CA1272201A - Process for the manufacture of fluorinated benzyltriazoles - Google Patents

Process for the manufacture of fluorinated benzyltriazoles

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CA1272201A
CA1272201A CA000506774A CA506774A CA1272201A CA 1272201 A CA1272201 A CA 1272201A CA 000506774 A CA000506774 A CA 000506774A CA 506774 A CA506774 A CA 506774A CA 1272201 A CA1272201 A CA 1272201A
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carbamoyl
triazole
formula
compound
alk
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French (fr)
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Rene Meier
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Novartis AG
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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
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/08Antiepileptics; Anticonvulsants
    • CCHEMISTRY; METALLURGY
    • 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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Abstract

Fluorinated Benzyltriazoles ABSTRACT OF THE DISCLOSURE
The invention relates to novel fluorinated 1-(.alpha.-phenylalkyl)-1H-1,2,3-triazoles of formula

Description

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The present invention relates to novel fluorinated 1-(a-phenylalkyl)-lH-1,2,3-triazoles of formula Ph-alk-N ~

1 ~2 wherein Ph is an o-fluorinated phenyl radical which may be additionally substituted by at least one further halogen atom, alk is lower alkylldene, R1 is hydrogen, lower alkyl or a carbamoyl group which is unsubstituted or substituted by lower alkanoyl or lower alkyl, and R2 is a carbamoyl group whi~h is unsubstituted or substituted by lower alkanoyl or lower alkyl, and to a process for the manufacture of said compounds, to pharmaceutical compositions containing said compounds and to the use of said compounds.
Possible additional halogen substituents of Ph are e.g. halogen atoms having an atomic number up to 35 inclusive such as fluorine, chlorine or, less preferably, bromine. A total of 5 halogen atoms may be present in the phenyl nucleus, which halogens may be, in addition to the o-fluoro substituent, 1 or 2 chlorine atom(s), 1 chlorine atom and 1 fluorine atom or 1 to 3 fluorine atom(s~ e.g.
1 or 2 fluorine a~om(s). A single addltional halogen atom is located e~g. in 4-, 5- or preferably 6-position.
Lower alkylidene may be C1-C4alkylidene, pre~erably methylene, and also ethylidene, 1,1-propylidene, 2,2-propylidene (isopropylidene) or 1,1-butylidene.
Lower alkyl may be C1-C4alkyl such aæ methyl or, less '~

,~ :
.
;

o~
-2- 21489-6930 preferably, ethyl, propyl, isopropyl, butyl, lsobutyl, sec-butyl or tert-butyl, but may also be a C5-C7alkyl group, e.g. a butyl, hexyl or heptyl group.
Carbamoyl substituked by lower alkanoyl or lower alkyl is preferably carbamoyl which is monosubstituted by lower alkanoyl or disubstituted by lower alkyl ancl is for example N-(Cl-C7)alkanoylcarhamoyl, preferably N-tC2-C5)alkanoylcarbamoyl, such as acetylcarbamoyl or pivaloylcarbamoyl or, most preferably, N,N-di(Cl-C4)alkylcarbamo~1 such as N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl.
The compounds o~ formula I have valuable pharmacological properties, ln particular a pronounced anticonvulsive activity, which may be observed, e.g. in mice in the form of a marked metrazole antagonism in the dosage range from about 30 to 300 mg/kg p.o. as well as in mice and rats in the form of a distinct protective action against convulsions induced by electroshock in the dosage range from about 1 to 25 mg~kg p.o. In this assay, the following values are obtained for the e~fective dose ED50 in mg/kg p.o. Iadministration 1 hour beforehand):
1-(2,6-difluorobenzyl)-lH-1,2,3-triazole-g-carboxamide: 17 (mice) and 3 (rats);
1-(o-fluorobenzyl)-lH-1,2,3-triazole-4-carboxamide: 17 (micer rats);
1-(2,6-difluorobenzyl)-lH-1,2,3-triazole-4,5-dicarboxamlde: 4 (mice, rats);
1-(6-chloro-2-fluorobenzyl)-lH-1,2,3-triazole-4,5-di~arboxamide:
~, - .
"' ,'~ ~
-; ~
: . . .: .. . .. .
-3- 21489-6930 7 (mice) and. 10 (ra~s), 1-(o-fluorobenzyl)-lH-1,2,3-triazole-4,5-dicarboxamide: 11 tmice) and. 10 (rate);
1-(6-chloro-2-fluorobenzyl)-lH-1,2-3-triazole-4-carboxamide:
11 (mice);
1-(2,5-difluorobenzyl)-lH-1,2,3-triazole-4,5-dicarboxamide:
6 (mice).
Compared with their known chlorinated analogues, ~he fluorinated 1-(a-phenylalkyl)-lH-1,2,3-triazoles of formula (I) have the advantage of improved anticonvulsive activity. Thus the following ED50 values were obtained in the above assay:
1-(o-chlorobenzyl-)-lH-1,2,3-triazole-4-carboxamide: 26 (mice) and 25 (rats), and 1-(o-chlorobenzyl)-lH-1,2,3-triazole-4,5-dicarboxamide: 40 (mice) and 43 (rats).
The compounds of the present invention are therefore better suited for the treatment of convulsions of different provenance, for example epilepsy, and may be used as anticonvulsive, e.g. antiepileptic, agents.
The invention relates in particular to compounds of formula (I), wherein Ph is o-fluorinated phenyl which may be additionally substituted by up to 3 halogen atoms inclusive having an atomic number of up to 35 inclusive, alk is C1-C4alkylidene, R
is hydrogen, C1-C4alkyl, carbamoyl, N-(C1-C7)alkanoylcarbamoyl or N,N-di(C1-C4)alkylcarbamoyl, and R2 is carbamoyl, N-(C1-C7)alkanoylcarbamoyl or N,N-di(C1 C4)alkylcarbamoyl.

i: .

