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NO772668L - ANALOGICAL PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE COMPOUNDS - Google Patents

ANALOGICAL PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE COMPOUNDS

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Publication number
NO772668L
NO772668L NO772668A NO772668A NO772668L NO 772668 L NO772668 L NO 772668L NO 772668 A NO772668 A NO 772668A NO 772668 A NO772668 A NO 772668A NO 772668 L NO772668 L NO 772668L
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Norway
Prior art keywords
formula
ethyl
methyl
guanidino
imidazolylmethylthio
Prior art date
Application number
NO772668A
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Norwegian (no)
Inventor
Graham John Durant
Charon Robin Ganellin
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Smith Kline French Lab
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Publication of NO772668L publication Critical patent/NO772668L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/26—Radicals substituted by sulfur atoms

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  • 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)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

"Analogifremgangsmåte for fremstilling farmakologisk aktive forbindelser" "Analogy method for the preparation of pharmacologically active compounds"

Denne oppfinnelse angår fremstilling av farmakologisk aktive forbindelser. Forbindelsene som fremstilles i henhold til oppfinnelsen, blokkerer histamin H2~reseptorer. Disse forbindelser kan eksistere som syreaddisjonssalter, men av praktiske grunner vil det i det følgende henvises til stam- .. forbindelsene. This invention relates to the preparation of pharmacologically active compounds. The compounds produced according to the invention block histamine H2-receptors. These compounds can exist as acid addition salts, but for practical reasons reference will be made below to the parent compounds.

Mange fysiologisk aktive stoffer utløser sine biologiske virkninger ved innvirkning med spesielle punkter som er kjent som reseptorer. Histamin er et slikt stoff og har en rekke biologiske virkninger. De biologiske virkninger av histamin som hemmes av midler som vanligvis kalles "antihistaminer", som mepyramin, difenhydramin og klorfeniramin er typiske eksempler på, formidles gjennom histamin H^-reseptorer (Ash og Schild, Brit, J. Pharmac. Chemother, _27, 427, (1966)) . Imidlertid vil andre biologiske virkninger av histamin ikke hemmes av "antihistaminer", og virkninger av denne type som hemmes av en forbindelse som er beskrevet av Black et al (Nature, 236, 385 (1972)) og er kalt burimamid, formidles gjennom reseptorer som er definert av Black et al som histamin H2-reseptorer. Således kan histamin f^-reseptorer defineres som de histamin-reseptorer som ikke blokkeres av mepyramin, men blokkeres av burimamid. Forbindelser som blokkerer histamin I^-reseptorer, omtales som histamin U^-antagonister. Many physiologically active substances trigger their biological effects by impact with special points known as receptors. Histamine is one such substance and has a number of biological effects. The biological actions of histamine which are inhibited by agents commonly called "antihistamines", of which mepyramine, diphenhydramine and chlorpheniramine are typical examples, are mediated through histamine H^ receptors (Ash and Schild, Brit, J. Pharmac. Chemother, _27, 427 , (1966)) . However, other biological actions of histamine will not be inhibited by "antihistamines", and actions of this type that are inhibited by a compound described by Black et al (Nature, 236, 385 (1972)) called burimamide are mediated through receptors that are defined by Black et al as histamine H2 receptors. Thus, histamine β-receptors can be defined as those histamine receptors that are not blocked by mepyramine, but are blocked by burimamide. Compounds that block histamine I^ receptors are referred to as histamine U^ antagonists.

Blokkering av histamin E^-reseptorer er nyttig for å hemme de biologiske virkninger av histamin som ikke hemmes av "antihistaminer". Histamin H2~antagonister er derfor f.eks. nyttige som midler for hemning av mavesyresekresjon, som anti-inflammatoriske midler og som midler som virker på det kardio- vaskulære system, f.eks. som inhibitorer for virkningene av histamin på blodtrykk. Ved behandling av visse tilstander, f.eks. betennelser og ved hemning av virkningene av histamin på blodtrykk, er en kombinasjon av histamin H^- og H2~antagonister nyttig. Blockade of histamine E₁ receptors is useful in inhibiting the biological effects of histamine that are not inhibited by "antihistamines". Histamine H2-antagonists are therefore e.g. useful as agents for inhibiting gastric acid secretion, as anti-inflammatory agents and as agents acting on the cardiovascular system, e.g. as inhibitors of the effects of histamine on blood pressure. When treating certain conditions, e.g. inflammations and in inhibiting the effects of histamine on blood pressure, a combination of histamine H^- and H2- antagonists is useful.

I tysk offentliggjørelsesskrift 2.504.794 har vi bl.a. beskrevet histamin I^-antagonister med formel 1: In German publication document 2,504,794 we have, among other things, described histamine I^-antagonists with formula 1:

Formel 1 Formula 1

12 12

hvor X og X er svovel, CHN02 eller NY, hvor Y er hydrogen, hydroksy, lavere alkyl, cyano eller C0NH„/W er NH eller, når 12 12 X og X begge er NH, svovel; R og R heterocyklisk-alky1-eller heterocyklisk-alkylti.oalkyl-grupper, og Q er et helt tall fra 2 til 8. where X and X are sulfur, CHN02 or NY, where Y is hydrogen, hydroxy, lower alkyl, cyano or CONH„/W is NH or, when 12 12 X and X are both NH, sulfur; R and R are heterocyclic-alkyl- or heterocyclic-alkylthioalkyl groups, and Q is an integer from 2 to 8.

Vi har nu overraskende funnet at visse beslektede forbindelser hvor q er større enn 8, også er nyttige som histamin H2~antagonister, og det er slike forbindelser som fremstilles i henhold til oppfinnelsen. We have now surprisingly found that certain related compounds where q is greater than 8 are also useful as histamine H2-antagonists, and it is such compounds that are prepared according to the invention.

Således fremstilles i henhold til oppfinnelsen forbindelser med formel 2 som er histamin H2~antagonister: Thus, in accordance with the invention, compounds of formula 2 are produced which are histamine H2-antagonists:

Formel 2 Formula 2

hvor X 3 og X 4, som kan være like eller forskjellige, hver er svovel, CHNO- eller NY, hvor Y er hydrogen, hydroksy, lavere alkyl, where X 3 and X 4 , which may be the same or different, are each sulfur, CHNO- or NY, where Y is hydrogen, hydroxy, lower alkyl,

3 4 3 4

cyano eller C0NH2; R og R , som kan være like eller forskjellige, betyr hver en gruppe med formel 3: cyano or C0NH2; R and R , which may be the same or different, each represent a group of formula 3:

Formel 3 Formula 3

hvor Het er en 2- eller 4-imidazolylring som eventuelt er substituert med lavere alkyl (fortrinnsvis metyl), halogen where Het is a 2- or 4-imidazolyl ring optionally substituted with lower alkyl (preferably methyl), halogen

(fortrinnsvis klor eller brom), trifluormety1 eller hydroksymetyl, en 2-pyridylring som eventuelt er substituert med lavere alkyl (fortrinnsvis metyl), halogen (fortrinnsvis klor eller brom), amino, hydroksy eller lavere alkoksy (fortrinnsvis metoksy), (preferably chlorine or bromine), trifluoromethyl or hydroxymethyl, a 2-pyridyl ring which is optionally substituted with lower alkyl (preferably methyl), halogen (preferably chlorine or bromine), amino, hydroxy or lower alkoxy (preferably methoxy),

en 2-tiazolylring, en 3-isotiazolylring.som eventuelt er substituert med brom, eller en tiadiazolylring som eventuelt er substituert med klor eller amino; Z er svovel eller en metylen-gruppe; m er 0, 1 eller 2, og n er 2 eller 3, forutsatt at summen av m og n er 3 eller 4, eller, når X 3 eller X:4<:>er svovel, CHNO-eller NCN, kan summen av m og ni den tilstøtende side-3 4 3 4 a 2-thiazolyl ring, a 3-isothiazolyl ring optionally substituted with bromine, or a thiadiazolyl ring optionally substituted with chlorine or amino; Z is sulfur or a methylene group; m is 0, 1 or 2, and n is 2 or 3, provided that the sum of m and n is 3 or 4, or, when X 3 or X:4<:>is sulphur, CHNO-or NCN, the sum of m and nine the adjacent side-3 4 3 4

kjede R og R også være 2; W er NH, og når X og X begge er NH, kan W også være svovel; p. er et helt tall fra 9 til 12; chain R and R also be 2; W is NH, and when X and X are both NH, W can also be sulfur; p. is an integer from 9 to 12;

eller et farmasøytisk godtagbart syreaddisjonssalt derav.or a pharmaceutically acceptable acid addition salt thereof.

Det vil forstås at den struktur som er vist på formel 2, bare er én av en rekke måter å angi forbindelsene på, og at andre tautomere former også omfattes av formelen. Det skal også forstås at på grunn av molekylstrukturens symmetri kan betydningene av It will be understood that the structure shown in formula 2 is only one of a number of ways of specifying the compounds, and that other tautomeric forms are also encompassed by the formula. It should also be understood that due to the symmetry of the molecular structure, the meanings of

3 4 3 4 3 4 3 4

R og R og X og X ombyttes. Hydrater, farmasøytisk godtagbare salter og hydratiserte farmasøytisk godtagbare salter av forbindelsene med formel 2 kan også fremstilles i henhold til oppfinnelsen. R and R and X and X are interchanged. Hydrates, pharmaceutically acceptable salts and hydrated pharmaceutically acceptable salts of the compounds of formula 2 can also be prepared according to the invention.

I beskrivelse og krav er betegnelsen "lavere alkyl" benyttet for alkylgrupper inneholdende fra 1 til 4 karbonatomer, og betegnelsen "lavere alkoksy" er benyttet for alkoksygrupper inneholdende fra 1 til 4 karbonatomer. In the description and claims, the term "lower alkyl" is used for alkyl groups containing from 1 to 4 carbon atoms, and the term "lower alkoxy" is used for alkoxy groups containing from 1 to 4 carbon atoms.

