NO763812L - - Google Patents
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- Publication number
- NO763812L NO763812L NO763812A NO763812A NO763812L NO 763812 L NO763812 L NO 763812L NO 763812 A NO763812 A NO 763812A NO 763812 A NO763812 A NO 763812A NO 763812 L NO763812 L NO 763812L
- Authority
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- Norway
- Prior art keywords
- formula
- het
- compound
- methyl
- reacted
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 31
- 150000001412 amines Chemical class 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000005864 Sulphur Substances 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- UCFFGYASXIPWPD-UHFFFAOYSA-N methyl hypochlorite Chemical group COCl UCFFGYASXIPWPD-UHFFFAOYSA-N 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 1
- -1 4-imidazolyl Chemical group 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 5
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 5
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- 239000003456 ion exchange resin Substances 0.000 description 4
- 229920003303 ion-exchange polymer Polymers 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- XLPKHGNAYJQMRC-UHFFFAOYSA-N 1-[2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]ethyl]-2-[2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]propyl]guanidine;trihydrochloride Chemical compound Cl.Cl.Cl.N1C=NC(C)=C1CSC(C)CNC(=N)NCCSCC=1NC=NC=1C XLPKHGNAYJQMRC-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 102000003710 Histamine H2 Receptors Human genes 0.000 description 2
- 108090000050 Histamine H2 Receptors Proteins 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- UBHDUFNPQJWPRQ-UHFFFAOYSA-N (5-methyl-1h-imidazol-3-ium-4-yl)methanol;chloride Chemical compound Cl.CC=1NC=NC=1CO UBHDUFNPQJWPRQ-UHFFFAOYSA-N 0.000 description 1
- KCOYHFNCTWXETP-UHFFFAOYSA-N (carbamothioylamino)thiourea Chemical class NC(=S)NNC(N)=S KCOYHFNCTWXETP-UHFFFAOYSA-N 0.000 description 1
- FNNQKDIXJANKOJ-UHFFFAOYSA-N 1,2-bis[2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]propyl]guanidine Chemical compound N1C=NC(C)=C1CSC(C)CNC(=N)NCC(C)SCC=1NC=NC=1C FNNQKDIXJANKOJ-UHFFFAOYSA-N 0.000 description 1
- CHCIGVSHMUCKSA-UHFFFAOYSA-N 1,2-bis[2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]propyl]guanidine;trihydrochloride Chemical compound Cl.Cl.Cl.N1C=NC(C)=C1CSC(C)CNC(=N)NCC(C)SCC=1NC=NC=1C CHCIGVSHMUCKSA-UHFFFAOYSA-N 0.000 description 1
- XSAXLPYZTXJUDU-UHFFFAOYSA-N 2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]ethylthiourea Chemical compound CC=1N=CNC=1CSCCNC(N)=S XSAXLPYZTXJUDU-UHFFFAOYSA-N 0.000 description 1
- HYSZRUJKUKKFRL-UHFFFAOYSA-N 2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]propan-1-amine Chemical compound NCC(C)SCC=1N=CNC=1C HYSZRUJKUKKFRL-UHFFFAOYSA-N 0.000 description 1
- BKYGRLQMOFGPPF-UHFFFAOYSA-N 2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]propan-1-amine;dihydrobromide Chemical compound Br.Br.NCC(C)SCC=1N=CNC=1C BKYGRLQMOFGPPF-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- HCZBCEYVAPRCDV-UHFFFAOYSA-N 2-sulfanylpropylazanium;chloride Chemical compound Cl.CC(S)CN HCZBCEYVAPRCDV-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
