NO157502B - ANALOGUE PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE TETRAZOLD DERIVATIVES. - Google Patents

ANALOGUE PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE TETRAZOLD DERIVATIVES. Download PDF

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NO157502B
NO157502B NO810637A NO810637A NO157502B NO 157502 B NO157502 B NO 157502B NO 810637 A NO810637 A NO 810637A NO 810637 A NO810637 A NO 810637A NO 157502 B NO157502 B NO 157502B
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methyl
tetrazol
thio
butyramide
ethyl
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NO810637A
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NO810637L (en
NO157502C (en
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Minoru Uchida
Takao Nishi
Kazuyuki Nakagawa
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Otsuka Pharma Co Ltd
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Description

Foreliggende oppfinnelse angår fremstilling av nye tetrazolderivater med farmakologisk virkning mot peptisk sår og tolvfingertarmsår. The present invention relates to the production of new tetrazole derivatives with pharmacological action against peptic ulcer and duodenal ulcer.

Forbindelsene fremstilt ifølge oppfinnelsen er tetrazolderivater av formel The compounds produced according to the invention are tetrazole derivatives of formula

hvori R<1> er hydrogen, C1_4 alkyl, cyclohexyl som eventuelt er substituert med C^_4 alkoxy, eller fenyl som eventuelt er substituert med C1-4 alkyl, wherein R<1> is hydrogen, C1-4 alkyl, cyclohexyl which is optionally substituted with C1-4 alkoxy, or phenyl which is optionally substituted with C1-4 alkyl,

A er svovel eller C^_4 alkylthio A is sulfur or C1-4 alkylthio

ler 0 eller 1, laughs 0 or 1,

B er C,_. alkylen, B is C,_. alkylene,

2 2

R er C^_4 alkoxy eller en gruppe R is C 1-4 alkoxy or a group

3 hvori R 3 in which R

og R 4er like eller forskjellige og er hver hydrogen; C^.g alkyl; C^.^ cycloalkyl som eventuelt er substituert med en gruppe valgt blant hydroxy, C^_4 alkanoyloxy, C^_4 alkoxy, and R 4 are the same or different and are each hydrogen; C 1-6 alkyl; C 1-4 cycloalkyl which is optionally substituted with a group selected from hydroxy, C 1-4 alkanoyloxy, C 1-4 alkoxy,

C-^_4 alkyl og N,N-di(C^_4 alkyl) amino; fenyl som eventuelt er substituert med én eller to substituenter valgt blant amino-sulfonyl, N,N-di(C^_4 alkyl)amino, C^_4 alkyl, halogen, C^_4 alkoxy og nitro; cyclohexyl-(C^_4)-alkyl, fenyl-(C^_4)-alkyl hvori fenylringen eventuelt er substituert med C-^_4 alkoxy; hydroxy-(C,-alkyl; pyridyl; 2-furylmethyl; eller 2-thienyl-3 4 C 1-4 alkyl and N,N-di(C 1-4 alkyl)amino; phenyl which is optionally substituted with one or two substituents selected from amino-sulfonyl, N,N-di(C 1-4 alkyl)amino, C 1-4 alkyl, halogen, C 1-4 alkoxy and nitro; cyclohexyl-(C 1-4 )-alkyl, phenyl-(C 1-4 )-alkyl in which the phenyl ring is optionally substituted with C 1-4 alkoxy; hydroxy-(C 1 -alkyl; pyridyl; 2-furylmethyl; or 2-thienyl-3 4

methyl; eller R og R kan sammen med nitrogenatomet som de er bundet til, danne en heterocyklisk gruppe valgt blant morfolino, piperidino og piperazino som eventuelt er substituert med C1-4 alkyl eller C^_4 alkanoyl, methyl; or R and R can, together with the nitrogen atom to which they are attached, form a heterocyclic group selected from morpholino, piperidino and piperazino which is optionally substituted with C1-4 alkyl or C4-4 alkanoyl,

forutsatt at presumed that

a) nårier 0 og R<1> er hydrogen eller alkyl med 1 til 4 carbonatomer, er R forskjellig fra alkoxy, og NR<3>r<4> er forskjellig fra amino; a) when 0 and R<1> is hydrogen or alkyl of 1 to 4 carbon atoms, R is different from alkoxy, and NR<3>r<4> is different from amino;

b) nårier 0 eller R<1> er n-butyl, er B ikke methylen og NR<3>R<4>b) when 0 or R<1> is n-butyl, B is not methylene and NR<3>R<4>

er ikke ethylamino; c) når i-er 0 og R 1 er fenyl og B er methylen, er R 2 forskjellig fra ethoxy, og NR 3 R 4 er forskjellig fra amino, is not ethylamino; c) when i is 0 and R 1 is phenyl and B is methylene, R 2 is different from ethoxy, and NR 3 R 4 is different from amino,

methylamino og benzylamino; methylamino and benzylamino;

d) nårier 0 og R 1 er fenyl og B er ethylmethylen, er R 2 ikke d) when 0 and R 1 are phenyl and B is ethylmethylene, R 2 is not

3 4 3 4

ethoxy, og NR R er ikke amino; ethoxy, and NR R is not amino;

e) når i er 0 og R<1> er cyclohexyl og B er ethylen eller methyl-3 4 e) when i is 0 and R<1> is cyclohexyl and B is ethylene or methyl-3 4

methylen, er NR R ikke amxno; og methylene, NR R is not amxno; and

f) nårier 0 og R<1> er cyclohexyl og B er dimethylmethylen, er f) when 0 and R<1> is cyclohexyl and B is dimethylmethylene, is

3 4 3 4

NR R forskjellig fra amino, diethylamino, benzylamino og NR R different from amino, diethylamino, benzylamino and

morfolino, morpholino,

og farmasøytisk akseptable salter derav. and pharmaceutically acceptable salts thereof.

Fra US patentskrift nr. 3 743 646 er det kjent 2H-tetrazolderivater med anti-inflammatoriske egenskaper som an-gis å gi mindre, mageirritasjon enn tilsvarende syrer. Sammen-ligningsforsøkene nedenunder viser imidlertid at disse forbindelsene ikke har like god virkning mot magesår som forbindelsene fremstilt ifølge oppfinnelsen. From US patent no. 3 743 646, 2H-tetrazole derivatives with anti-inflammatory properties are known which are stated to cause less stomach irritation than corresponding acids. The comparison tests below show, however, that these compounds do not have as good an effect against stomach ulcers as the compounds produced according to the invention.

Forbindelsene fremstilt ifølge oppfinnselsen har profylaktisk eller terapeutisk aktivitet overfor peptisk og/ eller tolvfingertarmsår, i særdeleshet stressår og indomethacLn-fremkalt sår med lite bivirkninger slik som sentralnerve-systemaktivitet, anti-cholinerg aktivitet og mavetømmende aktivitet, og er anvendbare som legemiddel for behandling av slike sår. The compounds produced according to the invention have prophylactic or therapeutic activity against peptic and/or duodenal ulcers, in particular stress ulcers and indomethacLn-induced ulcers with little side effects such as central nervous system activity, anti-cholinergic activity and gastric emptying activity, and are applicable as a drug for the treatment of such wound.

Fremstillingen av forbindelsene er kjennetegnet ved at The production of the compounds is characterized by that

a) en carboxylsyreforbindelse av formel a) a carboxylic acid compound of formula

hvori R"<1>", A, -£og B er som ovenfor definert, eller et reaktivt derivat derav, omsettes med et amin av formel: in which R"<1>", A, -£ and B are as defined above, or a reactive derivative thereof, is reacted with an amine of formula:

hvori R 3 og R 4 er som ovenfor definert, eller et reaktivt derivat derav, in which R 3 and R 4 are as defined above, or a reactive derivative thereof,

b) et 5- mercaptotetrazolderivat av formel b) a 5-mercaptotetrazole derivative of formula

hvori R og A er som ovenfor definert og - t' er 1, omsettes in which R and A are as defined above and - t' is 1, is converted

med et haloalkancarboxylsyrederivat av formel: with a haloalkanecarboxylic acid derivative of formula:

hvori X er et halogen og B og R 2 er som ovenfor definert, wherein X is a halogen and B and R 2 are as defined above,

c) et carboxylsyreamid av formel: c) a carboxylic acid amide of formula:

R<5>OOC-B-CONHR<1> (VIII) R<5>OOC-B-CONHR<1> (VIII)

hvori B og R<1> er som ovenfor definert og R<5> er alkyl med 1-6 carbonatomer, omsettes med fosforpentaklorid og deretter med hydrogenazid, eller in which B and R<1> are as defined above and R<5> is alkyl with 1-6 carbon atoms, reacted with phosphorus pentachloride and then with hydrogen azide, or

d) en tetrazolforbindelse av formel: d) a tetrazole compound of formula:

hvori R er som ovenfor definert, D er alkylen med 1-6 carbonatomer og X er et halogen, omsettes med en mercaptoforbindelse med formel: in which R is as defined above, D is the alkylene with 1-6 carbon atoms and X is a halogen, is reacted with a mercapto compound of formula:

hvori B og R er som ovenfor definert, in which B and R are as above defined,

hvoretter, om ønsket, et erholdt tetrazolderivat av formel after which, if desired, an obtained tetrazole derivative of formula

hvori R<1>, A, i/og B er som ovenfor definert, underkastes forestring, og/eller et erholdt tetrazolderivat av formel: in which R<1>, A, i/and B are as defined above, subjected to esterification, and/or an obtained tetrazole derivative of formula:

hvori r\ A, og B er som ovenfor definert, og R^ er alkyl med 1 til 6 carbonatomer, underkastes hydrolyse, og/eller et erholdt tetrazolderivat omdannes til et farmasøytisk akseptabelt salt derav. wherein r\ A, and B are as defined above, and R^ is alkyl with 1 to 6 carbon atoms, is subjected to hydrolysis, and/or a tetrazole derivative obtained is converted into a pharmaceutically acceptable salt thereof.

Forbindelser (Ia) som er forbindelser av formel (I) 2 Compounds (Ia) which are compounds of formula (I) 2

hvori R er gruppen wherein R is the group

fremstilles ved en fremgangsmåte som vist i etter- produced by a method as shown in the following

følgende reaksjonsskjema I: the following reaction scheme I:

Reaksjonsskjerna I Reaction nucleus I

hvori R<1>, R<3>, R<4>, A, B og 1 er som ovenfor angitt. wherein R<1>, R<3>, R<4>, A, B and 1 are as indicated above.

Fremgangsmåten som vist i Reaksjonsskjerna I utføres ved å underkaste en carboxylsyre (II) og et amin (III) i en amido-bindings-dannende reaksjon. The method shown in Reaction Core I is carried out by subjecting a carboxylic acid (II) and an amine (III) to an amido bond-forming reaction.

I den ovenfor angitte fremgangsmåte kan en forbindelse med en aktivert carboxylgruppe anvendes i stedet for carboxylsyren (II) og en forbindelse med en aktivert amino-gruppe i stedet for aminet (III). Den amidobindings-dannende reaksjon innbefatter en hvilken som helst konven-sjonell prosess slik som (i) et blandet syreanhydrid-metoden, dvs. en prosess omfattende omsetning av carboxylsyren (II) In the above-mentioned method, a compound with an activated carboxyl group can be used instead of the carboxylic acid (II) and a compound with an activated amino group instead of the amine (III). The amido bond-forming reaction includes any conventional process such as (i) a mixed acid anhydride method, i.e. a process involving reaction of the carboxylic acid (II)

med et alkylhalocarboxylat under dannelse av et blandet syreanhydrid, og omsetning av det blandede syreanhydrid med aminet (III); (ii) en aktivert estermetode, dvs. en fremgangsmåte omfattende omdannelse av carboxylsyren (II) til en aktiv ester, for eksempel p-nitrofenylester, N-hydroxy-succinimidester eller N-hydroxybenzoetriazolester, og omsetning av den aktive ester med aminet (III); (iii) carbodi-imidmetoden, dvs. en fremgangsmåte omfattende kondensering av carboxylsyren (II) med aminet (III) i nærvær av et dehy-dratiseringsmiddel slik som dicyclohexylcarbodiimid eller carbonyldiimidazol; (iv) carboxylsyrehalogenidmetoden, dvs. en prosess omfattende omsetning av en halogenidforbindelse av carboxylsyren (II) med aminet (III); (v) en prosess omfattende omdannelse av carboxylsyren (II) til en syreanhydrid-forbindelse derav, ved anvendelse av et dehydratiserings-middel slik som eddiksyreanhydrid, og deretter omsetning av det resulterende syreanhydrid med aninet(III); og (vi) en prosess omfattende omdannelse av carboxylsyren (II) til en ester med en lavere alkohol, og derettet omsetning av den resulterende ester med aminet (III) under et høyt trykk og ved en høy temperatur. Blant disse prosesser er den blandede syreanhydridmetode og carboxylsyrehalogenidmetoden foretrukket. Det alkylhalocarboxylat som anvendes i den blandede syreanhydridmetode innbefatter eksempelvis methylklorformiat, methylbromformiat, ethylklorformiat, ethylbromformiat, isobutylklorformiat, og lignende. Det blandede syreanhydrid with an alkylhalocarboxylate to form a mixed acid anhydride, and reacting the mixed acid anhydride with the amine (III); (ii) an activated ester method, i.e. a method comprising converting the carboxylic acid (II) into an active ester, for example p-nitrophenyl ester, N-hydroxy-succinimide ester or N-hydroxybenzoetriazole ester, and reacting the active ester with the amine (III) ; (iii) the carbodiimide method, i.e. a method comprising condensation of the carboxylic acid (II) with the amine (III) in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole; (iv) the carboxylic acid halide method, i.e. a process comprising reacting a halide compound of the carboxylic acid (II) with the amine (III); (v) a process comprising converting the carboxylic acid (II) into an acid anhydride compound thereof, using a dehydrating agent such as acetic anhydride, and then reacting the resulting acid anhydride with the anine (III); and (vi) a process comprising converting the carboxylic acid (II) into an ester with a lower alcohol, and thereby reacting the resulting ester with the amine (III) under a high pressure and at a high temperature. Among these processes, the mixed acid anhydride method and the carboxylic acid halide method are preferred. The alkyl halocarboxylate used in the mixed acid anhydride method includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. The mixed acid anhydride

kan fremstilles ved den velkjente Schotten-Baumann-reaksjon, og kan anvendes for den etterfølgende reaksjon med aminet (III) uten isolering fra reaksjonsblandingen. Schotten-Baumann-reaks jonen kan utføres i nærvær av en basisk forbindelse. Den basiske forbindelse innbefatter alle forbindelser som vanligvis anvendes i Schotten-Baumann-reaksjonen, for eksempel organiske baser slik som triethylamin, trimethylamin, pyridin, dimethylanilin, N-methylmorfolin, 1,5-diazabicyclo-[4.3.0]nonen-5 (DBN), 1,5-diazabicyclo[5.4.0]undecen-5 (DBU), 1,4-diazabicyclo[2.2.2]octan (DABCO) eller lignende, og uorganiske baser slik som kaliumcarbonat, natriumcarbonat, kaliumhydrogencarbonat, natriumhydrogencarbonat eller lignende. Reaksjonen utføres vanligvis ved en temperatur på fra -20 til 100° C, fortrinnsvis fra 10 til 50° C, i fra 5 minutter til 10 timer. can be prepared by the well-known Schotten-Baumann reaction, and can be used for the subsequent reaction with the amine (III) without isolation from the reaction mixture. The Schotten-Baumann reaction can be carried out in the presence of a basic compound. The basic compound includes all compounds commonly used in the Schotten-Baumann reaction, for example organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo-[4.3.0]nonen-5 (DBN ), 1,5-diazabicyclo[5.4.0]undecene-5 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) or the like, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate or the like . The reaction is usually carried out at a temperature of from -20 to 100°C, preferably from 10 to 50°C, for from 5 minutes to 10 hours.

Den blandede syreanhydridmetode utføres vanligvis The mixed acid anhydride method is usually carried out

i et egnet løsningsmiddel. Løsningsmidlet innbefatter alle løsningsmidler som er kjent anvendt i denne metode, for eksempel halogenerte hydrocarboner slik som methylenklorid, kloroform eller diklorethan, aromatiske hydrocarboner slik som benzen, toluen eller xylen, ethere slik som diethylether, tetrahydrofuran eller dimethoxyethan, estere slik som methylacetat eller ethylacetat, aprotiske polare løsningsmidler slik som dimethylformamid, dimethylsulfoxyd eller hexamethylfosforsyretriamid, og lignende. Carboxylsyren (II), alkylhalocarboxylatet og aminet (III) anvendes vanligvis i en slik mengde at alkylhalocarboxylatet og aminet (III) hver er minst ekvimolar med carboxylsyren (II), fortrinnsvis 1 - 1,5 mol til 1 mol carboxylsyre (II). in a suitable solvent. The solvent includes all solvents known to be used in this method, for example halogenated hydrocarbons such as methylene chloride, chloroform or dichloroethane, aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as diethylether, tetrahydrofuran or dimethoxyethane, esters such as methyl acetate or ethyl acetate, aprotic polar solvents such as dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide, and the like. The carboxylic acid (II), the alkyl halocarboxylate and the amine (III) are usually used in such an amount that the alkyl halocarboxylate and the amine (III) are each at least equimolar with the carboxylic acid (II), preferably 1 - 1.5 mol to 1 mol carboxylic acid (II).

Carboxylsyrehalogenidmetoden utføres ved å omsette carboxylsyren (II) med et halogeneringsmiddel under dannelse av en halogenidforbindelse av carboxylsyren (II), og deretter omsetning av det resulterende carboxylsyrehalogenid med aminet (III) etter isolering og rensing av halogenidet fra reaksjonsblandingen eller uten isolasjon. The carboxylic acid halide method is carried out by reacting the carboxylic acid (II) with a halogenating agent to form a halide compound of the carboxylic acid (II), and then reacting the resulting carboxylic acid halide with the amine (III) after isolation and purification of the halide from the reaction mixture or without isolation.

Reaksjonen mellom carboxylsyren (II) og halogeneringsmidlet utføres i nærvær eller fravær av et løsningsmiddel. Løsningsmidlet innbefatter alle løsningsmidler som ikke gir uønsket effekt på reaksjonen, for eksempel aromatiske hydrocarboner slik som benzen, toluen eller xylen, halogenerte hydrocarboner slik som kloroform, methylenklorid eller carbontetraklorid, ethere slik som dioxan, tetrahydrofuran eller diethylether, aprotiske polare løsningsmidler slik som dimethylformamid eller dimethylsulfoxyd og lignende. Halogeneringsmidlet innbefatter et hvilket som helst konvensjonelt halogeneringsmiddel som kan omdanne hydroxygruppen i carboxylgruppen til halogen, for eksempel thionylklorid, fosforoxyklorid, fosforoxybromid, fosforpentaklorid, fosforpentabromid eller lignendeø The reaction between the carboxylic acid (II) and the halogenating agent is carried out in the presence or absence of a solvent. The solvent includes all solvents that do not have an undesirable effect on the reaction, for example aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride, ethers such as dioxane, tetrahydrofuran or diethyl ether, aprotic polar solvents such as dimethylformamide or dimethylsulfoxide and the like. The halogenating agent includes any conventional halogenating agent that can convert the hydroxy group in the carboxyl group to halogen, for example thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide or the like

Forholdet mellom mengden av carboxylsyren (II) og halogeneringsmidlet er ikke kritisk, men når reaksjonen utføres i fravær av et løsningsmiddel, anvendes den sistnevnte dvs. syren (II) i et stort overskudd, og når reaksjonen utføres i nærvær av løsningsmiddel, anvendes den sistnevnte i en mengde ekvivalent eller mer med den første, fortrinnsvis 2 til 4 mol til 1 mol av den førstnevnte. Reaksjonstemperaturen og reaksjonstiden er ikke kritisk, men reaksjonen utføres vanligvis ved en temperatur på fra romtemperatur til 100° C, fortrinnsvis 50 - 80° C, i fra 30 minutter til 6 timer. The ratio between the amount of the carboxylic acid (II) and the halogenating agent is not critical, but when the reaction is carried out in the absence of a solvent, the latter i.e. the acid (II) is used in a large excess, and when the reaction is carried out in the presence of a solvent, the latter is used in an amount equivalent or more to the first, preferably 2 to 4 moles to 1 mole of the former. The reaction temperature and reaction time are not critical, but the reaction is usually carried out at a temperature of from room temperature to 100° C, preferably 50 - 80° C, for from 30 minutes to 6 hours.

Reaksjonen mellom carboxylsyrehalogenidet og aminet (III) utføres vanligvis i nærvær av et dehydrohalogeneringsmiddel. Dehydrohalogeneringsmidlet er vanligvis basiske forbindelser. De basiske forbindelser som anvendes som dehydrohalogeneringsmiddel innbefatter alle konvensjonelle forbindelser, for eksempel uorganiske baser slik som natriumhydroxyd, kaliumhydroxyd, natriumcarbonat, kaliumcarbonat, natriumhydrogencarbonat, kaliumhydrogencarbonat eller sølv-carbonat, alkalimetaller slik.som natrium eller kalium, alkoholater slik som natriummethylat eller natriumethylat, organiske baser slik som triethylamin, pyridin, N,N-dimethyl-aminopyridin, 1,5-diazabicyclo[4.3.0]nonen-5 (DBN), 1,5-azabicyclo[5.4.0]undecen-5 (DBU) eller 1,4-diazabicyclo[2.2.2]-octan (DABCO)] eller lignende. Aminet (III) kan anvendes i et stort overskudd til stede for å anvende dehydrohalogeneringsmidlet. Reaksjonen kan utføres i nærvær eller fravær av et løsningsmiddel. Løsningsmidlet innbefatter ethvert inert løsningsmiddel som ikke gir uønsked effekt på reaksjonen, for eksempel halogenerte hydrocarboner slik som kloroform, methylenklorid eller carbontetraklorid, ethere slik som diethylether, tetrahydrofuran eller dioxan, aromatiske hydrocarboner slik som benzen, toluen eller xylen, estere slik som methylacetat eller ethylacetat, aprotiske polare løsningsmidler slik som N,N-dimethylformamid, dimethylsulfoxyd eller hexamethylfosforsyretriamid og lignende. The reaction between the carboxylic acid halide and the amine (III) is usually carried out in the presence of a dehydrohalogenating agent. The dehydrohalogenating agent is usually basic compounds. The basic compounds used as dehydrohalogenating agents include all conventional compounds, for example inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or silver carbonate, alkali metals such as sodium or potassium, alcoholates such as sodium methylate or sodium ethylate, organic bases such as triethylamine, pyridine, N,N-dimethyl-aminopyridine, 1,5-diazabicyclo[4.3.0]nonen-5 (DBN), 1,5-azabicyclo[5.4.0]undecene-5 (DBU) or 1 ,4-diazabicyclo[2.2.2]-octane (DABCO)] or the like. The amine (III) can be used in a large excess present to use the dehydrohalogenating agent. The reaction can be carried out in the presence or absence of a solvent. The solvent includes any inert solvent that does not adversely affect the reaction, for example halogenated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran or dioxane, aromatic hydrocarbons such as benzene, toluene or xylene, esters such as methyl acetate or ethyl acetate , aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxyd or hexamethylphosphoric acid triamide and the like.

Forholdet mellom mengden av carboxylsyrehalogenid og aminet (III) er ikke kritisk, men når reaksjonen utføres i fravær av et løsningsmiddel, anvendes den sistnevnte, dvs. aminet (III) i en stor overskuddsmengde, og når reaksjonen utføres i nærvær av et løsningsmiddel, anvendes det sistnevnte vanligvis i en mengde ekvivalent eller mer av den førstnevnte, fortrinnsvis 1 til 2 mol til 1 mol av den førstnevnte. Reaksjonstemperaturen og reaksjonstiden er ikke kritisk, men reaksjonen utføres vanligvis ved en temperatur på fra -30 til 100° C, fortrinnsvis 0 - 50° C, i fra 30 minutter til 12 timer. The ratio between the amount of carboxylic acid halide and the amine (III) is not critical, but when the reaction is carried out in the absence of a solvent, the latter, i.e. the amine (III) is used in a large excess, and when the reaction is carried out in the presence of a solvent, the latter usually in an amount equivalent or more of the former, preferably 1 to 2 moles to 1 mole of the former. The reaction temperature and reaction time are not critical, but the reaction is usually carried out at a temperature of from -30 to 100° C, preferably 0 to 50° C, for from 30 minutes to 12 hours.

Forbindelsene (Ib) som er forbindelsene av formel (I) hvori SL er 1, fremstilles ved en prosess som vist i det etterfølgende Reaksjonsskjerna II: The compounds (Ib), which are the compounds of formula (I) in which SL is 1, are produced by a process as shown in the following Reaction Core II:

Reaksjonsskjerna II Reaction nucleus II

hvori SL' er 1, X er halogen og R 1 , R 2 og A er som tidligere angitt. wherein SL' is 1, X is halogen and R 1 , R 2 and A are as previously indicated.

Dehydrohalogeneringsreaksjonen av et 5-mercaptotetrazolderivat (IV) og et haloalkancarboxylsyrederivat (V) The dehydrohalogenation reaction of a 5-mercaptotetrazole derivative (IV) and a haloalkanecarboxylic acid derivative (V)

i det ovenfor angitte Reaksjonsskjema II, utføres vanligvis i nærvær av samme dehydrohalogeneringsmiddel som anvendt i det ovenfor angitte Reaksjonsskjema I. Reaksjonen kan ut-føres i nærvær eller fravær av et løsningsmiddel. Løsnings-midlet innbefatter alle inerte løsningsmidler som ikke gir uønsket effekt på reaksjonen, for eksempel alkoholer slik som methanol, ethanol, propanol, butanol eller ethylenglycol, ethere slik som diethylether, tetrahydrofuran, dioxan, mono-glym eller diglym, ketoner slik som aceton eller methylethyl-keton, aromatiske hydrocarboner slik som benzen, toluen eller xylen, estere slik som methylacetat eller ethylacetat, aprotiske polare løsningsmidler slik som N,N-dimethylformamid, dimethylsulfoxyd eller hexamethylfosforsyretriamid og lignende. Envidere er det fordelaktig å utføre reaksjonen i nærvær av et metalljodid slik som natriumjodid eller kaliumjodid. in the above-mentioned Reaction Scheme II, is usually carried out in the presence of the same dehydrohalogenating agent as used in the above-mentioned Reaction Scheme I. The reaction can be carried out in the presence or absence of a solvent. The solvent includes all inert solvents that do not have an undesirable effect on the reaction, for example alcohols such as methanol, ethanol, propanol, butanol or ethylene glycol, ethers such as diethylether, tetrahydrofuran, dioxane, monoglyme or diglyme, ketones such as acetone or methylethyl ketone, aromatic hydrocarbons such as benzene, toluene or xylene, esters such as methyl acetate or ethyl acetate, aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide and the like. Furthermore, it is advantageous to carry out the reaction in the presence of a metal iodide such as sodium iodide or potassium iodide.