I en foretrukket gruppe forbindelser er R 3 og R 4like.In a preferred group of compounds, R 3 and R 4 are the same.

3 4' 3 4'

R og/eller R er fortrinnsvis Het-(CH2S(CH2)2~, og det fore-trekkes særlig at Het er en 4-imidazolylring, eventuelt substituert med metyl eller halogen, en 2-tiazolylring, en 3-isotiazoly1-ring eller en 2-pyridylring som eventuelt er substituert med metyl, metoksy, klor eller brom. R and/or R is preferably Het-(CH2S(CH2)2~, and it is particularly preferred that Het is a 4-imidazolyl ring, optionally substituted with methyl or halogen, a 2-thiazolyl ring, a 3-isothiazolyl ring or a 2-pyridyl ring optionally substituted with methyl, methoxy, chlorine or bromine.

Fortrinnsvis, er X 3 eller X 4NH, og særlig foretrukketPreferably, X 3 or X 4 is NH, and particularly preferred

er både X"^ og X^ NH. Fortrinnsvis er p 9 eller 10. Eksempler på særlige forbindelser er: 1, 9-bis- [N1 -(2- ( 5-metyl-4-imidazolylmety ltio) etyl) - guanidino]nonan, both X"^ and X^ are NH. Preferably p is 9 or 10. Examples of particular compounds are: 1,9-bis-[N1-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino] nonan,

1.9- bis-[N'-cyano-N"-(2-(5-metyl-4-imidazolyImetyltio)-. etyl)guanidino]nonan, 1,9-bis-[N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)-.ethyl)guanidino]nonane,

1.10- bis-[N1-(2-(5-mety1-4-imidazolylmetyltio)etyl)-guanidino]dekan, 1.10-bis-[N1-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]decane,

1,12-bis-[N<1->(2-(5-metyl-4-imidazolylmetyltio)etyl)-guanidino]dodekan, • 1,10-bis-[N'-(2-(2-tiazolylmetyltio)etyl)guanidino]-dekan 1,12-bis-[N<1->(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]dodecane, • 1,10-bis-[N'-(2-(2-thiazolylmethylthio) ethyl)guanidino]-decane

Forbindelser med formel 2 hvor W er NH, og X 3 og X4 er svovel, CHN02, NH, N(lavere alkyl), NCN eller CONH2, kan fremstilles ved en fremgangsmåte som vist på skjema 1.. Compounds with formula 2 where W is NH, and X 3 and X 4 are sulphur, CHN02, NH, N(lower alkyl), NCN or CONH2, can be prepared by a method as shown in scheme 1..

På skjema' 1 er A lavere alkyl, R 3 og R 4, som kan være like eller forskjellige, er som angitt under formel 2, og og X^, som kan være like eller forskjellige, er svovel, CHN02, NH, N(lavere alkyl)', NCN eller NY' hvor Y<1>er en guanidin-beskyttende gruppe så som benzoyl, benzyloksykarbonyl eller etoksykårbonyl. På skjema 1 er X^ fortrinnsvis ikke NH eller N(lavere alkyl) med mindre R 3 er like R 4. Forbindelser med 3 4 3 4 formel 2 hvor X og X begge er NH' og R ikke er lik R , kan fremstilles ved syrehydrolyse av forbindelser med. formel 6 5 6 hvor X og X er NCN eller N-benzoyl. Forbindelser med formel 2 hvor X 3 og/eller X 4 er CONH,,, kan fremstilles ved hydrolyse under milde syrebetingelser av det tilsvarende cyano-5 6 In scheme' 1, A is lower alkyl, R 3 and R 4 , which may be the same or different, are as indicated under formula 2, and and X^ , which may be the same or different, are sulfur, CHN0 2 , NH, N( lower alkyl)', NCN or NY' where Y<1> is a guanidine protecting group such as benzoyl, benzyloxycarbonyl or ethoxycarbonyl. In scheme 1, X^ is preferably not NH or N(lower alkyl) unless R 3 is equal to R 4. Compounds with 3 4 3 4 formula 2 where X and X are both NH' and R is not equal to R , can be prepared by acid hydrolysis of compounds with. formula 6 5 6 where X and X are NCN or N-benzoyl. Compounds of formula 2 where X 3 and/or X 4 is CONH,,, can be prepared by hydrolysis under mild acid conditions of the corresponding cyano-5 6

guanidin med formel 6 hvor X og/eller X er NGN. guanidine of formula 6 where X and/or X is NGN.

Trinn .1 av vei A kan utføres i nærvær av eller fravær av et oppløsningsmiddel. Fortrinnsvis utføres denne reaksjon under anvendelse av et overskudd av aminet NH~ (CH_) NH„ som opp-^ løsningsmiddel. Fortrinnsvis utføres trinn 2 i vei Ai fravær av et oppløsningsmiddel eller i nærvær av et polart oppløsnings-middel så som en lavere alkohol eller pyridin. Fortrinnsvis utføres denne omsetning ved forhøyet temperatur, f.eks.. 100°C. Når R og R er like og X^ og X^ er like, kan trinn 1 og trinn 2. i. vei A utføres samtidig, uten isolering av mellomproduktet med formel 5. Step .1 of Route A can be carried out in the presence or absence of a solvent. Preferably, this reaction is carried out using an excess of the amine NH - (CH - ) NH - as solvent. Preferably, step 2 in route Ai is carried out in the absence of a solvent or in the presence of a polar solvent such as a lower alcohol or pyridine. Preferably, this reaction is carried out at an elevated temperature, e.g. 100°C. When R and R are equal and X^ and X^ are equal, step 1 and step 2. i. path A can be carried out simultaneously, without isolation of the intermediate of formula 5.

Fortrinnsvis utføres begge trinn av vei B i et polart oppløsningsmiddel, så som en lavere alkohol eller pyridin, og ved forhøyet temperatur, f.eks. 100°C. Når R^ ikke er deri samme 4 3 Preferably, both steps of pathway B are carried out in a polar solvent, such as a lower alcohol or pyridine, and at elevated temperature, e.g. 100°C. When R^ is not therein the same 4 3

som R , anvendes fortrinnsvis én ekvivalent av aminet R NH_as R, one equivalent of the amine R NH_ is preferably used

i første, trinn av vei B, og1 et overskudd av aminet R 4NH2 anvendes i annet trinn. in the first, step of path B, and1 an excess of the amine R 4NH2 is used in the second step.

Forbindelser med formel R^NH2kan fremstilles ved frem-gangsmåter beskrevet i britiske patenter 1.305.547, 1.338.169 Compounds of formula R^NH2 can be prepared by methods described in British patents 1,305,547, 1,338,169

og 1.421.999 og tysk offentliggjørelsesskrift 2.634.433. and 1,421,999 and German publication document 2,634,433.

5 5

Forbindelser med formel 4 hvor X er svovel, kan fremstilles fra et amin med formel R 3NH2 ved suksessiv omsetning derav med karbondisulfid og et alkyleringsmiddel, så som metyljodid. Compounds of formula 4 where X is sulphur, can be prepared from an amine of formula R 3NH 2 by successive reaction thereof with carbon disulphide and an alkylating agent, such as methyl iodide.

Forbindelser med formel 4 hvor X^ er CHN02, N-benzoyl eller NCN, kan fremstilles ved at en forbindelse med formel 9' Compounds of formula 4 where X^ is CHN02, N-benzoyl or NCN, can be prepared by a compound of formula 9'

(AS)2C=X<5>(AS)2C=X<5>

Formel 9Formula 9

mhevod r en. ekevr ivCaHNlOen-t , mNe-bngedne zoyav l eelt leamr i.Nn CmNe, d og foA rmeer l aR l3NkyHl2. , beDhenannde leoms-setning utføres hensiktsmessig i et oppløsningsmiddel så som etanol. Forbindelsene med formel 4 hvor X^ er CHNC^, kan alternativt fremstilles ved å behandle 1-metylsulfinyl-l-metyltio-2-nitroetylen (beskrevet i tysk offentliggjørelsesskrift 2.634.430) med en ekvivalent mengde av et amin med for5mel R 3NH„. mhevod r one. ekevr ivCaHNlOen-t , mNe-bngedne zoyav l eelt leamr i.Nn CmNe, d and foA rmeer l aR l3NkyHl2. , the second leoms reaction is conveniently carried out in a solvent such as ethanol. The compounds of formula 4 where X^ is CHNC^ can alternatively be prepared by treating 1-methylsulfinyl-1-methylthio-2-nitroethylene (described in German Publication No. 2,634,430) with an equivalent amount of an amine of formula R 3NH„.

Forbindelsene med formel 4 hvor.X er NH, fremstilles hensiktsmessig ved alkylering av et tiourinstoff med formelen R 3 NHCSNH„. Disse tiourinstof' fer • kan fremstilles ved å behandle et amin med formel R 3NH2 med benzoylisotiocyanat og å hydrolysere produktet under alkaliske betingelser.- The compounds of formula 4 where X is NH are suitably prepared by alkylation of a thiourea with the formula R 3 NHCSNH„. These thioureas • can be prepared by treating an amine of formula R 3NH2 with benzoyl isothiocyanate and hydrolyzing the product under alkaline conditions.

Forbindelsene med formel 7 kan fremstilles ved metoder analoge med de som er beskrevet for fremstilling av forbindelser med formel 4. The compounds of formula 7 can be prepared by methods analogous to those described for the preparation of compounds of formula 4.

Forbindelsene med formel 2 hvor X 3 og/eller X 4er NY ogThe compounds of formula 2 where X 3 and/or X 4 are NY and

Y er hydroksy eller lavere alkyl, kan fremstilles fra de til-Y is hydroxy or lower alkyl, can be prepared from the

3 4 3 4

svarende tiourinstoffer med formel. 2 hvor X og/eller X er svovel, corresponding thioureas with formula. 2 where X and/or X is sulphur,

3 4 ■' ~ 3 4 ■' ~

og hverken X eller X er NH, ved alkylering av tiourinstoffet, f.eks. ved behandling med hydrogenklorid i metanol eller med metyljodid, og derefter behandling av det resulterende isotiourinstoff med henholdsvis hydroksylamin eller et lavere alkylamin. and neither X nor X is NH, by alkylation of the thiourea, e.g. by treatment with hydrogen chloride in methanol or with methyl iodide, and then treatment of the resulting isothiourea with hydroxylamine or a lower alkylamine, respectively.

