DK167681B1 - 3-BENZYL-3H-1,2,3-TRIAZOLOOE4,5-DAAPYRIMIDINES IN FREE OR SALT FORM, PROCEDURES FOR THEIR PREPARATION, THEIR USE AS A MEDICINAL PRODUCT AND THE PREPARATION OF A PHARMACEUTICAL PREPARATION OF A PHARMACEUTICAL PREPARATION - Google Patents

Abstract

Novel 3H-1,2,3-triazolo[4,5-d]pyrimidine derivatives, in particular substituted 3-benzyl-3H-1,2,3-triazolo[4,5-d]pyrimidines of the formula <IMAGE> in which Ph denotes a phenyl radical which is substituted by halogen, lower alkyl, trifluoromethyl and/or cyano, R1 represents an amino group which is free or substituted by aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and/or by acyl substituents and R2 represents hydrogen, lower alkyl or an amino group which is free or substituted by aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and/or by acyl substituents, and their salts. These compounds can be used as pharmaceutical active substances and can be prepared in a manner known per se.

Description

in DK 167681 B1

The present invention relates to novel substituted 3-benzyl-3H-1,2,3-triazolo [4,5-d] pyrimidines which are characterized in that they have the general formula 5 ©.

R 2 is N, CH 2 -Ph where Ph is a halogen having an atomic number up to and including 35, C (1-7) -alkyl, trifluoromethyl and / or cyano-substituted phenyl group, R 1 is amino, N-mono-C (1- 7) -alkylamino, N, N-di-C (1-7) -alkylamino, wherein the two N-alkyl groups may be the same or different, N- (C (1-4)) -alkoxy-C (1-7 ) -alkyl) -amino, N- (hydroxy-C (1-7) -alkyl) -amino, N- (hydroxy-C (1-7) -alkyl) -NC (1-7) -alkyl-amino, N-mono-C (3-8) -cycloalkylamino, N, N-di-C (3-8) -cycloalkylamino, wherein the two N -cycloalkyl groups may be the same or different, NC (3-8) - cycloalkyl-NC (1-7) -alkyl-amino, N-mono- (C (3-8) -cycloalkyl-C (1-7) -alkyl) -amino, N, N-di- (C (3- 8) -cycloalkyl-C (1-7) -alkyl) -amino wherein the two N- (cycloalkylalkyl) groups may be the same or different, N- (C (3-8) -cycloalkyl-C (1-7) ) -alkyl) -NC (1-7) -alkyl-amino, NC (2-5) -alkanoylamino or NC (2-5) -alkanoyl-NC (1-7) -alkyl-amino, and Rg is hydrogen , C (1-7) alkyl, amino, N-mono-C (1-7) alkylamino, N, N-di-C (1-7) alkylamino, wherein the two N-alkyl groups can be be the same or different, N- (C (1-4) -alkoxy-C (1-7) -alkyl) -amino, N-25 (hydroxy-C (1-7) -alkyl) -amino, N- ( hydroxy-C (1-7) alkyl) -NC (1-7) -alkyl) -amino, N-mono-C (3-8) -cycloalkylamino, N, N-di-C (3-8) - cycloalkylamino wherein the two N-cycloalkyl groups may be the same or different, NC (3-8) -cycloalkyl-NC (1-7) -alkylamino, N-mono- (C (3-8) -cycloalkyl) C (1-7) -alkyl) -amino, N, N-di- (C (3-8) -cycloalkyl-C (1-7) - 2 DK 16768 in B1-alkyl) -amino, wherein the two N - (cycloalkylalkyl) groups may be the same or different, N- (C (3-8) -cycloalkyl-C (1-7) -alkyl) -NC (1-7) -alkylamino, NC (2-5 ) -alkanoylamino or 5 NC (2-5) -alkanoyl-NC (1-7) -alkylamino, in free form or in salt form, provided that R2 in a compound of formula (I) in free form, wherein R 1 is N, N-di-C (1-6) alkylamino, wherein the two NC (1-6) alkyl groups are the same or different, N-mono-C (1-6) -alkyl -amino or amino, is different from hydrogen and from C 1 -C 6 alkyl when Ph means phenyl which is monosubstituted by halogen with a atomic numbers up to and including 35 or with trifluoromethyl, and a compound of formula (I) in free form, wherein either Ph is o-fluorophenyl, R 1 is N-monomethyl or amino, and R 2 is hydrogen or methyl, or wherein Ph is o-fluorophenyl, o-chlorophenyl or m-trifluoromethyl-phenyl, N, N-dimethyl and R 2 are hydrogen, or wherein Ph is m-fluorophenyl, p-fluorophenyl, o-chlorophenyl, o trifluoromethylphenyl, m-trifluoromethylphenyl or p-trifluoromethylphenyl, R 1 is N-monomethyl thylamino and R 2 is hydrogen.

From Liebig's Ann. Chem. (1984), 1848, the compound is known 7-amino-3- (4-chlorobenzyl) -5-methyl-3H-1,2,3-triazolo [4,5-d] pyrimidine, but a pharmacological activity of however, this connection is not discussed. Due to the above premise, this compound is excluded from the scope of the present invention, and the same applies to a variety of 3H-1,2,3-triazolo [4,5-d] pyrimidines described in DE No. 2714254-A and having anti-psoriasis activity.

The phenyl group Ph may contain at most 3, preferably 1 or 2, of said substituents, where the substituents in the case of more than one substituent may be the same or different. The substituents are preferably bound in the ortho position or otherwise in the meta-position, but may also be bound in the para position. Examples include: o- and m- and p-halo-phenyl, 2,6-5 dihalo-phenyl, 2,3- and 2,5-dihalo-phenyl and 2,3,6- and 2,5,6-trihalo-phenyl, oC (1-7) -alkyl-phenyl, m- and p -C (1-7) -alkylphenyl, m-trifluoromethyl-phenyl, and o- and p-trifluoromethyl-phenyl, o- and m-cyano-phenyl, and p-cyanophenyl.

For example, the phenyl group Ph may contain at most 3, preferably 1 or 2, halogen substituents which are preferably bound in the ortho position or otherwise in the meta position. Examples include o-halo-phenyl and 2,6-dihalo-phenyl, 2,3- and 2,5-di-halo-phenyl, and 2,3,6- and 2,5,6-trihalo-phenyl.

Halogen is halogen with an atomic number of up to and including 35, such as fluorine, chlorine or other bromine.

C (1-7) alkyl is, for example, C (1-4) alkyl such as methyl, ethyl, n-propyl, isopropyl or n-butyl, as well as secondary-butyl, isobutyl or tertiary butyl, but can also be a C (5-7) alkyl group, i.e. a pentyl, hexyl or heptyl group.

N-Mono-C (1-7) alkylamino is especially N-C (1-4) alkyl amino such as N-methyl or N-ethylamino.

In particular, N, N-Di-C (1-7) alkylamino are N, N-di-C (1-4) alkylamino, wherein the two N-alkyl groups may be the same or different, such as N, N-dimethyl, Ν, Ν-diethyl, NN-diisopropyl or N-butyl-N-methylamino.

N- (C (1-7) -alkoxy-C (1-7) -alkyl) amino is, for example, N-30 (C (1-4) -alkoxy), such as methoxy or ethoxy, C (1-7) ) -alkyl) - especially N- (C (1-4) -alkoxy- such as methoxy or ethoxy-, C (1-4) -alkyl) amino, such as N- (methoxy-methyl) -4 UK / 031b1 amino or N- (1-methoxyethyl) amino.

N- (Hydroxy-C (1-7) -alkyl) amino is especially N- (hydroxy-C (1-4) -alkyl) amino, such as N- (hydroxymethyl) amino or N- (1-hydroxyethyl) amino .

N- (Hydroxy-C (1-7) alkyl) -NC (1-7) alkylamino is especially N- (hydroxy-C (1-4) alkyl) -NC (1-4) alkyl -amino, such as N- (1-hydroxyethyl) -N-methyl-amino or N- (hydroxymethyl) -N-ethyl-amino.

N-C (3-8) -Cycloalkylamino is especially N-C (3-6) -cycloalkylamino, such as N-cyclopropyl or N-cyclohexylamino.

N, N-Di-C (3-8) -cycloalkylamino is especially N, N-di-C (3-6) -cycloalkylamino, wherein the two N-cycloalkyl groups may be the same or different, such as Ν, Ν- dicyclohexyl or N-cyclohexyl-N-cyclopropylamino.

NC (3-8) -Cycloalkyl-NC (1-7) -alkyl-amino is especially NC (3-6) -cycloalkyl-NC (1-4) -alkyl-amino, such as N-cyclopropyl-N-methyl-amino. or N-cyclohexyl-N-ethylamino.

N- (C (3-8) -Cycloalkyl-C (1-7) -alkyl) amino is especially N- (C (3-6) -20-cycloalkyl-C (1-4) -alkyl) amino, such as N - (cyclopropylmethyl) amino or N- (1-cyclohexylethyl) amino. In particular, N, N-Di- (C (3-8) -cycloalkyl-C (1-7) -alkyl) amino is N, N-di (C (3-6) -cycloalkyl-C (1-4)) -alkyl) amino, wherein the two N- (cycloalkylalkyl) groups may be the same or different, such as N, N-di (cyclopropylmethyl) amino or N- (cyclopropylmethyl) -N- (1-cyclohexylethyl) amino .

N- (C (3-8) -Cycloalkyl-C (1-7) -alkyl) -NC (1-7) -alkylamino is especially NC (3-6) -cycloalkyl-C (1-4) - alkyl) -NC (1-4) alkylamino, such as N- (cyclopropylmethyl) -N-ethylamino or N- (1-cyclohexylethyl) -N-methylamino.

DK-167681 B1 C (2-5) -Alkanoyl is e.g. acetyl, propionyl, butyryl, iso-butyryl or pivaloyl.

N-C (2-5) -alkanoylamino is, for example, N-acetyl, N-propionyl, N-butyryl or N-pivaloylamino.

NC (2-5) -alkanoyl-NC (1-7) alkylamino is especially NC (2-5) -alkanoyl-NC (1-4) -alkylamino such as, N-acetyl-N-propyl -amino or N-butyryl-N-methylamino.

The compounds of formula (I) can form salts over their 10 basic centers. Salts of the compounds of formula (I) are, therefore, particularly similar acid addition salts, preferably pharmaceutically acceptable acid addition salts. These are formed, for example, with strong inorganic protonic acids, such as mineral acids, e.g. sulfuric acid, a phosphoric acid or a hydrogen halide acid, with strong organic carboxylic acids, such as alkanecarboxylic acids, e.g. acetic acid, such as optionally unsaturated dicarboxylic acids, e.g. malonic, maleic or fumaric acid, or such as hydroxycarboxylic acids, e.g. tartaric or citric acid, or with sulfonic acids such as alkane or optionally substituted benzenesulfonic acids, e.g. methane or p-toluenesulfonic acid.

The invention further encompasses pharmaceutically unacceptable salts, as these can be used, for example, for the isolation or purification of free compounds of formula (I) as well as their pharmaceutically acceptable salts.

The novel compounds of formula (I) and their pharmaceutically acceptable salts have valuable pharmacological properties, in particular a pronounced anticonvulsant effect, which can be detected, for example, in mice by a pronounced metrazole antagonism in a dose range of from ca. 10 mg / kg p.o. and in mice and rats by means of a pronounced protective effect against convulsions triggered by electrocution, in the dose range of ca. 3 mg / kg p.o.

UK lb / b »T bl 6

Therefore, the compounds of formula (I) and their pharmaceutically acceptable salts are particularly suitable for the treatment of convulsions of various kinds, e.g. for the treatment of epilepsy. Accordingly, they can be used as anticonvulsant, for example, antiepileptic, active drug substances.

Accordingly, the present invention further relates to the compounds of formula (I) or a pharmaceutically useful salt thereof for use in a method of prophylactic and / or therapeutic treatment of the animal or human body, especially for use as an anticonvulsant active agent, and for preparation of a pharmaceutical composition, preferably an anticonvulsant active composition.

