DK157132B - Analogy process for preparing guanidinothiazole compounds or acid addition salts thereof - Google Patents

Description

DK 157132 BDK 157132 B

Den foreliggende opfindelse angâr en analogifremgangs-mâde til fremstilling af hidtil ukendte guanidinothia-zolforbindelser, der er nyttige som inhibitorer for mavesyre-sekretion.The present invention relates to an analogous process for the preparation of novel guanidinothiazole compounds which are useful as inhibitors of gastric acid secretion.

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If0lge den foreliggende opfindelse tilvejebringes hidtil ukendte guanidinothiazolforbindelser med den almene formel (I) som vist og beskrevet i krav l's indledende del, samt de syreadditionssalte af guanidinothiazolforbindel-10 serne, der er anvendelige til medicinske formai. Eksemp-ler pâ substituenter-, som kan indgâ i den omtalte almene formel er for en alkylgruppe: methyl, ethyl, isopropyl og butyl; for en alkenylgruppe: vinyl, allyl og isopro-penyl; for en alkenylgruppe: ethynyl, propenyl og butyn-15 yl; for en acylaminogruppe: acetyl og propionyl; yder- ligere kan en phenyl- eller naphthylgruppe hâve en eller flere substituenter sâsom et halogenatom, en hydroxyl-gruppe, en aminogruppe eller en alkoxygruppe med 1-5 carbonatomer.According to the present invention there are provided novel guanidinothiazole compounds of general formula (I) as shown and described in the preamble of claim 1, as well as the acid addition salts of the guanidinothiazole compounds useful for medical purposes. Examples of substituents which may be included in the general formula are for an alkyl group: methyl, ethyl, isopropyl and butyl; for an alkenyl group: vinyl, allyl and isopropenyl; for an alkenyl group: ethynyl, propenyl and butynyl; for an acylamino group: acetyl and propionyl; further, a phenyl or naphthyl group may have one or more substituents such as a halogen atom, a hydroxyl group, an amino group or an alkoxy group having 1 to 5 carbon atoms.

2020

Forbindelserne med den omtalte almene formel I danner yderligere let syreadditionssalte, og der eksisterer ligeledes tautomere forbindelser til disse forbindelser ved placeringep af N-R 25 //The compounds of the general formula I further form light acid addition salts, and there are also tautomeric compounds to these compounds at the location of N-R 25 //

-C-C

\ NH-R2 30 Opfindelsen omfatter ligeledes fremstilling af disse syreadditionssalte og fremstilling af de tautomere forbindelser til forbindelserne med den almene formel I.The invention also encompasses the preparation of these acid addition salts and the preparation of the tautomeric compounds for the compounds of the general formula I.

Som ovenfor nævnt danner de omhandlede guanidinothiazol-35 forbindelser let syreadditionssalte, der er i stand til at blive anvendt til medicinske formâl. Som sâdanne 2As mentioned above, the guanidinothiazole compounds of this invention readily form acid addition salts capable of being used for medicinal purposes. As such 2

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salte kan nævnes saltene af guanidinothiazolforbindel-serne med uorganiske eller organiske syrer. Eksempler pâ salte med en uorganisk syre er hydrochlorider, hydro-bromider og sulfater. Eksempler pâ salte med særligt an-5 vendelige organiske syrer er saltene med alifatiske car-boxylsyrer sâsom eddikesyre, maleinsyre og fumarsyre.salts may be mentioned the salts of the guanidinothiazole compounds with inorganic or organic acids. Examples of salts with an inorganic acid are hydrochlorides, hydrobromides and sulfates. Examples of salts with particularly useful organic acids are the salts with aliphatic carboxylic acids such as acetic acid, maleic acid and fumaric acid.

Det er et f0rste træk i forbindelse med denne opfindel-se, at de forbindelser, der er fremstillet if0lge opfin-10 delsen, har en inhiberende virkning pâ mavesyre, og at denne virkning ikke forarsages af en anticholinerg virkning. Eftersom konventionelle kommercielt tilgængelige inhibitorer for mavesyre-sekretion sædvanligvis er base-ret pâ den anticholinerge virkning, og eftersom man har 15 pâvist u0nskede bivirkninger forârsaget af den anticholinerge virknirig, er de omhandlede forbindelser nyttige sorti en ny type inhibitorer for mavesyre-sekretion.It is a first feature of this invention that the compounds prepared according to the invention have an inhibitory effect on gastric acid and that this effect is not caused by an anticholinergic effect. Since conventional commercially available inhibitors of gastric acid secretion are usually based on the anticholinergic effect, and since undesirable side effects have been demonstrated by the anticholinergic activity, the compounds of this invention are useful in a new type of inhibitors of gastric acid secretion.

Det er et andet traak ved den foreliggende opfindelse, at 20 nogle af de omhandlede forbindelser udviser en virkning til inhibering af mavesyre-sekretion gennem en histamin H2~receptor. Ash og Schild har foreslâet at klassificere histamin-receptorer i H^-receptorer og ikke-Hi-recepto-rer eller H2-receptorer, se "Brit. J. of Pharmacol.It is another feature of the present invention that some of the compounds of this invention exhibit an effect of inhibiting gastric acid secretion through a histamine H2 receptor. Ash and Schild have proposed to classify histamine receptors into H 1 receptors and non-H 1 receptors or H 2 receptors, see "Brit. J. of Pharmacol.

25 Chemother.", 27, 427 (1966) og Black et al., "Nature", 236, 385 (1972). Histaminets indvirkning pâ mavesyre-sekretion og pâ hjertefrekvensen i isoleret atrium fra marsvin mildnes af en H^-receptor, og disse histamin-virkninger inhiberes ikke ved konventionelle antihist-30 aminer, sâsom mepyramin, men de modvirkes af blokerings-midler for H2~receptorer, sâsom metiamid.25 Chemother. ", 27, 427 (1966) and Black et al.," Nature ", 236, 385 (1972). The effect of histamine on gastric acid secretion and on the heart rate in isolated guinea pig atrium is mitigated by an H and these histamine effects are not inhibited by conventional antihistamines, such as mepyramine, but are counteracted by blocking agents for H2 receptors, such as methiamide.

Eftersom et blokeringsmiddel for en histamin H2~receptor udviser en virkning til inhibering af den grundliggende 35 sekretion af mavesyre og den sekretion af mavesyre, der fremkaldes af gastrin eller af mad, kan det anvendes ved 3Since a blocking agent for a histamine H2 receptor exhibits an effect of inhibiting the basal secretion of gastric acid and the secretion of gastric acid induced by gastrin or food, it can be used in 3

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behandling af mavesâr og sâr pâ tolvfingertarmen forâr-saget af hypersekretion af mavesyre.Treatment of gastric and duodenal ulcers in the spring of hypersecretion of gastric acid.

Hidtil kender man forbindelser, som viser samme træk som 5 de omhandlede forbindelser, f.eks. forbindelserne omtalt i belgisk patentskrift nr. 804 145; 866 156; 867 105; 867 594; i OSA patentskrift nr. 3 950 333 osv., men de omhandlede forbindelser er aile hidtil ukendte forbindelser, som har en anderledes struktur, og som udviser 10 bedre farmakologiske egenskaber end de kendte forbindelser.Heretofore, compounds are known which exhibit the same features as the compounds of the present invention, e.g. the compounds disclosed in Belgian Patent Specification 804 145; 866 156; 867 105; 867,594; in OSA Patent No. 3,950,333, etc., but the compounds of the present invention are all novel compounds having a different structure and exhibiting 10 better pharmacological properties than the known compounds.

De omhandlede forbindelser kan indgives pérorait eller parenteralt, men man foretraskker pérorai indgift. De om-15 handlede forbindelser anvendes som de frie baser eller som farmakologisk acceptable salte deraf, og de anvendes i almindelighed som medicinske eller farmaceutiske blan-dinger med bærestoffer eller fortyndingsmidler som al-mindeligt anvendt ved fremstilling af lægemidler. Nâr 20 det drejer sig om pérorai indgift, er det mest bekvemt at anvende de medicinske blandinger med de omhandlede forbindelser i form af kapsler eller tabletter, men de kan ligeledes anvendes i form af præparater med forsin-ket frigivelse, Blandingerne kan yderligere anvendes som 25 præparater med sukkerovertræk eller som sirupper. Dose-ringerne til pérorai indgift er· fra 50-800 mg pr. dag, og det er rimeligt at indgive lægemidlet i fra 1 til 4 opdelte doseringer.The compounds of this invention may be administered orally or parenterally, but peroral administration is preferred. The present compounds are used as the free bases or as pharmacologically acceptable salts thereof, and are generally used as medical or pharmaceutical compositions with carriers or diluents as commonly used in the manufacture of drugs. In the case of oral administration, it is most convenient to use the medicinal compositions of the subject compounds in the form of capsules or tablets, but they may also be used in the form of delayed-release preparations. preparations with sugar coating or as syrups. The dose rings for peroral administration are · from 50-800 mg per day. per day and it is reasonable to administer the drug in 1 to 4 divided doses.

30 De omhandlede forbindelser vist ved den almene formel I er inhibitorer for mavesyre-sekretion fremkaldt af hi-stamin, hvilket vil blive pâvist gennem de i det f0lg-ende beskrevne afpr0vninger.The present compounds shown by the general formula I are inhibitors of gastric acid secretion induced by hi -amine, which will be demonstrated through the tests described below.

35 435 4

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(i) Mavesyre-sekretion i anæstetiserede hunde:(i) Stomach acid secretion in anesthetized dogs:

Almindelige blandingshunde, der vejede 5 til 15 kg, blev nægtet f0de i 24 timer og derpâ anæstetiseret intraven-5 0st med pentobarbital (30 mg/kg). Man indf0rte en kanyle af rustfrit stâl gennem ventrikelvæggen i maven efter ligation af pylorus og eâophagus (Okabe, S. et al.,:Ordinary mixed dogs weighing 5 to 15 kg were denied food for 24 hours and then anesthetized intravenously with pentobarbital (30 mg / kg). A stainless steel cannula was inserted through the ventricular wall into the abdomen after ligation of the pylorus and eophagus (Okabe, S. et al.,

Japan J. Pharmacol. 27, 17-22, 1977). Mavesaften blev opsamlet fra mavekanylen ved frit udl0b hvert 15. minut.Japan J. Pharmacol. 27, 17-22, 1977). The gastric juice was collected from the gastric cannula by free expiration every 15 minutes.

10 De forbindelser, der skulle afpr0ves, blev indgivet in-traven0st, efter at mavesekretionen, som blev fremkaldt ved kontinuert intraven0s infusion af histamin (160 pg/kg/time) havde nâet en stabil tilstand. Syreindholdet i mavesaften blev mâlt ved titrering med 0,05 n NaOH 15 under anvendelse af en automatisk titrator (Kyoto Electronics Manufacturing Co., AT-107). Den procentvise in-hibering af mavesekretionen for hver dosering af læge-midlerne blev beregnet ud fra forskellen mellem produk-tionen af syre f0r lægemidlet, og den minimale produk-20 tion af syre, som sædvanligvis blev opnâet inden for 45 minutter efter indgift af lægemidlet. Den dosis, der fremkaldte 50% inhibering af syreproduktionen, blev fundet ud fra en kurve dosis-respons, i hvilke inhiberin-gen blev optegnet semilogaritmisk i forhold til doserin-25 gen. De opnâede data er vist i tabel I under den s0jle, der er betegnet (A).The compounds to be tested were administered intravenously after the gastric secretion induced by continuous intravenous infusion of histamine (160 µg / kg / hour) had reached a stable state. The acid content of the gastric juice was measured by titration with 0.05 n NaOH using an automatic titrator (Kyoto Electronics Manufacturing Co., AT-107). The percent inhibition of gastric secretion for each dosing of the drugs was calculated from the difference between the production of acid before the drug and the minimum production of acid, which was usually obtained within 45 minutes of administration of the drug. . The dose that induced 50% inhibition of acid production was found from a curve dose response in which the inhibition gene was recorded semilogarithmically relative to the dose dose. The data obtained are shown in Table I under the column designated (A).

(ii) Mavesyre-sekretion hos rotter med pylorus-ligatur: 30 Wistar hanrotter, der vejede ca. 200 g, blev nægtet f0de i 24 timer, men fik fri adgang til vand forud for ekspe-rimenterne og i hvert sit bur. Pylorus blev ligateret under etheranæstesi i overensstemmelse med metoden be-skrevet af Shay et al. (Gastroenterol. 5, 43-61, 1954).(ii) Stomach acid secretion in rats with pylorus ligature: 30 Wistar male rats weighing ca. 200 g, was denied food for 24 hours but allowed free access to water prior to the experiments and in each cage. Pylorus was ligated under ether anesthesia according to the method described by Shay et al. (Gastroenterol. 5, 43-61, 1954).

35 De forbindelser, der skulle afpr0ves, blev indf0rt i tolvfingertarmen umiddelbart efter ligateringen af py- 5The compounds to be tested were introduced into the duodenum immediately after the ligation of the piperine.

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lorus. Dyrene blev slagtet 4 timer efter indgiften af lægemidlet, og maveindholdet blev opsamlet. Surhedsgra-den af mavesaften blev malt ved titrering med 0,05 n NaOH under anvendelse af en automatisk titrator (Kyoto 5 Electronics Manufacturing Co., AT-107). Den procentvise inhibering af mavesekretionen for hver dosering af læge-midlerne blev beregnet fra produktionen af syre i kon-trolgrupper og i behandlede grupper. EDso-værdierne blev bestemt ved den sâkaldte probit-metode. De opnâede data 10 er vist i tabel I under s0jlen betegnet med (B).LORUS. The animals were slaughtered 4 hours after administration of the drug and the stomach contents were collected. The acidity of the gastric juice was ground by titration with 0.05 n NaOH using an automatic titrator (Kyoto 5 Electronics Manufacturing Co., AT-107). The percent inhibition of gastric secretion for each dosing of the drugs was calculated from the production of acid in control groups and in treated groups. The ED 50 values were determined by the so-called probit method. The data obtained 10 is shown in Table I under the column denoted by (B).

(iii) Akut toxicitet hos mus: Lægemidlerne blev indspr0jtet intraven0st til ICR han-15 mus, der vejede ca. 35 g, med en hastighed pâ 0,1 ml/10 mg/10 sek., og dyrene blev holdt under observation i 7 d0gn. LD50-værdierne blev bestemt ved den sâkaldte op-og-ned-metode under anvendelse af 10 dyr. Disse data er vist i tabel 1 under s0jlen, der er betegnet (C).(iii) Acute toxicity in mice: The drugs were injected intravenously to ICR male 15 mice weighing approx. 35 g, at a rate of 0.1 ml / 10 mg / 10 sec, and the animals were kept under observation for 7 days. The LD50 values were determined by the so-called up-and-down method using 10 animals. This data is shown in Table 1 below the column designated (C).

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De omhandlede guanidinothiazolforbindelser med den alme-ne formel I kan fremstilles ved f0lgende fremgangsmâder.The present guanidinothiazole compounds of general formula I can be prepared by the following methods.

Premgangsmâde 1: 5 ./tlv " V.Pre-Procedure 1: 5 ./tlv "V.

\X / II2 / / bi-wI2 / -V \l 15 15 R-.NHX /VN'Tr(CI12)r,-Y-(CH?) -C^N_R1\ X / II2 / / bi-wI2 / -V \ l 15 R-.NHX / VN'Tr (CI12) r, -Y- (CH?) -C ^ N_R1

2 10 2 Π \ J2 10 2 Π \ J

1ψ' Nll-Rg A1 20 I de oven for anf0rte- formler betyder R* en alkylgruppe med 1-5 carbonatomer, og R, R]_, R2, Y, m og n har den i krav 1 anf0rte betydning.In the above formulas, R * means an alkyl group of 1 to 5 carbon atoms, and R, R 1, R 2, Y, m and n have the meaning set forth in claim 1.

Denne omsætning udf0res enten derved, at man omsætter 25 udgangsmaterialeforbindelsen med formlen ΙΙχ og en reak-tionsdygtig mængde af ami;nen med formlen IHi eller ved, at man omsætter udgangsmaterialeforbindelsen med formlen Il2 med en reaktionsdygtig mængde af aminen med formlen IIl2· De aminer, der er vist med formlerne ΙΙΙχ eller 30 III2, og som anvendes ved omsætningen, er sâdanne, som er i stand til at fremstille det 0nskede reaktionspro-dukt Ii ved omsætning med udgangsmaterialeforbindelsen ΙΙχ eller II2.This reaction is carried out either by reacting the starting material compound of formula ΙΙχ with a reactive amount of the amine of formula IHi or by reacting the starting material compound of formula II2 with a reactive amount of the amine of formula II shown by formulas ΙΙΙχ or III III and used in the reaction are those capable of preparing the desired reaction product II by reaction with the starting material compound ΙΙχ or II2.

35 Eksempler pâ aminer, som de er vist med formlen ΙΙΙχ, er ammoniak (ammoniumchlorid); en alkylamin med 1-5 carbon- 8Examples of amines as shown by formula ΙΙΙχ are ammonia (ammonium chloride); an alkylamine having 1-5 carbon-8

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atomer, sâsom methylamin, dimethylamin, ethylamin eller isopropylamin; en alkenylamin med 1-5 carbonatomer, sâsom allylamin eller 2-butenylamin; en alkynylamin med 1-5 carbonatomer, propargylamin eller pentynylamin. Ek-5 sempler pâ en amin, sâledes som den er vist med formel IIl2, er ammoniak (ammoniumchlorid); cyanamid; urinstof, hydroxylamin; O-alkylhydroxylamin med 1-5 carbonatomer i alkyldelen sâsom o-methylhydroxylamin eller o-butylhy-droxylamin; en acylamin med 1-5 carbonatomer sâsom acet-10 amid; acylhydrazin med 1-5 carbonatomer, sâsom acetylhy-drazin eller benzoylhydrâzin; benzensulfonylhydrazin; semicarbazid; benzylamin eller phenethylamin; en alkyl-sufonamid med 1-5 carbonatomer, sâsom methansulfonamid eller ethansulfonamid; halogen-alkylsulfonamid med 1-5 15 carbonatomer i alkyldelen, sâsom trifluormethansulfon- amid; substitu'eret eller usubstitueret benzensulfonamid, φ p-chlorbenzensulfonamid eller p-aminobenzensulfonamid; suifamid; et alkylsulfamid med 1-5 carbonatomer i alkyldelen, sâsom methylsulfamid eller diethylsulfamid; phe-20 nylsulfamid eller naphthylsulfamid; benzylsulfamid; eller glycin.atoms, such as methylamine, dimethylamine, ethylamine or isopropylamine; an alkenylamine having 1 to 5 carbon atoms, such as allylamine or 2-butenylamine; an alkynylamine having 1-5 carbon atoms, propargylamine or pentynylamine. Examples of an amine, as shown by Formula II, are ammonia (ammonium chloride); cyanamide; urea, hydroxylamine; O-alkylhydroxylamine having 1-5 carbon atoms in the alkyl moiety such as o-methylhydroxylamine or o-butyl hydroxylamine; an acylamine having 1-5 carbon atoms such as acetamide; acylhydrazine having 1-5 carbon atoms, such as acetylhydrazine or benzoylhydrazine; benzensulfonylhydrazin; semicarbazide; benzylamine or phenethylamine; an alkylsulfonamide having 1 to 5 carbon atoms, such as methanesulfonamide or ethanesulfonamide; haloalkylsulfonamide having 1 to 15 carbon atoms in the alkyl moiety such as trifluoromethanesulfonamide; substituted or unsubstituted benzenesulfonamide, φ p-chlorobenzenesulfonamide or p-aminobenzenesulfonamide; suifamid; an alkyl sulfamide having 1 to 5 carbon atoms in the alkyl moiety, such as methylsulfamide or diethylsulfamide; phenylsulfamide or naphthylsulfamide; benzylsulfamide; or glycine.

