PH26444A - 3H-1,2,3-triazolo [4,5-d] pyrimidines - 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

— —_— - C0 . : Ley yy . i : 3H-1,2,3-TR1AZOLO[4,5-d])pyrimidines .

The invention relates to novel 3H-1,2,3- triazolo[4,5-d)pyrimidine derivatives, espe- cially substituted 3-benzyl-3H-1,2,3-triazolo : (4,5-d)-pyrimidines of the general formula i eee - '

Ss -¥. . Te :

Co » Ce “nn i ' Ss i . - - rR Sr \ © CHp-Ph 15 . . - in which Ph represents a phenyl radical

Te substituted by halogen, lower alkyl, triflou- romethyl and/or by cyano, R, represents a 20 . [ree amino group or an amino group that is substituted aliphatically, cycloaliphatically, cycloaliphatically-aliphaticelly and/or by acyl, and R, represents hydrogen, lower alkyl, a free amino group, or an amino group that is :

Cor rm 2) r , wir) Cy

SN SR gpm ORE substituted aliphatically, cycloatiphatically, cycloaliphatically-aliphatically and/or by acyl, and the salts thereof, to processes ’ for the manufacture of such compounds to phar- maceutical preparations containing them, and to their use as active ingredients in medi- caments.

The phenyl radical Ph may have up to and : including 3, but preferably 1 or’2, of the : So mentioned substituents and where it {is poly- ; substituted the substituents may be the same or different. Each of the substituents is bonded preferably in an ortho-position or, less preferably, in a meta-position, but may also be bonded in a para-position, The fol- lowing may be ment foned as examples: o- and n- and also p~-halophenyl, 2,6~-dihalophenyl, : also 2,3- and 2,5-dihalopheny!l as well as 2,3,6- ‘ 20 and 2,3,6-trihalopheny!l, o-lower alkylphenyl, also m- and p-lower alkylphenyl, m-trifluoro- methylphenyl, also o- and p-trifluoromethylphenyl, and o- and m-cyanophenyl, and also p-cyanophenyl.

FE — . 24

The phenyl radical Ph may have, for example, up to and including 3, preferably 1 or 2 halogen suhstituents, each of which is bonded ’ preferably in an ortho-position or, less prefe- rably, in a meta-position. THe following may be mentioned as examples: o-halophenyl and 2,6-dihalophenyl, and also 2,3-and 2,5-dihalo- phenyl as well as 2,3,6- and 2,9,6-trihalophenyl.

Amino groups R, and R, that are substituted aliphatically, cycloaliphatically, cycloalipha~- tically-aliphatically and/or by acyl are, for example, amino groups monosubstituted by an aliphatic, cycloaliphatic or cycloaliphatic- oC aliphatic radical or ty acyl, or amino groups ’ disubstituted by aliphatic, cycloaliphatic or cycloaliphatic-aliphatic radicals, or by an aliphatic radical as well as a cycloaliphatic : radical or acyl. Suitable aliphatic radicals are, for example: lower alkyl, lover alkoxy- : lower alkyl and hydroxy-lower alkyl; a suitable cycloaliphatic radical is, for example y cycloalkyl; a suitable cycloapiphatic-aliphatic radical is, for example, cycloalkyl-lower alkyl,

Lay yy and a suitable acy! radical is, for example, lower alkanoyl. The following may be mentioned as examples of radicals R, and R,: amino,

N-mono- and N,N-di-lower alkylamino, N-{(lower alkoxy-lower alkyl)amino, N-(hydroxy-lower alkyl) amino, N-(hydroxy-lower alkyl)~N-lower alkyl- amino, N-mono® and N,N-di-cycloalkylamino, -

N-cycloalkyl-N-lower alkylamino, N-mono- and

N,N-di-(cycloalkyl-lower alkyl)amino, N-(cyclo- alkyl-lower alkyl )-N-lower alkylamino, N-lower : alkanoylamino and N-lower alkanoyl-N-lower i alkylamino.

The invention relates, for example, to novel compounds of the general formula I in which Ph represents a phenyl radical that is substituted by at least one halogen atom, R, . represents a free amino group or an amino group that is substituted aliphatically, cyclo- aliphatically, cycloaliphatically-aliphatically and/or by acyl, and R, represents hydrogen, lower alkyl, a free amino group, or an amino group that is substituted aliphactically, cyclo- aliphatically, cycloaliphatically-aliphatically

US .

Ie yy and/or by acyl, and the salts thereof, to pro- cesses for the manufacture of such compounds, to pharmaceutical preparations containing them and to the use thereof as active ingredients in medicaments.

Hereinhefore and hereinafter, unless defined otherwise, organic groups and compounds referred to as "lower" preferably contain up to and including 7, especially up to and Including 4, carbon atoms (C-atoms).

Halogen is, for exsmple, halogen having an atomic number of up to and including 35, such as fluorine, chlorine or, less preferably, bromine. ‘ Lower alkyl is, for example, C,~C,-alkyl, such . as methyl, ethyl, n-propyl, isopropyl or n- butyl, or also secondary butyl, isobutyl or : tertiary butyl, but it can also be a Cg-Cy- alkyl group, i.e. a pentyl, hexyl or heptyl groups.

N-mono-lower alkylamino is, for example,

N-C,-C,-alkylamino, especially N-C,-C,- alkylamino, such as N-methylamino or N-ethyl- amino.

N,N-di-lower alkylamino,is, for example,

N,N-di-C,-C,-alkylamino, especially N,N-di-

C,~C,-alkylamino, in each of which the two

N-alkyl groups may be the same or different, such as N,N-dimethyl-, N,N-diethyl-, N,N-diiso- propyl- or N-butyl-N-methyl-amino.

N-(lower alkoxy-lower alkyl)amino is, for example, N-(C, -C,~alkoxy-, such as methoxy- or ethoxy-, C,-C,-alkyl)amino, especlally

N-(C,-C, ~alkoxy~, such as methoxy~- or ethoxy-, . C,-C,-alkyl)amino, such as N-(methoxy-methyl) . amino or N-(l-methoxyethy!)amino.

H-(hydroxy-lower alkyl)amino is, for example,

N-(hydroxy-C -C,-alkyl)-amino, especially N- (hydroxy-C, -C,-alkyl)-amino, such as N(hydroxy-

J fy methyl)amino or N-(l-hydroxyethyl)amino.

N-(hydroxy-lower alkyl)-N-lower alkylamino is, for example, N-(hydroxy~C,-C,~alkyl)=-N- c,-C,-alkylamine, especially N-(hydroxy-C, -C.- alkyl)-N-C -C, —allkylamino, such as N-(l-hydroxy- ethyl)-N-methylamino or N-(hydroxymethyl)-N- ethylamino.

N-monocycloalkylamino is, for example,

N-C,-Cg-cycloalkylamino, especially N-C,-Cg- cycloalkylamino, such as N-cyclopropylamino or N-cyclohexylamino.

N,N-dicycloalkylamino is, for example,

N,N-di-C,-Cg-cycloalkylamino, especially N,N- di-C,-C -cycloalkylamine, in each of which the . two N-cycloalkyl groups may be the same OF different, such as N,N-dicyclohexylamino or

N-cytlohexyl-N-cyclopropylamina.

N-cycloalkyl-N-lower alkylamino is, for example, N-C,-Cg-cycloalkyl-N-C,~C,=alkylanino,

all especially N-C,-C -cycloalkyl-N-C -C, ~alkyl- amino, such as N-cyclopropyl-N-methylamino or

N-cyclohexyl-lN-ethylamino.

N-mono(cycloalkyl-lower alkyl)amino is, for example, N-(C,~Cg-cycloalkyl-C -Cjalkyl) : amino, especially N-(C,-Cc-cycloalkyl-C -C, - alkyl)amino, such as N-(cyclopropylmethyl)amino or N-(l-cyclohexylethyl})amino. : N.N-di(cycloalkyt-lower alkyl)amino is, for example, N,N-di(C,-Cg-cycloalkyl-C,-C,- alkyl)amino, especially N,N-di(C,-C -cycloalkyl-

C,~C,-alkyl)amino, in each nf which the two

N-(cycloalkylalky!l) groups may be the same or different, such as N,N-di(cyclopropylmethyl)amino or N-(cyclopropylmethyl)-N-(l-cyclohexylethyl)- amino.

N-(cycloalkyl-lower alkyl)-N-lower alkyl- amino is, for example, N~(C,~Cg-cycloalkyl-

C,-C,-alkyl)-N-€ -C,-alkylamino, especially

N-(C,-C -cycloalkyl-C -C, ~alkyl)-N-C -C, -alkyl~ amino, such as N-{cyclopropylmethyl)-N-ethyl- amino or N-(l-cycldhexylethyl)-N-methylamino. :

fey gy

Lower alkanoyl is, for example, Cy-Cs- alkanoyl, such as acetyl, propionyl, butyryl, isobutyryl or pivaloy!. oe ’ N-lower alkanoylamino is, for example,

N-C,-C.-alkanoylamino, such as N-acetyl~-, ‘N-propionyl-, N-butyryl- or N-pivaloyl-amino.

N-lower alkanoyl-N-lower alkylamino is, for example, N-C,=Cg~alksnoyl-N-C ~C, -alkyl- amino, especially N-C,-C.-alkanoyl-N-C,-C, - alkylamino, such as N-acetyl-N-propylamino or

N-butyryl-N-methylamino.

The compounds I are able to form salts by way of their basic centres. Salts of compounds 1 are therefore especially corresponding acid “ addition salts, preferably pharmaceutically acceptable acid addition salts. These are formed, for example, with strong inorganic pro- tonic acids, such as mineral acids, for example sulphuric acid, a phosphoric acid or a hydro- halic acid, with strong organic carboxylic acids, such as lower alkanecarboxylic acids, for example

. acetic acid, optionally unsaturated dicarbo- xylic acids, for example malonic, maleic or fumaric acid, or hydroxycarboxylic acids, for example tartaric or citric acid, or with sulphonic acids, such as lower alkanesulphonic or optionally substituted benzenesulphonic acids, for example methanesulphonic or P- toluenesulphonic acid.

Also included are salts that are unsuitable i for pharmaceutical uses, since these can be used, for example, for the isolation or puri- fication of free compounds I and the pharmaceu- tically acceptable salts thereof. : The novel compounds I and the pharmaceu- tically acceptable salts thereof have valuable pharmacological properties, especially a pro-. nounced anticonvulsive activity, which may be ’ 20 demonstrated, for example, by way of a marked metrazole antagonism when administered mw mice

In a dosage range of from approximately 10 mg/kg p.o., and by way of a pronounced pro- tective action against convulsions induced by

Lay yy electric shock when administered to mice and i rats in a dosage range of [rom approximately 3 mg/Kg p.o..

The compounds 1 and the pharmaceutically acceptable salts thereof are accordingly especially suitable for the treatment of .con= vulsions of various origins, for example for the treatment of epilepsy. They can accordingly be used as anticonvulsive, for example anti- epileptic, active ingredients in medicaments.

The industrial production of the active subs- ‘tances may also be included.

The invention relates in the first place to compounds of formula I inwhich Ph represents . a phenyl radical substituted by halogen, lower . alkyl, trifluoromethyl and/or by cyano, R, : represents amino, N-mono- or N,N~di-lower alkyl- ’ 20 amino, N-(lower alkoxy-lower alkyl)amino, N- (hydroxy-lower alkyl)amino, N-(hydroxy-lower : alkyl)-N-lower alkylamino, N-mono- or N,N-di- cycloalkylamino, N-cycloalkyl-N-lower alkylamino,

Ite { \ {

N-mono-— OF N,N-di-(cycloalkyl-lower alkyl)amino,

N-(cycloalkyl-lower alkyl)-N-lower alkylamino,

N-lowver alkanoylamino or N-lower alkanoyl-N- lower alkylamino, and R, represents hydrogen, lower alkyl, amino, N-mono- or N,N-di-lower ’ alkylamino, N-(lower alkoxy-lower alkyl)amino,

N-(hydroxy-lower alkyl)-anino, N-(hydroxy-lower alkyl)-N-lower alkylamino, N-mono-— OF N,N-di- cycloalkylamino, Nocyeloalkyl-N-louer alkylamino, . 10 N-mono~— OF N,N-di-(cycloalkyl-lower alkyl)amino,

N-(cycloalkyl-lowet alkyl)-N-lower alkylamino,

N-lower alkanoylamino or N-lower alkanoyl-N- lower alkylamino, and the salts thereof.

