SUBSTITUTED 6-ARYL-1,2,4-TRIAZOLO[4,3- B]PYRIDAZINES - THEIR PREPARATION AND THEIR USE

DERIVES DE SUBSTITUTION DE 6-ARYL-1,2,4-TRIAZOLO [4,3-B]PYRIDAZINES; PREPARATION ET UTILISATION

English Abstract

Abstract of the disclosure
New compounds of the general formula I
<IMG> (I)
and salts thereof with a physiologically acceptable acid
and a process for their preparation are described.
The new compounds have an anxiolytic and anti-
convulsive action.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the
Formula I
<IMG>
(I)
and salts thereof with a physiologically acceptable acid,
wherein Formula R1 and R2 are identical or different and
represent hydrogen, alkyl groups having 1 - 6 carbon
atoms phenyl or chlorine, R3 represents hydrogen, linear
or branched alkyl having 1 - 6 carbon atoms or phenyl
which may be monosubstituted, disubstituted or
trisubstituted by fluorine, chlorine, bromine, iodine,
trifluoromethyl or alkyl having 1 - 4 carbon atoms, and
R4 represents linear or branched alkyl having 1 - 6
carbon atoms, cycloalkyl having 3 - 8 carbon atoms,
phenylalkyl which has 1 - 4 carbon atoms in the alkyl
part and may be monosubstituted, disubstituted or
trisubstituted in the phenyl part by fluorine, chlorine,
bromine, iodine, trifluoromethyl or alkyl having 1 - 4
carbon atoms, alkylcarbonyl having 1 - 6 carbon atoms in
the alkyl part, cycloalkylcarbonyl having 5 - 7 carbon
atoms in the cycloalkyl part or benzoyl which may be
monosubstituted, disubstituted or trisubstituted by
26

fluorine, chlorine, bromine, iodine, trifluoromethyl or
alkyl having 1 - 4 carbon atoms, or represents Ar, and
wherein Ar represents aromatic radicals, selected from the group
consisting of phenyl, biphenyl, phenoxyphenyl, phenylthiophenyl,
phenylsulfinylphenyl, phenylsulfonylphenyl, 1-naphthyl,
2-naphthyl, 2-thienyl, 3-thienyl, 2-furyl, 2 pyrrolyl,
1-methyl-2-pyrrolyl or 2-, 3- or 4-pyridyl, each of
which may be substituted by one, two, three, four or
five radicals selected from fluorine, chlorine, bromine,
iodine, alkyl groups having 1 - 6 carbon atoms, cycloalkyl
groups having 3 - 8 carbon atoms, phenylalkyl groups
having 1 - 4 alkyl carbon atoms, alkoxy or alkylthio
groups having in each case 1 - 6 carbon atoms, hydroxyl,
nitro, cyano, trifluoromethyl or carboxyl groups, esters
of the latter with C1-C6-alcohols, aminocarbonyl, amino
acetamino or alkoxycarbonylamino having 1 - 6 carbon
atoms in the alkyl radical, and wherein
<IMG>
can also represent a radical of the general Formula II
<IMG> (II)
27

wherein X represents CH2, CHR5, C=O, O, S or NR5
wherein R5 represents hydrogen, alkyl having 1 - 6
carbon atoms, cycloalkyl having 3 - 8 carbon atoms,
alkylcarbonyl having 1 - 6 carbon atoms in the alkyl
radical, alkoxycarbonyl having 1 - 4 carbon atoms in
the alkoxy radical, phenylalkyl which may be
substituted having 1 - 4 carbon atoms in the alkyl
radical, phenyl which may be substituted or benzoyl
which may be substituted, it being possible for each
of the phenyl rings to be monosubstituted, disubstituted
or trisubstituted by fluorine, chlorine, bromine,
iodine, trifluoromethyl or alkyl having 1 - 6 carbon
atoms, and m and n represent 1, 2 or 3, with the
exception of the compounds of the Formula I in which
R1, R2 and R3 represent hydrogen, R4 represents phenyl
and Ar represents phenyl, 4-methylphenyl or 4-bromophenyl,
which comprises:
a) cyclizing a compound of the Formula III
<IMG> (III)
wherein R1, R2, R3, R4, and Ar have the meanings
indicated for Formula I and Z represents O or
S, by heating, if appropriate with the addition
28

of a condensation agent, to give a compound
of the Formula I or,
b) reacting a compound of the Formula IV
<IMG> (IV)
wherein R6 represents chlorine, bromine or
methylthio and Ar, R1 and R2 have the meanings
indicated for Formula I, with an amine of the
Formula V
<IMG> (V)
wherein R3 and R4 - if appropriate together with
the nitrogen atom - have the meanings indicated
for Formula I, or,
c) reacting, if appropriate with the addition of a
condensation agent or catalyst, a compound of
the Formula VI
<IMG> (VI)
29

or one of its salts wherein Ar, R1 and R2
have the meanings indicated for Formula I,
with a compound of the Formula VII
R4-Y (VII)
in which R4 has the meaning indicated for
Formula I and Y represents a leaving group, selected
from the group consisting of fluorine, chlorine,
bromine, iodine, <IMG> or the tosylate
radical.
2. A compound of the Formula I, as defined in claim 1, or a
physiologically acceptable acid addition salt thereof.
3. A pharmaceutical composition having an anxiolytic and
anticonvulsive action, which comprises a
pharmaceutically acceptable excipient or auxiliary and,
as the active ingredient, a compound of the Formula I as
claimed in Claim 1.
4. The process as claimed in claim 1(a).
5. The process as claimed in claim 4, wherein R1, R2 and
R4 are hydrogen, R3 is phenyl or phenyl monosubstituted
by fluorine or chlorine and Ar is 4-fluorophenyl.
-30-