3 4 Forbindelsene med formel 2 hvor X og/eller X er NCN, kan alternativt fremstilles fra de tilsvarende tiourinstoffér med formel 2 hvor X<3>og/eller X<4>er svovel, og hverken X<3>eller X<4>3 4 The compounds of formula 2 where X and/or X is NCN can alternatively be prepared from the corresponding thioureas of formula 2 where X<3> and/or X<4> is sulphur, and neither X<3> nor X<4 >

er NH, ved alkylering og behandling av produktet med cyanamid-is NH, by alkylation and treatment of the product with cyanamide-

og en sterk base så som kalium-t-butoksyd.and a strong base such as potassium t-butoxide.

3 ■ 4 Forbindelsene med formel 2 hvor X eller X er NCN kan også fremstilles fra de tilsvarende forbindelser med formel. 2 hvor X 3 eller X 4er svovel, ved omsetning av sistnevnte med et tungmetallsalt av cyanamid så som bly-, kvikksølv- eller kadmium-cyanamid i et oppløsningsmiddel så som acetonitril og/eller dimetylformamid. 3 4 Forbindelsene med formel 2 hvor W er svovel og X og X begge er NH, kan fremstilles ved alkylering av et tiourinstoff 3 3 3 ■ 4 The compounds of formula 2 where X or X is NCN can also be prepared from the corresponding compounds of formula. 2 where X 3 or X 4 is sulphur, by reacting the latter with a heavy metal salt of cyanamide such as lead, mercury or cadmium cyanamide in a solvent such as acetonitrile and/or dimethylformamide. 3 4 The compounds of formula 2 where W is sulfur and X and X are both NH can be prepared by alkylation of a thiourea 3 3

med formelen R NHCSNH2hvor R er som-angitt under formel 2,with the formula R NHCSNH2where R is as indicated under formula 2,

med et dihalogenalkan med formelen Hal-(CH2)p-Hal, hvor Hal betyr klor, brom eller jod.. Fortrinnsvis utføres omsetningen med et syreaddisjonssalt av tiourinstoffet. Fortrinnsvis er Hal brom, og omsetningen utføres i et oppløsningsmiddel så som etanol. with a dihaloalkane of the formula Hal-(CH2)p-Hal, where Hal means chlorine, bromine or iodine. The reaction is preferably carried out with an acid addition salt of the thiourea. Preferably, Hal is bromine, and the reaction is carried out in a solvent such as ethanol.

3 4 3 4

Når R ikke er lik R , utføres omsetningen i to trinn. Fortrinnsvis vil det være et overskudd av forbindelsen med formel Hal-(CH2) p-Hal i første trinn av omsetningen. When R is not equal to R , the turnover is performed in two steps. Preferably, there will be an excess of the compound of formula Hal-(CH 2 ) p-Hal in the first step of the reaction.

Forbindelsene med formel 2 blokkerer histamin H2~reseptorer, dvs. at de hemmer de biologiske virkninger av histamin som ikke hemmes av "antihistaminer" så som mepyramin, men som hemmes av. burimamid. Det er f. eks., funnet åt forbindelsene fremstilt ifølge oppfinnelsen hemmer histamin-stimulert utskillelse av mavesyre fra lumen-perfuserte maver hos rotter bedøvet med uretan, i doser fra 0,5 til 256 mikromol pr. kg intravenøst. Denne metode er beskrevet i' den ovennevnte artikkel av Ash og Schild. Aktiviteten av disse forbindelser som histamin H2~antagonister vises også ved deres evne til å hemme andre virkninger av histamin, som i henhold til den ovennevnte artikkel av Ash og Schild, The compounds of formula 2 block histamine H2-receptors, i.e. they inhibit the biological effects of histamine which are not inhibited by "antihistamines" such as mepyramine, but which are inhibited by. Burimamide. It has, for example, been found that the compounds produced according to the invention inhibit histamine-stimulated secretion of gastric acid from lumen-perfused stomachs in rats anesthetized with urethane, in doses from 0.5 to 256 micromol per kg intravenously. This method is described in the above-mentioned article by Ash and Schild. The activity of these compounds as histamine H2-antagonists is also shown by their ability to inhibit other effects of histamine, as according to the above-mentioned article by Ash and Schild,

ikke formidles av histamin H^-reseptorer. F.eks. hemmer de virkningene av histamin på isolert marsvin-forkammer og isolert rotte-uterus. not mediated by histamine H^ receptors. E.g. inhibit the effects of histamine on isolated guinea pig atrium and isolated rat uterus.

Forbindelsene fremstilt ifølge oppfinnelsen hemmer den basale utskillelse av mavesyre og også den som stimuleres av pentagastrin eller av mat. The compounds produced according to the invention inhibit the basal secretion of gastric acid and also that which is stimulated by pentagastrin or by food.

Ved en vanlig prøve, så som måling av blodtrykk hos en bedøvet rotte, kan man dessuten påvise forbindelsenes virkning til å hemme vasodilator-virkningen av histamin. Styrken av forbindelsenes aktivitet illustreres ved den effektive dose' som. frembringer 50% hemning av mavesyre-sekresjonen hos en bedøvet rotte, og den dose som frembringer 50% hemning av histamin-frembragt tachykardi i et isolert marsvin-forkammer. In a common test, such as measuring blood pressure in an anesthetized rat, the effect of the compounds to inhibit the vasodilator effect of histamine can also be demonstrated. The strength of the compounds' activity is illustrated by the effective dose' which. produces 50% inhibition of gastric acid secretion in an anesthetized rat, and the dose that produces 50% inhibition of histamine-evoked tachycardia in an isolated guinea pig atria.

For terapeutisk anvendelse vil de farmakologisk aktive forbindelser fremstilt i henhold til oppfinnelsen normalt bli administrert som farmasøytiske preparater inneholdende som eneste eller som en vesentlig aktiv bestanddel minst én slik forbindelse i baseform eller i form av et addisjonssalt med en farmasøytisk For therapeutic use, the pharmacologically active compounds produced according to the invention will normally be administered as pharmaceutical preparations containing as the only or as a substantially active ingredient at least one such compound in base form or in the form of an addition salt with a pharmaceutical

.godtagbar syre og sammen med et.farmasøytisk bæremiddel. Slike addisjonssalter omfatter saltene med saltsyre, bromhydrogensyre, jodhydrogensyre, svovelsyre og maleinsyre, og kan hensiktsmessig fremstilles fra de tilsvarende baser med formel 2 ved standard metoder, f.eks. ved behandling av'basen med en syre i en lavere .acceptable acid and together with a.pharmaceutical carrier. Such addition salts include the salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and maleic acid, and can conveniently be prepared from the corresponding bases with formula 2 by standard methods, e.g. by treating the'base with an acid in a lower

Farmasøytiske preparater inneholdende et farmasøytisk bæremiddel og en forbindelse med formel 2 eller et farmasøytisk godtagbart syreaddisjorissalt derav kan anvendes til blokkering av histamin ^-reseptorer ved administrering av en forbindelse med formel 2 eller et'farmasøytisk godtagbart syreaddisjonssalt. derav i egnet preparatform. Det anvendte farmasøytiske bæremiddel kan f.eks. være et fast stoff eller en væske. Eksempler på faste bæremidler er laktose, mais- eller potet- eller modifisert stivelse, dikalsiumfosfat, terra alba, sukrose, celluloser, talk, gelatin, mikrofin kiselsyre, agar, pektin, akasiegummi, magnesiumstearat, stearinsyre og lignende. Eksempler på flytende bæremidler er sirup, jordnøttolje, olivenolje, alkohol, propylen-glykol, po,lyety lenglykoler, vann og lignende. Pharmaceutical preparations containing a pharmaceutical carrier and a compound of formula 2 or a pharmaceutically acceptable acid addition salt thereof can be used to block histamine 2 receptors by administering a compound of formula 2 or a pharmaceutically acceptable acid addition salt. hence in a suitable preparation form. The pharmaceutical carrier used can e.g. be a solid or a liquid. Examples of solid carriers are lactose, corn or potato or modified starch, dicalcium phosphate, terra alba, sucrose, celluloses, talc, gelatin, microfine silicic acid, agar, pectin, gum acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, alcohol, propylene glycol, polyethylene glycols, water and the like.

En rekke forskjellige farmasøytiske former kan anvendes. A number of different pharmaceutical forms can be used.

Hvis således et fast bæremiddel anvendes, kan preparatet If a solid carrier is thus used, the preparation can

tabletteres, anbringes i en hard gelatinkapsel i pulver- eller pellet-form, eller i form av en pastill eller sugetablett. Mengden av fast bæremiddel vil variere i stor utstrekning, men vil fortrinnsvis være fra ca. 25 mg til ca. 1 g. Hvis et flytende bæremiddel anvendes, kan preparatet være i form av en sirup, emulsjon, myk gelatinkapsel, steril, injiserbar væske eller en vandig eller ikke-vandig flytende suspensjon. Andre tilsetnings-' stoffer, så som konserveringsmidler, f.eks. antioksydasjonsmidler eller antibakterielle midler, og/eller smaksstoffer eller farve-midler kan også innføres. De flytende former kan også fremstilles i myke gelatinkapsler eller mikrpkapsler. Den sterile opp-løsning kan fremstilles i ampuller, flasker med flere doser eller engangssprøyter med enhetsdoser. Preparatet kan også være i en halvfast form så som en krem, pasta, salve eller gel, eller en væske eller aerosol for lokal administrering. tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a lozenge or lozenge. The amount of solid carrier will vary widely, but will preferably be from approx. 25 mg to approx. 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile, injectable liquid or an aqueous or non-aqueous liquid suspension. Other additives, such as preservatives, e.g. antioxidants or antibacterial agents, and/or flavorings or coloring agents can also be introduced. The liquid forms can also be prepared in soft gelatin capsules or microcapsules. The sterile solution can be prepared in ampoules, multi-dose bottles or single-dose syringes. The preparation can also be in a semi-solid form such as a cream, paste, ointment or gel, or a liquid or aerosol for local administration.