The invention relates especially to com-

Co pounds of formula 1 {n which Ph represents a phenyl radical that is gubstituted by at least . one halogen atom, Ry represents amino, N-mono~ or N,N-di-lower alkylamino, N-(lower alkoxy” lower alkyl)amino, N-(hydroxy-lover atkyl) amino, N-{(hydroxy-lower alkyl)-N-lower alkylamino,

N-mono- OF N,N-di-cycloalkylamino, N-cycloalkyl-

N-lowver alkylamino, N-mono- OY N,N-di(cyclalkyl~ lower alkyl)amino, N-(cycloalkyl-lower alkyl)-

ee . — - EE —

Jey } N-lower alkylamino, N-lower alkanoylamino or

N-lower alkanoyl-N-lower alkylamino and R, represents hydrogen, lower alkyl, amino, N- ’ mono- or N,N-di-lower alkylamino, N-(lower alkoxy-lowver alkyl)amino, N-(hydroxy-lower alkyl)- amino, N-(hydroxy-lower alkyl)-N-lower alkyl- amino, N-mono- or N,N-dicycloalkylamino, N- cycloalkyl-N-lower alkylamino, N-mono- or N,N- di{cycloalkyl-lover alkyl)amino, N-(cycloalkyl- lower alkyl)-H-lower alkylamino, N-lower alkanoyl- amino or N-lower alkanoyl-N-lower alkylamino, and the salts thereof. :

The invention relates especially to compounds of formula I in which Ph represents 2-, 3- or 4-halophenyl, such as 2-fluoro-, 3-fluoro-, 4-ftuoro- or 2-chloro-phenyl, 2,3-, 2,5- or . 2,6-dihalophenyl, such as 2,3-, 2,5- or 2,6- difluorophenyl or f~chloro-2-fluorophenyl, 2-, ’ 20 3- or 4-C -C,-alkylphenyl, such as 2-methyl- phenyl, 2-, 3- or 4-vrifluoromethylphenyl or 2-, 3- or 4-cyanophenyl, wherein halogen may in each case be halogen having an atomic number of up to and including 35, Ry represents amino,

defi : N-C,~C, -alkylamino, such as N-methylamino or

N-ethylamino, N,N-ei-C,-C,-alkylamino, such as : N,N-dimethylamino, N,N-diethylamino or N-butyl- ’ N-methylamino, N-C,-C.-cycloalkylamino, such as N-cyclopropylamino or N-cyclohexylamino, or N-lower alkanoylamino, such as N-acetylamino,. and R, represents hydrogen, €,-C,-alkyl, such ag methyl or ethyl, amino, N-C,-C,-alkylamino, such as N-methylamino or N-ethylamino, N,N- di-Cc -C,-alkylamino, such as N,N-dimethylamino, : N,N-diethylamino or N-butyl-N-methylamino, \ N-C,-C.-cycloalkylamino, such as N-cyclopropyl- amino or N-cyclohexylamino, or N-lower alkanoyl- amino, such as N-acetylamino, and the salts thereof.

The invention relates especially to compounds . of formula I in which Ph represents 2-halo- phenyl that may in addition be substituted in ’ 20 the 3-, 5- or 6-position by halogen having an atomic number of up to and including 35, such as fluorine or chlorine, such as 2-chloro- or 2-fluoro~-phenyl, 2,3-, 2,5- or 2,6-difluoro- phenyl or 6-chloro-2-fluorophenyl, Ry represents

<a 4y amino, N-C, -C,-alkylamina, such as N-methyl- amino, or N-ethylamino, N,H-di-C,~C,-alkyl- ~ amino, such as N,N-dimethylamino, N,N-diethyl- amino or N-butyl-N-methylamino, N-C,-Cc-cyclo- alkylamino, such as N-cyclopropylamino or : N-cyclohexylamino, or N-lower alkanoylamino, such as N-acetylamino, and R, represents hydrogen,

C,~C,-alkyl, such as methyl or ethyl, amino,

N-C, -C,-alkylamino, such as N-methylamino or

N-ethylamino, N,N-di-C ~C, ~alkylamino, such as

N,N-dimethylamino, N,N-diethylanino or N-butyl-

N-methylamino, N-C,-Cc-cycloalkylamino, such as

N-cyclopropylamino or N-cyclohexylamino, or N- lower alkanoylamino, such as N-acetylamino, and : the salts thdreof. }

The invention relates more especially . to compounds of formula I in which Ph represents 2- or 3-fluorophenyl, 2-chlorophenyl, 2,6- difluorophenyl or 2-¢,-C,-alkylphenyl, such as 2-methylphenyl, R, represents N-C,-C,- alkylsmino, such as N-methylamino or N-ethyl- amino, N,l-di-C -C -alkylamino, such as N,N-

Jee | of dimethylamino, N,N-diethylamino or N-butyl-

N-methylamino, or N-C,-C,-cycloalkylamino, such as N-cyclopropylamino or N-cyclohexyl-~- amino, and R, represents hydrogen, C Cur alkyl, such as methyl or ethyl, or amino, and “the salts thereof.

THR2 invention relates especially to compounds of formula I in which Ph represents 2-fluorophenyl which may in addition be sub- tituted in the 5- or 6-position by halogen having an atomic number of up to and including 35, such as fluorine or chlorine, such as 2-fluoro- phenyl, 2,5-0or 2,6-di-fluorophenyl or 6-chloro- 2-fluorophenyl, R, represents amino, N-C,-C,- alkylamino, such as N-methylamino or N-ethyl- amino, N,N-di-C,-C,-alkylamino, such as N,N- . dimethylamino, N,N-diethylamino or N-butyl-

N-methylamino, or N-C,-C -cycloalkylamino, such ’ 20 as N-cyclopropylamino or N-cyclohexylamino, . and R, represents hydrogen, €C,-C,-alkyl, subh as methyl or ethyl, or amino, and the salts . thereof.

The invention relates more especially to compounds of formula I in which Ph represents 2-fluorophenyl or 2,6-difluorophenyl, Ry represents amino, N-C,-C,-alkylamino, such as

N-methylamino, or N,N-di-C -C, ~alkylamino, such as N,N-dimethylamino, and R, represents hydro- ‘ gen or C,-C,-alkyl, such as methyl, and the - galts thereof. . 10 The invention relates most especially to compounds of formula I in which Ph represents 2-fluorophenyl, Ry represents N-C,-C,-alkyl- : amino, such as N-methylamino, or N,N-di-C,-C, - alkylamino, such as N,N-dimebtbylamino, and

R, represents hydrogen or amino, and the salts thereof. . The invention relates specifically to the " novel compounds of formula 1 mentioned in the ’ 20 Examples and the salts thereof.

The invention also relates to a process R for the manufacture of compounds I and the salts thereof which is based on techniques that | ot defy are known per se and is characterised in that a) in a compound of formula : i

Ny od A ~~ % “ N\ ! - ~ lS (11),

Z

: 10 2

CH9-Ph in which Z, represents a nucleofugal leaving gorup X, and zZ, represents a nacleofugal leaving ‘group X, or a radical Ros or in which z, is } a radical Ry and Z, represents a nucleofugal leaving group X,, or ina tautomer and/or salt thereof, Z, is converted into R, and/or Z, ; is converted into Ros or : . -20- l cet yt b) the compound Y-H is eliminated from a compound of formula

Ry

B N

Zz ~~ SN

N- . NL

PN N

2 | | J : ’ oe / (111)

Y Sn

C -

H H, Ph . in which Y represents hydooxy, mercapto Or ’ optionally aliphatically substituted amino, or from a tautomer and/or salt thereof, or . ¢) [for the manufacture of a compound I, in which R, represents amino, or a salt thereof, a compound of formula

2afyy

IS

J! .

Y —N ’ AN a

I i 5 . J (iv), tn" oe

Ci, -Ph in which one of the radicals Y, and Ty ‘ represents cyano and the other represents hydregen, or a tautomer and/or a salt thereof, "is cyclised, or d) a salt of formula

I"

WZ ~~ 9

I

"wm (Vv),

R, N CH,-Ph

Fey - in which A represents the anion of a protonic ‘ acid, is cyclised, or ea) a compound of formula

R

] pa ~~ LN «

N N

[I /

PE tN / (v1) re a pad = N ’

R ® 2

H or a salt thereof is reacted with a compound of formula X,~CH,-Ph (vil), in which X, represents a nucleofugal leaving group, and . {f desired, in each case an isomeric mixture that may he obtained in accordance with the process is separated into the components and the isomer of formula I is isolated, a compound I obtained according to the process of by another method is converted into a

Jay different compound 1, a free compound I obtained according to the process is converted into a salt, 2 salt of a compound 1 obtained according to the process is converted into the free compound I or into different salt of compound I, andfor a stercoisomeric mixture that may be obtained according to the process is separated into the stereoisomers and the desired sterecisomer is isolated.

: : The reactions of the process that are described hereinbefore and hereinafter, and also the manufacture of novel starting materials and intermediates, are carried out in a manner known per se.

Even if this is not expressly mentioned, ahe reactions are carried out, analogously to the methods of reaction and ] formation of known starting materials and intermediates, under the reaction conditions customary in each case, for example as required with cooling, alt room temperature or with heating, for example in a temperature range of from approximately -10°C to approximately +250°%C, preferably [rom approximately 20°C to

A — oc yyy approximately 200°C, with the use of the auxiliary agents that are customary in each case, such as catalysts, condensing agents - and solvolysis agents, in the absence OT, customarily, in the presence of a suitable solvent or diluent or 4a mixture thereof, optidénally in a closed vessel, in an inert gas atmosphere and/or under anhydrous conditions.

Each of the starting materials of formulae 11, 111, IV, v, V1 and yil listed hereinbefore and hereinafter that are used for the manu- facture of compounds 1 and the salts thereof "is either known or can be produced by methods that are known per Sse. Starting materials with basic centres may be in the form of salts, guch as acid addition salts, for example with the acids listed hereinbefore. : 20 Salts of compounds 11, 111 or 1V or, where applicable, their respective tautomers, are especially acid addition salts, preferably with strong inorganic acids, for example ‘

2e4y4y analogous to the kind mentioned hereinbefore for acid addition salts of compounds I. : Tautomers of starting compounds II used in process variant a), or salts thereo, may occur, for example, when in compounds II or salts thereof the groups Z, and/or Z, represent hydroxy or mercapto and/or one of the groups

Z, and 2, represents optionally mono-subs- tituted amino. Accordingly, for example, compounds II or salts thereof having enol, enthiol and/or enamine partial structures may ’ . also be in protomeric form, that is to say in the formof corresponding oxo, thioxo and/or imino tautomers, and/or may be in dynamic ] equilibrium with the latter.

Nucleofugal leaving groups X, and X, in compounds Il are, {or example, optionally etherified or esterified hydroxy or mercapto groups, sulphinyl and sulphonyl groups, or sulphonium groups. Etherified hydroxy ib, for example, lower alkoxy, such as methoxy, or optionally substituted phenyl-lower alkoxy,

Lei such as optionally substituted benzyloxy.

Esterified hydroxy is especially hydroxy esterified bv a mineral acid or an organic sulphonic acid, especially halogen, such as chlorine, bromine or iodine, sulphonyloxy, such as optionally halo-substituted lower alkanesulphonyloxy, for example methanesulphonyl- oxy or trifluoromethanesulphonyloxy, cycloalkane- sulphonyloxy, for example cyclohexanesulphonyl- oxy, or benzenesulphonyloxy optionally substituted by lower alkyl or by halogen, for example benzene- sulphonyloxy, p-bromophenylsulphonyloxy or p-toleuenesulphonyloxy, or lower alkanoyloxy, for example acetoxy. Etherified mercapto is, for example, lower alkylthio, such as methylthio, optionally substituted arylthio, such as optionally substituted phenyl-thio or naphthylcthio, for example phenylthio, p-tolylthio or naphthyl- thio, or optionally substituted aryl-lower alkylthio, such as optionally substituted benzyl- or naphthyl-methylthio, for example benzylmethyl- | ’ thio, p-bromobenzylmethylthio or naphthylmethyl- thio. Esterified mercapto groups are, for

Janfy { example, lower alkanoylthio groups, such as acetylthio. Sulphinyl groups are, for. example, lower alkanesulphinyl groups, such as methanesulphinyl, optionally substituted arylsulphinyl gorups, such as optionally substituted benzene- or naphthyl-sulphinyl, for example p-toluene- or naphthyl-sulphinyl, or optionally substituted benzylsulphinyl, such as benzyl- or p-chlorobenzyl-sulphinyl.