- OVFUUSPKWADLNJ-UHFFFAOYSA-N 5-methyl-4-nitro-2-(4-nitrophenyl)-4h-pyrazol-3-one Chemical compound O=C1C([N+]([O-])=O)C(C)=NN1C1=CC=C([N+]([O-])=O)C=C1 OVFUUSPKWADLNJ-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- NPPYCTSQYCMZIB-UHFFFAOYSA-N [amino(methylsulfanyl)methylidene]-[2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]ethyl]azanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CSC(N)=[NH+]CCSCC=1N=CNC=1C.CSC(N)=[NH+]CCSCC=1N=CNC=1C NPPYCTSQYCMZIB-UHFFFAOYSA-N 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 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
- 235000010233 benzoic acid Nutrition 0.000 description 1
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 description 1
- UHNOAGDNODCLKN-UHFFFAOYSA-N bromine;pyridine Chemical group [Br].C1=CC=NC=C1 UHNOAGDNODCLKN-UHFFFAOYSA-N 0.000 description 1
- RIMGDBZXWSGBQN-UHFFFAOYSA-N burimamide Chemical compound CNC(=S)NCCCCC1=CN=C[N]1 RIMGDBZXWSGBQN-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 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
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002541 isothioureas 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
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- OPGQGYQPVOWUOO-UHFFFAOYSA-N methyl n'-[2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]ethyl]carbamimidothioate;hydroiodide Chemical compound I.CSC(=N)NCCSCC=1N=CNC=1C OPGQGYQPVOWUOO-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- MCWKMMXOIRBRQD-UHFFFAOYSA-N n-(dichloromethylidene)benzamide Chemical compound ClC(Cl)=NC(=O)C1=CC=CC=C1 MCWKMMXOIRBRQD-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-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
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)
Description
Denne oppfinnelse angår en fremgangsmåte for fremstillingThis invention relates to a method for manufacturing
av farmakologisk aktive forbindelser. Forbindelsene som frem-of pharmacologically active compounds. The compounds that
stilles ved fremgangsmåten ifølge oppfinnelsen, har nyttig histamin H2-antagonistaktivitet• Disse forbindelser kan eksistere som syreaddisjonssalter, men av praktiske grunner vil det i det følgende henvises til stamforbindelsene.Histamin H2~antagonister kan defineres som forbindelser som blokkerer histamin H2~reseptorer. Histamin H2-reseptorer blokkeres ikke av mepyramin og typiske "antihistaminer" (histamin H-^-reseptorantagonister) , men blokkeres av burimamid (se Black et al. Nature, 236, 385 (1972)). produced by the method according to the invention, has useful histamine H2-antagonist activity • These compounds can exist as acid addition salts, but for practical reasons reference will be made below to the parent compounds. Histamine H2-antagonists can be defined as compounds that block histamine H2-receptors. Histamine H 2 receptors are not blocked by mepyramine and typical "antihistamines" (histamine H 2 -receptor antagonists), but are blocked by burimamide (see Black et al. Nature, 236, 385 (1972)).
Histamin ^-antagonister er nyttige som inhibitorer for mavesyre-sekresjon, som antiinflammatoriske midler og som midler som virker på det kardiovaskulære system. Histamine ^-antagonists are useful as inhibitors of gastric acid secretion, as anti-inflammatory agents and as agents acting on the cardiovascular system.