6. A compound of the Formula I, as defined in claim 1,
wherein R1, R2 and R4 are hydrogen, R3 is phenyl or
phenyl monosubstituted by fluorine or chlorine and Ar is
4-fluorophenyl.
7. A process for the preparation of 6-(4-fluorophenyl)-3-
phenylamino-1,2,4-triazolo[4,3-b]-pyridazine which
comprises reacting 3-(4-fluorophenyl)-6-hydrazinopyridazine
with phenyl isothiocyanate and heating with dicyclohexylcarb-
odiimide.
8. 6-(4-Fluorophenyl)-3-phenylamino-1,2,4-triazolo[4,3-b]-
pyridazine.
31

Description

- 2 ~ 656~
HOE 83/F 047
The ;nvent;on relates to new substituted 6-aryl-
1~2,4-triazoloC4,3-b3pyridazines of the general formula I
~,~ R2
Ar ~- N `
N _ N
N
:R4 R3
..
and salts thereof w;th a phys;olog;cally acceptable acid~
in which formula R1 and R2 are ;dent;cal or different
and represent hydrogen, alkyl ~roups hav;ng 1~6 carbon
atoms, phenyl or chlorine, R3 represents hydroyen,
linear or branched alkyl hav;ng 1-6 carbon atoms or
phenyl wh;ch is opt;onally monosubst;tuted, disubst;tuted
10 o.r trisubstituted.by fluor;ne, chlor;ne, brom;ne,- ;od;ne, q
: trifluoromethy! or alkyl having 1 4 carbon atoms, and R4
denotes l;near or branched alkyl having 1-6 carbon atoms,
cycloalkyl hav;ng 3-8 carbon atorns, phenylalkyl which has
1-4 carbon atoms in the alkyl part and is optionally
onosubstituted, disubstituted or trisubst;tuted ;n the
phenyl part by fluor;ne, chlorine, brom;ne, 10dine, tri-
fluoromethyl or alkyl having 1-4 carbon atoms, alkyl-
carbonyl hav;ng 1-6 carbon atoms in the alkyl part,
cycloalkyLcarbonyl havin~ 5~7 carbon atoms ;n the cyclo-
- 20 alkyl par~ or ben7.0yl wh;ch is opt;onally monosubst;tuted,

~ 3
disubst;tu~ed or ~risubst;tuted by-fluor;ne, chlor;ne~
brom;ne, ;od;ne, tr;fluoromethyl or alkyl having 1~4 car-
bon atoms, or denotes ~r, and in wh;ch Ar represents
aromatic radicals, such as phenyl, biphenyl, phenoxy-
phenyl, phenylth;ophenyl, phenylsulfinylphenyl~ phenyl-
sulfonylphenyl, 1-naphthyl, 2-naphthyl, 2 thienyl, 3-
thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl or 2-,
3- or 4Npyr;dyl, each of which can optiona;ly be substi-
tuted by one, two, three, four or five radicals such as
fluor;ne, chlorine, bromine, iodine, alkyl groups having
~-6 carbon ato~s, cycloalkyl groups having 3-8 carbon
atoms, phenylalkyl groups having ~-4 alkyl carbon atoms,
alkoxy or alkylthio groups having ;n each case 1-6 carbon
atoms, hydroxyl, nitro, cyano~ trifluoromethyl or car-
boxyl groups, esters of the la~ter with C1-C6-alcohols,
aminocarbonyl, amino, acetamino or alkoxycarbonylam;no
hav;ng 1-6 carbon atoms ;n the alkyl radical, and in
R3
~h;ch ~ N / can also represent a radical of the
~eneral formula II
~( C~12 )hi~
--N X tII)
~c~2~n J
in wh;ch X denctes CH2, CHR5, C=O, O, S or NR5 in
~h;ch R5 denotes hydrogen~ alkyl hav ng 1 6 carbon atoms,
cycloalkyl having 3-8 carbon atoms, alkylcarbonyl hav;ng
1-6 carbon atoms in the alkyl radical, alkoxyc3rbonyl