De farmasøytiske preparater fremstilles ved vanlige metoder som omfatter f.eks; blanding, granulering og komprimering eller oppløsning av bestanddelene alt eftersom det passer for det ønskede preparat. The pharmaceutical preparations are produced by usual methods which include, for example; mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired preparation.

Den aktive bestanddel vil være.til stede i preparateneThe active ingredient will be present in the preparations

i en mengde som.er effektiv til å blokkere histamin H2_reseptorer. in an amount which is effective in blocking histamine H2_receptors.

Administreringsveien kan være oral eller parénteral. The route of administration can be oral or parenteral.

Fortrinnsvis inneholder hver enhetsdose den aktive bestanddel i en mengde fra ca. 50 til ca. 250 mg. Preferably, each unit dose contains the active ingredient in an amount from approx. 50 to approx. 250 mg.

Den aktive bestanddel .administreres fortrinnsvis 1 til 6 ganger daglig. Den daglige dosemengde vil fortrinnsvis være fra ca. 150 til ca. 1500 mg. The active ingredient is preferably administered 1 to 6 times daily. The daily dosage will preferably be from approx. 150 to approx. 1500 mg.

Hensiktsmessig tilberedes preparatet i en doseringsform som passer til den ønskede administreringsmetode, f.eks. som en tablett, kapsel, injiserbar oppløsning eller som en krem eller salve.for lokal administrering. Appropriately, the preparation is prepared in a dosage form that suits the desired administration method, e.g. as a tablet, capsule, injectable solution or as a cream or ointment. for local administration.

De følgende eksempler, hvor alle temperaturer er i °C, skal tjene til å illustrere oppfinnelsen ytterligere: Eksempel 1 The following examples, where all temperatures are in °C, shall serve to further illustrate the invention: Example 1

1, 10- bis-[ N'-( 2-( 5- metyl- 4- imidazolyImetyltio) etyl) guanidino] dekan (a) En oppløsning av N-[2-(5-metyl-4-imidazolylmetyltio)-etyl ] tiourinstof f (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-imidazolylmetyltio) etyl ] is.otiouroniumjodid (2,3 g) sm.p. 128-131°. 1, 10- bis-[ N'-( 2-( 5- methyl- 4- imidazolylmethylthio) ethyl) guanidino] decane (a) A solution of N-[2-(5-methyl-4- imidazolylmethylthio)-ethyl ] Thiourea (2.29 g) and methyl iodide (1.56 g) in methanol (5 mL) were kept at room temperature for 18 h to give S-methyl-N-[ 2-(5-methyl-4-imidazolylmethylthio ) ethyl ] is.othiouronium iodide (2.3 g) m.p. 128-131°.

(b) 1,10-diaminodekan (1., 72 g) ble satt til en oppløsning(b) 1,10-diaminodecane (1., 72 g) was added to a soln.

av S-metyl-N-[2-(5-metyl-4-imidazolylmetyltio)etyl]-isotiouronium-jodid- (7,44 g) i vann (25 ml) og blandingen ble oppvarmet under, tilbakeløpskjøling i 2 timer. Efter konsentrering ble residuet omdannet til dipikratet med en vandig oppløsning- av natrium-pikrat. Omkrystallisering fra etanol ga tittelfprbindelsen som dipikratet (4,79 g), sm.p. 104-105°" C26H48N10S2(C6H3N3°7)2*H2° krever: c 4 3,8; H 5,4; N 21,5; S 6,2% of S-methyl-N-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-isothiouronium iodide (7.44 g) in water (25 ml) and the mixture was heated under reflux for 2 hours. After concentration, the residue was converted to the dipicrate with an aqueous solution of sodium picrate. Recrystallization from ethanol gave the title compound as the dipyrate (4.79 g), m.p. 104-105°" C26H48N10S2(C6H3N3°7)2*H2° requires: c 4 3.8; H 5.4; N 21.5; S 6.2%

funnet: C 43,65,H 5,4, N 21,1, S 6,0%. found: C 43.65, H 5.4, N 21.1, S 6.0%.

Dipikratet ble oppløst i vandig metanol og behandlet med ionebytterharpiks "IRA 400" (Cl ) for å gi dihydrokloridet av titte1forbindeIsen. The dipicrate was dissolved in aqueous methanol and treated with ion exchange resin "IRA 400" (Cl ) to give the dihydrochloride of the title compound.

Eksempel 2 Example 2

l, 12- bis-[ N'-( 2-( 5- mety1- 4- imidazolyImetyltio) etyl) guanidino]-dodekan 1,12-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]-dodecane

Anvendelse av 1,12-diaminododekan istedenfor 1,10-diaminodekan ved fremgangsmåten ifølge eksempel 1 (b) resulterte i fremstilling av dipikratet av tittelforbindelsen, sm.p. 68-70°. C28H52HiOS2(C6H3N3Q7)2 krever: c 45'7' H 5#6; N 21,3; S 6,1%, Use of 1,12-diaminododecane instead of 1,10-diaminodecane in the method according to example 1 (b) resulted in the preparation of the dipicrate of the title compound, m.p. 68-70°. C28H52HiOS2(C6H3N3Q7)2 requires: c 45'7' H 5#6; N 21.3; S 6.1%,

funnet: C 45,75; H 5,6; N 20,75; S 6,0%. found: C 45.75; H 5.6; N 20.75; S 6.0%.

Dipikratet ble oppløst i vandig metanol og behandlet med ionebytterharpiks "IRA 400" (Cl ) for å gi dihydrokloridet av tittelforbindelsen. The dipicrate was dissolved in aqueous methanol and treated with ion exchange resin "IRA 400" (Cl ) to give the dihydrochloride of the title compound.

Eksempel 3 1. 9- bis-[ N'-( 2-( 5- metyl- 4- imidazolylmetyltio) etyl) guanidino] nonan Anvendelse av 1,9-diaminononan istedenfor 1,10-diaminb-dekan ved fremgangsmåten ifølge eksempel 1(b) resulterte i fremstilling av dipikratet av tittelforbindelsen, sm.p. 90-93°. Dipikratet ble oppløst i vandig metanol og behandlet med ionebytterharpiks "IRA 400"(Cl ) for å gi dihydrokloridet av tittelforbindelseni Example 3 1. 9-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]nonane Use of 1,9-diaminononane instead of 1,10-diaminob-decane in the method according to example 1( b) resulted in the preparation of the dipicrate of the title compound, m.p. 90-93°. The dipicrate was dissolved in aqueous methanol and treated with ion exchange resin "IRA 400" (Cl ) to give the dihydrochloride of the title compound

Eksempel 4 Example 4

1. 10- bis-[ N'-( 2-( 2- tiazolylmetyltio) etyl) guanidino] dekan1. 10- bis-[ N'-( 2-( 2- thiazolylmethylthio) ethyl) guanidino] decane

a) En blanding av S-metyl-N-cyano-N1 -(2-(2-tiazolylmetyltio) etyl)-iostiourinstoff (2,72 g), 1,10-diaminodekan a) A mixture of S-methyl-N-cyano-N1-(2-(2-thiazolylmethylthio)ethyl)-isothiourea (2.72 g), 1,10-diaminodecane

(0,9 g) og etanol (5 ml) ble oppvarmet på dampbad i 20 timer, og blandingen ble kromatografert på silikagel ved eluering med etylacetat/isopropanol (5:1). Råproduktet ble omkrystallisert fra vandig etanol for å gi 1,10-bis-[N1-cyano-N"-(2-(2-tiazolylmetyltio)etyl)guanidino]dekan (0,49 g), sm.p. 74-75°. C26H40N10S4 krever: c 50'3; H 6'5?N 22,6; S 20,7%, (0.9 g) and ethanol (5 ml) were heated on a steam bath for 20 hours, and the mixture was chromatographed on silica gel eluting with ethyl acetate/isopropanol (5:1). The crude product was recrystallized from aqueous ethanol to give 1,10-bis-[N1-cyano-N"-(2-(2-thiazolylmethylthio)ethyl)guanidino]decane (0.49 g), mp 74-75 °. C26H40N10S4 requires: c 50'3; H 6'5?N 22.6; S 20.7%,

funnet: C 50,15; H 6,6; N 22,7; S 20,7%. found: C 50.15; H 6.6; N 22.7; S 20.7%.

b) 1,10-bis[N<1->cyano-N"-(2-(2-tiazolylmetyltio)etyl)-guanidino]dekan (2,0 g) ble tilbakeløpsbehandlet med konsentrert b) 1,10-bis[N<1->cyano-N"-(2-(2-thiazolylmethylthio)ethyl)-guanidino]decane (2.0 g) was refluxed with conc.

saltsyre (25 ml) i 24 timer, og blandingen ble inndampet til tørrhet. Residuet ble utgnidd med iskold etanol, ammoniumklorid ble frafiltrert, og filtratet ble inndampet for å gi tittelforbindelsen, som ble omdannet til dipikratet med et overskudd av natriumpikrat-oppløsning. Dipikratet ble omkrystallisert fra nitrometan og hadde smeltepunkt 155-157°. hydrochloric acid (25 mL) for 24 h, and the mixture was evaporated to dryness. The residue was triturated with ice-cold ethanol, ammonium chloride was filtered off, and the filtrate was evaporated to give the title compound, which was converted to the dipicrate with an excess of sodium picrate solution. The dipicrate was recrystallized from nitromethane and had a melting point of 155-157°.