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-4- 2148~-6930 The invention relates preferably to compounds of formula (I), wherein Ph is o-fluorinated phenyl which may be additionally substituted by up to 2 chlorine atoms inclusive, by 1 fluorine atom and 1 chlorine atom, or by up to 2 fluorine atoms inclusive, and is e.g. o-fluorophenyl, 2,3-, 2,4-, 2,5- or 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, and also 2,4,6-trifluorophenyl; alk is C1-C4alkylidine such as methylene, and also ethylidene or 2,2-propylidene; R1 is hydrogen, C1-C4alkyl such as methyl, or is carbamoyl, N-(C2-C5)alkanoylcarbamoyl such as acetylcarbamoyl or pivaloylcarbamoyl, or N,N-di(C1-C4)alkylcarbamoyl such as dimethylcarbamoyl; and R2 is carbamoyl, N-(C2-C5)alkanoylcarbamoyl such as acetylcarbamoyl or pivaloylcarbamoyl, or N,N-di(C1-C4)alkylcarbamoyl such as dimethylcarbamoyl.
The invention further relates in particular to compounds of formula (I), wherein Ph is o-fluorinated phenyl which may be additionally substituted by 1 chlorine atom, by 1 fluorine atom and 1 chlorine atom, or by up to 2 fluorine atoms inclusive, and is e.g. o-fluorophenyl, 2,3-, 2,4-, 2,5- or 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, and also 2,4,6-trifluorophenyl; alk is C1-C4alkylidene, preferably 1,1-(C1-C4)alXylidene such as methylene; R1 is hydrogen, C1-C4alkyl such as methyl, or is a radical R2; and R2 is carbamoyl or, less preferably, N-(C2-C5)alkylcarbamoyl such as acetylcarbamoyl, or N,N-di(C1-C4alkyl)carbamoyl such as dimethylcarbamoyl; for example compounds of formula (I), wherein Ph is o-fluorophenyl, 2,3-, 2,4-, 2,5- or ~ .. .. ... . .

,, ~"~'' ~', ' ~7~
-5- 21~8g-6930 2,6-difluorophenyl or 6-chloro-2-fluorophenyl, alk i6 methylene, R1 is hydroyen or unsubstituted carbamoyl, and R2 is unsubstituted carbamoyl.
More particularly, the invention relates to compounds of formula (I), wherein Ph is o-fluorophenyl or 2,6-difluorophenyl, alk is methylene, R1 is hydrogen or unsubstituted carbamoyl and R2 is unsubstituted carbamoyl.
Most particularly, the invention relates to compounds of formula (I), wherein Ph is 2,6-difluorophenyl, alk is methylene, R1 is hydrogen, C1-C4alkyl such as methyl, or is a radical R2, and R2 is carbamoyl or, less preferably, N-(C2-C5)-alkanoylcarbamoyl such as acetylcarbamoyl, or is N,N-di(C1-C4-)alkylcarbamoyl such as dimethylcarbamoyi.
First and foremost, the invention relates to compounds of formula (I), wherein Ph is o-fluorophenyl,2,5-difluorophenyl, 2,6-difluorophenyl or 2-chloro-6-fluorophenyl, alk is methylene and R1 and R2 are both carbamoyl; and further to compounds of formula (I), wherein Ph is 2,6-difluorophenyl, alk is methylene, R1 is hydrogen or carbamoyl and R2 is carbamoyl.
The process for the manufacture of compounds of formula (I) makes use of methods which are known per se, and comprises a) reacting a compound of the formula Ph - alk - N3 (II) with a compound of formula R1 ~ I = I R2 (III) Yl Y2 wherein Y1 is hydroxy and Y2 is hydroyen, or Y1 and Y2 together form an additional bond, or with a salt and/or i , .. .

....

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-6- 21489-6930 tautomer thereof, or b) reacting a compound of formula Ph - alk - Z (IV) wherein Z is halogen, lower alkane sulphonyloxy or unsubstituted or substituted benzenlesulphonyloxy, with a lH-1,2,3-triazole derivative of formula ~ N
H-N I (V) ~--1R

or with a salt thereof, or c) for the preparation of a compound of the formula tI), wherein either R1 is hydrogen, carbamoyl, N-lower alkanoylcarbamoyl or N,N-di-lower alkylcarbamoyl and R2 is carbamoyl or N,N-di-lower alkylcarbamoyl or R1 is carbamoyl or N,N-di-lower alkylcarbamoyl and R2 is carbamoyl, N-lower alkanoylcarbamoyl or N,N-di-lower alkylcarbamoyl, in a compound of formula /N- N
Ph-alk-~ ¦ (VI) ~--'1 y wherein Y~ denotes carboxy, lower alkoxycarbonyl, halocarbonyl or cyano YA and Y5 is a group R1 or denotes carboxy, lower alkoxycarbonyl, halocarbonyl or cyano YB or Y~ is a group R2 and Y5 denotes carboxy, lower alkoxycarbonyl, halocarbonyl or cyano YB
converting YA and/or YB into carbamoyl or N,N-di-lower ,~J ~l '' `.

: :
,:: , ~, J i';~ f ~
-7- 21~89-6930 alkylcarbamoyl, obtained into the individual isomers and isolating the isomer of formula (I) and, if desired, converting a compound of the formula (I) obtained according to the process in~o another compound o~ formula (I) and/or resolving a mixture of enantiomers or diastereoisomers obtained according to the process into the individual components.
Suitable startiny materials of formula (III) for process variant a) and tautomers thereof are e.g. compounds of formulae R1-C-C-R2 (IIIa) and R1-C(-0)-CH2-R2 (IIIb). Salts thereof are e.g. alkali metal salts, such as sodium salts, of eompounds of formula (IIIa), which can be obtained therefrom and from alkali metal alcoholates, e.g. sodium methanolate.
The reaction of compound II with compound III is carried out in known manner, conveniently in an inert solvent and, if necessary, in the presence of a condensing agent and~or at elevated temperature. Examples of inert solvents are aromatic or araliphatic hydrocarbons such as benzene or toluene, or ethers such as tert-butoxymethane, tetrahydrofuran or dioxane.
Preferred embodiments of this process arè for example the reaction of an azide of formula (II) with a compound of formula (IIIa) in benzene ordioxane, in the temperature range from 6~ to 120C, preferably at boiling temperature.
The starting materials of formula tIII) and some of those of formula (II) are known. Novel starting materials of formula (II) can be prepared by methods analogous to those employed for obtaining the known compounds, for example by reacting a compound of formula Ph-alk-Z (IV), ~Jherein Z is . .