2~68
- 4 -
hav;ng 1-4 carbon atoms in the aLko~y radical, op~ionally
subst;tuted phenylalkyl having 1-4 carbon atoms ;n the
alkyl radical, opt;onally subst;tuted phenyl or option~
aLly substituted benzoyl, it being possible for each of
the phenyl rings to be monosubstituted, disubstituted or
trisubst;tuted by fluorine, chlorine, brom;ne, iod;ne,
tr;fluoromethyl or alkyl having 1-6 carbon atoms, and m
and n denote 1, 2 or 3.
Amongst the compounds o-f the general formula I,
preference attaches to those in which R1 and R2 are
identical or different and denote hydrogen, methyl,
ethyl, phenyl or chlorine, R3 denotes hydrogen or alkyl
hav;ng 1-6 carbon atoms, R4 denotes linear or branched
alkyl having 1-6 carbon atoms, cycloalkyl having 3-8
carbon atoms, or phenylalkyl which has 1-4 carbon atoms
;n the alkyl part and ;s opt;onally monosubst;tuted or
d;subst;tuted ;n the phenyl part by fluorine, chlorine,
bromine, iodine, trifluoromethyl or alkyl having 1-4
carbon atoms, or denotes Ar, and Ar denotes phenyl~ b;-
phenyl, phenoxyphenyl, phenylthiophenylr 2-thienyl, 3-
th;enyl~ 2-furyl or 2~, 3- or 4-pyridyl, each o-f which
can optionally be monosubstituted, d;subst;tuted or tri-
substituted by fluor;ne, chlorine, brom;ne, trifluoro-
methyl, alkyl groups having 1-6 carbon atoms or cyclo-
alkyl groups hav;ng 3~6 carbon atoms, or those in which
-N/ has the meanings ;ndicated for formula II.
R Compounds of the formula I wh;ch are particularly
preferred are those ;n which R1 and ~2 are idemtical or
,

i8
-- 5 --
different ano denote hydrogen, methyl or ethyl, R3 denotes
hydrogen or alkyl having 1-o carbon atoms, R4 denotes
linear or branched alkyl having 1-~ carbon atoms, cyclo-
alkyl having 5 or 6 carbon atoms, oenzyl or phenylethyl
which is optionally monosubstitut~ed or disubstituted in
the phenyl ring by fluorine, chlorine, trifluoromethyl,
methyl or ethyl~ or denotes Ar, and Ar denotes phenyl~
phenoxyphenyl, phenylth;ophenyl, 2 thienyl, 3-thienyl,
2-furyl or 3-pyridyl~ each of wh;ch ;s optionally mono~
subst;tuted or disubst;tuted by fluorine, chlor;ne~ tr;-
- fluoromethyl, methyl or ethyl.
Compounds of the formula I ;n which R1, R2 and
R3 denote hydrogen, R4 denotes phenyl and Ar denotes
phenyl, 4-methylphenyl or 4-bromophenyl are, however, not
1S cla;med. These compounds have been descr;bed ;n Rev~
Roum. Ch;m. 10, 641 (1965) and Rev. Med. Ch;r. 81, 469
~1977), and are stated to have an antihypertensive act;on
;n some cases~ As opposed to this, the compounds, accord-
ing to the invention, of the formula I have an anxiolytic
and ant;convulsive action.
The invent;on also relates to a process for the
preparat;on of these compounds and pharmaceutical formu-
lations of these compounds and to their use as drugs.
The process for the preparation of the compounds of the
formula I compr;ses
a) cycl;z;ng a compound of the formula III

,5~3
-- 6
~,1 R2
\ ~ Z R
i~==C 11 / ~III)
Ar ~ ~ NH-N~I-c_N\ 4
N-N
;n ~h;ch Ar, R1, R2, R3 and R~ have the meanings
indicated for formula I and Z represents 0 or S, by
heat;ng, ;f appropriate with the addition of a condensa-
5 tion agent, to g;ve a compound of the formula I orb) react;ng a compound of the formula IV
- 1 R2
Ar~ ~=N
I V )
~i
R
in which R~ denotes chlor;ne, bromine or Methylthio and
Ar, R1 and R2 have the mean;ngs indicated for form~lla
; 10 I, w;th an am;ne of the formula V
~R3
H-N 4 ~V3
R
in which R3 and R4 - if aporopriate together w;th the
nitrogen atom - have the mean;ngs indicated for formula
I, or
c~ react;ng, if appropriate w;th the addition of a con-
densation agent or catalyst, a compound of the formula VI

56~3
-- 7 --
Rl R2
~r \~1 r ( v I,
--N
~T
~H2
- or one of ;ts saLts in which Ar, R1 and R2 have the
mean;ngs indicated for formula I, with a com~ound of the
formula VII
R4-Y (VII)
in ~h;ch R4 has the meaning indicated for formula I and
Y represents a leav;ng group, such as, for example,
O
fluorine, chlorine, bromine, iodine, -û~C-R3 or the
tosylate radical.
In process a), the starting materials of the
formula III are obtained, for example, by reacting aryl-
hydraz;nopyridaz;nes o~ the formula VIII
~1 ~2
VIII)
Ar~ T~N~ 2
in wh;ch R1~ R2 and Ar have the meanings ind1cated for
15 formula I, w;th isocyanates or isothiocyanates of the
formula IX
R4-N=C-Z (IX)
;n which R4 and Z have the mean;ngs ;ndicated for formula
I and III, respectivelyr by heating at 40~15CC~ advan-
ta~qeously in a solvent, such as, for exdmple~ methanol,
., .