C24H42N8S4 (C6H3N3°7) 2 krever: c 42'°; H 4 > 7 ? N 19,1; S 12,5%, C24H42N8S4 (C6H3N3°7) 2 requires: c 42'°; H 4 > 7 ? N 19.1; S 12.5%,

funnet: C 41,55; H 4,8; N 19,1; S 11,8%. found: C 41.55; H 4.8; N 19.1; S 11.8%.

Dipikratet ble omdannet til tetrahydrokloridet av tittelforbindelsen ved behandling med "IRA 400" (Cl ) og surgjøring til pH 2 med konsentrert saltsyre. The dipicrate was converted to the tetrahydrochloride of the title compound by treatment with "IRA 400" (Cl ) and acidification to pH 2 with concentrated hydrochloric acid.

Eksempel 5 Example 5

1, 9- bis-[ N'-( 2-( 5- metyl- 4- imidazolyImetyltid) etyl) tioureido] nonan En blanding av S-metyl-N-[2-(5-metyl-4-imidazolylmetyltio)-etyl]ditiokarbamat, 1,9-diaminononan og isopropanol kokes under tilbakeløpskjøling i 24 timer, og blandingen inndampes til tørrhet, og residuet renses ved kromatografi på silikagel for å gi tittelforbindelsen. 1, 9- bis-[ N'-( 2-( 5- methyl- 4- imidazolylmethyltide) ethyl) thioureido] nonane A mixture of S-methyl-N-[2-(5-methyl-4- imidazolylmethylthio)-ethyl ]dithiocarbamate, 1,9-diaminononane and isopropanol are refluxed for 24 hours and the mixture is evaporated to dryness and the residue is purified by chromatography on silica gel to give the title compound.

Eksempel 6 Example 6

1, 9- bis-[ 1-( 2-(( 5- metyl- 4- imidazolyl) metyltio) etylamino)- 2-nitrovinyl- l- amino] nonan 1, 9- bis-[ 1-( 2-(( 5- methyl- 4- imidazolyl) methylthio) ethylamino)- 2- nitrovinyl- 1- amino] nonane

En oppløsning av l-nitro-2-metyltio-2-[2-((5-metyl-4-imidazolyl)metyltio)etylamino]etylen (1,15 g) og 1,9-diaminononan (0,31 g) i etanol (15 ml) oppvarmes under tilbakeløpskjøling i 2 timer. Produktet renses på en ionebytterharpiks ("CG 50" (H+)) og derefter på silikagel for å gi tittelforbindelsen. A solution of 1-nitro-2-methylthio-2-[2-((5-methyl-4-imidazolyl)methylthio)ethylamino]ethylene (1.15 g) and 1,9-diaminononane (0.31 g) in ethanol (15 ml) is heated under reflux for 2 hours. The product is purified on an ion exchange resin ("CG 50" (H+)) and then on silica gel to give the title compound.

Eksempel 7Example 7

a) 1,9-diaminononan behandles med 2 mol dimetyl-N-cyano-ditiokarbamat i etanol ved romtemperatur for å gi 1,9-bis-(N<1->cyåno-S-metyltioureido)nonan. b) 1,9-bis-(N<1->cyano-S-metyltioureido)nonan behandles med én ekvivalent 2-(5-metyl-4-imidazol.ylmetyltio) etylamin og blandingen tilbakeløpsbehandles i pyridin i 12 timer. Pyridinet fjernes ved avdampning, og residuet renses ved kromatografi på silikagel for å gi 1-(N'-cyano-S-metyltioureido)-9-[N<1->cyano-N"-(2-(5-metyl-4-imidazolylmétyltio)etyl)guanidino]nonan. c) 1-(N'-cyano-S-metyltioureido)-9-[N<1->cyano-N"-(2-(5-metyl-4-imidazolylmetyltio)etyl)guanidino]nonan behandles med 2 mol 2-(2-tiazolylmetyltio)etylamin, og blandingen tilbakeløps-behandles i pyridin i 12 timer. Pyridinet fjernes ved avdampning, og residuet renses ved kromatografi på silikagel for å gi 1-[N'-cyano-N"-(2-(2-tiazolylmetyltio)etyl)guanidino]-9-[N'-cyano-N"-(2-(5-metyl-4-imidazolylmetyltio)etyl)guanidino]nonan. a) 1,9-diaminononane is treated with 2 moles of dimethyl-N-cyano-dithiocarbamate in ethanol at room temperature to give 1,9-bis-(N<1->cyano-S-methylthioureido)nonane. b) 1,9-bis-(N<1->cyano-S-methylthioureido)nonane is treated with one equivalent of 2-(5-methyl-4-imidazolylmethylthio)ethylamine and the mixture is refluxed in pyridine for 12 hours. The pyridine is removed by evaporation, and the residue is purified by chromatography on silica gel to give 1-(N'-cyano-S-methylthioureido)-9-[N<1->cyano-N"-(2-(5-methyl-4 -imidazolylmethylthio)ethyl)guanidino]nonane. c) 1-(N'-cyano-S-methylthioureido)-9-[N<1->cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl )guanidino]nonane is treated with 2 mol of 2-(2-thiazolylmethylthio)ethylamine, and the mixture is refluxed in pyridine for 12 hours. The pyridine is removed by evaporation, and the residue is purified by chromatography on silica gel to give 1-[N'-cyano-N"-(2-(2-thiazolylmethylthio)ethyl)guanidino]-9-[N'-cyano-N"- (2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]nonane.

Dette guanidin tilbakeløpsbehandles med konsentrert saltsyre i 24. timer for å gi 1-[N<1->(2-(2-tiazolylmetyltio)etyl)-guanidino]-9-[N1 -(2-(5-metyl-4-imidazolyImetyltio)etyl)guanidino]-nonan-tetrahydroklorid. d) Anvendelse av (a) 2-(2-imidazolylmetyltio)etylamin, This guanidine is refluxed with concentrated hydrochloric acid for 24 hours to give 1-[N<1->(2-(2-thiazolylmethylthio)ethyl)-guanidino]-9-[N1 -(2-(5-methyl-4- imidazolylmethylthio)ethyl)guanidino]nonane tetrahydrochloride. d) Use of (a) 2-(2-imidazolylmethylthio)ethylamine,

(b) 2-(4-imidazolylmetyltio)etylamin,(b) 2-(4-imidazolylmethylthio)ethylamine,

(c) 2-(5-brom-4-imidazolylmetyltio)-etylamin,(c) 2-(5-bromo-4-imidazolylmethylthio)-ethylamine,

(d) 2-(5-trifluormetyl-4-imidazolylmetyltio)etylamin, (e) 2-(5-hydroksymetyl-4-imidazolylmetyltio)etylamin, (f) 2-(2-pyridylmetyltio) et<y>lamin,. (g) 2-(3-metyl-2-pyridylmetyltio)étylamin (h) 2-(3-metoksy-2-pyridylmetyltio)etylamin, (i) 2-(3-klor-2-pyridylmetyltio)etylamin, (d) 2-(5-trifluoromethyl-4-imidazolylmethylthio)ethylamine, (e) 2-(5-hydroxymethyl-4-imidazolylmethylthio)ethylamine, (f) 2-(2-pyridylmethylthio)eth<y>amine,. (g) 2-(3-methyl-2-pyridylmethylthio)ethylamine (h) 2-(3-methoxy-2-pyridylmethylthio)ethylamine, (i) 2-(3-chloro-2-pyridylmethylthio)ethylamine,

(j) 2-(3-amino-2-pyridylmetyltio)etylamin,(j) 2-(3-amino-2-pyridylmethylthio)ethylamine,

(k) 2-(3-hydroksy-2-pyridylmetyltio)etylamin,(k) 2-(3-hydroxy-2-pyridylmethylthio)ethylamine,

(1) 2-(3-isotiazolylmetyltio)etylamin,(1) 2-(3-isothiazolylmethylthio)ethylamine,

(m)■ 2-(4-brom-3-isotiazolylmetyltio)etylamin,(m)■ 2-(4-bromo-3-isothiazolylmethylthio)ethylamine,

(n) 2-(3-(1,2,5)-tiadiazolylmetyltio)etylamin(n) 2-(3-(1,2,5)-thiadiazolylmethylthio)ethylamine

(o) 2-(4-klor-3-(1,2,5)-tiadiazolylmetyltio)etylamin, (p) 2-(5-amino-2-(1,3,4)-tiadiazolylmetyltio)etylamin istedenfor 2-(2-tiazolylmetyltio)etylamin ved fremgangsmåte (c) ovenfor gir henholdsvis: (o) 2-(4-chloro-3-(1,2,5)-thiadiazolylmethylthio)ethylamine, (p) 2-(5-amino-2-(1,3,4)-thiadiazolylmethylthio)ethylamine instead of 2- (2-thiazolylmethylthio)ethylamine by method (c) above gives respectively:

(a) 1-[N'-cyano-N"-(2-(2-imidazolylmetyltio)etyl) - guanidino]-9-[N'-cyaho-N"-(2-(5-metyl-4-imidazolyImetyltio)etyl)-guanidino]nonan, (b) 1-[N'-cyano-N"-(2-(4-imidazolylmetyltio)etyl)-guanidino] -<-9-'[N 1 -cyano-N"- (2- (5-metyl-4-imidazolylmetyltio) - etyl)guanidino]nonan, (c) 1-[N<1->cyano-N"-(2-(5-brom-4-imidazolylmetyltio)etyl)-guanidino]-9-[N'-cyano-N"-(2-(5-mety1-4-imidazolylmetyltio)etyl)-guanidino]rtonan, (d) 1- [N 1 -cyano-N"-(2- ('5-trif luormetyl-4-imidazolylmetyltio) etyl)guanidino]-9-[N'-cyano-N"-(2-(5-mety1-4-imidazolylmetyltio) etyl)guanidino]nonan, (e) 1-[N<1->cyano-N"-(2-(5-hydroksymety1-4-imidazolylmetyltio)etyl)guanidino]-9-[N'-cyano-N"-(2-(5-metyl-4-imidazolylmetyltio)etyl)guanidino]nonan, (f) 1-[N'-cyano-N"-(2-(2-pyridylmetyltio)etyl)guanidino]-9-[N'-cyano-N"-(2-(5-metyl-4-imidazolylmetyltio)etyl)guanidino]-nonan, (g) 1-[N'-cyano-N"-(2-(3-metyl-2-pyridylmetyltio)etyl)-guanidino]-9-[N'-cyano-N"-(2-(5-mety1-4-imidazolylmetyltio)etyl)-guanidino]nonan, (h) 1-[N'-cyano-N"-(2-(3-metoksy-2-pyridylmetyltio)-etyl)guanidino]-9-[N'-cyano-N"-(2-(5-metyl-4-imidazolylmetyltio)-etyl)guanidino]nonan, (i) 1-[N'-cyano-N"-(2-(3-klor-2-pyridylmetyltio)etyl)-guanidino]-9-[N'-cyano-N"-(2-(5-mety1-4-imidazolylmetyltio)-etyl)guanidino]nonan, (j) 1-[N'-cyano-N"-(2-(3-amino-2-pyridylmetyltio)etyl)-guanidino ] -9- [N 1 - cyano-N" - ( 2- (5-me ty 1-4-^imidazolylmety ltio) etyl) - guanidino]nonan, (k) 1-[N<1->cyano-N"-(2-(3-hydroksy-2-pyridylmetyltio)etyl)-guanidino] -9 - [N '-cyano-N" - (2-, (5-me.ty 1-4 -imidazolylmetyltio) etyl) - guanidino]nonan, (1) 1-[N<1->cyano-N"-(2-(3-isotiazolylmetyltio)etyl)-guanidino]-9-[N<1->cyano-N"-(2-(5-metyl-4-imidazolylmetyltio)etyl)-guanidino]nonan, (m) 1-[N '-cyano-N"-(2-(4-brom-3_isotiazolylmetyltio).-etyl)guanidino]-9-[N'-cyano-N"-(2-(5-mety1-4-imidazolyImetyltio)-etyl)guanidino]nonan, (a) 1-[N'-cyano-N"-(2-(2-imidazolylmethylthio)ethyl)-guanidino]-9-[N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio) )ethyl)-guanidino]nonane, (b) 1-[N'-cyano-N"-(2-(4-imidazolylmethylthio)ethyl)-guanidino]-<-9-'[N 1 -cyano-N"- (2-(5-methyl-4-imidazolylmethylthio)-ethyl)guanidino]nonane, (c) 1-[N<1->cyano-N"-(2-(5-bromo-4-imidazolylmethylthio)ethyl)- guanidino]-9-[N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]rtonane, (d) 1- [N 1 -cyano-N"-(2- ('5-trifluoromethyl-4-imidazolylmethylthio)ethyl)guanidino]-9-[N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]nonane, (e) 1- [N<1->cyano-N"-(2-(5-hydroxymethyl-4-imidazolylmethylthio)ethyl)guanidino]-9-[N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio) )ethyl)guanidino]nonane, (f) 1-[N'-cyano-N"-(2-(2-pyridylmethylthio)ethyl)guanidino]-9-[N'-cyano-N"-(2-(5 -methyl-4-imidazolylmethylthio)ethyl)guanidino]-nonane, (g) 1-[N'-cyano-N"-(2-(3-methyl-2-pyridylmethylthio)ethyl)-guanidino]-9-[N '-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]nonane, (h) 1-[N'-cyano -N"-(2-(3-methoxy-2-pyridylmethylthio)-ethyl)guanidino]-9-[N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)-ethyl)guanidino] nonane, (i) 1-[N'-cyano-N"-(2-(3-chloro-2-pyridylmethylthio)ethyl)-guanidino]-9-[N'-cyano-N"-(2-(5 -methyl-4-imidazolylmethylthio)-ethyl)guanidino]nonane, (j) 1-[N'-cyano-N"-(2-(3-amino-2-pyridylmethylthio)ethyl)-guanidino]-9- [N 1 - cyano-N" - ( 2-(5-methyl 1-4-^imidazolylmethylthio) ethyl) - guanidino]nonane, (k) 1-[N<1->cyano-N"-(2-( 3-hydroxy-2-pyridylmethylthio)ethyl)-guanidino]-9-[N '-cyano-N"-(2-, (5-methyl 1-4-imidazolylmethylthio)ethyl)-guanidino]nonane, (1 ) 1-[N<1->cyano-N"-(2-(3-isothiazolylmethylthio)ethyl)-guanidino]-9-[N<1->cyano-N"-(2-(5-methyl-4 -imidazolylmethylthio)ethyl)-guanidino]nonane, (m) 1-[N'-cyano-N"-(2-(4-bromo-3_isothiazolylmethylthio).-ethyl)guanidino]-9-[N'-cyano-N "-(2-(5-methyl-4-imidazolylmethylthio)-ethyl)guanidino]nonane,

(n) 1-[N'-cyano-N"-(2-(3-(1,2,5)-tiadiazolylmetyltio)-etyl)guanidino]-9-[N'-cyano-N"-(2-(5-metyl-4-imidazolylmetyltio)-etyl)guanidino]nonan,. (n) 1-[N'-cyano-N"-(2-(3-(1,2,5)-thiadiazolylmethylthio)-ethyl)guanidino]-9-[N'-cyano-N"-(2- (5-methyl-4-imidazolylmethylthio)-ethyl)guanidino]nonane,.

(o) 1-[N'-cyano-N"-(2-(4-klor-3-(1,2,5)-tiadiazolyl-metyltio) etyl)guanidino]-9-[N1-cyano-N"-(2-(5-mety1-4-imidazolylmetyltio) etyl)guanidino]nonan, (o) 1-[N'-cyano-N"-(2-(4-chloro-3-(1,2,5)-thiadiazolyl-methylthio)ethyl)guanidino]-9-[N1-cyano-N" -(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]nonane,

(p) 1-[N'-cyano-N"-(2-(5-amino-2-(1,3,4)-tiadiazolyl-metyltio) etyl)guanidino]-9-[N'-cyano-N"-(2-(5-metyl-4-imidazolylmetyltio)etyl)guanidino]nonan, (p) 1-[N'-cyano-N"-(2-(5-amino-2-(1,3,4)-thiadiazolyl-methylthio)ethyl)guanidino]-9-[N'-cyano-N "-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]nonane,

og syrehydrolyse gir de tilsvarende N,N'-substituerte guanidin-derivater. and acid hydrolysis gives the corresponding N,N'-substituted guanidine derivatives.

Behandling av de ovennevnte aminer med benzoyl-isotiocyanat og hydrolyse av produktene gir'de tilsvarende tiourinstoffer, som, når de anvendes istedenfor N-[2-(5-mety1-4-imidazolylmetyltio)-etyl]tiourinstoff ved fremgangsmåten ifølge eksempel 1, kan omdannes til bis-guanidinodekaner. Treatment of the above-mentioned amines with benzoyl isothiocyanate and hydrolysis of the products gave the corresponding thioureas, which, when used instead of N-[2-(5-methyl-4-imidazolylmethylthio)-ethyl]thiourea in the method according to example 1, can are converted to bis-guanidinodecane.

Eksempel 8Example 8

(i) Omsetning av 2-klor-3-nitropyridin med 2- (2-cyanoetyl) — malonsyre-dietylester og natriumhydrid i tetrahydrofuran gir 1-(3-nitro-2-pyridyl)-1,1-bis-(karbetoksy)butyronitril, sm.p. (i) Reaction of 2-chloro-3-nitropyridine with 2-(2-cyanoethyl)-malonic acid diethyl ester and sodium hydride in tetrahydrofuran gives 1-(3-nitro-2-pyridyl)-1,1-bis-(carbethoxy) butyronitrile, m.p.

■ 93,5-94,5°, som efter alkalisk hydrolyse og surgjøring gir ■ 93.5-94.5°, which after alkaline hydrolysis and acidification gives

2- (3-cyanopropyl) -3-n'itropyridin-hydroklorid , sm. p. 14 2-14 5 , 5° . Reduksjon med hydrogen og palladium på trekull, gir 3-amino-2-(3-cyanopropyl)pyridin, og behandling av denne forbindelse med natriumnitritt og svovelsyre og påfølgende oppvarmning gir 2-(3-cyanopropyl)-3-hydroksypyridin. Metylering med metyljodid og natriumetoksyd i dimetylsulfoksyd og påfølgende reduksjon med litiumåluminiumhydrid gir 4-(3-metoksy-2-pyridyl)butylamin. Reduksjon av 3-amino-2-(3-cyanopropyl)-3-hydroksypyridin med litiumåluminiumhydrid gir 4-(3-amino-2-pyridyl)butylamin. Diazotering av 4-(3-amino-2-pyridyl)butylamin ved pH 1 og be-■ handling méd kobber(I)klorid eller kobber(I)bromid, gir henholdsvis 4-(3-klor-2-pyridyl)butylamin og 4-(3-brom-2-pyridyl)butylamin. (ii) Anvendelse av (a) 4-(4-imidazolyl)butylamin, 2-(3-cyanopropyl)-3-nitropyridine hydrochloride, sm. p. 14 2-14 5 , 5° . Reduction with hydrogen and palladium on charcoal gives 3-amino-2-(3-cyanopropyl)pyridine, and treatment of this compound with sodium nitrite and sulfuric acid and subsequent heating gives 2-(3-cyanopropyl)-3-hydroxypyridine. Methylation with methyl iodide and sodium ethoxide in dimethylsulfoxide and subsequent reduction with lithium aluminum hydride gives 4-(3-methoxy-2-pyridyl)butylamine. Reduction of 3-amino-2-(3-cyanopropyl)-3-hydroxypyridine with lithium aluminum hydride gives 4-(3-amino-2-pyridyl)butylamine. Diazotization of 4-(3-amino-2-pyridyl)butylamine at pH 1 and treatment with copper (I) chloride or copper (I) bromide gives respectively 4-(3-chloro-2-pyridyl)butylamine and 4-(3-Bromo-2-pyridyl)butylamine. (ii) Use of (a) 4-(4-imidazolyl)butylamine,