':' ~`

~7~0~
-8- 21489-6930 reactlve esterified hydroxy such as halogen, e.g. chlorine, bromine or iodine, or sulfonyloxy such as :Lower alkanesulfonyloxy, unsubstituted or substituted benzenesulfonyloxy such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy or p-hromosulfonyloxy, or fluorosulfonyloxy, with an alkali metal azide, e.g. wi.th sodium azine, for example ln dimethylsulfoxide or dimethyl~ormamide, or by reacting an alcohol corresponding to the formula (IV) (Z 2 hydroxy), in the presence of triphenylphosphine and an azodicarboxylate, e.g. diethyl azodicarboxylate, with hydrazoic acid, for example in toluene.
In starting materials IV for process variant b), Z is e.g. halogen, reactive esterified hydroxy is e.g. halogen, for example chlorine, bromine or iodine, or sulfonylo~y such as lower alkanesulfonyloxy or unsubstituted or substituted benzenesulfonyloxy such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p~toluenesulfonyloxy or p-bromosulfonyloxy.
Salts of compounds (V) are e.g. alkali metal salts or alkaline earth metal salts thereof such as sodium, potassium or calcium salts.
The reaction is carried out in conventional manner, for example in the presence of a basic condensing agent or conveniently by using the component of formula (V) in salt form, if necessary with heating, preferably in a solvent or diluent.
Examples of basic condensing agents are those that form salts with the component of formula (V)l e.g. alkali metal alcoholates such as sodium methanolate or sodium ethanolate, alkali metal amides or alkaline earth metal amides such as sodium amide or lithium ~i : .: , '~
:, ,, .

-:;
:

~l~'7~
-9- 21489-6930 diisopropylamide. As already mentioned, the conversion of the component of formula (V) into a salt thereof i,5 best carried out beforehand, e.g. by reaction with one of the above-~entioned bases. Preferred solvents for car;rying out the reaction in the presence of an alcoholate are the corresponding alcoholates. For carrying out the reaction in the presence of amides, it is pre~erred to use e.g. aprotic organic solvents such as lower alkyl amides or phosphoric acid, e.g. hexamethylphosphoramide, alkanoic acid amides such as dimethylformam:ide, or di-lower alkylsulfoxides such as dimethylsulfoxide. Isomers obtained as by-products in the process of the invention may be separated from the desired compounds of formula (I).
The starting compounds (IV) and (V), if not already known, may be prepared in conventional manner. Thus compounds of formula (IV) may be obtained by reactively esterifying an appropriate alcohol (IV; ~ = hydroxy), for example with thionyl chloride, phosphorus tribromide or a sulfonyl chloride. Compounds (V) may be prepared by reacting trimethylsilyl azide or hydrazoic acid with a compound of formula Rl-C-C-R (IIIa) or Rl-~(=O)~CH2-R2 IIIIb), wherein Rl is preferably carbamoyl or N,N-di-lower alkylcarbamoyl, and removing the silyl group by mild hydrolysis from a 1-trimethylsilyltriazole derivative, where obtained, if desired after lower alkylating or lower alkanoylating a carbamoyl group R2 and/or Rl as described below for compounds of formula (I). It is, however, also possible to react trimethylsilyl azide with a compound of formula ~2~
-10- 21~9-6930 Y -C-C-Y (VIIa) or R1--C(=O)-CH2 Y~ (VlIb), wherein Y4 is a radical YA which is convertible into carbamoyl or N,N-di-lower alkylcarbamoyl, for example esterified ~arboxy such as lower alkoxycarbonyl, or cyano, and Y5 is hydrogen or preferahly a radical YB which is convertible in~o carbamoyl or N,N-di-lower alkylcarbamoyl and which is preferably identical with YA, and to convert YA and/or YB into carbamoyl or N,N-di-lower alkylcarbamoyl in the case of esterified carboxy e.g. by ammonolysis (reaction with ammonia) and, in the case of cyano, e.g. by hydrolysis, with simultaneous removal of the trimethylsilyl group.
In process varian~ c), radicals YA and/or YB which are convertible into carbamoyl or N,N-di-lower alkylcarhamoyl are, for example, carboxyl groups which are in the free or salt form, lower alkoxycarbonyl groups, halocarbonyl groups, such as chlorocarbonyl groups, or also ~yano groups.
Carboxyl groups in salt form are e.g. carboxyl groups which are in the form of ammonium salts derived from ammonia or a di-lower alkylamine, and also in the form of metal salts, e.g.
alkali metal salts or alkaline earth metal salts.
The conversion of the groups YA and/or YB into carbamoyl or N,N-di-lower alkylcarbamoyl is effected in known manner, starting from carboxyl, lower alkoxycarbonyl and halocarbonyl, by solvolysis, i.e. hydrolysis, or by ammonolysis or aminolysis (reaction with ammonia or a di-lower alkylamine respectively).

..
~,",~

~7;~
-11- 21489-G930 For example, by means of hydrolysis cyano groups can be converted in~o carbamoyl, e.g. in the presen~ of a basic hydrolysing agent such as an alkali metal hydroxide, e.g. sodium or potassium hydroxide, i~ necessary in the presence of a peroxy compound, e.g. hydrogen peroxide.
By means of ammonolysis or aminolysis it is possible to convert carboxyl, lower alkoxycarbonyl and halocarbonyl into carbamoyl or N,N-di-lower alkylcarbamoyl. The reaction is performed, if necessary, in the prasence of a condensing agent and preferably in an inert solvent. Suitable condensing agents are basic condensing agents, prefarably ammonia or an excess of the amine employed for the aminolysis, starting from halocarbonyl, and also alkali metal hydroxides or alkali metal carbonates or tertiary organic nitrogen bases such as tri.-lower alkylamines or tertiary heteroaromatic nitrogen bases such as triethylamine or pyridine. Free carboxyl groups can be ~onverted into carbamoyl by dehydration of the ammonium salts obtained as intermediates, e.g.
by heating or by treatment with dehydratlng agents such as acid anhydrides, e.g. phosphorus pentoxide and the like, or of carbodiimides, e.g. ~,N'-dicyclohexylcarbodiimide. A particularly preferred embodiment of this process variant comprises reacting a compound of formula (VI), where:Ln Y4 is lower alkoxycarbonyl and Y5 is hydrogen, lower alkyl or lower alkoxycarbonyl, with an excess of ammonia or of a di-lower alkylamine and, if desired, in a resultant compound, wherein R2 and/or R1 are unsubstituted carbamoyl, lower alkanoylating R2 and/or R1.
The starting materials of formula ~VI), if not known, may be prepared in conventional manner, for example by reacting an ~ ', ` !