-- 8 --
ethanol, ;sopropanol, diisopropyl ether, dioxane, tetra-
hydrofuran, toluene, methylene chloride, chloroform or
dichloroethane.
The compounds of the formuLa III are converted
;nto compounds of the formula I by heating at 40-150C,
for example in one of the solvents mentioned and, if
appropriate~ with the add;tion of a c-ondensat;on a~ent,
such as, for example, glacial acet;c acid, cyclohexyl-
carbodi;mide, 1-hydroxybenztriazole, phosphorus oxy-
chloride, phosphorus oxychLoride/N,N-dimethylaniline,
phosphorus oxybrom;de, phosphorus pentachloride~ th;onyl
chlor;de, mercury oxide or lead ox;de. The compounds of
the general formula III can also be obtained by react;n~
chloropyridaz;nes of the formula X
Rl R2
Ar~l ~X)
N--M
in wh;ch Ar, R1 and R2 have the meanings indicated ~or
formula I, ~I;th substituted sem;carbaz;des or thiosemi~
carbaz;des of the formula XI
Z R3
H2N-NH-c-N~ 4 (XI)
2n ;n wh;ch R3, R4 and Z have the meanings indicated for
formula I, by heating at 4û 150~C, for example in one
of the solvents ment;oned or ;n DMF, GMS0 or acetonitri-e.
For process b), the starting mater;als of the formula IV
are reacted" by heat;ng arylhydrazinopyridazines VIII

9 --
w;th for~;c acid or esters thereof tfor R6 = H)~ phosgene,
chloroformic acld esters, a d;alkyl pyrocarbonate or a
d;alkyl carbonate (for R6 = OH) or carbon disuLfide and
an alkal; (for R6 - SH), ;f appropr;ate with the addi-
t;on of a solvent or diluent~ such as chloroform, toluene~d;oxane, ethyl acetate, water or ethanol, to give a com-
pound of the formula IV' in ~h;ch R6 denotes H, 0~ or
SH~ The corresponding compounds IV ;n wh;ch R6 = Br,
Gl or SCH3 are obtained there~rom by heatin~ w;th brom~
1D ;ne ;n glacial acetic acid/sodium acetate tin the case
of R~ = H), phosphorus oxychloride t;n the case of Rb
- OH) or methyl ;odide or dimethyl sulfate tin the case
of R = SH).
The reaction of the compounds of the formula IV
w;th amines of the formula V is effected ;n accordance
w;th process b) w;thout a solvent or in an inert solvent,
such as methanol, isopropanol, 2-methoxyethanol, tetra
h~drofuran~ dioxane, toluene, chloroform, DMF, DMSO,
aceton;trile, acetone or ethyl acetate, at temperatures
of 20-200C, preferably 50-150C~ under normal pressure
or under pressure in an autoclave. The reaction wit
gaseous am;nes can be carried out under normal pressure
by p3s(sing the latter ;nto the mixture or can likewise
be carr;ed out under pressure. If appropriate, a cata-
lyst, such as copper(I) chloride or other coppertI) salts,can be added in order to accelerate the reaction~
In process c), the reaction of the compour)ds of
the formula VI~ which are obtained, for exa~ple, by
cyclizin~ arylhydrazinopyr;dazines of the formula V
.
.

- 10 -
by means of cyanogen chloride or cyanogen bromide, with
compounds of the formula VII is effected in the absence
or presence of a solvent or d;luent, such as, for
example, acetone, methyl ethyl ketone, ethyl acetate,
toluene, xylene~ dioxane9 tetrahydrofuran, D~F, DMS0,
aceton;trile, methylene chloride~ chloroforM or dichloro-
ethane.
If appropr;ate, it ;s poss;ble to add ;nor~anic
or organ;c bases, such as, for exaMple, sod;u~ hydroxide,
tr;ethylam;ne or pyrid;ne, ;n order to b;nd any ac;ds
formed ;n the react;on, or, espec;ally ;n the case of
the reaction w;th acid anhydrides, to add catalytic
alnounts of a strong acid, such as, for example, hydro-
chloric ac;d, sulfur;c ac;d or tr;fluoroacet;c ac;d
Arylhydraz;nopyr;daz;nes of the formula VIII are
known, for example from J. Heterocycl;c Chem. 15, 881
(1978~, or can be prepared from chlorine compounds of the
formula X us;ny hydraz;ne hydrate ;n accordance with pro-
cesses known from the literature ~The Chem;stry of
Heterocyclic Compounds, Volume 28 Pyr;daz;nes, Editors
A. ~1e;ssberger and E.C. Taylor, John W;ley, New York
1973). The two literature references also describe the
synthesis of the chlorine compounds X and their precur-
sors.
If the compounds of the formula I are obtained in
accordance ~;th the processes descr;bed in the form of
salts, the appropriate base can be set free from the
latter by means of ammon;a, amines or hydroxidej~ The
free bases of the formula I can he converted ;nto the
,