Forbindelsene som fremstilles ifølge foreliggende fremgangsmåte, har den generelle formel I: The compounds produced according to the present method have the general formula I:
hvor Het^ og Het^hver kan bety imidazol som eventuelt er substituert med metyl eller brom; pyridin som eventuelt er substituert med hydroksyl, metoksy, klor eller brom; tiazol eller isotiazol; X er svovel, NH, NOH, NCN eller CHN02; og B-j^ og B2er lavere alkylengrupper slik at enten er B1(CH2)2eller (CH-^-j °9 hvor R er metyl eller etyl, ellerB^ogB2er begge valgt fra Det vil forstås at den struktur som er vist i formel I, bare er en av flere mulige former og at andre tautomere former også omfattes av formelen. Med betegnelsen "lavere alkyl" skal her forstås en alkylgruppe inneholdende fra 1 til.4 karbonatomer. I en foretrukket gruppe forbindelser er B, (CH2)2, °9 where Het^ and Het^ can each mean imidazole optionally substituted with methyl or bromine; pyridine optionally substituted with hydroxyl, methoxy, chlorine or bromine; thiazole or isothiazole; X is sulfur, NH, NOH, NCN or CHN02; and B-j^ and B2 are lower alkylene groups such that either B1 is (CH2)2 or (CH-^-j °9 where R is methyl or ethyl, or B^ and B2 are both selected from It will be understood that the structure shown in formula I, is only one of several possible forms and that other tautomeric forms are also covered by the formula. The term "lower alkyl" is here understood to mean an alkyl group containing from 1 to 4 carbon atoms. In a preferred group of compounds, B, (CH2)2, ° 9
Det foretrekkes også at Het^ og Het2er valgt It is also preferred that Het 2 and Het 2 are selected
fra 4-imidazolyl som eventuelt er substituert med 5-metyl eller 5-brom; 2-pyridyl som eventuelt er substituert med 3-hydroksyl, 3-metoksy, 3-brom eller 3-klor; 2-tiazolyl og 3-isotiazolyl. from 4-imidazolyl optionally substituted with 5-methyl or 5-bromo; 2-pyridyl which is optionally substituted with 3-hydroxyl, 3-methoxy, 3-bromo or 3-chloro; 2-thiazolyl and 3-isothiazolyl.
X er fortrinnsvis NH, NCN, svovel eller CHN02.X is preferably NH, NCN, sulfur or CHN02.
Forbindelsene med formel I kan fremstilles fra de tilsvarende aminer med formlene Ila og Ilb. The compounds of formula I can be prepared from the corresponding amines of formulas IIa and IIb.
hvor Het^, Het2, B^ og B2har de ovenfor angitte betydninger. where Het^, Het2, B^ and B2 have the meanings given above.
Fremstilling av en forbindelse med formel I hvor X er NH, skjer ved at aminet med formel Ila eller Ilb omsettes med et isotiourinstoff med henholdsvis formel Illb eller Illa: hvor Het^, Het2, B^ og B2har de ovenfor angitte betydninger, og A er lavere alkyl. Isotiourinstoffet med formel Illa dannes fra det tilsvarende amin med formel. Ila ved omsetning av sistnevnte med benzoylisotiocyanat for å danne en forbindelse med formel IV: Preparation of a compound of formula I where X is NH takes place by reacting the amine of formula Ila or Ilb with an isothiourea of formula Illb or Illa, respectively: where Het^, Het2, B^ and B2 have the meanings given above, and A is lower alkyl. The isothiourea of formula Illa is formed from the corresponding amine of formula. Ila by reacting the latter with benzoyl isothiocyanate to form a compound of formula IV:
hvor Het^og B-^har de ovenfor angitte betydninger, og Q er benzoyl, denne forbindelse hydrolyseres for å danne det tilsvarende tiourinstoff hvor Q er hydrogen, og sistnevnte forbindelse omsettes med et lavere alkylhalogenid så som et lavere alkyljodid. På samme måte kan isotiourinstoffet med formel Illb fremstilles fra aminet med formel Ilb. where Het^ and B-^ have the meanings given above, and Q is benzoyl, this compound is hydrolyzed to form the corresponding thiourea where Q is hydrogen, and the latter compound is reacted with a lower alkyl halide such as a lower alkyl iodide. In the same way, the isothiourea of formula IIb can be prepared from the amine of formula IIb.