~72;~
-lla- 214~g 6930 azide of formula Ph - alk - N3 (II) with a compound of formula Y -C-C-Y (VIIa) or R1-C(=O)-cH2 Y4 (VIIb) for example as described in process variant a). If necessary, directly obtained esters or nitrile~ of formula (VI) (Y4 and/or Y5 = lower alkoxycarbonyl or cyano) can be hydrolysed under basic condittons, e.g. with aqueous alcoholic sodium hydroxide solution, to the corresponding acid, and acids of formula (VI) (Y4 and/or Y5 - carboxy), which are obtained direct or by hydrolysis of corresponding esters or nitriles, can be converted e.g. with thionyl chloride into the acid chloride.
In compounds of formula (I) it is possible to convert N-uns~lbstituted carbamoyl into N-lower alkanoylcarbamoyl by treatment with a lower alkanoylating agent, or to convert unsubstituted carbamoyl into N,N-di-lower alkylcarbamoyl by treatment with a lower alkylating agent.
Lower alkanoylating agents are e.y. lower alkanecarboxylic acid anhydrides such as acetic anhydride ox the mixed anhydride of formic and acetic acid~ or lower alkanecarboxylic acid chlorides such as acetyl chloride. The reaction with these compounds is carried out in conventional manner, if necessary in the presence of a base, e.g. triethylamine or pyridine, or in the presence of a mineral acid, e.g. sulfuric acid, if an acid anhydride is used as alkanoylating agent.
Lower alkylating agents are e.g. reactive esters, such as esters of hydrohalic acids, sulfuric acid or sulfonic acid with lower alkanols and are lower alkyl halides, e.g. methyl iodide, B~

o~

-llb- 21489-6930 di-lower alkyl sulfates, e.g. dimethyl sulfate, or ]ower alkyl esters of alipha~ic or aromatic sulfonic acids, in particular of lower alkanesulfonic acids or unsubstituted or substituted benzenesulfonic acids, e.y.

.

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lower alkylmethanesulEonates, lower alkylethanesulfonates, lower alkylbenzenesulfonutes or lower alkyl-p-toluenesulEonates. The lower alkylation i8 carried out ln conventional manner, e.g. under basic conditions, as in the presence of an alkali metal hydroxide, e.g.
potassium hydroxide, as well as preEerably in the presence of a phase transfer catalyst, e.g. tetrabutylammonium bromide or benzyltrimethylammonlum chloride.

The separation of mixtures of isomers, exemplary of which are mixtures of enantiomers and diasteroisomers of compounds of formula ~I) containing at least one asymmetrlcal carbon atom, as well a9 mixtures of compounds of formula (I) and isomers thereof, is effected in known manner. Diastereoisomers and mixtures of com-pounds of formula ~I) and isomers thereof may be separated e.g. on the basis of the different physical properties of the components by conventional methods of separation such as fractional cryatallisat-ion, chromatographic methods and the like. A suitable method of separating mixtures of enantiomers is for example fractional crystallisation from an optically active solvent or chromatography over an optically active stationary andlor mobile phase. It is, however, also possible to separate a mixture of enantiomers into the corresponding diastereoisomeric acyl derivatives, for example by reaction with an optically active acid chloride~ to separate said diastereoisomers into the indivudual components and to isolate the pure enantiomers therefrom, for example by mild treatment with an acid.

Novel starting compounds, e.g. of formulae (V) and (VI), which have been specially developed for synthesising the compounds of the invention, in particular the selected compounds that lead to the compounds of formula (I) referred to at the outset as being especially preferred, the methods of preparing them and the use thereof as intermediates, likewise constitute objects of the invention.

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-13- 21~89-6930 The compounds of formula ~I) may be used for example in the form of pharmaceutical compositions that contain a therapeutically effective amount of active ingred~ent, optionall~
together with inorganic or organic, solid or liquid pharmaceutically acceptable carriers that are suitable for enteral, e.g. oral, or parenteral administration. Hence the compositions employed are tablets or gelatin capsules which contain the active ingredient together wlth diluents, e.g.
lactose, dextrose, saccharose, mannitol, sorbitol, cellulose and/or glyeine, and/or lubricants, e.g. silica, talcum, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets also contain binders, e.g.
magnesium aluminium silicate, starches such as maize, corn, rice or arrow root starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone and, if desired, disintegrators, e.g. starches, agar, alginic acid or a salt thereof such as sodium alginate, and/or effervescent mixtures, or adsorption agents, colourants, flavouring matters and sweeteners. The compounds of formula (I) may also be used in the form of compositions for parenteral administration or of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions which, e.g. in the case of lyophilised formulations that contain the active ingredient alone or together with a carrier, e.g. mannitol, may be prepared prior to use. The pharmaceutical compositions may be sterilised and/or may contain ad~uvants~ e.g. preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. The pharmaceutical compositions of the -13a- 21489-6930 invention may, if desired contain further pharmacologically active substances, are prepared in a manner known per se, e.g. by conventional mixing, granulating, confectioning, dissolving or lyophilising methods, and contain f.rom about 0.1 to 100~ , preferably from about 1 to 50% (lyophilisates up to 100%), of active ingredient.
The invention also relates to the use of compounds of formula (I) preferably in the form of pharmaceutical compositions.
The dosage may depend on different factors, such as the mode of application, ,~` " ~ ' , ;

~7~0~

species, age and/or the individual condition of the patient. The daily doses for oral administration are in the range from about I
to 50 mg/kg, in single doses of about 1 to 25 kg/mg, and for warm-blooded animals having a body weight of about 70 kg, preferably in daily doses of about 0.070 to 3.5 g.