~2~i5~
correspond;ng sal1:s by means oF physiolog;caLly accep~
able acids. Suitable ac;ds are inorganic or orsanic
acids, such as hydrochloric or hydrobromic acid, phos-
phor;c ac;d, acet;c acid, benzoic ac;d, c;tr;c acid,
male;c acid~ fumar;c acid, lact;c ac;d, tartaric acid,
succin;c acid or acetylglycine.
The compounds, according to the ;nvention, of
the formula I are su;table for the preparation of drugsn
The drugs can conta;n one or more of the compounds
according to the invention or mixtures thereof with o.her
pharmaceutically active substances. The customary
pharmaceutical excipients and auxiliaries and kno~n
pharmaceutical processes can be used to prepal~ the
drugs. The dru~s can be adm;nistered enterally, paren~
terally, orally or perl;ngually. For example, adnlirlis--
tration can be ef~ected in the form of tablets, capsules,
; pills, coated tablets, suppos;tories, jellies, creams~
~wders, liquids, dustiny powders or aerosols. The
followin~ are examples of suitable liquids: o;ly or
aqueous solutions or suspens;ons~ emulsions and inject-
able solutions or suspens;ons.
The compounds accord;ng to the ;nvention can also
be used as intermediates for the preparation o~ other
drugs.
The following compounds according to the ;nven-
tion may be mentioned: (the abbreviation "TP" is used
in the follo~ing text for the root name "102,4-triazolo-
[4,3 b~pyr;dazine'~.)
h~(3-Fluorophenyl)~3-phenylam;no-Tpr 6~t4 Fluoro

6B
12 -
phenyl)-3-ph~nyl~mino-TP, 6-~3-trifluoromethylphenyl~ 3
phenylaM;no-TP, ~-(3,4-difluorophenyl)-3 phenylamino~lP,
6-(4~phenoxyphenyl)~3-phenylam;no-TP, 6-(4 phenylth;o-
phenyl~-3-phenylamino-TP, 6-t4-(4-fluorophenoxy)phenyl)-
3-phenylamino-TP, 6-t3-chlorophenyl)-3-phenylamino-TP,
6 (3-bromophenyl)-3-phenylamino-TP, 6-(5-chloro-2-thienyl)-
3-phenylamino-TP, 6-~3-fluorophenyl)-3-(substituted-
phenylamino)-TP, 6-(4-fluorophenyl)-3-(substituted-
phenylamino) TP, 6-(3-trifluoromethylphenyl)-3-(subs~i-
1~ tuted-phenylamino)-TP, 6-(3,4-d;fluorophenyl~-3~(sub-
stituted-phenylamino)-TP, 6-t4-phenoxyphenyl)~3-(sub-
stituted-phenylamino)~TP, 6-tlt-phenylthiophenyl)-3-~sub-
stituted-phenylamino)-TP, 6-(L-(4-fluorophenoxy~phenyl~-
3-~subslitut~d-phenylamino)-TP,. 6-(3-chlorophenyl)-3-
~S (subst;tuted-phenylam;no) TP, 6-(3-~romophenyl)-3-(sub~
stituted-phenylamino)-TP and 6-(S-chloro-2-th;enyl~-3-
(subst,tuted-phenylamino)-TP,
;n ~Ihich "substituted-phenyl" represents, in particular,
2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-,
; 20 3- or 4-bromophenyl~ 2-, 3- or 4-trifluoromethylphenyl,
3,4-dichlorophenyl, 3,4-difluorophenylr 2r4-dichloro
phenyl, 2,4-difluorophenyl~ 2,5-diclllorophenyl, 2,5-di-
fluorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,
2,6~dichlorophenyl or 2,6-difluorophenyl.
6-(3-Fluorophenyl)-3-~N~methyl-N-phenylam;r,o)-TP,
6-t4-fluorophenyl)-3-(~-methyl~N-phenylamino)~TP, 6 (3-
trifluoromethylphenyl)-3-(N-methyl~N~phenylamino)-TP, 6-
.
~3,4~dlfluorophenyl~-3-(N-me';hyl-N phenylamino)~TP, 6~(4-
phenoxyphenyl)-3-(N-methyl-N-phenylan1;no)-TP, 6~4-
.. . .

5~
~ S3 -
phenyLthiophenyl)-3-(r~-methyl-N~phenylamino) TP, 6-~4-(4-
fluorophenoxy)phenyl~-3~(N-methyl-N-phenylarDino~TP, 6
t3-clllorophenyl)-3-(N-methyl-N-phenylam;no)-TP, o-(3~
bromophenyl)~3-(N-methyl-N-?henylamino)-TP, 6-~5-chloro-
2-th;enyl) 3-(N-methyl-N-phenylarnino)-TP~ 6-~3-fluoro-
- phenyl)-3-(N-methyl-N-substituted-phenylamino)-TP, 6-(4-
fluorophenyl)-3-(N-methyl-N-substituted-phenylamino~TPf
6-(3-tr;f(uoromethylphenyl)-3-tN-methyl-N-substituted-
phenylamino)-TP~ 6-(3,4 difluorophenyl)~3-(N ~ethyl-N-
subs.;tuted-phenylamino)-TP~ 6-(4-phenoxyphenyl)-3-(N-
methyl-N-subs~;tuted phenylam;no)-TP, 6-(4-phenylthio-
phenyl)-3-(PJ-methyl N-substituted-pllenylamino)-TP, 6-
~~4-fluorophenoxy)-phenyl)~3 tN-methyl-N-substituted-
phenylam;no)-1P, 6-t3~chlorophenyl)-3-(N-methyl-N-sub~
stituted~phenylamino)-TP, 6-(3-bronlophenyl)-3 (N methyl-
N-substituted-phenylam;no)-TP and 6 (5-chloro 2~thienyl)-
3-(N-me~hyl-N subst;tuted-phenylam;no)-TP,
;n which "subst;tuted-phenyl" represents, in particular,
2-, 3 or 4-fluorophenyl, 2~, 3~ or ~ chloropheryl, 2-,
3- or 4-brornophenyl, 2-, 3- or 4-tr;fluoromethylphenyl,
3,4-dichlorophenyl, 3,4-difluorophenyL, 2~4-dichloro-
phenyl, 2,4~difluorophenyl, 2,5 dichlorophenyl~ ~,5-di-
fluorophenyl, 3,5-dichlorophenyl, 305-difluorophenyl,
~,6-dichloropllenyl or 2r6 d;fluorophenyl.
6-(3-Fluoropheny!~-3 acetamino-TP, o-~4 fluoro-
phenyl)-3-acetamino-TP, 6-(3-tr;fluoromethylphenyl)-3-
acetam;no~TPf 6-(3,4~d;fluorophenyL)-3-acetam;no TP, 6-
~4~phenoYypheny'~-3~acetamino TP, 6-(4-phenylthiophenyl)-
3-acetam;no-TP, 6-(4-(4-fluoropherloYm~pherlyl)-3-acet-