Sulphonyl groups are, for example, lower alkanesulphonyl! gorups, such as methansulphonyl, optionally substituted arylsulphonyl groups, such as optionally substituted benzene- or naphthyl-sulphonyl, for example benzene- or naphthyl-sulphonyl, or optionally substituted benzylsulphonyl, such as benzyl- or p-methylbenzyl- sulphonyl. Sulphonium groups are, for . example, d-lower alkylsulphonium groups, such as dimethylsulphonium.

The conversion of x, and/or X, in compounds 11, tautomers thereof and their respective salts into radicals R, and/or R, is carried out by reaction with compounds of formula H-R,

UU JV _ — ’ G 2a4y (11b) and/or H-R, (113), or a salt of either, ‘ with the removal of compounds X,-H and/or

X,-H.

The reaction of compounds Il, tautomers thereof and their respective salts with compounds IIb and/or IIj or their respective salts is carried out in customary manner, for example while coddling, at room temperature or while heating, for example in a temperature range of from approximately -20 to approxi- mately +250, preferably from approximately -10 to approximately +200°%C, optionally in . the presence of an inert solvent or diluent or ce a mixture thereof, optionally in the presence of a water-binding agent, optionally in the presence of a basic agent and/or under an inert - gas, such as nitrogen. ’ Suitable inert solvents or diluents arg, for example, water, cyclic ethers, aromatic hydrocarbons, N,N-di-lover alkyl-lower alkanoic acid amides, phosphoric acid lower alkylamided,

di-lower alkyl sulphoxides,cyclic amines and, especially, optionally in the form of mixtures with water. lower alkanols, such as tetrahydro- furan, dioxan, benzene, toluene, xylene,

N,N-dimethyl formamide, hexamethylphosphoric acid triamide, dimethyl sulphoxide, N-methylmorpholine and, especially, optionally in the form of mix- ture with water, methanol and ethanol. It is ' : also possible for the manufacture of compounds I fn which at least one of the radicals Ry and : R, represents an amino group substituted as indicated, or salts thereof, for corresponding amines H-R | (11h; R, = amino substituted as indicated) and/or H-R, (1133 R, = amino substituted as indicated), which at the reaction temperatures can be handled in liquid form, to be used in excess and employed as solvents ] or diluents and/or cosolvents, optionally also in dissolved form, for example in the form of aqueous solutions. oo

Water~hinding agents are, for example, oxides of phosphorus, such as phosphorus pentoxide, sulphates of alkali metals or

Jeqyy alkaline earth metals, such as sodium or calcium sulphate, halides of alkaline earth metals, such as calcium chlnride, or carbodi- fmides, such as N,N'-dicyclohexylcarbodiimide. 3 .

Basic agents are, for example, alkali meta or alkaline earth metal hydroxides, hydrides, amides, lower alkanolates, carbonates, - di-lower alkyl amides or lower alkylsilyl amides, lower alkylamines, optionally N-lower alkylated cycloalkylamines, basic heterocycles, ammonium hydroxides and also carboxyclic amines. The following examples may be mentioned: sodium hydroxide, hydride, amide and methanolate, potassium tert. .-butanolate, potassium carbonate, lithium diisopropylamide, potassium bis(tri- methylsilyl)amide, calcium hydride, triethyl- ] amine, cyclohexylamine, N-cyclohexy!-N,N- dimethylamine, pyridine, benzyltrimethylammonium i ‘ 20 hydroxide and 1,5-diazabicyclol5.4.0Jundec-5~ ene (DBU). For the manufacture of compounds 1 in which at least one of the radicals R, and

R, represents an amino group substituted as ot

“yyy indicated, or salts thereof, there may pre- ferably be used instead of an additional basic agenlL corresponding amines H-R, (11b;

R, = amino substituted as indicated) and/or

H-R, (113; R, = amino substituted as indicated), which in such cases are advantageously employed in excess.

In a preferred form of process variant a) a compound of formula

I

! N,

ZN N\

N ’ N

N

> | | J (11a), 5 Sen” AN 2 :

CH, -Ph in which x represents a nucleofugal leaving group, preferahly hydroxy or halogen, such as chlorine or bedmine, or a tautomer, for example a corresponding 6H-7-oxo compound,

Dey and/or a slat thereof is reacted with ammonia or an amine of formula H-R, (11b) or a salt thereof to remove 2 compound X,-H. -

The conversion of x, in compounds Ila, “. tautomers thereof and their respective salts “ into a radical R, (removal of X,-8) is carried out in customary manner, for exsmple at room temperature OF while heating, for example in a temperature range of from - approximately 20 to approximately 250°¢C, pre- . ferably from approximately 20 to approximately 200°C, optionally in the presenee of an inert solvent or diluent, for example of the kind judicated hereinbefore, or 8 mixture thereof, optionally in the presence of a basic agent, for example of the kind mentioned hereinbefore, i optionally in the presence ofl a water-binding agent, for example of the kind indicated hereinbefore, and/or under an inert gas, such as nitrogen.

In a further preferred form of process variant a), to produce compounds 1 in which 25 .

Ley hereinbefore for the conversion of compounds 11a, tautomers thereof and their respective salts into compounds I or salts thereof.

In a further preferred form of process variant a), to manufacture compounds I in which R, represents hydrogen, or salts thereof, a compound [Ic in which X, represents a nucleofugal leaving group, preferably halogen, such as chlorine or bromine, or a aut omer and/or galt thereof, is reduced, oo Suitable reducing agents are, for example,

Raney nickel and hydrogen. Reduction with

Raney nickel is carried out in customary manner, for example by reacting a solution of the metal in a lower alkanol, such as methanol, while heating, for example in a By temperature range of from approximately 20 206 to approximately 140°¢, preferably from approximately 50 to approximately 100°C. } Reduction with hydrogen is advantageously carried out in the presence of a hydrogenation ca- talyst. Suitable hydrogenation catalysts

Duy fi

R, has a meaning other than hydrogen, or salts thereof, a compound of formula

R

I ‘ rN . HN / (11c), - No Nu 2

CH,-FPh in which xX, represents a nucleofugal leaving group, preferably hydroxy or halogen, such as ot chlorine or bromine, or a tautomer and/or salt thereof, is reacted with a compound of formula H-R, (113; Ry 4 hydrogen), or a salt thereof, to remove a compound X,-H.

The conversion of %, in compounds Ilc, tautomers thereof and their respective salts into a group R, having a meaning other than hydrogen (removal of X,-H) is carried out in customary manner, for example as described are, for example, elements of sub-group VIII of the Periodic Table of Elements or de- rivatives thereof, such as palladium, platinum, platinum oxide, ruthenium, rhodium, a tris(triphenylphosphane)-rhodium(1) halide, for example chloride, or Raney nickel, the cata- ; lyst optionally being applied to a support material, such as active carbon, alkalimmetal carbonate or sulphate or a silica gel.

The catalytic hydrogenation is preferably carried out in a polar solvent or diluent, especially in a lower alkanol, such as methanol, or in a strong inorganic acid, such as a hydrohalic acid, for example hydrochloric acid, or a strong organic carboxylic acid, especially aqueous acetic acid or glacial acetic acid, . with cooling or heating, preferably in a } temperature range of from approximately -10 to approximately +120°%¢C, especially from approximately 0 to approximately 100°¢c, especially advantageously at room Lemperature. : In a further preferred form of process variant a), starting from a compound formula 25 .

204yy

X,

J N

ALIN

I iso (11d),

X2

CH,-Ph in which each of < and X, represents a nucleofugal leaving group of the kind described hereinbefore, preferably hydroxy or halogen, such . as chlorine or bromine, or a tautomer and/or salt thereof, in succession the xX, group is replaced by an R, radical and the X, group is replaced by an R, radical. Thus, for example, preferably a compound [1d or a tautomer . and/or slat thereof may first of all be reacted with ammonia or an amine of formula H-R (11b) or a salt thereof to remove a compound

X, -H, and the resulting intermediate IIc or a tautomer and/or salt thereof may then be converted into a compound of formula I in which oy

R, represents free amino, amino substituted as indicated, or hydrogen, or into a salt ~ thereof, by reaction with ammonia or an amine of formula R-R, (1tj; R, = free amino . 5 or amino subsiftuted as indicated) or 2 salt thereof to remove a compound X,-H, or by reducticn, for exmaple by the action of Raney nickel or by catalytic hydrogenation of the : kind described hereinbefore.

The conversion of X, and x, in compounds 11d, tautomers thereof and their respective " salts into R, and Ry» respectively, is carried out in customary manner, {or example as des- cribed hereinbefore for the corresponding conversion of compounds Ila and lc, respectively, tautomers thereof and their respective salts into compounds 1 or salts thereof, and the {ntermediate Ilc ‘Which may first be obtained from 11d does not need to be isolated but is . advantageously further reacted in situ, without additional purification, to form a compound 1 or a salt thereof. -

Lay

The compounds 11b and I1j and their res- pective salts are known. The compounds Ila,

IIc and 11d in which x, and/or X, is(are) halogen, tautomers thereof and their respective salts can be manufactured analogously to known methods, for example hy reaction of a compound of formula yy! ba : No re - - h . y, ' \, , vy WN X (11e), , /

Y, oN TNs vs b dip-r i ] in which either Y' and Y" together represent optionally functionally modified oxo Xqo YT, represents hydrogen and either Y, represents

R, and Y, and Y, together represent an additional bond, or Y, and Ti together represent optionally functionally modified oxo Xq and Y, represents hydrogen, or in which Y" represents Ryo Y' and i ~38~

~ : ayy

Y, together represent an additional bond, Y, ~ and Yq together represent optionally functionally ~ modified oxo Y,, and Y, represents hydrogen, or a tautomer and/or salt thereof, with a halogenating agent, and optional further reaction, in customary manner, of a resulting compound

Ila, IIc or IId in which each of X, and X, represents halogen, or of a tautomer and/or salt thereof, with a compound of formula X,-H and/or ’

X,-H in which each of X, and Xy independently of the other, represents one of the above-described nucleofugal leaving groups other than halogen.

Optionally functionally modified oxo Xq in compounds Ile, tautomers thereof and their . respective salts is, for example, thioxo or optionally substituted imino, but preferably oxo. Optionally : substituted imino is, for example, a group =N-R', in which R' has the same meaning as in the partial structure —~NHR', which represents a radical R, and/or Ry» such as imino, N-lower alkylimino, N-cycloalkylimino or .N-lower al- kanoylimino. .

What has been said hereinbefore concerning salts and/or tautomers of Compounds 11 applies in an analogous manner to salts and/or tautomers . of compounds 1]a. Thus, especially correg- ponding keto/enol, thioketo/enthio] and/or imino/enamine tautomers are possible.

Halogenating agents are, for example, halides of phosphorus or sulphur, such ag phos- phorus thihalides, phosphorus pentahalides, phosphorus oxytrihalides, thionyl halides or

Bulphury] halides, for example phosphorus tri- chloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxytrichloride, thionyl chloride or sulphury] chloride, but may algo be, for example, acid halides, such ag acid chlorides, of carbonic acid, for example phosgene.

The reaction of a compound Ile or ga tautomer and/or salt thereof with a halogenating agent is carried out under customary reaction con- ditions, for example while heating, for example in a temperature range of from approximately 20 -4 0-

: geifyy to approximately 200°C, and in an inert solvent, such as 28 halo-lower alkane, for example tetrachloromethane, but preferably using a solution or suspension of compound lle ’ or a tautomer and/or salt thereof in an excess of the halogenating agent.

Thus, for example, 3 compound 11a in which

Xx, is halogen, such as chtorine, or 3 tautomer . and/or salt thereof, is obtained by reacting 8 compound lle tn which Y' and Y" together represent ) an Xq gTOouUp, preferably 0X0, A represents hydrogen, XY, represents an Ry group and Yq and

Y, together represent an additional bond, Or 8 : tautomer and/or salt thereof, with a halogenating } agent, for example phosphorus oxytrichioride, : . it being possible for the corresponding compound lle or a tautomer sndjor salt thereof to be obtained, for example, bY reaction of a compound of formula -41-

2ayyy j

I ne CoN oo EN

I N (111) / aN SN / 2

CH,-Ph or a salt thereof with a compound of formula : R,-X (11g), in which X represents the functional groups of a carboxylic acid or of a functional drrivative thereof, for example a carboxy group of the formula -C(=0)-OH or a lower alkoxy- carbonyl group of the formula ~C(=0)-0Alk in which Alk represents lower alkyl, such as methyl, but especially a halocarbonyl group of the formula ~C(=0)-Hal, in which Hal represents halo- gen, such as chlorine or bromine, an amide group of the formula -C(=0)Am, in which Am represents optionally substituted amino, for example amino, : N-lower alkylamino, such as N-methylamino, or

N,N-di-lower alkylamino, such as N,N-dimethyl- or N,N-diisopropyl-amino, or an orthoester group —42- . EE

2c oo of the formula -C(0-Alk),, in which Alk repre- sents lower alkyl, such as ethyl, or (optionally with 2 salt thereof, under customary reaction conditions, for example in the presence of a condensing agent, such as a basic agent, and/or while heating, for example in a temperature range of from approximatley 20 to approximately 200°C.