The invention also relates to a pharmaceutical composition which is characterized in that it contains as an active substance a compound of formula (I) or a pharmaceutically useful salt thereof, in particular an anticonvulsant active substance, optionally together with conventional pharmaceutical excipients, and a process for preparing such a pharmaceutical composition by processing a compound of formula (I) or a pharmaceutically useful salt thereof, optionally by admixture of conventional pharmaceutical auxiliaries, to pharmaceutical compositions. '

The invention relates in particular to compounds of formula (I) wherein, taking into account the above condition, Ph means one having at least one halogen atom having an atomic number up to and including 35 substituted phenyl group, in free or salt form, and a compound having formula (I) in free form wherein either

Ph is o-fluorophenyl, is N-monomethylamino or amino, and R 2 is hydrogen or methyl, or wherein Ph is o-fluorophenyl, R 1 is N, N-dimethyl amino, and R 9 is hydrogen.

DK 167681 B1 7

The invention particularly relates to compounds of formula (I) wherein, taking into account the above-mentioned condition, Ph means 2-, 3- or 4-halo-phenyl, 2,3-, 2,5- or 2,6-dihalo-phenyl, 2 -, 3- or 4-O (1-4) - alkylphenyl, 2-, 3- or 4-trifluoromethylphenyl or 2-, 3- or 4-cyanophenyl, wherein in each case halogen has an atomic number up to and with 35, R 1 means amino, N-mono-C (1-4) -alkyl-amino, N, N-di-C (1-4) -alkyl-amino, NC (3-6) -cycloalkyl-amino or NC (2-5) -alkanoyl-amino, and R 2 is hydrogen, C (1-4) -alkyl, amino, N-mono-C (1-4) -alkyl-amino, N, N-di-C (1-4) -alkylamino, N-C (3-6) -cycloalkylamino or NC (2-5) -alkanoylamino, in free or salt form, and a compound of formula (I) in free form in which either

Ph is o-fluorophenyl, R 1 is N-monomethylamino or amino, and R 2 is hydrogen or methyl, or wherein Ph is o-fluorophenyl, o-chlorophenyl or m-trifluoromethyl-phenyl, R 2 is N, N-dime thyl amino, and R 2 is hydrogen, or 20 wherein

Ph is m-fluorophenyl, p-fluorophenyl, o-chlorophenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl or p-trifluoromethylphenyl, R 2 is N-monomethylamino and R 2 is hydrogen.

The invention relates in particular to compounds of formula (I) wherein, taking into account the above-mentioned condition, Ph means 2-halogenophenyl, which at the 3-, 5- or 6-position can be further substituted by halogen wherein halogen in each case has an atomic number up to and including 35, in free or salt form, and a compound of formula (I) in free form wherein either Ph is o-fluorophenyl, R 1 is N-monomethylamino or amino, and R 2 is hydrogen or methyl, or wherein Ph is o-fluorophenyl, R 1 is N, N-dime thyl amino, and R 9 is hydrogen.

UK lb / top l p 8

The invention particularly relates to compounds of formula (I) wherein, taking into account the above-mentioned condition, Ph means 2- or 3-fluorophenyl, 2-chloro-phenyl, 2,6-difluorophenyl or 2-C (1- 4) -alkylphenyl, means N-mono-C (1-4) -alkylamino, N, N-di-C (1-4) -alkylamino or NC (3-6) -cycloalkylamino, and R 2 represents hydrogen, C ( 1-4) -alkyl or amino, in free form or in salt form and a compound of formula (I) wherein either Ph is o-fluorophenyl, R 1 is N-monomethylamino or amino, and R 2 is hydrogen or methyl, or wherein Ph is o-fluorophenyl or o-chlorophenyl, R 1 is N, N-dimethylamino, and R 2 is hydrogen, or wherein

Ph is m-fluorophenyl or o-chlorophenyl, R 1 is N-monomethylamino, and R 2 is hydrogen.

The invention relates in particular to compounds of formula (I) wherein, taking into account the above-mentioned condition, Ph means 2-fluorophenyl, which at the 5- or 6-position can be substituted by halogen with an atomic number up to and including 35 R 1 is amino, N-mono-C (1-4) alkylamino, N, N-di-C (1-4) alkylamino or NC (3-6) -cycloalkylamino, and R 2 is hydrogen, C (1-4) -alkyl or amino, in free or salt form and a compound of formula (I) in free form wherein either Ph is of luorphenyl, R 1 is N-monomethyl amino or amino, and R 9 is hydrogen or methyl , or wherein '

Ph is o-f luorphenyl, R 1 is N, N-dimethyl amino, and R 9 is hydrogen.

The invention particularly relates to compounds of formula 30 (I) wherein, taking into account the above stated for release, Ph means 2-fluoro- or 2,6-difluorophenyl, R 1 is amino, N-mono-C (1-4) -alkylamino or N, N-di-C (1-4) -alkylamino, and R 2 is hydrogen or C (1-4) -alkyl, in free or salt form, and a compound of formula (I) in free form in which either

Ph is o-fluorophenyl, R 1 is N-monomethyl amino or amino, and R 2 is hydrogen or methyl, or wherein

Ph is o-fluoro phenyl, N, N-dimethylamino and R 2 are hydrogen.

The invention relates primarily to compounds of formula (I) wherein, taking into account the above condition, Ph is 2-fluorophenyl, R 1 is N-mono-C (1-4) alkylamino or N, N-di C (1-4) alkylamino, and R 2 represents hydrogen or amino, in free form or in salt form 10, and a compound of formula (I) in free form wherein either Ph is o-fluorophenyl, R 1 is N-monomethyl thamino or amino, and R 2 is hydrogen or methyl or wherein Ph is o-fluorophenyl, R 1 is Ν, Ν-dime thyl amino, and R 2 is hydrogen.

In particular, the invention relates to the novel compounds mentioned in the Examples with form (I) and salts thereof.

The present invention also relates to a process for the preparation of compounds of formula (I) or a salt thereof, which is based on methods known in the art and characterized by a) in a compound having the formula y (id, ζζ S / No CH2-Ph wherein Zi means a nucleofuge cleavage group X ±, and z2 means a nucleofug cleavage group X2 or a group R2, or wherein Zi means a group R 1 and Z2 means a nucleofug cleavage group X2, or in a tautomer and / or a salt thereof, Χχ converts to R 1 by reaction with a compound of formula DK 167681 B1 10 H-% (IIb) while decomposing a compound X 1 -H and / or converts X 2 to R 2 by reaction with a compound of formula 5 H-R2 (Hg) while cleavage of a compound X2-H, or b) from a compound of the formula in Ν '* z \ f V * \. (ΠΙ),

r'YY

H CH; -Ph wherein Y is hydroxy, mercapto or optionally aliphatic-substituted amino, or from a tautomer and / or a salt thereof eliminates the compound YH, or c) cyclizes a salt of the formula / W θ (V), • v * —Ml

Ra V

wherein A is the anion of a protonic acid, or d) converts a compound of formula ✓v \? ? > (VI) ni S / jj or a salt thereof having a compound of formula X X -CH₂-Ph (VII), wherein X X is a nucleofug leaving group and, if desired, optionally separating according to the process, isomer blending is formed in the constituents and isolates the isomer of formula (I), and f) if desired converts a compound of formula (I) or otherwise formed into another compound of formula (I), and g) if desired converts a free compound formed of the formula (I) into a salt or converts a salt formed according to the process of a compound of formula (X) to the free compound of formula (I) or to another salt of the compound having formulas (I) and h), if desired, separate an optionally formed stereoisomer mixture into stereoisomers and isolate the desired stereoisomer.

A particular embodiment of the process for the preparation of compounds of formula (I) wherein amino or a salt thereof is characterized in that a) cyclises a compound of formula

v A

a 20> v / n Vph wherein one of the groups Ya and means cyano and the other means hydrogen, or a tautomer and / or a salt thereof, and b) if desired, optionally separates according to the method formed isomeric blend into the constituents and isolates the isomer of formula (I), and c) if desired, transforms a compound of formula (I) formed into another compound of formula (1) and, if desired, converts a compound of formula (I) free compound of formula (I) into a salt or converting a salt formed according to the method of a compound of DK 167681 B1 to the free compound of formula (I) or to another salt of the compound of formula (I) and e) optionally separates a stereoisomer mixture formed in accordance with the method 5 into stereoisomers and isolates the desired stereoisomer.

The reactions described above and the following according to the process as well as the preparation of new starting materials or intermediates are carried out in a manner known per se. Work is carried out in a similar manner to the reaction and formation of known starting materials or intermediates, even when not explicitly mentioned, under the usual reaction conditions, e.g. as required during cooling, at room temperature or under heating, for example, within a temperature range of from approx. -10 to approx. 250 ° C, preferably from ca. 20 to approx. 200 ° C, using the usual adjuvants, such as catalysts, condensation and solvents, in the absence or usually in the presence of a suitable solvent or diluent or a mixture thereof, optionally in a closed container, under inert gas atmosphere and / or under anhydrous conditions.

The starting materials mentioned above and in the formulas (II), (III), (IV), (V), (VI) and 25 (VII) used in the preparation of the compounds of formula I and salts thereof, are either known or may be manufactured in a manner known per se. Starting materials with basic centers may also be in the form of salts, such as acid addition salts, for example, with the acids listed above.

Salts of the compounds of formula (II), (III) or (IV) or, optionally, their tautomers are especially acid addition salts, preferably with strong inorganic or organic acids, e.g. corresponding to the species mentioned above for acid addition salts of the compounds of formula (I).

DK 167681 B1 13

For example, tautomers of the starting compounds of formula (II) or salts thereof used may occur when the groups af and / or Z2 in the compounds of formula II or salts thereof are hydroxy or mercapto and / or one of the groups Ζχ and Z2 optionally monosubstituted amino. Accordingly, the compounds of formula II or salts thereof, e.g. with enol, enthiol and / or enamine moieties also in protomeric form, i.e. as corresponding oxo, thioxo and / or imino automators and / or be in dynamic balance with these.

Nucleofuge cleavage groups X 1 or X 2 in the compounds of formula II are, for example, optionally etherified or esterified hydroxy or mercapto groups, sulfinyl and sulfonyl groups, and sulfonium groups. Ethereal hydroxy is, for example, lower alkoxy such as methoxy, or optionally substituted phenyllavaloxy such as optionally substituted benzyloxy. In particular, esterified hydroxy is esterified hydroxy esterified with an organic sulfonic acid, primarily halogen such as chlorine, bromine or iodine, sulfonyloxy such as optionally halogen substituted lower alkanesulfonyloxy, e.g. methane or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy, e.g.

Cyclohexane sulfonyloxy, or optionally with lower alkyl or halogen substituted benzenesulfonyloxy, e.g. benzene, p-bromophenyl or p-toluenesulfonyloxy, and lower alkanoyl-oxy, e.g. acetoxy. Ethernet mercapto is e.g. lower alkylthio, such as methylthio, optionally substituted arylthio, such as optionally substituted phenyl or naphthylthio, for example phenyl, p-tolyl or naphthylthio, or optionally substituted aryl avalkylthio, such as optionally substituted benzyl or naphthylmethyl, for example. benzyl, p-bromobenzyl or naphthylmethylthio. For example, esterified mercapto groups are low alkanoylthio groups such as acetylthio. Sulfinyl groups are, for example, lower alkanesulfinyl groups such as methane sulfinyl, optionally substituted arylsulfinyl groups, such as optionally substituted benzene or naphthylsulfinyl, for example p-toluene or naphthylsulfinyl, or optionally substituted benzylsulfonyl or benzylsulfinyl Sulfonyl groups are, for example, lower alkanesulfonyl groups such as methanesulfonyl, optionally substituted arylsulfonyl groups, such as optionally substituted benzene or naphthylsulfonyl, for example benzene or naphthylsulfonyl, or optionally substituted benzylsulfonyl, such as benzylsulfonyl Sulfonium groups are, for example, dilavalkyl sulfonium groups such as dimethylsulfonium.