5~3
- 14 ~
am;no-TP, 6~3 chloropherlyl)~3-acetamiro-TP, 6-(3-bromo-
phenyl)-3-acetam;no-TP, 6 (S-chloro-2 thienyl)-3-acet-
amino-TP, 6-(3-fluorophenyl)-3 benzoylamino-TP~ 6-(4-
fluorophenyl)-3-benzoyiamino-TP, 6-(3-trifluoromethyl-
phPnyl)-3 benzoylarnino-TP, 6-53,4-d;fluorophenyl)-3~
benzoylamino-TP, 6 (4-phenoxyphenyl) 3-benzoylamino-TP,
6-(4-phenylthiopnenyl)-3-benzoylarnino-TP~ 6-(4-(4-fluoro-
phenoxy)phenyl)-3-benzoylamino-TP, 6-(3-chlorophenyl~-3
benzoylamino-TP, 6-(3-bromophenyl)-3-benzoylamino-TP~ 6
(5~chloro~2-thienyl)-3-benzoylamino-TP, 6-(3-fluoro-
phenyl)~3~(substituted-benzoylamino)-TP, ~-~4-fluoro-
phenyl)~3-(substitu~ed-benzoylamino)-TP, 6-(3-trifluoro-
methylphenyl)-3-(substituted-benzoylamino)-TP, 6-~3,4-
d;fluorophenyl)-3~(substituted-benzoylamino)-TP, 6-(4-
phenoxyphenyl)-3-~substituted-benzoylamino~-TP, 6-(4-
phenylthiophenyl)-3-(substituted-benzoylamino)-TP, ~-t4-
(4-fluorophenoxy)phenyl~-3-~subs.ituted-ben20ylamino)-TP,
~-(3~chlorophenyl)-3-(substituted-bonzoylamino)-TP, 6-(3-
brornophenyl)-3-(substituted~benzoylamino~-TP and 6-(5
chloro-2 thienyl)-3-(substituted-benzoylamino) TP,
in which fsubst;tuted benzoyl represents, in particular,
2-, 3- or 4-fluorobenzoyl, 2-, 3- or 4-chlorobenzoyl, 2-,
3- or 4-bromobenzoyl, 2-, 3- or 4-tr;fluoromethylbenzoyl~
3,4-dichlorobenzoyl, 3~4-difluorobenzoyl, 2,5 dichloro-
benzoyl, 2,5-difluorobenzoyl, 3,5-dichlorobenzoyl, 3,5-
difluorobenzoyl, 2,6-dichlorobenzoyl or 2~6-d;fluoro-
benzoyl.
6-~3 F'uorophenyl~3-~substituted~amino)-TP, 6-
(4-fluorophenyl)-3-(substituted-amino) TP~ 6 ~3-tr;fluoro-

~&~
15 -
~ethylphenyl) 3-(substituted-alTIino)-~TP, 6-~3,4 difluoro-
phenyl)-3-(substituted amino~ TP, ~-~4-phenoxyphenyl)-~-
(substituted-amino)-TP, 6-t4-phenylthiophenyl) 3-(sub-
st;tuted-amino)-TP~ 6 (4-(4-fluorophenoxy)phenyl)-3-~sub-
st;tuted-amino)-TP, 6 ~3~chlorophenyl)-3 (substituted-
amino)-TP~ 6-(3-broMophenyl)-3-tsubstituted-amino~-TP
and 6-~5-chloro-2-thienyl)-3-(subs~ituted-amino)-TP,
;n which "substituted-ar,l;no" represents; ;n particular,
d;methylam;no, d;ethylam;no, 1-pyrrol;d-inyl, piperidino~
morpholino~ ti1iomorphol;no, 1-piperazinyL~ 4-me~hyl-1-
p;peraz;nyl, 4~phenylpiper;d;no~ 4-phenyl-1-p;perazinyl,
~t-p;per;don~1 yl and 4-ethoxycarbonyl-1-piperaz;nyl.
The corr~pounds~ according to the ;nvention, of the
formula I act on the central nervous system; in par~;cu-
lar, they have an anx;olytic and ant;convulsive action.Poss;ble ;ndicat;ons are, therefore, sleeplessness,
ernot;onal tens;on and autonom;c depress;on.
The pharmaceut;cal formulations generally contain
1 to 10,~ of the act;ve component(s) accordirlg to the
inv~ntlon.
The anxiolytic action of the compounds of the
formula I ;s accompan;ed by a ver~ sli~ht sedation and
by good tolerance (LD5~ ~ 300 mg/kg i.p. on
mice). ~his ;s shown by ;nvestig3t;0ns ;n which the
effect of the compounds according to the invent;on on
motor activityr hexobarbit3l-;nduced narcosis and card;-
azol spasms ;n ~;ce was determ;ned. In addit;on~ the
Geller anx;olytic test and the L;c~-shoc~ test on rats
were also used~

