NO762659L - - Google Patents
Info
- Publication number
- NO762659L NO762659L NO762659A NO762659A NO762659L NO 762659 L NO762659 L NO 762659L NO 762659 A NO762659 A NO 762659A NO 762659 A NO762659 A NO 762659A NO 762659 L NO762659 L NO 762659L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- sulfur
- amine
- methylthio
- lower alkyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 25
- -1 5-hydroxymethyl-4-imidazolyl Chemical group 0.000 claims description 18
- 150000001412 amines Chemical class 0.000 claims description 17
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 239000011593 sulfur Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 11
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 10
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Chemical group 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- JVYMKTAPCLSXLC-UHFFFAOYSA-N COClO Chemical group COClO JVYMKTAPCLSXLC-UHFFFAOYSA-N 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 3
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 3
- NXGHEDHQXXXTTP-UHFFFAOYSA-N 1,1-bis(methylsulfanyl)-2-nitroethene Chemical group CSC(SC)=C[N+]([O-])=O NXGHEDHQXXXTTP-UHFFFAOYSA-N 0.000 claims description 2
- XTBZYMOXUSCADZ-UHFFFAOYSA-N 1-methylsulfanyl-1-methylsulfinyl-2-nitroethene Chemical group CSC(S(C)=O)=C[N+]([O-])=O XTBZYMOXUSCADZ-UHFFFAOYSA-N 0.000 claims description 2
- ZWZCQZCIZDUWOS-UHFFFAOYSA-N 1-methylsulfanyl-2-nitroethene Chemical group CSC=C[N+]([O-])=O ZWZCQZCIZDUWOS-UHFFFAOYSA-N 0.000 claims description 2
- JUJABTAZEDTRRH-UHFFFAOYSA-N CS(C)C(S)=NC#N Chemical compound CS(C)C(S)=NC#N JUJABTAZEDTRRH-UHFFFAOYSA-N 0.000 claims description 2
- GJEAMHAFPYZYDE-UHFFFAOYSA-N [C].[S] Chemical compound [C].[S] GJEAMHAFPYZYDE-UHFFFAOYSA-N 0.000 claims description 2
- 150000003973 alkyl amines Chemical class 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- IULFXBLVJIPESI-UHFFFAOYSA-N bis(methylsulfanyl)methylidenecyanamide Chemical compound CSC(SC)=NC#N IULFXBLVJIPESI-UHFFFAOYSA-N 0.000 claims description 2
- SSGODMHQNTWPOX-UHFFFAOYSA-N cyanothiourea Chemical compound NC(=S)NC#N SSGODMHQNTWPOX-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 11
- 229960001340 histamine Drugs 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- BJERXDWXCSKSCV-UHFFFAOYSA-N ethyl 5-(ethoxymethyl)-1h-imidazole-4-carboxylate Chemical compound CCOCC=1NC=NC=1C(=O)OCC BJERXDWXCSKSCV-UHFFFAOYSA-N 0.000 description 2
- XHTHQRRQGWLZTB-UHFFFAOYSA-N ethyl 5-(ethoxymethyl)-2-sulfanylidene-1,3-dihydroimidazole-4-carboxylate Chemical compound C(C)OC(=O)C=1N=C(NC1COCC)S XHTHQRRQGWLZTB-UHFFFAOYSA-N 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 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
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- SODVIWFIWHJBNS-UHFFFAOYSA-N 1H-imidazole dihydrobromide Chemical compound Br.Br.C1=CNC=N1 SODVIWFIWHJBNS-UHFFFAOYSA-N 0.000 description 1
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- UFGQOXPKGIWTQF-UHFFFAOYSA-N [5-(2-aminoethylsulfanylmethyl)-1h-imidazol-4-yl]methanol Chemical compound NCCSCC=1NC=NC=1CO UFGQOXPKGIWTQF-UHFFFAOYSA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- RIMGDBZXWSGBQN-UHFFFAOYSA-N burimamide Chemical compound CNC(=S)NCCCCC1=CN=C[N]1 RIMGDBZXWSGBQN-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940097265 cysteamine hydrochloride Drugs 0.000 description 1
- 238000006477 desulfuration reaction Methods 0.000 description 1
- 230000023556 desulfurization Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- 229960000582 mepyramine Drugs 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- SDDKIZNHOCEXTF-UHFFFAOYSA-N methyl carbamimidothioate Chemical compound CSC(N)=N SDDKIZNHOCEXTF-UHFFFAOYSA-N 0.000 description 1
- VYHVQEYOFIYNJP-UHFFFAOYSA-N methyl thiocyanate Chemical compound CSC#N VYHVQEYOFIYNJP-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- 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
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
- C07D233/90—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)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
FARMAKOLOGISK AKTIVE FORBINDELSER.PHARMACOLOGICALLY ACTIVE COMPOUNDS.
