DK169720B1 - Fluorinated 1- (alpha-phenylalkyl) -1H-1,2,3-triazole compounds as well as their preparation and pharmaceutical preparations containing such compounds - Google Patents

Fluorinated 1- (alpha-phenylalkyl) -1H-1,2,3-triazole compounds as well as their preparation and pharmaceutical preparations containing such compounds Download PDF

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DK169720B1
DK169720B1 DK175686A DK175686A DK169720B1 DK 169720 B1 DK169720 B1 DK 169720B1 DK 175686 A DK175686 A DK 175686A DK 175686 A DK175686 A DK 175686A DK 169720 B1 DK169720 B1 DK 169720B1
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triazole
carbamyl
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carboxamide
difluorobenzyl
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Rene Meier
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Ciba Geigy Ag
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00Compounds containing azido groups
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/08Antiepileptics; Anticonvulsants
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/40Halogenated unsaturated alcohols
    • C07C33/46Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/041,2,3-Triazoles; Hydrogenated 1,2,3-triazoles

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Description

i DK 169720 B1in DK 169720 B1

Opfindelsen angår hidtil ukendte fluorerede l-(a-phenylalk-yl)-lH-l,2,3-triazolforbindelser med den almene formel g Ph-alk-N^ ^ (I) ki kz 10 hvori pH betyder en i o-stillingen med fluor og eventuelt yderligere med mindst ét yderligere halogenatom substitueret phenylgruppe, alk betyder methylen eller lavalkyliden, betyder hydrogen, lavalkyl eller en usubstitueret eller med lavalkanoyl eller lavalkyl substitueret carbamylgruppe, og 15 R2 betyder en usubstitueret eller med lavalkanoyl eller lavalkyl substitueret carbamoylgruppe, en fremgangsmåde til fremstilling af disse forbindelser samt farmaceutiske præparater indeholdende forbindelser med formlen (I).The invention relates to novel fluorinated 1- (a-phenylalkyl) -1H-1,2,3-triazole compounds of the general formula g Ph-alk-N 2 (I) ki kz wherein pH means a at the o-position with fluorine and optionally further with at least one additional halogen atom substituted phenyl group, alk means methylene or lower alkylidene, means hydrogen, lower alkyl or an unsubstituted or lower alkanoyl or lower alkyl substituted carbamyl group, and R2 represents an unsubstituted or lower alkanoyl or lower alkyl substituted carbamo group for the preparation of these compounds as well as pharmaceutical compositions containing compounds of formula (I).

20 Som yderligere halogensubstituenter i Ph kan eksempelvis nævnes halogenatomer med et atomnummer på højst 35, såsom fluor, chlor eller i anden række brom. I alt kan der forekomme 5 halogensubstituenter, foruden o-fluorsubstituenten eksempelvis 1 eller 2 chloratomer, 1 chlor- og 1 fluoratom 25 eller 1-3, f.eks. 1 eller 2 fluoratomer. Et enkelt yderligere halogenatom er eksempelvis bundet i 4-, 5 eller især 6-stil-1ingen.For example, as additional halogen substituents in Ph, halogen atoms having an atomic number not exceeding 35, such as fluorine, chlorine or other bromine, may be mentioned. In total, there may be 5 halogen substituents, in addition to the o-fluoro substituent, for example, 1 or 2 chlorine atoms, 1 chlorine and 1 fluorine atom 25 or 1-3, e.g. 1 or 2 fluorine atoms. For example, a single additional halogen atom is bonded in the 4-, 5 or especially the 6-position.

Lavalkyliden er eksempelvis methylen eller C2-4-alkyliden, 30 især methylen, ethyliden, 1,1-propyliden, 2,2-propyliden (isopropyliden) eller 1,1-butyliden.The lower alkylidene is, for example, methylene or C2-4 alkylidene, especially methylene, ethylidene, 1,1-propylidene, 2,2-propylidene (isopropylidene) or 1,1-butylidene.

Lavalkyl er eksempelvis C^-alkyl, såsom methyl eller i anden række ethyl, propyl, isopropyl, butyl, isobutyl, sek-35 butyl eller tert-butyl, men kan også være en C5_7-alkylgrup-pe, f.eks. pentyl, hexyl eller heptyl.Low alkyl is, for example, C 1-4 alkyl, such as methyl or other ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but can also be a C 5-7 alkyl group, e.g. pentyl, hexyl or heptyl.

2 DK 169720 B12 DK 169720 B1

Carbamyl substitueret med lavalkanoyl eller lavalkyl er især monosubstitueret med lavalkanoyl eller disubstitueret med lavalkyl og betyder eksempelvis N-Ci_7-alkanoylcarbamyl, i første række N-C2-5~alkanoylcarbamoyl, såsom acetyl- eller 5 pivaloylcarbamoyl, eller først og fremmest N,N-di-C1.4-alk-ylcarbamyl, såsom Ν,Ν-dimethylcarbamyl eller Ν,Ν-diethylcarbamyl.Carbamyl substituted with lower alkanoyl or lower alkyl is especially monosubstituted with lower alkanoyl or disubstituted with lower alkyl and means, for example, N-C 1-7 alkanoylcarbamyl, primarily N-C2-5 alkanoylcarbamoyl such as acetyl or pivaloylcarbamoyl, or first and foremost N di-C 1-4 -alkylcarbamyl such as Ν, Ν-dimethylcarbamyl or Ν, Ν-diethylcarbamyl.

Fra EP offentliggørelsesskrift nr. 114.347 kendes chlorerede 10 l-phenyllavalkyl-lH-l,2,3-triazolforbindelser med antikon-vulsiv virkning. De fluorerede forbindelser med formlen (I) har en overraskende bedre antikonvulsiv virkning end de nært beslægtede kendte chlorerede forbindelser, hvilket fremgår af nedenstående farmakologiske data.EP-A-114,347 discloses chlorinated 10 l-phenyllavalkyl-1H-1,2,3-triazole compounds having anticonvulsant activity. The fluorinated compounds of formula (I) have a surprisingly better anticonvulsant effect than the closely related known chlorinated compounds, as shown in the pharmacological data below.

1515

Forbindelserne ifølge opfindelsen har værdifulde farmakologiske egenskaber, især en udtalt antikonvulsiv virkning, der eksempelvis kan påvises på mus ved hjælp af en tydelig metrazol-antagonisme i et dosisområde fra ca. 30 til ca.The compounds of the invention have valuable pharmacological properties, in particular a pronounced anticonvulsant effect, which can be detected, for example, on mice by a clear metrazole antagonism in a dose range of from ca. 30 to approx.

20 300 mg/kg p.o. samt på mus og rotter ved hjælp af en udtalt beskyttelsesvirkning mod konvulsioner udløst af elektrochok i et dosisområde fra ca. 1 til ca. 50, i de fleste tilfælde fra ca. 1 til ca. 25 mg/kg p.o. Med denne model opnås eksempelvis følgende værdier for den effektive dosis ED,-q i 25 mg/kg p.o. (1 times forapplikation): 1-(2,6-Difluorbenzyl)-lH-l,2,3-triazol-4-carboxamidi 17 (mus) og 8 (rotte) , 1-(o-fluorbenzyl)-lH-l,2,3-triazol-4-carboxamid: 17 (mus, rotte), 30 1-(2,6-difluorbenzyl)-lH-l,2,3-triazol-4,5-dicarboxamid: 4 (mus, rotte), 1-(6-chlor-2-fluor- benzyl)-1H-1,2,3-triazol-4,5-dicarboxamid: 7 (mus) og 10 (rotte), 1-(o-fluorbenzyl)-lH-l,2,3-triazol-4,5-dicarboxamid: 6 (mus) 35 og 10 (rotte), 1-(6-chlor-2-fluor- benzyl)-1H-1,2,3-triazol-4-carboxamid: 11 (mus) og 1-(2,5-difluorbenzyl)-lH-l,2,3-triazol-4,5-dicarboxamid: 6 (mus).300 mg / kg p.o. and in mice and rats by means of a pronounced protective effect against convulsions triggered by electroshock in a dose range of about 1 to approx. 50, in most cases from ca. 1 to approx. 25 mg / kg p.o. With this model, for example, the following values for the effective dose of ED, -q in 25 mg / kg p.o. (1 hour pre-application): 1- (2,6-Difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide 17 (mouse) and 8 (rat), 1- (o-fluorobenzyl) -1H-1 , 2,3-triazole-4-carboxamide: 17 (mouse, rat), 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide: 4 (mouse, rat) ), 1- (6-chloro-2-fluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide: 7 (mouse) and 10 (rat), 1- (o-fluorobenzyl) - 1H-1,2,3-triazole-4,5-dicarboxamide: 6 (mouse) and 10 (rat), 1- (6-chloro-2-fluorobenzyl) -1H-1,2,3-triazole -4-carboxamide: 11 (mice) and 1- (2,5-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide: 6 (mice).

3 DK 169720 B13 DK 169720 B1

De omhandlede fluorerede l-(a-phenylalkyl)-lH-l,2,3-triazol-forbindelser med formlen (I) har som nævnt ovenfor en bedre antikonvulsiv virkning end de fra EP offentliggærelsesskrift nr. 114.347 kendte analoge chlorforbindelser med antikonvul-5 siv virkning. Med de kendte analoge chlorforbindelser fås ved anvendelse af ovenstående model eksempelvis følgende ED5o~værdier: l-(o-chlorbenzyl)-lH-l,2,3-triazol-4-carboxamid: 26 (mus) 10 og 25 (rotte) og 1- (o-chlorbenzyl)-1H-1,2,3-triazol-4,5-dicarboxamid: 40 (mus) og 43 (rotte).The fluorinated 1- (α-phenylalkyl) -1H-1,2,3-triazole compounds of formula (I), as mentioned above, have a better anticonvulsant effect than analogous chlorine compounds known from EP Publication No. 114,347. reed effect. With the known analogous chlorine compounds, using the above model, for example, the following ED 50 values are obtained: 1- (o-chlorobenzyl) -1H-1,2,3-triazole-4-carboxamide: 26 (mouse) 10 and 25 (rat) and 1- (o-chlorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide: 40 (mouse) and 43 (rat).

Forbindelserne ifølge opfindelsen er således særdeles vel-15 egnede til behandling af konvulsioner af forskellig art, eksempelvis til behandling af epilepsi, og de kan anvendes som antikonvulsive, eksempelvis antiepileptiske, lægemidler.Thus, the compounds of the invention are very suitable for the treatment of various convulsions, for example for the treatment of epilepsy, and they can be used as anticonvulsants, for example antiepileptic drugs.

Opfindelsen angår i første række forbindelser med formlen 20 I, hvori Ph betyder en i o-stilling med fluor og eventuelt yderligere med op til 3 halogenatomer med et atomnummer på op til 35 substitueret phenylgruppe, alk betyder methylen eller C2-4-alkyliden, betyder hydrogen, C1_4~alkyl, carb- amyl, N-C^.y-alkanoylcarbamyl eller N,N-di-Ci_4-alkylcarb-25 amyl, og R2 betyder carbamyl, N-C^.y-alkanoylcarbamyl eller N,N-di-C1_4-alkylcarbamyl.The invention relates primarily to compounds of formula 20 I wherein Ph means one at the o-position with fluorine and optionally further with up to 3 halogen atoms having an atomic number of up to 35 substituted phenyl group, alk means methylene or C2-4 alkylidene, means hydrogen, C 1-4 alkyl, carbamyl, NC 1-6 alkanoylcarbamyl or N, N-di-C 1-4 alkylcarbamyl, and R2 means carbamyl, NC 1-6 alkanoylcarbamyl or N, N-di-C 1-4 alkylcarbamyl.

Opfindelsen angår fortrinsvis forbindelser med formlen I, hvori Ph betyder en i o-stilling med fluor og eventuelt 30 yderligere med op til 2 chloratomer, 1 fluor- og l chloratom eller op til 2 fluoratomer substitueret phenylgruppe, såsom o-fluorphenyl, 2,3-, 2,4-, 2,5- eller 2,6-difluorphenyl, 2- chlor-6-fluorphenyl, endvidere 2,4,6-trifluorphenyl, alk betyder methylen, ethyliden eller 2,2-propyliden, Rj betyder 35 hydrogen, C1_4-alkyl, såsom methyl, carbamyl, N-C2_5-alkan-oylcarbamyl, såsom acetyl- eller pivaloylcarbamyl, eller 4 DK 169720 B1 N,N-di-Ci_4-alkylcarbamyl, såsom dimethylcarbamyl, og R2 betyder carbamyl, N-C2_5-alkanoylcarbamyl, såsom acetyleller pivaloylcarbamyl, eller N,N-di-Ci_4-alkylcarbamyl, såsom dimethylcarbamyl.The invention preferably relates to compounds of formula I wherein Ph means an in-position with fluorine and optionally further with up to 2 chlorine atoms, 1 fluorine and 1 chlorine atom or up to 2 fluorine atoms substituted phenyl group such as o-fluorophenyl, 2.3 -, 2,4-, 2,5- or 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, further 2,4,6-trifluorophenyl, alk means methylene, ethylidene or 2,2-propylidene, R hydrogen, C1-4 alkyl such as methyl, carbamyl, N-C2-5 alkanoylcarbamyl, such as acetyl or pivaloylcarbamyl, or N, N-di-C1-4 alkylcarbamyl such as dimethylcarbamyl, and R2 means carbamyl, N- C2-5 alkanoylcarbamyl such as acetyl or pivaloylcarbamyl, or N, N-di-C1-4 alkylcarbamyl such as dimethylcarbamyl.