Omsætningen udf0res sædvanligvis i et opl0sningsmiddel, og egnede opl0sningsmidler omfatter f.eks. organiske op-25 l0sningsmidler sâsom methanol, éthanol, isopropanol, chloroform, ether, tetrahydrofuran, benzen etc. Man foretrækker, at disse opl0sningsmidler ikke indeholder vand. Der er ingen særlige restriktioner med hensyn til reaktionstemperaturen, men omsætningen udfpres fortrins-30 vis ved stuetemperatur eller under opvarmning. Man foretrækker ligeledes, at omsætningssystemet befinder sig i en neutral til basisk tilstand.The reaction is usually carried out in a solvent, and suitable solvents include e.g. organic solvents such as methanol, ethanol, isopropanol, chloroform, ether, tetrahydrofuran, benzene, etc. It is preferred that these solvents contain no water. There are no particular restrictions on the reaction temperature, but the reaction is preferably expressed at room temperature or under heating. It is also preferred that the circulation system be in a neutral to basic state.

35 935 9

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Produktionsfremgangsmâde 2: /Ν'-γ-ίαι.,) -Y-icu.j -c >N-f ΙΓ 2 " 2 " '"u-u· n.Production Method 2: / Ν'-γ-ίαι.,) -Y-icu.j -c> N-f ΙΓ 2 "2" '"u-u · n.

5 R4_*NH2 Iri35 R4_ * NH2 Iri3

VV

R-NH\ //V"(ci1 oL-Y-ÎCHo) -cr° 10 >-«-C I 2m 2n Nih-r. h I de oven for anf0rte formler har R, R', R4, Y, ra og n den i forbindelse med krav 1 anf0rte betydning.R-NH \ // V "(ci1 oL-Y-ÎCHo) -cr ° 10> -« - CI 2m 2n Nih-r. H In the above formulas, R, R ', R4, Y, ra and n the meaning set forth in claim 1.

15 Denne omsaetning udf0res derved, at inan omsætter udgangs-materialeforbindelser med formlen II3 med en reaktions-dygtig mængde af aminen med formlen III3. Udgangsmateri-aleforbindelsen med formlen II3 fremstilles ved, at man hydrolyserer pâ konventionel mâde udgangsmaterialefor-20 bindelsen med formlen ΙΙχ eller Il2, hvori R3 eller R2 betyder et hydrogenatom. Eksempler pâ aminen, som be-skrevet ved formlen III3, er ammoniak; en alkylamin med 1-5 carbonatomer, sâsom methylamin, ethylamin eller iso-propylamin; hydroxylamin. Reaktionsbetingelserne sâsom 25 det til reaktionen anvendte opl0sningsmiddel, reaktions-temperaturen etc. er de samme, som er anvendt ved frem-stillingsmetode 1.This reaction is carried out by reacting starting material compounds of formula II3 with a reactive amount of the amine of formula III3. The starting material compound of formula II3 is prepared by hydrolyzing in conventional manner the starting material compound of formula ΙΙχ or II2 wherein R3 or R2 represents a hydrogen atom. Examples of the amine as described by formula III3 are ammonia; an alkylamine having from 1 to 5 carbon atoms, such as methylamine, ethylamine or isopropylamine; hydroxylamine. The reaction conditions such as the solvent used for the reaction, the reaction temperature, etc., are the same as used in Preparation Method 1.

Som andre fremgangsmâder til fremstilling af de om-30 handlede forbindelser kan yderligere nævnes fremgangsmâder, sâsom omsætningen til gensidig omdannelse af R^ eller R2 i det 0nskede produkt I og lignende. Der kan nævnes f0lgende processer.Other methods of preparing the compounds of the invention may be further mentioned, such as the reaction for the mutual conversion of R 2 or R 2 in the desired product I and the like. The following processes can be mentioned.

35 Forskellige specifikke udf0relsesformer for fremgangs-mâden if0lge opfindelsen er genstand for krav 2-7.Various specific embodiments of the method according to the invention are the subject of claims 2-7.

1010

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Fremgangsmâden if0lge den foreliggende opfindelse vil yderligere blive forklaret ved de efterf0lgende anf0rte eksempler. I de efterf0lgende eksempler er smp.. Anal., NMR og Mass..forkortelser for henholdsvis smeltepunkt, 5 elementæranalyseværdier, kernemagnetresonansspektrum og massespektrum.The process of the present invention will be further explained by the following examples. In the following examples, mp Anal., NMR and Mass. Abbreviations for melting point, 5 elemental analysis values, nuclear magnetic resonance spectrum and mass spectrum, respectively.

10 15 20 25 30 35 EKSEMFEL 1 11EXAMPLE 1 11

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H2N\c=n ^N0H h2n/" —^¾50¾0¾0^^ I 35 ml methanol opl0stes 4,72 g methyl-3-[(2-guanidino-thiazol-4-yl) -methylthio jpropionimidat, og derpâ blev der til oplosningen sat 25 ml af en methanolisk opl0sning af 5 fri hydroxylamin, der var fremstillet ved behandling af 1,2 g hydroxylaminhydrochlorid med 0,93 g natriummethoxid. Efter omrering af blandingen i 2 timer ved stuetemperatur blev oplesningsmidlet afdestilleret under vacuum, og den dannede inddampningsrest blev renset ved seôlechromatografi 10 under anvendelse af et blandet oplesningsmiddel af chloro-form og methanol som fremkaldervæske, og det blev omkrystal-liseret ud fra methanol-acetone til dannelse af 1,3 g 3- [ ( 2-guanidinothiazol-4-yl ) methylthio Jpropionamidoxim. Dette produkt har folgende fysiske-kemiske egenskaber: • 15 (i) Smeltepunkt: 177-179°C (dekomp.)In 35 ml of methanol was dissolved 4.72 g of methyl 3 - [(2-guanidino-thiazol-4-yl) methylthio] propionimidate and then the solution was added. added 25 ml of a methanolic solution of 5 free hydroxylamine prepared by treating 1.2 g of hydroxylamine hydrochloride with 0.93 g of sodium methoxide. After stirring the mixture for 2 hours at room temperature, the solvent was distilled off under vacuum and the resulting evaporation residue purified by Seo-chromatography using a mixed solvent of chloroform and methanol as the developing liquid and it was recrystallized from methanol-acetone to give 1.3 g of 3- [(2-guanidinothiazol-4-yl) methylthio This product has the following physicochemical properties: • 15 (i) Melting point: 177-179 ° C (decomp.)

(ii) Elementæranalyse for CgH^^NgOS2» I/4H2O CH N(ii) Elemental Analysis for CgH ^^ NNgOS₂ »I / 4H₂O CH N

Beregnetî - 34,46# 5,24# 30,14#Calculated - 34.46 # 5.24 # 30.14 #

Fundetî 34,78# 5,23# 30,06# 20 Derudover fremstillede man methyl-3- [ ( 2-guanidinothiazol- 4-yl ) methylthio Jpropionimidat, der blev anvendt som udgangs-materiale i dette eksempel, og som blev fremstillet ved folgende metode.Found 34.78 # 5.23 # 30.06 # 20 In addition, methyl 3- [(2-guanidinothiazol-4-yl) methylthio] propionimidate was used as the starting material in this example, which was prepared by following method.

(a)(A)

Kv ch«sch9ck0cnKv ch «sch9ck0cn

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12 I en blanding af 490 ml vand og 320 ml éthanol blev op-lest 98,1 g S-(2-aminothiazol-4-yl-methyl)isothiourinstof- 2-hydrochlorid (se; "J. Amer. Chem. Soc.n, 68, 2155-2159 (1946) i en nitrogenstrem, og efter tilsætning af 37,0 g 5 chlorpropionitril, blev blandingen afkelet til 0-10 °C, og en oplosning af 45,1 g natriumhydroxid i 450 ml vand blev til denne blandlng tilsat drâbe for drâbe. Derefter blev blandingen holdt under omrering i 1 time ved 0-10 °C og yderligere i 1 time ved stuetemperatur, og det sâledes 10 fremstillede produkt blev ekstraheret fire gange med hver 600 ml chloroform.12 In a mixture of 490 ml of water and 320 ml of ethanol was dissolved 98.1 g of S- (2-aminothiazol-4-yl-methyl) isothiourea-2-hydrochloride (see; J. Amer. Chem. Soc. n, 68, 2155-2159 (1946) in a nitrogen stream, and after the addition of 37.0 g of chloropropionitrile, the mixture was cooled to 0-10 ° C and a solution of 45.1 g of sodium hydroxide in 450 ml of water was added. This mixture was added drop by drop, then the mixture was kept under stirring for 1 hour at 0-10 ° C and further for 1 hour at room temperature, and the product thus obtained was extracted four times with 600 ml of chloroform each.

Det sâledes fremstillede chloroformlaglag blev vasket med vand og terret med vandfrit magne siumsulfat. Derpâ blev oplosningsmidlet inddampet under vacuum, og de udskilte 15 krystaller blev opsamlet ved filtrering til dannelse af 47,2 g 3-(2-aminothiazol-4-yl-methylthio)propionitril, der udviste et smeltepunkt pâ 104-106°C.The chloroform layer thus prepared was washed with water and tarred with anhydrous magnesium sulphate. The solvent was then evaporated under vacuum and the separated crystals were collected by filtration to give 47.2 g of 3- (2-aminothiazol-4-yl-methylthio) propionitrile, mp 104-106 ° C.

(b) _ __ 5 /N^ CH0SCH..CH„CN(b) _ __ 5 / N ^ CH0SCH..CH „CN

^-corAn-^ y I 500 ml acetone oplestes 50 g S-(2-aminothiazol-4-yl-methylthio)propionitril, og efter tilsætning dertil af 20 45 g benzoylisocyanat blev blandingen holdt under tilbage--CorAn-1 y In 500 ml of acetone, 50 g of S- (2-aminothiazol-4-yl-methylthio) propionitrile was dissolved and after addition thereto of 45 g of benzoyl isocyanate the mixture was kept under reflux.

svaling Og opvarmning i 5 timer. Derefter blev oplosningsmidlet inddampet under vacuum, og de udskilte krystaller blev opsamlet ved filtrering til dannelse af 79,4 g af nâleformede krystaller af 3-[2-(3-benzoylthioureido)thiazol-4-yl-25 methylthio jpropionitril, der udviste et smeltepunkt pâ 158-160°Ccooling and heating for 5 hours. Then, the solvent was evaporated in vacuo and the precipitated crystals were collected by filtration to give 79.4 g of needle-shaped crystals of 3- [2- (3-benzoylthioureido) thiazol-4-yl-methylthio] propionitrile having a melting point at 158-160 ° C

(~\ «5(~ \ «5

,j W v^CH2SCH2CK2CN, j W v ^ CH2SCH2CK2CN

H2NCNH—y JJH2NCNH — y YY

1313

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I en blanding af 1400 ml acetone og 350 ml methanol blev oplest 80 g 3-[2-(3*-benzoylthioureido)thiazol-4-yl-methylthio ]propionitril, og efter tilsætning af en op-lasning af 20 g kaliumcarbonat i 300 ml vand blev 5 blandingen holdt under omrering i 5 timer ved 50 °C. Der-pâ blev oplasningsmidlerae inddampet under vacuum, og den dannede inddampningsrest blev sat til 2000 ml isvand efterfulgt af omroring i lebet af 24 timer, og de ud-fældede krystaller blev opsamlet ved filtrering til dan-10 nelse af 53 »3 g af 3- (2-thioureidothiazol-4-yl-methyl- thio)propionitril, der udviste et smeltepurikt pâ 135-137°C.In a mixture of 1400 ml of acetone and 350 ml of methanol was dissolved 80 g of 3- [2- (3 * -benzoylthioureido) thiazol-4-yl-methylthio] propionitrile, and after the addition of a solution of 20 g of potassium carbonate in 300 ml. of water, the mixture was kept under stirring for 5 hours at 50 ° C. Then, the solvent was evaporated under vacuum and the resulting evaporation residue was added to 2000 ml of ice water followed by stirring for 24 hours and the precipitated crystals were collected by filtration to give 53 »3 g of 3 - (2-thioureidothiazol-4-yl-methylthio) propionitrile, showing a melt purity of 135-137 ° C.

(d) y(d) y

SS

I 200 ml éthanol blev oplast 15 g 3-(2-thioureidothiazol- 4-yl-methylthio)propionitril, og efter tilsætning dertil af 12,4 g methyliodid blev blandingen opvàrmet under tilbage-15 svaling i 1 time. Derpâ blev oplesningsmidlet inddampet under vacuum, og de udskilte krystaller blev opsamlet ved filtrering til dannelse af 20,9 g 3-[2-(S-methylisothio-ureido ) thiazol-4-yl-methylthio Jpropionitril, hydroidid, der udviste et smeltepunkt pâ 148-149°C (dekomp.).In 200 ml of ethanol, 15 g of 3- (2-thioureidothiazol-4-yl-methylthio) propionitrile was charged, and after addition to 12.4 g of methyl iodide, the mixture was heated under reflux for 1 hour. Then, the solvent was evaporated in vacuo and the separated crystals were collected by filtration to give 20.9 g of 3- [2- (S-methylisothio-ureido) thiazol-4-yl-methylthio] propionitrile, hydroid which exhibited a melting point of 148-149 ° C (decomp.).

(e) HA r vS" 'V CH2SC(e) HA r vS "'V CH2SC

HJ ·HJ ·

c Oc O

20 I 200 ml methanol indeholdende 17,0 g (1,0 mol) ammoniak oplestes 20 g (0,05 mol) 3-[2-(S-methylisothioureido)-thiazol-4-yl-methylthioJpropionitril,hydroiodid og 2,68 g (0,05 mol) ammoniumchlorid, og oplesningen blev opvarmetIn 200 ml of methanol containing 17.0 g (1.0 mole) of ammonia, 20 g (0.05 mole) of 3- [2- (S-methylisothioureido) -thiazol-4-yl-methylthio] propionitrile, hydroiodide and 2.68 were dissolved. g (0.05 mole) of ammonium chloride and the solution heated

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14 i et forseglet ror til 80-90°C i 15 timer.14 in a sealed tube to 80-90 ° C for 15 hours.

Efter afkoling af reaktionsblandingen blev oplasnings-midlet afdestilleret imder vacuum. Til den dannede ind-dampningsrest blev tilsat 200 ml vand, og blandingen 5 blev gjort alkalisk ved tilsætning af en mættet vandig oplosning af kaliumcarbonat. Derpâ blev det udskilte brune bundfald opsamlet ved filtrering, t0rret i luften og omkrystalliseret ud fra aeetone til dannelse af 6,2 g 3-(2-guanidinothiazol-4-yl-methylthio)propionitril, der 10 udviste et smeltepunkt pâ 132°C.After cooling the reaction mixture, the solvent was distilled off under vacuum. To the evaporation residue formed was added 200 ml of water and the mixture 5 was made alkaline by the addition of a saturated aqueous solution of potassium carbonate. Then, the precipitated brown precipitate was collected by filtration, dried in the air and recrystallized from ethylene to give 6.2 g of 3- (2-guanidinothiazol-4-yl-methylthio) propionitrile, exhibiting a melting point of 132 ° C.

(f) ll2f'>c=K-<" X s-m(f) l2f '> c = K- <"X s-m

W HpN CH0SCH>CHp(XW HpN CH0SCH> CHp (X

^ 2 2 ^ ^0CH3 I en blanding af 60 ml vandfrit methanol og 120 ml vandfrit chloroform blev oplest 10 g 3-(2-guanidinothiazol-4-yl-methylthio)propionitril, og efter nedkeling af oplosningen til 0-10°C i en nitrogenstrem og efter gennembobling gennem 15 gasformig t0r hydrogenchlorid igennem 3 timer fik oplosningen lov til at henstâ i en lukket beholder ved 0-4°C i 20 timer.In a mixture of 60 ml of anhydrous methanol and 120 ml of anhydrous chloroform, 10 g of 3- (2-guanidinothiazol-4-yl-methylthio) propionitrile was dissolved, and after cooling the solution to 0-10 ° C. a nitrogen stream and after bubbling through 15 gaseous dry hydrogen chloride for 3 hours, the solution was allowed to remain in a sealed container at 0-4 ° C for 20 hours.

Derpâ blev oplosningsmidlerne afdestilleret under vacuum, og den koncentrerede inddampningsrest blev hældt ud i 20 200 ml isvand indeholdende 30 g kaliumcarbonat, og oplos- ningen af blandingen blev ekstraheret tre gange med 150 ml chloroform indeholdende 20% methylalkohol.Then, the solvents were distilled off under vacuum and the concentrated evaporation residue was poured into 20 200 ml of ice water containing 30 g of potassium carbonate and the solution of the mixture was extracted three times with 150 ml of chloroform containing 20% methyl alcohol.

Det organiske lag blev torret over vandfrit magnesiumsulfat, og oplosningsmidlet blev afdestilleret under vacuum til 25 dannelse af 10,3 g methyl-3-[(2-guanidinothiazol-4-yl)-methylthio Jpropionimidat.The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under vacuum to give 10.3 g of methyl 3 - [(2-guanidinothiazol-4-yl) methylthio] propionimidate.

EKSEMPEL 2 15EXAMPLE 2 15

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Idet man gik frem analogt med fremgangsmâden i eksempel 1 blev fremstillet folgende forbindelse.Following analogous to the procedure of Example 1, the following compound was prepared.

'W'I'wi

H2N CHpSCHpCHpC^ 0CK3 ^nh2H2N CHpSCHpCHpC ^ 0CK3 ^ nh2

CKCOOHCKCOOH

H uH u

CHCOOHCHCOOH

o-methyl-3- [ ( 2-guanidinothiazol-4-yl)methylthio jpropion-3 amidoxim,maleat.o-methyl-3- [(2-guanidinothiazol-4-yl) methylthio] propion-3-amidoxime, maleate.