~,Z4~
- 16 -
The lo~est dose still effective in the tests
;nd;cated above is, for e~ample, 5 mg/kg on oral adm;n;s-
trat;on, 2.5 mglkg on sublingual adm;nistration and 1 mg
kg on intravenous adm;n;stration. Examples of suitable
general dose ranges for act;on ~an;mal test as above)
are: 5 to 50 mg/kg on oral adm;n;strat;on, 2.5 ~o 25 Mg
kg on subl;ngual administrat;on and 1 to 10 mg~kg on
intravenous administrat;on.
For example, 1 to 3 tablets conta;n;ng 10 to 100
mg of act;ve substance can be adm;nistered 3 t;mes a day
or~ in the case of intravenous injection, for example, an
ampoule of 2 to ml capac;ty conta;n;ng 0.5 to 5 mg of
substance can be adm;n;stered 1 to 3 times a clay.
Example 1
3~ ohexylamino-6~ yl~1L2~tr;azoloC4L~-b]~y---d
ine hydrochlor;de
5 ~ of 3-hydrazino-6-phenylpyridaz;ne (formula
~III, melting point 146C) are d;ssolved in 50 ml of
hot ethanol~ and 3~8 9 of cyclohexyl ;sothiocyanate are
added. The mixture is st;rred for two hours under reflux
and cooled to 0C, and the product ;s filtered off with
suction, washed w;th ethanol and dried~ The result;ng
;ntermed;ate (formula Ill, Z-S~ ;s heated w;th 6.1 g of
d;cyclohexylcarbod;im;de in 50 ml of 2-methoxyethanol for
S hours at reflux temperature. The react;on solution ;s
evaporated to dryness under reduced pressure, and the
res;due ;s crystallized twice from isopropanol. Treat-
mcnt with ethanol;c hydrochloric acid gives the hydro-
chior;de, wh;ch is filtered off w;th suctionr washed with
. .

~41~6~3
- ~7
ethanol and dr;ed, melting point 2~8~C.
Example 2-
3-Benzylamino~-Dhen~ ,2 4-triazolo[4~b]~y~
h~drochlor;de
8 g of 3-hydrazino-6-pherlylpyridazine are d;s-
solved in 7U ml of hot ethanolr 7 g of benzyl isothio-
cyanate are added and the m;xture ;s stirred under reflux
: for one hour. After cooling~ the inter~ediate stage
(formula III, Z~S~ is filtered off with suction, washed
with ethanol, dr;ed ar,d then heated with 8.9 g of d;cyclo-
hexylcarbod;imide in 50 Ml of 2 me~hoxyethanol for S
hours at reflux temperature~
The mixture is concentrated and ethanol;c hydro
chlor;c acid is added, after ~hich the mixture ;s e~apo-
rated to dryness and the residue is recrystalli~ed oncefrom glacial acetic acid and once from toluene and washed
w;th d; sopropyl ether, meltincJ point 236C (decomposit;or
Ex~
6-(4-Fluorophenyl)-3-m hylamino 1L~ triazolo[4~-b~-
~ daz;ne ~drochloride
1.65 inl of methyl ;socyanate in 10 ml of dioxaneare added dropwise to S g of 3 t4-fluorophenyl)-6-
hydraz;nopyridazine (formula VIII, meltin~ point 194C)
in 40 ~l of bo;ling dioxane. The solution ;s heaced at
reflux temperature for A further two hours and concentra-
ted under reduced pressure, the res;due is stirred
with ethanol~ and the product ;s filtered off u;th suc-
tion and dr;ed. rhe interMediate ~formula III, 7~0~ is
heated with phosphorus oxychloride for 4 hours at reflux