Den foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstilling av farmakologisk aktive forbindelser og farmasoytiske midler som inneholder disse forbindelser. Forbindelsene, frem-stilt ved fremgangsmåten ifolge oppfinnelsen, er nyttige som histamin ^-antagonister og kan eksistere som syreaddisjons-.salter, men av bekvemmelighetsgrunner vil stamforbindelsene bli omtalt i den foreliggende beskrivelse. Histamin ^-antagonister kan defineres som forbindelser, som blokkerer histamin B.^-reseptorer. Histamin ^-reseptorer blokkeres ikke av mepyramin og typiske "antihistaminer", men blokkeres av burimamid (se Black med flere Nature 236, 385 (1972)). Histamin ^-antagonister er nyttige som inhibitorer for mavesyresekresjon som antiinflam-matoriske midler og som midler, som virker på det kardiovaskulære system. The present invention relates to a method for the production of pharmacologically active compounds and pharmaceutical agents containing these compounds. The compounds, produced by the method according to the invention, are useful as histamine 3 antagonists and may exist as acid addition salts, but for reasons of convenience the parent compounds will be discussed in the present description. Histamine B antagonists can be defined as compounds which block histamine B receptors. Histamine ^ receptors are not blocked by mepyramine and typical "antihistamines", but are blocked by burimamide (see Black et al. Nature 236, 385 (1972)). Histamine 3 antagonists are useful as inhibitors of gastric acid secretion, as anti-inflammatory agents, and as agents acting on the cardiovascular system.
Fremgangsmåteproduktene ifolge oppfinnelsen representeres ved formelen 1: The process products according to the invention are represented by formula 1:
Formel 1. Formula 1.
hvor n er 2 eller 3, Z er svovel eller metylen, X er svovel, CHNC>2eller NCN, Y er hydrogen, lavere alkyl eller HetCH2Zr(CH2)n,, Z' er svovel.eller metylen, ri' er 2 eller 3 og Het er 5-hydroksymetyl-4-imidazolyl, en imidazolring, som eventuelt er substituert med metyl eller brom, en pyridinring, som eventuelt er substituert where n is 2 or 3, Z is sulfur or methylene, X is sulfur, CHNC>2 or NCN, Y is hydrogen, lower alkyl or HetCH2Zr(CH2)n,, Z' is sulfur or methylene, ri' is 2 or 3 and Het is 5-hydroxymethyl-4-imidazolyl, an imidazole ring, which is optionally substituted with methyl or bromine, a pyridine ring, which is optionally substituted
med hydroksy, metoksy, klor eller brom, en tiazolring eller en isotiazolring. with hydroxy, methoxy, chlorine or bromine, a thiazole ring or an isothiazole ring.
Overalt i den foreliggende beskrivelse forstår man ved uttrykket "lavere alkyl", en alkylgruppe som inneholder fra 1-4 karbon-atomer. Throughout the present description, the term "lower alkyl" means an alkyl group containing from 1 to 4 carbon atoms.
En foretrukken gruppe forbindelser med formelen 1 er den, hvoriA preferred group of compounds of formula 1 is that wherein
Y er lavere alkyl, især metyl. En annen foretrukken gruppe er den, hvori Z er svovel og n er 2. X ér fortrinnsvis CHNO^eller NCN, Z<1>er fortrinnsvis svovel, n<1>er fortrinnsvis 2 og Het er fortrinnsvis 5-metyl-4-imidazolyl, 5-brom-4-imidazolyl, 3-hydroksy-2-pyridyl, 3-metoksy-2-pyridyl, 3-klor-2-pyridyl, 3-brom-2-pyridyl, 2-tiazolyl eller 3-isotiazolyl. Y is lower alkyl, especially methyl. Another preferred group is that in which Z is sulfur and n is 2. X is preferably CHNO^or NCN, Z<1> is preferably sulfur, n<1> is preferably 2 and Het is preferably 5-methyl-4-imidazolyl , 5-bromo-4-imidazolyl, 3-hydroxy-2-pyridyl, 3-methoxy-2-pyridyl, 3-chloro-2-pyridyl, 3-bromo-2-pyridyl, 2-thiazolyl or 3-isothiazolyl.