55

Opfindelsen angår først og fremmest forbindelser med formlen I, hvori Ph betyder en i o-stilling med fluor og eventuelt yderligere med 1 chloratom, 1 fluoratom og 1 chloratom eller op til 2 fluoratomer substitueret phenyl, såsom o-fluor-10 phenyl, 2,3-, 2,4-, 2,5- eller 2,6-difluorphenyl, 2-chlor-6-fluorphenyl, endvidere 2,4,6-trifluorphenyl, alk betyder methylen eller C2-4-alkyliden, især methylen, R]_ betyder hydrogen, C^^-alkyl, såsom methyl, eller en gruppe R2, og R2 betyder carbamyl eller i anden række N-C2_5-alkanoylcarb-15 amyl, såsom acetylcarbamyl, eller N,N-di-C1_4-alkylcarbamyl, såsom dimethylcarbamyl, eksempelvis forbindelser med formlen I, hvori Ph betyder o-fluorphenyl, 2,3-, 2,4-, 2,5- eller 2,6-difluorphenyl eller 6-chlor-2-fluor-phenyl, alk betyder methylen, R^ betyder hydrogen eller usubstitueret carbamyl, 20 og R2 betyder usubstitueret carbamyl.The invention relates primarily to compounds of formula I wherein Ph means a fluorine at the o-position and optionally further with 1 chlorine atom, 1 fluorine atom and 1 chlorine atom or up to 2 fluorine atoms substituted phenyl such as o-fluoro-phenyl, 2, 3-, 2,4-, 2,5- or 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, furthermore 2,4,6-trifluorophenyl, alk means methylene or C2-4 alkylidene, especially methylene, R represents hydrogen, C 1-4 alkyl, such as methyl, or a group R 2, and R 2 represents carbamyl or otherwise N-C 2-5 alkanoylcarbamyl such as acetylcarbamyl or N, N-di-C 1-4 alkylcarbamyl; such as dimethylcarbamyl, for example, compounds of formula I wherein Ph means o-fluorophenyl, 2,3-, 2,4-, 2,5- or 2,6-difluorophenyl or 6-chloro-2-fluoro-phenyl, alk means methylene , R 2 represents hydrogen or unsubstituted carbamyl, and R 2 represents unsubstituted carbamyl.

Opfindelsen angår især forbindelser med formlen I, hvori Ph betyder o-fluorphenyl eller 2,6-difluorphenyl, alk betyder methylen, R^ betyder hydrogen eller usubstitueret 25 carbamyl, og R2 betyder usubstitueret carbamyl.In particular, the invention relates to compounds of formula I wherein Ph means o-fluorophenyl or 2,6-difluorophenyl, alk means methylene, R 4 represents hydrogen or unsubstituted carbamyl, and R 2 means unsubstituted carbamyl.

Opfindelsen angår fortrinsvis forbindelser med formlen I, hvori Ph betyder 2,6-difluorphenyl, alk betyder methylen, R^ betyder hydrogen, C^_^-alkyl, såsom methyl, eller en 20 gruppe R2/ og R2 betyder carbamyl eller i anden række N-C2_5“alkanoylcarbamyl, såsom acetylcarbamyl, eller N,N-di-C^_4-alkylcarbamyl, såsom dimethylcarbamyl.The invention preferably relates to compounds of formula I wherein Ph is 2,6-difluorophenyl, alk is methylene, R 1 is hydrogen, C 1-6 alkyl, such as methyl, or a group R 2 N-C 2- 5 alkanoylcarbamyl, such as acetylcarbamyl, or N, N-di-C 1-4 alkylcarbamyl, such as dimethylcarbamyl.

Opfindelsen angår i allerførste række forbindelser med 35 formlen I, hvori Ph betyder o-fluorphenyl, 2,5-difluor-phenyl, 2,6-difluorphenyl eller 2-chlor-6-fluor-phenyl, alk betyder methylen,og R-j^ og R2 begge betyder carbamyl, DK 169720 Bl s samt forbindelser med formlen I, hvori Ph betyder 2,6-di-fluorphenyl, alk betyder methylen, betyder hydrogen eller carbamyl, og R2 betyder carbamyl.The invention relates in the very first series of compounds of formula I wherein Ph means o-fluorophenyl, 2,5-difluoro-phenyl, 2,6-difluorophenyl or 2-chloro-6-fluoro-phenyl, alk means methylene, and R R 2 is both carbamyl, DK 169720 B 1 s and compounds of formula I wherein Ph is 2,6-difluorophenyl, alk is methylene, is hydrogen or carbamyl, and R 2 is carbamyl.

5 Forbindelserne med formlen I kan fremstilles under anvendelse af i og for sig kendte fremgangsmåder. Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man a) omsætter en forbindelse med formlen 10 Ph - alk - N3 (II) med en forbindelse med formlenThe compounds of formula I can be prepared using methods known per se. The process of the invention is characterized in that a) reacting a compound of formula 10 Ph - alk - N3 (II) with a compound of formula

Ri - I = I - r2 (iii) 15 hvori Y1 betyder hydroxy, og Y2 betyder hydrogen, eller Y1 og Y2 saitimen betyder en yderligere binding, eller et salt og/eller en tautomer deraf eller b) omsætter en forbindelse med formlen 20R 1 - I = I - r 2 (iii) wherein Y 1 is hydroxy and Y 2 is hydrogen or Y 1 and Y 2 are the additional bond, or a salt and / or tautomer thereof, or b) reacting a compound of formula 20

Ph - alk - Z (IV) hvori Z betyder reaktionsdygtigt forestret hydroxy, med et 1H-1,2,3-triazolderivat med formlen 25 ]=*-Rz 30 eller et salt deraf eller c) i en forbindelse med formlenPh - alk - Z (IV) wherein Z is reactively esterified hydroxy, with a 1H-1,2,3-triazole derivative of formula 25] = * - Rz 30 or a salt thereof or c) in a compound of formula

Ph-alk-<H (VI) ·=·-Υι* 35 i, 0 DK 169720 B1 6 hvori Y^ betyder en gruppe YA, som kan omdannes til usubsti-tueret eller lavalkylsubstitueret carbamyl, og betyder en gruppe R^ eller en gruppe Υβ, som kan omdannes til usub-stitueret eller lavalkylsubstitueret carbamyl, eller Y4 be-5 tyder en gruppe R2, og Y^ betyder en gruppe Υβ, som kan omdannes til usubstitueret eller lavalkylsubstitueret carbamyl, omdanner Y^ og/eller Υβ til usubstitueret eller lavalkylsubsti tueret carbamyl, om nødvendigt adskiller en dannet isomer-blanding i komponenterne og isolerer isomeren med formlen I 10 og, om ønsket, omdanner en fremstillet forbindelse til en anden forbindelse med formlen I og/eller adskiller en fremstillet enantiomer- eller diastereomerblanding i komponenterne.Ph-alk- <H (VI) · = · -Υι * 35 i, wherein Y 1 represents a group YA which can be converted to unsubstituted or lower alkyl substituted carbamyl and represents a group R group Υβ which can be converted to unsubstituted or low alkyl substituted carbamyl, or Y4 represents a group R 2 and Y 1 represents a group Υ β which can be converted to unsubstituted or low alkyl substituted carbamyl, Y 2 and / or Υβ converted to unsubstituted or lower alkyl substituted carbamyl, if necessary, separates a formed isomer mixture into the components and isolates the isomer of formula I 10 and, if desired, converts a prepared compound into another compound of formula I and / or separates a prepared enantiomer or diastereomer mixture in the components .

Som udgangsforbindeiser med formlen III ved fremgangsmåde a) 15 og tautomerer deraf kan eksempelvis anvendes forbindelser med formlerne R1-C5C-R2 (Illa) og R^-C (=0)-CH2~R2 (Hib).As starting compounds of formula III by process a) and tautomers thereof, for example, compounds of formulas R1-C5C-R2 (IIa) and R1 -C (= O) -CH2 ~ R2 (Hib) can be used.

Salte deraf er eksempelvis alkalimetalsalte, f.eks. natriumsalte af forbindelserne med formlen Illa, som kan dannes ud fra disse forbindelser og alkalimetalalkanolater, f.eks.Salts thereof are, for example, alkali metal salts, e.g. sodium salts of the compounds of formula IIla which can be formed from these compounds and alkali metal alkanolates, e.g.

20 natriummethanolat.Sodium methanolate.

Omsætningen af forbindelser med formlen II med forbindelser med formlen III gennemføres på sædvanlig måde, fordelagtigt i et indifferent opløsningsmiddel, om nødvendigt i nærværel-25 se af et kondensationsmiddel og/eller ved forhøjet temperatur. Indifferente opløsningsmidler er eksempelvis aromatiske eller araliphatiske carbonhydrider, såsom benzen eller toluen, eller ethere, såsom tert-butoxymethan, tetrahydrofuran eller dioxan.The reaction of compounds of formula II with compounds of formula III is carried out in the usual manner, advantageously in an inert solvent, if necessary in the presence of a condensing agent and / or at elevated temperature. Inert solvents are, for example, aromatic or araliphatic hydrocarbons such as benzene or toluene, or ethers such as tert-butoxymethane, tetrahydrofuran or dioxane.

3030

Foretrukne udførelsesformer for denne fremgangsmåde er eksempelvis omsætningen af et azid med formlen II med en forbindelse med formlen Illa i benzen eller dioxan ved temperaturer på fra ca. 60-120°C, fortrinsvis ved kogetemperatur.Preferred embodiments of this process are, for example, the reaction of an azide of formula II with a compound of formula IIa in benzene or dioxane at temperatures of from ca. 60-120 ° C, preferably at boiling temperature.

35 0 7 DK 169720 B135 0 7 DK 169720 B1

Udgangsforbindelserne med formlen III og delvis også udgangsforbindelserne med formlen II er kendte forbindelser. Hidtil ukendte udgangsforbindelser med formlen II kan fremstilles analogt med de kendte forbindelser, f.eks. ved omsætning af 5 en forbindelse med formlen Ph-alk-Z (IV), hvori Z betyder reaktionsdygtigt forestret hydroxy, såsom halogen, f.eks. chlor, brom eller iod, eller sulfonyloxy, såsom lavalkan-sulfonyloxy, eventuelt substitueret benzensulfonyloxy, såsom methan-, ethan-, benzen-, p-toluen- eller p-brombenzen-10 sulfonyloxy, eller fluorsulfonyloxy, med et alkalimetalazid, f.eks. med natriumazid, eksempelvis i dimethylsulfoxid eller dimethylformamid, eller ved,at man omsætter en alkohol (Z = hydroxy) i nærværelse af triphenylphosphin og en azodicarboxyl-syreester, f.eks. azodicarboxylsyrediethylester, med hydrogen-15 azidsyre, f.eks. i toluen.The starting compounds of formula III and partly also the starting compounds of formula II are known compounds. New starting compounds of formula II can be prepared analogously to the known compounds, e.g. by reacting 5 a compound of the formula Ph-alk-Z (IV) wherein Z is reactively esterified hydroxy such as halogen, e.g. chlorine, bromine or iodine, or sulfonyloxy, such as lower alkanesulfonyloxy, optionally substituted benzenesulfonyloxy, such as methane, ethane, benzene, p-toluene or p-bromobenzene sulfonyloxy, or fluorosulfonyloxy, with an alkali metal azide, e.g. . with sodium azide, for example, in dimethyl sulfoxide or dimethylformamide, or by reacting an alcohol (Z = hydroxy) in the presence of triphenylphosphine and an azodicarboxylic acid ester, e.g. azodicarboxylic acid diethyl ester, with hydrogen azide acid, e.g. in toluene.

I udgangsforbindelser med formlen IV ved fremgangsmåde b) betyder reaktionsdygtigt forestret hydroxy eksempelvis halogen, f.eks. chlor, brom eller iod, eller sulfonyloxy, 20 såsom lavalkansulfonyloxy, eventuelt substitueret benzensulf onyloxy, såsom methan-, ethan-, benzen-, p-toluen-eller p-brombenzensulfonyloxy, eller fluorsulfonyloxy.In starting compounds of formula IV by process b), reactively esterified hydroxy means, for example, halogen, e.g. chlorine, bromine or iodine, or sulfonyloxy, such as lower alkanesulfonyloxy, optionally substituted benzenesulfonyloxy, such as methane, ethane, benzene, p-toluene or p-bromobenzene sulfonyloxy, or fluorosulfonyloxy.

Salte af forbindelser V er eksempelvis alkalimetalsalte 25 eller jordalkalimetalsalte, såsom natrium-, kalium- eller calciumsalte.Salts of compounds V are, for example, alkali metal salts or alkaline earth metal salts such as sodium, potassium or calcium salts.

