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