Compounds llc in which X, is halogen, such asichlorine, or tautomers and/or salts thereof, are obtained, for example, by reacting a compound

Ile in which Y' and Y" together represent a . «N~R' group in which R' has the same meaning as in the partial structure ~NHR', which rpe- . presents a radical Ry» Y, and Y, represent . hydrogen and Y, and Y, together represent an

X, group, preferably oxo, or a tautomer and/or salt thereof, with a halogenating agent, for example phosphorus oxytrichloride, it being possible for the corresponding compound lle or a tautomer and/or salt thereof to be obtained, ~ for example, by reaction of a compound of betyy formula

NR'

H,N —I _ AN > | | N (11h), oo J

HN ~¥ 2 . CH,-Ph : which in turn is obtainable from a compound

I1f or a salt thereof by customary reaction with a compound of formula NH,R' (111i) or a salt thereof, or by reaction of a tautomer and/or salt thereof, whéh a doubled acid de- rivative of carbonic acid, for example urea or phosgene, under the customary reaction con- ditions, for example in the presence of a con- densing agent, such as a basic agent, and/or while heating, for example in a temperature range of from approximately 20 to approximately 200°c. : Compounds 11d, in which X, and X, are. halogen, such as chlorine, or salts thereof, —h4-

’ 2 eyy } " are obtained, for example, by reacting =a compound Ile, in which Y' and Y" together and ’

Y, nd LE together in each case represent oxo, . and Y, and Y, each represents hydrogen, or a tautomer and/or salt thereof, with a halo- genating agent, for example hosphorus oxytri- chloride, and the corresponding compound Ile or a tautomer and/or salt thereof being ma- nufactured, for example, by reacting 8 compound 11f tor a salt thereof with a doubled acid : derivative of carbonic acid, for example urea or phosgene, under customary readtion conditions.

In an especially preferred form of process, a compound lle or a tautomer and/or salt thereof : can be converted in the manner described here- inbefore into a compound Ila, IIc or 11d, or into a tautomer and/or salt thereof in each case, and the® without additonal purification or isolation, the resulting intermediate 1fa, ) ' 11c or 11d is converted in situ into a compound 1 or a salt thereof, the operation preferably . being carried out in an aromatic hydrocarbon, for example toluene or xylene. ‘ -4 5

9efyd

Th» compounds Ila, Tlc and 11d, tautomers thereof and their respective salts can also be produced in a manner analogous to that described under process variant d) by starting from a corresponding salt of formula fi

ZZ ~~. 0

N . | A (Vb), ~~ —* zy” AYE Se

CH,-Ph in which Zz, is a nucleofugal leaving group

X, and 7, is a nucleofugal leaving group X, : or an R, radical, or in whibh Z, is an R, : radical and 2, is a nucleofugal leaving group x, and in which A represents the anion of a protonic acid, and cyclising this salt Vb in a manner analogous to that described under process variant d).

0 Ce f yy

What has been said hereinbefore concerning tautomers and/or salts of compounds 11 applies . in an analogous wanner tO the tautomers and/or salts of the starting compounds 111 used in process variant b).

Optionally aliphatically substituted amino Y in compounds 1711, tautomers thereof and thelr respective salts is, for example, one of the corresponding amino groups 1isted hereinbefore in the definition of the radicals

R, and Ry» but can also be a different amino group, such as anilino.

The elimination of the compound Y~-H from compounds 111, tautomers thereof and thelr respective salts {s carried out in customary manner, for example in an {nert solvent or diluent, for example of the kind menpioned under process variant a), by heating, for example in a temperature range of from appro- ximately 40 to approximately 250°C, preferably from approximately 80 to approximately 200°C,

2ayy and/or by treatment with an acid. Acids suitable for that purpose are, for example, mineral acids or anhydrides or ascidic salts thereof, for example hydrohalic acids, sul - phuric acid, alkali metal hydrogen sulphates, phosphoric acid, polyphosphoric acid, phosphorus pentoxide, phosphorus trichloride or phosphorus oxytrichloride, organic sulphonic acids, such - as p-toluenesulphonic acid, or carboxylic acids or their anhydrides or halides, such as lower ‘ alkanoic acids and their enhydrides or halides, for example acetic acid, acetic anhydride or acetyl chloride, and also buffered acid solutions, for example phosphate or acetate buffers, or hydrohalides of nitrogen bases, for example ammonium or pyridinium chloride.

In a preferred form of process variant b), for example a compound 111 in which Y represents hydroxy, or a tautomer and/or salt thereof, is converted into a compound 1 or a salt thereof by heating at from 100 vo 200°C in an inert solvent, for example a lower alkanoic acid

Daqyy . amide, such as formamide or acetamide, with the discharge of an equivalent of water.

Owing to the fact that the corresponding starting compounds 1I1 are readily available, process variant b) is especially suitable for the manufacture of compounds 1 in which R, is amino, or the salts thereof. Thus, starting compounds III of this kind, tautomers thereof and their respective salts can be obtained analogously to known methods and are preferably manufactured in situ, for example by cyclising a compound of formula

Yg—— N T==C. CN

IN ST

Te N\

N “(111a),

Y nN ~ ’ ~~ N. 7

H CH,-Ph 2 in which either Tg and Y, represent hydrogen and Yo represents a group of the formula ~4H9- -

Defy

R,=C(=X,)-NH- (111b), or Yo and Y, together represent an additional bond and Y, represents a group of the formula R,=C(Y) (NH, )-NH~- (1lle), or a tautomer and/or salt thereof, the compound 111 or a tautomer and/or slat thereof formed as intermediate generally being further reacted in accordance with the invention without being isolated.

In groups of the formula I11b X, represents optionally functionally modified oxo, such as oxo, thioxo, or optionally substituted imino, such as imino, N-lower alkylimino, N-cyclo- alkylimino or N-lower alkanoylimino, or also optionally substituted N-benzoylimino, N-~lower alkanesulphonylimino or N-arylimino. . ' What has been said hereinbefore regarding salts and/or tautomers of compounds 11 applies in an analogous manner to salts and/or tautomers of compounds Illa. :

Do yy

The cyclisation of compounds Illa, tautomers thereof, and their respective salts and optionally . the subsequent in situ elimination of Y-H from the resulting compounds Ill or tautomers and/or salts thereof is carried out in customary manner, for example under neutral, acidic or ’ basic conditions, if necessary in the presence of an acid or a basic agent, in the prespuce of an inert solvent or diluent, at room tem- perature or, preferably, while heating, for ' example in a temperature range of from appro- ximately 20 to approximately 250°C, and/or undr an inert gas, such as nitrogen. The acids, basic agents and inert solvents or diluents used may be, for example, the corresponding agents listed under process variant a). In an especially advantageous manner, however, the inert solvent or diluent may alternatively be a lower alkanoic acid amide, such as formamide or acetamide.

In an especially preferred form of process, e for example a compound IIIa in which Y. and ,

9eifyy represent hydrogen and Ye represent an

R,=C(=0)-NH- group (111b), or Y, and Ye to- gether represent an additional bond and ¥, represents an R,-C(OH) (NH, )~NH- group (Illc), or a tautomer and/or salt thereof, is cyclised by heating for several hours, for example in a temperature range of from appro- ximately B80 to approximately 200°C, in a lower alkanoic acid amide, such as formamide or acetamide, and a further reaction of the resulting . compound 111 in which Y is hydroxy, or of a tautomer and/or salt thereof, occure in situ under the reaction conditions to yield the desired end produc¢t of formula I or =a salt : 15 thereof. In an analogous manner coreesponding compounds 111a having groups 111b in which X, is imino, or groups IIIc in which Y is amino, or tautomers and/or salts thereof, may be v cyclised in an {inert solvent, such as a halo- 20 . alkane, for example tetrachloromethane, and further reacted to form compounds 1 or salts thereof.

2yy

The compounds Illa, tautomers thereof and their respective salts are obtained from - compounds of the formula

NC . N_ : lo ’ (111d) re : /

H,N RE ’

CH,-Ph or salts thereof by reaction with a compound of formula R,-C(=X,)-NH, (11le), in which X, represents optionally functionally modified oxo, for example of the kind described for group 111b, or salts thereof, the operation being carried out analogously to known processes, for example at room temperature OF preferably while heating, for example in 8 temperature range of from approximately 20 to approximately 250°¢C,

yey yy under neutral, acidic or basic conditions, if necessary in the presence of an acid or a basic agent, for example of the kind mentioned . hereinbefore, in the presence of an inert \ ~5 solvent or diluent, for example of the kind mentioned hereinbefore, and/or under an Inert i gas, such as nitrogen. The inert solvent or diluent used may be especially also a lower alksnoic acid amide, such as formamide or | acetamide.

In an especially preferred form of process a compound 171d or & salt thereof is reacted with a large excess of a compound 11le (x, repre- ’ sents optionally functionally modified oxo, preferably oxo), for example in formamide or acetamide (x, = oxo, R, = hydrogen or methyl), while heating, for example in a temperature range of from approximately 80 to approximately 200°C, to form a compound Illa or a tautomer and/or salt thereof, the reactant 1Ile simul- taneously acting as solvent or diluent.

Sey

Advantageously, though, the compounds 11la, tautomers thereof and their respective salts . are also produced in situ and further reacted, without isolation, to form compounds 111 or tautomers and/or salts thereof, which in turn are further reacted, in the manner described above, generally also in situ, to form compounds

I or salts thereof.

THus, in the manner of a one-pot reaction, . compound 111d or a salt thereof may be reacted, while heating, with a large excess of a compound

I11e (x, represents optionally funciionally modified oxo, preferably oxo), for example in formamide or acetamide (x, = 0x0, R, = hydrogen or methyl), during which reaction first of all a compound Illa or a tautomer and/or salt thereof is formed, after which cyclisation to form a compound 1I1 or a tautomer and/or salt thereof : 20 occurs in situ with the application of heat being maintained, and this in turn is followed by an in-situ elimination of a compound Y-H (Y = hydroxy) to yield a compound 1 (R, = amino, R, is, for example, hydrogen or methy!) or a salt thereof. -

Jy

WHat has been said hereinbefore concerning . tautomers and/or salts of compounds I1 applies in an analogous manner to the tautomers and/or salts of the starting naterials IV used in process variant c).

The cyclisation of compounds IV, tautomers thereof and their respective salts to compounds I ifn which R, represents amino, or salts thereof, is carried out under customary cyclisation con- ditions, for example in a manner analogous to that described under process varfant b) for the cyclisation of compounds Illa to compounds I11,

The starting materials IV, tautomers thereof and their respective salts can be obtained analogously to known methods, for example by reaction of a compound of formula

Ry ; 7 IN NN .

HN N

(Iva)

Pa J

HN ~on”

CR,-Ph vagy or a tautomer and/or salt thereof with a compound of the formula X ~C=N (1Vb), in which X, re- presents a nucleofugal leaving group, for example of the kind described under process variant a), preferably halogen, such as chlorine or bromine, or free amino, or amino substituted as indicated for radicals R, and Ry, the reaction : being carried out under customary reaction con- ditions, for example at room temperature or while heating, in an inert solvent or diluent, for example of the kind mentioned hereinbefore, optionally in the presence of a condensing agent, for example a basic agent, for example of the kind described hereinbefore, and/or under an inert gas, subh as nitrogen,

What has been said hereinbefore concerning tautomers and/or salts of compounds I1 applies in an analogous manner to the tautomers and/or salts of the compounds IVa. }

In a preferred form of process the compounds

IV or tautomers and/or salts thereof are not

2a yy isolated but are produced in situ and cydtlised in accordance with the invention, without isolation or additional purification, to form compounds 1 or salts thereof.

The compounds IVa, tautomers thereof and their respective salts can be produced ana- logously to known methods, for example by reaction of a compound I1Id or a galt thereof with ammoiia or an amine of formula H-R (IIb) or a salt thereof ander customary reaction conditions. ] Anions A of pootonic acids in salts of ~ formula V, which are usdd as starting materials according to process variamt d), are, for example, anions of the acids mentioned hereinbefore for the format fon of acid addition salts of compounds 1, especially anions of strong inorganic protonic acids, such as anions of } 20 mineral acids, {or example sulphuric acid, a photphoric acid or a hydrohalic acid, or tetrafluoroboric acid, or anions of strong organic i carboxylic acids, such as lower alkanecarboxylic 25 .