Omsætningen gennemføres på sædvanlig måde, f.eks. i nærværelse af et basisk kondensationsmiddel eller fordelagtigt, 30 idet man anvender forbindelsen med formlen V som salt, om nødvendigt under opvarmning, fortrinsvis i et opløsningseller fortyndingsmiddel. Basiske kondensationsmidler er eksempelvis sådanne, som danner salte med forbindelsen med 35 DK 169720 B1 8 0 formlen V, såsom alkalimetalalkoholater, f.eks. natrium-methanolat eller natriumethanolat, alkalimetal- eller jord-alkalimetalamider, f.eks. natriumamid eller lithiumdiiso-propylamid. Som nævnt foretages omdannelsen af forbindelsen 5 med formlen V til et salt deraf fordelagtigt forud for reaktionen, f.eks. ved omsætning med en af de nævnte baser. Opløsningsmidler er ved gennemførelse af omsætningen i nærværelse af et alkoholat fortrinsvis tilsvarende alkoholer og ved gennemførelse i nærværelse af amider eksempelvis apro-10 tiske organiske opløsningsmidler, såsom phosphorsyrelav-alkylamider, f.eks. hexamethylphosphorsyretriamid, alkan-syreamider, f.eks. dimethylfomamid, eller dilavalkylsulfoxider, f.eks. dimethylsulfoxid. Isomerer dannet ved fremgangsmåden ifølge opfindelsen som biprodukter kan eventuelt adskilles 15 fra de ønskede forbindelser med formlen I.The reaction is carried out in the usual manner, e.g. in the presence of a basic condensing agent or advantageously, using the compound of formula V as salt, if necessary during heating, preferably in a solvent or diluent. For example, basic condensing agents are those which form salts with the compound of formula V such as alkali metal alcoholates, e.g. sodium methanolate or sodium ethanolate, alkali metal or alkaline earth metal amides, e.g. sodium amide or lithium diisopropylamide. As mentioned, the conversion of compound 5 of formula V into a salt thereof is advantageously preceded by the reaction, e.g. by reaction with one of the bases mentioned. Solvents, when carrying out the reaction in the presence of an alcoholate, are preferably similar to alcohols and when carried out in the presence of amides, for example, aprotic organic solvents such as phosphoric acid-lower alkyl amides, e.g. hexamethylphosphoric triamide, alkanoic acid amides, e.g. dimethyl fomamide, or dilavalkyl sulfoxides, e.g. dimethyl sulfoxide. Isomers formed by the process of the invention as by-products can optionally be separated from the desired compounds of formula I.

Såfremt udgangsforbindelserne med formlerne IV og V ikke er kendte forbindelser, kan de fremstilles på i og for sig kendt måde. Forbindelserne med formlen IV kan eksempelvis 20 fremstilles ved, at man foretager reaktionsdygtig forestring af en tilsvarende alkohol (IV, Z = hydroxy), f.eks. ved hjælp af thionylchlorid, phosphortribromid eller et sulfonyl-chlorid. Forbindelser med formlen V kan fremstilles ved, at man omsætter trimethylsilylazid eller hydrogenazidsyre med 25 en forbindelse med formlenIf the starting compounds of formulas IV and V are not known compounds, they can be prepared in a manner known per se. For example, the compounds of Formula IV can be prepared by reacting esterified with a corresponding alcohol (IV, Z = hydroxy), e.g. by means of thionyl chloride, phosphorus tribromide or a sulfonyl chloride. Compounds of formula V can be prepared by reacting trimethylsilylazide or hydrogen azide acid with a compound of formula

Ri-C=C-R2 (Illa) eller Ri-C(*0)-CH2-R2 (Hib) hvori Rj, især betyder usubstitueret eller med lavalkyl sub-30 stitueret carbamyl, og i et eventuelt dannet 1-trimethyl- silyltriazolderivat fraspalter silylgruppen, om ønsket efter lavalk(ano)ylering af carbamyl R2 og/eller R1 som anført nedenfor for forbindelser med formlen I, ved mild hydrolyse.R 1 -C = C-R 2 (IIa) or R 1 -C (* O) -CH 2 -R 2 (Hib) wherein R 1, in particular, means unsubstituted or lower alkyl substituted carbamyl, and in an optionally formed 1-trimethylsilyl triazole derivative , if desired after low alk (ano) ylation of carbamyl R2 and / or R1 as set forth below for compounds of formula I, by mild hydrolysis.

Man kan imidlertid også omsætte trimethylsilylazid med en 35 forbindelse med formlen 0 9 DK 169720 B1 Y5-C=C-Yi* (Vila) eller Ri-C(=0)-CH2-Yi, (Vllb) hvori Y4 betyder en gruppe YA, som kan omdannes til usub-5 stitueret eller lavalkylsubstitueret carbamyl, f.eks. for-estret carboxy, såsom lavalkoxycarbonyl, eller cyano, og Y5 betyder hydrogen eller fortrinsvis en gruppe Υβ, som kan omdannes til usubstitueret eller lavalkylsubstitueret carbamyl, og som fortrinsvis er identisk med Y , og omdan-However, it is also possible to react trimethylsilylazide with a compound of the formula 0 Y5-C = C-Yi * (Vila) or Ri-C (= O) -CH2-Yi, (V11b) wherein Y4 represents a group YA which can be converted to unsubstituted or lower alkyl substituted carbamyl, e.g. esterified carboxy, such as lower alkoxycarbonyl, or cyano, and Y 5 represents hydrogen or preferably a group Υβ which can be converted to unsubstituted or lower alkyl substituted carbamyl and which is preferably identical to Y

AA

10 ner Y_ og/eller Y_ til usubstitueret eller lavalkylsubsti-tueret carbamyl, i tilfælde af forestret carboxy eksempelvis ved ammonolyse (omsætning med ammoniak) eller i tilfælde af cyano eksempelvis ved hydrolyse, hvorved også trimethyl-silylgruppen fraspaltes.10 to Yst and / or Y_ to unsubstituted or lower alkyl substituted carbamyl, in the case of esterified carboxy, for example, by ammonolysis (reaction with ammonia) or in the case of cyano, for example, by hydrolysis, thereby also decomposing the trimethylsilyl group.

1515

Grupper YA og/eller Υβ, som ifølge fremgangsmåde c) kan omdannes til usubstitueret eller lavalkylsubstitueret carbamyl, er eksempelvis frie eller på en saltform eller anhydridform foreliggende carboxylgrupper, usubstituerede eller lavalkyl- 20 substituerede amidinogrupper eller forestrede carboxygrupper, endvidere cyanogrupper.Groups YA and / or Υβ, which according to process c) can be converted to unsubstituted or low-alkyl-substituted carbamyl, are, for example, free or in a salt or anhydride form, carboxyl groups, unsubstituted or low-alkyl substituted amidino groups or esterified carboxy groups, or further.

Forestrede carboxygrupper er eksempelvis carboxygrupper forestret med en lavalkanol eller en lavalkylmercaptan, dvs.Esterated carboxy groups are, for example, carboxy groups esterified with a low alkanol or a low alkyl mercaptan, ie.

25 lavalkoxy- eller lavalkylthiocarbonylgrupper, men de kan også være forestret med en vilkårlig anden alkohol eller mercaptan, f.eks. med en eventuelt substitueret phenol eller thiophenol.25 lower alkoxy or lower alkylthiocarbonyl groups, but they may also be esterified with any other alcohol or mercaptan, e.g. with an optionally substituted phenol or thiophenol.

30 på saltform foreliggende carboxygrupper er eksempelvis på en af ammoniak eller en dilavalkylamin afledt ammoniumsaltform foreliggende carboxygruppe, endvidere på metalsal tf orm, f.eks. alkalimetal- eller jordalkalimetalsaltform, foreliggende carboxygruppe.For example, a carboxy group present in salt form is an ammonium salt form derived from an ammonia or a dilavalkylamine carboxy group, furthermore on metal salts of worm, e.g. alkali metal or alkaline earth metal salt form, present carboxy group.

35 o 10 DK 169720 B1 På anhydridform foreliggende carboxygrupper er eksempelvis på en halogenidform foreliggende carboxygruppe, såsom chlor-carbonyl, men kan også være anhydridiseret med en reaktiv carboxylsyre og eksempelvis betyde alkoxycarbonyloxycarbonyl 5 eller trifluoracetoxycarbonyl.For example, in anhydride form, there are carboxy groups present in a halide form such as chlorocarbonyl, but may also be anhydrided with a reactive carboxylic acid and, for example, may mean alkoxycarbonyloxycarbonyl 5 or trifluoroacetoxycarbonyl.

Omdannelsen af de nævnte grupper og/eller Υβ til eventuelt lavalkyleret carbamyl gennemføres på sædvanlig måde ud fra frie, forestrede eller på anhydridform forelig-10 gende carboxygrupper og usubstituerede eller lavalkylsubsti-tuerede amidinogrupper ved solvolyse, dvs. hydrolyse eller ammonolyse eller aminolyse (omsætning med ammoniak eller en dilavalkylamin).The conversion of said groups and / or Υβ to optionally low alkylated carbamyl is carried out in the usual manner from free, esterified or in anhydride form, carboxy groups and unsubstituted or low alkyl substituted amidino groups by solvolysis, i.e. hydrolysis or ammonolysis or aminolysis (reaction with ammonia or a dilavalkylamine).

15 Ved hydrolyse kan man eksempelvis omdanne cyanogrupper til carbamyl eller usubstituerede eller lavalkylsubstituerede amidinogrupper Y og/eller Y_ til usubstitueret eller lav- A i3 alkylsubstitueret carbamyl. Hydrolysen af cyanogrupper gennemføres eksempelvis i nærværelse af basiske hydrolyse-20 midler, såsom alkalimetalhydroxider, f.eks. natrium- eller kaliumhydroxid, om nødvendigt i nærværelse af peroxyforbin-delser, f.eks. hydrogenperoxid. Hydrolysen af amidinogrupper gennemføres eksempelvis i et surt hydrolysemiddel, såsom en mineralsyre, en sulfonsyre eller en carboxylsyre, f.eks.For example, by hydrolysis, cyano groups can be converted to carbamyl or unsubstituted or low-alkyl substituted amidino groups Y and / or Y_ to unsubstituted or low-A3 alkyl-substituted carbamyl. The hydrolysis of cyano groups is carried out, for example, in the presence of basic hydrolysis agents such as alkali metal hydroxides, e.g. sodium or potassium hydroxide, if necessary in the presence of peroxy compounds, e.g. hydrogen peroxide. The hydrolysis of amidino groups is carried out, for example, in an acidic hydrolyzing agent such as a mineral acid, a sulfonic acid or a carboxylic acid, e.g.

25 svovlsyre, phosphorsyre, saltsyre eller en anden hydrogen- halogenidsyre, p-toluensulfonsyre eller en anden organisk sulfonsyre, eller en lavalkansyre, såsom eddikesyre, fortrinsvis i katalytiske mængder.Sulfuric acid, phosphoric acid, hydrochloric acid or another hydrogen halide acid, p-toluenesulfonic acid or other organic sulfonic acid, or a low alkanoic acid such as acetic acid, preferably in catalytic amounts.

30 Ved ammonolyse eller aminolyse kan man eksempelvis omdanne frie eller på saltform eller anhydridform foreliggende eller forestrede carboxygrupper til usubstitueret eller lav-alkylsubstitueret carbamyl. Omdannelsen gennemføres om nødvendigt i nærværelse af et kondensationsmiddel, fordelagtigt 35 i et indifferent opløsningsmiddel. Som kondensationsmidler DK 169720 B1 11 o kan anvendes basiske kondensationsmidler/ først og fremmest ammoniak eller til aminolysen anvendte aminer i overskud, ud fra på anhydridform foreliggende carboxy endvidere alkali-metalhydroxider eller -carbonater eller tertiære organiske 5 nitrogenbaser, såsom trilavalkylaminer eller tertiære hetero-aromatiske nitrogenbaser, såsom triethylamin eller pyridin. Frie carboxygrupper kan omdannes til carbamyl under dehydra-tisering af de intermediært dannede ammoniumsalte, f.eks. ved opvarmning eller indvirkning af vandfjernende midler, 10 såsom syreanhydrider, f.eks. phosphorpentoxid, og lignende, eller carbodiimider, f.eks. l^N'-dicyclohexylcarbodiimid.For example, by ammonolysis or aminolysis, free or saline or anhydride forms or esterified carboxy groups can be converted to unsubstituted or low-alkyl-substituted carbamyl. If necessary, the conversion is carried out in the presence of a condensing agent, advantageously in an inert solvent. Also used as condensing agents are basic condensing agents / primarily ammonia or amines used in excess in the anhydride form from an anhydride form, carboxy also alkali metal hydroxides or carbonates or tertiary organic nitrogen bases such as trilavalkylamines or tertiary alkyl amines nitrogen bases such as triethylamine or pyridine. Free carboxy groups can be converted to carbamyl during dehydration of the intermediate ammonium salts, e.g. by heating or acting on water-removing agents, such as acid anhydrides, e.g. phosphorus pentoxide, and the like, or carbodiimides, e.g. l ^ N'-dicyclohexylcarbodiimide.

En særligt foretrukken udførelsesform for denne fremgangsmåde er karakteriseret ved, at man omsætter en forbindelse med formlen VI, hvori betyder forestret carboxy, og Y^ 15 betyder hydrogen, lavalkyl eller eventuelt forestret carboxy, med overskud af ammoniak eller en dilavalkylamin og, om ønsket, i en fremstillet forbindelse, hvori R2 og eventuelt betyder usubstitueret carbamyl, lavalkanoylerer R2 og eventuelt R^.A particularly preferred embodiment of this process is characterized by reacting a compound of formula VI wherein esterified is carboxy and Y 15 is hydrogen, lower alkyl or optionally esterified carboxy, with excess ammonia or a dilavalkylamine and, if desired, in a prepared compound wherein R 2 and optionally means unsubstituted carbamyl, lower alkanoylates R 2 and optionally R 2.