Den til omsætningen anvendte aminî i^NOCH^The amine used for the reaction is NOTCH

Produktets fysisk-kemiske egenskaber:Physico-chemical properties of the product:

(i) Smeltepunkt: 161-164°C(i) Melting point: 161-164 ° C

(ii) Elementæranalyse for(ii) Elementary analysis for

C H NC H N

10 Beregnet: 38,00% 5,01% ' 18,99%Calculated: 38.00% 5.01% 18.99%

Fundet: 38,04% 4,94% 19,31% EKSEMPEL 3 H2N\ ^ CHpSCHpCH 2Found: 38.04% 4.94% 19.31% EXAMPLE 3 H2N \ ^ CHpSCHpCH 2

v>!,XsJv> !, XSJ

Til 1,9 g ethyl-3-[(2-guanidinothiazol-4-yl)methylthio]-propionimidazat blev tilsat 10 ml af en ethanolisk oplos-15 ning af 0,28 g cyanamid, og blandingen fik lov at henstâ natten over ved stuetemperatur. Derpâ blev oplesnings-midlet afdestilleret fra reaktionsblandingen under vacuum, og den dannede inddampningsrest blev renset ved hjælp af chromatografi pâ en silicagel-sojle under anvendelse af en 20 oplosningsmiddelblanding af chloroform og methanolTo 1.9 g of ethyl 3 - [(2-guanidinothiazol-4-yl) methylthio] propionimidazate were added 10 ml of an ethanolic solution of 0.28 g of cyanamide and the mixture was allowed to stand overnight at room temperature. Then, the solvent was distilled off from the reaction mixture under vacuum and the resulting evaporation residue was purified by chromatography on a silica gel column using a solvent mixture of chloroform and methanol.

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16 som fremkaldervæske til dannelse af 1,35 g N-cyano-3-[ ( 2-guanidinothiazol-4-yl)methylthio ]propionamidin. Reaktionsprodüktet viste folgende fysisk-kemiske egen-skaber: (i) Smeltepunkt: 102,5-104°C (omkrystalliseret ud fra methanol-ether).16 as the developing liquid to give 1.35 g of N-cyano-3- [(2-guanidinothiazol-4-yl) methylthio] propionamidine. The reaction product showed the following physicochemical properties: (i) Melting point: 102.5-104 ° C (recrystallized from methanol ether).

(ii) Elementæranalyse for CgH-^^NyS^:(ii) Elemental Analysis for C

C H NC H N

Beregnet: 38,15% 4,62% 34,60%Calculated: 38.15% 4.62% 34.60%

Fundet: 37,84% 4,59% 34,26% EKSEMPEL 4-8Found: 37.84% 4.59% 34.26% EXAMPLES 4-8

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1717

Idet man gik frem analogt med omsætningsfremgangsmâden \ i eksempel 3 blev f0lgende forbindelser fremstillet:Proceeding analogously to the reaction procedure in Example 3, the following compounds were prepared:

Eksempel 4: ^mz ti 7r y ** CH9SCxL,CH9Cv h2"\c=n__^ f 2 2 2 ^îich2c=chExample 4: ^ mz to 7r y ** CH9SCxL, CH9Cv h2 "\ c = n __ ^ f 2 2 2 ^ ichich2c = ch

Hjfi \ s y* 5 N-(2-propinyl)*-3-[ (2-guanidinotMazol-4-yl)methylthio ]- propionamidin.Helps y * 5 N- (2-propinyl) * - 3- [(2-guanidinotazol-4-yl) methylthio] propionamidine.

Den til omsætning anvendte amin: I^NCI^SCHThe amine used for conversion: I ^ NCI ^ SCH

Reaktionsproduktets fysiskkemiske egenskaber: (i) Massespektrum: m/e 296(M+) 10 (ii) NMR spektra (DMS0-d6 + CD30D) S: 2,30 (2H, 7· SCILjCH/,)!!! 2,83 (1H, t, CH5C=CH) 2,70 (2H, t J c c * 3,60 (2H, S, >CH2S”), 3,70 (2H, d, NCH^CH), 6,48 (1H, S, Λ V S H' 15 Eksempel 5 : KHp ' ττ λτ ✓ N w CKpSCHpCHpC^ Z /r~\Physicochemical properties of the reaction product: (i) Mass spectrum: m / e 296 (M +) 10 (ii) NMR spectra (DMSO-d6 + CD30D) S: 2.30 (2H, 7 · SCILjCH /,) !!! 2.83 (1H, t, CH 5 C = CH) 2.70 (2H, t J cc * 3.60 (2H, S,> CH 2 S 2)), 3.70 (2H, d, NCH 3 CH), 6, 48 (1H, S, Λ VSH '15 Example 5: KHp' ττ λτ ✓ N w CKpSCHpCHpC ^ Z / r ~ \

y 2 2 2 v-Oy 2 2 2 v-O

N-benzyl-3- [ ( 2-guanidinothiazol-4-yl )methylthio ]propion-amidin.N-benzyl-3- [(2-guanidinothiazol-4-yl) methylthio] propionamidine.

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1818

Den til omsætning anvendte amin: I^NCHg··^ ^The amine used for conversion: I ^ NCHg ·· ^^

Slutproduktets fysiskkemiske egenskaber: (i) Massespektrum: m/e 241 (M-NHgC^CgH^) (il) NMR spektra (DMSO-dg): 5 cf: 2,38 (2H, t') rSCH«CH«), 3,60 (2H, S, VCH^S”), 2,75 (2H, tj ^ / * 4,17 (2H, S, NCH2-(Q> ), 6,45 (1H, S, ),Physicochemical properties of the final product: (i) Mass spectrum: m / e 241 (M-NH 3 Cl 2 C 2 H 2) (1l) NMR spectra (DMSO-d 6): δ cf: 2.38 (2H, t ') rSCH (CH 3.60 (2H, S, VCH 3 S), 2.75 (2H, tj 2 / 4.17 (2H, S, NCH 2 - (Q>), 6.45 (1H, S,),

Hx_FHx_F

7,30 (5H, S, -f>H ).7.30 (5H, S, -f> H).

Eksempel 6: — tt -v- Ptj °γ>ϊι pï- r c trm 2 >c=K-Y ^ 2 2 ‘2^îh H2Îiy \s^- 10 3-[ (2-guanidinothiazol-4-yl)methylthio]propionamidin, hydrochlorid.Example 6: - tt -v- Ptj ° γ> ϊι pï-rc trm 2> c = KY ^ 2 2 '2 ^ îh H2Îiy \ s ^ - 10 3- [(2-guanidinothiazol-4-yl) methylthio] propionamidine , hydrochloride.

Den til omsætning anvendte amin: NH^ClThe amine used for conversion: NH 2 Cl

Slutproduktets fysiskkemiske egenskaber: (i) Smeltepunkt: 109-112°C.Physicochemical properties of the final product: (i) Melting point: 109-112 ° C.

13 (ii) Elementær analyse for C8H15N6S2Clî13 (ii) Elemental analysis for C8H15N6S2Cl2

C H NC H N

Beregnet 32,5990 5,13% 28,51%Calculated 32.5990 5.13% 28.51%

Fundet 32,33% 5,01% 28,28%.Found 32.33% 5.01% 28.28%.

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1919

Eksempel 7: — /1¾ u ,r „ ^ CH9SCH9CK9CvN * /r^\ H2f 2 2 2 ^K.NHCCM^ Η2ΗΧ \gj ' N-benzoyl-3- [ ( 2-guanidinothiazol-4-yl )methylthlo ] -propionamidrazon.Example 7: - / 1¾, R „S CH9SCHCCK9C /N * / R ^ \ H2f 2 2 2 ^ K.NHCCM ^ΗΗΗΧΗΧ gj N-Benzoyl-3- [(2-guanidinothiazol-4-yl) methylthlo] propionamidrazone .

Den til omsætning anvendte amin: HgNNHCO— 5 Slutproduktets fysiskkemiske egenskaber: (i) Smeltepunkti 103-106°C.The amine used for the reaction: HgNNHCO-5 Physicochemical properties of the final product: (i) Melting point 103-106 ° C.

(ii) Elementær analyse for C15H19N70S2!(ii) Elemental Analysis for C15H19N70S2!

C H NC H N

Beregnetî 47,73% 5,01% 25,97%Calculated 47.73% 5.01% 25.97%

Fundet: 47,43% 5,00% 25,72% 10 Eksempel 8: "2]Np ,τ I ^ ^ ^ ^ îi-NHCOCH, \s J 3 N-acetyl-3- [ ( 2-guanidinothiazol-4-yl)methylthio ]propion-amidrazon.Found: 47.43% 5.00% 25.72% Example 8: "2] Np, τ I ^ ^ ^ ^-NHCOCH, \J 3 N-acetyl-3- [(2-guanidinothiazole-4 -yl) methylthio] propionic amidrazone.

Den til omsætning anvendte amin: HgNNHCOCH^The amine used for the reaction: HgNNHCOCH

Slutproduktets fysiskkemiske egenskaber: 15 (i) Smeltepunktï 163-166°C.Physicochemical properties of the final product: (i) Melting point 163-166 ° C.

(ii) Elementær analyse for C10H17N^0S2ï(ii) Elemental analysis for C 10 H 17 N 2 O 2 S 2

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2020

C H NC H N

Beregnet: 38,08% 5,43% 31,09%Calculated: 38.08% 5.43% 31.09%

Fundet: 37,86% 5,62% 30,73% EKSEMPET, 9 m2 „ N ,CH,SCK,CH„C^ .2HC1 2 >C=N-<^ Y 2 2 2 ^BOOBHa V \s< I en blanding af 15 ml éthanol og 10 ml chloroform blev 5 oplost 0,5 g N-cyano-3-[(2-guanidinothiazol-4-yl)- ® methylthio Jpropionamidin, og efter at man havde ledt gennem oplosningen ter gasformig hydrogenchlorid i 1,5 timer under afkoling med isvand, blev reaktionsblandin-gen inddampet under vakuum. Til inddampningsresten blev 0 sat 10 ml éthanol, blandingen blev igen inddampet under vakuum. Den dannede inddampningsrest blev oplost i en lille mængde éthanol og efter tilsætning dertil af ether og henstand natten over blev de udskilte krystaller op-samlet ved filtrering til dannelse af 0,55 g N-carbamoyl-5 3-[(2-guanidinothiazol-4-yl)methylthio]propionamidin,di- hydrochlorid. Reaktionsprofuktet viste f0lgende fysisk-kemiske egenskaber: (i) Smeltepunkt: 171-173°C.Found: 37.86% 5.62% 30.73% EXAMPLE, 9 m2 "N, CH, SCK, CH" C2 .2HC1 2> C = N - <^ Y 2 2 2 ^ BOOBHa V \ s <I a mixture of 15 ml of ethanol and 10 ml of chloroform was dissolved 0.5 g of N-cyano-3 - [(2-guanidinothiazol-4-yl) - methylthio] propionamidine and after passing through the solution ter gaseous hydrogen chloride in 1.5 hours while cooling with ice water, the reaction mixture was evaporated under vacuum. To the residue 0 was added 10 ml of ethanol, the mixture was again evaporated under vacuum. The resulting evaporation residue was dissolved in a small amount of ethanol and after addition to ether and standing overnight, the precipitated crystals were collected by filtration to give 0.55 g of N-carbamoyl-5 3 - [(2-guanidinothiazole-4 -yl) methylthio] propionamidine, hydrochloride. The reaction product showed the following physicochemical properties: (i) Melting point: 171-173 ° C.

(ii) Elementær analyse for Ο^Η-^Ν,^ΟΟ^ :(ii) Elemental analysis for Ο ^ Η- ^ Ν, ^ ΟΟ ^:

) C H N) C H N

Beregnet: 28,88% 4,58% 26,19%Calculated: 28.88% 4.58% 26.19%

Fundet: 28,73% 4,64% 25,78% 21 EKSEMPEL 10Found: 28.73% 4.64% 25.78% EXAMPLE 10

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CH.NH /S^nCH.NH / S ^ n

3.>0=Ν“Λν J! ^KCN3.> 0 = Ν “Λν J! ^ KCN

NHo ' M cpp mz n' Z i» οιΐ2θθπ.2'-'^2ν'\ x NH2 I 30 ml éthanol blev oplost 6,4 g methyl-3-(2-methyl-guanidinothiazol-4-ylmethylthio)propionimidat, og efter tilsætning dertil af 0,9 g cyanamid og omrering af 5 blandingen i 2 timer ved stuetemperatur blev oplos- ningsmidlet afdestilleret under vakuum. Den dannede inddampningsrest blev renset ved soôlechromatografi under anvendelse af en blanding af chloroform og éthanol soin fremkaldervæskef og den blev omkrystalliseret ud 10 fra éthanol til dannelse af 2,0 g.N-cyano-3-(2-methyl- guanidinothiazol-4-ylmethylthio)propionamid, der ud-viste et smeltepunkt pâ 144-145°C.In 30 ml of ethanol, 6.4 g of methyl 3- (2-methyl-guanidinothiazol-4-ylmethylthio) propionimidate and dissolved 6.4 g of methyl ethanol were dissolved. after adding 0.9 g of cyanamide and stirring the mixture for 2 hours at room temperature, the solvent was distilled off under vacuum. The resulting evaporation residue was purified by column chromatography using a mixture of chloroform and ethanol soin developing liquid and it was recrystallized from ethanol to give 2.0 gN-cyano-3- (2-methylguanidinothiazol-4-ylmethylthio) propionamide which exhibited a melting point of 144-145 ° C.

Elementær analyse for :Elementary analysis for:

C H NC H N

15 Beregnet : 40,39% 5,08% 32,97%Calculated: 40.39% 5.08% 32.97%

Pundet: 40,13% 5,00# 32,68% EKSEMPEL 11 c'"3-d\c.v_y ^ -ru / JL /KCONHp λ“2 X CH0SCH9CH9CCT , 2KC1 ^ ^ - χΓίΗ2 ' I en blanding af 20 ml éthanol, 30 ml chloroform og 10 ml methanol blev oplost 1,0 g N-cyano-3- (2-methylguanidino-20 thiazol-4-ylmethylthio)propionamidin, og efter koling af oplosningen til 0-5 °C og gennembobling af gasformig hydrogenchlorid i 1 time blev oplosningsmidlerne afdestilleret under vakuum. Den sâledes dannede inddampnings-Pound: 40.13% 5.00 # 32.68% EXAMPLE 11 c '"3-d \ c.v_y ^ -ru / JL / KCONHp λ" 2 X CH0SCH9CH9CCT, 2KC1 ^^ - χΓίΗ2' In a mixture of 20 ethanol, 30 ml chloroform and 10 ml methanol were dissolved 1.0 g of N-cyano-3- (2-methylguanidino-20-thiazol-4-ylmethylthio) propionamidine, and after cooling the solution to 0-5 ° C and bubbling through gaseous hydrogen chloride for 1 hour, the solvents were distilled off in vacuo.

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22 rest blev omkrystalliseret fra éthanol til dannelse af 1,2 g N-carbamoyl-3-(2-methylguanidinothiazol-4-ylmethyl-thio)propionamidin,dihydrochloridt der viste et smelte-punkt pâ 180-182°C.Twenty-two residues were recrystallized from ethanol to give 1.2 g of N-carbamoyl-3- (2-methylguanidinothiazol-4-ylmethyl-thio) propionamidine, dihydrochloride, showing a melting point of 180-182 ° C.

5 Elementær analyse for , 1/21^0 :5 Elemental Analysis for, 1/21 ^ 0:

C H NC H N

Beregnet: 30,2396 5,07% 24,68%Calculated: 30.2396 5.07% 24.68%

Fundet: 30,52% 5,06% 24,41% EKSEMPEL 12Found: 30.52% 5.06% 24.41% Example 12

^ S^ S

/0=N j] NNHS o fj/ 0 = N j] NNHS o fj

»2» % ^ CK2SCH20H2C^ ^ 2 W»2»% ^ CK2SCH20H2C ^^ 2 W

kd2 I 49 ml methanol blev oplost 2,0 g methyl-3-(2-guanidino-10 thiazol-4-ylmethylthio)propionimidat og 1,21 g benzen- sulfonylhydrazin, og efter omroring af oplesningen i 24 timer ved stuetemperatur blev oplosnlngsmidlet afde-stilleret under vakuum. Derpâ blev den sâledes dannede inddampningsrest renset ved s0 j1echromât0grafi under an-15 vendelse af en blanding af chlonoform og methanol som 3-(2-guanidinothiazol-4-ylmethylthio )propionamidrazon, . der udviste et smeltepunkt pâ 159,5-161°C.kd2 In 49 ml of methanol were dissolved 2.0 g of methyl 3- (2-guanidino-10-thiazol-4-ylmethylthio) propionimidate and 1.21 g of benzenesulfonylhydrazine, and after stirring the solution for 24 hours at room temperature, the solvent was evaporated off. -stilled under vacuum. The evaporation residue thus formed was purified by chromatography using a mixture of chlonoform and methanol as 3- (2-guanidinothiazol-4-ylmethylthio) propionamidrazone. exhibiting a melting point of 159.5-161 ° C.

Elementær analyse for C^H^NyO^S·^:Elemental Analysis for C

C H NC H N

20 Beregnet: 40,66% 4,63% 23,71%Calculated: 40.66% 4.63% 23.71%

Fundet: 40,30% 4,54% 23,46% EKSEMPEL 13 23Found: 40.30% 4.54% 23.46% EXAMPLE 13 23

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H < \ jL· ^NCHpCOOHH <\ jL · ^ NCHpCOOH

2*’ X N CH2SCH2CH2C^ 2 .2 * 'X N CH2SCH2CH2C2.

—1^2 I 20 ml methanol blev bragt i suspension 2 g methyl- 3- ( 2-guanidinothiazol-4-ylmethylthio )propionimidat og derpâ blev tilsat til suspensionen en oplesning af 5 0,5 g glycin i 5 ml vand. Efter omroring af blandingen i 2 timer ved stuetemperatur blev oplosningsmidlet af-destilleret under vakuum, og den sâledes dannede ind-dampningsrest blev omkrystalliseret ud fra en blanding af vand og acetone til dannelse af 1,0 g 3-(2-guanidino-10 thiazol-4-ylmethylthio)propionamidinoglycin, der udviste et smeltepunkt pâ 140-141 °C (dekomponering).In 20 ml of methanol 2 g of methyl 3- (2-guanidinothiazol-4-ylmethylthio) propionimidate were suspended in suspension and then a solution of 5 0.5 g of glycine in 5 ml of water was added to the suspension. After stirring the mixture for 2 hours at room temperature, the solvent was distilled off in vacuo and the evaporation residue thus formed was recrystallized from a mixture of water and acetone to give 1.0 g of 3- (2-guanidino-10thiazole) -4-ylmethylthio) propionamidinoglycine, exhibiting a melting point of 140-141 ° C (decomposition).