The conversion of Χχ and / or Xg into the compounds of formula 15 II, their tautomers and their salts to the groups and / or R 2 is accomplished by reaction with compounds of the formula HR 2 (lib) and / or H-R 2 (II j) or a salt thereof during cleavage of the compounds X 1 -H and / or X 2 -H.

The reaction of the compounds of formula II, their 20 tautomers and their salts with the compounds of formula IIb. and / or formula IIj or their salts are carried out in a known manner, for example, under cooling, at room temperature or under heating, e.g. within the temperature range of approx. -20 to approx. 250 ° C, preferably from ca. -10 to 25 approx. 200 ° C, optionally in the presence of an inert solvent or diluent or a mixture thereof, optionally in the presence of a water-binding agent, optionally in the presence of a basic agent and / or under inert gas such as nitrogen.

As inert solvents or diluents may be mentioned, for example, water, cyclic ethers, aromatic hydrocarbons, N, N-dilavalkylavalkanoic acid amides, phosphoric acidavalkylamides, dilavalkylsulfoxides, cyclic amines and especially, optionally in the form of mixtures with water, low alkanol, such as tetrahydrofuran, , Toluene, xylene, N, N-dimethylformamide, hexamethylphosphoric acid triamide, dimethylsulfoxide, N-methylmorpholine, and especially, optionally in the form of mixtures with water, methanol and ethanol. Likewise, for the preparation of compounds of formula I wherein at least one of the groups R 1 and R 2 is one as substituted amino group, or of their salts, similar amines Η-R 1 (Ilb, R 1 = as substituted amino) and / or H-R 2 (H 2, R 2 -10 as substituted amino), which at the reaction temperatures can be handled in liquid form, in excess and as a solvent and diluent and / or co-solvent, optionally also in dissolved form, e.g. as aqueous solution.

Water binding agents are e.g. phosphorus oxides such as phosphorus pentoxide, alkali metal or alkaline earth metals such as sodium or calcium sulfate, alkaline earth metal halides such as calcium chloride, or carbodiimides such as N, N'-dicyclohexylcarbodiimide.

Basic agents are, for example, alkali metal or alkaline earth metal hydroxides, hydrides, amides, -lavalkanol atoms, carbonates, -dilavalkylamides or -lavalkyl-silylamides, lower alkylamines, optionally N-lower alkylated cycloalkylamines, basic heterocyclic compounds, amines. For example, sodium hydroxide, hydride, amide, methanolate, potassium tert-butanolate, carbonate, lithium diisopropylamide, potassium bis (trimethylsilyl) amide, calcium hydride, triethylamine, cyclohexylamine, N-cyclohexyl-N, N-dimethyl amine, pyridine, benzyl trimethyl ammonium hydroxide and 1,5-diaza-bicyclo [5.4.0] undec-5-ene (DBU). Instead of an additional basic agent, in the preparation of compounds of formula I wherein at least one of the groups and R 2 is one as substituted amino group, or of their salts, corresponding amines HR 2 (Ilb, R indicated substituted amino) and / or H-R2 (IIj, R2 * as indicated substituted amino), which is advantageously used in excess.

16 UK lb / b »T ΒΊ In a preferred embodiment of process a) a compound of formula I 1 '> (Ha) is reacted;

R 2 is R 2 -Ph where Χχ is a nucleofug leaving group, preferably hydroxy or halogen, such as chlorine or bromine, or a tautomer, e.g. a corresponding 6H-7-oxo compound, 10 and / or salt thereof with ammonia or an amine of the formula H-Rx (Ilb) or a salt thereof while decomposing a compound Χχ-Η.

The conversion of Χχ into the compounds of formula IIa, their tautomers and their salts into a group Rx (cleavage 15 of Χχ-Η) is carried out in a known manner, for example at room temperature or under heating, e.g. within the temperature range from approx. 20 to approx. 250 ° C, preferably from ca. 20 to approx. 200 ° C, optionally in the presence of an inert solvent or diluent, e.g. of the aforementioned species, or an inhalation thereof, optionally in the presence of a basic agent, for example of the above-mentioned species, optionally in the presence of a water-binding agent, e.g. of the aforementioned kind, and / or under inert gas such as nitrogen.

In a further preferred embodiment of process a) for the preparation of compounds of formula I wherein R 2 is different from hydrogen or of their salts, a compound of formula DK 167681 B1 17 (XX) is reacted (Ile), χζ V 'γ CH 2 - Ph wherein X 2 is a nucleofugue leaving group, preferably hydroxy or halogen such as chlorine or bromine, or a tautomer and / or a salt thereof having a compound of formula H-R2 (IIj, R2 * hydrogen), or a salt thereof while decomposing a compound of formula X2-H.

The conversion of X2 into compounds of formula Ile, their tautomers and their salts into a hydrogen-different group R2 (decomposition of X2-H) is carried out in known manner, e.g. as mentioned above for converting compounds of formula Ila, their tautomers and their salts into compounds of formula I or their salts.

In a further preferred embodiment of process a) for the preparation of compounds of formula I wherein R 2 is hydrogen or of their salts, a compound of formula Ile wherein X 2 is a nucleofuge leaving group, preferably halogen such as chlorine or bromine, is reduced. , or a tautomer and / or a salt thereof.

»20 As a reducing agent, for example, Raney nickel or hydrogen can be used. The reduction with Raney nickel is carried out in a known manner, e.g. by reacting a solution of the metal in a low alkanol, such as methanol, under heating, for example, within the temperature range of 25, from approx. 20 to approx. 140 ° C, preferably from ca. 50 to approx. 100 ° C. The reduction with hydrogen is advantageously carried out in the presence of a hydrogenation catalyst. As such, e.g. an element of VIII. side group in the periodic table or a derivative thereof, such as palladium, platinum, platinum oxide, ruthenium, rhodium, a tris (tri-phenylphosphine) -rhodium (I) halide, e.g. chloride, or Raney nickel, where the catalyst may optionally be supported on a support material such as activated carbon, alkali metal carbonate or sulfate or a silica gel. The catalytic hydrogenation is preferably carried out in a polar solvent or diluent, especially in a low alkanol such as methanol, or in a strong inorganic acid such as hydrogen halide acid, e.g. hydrochloric acid, or 10 strong organic carboxylic acid, especially aqueous acetic acid or glacial acetic acid. Work is done during cooling or heating, preferably within a temperature range of from approx. -10 to approx. 120 ° C, especially from approx. 0 to approx. 100eC, especially with advantage of room temperature.

In a further preferred embodiment of method a), from a compound of formula ί S> (Fire),

x <V Y

CH2-Ph wherein Χχ and X2 are a nucleofuge leaving group of the kind described above, preferably hydroxy or halogen, such as chlorine or bromine, or from a tautomer and / or salt thereof, substitute the group Χχ with a group Rx and the group respectively X2 with a group R2. Thus, e.g. preferably a compound of formula Ild or a tautomer and / or a salt thereof is first reacted with ammonia or an amine of formula HR 2 (IIb) or a salt thereof under decomposition of a compound of formula Χχ-Η, and the intermediate formed The ile or a tautomer and / or a salt thereof is then converted by reaction with ammonia or an amine of the formula H-R2 (III, R 2 = free or as substituted amino) or a salt thereof under decomposition of a compound of the formula X H or by reduction, for example by the action of Raney nickel or by catalytic hydrogenation of the kind described above, to a compound of formula I wherein R 2 is free or as substituted amino or hydrogen as above, or a salt thereof.

The conversion of X 1 and X 2 into compounds of formula Ild, their tautomers and their salts into R 1 and R 2, respectively, is carried out in known manner, for example, as described above for the corresponding conversions of compounds 10 of formula X 1a and formula Ile, their tautomers and their salts. for compounds of formula I or their salts, wherein the intermediate of formula Ile first formed from formula Ile may not be isolated, but advantageously is reacted in situ without further purification to a compound of formula I and its salt, respectively.

The compounds of formula IIb and of formula IIj and their salts are known. The compounds of formula Ila, of formula Ile and of formula Ild, wherein Χχ and / or X 2 are halogen, their tautomers and their salts, can be prepared according to known methods, for example by reacting a compound of formula y. y ..

\ / V \ 1> · <Πβ), * —fy Y3 Yk CH2-Ph wherein either Y 'and Y' together are optionally functionally converted οχο X3, Υχ means hydrogen, and either Y2 is R2, 25 and Y3 and Y4 together is a further bond, or Y2 and Y3 together are optionally transformed οχο X3 and Y4 are hydrogen, or wherein Y "is Rj, Y 'and Y4 together are an additional bond, Y2 and Y3 together are optionally converted οχο X3, and Y 4 is hydrogen, 30 or a tautomer and / or a salt thereof with a halogenation agent Ib and bbl B1 agent and optionally carried out in the usual manner by reacting a formed compound of formula IIa,

Ile or Ild, wherein and X 2 is halogen, or a tautomer and / or a salt thereof having a compound of formula X 1 -H and / or X 2 -H wherein X 2 and X 2 are each of the The above described nucleofuge cleavage groups which are different from halogen.

Optionally functionally converted oxo X3 in compounds of formula Ile, their tautomers and their salts are, for example, thioxo or optionally substituted imino, but preferably oxo. Optionally substituted imino is, for example, a group = N-R 'wherein R 1 has the same meaning as in the sub-structure -NHR 1, which is a group R 1 and / or R 2, such as imino, N-lower alkylimino, N-cycloalkylimino or N- lavalkanoylimino.

For salts and / or tautomers of compounds of formula Ile, by analogy with the above, apply to salts and / or tautomers of compounds of formula II.

Thus, for example, corresponding keto / enol, thioketo / enthiol and / or imine / enamine tautomerics are possible.

Halogenating agents are, for example, halides of phosphorus or sulfur, such as phosphorus trihalides, phosphorus pentahalides, phosphorus oxy trihalides, thionyl halides or sulfuryl halides, e.g. phosphorus trichloride, bromide, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride or sulfuryl chloride, but may also be, for example, acid halides, such as acid chlorides, of carbonic acid, for example phosgene.

The reaction of a compound of formula Ile or a tautomer and / or a salt thereof with a halogenating agent is carried out under the usual reaction conditions, for example under heating, e.g. within the temperature range from approx. 20 to approx. 200 ° C, and in an inert solvent such as a haloalkane, e.g. tetrachloromethane, but preferably in the form of a solution or suspension of the compound of formula Ile or a tautomer and / or a salt thereof in excess of the halogenating agent.

Thus, for example, one obtains a compound of formula IIa wherein X 1 is halogen, such as chlorine, or a tautomer and / or salt thereof, by reacting a compound of formula Ile wherein Y 1 and Y 2 together are the group X 3, preferably oxo, Y 1 is hydrogen, Y 2 is the group R 2, and Y 3 and Y 4 together form an additional bond, or of a tautomer and / or a salt thereof with a halogenating agent, for example phosphorus oxychloride, wherein the corresponding compound of formula Ile or a tautomer and / or a salt thereof can be obtained, for example, by reacting a compound of the formula η ** Λ a [i> (iif)

'Η2ι / Y

CH2-Ph or a salt thereof having a compound of formula R2-X20 (equals) wherein X is the functional group of a carboxylic acid or a functional derivative thereof, for example a carboxylic group of the formula -C (= O) -OH or a lower alkoxy carbonyl group of formula -C (= O) -O-Alk wherein Alk is lower alkyl such as methyl, in particular a halocarbonyl group of formula -C (= O) -Hal wherein Hal is halogen, - such as chlorine or bromine, an amide group of formula -C (= O) -Am, wherein Am is optionally substituted amino, for example, amino, N-lower alkylamino such as N-methylamino, or N, N-dilavalkylamino such as Ν, Ν-dimethyl- or Ν , Ν-diisopropyl-amino, or an ortho ester group of formula -C (O-Alk) 3, wherein Alk is lower alkyl such as ethyl, or optionally a salt thereof under normal reaction conditions, for example, in the presence of a condensing agent, such as a basic agent, and / or under heating, e.g. within the temperature range of approx. 20 to approx. 200 ° C.