2020

Udgangsforbindelserne med formlen VI kan i det tilfælde, at de er hidtil ukendte forbindelser, fremstilles på sædvanlig måde, eksempelvis ved, at man omsætter et azid med formlen 25 Ph - alk - N3 (II) med en forbindelse med formlenThe starting compounds of formula VI may, in the case of novel compounds, be prepared in the usual manner, for example by reacting an azide of formula 25 Ph - alk - N3 (II) with a compound of formula

Ys-CsC-Yu (Vila) eller Ri-C(«0)-CH2-Yi, (Vllb) 30 eksempelvis på samme måde som beskrevet under fremgangsmåde a). Om nødvendigt kan primært dannede estere eller nitriler med formlen VI (Y^ og eventuelt Υβ = forestret carboxy eller cyano) hydrolyseres under basiske betingelser, f.eks. ved 35 hjælp af vandig-alkoholi.sk natriumhydroxidopløsning, til den 12 0 DK 169720 B1 tilsvarende syre, og primært eller ved hydrolyse af tilsvarende estere eller nitriler dannede syrer med formlen VI (Y^ og eventuelt Υβ = carboxy) omdannes til syrechloridet, f.eks. med thionylchlorid.Ys-CsC-Yu (Vila) or Ri-C («O) -CH2-Yi, (Vllb), for example, in the same manner as described under process a). If necessary, primarily formed esters or nitriles of formula VI (Y 2 and optionally Υ β = esterified carboxy or cyano) can be hydrolyzed under basic conditions, e.g. by means of aqueous alcoholic sodium hydroxide solution, to the corresponding acid, and, primarily or by hydrolysis of corresponding esters or nitriles, acids of formula VI (Y Y and optionally Υβ = carboxy) are converted to the acid chloride, f .g. with thionyl chloride.

55

Som omdannelsesreaktioner for fremstillede forbindelser med formlen I til andre forbindelser med formlen I kan især nævnes substitutionsreaktioner ved N-usubstituerede eller N-monolavalkylerede carbamylgrupper R2 og/eller samt adskil-10 leisen af fremstillede isomerblandinger.As conversion reactions for prepared compounds of formula I to other compounds of formula I, in particular, mention may be made of substitution reactions of N-unsubstituted or N-monolavalkylated carbamyl groups R 2 and / or the separation of prepared isomer mixtures.

I forbindelser med formlen I kan man således ved behandling med et lavalkanoyleringsmiddel omdanne N-usubstitueret carbamyl til N-lavalkanoylcarbamyl eller ved behandling med et lavalkyle-15 ringsmiddel omdanne usubstitueret carbamyl til N,N-dilavalkyl-carbamyl og/eller N-monolavalkylcarbamyl til N,N-dilavalkyl-carbamyl. N-MonolavalkyIderivater af forbindelser med formlen I kan eksempelvis fremstilles ud fra tilsvarende udgangsforbindelser med formlerne III, V eller VI, især VI.Thus, in compounds of formula I, by treatment with a low alkanoylating agent, N-unsubstituted carbamyl can be converted to N-low alkanoylcarbamyl or by treatment with a low alkylating agent convert unsubstituted carbamyl to N, N-dilavalkyl carbamyl and / or N-monolavalkylcarbamyl , N-di-lower carbamyl. For example, N-monoalkyl derivatives of compounds of formula I may be prepared from corresponding starting compounds of formulas III, V or VI, especially VI.

2020

Som eksempler på lavalkanoyleringsmidler kan nævnes lavalkan-carboxylsyreanhydrider, såsom eddikesyreanhydrid eller det blandede anhydrid af myresyre og eddikesyre, eller lavalkan-carboxylsyrechlorider, såsom acetylchlorid. Omsætningen med 25 disse gennemføres på sædvanlig måde, om nødvendigt i nærværelse af en base, f.eks. triethylamin eller pyridin, eller i tilfælde af omsætning med syreanhydrider i nærværelse af en mineralsyre, f.eks. svovlsyre.Examples of low alkanoylating agents include low alkanoic carboxylic anhydrides such as acetic anhydride or the mixed anhydride of formic acid and acetic acid, or low alkanoic carboxylic acid chlorides such as acetyl chloride. The reaction with these 25 is carried out in the usual manner, if necessary in the presence of a base, e.g. triethylamine or pyridine, or in the case of reaction with acid anhydrides in the presence of a mineral acid, e.g. sulfuric acid.

30 som eksempler på lavalkyleringsmidler kan nævnes reaktive estere, såsom hydrogenhalogenidsyreestere, svovlsyreestere eller sulfonsyreestere, af lavalkanoler, såsom lavalkyl-halogenider, f.eks. methyliodid, dilavalkylsulfater, f.eks. dimethylsulfat, eller lavalkylestere af aliphatiske eller 35 aromatiske sulfonsyrer, især af lavalkansulfonsyrer eller DK 169720 Bl 13 0 eventuelt substituerede benzensulfonsyrer, f.eks. lavalkyl-methansulfonater, lavalkylethansulfonater, lavalkylbenzen-sulfonater eller lavalkyl-p-toluensulfonater. Lavalkylerin-gen gennemføres på sædvanlig måde, eksempelvis under basiske 5 betingelser, såsom i nærværelse af et alkalimetalhydroxid, f.eks. kaliumhydroxid, samt fordelagtigt en faseoverføringskatalysator, f.eks. tetrabutylammoniumbromid eller benzyl-trimethy lammoniumchlorid.Examples of low alkylating agents include reactive esters, such as hydrogen halide acid esters, sulfuric acid esters or sulfonic acid esters, of low alkanols such as low alkyl halides, e.g. methyl iodide, dilavalkyl sulfates, e.g. dimethyl sulfate, or low alkyl esters of aliphatic or aromatic sulfonic acids, especially of low alkanesulfonic acids or optionally substituted benzenesulfonic acids, e.g. low alkyl methanesulfonates, low alkyl ethanesulfonates, low alkyl benzene sulfonates or low alkyl p-toluenesulfonates. The low alkylation is carried out in the usual manner, for example under basic conditions, such as in the presence of an alkali metal hydroxide, e.g. potassium hydroxide, and advantageously a phase transfer catalyst, e.g. tetrabutylammonium bromide or benzyl trimethyl lammonium chloride.

10 Adskillelsen af isomerblandinger, der eksempelvis kan være enantiomer- eller diastereomerblandinger af forbindelser med formlen I med mindst ét asymmetrisk carbonatom samt blandinger af forbindelser med formlen I og isomerer deraf dannet ved fremgangsmåden, gennemføres på sædvanlig måde. Dia-15 stereoisomerblandinger samt blandinger af forbindelser med formlen I og isomerer deraf dannet ved fremgangsmåden kan eksempelvis adskilles på grund af komponenternes forskellige fysiske egenskaber ved hjælp af sædvanlige fysiske adskillelsesmetoder, f.eks. ved fraktioneret krystallisa-20 tion, kromatografifremgangsmåder og lignende. Til adskillelsen af enantiomerblandinger er eksempelvis fraktioneret krystallisation fra et optisk aktivt opløsningsmiddel eller kromatografi på en optisk aktiv stationær og/eller mobil fase egnet. Man kan imidlertid også omdanne en enantiomer-25 blanding, f.eks. ved omsætning med et optisk aktivt syre-chlorid, til de tilsvarende diastereomere acylderivater, som adskilles i komponenterne, hvorfra de rene enantiomerer frigøres, f.eks. ved mild syrebehandling.The separation of isomer mixtures, which may be, for example, enantiomeric or diastereomeric mixtures of compounds of formula I having at least one asymmetric carbon atom as well as mixtures of compounds of formula I and isomers thereof formed by the process are carried out in the usual manner. For example, diastereomer isomer mixtures as well as mixtures of compounds of formula I and isomers thereof formed by the process can be separated due to the various physical properties of the components by conventional physical separation methods, e.g. by fractional crystallization, chromatography methods and the like. For example, for the separation of enantiomeric mixtures, fractional crystallization from an optically active solvent or chromatography on an optically active stationary and / or mobile phase is suitable. However, one can also convert an enantiomeric mixture, e.g. by reaction with an optically active acid chloride, to the corresponding diastereomeric acyl derivatives which are separated into the components from which the pure enantiomers are released, e.g. by mild acid treatment.

30 Forbindelserne ifølge opfindelsen med formlen I kan eksempelvis anvendes i fom af farmaceutiske præparater, som indeholder en terapeutisk virksom mængde af den aktive forbindelse, eventuelt sammen med uorganiske eller organiske, faste eller flydende, farmaceutisk anvendelige bærestoffer, 35 som er egnede til enteral, f.eks. oral, eller parenteral indgift. Man anvender således tabletter eller gelatinekapsler, 14 o DK 169720 B1 som indeholder det aktive stof sammen med fortyndingsmidler, f.eks. lactose, dextrose, saccharose, mannitol, sorbitol, cellulose og/eller glycin, og/eller smøremidler, f.eks. kiseljord, talkum, stearinsyre eller salte deraf, såsom magnesium- eller calciumstearat, og/eller polyethylenglycol.For example, the compounds of the invention of formula I may be used in the form of pharmaceutical compositions containing a therapeutically effective amount of the active compound, optionally together with inorganic or organic solid or liquid pharmaceutically useful carriers suitable for enteral, e.g. .g. oral, or parenteral administration. Thus, tablets or gelatin capsules, which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and / or lubricants, e.g. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol.

66

Tabletter kan endvidere indeholde bindemidler, f.eks. magnesiumaluminiumsilic.at, stivelse, såsom majs-, hvede-, ris- eller pileurtstivelse, gelatine, traganth, methyl-cellulose, natriumcarboxylmethylcellulose og/eller poly-vinylpyrrolidon, og, om ønsket, desintegreringsmidier, 10 f.eks. stivelse, agar, alginsyre eller et salt deraf, såsom natriumalginat, og/eller bruseblandinger, eller adsorptionsmidler, farvestoffer, smagsstoffer og sødemidler. Endvidere kan forbindelserne ifølge opfindelsen anvendes i form af præparater til parenteral indgift eller i form af infusions- 16 opløsninger. Sådanne opløsninger er fortrinsvis isotoniske. vandige opløsninger eller suspensioner, idet disse kan fremstilles inden brugen, f.eks. ved lyofiliserede præparater, som indeholder det aktive stof alene eller sammen med et bæremateriale, f.eks. mannitol. De farmaceutiske præpa- 20 rater kan være steriliserede og/eller indeholde hjælpestoffer, f.eks. konserveringsmidler, stabiliseringsmidler, fugtemidler og/eller emulgeringsmidler, opløselighedsfrem-mende stoffer, salte til regulering af det osmotiske tryk og/eller puffere. De omhandlede farmaceutiske præparater, der om ønsket kan indeholde andre farmakologisk virksomme forbindelser, fremstilles på i og for sig kendt måde, f.eks. ved hjælp af konventionelle blandings-, granulerings-, dragerings-, opløsnings- eller lyofiliseringsfremgangsmåder, ' og de indeholder fra ca. 0,1 til 100%, især fra ca. 1 tilTablets may further contain binders, e.g. magnesium aluminum silicate, starch such as corn, wheat, rice or pile herb starch, gelatin, tragacanth, methyl cellulose, sodium carboxyl methyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrating agents, e.g. starch, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, dyes, flavors and sweeteners. Furthermore, the compounds of the invention may be used in the form of parenteral administration preparations or in the form of infusion solutions. Such solutions are preferably isotonic. aqueous solutions or suspensions, these can be prepared before use, e.g. by lyophilized preparations containing the active substance alone or together with a carrier material, e.g. mannitol. The pharmaceutical compositions may be sterilized and / or contain adjuvants, e.g. preservatives, stabilizers, wetting agents and / or emulsifiers, solubility promoting agents, salts for controlling the osmotic pressure and / or buffers. The present pharmaceutical compositions, which if desired may contain other pharmacologically active compounds, are prepared in a manner known per se, e.g. using conventional mixing, granulating, coating, dissolving or lyophilization methods, and containing from ca. 0.1 to 100%, especially from ca. 1 to

uOuO

ca. 50%, lyofilisater op til 100% aktivt stof.ca. 50%, lyophilisates up to 100% active substance.

Opfindelsen angår ligeledes farmaceutiske præparater indeholdende forbindelser med formlen I sammen med gængse hjælpe-35 stoffer. Doseringen kan afhænge af forskellige faktorer, såsom applikationsmåde, art alder og/eller individuel tilstand.The invention also relates to pharmaceutical compositions containing compounds of formula I together with common excipients. The dosage may depend on various factors such as mode of application, species age and / or individual condition.

DK 169720 B1 0 15DK 169720 B1 0 15

Dagsdosis ligger ved oral applikation mellem ca. l og ca.The daily dose for oral application is between approx. l and approx.

50 mg/kg i enkeltdoser på fra ca. 1 til 25 mg/kg og for mennesker eller varmblodede dyr med en legemsvægt på ca. 70 kg fortrinsvis i dagsdoser på fra ca. 0,070 g til ca. 3,5 g.50 mg / kg in single doses of approx. 1 to 25 mg / kg and for humans or warm blooded animals with a body weight of approx. 70 kg preferably in daily doses of approx. 0.070 g to approx. 3.5 g.

55

Opfindelsen belyses nærmere ved hjælp af de efterfølgende eksempler.The invention is further illustrated by the following examples.