(b) 4-(3-metoksy-2-pyridyl)butylamin,(b) 4-(3-methoxy-2-pyridyl)butylamine,

(cj 4-(3-klor-2-pyridyl)butylamin,(cj 4-(3-chloro-2-pyridyl)butylamine,

(d) 4-(3-brom-2-pyridyl)butylamin,(d) 4-(3-bromo-2-pyridyl)butylamine,

(e) 4-(3-amino-2-pyridyl)butylamin, istedenfor 2-(2-tiazolylmetyltio)etylamin ved fremgangsmåten ifølge eksempel 7 (c) gir henholdsvis (a) 1-[N'-cyano-N"-(4-(4-imidazolyl)butyl)guanidino]-9-[N<1->cyano-N"-(2-(5-mety1-4-imidazolylmetyltio)etyl)guanidino]-nonan, (b) 1- [N1-cyano-N"-(4-(3-metoksy-2-pyridyl)butyl)-guanidino]-9-[N'-cyano-N"-(2-(5-metyl-4-imidazolylmetyltio)etyl)-guanidino]nonan. (c) 1-[N'-cyano-N"-(4-(3-klor-2-pyridyl)butyl)-guanidino]-9-[N'-cyano-N"-(2-(5-metyl-4-imidazolylmetyltio)etyl)-guanidino]nonan, (d) 1-[N'-cyano-N"-(4-(3-brom-2-pyridyl)butyl)guanidino]-9-[N'-cyano-N"-(2-(5-metyl-4-imidazolylmetyltio)etyl)guanidino]-nonan, (e) 1- [N'-cyano-N"-(4-(3-amino-2-pyridyl)butyl)-guanidino] -9 - [N 1 - cyano-N" - (2- ( 5-^me ty 1-4-imidazolylme ty ltio) etyl) - guanidino]nonan, (e) 4-(3-amino-2-pyridyl)butylamine, instead of 2-(2-thiazolylmethylthio)ethylamine in the method according to example 7 (c) gives respectively (a) 1-[N'-cyano-N"-(4-(4-imidazolyl)butyl)guanidino]-9-[N <1->cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]-nonane, (b) 1- [N1-cyano-N"-(4-(3-methoxy-2 -pyridyl)butyl)-guanidino]-9-[N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]nonane. (c) 1-[N'-cyano-N"-(4-(3-chloro-2-pyridyl)butyl)-guanidino]-9-[N'-cyano-N"-(2-(5-methyl -4-imidazolylmethylthio)ethyl)-guanidino]nonane, (d) 1-[N'-cyano-N"-(4-(3-bromo-2-pyridyl)butyl)guanidino]-9-[N'-cyano -N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]-nonane, (e) 1- [N'-cyano-N"-(4-(3-amino-2-pyridyl)butyl ),

og syrehydrolys.e gir de tilsvarende N ,N'-substituerte guanidin-derivater. and acid hydrolysis give the corresponding N,N'-substituted guanidine derivatives.

Behandling av de ovennevnte aminer med benzoyl-isotiocyanat -og hydrolyse av produktene gir de tilsvarende tiourinstof fer, som, når de anvendes istedenfor N-[2-(5-metyl-4- imidazolylmetyltio)etyl]tiourinstoff ved fremgangsmåten ifølge eksempel 1, kan omdannes til bis-guanidinodekaner. Treatment of the above-mentioned amines with benzoyl isothiocyanate and hydrolysis of the products gives the corresponding thioureas, which, when used instead of N-[2-(5-methyl-4-imidazolylmethylthio)ethyl]thiourea in the method according to example 1, can are converted to bis-guanidinodecane.

Eksempel 9Example 9

Anvendelse avApplication of

(a) 2-(2-(4-imidazolyl)etyltio)etylamin,(a) 2-(2-(4-imidazolyl)ethylthio)ethylamine,

(b) 3-(4-imidazolylmetyltio)propylamin, . (b) 3-(4-imidazolylmethylthio)propylamine, .

(c) 3-(2-tiazolyl)propylamin(c) 3-(2-thiazolyl)propylamine

istedenfor 2-(2-tiazolylmetyltio)etylamin ved fremgangsmåten ifølge eksempel 7(c.) gir henholdsvis: • instead of 2-(2-thiazolylmethylthio)ethylamine in the method according to example 7(c.) gives respectively: •

(a) 1-[N'-cyano-N"-(2-(2-(4-imidazolyl)etyltio)etyl)-guanidino]-9-[N'-cyano-N"-(2-(5-mety1-4-imidazolylmetyltio)etyl)-guanidino]nonan, (b) 1-[N<1->cyano-N"-(3-(4-imidazolylmetyltio)propyl)-guanidino] -9- [N ' -cyano-N"- (2- (5-metyl-4-imidazolylme.tyltio) etyl) - guanidino]nonan, (c) 1-[N<1->cyano-N"-(3-(2-tiazolyl)propyl)guanidino]-9-[N<1->cyano-N"-(2-(5-metyl-4-imidazolylmetyltio)etyl)guanidino]-nonan, (a) 1-[N'-cyano-N"-(2-(2-(4-imidazolyl)ethylthio)ethyl)-guanidino]-9-[N'-cyano-N"-(2-(5- methyl 1-4-imidazolylmethylthio)ethyl)-guanidino]nonane, (b) 1-[N<1->cyano-N"-(3-(4-imidazolylmethylthio)propyl)-guanidino]-9- [N'-cyano -N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]nonane, (c) 1-[N<1->cyano-N"-(3-(2-thiazolyl)propyl )guanidino]-9-[N<1->cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]-nonane,

og syrehydrolyse av de førstnevnte to produkter gir de tilsvarende N,N<1->substituerte guanidin-derivater. and acid hydrolysis of the former two products gives the corresponding N,N<1->substituted guanidine derivatives.

Eksempel 10-N-[2-(5-metyl-4-imidazolylmetyltio)etyl]tiourinstoff-hydrobromid tilbakeløpsbehandles med .1,9-dibromnonan i etanol for å gi 1,9-bis-[S-(N-(2-(5-metyl-4-imidazolylmetyltio)etyl))-isotioureido]nonah-tetrahydrobromid. Example 10-N-[2-(5-methyl-4-imidazolylmethylthio)ethyl]thiourea hydrobromide is refluxed with .1,9-dibromononane in ethanol to give 1,9-bis-[S-(N-(2- (5-Methyl-4-imidazolylmethylthio)ethyl)-isothioureido]nonah tetrahydrobromide.

Eksempel 11Example 11

Behandling av 1,9-bis-[N'-cyano-N"-(2-(5-mety1-4-imidazolylmetyltio) etyl)guanidino]nonan med fortynnet saltsyre ved 40° gir 1,9-bis-[N'-karbamoy1-N"-(2-(5-mety1-4-imidazoly1-metyltio)etyl)guanidino]nonan. Treatment of 1,9-bis-[N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]nonane with dilute hydrochloric acid at 40° gives 1,9-bis-[N' -carbamoyl-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidino]nonane.

Eksempel 12Example 12

1) Tørt hydrogenklorid bobles gjennom en oppløsning av l,9-bis-[N'-(2-(5-mety1-4-imidazolylmetyltio)etyl)tioureido]-nonan i metanol ved 80° i 12 timer, og oppløsningsmidlet fjernes for å gi 1,9-bis-[S-mety1-N'-(2-(5-metyl-4-imidazolylmetyltio)-etyl)iostioureido]nonan-tetrahydroklorid. 2) Dette produkt behandles med (a) hydroksylamin-hydroklorid og kaliumbikarbonat i tørt dimetylformamid eller (b) metylamin i etanol, for å gi henholdsvis (a) 1,9-bis-[N1-hydroksy-N"-(2-(5-mety1-4-imidazolylmetyltio)etyl)guaniidno]-nonan, eller (b) 1,9-bis-[N'-mety1-N"-(2-(5-metyl-4-imidazolylmetyltio)etyl)guanidino]nonan. 1) Dry hydrogen chloride is bubbled through a solution of 1,9-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido]-nonane in methanol at 80° for 12 hours, and the solvent is removed for to give 1,9-bis-[S-methyl-N'-(2-(5-methyl-4-imidazolylmethylthio)-ethyl)isothioureido]nonane tetrahydrochloride. 2) This product is treated with (a) hydroxylamine hydrochloride and potassium bicarbonate in dry dimethylformamide or (b) methylamine in ethanol to give, respectively, (a) 1,9-bis-[N1-hydroxy-N"-(2-( 5-methyl-4-imidazolylmethylthio)ethyl)guanidino]nonane, or (b) 1,9-bis-[N'-methyl-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino] none.