Compounds of formula Ile wherein X 2 is halogen such as chlorine or their tautomers and / or salts are obtained, for example, by reacting a compound of formula Ile wherein Y 'and Y' together are a group = N-R ', wherein R 'has the same meaning as in the sub-structure -NHR', which means a group Rx, Υχ and Y4 is hydrogen, and Y2 and Y3 together are a group X3, preferably oxo, or a tautomer and / or a salt thereof with a halogenating agent, for example phosphorus oxychloride, wherein the corresponding compound of formula Ile or a tautomer and / or salt thereof is obtained, for example, by reacting a compound of formula

w - \ / K

ji j; n (uh),

Hsi / Nr ch2-pv, which in turn is formed from a compound of formula IIf or a salt thereof by usual reaction with a compound of formula NI ^R '(Hi) or a salt thereof, or of a tautomer and / or a salt thereof with a double acid derivative of carbonic acid, for example urea or phosgene, under normal reaction conditions, for example in the presence of a condensing agent such as a basic agent, and / or under heating, e.g. within the temperature range of approx. 20 to approx. 200 ° C.

Compounds of formula Ild wherein Χχ and X2 are halogen such as chlorine or their salts are obtained, for example, by reacting a compound of formula Ile wherein Y 'and Y "and Y2 and Y3 together are oxo, and Υχ and Y4 is hydrogen, or a tautomer and / or a salt thereof with a halogenating agent, for example phosphorus oxytrichloride, wherein the corresponding compound of formula Ile or a tautomer and / or a salt thereof is formed, for example, by reaction with a compound of the formula Ilf or a salt thereof with a double acid derivative of carbonic acid, for example urea or phosgene, under normal reaction conditions.

In a particularly preferred embodiment, a compound of formula Ile or a tautomer and / or a salt thereof as described above can be converted to a compound of formula Ila, Ile or Ild or a tautomer and / or a salt thereof and then without further purification. or isolation converting the formed intermediate of formula Ila, Ile or Ild in situ to a compound of formula 15I or its salt, whereby preferably it is worked in an aromatic hydrocarbon, e.g. toluene or xylene.

The compounds of formula Ila, Ile and Fire, their tautomers and their salts can also be prepared according to the procedure described below), starting from a corresponding salt of formula \ I M Θ ί ['A0 (Vb) , wherein S 1 is a nucleofug cleavage group X 2 and Z 2 is a nucleofug cleavage group X 2 or a group R 2 or wherein is a group R 2 and Z 2 is a nucleofug cleavage group X 2 and wherein A is the anion of a protonic acid, and cyclize this salt of formula Vb in a similar manner as described under process d).

For the tautomers and / or salts of those used in process b). starting compounds of formula III 30, as mentioned above, apply to tautomers and / or salts of compounds of formula II in a similar manner.

24 UK Ιϋ / bbl bl

Optionally, aliphatic substituted amino Y in compounds of formula III, their tautomers and their salts are also as set forth above for the groups and R 2, but may also be amino which is different therefrom, such as anilino.

The elimination of compound Y-H from compounds of formula III, their tautomers and their salts is carried out in the usual manner, for example in an inert solvent or diluent, for example of the kind mentioned in process a), by heating, e.g. within the temperature range from approx. 40 to approx. 250 ° C, preferably from ca. 80 to approx. 200 ° C, and / or by acid treatment. Suitable acids are, for example, mineral acids, or their anhydrides or acid salts, e.g. hydrogen halide acids, sulfuric acid, alkali metal hydrogen sulfates, phosphoric acid, polyphosphoric acid, phosphorus pentoxide, phosphorus trichloride or phosphorus oxytrichloride, organic sulfonic acids such as p-toluenesulfonic acid, or carboxylic acids or their anhydrides or halides, such as their lower alkanoic acids or their anhydrides, . acetic acid, acetic anhydride or acetyl chloride, as well as buffered acid solutions, e.g. phosphate or acetate buffer, or hydrohalides of nitrogen bases, e.g.

Ammonium or pyridinium chloride.

For example, in a preferred embodiment of process b), a compound of formula III wherein Y is hydroxy, or a tautomer and / or a salt thereof is converted by heating to from 100 to 200 ° C in an inert solvent, e.g. lower alkanoic acid amide, such as formamide or acetamide, in the secretion of an equivalent water to a compound of formula I or a salt thereof.

Due to the ease of access therein to corresponding starting compounds of formula III, process b) is particularly suitable for the preparation of compounds of formula I, wherein DK 167681 B1

R 2 is amino, or salts thereof. Thus, starting compounds of formula III, their tautomers and their salts are obtained according to known methods, and they are preferably prepared in situ e.g. by cyclizing a compound of formula w'y H CH2-Ph wherein either Y5 and Y7 are hydrogen and Yg is a group of formula R2 ~ C (= X3) -NH- (Hib) or Y5 and Yg together represent 10 a further bond, and Y7 means a group of formula R2-C (Y) (NH2) -NH- (IIIc), or of a tautomer and / or a salt thereof, wherein the intermediate formed compound of formula III or a tautomer and / or a salt thereof normally reacts further according to the invention without isolation.

In groups of formula IIIb, X 3 optionally means functionally converted oxo such as oxo, thioxo or optionally substituted imino such as imino, N-lower alkylimino, N-cycloalkylimino or N-lower alkanoylimino, and optionally substituted N-benzoylimino, N lower alkanesulfonylimino or N-arylimino.

For salts and / or tautomers of compounds of formula IIa, similar to the above, applies to salts and / or tautomers of compounds of formula II.

The cyclization of compounds of formula IIa, their tautomers and their salts and optionally the subsequent in situ elimination of Y-H from the formed compounds of formula III or their tautomers or salts is carried out in a known manner, e.g. under neutral, acidic or basic conditions, if necessary in the presence of an acid or υκ ιυ / οΰ i d in a basic agent, in the presence of an inert solvent or diluent, at room temperature or preferably under heating, e.g. within the temperature range of approx. 20 to approx. 250 ° C, and / or under inert gas atmosphere such as nitrogen. For example, as acids, basic agents and inert solvents or diluents, the corresponding agents listed in process a) may be used. As an inert solvent or diluent, a low alkanoic acid amide such as formamide or acetamide can also be used with particular advantage.

For example, in a particularly preferred embodiment, a compound of formula IIa is cyclized wherein Y5 and Y7 are hydrogen and Yg is a group R2-C (= O) -NH- (Hib), or Y5 and Yg together form an additional bond. and Y7 is a group R2-C (OH) (NH2) -NH- (IIIc), or a tautomer and / or a salt thereof at several hours of heating, for example, within the temperature range of from ca. 80 to approx. 200 ° C, in a lower alkanoic acid amide such as formamide or acetamide, whereby, under the reaction conditions, a further reaction of the formed compound of formula III wherein Y is hydroxy or of a tautomer and / or a salt thereof to the desired end product of formula I or a salt thereof. By analogy, 25 similar compounds of formula IIa may be cyclized with groups of formula mb wherein X3 is amino, or with groups of formula IIIc wherein Y is amino, or tautomers and / or salts thereof in an inert solvent such as a haloalkane, for example tetrachloromethane, and further react to compounds of formula I or their salts.

The compounds of formula Illa, their tautomers and their salts are obtained from compounds of formula DK 167681 B1 27 NCS / II / (IIld)

Hz / j atiz-Ph or their salts by reaction with a compound of formula R2 ~ C (= X3) -NH2 (IIle), wherein X3 is optionally converted oxo, for example of the species or salts mentioned in the group of formula Hib thereof, working according to known methods, for example at room temperature or preferably under heating, e.g. within a temperature range of approx. 20 to approx.

10 250 ° C, under neutral, acidic or basic conditions, if necessary in the presence of an acid or a basic agent, for example of the aforementioned kind, in the presence of an inert solvent or diluent, e.g. of the kind mentioned above, and / or under inert gas atmosphere, such as nitrogen.

Also used as an inert solvent or diluent is a lower alkanoic acid amide such as form or acetamide.

In one particularly preferred embodiment, a compound of formula IIld or a salt thereof is reacted with a large excess of a compound of formula IIl (X3 optionally functionally converted oxo, preferably oxo), for example in formamide or acetamide ((X3 = oxo, R2 = hydrogen or methyl), under heating, for example, within a temperature range of from about 80 to about 200 ° C, to a compound of formula IIa or a tautomer and / or a salt thereof, wherein the reaction components of formula II solvents or diluents.

The compounds of formula IIla, their tautomers and their salts are also advantageously prepared in situ and further reacted without isolation to compounds of formula III

28 wolf I / bol b1 or their tautomers and / or their salts, which again, as described above, also normally react further in situ to compounds of formula I or their salts.

Thus, a compound of the formula Uld or a salt thereof can be reacted under heating with a large excess of a compound of the formula IIle (X3 optionally functionally converted oxo, preferably oxo), for example in formamide 10 or acetamide (X3 = oxo, R2 = hydrogen or methyl), in a single-container reaction, first forming a compound of formula IIa or a tautomer and / or a salt thereof, after which the cyclization in maintaining the heat supply in situ evolves to a compound of formula III or a tautomer and / or a salt thereof, again followed by an in situ elimination of a compound YH (Y = hydroxy) to a compound of formula I (R 1 amino, R 2 e.g. hydrogen or methyl) or a salt thereof.

For the tautomers and / or salts of the starting materials of formula IV used in process c), the foregoing applies to tautomers and / or salts of compounds of formula II.

The cyclization of compounds of formula IV, their tautomers and their salts to compounds of formula I wherein R 2 is amino or their salts are carried out under normal cyclization conditions, for example in the same manner as described under process b) for cyclization of compounds of formula IIa to 30 compounds of formula III.

The starting materials of formula IV, their tautomers and their salts can be obtained using known methods, for example by reacting a compound of formula DK 167681 B1 29 i1 h / 1 'y (Iva)

Ha / Y

CH 2 -Ph or of a tautomer and / or a salt thereof having a compound of the formula XC-C = N (iVb), wherein X₂ is a nucleogear cleavage group, for example of the kind described in process a), preferably halogen , such as chlorine or bromine, or freely or as substituted amino indicated for the groups or R 2, thereby working under normal reaction conditions, for example at room temperature or under heating, in an inert solvent or diluent, e.g. of the kind mentioned above, optionally in the presence of a condensing agent, for example a basic agent, e.g. of the above-mentioned kind, and / or under inert gas atmosphere, such as nitrogen.

For the tautomers and / or salts of compounds of formula IVa, the above applies to tautomers and / or salts of compounds of formula II.

In a preferred embodiment, the compounds of formula IV or their tautomers and / or their salts are not isolated, but are generated in situ and cyclized according to the invention to compounds of formula I or their salts without isolation or further purification.

The compounds of formula IVa, their tautomers and their salts can be prepared analogously to known methods, for example by reacting a compound of formula Wld or a salt thereof with ammonia or an amine of formula HR 2 (Hb) or a salt thereof under normal reaction conditions. .

30

UlV Ιϋ / Οΰ I b I

For example, anions A of protonic acids in salts of formula V used as starting materials according to process d) are anions of the above-mentioned acid forming salts of compounds of formula I, especially anions of strong inorganic protonic acids such as anions of mineral acids, e.g. sulfuric acid, of a phosphoric acid or a hydrogen halide acid, or of tetrafluoroboronic acid, or anions of strong organic carboxylic acids such as lower alkane carboxylic acids, e.g. formic or acetic acid, for example, the sulfate, phosphate, chloride, bromide, tetrafluoroborate or acetate ions.

The cyclization of salts of formula V to compounds of formula I or their salts is carried out analogously to known processes under normal reaction conditions, for example in a solvent or diluent, preferably in water, and / or under cooling, at room temperature or under heating, for example before for the temperature range of approx. -20 to approx. 150 ° C, preferably from ca.