Eksempel 1 10 73,5 g (0,25 mol) 1-(o-fluorbenzyl)-lH-l,2,3-triazol-4,5- dicarboxylsyredimethylester opløses i 1000 ml methanol. Opløsningen sættes til en autoklave, hvori der under tryk indføres 250 g ammoniak, og autoklaven henstår i 24 timer ved 100°C. Derefter foretages afkøling, det udkrystallise-15 rede produkt frasuges, vaskes med methanol og omkrystalliseres fra dioxan/toluen. Man får l-(o-fluorbenzyl)-lH-l,2,3-triazol-4,5-dicarboxamid med smp. 197-199°C.Example 1 73.5 g (0.25 mol) of 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester are dissolved in 1000 ml of methanol. The solution is added to an autoclave in which 250 g of ammonia is pressurized and the autoclave is left at 100 ° C for 24 hours. Cooling is then carried out, the crystallized product is extracted, washed with methanol and recrystallized from dioxane / toluene. There is obtained 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, m.p. 197-199 ° C.

Udgangsmaterialet kan eksempelvis fremstilles på følgende 20 måde: Til en til 90°C opvarmet opløsning af 41,5 g (0,275 mol) o-fluor-benzylazid i 50 ml toluen sættes dråbevis en opløsning af 40 g (0,282 mol) acetylendicarboxylsyredimethylester i 500 ml toluen. Efter yderligere 5 timer ved 90°c fjernes toluenet, og efter afkøling frasuges det udkrystalliserede 25 stof. Efter omkrystallisation fra en blanding af diethyl-ether og petroleumsether (lsl) får man således l-(o-fluor-benzyl)-1H-1,2,3-triazol-4,5-dicarboxylsyredimethylester med smp. 49-51°C.For example, the starting material can be prepared as follows: To a solution of 41.5 g (0.275 mole) of o-fluorobenzyl azide in 50 ml of toluene heated to a solution of 40 g (0.282 mole) of acetylenedicarboxylic acid dimethyl ester in 500 ml toluene. After an additional 5 hours at 90 ° C, the toluene is removed and upon cooling, the crystallized substance is suctioned off. Thus, after recrystallization from a mixture of diethyl ether and petroleum ether (lsl), 1- (o-fluoro-benzyl) -1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester is obtained, m.p. 49-51 ° C.

3030

Eksempel 2 59 g (0,26 mol) 1-(o-fluorbenzyl)-lH-l,2,3-triazol-4-carboxylsyre opvarmes med 300 ml thionylchlorid i 1 time 35 til tilbagesvaling. Overskud af thionylchlorid afdestille- 0 16 DK 169720 B1 res i vakuum, det tilbageblevne 1-(o-fluorbenzyl)-1H-1,2,3-triazol-4-carboxylsyrechlorid opløses i 500 ml toluen, og denne opløsning sættes dråbevis ved 5-10°C til 500 ml koncentreret vandig ammoniakopløsning. Det udfældede produkt 5 frasuges, vaskes med vand og omkrystalliseres fra ethanol.Example 2.5 59 g (0.26 mol) of 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid are heated with 300 ml of thionyl chloride for 1 hour to reflux. Excess thionyl chloride is distilled off in vacuo, the remaining 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid chloride is dissolved in 500 ml of toluene and this solution is added dropwise at 5 -10 ° C to 500 ml of concentrated aqueous ammonia solution. The precipitated product 5 is aspirated, washed with water and recrystallized from ethanol.

På denne måde fremstilles 1- (o-fluorbenzyl)-1H-1,2,3-triazol~ 4-carboxamid med smp. 220-222°C.In this way, 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4-carboxamide is prepared, m.p. 220-222 ° C.

Udgangsmaterialet kan eksempelvis fremstilles på følgende 10 måde: En opløsning af 50 g (0,33 mol) o-fluorbenzylazid, 23,1 g (0,33 mol) propyncarboxylsyre og 400 ml toluen omrøres i 24 timer ved 70°C. Det udfældede produkt frasuges efter afkøling til stuetemperatur, hvorpå der vaskes med toluen og derpå med diethylether. På denne måde fremstilles 15 1-(o-fluorbenzyl)-1H-1,2,3-triazol-4-carboxylsyre med smp.The starting material may be prepared, for example, in the following manner: A solution of 50 g (0.33 mol) of o-fluorobenzyl azide, 23.1 g (0.33 mol) of propynecarboxylic acid and 400 ml of toluene is stirred for 24 hours at 70 ° C. The precipitated product is aspirated after cooling to room temperature, then washed with toluene and then with diethyl ether. In this way, 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid is prepared with m.p.

151°C (sønderdeling).151 ° C (dec.).

Eksempel 3Example 3

Analogt med den ovenfor i eksempel 1 beskrevne fremgangsmåde 20 fremstilles ud fra 2,6-difluorbenzylazid og acetylendi-carboxylsyredimethylester over 1-(2,6-difluorbenzyl)-lH- 1.2.3- triazol-4,5-dicarboxylsyredimethylester (smp. 62-65°C) 1-(2,6-difluorbenzyl)-1H-1,2,3-triazol-4,5-dicarboxamid med smp. 203-205°C (fra methanol).Analogous to the procedure 20 described above in Example 1, is prepared from 2,6-difluorobenzyl azide and acetylenedicarboxylic acid dimethyl ester over 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester (mp 62 -65 ° C) 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, m.p. 203-205 ° C (from methanol).

2525

Eksempel 4Example 4

Analogt med den ovenfor i eksempel 2 beskrevne fremgangsmåde fremstilles ud fra 2,6-difluorbenzylazid over 1-(2,6-difluor-30 benzyl)-1H-1,2,3-triazol-4-carboxylsyre med smp. 160-162°C (fra acetonitril, sønderdeling) 1-(2,6-difluorbenzyl)-1H- 1.2.3- triazol-4-carboxamid med smp. 237-240°C (fra ethanol).Analogous to the process described in Example 2, is prepared from 2,6-difluorobenzyl azide over 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid, m.p. 160-162 ° C (from acetonitrile, decomposition) 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide, m.p. 237-240 ° C (from ethanol).

3535

Eksempel 5 17 DK 169720 B1Example 5 17 DK 169720 B1

Analogt med den ovenfor i eksempel 1-4 beskrevne fremgangsmåde kan endvidere fremstilles følgende forbindelser: 1-(2,3-difluorbenzyl)-1H-1,2,3-triazol-4-carboxamid, 5 1-(2,4-difluorbenzyl)-1H-1,2,3-triazol-4-carboxamid og 1-(2,5-difluorbenzyl)-1H-1,2,3-triazol“4-carboxamid.Further, by analogy to the process described in Examples 1-4, the following compounds may be prepared: 1- (2,3-difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide, 1- (2,4-difluorobenzyl) ) -1H-1,2,3-triazole-4-carboxamide and 1- (2,5-difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide.

Eksempel 6Example 6

Analogt med den ovenfor i eksempel 2 beskrevne fremgangsmåde fremstilles ud fra 1-(6-chlor-2-fluor-benzyl)-1H-1,2,3-10 triazol-4-carboxylsyre 1-(6-chlor-2-fluor-benzyl)-lH-l,2,3-triazol-4-carboxamid med smp. 274-276°C (fra iseddike).Analogous to the procedure described in Example 2, is prepared from 1- (6-chloro-2-fluoro-benzyl) -1H-1,2,3-triazole-4-carboxylic acid 1- (6-chloro-2-fluoro -benzyl) -1H-1,2,3-triazole-4-carboxamide, m.p. 274-276 ° C (from glacial acetic acid).

Udgangsmaterialet kan eksempelvis fremstilles på følgende måde: En blanding af 98 g (0,678 mol) 6-chlor-2-fluor-toluen, 91,5 g (0,678 mol) sulfurylchlorid og 0,2 g dibenzoylperoxid 15 omrøres i 3 timer ved 100-110°C, hvorpå den destilleres. På denne måde får man 6-chlor-2-fluor-benzylchlorid, kp.^ = 78-82°C.The starting material can be prepared, for example, as follows: A mixture of 98 g (0.678 mole) of 6-chloro-2-fluoro-toluene, 91.5 g (0.678 mole) of sulfuryl chloride and 0.2 g of dibenzoyl peroxide is stirred for 3 hours at 100 ° C. 110 ° C, then distilled. This gives 6-chloro-2-fluoro-benzyl chloride, b.p. = 78-82 ° C.

Til en suspension af 47 g (0,722 mol) natriumazid i 400 ml dimethylsulfoxid sættes dråbevis ved 20-40°C 123 g (0,687 20 mol) 6-chlor-2-fluor-benzylchlorid. Efter omrøring i 4 timer ved stuetemperatur fortyndes blandingen med 1 liter isvand, og der ekstraheres med cyclohexan. Efter afdestilla-tion af opløsningsmidlet destilleres remanensen. På denne måde får man 6-chlor-2-fluor-benzylazid, kp15 = 99-100°C.To a suspension of 47 g (0.722 mole) of sodium azide in 400 ml of dimethyl sulfoxide is added dropwise at 20-40 ° C 123 g (0.687 mole) of 6-chloro-2-fluoro-benzyl chloride. After stirring for 4 hours at room temperature, the mixture is diluted with 1 liter of ice water and extracted with cyclohexane. After distilling off the solvent, the residue is distilled. This gives 6-chloro-2-fluoro-benzyl azide, bp15 = 99-100 ° C.

25 27,5 g (0,15 mol) 6-chlor-2-fluor-benzylazid og 10,5 g (0,15 mol) propyncarboxylsyre i 300 ml toluen opvarmes i 3 timer til 90°C. Efter afkøling frasuges krystallerne, som omkrystalliseres fra acetonitril. På denne måde får man 1-(6-chlor-2-fluor-benzyl)-1H-1,2,3-triazol-4-carboxyl-30 syre med smp. 182°C (sønderdeling).27.5 g (0.15 mol) of 6-chloro-2-fluoro-benzyl azide and 10.5 g (0.15 mol) of propynecarboxylic acid in 300 ml of toluene are heated at 90 ° C for 3 hours. After cooling, the crystals which are recrystallized from acetonitrile are suctioned off. This gives 1- (6-chloro-2-fluoro-benzyl) -1H-1,2,3-triazole-4-carboxylic acid with m.p. 182 ° C (dec.).

DK 169720 B1 18DK 169720 B1 18

Eksempel 7Example 7

Analogt med den ovenfor i eksempel 1 beskrevne fremgangsmåde fremstilles ud fra 6-chlor-2-fluor-benzylazid og acetylendi-carboxylsyredimethylester over 1-(6-chlor-2-fluor-benzyl)-1H-5 l,2,3-triazol-4,5-dicarboxylsyredimethylester (smp. 88-90°C) 1-(6-chlor-2-fluor-benzyl)-1H-1,2,3-triazol-4,5-dicarboxamid med smp. 214-216°C (fra iseddike).Analogous to the procedure described in Example 1, is prepared from 6-chloro-2-fluoro-benzyl azide and acetylenedi-carboxylic acid dimethyl ester over 1- (6-chloro-2-fluoro-benzyl) -1H-1,2,3-triazole -4,5-dicarboxylic acid dimethyl ester (mp 88-90 ° C) 1- (6-chloro-2-fluoro-benzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, m.p. 214-216 ° C (from glacial acetic acid).

Eksempel 8Example 8

Analogt med den ovenfor i eksempel 1 beskrevne fremgangsmåde 10 fremstilles ud fra 2,5-difluorbenzylazid (kp^,. = 82-84°C) over 1-(2,5-difluorbenzyl)-1H-1,2,3-triazol-4,5-dicarboxyl-syredimethylester 1- (2,5-difluorbenzyl)-1H-1,2,3-triazol-4,5-dicarboxamid med smp. 191-192°C (fra dioxan/toluen).Analogous to the procedure 10 described above in Example 1, is prepared from 2,5-difluorobenzyl azide (bp = 82-84 ° C) over 1- (2,5-difluorobenzyl) -1H-1,2,3-triazole -4,5-dicarboxylic acid dimethyl ester 1- (2,5-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, m.p. 191-192 ° C (from dioxane / toluene).

Eksempel 9 15 Analogt med den ovenfor i eksempel 1 beskrevne fremgangsmåde fremstilles ud fra 2,4-difluorbenzylazid (kp^ = 80-83°C) over 1-(2,4-difluorbenzyl)-1H-1,2,3-triazol-4,5-dicarboxyl-syredimethylester med smp. 75-76°C (fra cyclohexan) 1-(2,4-difluorbenzyl)-1H-1,2,3-triazol-4,5-dicarboxamid med smp.Example 9 Analogous to the procedure described in Example 1, is prepared from 2,4-difluorobenzyl azide (bp = 80-83 ° C) over 1- (2,4-difluorobenzyl) -1H-1,2,3-triazole -4,5-dicarboxylic acid dimethyl ester with m.p. 75-76 ° C (from cyclohexane) 1- (2,4-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, m.p.

20 183-185°C (fra dioxan/toluen).203-185 ° C (from dioxane / toluene).

Eksempel 10Example 10

Analogt med den ovenfor i eksempel 1 beskrevne fremgangsmåde fremstilles ved omsætning med dimethylamin 1-(2,6-difluorbenzyl) -1H-1,2,3-triazol-4,5-dicarboxylsyredi(Ν,Ν-dimethyl)-25 amid med smp. 130-133°c (fra tert-butoxymethan).Analogous to the procedure described in Example 1, is prepared by reaction with dimethylamine 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxylic acid di (Ν, Ν-dimethyl) -25 amide with mp. 130-133 ° C (from tert-butoxymethane).

