NO810681L - Fremgangsmaate for fremstilling av farmasoeytisk aktive triazolderivater. - Google Patents
Fremgangsmaate for fremstilling av farmasoeytisk aktive triazolderivater.Info
- Publication number
- NO810681L NO810681L NO810681A NO810681A NO810681L NO 810681 L NO810681 L NO 810681L NO 810681 A NO810681 A NO 810681A NO 810681 A NO810681 A NO 810681A NO 810681 L NO810681 L NO 810681L
- Authority
- NO
- Norway
- Prior art keywords
- methyl
- active
- pharmasoeytic
- procedure
- preparation
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 6
- 238000002360 preparation method Methods 0.000 title description 3
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 abstract description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 150000004677 hydrates Chemical class 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- 239000002243 precursor Substances 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229960001340 histamine Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 102000000543 Histamine Receptors Human genes 0.000 description 2
- 108010002059 Histamine Receptors Proteins 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- FOUIGAKKYKKGDU-UHFFFAOYSA-N methyl n-(benzylideneamino)-n-methyl-n'-(2-methylsulfanylacetyl)carbamimidothioate Chemical compound CSCC(=O)N=C(SC)N(C)N=CC1=CC=CC=C1 FOUIGAKKYKKGDU-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- VGOXAGARRCHYTK-UHFFFAOYSA-N 2-methyl-5-(methylsulfanylmethyl)-n-[3-[3-(piperidin-1-ylmethyl)phenoxy]propyl]-1,2,4-triazol-3-amine Chemical compound CN1N=C(CSC)N=C1NCCCOC1=CC=CC(CN2CCCCC2)=C1 VGOXAGARRCHYTK-UHFFFAOYSA-N 0.000 description 1
- OWXCYFUNGFTAMS-UHFFFAOYSA-N 2-methylsulfanylacetyl chloride Chemical compound CSCC(Cl)=O OWXCYFUNGFTAMS-UHFFFAOYSA-N 0.000 description 1
- VQSXCZMVUMSITD-UHFFFAOYSA-N 3-[3-(piperidin-1-ylmethyl)phenoxy]propan-1-amine Chemical compound NCCCOC1=CC=CC(CN2CCCCC2)=C1 VQSXCZMVUMSITD-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 206010022714 Intestinal ulcer Diseases 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000000138 effect on histamine Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JBRVFULKGKTODB-UHFFFAOYSA-N methyl n-(benzylideneamino)-n-methyl-n'-(2-methylsulfonylacetyl)carbamimidothioate Chemical compound CS(=O)(=O)CC(=O)N=C(SC)N(C)N=CC1=CC=CC=C1 JBRVFULKGKTODB-UHFFFAOYSA-N 0.000 description 1
- FOEMBEGJQSAFSE-UHFFFAOYSA-N methyl n-(benzylideneamino)-n-methylcarbamimidothioate;hydrochloride Chemical compound Cl.CSC(=N)N(C)N=CC1=CC=CC=C1 FOEMBEGJQSAFSE-UHFFFAOYSA-N 0.000 description 1
- -1 methylsulfonyl acetate chloride Chemical compound 0.000 description 1
- IXEGSTUUYSHYCN-UHFFFAOYSA-N n-(benzylideneamino)-n-methylmethanamine Chemical compound CN(C)N=CC1=CC=CC=C1 IXEGSTUUYSHYCN-UHFFFAOYSA-N 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 230000000069 prophylactic 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
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000005245 right atrium Anatomy 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- JEYKZWRXDALMNG-UHFFFAOYSA-N sufotidine Chemical compound CN1N=C(CS(C)(=O)=O)N=C1NCCCOC1=CC=CC(CN2CCCCC2)=C1 JEYKZWRXDALMNG-UHFFFAOYSA-N 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/14—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
Farmasøytisk aktive triazolderivater med følgende formel (I). hvor R, og R, hver er hydrogen eller alkyl eller danner sammen med nitrogenatomet en ring.eller fysiologisk godtagbare salter, hydrater og bioforløpere derav.Spesielt har de nye forbindelser vikrning på histamin-reseptorer.Fremstillingen foregår ved hjelp av konvensjonelle metoder.
Description
Foreliggende oppfinnelse gjelder•fremgangsmåte for fremstilling av jf-a-r-ma-aøyti-s-^ aktive triazolderivatfe-r-j med virkning på histamin-reseptorer.