Forholdet mellom mengden av forbindelsen (IV) og forbindelsen (V) er ikke kritisk, men når reaksjonen utføres i fravær av et løsningsmiddel, anvendes den sistnevnte, dvs. forbindelsen (V) i en stor overskuddsmengde, og når reaksjonen utføres i nærvær av et løsningsmiddel, anvendes den sistnevnte i en mengde på 1 - 5 mol, fortrinnsvis 1-2 mol, til 1 mol av den førstnevnte. Reaksjonstemperaturen og reaksjonstiden er ikke kritiske, men reaksjonen utføres vanligvis ved en temperatur på fra -30 til 200° C, fortrinnsvis 0 - 160° C, i fra 1 til 3 0 timer. The ratio between the amount of the compound (IV) and the compound (V) is not critical, but when the reaction is carried out in the absence of a solvent, the latter, i.e. the compound (V) is used in a large excess amount, and when the reaction is carried out in the presence of a solvent, the latter is used in an amount of 1-5 mol, preferably 1-2 mol, to 1 mol of the former. The reaction temperature and reaction time are not critical, but the reaction is usually carried out at a temperature of from -30 to 200° C, preferably 0 to 160° C, for from 1 to 30 hours.

Forbindelser (Ic) som er forbindelser av formel (I) Compounds (Ic) which are compounds of formula (I)

2 2

hvori i er 0 og R er c^ 4 alkoxy, fremstilles ved en prosess som vist i etterfølgende Reaksjonsskjerna III: in which i is 0 and R is c 4 alkoxy, is produced by a process as shown in the following Reaction Core III:

Reaksjonsskj erna III hvori R"*" og B er som ovenfor definert, og R^ er C^_^ alkyl. Omsetningen av en carboxylsyre (VI) og et amin (VII) i det ovenfor angitte Reaksjonsskjema III kan fortrinnsvis utføres under de samme betingelser som vist ved den blandede syreanhydridmetode og carboxylsyrehalogenidmetode som angitt i det tidligere omtalte Reaksjonsskjema I. Reaction core III in which R"*" and B are as defined above, and R^ is C^_^ alkyl. The reaction of a carboxylic acid (VI) and an amine (VII) in the above-mentioned Reaction Scheme III can preferably be carried out under the same conditions as shown by the mixed acid anhydride method and carboxylic acid halide method as indicated in the previously mentioned Reaction Scheme I.

Omsetningen av et haloamid (VIII) med fosforpenta-klor: PCI5, utføres fortrinnsvis i et løsningsmiddel. Løs-ningsmidlet innbefatter alle inerte løsningsmidler som ikke gir uønsket effekt på reaksjonen, f.eks. aromatiske hydrocarboner slik som benzen, toluen eller xylen, halogenerte aromatiske hydrocarboner slik som klorbenzen eller bromben-zen, ethere slik som diethylether eller dioxan, alifatiske hydrocarboner slik som n-hexan eller n-heptan og lignende. Forholdet mellom mengden av haloamidet (VIII) og PCI5 er The reaction of a haloamide (VIII) with phosphorus pentachloro: PCI5 is preferably carried out in a solvent. The solvent includes all inert solvents that do not have an undesirable effect on the reaction, e.g. aromatic hydrocarbons such as benzene, toluene or xylene, halogenated aromatic hydrocarbons such as chlorobenzene or bromobenzene, ethers such as diethyl ether or dioxane, aliphatic hydrocarbons such as n-hexane or n-heptane and the like. The ratio between the amount of the haloamide (VIII) and PCI5 is

ikke kritisk, men vanligvis anvendes sistnevnte, dvs. PCl^not critical, but usually the latter is used, i.e. PCl^

i en mengde på 1 til 2 mol, fortrinnsvis 1 til 1,2 mol til 1 mol av den førstnevnte. Reaksjonstemperaturen og reaksjonstiden er ikke kritisk, men reaksjonen vil vanligvis utføres ved en temperatur på fra -20 til 50° C, fortrinnsvis 0 til 25° C i 30 minutter til 5 timer. in an amount of 1 to 2 mol, preferably 1 to 1.2 mol to 1 mol of the former. The reaction temperature and reaction time are not critical, but the reaction will usually be carried out at a temperature of from -20 to 50° C., preferably 0 to 25° C. for 30 minutes to 5 hours.

Ved den ovenfor angitte omsetning mellom haloamidet (VIII) og PCI5 dannes et haloiminderivat, og denne forbindelse omsettes deretter med hydrogenaiz: HNg uten isolering fra reaksjonsblandingen. Reaksjonen utføres vanligvis i et egnet løsningsmiddel slik som benzen, xylen, diethylether, n-hexan, eller lignende. Hydrogenazidet anvendes vanligvis i en mengde på 1 til 5 mol, fortrinnsvis 1 til 3 mol, til 1 mol av haloiminderivatet. Reaksjonen utføres vanligvis ved en temperatur på 0 til 150° C i 3 timer til 2 dager. In the above-mentioned reaction between the haloamide (VIII) and PCI5, a haloimine derivative is formed, and this compound is then reacted with hydrogenaiz: HNg without isolation from the reaction mixture. The reaction is usually carried out in a suitable solvent such as benzene, xylene, diethyl ether, n-hexane, or the like. The hydrogen azide is usually used in an amount of 1 to 5 mol, preferably 1 to 3 mol, to 1 mol of the haloimine derivative. The reaction is usually carried out at a temperature of 0 to 150°C for 3 hours to 2 days.

Forbindelser av formel (Id) som er forbindelser av formel (I) hvori A er . ci _ 4 alkylthio, fremstilles ved en fremgangsmåte som vist i etterfølgende Reaksjonsskjema IV: Compounds of formula (Id) which are compounds of formula (I) in which A is . ci _ 4 alkylthio, is prepared by a method as shown in the following Reaction scheme IV:

Reaksjonsskjema IV Reaction scheme IV

hvori X, R , R' og B er som ovenfor definert, og D er C^g alkylen. wherein X, R , R' and B are as defined above, and D is C 1-8 alkylene.

I Reaksjonsskjema IV, utføres omsetningen av en forbindelse (IX) og en forbindelse (VII) og omsetningen av en forbindelse (X) og PCI5, etterfulgt av en omsetning med NH-j under de samme reaksjonsbetingelser som ved omsetning av forbindelsen (VI) og forbindelsen (VII) og omsetning av forbindelsen (VIII) og PCI5 etterfulgt av omsetning med HN3 i det ovenfor angitte Reaksjonsskjema III. Omsetning av en forbindelse (XI) og en forbindelse (XII) utføres under samme reaksjonsbetingelser som ved omsetning av forbindelse (IV) og forbindelse (V) i det tidligere beskrevne Reaksjonsskjema II. In Reaction scheme IV, the reaction of a compound (IX) and a compound (VII) and the reaction of a compound (X) and PCI5, followed by a reaction with NH-j are carried out under the same reaction conditions as in the reaction of the compound (VI) and the compound (VII) and reaction of the compound (VIII) and PCI5 followed by reaction with HN3 in the above-mentioned Reaction Scheme III. Reaction of a compound (XI) and a compound (XII) is carried out under the same reaction conditions as in the reaction of compound (IV) and compound (V) in the previously described Reaction scheme II.

Ennvidere kan forbindelser av formel (le) som er forbindelser av formel (I) hvor R 2 er C, . alkoxy, og forbindelser (If) som er forbindelser av formel (I) hvori R 2 er hydroxy, omdannes resiprokt til hverandre ved å underkaste disse hydrolyse eller forestring, som vist i etterfølgende Furthermore, compounds of formula (Ie) which are compounds of formula (I) where R 2 is C, . alkoxy, and compounds (If) which are compounds of formula (I) in which R 2 is hydroxy, are reciprocally converted to each other by subjecting them to hydrolysis or esterification, as shown in the following

Reaksjonsskjema V Reaction form V

1 5 1 5

hvori A, SL, B, R er som ovenfor angitt og R er C1-6 alkyl. wherein A, SL, B, R are as above and R is C1-6 alkyl.

Hydrolyse av forbindelsen (le) kan utføres etter kjente metoder, for eksempel i nærvær av en basisk forbindelse slik som natriumhydroxyd, kaliumhydroxyd eller barium-hydroxyd, eller en mineralsyre slik som svovelsyre, saltsyre eller borsyre. Denne hydrolyse utføres fortrinnsvis i et egnet løsningsmiddel. Løsningsmidlet innbefatter alle konvensjonelle løsningsmidler som ikke gir uønsket virkning på reaksjonen, og egnede eksempler er vann og lavere alkoholer slik som methanol, ethanol, isopropanol eller lignende. Reaksjonstemperaturen og reaksjonstiden er ikke kritiske, Hydrolysis of the compound (le) can be carried out according to known methods, for example in the presence of a basic compound such as sodium hydroxide, potassium hydroxide or barium hydroxide, or a mineral acid such as sulfuric acid, hydrochloric acid or boric acid. This hydrolysis is preferably carried out in a suitable solvent. The solvent includes all conventional solvents which do not have an undesirable effect on the reaction, and suitable examples are water and lower alcohols such as methanol, ethanol, isopropanol or the like. The reaction temperature and reaction time are not critical,

men hydrolysen utføres vanligvis ved en temperatur på fra romtemperautr til 150° C, fortrinnsvis 50 til 110° C i fra 30 minutter til 10 timer. but the hydrolysis is usually carried out at a temperature of from room temperature to 150°C, preferably 50 to 110°C for from 30 minutes to 10 hours.

Forestring av forbindelsene (If) kan vanligvis utføres ved å omsette disse med en lavere alkohol i nærvær av en katalysator. Katalysatoren innbefatter alle katalysa-torer som vanligvis anvendes i konvensjonelle forestringer, for eksempel uorganiske syrer slik som hydrogenkloridgass, konsentrert svovelsyre, fosforsyre, polyfosforsyre, bortri-fluorid eller perklorsyre; organiske syrer slik som trifluor-eddiksyre, trifluormethansulfonsyre, nafthalensulfonsyre, p-toluensulfonsyre, benzensulfonsyre eller ethansulfonsyre; syreanhydrider slik som trifluormethansulfonsyreanhydrid; thionylklorid; acetori-dimethylacetal og lignende. Kation-bytterharpikser anvendes også som katalysator. Mengden av katalysator er ikke kritisk, men velges innen det område som vanligvis anvendes. Esterification of the compounds (If) can usually be carried out by reacting these with a lower alcohol in the presence of a catalyst. The catalyst includes all catalysts that are usually used in conventional esterifications, for example inorganic acids such as hydrogen chloride gas, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride or perchloric acid; organic acids such as trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalene sulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid or ethanesulfonic acid; acid anhydrides such as trifluoromethanesulfonic anhydride; thionyl chloride; acetori-dimethyl acetal and the like. Cation exchange resins are also used as catalysts. The amount of catalyst is not critical, but is chosen within the range that is usually used.

Forestringen kan utføres i nærvær eller fravær av et løsningsmiddel. Løsningsmidlet innbefatter alle løsnings-midler som normalt anvendes i konvensjonelle forestrings-reaksjoner, f.eks. aromatiske hydrocarboner slik som benzen, toluen eller xylen, halogenerte hydrocarboner slik som di-klormethan, diklorethan, kloroform eller carbontetraklorid, ethere slik som diethylether, tetrahydrofuran, dioxan eller ethylenglucol-monoethylether og lignende. Forholdet mellom mengden av forbindelsene (If) og den lavere alkohol er ikke kritisk, men når reaksjonen utføres i fravær av et løsnings-middel, anvendes fortrinnsvis den sistnevnte, dvs. den lavere alkohol i en stor overskuddsmengde, og når reaksjonen utføres i nærvær av et løsningsmiddel, anvendes den sistnevnte i en mengde på 1 til 5 mol, fortrinnsvis 1 til 2 mol, til 1 mol av førstnevnte. Det er også fordelaktig å utføre forestringen i nærvær av et tørkemiddel slik som vannfri kobbersulfat, vannfri calsiumsulfat eller fosforpentaklorid, med hvilket produsert vann taes ut fra reaksjonssystemet og utbyttet av det ønskede produkt økes. Reaksjonstemperaturen er ikke kritisk, men reaksjonen utføres vanligvis ved en temperatur på -20 til 200° C, fortrinnsvis fra 0 til 150° C. Videre kan reaksjonstiden variere med type av utgangsmateriale og andre reaksjonsbetingelser, men er vanligvis innen området 10 minutter til 20 timer. The esterification can be carried out in the presence or absence of a solvent. The solvent includes all solvents normally used in conventional esterification reactions, e.g. aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran, dioxane or ethylene glycol monoethyl ether and the like. The ratio between the amount of the compounds (If) and the lower alcohol is not critical, but when the reaction is carried out in the absence of a solvent, the latter is preferably used, i.e. the lower alcohol in a large excess amount, and when the reaction is carried out in the presence of a solvent, the latter is used in an amount of 1 to 5 mol, preferably 1 to 2 mol, to 1 mol of the former. It is also advantageous to carry out the esterification in the presence of a drying agent such as anhydrous copper sulphate, anhydrous calcium sulphate or phosphorus pentachloride, with which produced water is removed from the reaction system and the yield of the desired product is increased. The reaction temperature is not critical, but the reaction is usually carried out at a temperature of -20 to 200° C, preferably from 0 to 150° C. Furthermore, the reaction time may vary with the type of starting material and other reaction conditions, but is usually within the range of 10 minutes to 20 hours .

I forestringsreaksjonen kan forbindelsene (If) hvori carboxylgruppen er aktivert, for eksempel carboxylsyre-haiogenid eller carboxylsyreanhydrid anvendes. Når et carboxylsyrehalogenid anvendes, anvendes de samme reaksjonsbetingelser som ved carboxylsyrehalogenidmetoden i Reaksjonsskjema I. Når et carboxylsyreanhydrid anvendes, behandles forbindelsene (If) med et konvensjonelt dehydratiserings-middel, under dannelse av et carboxylsyreanhydrid, og det resulterende anhydrid omsettes deretter med en lavere alkohol på vanlig måte. In the esterification reaction, the compounds (If) in which the carboxyl group is activated, for example carboxylic acid halide or carboxylic acid anhydride, can be used. When a carboxylic acid halide is used, the same reaction conditions are used as in the carboxylic acid halide method in Reaction Scheme I. When a carboxylic acid anhydride is used, the compounds (If) are treated with a conventional dehydrating agent, forming a carboxylic acid anhydride, and the resulting anhydride is then reacted with a lower alcohol of usual way.

De utgangsforbindelser som anvendes i de ovenfor angitte Reaksjonsskjema I til V er delvis kjente. Eksempelvis kan forbindelsene (II) som anvendes i Reaksjonsskjema I fremstilles ved de fremgangsmåter som er vist i Reaksjonsskjema II, III, IV og V. Andre utgangsforbindelser (III) er delvis kjente og fremstilles ved de fremgangsmåter som er vist i det etterfølgende Reaksjonsskjema VI og VII. The starting compounds used in the above-mentioned Reaction Schemes I to V are partially known. For example, the compounds (II) used in Reaction Scheme I can be prepared by the methods shown in Reaction Schemes II, III, IV and V. Other starting compounds (III) are partially known and are prepared by the methods shown in the subsequent Reaction Scheme VI and VII.

Reaksjonsskjema VI Reaction scheme VI

Reaksjonsskjema VII Reaction form VII

3 4 3 4

ivori R og R er som tidligere angitt, og X er et halogen. ivori R and R are as previously indicated, and X is a halogen.

I de ovenfor angitte Reaksjonsskjema VI og VII ut-føres reaksjonen mellom et amin (XIII) og en halogenforbindelse (XIV) og reaksjonen mellom et amin (XV) og halogenforbindelse (XVI) under de samme reaksjonsbetingelser som anvendes ved iehydrohalogeneringsreaksjonen i Reaksjonsskjema II. In the above-mentioned Reaction Schemes VI and VII, the reaction between an amine (XIII) and a halogen compound (XIV) and the reaction between an amine (XV) and halogen compound (XVI) are carried out under the same reaction conditions as are used in the hydrohalogenation reaction in Reaction Scheme II.

Forbindelsene (IV) anvendt i Reaksjonsskjema II er tjente, og andre utgangsforbindelser (V) er delvis kjente. Eksempelvis fremstilles forbindelser (Va) som er The compounds (IV) used in Reaction Scheme II have been obtained, and other starting compounds (V) are partially known. For example, compounds (Va) are produced which are

forbindelser (V) hvori compounds (V) in which

/ed en fremgangsmåte som /ist i det etterfølgende Reaksjonsskjema VIII: Reaksjonsskjema VIII /ed a method as /ist in the following Reaction scheme VIII: Reaction scheme VIII

o 4 and 4

hvori X, B, R og R er som tidligere angitt. wherein X, B, R and R are as previously indicated.

Reaksjonen mellom en kjent halocarboxylsyre (XVII) og et amin (III) kan utføres under de samme reaksjonsbetingelser som ble anvendt i den amidobindings-dannende reaksjon i Reaksjonsskjema I. The reaction between a known halocarboxylic acid (XVII) and an amine (III) can be carried out under the same reaction conditions as were used in the amido bond-forming reaction in Reaction Scheme I.

Utgangsforbindelsene anvendt i Reaksjonsskjema III og VI er kjent. Utgangsforbindelsene anvendt i Reaksjonsskjema V kan fremstilles ved samme prosess som anvendt i Reaksjonsskjemaer II - IV. The starting compounds used in Reaction Schemes III and VI are known. The starting compounds used in Reaction Scheme V can be prepared by the same process as used in Reaction Schemes II - IV.

Forbindelsene (I) som har en syregruppe kan omdannes til et salt med en farmasøytisk akseptabel basisk forbindelse. Den basiske forbindelse innbefatter metallhydroxyder slik som natriumhydroxyd eller kaliumhydroxyd, alkalimetallalkoholater slik som natriummethylat eller kaliumethylat og lignende. Forbindelsene (I) som har en basisk gruppe kan også omdannes til et salt med en farmasøytisk akseptabel syre. De farma-søytisk akseptable syrer innbefatter uorganiske syrer slik som svovelsyre, salpetersyre, saltsyre eller hydrobromsyre, The compounds (I) having an acid group can be converted into a salt with a pharmaceutically acceptable basic compound. The basic compound includes metal hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal alcoholates such as sodium methylate or potassium ethylate and the like. The compounds (I) having a basic group can also be converted into a salt with a pharmaceutically acceptable acid. The pharmaceutically acceptable acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid or hydrobromic acid,

og organiske syrer slik som eddiksyre, p-toluensulfonsyre, ethansulfonsyre, oxalsyre, maleinsyre, ravsyre eller benzoe-syre. and organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, succinic acid or benzoic acid.

Forbindelsene erholdt ved de ovenfor angitte fremgangsmåter kan lett isoleres fra reaksjonsblandingen og ren-ses ved konvensjonelle metoder. Eksempelvis kan isoleringen utføres ved utfelling, ekstraksjon, omkrystallisasjon, destillering, kolonnekromatografi, preparativ tynnskiktskromatografi og lignende. The compounds obtained by the methods indicated above can be easily isolated from the reaction mixture and purified by conventional methods. For example, the isolation can be carried out by precipitation, extraction, recrystallization, distillation, column chromatography, preparative thin-layer chromatography and the like.

Forbindelsene (I) eller deres farmasøytisk akseptable salter ifølge oppfinnelsen er nyttige for behandling av peptisk og tolvfingertarmsår, og kan vanligvis anvendes i form av konvensjonelle farmasøytiske preparater. The compounds (I) or their pharmaceutically acceptable salts according to the invention are useful for the treatment of peptic and duodenal ulcers, and can usually be used in the form of conventional pharmaceutical preparations.

Forsøksrapport Trial report

Farmakologiske tester: Pharmacological tests:

De farmakologiske virkninger av forbindelsene (I) fremstilt ifølge oppfinnelsen ble testet ved hjelp av vanlig kjente fremgangsmåter som er omtalt nedenunder. Testforbind-elsene var følgende: I . N, N-D i et hy 1-4-0-met hyl-1 ,2,3,4-tetrazol-5-yl)thio-butyramid (fremstilt ifølge eksempel 1) 2. N-Ethyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol<->5-yl)thio-butyramid (eks. 2) 3. N-Ethy1-N-cyclohexyl-5-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-valeramid (eks. 62) 4. N-Ethyl-N-cyclohexyl-5-O - fenyl-1,2,3,4 - The pharmacological effects of the compounds (I) produced according to the invention were tested using commonly known methods which are discussed below. The test compounds were the following: I . N, N-D in a hy 1-4-0-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (prepared according to example 1) 2. N-Ethyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol<->5-yl)thio-butyramide (ex. 2) 3. N-Ethy1-N-cyclohexyl-5-(1-methyl-1,2, 3,4-tetrazol-5-yl)thio-valeramide (ex. 62) 4. N-Ethyl-N-cyclohexyl-5-O - phenyl-1,2,3,4 -

tetrazol-5-yl)valeramid (eks. 115) tetrazol-5-yl)valeramide (ex. 115)

5. N,N-Diethy1-5-O-cyclohexyl-1,2,3,4-tetrazol-5-yl)valéramid (eks. 72) 6. N-Cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 8) 7. N-[4-(N,N-Dimethylamino) fenyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 37) 8. N-Ethyl-N-(2-hydroxycyclohexyl)-4-(1-methyl-1 ,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 48) 9. N-Ethyl-N- fenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 3) 10. N-Ethyl-N-(2-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 42) II . N-Cyclohexyl-N-[2-(3,4-dimethoxyfenyl)-ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks.20) 12. N,N-Diethyl-3-[1-(4-ethylfenyl )-1,2,3,4-tetrazol-5-ylImethylthio-propionamid (eks. 79) 13. N-Furf ur yl-1»-(1-methyl-1 ,2,3,4-tetrazol-5-yl)thio-butyraraid (eks. 35) 5. N,N-Diethy1-5-O-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramide (ex. 72) 6. N-Cyclohexyl-4-(1-methyl-1,2 ,3,4-tetrazol-5-yl)thio-butyramide (ex. 8) 7. N-[4-(N,N-Dimethylamino) phenyl]-4-(1-methyl-1,2,3,4 -tetrazol-5-yl)thio-butyramide (ex. 37) 8. N-Ethyl-N-(2-hydroxycyclohexyl)-4-(1-methyl-1 ,2,3,4-tetrazol-5-yl) thio-butyramide (ex. 48) 9. N-Ethyl-N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 3) 10. N -Ethyl-N-(2-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 42) II . N-Cyclohexyl-N-[2-(3,4-dimethoxyphenyl)-ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex.20) 12 N,N-Diethyl-3-[1-(4-ethylphenyl)-1,2,3,4-tetrazol-5-ylmethylthio-propionamide (ex. 79) 13. N-Furfuryl-1»-( 1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyraride (ex. 35)

11». N, N-Diethyl-3-( 1-ethyl-1 , 2, 3 , 4-tet razol-5 - 11". N, N-Diethyl-3-( 1-ethyl-1 , 2, 3 , 4-tet razol-5 -

yl)methylthio-propionamid (eks. 78) yl)methylthio-propionamide (ex. 78)

20. N-Ethyl-N-cycloheptyl-1»-( 1 - methyl-1 ,2,3,4-tetrazol-5-yl)thlo-butyramid (eks. 57) 21. N,N-D i isopropyl-4 -(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 17) 22. N-Isopropyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 46) 23. 5-(3-Piperidylcarbonylpropylthlo)-1-methyl-1,2,3,4-tetrazol • (eks. 56) 24. N-[2-(3,4-Dimethoxy fenyl )ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid -(eks. 6) 25. N-(2-Pyridyl)-4-(1-methyl-1,2,3.4-tetrazol-5 - 20. N-Ethyl-N-cycloheptyl-1»-(1-methyl-1,2,3,4-tetrazol-5-yl)chloro-butyramide (ex. 57) 21. N,N-D in isopropyl-4 - (1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 17) 22. N-Isopropyl-N-cyclohexyl-4-(1-methyl-1,2,3, 4-tetrazol-5-yl)thio-butyramide (ex. 46) 23. 5-(3-Piperidylcarbonylpropylthio)-1-methyl-1,2,3,4-tetrazole • (ex. 56) 24. N-[ 2-(3,4-Dimethoxy phenyl )ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide -(ex. 6) 25. N-(2- Pyridyl)-4-(1-methyl-1,2,3.4-tetrazol-5 -

yl)thio-butyramid (eks. 91) yl)thio-butyramide (ex. 91)