The invention is illustrated by the following Examples.

Example 1: 73.5 g (0.25 mole) of dimethyl l-(o-fluorobenzyl)-lH-1,2,3-triazole-4,5-dicarboxylate are dissolved in 1000 ml of methanol. Then 250 g of ammonia are introduced into the autoclave under pressure and the reaction mixture is kept for 24 hours at 100C. The batch is then cooled arld the crystallised product is filtered with suction, washed with methanol and recrystallised from dioxane/toluene, affording l-(o-fluorobenzyl)-lH-1,2,3-triazole-4,5-dicarboxamide with a melting point oE 197-199C.

The starting material may be prepared as follows:
A solutioD of 40 g (0.282 mole) of dimethyl acetylenedicarboxylate in 500 ml of toluene is added dropwise to a solution of 41.5 g (0.255 mole~ of o-iluorobenzyl azide in 50 ml of toluene, which solution has been heated to 90C. ~fter a further 5 hours at 90C, the toluene is stripped off, the reaction mixture is cooled and the crystalline product is filtered with suction. Recrystallisation from a 1:1 mixture of diethyl etherlpetroleum ether yields dimethyl l-(o-fluorobenzyl)-lH-1,2,3-triazole-4,5-dicarboxylate with a melting point of 49-51C.

Example 2: 59 g (0.26 mole) of 1-(o-fluorobenzyl)-lH-1,2,3-triazole-4,5-carboxylic acid and 300 ml of thionyl chloride are heated for 1 hour to re1ux. Excess thionyl chloride is distilled off in vacuo and the residual l-(o-fluorobenzyl)-lH-1~2,3-triazole-4-ca}boxylic acid chloride is dissolved in 500 ml of toluene. The solution i9 added dropwise at 5-10C to 500 ml of a concentrated aqeous ammonia solution. The precipitated product is filtered with suction~ washed , ., ~ ' .

'7~

with water and recrystallised from ethanol, affording l-~o-fluoro-benzyl)-lH-1,2,3-triazole-4-carboxamide with a melting pOillt of 22~-222C.

The starting material may be prepared as follows:
A solution of 50 g (0.33 mole) of o-fluorobenzyl azide, 23.1 g ~0.33 mole) of propinecarboxylic acid and 400 ml of toluene is stirred for 24 hours at 70C. After the reaction mixture has cooled to room temperature, the precipitated product is filtered with suction and washed first with toluene and then with diethyl ether, affording l-(o-fluorobenzyl)-lH-1,2,3-triazole-4-carboxylic acicl with a melting point of 151C (dec.).

Example 3: Following the procedure described in Example 1, 1-(2,6-difluorobenzyl)-lH-1,2,3-triazole-4,5-dicarboxamide with a melting point of 203-205C (recrystallisation from methanol) is obtained from 2,6-difluorobenzyl azide and dimethyl acetylenedicarboxylate via dimethyl 1-(2,6-difluorobenzyl)-lH-1,2,3-triazole-4,5-dicarbox-ylate.

Example 4: Following the procedure described in Example 2, 1-(2,6-difluorobenzyl)-lH-1,2,3-triazole-4-carboxamide with a melting point of 237-240C (recrystallisation from ethanol) is obtained from 2,6-difluorobenzyl azide via 1-(2,6-difluorobenzyl)-~lH-1,2,3-triazole-4-carboxylic acid, with a melting point of 160-162C
(recrystallisation from acetonitrile; decomposition~.

Example 5: The following compounds can also be prepared in accordance with the procedures described in Examples 1-4:
1-(2,3-difluorobenzyl)-lH-1,2,3-triazole-4-carboxamide, 1-(2,4-difluorobenzyl)-lH-1,2,3-triazole-4-carboxamide and 1-(2,5-difluorobenzyl)-lH-1,2,3-triazole-4-carboxamide.

~7Z~O~

~ 16 -Example_6: Following the procedure described in Example 2, 1-(6 chloro-2~fluorobenzyl~-1H~1>2,3-triazole-4-carboxamide with a melting point of 274-276C (recrystallisation from glacial acetic acid) is obtained from 1-(6-chloro-2--fluorobenzyl)-lH-1,2,3-triazole-4-carboxylic acld.

The starting material may be prepared as follows:
A mixture of 9ô g (0.678 mole) of 6-chloro-2-fluorotoluene, 91.5 g (0.678 mole) of sulfuryl chloride an~ 0.2 g of dibenzoyl peroxide i9 stirred for 3 hours at 100-110C and then distilled, affording 6-chloro-2-fluorobenzyl chloride with a boiling point in the range from 78-82C.

123 g of (0.687 mole) of 6-chloro-2-fluorobenzyl chloride are added dropwise at 20-40C to a suspension of 47 g (0.722 mole) of sodium azide in 400 ml of dimethylsulfoxide. The mixture is stirred for 4 hours at room temperature, then diluted wikh ice-water and extracted with cyclohexane. The solvent is removed by di~tillation and the residue is distilled, affording 6-chloro-2-fluorobenzyl azide; bpls = 99-100C.

27.5 g (0.15 mole) of 6-chloro-2-fluorobenzyl azide and 10.5 g (0.15 mole) of propinecarboxylic acid in 300 ml of toluene are heated for 3 hours to 90C. After cooling, the ~rystals are filtered with suction and recrystallised from acetonitrile to give 1-(6-chloro-2-fluorobenzyl)-lH-1,2,3~triazole-4-carboxylic acid with a melting point of 182C (dec.).

Example 7: Following the procedure described in Example 1, 1-(6-chloro-2-fluorobenzyl)-lH-1,2,3-triazole-4,5-dicarboxamide with a melting point of 214-216C (recrystallisation from glacial acetic acid) is obtained from 6-chloro-2-fluorobenzyl azide and dimethyl acetylenedicarboxylate via dimethyl l-(6-chloro-2-~luorobenzyl)-lH-1,2,3-triazole-4,5-dicarboxylate.