Eksempel 11Example 11

Analogt med den ovenfor i eksempel 1 beskrevne fremgangsmåde fremstilles ud fra 2,3-difluorbenzylazid og acetylendicarboxyl-syredimethylester over 1-(2,3-difluorbenzyl)-1H-1,2,3-triazol-30 4,5-dicarboxylsyredimethylester 1-(2,3-difluorbenzyl)-1H- 1,2,3-triazol-4,5-dicarboxamid med smp. 183-185°C (fra ethylacetat/benzen).Analogous to the procedure described in Example 1, is prepared from 2,3-difluorobenzyl azide and acetylenedicarboxylic acid dimethyl ester over 1- (2,3-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester 1- (2,3-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, m.p. 183-185 ° C (from ethyl acetate / benzene).

DK 169720 B1 19DK 169720 B1 19

Eksempel 12Example 12

Analogt med den ovenfor i eksempel 2 beskrevne fremgangsmåde fremstilles ud fra 1-(2,6-difluorbenzyl)-5-methyl-lH-l,2,3-triazol-4-carboxylsyre 1- (2,6-difluorbenzyl)-5-methyl-lH-5 l,2,3-triazol-4-carboxamid med smp. 208-210°C (fra methanol).Analogous to the procedure described in Example 2, is prepared from 1- (2,6-difluorobenzyl) -5-methyl-1H-1,2,3-triazole-4-carboxylic acid 1- (2,6-difluorobenzyl) -5 -methyl-1H-5,2,3-triazole-4-carboxamide, m.p. 208-210 ° C (from methanol).

Udgangsmaterialet fremstilles på følgende måde: 2,53 g (0,11 mol) natrium opløses i 60 ml alkohol, hvorpå der tilsættes en blanding af 16,9 g (0,1 mol) 2,6-difluorbenzylazid og 14,3 g (0,11 mol) aceteddikesyreester i 60 ml alkohol, og blandin-10 gen opvarmes i 18 timer til tilbagesvaling. Efter tilsætning af 120 ml 1 N natriumhydroxidopløsning koges blandingen i yderligere 2 timer med tilbagesvaling, hvorpå den fortyndes med 200 ml vand og syrnes under afkøling med saltsyre til pH-værdien 1. Det udfældede produkt frasuges, vaskes med 15 vand, derpå med ether og tørres. Man får således 1-(2,6-difluorbenzyl)-5-methyl-lH-l,2,3-triazol-4-carboxylsyre med smp. 166-167°C.The starting material is prepared as follows: 2.53 g (0.11 mol) of sodium is dissolved in 60 ml of alcohol, to which is added a mixture of 16.9 g (0.1 mol) of 2,6-difluorobenzyl azide and 14.3 g ( 0.11 mole) of acetic acid ester in 60 ml of alcohol and the mixture is heated for 18 hours to reflux. After adding 120 ml of 1 N sodium hydroxide solution, the mixture is boiled for a further 2 hours at reflux, diluted with 200 ml of water and acidified under cooling with hydrochloric acid to pH 1. The precipitated product is filtered off, washed with 15 water, then ether. dried. There is thus obtained 1- (2,6-difluorobenzyl) -5-methyl-1H-1,2,3-triazole-4-carboxylic acid, m.p. 166-167 ° C.

Eksempel 13Example 13

Analogt med den ovenfor i eksempel 1 beskrevne fremgangsmåde 20 fremstilles ud fra 1-[1-(2,6-difluorphenyl)-ethyl]-1H-1,2,3-triazol-4-carboxylsyreethylester 1-[1-(2,6-difluorphenyl)-ethyl]-lH-l,2,3-triazol-4-carboxamid med smp. 205-207°C (fra methanol).Analogous to the procedure 20 described above in Example 1, is prepared from 1- [1- (2,6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxylic acid ethyl ester 1- [1- (2, 6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxamide, m.p. 205-207 ° C (from methanol).

Udgangsmaterialet fremstilles på følgende måde: Ved reduktion 25 af 10,2 g(66 mmol) 2>6-difluoracetophenon med 2,5 g (65 mmol) lithiumaluminiumhydrid i ether får man 1-(2,6-difluorphenyl)-ethanol i fom af en farveløs olie.The starting material is prepared as follows: By reducing 25.2 g (66 mmol) of 2> 6-difluoroacetophenone with 2.5 g (65 mmol) of lithium aluminum hydride in ether, 1- (2,6-difluorophenyl) ethanol in of a colorless oil.

10 g (63 mmol) 1-(2,6-difluorphenyl)ethanol opløses i 150 ml hydrogenazidsyreopløsning (1,2 N i toluen), der tilsættes 30 22,8 g (200 mmol) trifluoreddikesyre, hvorpå blandingen hen står i 24 timer ved stuetemperatur. Efter fortynding med 300 ml hexan vaskes først med vand, derpå med natriumhydrogen- DK 169720 B1 20 carbonatopløsning til syrefri reaktion, hvorpå opløsningen tørres med natriumsulfat, og opløsningsmidlet fjernes under fomindsket tryk ved 40-50°c. Remanensen opløses i 100 ml hexan, opløsningen filtreres gennem 50 g kiselgel, hvorpå 5 der på ny inddampes. På denne måde får man 1-(2,6-difluor-phenyl)ethylazid i form af en farveløs olie.10 g (63 mmol) of 1- (2,6-difluorophenyl) ethanol are dissolved in 150 ml of hydrogen azide acid solution (1.2 N in toluene), and 22.8 g (200 mmol) of trifluoroacetic acid are added and the mixture is left for 24 hours at room temperature. After dilution with 300 ml of hexane, wash first with water, then with sodium hydrogen carbonate solution for acid-free reaction, then the solution is dried with sodium sulfate and the solvent is removed under reduced pressure at 40-50 ° C. The residue is dissolved in 100 ml of hexane, the solution is filtered through 50 g of silica gel and then evaporated again. This gives 1- (2,6-difluoro-phenyl) ethyl azide in the form of a colorless oil.

6,5 g (35 mmol) 1-(2,6-difluorphenyl)ethylazid og 2,45 g (35 mmol) propyncarboxylsyre opvarmes i 50 ml toluen i 24 timer til 60-70°C. Efter afkøling ekstraheres blandingen 10 med 100 ml 1 N natriumhydroxidopløsning, og efter syrning med saltsyre får man 1-[1-(2,6-difluorphenyl)ethyl]-1H- 1.2.3- triazol-4-carboxylsyre med smp. 135-138°c (sønderdeling) .6.5 g (35 mmol) of 1- (2,6-difluorophenyl) ethyl azide and 2.45 g (35 mmol) of propynecarboxylic acid are heated in 50 ml of toluene for 24 hours to 60-70 ° C. After cooling, the mixture is extracted with 100 ml of 1 N sodium hydroxide solution and, after acidification with hydrochloric acid, gives 1- [1- (2,6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxylic acid, m.p. 135-138 ° C (dec.).

7,1 g (26,6 mmol) 1-[1-(2,6-difluorphenyl)ethyl]-lH-l,2,3-15 triazol-4-carboxylsyre opvarmes med 150 ml ethanol og 1 ml svovlsyre i 10 timer til tilbagesvaling. Efter oparbejdning får man 1-[1- (2,6-difluorphenyl)ethyl]-1H-1,2,3-triazol-4-carboxylsyreethylester med smp. 118-121°C.7.1 g (26.6 mmol) of 1- [1- (2,6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxylic acid are heated with 150 ml of ethanol and 1 ml of sulfuric acid for 10 hours. hours for reflux. After working up, 1- [1- (2,6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxylic acid ethyl ester is obtained, m.p. 118-121 ° C.

Eksempel 14 20 Analogt med den ovenfor i eksempel 1 beskrevne fremgangsmåde fremstilles ud fra 1-{2-[2-(2,6-difluorphenyl)propyl]}-1Η- 1.2.3- triazol-4-carboxylsyreethylester l-{2- [2- (2,6-difluorphenyl) propyl]}-1H-1,2,3-triazol-4-carboxamid med smp. 203-205°C (fra methanol).Example 14 Analogously to the procedure described in Example 1, is prepared from 1- {2- [2- (2,6-difluorophenyl) propyl]} - 1Η-1,2,3-triazole-4-carboxylic acid ethyl ester 1- {2- [2- (2,6-difluorophenyl) propyl]} -1H-1,2,3-triazole-4-carboxamide, m.p. 203-205 ° C (from methanol).

25 ' Udgangsmaterialet fremstilles på følgénde måde: Til 28 g (150 mmol) 2,6-difluorbenzoesyreethylester i 200 ml ether sættes dråbevis og langsomt 120 ml 3-M opløsning af methyl-magnesiumchlorid i tetrahydrofuran. Efter 1 times tilbagesvaling og oparbejdning med 10%'s ammoniumchloridopløsning 30 får man 2- (2,6-dif luorphenyl) -propan-2-ol med kp^ = 74-76°C.The starting material is prepared as follows: To 28 g (150 mmol) of 2,6-difluorobenzoic acid ethyl ester in 200 ml of ether is added dropwise and slowly 120 ml of 3-M solution of methyl magnesium chloride in tetrahydrofuran. After 1 hour refluxing and working up with 10% ammonium chloride solution 30, 2- (2,6-difluorophenyl) -propan-2-ol with bp = 74-76 ° C is obtained.

20,6 g (120 mmol) 2-(2,6-difluorphenyl)-propan-2-ol opløses i 300 ml hydrogenazidsyreopløsning (1 N i benzen), hvorpå DK 169720 B1 21 der tilsættes 22,8 g (200 mmol) trifluoreddikesyre. Efter 24 timer ved stuetemperatur fortyndes med 500 ml hexan, hvorpå der vaskes med vand og derpå med natriumhydrogen-carbonatopløsning til syrefri reaktion, hvorefter der 5 tørres med natriumsulfat, opløsningsmidlet afdampes, og remanensen destilleres. På denne måde får man 2-(2,6-difluor-phenyl)-2-azido-propan med kp^5 = 85-87°C.20.6 g (120 mmol) of 2- (2,6-difluorophenyl) propan-2-ol are dissolved in 300 ml of hydrogen azide acid solution (1 N in benzene), to which 22.8 g (200 mmol) is added. trifluoroacetic acid. After 24 hours at room temperature, dilute with 500 ml of hexane, then wash with water and then with sodium hydrogen carbonate solution for acid-free reaction, then dry with sodium sulfate, evaporate the solvent and distill the residue. In this way 2- (2,6-difluoro-phenyl) -2-azido-propane is obtained having bp = 5 = 85-87 ° C.

10 g (51 mmol) 2-(2,6-difluorphenyl)-2-azido-propan omsættes med 3,6 g (51 mmol) propyncarboxylsyre i 100 ml toluen, 10 og reaktionsblandingen oparbejdes på samme måde som beskrevet i eksempel 12. Man får l-{2-[2-(2,6-difluorphenyl)propyl]}-lH-l,2,3-triazol-4-carboxylsyre med smp. 173°C (sønderdeling).10 g (51 mmol) of 2- (2,6-difluorophenyl) -2-azido-propane are reacted with 3.6 g (51 mmol) of propynecarboxylic acid in 100 ml of toluene, and the reaction mixture is worked up in the same manner as described in Example 12. There is obtained 1- {2- [2- (2,6-difluorophenyl) propyl]} -1H-1,2,3-triazole-4-carboxylic acid, m.p. 173 ° C (dec.).

Efter forestring af denne syre med 50 ml ethanol og 0,5 ml koncentreret svovlsyre får man 1-{2-[2-(2,6-difluorphenyl)-15 propyl]}-lH-l,2,3-triazol-4-carboxylsyreethylester som en lysegul tyktflydende olie, som uden yderligere rensning kan anvendes til omsætning med ammoniak.After esterification of this acid with 50 ml of ethanol and 0.5 ml of concentrated sulfuric acid, one obtains 1- {2- [2- (2,6-difluorophenyl) -propyl]} - 1H-1,2,3-triazole-4 -carboxylic acid ethyl ester as a pale yellow viscous oil which can be used for ammonia reaction without further purification.

Eksempel 15Example 15

Analogt med den ovenfor i eksempel 1 beskrevne fremgangsmåde 20 fremstilles ud fra 2-(2,6-difluorphenyl)-2-azido-propan og acetylendicarboxylsyredimethylester over l-{2-[2-(2,6-difluorphenyl) propyl]}-1Η-1,2,3-triazol-4,5-dicarboxylsyre-dimethylester (smp. 100-102°c) l-{2-[2-(2,6-difluorphenyl)-propyl]}-lH-l,2,3-triazol-4,5-dicarboxamid med smp.Analogous to the procedure 20 described above in Example 1, is prepared from 2- (2,6-difluorophenyl) -2-azido-propane and acetylenedicarboxylic acid dimethyl ester over 1- {2- [2- (2,6-difluorophenyl) propyl]} - 1Η-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester (mp 100-102 ° c) 1- {2- [2- (2,6-difluorophenyl) propyl]} -1H-1, 2,3-triazole-4,5-dicarboxamide, m.p.

25 177-178°C (fra ethylacetat/hexan).257-178 ° C (from ethyl acetate / hexane).