26. N,N-D imethyl-4 -(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramld (eks. 53) 27. N-Ethyl-N-cyclopentyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 44) 28 N-Ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid <eks- 45> 29. N-Ethyl-N-cyclohexyl-4-( 1- fenyl -1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 58) 30. 5-C 3-(4-Acetyl-1-piperazinylcarbonylJpropyl-thio]-1-methyl-1 , 2, 3, 4-tetrazol (eks. 135) 31. 5-(3- Horfo linocarbonylpropylthio)-1-methyl-1,2,3,4-tetrazol (eks. 130) 32. N-Ethyl-N-cyclohexy1-3-(1-ethyl-1,2,3,4-tetrazol-5-yl)methylthio-propionamid (eks. 80) 33. Methyl 4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyrat (eks. 190) 34. N-Methyl-N-(2-thienylmethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 90) 36. N-(4-Sulfamoylfenyl )-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid^ (eks. 36) 37 N-(2-Methyl-3-klor-fenyl)-4-(1-methyl-1 ,2,3,4-tetrazol-5-yl)thio-butyramid -(eks. 38) 38. N-(4-Nitro fenyl. )-4-( 1 -methyl-1 ,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 39) 39. N,N-Diethyl-3-(1-ethyl-1,2,3,4-tetrazol-5-yl)methylthio-propionamid (eks. 78) 40. N-(4-Methoxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 64) 41 . N-Butyl-N-cyclohexy 1-4-0 -methyl-1 ,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 14) 42. N-Ethyl-N-cyclooctyl-4-O-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 181) 43. N-[4-(N,N-Dimethylamino) f enyl. ]-4-(1-methyl-1 , 2, 3,4-tetrazol-5-yl)thio-butyramid (eks. 165) 44. N,N-Dicyclohexy1-4-(1-methyl-1 ,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 147) 46. N-Cyclododecanyl-4-0-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 10) 47 N-n-Hexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramid. (eks. 7) 48. N-Ethyl-N-(2-acetyloxycyclohexyl)-4-(1 - methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid. (eks. 98) 49. N-(4-Methylcyclohexyl)-4-(1-methyl-1 ,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 65) 50. N-[4-(N,N-Dimethylamino)cyclohexy1]-4-(1 - methyl-1 , 2, 3, 4-tetrazol-5-yl )thio-but-yramid (eks. 66) 51. N-Ethyl-N-cyclohexy1-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-acetamid (eks. 60) 52. 5-C3-(4-Methylpiperazinocarbonyl)propylthio]-1-methyl-1,2,3,4-tetrazol (eks. 55) 53- N Ethyl-N-cyclohexyl-4-[1-(2-methoxycyclo-hexyl)-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 67) 54. N-Butyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramid (eks. 11) 55. N-Benzyl-N-[2-(3,4-dimethoxyfenyl )ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 22) 56. N-(2-Methoxyfenyl )-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 40) 57. N-Cyclohexyl-N-(2-hydroxyethyl)-4-(1 -methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (eks. 30) 26. N,N-D imethyl-4 -(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramld (ex. 53) 27. N-Ethyl-N-cyclopentyl-4-(1 -methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 44) 28 N-Ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol -5-yl)thio-butyramide <ex- 45> 29. N-Ethyl-N-cyclohexyl-4-(1-phenyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 58) 30. 5-C 3-(4-Acetyl-1-piperazinylcarbonylJpropyl-thio]-1-methyl-1 , 2, 3, 4-tetrazole (ex. 135) 31. 5-(3- Horfo linocarbonylpropylthio)- 1-methyl-1,2,3,4-tetrazole (ex. 130) 32. N-Ethyl-N-cyclohexy1-3-(1-ethyl-1,2,3,4-tetrazol-5-yl)methylthio -propionamide (ex. 80) 33. Methyl 4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyrate (ex. 190) 34. N-Methyl-N-(2 -thienylmethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 90) 36. N-(4-Sulfamoylphenyl )-4-(1-methyl- 1,2,3,4-tetrazol-5-yl)thio-butyramide^ (ex. 36) 37 N-(2-Methyl-3-chloro-phenyl)-4-(1-methyl-1,2,3 ,4-tetrazol-5-yl)thio-butyramide -(ex. 38) 38. N-(4-Nitro phenyl. )-4-( 1 -methyl-1 ,2,3,4-tetrazol-5-yl )thio-butyramide (ex. 39) 39. N,N-Diethyl-3-(1-ethyl-1,2,3,4-tetrazol-5-yl)methylthio-propionamide (ex. 78) 40. N-(4-Methoxycyclohexyl)-4 -(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 64) 41 . N-Butyl-N-cyclohexy 1-4-0 -methyl-1 ,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 14) 42. N-Ethyl-N-cyclooctyl-4-O -methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 181) 43. N-[4-(N,N-Dimethylamino)phenyl. ]-4-(1-methyl-1 , 2, 3,4-tetrazol-5-yl)thio-butyramide (ex. 165) 44. N,N-Dicyclohexy1-4-(1-methyl-1 ,2, 3,4-tetrazol-5-yl)thio-butyramide (ex. 147) 46. N-Cyclododecanyl-4-0-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 10) 47 N-n-Hexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide. (ex. 7) 48. N-Ethyl-N-(2-acetyloxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide. (ex. 98) 49. N-(4-Methylcyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 65) 50. N-[4 -(N,N-Dimethylamino)cyclohexy1]-4-(1 - methyl-1 , 2, 3, 4-tetrazol-5-yl )thio-but-yramide (ex. 66) 51. N-Ethyl-N- cyclohexy1-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-acetamide (ex. 60) 52. 5-C3-(4-Methylpiperazinocarbonyl)propylthio]-1-methyl-1 ,2,3,4-tetrazole (ex. 55) 53- N Ethyl-N-cyclohexyl-4-[1-(2-methoxycyclo-hexyl)-1,2,3,4-tetrazol-5-yl)thio -butyramide (ex. 67) 54. N-Butyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide (ex. 11) 55. N-Benzyl-N -[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 22) 56. N-(2- Methoxyphenyl )-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 40) 57. N-Cyclohexyl-N-(2-hydroxyethyl)-4-(1 -methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 30)

Sammenligningsforbindelser: Comparative compounds:

A. 2-(3-Bromfenyl)-5-(2-carbamoylethyl)-1,2,3,4-tetrazol (beskrevet i US patentskrift nr. 3 743 646) A. 2-(3-Bromophenyl)-5-(2-carbamoylethyl)-1,2,3,4-tetrazole (described in US Patent No. 3,743,646)

B. 2-(3-Bromfenyl)-5-(2-piperidinocarbonylethyl)-1,2,3,4-tetrazol (beskrevet i US patentskrift nr. 3 743 646) B. 2-(3-Bromophenyl)-5-(2-piperidinocarbonylethyl)-1,2,3,4-tetrazole (described in US Patent No. 3,743,646)

Farmakologisk test 1: Pharmacological test 1:

De farmakologiske virkninger av forbindelsene (I) ble testet ved hjelp av en Shay rottemageportombindingsmetode The pharmacological effects of the compounds (I) were tested using a Shay rat gastric portoma ligation method

(jfr. H. Shay et al: Gastroenterol., Vol. 5, side 42, 1945) (cf. H. Shay et al: Gastroenterol., Vol. 5, page 42, 1945)

som er den mest populære metode for testing av sekresjons-inhiberende virkning på magesaft. Testen ble utført ved å bruke Wistar hannrotter som veide ca. 170 g og hadde fastet i 2 4 timer. which is the most popular method for testing the secretion-inhibiting effect on gastric juice. The test was carried out using male Wistar rats weighing approx. 170 g and had fasted for 2 4 hours.

Testforbindelsene ble administrert subkutant 3 0 minutter før mageportombinding i en dose på 150 mg/kg og volumet, den totalte surhet og/eller pepsinaktiviteten til magesaften ble målt 4 timer etter ombindingen. Som en kontroll ble en fysiologisk saltvannsoppløsning administrert i stedet for testforbindelsen. Det inhiberende forhold (%) for testforbindelsene ble beregnet når de inhiberende virkninger av kontrollen ble bestemt som null. Resultatene er vist i tabell 1. The test compounds were administered subcutaneously 30 minutes before gastric port ligation at a dose of 150 mg/kg and the volume, total acidity and/or pepsin activity of the gastric juice was measured 4 hours after ligation. As a control, a physiological saline solution was administered instead of the test compound. The inhibitory ratio (%) of the test compounds was calculated when the inhibitory effects of the control were determined to be zero. The results are shown in table 1.

I tabell 1 ble det inhiberende forhold (%) vurdert på følgende måte: In table 1, the inhibitory ratio (%) was assessed as follows:

-: mindre enn 10% -: less than 10%

+: 10 til mindre enn 50% +: 10 to less than 50%

++: mer enn 50% ++: more than 50%

Farmakologist test 2: Stress-indusert magesår Pharmacologist test 2: Stress-induced gastric ulcer

Etter at Wistar hannrotter som veide ca. 170 g, var blitt fastet i 24 timer, ble rottene sperret inne. i stress-bur og dyppet i vannbad ved 23°C opp til brystet på dyrene. Etter 7 timer ble rottene avlivet og magesekken ble isolert. 10% formalin (8 ml) ble helt inn i den isolerte magesekk og den ble hensatt. Magesekken ble skåret opp langs den største krumning og lengden av hvert sår på membranen ble målt. Summen av lengdene til alle sårene ble angitt som sårindeks (Ul). Testforbindelsen ble administrert oralt til rottene før de ble stengt inne i et stress-bur i form av 0,5% CMC-suspen--3 After male Wistar rats weighing approx. 170 g, had been fasted for 24 hours, the rats were confined. in a stress cage and immersed in a water bath at 23°C up to the chest of the animals. After 7 hours, the rats were euthanized and the stomach was isolated. 10% formalin (8 ml) was poured into the isolated stomach and it was set aside. The stomach was cut open along the greatest curvature and the length of each wound on the membrane was measured. The sum of the lengths of all the wounds was given as the wound index (Ul). The test compound was administered orally to the rats before they were closed in a stress cage in the form of 0.5% CMC suspension--3

sjon i en konsentrasjon på 1 x 10 mol. Som en kontroll ble oppløsningsmidlet alene (CMC-oppløsning) administrert på samme måte. tion in a concentration of 1 x 10 mol. As a control, the solvent alone (CMC solution) was administered in the same manner.

Det inhiberende forhold (%) på stress-magesår for testforbindelsene ble beregnet ved hjelp av den følgende ligning: The inhibitory ratio (%) on stress ulcer for the test compounds was calculated using the following equation:

Resultatene er vist i tabell 2. The results are shown in table 2.

I tabell 2 ble det inhiberende forhold (%) vurdert på følgende måte: In table 2, the inhibitory ratio (%) was assessed as follows:

-: mindre enn 20% -: less than 20%

+: 30 - 60% +: 30 - 60%

++: mer enn 60% ++: more than 60%

Farmakologisk test 3: Eddiksyre-indusert magesår Pharmacological test 3: Acetic acid-induced gastric ulcer

Det ble brukt Wistar hannrotter. Under bedøvelse ble buken til rottene åpnet for å blottlegge magesekken og deretter ble 30% vandig eddiksyre (0,015 ml) injisert under den serøse hinne beliggende i grenseområdet mellom de egent-lige magesekkjertler og mageportkjertler, og deretter ble buken lukket, slik at et eksperimentelt magesår ble indusert. Male Wistar rats were used. Under anesthesia, the abdomen of the rats was opened to expose the stomach and then 30% aqueous acetic acid (0.015 ml) was injected under the serous membrane located in the border area between the gastric glands proper and gastric portal glands, and then the abdomen was closed, so that an experimental gastric ulcer was induced.

Testforbindelseneble administrert oralt i den dose The test compounds were administered orally at that dose

som er vist i tabell 3 i form av 0,5% CMC-suspensjon eller which is shown in Table 3 in the form of 0.5% CMC suspension or

-oppløsning to ganger daglig i 12 dager etter at det eddiksyre-induserte magesår hadde oppstått. Som en kontroll ble opp-løsningsmidlet (CMC-oppløsningen) alene administrert på -solution twice daily for 12 days after the acetic acid-induced gastric ulcer had occurred. As a control, the solvent (CMC solution) alone was administered

samme måte. same way.

Etter at den nydannede slimhinne var fjernet rundt magesårene, ble de åpne sårområder målt med et mikrometer og summen av sårområder ble angitt som sårindeks (Ul). Det inhiberende forhold (%) ved eddiksyre-indusert magesår for testforbindelsen ble beregnet på samme måte som i farmakologisk test 2. After the newly formed mucosa was removed around the gastric ulcers, the open wound areas were measured with a micrometer and the sum of wound areas was given as the wound index (Ul). The inhibitory ratio (%) in acetic acid-induced gastric ulcer for the test compound was calculated in the same way as in pharmacological test 2.

Resultatene er vist i tabell 3. The results are shown in table 3.

I tabell 3 ble det inhiberende forhold (%) vurdert på følgende måte: In table 3, the inhibitory ratio (%) was assessed as follows:

-: mindre enn 10% -: less than 10%

+: 30 til 60% +: 30 to 60%

++: mer enn 60% ++: more than 60%

Farmakologisk test 4: Indomethacin-indusert magesår Pharmacological test 4: Indomethacin-induced gastric ulcer

Etter at Wistar hannrotter som veide ca. 160 g hadde vært fastet i 24 timer, ble indomethacin administrert subkutant til rottene i en dose på 2 0 mg/kg i form av en suspensjon i en blanding av 0,5% CMC og en liten mengde "Tween 80" (dvs. polyoxyethylensorbitanmonooleat). Rottene ble avlivet etter 5 timer og magesekken ble isolert. Det ble helt 10% formalin (8 ml) inn i den isolerte magesekk og den ble hensatt. Magesekken ble skåret opp langs den største krumningen og lengden av hvert sår på membranen ble målt, After male Wistar rats weighing approx. 160 g had been fasted for 24 hours, indomethacin was administered subcutaneously to the rats at a dose of 20 mg/kg in the form of a suspension in a mixture of 0.5% CMC and a small amount of "Tween 80" (ie polyoxyethylene sorbitan monooleate ). The rats were euthanized after 5 hours and the stomach was isolated. 10% formalin (8 ml) was poured into the isolated stomach and it was set aside. The stomach was cut open along the greatest curvature and the length of each wound on the membrane was measured,

og basert på disse resultatene ble det inhiberende forhold ved det indomethacin-induserte magesår for testforbindelsene beregnet på samme måte som i farmakologisk test 2. Testforbindelsene ble administrert oralt til rottene i en konsentrasjon på 3 x 10 <4> mol i form av 0,5% CMC-suspensjon 3 0 minutter før administrasjon av indomethacin. and based on these results, the inhibitory ratio of the indomethacin-induced gastric ulcer of the test compounds was calculated in the same manner as in pharmacological test 2. The test compounds were administered orally to the rats at a concentration of 3 x 10<4> mol in the form of 0.5 % CMC suspension 30 minutes before administration of indomethacin.

Resultatene er vist i tabell 4.. The results are shown in table 4.

I tabell 4 ble det inhiberende forhold (%) vurdert på følgende måte: +: 30 - 60% ++: mer enn 60% In table 4, the inhibitory ratio (%) was assessed as follows: +: 30 - 60% ++: more than 60%

Akutt toksisitet: Acute toxicity:

Testforbindelsene ble administrert oralt til Wistar hannrotter og den dødelige halveringsdose (LD^q) ble målt. Resultatene er vist i tabell 5. The test compounds were administered orally to male Wistar rats and the lethal half dose (LD^q) was measured. The results are shown in table 5.

De etterfølgende referanseeksempler illustrerer fremstillingen av utgangsforbindelser, mens eksemplene illustrerer oppfinnelsen. The following reference examples illustrate the production of starting compounds, while the examples illustrate the invention.

Referanseeksempel 1 Reference example 1

Til 400 ml ethylacetat ble tilsatt 26 ml N-methylcyclohexylamin, og til blandingen ble tilsatt dråpevis under omrøring 25 ml 4-klorbutyrylklorid og 33,5 ml triethylamin i løpet av 2 0 minutter mens den indre temperatur ble holdt ved 10 - 20° C ved iskjøling. Blandingen ble ytterligere omrørt ved romtemperatur i 1 time. Etter omsetningen ble vann tilsatt til reaksjonsblandingen. Det organiske lag ble vasket med vann og en vandig mettet kaliumcarbonatløsning, 10 %-ig vandig saltsyre og vann, og ble deretter tørket over vannfritt natriumsulfat. Etter filtrering av natriumsulfat ble modervæsken konsentrert og destillert under redusert trykk under dannelse av N-methyl-N-cyclohexyl-4-klorbutyra-mid (41,5 g), k.p. 133 - 136°C/2mmHg. To 400 ml of ethyl acetate was added 26 ml of N-methylcyclohexylamine, and to the mixture was added dropwise with stirring 25 ml of 4-chlorobutyryl chloride and 33.5 ml of triethylamine during 20 minutes while the internal temperature was maintained at 10-20°C at ice cooling. The mixture was further stirred at room temperature for 1 hour. After the reaction, water was added to the reaction mixture. The organic layer was washed with water and an aqueous saturated potassium carbonate solution, 10% aqueous hydrochloric acid and water, and was then dried over anhydrous sodium sulfate. After sodium sulfate filtration, the mother liquor was concentrated and distilled under reduced pressure to give N-methyl-N-cyclohexyl-4-chlorobutyramide (41.5 g), m.p. 133 - 136°C/2mmHg.

Referanseeksempel 2 Reference example 2

2,6 g N-ethyl-cyclohexylamin ble løst i 20 ml tørr benzen. Til løsningen ble dråpevis tilsatt under om-røring 2,6 g kloracetylklorid og 2,4 g triethylamin under isavkjøling. Blandingen ble omrørt under isavkjøling i 1 time, og ytterligere 1 time ved romtemperatur. Reaksjonsblandingen ble helt over på isvann og ekstrahert med ether. Etherlaget ble vasket med vandig natriumhydrogencarbonat-løsning og en vandig mettet natriumkloridløsning, og ble tørket over vannfritt magnesiumsulfat. Etter avdestillering av ^løsningsmidlet ble det resulterende residuum destillert under redusert trykk under dannelse av N-ethyl-N-cyclohexyl-kloracetamid (3 g), k.p. 118 - 120° C/0,2 mmHg. 2.6 g of N-ethyl-cyclohexylamine was dissolved in 20 ml of dry benzene. 2.6 g of chloroacetyl chloride and 2.4 g of triethylamine were added dropwise to the solution with stirring under ice cooling. The mixture was stirred under ice cooling for 1 hour, and a further 1 hour at room temperature. The reaction mixture was poured into ice water and extracted with ether. The ether layer was washed with aqueous sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution, and was dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting residue was distilled under reduced pressure to give N-ethyl-N-cyclohexyl-chloroacetamide (3 g), m.p. 118 - 120°C/0.2mmHg.

Referanseeksempel 3 og 4 Reference examples 3 and 4

På samme måte som beskrevet i Referanseeksempel 2, In the same way as described in Reference Example 2,

ble følgende forbindelser fremstilt: N-ethyl-N-cyclohexyl-4-klorbutyramid, k.p. 120 - 130°C/1,5 mmHg the following compounds were prepared: N-ethyl-N-cyclohexyl-4-chlorobutyramide, b.p. 120 - 130°C/1.5 mmHg

N-ethyl-N-cyclohexyl-3-klorpropionamid, k.p. 103 - 110°C/0,15 mmHg N-ethyl-N-cyclohexyl-3-chloropropionamide, m.p. 103 - 110°C/0.15 mmHg

Referanseeksempel 5 Reference example 5

6 g monomethyladipat ble tilsatt 10 ml thionylklorid, og blandingen ble kokt under tilbakeløpskjøling i 1 time. Overskudd av thionylklorid ble destillert fra, og benzen ble tilsatt til residuet hvorpå thionylklorid ble ytterligere fjernet ved azeotrop destillasjon. 6 g of monomethyl adipate was added to 10 ml of thionyl chloride, and the mixture was refluxed for 1 hour. Excess thionyl chloride was distilled off and benzene was added to the residue whereupon thionyl chloride was further removed by azeotropic distillation.

Separat ble 4,2 g anilin og 5,2 g kaliumcarbonat løst i 100 ml aceton og 15 ml vann. Til blandingen ble dråpevis tilsatt under omrøring kloridforbindelsen erholdt som ovenfor angitt under isavkjøling. Blandingen ble omrørt under isavkjøling i 1 time og derpå i 2 timer ved romtemperatur. Etter destillering av aceton, ble vann tilsatt til residuet, og blandingen ble ekstrahert med kloroform. Kloroformlaget ble vasket med vandig mettet natriumkloridløsning og tørket over magnesiumsulfat. Kloroform ble destillert fra under dannelse av methylfenyladipinamat (9 g). Separately, 4.2 g of aniline and 5.2 g of potassium carbonate were dissolved in 100 ml of acetone and 15 ml of water. To the mixture was added dropwise with stirring the chloride compound obtained as stated above under ice cooling. The mixture was stirred under ice cooling for 1 hour and then for 2 hours at room temperature. After distillation of acetone, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. Chloroform was distilled off to give methylphenyladipinamate (9 g).

NMR: ^<CDC1>3 1,40 - 1,90 (4H, m) , 2,10 - 2,50 (4H, m) , NMR: ^<CDC1>3 1.40 - 1.90 (4H, m) , 2.10 - 2.50 (4H, m) ,

ppm ppm

3,66 (3H, s), 6,80 - 7,70 (5H, m), 8,55 3.66 (3H, s), 6.80 - 7.70 (5H, m), 8.55

(1H, br.s) (1H, br.s)

Referanseeksempler 6 og 7 Reference Examples 6 and 7

På samme måte som beskrevet i Referanseeksempel 5 ble følgende forbindelser fremstilt: Nethyl-N-cyclohexyladipinamat, lysebrune prismer (omkrystallisert fra methanol-vann), sm.p. 72 - 74° C, In the same manner as described in Reference Example 5, the following compounds were prepared: Nethyl-N-cyclohexyladipinamate, light brown prisms (recrystallized from methanol-water), m.p. 72 - 74° C,

Methyl-N-methyladipinamat, fargeløs væske, k.p. Methyl-N-methyladipinamate, colorless liquid, b.p.

136 - 140°C/0,7 mmHg. 136 - 140°C/0.7mmHg.

Referanseeksempel 8 Reference example 8

46,5 ml av en 40 %-ig vandig methylaminløsning ble oppløst i 300 ml aceton. Til løsningen ble tilsatt 45,6 g kaliumcarbonat og 100 ml vann, hvorpå det dråpevis ble tilsatt under omrøring 24,3 ml kloradetylklorid under isavskjø-ling. Blandingen ble omrørt under isavkjøling i 1 time og ytterligere 2 timer ved romtemperatur. Etter avdestillering av acetonet, ble vann tilsatt til residuet, og blandingen ble ekstrahert med kloroform. Kloroformlaget ble vasket med en vandig mettet natriumkloridløsning og tørket over magne- 46.5 ml of a 40% aqueous methylamine solution was dissolved in 300 ml of acetone. 45.6 g of potassium carbonate and 100 ml of water were added to the solution, whereupon 24.3 ml of chloroethyl chloride was added dropwise with stirring under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and a further 2 hours at room temperature. After distilling off the acetone, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with an aqueous saturated sodium chloride solution and dried over magnetic

siumsulfat. Etter avdestillering av kloroform, ble residuet destillert under redusert trykk under dannelse av N-methyl-kloracetamid (15,5 g), farveløs væske, k.p. 107 - 109°C/27mmHg. Referanseeksempel 9 sium sulfate. After distillation of chloroform, the residue was distilled under reduced pressure to give N-methyl-chloroacetamide (15.5 g), colorless liquid, m.p. 107 - 109°C/27mmHg. Reference example 9

10,8 g N-methyl-kloracetamid ble løst i 100 ml benzen, og til blandingen ble tilsatt under omrøring 10,8 g fosforpentaklorid ved en temperatur under 15° C. Blandingen ble omrørt ved romtemperatur i 1 time og fikk deretter stå over natten. Blandingen ble langsomt kokt under tilbakeløps-kjøling i 2 timer. Reaksjonsblandingen ble konsentrert, og tilsatt is-vann, og blandingen ble ekstrahert med kloroform. Kloroformlaget ble vasket med vann, en fortynnet vandig natriumhydroxydløsning og vann, tørket over magnesiumsulfat og destillert for å fjerne kloroform. Det resulterende residuum ble underkastet kolonnekromåtografi (Wakogel C-200, fremstilt av Wako Pyre Chemical Industry, elueringsmiddel, kloroform: methanol = 50:1, V/V) for å isolere 8,5 g 1-methyl-5-klormethyl-l,2,3,4-tetrazol. 10.8 g of N-methyl-chloroacetamide was dissolved in 100 ml of benzene, and to the mixture was added with stirring 10.8 g of phosphorus pentachloride at a temperature below 15° C. The mixture was stirred at room temperature for 1 hour and then allowed to stand overnight . The mixture was slowly boiled under reflux for 2 hours. The reaction mixture was concentrated, and ice-water was added, and the mixture was extracted with chloroform. The chloroform layer was washed with water, a dilute aqueous sodium hydroxide solution and water, dried over magnesium sulfate and distilled to remove chloroform. The resulting residue was subjected to column chromatography (Wakogel C-200, manufactured by Wako Pyre Chemical Industry, eluent, chloroform: methanol = 50:1, V/V) to isolate 8.5 g of 1-methyl-5-chloromethyl-1, 2,3,4-tetrazole.

Eksempel 1 Example 1

2 g 4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-smørsyre ble løst i 30 ml tørr tetrahydrofuran, og til blandingen ble tilsatt 1,1 g triethylamin. Til blandingen ble dråpevis tilsatt under omrøring 1,5 g isobutylklorformiat under is-avkjøling. Blandingen ble omrørt ved romtemperatur i 30 minutter. Til blandingen ble ytterligere dråpevis tilsatt 0,9 g diethylamin under omrøring ved romtemperatur, og blandingen ble omrørt i 2 timer. Blandingen ble konsentrert under redusert trykk, og det resulterende residuum ble renset ved at dette ble underkastet kolonnekromåtografi (Kieselgel 60). Ved eluering med n-hexan-ethylacetat (1:1) ble det erholdt N,N-diethy1-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid (1,4 g), farveløs væske, nD 17 ' 5 = 1,5227. 2 g of 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid was dissolved in 30 ml of dry tetrahydrofuran, and 1.1 g of triethylamine was added to the mixture. 1.5 g of isobutyl chloroformate was added dropwise to the mixture with stirring under ice-cooling. The mixture was stirred at room temperature for 30 minutes. A further 0.9 g of diethylamine was added dropwise to the mixture with stirring at room temperature, and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure and the resulting residue was purified by subjecting it to column chromatography (Kieselgel 60). Elution with n-hexane-ethyl acetate (1:1) gave N,N-diethy1-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (1,4 g), colorless liquid, nD 17 ' 5 = 1.5227.

NMR. 6CDC13 1,04 (3H, t, J = 7Hz); 1,12 NMR. 6CDCl3 1.04 (3H, t, J = 7Hz); 1.12

ppm ppm

(3H, t, J = 7Hz), 1,90 - 2,70 (4H, m), 3,00 - (3H, t, J = 7Hz), 1.90 - 2.70 (4H, m), 3.00 -

3,60 (6H, m), 3,88 (3H,s) 3.60 (6H,m), 3.88 (3H,s)

Elementæranalyse for C^qH-^N^OS : Elemental analysis for C^qH-^N^OS :

Beregnet (%): C 46,67 H 7,44 N 27,21 Calculated (%): C 46.67 H 7.44 N 27.21

Funnet (%): C 46,78 H 7,51 N 27,29 Found (%): C 46.78 H 7.51 N 27.29

Eksempel 2- 5 Example 2-5

På samme måte som beskrevet i eksempel 1 ble følgende forbindelser erholdt fra egnede utgangsmaterialer: (2) N-ethyl-N-cyclohexyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nQ 17 ' 5 = 1,5327 cnci NMR: 6 ^3 0,90 - 1,40 (3H, m), 1,20 - 2,00 (10H, m), 2,00 - 2,80 (4H, m), 3,00 - 3,60 (6H, m), 3,95 (3H, s), 3,50 - 4,50 (1H, m) (3) N-ethyl-N-fenyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, lysegul væske, nn 2 6 = 1,553 4 enn NMR: 6 ppj^ 3 1,12 (3H, t, J = 7Hz), 1,70 - 2,40 (4H, m) , 3,32 (2H, t, J = 7Hz), 3,74 (2H, q, J = 14Hz, 7Hz), 3,90 (3H, s), 7,00 - 7,60 (5H, m) (4) 5-(3-morfolinocarbonylpropylthio)-1-methyl-1,2,3,4-tetrazol, hvite nåler (omkrystallisert fra petroleumether-ethanol), sm.p. 71 - 73° C. (5) 5- [3- (4-acetylpiperadinocarbonyl)propylthio]-1-methyl-l,2,3,4-tetrazol, hvitt krystallinsk pulver (omkry-stallsert fra ligroin-aceton), sm.p. 90 - 91,5° C. In the same manner as described in Example 1, the following compounds were obtained from suitable starting materials: (2) N-ethyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio- butyramide, colorless liquid, nQ 17 ' 5 = 1.5327 cnci NMR: 6 ^3 0.90 - 1.40 (3H, m), 1.20 - 2.00 (10H, m), 2.00 - 2 .80 (4H, m), 3.00 - 3.60 (6H, m), 3.95 (3H, s), 3.50 - 4.50 (1H, m) (3) N-ethyl-N -phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, pale yellow liquid, nn 2 6 = 1.553 4 than NMR: 6 ppj^ 3 1.12 (3H, t, J = 7Hz), 1.70 - 2.40 (4H, m) , 3.32 (2H, t, J = 7Hz), 3.74 ( 2H, q, J = 14Hz, 7Hz), 3.90 (3H, s), 7.00 - 7.60 (5H, m) (4) 5-(3-morpholinocarbonylpropylthio)-1-methyl-1,2 ,3,4-tetrazole, white needles (recrystallized from petroleum ether-ethanol), m.p. 71 - 73° C. (5) 5-[3-(4-acetylpiperadinocarbonyl)propylthio]-1-methyl-1,2,3,4-tetrazole, white crystalline powder (recrystallized from ligroin-acetone), sm .p. 90 - 91.5° C.