"

Example 8: Following the procedure described in Example 1, 1-(2,5-difluorobenzyl)-lH-1~2,3-triazole-4,5-dicarboxamide with a melting point of 191-192C (recrystallisation from dioxane/toluene) is obtained from 2,5-difluorobenzyl azide ~bpls - 82-84C) via dimethyl 1-(2,5-difluorobenzyl)-lH-1,2,3-triazole-4,5-dicarboxylate.

Example 9: Following the procedure described in Example 1, 1-(2,4-difluorobenzyl)-lH-1,2,3-triazole-4,5-dicarboxamide with a melting point of 183-185C (recrys~allisation from dioxane/toluene) i9 obtained from 2,4-difluorobenzyl azicle (bpls = 80-83C) via dimethyl 1-(2,4-difluorobenzyl)-lH-1,2,3-triazole-4,5-dicarboxylate wi~h a melting point of 7S-76C (recrystallisation from cyclohex-ane).

Example 10: Following the procedure described ln Example 1, ~,N-dimethyl 1-(2,6-difluorobenzyl)-lH-1,2,3-triazole-4,5-dicarboxamide with a melting point of 130-133C (recrystallisation from (tert-butoxymethane) i8 obtained by reaction with dimethylamine.

Example 11: Following the procedure described in Example 1, 1-(2,3-difluorobenzyl)-lH-1,2,3-triazole-4,5-dicarboxamide with a melting point of 183-185C (recrystallisation from ethyl acetate/benzene) is obtained from 2,3-difluorobenzyl azide and dimethyl acetylenedi-carboxylate via dimethyl 1-(2,3-difluorobenzyl)-lH-1,2,3-triazole 4~5-dicarboxylate.

Example 1?: Following the procedure described in Example 2, 1 (2,6-difluorobenzyl)-5-methyl-lH-1,2,3-triazole-4-carboxamide with a melting point of 208-210C is obtained from 1-(2,6-difluorobenzyl)-lH-1,2,3-triazole-4-carboxylic acid.

The starting material is prepared as follows:
2.53 g (0.11 mole? of sodium are dissolved in 60 ml of alcohol, then a mixture of 16.9 g (0.1 mole) of 2,6-dlfluorobenzyl azide and 14.3 g (0.11 mole~ of ethyl aretate in 60 ml of alcohol is added and , , . . , ~i~7~

- l8 -the batch i5 heated for 16 hours to reflux. After addition of 120 ml of normal sodium hydroxlde solution, the reaction mixture is refluxed for another 2 hours, then diluted with 200 ml of water and acidified to pH 1 with hydrochloric acid while cooling. The preci-pitated product is filtered with suction, washed first with water and then with ether and dried, affording 1-(2,6-difluorobenzyl)-5-methyl-lH-1,2,3-triazole-4-carboxylic acid with a melting point of 166-167C.

Example 13: Following the procedure described in Example 1, 1-11-(2,6-difluorophenyl)ethyl]-lH-1,2,3-triazole-4-carboxamide with a melting point of 205-207C (recrystalli3ation from methanol? is obtained from ethyl 1-[1-(2,6-difluorophenyl)ethyl]-1~-1,2,3-tri-azole-4-carboxylate.

The starting material is prepared as follows:
Reduction of 10.2 g (66 millimoles) of 2,6-difluoroacetophenone with 2.5 g (65 millimoles) of llthium aluminium hydride in ether affords 1-(2,6-difluorophenyl)ethanol as a colourless oil.

10 g (63 millimoles) of 1-(2,6-difluorophenyl)ethanol are dissolved in 150 ml of hydrazoic acid (1.2 N in toluene). To this solution are added 22.8 g (200 millimoles) of trifluoroacetic acid and the reaction mixture is allowed to stand for 24 hours at room tempera-ture. After dilution with 300 ml of hexane~ the reaction solution is washed first with water, then with sodium bicarbonate solution until free of acid and dried over sodium sulfate. The solvent is subsequently removed at 40-50C under reduced pressure. The residue is dissolved in 100 ml of hexane and the solution is filtered through 50 g o~ silica gel and concentrated by evaporation once more, affording 1-(2~6-difluorophenyl)ethyl azide as a colourless oil.

6.5 g (35 millimoles) of 1-(2,6-difluorophenyl)ethyl azide and 2.45 g (35 millimoles) of propinecarboxylic acid in 50 ml of toluene are heated for 24 hours to 60-70C. The cooled reaction mixture is : ~: ' :- ' . ~

::

'' ~'` '~ :

J~i`~3L

extracted with 100 ml of lN sodium hydroxide solution and the extract is acidlfied with hydrochloric acid to give 1-~1-(2,6-di-fluorophenyl)ethyl-lH-1,2,3-triazole-4-carboxylic acid with a melting point of 135-138C (dec.).

7.1 g (26.6 millimoles) of 1-[1-(2,6-difluorophenyl)ethyl]-lH-1,2,3-triazole-4-carboxylic acid, 150 ml of ethanol and 1 ml of sulfuric acid are heated for 10 hours to reflux. Working up gives ethyl 1-~1-(2,6-difluorophenyl)ethyl]-lH-1,2,3-triazole-4-carbo~ylate with a melting point of 118-121C.

Example 14: Followlng the procedure of Example 1, 1-~2-[2-(2,6-di-fluorophenyl)propyl~-lH-1,2,3-triazole-4-carboxamide with a melting point of 203-205C (recrystallisation from methanol) is obtained from ethyl 1-{2-[2-(2,6-difluorophenyl)propyl~-lH-1,2,3-triazole-4-carboxylate.

The starting material is prepared as follows:
120 ml of a 3 molar solution of methylmagnesium chloride in tetrahy-drofuran are added slowly dropwise to 28 g (150 millimoles~ of ethyl 2,6-difluorobenzoate in 200 ml of ether. After 1 hour under reflux and working up with 10 % ammonlum chloride solution, 2-(2,6-difluoro~
phenyl)propan-2-ol with a boiling point of bpl 2 = 74-76C is obtained.