Alternativt kan forbindelsene med formel I hvor X er NH, fremstilles ved at en forbindelse med formel V: Alternatively, the compounds of formula I where X is NH can be prepared by a compound of formula V:
hvor A er lavere alkyl og X"*" er NQ, idet Q er benzoyl, omsettes først med en ekvimolar mengde av et av aminene med formel Ila eller Ilb, og derefter omsettes det resulterende produkt med det annet amin med formel Ilb eller Ila. Endelig fjernes benzoyl-gruppen ved hydrolyse. I dette tilfelle, hvor det ønskes å frem-stille forbindelsen med formel I hvor hver Het^og B^er identisk med tilsvarende Het2og B2, kan forbindelsen med formel V omsettes i en enkeltrinnsreaksjon med to eller flere ekvivalenter av aminet med formel Ila. Ved en variasjon av denne metode kan forbindelsen med formel II erstattes med en forbindelse med formelen C12C=X hvor X har den ovenfor angitte betydning. ;Omsetningene som er beskrevet i det foregående avsnitt, kan også anvendes for fremstilling av forbindelser med formel I hvor X er en NCN eller CHN02. I dette tilfelle er X<1>i formel V NCN eller CHN02, og det siste hydrolysetrinn er selvsagt ikke nødvendig. ;Forbindelsene med formel I hvor X er svovel, fremstilles ved at aminet med formel Ila eller Ilb omsettes med en ditio-karbamidsyreester med formel VIb eller Via. ; hvor Het^, Het2, B^og B2har de ovenfor angitte betydninger, og A er lavere alkyl. Ditiokarbamidsyreestrene med formel Via og VIb dannes fra de tilsvarende aminer med formel Ila og Ilb ved omsetning av sistnevnte med karbondisulfid og et lavere alkyl- ;halogenid eller -sulfat. Når. Het^og er identisk med henholdsvis Het2 og B2, kan de ønskede forbindelser med formel I hvor X er svovel, fremstilles direkte ved at karbondisulfid omsettes med 2 ekvivalenter av aminet med formel II. ;Forbindelsene med formel I hvor X er NOH, kan fremstilles fra de forbindelser hvor X er svovel, ved at sistnevnte forbindelse omsettes med et lavere alkylhalogenid for å danne det tilsvarende isotiourinstoff, og derefter omsettes dette isotio-urinstof f med hydroksylamin. ;Aminene med formel II kan fremstilles ved at en forbindelse med formel VII ; hvor Het har samme betydning som Het^og Het2i formel I og L er hydroksyl, halogen eller metoksy, omsettes med en amintiol med formel VIII ; hvor B"*" har samme betydning som B^og B2i formel I. Amintiplene med formel VIII er kjente forbindelser. where A is lower alkyl and X"*" is NQ, Q being benzoyl, is first reacted with an equimolar amount of one of the amines of formula Ila or Ilb, and then the resulting product is reacted with the other amine of formula Ilb or Ila. Finally, the benzoyl group is removed by hydrolysis. In this case, where it is desired to produce the compound of formula I where each Het 2 and B 2 are identical to the corresponding Het 2 and B 2 , the compound of formula V can be reacted in a single-step reaction with two or more equivalents of the amine of formula IIa. In a variation of this method, the compound of formula II can be replaced with a compound of the formula C12C=X where X has the above meaning. The reactions described in the previous section can also be used for the preparation of compounds of formula I where X is an NCN or CHN02. In this case, X<1> in formula V is NCN or CHN02, and the last hydrolysis step is of course not necessary. The compounds of formula I where X is sulphur, are prepared by reacting the amine of formula Ila or Ilb with a dithiocarbamic acid ester of formula VIb or Via. ; where Het₂, Het₂, B₂ and B₂ have the meanings given above, and A is lower alkyl. The dithiourea esters of formula Via and VIb are formed from the corresponding amines of formula Ila and Ilb by reacting the latter with carbon disulfide and a lower alkyl halide or sulfate. When. Het^ and is identical to Het2 and B2 respectively, the desired compounds of formula I where X is sulphur, can be prepared directly by reacting carbon disulphide with 2 equivalents of the amine of formula II. The compounds of formula I where X is NOH can be prepared from the compounds where X is sulphur, by reacting the latter compound with a lower alkyl halide to form the corresponding isothiourea, and then reacting this isothiourea with hydroxylamine. The amines of formula II can be prepared by a compound of formula VII; where Het has the same meaning as Het^ and Het2 in formula I and L is hydroxyl, halogen or methoxy, is reacted with an amine thiol of formula VIII; where B"*" has the same meaning as B^ and B2 in formula I. The amine groups of formula VIII are known compounds.