Visse, nye, heterocykliske derivater er funnet som har. kraftig aktivitet som H2~antagonister. Disse forbindelser, som er nærmere beskrevet nedenfor, oppviser eksempelvis inhibering av avsondring av magesyre når dette stimuleres via histamin-reseptorer (Ash og Schild, Brit. J. Pharmacol. Chemother., 1966, 27, 427). Deres evne til å gjøre dette kan demonstreres på perfusert rottemage ved bruk av den metode som er beskrevet i DE off. skrift 2.734.070, modifisert ved bruk av natrium-pentobarbiton (50 mg/kg) som bedøvelsesmiddel istedenfor uretan, og hos hunder som er ved bevissthet, utstyrt med Heidenhain-poser ved bruk av den metode som er beskrevet av Black et al., Nature, 1972, 236, 385. Videre motvirker forbindelsen virkningen på histamin på sammentrekningsfrekvensen på isolert høyre atrium hos marsvin, men modifiserer ikke histamininduserte sammentrek-ninger av isolert, glatt mage-tarm-muskel som formidles via H^-reseptorer.
Forbindelser med histamin H2-blokkerende aktivitet kan anvendes ved behandling av tilstander hvor det er en fordel å senke magesurheten, spesielt ved mage- og tarm-sår, som profylak-tisk foranstaltning ved kirurgiske inngrep og ved behandling av allergiske og inflammatoriske tilstander hvor histamin er en kjent formidler. Således kan de eksempelvis anvendes enten alene eller i kombinasjon med andre aktive ingredienser ved behandling av allergiske og inflammatoriske tilstander i huden.
Foreliggende oppfinnelse tilveiebringer forbindelser med den generelle formel: (i) SiUvk/cå4- ^/k^/^" *^^4 ' ;Viktig informasjon;Av arkivmessige grunner har Patentstyret for denne allment tilgjengelige patentsøknad kun tilgjengelig dokumenter som inneholder håndskrevne anmerkninger, kommentarer eller overstrykninger, eller som kan være stemplet "Utgår" eller lignende. Vi har derfor måtte benytte disse dokumentene til skanning for å lage en elektronisk utgave. ;Håndskrevne anmerkninger eller kommentarer har vært en del av saksbehandlingen, og skal ikke benyttes til å tolke innholdet i dokumentet. ;Overstrykninger og stemplinger med "Utgår" e.l. indikerer at det under saksbehandlingen er kommet inn nyere dokumenter til erstatning for det tidligere dokumentet. Slik overstrykning eller stempling må ikke forstås slik at den aktuelle delen av dokumentet ikke gjelder. ;Vennligst se bort fra håndskrevne anmerkninger, kommentarer eller overstrykninger, samt eventuelle stemplinger med "Utgår" e.l. som har samme betydning. fvr^ Å f ;jjSåie-desJkån eksempelvisyforb^nd else^ fH^ bffi formel JlQy fremstil- ^ les ved ringslutning av en forbindelse med formel JfV-)-^( JT ^; ;r-RT-R^N-A-l-ke^-eH-T-)—¥flCH0) a NHC-N-N= Z 12 2 n l 2 i\i „ 3 N-C^e^SD^ C — / ^ ;hvor ^<y>^b_ei^£-Gve-vol-oller mer- foreL-ru-kke-tr-e-ksyge-fi—egj Z betyr to/V hydrogenatomer, i fravær av eller nærvær av et løsningsmiddel, f.eks. aceton eller vann, og eventuelt med oppvarming. ;Det kan være hensiktsmessig å fremstille forbindelse^ med k formel (\) hvor Z betyr to hydrogenatomer,in situ ved å behandle en forbindelse med formel (kf hvor Z betyr en toverdig beskyt-telsesgruppe som lett kan fjernes for å gi to hydrogenatomer, f.eks. en benzylidengruppe, med en syre, f.eks. saltsyre, fortrinnsvis med oppvarming,og under slike betingelser vil normalt ringslutning for å gi forbindelses med formel (I) inntre. ;Generelt kan mellomprodukteÆ>_rae,d form^sn^f. (x) (p^T^SjyT:rem- /\ stilles fra diamine^ med formel ved metoder som er analoge med dersom er beskrevet i GB-patent . V 2.047.238^^gf2.023.133k7"-i-ebpekL-ivtj. fortrinnsvis i beskyttet form f.eks. som et ftalimid, med på-følgende spaltning av ftalimidgruppen ved bruk av eksempelvis hydrazinhydrat. ;tD-e-r—-hve^ raroduktet ffa?a—er\ av de ovennevnte fremgangsmåter ~ <v •e-r en fri base /&g^et~-^eve.s--e"t~-s-a-rt7j kan^sali^ejr^dannes på kon-vensjonell måte. En generelt hensiktsmessig metode for å danne salteae, er således eksempelvis å blande passende mengder fri base og syre i et passende løs■r ningsmiddel, f.eks. en alkohol ^ mmsJ f.eks. etanol, eller en ester, p©jf| f. eks . etylacetat. ;Oppfinnelsen skal illustreres ved hjelp av følgende eksempler og fremstillinger. ;I de følgende eksempler og preparater er temperaturer an-gitt i °C. "T.l.c." refererer til tynnsjiktskromatografi9og denne og den preparative kromatograferingen ble utført på silika^ ;Fremstilling jz . ;*cfH Metyl-N- [2- (metyltio) acetyl ]-l-metyl-2- (f enylmetylen) hydra-zin- karboksimidotioat..