Forbindelsene med formelen 1, hvor X er CHNO^eller NCN kan fremstilles ved en fremgangsmåte, som omfatter trinnet The compounds of the formula 1, where X is CHNO^or NCN can be prepared by a process which comprises the step
I formelene 2, 3 og 4 er Het, Z og n som definert i formel 1, X er CHN02eller NCN, Q er lavere alkyl, B er SQ', OQ' (hvor Q' er lavere alkyl) eller NHY, hvor Y er som det er definert i formel 1, og A er svovel, oksygen eller, når X er CHN02og B er SQ<1>, SO. In formulas 2, 3 and 4, Het, Z and n are as defined in formula 1, X is CHN02 or NCN, Q is lower alkyl, B is SQ', OQ' (where Q' is lower alkyl) or NHY, where Y is as defined in formula 1, and A is sulfur, oxygen or, when X is CHN02 and B is SQ<1>, SO.
Noen foretrukkene fremgangsmåter, som faller innenfor dette almene skj erna er: 1) r Når QA og B begge er metyltio og X er NCN i formel 3. Dirnetyl-N-cyanoditioimidokarbonat behandles med en opplosning av en ekvivalent av et amin med formelen 2 ved romtemperatur og det frekomne N-cyanoisotiourinstoff behandles med et overskudd av et Some preferred methods, which fall within this general scheme are: 1) r When QA and B are both methylthio and X is NCN in formula 3. Dirnetyl-N-cyanodithioimidocarbonate is treated with a solution of one equivalent of an amine of formula 2 at room temperature and the resulting N-cyanoisothiourea is treated with an excess of et
amin INt^Y, hvor Y er som definert i formel 1.amine INt^Y, where Y is as defined in formula 1.
2) Når QA er. metylsulfinyl. B er metyltio og X er CHN02i formel 3. 1-metyltio-l-metylsulfinyl-2-nitroetylen behandles med en opplosning av en ekvivalent av et amin med formelen 2 ved ca. romtemperatur, og den fremkomne substituerte l-metyltio-2-nitroetylen behandles med et overskudd av et amin NH2Y, hvor Y 2) When QA is. methylsulfinyl. B is methylthio and X is CHN02 in formula 3. 1-methylthio-1-methylsulfinyl-2-nitroethylene is treated with a solution of one equivalent of an amine of formula 2 at approx. room temperature, and the resulting substituted 1-methylthio-2-nitroethylene is treated with an excess of an amine NH2Y, where Y
er som definert i formel 1. Når X er CHNO^. foretrekkes, det i alminnelig "het at QA er metyltio og B er metylsulf inyl eller is as defined in formula 1. When X is CHNO^. is preferred, generally that QA is methylthio and B is methylsulfinyl or
NHY. NHY.
3) Når QA og B begge er metyltio og X er CHN02 eller NCN i formel 3. N-cyano-dimetylditioimidokarbonat eller 1,1-bis-metyltio-2-nitroetylen behandles med minst to ekvivalenter av et amin med formel 2 og blandingen oppvarmes i pyridin for å danne en forbindelse med formel 1, hvor X er CHN02 eller NCN og Y er HetCH2Z'(CHj) ,, hvor Het er 5-hydroksymetyl-4-imidazolyl og Z<1>og n' er identiske med Z og n. 3) When QA and B are both methylthio and X is CHN02 or NCN in formula 3. N-cyano-dimethyldithioimidocarbonate or 1,1-bis-methylthio-2-nitroethylene is treated with at least two equivalents of an amine of formula 2 and the mixture is heated in pyridine to form a compound of formula 1, wherein X is CHN02 or NCN and Y is HetCH2Z'(CHj),, where Het is 5-hydroxymethyl-4-imidazolyl and Z<1>and n' are identical to Z and n.