Elementær analyse for cioH16^6^2^2,21/41^0:Elemental analysis for c 10 H 16 ^ 6 ^ 2 ^ 2.21 / 41 ^ 0:

C . H NC. H N

Beregnet: 33,65% 5,79% 23,55%Calculated: 33.65% 5.79% 23.55%

Fundetï 33,82% 5,43% 23,65% 15 EKSEMPEL 14 H2N . CHoSCHoCH^C^ ' ’ ’Found 33.82% 5.43% 23.65% Example 14 H2N. CHoSCHoCH ^ C ^ '' '

d d d ÎJHGNd d d ÎJHGN

I 35 ml methanol blev oplest 5,1 g methyl-3-(2~guanidino-thiazol-4-methylthio)propionimidat, og efter tilsætning af 0,9 g cyanamid til oplesningen og omroring af blandingen i 24 timer ved stuetemperatur blev oplesningsmidlet af-20 destilleret under vakuum. Derpâ blev den sâledes dannede inddampningsrest renset ved soôlechromatografi under an-vendelse af en blanding af chloroform og methanol som frem- 24In 35 ml of methanol were dissolved 5.1 g of methyl 3- (2-guanidino-thiazole-4-methylthio) propionimidate, and after adding 0.9 g of cyanamide to the solution and stirring the mixture for 24 hours at room temperature, the solvent of -20 distilled under vacuum. Thereupon the evaporation residue thus formed was purified by column chromatography using a mixture of chloroform and methanol as the 24

DK 157132 BDK 157132 B

kaldervæske, hvorved dannes 4,8 g N-cyano-3-(2-guanidino-thiazol-4-ylmethylthio)propionamidin og 0,3 g Ν,Ν1-dicyano-3- ( 2-guanidinothiazol-4-ylmethylthio )propion-amidin, der udviste et smeltepimkt pâ 223-224°C (de-5 komponering).cold liquid to give 4.8 g of N-cyano-3- (2-guanidino-thiazol-4-ylmethylthio) propionamidine and 0.3 g of Ν, Ν1-dicyano-3- (2-guanidinothiazol-4-ylmethylthio) propionamide. amidine exhibiting a melting point of 223-224 ° C (decomp.).

Massespektrum (FD méthode); m/e 309 (M+ + 1) NMR (dgDMSO): 2,5-2,8(4H,m, -SCH2CH2-), 3,75(2H,s, -CH2S-) 7,10(lH,s,_^rS-trH ), 8,10(4H,bs, Η2Ν\£=Ν_ ) • h2it EKSEWPEL 15 H2N\ * - d /C=N—ςν II . . ^iut«0*.«2 ^ ur-2 10 Til en oplosning af 246,6 mg kaliumtert.-butoxid i 10 ml vandfrit methanol blev tilsat 245,3 mg semicarbazid,hydro-chlorid under isafkoling, og efter omroring af blandingen i 10 minutter ved stuetemperatur blev en opl0sning af 540 mg methyl-3-[(2-guanidinothiazol-4-yl)thiomethyl]-15 propionimidat sat til blandingen. Efter omroring af blan dingen i 2 dage ved stuetemperatur blev oplesningsmidlet afdestilleret under vakuum, og den sâledes dannede ind-dampningsrest blev renset ved sojlechromatografi pâ sili-cagel under anvendelse af en blanding af chloroform og 20 methanol til dânnelse af 0,4 g N-carbamoylamino-3-[(2- guanidinothiazol-4-yl)methylthio]propionamidin. Dette pro-dukt blev oplost i 5 ml methanol, og efter tilsætning af 0,4 g maleinsyre til oplosningen og omroring af blandingen i 10 minutter blev oplosningsmidlet afdestilleret, 20 ml 25 acetone blev sat til inddampningsresten, og uoploselige bestanddele blev frafiltreret til dânnelse af 0,3 g N-Mass spectrum (FD method); m / e 309 (M + + 1) NMR (dgDMSO): 2.5-2.8 (4H, m, -SCH2CH2-), 3.75 (2H, s, -CH2S-) 7.10 (1H, s , _ ^ rS-trH), 8.10 (4H, bs, Η2Ν \ £ = Ν_) • h2it EXAMPLE 15 H2N \ * - d / C = N — ςν II. . To a solution of 246.6 mg of potassium tert.-butoxide in 10 ml of anhydrous methanol was added 245.3 mg of semicarbazide, hydrochloride under ice-cooling, and after stirring the mixture in 10 minutes at room temperature, a solution of 540 mg of methyl 3 - [(2-guanidinothiazol-4-yl) thiomethyl] propionimidate was added to the mixture. After stirring the mixture for 2 days at room temperature, the solvent was distilled off in vacuo and the evaporation residue thus formed was purified by silica gel soybean chromatography using a mixture of chloroform and methanol to give 0.4 g of N carbamoylamino-3 - [(2-guanidinothiazol-4-yl) methylthio] propionamidine. This product was dissolved in 5 ml of methanol, and after adding 0.4 g of maleic acid to the solution and stirring the mixture for 10 minutes, the solvent was distilled off, 20 ml of 25 acetone was added to the evaporation residue, and insoluble ingredients were filtered off to form 0.3 g N-

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25 carbamoylamino-3- [ ( 2-guanidinothiazol-4-yl )methylthio ] -propionamidin,dimaleat,monohydrat, der udviste et smel-tepurikt pâ 109-111°C.25 carbamoylamino-3- [(2-guanidinothiazol-4-yl) methylthio] propionamidine, dimaleate, monohydrate, exhibiting a melting purity of 109-111 ° C.

Elementær analyse for C^yE^gNgSgO:Elemental Analysis for C

C H N SC H N S

5 Beregnet; 36,04% 4,59% 19,79% 11,30%5 Calculated; 36.04% 4.59% 19.79% 11.30%

Fundet: 36,01% 4,53% 19,55% 11,37% EKSEMPEL 16 26Found: 36.01% 4.53% 19.55% 11.37% EXAMPLE 16 26

DK 157132 BDK 157132 B

S- H0ÏÏ.S- H0ÏÏ.

2 >C=N-<^ Il A\OH2> C = N - <^ Il A \ OH

K9N CH0SCH9CH?C \K9N CH0SCH9CH? C \

2 2 2 2 ‘KHCK2 2 2 2 'KHCK

Til 5,2 g methyl-N-cyano-3-[(2-guanidinothiazol-4-yl)-methylthio]propionimidat blev tilsat 50 ml af en methano-lisk oplesnlng af 40# methylamin, og efter henstand i 20 5 timer ved stuetemperatur af blandingen·, blev oplosnings- midlet afdestilleret under vakuum. Den sâledes dannede ind-dampningsrest blev renset ved S0jlechromatografi under anvendelse af en blanding af chloroform og methanol som fremkaldervæske, det sâledes oprensede produkt blev om-10 dannet til maleatet i acetone og omkrystalliseret ud fra metbanol til dannelse af 1,0 g N-cyano-N1 -3- ( 2-guanidino-thiaz ol-4-ylmethylthio ) propionam idin, der udviste et smel-tepuhkt 159 - 161° C.To 5.2 g of methyl N-cyano-3 - [(2-guanidinothiazol-4-yl) methylthio] propionimidate was added 50 ml of a methanolic solution of 40 # methylamine, and left for 20 hours at at room temperature of the mixture ·, the solvent was distilled off under vacuum. The evaporation residue thus formed was purified by column chromatography using a mixture of chloroform and methanol as the developing liquid, the thus purified product was converted to the acetate maleate and recrystallized from metbanol to give 1.0 g of N-cyano -N1 -3- (2-guanidino-thiazol-4-ylmethylthio) propionamide, exhibiting a melting point 159 - 161 ° C.

Elementæranalyse for 0η N^O^Sp, I/2H2OÎElemental analysis for 0η N ^ O ^ Sp, I / 2H2OÎ

C H NC H N

Beregnet for 39,99# · 4,61# 20,40#Calculated for 39.99 # · 4.61 # 20.40 #

Fundet: 39,89# 4,69# 20,24#Found: 39.89 # 4.69 # 20.24 #

Det methyl-{N-cyano-3- [ ( 2-guanidinothiazol-4-yl)methyl-15 thio]}propionimidat, der blev anvendt i eksemplet som râ-materiale, fremstilles ved folgende fremgangsmâde.The methyl {N-cyano-3- [(2-guanidinothiazol-4-yl) methyl-15thio]} propionimidate used in the example as a raw material is prepared by the following procedure.

I en blanding af 90 ml skarpt terret chloroform og 5ml skarpt terret methanol blev oplest 7,5 g 3-(2-guanidino-thiazol-4-ylmethylthio)propionitril, og efter afkoling af 20 oplesningen til 0 - 10° C i nitrogenstrsm og gennembobling derigennem af 25 g gasformig hydrogenchlorid fik oples-ningen lov til at henstâ i 48 timer ved 0 - 10° C. Op-7.5 g of 3- (2-guanidino-thiazol-4-ylmethylthio) propionitrile were dissolved in a mixture of 90 ml of sharply terraced chloroform and 5 ml of sharply terrained methanol, and after cooling the solution to 0-10 ° C in nitrogen stream. Bubbling through 25 g of gaseous hydrogen chloride allowed the solution to stand for 48 hours at 0-10 ° C.

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27 I0 sningsmidlet blev derpâ afdestilleret under vakuum, og den sâledes dannede inddampningsrest blev opl0st i 50 ml skarpt t0rret methanol, og efter tilsætning dertil af 1,3 g cyanamid blev blandingen omrort 3,5 timer ved stuetempera-5 tur. Derefter blev oplo sningsmidlet afdampet under vakuum. Efter tilsætning til den sâledes dannede inddampningsrest af 50 ml isvand, hvori var oplost 12 g kaliumcarbonat, blev produktet ekstraheret 3 gange med hver 50 ml chloro-form. Det sâledes dannede ekstrakt blev torret med vand-10 frit magnesiumsulfat, og derpâ blev oplosningsmidlet afdestilleret under vakuum.The solvent was then distilled off in vacuo and the thus obtained evaporation residue was dissolved in 50 ml of sharply dried methanol, and after adding thereto 1.3 g of cyanamide the mixture was stirred for 3.5 hours at room temperature. Then, the solvent was evaporated in vacuo. After adding to the thus-evaporated residue of 50 ml of ice water, in which was dissolved 12 g of potassium carbonate, the product was extracted 3 times with each 50 ml of chloroform. The extract thus formed was dried over anhydrous magnesium sulfate and then the solvent was distilled off under vacuum.

EKSEMPEL 17 S -EXAMPLE 17 S -

i CHC00Hin CHC00H

2 \r_N—Z i \\ O Oïl n-J Q 52 \ r_N — Z i \\ O Oil n-J Q 5

H5N 2 CHC00HH5N 2 CHC00H

I 10 ml dimethylformamid blev oplost 1,2 g 3- [2-guanidino-thiazol-4-ylmethylthio]propionainidin, og efter tilsætning 15 af 0,4 g triethylamin til oplesning og nedkoling af blandingen til under 15° C blev en oplosning af 1,4 g ace-tylchlorid i. 3 ml chloroform tilsat drâbe for drâbe til denne blanding. Derefter blev blandingen omrert i 30 mi-nutter ved stuetemperatur, og derpâ blev oplosningsmidlet 20 afdestilleret. Til den sâledes dannede inddampningsrest blev tilsat en oplosning af 0,8 g kaliumcarbonat i 2ml vand. Efter af destination af vandet blev inddampnings-resten underkastet sîlicagelsojlechromatografi, og reak-tionsproduktet blev fremkaldt med en blanding af chloro-25 form og methanol. Derpâ blev elueringsmidlet afdestilleret til dannelse af 0,3 g N,Nl-diacetyl-3-(2-guanidinothia-zol-4-ylmethylthio )propionamidin. Reaktionsproduktet blev sat til en oplosning af 0,2 g maleinsyre i 10 ml acetone efterfulgt af omroring i 30 minutter ved stuetemperatur.In 10 ml of dimethylformamide was dissolved 1.2 g of 3- [2-guanidino-thiazol-4-ylmethylthio] propionamide, and after the addition of 0.4 g of triethylamine to dissolve and cool the mixture to below 15 ° C, a solution of 1.4 g of acetyl chloride in. 3 ml of chloroform added drop by drop to this mixture. Then the mixture was stirred for 30 minutes at room temperature, and then the solvent 20 was distilled off. To the evaporation residue thus formed was added a solution of 0.8 g of potassium carbonate in 2 ml of water. After distillation of the water, the residue was subjected to silica gel column chromatography and the reaction product was developed with a mixture of chloroform and methanol. The eluent was then distilled off to give 0.3 g of N, N1-diacetyl-3- (2-guanidinothiazol-4-ylmethylthio) propionamidine. The reaction product was added to a solution of 0.2 g of maleic acid in 10 ml of acetone followed by stirring for 30 minutes at room temperature.

30 Det dannnede bundfald blev opsamlet ved filtrering til dan-The precipitate formed was collected by filtration to form

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28 nelse af 0,2 g N, N * -diacetyl-3- ( 2-guan i dinothiaz ol-4-ylmethylthio )propionamidin, 1/2 maleat, H2O, der udviste et smeltepunkt pâ 180 - 181° C.28 g of 0.2 g of N, N * -diacetyl-3- (2-guan in dinothiaz ol-4-ylmethylthio) propionamidine, 1/2 maleate, H 2 O, exhibiting a melting point of 180 - 181 ° C.

Elementæranalyse for;Elementary analysis for;

C H N SC H N S

Beregnet: 40,19# 4,52# 20,00# 15,30#Calculated: 40.19 # 4.52 # 20.00 # 15.30 #

Fundet; 39,91# 4,53# 20,01# 15,27# 5 EKSEMPEL 18 'l ^0 |HC1found; 39.91 # 4.53 # 20.01 # 15.27 # 5 EXAMPLE 18

H2NH2N

I 30 ml af en methanoli.sk af 40# methylamin blev oplost 3 g methyl-3- (2-guanidinothiazol-4~ylmethylthio )propionat, og efter henstand af oplosningen i 24 timer ved stuetempe-ratur blev oplasningen afdestilleret under vakuum. Den sâ-10 ledes dannede inddampningsrest blev renset ved sajlechroma- tografi under anvendelse af en blanding af chloroform og methanol som fremkaldervæske, og det sâledes rensede reaktionsprodukt blev omdannet til hydrochloridet ved be-handling med saltsyTe og derpâ omkrystalliseret ud fra 15 en blanding af isopropanol og ethylacetat til dannelse af 1,5 g N-methyl-3- ( 2-guanidinithiazol-4-ylmethylthio )pro-pionam id, hydrochlorid, der udviste et smeltepunkt pâ 126 -127° C.In 30 ml of a methanol of 40 # methylamine was dissolved 3 g of methyl 3- (2-guanidinothiazol-4-ylmethylthio) propionate and after standing the solution for 24 hours at room temperature, the solution was distilled off under vacuum. The evaporation residue thus formed was purified by column chromatography using a mixture of chloroform and methanol as the developing liquid, and the thus purified reaction product was converted to the hydrochloride by treatment with salt surface and then recrystallized from a mixture of ice and ethyl acetate to give 1.5 g of N-methyl-3- (2-guanidinithiazol-4-ylmethylthio) propionamide hydrochloride, which had a melting point of 126 -127 ° C.

Elementæranalyse for ^9^6^5^2^Elemental Analysis for ^ 9 ^ 6 ^ 5 ^ 2 ^

C H NC H N

Beregnet: 34,89# 5,20# 22,60#Calculated: 34.89 # 5.20 # 22.60 #

Fundet; 34,51# 5,19# 22,55#found; 34.51 # 5.19 # 22.55 #

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2929

Det som râmateriale i dette eksempel anvendte methyl- 3-(2-guanidinothiazol-4-ylmethylthio)propionat blev frem-stillet ved felgende metode.The methyl-3- (2-guanidinothiazol-4-ylmethylthio) propionate used as the raw material in this example was prepared by the following method.

I en blanding af 60 ml methanol og 120 ml chloroform blev 5 oplest 10 g 3- (2-guanidinothiazol-4-ylmethylthio )propio-nitril, og efter nedkoling af oplesningen til 0 - 10° C og gennembobling derigennem af 30 g gasformig hydrogen-chlorid fik oplosningen lov til at henstâ i 20 timer ved 0 - 10° C. Til reaktionsblandingen blev tilsat 0,7 ml 10 vand, og efter henstand af blandingen i 20 timer ved stue-temperatur blev reaktionsblandingen sat til 250 ml isvand, der indeholdt 120 g kaliumcarbonat, og derpâ ekstraberet 4 gange hver med 100 ml chloroform indeholdende 20% methanol. Det dannede ekstrakt blev inddampet under vakuum,In a mixture of 60 ml of methanol and 120 ml of chloroform, 5 g of 3- (2-guanidinothiazol-4-ylmethylthio) propionitrile were dissolved, and after cooling the solution to 0-10 ° C and bubbling through 30 g of gaseous hydrogen. Chloride was allowed to stand for 20 hours at 0 - 10 ° C. To the reaction mixture was added 0.7 ml of 10 water and after standing for 20 hours at room temperature, the reaction mixture was added to 250 ml of ice water. containing 120 g of potassium carbonate, and then extracted 4 times each with 100 ml of chloroform containing 20% methanol. The resulting extract was evaporated in vacuo,

Og inddampningsresten blev renset ved S0jlechromatografi 15 under anvendelse af en blanding af chloroform og methanol som fremkaldervæske til dannelse af 5,0 g methyl-3-(2-guanidino-thiazol-4-ylmethylthio)propionat, der udviste et smelte-punkt pâ 106 - 107° C.And the residue was purified by column chromatography using a mixture of chloroform and methanol as the developing liquid to give 5.0 g of methyl 3- (2-guanidino-thiazol-4-ylmethylthio) propionate, which had a melting point of 106 - 107 ° C.

EKSEMPEL 19 ii2*’>c=n—^ H2K- X^CH2SCn2CH2CNRE0a 20 Idet man gik frem analogt med fremgangsmâden i eksempel 18; men idet man anvendte hydroxylamin i stedet for me-thylamin, blev fremstillet 3-(2-guanidinothiazol-4-ylme-thylthio)propionhydroxamsyre. Reaktionsproduktet udviste felgende kemiske egenskaber; 25 (i) smeltepunkt; 155 - 156° C.EXAMPLE 19 ii2 *> c = n— ^ H2K- X ^ CH2SCn2CH2CNRE0a By analogous to the procedure of Example 18; but using hydroxylamine instead of methylamine, 3- (2-guanidinothiazol-4-ylmethylthio) propionic hydroxamic acid was prepared. The reaction product exhibited decomposing chemical properties; (I) melting point; 155 - 156 ° C.