20 to approx. 100 ° C.

The starting materials of formula V are known or can be prepared according to known methods, for example by reacting a compound of formula Z Z 2 2 II (Va) R * 2 V Nih CH 2 -Ph 25 or a salt thereof with nitric acid, thereby producing under the normally used reaction conditions, for example in a solvent or diluent, preferably in water, and / or under cooling, at room temperature or under heating, for example within a temperature range of from ca. -20 to approx. 150 ° C. Nitric acid is thus preferably prepared in situ, for example, by reacting an alkali metal nitrite such as sodium nitrite with a strong protonic acid, for example a hydrogen halide acid such as hydrochloric acid, or a low alkane carboxylic acid such as formic acid or glacial acetic acid.

In a particularly preferred embodiment of process d), the compounds of formula Va or their salts as mentioned above are reacted with, for example, in situ, nitric acid, and the previously formed salts of formula V are then cyclized in situ according to the invention without isolation and / or further purification to the desired compounds of formula I or their salts.

The compounds of formula Va or their salts are known or can be prepared according to known methods.

Salts of the starting materials of process VI of formula VI are in particular metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or transition metal salts, e.g. pharmaceutically acceptable transition metal salts, for example zinc or copper salts thereof.

Nucleofuge cleavage groups Xj in compounds of formula VII are, for example, those mentioned under process a).

The reaction of a compound of formula VI with a compound of formula VII is carried out in a known manner, e.g. in the presence of a basic condensing agent or advantageously using the constituents of the compound of formula VI in the form of one of their metal salts, at room temperature or preferably under heating, for example, within a temperature range of from ca. 20 DK 167681 B1 32 to approx. 200 ° C, especially from approx. 50 to approx. 150 ° C, in an inert solvent or diluent, for example as mentioned above, and / or under inert gas atmosphere, such as nitrogen. As basic condensing agents, in particular, basic condensing agents are used which form salt with the ingredients of formula VI, in particular the basic agents mentioned in process a). As mentioned, the conversion of the constituent of formula VI to one of its salts is advantageously carried out in advance, for example by reaction with one of the said basic agents.

The starting materials of formula VI are known or can be prepared according to known processes, for example corresponding to method d) by cyclization of the corresponding salts of formula V, which at the 4-position instead of the group -NH-CH2-Ph has an unsubstituted amino group . The starting materials of formula VII are known or can be prepared according to known methods.

The compounds of formula I provided by the process of the invention or otherwise can be converted to other compounds of formula I by converting one or more variables of general formula I to other variables.

Thus, in compounds of formula I, unsubstituted amino R 1 and / or R 2 can be converted to N-mono- or N, N-dilavalkyl amino, likewise N-monolavalkylamino R 1 and / or R 2 to Ν, Ν-dilavalkylamino, for example by treatment with a reactive ester of a lower alkanol such as a lower alkyl halide, e.g. -bromide or iodide, low alkanesulfonate, e.g. methanesulfonate, an optionally substituted aryl sulfonate such as benzene or p-toluenesulfonate, or a dilavalkyl sulfate, e.g. dimethyl sulfate, preferably under basic conditions such as in the presence of sodium hydride or sodium hydroxide solution or potassium hydroxide solution and advantageously in the presence of a phase transfer catalyst such as tetrabutylammonium bromide or benzyltrimethylammonium chloride. Thereby, only one N-lower alkyl group can be introduced, or in a single reaction step several, especially 2 and at most 4, N-lower alkyl groups can also be introduced. It is also possible in successive reaction steps using suitable low alkyl constituents to introduce various N-lower alkyl groups into unsubstituted amino or N-monolavalkyl-10 amino R 2 and / or R 2. This N-alkylation process gives compounds of formula I in which all N-lower alkyl groups introduced in the same reaction step are the same.

Similarly, an N-lower alkyl group may also be introduced into N- (hydroxylavalkyl) amino, N-mono-cycloalkyl-amino, N-mono (cycloalkylavalkyl) amino, and N-lower alkanoyl-amino R 2 and / or R 2 N- (hydroxylavalkyl) -N-low alkylamino, N-cycloalkyl-N-lowalkylamino, N- (cycloalkylalkyl) -N-lowalkylamino and N-lowalkanoyl-N-lowalkylamino R 2 and / or R 2 .

Likewise, unsubstituted amino R 2 and / or R 2 may also be converted by correspondingly appropriate variation of the alkylation compounds by introducing an N- (lower alkoxylavalkyl) group into N- (lower alkoxyl avalkyl) amino R 2 and / or R 2, by introducing an N - (hydroxylavalkyl) group 25 of N- (hydroxylavalkyl) amino R 1 and / or R 2 / by introducing one or more, especially 2 and at most 4, N-cycloalkyl group (s) into N-mono- or Ν, Ν- dicycloalkylamino R 1 and / or R 2 or by introduction of one or more, in particular 2 and at most 4, N- (cycloalkylalkyl) group (s) into N-mono- or N, N-di-30 (cycloalkylalkyl) amino R 1 and / or R 2, further N-lower alkylamino R 1 and / or R 2, by introducing an N- (hydroxyl avalkyl) group into N- (hydroxyl avalkyl) -N-low alkyl amino R 1 and / or R 2, introducing an N-cyclo -alkyl group in N-cycloalkyl-N-low alkylamino R 1 and / or R 2 or by introduction of an N- (cycloalkylavalkyl) group into N- (cycloalkylavalkyl) -N-low alkyl amino R 1 and / or R 2 167681 B1 34 end further N-monocycloalkylamino R 2 and / or R 2 by introducing an N-cycloalkyl group into Ν, Ν-dicycloalkylamino R 1 and / or R 2 further N-mono (cycloalkylavalkyl) amino R 1 and / or R 2 by introducing an N- ( cycloalkylalkyl) group in N, N-di- (cycloalkylalkyl) amino R 2 and / or R 2.

Furthermore, by N-acylation, unsubstituted amino R 1 and / or R 2 can be converted to N-lower alkanoylamino R 1 and / or R 2, for example, by reaction with a lower alkanoic acid such as formic, acetic or propionic acid, or with a reactive derivative of such an acid, e.g. an acid halide such as acid chloride, ester or especially with an anhydride, e.g. acetyl chloride or acetic anhydride. Likewise, N-lower alkylamino R 1 and / or R 2 can be converted to N-lower alkanoyl-N-low alkyl amino R 2 and / or R 2. Thus, it is again possible to convert only one N-acyl group or, in one reaction step, to N-acylate both amino or N-lower alkylamino R 2 and amino or N-lower alkylamino R 2. Also, in successive reaction steps using 20 suitable acylating agents, it is possible to introduce various N-acyl groups into unsubstituted amino or N-lower alkylamino R 1 and R 2 -X all cases of compounds of formula I wherein all N-acyl groups which are are introduced in the same reaction step, are similar.

Furthermore, N-lower alkanoylamino R 1 and / or R 2 can be converted to unsubstituted amino R 1 and / or R 2, for example by reduction, i.e. by substituting acyl group (n / r) with hydrogen to which the usual reduction systems and reaction conditions are used, e.g. diborane, lithium aluminum hydride in tetrahydrofuran, diethyl ether or dioxane, sodium borohydride / cobalt (II) chloride, sodium borohydride / trifluoroacetic acid or trihalo silanes, e.g. trichlorosilane. Furthermore, N-lower alkanoylamino R 2 and / or R 2 can also be converted to unsubstituted amino R 2 and / or R 2 by hydrolysis, thereby working under the usual reaction conditions, for example, DK 167681 B1 35 in aqueous solution in the presence of a basic agent. , especially e.g. in the presence of an alkali metal hydroxide or low alkanolate such as sodium or potassium hydroxide or sodium methanolate, preferably in an organic solvent or diluent or co-solvent, and / or under heating, preferably within a temperature range of from 20 to approx. 150 ° C, especially from approx. 40 to approx. 100 ° C. Thus, depending on the number of equivalents of the reducing agent or of the basic agent used, it is possible to reduce or hydrolyze one or, if present, both acyl groups to unsubstituted amino or R 2.

The new compounds and their salts can form stereoisomers, for example diastereomers or enantiomers, depending on the number of 15 asymmetric carbon atoms. For example, asymmetric carbon atoms may occur in the compounds of formula I or their salts in corresponding lower alkyl groups r 2 · 20 Formed isomeric and diastereomeric mixtures can be divided according to common physical isolation methods, for example, by distillation, crystallization and / or chromatography, due to the various physical properties of the components. .

Formed enantiomeric mixtures, e.g. racemates can be separated according to known methods in the enantiomers, for example, by recrystallization of an optically active solvent, chromatography on chiral adsorbents, by suitable microorganisms, by cleavage with specific, immobilized enzymes, to form containment compounds, e.g. . using chiral crown ether complexing only one enantiomer, or converting it to diastereomeric salts, e.g. by reacting a basic final racemate with an optically active acid such as carboxylic acid, e.g. tartaric or sulfonic acid, e.g. camphor sulfonic acid, and isolation of the diastereomeric mixture thus formed, e.g. due to varying solubility levels, to diastereomers from which the desired enantiomer can be released by the action of suitable agents. It is advantageous to isolate the most active stereoisomer.

Furthermore, formed free compounds of formula I with basic centers can be converted to acid addition salts in a manner known per se, e.g. by reacting a solution of the free compound in a usable solvent or solvent mixture with one of the aforementioned acids or with a solution thereof or with a useful anion exchanger.

Formed acid addition salts of compounds of formula I can be converted in a manner known per se to the free compounds, e.g. by treatment with a base such as an alkali metal hydroxide, a metal carbonate or hydrogen carbonate, or ammonia, or with a suitable anion exchanger.

Formed acid addition salts of compounds of formula I can be converted into other acid addition salts in a manner known per se, e.g. by treating a salt of an organic acid with a suitable metal salt, such as a sodium, barium or silver salt, of an acid in a suitable solvent, in which an inorganic insoluble salt is formed and thus separates from the reaction mixture.

The novel compounds of formula I and their salts may also be obtained in the form of their hydrates and / or include other solvents used, e.g. optionally for crystallization of substances which are in solid form.

Depending on the process or reaction conditions, the compounds of formula I may be obtained in free form or in the form of their salts.

According to the close relationship between the new compounds of formula I in free form and in the form of their salts, in the foregoing and in the following, free compounds of formula I according to content and purpose may also be understood as corresponding salts or by salts also the corresponding free compounds of formula I.

The invention also relates to the embodiments of the method according to which one of the intermediate compounds is formed at any stage of the process and carries out the remaining steps or uses a starting substance in the form of a salt or in particular forms it under the reaction conditions.

New starting materials specially developed for the preparation of the subject compounds, in particular those starting materials leading to the initially designated compounds of formula I, processes for their preparation and their use as intermediates are also encompassed by the invention.

The invention also relates to the use of the novel compounds of formula I or their pharmaceutically acceptable salts, especially as pharmacological, primarily anti-convulsively active, active substances. They can be used, preferably in the form of pharmaceutical compositions, in a method for the prophylactic and / or therapeutic treatment of animals or humans, especially as anticonvulsants, e.g. for the treatment of convulsions of various kinds, for example for the treatment of epilepsy.

The invention also relates to pharmaceutical compositions containing a compound of formula I or a pharmaceutically useful salt thereof as active ingredient, and to processes for their preparation.

DK 167681 B1 38

The present pharmaceutical compositions are those which contain a therapeutically active amount of the subject active substance, optionally together with other inorganic or organic, solid or liquid, pharmaceutically acceptable excipients and which can be used for enteral, e.g. oral, or parenteral administration to humans and warm-blooded animals. Thus, pharmaceutical preparations in dosage unit forms such as dragees, 10 tablets, capsules or suppositories are preferably used, as well as ampoules containing the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycerol, and / or lubricants, e.g. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. The tablets may optionally contain binders, e.g. magnesium aluminum silicate, starches such as corn, wheat, rice or pile herb starch, gelatin, tragacanth, methyl cellulose, sodium carboxyl methyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or shower mixtures, adsorbents, dyes, flavors and / or sweeteners. Furthermore, the novel compounds of formula I 25 can be used in the form of parenteral administration preparations or as infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, whereby e.g. by lyophilized preparations containing the active substance alone or together with a carrier material, e.g. mannitol, can be prepared before use.