2eygy acids, for example formic acid or acetic acid, for example the sulphate, phosphate, chloride, bromide, tetrafluoroborate or acetate fon.

The cyclisation of salts of formula V to compounds I or salts thereof if carried out analogously to known methods under customary reaction conditions, for example in 8s solvent or diluent, preferably in water, and/or while cooling, at room temperature or while heating, for exapple in a temperature range of from approxi- mately -20 to approximately +150%, preferably from approximately 0 to approximately +100°cC.

The starting materials V are know or -can be produced analogously to known methods, for example by reaction of a compound of formula :

Rj ’

NH, 4 ’ NN ~~

Te (va)

EQN LIN ot

Ry No he

CHy-Ph

Fey or a salt thereof with nitrous acid, the reaction being carried out under the condftion customa- rily used, for example in a solvent or diluent, preferably in water, and/or while cooling, at room temperature or while heating, for example in a temperature rangé of from approximately -20 to approximately +150°C. THe nitrous acid is preferably produced in situ, for example by reacting am alkali metal nitrite, such as sodium nitrite, with a strong protonic acid, for example . a hydrohalic acid, such as hydrochloric acid, or a lower alkanecarboxylic acid, such as formic acid or glacial acetic acid.

In an especially preferred form of process variant d), the compounds Va or salts thereol¥ are reacted as described hereinbefore with, for example, nitrous acid that has heen produced in situ, and the salts V initially formed are then, without isolation and/or additional pupification, cyclised in situ in accordance with the invention to the desjved compounds I or salts thereof.

Pp ey

The compounds Va or salts thereof are known or can be produced anslogously to known methods.

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

Nucleofugal leaving groups xX, in compounds

Vil are, for example, those of the kind indicated under process variant a). . The reaction of a compound VI wlth compound VII is carried out in customary manner, for example in the presence of a basic condensing agent or, advantageously, by using the component of formula VI in the form of one of its metal salts, at room temperature or, preferably, while heating, for example in a temperature range of from approximately 20 to approximately 200°C,

CY especially from spproximately 50 to approxi- mately 150%¢C, in an inert solvent or diluent, . for example of the kind mentioned hereinbefore, and/or under an inert gas, such as nitrogen.

Suitable basic condensing agents are especially basic condensing agents that form salts with component VL, for example the basic agents men- tioned under process varlant a). As mentioned, the conversion of component VI into one of its salts is especially advantageously carried out } in advance, for example, by reaction with one of the mentioned basic agents.

The starting materials VI are known or can be produced analogously to known methods, for example corresponding to process variant d) by cyclisation of corresponding salts V, which carry an unsubstituted amino group in the 4- position instead of =a ~NH-CH,-Ph group. The starting materials VII are known or can be obtained analogously to known methods.

Compounds of formula 1 obtainable in accordance with the process or in some other betyy way can be converted into different compounds of formula ! by converting one or more variables of the general formula I into other variables.

For example, unsubstituted amino R, and/or

R, in compounds I can be converted into N-mono- or N,N-di-lower alkylamino, and N-mono-lower alkylamino R, and/or R, can be converted into

N,N-di-lower alkylaminb, for example by treatment with a reactive ester of a lower alkanol, wuch as a lower alkyl halide, for example a lower alkyl bromide or iodide, a lower alkanesulphonate, for example methanesulphonate, an optionally substituted arylsulphonate, such as benmenesul- phonate or p-toleuenesulphonate, or a di-lower alkyl! sulphate, for example dimethyl sulphate, preferably under basic conditions, such as in . the presence of sodium hydride or of sodium hydroxide sotution or potassium hydroxide solution and advantageously in the presence of a phase transfer catalyst, such as tetrabutyl- ammonium bromide or benzyltrimethylammonium chloride. In the course of such a conversion either only one N-lower alkyl group may be oo

Ley introduced, or it is possible in a single re- action sep also for several, especially from 2 up to and including 4, N-lower alkyl groups to be introduced. it is also possible in successive reaction steps with suitable mlection of the lower alkyl components for dif- ferent N-lower alkyl groups to be introduced fnto unsubstituted amino or N-morio-lowert alkylamino R, and/or R,. According to this method of N-alkylation, in each case compounds { are obtained in which the N-lower alkyl groups {ntroduced in the same reaction step are all the same. ‘

In analogous manner it is also possible for a N~lower alkyl group to be introduced into N-(hydroxy-lower alkyl)amino, N-monocyclo- alkylamino, N-mono(cycloalkyl-lower alkyl)amino and N-lower alkanoylamino R, and/or R,, re- sulting in N-{(hydroxy-lower alkyl)-N-lower alkylamino, N-cycldalkyl-N-lowver alkylamino,

N-(cycloalkyl-lower alkyl)-N-lower alkylamino and N-lower aslkanoyl-N-lower alkylamino R, and/or R,-

2d yy ’ Similarly, with corresponding expedient modification of the alkylation components it is also possible to convert unsubstituted amino R, and/or R, {nto N-(lower alkoxy-lower alkyl )amino R, and/or R, by the introduction of a N-(lower alkoxy-lower alkyl) group, into

N-(hydroxy-lower alkyl)amino Ry and/or R, by the introduction of a N-(hydroxy-lower alkyl) group, into N-mono- or N,N-di-cycloalkylamino

R, and/or R, by the introduction of one or more, especiallyfifrom 2 up to and including 4,

N-cycloalkyl group(s), or into N-mono- or

N,N-di-(cycloalkyl-lower alkyl )amino Ry and/or by the introduction of one or more especially from 2 up to and including 4, N-(cycloalkyl- lower alkyl) group(s), and also to convert : N-lower alkylamino R, and/or R, into N-(hydroxy- lower )alkyl)-N-lower alkylamino Ry and/or R, by the introduction of a N-(hydroxy-lower alkyl) group, into N-cycloalkyl-N-lower alkylamino

R, and/or R, by the introduction of a N-cyclo- alkyl group, or into N-(cycloalkyl-lower alkyl)-

N-lower alkylamino Ry and/or Ry by the intro- duction of a N-(cycloalkyl-lower alkyl) group,

2 yyy ) and furthermore to convert N-monocycloalkylamina

R, and/or R, into N,N-dicycloalkylamino R, and/or R, by the introduction of a N-cyclo-~ alkyl group as well as to convert N-mono-(cyclo- alkyl-lower alkyl)amine R, and/or R, into N,N- di(cycloalkyl-lower alkyl)aminoe R, and/or R, by the introduction of a N-(cycloalkyl-lower alkyl) group.

Furtherrdtes, unsubstituted amino R, and/or }

R, can be converted into N-lower alkanoylamino

R, and/or R, by N-acylation, for example by reaction with a lower alkanoic scid, such ag formic, acetic or propionic acid, or a reactive derivative of such an acid, for example an acid halide, such as an acid chloride, an ester or, especially, an anhydride, for example acetyl chloride or acetic anhydride, Similarly,

N-lower alkylamino R, and/or R, can be converted into N-lower alkanoyl-N~lower alkylamino R, and/or R,. In these conversion it is again possible either to introduce only one N-acyl group, or to N-acylate both amino or N-lower alkylamine R, and amino or N-lower alkylamino

9 te foes

R, in one reaction step. It is also possible . by suitable selection of the acylating agents to introduce different N-acyl groups into un- . substituted amino or N-lower alkylamino R, and

R, in successive reaction steps. In each case compounds I are obtained in which the N-acyl groups that are introduced in the same reaction step are all the same.

Also, N-lower alkanoylamino R, and/or R, } can be converted into unsubstituted amino

R, and/or Ry» for example by reducfson, that is exchange of the acyl group(8) for hydrogen, for which purpose customary reduction system and reaction conditions are suitable, for example diborane, lithium aluminium hydride . in tetrahydrofuran, diethyl ether or dioxan, sodium borohydride/cobalt(I1) chloride, sodium borohydride/trifluoroacetic acid or trihalo- silanes, such as trichlorosilane. Furthermore,

N-lower alkanoylamino R, and /or R, can also be converted into unsubstituted amino R, and/or : R, by hydrolysis, the hydrolysis being carried \ -6 7-

egy out under customary reaction conditions, for example in aqueous solution, in the presence of a basic agent, especially, for example, in the presence of an alkali metal hydroxide or lower alkanolate, such as sodium or : potassium hydroxide or sodium methanolate, preferably in an organic solvent or diluent or cosolvent and/or while heating, preferably in a temperature range of from approximately 20 to approximately 150°, especially from . approximately 40 to approximately 100°C. In this process it is possible, depending on the number of equivalents of reducing agent or of basic agent used, to reduce or hydrolyse, respectively, only one or, if present, both sey group(s) to unsubstituted amino R, or

Ry» as the case may be.

Depending on the number of asymmetric carbon atoms, the novel compounds and their galts can form stereoisomers, for example diastereoisomers or enantiomers. Asymmetric carbon atoms may occur, for example in compounds

I or salts thereof, in corresponding lower alkyl! radicals Ry.

: | Gry

Resulting mixtures of isomers and mixtures of diastereisomers may be separated into their Te components on the basis of the different physical properties thereof by customary physical se- parating methods, for example by distillation, crystallisation and/or chromatography.

Resulting mixtures of enantiomers, for : example racemates, may be resolved according to ) known methods into the enantiomers, for example by recrystallisation from an optically active solvent, chromatography on chiral adsorbents, with the aid of suitable microorganisms, by cleaving with specific immobilised enzymes, by way of the formation of inclusion compounds, for example using chiral Crown ethers, in which process only one enantiomer is complexed, or by conversion into diastereoisomeric salts, for example by reaction of a basic end product racemate with an optically active acid, such as carboxylic acid, for example tartaric or malic acid, or sulphonic acid, for example camphorsulphonic acid, and separation of the ‘ 25

2d by diastereoisomeric mixtures obtained in this manner, [or example on the basis of the diffe- rent solubilities, into the diastereoisomers from which the desired enantiomer can be freed by the action of suitable agents. Advanta- geously, the more active stereoisomer is iso- lated in each case.

Further, resulting free compounds of the formula 1 having basic centres can be converted in a manner known per se into acid addition salts, for example by reacting a solution of "the free compound in a suitable solvent or mixoure of solvents with one of the afore- mentioned acids or with a solution thereof or wtih a suitable ion exchanger.

Resulting acid additians salts of compounds of the formula I can be converted in a manner known per se into the free compounds, for example by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or hydrogen carbonate, or ammonia, or with a suitable ion exchanger.

. ° | ZC yyy

Resulting acid addition salts of compounds of the formula 1 can he converted in a manner known per se into different acid addition salts, for example by treatment of a salt of * 5 an organic acid with a suitable metal salt, such as a sodium, barium or silver salt, of san acid in a suitable solvent in which the inorganic galt being formed is insoluble and thus deparates out from the reaction mixture. :

The novel compounds of the formula 1 and their salts can also be obtained in the form of their hydrates and/or may include other solvents, for example solvents optionally used for the crystallisation of substances present in solid form.

Depending on the procedure and reaction conditions, the compounds of the formulae I may be obtained in free form or in the form of . their salts.

Owing to the close relationship between the novel asnpounds of the formula I in free

2ayyy form and in the form of their salts, herein- before and hereinafter references to the free compoudds of the formula I shall, where appropriate, also include the corresponding salts, and references to salts shall, where appropriate, also include the corresponding free compounds of the formula I. : The invention relates also to those forms of the process in which one of the compounds obtainable as intermediate at any stage of the process is used ss starting material and the remaining steps are carried out, or 8 starting material {is usdd in the form of a salt or, especially, is formed under the re- action conditions.

The invention relates also to novel starting materials that have been developed specifically for the manufacture of the compounds according to the invention, especially the selection of starting materials resulting in the compounds of formula 1 referred to at the beginning as

CeYyy béing preferred, to processes for the manufac- ture thereof, and to their use as intermediates.

The invention likewise relates to the use of the novel compounds of formula I and the pharmaceutically acceptable salrs thereof, especially as pharmacological, espedially anti- convulsively effective, active substances, in which case they may be used, preferably in the formogf. pharmaceutical preparations, in a method for the prophylactic and/or therapeutic treat- ment of the animal or human body, especially as - anticonvulsives, for example for the treatment of convulsions of various origins, for example for the treatment of epilepsy.

The invention relates also to pharmaceu~ _ tical preparations that contain a compound of the formula I or a pharmaceutically acceptable salt thereof as active ingredient, and to processes for the manufacture thereof.