DK 157132 BDK 157132 B

30 (ii) NMR (DMSO-dg ) S: 2f24 (2H, t, -CH2-C^° ) 2,66 (2Ή, t, -SCH2CH2~) 3r58 (2H, s, -*CH2S-)(Ii) NMR (DMSO-d 6) δ: 2f24 (2H, t, -CH 2 -C 3) 2.66 (2Ή, t, -SCH 2 CH 2 -) 3r58 (2H, s, - * CH 2 S-)

6*48 (1H, s, T^H6 * 48 (1H, s, T ^ H

(iii) Mass.(FD méthode m/e 276 (M+ + 1) EKSEMPEL 20 ' Hpî'ïX ^ CK SCH2Cn2C< i, ^ «iip I en blanding af 30 ml éthanol og 30 ml vand blev oplest 5,0 g methyl-3-(2-guanidinothiazol-4-ylmethylthio)propion-imidat, og efter at oplasningerne fik lov til at henstâ 5 i 20 timer ved 40° C blev oplesningsmidlet afdestilleret under vakuum. Den· sâledes dannede inddampningsrest blev ren-set ved sojlechromatografi under af anvendelse af en blanding af chloroform og methanol og derpâ omkrystalliseret ud fra methanol til dannelse af 3,2 g 3-(2-guanidinothia-10 zol-4-ylmethylthio)propionamid, der udviste et smeltepuhkt pâ 193 - 194° C (dekomponering).(iii) Mass. (FD Method m / e 276 (M + + 1) EXAMPLE 20 HppîXX CK SCH₂Cn₂C <i) In a mixture of 30 ml of ethanol and 30 ml of water was read 5.0 g of methyl -3- (2-guanidinothiazol-4-ylmethylthio) propion imidate, and after the solutions were allowed to stand for 5 hours at 40 ° C, the solvent was distilled off in vacuo. The residue thus obtained was purified by soy chromatography using a mixture of chloroform and methanol and then recrystallized from methanol to give 3.2 g of 3- (2-guanidinothiazole-4-ylmethylthio) propionamide which showed a melting point of 193 - 194 ° C ( decomposition).

Elementæranalyse for CgH-^^N^0S2 :Elemental analysis for CgHH - ^^N₂O₂:

C H NC H N

Beregnet: 37,05% 5,05% 27,00%Calculated: 37.05% 5.05% 27.00%

Fundet: 36,97% 5,06% 26,84% EKSEMPEL 21 ^ \ Γ*—M —0Found: 36.97% 5.06% 26.84% EXAMPLE 21

Ko N CHoSCHpCKoC"Ko N CHoSCHpCKoC "

d *» £ £ £ ^ lVTIJCfAd * »£ £ £ ^ lVTIJCfA

iïixuÎ-/ 2a1aa"2 31iïixuÎ- / 2a1aa "2 31

DK 1 57132 BDK 1 57132 B

I 50 ml 1 n HCl blev opl0st 2,5 g N-sulfamoyl-3-(2-guani-dinithiazol-4-ylmethylthio)propionamidin, og efter omraring af oplasningen i 2 timer ved 40° C blev de udskilte kry-staller indsamlet ved filtrering og omkrystalliseret ud 3 af en blanding af methanol og ethylacet&t til daimelse af 1,65 g 3-(2-guanidinothiazol-4-ylmethylthio)propionylsul-famid, hydrochlorid, der udviste et smeltepunkt pâ 166 -167° C.In 50 ml of 1 n HCl was dissolved 2.5 g of N-sulfamoyl-3- (2-guanidinothiazol-4-ylmethylthio) propionamidine, and after stirring the solution for 2 hours at 40 ° C the separated crystals were collected. by filtration and recrystallized out 3 of a mixture of methanol and ethyl acetate to give 1.65 g of 3- (2-guanidinothiazol-4-ylmethylthio) propionyl sulfamide, hydrochloride, exhibiting a melting point of 166 -167 ° C.

Elementæranalyse for CgH-^^NgO^S-jCl * ^0 ·Elemental Analysis for CgH - ^^NgO ^S-JCl * ^O ·

C H NC H N

Beregnet; 24,46$ 4,36$ 21,39$calculated; $ 24.46 $ 4.36 $ 21.39 $

Fundet: 24,78$ 4,23$ 21,61$ EKSEMPEL 22 H2Î<>c=n—^ 1 __ ^nso2he2 lui2 10 I 30 ml methanol blev oplast 4,09 g methyl-3-[(2-guani-dinothiazol-4-yl )methylthio Jpropionimidat, og derpâ blev til oplosningen under tilbagesvaling tilsat 15 ml af en methanolisk oplesning af 2,88 g sulfamid. Efter tilbagesvaling i ca. 3 timer blev oplasningsmidlet afdestilleret 15 under vakuum, og den dannede.inddampningsrest blev renset ved silicagelsajlechromatografi under anvendelse af en blanding af chloroform og methanol (20:1-> 10:1) som fremkaldervæske til dannelse af 3,26 g N-sulfamoyl-3-C(2-guanidinothiazol-4=yl )methylthio jpropionamidin. Reaktions-20 produktet udviste f0lgende fysiske-kemiske egenskaber: i) Smeltepunkt: 163 - 164° C.Found: 24.78 $ 4.23 $ 21.61 EXAMPLE 22 H2Î <> c = n— ^ 1 __ ^ nso2he 2 lui2 dinothiazol-4-yl) methylthiopropionimidate, and then to the solution under reflux was added 15 ml of a methanolic solution of 2.88 g of sulfamide. After refluxing for approx. For 3 hours, the solvent was distilled off under vacuum and the resulting evaporation residue was purified by silica gel column chromatography using a mixture of chloroform and methanol (20: 1-> 10: 1) as the developing liquid to give 3.26 g of N-sulfamoyl. 3-C (2-guanidinothiazol-4 = yl) methylthiopropionamidine. The reaction product exhibited the following physicochemical properties: i) Melting point: 163 - 164 ° C.

DK 157132 BDK 157132 B

32 ii) Elementæranalyse for C8H15N7°2S3:32 ii) Elemental analysis for C8H15N7 ° 2S3:

C H NC H N

Beregnet 28,48% 4,48% 29,06%Calculated 28.48% 4.48% 29.06%

Fundeti 28,37% 4,48% 28,97% iii) N M R sjaektra (DMSO-dg) cf : 2,50 (2H, m, -SCH2CH2-), 2,65 (2H, m, -SCH2CH2-), 3,60 (2H, s, Λ CH2S-),Found 28.37% 4.48% 28.97% iii) NMR Scheektra (DMSO-dg) cf: 2.50 (2H, m, -SCH2CH2-), 2.65 (2H, m, -SCH2CH2-), 3.60 (2H, s, Λ CH 2 S-),

• 6,45 (1H, s, ^>- J6.45 (1H, s, s) - J

iv) Massespektrum (FD méthode), m/e 338iv) Mass spectrum (FD method), m / e 338

DK 157132 BDK 157132 B

33 EKSEMPEL 23EXAMPLE 23

K2N\~ ÏÏS0oCH, ECCOOKK2N \ ~ ÏÏS0oCH, ECCOOK

/c=^*-\ L 11 2 3 li/ c = ^ * - \ L 11 2 3 li

*2* ^4 ^ ch2sCH2CH2C-NH2“ } HCCOOH* 2 * ^ 4 ^ ch2SCH2CH2C-NH2 “} HCCOOH

a) I 10,2 ml methanol blev opl0St 1,27 g methyl-3- [(2-gua-nidinothiazol-4-yl)methylthio]propionimidat og 0,86 g methansulfonamid, og efter omsaetning i 48 timer ved stue-temperatur blev oplesningsmidlet afdestilleret under va- 5 kuum. Derpâ blev den dannede inddampningsrest renset ved silicagelsojlechromatografi under anvendelse af en blanding af chloroform og methanol (20:1 10:1) til dannelse af 1,44 g amorft N-methansulfonyl-3-C(2-guanidinothiazol-4-yl)-methylthio]propionamidin. Reaktionsproduktet udviste 10 folgende fysisk kemiske egenskaber: i) NMR spektra (CD^OD) S : 2 j 5b ( 2H, cl, — SCn2^112- )» 2,76 (2x4, d, -SÇHpCHp- ), 2.91 (34» s, —CK-3 ), 3,0? (2ïi, S, '^'CE S— 1 —2 6,50 (1H, s, SjXck,s- >· ii) Massespektrum (El metode): m/e 336.a) In 10.2 ml of methanol was dissolved 1.27 g of methyl 3- [(2-guanidinothiazol-4-yl) methylthio] propionimidate and 0.86 g of methanesulfonamide, and after reacting for 48 hours at room temperature the solvent was distilled off under vacuum. Then, the resulting evaporation residue was purified by silica gel column chromatography using a mixture of chloroform and methanol (20: 1 10: 1) to give 1.44 g of amorphous N-methanesulfonyl-3-C (2-guanidinothiazol-4-yl) - methylthio] propionamidine. The reaction product exhibited the following physical chemical properties: i) NMR spectra (CD 3 OD) δ: 2 δ 5b (2H, cl, - SCn 2 ^ 112-) δ 2.76 (2x4, d, -SÇHpCHp-), 2.91 (34 »S, —CK-3), 3.0? (2i, S, 13 CE CE S -1 -1 6.50 (1H, s, SjXck, s-> · ii) Mass Spectrum (E1 method): m / e 336.

b) N-methansulfonyl-3-[(2-guanidinothiazol-4-yl)-methylthio] propionamidin, der var fremstillet pâ denne mâde, blev oplost i acetone, og derpâ blev til oplesningen tilsat drâ-be for drâbe en acetoneoplosning af 0,5 g maleinsyre, hvor- 15 ved der udskilledes krystaller. Krystallerne blev opsam- let ved filtrering til dannelse af N-methansulfonyl-3-^(2-guani dino thi az ο 1 - 4- yl ) - methy1thi0]propionamidin, maleat. Reaktionsproduktet viste felgende fysisk kemiske egenskaber:b) N-methanesulfonyl-3 - [(2-guanidinothiazol-4-yl) methylthio] propionamidine prepared in this manner was dissolved in acetone and then added dropwise to drop an acetone solution of 0 , 5 g of maleic acid, thereby separating crystals. The crystals were collected by filtration to give N-methanesulfonyl-3- (2-guanine dino thi az ο 1- 4-yl) -methylthio] propionamidine, maleate. The reaction product showed the following physical chemical properties:

34 DK 157132 B34 DK 157132 B

i) Smeltepunkt: 195-197°Ci) Melting point: 195-197 ° C

ii) Elementær analyse for ci3H20%^6S3:ii) Elemental analysis for ci3H20% ^ 6S3:

C H NC H N

Beregnet 34^51$ 4,45^ 10^57^ , -j a 4 »49/£ 18.125-0Calculated 34 ^ 51 $ 4.45 ^ 10 ^ 57 ^, -j a 4 »49 / £ 18,125-0

Fundet 3^°-^ { EKSEMPEL 24 h2n H2N/C NA.JLc, SC:, j— c^NS02"C~^ 2 i'i CiApSCxlr^CxipC V \ i/ XN H2 X 8 ml methanol blev oplost 800 mg methyl-3-L(2-guanidino-thiazol-4-yl)methylthio]propionimidat samt 590 mg benzen-sulfonamid, og efter at hâve ladet omsætningen foregâ i 24 timer ved siuetemperatur blev oplesningsmidlet afdestil-5 leret under vakuum. Den dannede inddampningsrest blev ren-set ved silicagels0jlechromatografi under anvendelse af en blanding af chloroform. og methanol (20:1->10:1) til dannel-se af 855 mg amorft N-benzensulfonyl-3-(2-guanidinothiazol- 4-yl)-methylthiopropionamid. Reaktionsproduktet udviste 10 folgende fysisk kemiske egenskaber: i) NMR spektra (DMSO-dg) £ : 2|60 (4H, m, -S-CH2CH2C^ ), 3;55 (23, s, ), 6,40 UH, s, ), N/ia 7^50 (3K, m, S02-Ç\H ), 7{6Q (2H, m, SO2~Çj ).Found 3 ° - ^ {EXAMPLE 24 H2N H2N / C NA.JLc, SC:, - c ^ NS02 "C ~ ^ 2 i CiApSCxlr ^ CxipC V \ i / XN H2 X 8 ml methanol was dissolved 800 mg methyl 3-L (2-guanidino-thiazol-4-yl) methylthio] propionimidate as well as 590 mg of benzenesulfonamide and after allowing the reaction to take place for 24 hours at room temperature, the solvent was distilled off under vacuum. was purified by silica gel column chromatography using a mixture of chloroform and methanol (20: 1-> 10: 1) to give 855 mg of amorphous N-benzenesulfonyl-3- (2-guanidinothiazol-4-yl) - The reaction product exhibited the following physical chemical properties: i) NMR spectra (DMSO-dg) δ: 2 | 60 (4H, m, -S-CH 2 CH 2 Cl 2), 3; 55 (23, s,), 6.40 UH , s,), N / ia 7 ^ 50 (3K, m, SO2-Ç \ H), 7 {6Q (2H, m, SO2 ~ Çj).

35 DK 157132 BDK 157132 B

ii) Massespektrum (FD metode): m/e 398 EKSEMPEL 25 H2t!^ _/S1 C=N—<\ ( /HS0oCH, H2N ^N GH2SGH2Ciï2G ^ ^ KH2 I 10 ml methanol blev oplest 1 g methyl-3- (2-guanidinothia-zol-4-yl)methylthio propionimidat og 0,38 g methansulfonamid, og efter at hâve ladet omsætningen foregâr i 48 timer ved stuetemperatur blev oplesningsmidlet afdestilleret under va-5 kuum. Derpâ blev den sâledes dannede inddampningsrest oplest i 3 ml .éthanol, og oplesningen fik lov til at nedkole, hvorved der udskilledes hvide krystaller. Krystallerne blev indsamlet ved filtrering og terret tll dannelse af 0,7 g N-methansulfonyl-3- (2-guanidinothiazol-4-yl)methylthio -10 propionamidin. Reaktionsproduktet udviste folgende fysisk kemiske egenskaber:ii) Mass Spectrum (FD method): m / e 398 EXAMPLE 25 H2t! 2-guanidinothiazol-4-yl) methylthio propionimidate and 0.38 g of methanesulfonamide, and after allowing the reaction to take place for 48 hours at room temperature, the solvent was distilled off under vacuum, then the residue formed was dissolved in 3 ml. Ethanol and the solution was allowed to cool down to give off white crystals. The crystals were collected by filtration and terraced to give 0.7 g of N-methanesulfonyl-3- (2-guanidinothiazol-4-yl) methylthio-10 propionamidine The reaction product exhibited the following physical chemical properties:

i) Smeltepunkt: 117-118°Ci) Melting point: 117-118 ° C

il) NMR spektra (CD^OD) : 2.60 (2H, m, -SCHgCHgC^ ), 2.80 (2K, m, -SCE2CH2C^ ), 2-92 (3H, s, S02CH3 ), 3.66 (2H, s, ) 6,50 (1H, », ).) NMR spectra (CD 3 OD): 2.60 (2H, m, -SCH 2 CH 2 Cl 2), 2.80 (2K, m, -SCE 2 CH 2 Cl 2), 2-92 (3H, s, SO 2 CH 3), 3.66 (2H, s,) 6.50 (1H, +,).

EKSEMPEL 26EXAMPLE 26

36 DK 157132 B36 DK 157132 B

'> ! /,NSO7~f V-ÎIHp H,N VT CH0SCH0CH0C^ \ — / 2 * 2 2 2 \ÎIH2 I 10 ml éthanol blev oplest 1 g methyl-3- [(2-guanidinothia-zol-4-yl)methylthiolpropionimidat og 0,69 g p-aminobenzen-sulfonamid, og efter at hâve ladet omsætningen foregâ i 48 timer ved stuetemperatur blev oplosningsmidlet afdestil-5 leret under vakuum. Den sâledes dannede inddampningsrest blev renset ved silicagelsaQlechromatografi under anvendel-se af en blanding af chloroform og methanol (20:1-910:1) til dannelse af 1,2 g N-(p-aminobenzensulfonyl)-3-(2-guani-dinothiazol-4-yl)-methylthio-propionamidin i form af et 10 amorft, fast stof. Reaktionsproduktet viste folgende fysisk kemiske egenskaber: NMR spektra (DMSO-dg) ξ : 2^0 (2K, n, -SCH2CH2cC ), 2,64 (2H, a, -SCH2CH2C^ ), 3p6 (2*i, s, 5,68 (2K, s -/j^-KTHg . ), 6,40 (1H, s, ^τ~1Γ~ ), (2H, d, ''7-N'd2. )j'>! /, NSO7 ~ f V-ÎIHp H, N VT CHOSCHOCHOC 3 0.69 g of p-aminobenzene sulfonamide and after allowing the reaction to proceed for 48 hours at room temperature, the solvent was distilled off under vacuum. The evaporation residue thus formed was purified by silica gel column chromatography using a mixture of chloroform and methanol (20: 1-910: 1) to give 1.2 g of N- (p-aminobenzene sulfonyl) -3- (2-guanine). dinothiazol-4-yl) methylthio-propionamidine in the form of an amorphous solid. The reaction product showed the following physical chemical properties: NMR spectra (DMSO-dg) ξ: 2ξ0 (2K, n, -SCH2CH2cC), 2.64 (2H, a, -SCH2CH2C2), 3p6 (2 * i, s, 5 , 68 (2K, s - / j ^ -KTHg.), 6.40 (1H, s, ^ τ ~ 1Γ ~), (2H, d, '' 7-N'd2.) J

'''H'' 'H

6^80 7.44 (2K, d, ), 3 *38 JïSO,,- 7.74/(2H, s, -c/ ^ ) 1^26 ^ 80 7.44 (2K, d,), 3 * 38 Iso, - 7.74 / (2H, s, -c /

37 DK 1S 713 2 B37 DK 1S 713 2 B

JJ

EKSEMPEL 27-28EXAMPLES 27-28

Idet man gik frem analogt med fremgangsmâden i eksem-pel 26, blev folgende forbindelser fremstillet.Proceeding analogously to the procedure of Example 26, the following compounds were prepared.

Eksempel 27: CK-^EN / ^Example 27: CK- ^ EN / ^

- >C=N~< Ji ^H302NH-> C = N ~ <Ji ^ H302NH

H2N \ï CH0SCH9CE?G^ 2 ά d nh2 N- suif amoyl-3- [( 2-N-methylguanidinothiazol-4-yl )methylthio^] propionamidin.H2N \ CH0SCH9CE? G ^ 2 ά d nh2 N-Suf amoyl-3- [(2-N-methylguanidinothiazol-4-yl) methylthio] propionamidine.