20.6 g (120 millimoles) of 2-(2,6-difluorophenyl)propan-2-ol are dissolved in 300 ml of hydrazoic acid solution (lN, in benzene~
and 22.8 g (200 millimoles) of trifluoroacetic acid are added to thia solution. After 24 hours at room temperature, the reaction solution is diluted with 500 ml of hexane, washed with water and then with sodium bicarbonate until free of acid and dried over sodium sulfate. The solvent is removed by evaporation and the residue is distilled, affording 2-(2,6-difluorophenyl)-2-azidopro-pane of bpls G 85-87C.

: .-,.,,: . :

~:7~

lo g (51 millimoles) of 2-(2,6-difluorophenyl)-2-azldopropane are reacted with 3.6 g (51 millimoles) of propinecarboxylic acid in 100 ml of toluene and worklng up is effected as described in Example 12, affording 1-~2-~2-(2,6-difluorophenyl)propyl}-lH-1,2,3-triazole-4-8 cArboxylic acid with a melting point of 173C (dec.).

Esterification of the above acid with 50 ml of ethanol and 0.5 ml of concentrated sulfuric acid gives ethyl 1-~2-[2-(2,6-difluorophenyl~-propyll-lH-1,2,3-triazole-4-carboxylate as a pale yellow vi6cous oil which can be used for the reaction with ammonia without further purification.

Example 15: Following the procedure described in Example 1, 1-{2-[2-(2,6-difluorophenyl)propyl]~-lH-1,2,3-triazole-4,5-dicarboxamide with a melting point of 177-178C (recrystallisation from ethyl acetatelhexane) i9 obtained from 2-(2,6-difluorophenyl)-2-azidopro-pana and dimethyl acetylenedicarboxylate via dimethyl 1-~2-[2-(2,6-di-fluorophenyl)propyl]~-lH-1,2,3-triazole-~,5-dicarboxylate (m.p.
100-102C).

Example 16: 16.9 g (0.1 mole) of 2,6-difluorobenzyl azide and 8.3 g (0.1 mole) of but-2-ynecarboxamide are heated in 20 ml of dioxane for 16 hours to 100C. After removing the dioxane by evaporation, the desired isomer is ssparated by column chromatography, to give 1-(2,6-difluorobenzyl)-5-methyl-lH-1,2,3-triazole-4-carboxamide with ~ melting point of 208-210C (recrystallisation from methanol).

Example 17: 2.81 g (10 millimoles) of 1-(2,6-difluorobenzyl)-lH
1,2,3-triazole-4,5-dicarboxamide, 20 ml of acetic anhydride and 2 drops of sul~uric acid are heated for 3 hours to 80C. After coollng, the mixture i8 stirred for 1 hour at 20-25C and the precipitated product is filtered with suction and washed with water.
Recrystallisation from methanol gives 1-(2,6-difluorobenzyl)-lH-1,2,3-difluorobenzyl)-lH-1,2,3-triazole-4,5-di-~N-acetyl)carboxamide with a melting point of 136-138C.

:., , ~': ,...

: .:~ . .
.:::- : ',' ::
::~ "'.~ '- ' Example 18: Following the procedure described in in Example 17, l-(2~6-difluorobenzyl~-lH-l~2~3-triazole-4-(N-acetyl)carboxamide with a melting point of 205-207C (recrystallisation from dioxane/toluene) is also obtained.

Example 19: Tablets which each contain 50 mg of l-~o-fluorobenzyl)-IH-1,2,3-triazole-4-carboxamide may be prepared as follows:

Composition (for 10,000 tablets) active ingredient 500.0 g lactose 500.0 g potato starch 352.0 g gelatin 8.0 g talcum 60.0 g magnesium stearate 10.0 g silica (highly dispersed)20.0 g ethanol q.S.

The active ingredient is mlxed with the lactose and 292 g of potato starch and thls mixture is moistened with an alcoholic solution of the gelatin and granulated through a sieve. After drying~ the granulate is mixed with the remainder of the potato starch, the talcu~, the magnesium stearate and the highly disperse silica and the mixture is compressed to tablets weighlng 145.0 g each and containing 50.0 mg of active ingredient. ]f desired, the tablets may be provided with a breaking notch for a finer adiustment of the dose.

Example 20: Film-coated tablets each containing lO0 mg of l-(o-fluorobenzyl~-lH-1,2,3-triazole-4-carboxamide may be prepared as follows:

' ' , , .
.: , .

~7~;~0~L

Composltion (for 1000 tablets) active ingredlent 100.00 g lactnse 100.00 g corn starch 70.00 g talcum 8.50 g calcium stearate 1.50 g hydroxypropylmethyl cellulose 2.36 g shellac 0.64 g water q. 8 .
methylene chloride q.s The active ln~redient, the lactose and 40 g of the corn starch are mixed and moistened with a paste prepared from 15 g of corn starch and water (with heating~ and the mixture i9 granulat~d. The granu-late is dried and mixed with the }emainder of the corn starch, talcum and the calcium stearate. The mixture i5 compressed to tablets weighing 280 g. The tablets are then coated with a solution o~ the hydroxypropylmethyl cellulose and the shellac in methylene chloride. The tablets have a final weight of 283 g.

Example 21: Tablets and coated tablets containing another compound of Examples 1-18 can also be prepared as described in Examples 19 and 20.