Forbindelser med formelen 1, hvor X er svovel, kan fremstilles ved å.:behandle en forbindelse med formelen L-E, hvor L er benzoyl, lavere alkyl eller Het-CH^1 (CH^, - og E er NCS eller NHCS,SMe med et amin med formelen 2 eller når L er (5-hydroksymetyl-4-imi-dazolyl)CH2Z(CH2)nmed et lavere alkylamin. Compounds of formula 1, where X is sulfur, can be prepared by treating a compound of formula L-E, where L is benzoyl, lower alkyl or Het-CH^1 (CH^, - and E is NCS or NHCS,SMe with an amine of formula 2 or when L is (5-hydroxymethyl-4-imidazolyl)CH 2 Z(CH 2 ) n with a lower alkyl amine.
Forbindelser med formelen 1, hvor X er svovel, Het er 5-hydroksy-metyl-4-imidazolyl og Z' og n<1>er identiske med Z og N, kan fremstilles ved å behandle svovelkarbonstoff med to ekvivalenter av et amin med formelen 2. Compounds of formula 1, where X is sulfur, Het is 5-hydroxy-methyl-4-imidazolyl and Z' and n<1> are identical to Z and N, can be prepared by treating sulfur carbon with two equivalents of an amine of the formula 2.
Aminene med formelen 2 kan fremstilles ifolge det almene skjema. The amines of formula 2 can be prepared according to the general scheme.
Fremstilling av aminet med formelen 2, hvor Z er metylen kan begynne med en forbindelse med formelen 6: Preparation of the amine of formula 2, where Z is methylene, can begin with a compound of formula 6:
Formel 6 Formula 6
hvor n har samme betydning som i formel 1 og E=N er en passende beskyttet'amingruppe, f.eks. ftalimido. Reaksjon med denne forbindelse med formel 6 med acetylen i et egnet opplosningsmiddel og i nærvær av en Lewis syre, f.eks. AlCl^gir forbindelsen where n has the same meaning as in formula 1 and E=N is a suitable protected'amine group, e.g. phthalimido. Reaction of this compound of formula 6 with acetylene in a suitable solvent and in the presence of a Lewis acid, e.g. AlCl^ gives the compound
med formelen 7:with formula 7:
E=N(CH2)n+2COCH=CHClE=N(CH2)n+2COCH=CHCl
Formel 7Formula 7
som ved behandling med trifenylfosfin gir forbindelsen med formelen 8: which on treatment with triphenylphosphine gives the compound of formula 8:
E=N(CH2)n+2COCH=CHPPh3ClE=N(CH2)n+2COCH=CHPPh3Cl
Formel 8Formula 8
Når denne forbindelse bringes til å reagere med S-metylisotio-urinstoff er produktet imidazolderivatet med formelen 9: When this compound is reacted with S-methylisothio-urea, the product is the imidazole derivative of formula 9:
Formel 9 Formula 9
og når denne behandles med natriummetoksyd (jfr. den fremgangsmåte, som er beskrevet i Lewis' og Webb's amerikanske patentansokning, inngitt 29. oktober 1975) er produktet forbindelsen med formelen 10: and when this is treated with sodium methoxide (cf. the method described in Lewis and Webb's US patent application, filed October 29, 1975) the product is the compound of formula 10:
Formel 10 Formula 10
Desulfurisering av forbindelsen med formelen 10 med Raney nikkel for å fjerne 2-metyltiogruppen og å behandle med konsentrert salt syre til omdannelse av metoksymetyl til en hydroksymetylgruppe og for å fjerne aminbeskyttelsesgruppen, gir aminet med formelen 2, hvor Z er metylen. Desulfurization of the compound of formula 10 with Raney nickel to remove the 2-methylthio group and treatment with concentrated hydrochloric acid to convert the methoxymethyl to a hydroxymethyl group and to remove the amine protecting group gives the amine of formula 2, where Z is methylene.
Histamin H^-antagonistvirkningen av forbindelsene med formelen 1 demonstreres ved hemningen av histaminstimulert sekresjon av mavesyre fra lysbestrålte (lumenperfuserte) maver av rotter, anestetisert med uretan i doser fra 0, 5 - 256 |i mol pr. kg intra-venost. Farmasoytiske midler, som har anvendelighet som histamin<H>2_antagonister kan fremstilles ved å blande en forbindelse med The histamine H 2 -antagonist action of the compounds of formula 1 is demonstrated by the inhibition of histamine-stimulated secretion of gastric acid from light-irradiated (lumen perfused) stomachs of rats, anesthetized with urethane in doses from 0.5 - 256 |i mol per kg intra-venous. Pharmaceutical agents, which have utility as histamine<H>2_antagonists can be prepared by mixing a compound with
den forste formel i krav 1 i grunnformen eller i form av et syre-addisjonssalt med en farmasoytisk anvendelig syre med et farmasoytisk anvendelig fortynningsmiddel eller bærestoff. the first formula in claim 1 in the basic form or in the form of an acid addition salt with a pharmaceutically usable acid with a pharmaceutically usable diluent or carrier.