(Metyltio)acetylklorid (5,6 g) ble tilsatt porsjonsvis til en oppløsning av metyl-l-mety1-2-(fenylmetylen)hydrazin-karboksimidotioat-hydrojodid (A) (10,4 g) i trietylamin (7,8 g) og diklorometan (55 ml) og blandingen omrørt ved romtemperatur i 2 timer. Blandingen ble vasket med vann og inndampet for å gi en olje som ble kromatografert ved bruk av 1:1 eter-petroleter (kp. 60-80°C) fulgt av eter for å gi tittelforbindelsen (4,6 g) som et kremfarget fast stoff, smp. 68-70°C.
SL
Fremstilling yS .
Metyl-l-metyl-N-[(metylsulfonyl)acetyl]-2-(fenylmetylen)hydra-zinkarboksimidotioat.
Til en omrørt oppløsning av metyl-l-metyl-2-(fenylmetylen)-hydrazinkarboksimidotioat-hydroklorid (5,71 g) og trietylamin (5,2 g) i diklormetan (100 ml) ble det tilsatt metylsulfonyl-acetatklorid (4,9 g) i diklormetan (20 ml) dråpevis i 0,5 time^ ved 20°C. Blandingen ble omrørt ved 20°C i 18 timer, vann (100 ml) ble tilsatt og fasene separert. Diklormetansjiktet ble vasket med vann, tørket og inndampet. Residuet ble krystallisert fra etanol for å gi tittelforbindelsen (2,7 g) som hvit-aktige nåler, smp. 149,5-150,5°C.
l^fl-metyl-3-metyltiometyl-N-[3-[3-(1-piperidinylmetyl)fenok- sy ] propyl ] - 1H - 1 , 2 , 4 - triazol | R3ihy ' droklorid - hemihydrat .
Metyl-N-[2-(metyltio)acetyl]-l-metyl-2-(fenylmetylen)hydra-zinkarboksimidotioat (2,95 g) og 3-[3-(1-piperidinylmetyl)fenok-sy]propanamin (2,48 g) ble oppvarmet til 55°C under vannpumpe-vakuum i 1 time. Ytterligere karboksimidotioat (0,3 g) ble så tilsatt og blandingen oppvarmet i ytterligere 0,5 timel|. Reaksjonsblandingen ble oppløst i toluen (15 ml) og 5N saltsyre (12 ml) og omrørt ved romtemperatur i 18 timer og fasene separert. Den vandige fasen ble gjort basisk til pH 8 med natriumbi-karbonatløsning, vasket med toluen, gjort basisk til pH 10 med natriumkarbonat og ekstrahert med etylacetat for å gi en olje, som ble kromatografert ved bruk av 3:1 etylacetat-métanol for å gi en olje (3,1 g). Denne olje (1,27 g) ble oppløst i eter og be-handlet med eterholdig hydrogenklorid for å gi et hvitt faststoff som ble omkrystallisert fra etylacetat-metanol for å gi tittelforbindelsen (0,37 g) som hvite krystaller, smp. 158-160°C.
/
Eksempel
l-metyl-3-metylsulfonylmetyl-N-[3-[3-(1-piperidinylmetyl)-f enoksy ] propyl] - 1H- 1, 2 , 4- triazol- 5- amin .