Eksempel 6 Example 6

45 mmol 4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-smørsyre ble løst i 50 ml tetrahydrofuran og i blandingen ble tilsatt 50 mmol DBU. Til blandingen ble dråpevis tilsatt under omrøring 50 mmol isobutylklorformiat under is-avkjøling, og blandingen ble omrørt ved romtemperatur i 3 0 minutter. Til blandingen ble dråpevis tilsatt 54 mmol 2-(3,4-dimethoxyfenyl)ethylamin og blandingen ble ytterligere omrørt ved romtemperatur i 2 timer. Etter at løsningsmidlet var destillert fra under redusert trykk, ble det resulterende residuum ekstrahert med kloroform. Kloroformlaget ble vasket med 5 %-ig saltsyre, en vandig mettet natriumhydrogen-carbonatløsning og en vandig mettet natriumkloridløsning, 45 mmol of 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid was dissolved in 50 ml of tetrahydrofuran and 50 mmol of DBU was added to the mixture. 50 mmol of isobutyl chloroformate was added dropwise to the mixture while stirring under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 54 mmol of 2-(3,4-dimethoxyphenyl)ethylamine was added dropwise to the mixture and the mixture was further stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, the resulting residue was extracted with chloroform. The chloroform layer was washed with 5% hydrochloric acid, an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution,

og ble tørket over vannfri natriumsulfat. Etter avdestillering av kloroform ble residuet underkastet kolonnekromatografi (Wakogel C-200, elueringsmiddel kloroform) for å isolere N-[2-(3,4-dimethoxyfenyl)ethyl]-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid (utbytte 41 %) som ble omkrystallisert fra hexan-kloroform, farveløse flak, sm.p. 70,5 - 71,5° C. and was dried over anhydrous sodium sulfate. After distilling off chloroform, the residue was subjected to column chromatography (Wakogel C-200, eluent chloroform) to isolate N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4- tetrazol-5-yl)thio-butyramide (yield 41%) which was recrystallized from hexane-chloroform, colorless flakes, m.p. 70.5 - 71.5° C.

Elementæranalyse for cigH23N503^: Elemental analysis for cigH23N503^:

Beregnet: C 52,59 % H 6,34 % N 19,16 % Calculated: C 52.59% H 6.34% N 19.16%

Funnet : C 52,51 % H 6,16 % N 19,10 % Found : C 52.51% H 6.16% N 19.10%

Eksempler 7- 58 Examples 7- 58

På samme måte som beskrevet i eksempel 6, ble følgende forbindelser fremstilt fra egnede utgangsmaterialer: (7) N-hexyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)-thio-butyramid, farveløse flak (omkrystallisert fra hexan-ether), sm.p. 41 - 42° C (8) N-cyclohexy1-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (hexan-ethylacetat), smøp. 116,5 - 117,5° C (9) N-cyclooctyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^<4> = 1,5323 (10) N-cyclododecanyl-4^(1-methyl-l,2,3,4-tetrazol-yl)thio-butyramid, farveløse nåler (hexanethylacetat), sm.p. 119 - 120° C (11) N-butyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)-thio-butyramid, farveløs væske, nj^'^ = 1,5198 (12) N-(2-hydroxyethyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nQ 14 ' 5 = 1,5350 (13) N-eth.yl-N-benzyl-4-(1-methyl-l,2,3,4-tetra-19 In the same manner as described in Example 6, the following compounds were prepared from suitable starting materials: (7) N-hexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless flakes (recrystallized from hexane-ether), m.p. 41 - 42° C (8) N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl acetate), sm. 116.5 - 117.5° C (9) N-cyclooctyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<4> = 1.5323 (10) N-cyclododecanyl-4^(1-methyl-1,2,3,4-tetrazol-yl)thio-butyramide, colorless needles (hexane ethyl acetate), sm.p. 119 - 120° C (11) N-butyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless liquid, nj^'^ = 1.5198 ( 12) N-(2-hydroxyethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nQ 14 ' 5 = 1.5350 (13) N -eth.yl-N-benzyl-4-(1-methyl-1,2,3,4-tetra-19

zol-yl)thio-butyramid, farveløs væske, nD = 1,5596 zol-yl)thio-butyramide, colorless liquid, nD = 1.5596

(14) N-butyl-N-cyclohexyl-4-(1-methyl-l,2,3,4- (14) N-butyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-

19 tetrazol-5-yl) thio-butyramid, farveløs væske, nQ = 1,522 19 tetrazol-5-yl) thio-butyramide, colorless liquid, nQ = 1.522

(15) N,N-dibutyl-4- (l-meithyl-1,2,3 ,4-tetrazol-5- (15) N,N-dibutyl-4-(1-methyl-1,2,3,4-tetrazol-5-

1 19 1 19

yl)thio-butyramid, farveløs væske, nQ = 1,5049 yl)thio-butyramide, colorless liquid, nQ = 1.5049

(16) N,N-dibenzyl-4-(1-methyl-l,2,3,4-tetrazol-19 (16) N,N-dibenzyl-4-(1-methyl-1,2,3,4-tetrazole-19

5-yl)thio-butyramid, farveløs væske, nn = 1,5773 5-yl)thio-butyramide, colorless liquid, nn = 1.5773

(17) N,N-diisopropyl-4-(1-methyl-l,2,3,4-tetrazol-19 5 (17) N,N-diisopropyl-4-(1-methyl-1,2,3,4-tetrazole-19 5

5-yl) thio-butyramid, farveløs væske;, nn ' = 1,511<1>5-yl)thio-butyramide, colorless liquid;, nn ' = 1.511<1>

(18) N,N-dicyclohexyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (hexan), sm.p. 91 - 92°C (19) N-benzyl-N-tert.-butyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (hexan), sm.p. 86,5 - 87,5° C (18) N,N-dicyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane), m.p. 91 - 92°C (19) N-benzyl-N-tert-butyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane), sm.p. 86.5 - 87.5° C

i in

(20) N-cyclohexyl-N-[2-(3,4-dimethoxyfenyl)-ethyl]-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^<6> = 1,54 70 (21) N-methyl-N-(2-thienylmethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^6 = 1,5706 (22) N-benzyl-N-[2-(3,4-dimethoxyfenyl)ethyl]-4- (1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^ = 1,5659 (23) N-[2-(3,4-dimethoxyfenyl)ethyl]-N-(2-hydroxy-ethyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thiobutyramid, 14 5 (20) N-cyclohexyl-N-[2-(3,4-dimethoxyphenyl)-ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid , n^<6> = 1.54 70 (21) N-methyl-N-(2-thienylmethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide , colorless liquid, n^6 = 1.5706 (22) N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol- 5-yl)thio-butyramide, colorless liquid, n^ = 1.5659 (23) N-[2-(3,4-dimethoxyphenyl)ethyl]-N-(2-hydroxy-ethyl)-4-(1- methyl-1,2,3,4-tetrazol-5-yl)thiobutyramide, 14 5

farveløs væske, nn ' = 1,5372 colorless liquid, nn ' = 1.5372

(24) N,N-dihexyl-4-(1-methyl-l,2,3,4-tetrazol-5- yl)thio-butyramid, farveløs væske, n^ = 1,5011 (25) N-ethyl-N-[2-(3,4-dimethoxyfenyl)ethyl]-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^<4> = 1,54 51 (26) N-tert.-butyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse plater (hexan-ethylacetat), sm.p. 71 - 73° C (27) N-ethyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)-thio-butyramid, farveløs væske, n^ = 1,5319 (28) N-benzyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)-thio-butyramid, farveløse nåler (hexan-ethylacetat), sm.p. 65 - 66° C (29) N-hexyl-N-cyclohexyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^ = 1,5182 (30) N-cyclohexyl-N-(2-hydroxyethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, 14 5 n^ ' ° = 1,5372 (31) N-fenyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)-thio-butyramid, farveløse nåler (hexan-ethylacetat), sm.ip. 106 - 107° C (32) N-(2-pyridyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (hexan-ethylaceta-^, sm.p. 95 - 96° C (33) N-(3-pyridyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse plater (ethylacetat), sm.p. 110,5 - 113° C (34) N-(2-pyrimidyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse granuler (hexan-ethylacetat), sm.p. 108 - 110° C (35) N-furfuryl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)-thio-butyramid, farveløse flak (hexan-ethylacetat), sm.p. 71 - 73° C I (36) N-(4-aminosulfonylfenyl)-4-(1-mehyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (methanol), sm.p. 169,5 - 170,5° C (37) N-[4-(N,N-dimethylamino)fenyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse prismer (hexan-ethylacetat) , sm-.p. 144 - 147° C (38) N-(2-methyl-3-klorfenyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (hexan-ethyl-acetat) , sm.p. 104,5 - 105,5° C (39) N- (4-nitrofeny1)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (ethylacetat), sm.p. 194 - 195° C (40) N-(2-methoxyfenyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (hexan-ethyl-acetat, sm.p. 79,5 - 82° C (41) N-methyl-N-(2-tetrahydropyranyl)-4-1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, 14 1 nj* = 1,5273 (42) N-ethyl-N-(2-pyridyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl) thio-butyramid, farveløs væske, njjj^ = 1,5623 (43) N-ethyl-N-(3-pyridyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl) thio-butyramid, 'farveløs væske, n^ = 1,5618 (44) N-ethyl-N-cyclopenty1-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nn = 1,5384 (45) N-ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nj1 = 1,5293 (46) N-isopropyl-N-cyclohexyl-4-(1-methyl-l,2,3,4-15 tetrazol-5-yl)thio-butyramid, farveløs væske, nn = 1,523 8 (47) N-ethyl-N-(4-hydroxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, = 1,5363 (48) N-ethyl-N-(2-hydroxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (hexan-ethylacetat), sm.p. 132 - 133° C (49) N-ethyl-N-(2-acetyloxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nj<1> = 1,5218 (50) N,N-dipropyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^ = 1,5151 (51) N-butyl-N-fenyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nQ 15 = 1,5509 (52) N-methyl-N-cyclohexyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, lysegul væske (24) N,N-dihexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^ = 1.5011 (25) N-ethyl- N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<4> = 1 .54 51 (26) N-tert-butyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless plates (hexane-ethyl acetate), m.p. 71 - 73° C (27) N-ethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless liquid, n^ = 1.5319 (28) N-benzyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless needles (hexane-ethyl acetate), m.p. 65 - 66° C (29) N-hexyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^ = 1.5182 (30) N-cyclohexyl-N-(2-hydroxyethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, 14 5 n^ ' ° = 1.5372 (31) N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless needles (hexane-ethyl acetate), m.ip. 106 - 107° C (32) N-(2-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethylaceta-^, mp 95 - 96° C (33) N-(3-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless plates (ethyl acetate) , mp 110.5 - 113° C (34) N-(2-pyrimidyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless granules (hexane-ethyl acetate), mp 108 - 110° C (35) N-furfuryl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless flakes (hexane-ethyl acetate), m.p. 71 - 73° C I (36) N-(4-aminosulfonylphenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide , colorless needles (methanol), mp 169.5 - 170.5° C (37) N-[4-(N,N-dimethylamino)phenyl]-4-(1-methyl-1,2,3 ,4-tetrazol-5-yl)thio-butyramide, colorless prisms (hexane-ethyl acetate), m.p. 144 - 147° C (38) N-(2-methyl-3-chlorophenyl)-4-(1 -methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl-acetate), m.p. 104.5 - 105.5° C (39) N- ( 4-nitrophenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (ethyl acetate), m.p. 194 - 195° C (40) N-(2-methoxyphenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl-acetate, mp 79.5 - 82° C (41) N-methyl-N-(2-tetrahydropyranyl)-4-1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, 14 1 nj* = 1.5273 (42) N-ethyl-N-(2-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, njjj ^ = 1.5623 (43) N-ethyl-N-(3-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, 'colorless liquid, n ^ = 1.5618 (44) N-ethyl-N-cyclopenty1-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nn = 1.5384 ( 45) N-ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nj1 = 1.5293 (46) N-isopropyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-15 tetrazol-5-yl)thio-butyramide, colorless liquid, nn = 1.523 8 ( 47) N-ethyl-N-(4-hydroxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, = 1.5363 (48) N-ethyl-N-(2-hydroxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl acetate ), sm.p. 132 - 133° C (49) N-ethyl-N-(2-acetyloxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nj< 1> = 1.5218 (50) N,N-dipropyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^ = 1.5151 ( 51) N-butyl-N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nQ 15 = 1.5509 (52) N-methyl -N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, pale yellow liquid

rn rn

NMR: 6UU-L4 1,00 - 2,00 (10H, br.), 1,80 - 2,70 NMR: 6UU-L4 1.00 - 2.00 (10H, br.), 1.80 - 2.70

ppm ppm

(4H, m), 2,73 (3H, d, J = 6Hz), 3,28 (2H, t, (4H, m), 2.73 (3H, d, J = 6Hz), 3.28 (2H, t,

J = 6Hz), 3,85 (3H, s), 3,20 - 4,50 (1H, m) J = 6Hz), 3.85 (3H, s), 3.20 - 4.50 (1H, m)

(53) N,N-dimethyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^ = 1,5327 (54) N-ethyl-N-cyclocyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^<6> = 1,5309 (55) 5-[3-(4-methylpiperazinocarbonyl)propyl-thio]-1-methyl-l,2,3,4-tetrazol,farveløse flak (hexan-ethyl-acetat) , sm.p. 65 - 68° C (56) 5-(3-piperidinocarbonylpropylthio)-1-methyl-25 (53) N,N-dimethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^ = 1.5327 (54) N-ethyl- N-cyclocyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<6> = 1.5309 (55) 5-[3-( 4-methylpiperazinocarbonyl)propyl-thio]-1-methyl-1,2,3,4-tetrazole, colorless flakes (hexane-ethyl-acetate), m.p. 65 - 68° C (56) 5-(3-piperidinocarbonylpropylthio)-1-methyl-25

1,2,3,4-tetrazol, farveløs væske, nQ = 1,5310 1,2,3,4-tetrazole, colorless liquid, nQ = 1.5310

(57) N-ethyl-N-cycloheptyl-4-(1-methyl-l,2,3,4-18 tetrazol-5-yl)thio-butyramid, farveløs væske, nQ = 1,5290 Eksempel 58 45 mmol 4-(1-fenyl-1,2,3,4-tetrazol-5-yl)thio-smørsyre ble løst i 50 ml tetrahydrofuran og til blandingen ble tilsatt 50 mmol DBU. Til blandingen ble det dråpevis tilsatt under omrøring 50 mmol isobutylklorformiat under is-avkjøling. Blandingen ble omrørt ved romtemperatur i 30 minutter. Til blandingen ble det dråpevis tilsatt 54 mmol N-ethylcyclohexylamin, og blandingen ble ytterligere omrørt ved romtemperatur i 2 timer.<1> Etter avdestillering av løs-ningsmidlet under redusert trykk ble residuet ekstrahert med kloroform. Kloroformlaget ble vasket med 5 %-ig vandig saltsyre, en vandig mettet nåtriumhydrogencarbonatløsning og en vandig natriumkloridløsning, og ble tørket over vann- (57) N-ethyl-N-cycloheptyl-4-(1-methyl-1,2,3,4-18 tetrazol-5-yl)thio-butyramide, colorless liquid, nQ = 1.5290 Example 58 45 mmol 4 -(1-phenyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid was dissolved in 50 ml of tetrahydrofuran and to the mixture was added 50 mmol of DBU. 50 mmol of isobutyl chloroformate was added dropwise to the mixture with stirring under ice-cooling. The mixture was stirred at room temperature for 30 minutes. 54 mmol of N-ethylcyclohexylamine was added dropwise to the mixture, and the mixture was further stirred at room temperature for 2 hours. <1> After distilling off the solvent under reduced pressure, the residue was extracted with chloroform. The chloroform layer was washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium bicarbonate solution and an aqueous sodium chloride solution, and was dried over water

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fritt natriumsulfat. Kloroform ble destillert fra, og det resulsterende residuum ble underkastet kolonnekromåtografi (Wakogel C-200, elueringsmiddel kloroform) for å isolere N-ethyl-N-cyclohexyl-4-(1-fenyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (utbytte: 43 %), farveløs væske, n^ 18 = 1,5590. Elementæranalyse for C^gH^OS: free sodium sulfate. Chloroform was distilled off, and the resulting residue was subjected to column chromatography (Wakogel C-200, eluent chloroform) to isolate N-ethyl-N-cyclohexyl-4-(1-phenyl-1,2,3,4-tetrazol-5 -yl)thio-butyramide (yield: 43%), colorless liquid, n^ 18 = 1.5590. Elemental analysis for C^gH^OS:

Beregnet: C 61,10 % H 7,29 % N 18,75 % Calculated: C 61.10% H 7.29% N 18.75%

Funnet : C 61,28 % H-7,38 % N 18,86 % Found : C 61.28% H-7.38% N 18.86%

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Eksempel 59 Example 59

På samme måte som beskrevet i eksempel 58, med det unntak at N,N-diethylamin ble anvendt i stedet for N-ethyl-N-cyclohexylamin, ble det erholdt N,N-diethyl-4-(1-fenyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, In the same manner as described in Example 58, with the exception that N,N-diethylamine was used instead of N-ethyl-N-cyclohexylamine, N,N-diethyl-4-(1-phenyl-1,2) was obtained ,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid,

n^<8> = 1,5592. n^<8> = 1.5592.

Eksempel 60 Example 60

45 mmol 2-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-eddiksyre ble løst i 50 ml tetrahydrofuran og til blandingen ble tilsatt 50 mmol DBU. Til blandingen ble det tilsatt dråpevis under omrøring 50 mmol isobutylformiat under is-avkjøling, og blandingen ble omrørt ved romtemperatur i 30 minutter. Til blandingen ble dråpevis tilsatt N-ethyl-cyclohexylamin under isavkjøling, og blandingen ble ytterligere omrørt ved romtemperatur i 2 timer. Etter avdestillering av løsningsmidlet under redusert trykk ble det resulterende residuum ekstrahert med,kloroform. Kloroformlaget ble vasket med 5 %-ig vandig saltsyre, en vandig mettet nåtrium-hydrogencarbonatløsning og en'vandig mettet natriumklorid-løsning og tørket over vannfritt natriumsulfat. Kloroform ble destillert fra og residuet under kastet kolonnekromåtograf i (Wakogel C-200, elueringsmiddel benzen:kloroform = 4:1, v/v) for å isolere N-ethyl-N-cyclohexyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-acetamid (utbytte: 52 %) som ble omkrystallisert fra ether-petroleumether, hvite prismer, sm.p. 60 - 71° C. 45 mmol of 2-(1-methyl-1,2,3,4-tetrazol-5-yl)thioacetic acid was dissolved in 50 ml of tetrahydrofuran and 50 mmol of DBU was added to the mixture. To the mixture, 50 mmol of isobutyl formate was added dropwise with stirring under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. N-ethyl-cyclohexylamine was added dropwise to the mixture under ice-cooling, and the mixture was further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the resulting residue was extracted with chloroform. The chloroform layer was washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. Chloroform was distilled from and the residue under throw column chromatograph in (Wakogel C-200, eluent benzene:chloroform = 4:1, v/v) to isolate N-ethyl-N-cyclohexyl-2-(1-methyl-1,2 ,3,4-tetrazol-5-yl)thioacetamide (yield: 52%) which was recrystallized from ether-petroleum ether, white prisms, m.p. 60 - 71° C.

Elementæranalyse for C^^^NgOS: Elementary analysis for C^^^NgOS:

Beregnet: C 50,86 % H 7,47 % N 24,71 % Calculated: C 50.86% H 7.47% N 24.71%

funnet : C 50,75 % H 7,55 % N 24,78 % found : C 50.75% H 7.55% N 24.78%

Eksempel 61 og 62 Examples 61 and 62

På samme måte som beskrevet i eksempel 60 ble følgende forbindelser fremstilt ved anvendelse av egnede utgangsmaterialer: (61) N-ethyl-N-cyclohexyl-3-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-propionamid, lysegul væske, n^ = 1,5273 (62) N-ethyl-N-cyclohexyl-5-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-valeramid, lysegul væske, nn 25 = 1,5227. Eksempel 63 45 mmol 4-(1-cyclohexyl-l,2,3,4-tetrazol-5-yl)-thio-smørsyre ble løst i 50 ml tetrahydrofuran og til blandingen ble tilsatt 50 mmol DBU. Til blandingen ble dråpevis tilsatt under omrøring isobutylklorformiat under isavkjøling, og blandingen ble omrørt ved romtemperatur i 30 minutter. Til blandingen ble dråpevis tilsatt 54 mmol N-ethylcyclohexylamin, og blandingen ble ytterligere omrørt ved romtemperatur i 2 timer. Etter avdestillering av løsningsmidlet under redusert trykk ble residuet ekstrahert med kloroform. Kloroformlaget ble vasket med 5 %-ig vandig saltsyre, en vandig mettet natriumhydrogencarbonatløsning og en vandig mettet natrium-kloridløsning, og tørket over vannfritt natriumsulfat. Kloroform blé destillert fra, og det resulterende residuum ble underkastet kolonnekromåtografi (Wakogel C-200, eluering-middel benzen:kloroform = 4:1, v/v) for å isolere N-ethyl-N-cyclohexyl-4-(1-cyclohexyl-l,2,3,4-tetrazol-5-yl)thiobutyramid In the same manner as described in Example 60, the following compounds were prepared using suitable starting materials: (61) N-ethyl-N-cyclohexyl-3-(1-methyl-1,2,3,4-tetrazol-5-yl) thio-propionamide, pale yellow liquid, n^ = 1.5273 (62) N-ethyl-N-cyclohexyl-5-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-valeramide, pale yellow liquid, nn 25 = 1.5227. Example 63 45 mmol of 4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)-thiobutyric acid was dissolved in 50 ml of tetrahydrofuran and 50 mmol of DBU was added to the mixture. Isobutyl chloroformate was added dropwise to the mixture while stirring under ice cooling, and the mixture was stirred at room temperature for 30 minutes. 54 mmol of N-ethylcyclohexylamine was added dropwise to the mixture, and the mixture was further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the residue was extracted with chloroform. The chloroform layer was washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Chloroform was distilled off, and the resulting residue was subjected to column chromatography (Wakogel C-200, eluent benzene:chloroform = 4:1, v/v) to isolate N-ethyl-N-cyclohexyl-4-(1-cyclohexyl -1,2,3,4-tetrazol-5-yl)thiobutyramide

18 18

(utbytte: 47 %), farveløs væske, nQ = 1,5290. Elementæranalyse for C^H^N^OS: (yield: 47%), colorless liquid, nQ = 1.5290. Elemental analysis for C^H^N^OS:

Beregnet: C 60,12 % H 8,76 % N 18,45 % Calculated: C 60.12% H 8.76% N 18.45%

Funnet : C 59,95 % H 8,62 % N 18,55 % Found : C 59.95% H 8.62% N 18.55%

Eksempel 64 Example 64

Til 50 ml methylenklorid ble tilsatt 45 mmol 4-(1-methyl-l,2,3,4-tetraz o1-5-yl)thio-smørsyre og 50 mmol N-methylmorfolin. Til blandingen ble det dråpevis tilsatt under omrøring 50 mmol methylklorformiat mens den indre temperatur ble holdt ved 10 - 20° C, ved iskjøling, og deretter ble blandingen omrørt ved romtemperatur i 30 minutter. Til blandingen ble tilsatt 54 mmol 2-méthoxycyclohexylamin, og blandingen ble omrørt ved samme temperatur i 4 timer. Etter 45 mmol of 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid and 50 mmol of N-methylmorpholine were added to 50 ml of methylene chloride. To the mixture, 50 mmol of methyl chloroformate was added dropwise with stirring while the internal temperature was kept at 10 - 20° C, by ice cooling, and then the mixture was stirred at room temperature for 30 minutes. 54 mmol of 2-methoxycyclohexylamine was added to the mixture, and the mixture was stirred at the same temperature for 4 hours. After

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omsetningen ble vann tilsatt reaksjonsblandingen. Det organiske lag ble fraskilt og vasket med fortynnet vandig natrium-hydroxydløsning, fortynnet saltsyre og vann, og ble tørket reaction, water was added to the reaction mixture. The organic layer was separated and washed with dilute aqueous sodium hydroxide solution, dilute hydrochloric acid and water, and was dried

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over natriumsulfat. Uorganiske materialer ble filtrert fra, og modervæsken ble konsentrert'. Det resulterende residuum ble underkastet kolonnekromåtografi (Wakogel C-200, elueringsmiddel : benzen:kloroform<1>= 4:1, v/v) for å isolere N- over sodium sulfate. Inorganic materials were filtered off and the mother liquor was concentrated. The resulting residue was subjected to column chromatography (Wakogel C-200, eluent : benzene:chloroform<1>= 4:1, v/v) to isolate N-

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(4-methoxycyclohexyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)-thio-butyramid (utbytte: 43 farveløs væske, n^ = 1,5263. Elementæranalyse for C^.jH23N502^ : (4-Methoxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide (yield: 43 colorless liquid, n^ = 1.5263. Elemental analysis for C^. jH23N502^ :

Beregnet: C 52,50 % H 7,79 % >N 23,55 % Calculated: C 52.50% H 7.79% >N 23.55%

Funnet : C 52,56 % H 7,71 % ;N 23,63 % Found : C 52.56% H 7.71% ;N 23.63%

Eksempel 65 Example 65

Til 50 ml tetrahydrofuran ble tilsatt 45 mmol 4-(l-methyl-1,2,3,4-tetrazol-5-yl)thio-smørsyre og 50 mmol pyridin, og blandingen ble dråpevis tilsatt under omrøring 50 mmol bromformiat mens den indre temperatur ble holdt ved 5 - 15° C ved iskjøling, og deretter ble 'blandingen omrørt ved romtemperatur i 1 time. Til blandingen ble tilsatt 55 mmol 4-methylcyclohexylamin, og blandingen ble ytterligere omrørt i 3 timer. Etter omsetningen ble løsningsmidlet destillert fra under redusert trykk, og residuet ble løst i kloroform. Kloroformlaget ble vasket med fortynnet vandig natriumhydroxyd-løsning, fortynnet saltsyre og vann, og ble tørket over natriumsulfat. Uorganiske materialer ble filtrert fra, og modervæsken ble konsentrert. Det resulterende residuum ble underkastet kolonnekromåtografi (Wakogel C-200, elueringsmiddel: benzen:kloroform = 4:1, v/v) for å isolere N-(4-methylcyclohexyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid (utbytte: 45 %). 45 mmol of 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid and 50 mmol of pyridine were added to 50 ml of tetrahydrofuran, and the mixture was added dropwise with stirring while 50 mmol of bromoformate temperature was maintained at 5-15°C by ice-cooling, and then the mixture was stirred at room temperature for 1 hour. 55 mmol of 4-methylcyclohexylamine was added to the mixture, and the mixture was further stirred for 3 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform. The chloroform layer was washed with dilute aqueous sodium hydroxide solution, dilute hydrochloric acid and water, and was dried over sodium sulfate. Inorganic materials were filtered off and the mother liquor was concentrated. The resulting residue was subjected to column chromatography (Wakogel C-200, eluent: benzene:chloroform = 4:1, v/v) to isolate N-(4-methylcyclohexyl)-4-(1-methyl-1,2,3, 4-tetrazol-5-yl)thio-butyramide (yield: 45%).