The pharmaceutical preparations according to the invention are Preparations that contain

2 yy a therapeutically effective amount of the active substance of the invention, optionally together with inorganic or organic, solid or liquid, . pharmaceutically acceptable adjuncts, and that are suitable for enteral, for example oral, or parenteral administration to warm-blooded animals,

Pharmaceutical preparations in dosage unit forms, such as dragees, tablets, capsules or supposi- tories and also ampoules, that contain the active ingredient together with diluents, for example : lactose, dextrose, saccharose, mannitol, sorbitol, cellulose and/or glycine, and/or lubricants, for example silica, talc, stearie acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, are preferably used.

Tablets may also contain binders, for example magnesium aluminium silicate, starches, such a8 corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodimm carboxy- methylcellulose and/or polyvinyl pyrrolidone and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent

Joye mixtures, adsorbents, colouring substances, flavourings and/or sweetness.

Also, the novel compounds of formula I may be used in the form of parenterally administrable preparations or in the form of infusion solutions.

Such solutions are preferably isotonic raqueous solutions or suspensions, it being possible, for example in the case of lyophillised preparations that contain the active ingredient on its own or together with a carrier, for example mannitol, to be prepared ' before use.

The pharmeceutical preparations may be sterilised and/or may contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.

The novel pharmacestical preparations . : which, if desired, may contain other pharma- cologically active substances, are produced in a manner known per se, for example by means of conventiongl mixing, granulating, confectioning, dissolving or lyophilising processes, and con- tain from approximately 0.17% to approximately guy 1007, especially from approximately 1% to approximately 50%, and in the case of lyo- philisses up to 100%, active ingredient.

The dosage may depend on various factors, such as mode of administration, species of warm-blooded animal, age and/or individual eondition. In the case of oral administration, } the daily dose administered is normally from ~ approximately 1 to approximately 30 mg/kg, : and in the case ol a warm-blooded animal weighing approximately 70 kg fs preferably from appro- . ximately 0.) g to approximately 3.0 g, and {tv is also possible for the daily dose to be divided for administration in several partial doses. \

The following Examples serve to illustrate the above-described invention but are not intended to limit the scope thereof in any way.

Temperatures are in degrees Celsius.

BN -~

Py

EXAMPLE 1

A soluifon of 9.22 g (35 mmol) of crude 7~-chloro-3-(2-fluorobenzyl)-3H-1,2,3-tria- zolol4,5-d]lpyrimidine in 150 ml of toluene is added dropwise, while stirring, to a mixvoure of 750 ml of ethanol and 200 ml of 40% aqueous ’ : methylamine solution. The whole is left to ] : stand for 15 hours at room temperature and then the solvent is distilled off under re- duced pressure. 500 ml of water are added to the residue. The precipitated product is filtered off with suction and recrystallised from methanol. In this manner 3-(2-fluoro- benzyl )-7-(N-methylamino)-3H-1,2,3-triazolo {4,5~d)pyrimidine having a melting point of 180-182% is obtained.

The 7-chlioro-3-(2~fluorobenzyl)-38-1,2, 3-

N ttiazolo~[4,5-d)pyrimidine can be obtained, for example, as follows: 70,5 g (0.3 mol) of S-amino-1-(2~fluoro- benzyl )-1H~1,2,3-triazole-4~carboxamide and

Ley yy 339 g (300 ml; 7.53 wol) of formamide are heated at a gentle boil for 2 hours. The reaction solution is then allowed to cool to approximately 100° and poured onto 2 1 of ice- water. The precipitated product is filtered off with suction and walhed with water.

Drying at 100° yields 3-(2-fluorobenzyl)-3H, 6H,7H-1,2,3-triazolol4,5-d]lpyrimidin-7-one having a melting point of 215-218°. : 18 g (73.5 mmol) of 3-(2-fluorobenzyl- 34,60,7H-1,2,3-triazolol4,5-d]-pyrimidin-7-one and 151 g (90 ml; 0.98 mol) of phosphorus oxytrichloride are heated under reflux for 4 hours and then, after having been cooled to room ’ temperature, diluted with 1 1 of toluene. Active carbon is added to the turbid solution and the whole is filtered through Hyflo. The filtrate is concentrated by evaporating under reduced pressure to approximately a quarter of its original volume. The crude 7-chloro- 3-(2-fluorobenzyl)=3H-1,2,3-triazolol4,5-d] pyrimidine can be further used in the form of the toluene solution without additional purification.

EXAMPLE 2 7-(N,N-dimethylamino)=3-(2-fluorobenzyl)- _3H-1,2,3-triazolo-[4,5-dlpyrimidine {s obtained {in a manner analogous to that described in

Example | starting from 7-chloro-3-(2-fluoro- benzyl)-3H-1,2,3-triasoto=[4,5-dlpyrimidine and using dimethylamine. It has a melting point of 117-119° after recrystallisation from toluene/cyclohexane.

EXAMPLE 3 6.9 g (26 mmol) of 3-(2,6-difluorobenzyl)- 38, 6H,7H-1,2,3-triazolol4,5-d]pyrimidin-7-one and 50.5 g (30 ml; 327 mmol) of phosphorus oxytrichloride are heated under reflux for 1 hour. After having been cooled to room tem- perature, the reaction solution is diluted with 300 ml of xylene. Active carbon is added to the turbid solution and the whole is filtered tbhrough Hyflo. . The filtrate is concentrated by evaporation udder reduced pressure at 60° -79~- ow

2adyy to approximately a quarter of its initial volume. This solution of crude 7-chloro- 38(2,6-difluorobenzyl)-3H-1,2,3-triazolo-~ {4,5-d]lpyrimidine in xylene is poured into a stirred mikture of 400 ml of ethanol and 100 ml of 40% aqheous methylamine solution. After one hour, the reaction mixture is concentrated by evaporation under reduced pressure and the residue {8s treated with water. The preci- piteted crude product is filtered off with : suction and recrystallised from methanol, The cesulting 3-(2,6-difluorobenzyl)-7-(N-methyl- amino-3H-1,2,3-triazolo-[4,5-d)pyrimidine has a melting point of 225-221°.

The 3-(2,6-difluorobenzyl)-3H,6H,7H~1,2,3~- triazolo-[4,5-d)pyrimidin-7-one can be produced, for example as follows: 7.6 g (30 mmol) of S-amino-1-(2,6-difluoro~ benzyl)-1H-1,2,3-triazole-4-carboxamide and B 84.7 g (75 ml; 1.88 mol) of formamide are heated under gentle reflux for 45 minutes. i 25

2c yy

After having been cooled to approximately 100°, the reaction solution is poured onto 400 ml of ice-water and the precipitated product is filtered off with suction. It is washed with water and dried. The resulting 3- (2,6-difluorobenzyl)-3H,6H,78-1,2,3-triazolo [4,5-d)pyrimidin-7-one has a melting point of 236-237°.

EXAMPLE 4

In a manner analogous to that described in Example 3 there is obtained, starting from 36(2-fluorobenzyl)-5-methyl-3H,6H,7R~1,2,3- triazolol4,5-d)lpyrimidin-7-one, 7-chloro-3- (2-fluorobenzyl)-5-methyl-3H-1,2,3-triazolo {4,5-d)pyrimidine and, from this, 3-(2-fluoro- benzyl)-S-methyl-7-{(N-methylamino)3H-1,2,3- titazolols,5-dlpyrinidine having a melting point } of 204-206° (from methanol).

The 3-(2-fluorobeneyl )}5-methyl-3H,6H,7H- 1,2,3-triazolol(4,5-d)pyrimidin-7-one can be oo obtained, for example, in a manner analogous to that described in Example 3 by heating 5.9 g (25 mmol) of 5-amino-1-(2-fluorobenzyl)- 1H-1,2,3-triazole-4-carboxamide and 59 g Nhe, (1 mol) of acetamide for two hours at 230°; it has a melting polnt of 218-220°. : EXAMPLE 5 5 g (23 mmol) of 5-amino-4-cyano-1-(2- fluorobenzyl)-1R-1,2,3-triazole and 45 g (40 ml; ‘ 1! mol) of formamide are heated for 3 hours at 180°. - The whole is cooled to room temperature and then diluted with 100 ml of water. The . precipitated product is filtered off with suction and recrystallised from 75% acetic acid. The resulting 7-amino-3(2-fluorobenzyl)-38-1,2,3~ triazolol4,5-dlpyrimidine has a melting point of 254-257°.

EXAMPLE 6

In a manner analogous to that described in

Example 5, 7-amino-3-(2-fluorobenzyl)-5-methyl-

2¢ fy 3H-1,2,3-triazolol4,5-g)pyrimidine having melting point of 242-244° is obtained by re- acting 5-amino-4-cyano-1-(2-fluorobenzyl)- 1H-1,2,3-triazote with acetamide.

EXAMPLE 7 : 1t is also possible for the following to be produced in a manner analogous to that des- cribed in Examples 1 to 6: . 7-(N-acetylamino)-3-(2-fluorobenzyl)-3H-1,2,3- ttiazolo{4,5-d]lpyrimidine and : 7-(N-acetyl-N-methylamino)=3-(2-fluorobenzyl)- i 3H-1,2,3-triazolol4,5-d)pyrimidine.

EXAMPLE 8

There is obtained in a manner analogous to tha. described in Example 3, starting from 3-(2- chlorobenzyl)-3H,6H,7H-1,2,3-triazolol4,5-d]

2aYy, : 71

Pyrimidin-7-one, 7-chloro-3-(2~chiorobenzy))- 3-1,2,3~triazo0l0l4,5-d) pyrimidine and, from this, by reaction with methylamine, 3-(2- chlorobenzyl)-7-(N-mechylamino)-3m-1,2, 3-¢ rq. : zolo(4,5-d)pyrimidine having a melting point of 192-194° (from ethanol) or, by reaction with dimethylamine, 3-(2-chlorobenzyl)-7-(N,N-di- methylamine) =31-1,2,3-trisz01004,5-d)-pyrinidine having a melting point of 131-133°C (from acetonitrile).

The 3-(2-chlorobenzy1)-3u, 60, 70-1,2, 5- triazolol4,5-d)pyrinmidine-7-one is obtained, for example, in a manner analogous to that described in Example 3, by heating S-amino- : 1=(2-chlorobenzy1)-10-1,2,3-triazole-4-carpo. xamide and formamide [m.p.: 285-288°¢ (decom- ’ position; from glacial acetic acfid)].

EXAMPLE 9

There is obtained in a manner analogous to that described in Example 3, starting from

“Cy 3-(2-methylbenzyl)-3H,6H,70-1,2,3-trfiazolo-~ (4,5-d)pyrimidine-7-one, 7-chloro-3-(2- methylbenzyl)-3H-1,2,3-triaeolo-[4,5-d] pyrimidine and, from this, by reaction with methylamine, 7-(N-methylamino)-3-(2-methyl- benzyl)-3H-1,2,3-triazolol4,5-d)lpyrinidine having a melting point of 193-195° (from methanol).

The 3~(2-methylbenzyl)-3H,6H,7H~-1,2,3~ triazolo(4,5~-d)pyrimidin-7-one is obtained, for example, in a manner analogous to that des- cribed in Example 3 by heating 5-amino-1- ’ (2-methylbenzyl)-1H-1,2,3-triazole-4~-carbo~ xamide and formamide [m.p.: 265-267° (from glacial acid)]. : EXAMPLE 10

There is obtained in a manner analogous to that described {n Example 3, starting from 3-(3-fluorobenzyl )-3U,6H,70~1,2,3-triazolo- (4,5-d)pyrimidine-7-one, 7-chloro-3-(3-fluoro- benzyl )~3H-1,2,3-triazolo [4,5-d)pyrimidine

. Jedlyy and, from this, by reaction with methylamine, 3-(3-fluorobenzyl)-7-(N-methylamino)-3H-~1, 2,3-triazolol4,5-d]pyrimidine having a melting point of 187-189" (from toluene).

The 3-(3-fluorobenzyl)-3R,6H,7H-1,2,3- triazolol4,5-d)lpyrimidin-7-one is obtained, for example, in a manner analogous to that described in Example 3 by heating 5-amino-1- (3-fluorobenzyl)-1H-1,2,3-triazole-4~-carbox~ : amide and formamide [m.p.: 235-237° (from 50% acetic acid)3.