Pereddiksyre (1,05 ml av en 6,IM oppløsning) i eddiksyre (7 ml) ble tilsatt til en iskjølt oppløsning av l-metyl-3-metyltiometyl-N-[3-[3-(1-piperidinylmetyl)fenoksy]propyl]-1H-1,2,4-triazol-5-amin (0,82 g) i eddiksyre (10 ml) med natriumace-tat (0,52 g) . Blandingen ble omrørt ved romtemperatur i 18 timer, natriumsulfitt (1,25 g) ble tilsatt og blandingen inndampet til tørrhet. Residuet ble gjort basisk til pH 8 med natriumbikar-bonatoppløsning, vasket med etylacetat, gjort basisk til pH 10 med natriumkarbonat og ekstrahert med etylacetat for å gi et skum (0,46 g). Dette ble krystallisert fra metylacetat-petroleter (kp. 60-80°C) for å gi tittelforbindelsen som et hvitt faststoff (0,22 g), smp. 121-122°C.
Funnet: C, 57,0; H, 7,4; N, 16,5;<C>20<H>31N5°3S krever: C'57,0; H'7,4; N'16'6%-
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8006806 | 1980-02-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO810681L true NO810681L (no) | 1981-08-31 |
Family
ID=10511754
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO810681A NO810681L (no) | 1980-02-28 | 1981-02-27 | Fremgangsmaate for fremstilling av farmasoeytisk aktive triazolderivater. |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US4670448A (no) |
| JP (2) | JPS56147777A (no) |
| KR (3) | KR850000668B1 (no) |
| AT (2) | AT380240B (no) |
| AU (1) | AU544357B2 (no) |
| BE (1) | BE887730A (no) |
| CA (1) | CA1158649A (no) |
| CH (1) | CH655104A5 (no) |
| CY (1) | CY1335A (no) |
| DE (1) | DE3107628A1 (no) |
| DK (1) | DK90681A (no) |
| ES (4) | ES8205208A1 (no) |
| FI (1) | FI76076C (no) |
| FR (1) | FR2477150A1 (no) |
| GB (1) | GB2075007B (no) |
| HK (1) | HK69186A (no) |
| IE (1) | IE50987B1 (no) |
| IL (1) | IL62229A (no) |
| IT (1) | IT1209846B (no) |
| KE (1) | KE3629A (no) |
| MY (1) | MY8500428A (no) |
| NL (2) | NL186812C (no) |
| NO (1) | NO810681L (no) |
| NZ (1) | NZ196365A (no) |
| SE (1) | SE448233B (no) |
| ZA (1) | ZA811331B (no) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57169452A (en) * | 1981-04-14 | 1982-10-19 | Teikoku Hormone Mfg Co Ltd | Novel phenoxyalkylamide derivative |
| EP0070097A1 (en) * | 1981-06-11 | 1983-01-19 | Glaxo Group Limited | 1,2,4-Triazole derivatives, processes for the preparation thereof and pharmaceutical compositions containing them |
| ES520031A0 (es) * | 1982-02-24 | 1984-04-01 | Glaxo Group Ltd | Un procedimiento para prepararacion de derivados del triazol. |
| CA1189508A (en) * | 1982-02-25 | 1985-06-25 | Roger Hayes | Heterocyclic derivatives as histamine h.sub.2- antagonists |
| GB8417194D0 (en) * | 1984-07-05 | 1984-08-08 | Boots Co Plc | Therapeutic agents |
| GB8628475D0 (en) * | 1986-11-28 | 1987-01-07 | Glaxo Group Ltd | Medicaments |
| GB8805268D0 (en) * | 1988-03-04 | 1988-04-07 | Glaxo Group Ltd | Medicaments |
| JP3328082B2 (ja) * | 1994-12-13 | 2002-09-24 | 日本カーバイド工業株式会社 | Ｎ−グアニジノチオ尿素塩及び３−アミノ−５−メルカプト−１，２，４−トリアゾールの製造方法 |
| EP1223932A4 (en) * | 1999-10-01 | 2003-01-15 | Smithkline Beecham Corp | COMPOUNDS AND METHODS |
| JP4564786B2 (ja) * | 2004-06-07 | 2010-10-20 | 株式会社日本ファインケム | １−置換―１―アミノグアニジン又はその塩、及びこれらの製造方法 |