Elementæranalyse for C^J^-jN^-OS: Elemental analysis for C^J^-jN^-OS:

Beregnet: C 52,50 % H 7,79 % N 23,55 % Calculated: C 52.50% H 7.79% N 23.55%

Funnet : C 52,31 % H 7,65 % N 23,80 % Found : C 52.31% H 7.65% N 23.80%

Eksempel 66 Example 66

45 mmol 4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-smørsyre ble løst i 50 ml tetrahydrofuran, og til løsningen ble tilsatt 50 mmol DBU. Til blandingen ble dråpevis tilsatt under omrøring 50 mmol isobutylklorformiat under isavskjøling, og blandingen ble omrørt ved romtemperatur i 30 minutter. 45 mmol of 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid was dissolved in 50 ml of tetrahydrofuran, and 50 mmol of DBU was added to the solution. 50 mmol of isobutyl chloroformate was added dropwise to the mixture while stirring under ice-cooling, and the mixture was stirred at room temperature for 30 minutes.

Til blandingen ble dråpevis tilsatt 54 mmol 4-(N,N-dimethyl-amino)cyclohexylamin og blandingen ble ytterligere omrørt ved romtemperatur i 2 timer. Etter avdestillering av løsnings-midlet under redusert trykk ble det resulterende residuum ekstrahert med kloroform. Kloroformlaget ble vasket med 5 %-ig vandig saltsyre, en vandig mettet natriumhydrogen-carbonatløsning og en vandig mettet natriumkloridløsning og ble deretter tørket over vannfritt natriumsulfat. Kloroform ble destillert fra, og det resulterende residuum ble underkastet silicagelkolonnekromatografi (Wakogel C-200, elueringsmiddel, benzen:kloroform = 4:1, v/v) for å isolere N-[4-(N,N-dimethylamino)-cyclohexyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)-thiobutyramid (utbytte: 47 %). 54 mmol of 4-(N,N-dimethylamino)cyclohexylamine was added dropwise to the mixture and the mixture was further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the resulting residue was extracted with chloroform. The chloroform layer was washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and was then dried over anhydrous sodium sulfate. Chloroform was distilled off, and the resulting residue was subjected to silica gel column chromatography (Wakogel C-200, eluent, benzene:chloroform = 4:1, v/v) to isolate N-[4-(N,N-dimethylamino)-cyclohexyl) -4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thiobutyramide (yield: 47%).

Elementæranalyse for C^I^gNgOS: Elemental analysis for C^I^gNgOS:

Beregnet: C 51,51 % H 8,03 % N 25,74 % Calculated: C 51.51% H 8.03% N 25.74%

Funnet : C 51,60 % H 8,22 % N 26,05 % Found : C 51.60% H 8.22% N 26.05%

Eksempel 67 Example 67

45 mmol 4-[1-(2-methoxycyclohexyl)-1,2,3,4-tetrazol-5-yl)thio-smørsyre ble løst i 50 ml tetrahydrofuran, og til løsningen ble tilsatt 50 mmol DBU. Til blandingen ble dråpevis tilsatt under omrøring 50 mmol isobutylklorformiat under isavkjøling, og blandingen ble omrørt ved romtemperatur i 30 minutter. Til blandingen ble dråpevis tilsatt 54 mmol N-ethyl-cyclohexylamin, og blandingen ble ytterligere omrørt ved romtemperatur i 2 timer. Løsningsmidlet ble destillert fra under redusert trykk, og residuet ekstrahert med kloroform. Kloroformlaget ble vasket med 5.%-ig vandig saltsyre, en vandig mettet natriumhydrogencarbonatløsning og en vandig mettet natriumkloridløsning og ble deretter tørket over vannfritt natriumsulfat. Etter avdestillering av kloroform 45 mmol of 4-[1-(2-methoxycyclohexyl)-1,2,3,4-tetrazol-5-yl)thiobutyric acid was dissolved in 50 ml of tetrahydrofuran, and 50 mmol of DBU was added to the solution. 50 mmol of isobutyl chloroformate was added dropwise to the mixture while stirring under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 54 mmol of N-ethyl-cyclohexylamine was added dropwise to the mixture, and the mixture was further stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue extracted with chloroform. The chloroform layer was washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution and was then dried over anhydrous sodium sulfate. After distilling off chloroform

ble det resulterende residuum' underkastet kolonnekromåtografi the resulting residue was subjected to column chromatography

(Wakogel C-200, elueringsmiddel, benzen:kloroform = 4:1, v/v) (Wakogel C-200, eluent, benzene:chloroform = 4:1, v/v)

for å isolere N-ethyl-N-cyclohexyl-4-(1-(2-methoxycyclohexyl)-1,2,3,4-tetrazol-5-yl]thiobutyramid (utbytte: 45 %). Elementæranalyse for C2QH35N5O2S: to isolate N-ethyl-N-cyclohexyl-4-(1-(2-methoxycyclohexyl)-1,2,3,4-tetrazol-5-yl]thiobutyramide (yield: 45%). Elemental analysis for C2QH35N5O2S:

Beregnet: C 58,65 % H 8,61 % N 17,10 % Calculated: C 58.65% H 8.61% N 17.10%

Funnet : C 58,25 % H 8,34 % N 17,20 % Found : C 58.25% H 8.34% N 17.20%

Eksempel 68 Example 68

45 mmol 4-[1-(4-ethylf enyl)-1,2 ,3 ,4-tetrazo,l-5-yl] - thio-smørsyre ble løst i 50 ml tetrahydrofuran, og til løs-ningen ble tilsatt 50 mmol DBU. Til blandingen ble dråpevis tilsatt under omrøring 50 mmol isobutylklorformiat under is-avkjøling, og blandingen ble omrørt ved romteperatur i 30 minutter. Til blandingen ble, dråpevis tilsatt 54 mmol N-ethyl-cyclohexylamin, og blandingen ble ytterligere omrørt ved romtemperatur i 2 timer. ! Løsningsmidlet ble destillert fra under redusert trykk, og det resulterende residuum ble ekstrahert med kloroform. Kloroformlaget ble vasket med 5 %-ig vandig saltsyre, en vandig mettet natriumhydrogen-carbonatløsning og en vandig mettet natriumkloridløsning og ble deretter tørket over vannfritt natriumsulfat. Kloroform ble destillert fra og det resulterende residuum underkastet kolonnekromåtografi (Wakogel C-200, elueringsmiddel, benzen: kloroform = 4:1, v/v) for å isolere N-ethyl-N-cyclohexyl-4-[1-(4-ethylfenyl)-1,2,3,4-tetrazol-5-yl]thio-butyramid 45 mmol of 4-[1-(4-ethylphenyl)-1,2,3,4-tetrazo,1-5-yl]-thiobutyric acid was dissolved in 50 ml of tetrahydrofuran, and 50 mmol of DBU. 50 mmol of isobutyl chloroformate was added dropwise to the mixture while stirring under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 54 mmol of N-ethyl-cyclohexylamine was added dropwise to the mixture, and the mixture was further stirred at room temperature for 2 hours. ! The solvent was distilled off under reduced pressure, and the resulting residue was extracted with chloroform. The chloroform layer was washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and was then dried over anhydrous sodium sulfate. Chloroform was distilled from and the resulting residue subjected to column chromatography (Wakogel C-200, eluent, benzene:chloroform = 4:1, v/v) to isolate N-ethyl-N-cyclohexyl-4-[1-(4-ethylphenyl) )-1,2,3,4-tetrazol-5-yl]thio-butyramide

19 19

(utbytte: 43 %), farveløs væske, nn = 1,5533. Elementæranalyse for C2^H^N,-OS: (yield: 43%), colorless liquid, nn = 1.5533. Elemental analysis for C2^H^N,-OS:

Beregnet: C 62,81 % H 7,78 % N 17,44 % Calculated: C 62.81% H 7.78% N 17.44%

Funnet : C 63,05 % H 7,84 % N 17,81 % Found : C 63.05% H 7.84% N 17.81%

Eksempel 69 Example 69

2,5 g 5-(l-fenyl-l,2,3,4-tetrazol-5-yl)valerinsyre ble løst i 50 ml dimethylforammid, og til løsningen ble tilsatt 1,1 g triethylamin. Til .blandingen ble dråpevis tilsatt under omrøring 1,5 g isobutylkloroformiat under isavkjøling, og blandingen ble omrørt ved romtemperatur i 3 0 minutter. 2.5 g of 5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeric acid was dissolved in 50 ml of dimethylformamide, and 1.1 g of triethylamine was added to the solution. To the mixture, 1.5 g of isobutyl chloroformate was added dropwise with stirring under ice cooling, and the mixture was stirred at room temperature for 30 minutes.

Til blandingen ble det dråpevis tilsatt under omrøring 0,9 g diethylamin ved romtemperatur, og blandingen ble omrørt i 2 timer. Etter avdestillering av dimethylformamid under redusert trykk ble aceton tilsatt til det resulterende residuum, og uløselig materiale ble filtrert fra. Modervæsken ble konsentrert og deretter renset ved kolonnekromåtografi (Kieselgel 60). Ved eluering med kloroform ble det erholdt N,N-diethyl-5-(l-fenyl-l,2,3,4-tetrazol-5-yl)valeramid (1,2 g), 25 To the mixture, 0.9 g of diethylamine was added dropwise with stirring at room temperature, and the mixture was stirred for 2 hours. After distilling off dimethylformamide under reduced pressure, acetone was added to the resulting residue, and insoluble material was filtered off. The mother liquor was concentrated and then purified by column chromatography (Kieselgel 60). Elution with chloroform gave N,N-diethyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide (1.2 g), 25

farveløs væske, nn = 1,53 03. colorless liquid, nn = 1.53 03.

Elementæranalyse for C,,H~oNc0: Elemental analysis for C,,H~oNc0:

-1 16 23 5 -1 16 23 5

Beregnet: C 56,40 % H 6,63 % N 21,92 % Calculated: C 56.40% H 6.63% N 21.92%

Funnet : C 56,69 % H 6,80 % N 21,71 % Found : C 56.69% H 6.80% N 21.71%

Eksempel 70 Example 70

2,5 g 5-(1-cyclohexyl-l,2,3,4-tetrazol-5-yl)-valerinsyre ble løst i 50 ml tetrahydrofuran, og til løsningen ble tilsatt 1,1 g triethylamin. Til blandingen ble dråpevis tilsatt under omrøring 1,5 g isobutylklorformiat under is-avkjøling, og blandingen ble omrørt ved romtemperatur i 30 minutter. Til blandingen ble dråpevis tilsatt under omrøring 1,5 g N-ethylcyclohexylamin ved romtemperatur, og blandingen ble ytterligere omrørt i 2 timer. Etter avdestillering av tetrahydrofuran, ble vann tilsatt til residuet, og blandingen ble ekstrahert med kloroform. Kloroformlaget ble vasket med en vandig mettet natriumkloridløsning og tørket over magnesiumsulfat. Kloroform ble destillert fra og det resulterende residuum ble underkastet kolonnekromåtografi (kiselgel 60, elueringsmiddel kloroform) for å isolere N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-l,2,3,4-tetrazol-5-yl)valeramid 12,6 g), 2.5 g of 5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)-valeric acid was dissolved in 50 ml of tetrahydrofuran, and 1.1 g of triethylamine was added to the solution. To the mixture was added dropwise with stirring 1.5 g of isobutyl chloroformate under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 1.5 g of N-ethylcyclohexylamine was added dropwise to the mixture with stirring at room temperature, and the mixture was further stirred for 2 hours. After distilling off tetrahydrofuran, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with an aqueous saturated sodium chloride solution and dried over magnesium sulfate. Chloroform was distilled off and the resulting residue was subjected to column chromatography (silica gel 60, eluent chloroform) to isolate N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl) valeramide 12.6 g),

25 25

farveløs væske, nQ = 1,4970. colorless liquid, nQ = 1.4970.

Elementæranalyse for C^qH^N^O: Elemental analysis for C^qH^N^O:

Beregnet: C 66,44 % H 9,76 % N 19,37 % Calculated: C 66.44% H 9.76% N 19.37%

Funnet : C 66,78 % H 9,56 % N 19,52 % Found : C 66.78% H 9.56% N 19.52%

Eksempel 71 Example 71

1,8 g 5-(1-methyl-l, 2 , 3, 4-tetrazol-5-yl) valeri.ansyre ble løst i 50 ml dimethylformamid, og til løsningen ble tilsatt 1,1 g triethylamin. Til blandingen ble dråpevis tilsatt under omrøring 1,5 g isobutylklorfgrmiat under isavkjølkng, 1.8 g of 5-(1-methyl-1,2,3,4-tetrazol-5-yl)valeric acid was dissolved in 50 ml of dimethylformamide, and 1.1 g of triethylamine was added to the solution. To the mixture, 1.5 g of isobutyl chloroform was added dropwise with stirring under ice cooling,

og blandingen ble omrørt ved romtemperatur i 30 minutter. and the mixture was stirred at room temperature for 30 minutes.

Til blandingen ble dråpevis tilsatt under omrøring 0,9 g diethylamin ved romtemperatur, og blandingen ble omrørt i To the mixture was added dropwise with stirring 0.9 g of diethylamine at room temperature, and the mixture was stirred in

2 timer. Dimethylformamid ble destillert fra under redusert trykk, og residuet ble renset ved kolonnekromåtografi (WAkogel C-200). Etter eluering med benzen-kloroform (1:1), ble eluatet destillert under redusert trykk under dannelse av N, N-diethyl- 5- (1-methyl-l, 2, 3l, 4-tetrazol-5-y 1) valer amid 2 hours. Dimethylformamide was distilled off under reduced pressure, and the residue was purified by column chromatography (WAkogel C-200). After elution with benzene-chloroform (1:1), the eluate was distilled under reduced pressure to give N,N-diethyl-5-(1-methyl-1,2,3l,4-tetrazol-5-y1)valer amide

(0,7 g), farveløs væske, k.p. 190 - 200° C (badtemperatur)/ 0,07 mmHg, n^<5> 1,4907. j (0.7 g), colorless liquid, b.p. 190 - 200° C (bath temperature)/ 0.07 mmHg, n^<5> 1.4907. j

Elementæranalyse for c;qH21N5^: Elemental analysis for c;qH21N5^:

Beregnet: C 55,20 % H 8,85 %; N 29,27 % Calculated: C 55.20% H 8.85%; N 29.27%

Funnet : C 55,48 % H 8,98o.%; N 29,43 % Found : C 55.48% H 8.98o.%; N 29.43%

Eksempel 72- 76 Example 72-76

På samme måte som beskrevet i eksempel 71 ble In the same way as described in example 71 was

i in

følgende forbindelser fremstilt under anvendelse av egnede utgangsmaterialer: j (72) N,N-diethyl-5-(1-cyclohexyl-l,2,3,4-tetrazol-5-yl)valeramid, farveløs væske, n^ = 1,4970 (73) N,N-diethyl-5-(1,2,3,4-tetrazol-5-yl)-valeramid, farveløs væske, nn2<5> = 1,4867 following compounds prepared using suitable starting materials: j (72) N,N-diethyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramide, colorless liquid, n^ = 1, 4970 (73) N,N-diethyl-5-(1,2,3,4-tetrazol-5-yl)-valeramide, colorless liquid, nn2<5> = 1.4867

(74) N-ethyl-N-cyclohexy1-5-(1-methyl-l,2,3,4- (74) N-ethyl-N-cyclohexy1-5-(1-methyl-1,2,3,4-

18 tetrazol-5-yl)valeramid, farveløs væske, NQ = 1,5085 (75) N-ethyl-N-cyclphexyl-5-(1-cyclohexyl-l,2,3,4-tetrazol-5-yl)valeramid, hvitt? krystallinsk pulver (ether), sm.p. 92 - 95° C (76) N-ethyl-N-cyclphexyl-5-(1-fenyl-l,2,3,4-tetrazol-5-yl)valeramid, hvite prismer (ether), sm.p. 73 - 75° C 18 tetrazol-5-yl)valeramide, colorless liquid, NQ = 1.5085 (75) N-ethyl-N-cyclphexyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramide , white? crystalline powder (ether), m.p. 92 - 95° C (76) N-ethyl-N-cyclphexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide, white prisms (ether), m.p. 73 - 75° C

Eksempel 77 Example 77

2 g 3-(1-methyl-l,2,3,4-tetrazol-5-yl)methylthio-propionsyre ble løst i 50 ml tétrahydrofuran, og til løsningen ble tilsatt 1,1 g triethylamin,. Til blandingen ble dråpevis tilsatt under omrøring 1,5 g isobutylklorformiat under isav-kjølkng, og blandingen ble omrørt ved romtemperatur i 30 minutter. Til blandingen ble dråpevis tilsatt under omrøring 0,9 g diethylamin ved den samme temperatur, og blandingen ble ytterligere omrørt i 3 timer. Etter avdestillering av løs-ningsmidlet ble det' resulterende residuum underkastet kolonnekromatografi (kiselgel 60, elueringsmiddel, kloroform: 2 g of 3-(1-methyl-1,2,3,4-tetrazol-5-yl)methylthio-propionic acid was dissolved in 50 ml of tetrahydrofuran, and 1.1 g of triethylamine was added to the solution. 1.5 g of isobutyl chloroformate was added dropwise to the mixture with stirring under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added dropwise with stirring 0.9 g of diethylamine at the same temperature, and the mixture was further stirred for 3 hours. After distilling off the solvent, the resulting residue was subjected to column chromatography (silica gel 60, eluent, chloroform:

i in

methanol = 50:1, v/v) for å isolere N,N-diethyl-3-(1-methyl-1,2,3,4-tetrazol-5-yl)methylthio-propionamid (1,5 g), farve-løs væske, n^<5> = 1,6200. methanol = 50:1, v/v) to isolate N,N-diethyl-3-(1-methyl-1,2,3,4-tetrazol-5-yl)methylthio-propionamide (1.5 g), colorless liquid, n^<5> = 1.6200.

Elementæraaålyse for C-^qH^Ni-OS: Elementary analysis for C-^qH^Ni-OS:

Beregnet: C 46,67 % H 7,44 % N 27,21 % Calculated: C 46.67% H 7.44% N 27.21%

Funnet : C 46,85 % H 7,61 % N 27,39 % Found : C 46.85% H 7.61% N 27.39%

Eksempel 78 - 80 Example 78 - 80

På samme måte som beskrevet i eksempel 77 ble In the same way as described in example 77 was

dé føljgeride forbindelser fremstilt under anvendelse av egnede utgangsmaterialer: (78) N,N-diethyl-3-(1-ethyl-l,2,3,4-tetrazol-5-yDmethylthio-propionamid, farveløse nåler (omkrystallisert fra ether), sm.p. 58 - 59° C (79) N,N-diethyl-3-[l-(4-ethylfenyl)-1,2,3 ,4-tetrazol-5-yl)]methylthio-propionamid, farveløs væske, nQ 25 = 1,5499 the following compounds prepared using suitable starting materials: (78) N,N-diethyl-3-(1-ethyl-1,2,3,4-tetrazol-5-yDmethylthio-propionamide, colorless needles (recrystallized from ether), mp 58 - 59° C (79) N,N-diethyl-3-[1-(4-ethylphenyl)-1,2,3,4-tetrazol-5-yl)]methylthio-propionamide, colorless liquid , nQ 25 = 1.5499

(80) N-ethyl-N-cyclohexyl-3-(1-ethyl-l,2,3,4- (80) N-ethyl-N-cyclohexyl-3-(1-ethyl-1,2,3,4-

18 tetrazol-5-yl)methylthio-propionamid, lys gul væske, nQ = 1,5277 18 tetrazol-5-yl)methylthio-propionamide, light yellow liquid, nQ = 1.5277

Eksempel 81 Example 81

10 ml thionylklorid ble tilsatt til 2 g 4-(l-methyl-1,2,3,4-tetrazol-5-yl)thio-smørsyre og blandingen ble kokt under tilbakeløpskjøling i 1 time. Etter at overskudd av thionylklorid var destillert fra under redusert trykk, ble tørr benzen tilsatt til residuet og den gjenværende lille mengde av thionylklorid ble fjernet som benzenazeotrop. Residuet ble løst i 50 ml tørr benzen, og til løsningen ble dråpevis tilsatt under omrøring 2,8 g N-methylcyclohexylamin under isavkjøling. Blandingen ble omrørt ved romtemperatur i 1 time og benzen ble tilsatt til reaksjonsblandingen. Blandingen ble vasket med fortynnet saltsyre, vandig mettet natriumbicarbonatløsning og deretter mettet vandig natrium-kloridløsning og ble tørket over natriumsulfat. Etter at benzen var destillert fra ble residuet underkastet kolonnekromatografi (Wakogel C-200) og kolonnen ble eluert med benzen-kloroform (4:1> v/v) under dannelse av N-methyl-N-cyclohexyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid (2,3 g), lys gul væske. 10 ml of thionyl chloride was added to 2 g of 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid and the mixture was refluxed for 1 hour. After excess thionyl chloride was distilled off under reduced pressure, dry benzene was added to the residue and the remaining small amount of thionyl chloride was removed as benzene azeotrope. The residue was dissolved in 50 ml of dry benzene, and 2.8 g of N-methylcyclohexylamine were added dropwise to the solution with stirring under ice cooling. The mixture was stirred at room temperature for 1 hour and benzene was added to the reaction mixture. The mixture was washed with dilute hydrochloric acid, aqueous saturated sodium bicarbonate solution and then saturated aqueous sodium chloride solution and was dried over sodium sulfate. After benzene was distilled off, the residue was subjected to column chromatography (Wakogel C-200) and the column was eluted with benzene-chloroform (4:1 > v/v) to give N-methyl-N-cyclohexyl-4-(1-methyl -1,2,3,4-tetrazol-5-yl)thio-butyramide (2.3 g), pale yellow liquid.