. .. :. -.-. .: . , : ,, ::: :
~ . :~. -" . .
.. ~ , : ~ .
:~:,:.. ,,, :

Claims (23)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A novel fluorinated 1-(.alpha.-phenylalkyl)-1H-1,2,3-triazole of the formula (I) (I) wherein Ph is an o-fluorinated phenyl radical which may be additionally sub-stituted by at least one further halogen atom; alk is lower alkylidene, R1 is hydrogen, lower alkyl or a carbamoyl group which is unsubstituted or substi-tuted by lower alkanoyl or lower alkyl, and R2 is a carbamoyl group which is unsubstituted or substituted by lower alkanoyl or lower alkyl.
2. A compound according to claim 1, wherein Ph is an o-fluorinated phenyl radical which may be additionally substituted by up to 3 halogen atoms inclusive having an atomic number of up to 35 inclusive, alk is C1-C4alkyl-idene, R1 is hydrogen, C1-C4alkyl, carbamoyl, N-(C1-C7)alkanoylcarbamoyl or N,N-di(C1-C4)alkylcarbamoyl, and R2 is carbamoyl, N-(C1-C7)alkanoylcarbamoyl or N,N-di(C1-C4)alkylcarbamoyl.
3. A compound according to claim 1 wherein, Ph is an o-fluorinated phenyl radical which may be additionally substituted by up to 2 chlorine atoms inclusive, by 1 fluorine atom and 1 chlorine atom, or by up to 2 fluorine atoms inclusive, alk is C1-C4alkylidene, R1 is hydrogen, C1-C4alkyl, carbamoyl, N-(C2-C5)alkanoylcarbamoyl or N,N-di(C1-C4)alkylcarbamoyl, and R2 is carbamoyl, N-(C2-C5)alkanoylcarbamoyl or N,N-di(C1-C4)alkylcarbamoyl.
4. A compound according to claim 1, wherein Ph is an o-fluorinated phenyl radical which may be additionally substituted by 1 chlorine atom, by 1 fluorine atom and 1 chlorine atom, or by up to 2 fluorine atoms inclusive, alk is C1-C4alkylidene, R1 is hydrogen, C1-C4alkyl, or is a radical R2; and R2 is carbamoyl or N,N-di(C1-C4)alkyl-carbamoyl.
5. A compound according to claim 1, wherein Ph is o-fluorophenyl, 2,3-, 2,4-, 2,5- or 2,6-difluorophenyl or 6-chloro-2-fluorophenyl, alk is methylene, R1 is hydrogen or carbamoyl and R2 is carbamoyl.
6. A compound according to claim 1, wherein Ph is o-fluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl or 2-chloro-6-fluoro-phenyl, alk is methylene and R1 and R2 are both carbamoyl.
7. 1-(o-Fluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide.
8. 1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide.
9. 1-(o-Fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide.
10. 1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide.
11. 1-(6-Chloro-2-fluoro-benzyl)-1H-1,2,3-triazole-4-carboxamide.
12. 1-(6-Chloro-2-fluoro-benzyl)-1H-1,2,3-triazole-4,5-dicarboxamide.
13. 1-(2,5-Difluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide.
14. 1-(2,6-Difluorobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide.
15. 1-[1-(2,6-Difluorophenyl)ethyl]-1H-1,2,3-triazole-4-carboxamide.
16. 1-{2-[2-(2,6-Difluorophenyl)propyl]}-1H-1,2,3-triazole-4-carboxamide.
17. 1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4-(N-acetyl)carboxamide.
18. 1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4,5-di-(N-acetyl)carboxamide.
19. A pharmaceutical composition containing as active ingredient a compound according to any one of claims 1, 8 and 10 in admixture to customary pharmaceutical auxilliaries.
20. A process for the preparation of a novel fluorinated 1-(.alpha.-phenylalkyl)-1H-1,2,3-triazle of formula (I) wherein Ph is an o-fluorinated phenyl radical which may be additionally substituted by at least one further halogen atom, alk is lower alkylidene, R1 is hydrogen, lower alkyl or a carbamoyl group which is unsubstituted or substituted by lower alkanoyl or lower alkyl, and R2 is a carbamoyl group which is unsubstituted or substituted by lower alkanoyl or lower alkyl, which process comprises a) reacting a compound of the formula pH - alk - M3 (II) with a compound of formula (III) wherein Y1 is hydroxy and Y2 is hydrogen, or Y1 and Y2 together form an additional bond, or with a salt and/or tautomer there of, or b) reacting a compound of formula Ph - alk - Z (IV) wherein Z is halogen, lower alkane sulphonyloxy or unsubstituted or substituted benzenesulphonyloxy, with a 1H-1,2,3-triazole derivative of formula (V) or with a salt thereof, or c) for the preparation of a compound of the formula (I), wherein either R1 is hydrogen, carbamoyl, N-lower alkanoylcarbamoyl or N,N-di-lower alkylcarbamoyl and R2 is carbamoyl or N,N-di-lower alkylcarbamoyl or R1 is carbamoyl or N,N-di-lower alkylcarbamoyl and R2 is carbamoyl, N-lower alkanoylcarbamoyl or N,N-di-lower alkylcarbamoyl in a compound of formula (VI) wherein Y4 denotes carboxy, lower alkoxycarbonyl, halocarbonyl or cyano YA and Y5 is a group R1 or denotes carboxy, lower alkoxycarbonyl, halocarbonyl or cyano YB or Y4 is a group R2 and Y5 denotes carboxy, lower alkoxycarbonyl, halocarbonyl or cyano YB converting YA and/or YB into carbamoyl or N,N-di-lower alkylcarbamoyl if necessary separating a mixture of isomers obtained into the individual isomers and isolating the isomer of formula (I) and, if desired, converting a compound of the formula (I) obtained according to the process into another compound of formula (I) and/or resolving a mixture of enantiomers or diastereoisomers obtained according to the process into the individual components.
21. A process according to claim 20, which comprises reacting a compound of formula (VI), wherein Y4 is lower alkoxycarbonyl and Y5 is hydrogen, lower alkyl or lower alkoxycarbonyl with an excess of ammonia or of a di-lower alkylamine and, if desired, in a compound so obtained in which R2 and/or R1 are unsubstituted carbamoyl, lower alkanoylating R2 and/or R1.
22. The use of a compound according to any one of claims 1, 8 and 10 for the preparation of a pharmaceutical composition.
23. A process for the preparation of a pharmaceutical composition according to claim 19, characterized in that the active ingredient is processed to form a pharmaceutical composition together with customary pharmaceutical auxiliaries.
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WO2014120994A1 (en) * 2013-01-31 2014-08-07 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
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FI93544B (en) 1995-01-13
DD245874A5 (en) 1987-05-20
DK175686D0 (en) 1986-04-17
FI861573A0 (en) 1986-04-14
IE58472B1 (en) 1993-09-22
IE861015L (en) 1986-10-18
HUT40792A (en) 1987-02-27

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