| EP4196793A1 (en) | 2020-08-11 | 2023-06-21 | Université de Strasbourg | H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1419994A (en) * | 1973-05-03 | 1976-01-07 | Smith Kline French Lab | Heterocyclicalkylaminotheterocyclic compounds methods for their preparation and compositions comprising them |
| DE2835695A1 (de) * | 1977-08-29 | 1979-03-15 | Yamanouchi Pharma Co Ltd | Neue heterocyclische verbindungen, verfahren zu ihrer herstellung und arzneimittel, die diese enthalten |
| AR228941A1 (es) * | 1978-04-26 | 1983-05-13 | Glaxo Group Ltd | Procedimiento para preparar nuevos derivados de 3,5-diamino-1,2,4-triazol que son activos contra receptores histaminicos |
| GB2023133B (en) * | 1978-04-26 | 1982-09-08 | Glaxo Group Ltd | Heterocyclic derivatives |
| NO800583L (no) * | 1979-03-02 | 1980-09-03 | Glaxo Group Ltd | Fremgangsmaate for fremstilling av farmakologisk aktive triazolderivater |
-
1981
- 1981-02-26 CH CH1288/81A patent/CH655104A5/fr not_active IP Right Cessation
- 1981-02-26 FR FR8103847A patent/FR2477150A1/fr active Granted
- 1981-02-27 NZ NZ196365A patent/NZ196365A/en unknown
- 1981-02-27 NO NO810681A patent/NO810681L/no unknown
- 1981-02-27 SE SE8101311A patent/SE448233B/sv not_active IP Right Cessation
- 1981-02-27 BE BE0/203963A patent/BE887730A/fr unknown
- 1981-02-27 IE IE431/81A patent/IE50987B1/en unknown
- 1981-02-27 DE DE19813107628 patent/DE3107628A1/de active Granted
- 1981-02-27 GB GB8106314A patent/GB2075007B/en not_active Expired
- 1981-02-27 CA CA000371889A patent/CA1158649A/en not_active Expired
- 1981-02-27 ES ES499931A patent/ES8205208A1/es not_active Expired
- 1981-02-27 IL IL62229A patent/IL62229A/xx unknown
- 1981-02-27 AT AT0093981A patent/AT380240B/de not_active IP Right Cessation
- 1981-02-27 DK DK90681A patent/DK90681A/da not_active Application Discontinuation
- 1981-02-27 FI FI810619A patent/FI76076C/fi not_active IP Right Cessation
- 1981-02-27 NL NLAANVRAGE8100979,A patent/NL186812C/xx not_active IP Right Cessation
- 1981-02-27 IT IT8147905A patent/IT1209846B/it active
- 1981-02-27 AU AU67933/81A patent/AU544357B2/en not_active Ceased
- 1981-02-27 ZA ZA00811331A patent/ZA811331B/xx unknown
- 1981-02-27 CY CY133581A patent/CY1335A/xx unknown
- 1981-02-28 JP JP2929381A patent/JPS56147777A/ja active Granted
- 1981-02-28 KR KR1019810000669A patent/KR850000668B1/ko active
-
1982
- 1982-02-16 ES ES509669A patent/ES509669A0/es active Granted
- 1982-12-16 ES ES518305A patent/ES8405775A1/es not_active Expired
-
1983
- 1983-02-10 US US06/465,616 patent/US4670448A/en not_active Expired - Fee Related
-
1984
- 1984-03-16 ES ES530741A patent/ES8506292A1/es not_active Expired
- 1984-05-08 AT AT0151084A patent/AT387774B/de not_active IP Right Cessation
- 1984-08-18 KR KR1019840004976A patent/KR850000682B1/ko not_active IP Right Cessation
- 1984-08-20 KR KR1019840004977A patent/KR850000676B1/ko not_active IP Right Cessation
-
1985
- 1985-12-30 MY MY428/85A patent/MY8500428A/xx unknown
-
1986
- 1986-04-16 KE KE3629A patent/KE3629A/xx unknown
- 1986-09-18 HK HK691/86A patent/HK69186A/xx unknown
-
1988
- 1988-02-29 JP JP63047352A patent/JPS6452763A/ja active Pending
- 1988-09-09 NL NL8802221A patent/NL8802221A/nl not_active Application Discontinuation
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