CC1 CC1

NMR: 6ppm4 1,00 - 2,00 (10 H, br), 1,80 - 2,70 (4 H, m), NMR: 6ppm4 1.00 - 2.00 (10 H, br), 1.80 - 2.70 (4 H, m),

2,73 (3H, d, J = 6Hz), 3,28 ;(2H, t, J = 6Hz), 3,85 2.73 (3H, d, J = 6Hz), 3.28 ; (2H, t, J = 6Hz), 3.85

(3H, s), 3,20 - 4,50 (1H, m) (3H, s), 3.20 - 4.50 (1H, m)

Elementæranalyse for C13H23N5OS: | Elemental analysis for C13H23N5OS: |

Beregnet: C 52,50 % H 7,79 % N '23,55 % Calculated: C 52.50% H 7.79% N '23.55%

Funnet : C 52,69 % H 7,83 % N.23,51 % Found : C 52.69% H 7.83% N.23.51%

Eksempel 82 - 100 Example 82 - 100

Under anveridelse av samme prosedyre som beskrevet i eksempel 81 ble følgende forbindelser fremstilt: Using the same procedure as described in Example 81, the following compounds were prepared:

i in

(82) N-ethyl-N-cyclohexyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, faryeløs væske, n^<7>'<5> = 1,5327 (83) N-ethyl-N-fenyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, lys gul væske, nD = 1,5534 (84) 5-(3-morfolinocarbonylpropylthio)-1-methyl-1,2,3,4-tetrazol-hvite nåler (omkrystallisert fra petroleum-3ther-ethanol), sm.p. 71 - 73° C (85) 5-[3-(4-acethylpiperazinocarbonyl)propyl-thio]-1-methyl-l,2,3,4-tetrazol-hvitt krystallpulver (omkrystallisert fra ligroin-aceton), sm.p. 90 - 91,5° C (86) N-[2-(3,4-dimethoxyfe nylethyl]-4-(1-methyl-1, 2,3,4-tetrazbl-5-yl) thio-butyramid', farveløse flak (omkrystallisert fra hexan-ethylacetat), sm.p. 70,5 - 71,5° C (82) N-ethyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<7>'<5> = 1 .5327 (83) N-ethyl-N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, light yellow liquid, nD = 1.5534 (84) 5-(3-morpholinocarbonylpropylthio)-1-methyl-1,2,3,4-tetrazole-white needles (recrystallized from petroleum-3-ether-ethanol), m.p. 71 - 73° C (85) 5-[3-(4-Acethylpiperazinocarbonyl)propyl-thio]-1-methyl-1,2,3,4-tetrazole white crystalline powder (recrystallized from ligroin-acetone), m.p. . 90 - 91.5° C (86) N-[2-(3,4-dimethoxyphenylethyl]-4-(1-methyl-1,2,3,4-tetrazbl-5-yl)thio-butyramide', colorless flakes (recrystallized from hexane-ethyl acetate), mp 70.5 - 71.5° C

(87) N-(2-hydroxyethyl)-4-(1-methyl-l,2,3,4- (87) N-(2-hydroxyethyl)-4-(1-methyl-1,2,3,4-

' 14 5 tetrazol-5-yl)thio-butyramid, farveløs væske, nn ' = 1,5350 ' 14 5 Tetrazol-5-yl)thio-butyramide, colorless liquid, nn ' = 1.5350

(88) N-ethyl-N-benzy1-4-(1-methyl-l,2,3,4-tetrazol-1 19 (88) N-ethyl-N-benzy1-4-(1-methyl-1,2,3,4-tetrazol-1 19

5-yl)thio-butyramid, farveløs væske, nn = 1,5596 5-yl)thio-butyramide, colorless liquid, nn = 1.5596

(89) N-cyclohexyl-N-[2-(3,4-dimethoxyfenyl)-ethyl]-4- (1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, njjj<**> = 1,5470 (90) N-methyl-N-(2-thienylmethyl)-4-(1-methyl- (89) N-cyclohexyl-N-[2-(3,4-dimethoxyphenyl)-ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid , njjj<**> = 1.5470 (90) N-methyl-N-(2-thienylmethyl)-4-(1-methyl-

1,2 , 3 ,4-tetrazol-5-yl) thio-butyråmdld, farveløs væske, n^ = 1,2 , 3 ,4-tetrazol-5-yl) thio-butyramdld, colorless liquid, n^ =

I IN

1,5706 1.5706

(91) N-(2-pyridyl)-4-(1-methyl-l,2,3,4-tetrazol-5- yl)thio-butyramid, farveløse nåler (hexan-ethylacetat), sm.p. 95 - 96° C (92) N-furfuryl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)-thio-butyramid, farveløse flak (hexan-ethylacetat), sm.p. 71 - 73° C (93) N-[4-(N,N-dimethylamino)fenyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse prismer (hexan-ethylacetat), sm.vp. 144 - 147° C (94) N-(2-methyl-3-klorfenyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (hexan-ethyl-acetat), sm.p. 104,5 - 105,5° C (95) N-methyl-N-(2-tetrahydropyranyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^<4> = 1,5273 (96) N-ethyl-N-cyclohexylmethyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n = 1,5293 (97) N-ethyl-B-(4-hydroxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butylamid, farveløs væske, nD q = 1,5363 (98) N-ethyl-N-(2-acetyloxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n = 1,5218 (99) 5-(3-piperidinocarbonylpropylthio)-1-methyl-1,2,3,4-tetrazol, farveløs væske, nn 25 = 1,5310(91) N-(2-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl acetate), m.p. 95 - 96° C (92) N-furfuryl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless flakes (hexane-ethyl acetate), m.p. 71 - 73° C (93) N-[4-(N,N-dimethylamino)phenyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless prisms (hexane-ethyl acetate), sm.vp. 144 - 147° C (94) N-(2-methyl-3-chlorophenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane- ethyl acetate), m.p. 104.5 - 105.5° C (95) N-methyl-N-(2-tetrahydropyranyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<4> = 1.5273 (96) N-ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n = 1.5293 (97) N-ethyl-B-(4-hydroxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butylamide, colorless liquid, nD q = 1.5363 (98) N-ethyl-N-(2-acetyloxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n = 1 .5218 (99) 5-(3-piperidinocarbonylpropylthio)-1-methyl-1,2,3,4-tetrazole, colorless liquid, nn 25 = 1.5310

(100) N-ethyl-N-cyclohexyl-4-(1-fenyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nQ 18 = 1,5590 Eksempel 101 10 ml thionylklorid ble tilsatt til 1,8 g 5-(l-fenyl-1,2,3,4-tetrazol-5-yl)valerinsyre og blandingen ble kokt under tilbakeløpskjøling i 1 time. Etter at overskudd av thionylklroid var destillert fra under redusert trykk, ble tørr benzen tilsatt til residuet, og den gjenværende lille mengde av thionylklorid ble fjernet som benzenazeotrop. Det resulterende residuum ble løst i 50 ml tørr pyridin, og til blandingen ble dråpevis tilsatt under omrøring 1,5 g N,N-diethylamin under isavkjølkng. Blandingen ble omrørt ved romtemperatur i 1 time og benzen ble tilsatt til reaksjonsblandingen. Blandingen ble vasket med fortynnet saltsyre, vandig mettet natriumbicarbonatløsning og vandig mettet natrium-kloridløsning og tørket over natriumsulfat. Etter at benzenet var destillert fra, ble residuet underkastet kolonnekromåtograf i (kiselgel 60) kolonnen ble eluert med kloroform under dannelse av N,N-diethyl-5-(1-fenyl-1,2,3,4-tetrazol-5-yl)- (100) N-ethyl-N-cyclohexyl-4-(1-phenyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nQ 18 = 1.5590 Example 101 10 ml thionyl chloride was added to 1.8 g of 5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeric acid and the mixture was refluxed for 1 hour. After excess thionyl chloride was distilled from under reduced pressure, dry benzene was added to the residue, and the remaining small amount of thionyl chloride was removed as the benzene azeotrope. The resulting residue was dissolved in 50 ml of dry pyridine, and to the mixture was added dropwise with stirring 1.5 g of N,N-diethylamine under ice-cooling. The mixture was stirred at room temperature for 1 hour and benzene was added to the reaction mixture. The mixture was washed with dilute hydrochloric acid, aqueous saturated sodium bicarbonate solution and aqueous saturated sodium chloride solution and dried over sodium sulfate. After the benzene was distilled off, the residue was subjected to column chromatography in (silica gel 60) the column was eluted with chloroform to give N,N-diethyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl )-

25 25

valeramid (2,1 g), farveløs væske, nQ = 1,5303. valeramide (2.1 g), colorless liquid, nQ = 1.5303.

Elementæranalyse for C16<H>23<N>5<0:>Elemental analysis for C16<H>23<N>5<0:>

Beregnet: C 63,76 % H 7,69 % N 23,24 % Calculated: C 63.76% H 7.69% N 23.24%

Funnet : C 63,88 % H 7,79 % N 23,31 % Found : C 63.88% H 7.79% N 23.31%

Eksempel 102 - 104 Example 102 - 104

Ved å gå frem som beskrevet i eksempel 101, ble følgende forbindelser erholdt: Proceeding as described in Example 101, the following compounds were obtained:

(102) N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-l,2,3, tetrazol-5-yl)valeramid, hvitt krystallinsk pulver (omkrysta lisert fra ether), sm.p. 92 95° C (102) N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-1,2,3,tetrazol-5-yl)valeramide, white crystalline powder (recrystallized from ether), m.p. 92 95° C

(103) N-ethyl-N-cyclohexy1-5-(1-methy1-1,2,3,4-18 tetrazol-5-yl)valeramid, farveløs væske, nn = 1,5085 (103) N-ethyl-N-cyclohexy1-5-(1-methy1-1,2,3,4-18 tetrazol-5-yl)valeramide, colorless liquid, nn = 1.5085

(104) N-ethyl-N-cyclohexyl-5-(1-fenyl-1,2,3,4-tetrazol-5-yl)valeramid, hvite prismer (ester), sm.p. 73 - 75° c (104) N-ethyl-N-cyclohexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide, white prisms (ester), m.p. 73 - 75° c

Eksempel 105 Example 105

2 g 4-(1-methyl-l,2;3,4-tetrazol-5-yl)thio-smørsyr og 1,4 g N-ethyl-N-cyclohexylamin ble tilsatt til et blandet løsningsmiddel av 20 ml dioxari og 20 ml methylenklorid, og til blandingen ble det dråpevis tilsatt under omrøring en løsning av 2,1 g N,N<1->dicyclohiex<y>lcarbodiimi<d> i 5 ml methylenklorid, som ble opprettholdt ved en temperatur på 10 - 20° C under omrøring mens man foretok utvendig kjøling i is. Etter tilsetning av løsningen ble omrøringen fortsatt ved den samme temperatur i 5 timer. Krystaller utskilt fra reaksjonsblandingen ble filtrert fra, og filtratet konsentrei under redusert trykk. Det resulterende residuum ble løst i 100 ml methylenklorid. Det organiske lag ble vasket med 5 %-ig vandig saltsyre, 5 %-ig vandig natriumbicarbonatløs-ning og vann, og ble tørket over natriumsulfat. Løsnings-midlet ble destillert fra under redusert trykk, og det resulterende residuum ble underkastet kolonnekromåtografi (Wakogel C-200) og kolonnen ble eluert med kloroform under dannelse av N-ethyl-N-cyclohexyl-4-(1-methyl-l,2,3,4-tetrazol 5-yl)thio-butyramid (0,8 g/, farveløs væske, n^<7>'<5> = 1,5327 Elementæranalyse for C^H^N^OS: 2 g of 4-(1-methyl-1,2;3,4-tetrazol-5-yl)thiobutyric acid and 1.4 g of N-ethyl-N-cyclohexylamine were added to a mixed solvent of 20 ml of dioxari and 20 ml of methylene chloride, and a solution of 2.1 g of N,N<1->dicyclohiex<y>lcarbodiimi<d> in 5 ml of methylene chloride was added dropwise with stirring, which was maintained at a temperature of 10 - 20° C with stirring while external cooling in ice was carried out. After addition of the solution, stirring was continued at the same temperature for 5 hours. Crystals separated from the reaction mixture were filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 100 ml of methylene chloride. The organic layer was washed with 5% aqueous hydrochloric acid, 5% aqueous sodium bicarbonate solution and water, and was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (Wakogel C-200) and the column was eluted with chloroform to give N-ethyl-N-cyclohexyl-4-(1-methyl-1,2 ,3,4-tetrazole 5-yl)thio-butyramide (0.8 g/, colorless liquid, n^<7>'<5> = 1.5327 Elemental analysis for C^H^N^OS:

Beregnet: C 53,99 % H 8,09 % N 22,49 % Calculated: C 53.99% H 8.09% N 22.49%

Funnet : C 54,12 % H 8,14 % N 22,56 % Found : C 54.12% H 8.14% N 22.56%

Eksempel 106 - 115 Example 106 - 115

Ved å gå frem på samme måte som beskrevet i eksempel 105, ble følgende forbindelser erholdt: By proceeding in the same manner as described in Example 105, the following compounds were obtained:

(106) N-ethyl-N-fenyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, lys gul væske, nn 2 6 = 1,5534 (106) N-ethyl-N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, light yellow liquid, nn 2 6 = 1.5534

(107) 5-(3-morfolinocarbonylpropylthio)-1-methyl, 1,2,3,4-tetrazol,hvite nåler (omkrystallisert fra petroleumether-ethanol), sm.p. 71 - 73° C (107) 5-(3-morpholinocarbonylpropylthio)-1-methyl, 1,2,3,4-tetrazole, white needles (recrystallized from petroleum ether-ethanol), m.p. 71 - 73° C

(108) N-[2-(3,4-dimethoxyfenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse flak (omkrystallisert fra hexan-ethylacetat), sm.p. 70,5 - 71,5° C (108) N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes (recrystallized from hexane- ethyl acetate), m.p. 70.5 - 71.5° C

(109) N-ethyl-N-benzyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nQ 19 = 1,5596 (109) N-ethyl-N-benzyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nQ 19 = 1.5596

(110) N-methyl-N-(2-thienylmethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^ = 1,5706 (110) N-methyl-N-(2-thienylmethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^ = 1.5706

(111) N-furfuryl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse flak, sm.p. 71 - 73° C (111) N-furfuryl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes, m.p. 71 - 73° C

(112) N-ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nn = 1,5293 (112) N-ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nn = 1.5293

(113) N-ethyl-N-cyclohexyl-4-(1-fenyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nQ = 1,5590 (113) N-ethyl-N-cyclohexyl-4-(1-phenyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nQ = 1.5590

(114) N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-l,2,3,4-tetrazol-5-yl)valeramid, hvitt krystallpulver (ether), sm.p. 92 - 95° C (114) N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramide, white crystalline powder (ether), m.p. 92 - 95° C

(115) N-ethyl-N-cyclohexyl-5-(1-fenyl-1,2,3,4-tetrazol-5-yl)valeramid, hvite prismer (ether), sm.p. 73 - 75° C (115) N-ethyl-N-cyclohexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide, white prisms (ether), m.p. 73 - 75° C

Eksempel 116 Example 116

3,2 g p-nitrofenyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyrat ble løst i 40 ml dimethylformamid, og til løsningen ble tilsatt 2,0 g cyclohexylamin. Reaksjonsblandingen fikk stå ved romtemperatur over natten, og ble deretter konsentrert under redusert trykk. Det resulterende residuum ble underkastet kolonnekromåtografi (Wakogel C-200) og kolonnen ble eluert med benzen-kloroform (4:1, v/v) og om- 3.2 g of p-nitrophenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyrate was dissolved in 40 ml of dimethylformamide, and 2.0 g of cyclohexylamine was added to the solution. The reaction mixture was allowed to stand at room temperature overnight, and was then concentrated under reduced pressure. The resulting residue was subjected to column chromatography (Wakogel C-200) and the column was eluted with benzene-chloroform (4:1, v/v) and re-

krystallisert fra hexan-ethylacetat under dannelse av N-cyclohexyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid (1,8 g), farveløse nåler, sm.p. 116,5 - 117,5 C. Elementæranalyse for C^2<H>21<N>5<OS:>crystallized from hexane-ethyl acetate to give N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (1.8 g), colorless needles, m.p. 116.5 - 117.5 C. Elemental analysis for C^2<H>21<N>5<OS:>

Beregnet: C 50,86 % H 7,47 % N 24,71 % Calculated: C 50.86% H 7.47% N 24.71%

Funnet : C 50,85 % H 7,37 % N 24,65 % Found : C 50.85% H 7.37% N 24.65%

Eksempel 117 - 123 Examples 117 - 123

Ved å gå frem som beskrevet i eksempel 116 ble følgende forbindelser erholdt: By proceeding as described in Example 116, the following compounds were obtained:

(117) Nrethyl-N-cyclohexyl-4-(1-methyl-l,2,3,4-17 5 tetrazol-5-yl)thio-butyramid, farveløs væske, nD ' = 1,532' (117) N-ethyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-175 tetrazol-5-yl)thio-butyramide, colorless liquid, nD' = 1.532'

(118) N-ethyl-N-fenyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, lys gul væske, nn2° 6 = 1,5534 (118) N-ethyl-N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, light yellow liquid, nn2° 6 = 1.5534

(119) N-[2-(3,4-dimethoxyfenyl)ethyl]-4-(1-methy; 1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse flak (hexan-ethylacetat), sm.p. 70,5 - 71,5° C (119) N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl; 1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes (hexane-ethyl acetate) , sm.p. 70.5 - 71.5° C

(120) N-furfuryl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse flak (hexan-ethylacetat), sm.p. 71 - 73° C (120) N-furfuryl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes (hexane-ethyl acetate), m.p. 71 - 73° C

(121) N-ethyl-N-cyclohexylmethyl-4-(1-methyl-1, 2 ,3 , 4-tetrazol-5-yl) thio-butyramid , farveløs væske, n^"<*>" = 1,5293 (121) N-ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^"<*>" = 1.5293

(122) N-ethyl-N-cyclohexyl-5-(1-fenyl-1,2,3,4-tetrazol-5-yl)valeramid, hvite prismer (ether), sm.p. 73 - 75° C (122) N-ethyl-N-cyclohexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide, white prisms (ether), m.p. 73 - 75° C

(123) N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramid, hvitt krystallpulver (ethei sm.p. 92 - 95° C (123) N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramide, white crystalline powder (ethei m.p. 92 - 95° C

Eksempel 124 Example 124

1,4 g methyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)-thio-butyrat, 0,5 g natriumethylat og 5 ml N-ethylcyclohexy] amin ble tilsatt til 50 ml ethanol, og blandingen ble omsatt i en autoklav ved 140 - 150° C under trykk på 110 ato i 6 1.4 g of methyl 4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thiobutyrate, 0.5 g of sodium ethylate and 5 ml of N-ethylcyclohexy]amine were added to 50 ml ethanol, and the mixture was reacted in an autoclave at 140 - 150° C under a pressure of 110 ato for 6

timer. Etter avkjøling ble reaksjonsblandingen konsentrert under redusert trykk, og det resulterende residuum ble løst i 200 ml kloroform.. Løsningen ble vasket med 1 %-ig vandig kaliumcarbonatløsning, fortynnet saltsyre og vann, og ble tørket over natriumsulfat. Etter at løsningsmidlet var hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in 200 ml of chloroform. The solution was washed with 1% aqueous potassium carbonate solution, dilute hydrochloric acid and water, and was dried over sodium sulfate. After the solvent was

destillert fra ble det resulterende residuum underkastet kolonnekromåtografi (Wakogel C-200) og kolonnen ble eluert med kloroform under dannelse av N-ethyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid (0,6 g), farveløs distilled from, the resulting residue was subjected to column chromatography (Wakogel C-200) and the column was eluted with chloroform to give N-ethyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5- yl)thio-butyramide (0.6 g), colorless

17 5 17 5

væske, nQ ' = 1,5327. liquid, nQ ' = 1.5327.

Elementæranalyse for C^I^^Nj-OS: Elemental analysis for C^I^^Nj-OS:

Beregnet: C 53,99 % H 8,09 % N 22,49 % Calculated: C 53.99% H 8.09% N 22.49%

Funnet : C 54,19 % H 8,21 % N 22,68 % Found : C 54.19% H 8.21% N 22.68%

Eksempel 125 - 127 Example 125 - 127

Ved å gå frem på samme måte som beskrevet i eksempel 124, ble følgende forbindelser erholdt: By proceeding in the same manner as described in Example 124, the following compounds were obtained:

(125) N-12-(3,4-dimethoxyfenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse flak (hexan-ethylacetat), sm.p. 70,5 - 71,5° C (125) N-12-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes (hexane-ethyl acetate), sm.p. 70.5 - 71.5° C

(126) N-fenyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)-thio-butyramid,i farveløse nåler (hexan-ethylacetat), sm.p. 106 - 107° C (126) N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, in colorless needles (hexane-ethyl acetate), m.p. 106 - 107° C

(127) N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramid, hvitt krystallinsk pulver (ether), sm.p. 92 - 95° C. (127) N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramide, white crystalline powder (ether), m.p. 92 - 95° C.

Eksempel 128 Example 128

3 g N-ethyl-N-cyclohexyl-kloracetamid og 1,8 g l-methyl-5-mercapto-l,2,3,4-tetrazol ble løst i 50 ml aceton, og til løsningen ble tilsatt kaliumcarbonat. Blandingen ble kokt i 3 timer under tilbakeløpskjøling, og aceton ble destillert fra under redusert trykk. Etter tilsetning av vann ble residuet ekstrahert med ether. Etherløsningen ble vasket med vandig mettet natriumkloridløsning og tørket over magnesiumsulfat. Etter at etheren var destillert fra ble det resulterende residuum omkrystallisert fra ether-petroleumether under dannelse av N-ethyl-N-cyclohexyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-acetamid (1,5 g), hvite prismer, sm.p. 69 -. 71° C 3 g of N-ethyl-N-cyclohexyl-chloroacetamide and 1.8 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole were dissolved in 50 ml of acetone, and potassium carbonate was added to the solution. The mixture was boiled for 3 hours under reflux, and acetone was distilled off under reduced pressure. After addition of water, the residue was extracted with ether. The ether solution was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. After the ether was distilled off, the resulting residue was recrystallized from ether-petroleum ether to give N-ethyl-N-cyclohexyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-acetamide (1.5 g), white prisms, m.p. 69 -. 71°C

Elementæranalyse for C,-H„,N.-OS: Elemental analysis for C,-H„,N.-OS:

Beregnet: C 50,86 % H 7,47 % N 24,71 % Calculated: C 50.86% H 7.47% N 24.71%

Funnet : C 50,78 % H 7,57 % N 24,75 % Found : C 50.78% H 7.57% N 24.75%

Eksempel 129 Example 129

6,6 g N-methyl-N-cyclohexyl-4-klorbutyramid ble løst i 50 ml tørr benzen, og til løsningen ble tilsatt 3,6 g l-methyl-5-mercapto-l,2,3,4-tetrazol, 4,5 g kaliumcarbonat o 0,2 g natriumjodid. Blandingen ble kokt under tilbakeløps-kjøling i 5 timer og fortynnet med benzen. Reaksjonsblandin gen ble vasket med vann, vandig mettet natriumbicarbonatløs-ning og vandig mettet natriumkloridløsning, og ble tørket over natriumsulfat. Etter at benzenet var destillert fra, ble det resulterende residuum underkastet kolonnekromåtograf (Wakogel C-200) og kolonnen ble eluert med benzen-kloroform (4:1, v/v) under dannelse av N-methyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-buryramid (5 g), lys gul væske. 6.6 g of N-methyl-N-cyclohexyl-4-chlorobutyramide was dissolved in 50 ml of dry benzene, and to the solution was added 3.6 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole, 4.5 g potassium carbonate and 0.2 g sodium iodide. The mixture was refluxed for 5 hours and diluted with benzene. The reaction mixture was washed with water, aqueous saturated sodium bicarbonate solution and aqueous saturated sodium chloride solution, and was dried over sodium sulfate. After the benzene was distilled off, the resulting residue was subjected to column chromatography (Wakogel C-200) and the column was eluted with benzene-chloroform (4:1, v/v) to give N-methyl-N-cyclohexyl-4-( 1-methyl-1,2,3,4-tetrazol-5-yl)thio-buryramide (5 g), pale yellow liquid.

-rn -rn

NMR: Sppjn'! 1/00 - .2,00 (10H, br.), 1,80 - 2,70 (4H, m) NMR: Sppjn'! 1/00 - .2.00 (10H, br.), 1.80 - 2.70 (4H, m)

2,73 (3H, d, J = 6Hz), 3,28 (2H, t, J = 6Hz), 2.73 (3H, d, J = 6Hz), 3.28 (2H, t, J = 6Hz),

3,85 (3H, s), 3,20 - 4,50 (1H, m) Elementæranalyse for C^3H23N^OS: 3.85 (3H, s), 3.20 - 4.50 (1H, m) Elemental analysis for C^3H23N^OS:

Beregnet: C 52,50 % H 7,79 % N 23,55 % Calculated: C 52.50% H 7.79% N 23.55%

Funnet : C 52,72 % H 7,85 % N 23,61 % Found : C 52.72% H 7.85% N 23.61%

Eksempel 130 Example 130

1,6 g l-methyl-5-mercapto-l,2,3,4-tetrazol, 0,9 g kaliumhydroxyd, 3,2 g natriumjodid og 5,1 g 3-morfolin-carbonylpropylklorid ble tilsatt til 3 0 ml ethanol, og blandingen ble omrørt ved 70 - 80° C i 4,5 timer. Etter at reaksjonen var fullført ble reaksjonsblandingen helt over i vandig mettet natriumkloridløsning, og de utfelte krystal ler ble fraskilt ved filtrering og vasket med vann. De således erholdte urene krystaller ble omkrystallisert fra ether-petroleumether under dannelse av 5-(3-morfolincarbonyl propylthio)-1-methyl-l,2,3,4-tetrazol(2,2 g), hvite nåler, sm.p. 71 - 73° C. 1.6 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole, 0.9 g of potassium hydroxide, 3.2 g of sodium iodide and 5.1 g of 3-morpholine-carbonylpropyl chloride were added to 30 ml of ethanol , and the mixture was stirred at 70-80° C. for 4.5 hours. After the reaction was completed, the reaction mixture was poured into aqueous saturated sodium chloride solution, and the precipitated crystals were separated by filtration and washed with water. The impure crystals thus obtained were recrystallized from ether-petroleum ether to give 5-(3-morpholinecarbonyl propylthio)-1-methyl-1,2,3,4-tetrazole (2.2 g), white needles, m.p. 71 - 73° C.

Elementæranalyse for cio<H>17°2S: Elemental analysis for cio<H>17°2S:

Beregnet: C 44,27 % H 6,37 % N 25,81 % Calculated: C 44.27% H 6.37% N 25.81%

Funnet : C 44,10 H 6,30 % N 25,59 % Found : C 44.10 H 6.30% N 25.59%

Eksempel 131 Example 131

1,6 g l-methyl-5-mercapto-l,2,3,4-tetrazol, 1,4 g natriumethylat, 1,6 g natriumjodid og 4,8 g N-cyclohexyl-3-klorbutyramid ble tilsatt til 30 ml ethanol, og blandingen ble kokt under tilbakeløpskjøling i 6 timer under omrøring. Etter at reaksjonen var fullført ble reaksjonsblandingen helt over i vandig mettet natriumkloridløsning. De utfelte krystaller ble fraskilt ved filtrering og vasket med vann. Det således erholdte urene krystaller ble omkrystallisert fra hexan-ethylacetat under dannelse av N-cyclohexyl-4-(1-methy1-1,2,3,4-tetrazol-5-yl)thio-butyramid, (2,1 g), farveløse nåler, sm.p. 116,5 - 117,5° C. 1.6 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole, 1.4 g of sodium ethylate, 1.6 g of sodium iodide and 4.8 g of N-cyclohexyl-3-chlorobutyramide were added to 30 ml ethanol, and the mixture was refluxed for 6 h with stirring. After the reaction was complete, the reaction mixture was poured into aqueous saturated sodium chloride solution. The precipitated crystals were separated by filtration and washed with water. The impure crystals thus obtained were recrystallized from hexane-ethyl acetate to form N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, (2.1 g), colorless needles, m.p. 116.5 - 117.5° C.