Eksempel 13Example 13

N-cyano-N'-[2-((5-mety1-4-imidazolylmetyltio)etyl]-S-metylisotiourinstoff settes til et overskudd av 1,9-diaminononan, og blandingen omrøres ved romtemperatur i 15 timer og ekstraheres med eter. Residuet renses ved kromatografi på silikagel under eluering med isopropanol for å gi N-cyano-N'-(9-aminononyl)-N"-[2-(5-mety1-4-imidazolylmetyltio)etyl]-guanidin. Dette aminononylguanidin tilbakeløpsbehandles i isopropanol med N-cyano-N'-[2-((5-methyl-4-imidazolylmethylthio)ethyl]-S-methylisothiourea is added to an excess of 1,9-diaminononane, and the mixture is stirred at room temperature for 15 hours and extracted with ether. The residue is purified by chromatography on silica gel eluting with isopropanol to give N-cyano-N'-(9-aminononyl)-N"-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-guanidine. This aminononylguanidine is refluxed in with isopropanol

(a) S-metyl-N<1->[2-(5-metyl-4-imidazolylmetyltio)-etyl]-tiourinstoff-hydrojodid, ' (b) S-metyl-N' - [-2- (2-tiazolylmetyltio) etyl] tiourinstof f-hydrojodid, (c) l-nitro-2-metyltio-2-t 2-( (5-metyl-4-imidazolyl).-metyltio)etylamino]etylen, (d) S-metyl-N-[2-((5-metyl-4-imidazolyl)metyltio)etyl]-ditiokarbamat, for å gi henholdsvis (a) 1-[N<1->cyano-N"-(2-(5-mety1-4-imidazolylmetyltio)etyl)-guanidino]-9-[N'-[2-(5-mety1-4-imidazolylmetyltio)etyl]-guanidino]-nonan, (b) 1-[N'-cyano-N"-(2-(5-metyl-4-imidazolylmetyltio)-etyl)guanidino]-9-[N'-[2-(2-tiazolylmetyltio)etyl]guanidino]nonan, (c) ' 1-[N'-cyano-N"-t2-(5-metyl-4-imidazolylmetyltio)-etyl) guanidino] -9- [1- (2- ('5-metyl-4-imidazolylmetyltio) etylamino) - 2-nitroviny1-1-amino]nonan, . (d) 1-[N'-cyano-N"-[2-(5-metyl-4-imidazolylmetyltio)-etyl]guanidino]-9-[N'-(2-(5-mety1-4-imidazolylmetyltio)etyl)-tioureido]nonan, og hydrolyse av disse produkter gir henholdsvis: (a) 1,9-bis-[N'-(2-(5-metyl-4-imidazolylmetyltio)etyl)-guanidino]nonan, (a) S-methyl-N<1->[2-(5-methyl-4-imidazolylmethylthio)-ethyl]-thiourea hydroiodide, ' (b) S-methyl-N' - [-2-(2-thiazolylmethylthio) ethyl] thiourea f-hydroiodide, (c) 1-nitro-2-methylthio-2-t 2-( (5-methyl-4 -imidazolyl).-methylthio)ethylamino]ethylene, (d) S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-dithiocarbamate, to give respectively (a) 1-[ N<1->cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]-9-[N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-guanidino ]-nonane, (b) 1-[N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)-ethyl)guanidino]-9-[N'-[2-(2-thiazolylmethylthio) ethyl]guanidino]nonane, (c) ' 1-[N'-cyano-N"-t2-(5-methyl-4-imidazolylmethylthio)-ethyl) guanidino] -9- [1- (2- ('5- methyl-4-imidazolylmethylthio)ethylamino)-2-nitrovinyl-1-amino]nonane, (d) 1-[N'-cyano-N"-[2-(5-methyl-4-imidazolylmethylthio)-ethyl]guanidino ]-9-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-thioureido]nonane, and hydrolysis of these products gives respectively: (a) 1,9-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]nonane,

'(b) 1-[N'-(2-(5-metyl-4-imidazolylmetyltio)etyl) - guanidino]-9-[N'-(2-(2-tiazolylaretyltio)etyl)guanidino]nonan, (c) 1-[N1 -(2-(5-mety1-4-imidazolylmetyltio)etyl)-guanidino]-9-[1-(2-(5-metyl-4-imidazolylmetyltio)etylamino)-2-nitrovinyl-l-amino]nonan, (d) 1-[N'-(2-(5-mety1-4-imidazolylmetyltio)etyl)-guanidino]-9-[N'-(2-(5-mety1-4-imidazolylmetyltio)etyl)-tioureido]nonan. '(b) 1-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]-9-[N'-(2-(2-thiazolylarethylthio)ethyl)guanidino]nonane, (c ) 1-[N1 -(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]-9-[1-(2-(5-methyl-4-imidazolylmethylthio)ethylamino)-2-nitrovinyl-1- amino]nonane, (d) 1-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]-9-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl )-thioureido]nonane.

Claims (1)

1. Analogifremgangsmåte for fremstilling av farmakologisk aktive forbindelser med formel 1: 1. Analogous method for the preparation of pharmacologically active compounds of formula 1: Formel 1 3 4 hvor X og X , som kan være like eller forskjellige., er svovel, CHNO- eller NY, hvor Y er hydrogen, hydroksy, lavere alkyl, 3 4 cyano eller CONH2; R og R , som kan være like eller forskjellige, betyr en gruppe med strukturen: Het-(CH0) Z(CH„) - 2 m 2 n hvor Het er en 2- eller 4-imidazolylring som eventuelt er substituert med lavere alkyl, halogen, trifluormetyl eller hydroksymetyl, en 2-pyridylring som eventuelt er substituert med lavere alkyl, halogen, amino, hydroksy eller lavere alkoksy, en 2-tiazolylring, en 3-isotiazolylring som eventuelt er substituert med brom, eller en tiadiazolylring som eventuelt er substituert med klor' eller amino; Z er svovel eller en metylen-gruppe; m er 0, 1 eller 2, og n er 2 eller 3, forutsatt at summen av m og n er 3 eller 4, eller når X 3 eller X 4 er svovel, CHNO^ eller NCN, kan summen av m og n i deri tilstøtende sidekjede R og R 4 ogsa være 2; W er NH, og når X <3> og X <4> begge er NH, kan W også være svovel, og p er et helt tall fra 9 til 12, karakterisert ved at 34 (a) når W er NH og X og X hver er svovel, CHNCy, NH, NCN eller N(lavere alkyl), behandles en forbindelse med formelen R 3NHE, hvor E er hydrogen eller Formula 1 3 4 where X and X , which may be the same or different, are sulfur, CHNO- or NY, where Y is hydrogen, hydroxy, lower alkyl, 3 4 cyano or CONH 2 ; R and R , which may be the same or different, mean a group with the structure: Het-(CH0) Z(CH„) - 2 m 2 n where Het is a 2- or 4-imidazolyl ring which is optionally substituted with lower alkyl, halogen, trifluoromethyl or hydroxymethyl, a 2-pyridyl ring which is optionally substituted with lower alkyl, halogen, amino, hydroxy or lower alkoxy, a 2-thiazolyl ring, a 3-isothiazolyl ring optionally substituted with bromine, or a thiadiazolyl ring optionally substituted with chlorine or amino; Z is sulfur or a methylene group; m is 0, 1 or 2, and n is 2 or 3, provided that the sum of m and n is 3 or 4, or when X 3 or X 4 is sulfur, CHNO^ or NCN, the sum of m and n in the adjacent side chain R and R 4 also be 2; W is NH, and when X <3> and X <4> are both NH, W can also be sulfur, and p is an integer from 9 to 12, characterized in that 34 (a) when W is NH and X and X are each sulfur, CHNCy, NH, NCN or N(lower alkyl), a compound is treated with the formula R 3NHE, where E is hydrogen or (hvor A er lavere alkyl, X 5 er X 3 eller -NY1 hvor Y' er en guanidin-beskyttende gruppe så som benzoyl, benzyloksykarbonyl eller etoksykarbonyl), med en forbindelse med formelen4 GNHR , hvor G er (where A is lower alkyl, X 5 is X 3 or -NY1 where Y' is a guanidine protecting group such as benzoyl, benzyloxycarbonyl or ethoxycarbonyl), with a compound of the formula 4 GNHR , where G is når E er hydrogen, og G er NH2 (CH2 )1 when E is hydrogen, and G is NH2 (CH2 )1 l år É er l year É is (hvor A og X"' er som ovenfor angitt, 6 4 o og X er X eller NY <1> hvor Y' er som ovenfor angitt), for a eliminere et merkaptan med formelen ASH, og når X^ eller X er NY <1> , fjernes den guanidin-beskyttende.gruppen for å gi forbindelser 3 4 hvor X eller X er NH; eller (b) når W er svovel og X 3 og X 4begge er NH, behandles en forbindelse med formelen Hal-(CH~) -Hal, hvor Hal er klor, brom eller jod, med et tiourinstoff med formelen R 3NHCSNH2, eller når R <3> ikke er lik R <4> , sukessivt med tiourinstof f er med formlene R3NHCSNH2 og R <4> NHCSNH2 ; eller (c) når W er NH og X 3 og X 4 begge er =NY (hvor Y er hydroksy eller lavere alkyl), behandles et isotiourinstoff med formelen (where A and X"' are as above, 6 4 o and X is X or NY <1> where Y' is as above), to eliminate a mercaptan of the formula ASH, and when X^ or X is NY <1> , the guanidine protecting group is removed to give compounds 3 4 where X or X is NH; or (b) when W is sulfur and X 3 and X 4 are both NH, a compound of the formula Hal-(CH~)-Hal, where Hal is chlorine, bromine or iodine, is treated with a thiourea of the formula R 3NHCSNH 2 , or when R <3> is not equal to R <4> , successively with thiourea f is of the formulas R3NHCSNH2 and R <4> NHCSNH2 ; or (c) when W is NH and X 3 and X 4 are both =NY (where Y is hydroxy or lower alkyl), an isothiourea is treated with the formula (hvor A er lavere alkyl), med en forbindelse med formelen YNH2 hvor Y er hydroksy eller lavere alkyl; eller(d) når X <3> eller X4 er ■=NCONH2, underkastes en forbindelse med formelen (where A is lower alkyl), with a compound of the formula YNH 2 where Y is hydroxy or lower alkyl; or(d) when X <3> or X4 is ■=NCONH2, is subjected to a compound of the formula 3 4 hvor X eller X er NCN, mild syrehydrolyse, og eventuelt fremstilles en forbindelse med formel 1 hvor X <3> og/eller X 4er NH, ved syrehydrolyse av en forbindelse med formel 43 4 where X or X is NCN, mild acid hydrolysis, and optionally a compound of formula 1 is prepared where X <3> and/or X 4 is NH, by acid hydrolysis of a compound of formula 4 1 hvor X og/eller X er NCN, og/eller eventuelt omdannes en fremstilt forbindelse til et syreaddisjonssalt derav.1 where X and/or X is NCN, and/or optionally, a prepared compound is converted into an acid addition salt thereof.
NO772668A 1976-07-28 1977-07-27 ANALOGICAL PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE COMPOUNDS NO772668L (en)

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