EXAMPLE 11

There is obtained in a manner analogous to that described in Example 3, starting from : 3-(4~-fluorobenzyl)-3H,6H,7H-1,2,3-triazolo- f{4,5-d] pyrimidine~7-one, 7-chloro-3-(4- fluorobenzyl)-3H-1,2,3-triazolo-[4,5~d]lpyrimidine and, from this, by reaction with methylamine, 35(4-fluorobenzyl)-7-(N-methylamino)~3H~1,2,3- triazolol4,5-d)pyrimidine having a melting point

9 Ivy of 221-223° [from ethyl acetate/ethanol (1:1)]. . The 3-(4-fluorobenzyl)-3H,6H,7H-1,2,3- triazolol4,5-d)pyrimidin-7-one is ohtained, for example, in a manner analogous to that des-~ cribed in Example 3 by heating S-amino-1- . (4-fluorobenzyl)-10~1,2,3-triazole-4-carboxamide and formamide [m.p.: 230-232° (crude product)].

EXAMPLE 12 2.8 g (10 mmol) of 5-amino-7-chloro-3- (2-fluorobenzyl)-3H,1,2,3-triazolol4,5-4d] pyrimidine are dissolved {n 150 ml of ethanol while heating at 40-50°, and 10 ml of an aqueous solution of dimethylémine (402) {is . added to the resulting solution. The reaction mixture is left to stand at room temperature ~ 20 for 2 hours. The precipitated product is then filtered off with suction and washed with water. Recrystallisation from ethanol yields

S-amino-7-(N,N-dimethylamino)-3-(2-fluorobenzyl)-

Jy yy 3H-1,2,3-triazolo{4,5-d]pyrimidine having a melting point of 165-167°.

The 5-amino-7-chloro-3-(2-fluorobenzyl)- 38-1,2,3-triszolol4,5~d)-pyrimidine can be produced, for example, as follows: 53 g (323 mmol) of 2-amino-4,6-dichloro- pyrimidine, 40.4 g (323 mmol) of 2-fluorobenzyl- amide add 33.4 g (330 mmol) of triethylamine ’ are dissolved in 806 ml of ethanol and the reaction mixture is heated under reflux ofor 20 hours, After 400 ml of ethanol have been distilled off, the residue is diluted with 500 ml of water, and the precipitated product is filtered off with suction and recrystallised from | 1 of toluene. In this manner 2-amino- - . b-chloro-6-(2-fluorobenzylamino)-pyrimidine having a melting point of 130-133" is obtained.

A solution of 11.5 g (90 mmol) of 4- chloroaniline in 33 ml of concentrated hydro- chloric acid and B0 ml of water is diazotised at from 0 to 5° with a solution of 6.2 g (90 mmol)

Aayyy of sodium nitrite in 30. ml of water.

This diazonium salt solution is then added drop- wise at from 14 to 17° to a mixture of 20.6 g (81.5 mmol) of 2-amino-4-chloro-6-(2- fluorobenzylamino)-pyrimidine and 68 g (500 : mmol) of crystalline sodium acetate in 500 ml of 65% acetic acid.

The reaction mixture is stirred for 40 hours at room temperature, and the precipitated product is then flltered off and washed several times with water.

Drying at room temperature over calcium chloride ylelds . 2-amino-h-chloro-6-(0-fluorobenzylamino)- pyrimidine-5-azo-(4'-chlorobenzane) in the form : of a yellow crystalline powder having a melting point of 215-225° (decomposition).

59 g (151 mmol) of 2-amino-4-chloro-6~- (o-fluorobenzylamino)-pyrimidine-5-azo-(4"'- chlorobenzene) are suspended in 3 1 of sO %

ethanol and 160 ml of acetic acid and 124 g (1.9 mol) of zinc dust is introduced into the suspension in portions et 70° over a period of | hour under argon.

The whole is stirred

Deyyy for a further 5 hours at 70° and then exceas zinc is removed by filtration. The filtrate is concentrated in vacuo to thalf its volume and then rendered strongly alkaline by bhe addition of 240 m) of concentrated sodium hydroxide solution, The product is extracted from the mixture using ethyl scetate. After the ethyl acetate has been distilled off, the residue ig recrystallised firar from toluene : and then from acetonitrile, In this manner dehloro-2,5-dlamino-6=(2-fluorobenzy) amine). pyrimidine is obtained in the form of brown- red crystals having a melting point of 180- 182°, 15 .

A solution of 4,5 8 (65 mmol) of sodium nitrite in 100 mi of water is added dropwise o at 0° to a suspension of 16 g (60 mmol) of 4- chlore-2,5-diamino-6-(2-fluorobensylanin)- pyrimidine in 200 ml of 25 X acetic acid while stirring vigorously, The whole ig stirred at room temperature for 2 hours and then the

Product is filtered off with suction. Re - crystallisation from ethyl acetate /hexane yields

* 2c Yyy 5~amino-7-chloro-3-(2~fluorobenzyl)-3H-1,2,3- triazolo[4,5-d]lpyrimidine having a melting point of 149-151°. . 5 EXAMPLE 13

S-amino-3-(2-fluorobenzyl)-7-(N-methyl~- amino 3H-1,2,3-triazolol4,5-d)pyrimidine having a melting point of 252-254% (dioxan/tolaene) is obtained in a manner analogous to that des- cribed in Example 12 by reacting 5-amino-7- chloro-3-(2-fluorobenzyl)-34-1,2,3-triagolo {4,5-d)pyrimidine with methylamine.

EXAMPLE 14

There is obtééined in a menner analogous to : “that described in Example 3, starting from 3- - (3-trifluoromethylbenzyl)-3H,6H,7H-1,2,3~ triazolo(4,5-)pyrimidin-7-one, 7-chloro-3-(3- tribluoromethylbenzy!})-31,1,2,3-triazolo(4,5-4d] pyrimidine and from this, by reaction with methylamine, 7-(methylamino)3-(3-trifluoromethyl- 25 .

2 GYyy benzyl)-3H-1,2,3triazo0lol4,5-d pyrimidine having a melting point of 211-213° (from ethyl acetate) or, by reaction wich dimethylamine, 77H, N-dimechylamine)-3-(3-criluoromethyi- benzyl)-3M-1,2,3-triazolol4,5-dIpyrinidine having 8a melting point of 100-101° (from methanol).

The 3-(3-trifiuoromethyibensyl)-3n, gu,

TH-1,2,3~triazolol4,5-d)pyrinidin-7-one is obtained, for example, in a manner analogous to that des - cribed in Example 3 by heating 5-amino-1~(3- trifluoromethylbenzy1)-11-1,2,3-triaz01e-4- carboxamide and formamide (m.p.: 202-2049),

EXAMPLE 15

A mixture of 0.82 g (10 mmol) of dimethyl- amine hydrochloride, 1.27 g (10 mmol) of N- cyclohexyl-N,N-dimethylanine and 1.42 g (10 mmol) of phosphorus pentoxide fs heated for 15 minutes at 200°, and then 0.49 g (2 mmol) of 3-(2-fluore- benzyl )-3yu, 61,78-1,2,3-triazolol4,5-d])pyrimidin- -7-one is added to the resulting mele. The reaction mixture {8s maintained at 200° for 2 hours, then cooled to 100° and treated with 25 ml of water. After having been cooled to room temperature, the precipitated 3 product is filtered off with suction, dissolved in 25 ml of ethyl acetate and the solution is

Co dried over sodium sulphate. The ethyl acetate solution is concentrated by evaporation, the residue is recrystallised from toluene/cyclo- hexane and in this manner 7-(N,N-dimethylamino)- 3-(2-fluorobenzyl)-3H,1,2,3-triazolol4,5-4d) pyrimidine having a melting point of 117-119° is obtained.

The 3-(2-fluorobenzyl)-3H,6H,7H-1,2,3~ triazolol4,5-d)lpyrimidin-7-one is obtained, for example, in a manner analogous to that des- cribed in Example 3 by heating 5-amino-1- } (2-fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide and formamide.

Jeryyy

EXAMPLE 16

In a manner analogous to that described in Example 12, 1.95 g (6.36 mmol) of 7-chloro- 3-(N,N-dimechylamino)-3-(2-fluorobenzyl )-3H- 1.2,3-triazolol4,5-d)pyrimidine are dissolved in 200 ml of warm ethanol, 7 ml of aqueous dimethylamine solution (40 X) are added and the mixture is left to stand for 30 minutes. After dilution with 200 ml of water, the product {is filtered off with suction and recrystallised from ethanol, In this manner 5,7-bis(N,N- dimethylamino)-3-(2-fluorobenzyl)-3n-1,2, 3- triazolol4,5-d]lpyrimidine having a melting point . of 123-25° is obtained.

The 7-chloro-5-(N,N-dimethylamino)=-3-(2~ fluorobenzy1)-30-1,2,3-triazolo-[4,5-d)pyrinidine . can be produced, for example, as follows:

Analogously to Example 12, 13.9 g (110 mmol ) of 2-fluorobenzylamine, 21.3 g (110 mmol) of 4,6-dichloro-2-(N,N-dimethylamino)-pyrimidine ayy and 11.5 g (114 mmol) of triethylamine are dissolved in 300 ml of absolute ethanol and - the mixture is heated under reflux for 48 hours. After the ethanol has been removed by distillation, water is added to the residue, the product is filtered off with suction and recyystallisation from cyclohexane yields 4- chloro-2-(N,N-dimethylamino)-6~(2-fluorobenzyl- amino)-pyrimidine having sa melting point of 71-73%, 4-chloro-2-(N,N-dimethylamino)-6-(o-{luoro- benzylamino)-pyrimidine~-5-azo-(4'~chlorobenzene) having a melting point of 175-176° (decomposition) is obtained analogously to Example 12 from 16 g (57 mmol) of 4-chloro-2-(N,N-dimethylamino)- 6-(2-fluorobenzylamino)-pyrimidine and 62 mmol + of p-chlorophenyl-diazonium chloride In aqueous acetic acid with 46.5 g (340 mmol) or crystalline sodium acetate.

The 4-chloro-2-(N,N-dimethylamino)-6~(o- fluorobenzylamino)-pyrimidine-5-azo-(4"'~-chloro- benzene) is reduced with zinc dust in ethanol/

Jey water /acetic acid analogously to Example 12 yielding 5-amino~4-~chloro-2-(N,N~-dimethylamino)- 6-(2-fluorobenzylamino)-pyrimidine having s : melting point of 103-105° (from cyclohexane).

By reacting 6.8 g (23 mmol) of S5-amino- b-chloro-2-(N,N-dimethylemino)-6-(2-fluoro- benzylamino)-pyrimidine {mn 150 ml of 50 X acetic acid with 1.84 g (26.7 mmol) of sodium nitrite analogously to Example 12, 7-chloro-5-(N,N~ : : dimethylamino)-3-(2-fluorobenzyl)-3H-1,2,3- triazolo(4,5-d)-pyrimidine having a melting point of 153-155 (from acetonitrile) is obtained. 1s EXAMPLE 17 5-(N,N~dimethylamino)~3-(2-fluorobenzyl)- } 7-(N-methylamino)-3H,1,2,3-triszolof4,5-4] pyrimidine having a melting point of 199-200° (from ethanol) is obtained in a manner analogous to that described in Example 16 using aqueous monomethylamine solution (40 2%). :

Cs 2 G4qy

EXAMPLE 18 ‘ It is also possible to produce the fol- lowing in a manner analogous to that described in Examples ! to 17: 7-(N-methylamino)-3-(2-tribluoromethylbenzyl)- 3H-1,2,3-triazolof[4,5-d]-pyrimidine, 7-(N-methylamino)-3-(4-trifluoromethylbenzyl)- 3H-1,2,3-triazolol4,5-d)-pyrimidine, 3-(2-cyanobenzyl)-7-(N-methylamino)-3H,1,2,3- triazolol4,5-d]lpyrimidine, : 3-(3-cyanobenzyl)-7-(N-methylamino)-3H-1,2,3- ttirzolol4,5-dlpyrimidine and 3-(4-cyanobenzyl)-7-(N-methylamino)-3H-1,2,3- triazolol4,5-d)pyrimidine.

24g

EXAMPLE 19

Tablets each containing 50 mg of the active ingredient, for example 3-(2-fluoro~- benzyl )-7-(N-methylamino)-3H-1,2,3-triazolo [4,5-d)-pyrimidine or a pharmaceutically acceptable salt thereof, can be produced as follows:

Composition (for 10,000 tablets): active ingredient 500.0 g lactose 500.0 g potato starch 3152.0 g gelatin 8.0 g 3 talc 60.0 g oo magnesium stearate 10.0 g silicon dioxide (highly dispersed) 20.0 g : ethanol q.8.