5 Den til omsætning anvendte amin: H2NSO2NH25 The amine used for reaction: H2NSO2NH2

Reaktionsproduktets fysiskkemiske egenskaber: i) Smeltepunkt: 163-164°C (omkrystalliseret ud fra anethanol) ii) Elementær analyse for CgH^yNyOgS^: C H îïPhysicochemical properties of the reaction product: i) Melting point: 163-164 ° C (recrystallized from anethanol) ii) Elemental analysis for C CH ^ yNyOgS ^: CH

Beregnet ^Calculated ^

Fundet ‘ < ' 30 j 47$ 4^84$ 27 j60?j ' Eksempel 28:Found "<" 30 j 47 $ 4 ^ 84 $ 27 j60? J "Example 28:

SS

K2N'-,r_v_X l ' .IiSOpNHp F NX CH2SCK2CH2CH2C^ K2JN nN^ 2 2 2 2 ^iîk N-suifamoyl-4- [(2-guanidinothiazol-4-yl)methylthioJ -butyr- 10K2N '-, r_v_X l' .IiSOpNHp F NX CH2SCK2CH2CH2C ^ K2JN nN ^ 2 2 2 2 ^ N N

Den til omsætningen anvendte amin: H2NS02NH2The amine used for the reaction: H2NSO2NH2

Reaktionsproduktets fysiskkemiske egenskaber:The physicochemical properties of the reaction product:

DK 157132 BDK 157132 B

38 i) Smeltepunkt: l59-l6l°C (omkrystalliseret fra éthanol) ii) Elementær analyse for C9H17N7S3°2:38 i) Melting point: l59-166 ° C (recrystallized from ethanol) ii) Elemental analysis for C9H17N7S3 ° 2:

C H NC H N

Beregnet ^0^76/* 4j88^ 27 ^9GJiCalculated ^ 0 ^ 76 / * 4j88 ^ 27 ^ 9GJi

Fundet 30,39?* 4j86fo 27η01-/= EKSEMPEL 29-32Found 30.39? * 4j86fo 27η01 - / = EXAMPLE 29-32

Idet man gâr frem analogt med fremgangsmâden i eksempel 23 blev fremstillet folgende produkter:By analogy with the procedure of Example 23, the following products were prepared:

Eksempel 29; g * 2Example 29; g * 2

^ \c=N —4 NSO^ \ c = N - 4 NSO

l^N CHgSCL^CHgC^ \=z/ N-benzylsulfamyl-3- [(2-guanidinothiazol-4-yl)methylthio] -propionamidin.= N / N-benzylsulfamyl-3- [(2-guanidinothiazol-4-yl) methylthio] propionamidine.

b: Maleatet deraf.b: The maleate thereof.

5 Den til omsætningen anvendte amin: HgKSOgNHCHg-^"^ Reaktionsproduktets fysiskkemiske egenskaber: a: i) NMR spektra (DMSO-dg): 39The amine used for the reaction: HgKSOgNHCHg - ^ "Physicochemical properties of the reaction product: a: i) NMR spectra (DMSO-dg): 39

DK 157132 BDK 157132 B

S: 2,50 (2K, SCH2CH2C\ ),S: 2.50 (2K, SCH2CH2C \),

2,64 ( 2H, tu, SCrl^C-'In^)-3 j60 (2H, s, ACh g- K2.64 (2H, tu, SCrl

4,02 (2K, d, CK2-0 ),4.02 (2K, d, CK2-0),

/s A/ s A

6,46 (1H, S, -<NX^S_ ), 6|Ô2 (4H, s, ), 7fl5 (IH, o, S02NHCH2-^^ ), 7 »24 (5K, s, )i6.46 (1H, S, - <NX ^ S_), 6 | Ô2 (4H, s,), 7fl5 (1H, o, SO2 NHCH2 - ^^), 7 »24 (5K, s,) i

AA

7*50, δ.30 (2H, s, -cCîsi )* b)7 * 50, δ.30 (2H, s, -cCis)

i) Smeltepunkt: 160-162°Ci) Melting point: 160-162 ° C

ii) Elementær analyse for cX9H25N7°6S3:ii) Elemental analysis for cX9H25N7 ° 6S3:

c H Nc H N

Beregnet 41,.38^ 4,64$> 18^04?*Calculated 41, .38 ^ 4.64 $> 18 ^ 04? *

Fundet 41,79/-¾ 4,64/3¾ 17-90/SFound 41.79 / -¾ 4.64 / 3¾ 17-90 / S

Eksempel 30: A’ v / 7 /CK-, a) ^C=N~\ ^NS092ï< 3 H2N \^CH2SCH2CH2C^ ^ ‘CH.Example 30: A 'v / 7 / CK-, a) ^ C = N ~ \ ^ NS092ï <3 H2N \ ^ CH2SCH2CH2C ^^ CH.

Kri 2 JGet 2 J

N - dime thyl s IIfamy1 » 3 ~ (2-guanidinotMazol~4-yl)methylthio -N - dime thyl s IIfamyl 1 3 - (2-guanidinotazol ~ 4-yl) methylthio -

DK 157132 BDK 157132 B

40 b) Maleatet deraf /CH3B) The maleate thereof / CH3

Den til omsætningen anvendte amin: HgNSOgNvThe amine used for the reaction: HgNSOgNv

Reaktionsproduktets fysiskkemiske egenskaber: a) i) NMR spektra (DMSO-dg): S : 2.59 (6H, d, liCH^ ),The physicochemical properties of the reaction product: a) i) NMR spectra (DMSO-dg): S: 2.59 (6H, d, 1CH2),

Jf 2,5-2^b (4H, n, SCH2CH2 ), 3764 (2K, s, ^CHgS.Cf 2.5-2 ^ b (4H, n, SCH2CH2), 3764 (2K, s, ^ CHgS.

6,50 (1H, s, ) 1 ii H2- ‘ f. ?_ Λ 6^84 (4H, s, ρ,ΐ)s 7170, 8^36 (2H, s, ) b)6.50 (1H, s,) 1 ii H2- 'f.? Λ 6 ^ 84 (4H, s, ρ, ΐ) s 7170, 8 ^ 36 (2H, s,) b)

i) Smeltepunkt: 183-186°Ci) Melting point: 183-186 ° C

ii) Elementær analyse for C14H23N7°6S3:ii) Elemental analysis for C 14 H 23 N 7 ° 6S3:

c H Nc H N

Beregnet 34}92^ 4?8l* 20,30*Calculated 34} 92 924 ?8l * 20.30 *

Fundet 34,82* 4f76* 19,96*Found 34.82 * 4f76 * 19.96 *

DK 157132 BDK 157132 B

4141

Eksempel 31: ^>0^ I /KS02C?3 F.y ^K-^ra2sœ2œzcXMj -5 „hcoohExample 31: ^> 0 ^ I / KS02C? 3 F.y ^ K- ^ ra2sœ2œzcXMj -5 "hcooh

2 )Z CHCOOH2) Z CHCOOH

N-trifluormethansulfonyl-3- (2-guanidinothiazol-4-yl)-methylthio propionamidin, dimaleat.N-trifluoromethanesulfonyl-3- (2-guanidinothiazol-4-yl) methylthio propionamidine, dimaleate.

Den til omsætningen anvendte amin: I^NSC^CF^ i) Smeltepunkt: 168-170°C (omkrystalliseret ud fra methyl-ethylketon) ii) Elementær analyse for :The amine used for the reaction: N + NSC + CF2 i) Melting point: 168-170 ° C (recrystallized from methyl ethyl ketone) ii) Elemental analysis for:

c H Nc H N

Beregnet 32^0^ 3^40# 13^50^ fundet 32f70^ 3f46# 14j00^Calculated 32 ^ 0 ^ 3 ^ 40 # 13 ^ 50 ^ found 32f70 ^ 3f46 # 14j00 ^

Eksempel 32:Example 32:

* H01T / S* H01T / S

a) 1 /C=N-^< ÿNSOpNKCH^ H0KX N^,t^~CK9SC H5CH3CC * .a) 1 / C = N - ^ <ÿNSOpNKCH ^ H0KX N ^, t ^ ~ CK9SC H5CH3CC *.

^ ά ά ά m2 N-methylsulfamyl-3- (2-guanidinothiazol-4-yl)methylthio -5 propionamidin· t>) Maleatet deraf.N-methylsulfamyl-3- (2-guanidinothiazol-4-yl) methylthio-5-propionamidine · Maleate thereof.

Den til omsætningen anvendte amin: ^NSC^NHCH^ ReaktionsprodUktets fysiskkemiske egenskaber: a).The amine used for the reaction: NS NSC NH NHCH f Physicochemical properties of the reaction product: a).

' 42'42

DK 157132 BDK 157132 B

i) NMR spektra (DMSO-dg): /: 2 7 45 (2H, cL, SKCH3 ), 2f55 (2K, m, SCH2ÇH2-cC ), 2t70 (2H, m, SÇHgOHg-C^ ), 3»60 (2H, s, -( J .. ) 6.46 (1H, s, ), 6.46 (1H, q, SO RHCH, ) 6.80 (4K, s, —U'K£~iï~ ) 1 h,n/ sït1SOz 7«4δ, 8 26 (2ΡΓ, s, -Cf^ ) ' 1 /v rj2 b).i) NMR spectra (DMSO-dg): /: 2 7 45 (2H, cL, SKCH3), 2f55 (2K, m, SCH2ÇH2-cC), 2t70 (2H, m, SÇHgOHg-C3), 3 »60 ( 2H, s, - (J ..) 6.46 (1H, s,), 6.46 (1H, q, SO RHCH,) 6.80 (4K, s, —U'K £ ~ iï ~) 1 h, n / s1t1SOz 7 «4δ, 8 26 (2ΡΓ, s, -Cf ^) '1 / v rj2 b).

i) Smeltepunkt: 181-184°Ci) Melting point: 181-184 ° C

ii) Elementær analyse for C^H^NyOgS^:ii) Elemental analysis for C

C H NC H N

Beregnet 33,40^ 4,53$ 20f97$Calculated 33.40 ^ 4.53 $ 20f97 $

Fundet 33,36$ 4^43p 20r63$ EKSEMPEL 53 Lægemiddelblanding --------' Tabletter til pérorai indgiftFound 33.36 $ 4 ^ 43p 20r63 $ EXAMPLE 53 Drug Mix -------- 'Tablets for Perorai Administration

Recept for 1000 tabletter:Prescription for 1000 tablets:

Aktiv bestanddel 260 gActive ingredient 260 g

Stivelse 37 g Mælkesukker 50 gStarch 37 g Milk sugar 50 g

Magnesiumstearat 3 g 43Magnesium stearate 3 g 43

DK 15 713 2 BDK 15 713 2 B

De ovenfor viste bestanddele blev granuleret pâ sædvanlig mâde under anvendelse af stivelsespasta som et bindemid-del, og derpâ slâet til tabletter med hver 9,5 nim diame-ter, EKSEMPEL 54The ingredients shown above were granulated in the usual manner using starch paste as a binder, and then beaten into tablets with each 9.5 µm diameter, Example 54

Lasgemiddelblanding ----- recept til in^ektionsbrugSolvent mixture ----- recipe for injection use

Recept for 2 ml injektionsvæske:Prescription for 2 ml solution for injection:

Aktiv bestanddel 260 mgActive ingredient 260 mg

Destilleret vand til injektionsbrug til dannelse af 2 ml 5 Destilleret vand til injektionsbrug blev sat til aktiv bestanddelen, Og aktivbestanddelen blev oplast, medens man gennemboblede en gasformig nitrogen til dannelse af en oplosning med en koncentration pâ 13% (en koncentra-tion pâ 1096 beregnet pâ basen). Efter filtrering af oples-10 ningen gennem et bakterie-filter blev 2,2 ml af oplæsnin-gen anbragt i 2 ml ampuller i sterilttilstend,og efter at rummet i ampulen var blevet fyldt med nitrogengas, blev ampullen forseglet.Distilled water for injection to form 2 ml 5 Distilled water for injection was added to the active ingredient, and the active ingredient was dissolved while bubbling a gaseous nitrogen to form a solution with a concentration of 13% (a concentration of 1096 calculated on the base). After filtering the solution through a bacterial filter, 2.2 ml of the solution was placed in 2 ml ampoules in sterile condition and after the space in the ampoule was filled with nitrogen gas, the ampoule was sealed.

EKSEMPEL 55 /NH viNCN' K N __- (Cfi„) .C^ iu»\ (C;i ) C x 2 |J 2 4 ^OCIL_* 2 >=N—<f Ί[ 2 4 '-KH, 1I0N ° H N/ C. ά I 10 ml methanolisk oplesning af 2,5 g methyl-5-(2-guani-15 dinothiazol-4-yl)pentanoimidat blev tilsat 0,6 g cyanamid, og oplesningen blev holdt under omrering ved stuetemperatur i 1,5 timer. Oplosningsmidlet blev afdestilleret, og til inddampningsresten blev tilsat 10 ml acetone. De udskilte krystaller blev frafiltreret, og reaktionsproduktet blev 20 renset under anvendelse af dimethylforaamid-vand. Det ren- 44EXAMPLE 55 / NH viNCN 'KN __- (Cfi'). C ^ iu »\ (C; i) C x 2 | J 2 4 ^ OCIL_ * 2> = N— <f 2 [2 4 '-KH, 1I0N ° HN / C. ά In 10 ml of methanolic solution of 2.5 g of methyl 5- (2-guanidinothiazol-4-yl) pentanoimidate, 0.6 g of cyanamide was added and the solution was stirred at room temperature for 1 h. 1.5 hours. The solvent was distilled off and 10 ml of acetone was added to the residue. The separated crystals were filtered off and the reaction product was purified using dimethylforamide water. It clean 44

DK 15 713 2 BDK 15 713 2 B

sede produkt blev oplost i en blanding af 0,7 ml eddikesyre, 8 ml éthanol og 16 ml vand, og til oplesningen blev tilsat 11,6 ml ln-NaOH oplosning. De bundfældede krystaller blev opsamlet ved filtrering til dannelse af 1,9 g N-cyano-5-5 ( 2-guanidinothiazol-4-yl )pentanoamidin.The resulting product was dissolved in a mixture of 0.7 ml of acetic acid, 8 ml of ethanol and 16 ml of water, and to the solution was added 11.6 ml of ln-NaOH solution. The precipitated crystals were collected by filtration to give 1.9 g of N-cyano-5- (2-guanidinothiazol-4-yl) pentanoamidine.

i) Smeltepunkt: 195-196°Ci) Melting point: 195-196 ° C

ii) Elementær analyse for cioH15N7Sii) Elemental analysis for cioH15N7S

c H Nc H N

Beregnet 45f27 5J70 36^.95Calculated 45f27 5J70 36 ^ .95

Fundet 45,13 5,82 36f62Found 45.13 5.82 36f62

Det i dette eksempel som râmateriale anvendte methyl-5-(2-guanidinothiazol-4-yl)pentanoimidat blev fremstillet ved folgende metode.The methyl-5- (2-guanidinothiazol-4-yl) pentanoimidate used in this example as a raw material was prepared by the following method.

(a) ckch^)4coci -—^ ci (ch2}4coch2ci I 300 ml af en etheroplosning af diazomethan, der var frem-10 stillet ud fra 43 g p-tosyl-N-methyl-N-nitrosoacetamid, blev tilsat under omrering 13 ml af en etheropl0 sning af 8 g 5-chlorvalerylchlorid drâbe for drâbe ved -5 til 0°C, og oplesningen fik lov til at benstâ ved samme temperatur i 2 timer. Gasformig hydrogenchlorid blev boblet gennem 15 reaktionsoplosningen ved 0°C og oplesningen fik lov at henstâ ved samme temperatur i 0,5 timer. 3?il oplosningen blev tilsat 100 ml vand, og etherlaget blev frasepareret.(a) ccch 2) 4coci -c ci (ch2} 4coch2ci In 300 ml of an ethereal solution of diazomethane prepared from 43 g of p-tosyl-N-methyl-N-nitrosoacetamide was added with stirring. 13 ml of an ether solution of 8 g of 5-chlorovaleryl chloride drop by drop at -5 to 0 ° C, and the solution was allowed to stand at the same temperature for 2 hours. Gaseous hydrogen chloride was bubbled through the reaction solution at 0 ° C and the solution was allowed to stand at the same temperature for 0.5 hours, 3 ml of the solution was added with 100 ml of water and the ether layer was separated.

Det vandige lag blev yderligere extraheret 2 gange med hver 100 ml ether. Etherlagene blev forenet, og den sâledes frem-20 stillede etheroplesning blev terret over vandfrit magnesium-sulfat, og oplosningsmidlet blev afdestilleret, og ind-dampningsresten blev destilleret under vakuum til dannelse af 8,2 g l,6-dichlorhexanon-2,· der udviste et kogepunkt pâ 120-125°C (14 mmHg).The aqueous layer was further extracted twice with each 100 ml of ether. The ether layers were combined and the ether solution thus prepared was triturated over anhydrous magnesium sulfate and the solvent was distilled off and the residue evaporated in vacuo to give 8.2 g of 6-dichlorohexanone-2 which showed a boiling point of 120-125 ° C (14 mmHg).

DK 157132 BDK 157132 B

45 (b) Η0Ν· ÎCH0).C1 C1CH2C0(CH9) Cl -} 2 Nc_v_/ |f “ 1 2 2 4 > h2N^ \ J J™1 h I 200 ml acetone-opl0sning af 23,5 g l,6-dichlorhexanon-2 blev tilsat 16,4 g guanylthiourinstof, og oplosningen blev holdt imder omrering i 2 dage. Oplesningsmidlet blev af-destilleret, og inddampningsresten blev renset ved silica-5 gelsojleehromatografi under anvendelse af en blanding af chloroform Og methanol som fxemkaldervæske til dannelse af 2-guanidino-4-(4-chlorbutyl)thiazol, hydrochlorid (dette produkt udviser et smeltepunkt pâ 113-ll4°C efter omkrystal-lisation fra en blanding af éthanol og ether). Dette hydro-10 chlorid blev oplost i 300 ml vand, og til oplosningen blev tilsat 100 ml vandig oplesning af 17,4 g kaliumcarbonat.45 (b) Η0Ν · ÎCH0) .C1 C1CH2C0 (CH9) Cl -} 2 Nc_v_ / | f “1 2 2 4> h2N ^ \ JJ ™ 1 h In 200 ml of acetone solution of 23.5 gl, 6-dichlorohexanone -2.4 g of guanylthiourea was added and the solution was kept under stirring for 2 days. The solvent was distilled off and the residue was purified by silica gel column chromatography using a mixture of chloroform and methanol as, for example, coolant to give 2-guanidino-4- (4-chlorobutyl) thiazole hydrochloride (this product has a melting point 113-114 ° C after recrystallization from a mixture of ethanol and ether). This hydrochloride was dissolved in 300 ml of water and to the solution was added 100 ml of aqueous solution of 17.4 g of potassium carbonate.

Den sâledes fremstillede oplesning blev extraheret 3 gange med henholdsvis 500 ml, 200 ml og 200 ml chloroform» Chloro-formextrakterne blev forenet og torret over vandfrit kalium-15 carbonat, og oplosningsmidlet blev afdestilleret. De fremstillede krystaller blev omkrystalliseret fra en blanding af ether og n-hexan til dannelse af 20 g 2-guanidino-4-(4-chlorbutyl)thiazol, der udviste et smeltepunkt pâ 83-84°C.The thus prepared solution was extracted 3 times with 500 ml, 200 ml and 200 ml of chloroform, respectively. The chloroform extracts were combined and dried over anhydrous potassium carbonate and the solvent was distilled off. The crystals prepared were recrystallized from a mixture of ether and n-hexane to give 20 g of 2-guanidino-4- (4-chlorobutyl) thiazole, exhibiting a melting point of 83-84 ° C.

