NO762659L - - Google Patents

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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
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formula
sulfur
amine
methylthio
lower alkyl
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NO762659A
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Norwegian (no)
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G R White
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Smith Kline French Lab
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    • 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

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  • 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)

. 1. Fremgangsmåte for fremstilling av en forbindelse med formelen: . 1. Procedure for preparing a compound of the formula: hvor n er 2 eller 3, Z er svovel eller metylen, X er CHNC^ eller NCN, Y er hydrogen, lavere alkyl eller HetCH 7' (CHj -, Z' er svovel eller metylen, n' er 2 eller 3, og Het er 5- hydroksymetyl-4-imidazolyl, en imidazolring, som eventué.lt ér substituert med metyl' eller brom, en pyridinring, som eventuelt er substituert med hydroksy, metoksy, klor eller brom, en tiazolring eller en isotiazolring, karakterisert ved behandling av en forbindel se med formelen where n is 2 or 3, Z is sulfur or methylene, X is CHNC^ or NCN, Y is hydrogen, lower alkyl or HetCH 7' (CHj -, Z' is sulfur or methylene, n' 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 with hydroxy, methoxy, chlorine or bromine, a thiazole ring or an isothiazole ring, characterized by treatment of a connection see with the formula hvor X er NCN eller CHNC^, Q er lavere alkyl, B er SQ', OQ' (hvor Q' er lavere alkyl) eller NHY (hvor Y har den ovennevnte betydning) og A er svovel, oksygen eller når X er CHNO^ og B er SQ <1> , SO, med en forbindelse med formelen where X is NCN or CHNC^, Q is lower alkyl, B is SQ', OQ' (where Q' is lower alkyl) or NHY (where Y has the above meaning) and A is sulfur, oxygen or when X is CHNO^ and B is SQ <1> , SO, with a connection of the formula hvor Z er svovel eller metylen og n er 2 eller 3. where Z is sulfur or methylene and n is 2 or 3. 2. Fremgangsmåte ifolge krav 1, karakterisert ved. at QA og B begge er metyltio og X er NCN, og at dimetyl-N-cyanoditioimidokarbonat behandles med opplosning av en ekvivalent av et amin med formelen 2. Procedure according to claim 1, characterized by. that QA and B are both methylthio and X is NCN, and that dimethyl-N-cyanodithioimidocarbonate is treated by dissolving an equivalent of an amine with the formula ved ca. romtemperatur og det fremkomne N-cyano-isotiourinstoff behandles med et overskudd av et amin NH^Y,\ hvor Y har den overnevnte betydning. at approx. room temperature and the resulting N-cyano-isothiourea is treated with an excess of an amine NH^Y,\ where Y has the above meaning. 3. Fremgangsmåte ifolge krav 1, hvor QA er metylsulfinyl, B er metyltio og X er CHNO2 , karakterisert ved at 1-metyltio-l-metylsulfinyl-2-nitroetylen behandles med en opplosning av en ekvivalent av et amin med formelen 3. Process according to claim 1, where QA is methylsulfinyl, B is methylthio and X is CHNO2, characterized in that 1-methylthio-1-methylsulfinyl-2-nitroethylene is treated with a solution of an equivalent of an amine with the formula ved ca. romtemperatur og den fremkomne substituerte l-metyltio-2-nitroetylen behandles med et overskudd av et amin NE^/ hvor Y har den overnevnte betydning. at approx. room temperature and the resulting substituted 1-methylthio-2-nitroethylene is treated with an excess of an amine NE^/ where Y has the above meaning. 4. Fremgangsmåte ifolge kravl, hvor QA og B begge er metyltio, karakterisert ved at N-cyanodi-metylditioimidokarbonat eller 1,1-bis-metyltio-2-nitroetylen behandles med minst to ekvivalenter av et amin med formelen 4. Process according to claim, where QA and B are both methylthio, characterized in that N-cyanodimethyldithioimidocarbonate or 1,1-bis-methylthio-2-nitroethylene is treated with at least two equivalents of an amine of the formula 5. Fremgangsmåte for fremstilling av en forbindelse med formelen 5. Method for producing a compound with the formula hvor n er 2 eller 3, Z er svovel eller metylen, X er svovel, Y er hydrogen, lavere alkyl eller HetCE^Z'(CK^)n,, hvor Z <1> er svovel eller metylen, h' er 2 eller 3 og Het er 5- hydroksymetyl-4-imida-zolyl, en imidazolring, isom eventuelt er substituert med metyl eller brom, en pyridinring, som eventuelt er substituert med hydroksy, metoksy, klor eller brom eller en tiazolring eller en isotiazolring, karakterisert ved behandling av en forbindelse med formelen L-E, hvor L er benzoyl, lavere alkyl eller Het-CHjZ'(CH2) , og E er NCS eller NHCS,SMe med et amin med formelen where n is 2 or 3, Z is sulfur or methylene, X is sulfur, Y is hydrogen, lower alkyl or HetCE^Z'(CK^)n,, where Z <1> is sulfur or methylene, h' 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 with hydroxy, methoxy, chlorine or bromine or a thiazole ring or an isothiazole ring, characterized by treatment of a compound of the formula L-E, where L is benzoyl, lower alkyl or Het-CHjZ'(CH2) , and E is NCS or NHCS,SMe with an amine of the formula eller når L er (5-hydroksymetyl-4-imidazolyl)CH2Z(CH2) med et lavere alkylamin.or when L is (5-hydroxymethyl-4-imidazolyl)CH 2 Z(CH 2 ) with a lower alkylamine. 6. Fremgangsmåte for fremstilling av en forbindelse av den forste formel i krav 5, hvor Het er 5-hydroksy-metyl-4-imida-zolyl og Z <*> og n' er identisk med Zogn, karakterisert ved behandling av svovelkarbon med et amin med formelen 6. Process for the preparation of a compound of the first formula in claim 5, where Het is 5-hydroxy-methyl-4-imidazolyl and Z <*> and n' is identical to Zogn, characterized by treatment of sulfur carbon with a amine with the formula
NO762659A 1975-07-31 1976-07-30 NO762659L (en)

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US4165378A (en) 1977-04-20 1979-08-21 Ici Americas Inc. Guanidine derivatives of imidazoles and thiazoles
USRE31588E (en) * 1977-06-03 1984-05-22 Bristol-Myers Company Imidazolylmethylthioethyl alkynyl guanidines
US4112234A (en) 1977-08-22 1978-09-05 Bristol-Myers Company Imidazolylmethylthioethyl alkynyl guanidines
US4233302A (en) 1977-12-23 1980-11-11 Glaxo Group Limited Amine derivatives and pharmaceutical compositions containing them
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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
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