The pharmaceutical compositions may be sterilized and / or contain adjuvants, e.g. preservatives, stabilizers, wetting and / or emulsifying agents, solubility agents, salts for regulating the osmotic pressure and / or buffering agents. The novel pharmaceutical compositions which, if desired, may contain additional pharmacologically active substances are prepared in a manner known per se, e.g. by conventional mixing, granulation, coating, dissolving or lyophilization procedures, and contains from ca. 0.1 to approx. 100%, especially from approx. 1 to approx. 50%, lyophilisate up to 100% 5 of the active substance.

The dosage may depend on various factors, e.g. the mode of application, the person or the nature of the warm-blooded animal, age and / or individual condition. The doses to be administered daily are usually in the case of oral 10 administration of between approx. 1 and approx. 30 mg / kg and for humans or warm-blooded animals weighing from approx. 70 kg, preferably between approx. 0.1 and approx. 3.0 g, whereby several sub-doses can also be administered for administration of a daily dose.

The invention is further illustrated by the following examples.

Example 1

A solution of 9.22 g (35 mmol) of crude 7-chloro-3- (2-fluoro-benzyl) -3H-1,2,3-triazolo [4,5-dipyrimidine in 150 ml of toluene 20 is added dropwise with stirring. to a mixture of 750 ml of ethanol and 200 ml of 40% aqueous methylamine solution. The mixture is allowed to stand for 15 hours at room temperature, after which the solvent is distilled off under reduced pressure. To the residue is added 500 ml of water. The precipitated product is extracted and recrystallized from methanol. There is thus obtained 3- (2-fluorobenzyl) -7- (N-methylamino) -3H-1,2,3-triazolo [4,5-d] pyrimidine, which melts at 180-182 ° C.

7-Chloro-3- (2-fluorobenzyl) -3H-1,2,3-triazolo [4,5-dipyrimidine is obtained, for example, as follows: 70.5 g (0.3 mole) of 5-amino-1 - (2-Fluorobenzyl) -1H-1,2,3-triazole-4-carboxamide and 339 g (300 ml, 7.53 mol) of formamide are heated for 2 hours to low boil. Next, the mixture is cooled to ca. 100 ° C and the reaction solution is poured onto 2 L of ice water. The precipitated product is aspirated and washed with 5 water. After drying at 100 ° C, 3- (2-fluorobenzyl) -3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one is obtained, m.p. 215-218 ° C.

18 g (73.5 mmol) of 3- (2-fluorobenzyl) -3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one and 151 g (90 ml, 0 98 moles of 10 phosphorus oxychloride are heated at reflux for 4 hours and diluted after cooling to room temperature with 1 L of toluene. Activated charcoal is added to the cloudy solution and filtered with "Hyflo" ®. The filtrate is evaporated under reduced pressure to ca. a quarter of its initial volume 15. The crude 7-chloro-3- (2-fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine can be further reacted in the form of the toluene solution without further purification.

Example 2 In a similar manner as described in Example 1, 7-chloro-3- (2-fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine is obtained using dimethylamine, 7 - (N, N-dimethylamino) -3- (2-fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine. After recrystallization from toluene / cyclohexane, it melts at 117-119 ° C.

Example 3 6.9 g (26 mmol) of 3- (2,6-difluorobenzyl) -3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one and 50.5 g Phosphorus oxychloride (30 ml, 327 mmol) is heated at reflux for 1 hour. After cooling to room temperature, the reaction solution is diluted with 300 ml of xylene. Activated charcoal is added to the cloudy solution and filtered with DK 167681 B1 41 "Hyflo" ®. The filtrate is evaporated under reduced pressure at 60 ° C to approx. a quarter of the output volume. This solution of crude 7-chloro-3- (2,6-difluorobenzyl) -3H-1,2,3-5 triazolo [4,5-d] pyrimidine in xylene is poured into a stirred mixture of 400 ml of ethanol and 100 ml. 40% aqueous methylamine solution. After 1 hour, the reaction mixture is evaporated under reduced pressure and the residue is treated with water. The precipitated crude product is extracted and recrystallized from methanol. The resulting 3- (2,6-difluoro-benzyl) -7- (N-methylamino) -3H-1,2,3-triazolo [4,5-d] pyrimidine has a m.p. at 225-227 ° C.

3- (2,6-Difluorobenzyl) -3H, 6H-7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one is obtained, for example, as follows: 7.6 g (30 mmol) -amino-1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide and 84.7 g (75 ml, 1.88 mol) of formamide are heated for 45 minutes under low reflux. After cooling to approx. At 100 ° C, the reaction mixture is poured into 400 ml of ice water and the precipitated product is suctioned off. This is washed 20 with water and dried. The resulting 3- (2,6-difluorobenzyl) -3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one melts at 235-237 ° C.

Example 4 In a similar manner as described in Example 3, 3- (2-fluorobenzyl) -5-methyl-3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidine-7 is obtained from -one, 7-chloro-3- (2-fluorobenzyl) -5-methyl-3H-1,2,3-triazolo [4,5-d] pyrimidine and thereof 3- (2-fluorobenzyl) -5-methyl 7- (N-methylamino) -3H-1,2,3-triazolo [4,5-dipyrimidine, melting at 204-206 ° C (of methanol).

3- (2-Fluorobenzyl) -5-methyl-3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one is obtained e.g. in a similar manner as described in Example 3, by heating for 5 hours g. 5.9 g (25 mmol) of 5-amino-1- (2-fluorobenzyl) -1H-1,2,3-triazole-4-carboxamide. and 59 g (1 mole) of acetamide to 230 ° C. It has a m.p. at 218-220 ° C.

Example 5 5 g (23 mmol) of 5-amino-4-cyano-1- (2-fluorobenzyl) -1H-1,2,3-triazole and 45 g (40 ml, 1 mol) of formamide are heated for 3 hours to 180 ° C. After cooling to room temperature, dilute with 100 ml of water. The precipitated product is aspirated and recrystallized from 75% acetic acid. The resulting 7-amino-3- (2-10 fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine melts at 254-257 ° C.

Example 6 In a similar manner as described in Example 5, reaction of 5-amino-4-cyano-1- (2-fluorobenzyl) -1H-1,2,3-triazole with acetamide 7-amino-3- (2) is obtained. -fluorobenzyl) -5-methyl-3H-1,2,3-triazolo [4,5-d] pyrimidine, which has a m.p. at 242-244 ° C.

Example 7 In a similar manner as described in Examples 1-6, one can further prepare: 7- (N-Acetylamino) -3- (2-fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] -pyrimidine and 7- (N-acetyl-N-methylamino) -3- (2-fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine.

Example 8 In a similar manner as described in Example 3, 3- (2-chlorobenzyl) -3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one, 7- chloro-3- (2-chlorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine and thereof by reaction with methylamine 3- (2-chlorobenzyl) - 7- (N-methylamino) -3H -1,2,3-triazolo [4,5-d] pyrimidine, m.p. 192-194 ° C (of ethanol) or by reaction with DK 167681 B1 43 dimethylamine 3- (2-chlorobenzyl) -7- (N, N-dimethylamino) -3H-1,2,3-triazolo [4,5- d] snip pyrimidine. 131-133 ° C (of acetonitrile).

3- (2-Chlorobenzyl) -3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one is obtained e.g. in the same manner as described in Example 3 by heating 5-amino-1- (2-chlorobenzyl) -1H-1,2,3-triazole-4-carboxamide and formamide [mp: 285-288 ° C (dec. of glacial acetic acid)].

Example 9 In a similar manner as described in Example 3, 3- (2-methylbenzyl) -3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one, 7- chloro-3- (2-methylbenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine and thereof by reaction with methylamine 7- (N-methylamino) -3- (2-methylbenzyl) -3H-1,2,3-triazolo [4,5-d] -pyrimidine, which melts at 193-195 ° C (of methanol).

3- (2-Methylbenzyl) -3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one is obtained in a similar manner as described in Example 3 by heating 5-amino-1- (2-methylbenzyl) -1H-1,2,3-20 triazole-4-carboxamide and formamide [mp: 265-267 ° C (glacial acetic acid)].

Example 10 In a similar manner as described in Example 3, from 3- (3-fluorobenzyl) -3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one, 7- chloro-3- (3-fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine and thereof by reaction with methylamine 3- (3-fluorobenzyl) 7- (N-methylamino) -3H-1 , 2,3-triazolo [4,5-d] pyrimidine, m.p. 187-189 ° C (of toluene).

3- (3-Fluorobenzyl) -3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one is obtained e.g. in a manner similar to that described in Example 3 by heating 5-amino-1- (3-fluorobenzyl) -1H-1,2,3- triazole-4-carboxamide and formamide [mp: 235-237 ° C (of 50% acetic acid)].

Example 11 5 In a similar manner as described in Example 3 is obtained from 3- (4-fluorobenzyl) -3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one, 7- chloro-3- (4-fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine and thereof by reaction with methylamine 3- (4-fluorobenzyl) 7- (N-methylamino) -3H -1,2,3-triazolo [4,5-d] pyrimidine with 10 m.p. 221-223 ° C [of ethyl acetate / ethanol (1: 1)].

3- (4-Fluorobenzyl) -3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one is obtained e.g. in a manner similar to that described in Example 3 by heating 5-amino-1- (4-fluorobenzyl) -1H-1,2,3-triazole-4-carboxamide and formamide [mp: 230-232 ° C (crude 15 cloth)].

Example 12 2.8 g (10 mmol) of 5-amino-7-chloro-3- (2-fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine are dissolved with heating to 40-50 ° C in 150 ml of ethanol, then 10 ml of an aqueous solution of dimethylamine (40%) is added to the 20 solution formed. The reaction mixture is left at room temperature for 2 hours. Next, the precipitated product which is washed with water is suctioned off. After recrystallization from ethanol, 5-amino-7- (N, N-dimethylamino) -3- (2-fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine is obtained, m.p.

165-167 ° C.

For example, 5-amino-7-chloro-3- (2-fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine is obtained as follows: 53 g (323 mmol) of 2-amino 4,6-dichloropyrimidine, 40.4 g (323 mmol) of 2-fluorobenzylamine and 33.4 g (330 mmol) of triethylamine are dissolved in 800 ml of ethanol and the reaction mixture is heated under reflux for 20 hours. After distilling off 400 ml of ethanol, the residue is diluted with 500 ml of water. The precipitated product is aspirated and recrystallized from 1 L of toluene. There is thus obtained 2-amino-4-chloro-6- (2-fluorobenzylamino) pyrimidine, which melts at 130-133 ° C.

A solution of 11.5 g (90 mmol) of 4-chloroaniline in 33 ml of concentrated hydrochloric acid and 80 ml of water is diazotized at 0-5 ° C with a solution of 6.2 g (90 mmol) of sodium nitrite in 30 ml of water. This diazonium salt solution is added dropwise at 14-17 ° C to a mixture of 20.6 g (81.5 mmol) of 2-amino-4-chloro-6- (2-fluorobenzylamino) pyrimidine and 68 g (500 mmol) crystalline sodium acetate in 500 ml of 65% acetic acid. The reaction mixture is stirred for 40 hours at room temperature. The precipitated product is extracted and washed several times with water. Thus, after drying at room temperature, over calcium chloride, 2-amino-4-chloro-6- (o-fluorobenzylamino) -pyrimidine-5-azo- (4'-chlorobenzene) is obtained as 20 yellow crystal powder, m.p. 215-225 ° C (dec.).