(c) r(cwi_„ h*n>«-/Y<cw" 20 Til 24 ml dimethyldulfoxid blev tilsat 4,9 g natriumcyanid, og den sâledes fremstillede blanding blev opvarmet til 70°C. Under omrering blev ved 70-75°C 19,5 g 2-guanidino-4-(4-chlorbutyl)thiazol sat til oplosningen, og oplasningen blev holdt under omrering ved samme temperatur i 3 timer.(c) r (cwi_ "h * n>" - / Y <cw "20 To 24 ml of dimethyldulfoxide was added 4.9 g of sodium cyanide and the mixture thus prepared was heated to 70 ° C. With stirring, at 70-75 19.5 g of 2-guanidino-4- (4-chlorobutyl) thiazole were added to the solution and the solution was kept under stirring at the same temperature for 3 hours.

DK 157132 BDK 157132 B

4646

Reaktionsblandingen blev k0let, og til oplssningen blev tilsat 100 ml chloroform. Efter frafiltrering af det ikke-opl0ste materiale blev opl0sningen inddampet, og inddamp-ningsresten blev renset ved silicagelssjlechromatografi 5 under anvendelse af en blanding af chloroform og methanol som fremkaldervæske til dannelse af 15 g 2-guanidino-4-(4-cyanobutyl)thiazol. Reaktionsproduktet udviste et smel-tepunkt pâ 104-105°C efter omkrystallisation ud fra en blanding af ethylacetat og n-hexan.The reaction mixture was cooled and 100 ml of chloroform was added to the solution. After filtration of the undissolved material, the solution was evaporated and the residue was purified by silica gel gel chromatography 5 using a mixture of chloroform and methanol as the developing liquid to give 15 g of 2-guanidino-4- (4-cyanobutyl) thiazole. The reaction product showed a melting point of 104-105 ° C after recrystallization from a mixture of ethyl acetate and n-hexane.

(d) NH(d) NH

10 10 g 2-guanidino-4-(4-cyanobutyl)thiazol blev bragt i sus pension i en blanding af 60 ml methanol og 110 ml chloroform, og gasformig hydrogenchlorid blev boblet gennem op-losningen under omrsring ved -5 til 5°C i 2 timer. Den sâledes fremstillede oplssning fik lov at henstâ ved 5°C i 15 2 dage, og oplosningsmidlet blev afdestilleret. Inddamp- ningsresten blev bragt i suspension i en blanding af chloroform og methanol, og. suspensionen blev hældt ud i is-vand indeholdende 60 g kaliumcarbonat. Chloroformlaget blev frasepareret, og det vandige lag blev extraheret 20 yderligere 3 gange med hver 150 ml chloroform· Extrakter-ne blev forenet og tsrret over vandfrit kaliumcarbonat. Oplssningsmidlet blev afdestilleret til dannelse af 11 g methyl-5-(2-guanidino-4-yl)pentanoimidat, der udviste et smeltepunkt pâ 143-145°C.10 g of 2-guanidino-4- (4-cyanobutyl) thiazole were suspended in a mixture of 60 ml of methanol and 110 ml of chloroform, and gaseous hydrogen chloride was bubbled through the solution with stirring at -5 to 5 ° C. for 2 hours. The thus prepared solution was allowed to stand at 5 ° C for 2 days and the solvent was distilled off. The evaporation residue was suspended in a mixture of chloroform and methanol, and. the suspension was poured into ice-water containing 60 g of potassium carbonate. The chloroform layer was separated and the aqueous layer was extracted 20 more 3 times with each 150 ml of chloroform. The extracts were combined and dried over anhydrous potassium carbonate. The solvent was distilled off to give 11 g of methyl 5- (2-guanidino-4-yl) pentanoimidate, which had a melting point of 143-145 ° C.

DK 157132 BDK 157132 B

47 EKSEMPEL 56EXAMPLE 56

/NCN/ NCN

H2N\ //V^CH2N \ // V ^ C

2 >=N-// (Γ XnH2 iï2N/ N/ ^NCONH9 1 g N-cyano-5-(2-guanidinothiazol-4-yl)pentanoamidin blev bragt i suspension i en blanding af 20 ml methanol og 30 ml chloroform. Gasformig hydrogenchlorid blev boblet gennem suspensionen i 1,5 timer ved -5 til 5°C, og reaktionsop-5 losningen blev inddampet under vakuum, Den olieagtige ind-dampningsrest blev omkrystalliseret ud fra en blanding af methanol og ether indeholdende en lille mængde vand til dannelse af 1,1 g N-carbamoÿl-5-(2-guanidinothiazol-4-yl) pentanoamidin, dihydrochlorid, monohydrat, der udvlste 10 et smeltepunkt pâ 148-150°C.2> = N - // (Γ XnH 2 in 2 N / N / 2 NCONH9 1 g N-cyano-5- (2-guanidinothiazol-4-yl) pentanoamidine was suspended in a mixture of 20 ml of methanol and 30 ml of chloroform. Gaseous hydrogen chloride was bubbled through the suspension for 1.5 hours at -5 to 5 ° C and the reaction solution was evaporated in vacuo. The oily residue was recrystallized from a mixture of methanol and ether containing a small amount of water. to give 1.1 g of N-carbamoyl-5- (2-guanidinothiazol-4-yl) pentanoamidine, dihydrochloride, monohydrate to give a melting point of 148-150 ° C.

Elementær analyse for C^QH^yN^OS, 2HC1, H2OElemental analysis for C ^ QH ^ yN₂O,, 2HCl1, H₂O

C H NC H N

Beregnet 32^09 5^.65 26^20Calculated 32 ^ 09 5 ^ .65 26 ^ 20

Fundet 32f10 5^5 26^06 EKSEMPEL 57 ^nso9nh„ h n /n>n^'(CH2)4C\ H2N/Found 32f10 5 ^ 5 26 ^ 06 EXAMPLE 57 ^ nso9nh «h n / n> n ^ '(CH2) 4C \ H2N /

DK 157132 BDK 157132 B

48 1,3 g methyl-5-(2-guanidinothiazol-4-yl)pentanoimidat og 1»1 S sulfamid blev oplost i 4,3 ml methanol, og oplosningen fik lov at henstâ natten over ved s tue temperatur. Oplos-ningsmidlet blev afdestilleret under vakuum, og inddamp-5 ningsresten blev renset ved silicagelsojlechromatografi under anvendelse af en blandlng af acetone og methanol som fremkaldervæske. De sâledes dannede krystaller blev oplost i en blanding af 0,4 ml eddikesyre, 4 ml éthanol og 8 ml vand, og de blev behandlet med aktivkul. Til fil-10 tratet herfra blev tilsat 6,6 ml ln N-NaOH, og de udfældede krystaller blev opsamlet ved filtrering til dannelse af 0,70 g N-sulfamoyl-5-(2-guanidinothiazol-4-yl)pentanoami-din, der udviste et smeltepunkt pâ 156-157°C.48 g of methyl 5- (2-guanidinothiazol-4-yl) pentanoimidate and 1 µL of sulfamide were dissolved in 4.3 ml of methanol and the solution was allowed to stand overnight at room temperature. The solvent was distilled off under vacuum and the residue was purified by silica gel oil chromatography using a mixture of acetone and methanol as the developing liquid. The crystals thus formed were dissolved in a mixture of 0.4 ml of acetic acid, 4 ml of ethanol and 8 ml of water and treated with activated charcoal. To this filtrate was added 6.6 ml of N-NaOH and the precipitated crystals were collected by filtration to give 0.70 g of N-sulfamoyl-5- (2-guanidinothiazol-4-yl) pentanoamide. which exhibited a melting point of 156-157 ° C.

Elementær analyse for C H nElemental analysis for C H n

Beregnet 33^.84 5^.36 30^70Calculated 33 ^ .84 5 ^ .36 30 ^ 70

Pundet 33,55 5,45 30,24Pound 33.55 5.45 30.24

Ved at folge en fremgangsmâde analog med det ovenfor an-15 forte eksempel blev fremstillet N-propylsulfamyl-5-(2-gu-anidinothiazol-4-yl)pentanoamidin, der udviste et smeltepunkt pâ 175-175°C (reaktionskomponenten: H2NSO2NH( CH2 ) 2^3 î reaktionstemperatur, tid og reaktionsbetingelser: tilbage-svaling under opvarmning, 5 timer).Following a procedure analogous to the above example, N-propylsulfamyl-5- (2-guanidinothiazol-4-yl) pentanoamidine was prepared which exhibited a melting point of 175-175 ° C (reaction component: H2NSO2NH ( CH2) 2 3 reaction temperature, time and reaction conditions: reflux under heating, 5 hours).

^ (CH,(CH,

DK 157132 BDK 157132 B

4949

Elementær analyse for ci2H23N7°2S2 C H nElemental analysis for c12 H23 N7 ° 2S2 C H n

Beregnet 39 f 87 6,41 27fl2Calculated 39 f 87 6.41 27fl2

Fundet 40,09 6,48 26,.87 EKSEMPEL 58Found 40.09 6.48 26 .87 EXAMPLE 58

^NFI^ NFI

HJ1 //N'N^(CH2)4C\ /C=N.—C |j NH2 ,IIC1 »2K \/HJ1 // N'N ^ (CH2) 4C \ /C=N.—C | j NH2, IIC1 »2K \ /

Til 5 ml af en methanolisk opl0sning af 0,64 g methyl-5-(2-guanidinothiazol-4-yl)pentanoimidat blev tilsat 0,084 g anunoniumchlorid, og oplosningen blev holdt under omrering ved stuetemperatur natten over. Til reaktionsopl0sningen 5 blev tilsat 5 ml acetone, og de udfældede krystaller blev opsamlet ved filtrering. De sâledes dannede krystaller blev omkrystalliseret ud fra vandig éthanol til dannelse af 0,37 g 5- (2-guanidinothiazol-4-yl)pentanoamidin, hydrochlorid.To 5 ml of a methanolic solution of 0.64 g of methyl 5- (2-guanidinothiazol-4-yl) pentanoimidate was added 0.084 g of anunonium chloride and the solution was kept under stirring at room temperature overnight. To the reaction solution 5 was added 5 ml of acetone and the precipitated crystals were collected by filtration. The crystals thus formed were recrystallized from aqueous ethanol to give 0.37 g of 5- (2-guanidinothiazol-4-yl) pentanoamidine hydrochloride.

Elementær analyse for C^H-j^NgS, HClElemental analysis for C ^H--NgS, HCl

C H NC H N

Beregnet 39/06 6^19 30^,36Calculated 39/06 6 ^ 19 30 ^, 36

Fundet 39,16 6,30 30^17 EKSEMPEL 39 ,NS°2Hf3-NII2Found 39.16 6.30 Example 17 EXAMPLE 39, NS ° 2Hf3-NII2

_ m '- CII-C00Hm - CII-C00H

E2N\ // n NH filE2N \ // n NH file

* XC=N—(/ IJ 2 J CIÎ-COOH* XC = N - (/ IJ 2 J CIÎ-COOH

H2NH2N

DK 157132 BDK 157132 B

5050

Til 5 ml methanol blev tilsat 0,64 g methyl-5-(2-guanidi-nothiazol-4-yl)pentanoimidat og 0,27 g p-aminobenzensul-fonamid, og oplosningen blev boldt under tilbagesvaling under opvarmning i 5 timer. Oplasningsmidlet blev afdestil-5 leret under vakuum, og inddampningsresten blev renset ved silicagels0jlechromatografi under anvendelse af chloroform-methanol som fremkàldervæske. Det sâledes fremstillede pro-dukt blev oplost i acetone, og til den dannede oplosning blev tilsat acetoneoplosning af 0,4 g maleinsyre. De ud-10 fældede krystaller blev omkrystalliseret ud fra methanol-ether til dannelse af 0,51 g N-(4-aminobenzensulfonyl)-5-(2-guanidinothiazol-4-yl)pentanoamidin, maleat, der udviste et smeltepunkt pâ 143-146°C.To 5 ml of methanol were added 0.64 g of methyl 5- (2-guanidi-nothiazol-4-yl) pentanoimidate and 0.27 g of p-aminobenzene sulfonamide, and the solution was refluxed under heating for 5 hours. The solvent was distilled off in vacuo and the residue was purified by silica gel column chromatography using chloroform-methanol as the coolant. The product thus prepared was dissolved in acetone, and to the resulting solution was added acetone solution of 0.4 g of maleic acid. The precipitated crystals were recrystallized from methanol-ether to give 0.51 g of N- (4-aminobenzenesulfonyl) -5- (2-guanidinothiazol-4-yl) pentanoamidine, maleate, which had a melting point of 143 ° C. 146 ° C.

Elementær analyse for ci9H25N7°6S2 c h nElemental analysis for c19 H25 N7 ° 6S2 c h n

Beregnet 44f61 4^93 19fi7Calculated 44f61 4 ^ 93 19fi7

Fundet 44f89 4,96 le 67Found 44f89 4.96 le 67

Ved at gâ frem analogt med omsætning i ovennævnte eksempel 15 (reaktionskomponentî /_y-so NH } » blev fremstillet N-ben- zensulfonyl-5-(2-guanidinothiazol-4-yl)pentanoamidin, malein-syresalt, der udviste et smeltepunkt pâ 162-164°C.Proceeding by analogy with reaction in the above Example 15 (reaction component / γ-so NH} N, N-benzenesulfonyl-5- (2-guanidinothiazol-4-yl) pentanoamidine, maleic acid salt, which had a melting point of 162-164 ° C.

H2N\ //'^T'(CH2)4C\ \=/H2N \ // '^ T' (CH2) 4C \ \ = /

2 XC=N—|T 4 XNH_ CH-COOH2 XC = N— | T 4 XNH_ CH-COOH

H?N \ J /11H? N \ J / 11

* . CH-COOH*. CH-COOH

Elementær analyse for ¢^19^24%¾¾Elemental analysis for ¢ ^ 19 ^ 24% ¾¾

C H NC H N

Beregnet 45(96 4r87 16,92Calculated 45 (96 4r87 16.92

Fundet 45,67 4T92 Xi5j81Found 45.67 4T92 Xi5j81

DK 157132 BDK 157132 B

5151

Ved at falge ovennævnte omsætningsfremgangsmâde (reaktions-komponent: H2nso2nh—), blev yderligere fremstillet N-cyclohexylsulfamyl-5-(2-guanidinothia2ol-4-yl)pentanoami-din, maleinsyresalt, der udviste et smeltepunkt pâ 130-5 131°C.By following the above reaction procedure (reaction component: H2nso2nh -), N-cyclohexylsulfamyl-5- (2-guanidinothiazol-4-yl) pentanoamide, maleic acid salt, which was m.p.

„ „>-κ y -* >„„> -Κ y - *>

2* NS^ CII-COOH2 * NS ^ CII-COOH

Elementær analyse for cigH3iN7°6S2Elemental analysis for cigH3iN7 ° 6S2

C H NC H N

Beregnet 44J09 6f04 18Γ94Calculated 44J09 6f04 18Γ94

Fundet 44,05* 6f00 18?66 EKSEMPEL 40Found 44.05 * 6f00 18? 66 EXAMPLE 40

.NCR C=CH.NCR C = CH

T ; - rC00HT; - rC00H

az CII-COOiIaz CII-COOiI

I 5 ml methanol blev oplest 0,64 g methyl-5-(2-guanidino-thiazol-4-yl)pentanoimidat og 0,09 g propargylamin blev sat til oplesningen, hvorpâ demie fik lov til at henstâ natten over ved stuetemperatur. Ople sningsmidlet blev af-10 destilleret, og inddampningsresten blev renset ved silicagel-S0jlechromatografi under anvendelse af ehloroform-methanol-triethylamin som fremkaldervæske. Det sâledes fremstillede olieagtige produkt blev oplest i acetone, og til acetone-oplesningen blev tilsat en oplesning af 0,4 g maleinsyre 15 i acetone. De udfældede krystaller blev opsamlet ved fil-trering og omkrystalliseret ud fra éthanol til dannelse af 0,14 g N-propargyl-5-(2-guanidinothiazol-4-yl)pentanoamidin, dimaleat.In 5 ml of methanol were dissolved 0.64 g of methyl 5- (2-guanidino-thiazol-4-yl) pentanoimidate and 0.09 g of propargylamine added to the solution, whereupon they were allowed to stand overnight at room temperature. The solvent was distilled off and the residue was purified by silica gel column chromatography using ehloroform-methanol-triethylamine as the developing liquid. The oily product thus prepared was dissolved in acetone and to the acetone solution was added a solution of 0.4 g of maleic acid in acetone. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 0.14 g of N-propargyl-5- (2-guanidinothiazol-4-yl) pentanoamidine, dimaleate.

5252

DK 157132 BDK 157132 B

Elementær analyse for ^Q^gNgOgSElemental Analysis for ^ Q ^ gNgOgS

C h nC h n

Beregnet 47^05 5,13 16,46Calcd 47 ^ 05 5.13 16.46

Fundet 46,75 5,20 16 34Found 46.75 5.20 16 34

Idet man gik frem analogt med omsætningsfremgangsmâden i ovennævnte eksempel (reaktionskomponent: h2nch2-£^) ), blev fremstillet N-benzyl-5- (2-guanidinothiazol-4-yl)pentanoami-din, dimaleat, der udviste et smeltepunkt pâ 92-94°C.Proceeding analogously to the reaction procedure of the above example (reaction component: H2NCH2-6)), N-benzyl-5- (2-guanidinothiazol-4-yl) pentanoamide, dimaleate, having a melting point of 94 ° C.

.NCH.NCH

H Nr /N\^^(CHq)C \—/ \\>ά y ^ >4“H Nr / N \ ^^ (CHq) C \ - / \\> ά y ^> 4 “

2 CH-COOH2 CH-COOH

Elementær analyse for ^z^qN^OqSElemental Analysis for ^ z ^ qN ^ OqS

c H nc H n

Beregnet; 51,24 5,37 14,94calculated; 51.24 5.37 14.94

Fundet 50,76 5,35 14.82 EKSEMPEL 41 V /v-<C(V4<KS°2C2H5 3 5 Til 5 ml methanol blev tilsat 0,17 g ethansulfonamid og 0,64 mg methyl-5-(2-guanidinothiazol-4-yl)pentanoimidat, og oplasningen blev holdt under tilbagesvaling under op-varmning i 5 timer. Oplesningsmidlet blev afdestilleret under vakuum, og inddampningsresten blev renset ved silica-10 gelsojlechromatografi under anvendelse af chloroform-me- thanol som fremkaldervæske til dannelse af 0,36 g N-ethyl-sulfonyl-5- (2-guanidinothiazol-4-yl)pentanoamidin, derFound 50.76 5.35 14.82 Example 41 V / v- <C (V4 <KS ° 2C2H5) To 5 ml of methanol was added 0.17 g of ethanesulfonamide and 0.64 mg of methyl 5- (2-guanidinothiazole-4 -yl) pentanoimidate and the solution was refluxed under heating for 5 hours, the solvent was distilled off in vacuo and the residue was purified by silica gel column chromatography using chloroform methanol as developing liquid to give 0.36 g of N-ethylsulfonyl-5- (2-guanidinothiazol-4-yl) pentanoamidine, which

DK 157132 BDK 157132 B

53 udviste et smeltepunkt pâ 115-116°C.53 showed a melting point of 115-116 ° C.