Histamin H2_antagonist-aktiviteten for forbindelsene med formel I påvises ved deres evne til å hemme histaminstimulért utskillelse av mavesyre fra lumen-perfuserte maver fra rotter bedøvet med uretan, i intravenøse doser fra 0,5 til 256 mikromol pr. kg. The histamine H 2 -antagonist activity of the compounds of formula I is demonstrated by their ability to inhibit histamine-stimulated secretion of gastric acid from lumen-perfused stomachs of rats anesthetized with urethane, at intravenous doses from 0.5 to 256 micromol per kg.
Farmasøytiske preparater som kan anvendes som histamin H2~antagonister, kan fremstilles ved at en forbindelse med formel I i baseform eller i form av et syreaddisjonssalt med en farmasøytisk godtagbar syre, blandes med et farmasøytisk godtag-bart fortynningsmiddel eller bæremiddel. Pharmaceutical preparations that can be used as histamine H2-antagonists can be prepared by mixing a compound of formula I in base form or in the form of an acid addition salt with a pharmaceutically acceptable acid with a pharmaceutically acceptable diluent or carrier.
De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere. The following examples shall serve to further illustrate the invention.
Eksempel 1 Example 1
N-[ 2-( 4- metyl- 5- imidazolylmetyltio) etyl]- N'-[ 2- ( 4- metyl- 5-imidazolylmetyltio) propyl] guanidin- trihydroklorid (i) En oppløsning av 4-hydroksymetyl-5-metylimidazol-hydroklorid (14,8 g) og 2-merkaptopropylamin-hydroklorid (12,8 g) i vandig bromhydrogensyre (48%, 100 ml) ble oppvarmet under tilbakeløpskjøling i 6 timer, konsentrert og omkrystal-lisert fra etanol-eter for å gi 2-[4-metyl-5-imidazolylmetyltio]-propylamin-dihydrobromid (30,0 g), sm.p. 177-178°. (ii) En oppløsning av N-[2-((5-metyl-4-imidazolyl)metyltio)-etyl]tiourinstoff (2,29 g) og metyljodid (1,56 g) i metanol (5 ml) ble holdt ved romtemperatur i 18 timer for å gi S-metyl-N-[2-((5-metyl-4-imidazolyl)metyltio)etyl]tiouroniumjodid (2,3 g), sm.p. 128-131°. Jodidet ble omdannet til det tilsvarende sulfat ved ionebytting på en ionebytterharpiks (IRA 401) i sulfatform. (iii) En oppløsning av 2-[4-metyl-4-imidazolylmetyltio]-propylamin (4,0 g, fra dihydrobromidet) og S-metyl-N-[2-((4-metyl-5-imidazolyl)metyltio)etyl]tiouroniumsulfat (3,35 g) i vann (25 ml) ble oppvarmet under tilbakeløpskjøling i 4 timer. Konsentrering, fulgt av rensning på ionebytterharpiks C.G. 50 (H<+>) med eluering med 0,02N saltsyre, behandling med natriumhydroksyd og pikrolonsyre ga N-[2-(4-metyl-5-imidazolylmetyltio)propyl]- guanidin-tripikrolonat(1,75 g, sm.p. 173-175°C, fra vandig dimetylformamid). N-[ 2-( 4- methyl- 5- imidazolylmethylthio) ethyl]- N'-[ 2-( 4- methyl- 5- imidazolylmethylthio) propyl] guanidine trihydrochloride (i) A solution of 4-hydroxymethyl-5-methylimidazole -hydrochloride (14.8 g) and 2-mercaptopropylamine hydrochloride (12.8 g) in aqueous hydrobromic acid (48%, 100 mL) were heated under reflux for 6 h, concentrated and recrystallized from ethanol-ether to give 2-[4-methyl-5-imidazolylmethylthio]-propylamine dihydrobromide (30.0 g), m.p. 177-178°. (ii) A solution of N-[2-((5-methyl-4-imidazolyl)methylthio)-ethyl]thiourea (2.29 g) and methyl iodide (1.56 g) in methanol (5 mL) was kept at room temperature for 18 hours to give S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiouronium iodide (2.3 g), m.p. 128-131°. The iodide was converted to the corresponding sulfate by ion exchange on an ion exchange resin (IRA 401) in sulfate form. (iii) A solution of 2-[4-methyl-4-imidazolylmethylthio]-propylamine (4.0 g, from the dihydrobromide) and S-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio) ethyl]thiouronium sulfate (3.35 g) in water (25 mL) was heated under reflux for 4 h. Concentration, followed by purification on ion exchange resin C.G. 50 (H<+>) with elution with 0.02N hydrochloric acid, treatment with sodium hydroxide and picrolonic acid gave N-[2-(4-methyl-5-imidazolylmethylthio)propyl]- guanidine tripicrolonate (1.75 g, m.p. 173-175°C, from aqueous dimethylformamide).
C16H27N7S2'3C10H8N4°5 krever: c 47^!'H 4'4'N 22,7, S 5,5% Funnet: C 46,9, H4,5, N 21,9, S 5,1%.) C16H27N7S2'3C10H8N4°5 required: c 47^!'H 4'4'N 22.7, S 5.5% Found: C 46.9, H4.5, N 21.9, S 5.1%.)
Tripikrolonatet ble suspendert i vandig étanol og behandlet med ionebytterharpiks IRA 400 (Cl~) og surgjort med saltsyre for å danne det tilsvarende trihydrokloridsalt. The tripicrolonate was suspended in aqueous ethanol and treated with ion exchange resin IRA 400 (Cl~) and acidified with hydrochloric acid to form the corresponding trihydrochloride salt.
(C16H27N7S2'3HC1 krever: cl 21,7%(C16H27N7S2'3HC1 requires: cl 21.7%
Funnet: Cl 22,1%).Found: Cl 22.1%).
E ksempel 2 Example 2
N, N'- bis-[ 2-( 4- metyl- 5- imidazolylmetyltio) propyl] guanidin, trihydroklorid N, N'- bis-[ 2-( 4- methyl- 5- imidazolylmethylthio) propyl] guanidine, trihydrochloride
(i) En oppløsning av 2-[4-metyl-5-imidazolylmetyltio]-propylamin (fra dihydrobromidet, 13,0 g) i etanol (50 ml) ble av-kjølt til 0°C og omrørt under gradvis tilsetning av benzoylimino- diklormetan (3,78 g). Efter tilsetningen ble reaksjonsblandingen satt til side ved romtemperatur i 2 timer og ble oppvarmet på dampbad i 0,5 time. Efter tilsetning til vann og fjernelse av uoppløselig materiale ved filtrering, ble filtratet regulert til pH 9. Det oppnådde råprodukt ble renset ved kromatografi på en kolonne av aluminiumoksyd fulgt av kromatografisk rensning på en kolonne av silikagel (kloroform-metanol) for å gi N-benzoyl-N\,-N"-bis-[2-(4-metyl-5-imidazolylmetyltio)-propyl]guanidin. (ii) Benzoylforbindelsen (3,2 g) ble hydrolysert i konsentrert saltsyre (40 ml) ved dampbad-temperatur i 5 timer. Efter av-kjøling, fortynning med vann og ekstrahering med eter for å fjerne benzoesyre, ble produktet renset som i eksempel 1 og konsentrert til pikrolonatet (1,35 g), sm.p. 230°C (spaltn.). (i) A solution of 2-[4-methyl-5-imidazolylmethylthio]-propylamine (from the dihydrobromide, 13.0 g) in ethanol (50 mL) was cooled to 0°C and stirred while gradually adding benzoyl imino- dichloromethane (3.78 g). After the addition, the reaction mixture was set aside at room temperature for 2 hours and was heated on a steam bath for 0.5 hour. After addition to water and removal of insoluble material by filtration, the filtrate was adjusted to pH 9. The crude product obtained was purified by chromatography on a column of alumina followed by chromatographic purification on a column of silica gel (chloroform-methanol) to give N- benzoyl-N\,-N"-bis-[2-(4-methyl-5-imidazolylmethylthio)-propyl]guanidine. (ii) The benzoyl compound (3.2 g) was hydrolyzed in concentrated hydrochloric acid (40 ml) on a steam bath temperature for 5 hours. After cooling, diluting with water and extracting with ether to remove benzoic acid, the product was purified as in Example 1 and concentrated to the picrolonate (1.35 g), m.p. 230°C (dec. ).