Elementæranalyse for C^2H2iN5OS: Elemental analysis for C^2H2iN5OS:

Beregnet: C 50,86 % H 7,47 % N 24,71 % Calculated: C 50.86% H 7.47% N 24.71%

Funnet : C 50,87 % H 7,35 % N 24,63 % Found : C 50.87% H 7.35% N 24.63%

Eksempel 132 - 186 Example 132 - 186

Ved å gå frem på samme måte som beskrevet i eksempel 128 - 131, ble følgende forbindelser fremstilt: By proceeding in the same way as described in examples 128 - 131, the following compounds were prepared:

(132) N,N-diethyl-4-(1-methyl-l,2,3,4-tetrazol-17 5 5-yl)thio-butyramid, farveløs væske, nQ ' =1,52 27 (132) N,N-diethyl-4-(1-methyl-1,2,3,4-tetrazol-17 5 5-yl)thio-butyramide, colorless liquid, nQ ' =1.52 27

(133) N-ethyl-N-cyclohexyl-4-(1-methyl-l,2,3,4-17 5 tetrazol-5-yl)thio-butyramid, farveløs væske, nQ ' = 1,5327 (133) N-ethyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-175 tetrazol-5-yl)thio-butyramide, colorless liquid, nQ' = 1.5327

(134) N-ethyl-N-fenyl-4-(1-methyl-l,2,3,4-tetra-2 6 zol-5-yl)thio-butyramid, lys gul væske, nn = 1,5534 (134) N-ethyl-N-phenyl-4-(1-methyl-1,2,3,4-tetra-2 6 zol-5-yl)thio-butyramide, light yellow liquid, nn = 1.5534

(13 5) 5-[3-(4-acetylpiperazinocarbony1)propy1-thio]-1-methyl-l,2,3,4-tetrazol, hvitt krystallpulver (omkrystallisert fra ligroin-aceton), sm.p. 90 - 91,5° C (13 5) 5-[3-(4-acetylpiperazinocarbonyl)propy1-thio]-1-methyl-1,2,3,4-tetrazole, white crystalline powder (recrystallized from ligroin-acetone), m.p. 90 - 91.5° C

(13 6) N-[2-(3,4-dimethoxyfenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse flak (hexan-ethylacetat), sm.p. 70,5 - 71,5° C (13 6) N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes (hexane-ethyl acetate ), sm.p. 70.5 - 71.5° C

(13 7) N-hexyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)-thio-butyramid, farveløse flak (omkrystallisert fra hexan-ether), sm.p. 41 - 42° C (13 7) N-hexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless flakes (recrystallized from hexane-ether), m.p. 41 - 42° C

(138) N-cyclooctyl-4-(1-methyl-l,2,3,4-tetrazol-14 (138) N-cyclooctyl-4-(1-methyl-1,2,3,4-tetrazol-14

5-yl)thio-butyramid, farveløs væske, nQ = 1,5323 5-yl)thio-butyramide, colorless liquid, nQ = 1.5323

(139) N-cyclododecanyl-4-(l-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (hexan-ethyl-acetat), sm.p. 119 - 120° C (139) N-cyclododecanyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl acetate), m.p. 119 - 120° C

(14 0) N-butyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)-thio-butyramid, farveløs væske, n^'5 = 1,5198 (14 0) N-butyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless liquid, n^'5 = 1.5198

(141) N-(2-hydroxyethyl)-4-(1-methyl-l,2,3,4-14 5 tetrazol-5-yl)thio-butyramid, farveløs væske, nn ' = 1,5350 (141) N-(2-hydroxyethyl)-4-(1-methyl-1,2,3,4-14 5 tetrazol-5-yl)thio-butyramide, colorless liquid, nn ' = 1.5350

(142) N-ethyl-N-benzyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nD 19 = 1,5596 (142) N-ethyl-N-benzyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nD 19 = 1.5596

(143) N-butyl-N-cyclohexyl-4-(1-methyl-l,2,3,4-19 tetrazol-5-yl)thio-butyramid, farveløs væske, nQ = 1,5222 (143) N-butyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-19 tetrazol-5-yl)thio-butyramide, colorless liquid, nQ = 1.5222

(144) N,N-dibutyl-4-(1-methyl-l,2,3,4-tetrazol-19 (144) N,N-dibutyl-4-(1-methyl-1,2,3,4-tetrazole-19

5-yl)thio-butyramid, farveløs væske, nD = 1,5049 5-yl)thio-butyramide, colorless liquid, nD = 1.5049

(14 5) N,N-dibenzyl-4-(1-methyl-l,2,3,4-tetrazol-19 (14 5) N,N-dibenzyl-4-(1-methyl-1,2,3,4-tetrazole-19

5-yl)thio-butyramid, farveløs væske, nn = 1,5773 5-yl)thio-butyramide, colorless liquid, nn = 1.5773

(146) N,N-diisopropyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nD 19 ' 5 = 1,5111 (146) N,N-diisopropyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nD 19 ' 5 = 1.5111

(14 7) N,N-dicyclohexyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (hexan), sm.p. (14 7) N,N-dicyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane), m.p.

91 - 92° C 91 - 92° C

(148) N-benzyl-N-tert.-butyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (hexan), sm.p. 86,5 - 87,5° C (14 9) N-cyclohexyl-N-[2-(3,4-dimethoxyfenyl)-ethyl]-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, (148) N-benzyl-N-tert-butyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane), m.p. 86.5 - 87.5° C (14 9) N-cyclohexyl-N-[2-(3,4-dimethoxyphenyl)-ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide,

16 16

farveløs væske, nn = 1,5470 colorless liquid, nn = 1.5470

(150) N-methyl-N-(2-thienylmethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, (150) N-methyl-N-(2-thienylmethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid,

n<*6> = 1,5706 n<*6> = 1.5706

(151) N-benzyl-N-[2-(3,4-dimethoxyfenyl)ethyl]-4- (1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nj<6> = 1,5659(151) N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nj<6> = 1.5659

(152) N,N-dihexyl-4-(1-methyl-l,2,3,4-tetrazol-5- yl)thio-butyramid, farveløs væske, n^<5> = 1,5011 (152) N,N-dihexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<5> = 1.5011

(153) N-ethyl-N-[2-(3,4-dimethoxyfenyl)-ethyl]-4- (1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^<4> = 1,5451 (153) N-ethyl-N-[2-(3,4-dimethoxyphenyl)-ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid , n^<4> = 1.5451

(154) N-tert.-butyl-4-(1-methyl-l,2,3,4-tetrazol-5- yl)thio-butyramid, farveløse flak (hexan-ethylacetat), sm.p. 71 - 73° C (154) N-tert-butyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes (hexane-ethyl acetate), m.p. 71 - 73° C

(155) N-ethyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)-thio-butyramid, farveløs væske, n 1,5319 (155) N-ethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless liquid, n 1.5319

(156) N-benzyl-4-(l-methyi-l,2,3,4-tetrazol-5-yl)-thio-butyramid, farveløse nåler (hexan-ethylacetat, sm.p. (156) N-benzyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless needles (hexane-ethyl acetate, m.p.

65 - 66° C 65 - 66° C

(157) N-cyclohexyl-N-(2-hydroxyethyl)-4-(1-methyl-14 5 1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nQ ' 1,5372 (157) N-cyclohexyl-N-(2-hydroxyethyl)-4-(1-methyl-14 5 1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nQ ' 1.5372

(158) N-fenyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)-thio-butyramid, farveløse nåler (hexan-ethylacetat), sm.p. 106 - 107° C (15 9) N-f enyl-4- (1-methyl-l, 2,3,4-tetraz.ol-5-yl) - thio-butyramid, farveløse nåler (hexan-ethylacetat^, sm.p. (158) N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless needles (hexane-ethyl acetate), m.p. 106 - 107° C (15 9) N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless needles (hexane-ethyl acetate^, m.p.

106 - 107° C 106 - 107° C

(160) N-(2-pyridyl)-4-(l-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (hexan-ethylacetat), sm.p. 95 - 96° C (160) N-(2-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl acetate), m.p. 95 - 96° C

(161) N-(3-pyridyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse plater (ethylacetat), sm.p. 110,5 - 113° C (161) N-(3-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless plates (ethyl acetate), m.p. 110.5 - 113° C

(162) N-(2-pyrimidyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse granuler (hexan-ethyl-acetat), sm.p. 108 - 110° C (162) N-(2-pyrimidyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless granules (hexane-ethyl acetate), m.p. 108 - 110° C

(163) N-furfuryl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse flak (hexan-ethylacetat), sm.p. 71 - 73° C (163) N-furfuryl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes (hexane-ethyl acetate), m.p. 71 - 73° C

(164) N-(4-aminosulfonylfenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (methanol), sm.p. 169,5 - 170,5° C (164) N-(4-aminosulfonylphenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (methanol), m.p. 169.5 - 170.5° C

(165) N-[4-(N,N-dimethylamino)fenyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse prismer (hexan-ethylacetat), sm.p. 144 - 147° C (165) N-[4-(N,N-dimethylamino)phenyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless prisms (hexane-ethyl acetate) , sm.p. 144 - 147° C

(166) N-(2-methyl-3-klorfenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (hexan-ethylacetat), sm.p. 104,5 - 105,5° C (166) N-(2-methyl-3-chlorophenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl acetate), sm. p. 104.5 - 105.5° C

(167) N-(4-nitrofenyl)-4-(l-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (ethylacetat), sm.p. 194 - 195° C (167) N-(4-nitrophenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (ethyl acetate), m.p. 194 - 195° C

(168) N-(2-méthoxyfenyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (hexan-ethyl-acetat ), sm.p. 79,5 - 82° C (168) N-(2-Methoxyphenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl-acetate), m.p. 79.5 - 82° C

(169) N-methyl-N-(2-tetrahydropyranyl)-4-(1-methy1-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n<*4> = 1,5273 (169) N-methyl-N-(2-tetrahydropyranyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n<*4> = 1 ,5273

(170) N-ethyl-N-(2-pyridy1)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)tyio-butyramid, farveløs væske, n^ = 1,5623 (170) N-ethyl-N-(2-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^ = 1.5623

(171) N-ethyl-N-(3-pyridyl)-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n<*6> = 1,5618 (171) N-ethyl-N-(3-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n<*6> = 1 ,5618

(172) N-ethyl-N-cyclopentyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nn 9 = 1,5384 (172) N-ethyl-N-cyclopentyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nn 9 = 1.5384

(173) N-ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, (173) N-ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid,

nj<1> = 1,5293 nj<1> = 1.5293

(174) N-isopropyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, (174) N-isopropyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid,

nj<5> = 1,5238 nj<5> = 1.5238

(175) N-ethyl-N-(4-hydroxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nQ 9= 1,5363 (175) N-ethyl-N-(4-hydroxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nQ 9 = 1.5363

(176) N-ethyl-N-(2-hydroxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløse nåler (hexan-ethylacetat) , sm.p. 132 133° C (176) N-ethyl-N-(2-hydroxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl acetate), sm. p. 132 133° C

(177) N-ethyl-N-(2-acetyloxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^<1> = 1,5218 (177) N-ethyl-N-(2-acetyloxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<1> = 1 ,5218

(178) N,N-dipropyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^<5> = 1,5151(178) N,N-dipropyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<5> = 1.5151

(179) N-butyl-N-fenyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^<5> = 1,5509 (179) N-butyl-N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<5> = 1.5509

(180) N,N-dimethyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^<6> = 1,5327 (180) N,N-dimethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<6> = 1.5327

(181) N-ethyl-N-cyclooctyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, n^ = 1,5309 (181) N-ethyl-N-cyclooctyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^ = 1.5309

(182) 5-[3-(4-methylpiperazinocarbonyl)propylthio]-1-methyl-l,2,3,4-tetrazol-farveløse granuler (hexan-ethyl-acetat) , sm.p. 65 - 68° C (182) 5-[3-(4-methylpiperazinocarbonyl)propylthio]-1-methyl-1,2,3,4-tetrazole colorless granules (hexane-ethyl acetate), m.p. 65 - 68° C

(183) 5-(3-piperidinocarbonylpropylthio)-1-methyl-25 ' (183) 5-(3-piperidinocarbonylpropylthio)-1-methyl-25'

1,2 ,3, 4-tetrazol-farveløs væske, nQ ..= 1,5310 1,2,3,4-tetrazole colorless liquid, nQ ..= 1.5310

(184) N-ethyl-N-cyclohexyl-3-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-propionamid, lys gul væske, nn 2 6 = 1,5273 (184) N-ethyl-N-cyclohexyl-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-propionamide, light yellow liquid, nn 2 6 = 1.5273

(185) N-ethyl-N-cyclohexyl-5-(1-methyl-l,2,3,4- (185) N-ethyl-N-cyclohexyl-5-(1-methyl-1,2,3,4-

25 tetrazol-5-yl)thio-valeramid, lys gul væske, nQ = 1,5227 25 tetrazol-5-yl)thio-valeramide, light yellow liquid, nQ = 1.5227

(186) N-ethyl-N-cyclohexyl-4-(1-fenyl-1,2,3,4- (186) N-ethyl-N-cyclohexyl-4-(1-phenyl-1,2,3,4-

18 tetrazol-5-yl)thio-butyramid, farveløs væske, nQ = 1,5590 Eksempel 187 18 tetrazol-5-yl)thio-butyramide, colorless liquid, nQ = 1.5590 Example 187

0,1 mol 1-methyl-5-mercaptomethyl-l,2,3,4-tetrazol ble løst i 100 ml aceton, og til løsningen ble tilsatt 0,12 mol N,N-diethyl-3-brompropionamid og 0,12 mol kaliumcarbonat. Blandingen ble kokt under tilbakeløpskjøling i 4 timer. Etter at acetonet var destillert fra under redusert trykk, ble vann tilsatt til residuet, og den vandige blanding ble ekstrahert med kloroform. Kloroformlaget ble vasket med vandig mettet natriumkloridløsning og tørket over magnesiumsulfat. Etter at løsningsmidlet var destillert fra, ble det resulterende residuum underkastet kolonnekromåtografi (kiselgel 60) og kolonnen ble eluert med kloroform-methanol (50:1, v/v) under dannelse av N,N-diethyl-3-(1-methyl-l,2,3,4-tetrazol-5-yl)methylthio-propionamid (utbytte 48 %), farveløs 0.1 mol of 1-methyl-5-mercaptomethyl-1,2,3,4-tetrazole was dissolved in 100 ml of acetone, and to the solution was added 0.12 mol of N,N-diethyl-3-bromopropionamide and 0.12 moles of potassium carbonate. The mixture was refluxed for 4 hours. After the acetone was distilled off under reduced pressure, water was added to the residue, and the aqueous mixture was extracted with chloroform. The chloroform layer was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. After the solvent was distilled off, the resulting residue was subjected to column chromatography (silica gel 60) and the column was eluted with chloroform-methanol (50:1, v/v) to give N,N-diethyl-3-(1-methyl- 1,2,3,4-tetrazol-5-yl)methylthio-propionamide (yield 48%), colorless

25 25

væske, nQ = 1,5200. liquid, nQ = 1.5200.

Elementæranalyse for C^pH^gN^OS: Elemental analysis for C^pH^gN^OS:

Beregnet; C 46,67 % H 7,44 % N 27,21 % Calculated; C 46.67% H 7.44% N 27.21%

Funnet : C 46,72 % H 7,53 % N 27,29 % Found : C 46.72% H 7.53% N 27.29%

Eksempel 188 og 189 Examples 188 and 189

Ved å gå frem på samme måte som beskrevet i eksempel 187 ble følgende forbindelser fremstilt: By proceeding in the same way as described in example 187, the following compounds were prepared:

(188) N,N-diethyl-3-[1-(4-ethylfenyl)-1,2,3,4-tetrazol-5-yl]methylthio-propionamid, farveløs væske, n^ = 1,5499 (188) N,N-diethyl-3-[1-(4-ethylphenyl)-1,2,3,4-tetrazol-5-yl]methylthio-propionamide, colorless liquid, n^ = 1.5499

(189) N-ethyl-N-cyclohexyl-3-(1-ethyl-l,2,3,4-tetrazol-5-yl)methylthio-propionamid, lys gul væske, nn 18= 1,5277 (189) N-ethyl-N-cyclohexyl-3-(1-ethyl-1,2,3,4-tetrazol-5-yl)methylthio-propionamide, light yellow liquid, nn 18= 1.5277

Eksempel 19 0 Example 19 0

11,6 g l-methyl-5-mercapto-l,2,3,4-tetrazol ble løst i 100 ml aceton og til løsningen ble tilsatt 21,7 g methyl-4-brombutyrat og 15 g kaliumcarbonat. Blandingen ble kokt under tilbakeløpskjøling i 4 timer. Etter at acetonet var destillert fra under redusert trykk, ble vann tilsatt til det resulterende residuum, og den vandige blanding ble ekstrahert med kloroform. Kloroformløsningen ble vasket med vandig mettet natriumkloridløsning og tørket over magnesiumsulfat. Etter at kloroformen var destillert fra ble residuet underkastet kolonnekromåtografi (Wakogel C-200) og kolonnen ble eluert med benzen-ether (5:1, v/v) . Eluatet ble destillert under redusert trykk under dannelse av 4-(l-methyl-1,2,3,4-tetrazol-5-yl)thio-butyrat (20 g), farveløs væske, k.p. 175 - 177°C/0,fl mmHg, n^<6> = 1,5083. Elementæranalyse for C^H^2N4OS: 11.6 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole were dissolved in 100 ml of acetone and 21.7 g of methyl-4-bromobutyrate and 15 g of potassium carbonate were added to the solution. The mixture was refluxed for 4 hours. After the acetone was distilled off under reduced pressure, water was added to the resulting residue, and the aqueous mixture was extracted with chloroform. The chloroform solution was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. After the chloroform had been distilled off, the residue was subjected to column chromatography (Wakogel C-200) and the column was eluted with benzene ether (5:1, v/v). The eluate was distilled under reduced pressure to give 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyrate (20 g), colorless liquid, m.p. 175 - 177°C/0.fl mmHg, n^<6> = 1.5083. Elemental analysis for C^H^2N4OS:

Beregnet: C 38,88 % H 5,59 % N 25,91 % Calculated: C 38.88% H 5.59% N 25.91%

Funnet : C 38,98 % H 5,67 % N 25,83 % Found : C 38.98% H 5.67% N 25.83%

Eksempel 191 og 192 Examples 191 and 192

Anvendelse av 1-fenyl- eller l-cyclohexyl-5-mercapto-1,2,3,4-tetrazol i stedet for l-methyl-5-mercapto-1,2,3,4-tetrazol ved fremgangsmåten ifølge eksempel 190 ga følgende forbindelser: Use of 1-phenyl- or 1-cyclohexyl-5-mercapto-1,2,3,4-tetrazole instead of 1-methyl-5-mercapto-1,2,3,4-tetrazole in the method according to example 190 gave the following compounds:

(191) methyl-4-(1-fenyl-1,2,3,4-tetrazol-5-yl)-18 (191) methyl-4-(1-phenyl-1,2,3,4-tetrazol-5-yl)-18

thio-butyrat, farveløs væske, nn = 1,5654 thio-butyrate, colorless liquid, nn = 1.5654

(192) methyl-4-(1-cyclohexyl-l,2,3,4-tetrazol- (192) methyl-4-(1-cyclohexyl-1,2,3,4-tetrazol-

18 18

5-yl)thio-butyrat, lys gul væske, nD = 1,5162 5-yl)thiobutyrate, pale yellow liquid, nD = 1.5162

Eksempel 193 Example 193

0,1 mol l-methyl-5-mercapto-l,2,3,4-tetrazol ble løst i 100 ml aceton, og til løsningen ble tilsatt dråpevis en løsning av 0,12 mol 4-broms-mørsyre og 0,25 mol natriumhydroxyd i 50 ml vann. Blandingen ble oppvarmet under om-røring til 50 - 60° C i 4 timer, og aceton ble destillert fra under redusert trykk. Det resulterende residuum ble surgjort med fortynnet saltsyre, mettet med natriumklorid og ekstrahert med kloroform. Kloroformløsningen ble vasket med vandig mettet natriumkloridløsning og tørket over magnesiumsulfat. 0.1 mol of 1-methyl-5-mercapto-1,2,3,4-tetrazole was dissolved in 100 ml of acetone, and to the solution was added dropwise a solution of 0.12 mol of 4-bromobutyric acid and 0.25 moles of sodium hydroxide in 50 ml of water. The mixture was heated with stirring to 50-60°C for 4 hours, and acetone was distilled off under reduced pressure. The resulting residue was acidified with dilute hydrochloric acid, saturated with sodium chloride and extracted with chloroform. The chloroform solution was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate.

Løsningsmidlet ble destillert fra og residuet underkastet kolonnekromåtografi (Kiselgel 60) og. kolonnen ble eluert med kloroform-methanol (10:1, v/v) under dannelse av 4-(l-methyl-1,2,3,4-tetrazol-5-yl)thio-smørsyre (utbytte 23 %) farveløs væske. The solvent was distilled from and the residue subjected to column chromatography (Kiselgel 60) and. the column was eluted with chloroform-methanol (10:1, v/v) to give 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid (yield 23%) colorless liquid .

NMR: <<5pp>£<l>3 1' 80 2'80 <6H' m) ' 3'42 (2H' t'NMR: <<5pp>£<l>3 1' 80 2'80 <6H' m) ' 3'42 (2H' t'

J = 7Hz), 3,96 (3H, s), 11,18 (1H, s) J = 7Hz), 3.96 (3H, s), 11.18 (1H, s)

Elementæranalyse for C-gH^N^C^S: Elemental analysis for C-gH^N^C^S:

Beregnet: C 35,63 %H 4,98 % N 27,70 Calculated: C 35.63% H 4.98% N 27.70

Funnet : C 35,79 %H 5,12 N 27,84 Found: C 35.79% H 5.12 N 27.84

Eksempel 194 og 195 Examples 194 and 195

Anvendelse av 1-fenyl- eller l-cyclohexyl-5-mercapto-1,2,3,4-tetrazol i stedet for l-methyl-5-mercapto-1,2,3,4-tetrazol ved fremgangsmåten ifølge eksempel 193 Use of 1-phenyl- or 1-cyclohexyl-5-mercapto-1,2,3,4-tetrazole instead of 1-methyl-5-mercapto-1,2,3,4-tetrazole in the method according to example 193

ga følgende forbindelser: gave the following compounds:

(194) 4-(1-fenyl-1,2,3,4-tetrazol-5-yl)thio-smør-onn syre, lys gul væske, NMR: 3 2,00 - 2,70 (4H, m) , (194) 4-(1-phenyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid, light yellow liquid, NMR: 3 2.00 - 2.70 (4H, m) ,

3,44 (2H, t, J = 7Hz), 7,55 (5H, s), 10,98 (1H, br.s) 3.44 (2H, t, J = 7Hz), 7.55 (5H, s), 10.98 (1H, br.s)

(195) 4-(1-cyclohexyl-l,2,3,4-tetrazol-5-yl)-thio-smørsyre, farveløse prismer (ether), sm.p. 67,5 - 69,5° C. Eksempel 196 1,6 g 2-mercaptopropionsyre ble løst i 4 5 ml IN vandig natriumhydroxydløsning, og til løsningen ble dråpevis tilsatt en løsning av 15,2 g l-methyl-5-klormethyl-l,2,3,4-tetrazol i 20 ml aceton under omrøring og under isavkjøling. Omrøringen ble fortsatt i 3 timer under isavkjøling. Aceton ble destillert fra og residuet surgjort med konsentrert saltsyre, mettet med natriumklorid og ble deretter ekstrahert med kloroform. Kloroformløsningen ble tørket over magnesiumsulfat. Etter at kloroform var destillert fra, ble residuet underkastet kolonnekromåtografi (Kieselgel 60) og kolonnen ble eluert med kloroform-methanol (10:1, v/v), under dannelse av 3-(1-methyl-l,2,3,4-tetrazol-5-yl)methylthio-propionsyre (2,1 g) som en farveløs væske, mn NMR: <5pp^x3 2,40 - 3,00 (4H, m) , 4,05 (2H, s) , (195) 4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)-thiobutyric acid, colorless prisms (ether), m.p. 67.5 - 69.5° C. Example 196 1.6 g of 2-mercaptopropionic acid was dissolved in 4 5 ml of IN aqueous sodium hydroxide solution, and to the solution was added dropwise a solution of 15.2 g of 1-methyl-5-chloromethyl-1,2,3,4-tetrazole in 20 ml acetone with stirring and under ice-cooling. Stirring was continued for 3 hours under ice cooling. Acetone was distilled off and the residue acidified with concentrated hydrochloric acid, saturated with sodium chloride and then extracted with chloroform. The chloroform solution was dried over magnesium sulfate. After chloroform was distilled off, the residue was subjected to column chromatography (Kieselgel 60) and the column was eluted with chloroform-methanol (10:1, v/v), yielding 3-(1-methyl-1,2,3,4 -tetrazol-5-yl)methylthio-propionic acid (2.1 g) as a colorless liquid, mn NMR: <5pp^x3 2.40 - 3.00 (4H, m) , 4.05 (2H, s) ,

4,12 (3H, s), 9,79 (1H, s) 4.12 (3H, s), 9.79 (1H, s)

Elementæranalyse for CgH^^N^ >2^: Elemental analysis for CgH^^N^ >2^:

Beregnet: C 35,63 % H 4,98 % N 27,70 % Calculated: C 35.63% H 4.98% N 27.70%

Funnet : C 35,81 % H 4,83 % N 27,83 % Found : C 35.81% H 4.83% N 27.83%

Eksempel 197 og 198 Examples 197 and 198

Ved å gå frem som beskrevet i eksempel 196 ble følgende forbindelser erholdt under anvendelse av egnede utgangsmaterialer: Proceeding as described in Example 196, the following compounds were obtained using suitable starting materials:

(197) 3-(1-ethyl-l,2,3,4-tetrazol-5-yl)methylthio-propionsyre, farveløse prismer (aceton-ether), sm.p. (197) 3-(1-ethyl-1,2,3,4-tetrazol-5-yl)methylthio-propionic acid, colorless prisms (acetone-ether), m.p.

68 - 70° C 68 - 70° C

(198) 3-[l-(4-ethylfenyl)-l,2,3,4-tetrazol-5-yl)-CDC1 methylthio-propionsyre, farveløs væske, NMR: ^ppm 3 (198) 3-[1-(4-ethylphenyl)-1,2,3,4-tetrazol-5-yl)-CDC1 methylthio-propionic acid, colorless liquid, NMR: ^ppm 3

1,28 (3H, t, J = 7Hz), 2,40 - 3,10 (6H, m), 3,97 (2H, s), 7,43 (4H, br.s.), 10,02 (1H, br.s) 1.28 (3H, t, J = 7Hz), 2.40 - 3.10 (6H, m), 3.97 (2H, s), 7.43 (4H, br.s.), 10.02 (1H, br.s)

Eksempel 199 Example 199

9 g methyl-N-fenyladipinamat ble løst i 70 ml benzen, og til løsningen ble tilsatt 9 g fosforpentaklorid under om-røring ved en temperatur under 15° C. Blandingen ble omrørt ved romtemperatur i 1 1/2 time og konsentrert til 1/3 av volumet under redusert trykk. En løsning av hydrogenazid i benzen (0,0172 mol/10 ml, 44,2 ml) ble dråpevis tilsatt til den resulterende iminokloridløsning under omrøring under is-avkjøling. Blandingen ble omrørt ved romtemperatur i 1 time, fikk stå over natten og ble deretter forsiktig kokt under tilbakeløpskjøling i 2 timer. Reaksjonsblandingen ble konsentrert og ble deretter tilsatt 50 ml is/vann og blandingen ble ekstrahert med kloroform. Kloroformløsningen ble vasket med vann, vandig fortynnet natriumhydroxydløsning og vann, og ble deretter tørket over magnesiumsulfat. Kloroform ble destillert fra og residuet underkastet kolonnekromåtografi (Wakogel C-200) og kolonnen ble eluert med benzen-ether (5:1, v/v) under dannelse av methyl-5-(1-fenyl-1,2,3,4-tetrazol-5-yl)-valerat (7,3 g) som en farveløs væske. 9 g of methyl-N-phenyladipinamate was dissolved in 70 ml of benzene, and to the solution was added 9 g of phosphorus pentachloride with stirring at a temperature below 15° C. The mixture was stirred at room temperature for 1 1/2 hours and concentrated to 1/ 3 of the volume under reduced pressure. A solution of hydrogen azide in benzene (0.0172 mol/10 mL, 44.2 mL) was added dropwise to the resulting imino chloride solution with stirring under ice-cooling. The mixture was stirred at room temperature for 1 hour, allowed to stand overnight and then gently boiled under reflux for 2 hours. The reaction mixture was concentrated and then 50 ml of ice/water was added and the mixture was extracted with chloroform. The chloroform solution was washed with water, aqueous dilute sodium hydroxide solution and water, and then dried over magnesium sulfate. Chloroform was distilled from and the residue subjected to column chromatography (Wakogel C-200) and the column eluted with benzene-ether (5:1, v/v) to give methyl-5-(1-phenyl-1,2,3,4 -tetrazol-5-yl)-valerate (7.3 g) as a colorless liquid.