Oppfinnelsen illustreres, men begrenses ikke, av folgende eksempler, hvori alle temperaturer er i grader celcius. The invention is illustrated, but not limited, by the following examples, in which all temperatures are in degrees Celsius.
E ksempel 1 Example 1
N- metyl- N'-\ 2-(( 5- hydroks ymetyl-4- imida zolyl) metyltio)- etyl] tio-urins toff. N- methyl- N'-\ 2-((5- hydroxymethyl-4- imidazolyl) methylthio)-ethyl] thio-urin's toff.
(i) 24,8 g etyi-a-oksimino-(3-okso-y-etoksybutyrat ble langsomt(i) 24.8 g of ethyl-α-oximino-(3-oxo-γ-ethoxybutyrate was slowly
i lopet av 30 min. satt til en avkjolt (15°) godt omrort opplosning/suspensjon av 58,5 g stannokloriddihydrat i 97 ml konsentrert saltsyre, og deretter ble det tilsatt 1,2 g pulver-isert tinn. Etter to timer ble blandingen fortynnet med 300 ml vann, avkjolt til 0° og hydrogen-sulfid ble så ledet inn i opp-løsningen, som deretter ble filtrert. Oppløsningens pH-verdi ble innstilt til ca. 1,0 med natriumhydroksyd og en vandig opplosning av 10,3 g ammoniumticyanat ble tilsatt sammen med ytterligere natriumhydroksyd for å innstille pH-verdien til ca. 2,0. Etter oppvarming under omroring til 95° i 15 min. ble reaksjonsblandingen o in the course of 30 min. was added to a cooled (15°) well-stirred solution/suspension of 58.5 g of stannous chloride dihydrate in 97 ml of concentrated hydrochloric acid, and then 1.2 g of powdered tin was added. After two hours, the mixture was diluted with 300 ml of water, cooled to 0° and hydrogen sulphide was then introduced into the solution, which was then filtered. The solution's pH value was set to approx. 1.0 with sodium hydroxide and an aqueous solution of 10.3 g of ammonium thicyanate was added along with additional sodium hydroxide to adjust the pH to about 2.0. After heating with stirring to 95° for 15 min. became the reaction mixture o
avkjolt til 0 og etter henstand fremkom et sandfarvet bunnfall, som etter omkrystallisasjon fra vann gav 11,9 g 4-etoksykarbonyl--5-etoksymetyl-2-merkaptoimidazol, cooled to 0 and after standing a sand-coloured precipitate appeared, which after recrystallization from water gave 11.9 g of 4-ethoxycarbonyl-5-ethoxymethyl-2-mercaptoimidazole,
smp. 162,5-163°. m.p. 162.5-163°.
(ii) Til en omrort opplosning ved 40° av 11,9 g 4-etoksykarbonyl-5-etoksymetyl-2-merkaptoimidazol i 700 ml etanol ble det satt 55 g Raney nikkel, og blandingen ble oppvarmet under tilbakelop i 2 1/2 time. Etter avkjoling, filtrering og inndampning av filtratet ble resten omkrystallisert fra vann for å gi 6,1 g 4-etoksy-karbonyl-5-etoksymetylimidazol, smp. 143-144°.(iii) 6,0 g 4-etoksykarbonyl-5-etoksymetylimidazol ble opplost i 48% vandig bromhydrogensyre (650 ml) og oppvarmet under tilbakelop med 3,4 g cysteaminhydroklorid i 17 timer. Inndampning av reaksjonsblandingen til torrhet og omkrystallisasjon av butanol/ eter (15:85) gav 10,9 g 4-karboksy-5-[2-(aminoetyltio)metylJimida-zoldihydrobrorriid, (ii) To a stirred solution at 40° of 11.9 g of 4-ethoxycarbonyl-5-ethoxymethyl-2-mercaptoimidazole in 700 ml of ethanol was added 55 g of Raney nickel, and the mixture was heated under reflux for 2 1/2 hours . After cooling, filtering and evaporating the filtrate, the residue was recrystallized from water to give 6.1 g of 4-ethoxy-carbonyl-5-ethoxymethylimidazole, m.p. 143-144°. (iii) 6.0 g of 4-ethoxycarbonyl-5-ethoxymethylimidazole was dissolved in 48% aqueous hydrobromic acid (650 ml) and heated under reflux with 3.4 g of cysteamine hydrochloride for 17 hours. Evaporation of the reaction mixture to dryness and recrystallization from butanol/ether (15:85) gave 10.9 g of 4-carboxy-5-[2-(aminoethylthio)methylimidazole dihydrochloride,
smp. 219-220°. m.p. 219-220°.