Pikrolonatet ble oppløst i vandig metanol og behandlet med ionebytterharpiks IRA 401 (Cl ) og surgjort med saltsyre for å gi N,N'-bis-[2-(4-metyl-5-imidazolylmetyltio)propyl]guanidin-trihydroklorid . The picrolonate was dissolved in aqueous methanol and treated with ion exchange resin IRA 401 (Cl ) and acidified with hydrochloric acid to give N,N'-bis-[2-(4-methyl-5-imidazolylmethylthio)propyl]guanidine trihydrochloride.
NMR-spekteret.for en oppløsning i D20 registrert vedThe NMR spectrum.for a solution in D20 recorded at
100 mHz viste de følgende resonanser:100 mHz they showed the following resonances:
Claims (2)
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GB46732/75A GB1573611A (en) | 1975-11-12 | 1975-11-12 | Heterocyclic thioalkyl-amines-guanidines and -thioureas |
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DE (1) | DE2649546A1 (en) |
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ES (1) | ES453263A1 (en) |
FI (1) | FI763209A (en) |
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GB (1) | GB1573611A (en) |
HU (1) | HU175667B (en) |
IE (1) | IE44103B1 (en) |
IL (1) | IL50748A0 (en) |
LU (1) | LU76162A1 (en) |
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NO (1) | NO763812L (en) |
NZ (1) | NZ182309A (en) |
PT (1) | PT65759B (en) |
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SU (1) | SU634668A3 (en) |
ZA (1) | ZA766201B (en) |
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1975
- 1975-11-12 GB GB46732/75A patent/GB1573611A/en not_active Expired
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- 1976-10-21 AU AU18900/76A patent/AU508143B2/en not_active Expired
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FR2331342B1 (en) | 1980-03-07 |
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IE44103B1 (en) | 1981-08-12 |
ATA819776A (en) | 1978-11-15 |
SE7611405L (en) | 1977-05-13 |
ZA766201B (en) | 1977-09-28 |
BE848108A (en) | 1977-05-09 |
DE2649546A1 (en) | 1977-05-26 |
FI763209A (en) | 1977-05-13 |
ES453263A1 (en) | 1978-01-16 |
HU175667B (en) | 1980-09-28 |
LU76162A1 (en) | 1977-05-18 |
NZ182309A (en) | 1978-07-10 |
AT350583B (en) | 1979-06-11 |
GB1573611A (en) | 1980-08-28 |
PT65759B (en) | 1978-04-27 |
FR2331342A1 (en) | 1977-06-10 |
JPS5262274A (en) | 1977-05-23 |
IE44103L (en) | 1977-05-12 |
NL7611590A (en) | 1977-05-16 |
AU1890076A (en) | 1978-04-27 |
SU634668A3 (en) | 1978-11-25 |
DK503176A (en) | 1977-05-13 |
CA1070316A (en) | 1980-01-22 |
PT65759A (en) | 1976-11-01 |
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