The active ingredient is mixed with the : lactose and 292 g of potato starch, and the : mixture is moistened with an alcoholic solution 23 -Qf-~ oo J yyy of the gelatin and granulated through a sieve.

After the granulate has been dried, the re- mainder of the potato starch, the talc, the } magnesium stearate and the highly dispersed silicon dioxide are mixed in and the mixture is compressed to form tablets each weighing 145.0 mg and containing 50.0 mg of active ing- redient which, if desired, may be provided with ‘ dividing notches for finer adaptation of the dose.

EXAMPLE 20

Film-coated tablets each containing 200 mg of active ingredient, for example 3-(2~fluoro- benzyl)-7-(N-methylamino)-3H-1,2,3-triazolo {4,5-dlpyrimidine or a pharmaceutically acceptable galt thereof, can be produced as follows:

Composition (for 500 tablets): active ingredient 100.0 g lactose 100.0 g corn starch 70.0 g 25 . -99-~ t tale 8.50 g : calcium stearate 1.50 g hydroxypropylmethylicellulose 1.18 g shellac 0.32 g water. q.8. dichloromethane q.s.

The active ingredient, the lactose and 40 g of the corn starch are mixed and moistened with a paste produced from 15 g of corn starch h and wager (while heating), and granulated. The granulate is dried, and the reminder of the corn starch, the talc and the calejium stearate are added and mixed with the granulate, The mixture is compressed into tablets (weight: 560 mg) and the tablets are film-coated with =o solution of hydroxypropylmethylcellulose and the shellac fin dichloromethane; final weight: 563 mg.

EXAMPLE 21

In a manner analogous to that described in Bxample 19 and 20 it is also possible to

. . Cr yy produce pharmaceutical preparations containing a different compound of formula I or a pharmaceyt ically acceptable salt thereof, for example according to Examples | to 18. 5 .

Claims (19)

: wd yyy Patent Claims

1. A compound of formula Ry B N

N- . N\ ro _ Xx. ot J Ry SN ¥ ) CH,~Ph in which Ph represents a phenyl radical subati- tuted by halogen, C,-C,-alkyl, trifluoromethyl and/or by cyano, Ry represents amino or N-mono- or N,N-di-C -C,-alkylamino, and R, represents hydrogen, C,-C,-alkyl, amino or ¥,N-di-C,-C 6 -alkylamino, in free form or in form of pharmaceutically acceptable salt, with the proviso, that in a compound of formula I in free form, wherein Ry represents N,N-di-C,-C, ~alkyl- amino in which the two N-C,-C,-alkyl groups may be the same or different, N-mono-C, -C,-alkylamino

Fed yy or amino, R, is other than hydrogen and other than C,-C,9alkyl, if Ph represents a phenyl radical which is monosubstituted by halogen or by trifluo- tromethyl, and a compound of formula I in [ree form wherein Ph is o-fluorophenyl, R, {is N-mono- methylamino or amino, and R, is hydrogen or methyl or wherein Ph is o-fluorophenyl, o-chlorophenyl or m-trifluoromethylphenyl, R, is N,N-di-methylamino, and R, is hydrogen or wherein Ph is m-fluorophenyl, p-fluorophenyl, o-chlorophenyl, o-trifluoromethyl- phenyl, n-trifluoromethy)phenyl or p-trifluoro-~ methylphenyl, R, ig N-mono-methylemino, and R, is hydrogen.

2. A compound according to claim | of formula I, in which, in consideration of the proviso men- tioned in claim t, Ph represents a phenyl radicsl that is substituted by at least one halogen atom, R, represents amino or N-mono- or N,N-di-C,-C,- alkylamino, and R, represents hydrogen, C,~C,-alkyl,

ly amino or N,N-di-C,-C, ~alkylamino, in free form or in form of a pharmaceutically acceptable salt, and a compound of formula 1 in free form wherein Ph is o-fluorophenyl, R, is N-mono-methylamino or amino, and R, is hydrogen or methyl or wherein Ph is o-fluorophenyl or o-chlerophenyl, R, is N,N- di-methylamino, and R, is hydrogen or wherein Ph is m-fluorophenyl, p-fluorophenyl or o-chloro- - phenyl, R, is Nemono-methylamino, and R, is hydrogen. : ©

3. A compound according to claim | of formula I, in which, In consideration 61 the proviso mentioned . fn claim 1, Ph represents 2-, 3- or 4-halophenyl, 2,6-dihalophenyl, 2- C,~C,-alkylphenyl, 2-, 3- or 4-trifluoromethylpheny] or 2-, 3- or h-cyanophenyl, wherein halogen may in each case be halogen having an stomic number of up to and including 35, R, rep- resents amino, N-mono-C,-C, -alkylamino or N,N- di-C,-C, ~alkylamino, and Ry represents hydrogen, Cy- c,-alkyl, amino or N,N-di-C,-C, -alkylamino, {n free form or in form of a pharmaceutically acceptable salt, and a compound co SCY yy of formula I in free form wherein Ph Is o-fluorophenyl, Ry is N-mono-methylamino or amino, and R, is hydro- gen or methyl or wherein Ph is o-fluorophenyl, o- chlorophenyl or m-trifluoromethylphenytl, R, is N,N- di-methylamino, and R, is hydrogen or wherein Ph is m-fluorophenyl, p-fluorophenyl, o-chlorophenyl, ’ o-trifluoromethylphenyl, m-trifluocromethylphenyl or p-trifluoromethylphenyl, R is N~-mono-methylamino, } and R, is hydrogen.

4, A compound according to claim 1 of formula I, in which, in consideration of the proviso mentioned in claim 1, Ph represents 2-halophenyl or 2,6-dihalo- phenyl, wherein halogen may in each case be halogen having an atomic number of up to and including 35, R, represents amino, N-mono-C, -C,-alkylamino or SR N,N-di-C,-C,-alkylamino, and R, represents hydrogen, C,-C alkyl, amino or N,N- di-C,-C,-alkylanino, in free form or in form of a pharmaceutically acceptable salt, and a compound of formula 1 in free form wherein Ph is o-fluorophenyl, R, {8s N-mono-methylamino or amino, and R, is hydrogen or methyl or wherein Ph is o-fluorophenyl or ayy o-chlorophenyl, R, fs N,N~-dl-methylamino, and R, is hydrogen or wherein Ph is o-chlorophenyl, R, is N-mono-methylamino, ‘and R, is hydrogen, ‘

5. A compound according to claim | of formuls I, in which, in consideration of the proviso men- ’ : tioned in claim 1 Ph represents 2- or 3-flurophenyl, 2-chlorophenyl, 2,6-difluorophenyl or 2-¢,-C,- alkylphenyl, Ry represents N-mono-C,-C,~alkylamino or N,N-di-C -C, ~alkylamino, and R, represents hydro- } gen, C,-C,-alkyl or amino, in free form or in form of a pharmaceutically acceptable salt, and a com- potind of (ormula I in free form wherein Ph {is o- fluorophenyl, R, is N-mono-methylamino, and R, is hydrogen or methyl or wheeein Ph is o-fluorophenyl or o-chlorophenyl, R, is N,N~di-methylamino, and R, is hydrogen or wherein Ph is m-fluorophenyl or o-chlorophenyl, Ry ia N-mono-methylamino, and R, is hydrogen.

6. A compound according to claim 1 of formula |, in which , in consideration of the proviso men- tioned in claim 3, Ph represents 2-fluorophenyl oo 2 yyy or 2,6-difluorophenyl, Ry represents amino, K- mono-C,-C,~alkylamino or N,N-di-C,-C, -alkyl- amino, and R, represents hydrogen or C,-C alkyl, in free form or in form of a pharmaceutically acceptable salt, and a compound of formula I in free form wherein Ph is o~fluorophenyl, R, is N-mono- methylamine or amino, and R, is hydrogen or methyl or wherein Ph is o-fluorophenyl, R, is N,N~-di~methy]- : amino, and R, is hydrogen.

7. A compound according © claim ) of formule 1, in which, in consideration of the proviso mentioned in claim 3, Ph represents 2-fluorophenyl, Ry represents N-gono-C,-C, -alkylamino or N,N-di-~ C,~C,-alkylamino, and R) represents hydrogen or amino, in free form or in form of a pharmaceutically acceptable salt, and a compound of formula I in free form wherein Ph is o-fluorophenyl, R, is N-mono- methylamino, and R, is hydrogen or wherein Ph is o-fluorophenyl, R, is N,N-di-methylamino, and R, is hydrogen.

i : yyy

8. A compound according to claim 1 being 3- (2-fluorobenzyl)-7-(N-méthylamino)~3H-1,2,3-triazolo {4,5~-d)pyrimidine or a pharmaceutically acceptable salt thereof.

: 9. A compound according to claim 1 being 7-(N,N- dimethylamino)~3-(2-fluorobenzyl)-3H-1,2,3- a triazolol4,5-dlpyrimidine or a pharmaceutically acceptable salt thereof,

10. A compound according to claim | being 3-(2,6- difluorobenzyl)-7-(N-methylamino)-3H1-1,2,3-triazolo [4,5-d)pyrimidine or a pharmaceutically acceptable salt thereof. .

11. A compound according to claim 1 being 3-(2- : fluorobenzyl)-5-methyl-7-(N-methylamino)-3H-1,2,3~ triazoloBa,5-d)pyrimidine or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1 being I-(2- : chlorobenzyl)-7-(N-methylamino)-30-1,2,3-triazolo {4,5-d)pyrimidine or a pharmaceutically acceptable salt thereof.

=. 2

13. A compound according to claim 1 being 3-(2- chlorobenzyl)-7-(N,N~dimethytamino)~3H~1,2,3- triazolo[4,5-d)pyrimidine or a pharmaceutically acceptable salt thereof.

14. A compound according to claim } being 7-(N~- methylamino)-3-(2-methylbenzyl)~3H-1,2,3-triszolo [4,5-d)pyrimidine or a pharmaceutically acceptable salt thereof. :

15. A compound according to claim 1 being 3-(3-fluo- tobenzyl)-7-(N-methylamino)-3H-1,2,3-triarolo(4,5-d] } pyrimidine or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 1 being 5-eamino- 7-(N,N-dimethylamino)~3-~(2-fluorobenzyl)-3H-1,2,3~ triazolo[4,5-d)}pyrimidine or a pharmaceutically acceptable salt thereof.

17. A pharmaceutically preparation containing an } anticonvulsively effective amount of s& compound according to claim 1 in free form or in form of a pharma- ceutically acceptable salt in addition to pharma- C ceutically acceptable adjuncts.

DC RE Ivy

18. A Pharmaceutical . preparation according to claim 17 containing an anticonvulsively effective amount of a8 compound of the formula i - N, ' = aN ~~ NN I y ING ON 7 (ny, SSN SN

R . 2 CH,-Ph - in which Ph is a phenyl radical which is mono-~ substituted by halogen or by trifluoromethyl, R, is N,N-di-C,-c,-alkylamino in which the two N-C,-C,- alkyl 8roups may be the same or different, N- mono-C,-C,-alkylanino or smino, and R, is hydrogen or C1-C4-alkyl, in form of a pharmaceutically acceptable salt in addition to pharmaceutically acceptable adjuncts.

-T Zoey yy

19. A pharmaceutical preparation according to claim 17 containing an anticonvulsively effective amount of a compound of the formula Ce . _N ~~ \, J (1), nd oN CN 2 CH,~Ph wherein Ph is o-fluorophenyl, R, is N-mono-methyl~- amino or amino, and R, is hydrogen or methyl or wherein Ph {8 o-fluorophenyl, o-chlorophenyl or m- trifluoromethylphenyl, R, is N,N-di-methylamino, and R, is hydrogen or wherein Ph is m-fluorophenyl, p= fluorophenyl, o-chlorophenyl, o-trifluoromethyl- ’ phenyl, m-trifluoromethylphenyl or p-trifluotomethyl- phenyl, R, is N-mono-methylamino, and R, is hydrogen, in free form or in form of a pharmeceutically acceptable salt, in addition to pharmaceutically acceptable adjuncts. -11t-

‘ Cl “eyyy 20, A pharmaceutical preparation suitable for en- teral or parenteral administration containing an anticonvulsively effective amount of a compound of the formula : R, J) N ra \\

nT (w,: / xy” Nw R, CH,-Ph in which Ph is a phenyl radical which is mono-subs- tituted by halogdn or by trifluoromethyl, R, is N,N- di-C,-C,-alkylamino in which the two N-C,-C,-alkyl groups may be the same or different, N-mono-C,-C, - alkylamino or amino, and R, is hydrogen or Pl Co alkyl, in free form, in addition to pharmaceutically an aceeptable adjuncts. i