59 g (151 mmol) of 2-amino-4-chloro-6- (o-fluorobenzylamino) -pyrimidine-5-azo- (4'-chlorobenzene) are suspended in 3 50% ethanol and 160 ml of acetic acid, and by During 1 hour under argon atmosphere, 70 g of zinc dust is added to the suspension 124 g (1.9 moles) portionwise. Stir for an additional 5 hours at 70 ° C and the excess zinc is filtered off. The filtrate is evaporated in vacuo to half the volume and then made strongly basic by the addition of 240 ml of concentrated sodium hydroxide solution. The product is extracted with ethyl acetate from the mixture. After distilling off the ethyl acetate, the residue is recrystallized first by toluene, then by acetonitrile. There is thus obtained 4-chloro-2,5-diamino-6- (2-fluorobenzylamino) pyrimidine in the form of tan crystals melting at 180-182 ° C.

DK 167681 Pg 46

To a suspension of 16 g (60 mmol) of 4-chloro-2,5-diamino-6- (2-fluorobenzylamino) pyrimidine in 200 ml of 25% acetic acid is added dropwise at 0 ° C with vigorous stirring. 4.5 g (65 mmol) of sodium nitrite in 100 ml of water. The mixture is stirred at room temperature for 2 hours and the product is aspirated. Thus, after recrystallization from ethyl acetate / hexane, 5-amino-7-chloro-3- (2-fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine is obtained, m.p. 149-151 ° C.

Example 13 In a similar manner as described in Example 12, reaction of 5-amino-7-chloro-3- (2-fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine with methylamine is obtained. 5-amino-3- (2-fluorobenzyl) -7- (N-methylamino) -3H-1,2,3-triazolo [4,5-d] pyrimidine, m.p. 252-254 ° C (dioxane / toluene).

Example 14 Similarly, as described in Example 3, is obtained from 3- (3-trifluoromethylbenzyl) -3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one, 7- chloro-3- (3-trifluoromethylbenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine and thereof by reaction with methylamine 7- (N-methylamino) -3- (3-trifluoromethylbenzyl) 3H-1,2,3-triazolo [4,5-d] pyrimidine, m.p. 211-213 ° C (of ethyl acetate) or by reaction with dimethylamine 7- (N, N-dimethylamino) -3- (3-trifluoromethylbenzyl) -3H-1,2,3-triazolo-25 [4,5-d ] pyrimidine, m.p. 100-101 ° C (of methanol).

3- (3-Trifluoromethylbenzyl) -3H, 6H, 7H-1,2,3-triazolo [4,5-d] -pyrimidin-7-one is obtained e.g. in a manner similar to that described in Example 3 by heating 5-amino-1- (3-trifluoromethylbenzyl) -1H-1,2,3-triazole-4-carboxamide and formamide (mp: 202-204 ° C).

DK 167681 B1 47

Example 15

A mixture of 0.82 g (10 mmol) of dimethyl amine hydrochloride, 1.27 g (10 mmol) of N-cyclohexyl-N, N-dimethylamine 5, and 1.42 g (10 mmol) of phosphorus pentoxide is heated. 15 min to 200 ° C and then to the molten mass is added 0.49 g (2 mmol) of 3- (2-fluorobenzyl) -3H, 6H, 7H-1,2,3-triazolo- [4,5-d ] pyrimidin-7-one. The reaction mixture is kept at 200 ° C for 2 hours, then cooled to 100 ° C and treated with 10 25 ml of water. After cooling to room temperature, the precipitated product is aspirated, dissolved in 25 ml of ethyl acetate and the solution is dried over sodium sulfate. The ethyl acetate solution is evaporated, the residue is recrystallized from toluene / cyclohexane to give 7- (N, N-dimethylamino) -3- (2-15 fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine with m.p. 117-119 ° C.

3- (2-Fluorobenzyl) -3H, 6H, 7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one is obtained in a similar manner as described in Example 3 by heating 5-amino-1 - (2-fluorobenzyl) -1H-1,2,3-triazole-4-carboxamide and formamide.

Example 16 In a similar manner as described in Example 12, 1.95 g (6.36 mmol) of 7-chloro-5- (N, N-dimethylamino) -3- (2-fluorobenzyl) -3H-1,2 is dissolved. 3-Triazolo [4,5-d] pyrimidine in 200 ml of warm ethanol, then 7 ml of aqueous dimethylamine solution (40%) is added and the mixture is left for 30 minutes. After dilution with 200 ml of water, the product is suctioned off and it is recrystallized from ethanol. There is thus obtained 5,7-bis- (N, N-dimethylamino) -3- (2-fluorobenzyl) -3H-1,2,3-triazolo-[4,5-dipyrimidine, m.p. 123-125 ° C.

7-Chloro-5- (N, N-dimethylamino) -3- (2-fluorobenzyl) -3H-1,2,3-triazolo [4,5-dipyrimidine may be prepared, for example, as follows: DK 167681 B1 48 As described in Example 12, 13.9 g (110 mmol) of 2-fluorobenzylamine, 21.3 g (110 mmol) of 4,6-dichloro-2- (N, N-dimethylamino) pyrimidine and 11.5 g of 5 are dissolved. (114 mmol) of triethylamine in 300 ml of absolute ethanol and the mixture is heated at reflux for 48 hours. After distilling off the ethanol, water is added to the residue, the product is suctioned off and after recrystallization of cyclohexane 4-chloro-2- (N, N-dimethylamino) -6- (2-fluorobenzyl-10-amino) -pyrimidine, m.p. 71-73 ° C.

In a similar manner as described in Example 12, 16 g (57 mmol) of 4-chloro-2- (N, N-dimethylamino) -6- (2-fluoro-benzylamino) -pyrimidine and 62 mmol of p-chlorophenyldiazonium chloride are obtained. in aqueous acetic acid with 46.5 g (340 mmol) of crystalline sodium acetate 4-chloro-2- (N, N-dimethylamino) -6- (o-fluorobenzylamino) -pyrimidine-5-azo- (4'-chlorobenzene) ) with m.p. 175-176 ° C (dec.).

In a similar manner as described in Example 12, 4-chloro-2- (N, N-dimethylamino) -6- (of fluorobenzylamino) -20-pyrimidine-5-azo- (4T-chlorobenzene) with zinc dust in ethanol / water acetic acid, thus obtaining 5-amino-4-chloro-2- (N, N-dimethylamino) -6- (2-fluorobenzylamino) pyrimidine, m.p.

103-105 ° C (of cyclohexane).

In a similar manner as described in Example 12, 6.8 g (23 mmol) of 5-amino-4-chloro-2- (N, N-dimethylamino) -6- (2-fluorobenzylamino) pyrimidine are obtained in 150 ml 50% acetic acid by reaction with 1.84 g (26.7 mmol) of sodium nitrite 7-chloro-5- (N, N-dimethylamino) -3- (2-fluorobenzyl) -3H-1,2,3-tri -azolo [4,5-d] pyrimidine, m.p. 153-155 ° C (of acetonitrile).

Example 17 In a similar manner as described in Example 16, using aqueous monomethylamine solution (40%) 5- (N, N- dimethylamino) -3- (2-fluorobenzyl) -7- (N-methylamino) -7- 3H-1,2,3-tr ± azolo [4,5-d] pyrimidine, m.p. 199-200 ° C (of ethanol).

Example 18 In a similar manner as described in Examples 1-17, 7- (N-methylamino) -3- (2-trifluoromethylbenzyl) -3H-1,2,3-triazolo [4,5-d ] pyrimidine, 7- (N-methylamino) -3- (4-trifluoromethylbenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine, 3- (2-cyanobenzyl) -7- (N-methylamino) -3H-1,2,3-triazolo [4,5-d] -pyrimidine, 3- (3-cyanobenzyl) -7- (N-methylamino) -3H-1,2,3-triazolo [4,5-d] -pyrimidine and 3- (4-cyanobenzyl) -7- (N-methylamino) -3H-1,2,3-triazolo [4,5-d] -pyrimidine.

Example 19

Tablets containing 50 mg of active substance per day. tablet, e.g. 3- (2-Fluorobenzyl) -7- (N-methylamino) -3H-1,2,3-triazolo [4,5-d] pyrimidine or a pharmaceutically acceptable salt thereof can be prepared as follows:

Composition (for 10000 tablets):

Active substance 500.0 g

Lactose 500.0 g 25 Potato starch 352.0 g

Gelatin 8.0 g

Talc 60.0 g

Magnesium stearate 10.0 g

Silica (high dispersion) 20.0 g Ethanol q.s.

DK 167681 B1 50

The active substance is mixed with lactose and 292 g of potato starch. The mixture is wetted with an alcoholic solution of gelatin and granulated through a sieve. After drying 5, the remainder of the potato starch, talc, magnesium stearate and the high-dispersion silica are mixed therein, and the mixture is compressed into tablets weighing 145.0 mg per day. tablet and an active substance content of 50.0 mg. If desired, the tablets may be provided with splits for finer dosage adjustment.

Example 20

Lacquer tablets containing 200 mg of active substance per day. tablet, e.g. 3-C (2-fluorobenzyl) -7- (N-methylamino) -3H-1,2,3-triazolo [4,5-d] pyrimidine or et. pharmaceutically acceptable salt thereof, may be prepared as follows:

Composition (for 500 tablets):

Active substance 100.00 g

Lactose 100.00 g

Corn starch 70.00 g 20 Talc 8.50 g

Calcium stearate 1.50 g

Hydroxypropyl methyl cellulose 1.18 g

Shellac 0.32 g

Water q.s.

Dichloromethane q.s.

The active substance, the lactose and 40 g of the corn starch are mixed, wetted with a paste made of 15 g of corn starch and water (under heating) and granulated. The granulate is dried, the rest of the corn starch, talc and calcium stearate are added and mixed with the granulate. The mixture is compressed into tablets (weight: 560 mg) and these are lacquered with a solution of hydroxypropylmethyl cellulose and shellac in dichloromethane. Final weight of DK 167681 B1 51 lactate tablet: 563 mg.

Example 21 In a similar manner as described in Examples 19 and 20, pharmaceutical compositions containing another compound of Formula I or a pharmaceutically acceptable salt thereof may also be prepared, for example according to Examples 1-18.

Claims (22)