Eksempel 16 16,9 g (0,1 mol) 2,6-difluorbenzylazid og 8,3 g (0,1 mol) but-2-in-carboxamid opvarmes i 20 ml dioxan i 16 timer til 100°C. Efter afdampning af dioxanet isoleres den ønskede 30 isomer ved søjlekromatografi. På denne måde får man 1-(2,6-difluorbenzyl)-5-methyl-lH-l,2,3-triazol-4-carboxamid med smp. 208-210°C (fra methanol).Example 16 16.9 g (0.1 mole) of 2,6-difluorobenzyl azide and 8.3 g (0.1 mole) of but-2-in-carboxamide are heated in 20 ml of dioxane for 16 hours at 100 ° C. After evaporation of the dioxane, the desired isomer is isolated by column chromatography. This gives 1- (2,6-difluorobenzyl) -5-methyl-1H-1,2,3-triazole-4-carboxamide, m.p. 208-210 ° C (from methanol).

Eksempel 17 DK 169720 B1 22 2,81 g (10 mmol) 1-(2,6-difluorbenzyl)-lH-l,2,3-triazol-4,5-dicarboxamid, 20 ml eddikesyreanhydrid og 2 dråber svovlsyre opvarmes til 80°c i 3 timer. Efter afkøling udrøres blandin-5 gen med 100 ml vand i 1 time ved 20-25°c, det udfældede produkt frasuges og vaskes med vand. Efter omkrystallisation fra 75 ml methanol får man 1-(2,6-difluorbenzyl)-IH-1,2,3-triazol-4,5-di(N-acetyl)carboxamid med smp. 136-138°c.Example 17 DK 169720 B1 22 2.81 g (10 mmol) of 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, 20 ml of acetic anhydride and 2 drops of sulfuric acid are heated to 80 ° c for 3 hours. After cooling, the mixture is stirred with 100 ml of water for 1 hour at 20-25 ° C, the precipitated product is suctioned off and washed with water. After recrystallization from 75 ml of methanol, 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-di (N-acetyl) carboxamide is obtained, m.p. 136-138 ° C.

Eksempel 18 10 Analogt med den ovenfor i eksempel 17 beskrevne fremgangsmåde fremstilles endvidere 1-(2,6-difluorbenzyl)-1H-1,2,3-triazol- 4-(N-acetyl)carboxamid med smp. 205-207°c (fra dioxan/toluen).Example 18 Analogously to the process described in Example 17, 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4- (N-acetyl) carboxamide is also prepared with m.p. 205-207 ° C (from dioxane / toluene).

Eksempel 19 1,4 g (12,5 mmol) acetylendicarboxylsyrediamid opløses ved 15 60°C i 10 ml dimethylsulfoxid. Der tilsættes 1,69 g (10 mmol) 2,6-difluorbenzylazid, og blandingen omrøres i 16 timer ved 80°C. Derefter fortyndes blandingen med 25 ml vand, hvorpå der sugefiltreres, produktet udrøres med 50 ml vand, omrøringen fortsættes i 30 minutter ved 50-60°C, hvorpå der på 20 ny frasuges, og produktet tørres og omkrystalliseres fra dioxan/ethanol. Man får 1-(2,6-difluorbenzyl)-1H-1,2,3-triazol-4,5-dicarboxamid med smp. 203-205°C.Example 19 Dissolve 1.4 g (12.5 mmol) of acetylenedicarboxylic acid diamide at 15 ° C in 10 ml of dimethyl sulfoxide. 1.69 g (10 mmol) of 2,6-difluorobenzyl azide is added and the mixture is stirred for 16 hours at 80 ° C. The mixture is then diluted with 25 ml of water, then suction filtered, the product is stirred with 50 ml of water, the stirring is continued for 30 minutes at 50-60 ° C, suctioned again and the product is dried and recrystallized from dioxane / ethanol. 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide is obtained, m.p. 203-205 ° C.

Eksempel 20Example 20

Tabletter indeholdende 50 mg 1-(o-fluorbenzyl)-1H-1,2,3-25 triazol-4-carboxamid pr. tablet kan fremstilles på følgende måde:Tablets containing 50 mg of 1- (o-fluorobenzyl) -1H-1,2,3-25 triazole-4-carboxamide per tablet can be prepared as follows:

Sammensætning (10.000 tabletter)Composition (10,000 tablets)

Aktivt stof 500,0 gActive substance 500.0 g

Lactose 500,0 g 30 Kartoffelstivelse 352,0 gLactose 500.0 g Potato starch 352.0 g

Gelatine 8,0 gGelatin 8.0 g

Talkum 60,0 g DK 169720 B1 23Talc 60.0 g DK 169720 B1 23

Magnesiumstearat 10,0 g • Siliciumdioxid (højdispers) 20,0 gMagnesium stearate 10.0 g • Silica (high dispersion) 20.0 g

Ethanol q.s.Ethanol q.s.

Det aktive stof blandes med lactose og 292 g kartoffel-5 stivelse, blandingen fugtes med en alkoholisk opløsning af gelatinen, hvorpå den granuleres gennem en sigte. Efter tørring tilblandes resten af kartoffelstivelsen, talkummet, magnesiumstearatet og det højdisperse siliciumdioxid, og den dannede blanding presses til tabletter på 145,0 mg 10 med et indhold af aktivt stof på 50,0 mg. Tabletterne kan om ønsket forsynes med delekærv til finere tilpasning af doseringen.The active substance is mixed with lactose and 292 g of potato starch, the mixture is moistened with an alcoholic solution of the gelatin and granulated through a sieve. After drying, the remainder of the potato starch, talcum, magnesium stearate and the high-dispersed silica are mixed and the resulting mixture is pressed into tablets of 145.0 mg 10 with an active substance content of 50.0 mg. If desired, the tablets may be provided with splits for finer adjustment of dosage.

Eksempel 21Example 21

Laktabletter indeholdende 100 mg 1-(o-fluorbenzyl)-1H-15 1,2,3-triazol-4-carboxamid pr. tablet kan fremstilles på følgende måde:Lactate tablets containing 100 mg of 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4-carboxamide per tablet can be prepared as follows:

Sammensætning (for 1000 tabletter)Composition (for 1000 tablets)

Aktivt stof 100,00 gActive substance 100.00 g

Lactose 100,00 g 20 Majsstivelse 70,00 gLactose 100.00 g 20 Corn starch 70.00 g

Talkum 8,50 gTalc 8.50 g

Calciumstearat 1,50 gCalcium stearate 1.50 g

Hydroxypropyl-methylcellulose 2,36 gHydroxypropyl methyl cellulose 2.36 g

Schellak 0,64 g 25 Vand q.s.Shellac 0.64 g 25 Water q.s.

Methylenchlorid q.s.'Methylene chloride q.s. '

Det aktive stof, lactosen og 40 g majsstivelse blandes, og blandingen befugtes med et klister fremstillet af 15 g majsstivelse og vand (under opvarmning), hvorpå blandingen gra-30 nuleres. Granulatet tørres, resten af majsstivelsen, talkummet og calciumstearatet tilsættes og blandes med granulatet. Blandingen presses til tabletter (vægt: 280 mg), som lakeres med en opløsning af hydropropylmethylcellulosen og schellak DK 169720 B1 24 i methylenchlorid. Den færdige laktablet har en slutvægt på 283 mg.The active substance, lactose and 40 g of corn starch are mixed and the mixture is wetted with an adhesive made from 15 g of corn starch and water (under heating) and the mixture is granulated. The granulate is dried, the rest of the corn starch, talcum and calcium stearate are added and mixed with the granulate. The mixture is pressed into tablets (weight: 280 mg), which is lacquered with a solution of hydropropylmethyl cellulose and shellac DK 169720 B1 24 in methylene chloride. The final lactate tablet has a final weight of 283 mg.

Eksempel 22 På samme måde som beskrevet i eksemplerne 20 og 21 kan der 5 også fremstilles tabletter eller laktabletter indeholdende en anden forbindelse ifølge eksemplerne 1-19.Example 22 In the same way as described in Examples 20 and 21, tablets or lacquer tablets containing another compound of Examples 1-19 can also be prepared.

Claims (12)