NMR: Spp^1<3> i'50 _ 2'10 (4H' m)' 2'30 <2H' t, J = 6Hz), NMR: Spp^1<3> i'50 _ 2'10 (4H' m)' 2'30 <2H' t, J = 6Hz),

2,90 (2H, t, J = 6Hz), 3,62 (3H, s), 7,30 - 7,70 2.90 (2H, t, J = 6Hz), 3.62 (3H, s), 7.30 - 7.70

(5H, m) (5H, m)

Elementæranalyse for C^2H16N4°2: Elemental analysis for C^2H16N4°2:

Beregnet: C 59,98 % H 6,20 % N 21,53 % Calculated: C 59.98% H 6.20% N 21.53%

Funnet : C 60,19 % H 6,32 % N 21,71 % Found : C 60.19% H 6.32% N 21.71%

Eksempel 200 - 202 Example 200 - 202

Ved å gå frem som beskrevet i eksempel 199, ble følgende forbindelser erholdt under anvendelse av egnede utgangsmaterialer: Proceeding as described in Example 199, the following compounds were obtained using suitable starting materials:

(200) methyl-5-(1-methyl-l,2,3,4-tetrazol-5-yl)-CDC1 3 (200) methyl-5-(1-methyl-1,2,3,4-tetrazol-5-yl)-CDC1 3

valerat, farveløs væske, NMR: 6ppm 1,50 " 2,20 (4H' m)' 2,36 (2H, t, J = 6Hz), 2,90 (2H, t, J = 6Hz) , 3,65 (3H, s), 4,05 (3H, s) valerate, colorless liquid, NMR: 6ppm 1.50 " 2.20 (4H' m)' 2.36 (2H, t, J = 6Hz), 2.90 (2H, t, J = 6Hz) , 3.65 (3H, s), 4.05 (3H, s)

(201) methyl-5-(1-cyclohexyl-l,2,3,4-tetrazol-5-yl)-valerat, farveløs væske, NMR: ^pp^<1>"3 1'00 " 2'20 d4H' m)• 2,38 (2H, t, J = 6Hz), 2,90 (2H, t, J = 6Hz), 3,70 (3H, s), 3,90 - 4,50 (1H, m) (201) methyl 5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)-valerate, colorless liquid, NMR: ^pp^<1>"3 1'00 " 2'20 d4H ' m)• 2.38 (2H, t, J = 6Hz), 2.90 (2H, t, J = 6Hz), 3.70 (3H, s), 3.90 - 4.50 (1H, m )

(202) methyl-5-(1,2,3,4-tetrazol-5-yl)valerat, farveløs væske, NMR: «Spp^<3>"<3> 1/50 - 2,20 (4H, m) , 2,34 (2H, (202) methyl 5-(1,2,3,4-tetrazol-5-yl)valerate, colorless liquid, NMR: «Spp^<3>"<3> 1/50 - 2.20 (4H, m ) , 2.34 (2H,

t, J = 6Hz), 3,02 (2H, t, J = 6Hz), 3,60 (3H, s) t, J = 6Hz), 3.02 (2H, t, J = 6Hz), 3.60 (3H, s)

Eksempel 203 Example 203

100 ml 20 %-ig vandig saltsyre ble tilsatt til 100 ml of 20% aqueous hydrochloric acid was added

9,3 g methyl-4-(1-fenyl-1,2,3,4-tetrazol-5-yl)valerat, og blandingen ble kokt under tilbakeløp i 4 timer. Etter av-kjøling ble vann tilsatt, og blandingen ble ekstrahert med kloroform. Kloroformløsningen ble ekstrahert med vandig, mettet natriumbicarbonatløsning. Det vandige lag ble surgjort med konsentrert saltsyre og igjen ekstrahert med kloroform. Sistnevnte kloroformekstrakt ble vasket med vandig mettet natriumkloridløsning og tørket over magnesiumsulfat. Kloroform ble destillert fra under dannelse av 5-(l-fenyl-1,2,3,4-tetrazol-5-yl)valerinsyre (8,2 g), lys gul væske. NMR: 6CDCl3 1,40 - 2,10 (4H, m), 2,33 (2H, t, J = 6Hz), 9.3 g of methyl 4-(1-phenyl-1,2,3,4-tetrazol-5-yl)valerate, and the mixture was refluxed for 4 hours. After cooling, water was added and the mixture was extracted with chloroform. The chloroform solution was extracted with aqueous saturated sodium bicarbonate solution. The aqueous layer was acidified with concentrated hydrochloric acid and again extracted with chloroform. The latter chloroform extract was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. Chloroform was distilled from to give 5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeric acid (8.2 g), pale yellow liquid. NMR: 6CDCl3 1.40 - 2.10 (4H, m), 2.33 (2H, t, J = 6Hz),

ppm ppm

2,92 (2H, t, J = 6Hz), 7,30 - 7,70 (5H, m), 10,56 (lH,s) 2.92 (2H, t, J = 6Hz), 7.30 - 7.70 (5H, m), 10.56 (lH,s)

Elementæranalyse for C-^H^N^C^: Elemental analysis for C-^H^N^C^:

Beregnet: C 58,52 % H 5,73 % N 22,75 % Calculated: C 58.52% H 5.73% N 22.75%

Funnet : C 58,61 % H 5,85 % N 22,88 % Found : C 58.61% H 5.85% N 22.88%

Eksempler 204 til 206 Examples 204 to 206

Ved å gå frem som beskrevet i eksempel 203 ble følgende forbindelser fremstilt under anvendelse av forbindelsene ifølge eksempel 200 til 202 som utgangsmateriale: Proceeding as described in Example 203, the following compounds were prepared using the compounds of Examples 200 to 202 as starting material:

(204) 5- (1-methyl-l, 2,3, 4-tetrazol-5-yl)valerin-syre, farveløse prismer (ether-ethanol), sm.p. 107 - 109° C, NMR: 6CDCl3 1,40 - 2,20 I4H, m), 2,28 (2H, t, J = 2,87 (204) 5-(1-methyl-1,2,3,4-tetrazol-5-yl)valeric acid, colorless prisms (ether-ethanol), m.p. 107 - 109° C, NMR: 6CDCl3 1.40 - 2.20 (14H, m), 2.28 (2H, t, J = 2.87

ppm ' ppm'

(2H, t, J = 6Hz), 4,02 (3H, s), 9,30 (1H, br.s) (2H, t, J = 6Hz), 4.02 (3H, s), 9.30 (1H, br.s)

(205) 5-(1-cyclohexyl-l,2,3,4-tetrazol-5-yl)-valerinsyre, farveløse prismer (omkrystallisert fra ethanol-vann), sm.p. 100 - 102° C (205) 5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)-valeric acid, colorless prisms (recrystallized from ethanol-water), m.p. 100 - 102° C

(206) 5-(1,2,3,4-tetrazol-5-yl)valerinsyre, farve-løs væske, NMR: 5<p>^~DMS° 1,30 - 2,00 (4H, m), 2,30 (2H, (206) 5-(1,2,3,4-tetrazol-5-yl)valeric acid, colorless liquid, NMR: 5<p>^~DMS° 1.30 - 2.00 (4H, m), 2.30 (2H,

t, J = 6Hz), 2,87 (2H, t, J = 6Hz) t, J = 6Hz), 2.87 (2H, t, J = 6Hz)

Eksempel 207 Example 207

150 ml 20 %-ig vandig saltsyre ble tilsatt til 150 ml of 20% aqueous hydrochloric acid was added

17 g methyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thiovalerat, og blandingen ble kokt under tilbakeløpskjøling i 2 timer. Etter avkjøling ble reaksjonsblandingen fortynnet med vann og ekstrahert med kloroform. Kloroformløsningen ble vasket med vandig mettet natriumkloridløsning og tørket over magnesiumsulfat. Kloroform ble destillert fra under dannelse av 4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-valerinsyre, farve-2 6 17 g of methyl 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiovalerate, and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with chloroform. The chloroform solution was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. Chloroform was distilled from to give 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-valeric acid, color-2 6

løs væske, nQ = 1,5133. loose liquid, nQ = 1.5133.

NMR: : <5pp£l3 1,80 - 2,80 (6H, m) , 3,42 (2H, t, J = NMR: : <5pp£l3 1.80 - 2.80 (6H, m) , 3.42 (2H, t, J =

7Hz), 3,96 (3H, s), 11,18 (1H, s) elementæranalyse for CgH^gN^C^S: 7Hz), 3.96 (3H, s), 11.18 (1H, s) elemental analysis for CgH^gN^C^S:

Beregnet: C 35,63 % H 4,98 % N 27,70 % Calculated: C 35.63% H 4.98% N 27.70%

Funnet : C 35,76 % H 5,11 % N 27,81 % Found : C 35.76% H 5.11% N 27.81%

Eksempel 208 og 209 Examples 208 and 209

Anvendelse av methyl-4-(1-fenyl- eller cyclohexyl-1,2,3,4-tetrazol-5-yl)thio-valerat i stedet for methyl-4-(l-methyl-1,2,3,4-tetrazol-5-yl)thio-valerat i fremgnagsmåten ifølge eksempel 207 ga følgende forbindelser: Use of methyl 4-(1-phenyl- or cyclohexyl-1,2,3,4-tetrazol-5-yl)thio-valerate instead of methyl-4-(1-methyl-1,2,3,4 -tetrazol-5-yl)thio-valerate in the procedure according to Example 207 gave the following compounds:

(208) 4-(l-fenyl-l,2,3,4-tetrazol-5-yl)thio-valerinsyre, lys gul væske, NMR: 5ppm 2'00 " 2'70 <4H'(208) 4-(1-phenyl-1,2,3,4-tetrazol-5-yl)thio-valeric acid, light yellow liquid, NMR: 5ppm 2'00 " 2'70 <4H'

m), 3,44 (2H, t, J = 7Hz), 7,55 (5H, s), 10,98 (1H, br.s) m), 3.44 (2H, t, J = 7Hz), 7.55 (5H, s), 10.98 (1H, br.s)

(209) 4-(1-cyclohexyl-l,2,3,4-tetrazol-5-yl)-thio-valerinsyre, farveløse prismer (ether), sm.p. 67,5 - 69,5° C (209) 4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)-thio-valeric acid, colorless prisms (ether), m.p. 67.5 - 69.5° C

Eksempel 210 Example 210

400 mg thionylklorid ble tilsatt til 10 ml methanol under omrøring og ytre avkjøling med is, og omrøringen ble fortsatt i 10 minutter. 500 mg 4-(1-fenyl-1,2,3,4-tetrazol-5-yl)thio-smørsyre ble tilsatt til løsningen, og blandingen ble omrørt ved romtemperatur i 2 timer. Reaksjonsblandingen ble helt over i en vandig mettet natriumkloridløsning (100 ml) og ble ekstrahert med kloroform. Kloroformlaget ble vasket med vandig mettet natriumbicarbonatløsning og vann, og ble tørket over natriumsulfat. Kloroform ble destillert fra og residuet underkastet kolonnekromåtografi (Wakogel C-200) og kolonnen ble eluert med benzen-ether (5:1, v/v) under dannelse av methyl-4-(1-fenyl-l,2,3,4-tetrazol-5-yl)thio-butyrat (350 mg), farveløs væske, nQ 18= 1,5654. 400 mg of thionyl chloride was added to 10 ml of methanol with stirring and external cooling with ice, and stirring was continued for 10 minutes. 500 mg of 4-(1-phenyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid was added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into an aqueous saturated sodium chloride solution (100 mL) and was extracted with chloroform. The chloroform layer was washed with aqueous saturated sodium bicarbonate solution and water, and was dried over sodium sulfate. Chloroform was distilled from and the residue subjected to column chromatography (Wakogel C-200) and the column eluted with benzene-ether (5:1, v/v) to give methyl-4-(1-phenyl-1,2,3,4 -tetrazol-5-yl)thio-butyrate (350 mg), colorless liquid, nQ 18 = 1.5654.

Elementæranalyse for C^2H14N4°2S: Elemental analysis for C^2H14N4°2S:

Beregnet: C 38,88 % H 5,59 % N 25,91 % Calculated: C 38.88% H 5.59% N 25.91%

Funnet : C 38,95 % H 5,61 % N.25,81 % Found : C 38.95% H 5.61% N.25.81%

Eksempel 211 Example 211

10 ml thionylklorid ble tilsatt til 2 g 4-(l-methyl-1,2,3,4-tetrazol-5-yl)thio-smørsyre og blandingen ble kokt under tilbakeløpskjøling i 1 time. Etter at overskudd av thionyklorid var destillert fra under redusert trykk, ble tørr benzen tilsatt til residuet, og den gjenværende lille mengde av thionylklorid ble fjernet som benzenazeotropen. 10 ml of thionyl chloride was added to 2 g of 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid and the mixture was refluxed for 1 hour. After the excess of thionyl chloride was distilled off under reduced pressure, dry benzene was added to the residue and the remaining small amount of thionyl chloride was removed as the benzene azeotrope.

Det således erholdte residuum ble løst i 50 ml tørr benzen, og til løsningen ble tilsatt 2 ml pyridin. 2 ml methanol ble dråpevis tilsatt under omrøring mens reaksjonsblandingen ble avkjølt med is.- Etter at blandingen var omrørt ved romtemperatur i 1 time ble benzenlaget vasket med fortynnet saltsyre, vandig mettet natriumbicarbonatløsning og vandig mettet natriumkloridløsning, og ble tørket over natriumsulfat. Benzenet ble destillert fra og residuet underkastet kolonne-karomatografi (Wakogel C-200) og kolonnen ble eluert med benzen-ether (5:1, v/v). Eluatet ble destillert under redusert trykk under dannelse av methyl-4-(1-methyl-l,2,3,4-tetrazol-5-yl)thio-butyrat (1,2 g), farveløs væske, k.p. The residue thus obtained was dissolved in 50 ml of dry benzene, and 2 ml of pyridine was added to the solution. 2 ml of methanol was added dropwise with stirring while the reaction mixture was cooled with ice.- After the mixture had been stirred at room temperature for 1 hour, the benzene layer was washed with dilute hydrochloric acid, aqueous saturated sodium bicarbonate solution and aqueous saturated sodium chloride solution, and was dried over sodium sulfate. The benzene was distilled from and the residue subjected to column chromatography (Wakogel C-200) and the column was eluted with benzene ether (5:1, v/v). The eluate was distilled under reduced pressure to give methyl 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyrate (1.2 g), colorless liquid, m.p.

175 - 177° C/0,8 mmHg. 175 - 177°C/0.8mmHg.

Elementæranalyse for C^H^2N4°2S: Elemental analysis for C^H^2N4°2S:

Beregnet: C 38,88 % H 5,59 % N 25,91 % Calculated: C 38.88% H 5.59% N 25.91%

Funnet : C 38,92 % H 5,53 % N 25,83 % Found : C 38.92% H 5.53% N 25.83%

Eksempel 212 Example 212

Ved å gå frem på samme måte som beskrevet i eksempel 63 ble det erholdt N,N-diethy1-4-(1-cyclohexyl-l,2,3,4-tetrazol-5-yl)thio-butyramid, farveløs væske, nD 20 = 1,5237. Proceeding in the same manner as described in Example 63, N,N-diethy1-4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)thio-butyramide was obtained, colorless liquid, nD 20 = 1.5237.

Eksempel 213 Example 213

Ved å gå frem på samme måte som beskrevet i eksempel 190 ble det erholdt methyl-4-[1-(4-ethylfenyl)-1,2,3,4- By proceeding in the same way as described in example 190, methyl-4-[1-(4-ethylphenyl)-1,2,3,4-

14 tetrazol-5-yl)thio-butyrat, lys gul væske, nn = 1,5581. 14 Tetrazol-5-yl)thio-butyrate, light yellow liquid, nn = 1.5581.

Eksempel 214 Example 214

Ved å gå frem på samme måte som beskrevet i eksempel 193 ble det erholdt 4-[1-(4-ethylfenyl)-1,2,3,4-tetrazol-5-yl)-thio-smørsyre, lys gul væske, NMR: ^ppm"^3 1,28 (3H, t, J 7,5 Hz), 2,00 - 2,90 (6H, m), 3,44 (2H, t, J = 7Hz), 7,36 Proceeding in the same manner as described in Example 193, 4-[1-(4-ethylphenyl)-1,2,3,4-tetrazol-5-yl)-thio-butyric acid was obtained, light yellow liquid, NMR : ^ppm"^3 1.28 (3H, t, J 7.5 Hz), 2.00 - 2.90 (6H, m), 3.44 (2H, t, J = 7Hz), 7.36

(2H, d, J = 9Hz), 7,48 (2H, d, J = 9Hz), 10,60 (1H, br.s). (2H, d, J = 9Hz), 7.48 (2H, d, J = 9Hz), 10.60 (1H, br.s).

Eksempel 215 - 220 Example 215 - 220

Ved å gå frem på samme måte som beskrevet i eksempel 71 og 77, ble de følgende forbindelser erholdt: By proceeding in the same manner as described in Examples 71 and 77, the following compounds were obtained:

(215) N-hexyl-5-(l-fenyl-l,2,3,4-tetrazol-5-yl)-valeramid, farveløse nåler (ethyl-acetat-hexan), sm.p. (215) N-hexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)-valeramide, colorless needles (ethyl acetate-hexane), m.p.

80,5 - 82,5° C 80.5 - 82.5° C

(216) N-isopropyl-N-cyclohexyl-5-(1-fenyl-1,2,3,4-tetrazol-5-yl)valeramid, farveløse nåler (ether), sm.p. 91 - 92,5° C (216) N-isopropyl-N-cyclohexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide, colorless needles (ether), m.p. 91 - 92.5° C

(217) N-ethyl-N-cyclohexyl-5-(1-fenyl-1,2,3,4-tetrazol-5-yl)butyramid, farveløse nåler (ether), sm.p. 77,5 - 80° C (217) N-ethyl-N-cyclohexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)butyramide, colorless needles (ether), m.p. 77.5 - 80° C

(218) N-butyl-5-(1-fenyl-1,2,3,4-tetrazol-5-yl)-butyramid, farveløse nåler (ethylacetat-hexan), sm.p. 76,5 - 78,5° C (218) N-butyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)-butyramide, colorless needles (ethyl acetate-hexane), m.p. 76.5 - 78.5° C

(219) N-cyclohexyl-5-(l-fenyl-1,2,3, 4-tetrazol-5-yl)valeramid, farveløse nåler (ethylacetat-hexan), sm.p. 100 - 102° C (219) N-cyclohexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide, colorless needles (ethyl acetate-hexane), m.p. 100 - 102° C

(220) N-methyl-N-cyclohexyl-5-(1-fenyl-1,2,3,4-tetrazol-5-yl)valeramid, farveløs oljesubstans, nD 21 = 1,5396 (220) N-methyl-N-cyclohexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide, colorless oily substance, nD 21 = 1.5396

Claims (1)

Analogifremgangsmåte for fremstilling av farmakologisk aktive tétrazolderivåtér av formel:Analogous method for the preparation of pharmacologically active tetrazole derivatives of formula: hvori R"*" er hydrogen, £^- 4 alkyl, cyclohexyl som eventuelt erwherein R"*" is hydrogen, £-4 alkyl, cyclohexyl which is optionally substituert med C^_^ alkoxy, eller fenyl som eventuelt ersubstituted with C^_^ alkoxy, or phenyl which is optionally substituert med C^_4 alkyl, A er svovel eller C1-4 alkylthio, JL er 0 eller 1, B er C, . alky.len, 2 R er C1-4 alkoxy eller en gruppesubstituted with C 1-4 alkyl, A is sulfur or C 1-4 alkylthio, JL is 0 or 1, B is C, . alkylene, 2 R is C 1-4 alkoxy or a group og R 4 er like eller forskjellige og er hver hydrogen; cj__gand R 4 are the same or different and are each hydrogen; cj__g alkyl; C^_^2 cycloalkyl som eventuelt er substituert med enalkyl; C^_^2 cycloalkyl which is optionally substituted with a gruppe valgt blant hydroxy, C1-4 alkanoyloxy, C^_4 alkoxy, C-L_4 alkyl og N,N-di(C^_4 alkyl) amino; fenyl som eventuelt ergroup selected from hydroxy, C 1-4 alkanoyloxy, C 1-4 alkoxy, C 1-4 alkyl and N,N-di(C 1-4 alkyl)amino; phenyl which is optionally substituert med én eller to substituenter valgt blant amino-substituted with one or two substituents selected from amino- sulfonyl, N,N-di(C1_4 alkyl)amino, C1-4 alkyl, halogen, C^_4 sulfonyl, N,N-di(C1-4 alkyl)amino, C1-4 alkyl, halogen, C^_4 alkoxy og nitro; cyclohexyl-(C^_4)-alkyl, fenyl-(C1-4)-alkylalkoxy and nitro; cyclohexyl-(C 1-4 )-alkyl, phenyl-(C 1-4 )-alkyl hvori fenylringen eventuelt er substituert med C^_4 alkoxy;wherein the phenyl ring is optionally substituted with C 1-4 alkoxy; hydroxy-(C,_.)-alkyl; pyridyl; 2-furylmethyl; eller 2-thienyl- 3 4hydroxy-(C 1-6 )-alkyl; pyridyl; 2-furylmethyl; or 2-thienyl- 3 4 methyl; eller R og R kan sammen med nitrogenatomet som demethyl; or R and R can together with the nitrogen atom as they er bundet til, danne en heterocyklisk gruppe valgt blantis bonded to, form a heterocyclic group selected from morfolino, piperidino og piperazino som eventuelt er substimorpholino, piperidino and piperazino which are optionally substituted tuert med C^_4 alkyl eller C^_4 alkanoyl, forutsatt at a) nårier 0 og R<1> er hydrogen eller alkyl med 1 til 4 carbontuated with C^_4 alkyl or C^_4 alkanoyl, provided that a) when 0 and R<1> are hydrogen or alkyl of 1 to 4 carbons atomer, er R fprskjellig fra alkoxy, og NR<3>R<4> er foratoms, R is different from alkoxy, and NR<3>R<4> is for skjellig fra amino; b) nårier 0 eller R1 er n-butyl, er B ikke methylen og NR<3>R<4 >different from amino; b) when 0 or R1 is n-butyl, B is not methylene and NR<3>R<4 > er ikke ethylamino; c) når i-er 0 og R 1 er fenyl og B er methylen, er R 2 for- 3 4is not ethylamino; c) when i is 0 and R 1 is phenyl and B is methylene, R 2 is for- 3 4 skjellig fra ethoxy, og NR R er forskjellig fra amino, methylamino og benzylamino; d) nårier 0 og R 1 er fenyl og B er ethylmethylen, er R 2 ikke 3 4different from ethoxy, and NR R is different from amino, methylamino and benzylamino; d) when 0 and R 1 are phenyl and B is ethylmethylene, R 2 is not 3 4 ethoxy, og NR R er ikke amino; e) nårier 0 og R<1> er cyclohexyl og B er ethylen eller methyl- 3 4ethoxy, and NR R is not amino; e) when 0 and R<1> is cyclohexyl and B is ethylene or methyl- 3 4 methylen, er NR R ikke amino ; og f) når Jt er 0 og R"*" er cyclohexyl og B er dimethylmethylen, er NR 3 R 4 forskjellig fra amino, diethylamino, benzylamino og morfolino,methylene, NR R is not amino; and f) when Jt is 0 and R"*" is cyclohexyl and B is dimethylmethylene, NR 3 R 4 is different from amino, diethylamino, benzylamino and morpholino, og farmasøytisk akseptable salter derav, karakterisert ved at a) en carboxylsyreforbindelse av formeland pharmaceutically acceptable salts thereof, characterized in that a) a carboxylic acid compound of formula hvori R<1>, A, -^og B er som ovenfor definert, eller et reaktivt derivat derav, omsettes med et amin av formel:in which R<1>, A, -^ and B are as defined above, or a reactive derivative thereof, is reacted with an amine of formula: hvori R og R er som ovenfor definert, eller et reaktivt derivat derav, b) et 5- mercaptotetrazolderivat av formelin which R and R are as defined above, or a reactive derivative thereof, b) a 5-mercaptotetrazole derivative of formula hvori R<1> og A er som ovenfor definert og t' er 1, omsettes med et haloalkancarboxylsyrederivat av formel:in which R<1> and A are as defined above and t' is 1, is reacted with a haloalkanecarboxylic acid derivative of formula: hvori X er et halogen og B og R 2 er som ovenfor definert, c) et carboxylsyreamid av formel: 1 5in which X is a halogen and B and R 2 are as defined above, c) a carboxylic acid amide of formula: 1 5 hvori B og R er som ovenfor definert og R er alkyl med 1-6 carbonatomer, omsettes med fosforpentaklorid og deretter med hydrogenazid, eller d) en tetrazolforbindelse av formel:in which B and R are as defined above and R is alkyl with 1-6 carbon atoms, reacted with phosphorus pentachloride and then with hydrogen azide, or d) a tetrazole compound of formula: hvori R<1> er som ovenfor definert, D er alkylen med 1-6 carbonatomer og X er et halogen, omsettes med en mercaptoforbindelse med formel: 2in which R<1> is as defined above, D is the alkylene with 1-6 carbon atoms and X is a halogen, is reacted with a mercapto compound of formula: 2 hvori B og R er som ovenfor definert,in which B and R are as above defined, hvoretter, om ønsket/ et erholdt tetrazolderivat avafter which, if desired/ an obtained tetrazole derivative of formelformula hvori R<1>, A, Voq B er som ovenfor definert, underkastes forestring, og/eller et erholdt tetrazolderivat av formel:in which R<1>, A, Voq B are as defined above, subjected to esterification, and/or an obtained tetrazole derivative of formula: hvori R 1 , A, - t/ og B er som ovenfor definert, og R 5 er alkyl med 1 til 6 carbonatomer, underkastes hydrolyse, og/eller et erholdt tetrazolderivat omdannes til et farmasøytisk akseptabelt salt derav.wherein R 1 , A, - t/ and B are as defined above, and R 5 is alkyl with 1 to 6 carbon atoms, is subjected to hydrolysis, and/or a tetrazole derivative obtained is converted into a pharmaceutically acceptable salt thereof.
NO810637A 1980-02-26 1981-02-25 ANALOGUE PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE TETRAZOLD DERIVATIVES. NO157502C (en)

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