(iv) En opplosning av 1,0.g 4-karboksy-5-[2-(aminoetyltio)metyl] imidazol dihydrobromid i 10 volum % svovelsyre (24 ml) ble elektrolysert i tre timer ved konstant strom (1,0 amp.) og 8-10 volt over en omrort kvikksolvkatode og platinaanode adskilt med en poros skive. (iv) A solution of 1.0 g of 4-carboxy-5-[2-(aminoethylthio)methyl] imidazole dihydrobromide in 10 vol% sulfuric acid (24 ml) was electrolyzed for three hours at constant current (1.0 amp. ) and 8-10 volts across a stirred mercury cathode and platinum anode separated by a porous disk.
Innstilling av pH-verdien til 9-10 med 8,3 g kaliumkarbonat og inndampning til torrhet gav en rest, som ble ekstrahert med varm isopropanol, og denne ekstrakt ble inndampet for å danne 0,4 g 5-hydroksymetyl-4-[2-(aminoetyltio)-metyl]-imidazol. (v) En vandig etanolisk opplosning (1:5, 6 ml) av 0,4 g 5-hydroksymetyl-4-[2-(aminoetyltio)metylJimidazol ble oppvarmet under tilbakelop med 0,2 g metyltiocyanat i 1/2 time. Etter avkjoling utskilte et bunnfallseg ved henstand og den overliggende væske ble inndampet for å danne en olje, som ble omkrystallisert fra acetonitril for å danne et hvitt fast stoff av 0,1 g N-metyl-N'-[2-((5-hydroksy-metyl-4-imidazolyl)-metyltio)etyl]tiourinstoff, smp. 138,5-139,5°. Adjusting the pH to 9-10 with 8.3 g of potassium carbonate and evaporating to dryness gave a residue, which was extracted with hot isopropanol, and this extract was evaporated to give 0.4 g of 5-hydroxymethyl-4-[2 -(aminoethylthio)-methyl]-imidazole. (v) An aqueous ethanolic solution (1:5, 6 ml) of 0.4 g of 5-hydroxymethyl-4-[2-(aminoethylthio)methylimidazole was heated under reflux with 0.2 g of methyl thiocyanate for 1/2 hour. After cooling, a precipitate separated on standing and the supernatant was evaporated to give an oil, which was recrystallized from acetonitrile to give a white solid of 0.1 g of N-methyl-N'-[2-((5- hydroxy-methyl-4-imidazolyl)-methylthio)ethyl]thiourea, m.p. 138.5-139.5°.
Funn: C, 41,59, H, 6,37, N, 21,38%, C H N OS_Found: C, 41.59, H, 6.37, N, 21.38%, C H N OS_
9 16 4 2 9 16 4 2
Beregnet: C, 41,51, H, 6,19, N, 21,52%.Calculated: C, 41.51, H, 6.19, N, 21.52%.