1. Fluorerede l-(a-phenylalkyl)-lH-l,2,3-triazolforbin-delser, kendetegnet ved, at de har den almene 5 formel Ph-alk-N^ | (χ) k k 10 hvori Ph betyder en i o-stillingen med fluor og eventuelt yderligere med mindst ét yderligere halogenatom substitueret phenylgruppe, alk betyder methylen eller lavalkyliden, betyder hydrogen, lavalkyl eller en usubstitueret eller med lavalkanoyl eller lavalkyl substitueret carbamylgruppe, og 15 R2 betyder en usubstitueret eller med lavalkanoyl eller lavalkyl substitueret carbamylgruppe.Fluorinated 1- (α-phenylalkyl) -1H-1,2,3-triazole compounds, characterized in that they have the general formula Ph-alk-N 2 | (χ) kk 10 wherein Ph means a phenyl group optionally substituted with at least one additional halogen atom with fluorine and optionally further with at least one additional halogen atom; means an unsubstituted or lower alkanoyl or lower alkyl substituted carbamyl group. 2. Forbindelser ifølge krav 1, kendetegnet ved, at Ph betyder en i o-stillingen med fluor og eventuelt 20 yderligere med op til 3 halogenatomer med et atomnummer på højst 35 substitueret phenylgruppe, alk betyder methylen eller C2-4-alkyliden, R^ betyder hydrogen, C1_4-alkyl, carb-arnyl, N-C^-y-alkanoylcarbamyl eller N,N-di-C1_4-alkylcarb-amyl, og R2 betyder carbamyl, N-Ci^-alkanoylcarbamyl eller 25 N,N-di-Ci_4-alkylcarbamyl.Compounds according to claim 1, characterized in that Ph is one at the o-position with fluorine and optionally 20 further with up to 3 halogen atoms having an atomic number of not more than 35 substituted phenyl group, alk means methylene or C2-4 alkylidene, R means hydrogen, C 1-4 alkyl, carb-arnyl, NC 1-6 alkanoylcarbamyl or N, N-di-C 1-4 alkylcarbamyl, and R 2 represents carbamyl, N-C 1-6 alkanoylcarbamyl or N, N-di-C 1-4 -alkylcarbamyl. 3. Forbindelser ifølge krav 1, kendetegnet ved, at Ph betyder en i o-stillingen med fluor og eventuelt yderligere med op til 2 chloratomer, 1 fluor- og 1 chloratom 30 eller op til 2 fluoratomer substitueret phenylgruppe, alk betyder C2_^-alkyliden, R^ betyder hydrogen, Cj^-alkyl, carbamyl, N-C^^-alkanoylcarbamyl eller N,N-di-C^_^-alkyl-carbamyl, og R2 betyder carbamyl, N-C2_cj-alkanoylcarbamyl eller N,N-di-C1_4-alkylcarbamyl. 35Compounds according to claim 1, characterized in that Ph is one at the o-position with fluorine and optionally further with up to 2 chlorine atoms, 1 fluorine and 1 chlorine atom or up to 2 fluorine atoms substituted phenyl group, alk means C2 R R represents hydrogen, Cj ^alk alkyl, carbamyl, NC ^^ - alkanoylcarbamyl or N, N-di-C ^ _ alkyl alkyl carbamyl, and R₂ means carbamyl, N-C₂cj alkanoylcarbamyl or N, N-di -C 1-4 alkylcarbamyl. 35 4. Forbindelser ifølge krav 1, kendetegnet ved, at Ph betyder en i o-stillingen med fluor og eventuelt DK 169720 B1 yderligere med 1 chloratom, 1 fluor- og 1 chloratom eller op til 2 fluoratomer substitueret phenylgruppe, alk betyder C2_4-alkyliden, betyder hydrogen, C^_4-alkyl eller en 5 gruppe R2/ og R2 betyder carbamyl eller N,N-di-C1_4-alkyl-carbamyl.Compounds according to Claim 1, characterized in that Ph is one further substituted with 1 chlorine, 1 fluorine and 1 chlorine atom or up to 2 fluorine atoms in the o-position with fluorine and optionally DK 169720 B1, alk means C2-4 alkylidene, represents hydrogen, C 1-4 alkyl or a group R 2 / and R 2 represents carbamyl or N, N-di-C 1-4 alkyl carbamyl. 5. Forbindelser ifølge krav 1, kendetegnet ved, at Ph betyder o-fluorphenyl, 2,3-, 2,4-, 2,5- eller 10 2,6-difluorphenyl eller 6-chlor-2-fluorphenyl, alk betyder methylen, R^ betyder hydrogen eller carbamyl, og R2 betyder carbamyl.Compounds according to claim 1, characterized in that Ph means o-fluorophenyl, 2,3-, 2,4-, 2,5 or 2,6-difluorophenyl or 6-chloro-2-fluorophenyl, alk means methylene R 2 represents hydrogen or carbamyl and R 2 represents carbamyl. 6. Forbindelser ifølge krav 1, kendetegnet 15 ved, at Ph betyder o-fluorphenyl, 2,5-di-fluorphenyl, 2,6- difluorphenyl eller 2-chlor-6-fluorphenyl, alk betyder methylen, og R^ og R2 begge betyder carbamyl.Compounds according to claim 1, characterized in that Ph means o-fluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl or 2-chloro-6-fluorophenyl, alk means methylene, and R 1 and R 2 are both means carbamyl. 7. Forbindelse ifølge krav 1, kendetegnet 20 ved, at den er 1-(2,6-difluorbenzyl)-1H-1,2,3-triazol-4,5- dicarboxamid.A compound according to claim 1, characterized in that it is 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide. 8. Forbindelse ifølge krav 1, kendetegnet ved, at den er l-(2,6-difluorbenzyl)-lH-l,2,3-triazol-4-25 carboxamid.Compound according to claim 1, characterized in that it is 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide. 9. Forbindelse ifølge krav 1, kendetegnet ved, at den er 1-(o-fluorbenzyl)-1H-1,2,3-triazol-4,5-dicarboxamid, 30 i-(o-fluorbenzyl)-1H-1,2,3-triazol-4-carboxamid, 1-(6-chlor-2-fluor-benzyl)-1H-1,2,3-triazol-4-carboxamid, 1-(6-chlor-2-fluor-benzyl)-1H-1,2,3-triazol-4,5-dicarboxamid, 1-(2,5-difluorbenzyl)-1H-1,2,3-triazol-4,5-dicarboxamid, 1-[1-(2,6-difluorphenyl)ethyl]-1H-1,2,3-triazol-4-carboxamid, 35 DK 169720 B1 1- (2,6-difluorbenzyl)-5-methyl-lH-l,2,3-triazol-4-carboxamid, 1-(2,6-difluorbenzyl)-1H-1,2,3-triazol-4,5-di(Ν,Ν-dimethyl)-carboxamid, 5 1- [1- (2,6-difluorphenyl)ethyl]-lH-l,2,3-triazol-4-carboxamid, l-{2-[2-(2,6-difluorphenyl)propyl]}-lH-l,2,3-triazol-4-carbox-amid, l-{2- [2-(2,6-difluorphenyl)propyl]}-lH-l,2,3-triazol-4,5-di-carboxamid, 10 1~ (2,6-difluorbenzyl)-1H-1, 2,3-triazol-4- (N-acetyl)carboxamid/ 1- (2,6-difluorbenzyl)-1H-1/2,3-triazol-4,5-di(N-acetyl)carboxamid, 1-(2,3-difluorbenzyl)-1H-1,2,3-triazol-4,5-dicarboxamid eller 1- (2,4-difluorbenzyl)-1H-1,2,3-triazol-4,5-dicarboxamid. 15A compound according to claim 1, characterized in that it is 1- (o-fluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, 1- (o-fluorobenzyl) -1H-1, 2,3-triazole-4-carboxamide, 1- (6-chloro-2-fluoro-benzyl) -1H-1,2,3-triazole-4-carboxamide, 1- (6-chloro-2-fluoro-benzyl) ) -1H-1,2,3-triazole-4,5-dicarboxamide, 1- (2,5-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide, 1- [1- ( 2,6-difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxamide 1- (2,6-difluorobenzyl) -5-methyl-1H-1,2,3-triazole -4-carboxamide, 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4,5-di (Ν, Ν-dimethyl) -carboxamide, 1- [1- (2,6) -difluorophenyl) ethyl] -1H-1,2,3-triazole-4-carboxamide, 1- {2- [2- (2,6-difluorophenyl) propyl]} -1H-1,2,3-triazole-4 -carboxamide, 1- {2- [2- (2,6-difluorophenyl) propyl]} -1H-1,2,3-triazole-4,5-di-carboxamide, 1 difluorobenzyl) -1H-1,2,3-triazole-4- (N-acetyl) carboxamide / 1- (2,6-difluorobenzyl) -1H-1 / 2,3-triazole-4,5-di (N- acetyl) carboxamide, 1- (2,3-difluorobenzyl) -1H-1,2,3-triazole-4,5-dicarboxamide or 1- (2,4-difluorobenzyl) -1H-1 , 2,3-triazole-4,5-dicarboxamide. 15 10. Farmaceutiske præparater, kendetegnet ved, at de indeholder en forbindelse ifølge et af kravene 1-9 foruden gængse farmaceutiske hjælpestoffer og/eller bærestoffer. 20Pharmaceutical compositions, characterized in that they contain a compound according to any one of claims 1-9 in addition to conventional pharmaceutical auxiliaries and / or carriers. 20 11. Fremgangsmåde til fremstilling af hidtil ukendte 1-(a-phenyllavalkyl)-lH-l,2,3-triazolforbindelser med den almene formelA process for the preparation of novel 1- (α-phenyllavalkyl) -1H-1,2,3-triazole compounds of the general formula 25 Ph-alk-N^1 I <I) hvori Ph betyder en i o-stillingen med fluor og eventuelt 30 yderligere med mindst ét yderligere halogenatom substitueret phenylgruppe, alk betyder methylen eller lavalkyliden, betyder hydrogen, lavalkyl eller en usubstitueret eller med lavalkanoyl eller lavalkyl substitueret carbamylgruppe, og R2 betyder en usubstitueret eller med lavalkanoyl eller med 35 lavalkyl substitueret carbamylgruppe, kendetegnet ved, at man 0 DK 169720 B1 a) omsætter en forbindelse med formlen Ph - alk - N3 (II) 5 med en forbindelse med formlen Ri - i = i - R2 (III) hvori Y1 betyder hydroxy,og Y2 betyder hydrogen, eller Y^ 10 og Y^ sammen betyder en yderligere binding, eller et salt og/eller en tautomer deraf eller b) omsætter en forbindelse; med formlen Ph - alk - Z (IV) 15 hvori Z betyder reaktionsdygtigt forestret hydroxy, med et 1H-1,2,3-triazolderivat med formlen «Π <v) Y=i-r2 20 1 eller et salt deraf eller c) i en forbindelse med formlen Ph-alk-N^J (VI) 25 »«i-Yi» Ϊ5 hvori Y^ betyder en gruppe Y^, som kan omdannes til usubsti-tueret eller lavalkylsubstitueret carbamyl, og Y^ betyder en gruppe ^ eller en gruppe Υβ, som kan omdannes til usub-30 stitueret eller lavalkylsubstitueret carbamyl, eller Y^ betyder en gruppe R2, og Y5 betyder en gruppe Υβ, som kan omdannes til usubstitueret eller lavalkylsubstitueret carbamyl, omdanner Y^ og/eller Υβ til usubstitueret eller lavalkylsubstitueret carbamyl, om nødvendigt adskiller 35 en dannet isomerblanding i komponenterne og isolerer isomeren med formlen I og, om ønsket, omdanner en fremstillet forbin- 0 DK 169720 B1 delse med formlen I til en anden forbindelse med formlen I . og/eller adskiller en fremstillet enantiomer- eller diastereo-merblanding i komponenterne, idet fremgangsmåden især er ejendommelig ved, at man omsætter en forbindelse med formlen VI, 5 hvori Y4 betyder forestret carboxy, og Y,. betyder hydrogen, lavalkyl eller eventuelt forestret carboxy, med et overskud af ammoniak eller en dilavalkylamin og, om ønsket, lavalkanoylerer og eventuelt R^ i en fremstillet forbindelse, hvori R^ og eventuelt R^ betyder usubstitueret carbamyl. 10 15 20 25 30 35Wherein Ph means an phenyl group optionally substituted by at least one additional halogen atom with fluorine and optionally 30 with at least one additional halogen atom, alk means methylene or lower alkylidene, means hydrogen, low alkyl or an unsubstituted or lower alkanoyl or lower alkyl substituted carbamyl group, and R 2 represents an unsubstituted or lower alkanoyl or lower alkyl substituted carbamyl group, characterized in that a compound of the formula Ph - alk - N3 (II) 5 is reacted with a compound of the formula R1 - i = i - R2 (III) wherein Y1 is hydroxy and Y2 is hydrogen, or Y1-10 and Y1 together represent an additional bond, or a salt and / or tautomer thereof, or b) reacting a compound; wherein: Z is reactively esterified hydroxy, with a 1 H-1,2,3-triazole derivative of the formula "Π <v) Y = i-r 2 20 1 or a salt thereof or c) in a compound of the formula Ph-alk-N ^ J (VI) 25 '' i-Yi 'Ϊ5 wherein Y ^ represents a group Y ^ which can be converted to unsubstituted or lower alkyl substituted carbamyl and Y ^ represents a group ^ or a group Υβ which can be converted to unsubstituted or lower alkyl substituted carbamyl, or Y 1 represents a group R 2 and Y 5 represents a group or lower alkyl substituted carbamyl, if necessary, separates a formed isomer mixture into the components and isolates the isomer of formula I and, if desired, converts a compound of formula I to another compound of formula I. and / or separating a prepared enantiomeric or diastereomeric mixture into the components, the process being particularly characterized by reacting a compound of formula VI, wherein Y4 is esterified carboxy, and Y1. means hydrogen, lower alkyl or optionally esterified carboxy, with an excess of ammonia or a dilavalkylamine and, if desired, lower alkanoyls and optionally R 1 in a compound prepared wherein R 1 and optionally R 2 represent unsubstituted carbamyl. 10 15 20 25 30 35
DK175686A 1985-04-18 1986-04-17 Fluorinated 1- (alpha-phenylalkyl) -1H-1,2,3-triazole compounds as well as their preparation and pharmaceutical preparations containing such compounds DK169720B1 (en)

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EP0151528B1 (en) * 1984-02-02 1990-07-04 Merck & Co. Inc. 5-(amino or substituted amino)-1,2,3-triazoles
AU2633897A (en) * 1996-04-19 1997-11-12 Novo Nordisk A/S Solid phase and combinatorial synthesis of substituted 1,2,3-triazoles and of arrays of substituted 1,2,3-triazoles
AU719148B2 (en) 1996-07-11 2000-05-04 Novartis Ag Process for preparing 1-substituted 4-cyano-1,2,3-triazoles
TW526195B (en) * 1997-06-10 2003-04-01 Novartis Ag Crystal modifications of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide and their use
TW513301B (en) * 1999-03-01 2002-12-11 Novartis Ag Pharmaceutical composition for treatment of neuropathic pain and affective and attention disorders
WO2004106329A2 (en) * 2003-06-03 2004-12-09 Dr. Reddy's Laboratories Ltd. Novel antiinfective compounds and their pharmaceutical compositions
IT1393368B1 (en) * 2009-03-23 2012-04-20 Dipharma Francis Srl METHOD FOR THE PREPARATION OF RUFINAMIDE
IT1395736B1 (en) 2009-08-04 2012-10-19 Dipharma Francis Srl CRYSTALLINE FORMS OF RUFINAMIDE
WO2011135105A1 (en) * 2010-04-30 2011-11-03 Laboratorios Lesvi, S.L. Improved process for preparing rufinamide intermediate
ITMI20110718A1 (en) 2011-04-29 2012-10-30 Dipharma Francis Srl PROCEDURE FOR PURIFICATION OF RUFINAMIDE
US20150368211A1 (en) * 2013-01-31 2015-12-24 The Johns Hopkins University Rufinamide and derivatives and their use in modulating the gating process of human voltage-gated sodium channels
US9771335B2 (en) * 2015-07-31 2017-09-26 The Johns Hopkins University Derivatives of rufinamide and their use in inhibtion of the activation of human voltage-gated sodium channels
CN108697662A (en) 2015-12-11 2018-10-23 奥胡斯大学 Rufinamide for treating myotonia
WO2021099481A1 (en) 2019-11-20 2021-05-27 Medichem, S.A. Solid composition containing rufinamide

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GB1511195A (en) * 1976-10-18 1978-05-17 Ici America Inc Triazole derivatives
FI834666A (en) * 1982-12-23 1984-06-24 Ciba Geigy Ag FOERFARANDE FOER FRAMSTAELLNING AV NYA ARALKYLTRIAZOLFOERENINGAR.

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ES8800176A1 (en) 1987-10-16
HU203327B (en) 1991-07-29
DK175686A (en) 1986-10-19
JPS61243068A (en) 1986-10-29
IL78510A (en) 1992-05-25
GR861004B (en) 1986-08-12
FI93544B (en) 1995-01-13
PT82400B (en) 1988-08-17
EP0199262B1 (en) 1991-02-27
FI93544C (en) 1995-04-25
IE58472B1 (en) 1993-09-22
KR900008810B1 (en) 1990-11-30
NO164295C (en) 1990-09-19
JPH0564949B2 (en) 1993-09-16
AU5631986A (en) 1986-10-23
DE3677626D1 (en) 1991-04-04
HUT40792A (en) 1987-02-27
ZA862873B (en) 1986-12-30
NO861486L (en) 1986-10-20
NO164295B (en) 1990-06-11
ES554024A0 (en) 1987-10-16
ES557641A0 (en) 1988-07-01
IE861015L (en) 1986-10-18
KR860008152A (en) 1986-11-12
EP0199262A3 (en) 1987-08-26
FI861573A0 (en) 1986-04-14
NZ215871A (en) 1989-01-27
MX9203628A (en) 1992-09-01
ES8802501A1 (en) 1988-07-01
AU599024B2 (en) 1990-07-12
IL78510A0 (en) 1986-08-31
CA1272201A (en) 1990-07-31
FI861573A (en) 1986-10-19
DK175686D0 (en) 1986-04-17
PH22568A (en) 1988-10-17
CY1751A (en) 1994-06-03
DD245874A5 (en) 1987-05-20
HK1494A (en) 1994-01-14
PT82400A (en) 1986-05-01
EP0199262A2 (en) 1986-10-29

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