N- (hydroxy-C (1-7) -alkyl) -amino, N- (hydroxy-C (1-7) -alkyl) -NC (1-7) -alkyl) -amino, N-mono-C (3-8) -cycloalkylamino, N, N-di-C (3-8) -cycloalkylamino, wherein the two N -cycloalkyl groups may be the same or different, NC (3-8) -cycloalkyl-NC (1- 7) -alkyl-amino, N-mono- (C (3-8) -cycloalkyl-DK-167681 B1 C (1-7) -alkyl) -amino, N, N-di- (C (3-8) - cycloalkyl-C (1-7) -alkyl) amino, wherein the two N- (cycloalkylalkyl) groups may be the same or different, N- (C (3-8) -cycloalkyl-C (1-7) -5 alkyl) -NC (1-7) -alkylamino, NC (2-5) -alkanoylamino or NC (2-5) -alkanoyl-NC (1-7) -alkylamino, in free form or in salt form , provided that R 2 in a compound of formula (I) in free form, wherein N, N-di-C (1-6) -alkyl-amino, wherein the two NC (1-6) -10 alkyl groups are the same or different, N-mono-C (1-6) alkyl amino or amino, is different from hydrogen and from C (1-6) alkyl when Ph means phenyl which is monosubstituted by halogen with an atomic number up to and including 35 or with trifluoromethyl, and 15 a compound of formula (I) in free form wherein either Ph is o-fluorophenyl, R 1 is N-monomethylamino or amino, and R 2 is hydrogen or methyl, or wherein Ph is o-fluorophenyl, o-chlorophenyl or m-trifluoromethyl. phenyl, R 1 is Ν, Ν-dimethylamino, and R 2 is hydrogen, or wherein Ph is m-fluorophenyl, p-fluorophenyl, o-chlorophenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl or p-trifluoromethylphenyl, R 1 is N-monomethyl amino and R 2 is hydrogen. A compound according to claim 1, characterized in that, taking into account the condition of claim 1, Ph means one having at least one halogen atom having an atomic number up to and including 35 substituted phenyl group, in free form or in salt form, and a compound having formula (I) in free form wherein either Ph is o-fluorophenyl, R 1 is N-monomethyl amino or amino, and R 2 is hydrogen or methyl or wherein Ph is o-fluorophenyl, R 2 is Ν, Ν-dimethylamino and R 2 is hydrogen. Compound according to claim 1, characterized in that, taking into account the premise stated in claim 1, DK 167681 B1 Ph means 2-, 3- or 4-halogenophenyl, 2,3-, 2,5- or 2,6 -dihalogenphenyl, 2-, 3- or 4-C (1-4) -alkyl-phenyl, 2-, 3- or 4-trifluoromethylphenyl or 2-, 3- or 5-cyanophenyl, wherein halogen in each case has an atomic number up to and including 35 means amino, N-mono-C (1-4) -alkyl-amino, N, N-di-C (1-4) -alkyl-amino, NC (3-6) - cycloalkylamino or NC (2-5) -alkanoylamino, and R 2 is hydrogen, C (1-4) -alkyl, amino, N-mono-C (1-4) -alkyl-amino, N, N -di-C (1-4) -alkylamino, NC (3-6) -cycloalkylamino or NC (2-5) -alkanoylamino, in free form or in salt form and a compound of formula (I) in free form wherein either Ph is o-fluorophenyl, R 2 is N-monomethylamino or amino, and R 2 is hydrogen or methyl, or wherein Ph is o-fluorophenyl, o-chlorophenyl or m-trifluoromethyl-phenyl, R 2 is N , N-dime thyl amino, and R 2 is hydrogen or wherein Ph are m-fluorophenyl, p-fluorophenyl, o-chlorophenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl or p-trifluoromethylphenyl, R 1 is N-monomethyl amino and R 2 is hydrogen. A compound according to claim 3, characterized in that, having regard to the condition of claim 1, Ph means 2-halo phenyl, which in the 3-, 5- or 6-position can be further substituted by halogen, wherein in each case the halogen has an atomic number up to and including 35, in free or salt form, and a compound of formula (I) in free form wherein either Ph is o-fluorophenyl, N-monomethylamino or amino, and R 2 is hydrogen or methyl, or wherein Ph is of luorphenyl, R 1 is N, N-dimethyl amino, and R 2 is hydrogen. A compound according to claim 3, characterized in that, taking into account the condition set forth in claim 1, Ph means 2- or 3-fluorophenyl, 2-chlorophenyl, 2,6-di-fluorophenyl or 2-C ( 1-4) -alkylphenyl, R 1 is N-mono-C (1-4) -alkylamino / N, N-di-C (1-4) -alkylamino or N-C (3-6) -cycloalkylamino, and R 2 means hydrogen, C 1 -C 4 alkyl or amino, in free or salt form, and a compound of formula (I) wherein either Ph is o-fluorophenyl, R 1 is N-monomethylamino or amino, and R 2 is hydrogen or methyl, or wherein Ph is o-fluorophenyl or o-chlorophenyl, R 2 is N, N-dimethylamino, and R 2 is hydrogen, or wherein Ph is m-fluorophenyl or o-chlorophenyl, R monomethylamino and R 2 is hydrogen. A compound according to claim 4, characterized in that, having regard to the condition of claim 1, Ph means 2-fluorophenyl, which at the 5- or 6-position can be substituted by halogen with an atomic number up to and including 35, R 1 is amino, N-mono-C (1-4) -alkylamino, N, N- di-C (1-4) -alkylanu.no or NC (3-6) -cycloalkylamino, and R 2 is hydrogen, C (1-4) -alkyl or amino, in free form or salt form, and a compound of formula ( I) in free form wherein either Ph is o-fluorophenyl, R 1 is N-monomethylamino or amino, and R 2 is hydrogen or methyl, or wherein Ph is o-fluorophenyl, R 1 is N, N-dimethylamino, and R 2 is Hydrogen. Compound according to claim 6, characterized in that, taking into account the condition set out in claim 1, Ph means 2-fluoro- or 2,6-difluorophenyl, R 1 is amino, N-mono-C (1-4) alkylamino or N, N-di-C (1-4) alkylamino, 30 and R2 means hydrogen or C (1-4) alkyl, in free form or in salt form and a compound of formula (I) in free form wherein either Ph is o-fluorophenyl, R 1 is N-monomethylamino or amino, and R 2 is hydrogen or methyl, or wherein Ph is o-fluorophenyl, R 1 is N, N-dimethyl amino, and R 2 is hydrogen. DK 167681 B1 A compound according to claim 6, characterized in that, taking into account the premise set out in claim 1, Ph means 2-fluorophenyl, R 1 is N-mono-C (1-4) alkylamino or N, N -di-C (1-4) alkylamino, and R 2 represents hydrogen or amino, in free form or in salt form, and a compound of formula (I) in free form wherein either Ph is o-fluorophenyl, R monomethylamino or amino and R 2 is hydrogen or methyl or wherein 10 Ph is o-fluorophenyl, R 1 is N, N-dimethyl amino and R 2 is hydrogen. A compound according to claim 1, characterized in that it is 3- (2-fluorobenzyl) -7- (N-methylamino) -3H-1,2,3-triazolo [4,5-d] pyrimidine, 7 - (N, N-dimethylamino) -3- (2-fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine, 3- (2,6-difluorobenzyl) - 7- (N-methylamino) -3H-1,2,3-triazolo [4,5-d] pyrimidine, 3- (2-fluorobenzyl) -5-methyl-7- (N-methylamino) -3H-1 , 2,3-triazolo [4,5-d] pyrimidine, 7-amino-3- (2-fluoro benzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine, 7-amino 3- (2-Fluorobenzyl) -5-methyl-3H-1,2,3-triazolo [4,5-d] pyrimidine, 7- (N-acetylamino) -3- (2-fluorobenzyl) -3H-1 , 2,3-triazolo [4,5-d] -pyrimidine or 7- (N-acetyl-N-methylamino) -3- (2-fluoro-benzyl) -3H-1,2,3-triazolo [ 4,5-d Jpyrimidine or a salt of any of these compounds. A compound according to claim 1, characterized in that it is 3- (2-chlorobenzyl) -7- (N-methylamino) -3H-1,2,3-triazolo [4,5-d] pyrimidine, 3 - (2-Chlorobenzyl) -7- (N, N-dimethylamino) -3H-1,2,3-triazolo [4,5-d] pyrimidine, 7- (N-methylamino) -3- ( 2-methylbenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine, 3- (3-fluorobenzyl) -7- (N-methylamino) -3H-1,2,3-triazolo [ 4,5-d] pyrimidine, 5-amino-7- (N, N-dimethylamino) -3- (2-fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine, 3 - (4-fluorobenzyl) 7- (N-methylamino) -3H-1,2,3-triazolo [4,5-d] -pyrimidine, 5-amino-3- (2-fluorobenzyl) -7- (N -methylamino) -3H-1,2,3-triazolo-35 [4,5-d] pyrimidine, 7- (N-methylamino) -3- (3-trifluoromethylbenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine, 7- (N, N-di-methylamino) -3- (3-trifluoromethylbenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine, 5,7-bis- (N, N-dimethylamino) -3- (2-fluorobenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine, 5- (N, N-di) -5-methylamino) -3- (2-fluorobenzyl) -7- (N-methylamino) -3H-1,2,3-triazolo [4,5-d] pyrimidine, 7- (N-methylamino) no) -3- (2-trifluoromethylbenzyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine, 7- (N-methylamino) -3- (4-trifluoromethylbenzyl) -3H- 1,2,3-tri-azolo [4,5-d] pyrimidine, 3- (2-cyanobenzyl) -7- (N-methylamino) -3H-1,2,3-triazolo [4,5 -d] pyrimidine, 3- (3-cyanobenzyl) -7- (N-methylamino) -3H-1,2,3-triazolo [4,5-d] pyrimidine or 3- (4-cyanobenzyl) -7 - (N-methylamino) -3H-1,2,3-triazolo [4,5-d] pyrimidine or a salt of any of these compounds. A compound according to any one of claims 1-10 or a pharmaceutically useful salt thereof for use in a method of prophylactic and / or therapeutic treatment of the animal or human body. A compound according to any one of claims 2, 4, 6, 7 or 20. or a pharmaceutically useful salt thereof for use in a method of prophylactic and / or therapeutic treatment of the animal or human body. A compound according to any one of claims 1-10 for use as an anticonvulsant active agent. A compound according to any one of claims 2, 4, 6, 7 or 9 for use as an anticonvulsant active agent. Pharmaceutical composition, characterized in that it contains as an active substance a compound according to any one of claims 1-10 or a pharmaceutically usable salt thereof, optionally together with conventional pharmaceutical excipients. Pharmaceutical composition, characterized in that the DK 167681 B1 contains as an active substance a compound according to any one of claims 2, 4, 6, 7 or 9 or a pharmaceutically applicable salt thereof, optionally together with conventional pharmaceutical excipients. Pharmaceutical composition according to claim 15 or 16, characterized in that it contains an anticonvulsant active substance. Process for the preparation of a compound of formula (I) or a salt thereof according to any one of claims 1-10, characterized in that a) in a compound of formula fV \ (II), zi'vV ah -Ph wherein Z 1 represents a nucleofuge cleavage group Χχ and Z2 means a nucleofuge cleavage group X2 or a group R2 or wherein a group Rj and Z2 means a nucleofug cleavage group X2, or in a tautomer and / or a salt thereof converts X ^ to by reaction with a compound of formula H-R 1 (Ilb) while decomposing a compound X 1 -H and / or converting X 2 to R 2 by reaction with a compound of formula H-R 2 (ug) under decomposition of a compound X 2 -H, or 25 b) from a compound of formula DK 167681 B1 ίΐ \ * (III), / γΥ H CH; -Ph wherein Y means hydroxy, mercapto or optionally aliphatic substituted amino, or from a tautomer and / or a salt thereof eliminates the compound YH, or c) cyclizing a salt of formula b ιΛ.-χ ® s A / -fa (v) - «ζ V tH.-Ph wherein A is the anion of a protonic acid, or d) reacting a compound of formula / Λ I > (VI) 10 κζ VY · or a salt thereof having a compound of formula X] -CEtø-Ph (VII), wherein X 1 is a nucleofuge cleavage group and e) optionally separates optionally according to process 15 the way the isomer mixture is formed in the constituents and isolates the isomer of formula (I), and f) if desired converts a compound formed according to the method or otherwise e of formula (I) into another compound of formula (I), and 20 g) if desired, convert a free compound of formula (I) formed into a salt or convert a salt formed according to the process of a compound of formula (I) I) to the free compound of formula (I) or DK 167681 B1 to another salt of the compound of formula (I) and h) optionally separates an optionally formed stereoisomer mixture into stereoisomers and isolates the desired stereoisomer. Process for the preparation of a compound of formula (I) wherein amino means or a salt thereof according to any one of claims 1-6, 8 or 10, characterized in that 10 a) cycles a compound of formula V 'x', (IV) wherein one of the groups Ya and represents cyano and the other means hydrogen, or a tautomer and / or a salt thereof, and b) optionally separates an optionally formed isomeric mixture into the components and isolates the isomer with and (c) if desired, convert a compound of formula (I) formed into another compound of formula (I), and d) if desired convert a free compound of formula (I) formed to a salt or converting a salt formed according to the method of a compound of formula (I) into the free compound of formula (I) or another salt of the compound of formula (I) and e) if desired separates an optionally formed according to the method ers oisomer mixture in stereoisomers and isolates the desired stereoisomer. Process for the preparation of a pharmaceutical composition according to any one of claims 15-17, characterized in that a compound according to one of claims 1-10 DK 167681 B1 or a pharmaceutically useful salt thereof is processed, optionally by admixture of conventional pharmaceutical excipients. , for pharmaceutical preparations. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically useful salt thereof for the preparation of a pharmaceutical composition, preferably an anticonvulsant active composition.