Elementær analyse for CnHgQÎÏgOgSgElemental Analysis for CnHgQÎÏgOgSg

C H NC H N

Beregnet 39^74 6?06 25,» 28Calculated 39 ^ 74 6? 06 25, »28

Fundet 39.10 6.07 25-12 r i r EKSEMPEL 42Found 39.10 6.07 25-12 years in Example 42

.NNHCOCFL.NNHCOCFL

H2N\c-Ν-//ΝΥ" I 5 ml methanol blev oplest 0,64 g methyl-5-(2-guanidino-thiazol-4-yl)pentanoimidat, og 0,27 g acetylhydrazin blev sat til oplesningen. Reaktionsoplesningen blev holdt under omrering ved stuetemperatur natten over, og de udfældede 5 krystaller blev opsamlet ved filtrering. Det sâledes frem-stillede produkt blev vasket med éthanol-ether til dannel-se af 0,27 g N-acetyl-5-(2-guanidinothiazol-4-yl)pentano-amidrazon, der udviste et smeltepunkt pâ 157-159°C»H2N \ c-Ν - // ΝΥ "In 5 ml of methanol was read 0.64 g of methyl 5- (2-guanidino-thiazol-4-yl) pentanoimidate and 0.27 g of acetylhydrazine was added to the solution. The reaction solution was kept under stirring at room temperature overnight and the precipitated 5 crystals were collected by filtration The product thus prepared was washed with ethanol ether to give 0.27 g of N-acetyl-5- (2-guanidinothiazole). 4-yl) pentanoamidrazone exhibiting a melting point of 157-159 ° C.

Elementær analyse for C11H19N70S C H NElemental Analysis for C11H19N70S C H N

_ . 44.43 6.44 32.97_. 44.43 6.44 32.97

Beregnet » ) (Calculated ») (

Fundet 44^06 6^37 32^60Found 44 ^ 06 6 ^ 37 32 ^ 60

Idet man gik frem med den samme omsætningsfremgangsmâde 10 som i ovennævnte eksempel (reaktionskomponent; h2nnhso2— blev fremstillet N-benzensulfonyl-5-(2-guanidinothiazol-4-yl)pentanoamidrazon, der udviste et smeltepunkt pâ 206-207°C.Proceeding with the same reaction procedure 10 as in the above example (reaction component; H2nhso

DK 157132 BDK 157132 B

54 .nnhso2-/~^ H^c=N_//Y(CH2>4Cn»2 ^54 .nnhso2- / ~ ^ H ^ c = N _ // Y (CH2> 4Cn »2 ^

Elementær analyse for ^15^21^7^2¾Elemental analysis for ^ 15 ^ 21 ^ 7 ^ 2¾

C H NC H N

Beregnet 45^55 5^35 24^.79Calculated 45 ^ 55 5 ^ 35 24 ^ .79

Fundet 45^33 5?38 24^79 EKSEMPEL 45 H0N' //X^(CV4C0NHCH3 /feN-/ |f H2»'/Found 45 ^ 33 5? 38 24 ^ 79 EXAMPLE 45 H0N '// X ^ (CV4C0NHCH3 / feN- / | f H2 »' /

Til 0,27 g 5-(2-guanidinothiazol-4-yl)propionsyreethyles-ter blev tilsat 1 ml 40# methanolisk oplasning af methylamin, og oplasningen fik lov til at henstâ ved stuetemperatur i 2 dage. De udfældede krystaller blev opsamlet ved filtre-5 ring og vasket med methanol og derpâ med ether til dannel-se af 0,2 g N-methyl-5-(2-guanidinothiazol-4-yl)pentansyre-amid. Dette produkt blev omkrystalliseret ud fra vandig methanol til dannelse af det rensede produkt, der udviste et smeltepunkt pâ 228-232°C.To 0.27 g of 5- (2-guanidinothiazol-4-yl) propionic acid ethyl ester was added 1 ml of 40 # methanolic solution of methylamine and the solution was allowed to stand at room temperature for 2 days. The precipitated crystals were collected by filtration and washed with methanol and then ether to give 0.2 g of N-methyl-5- (2-guanidinothiazol-4-yl) pentanoic acid amide. This product was recrystallized from aqueous methanol to give the purified product which had a melting point of 228-232 ° C.

Elementær analyse for C^qH^N^OSElemental Analysis for C ^ qH ^ N ^ OS

C H nC H n

Beregnet 47^04 6^71 27^43 FUndrt 6,54 27,68Calculated 47 ^ 04 6 ^ 71 27 ^ 43 Found 6.54 27.68

DK 157132 BDK 157132 B

5555

Den soin râmateriale i dette eksempel anvendte 5-(2-guani-dinothiazol-4-yl)pentansyreethylester blev fremstillet ved fslgende metode.The soin feedstock used in this example used 5- (2-guanidinothiazol-4-yl) pentanoic acid ethyl ester was prepared by the following method.

(a) y mi ha // v- (CV4< «>*-{ y 2 2 g 2-guanidino-4-(4-cyanobutyl)thiazol blev bragt i sus-5 pension i en blanding af 15 ml éthanol og 25 ml chloroform, og gasformig hydrogenchlorid blev boblet gennem oplosningen under omrering ved -5 til 5°C igennem 2 timer. Den sâledes fremkomne oplssning fik lov til at henstâ ved 5°C i 4 da-ge, og oplesningsmidlet blev afdestilleret under vakuum.(a) y mi ha // v- (CV4 <4> * - {y 2 2 g of 2-guanidino-4- (4-cyanobutyl) thiazole was suspended in a mixture of 15 ml of ethanol and 25 of chloroform and gaseous hydrogen chloride were bubbled through the solution with stirring at -5 to 5 ° C for 2 hours, the resulting solution was allowed to stand at 5 ° C for 4 days and the solvent was distilled off under vacuum.

10 Inddampningsresten blev bragt i suspension i éthanol, og suspensionen blev hældt ud i isvand indeholdende 15 g ka-liumcarbonat. De udskilte krystaller blev opsamlet ved fil-trering, vasket med vand og ether til dannelse af 2,1 g ethyl-5-(2-guanidinothiazol-4-yl)pentanoimidat, der udviste 15 et smeltepunkt pâ 138-139°C· (b)The evaporation residue was suspended in ethanol and the suspension was poured into ice water containing 15 g of potassium carbonate. The separated crystals were collected by filtration, washed with water and ether to give 2.1 g of ethyl 5- (2-guanidinothiazol-4-yl) pentanoimidate, exhibiting a melting point of 138-139 ° C ( b)

ycN HycN H

«2Nx //N'N^'(CH2)4C\ >=N—(' Il xOCH CH,«2Nx // N'N ^ '(CH2) 4C \> = N— (' Il xOCH CH,

' . V'. V

Λ ^ «2<\ /\^(CH2>4C00C!12C«3Λ ^ «2 <\ / \ ^ (CH2> 4C00C! 12C« 3

DK 157132 BDK 157132 B

5656

Til 1,2 g ethyl-5-(2-guanidinothiazol-4-yl)pentanoimidat blev tilsat 30 ml éthanol og 3 ml vand. Den sâledes frem-stillede oplosning blev gjort kraftigt sur med ethanolisk saltsyre, og den blev opvarmet til 50°C i 10 minutter.To 1.2 g of ethyl 5- (2-guanidinothiazol-4-yl) pentanoimidate were added 30 ml of ethanol and 3 ml of water. The solution thus prepared was strongly acidified with ethanolic hydrochloric acid and heated to 50 ° C for 10 minutes.

5 Efter koling blev 30 ml chloroform og 30 ml vand sat til reaktionsblandingen. Oplosningen blev gjort alkalisk med kaliumcarbonat, og chloroformlaget blev frasepareret.After cooling, 30 ml of chloroform and 30 ml of water were added to the reaction mixture. The solution was made alkaline with potassium carbonate and the chloroform layer was separated.

Det vandige lag blev yderligere extraheret 2 gange med hver 20 ml chloroform. Chloroformlagene blev forenet og 10 torret over vandfrit magnesiumsulfat. Oplesningsmidlet blev afdestilleret under vakuum og inddampningsresten blev renset ved sojlechromatografi under anvendelse af chloro-form-methanol som fremkaldervæske til dannelse af 2,0 g 5-(2-guanidinothiazol-4-yl)pentansyreethylester. Dette pro-15 dukt blev omkrystalliseret ud fra éthanol til dannelse af det rensede produkt, der udviste et smeltepunkt pâ 109-110°C.The aqueous layer was further extracted twice with each 20 ml of chloroform. The chloroform layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo and the residue was purified by column chromatography using chloroform-methanol as the developing liquid to give 2.0 g of 5- (2-guanidinothiazol-4-yl) pentanoic acid ethyl ester. This product was recrystallized from ethanol to give the purified product, which had a melting point of 109-110 ° C.

EKSEMPEL 44EXAMPLE 44

^NOH^ NOH

h2nxc=n /γ(<:#2)ΑΚΗ2 b2n/ \sJJh2nxc = n / γ (<: # 2) ΑΚΗ2 b2n / \ sJJ

0,13 g hydroxylamin, hydrochlorid og 0,117 g natriumhydroxid blev oplost i 5 ml methylalkohol. Efter tilsætning af 0,64 g 20 methyl-5-(2-guanidinothiazol-4-yl)pentanoimidat fik reaktionsblandingen lov at henstâ ved stuetemperatur i 3 dage. Oplesningsmidlet i reaktionsblandingen blev afdestilleret, og inddampningsresten blev krystalliseret ved tilsætning af ethylalkohol og vand. De sâledes opnâede krystaller blev 25 oplost i 0,4 ml eddikesyre, 4 ml ethylalkohol og 8 ml vand, og de blev behândlet med aktivkul. Til. filtratet derfra blev tilsat 6,6 ml ln natriumhydroxid, og de udfældede krystal-0.13 g of hydroxylamine, hydrochloride and 0.117 g of sodium hydroxide were dissolved in 5 ml of methyl alcohol. After the addition of 0.64 g of 20 methyl-5- (2-guanidinothiazol-4-yl) pentanoimidate, the reaction mixture was allowed to stand at room temperature for 3 days. The solvent in the reaction mixture was distilled off and the residue was crystallized by the addition of ethyl alcohol and water. The crystals thus obtained were dissolved in 0.4 ml of acetic acid, 4 ml of ethyl alcohol and 8 ml of water and treated with activated charcoal. To. the filtrate therefrom was added 6.6 ml of sodium hydroxide and the precipitated crystal

„ DK 157132 B"DK 157132 B

57 1er blev opsamlet ved filtrering til dannelse af 0,24 g 5-(2-guanidillO'thiazol-4-yl)pemtanoainidoxid, der udviste et smeltepunkt pâ l67-l68°C.57 ls were collected by filtration to give 0.24 g of 5- (2-guanidyl) -thiazol-4-yl) pemtanoamide oxide, exhibiting a melting point of 167-168 ° C.

Elementær analyse for C^H^^NgOSElemental analysis for C

c H Nc H N

Beregnet 42 j17 6^.29 32,79Calculated 42 J17 6 ^ .29 32.79

Fundet 42,24 6,39 32,47Found 42.24 6.39 32.47

Claims (7)

1. Analogifremgangsmâde til fremstilling af guanidino-5 thiazolforbindelser med den almene formel } -y_(cho) -a /C=N~X lj 2 m 2 n (l) 'ψ' XS> K J 10 hvori R betyder et hydrogenatom eller en alkylgruppe med 1-5 carbonatomer, Y betyder et svovlatom eller en methy-lengruppe, m og n betyder hver et helt tal 1-3, A betyder en gruppe med formlen 15 - ^N_R1 eller -CONH-R4 hvori igen R^ betyder et hydrogenatom, en cyangruppe, en carbamoylgruppe, en ureidogruppe, en hydroxylgruppe, en alkoxygruppe med 1-5 carbonatomer, en alkanoylgruppe med 20 1-5 carbonatomer, en sulfamoylgruppe, en phenylalkyl- eller naphthylalkylgruppe med 1-5 carbonatomer i alkyl-delen, en carboxymethylgruppe eller en gruppe med formlen -SO2-R3, hvori R3 betyder en alkylgruppe med 1-5 carbonatomer, en halogenor-alkylgruppe med 1-5 carbonato-25 mer, en usubstitueret eller substitueret phenyl- eller naphthylgruppe, en aminogruppe, en mono- eller di-alkyl-aminogruppe med 1-5 carbonatomer, en phenyl- eller naph-thylaminogruppe eller en phenylalkyl- eller naphthylal-kylaminogruppe med 1-6 carbonatomer i alkyldelen, og R2 30 betyder et hydrogenatom, en alkylgruppe med 1-5 carbonatomer, en alkenylgruppe med 1-5 carbonatomer, en alky-nylgruppe med 1-5 carbonatomer, en cyanogruppe eller en gruppe med 1-5 carbonatomer, og R4 betyder et hydrogenatom, en alkylgruppe med 1-5 carbonatomer, en hydroxyl-35 gruppe eller en sulfamoylgruppe, samt syreadditionssalte af sâdanne forbindelser, kendetegnet ved, at DK 157132 B man omsætter en forbindelse med formlen R-NHv ,N^(CH ) -Y-(CH_) -C^ 2™ 2n N H2N/ ''s-— 5 hvori R' betyder en alkylgruppe med 1-5 carbonatomer, X betyder et oxygenatom, N-R^ eller N-R2, og hvori R, R^, R2, Y, m og n har den i kravets indledende del anf0rte betydning, med en amin med formlen R5-NH2 , hvor R5 har en af de for grupperne Ri, R2 eller R4 oven for angivne 10 betydninger, hvorefter reaktionsproduktet om 0nsket overf0res i et tilsvarende syreadditionssalt.An analogous process for the preparation of guanidino-thiazole compounds of the general formula} -y_ (cho) -a / C = N ~ X lj 2 m 2 n (l) 'ψ' XS> KJ 10 wherein R is a hydrogen atom or a alkyl group having 1-5 carbon atoms, Y means a sulfur atom or a methylene group, m and n each represent an integer of 1-3, A means a group of the formula 15 - ^ N_R1 or -CONH-R4 wherein again R a hydrogen atom, a cyano group, a carbamoyl group, an ureido group, a hydroxyl group, an alkoxy group of 1-5 carbon atoms, an alkanoyl group of 1-5 carbon atoms, a sulfamoyl group, a phenylalkyl or naphthylalkyl group of 1-5 carbon atoms in the alkyl moiety, a carboxymethyl group or a group of the formula -SO 2 -R 3 wherein R 3 represents an alkyl group of 1 to 5 carbon atoms, a halo-alkyl group of 1 to 5 carbon atoms, an unsubstituted or substituted phenyl or naphthyl group, or di-alkyl amino group having 1 to 5 carbon atoms, a phenyl or naphthylamine and a group or a phenylalkyl or naphthylalkylamino group of 1-6 carbon atoms in the alkyl moiety, and R2 represents a hydrogen atom, an alkyl group of 1-5 carbon atoms, an alkenyl group of 1-5 carbon atoms, an alkynyl group of 1-5 carbon atoms, a cyano group or a group having 1-5 carbon atoms, and R4 means a hydrogen atom, an alkyl group having 1-5 carbon atoms, a hydroxyl group or a sulfamoyl group, as well as acid addition salts of such compounds, characterized in that DK 157132 B compound of the formula R-NHv, N 1 (CH) -Y- (CH 2) -C 2 2N 2 H 2 N / N 5 - wherein R 1 represents an alkyl group of 1 to 5 carbon atoms, X represents an oxygen atom, NR 1 or N-R 2 and wherein R, R 2, R 2, Y, m and n are as defined in the preamble of the claim, with an amine of formula R 5 -NH 2, wherein R 5 is one of the groups R 1, R 2 or R 4 above 10 meanings, after which the desired reaction product is transferred into a corresponding acid addition salt. 2. Fremgangsmàde if0lge krav 1, kendetegnet ved, at man omsætter en forbindelse med formlenMethod according to claim 1, characterized in that a compound of the formula is reacted 15. R R-NHv ïï^pr-(CIL·) -Y-(CH ) -C^~“l | 2 m · 2 " 'Nt-R' K// - \-> ... hvori R, R', R]_, Y, m og n har den i krav 1 anf0rte be- 20 tydning, med en amin med formlen R2-NH2, hvori R2 har den i krav 1 anf0rte betydning.15. R R -NHv-pr- (CIL ·) -Y- (CH) -C ^ ~ “l | 2 m · 2 "'Nt-R' K // - \ -> ... wherein R, R ', R], Y, m and n are as defined in claim 1, with an amine having the formula R2-NH2 wherein R2 is as defined in claim 1. 3. Fremgangsmàde if0lge krav lr kendetegnet ved, at man omsætter en forbindelse med formlen 25 R-NHv (CH2) -Y-(eH ) -C^N~R2 ¥/cnJ 2n 2n hvori R, R', R^, Y, m og n har den i krav 1 anf0rte be- 30 tydning, med en amin med formlen R1-NH2, hvori R^ har den i krav 1 anf0rte betydning.Process according to claim 1, characterized in that a compound of the formula 25 R-NHv (CH2) -Y- (eH) -C ^ N ~ R2 ¥ / cnJ 2n 2n wherein R, R ', R ^, Y is reacted , m and n are as defined in claim 1, with an amine of formula R 1 -NH 2 wherein R 1 is as defined in claim 1. 4. Fremgangsmàde if0lge krav 1, kendetegnet ved, at man omsætter en forbindelse med formlen 35 DK 157132 B R-N1U ( CH ) -Y- (CH ) -C ^ ° V>-<T hvori R, R1, Y, m og n har den i krav 1 anf0rte betyd-5 ning, med en amin med formlen R4—NH2, hvori R4 har den i krav 1 anf0rte betydning.Process according to claim 1, characterized in that a compound of formula 35 is reacted. R-N1U (CH) -Y- (CH) -CC ° V> - <T wherein R, R1, Y, m and n is as defined in claim 1, with an amine of formula R4-NH2, wherein R4 is as defined in claim 1. 5. Fremgangsmâde if0lge krav 1, kendetegnet ved, at den omtalte omsætning udf0res i et organisk op- 10 l0sningsmiddel, som ikke indeholder vand.Process according to claim 1, characterized in that said reaction is carried out in an organic solvent which does not contain water. 6. Fremgangsmâde if0lge krav 1, kendetegnet ved, at den omtalte omsætning udf0res ved stuetemperatur eller under opvarmning. 15Process according to claim 1, characterized in that the said reaction is carried out at room temperature or under heating. 15 7. Fremgangsmâde if0lge krav lf kendetegnet ved, at den omtalte omsætning udf0res under neutrale eller basiske reaktionsbetingelser. 20 25 30 35Process according to Claim 1f, characterized in that the said reaction is carried out under neutral or basic reaction conditions. 20 25 30 35