Eksempel 2 Example 2
N-metyl- N' - cyano- KP-f2-(( 5- hydroksvmetvl- 4- imida zolyl)- metyltio) etylIquanidin N-methyl-N'-cyano-KP-f2-((5- hydroxymethyl-4- imidazolyl)-methylthio) ethylIquanidine
Til en opplosning av 0,4 g 5-hydroksymetyl-4-(2-aminoetyltio)metyl-imidazol i 3 ml etanol ble det satt en etanolisk opplosning av dimetylcyanoditioimidokarbonat (0,3 g), og det ble omrort ved 15° i 2 timer. Avdampning av opplosningsmiddelet gav som en olje To a solution of 0.4 g of 5-hydroxymethyl-4-(2-aminoethylthio)methyl-imidazole in 3 ml of ethanol was added an ethanolic solution of dimethylcyanodithioimidocarbonate (0.3 g), and it was stirred at 15° for 2 hours. Evaporation of the solvent gave as an oil
• S-metyl-N-cyano-N1-[2-((5-hydroksymetyl-4-imidazolylmetyltio)etyl ] isotiourinstoff, hvortil det ble satt et overskudd av en etanolisk opplosning av metylamin (7 g). Etter omroring i 70 timer ble reaksjonsblandingen renset ved preparativ tyntlagskromatografi for å danne tittelproduktet som en olje (0,1 g). Produktets struk-tur, ble bekreftet ved NMR-spektrum i D20 som viste folgende resonanser: • S-methyl-N-cyano-N1-[2-((5-hydroxymethyl-4-imidazolylmethylthio)ethyl ] isothiourea, to which was added an excess of an ethanolic solution of methylamine (7 g). After stirring for 70 hours the reaction mixture was purified by preparative thin layer chromatography to give the title product as an oil (0.1 g). The structure of the product was confirmed by NMR spectrum in D 2 O which showed the following resonances:
Claims (6)
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GB31968/75A GB1565647A (en) | 1975-07-31 | 1975-07-31 | Pharmacologically active compounds 4-substituted-imidazole-5-methanols |
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BE (1) | BE843840A (en) |
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DK (1) | DK316376A (en) |
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FR (1) | FR2319341A1 (en) |
GB (1) | GB1565647A (en) |
GR (1) | GR61114B (en) |
HU (1) | HU174068B (en) |
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US4165378A (en) | 1977-04-20 | 1979-08-21 | Ici Americas Inc. | Guanidine derivatives of imidazoles and thiazoles |
GR62452B (en) | 1977-04-20 | 1979-04-12 | Ici Ltd | Preparation process of guanidine derivatives |
US4112234A (en) | 1977-08-22 | 1978-09-05 | Bristol-Myers Company | Imidazolylmethylthioethyl alkynyl guanidines |
USRE31588E (en) * | 1977-06-03 | 1984-05-22 | Bristol-Myers Company | Imidazolylmethylthioethyl alkynyl guanidines |
US4233302A (en) | 1977-12-23 | 1980-11-11 | Glaxo Group Limited | Amine derivatives and pharmaceutical compositions containing them |
EP0008596A1 (en) * | 1978-09-04 | 1980-03-19 | DEVINTER Europe S.A. Société anonyme dite: | Preparation of 4-hydroxymethyl-imidazole derivatives from the corresponding 4-imidazole carboxylic acid esters |
US4200760A (en) * | 1978-09-26 | 1980-04-29 | Bristol-Myers Company | Imidazolylalkylthioalkylamino-ethylene derivatives |
JPS5914460B2 (en) * | 1978-12-27 | 1984-04-04 | 相互薬工株式会社 | Production method of cimetidine, an anti-H↓2 receptor |
CN103288742A (en) * | 2013-06-04 | 2013-09-11 | 四川百利药业有限责任公司 | Preparation method for high-purity ingavirin raw material |
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 |
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- 1976-07-30 AU AU16447/76A patent/AU508262B2/en not_active Expired
- 1976-07-30 JP JP51092242A patent/JPS5219663A/en active Pending
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DE2634430A1 (en) | 1977-02-10 |
GR61114B (en) | 1978-09-13 |
CA1075702A (en) | 1980-04-15 |
ES450309A1 (en) | 1977-12-01 |
HU174068B (en) | 1979-10-28 |
RO72312B (en) | 1984-03-31 |
BE843840A (en) | 1977-01-06 |
IL50006A0 (en) | 1976-09-30 |
ZA763686B (en) | 1977-05-25 |
DD125205A5 (en) | 1977-04-06 |
PT65377A (en) | 1976-08-01 |
SE7608478L (en) | 1977-02-01 |
FR2319341B1 (en) | 1979-01-12 |
NL7608505A (en) | 1977-02-02 |
DK316376A (en) | 1977-02-01 |
SU655310A3 (en) | 1979-03-30 |
FI762191A (en) | 1977-02-01 |
LU75495A1 (en) | 1977-03-03 |
AT356668B (en) | 1980-05-12 |
CS203054B2 (en) | 1981-02-27 |
FR2319341A1 (en) | 1977-02-25 |
ATA552376A (en) | 1979-10-15 |
AU1644776A (en) | 1978-02-02 |
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