5~i~
- 1E3 ~
temperature~ The reaction solution ;5 hydrolyzed caut
;ously w;th ;ce. The prec;pitated hydrochlor;de of the
product is filtered off with suction, washed with water,
extracted by boiling w;th isopropanol, f;ltered off w;th
suct;on and dr;ed, melt;ng po;nt 297C~
Example 4:
~-(4~ Lg~ y~ phenylamino~ triazoloc4~3 b~
zine
~
5 g of 3-t4-fluorophenyl)-6-hydrazinopyridazine
and 3.7 g of phenyl isothiocyanate ;n S0 ml of ethanol
are sti red under reflux for 3 hours. After cool;ng,
the intermed;ate tformula III, Z=S) ;s f;ltered off with
suction, washed with ethanol and dried, melt;ng po;nt
223C ts i nter;nc~
7.S 0 of th;s ;ntermed;ate are heated w;th S g
of d;cyclohexylcarbod;;mide ;n 50 ml of 2~methoxyethanol
for 2 hours at reflux temperature. The prec;p;tate which
is formed on cool;ng ;s filtered off w;~h suction, ~Jashed
with ethanol and recrystall;zed from ;sopropanol, melt;ng
20 poin~ 265~.
Exam~le 5:
__
3~4-~hl~ 'n) 6~t4-fluorop~ 2~triazol
azin~
4.1 g of 4-chlorophenyl ;socyanate, d;ssolved in
1S ml of dioxane, are added dropwise to 5 g of 3~t4-
fluorophenyl)-6 hydrazinopyridazine in 40 ml of dioxane,
and the m;xture ;s heated for 2.5 hours at reflux tem
perature. After coolingf the product ;s tiltered off
witll suct;on~ washed with ;sopropanol and dried, melt;n~

~ 19 ~ 56 8
point 223C. 5 9 of this intermediate (Formùla III~
Z=0) are heated ;n 40 ml of dry toluene ~l;th 3.5 ml of
N,N-d;methylan;l;ne and 1.~ ml of phosphorus oxychloride
for 3 hours at reflux temperature. After cooling, the
toluene ;s removed by decarltation and the o;ly res;due
wh;ch remains ;s st;rred w;th 2N I~Cl~ The sol;d
(hydrochloride, melt;ng point 286C) i5 f;ltered off
with suction and boiled up with semi-concentrated ammon;a;
after cooling, the base ;s f;ltered off with suction and
recrystall;zed from ;sopropanol, Meltin~ po;nt 257C~
Example 6:
3~3-FLuorpphenylam;no~-6-(3-tr;fluorometh~phe~
1 2 4~tr;azolo~4~3-b~p~daz;ne
5 g of ~-hydrazino-6-t3-trifluoromethylphenyl~-
pyr;dazine (formula VIII, melting point 167C~ in 40 Ml
; of ethanol are ~armed to abou~ 50C. 3c3 9 of 3-fluoru-
phenyl isothiocyanate, d;ssolved in 10 ml of ethanolr are
added dropwise, the rnixture is heated for 3 hours at
reflux temperature and, after cool;ng, the result;ng pre-
c;p;~ate ;s f;ltered off w;th suction. P.-Fter ;t has been
washed w;th ethanol and dr;ed~ 6 9 of the intermed;ate
(forlnula III, Z=S), melt;ng po;nt 164C, are heated ;n
40 ml of toluene with 3.8 ml of NrN-d;methylanll;ne and
1.5 Inl of phosphorus oxychlor;de for 3 hours at ref;ux
temperature. After cooling, the toluene phase ;s removed
by decantat;on and the o;ly res;due which rema;ns ;s
st;rred w;th 2N HCl~ The solld (hydrochlor;de) thus
formed ;s f;ltered off with suction and bo;led up w;th
senl,~concentrated ammonia~ alld~ wher~ cold, the product

~o - ~ :
(base) ;s filterecJ off ~;th suction. Melting point
~09C, af~er recrystall;zation from cJlac;al acetic
acid/water.
Example 7:
-
3-(4-FI )-6-~4-phenylthiop~y~)-1f~4
tr;azolo[4 3-b~pyridazine hydrochloride
5 g of 3~hydrazino-6-(4-phenyl~hiophenyl)-
pyr;daz;ne (formula VIII, n~elting point 142C) in 40 ml
of ethanol are heated to reflux ternperature. 2.9 g of
4-fluorophellyl isothiocyanate in 10 ml of ethanol are
added dropw;se slowly, and the mixture is heated for a
total of 3 hours at reflux temperature. After cool;ng,
the precipitate is f;ltered off w;th suct;on, washed with
ethanol and dried, melting point 188C. 6 g o~ th;s
;ntermediate (formula III, Z-S) are st;rred under reflux
for S hours with 3 g of dicyclohexylcarbodiimide in 40 ml
of 2-methoxyethanol. After cooling, the product is
f;ltered off and washed with isopropanolv 1he precipi-
tate is boiled up w;th ethanolic hydrochloric acid, the
mixture ;s concentrated, and the product is f;ltered off
w;th suct;onr washed with ethanol and dried, Meltina
po;nt 263C.
The foLlowing compounds can be prepared analo-
gously to Examples 1 - 7: the root name "1r2,4-triazolo-
C4,3~b~pyr;dazine" is abbreviated to "TP" ;n the follow-
;ng text.
3. 3-Methylamino~6-phenyl-rP HCl~ melting po;nt 254Co
9. 3-Propylanl;no-6-phenyl-TP HCl, melting point 206C.
10~ 3-Hexylamino~6-phenyl-TP HCl~ meltin0 point~ 164C.

~ 21 ~ 568
11. 3-(3-FLuorophenylamino) 6-phenyl-TP HCl ~elting
point 266C tdecomposition).
12. 3-~4 Fluorophenyla~ino)-6-phenyl-TP HCl melt;ng
point 264C.
13. 3~(3-Chlorophenylamino)-6-phenyl-TP HCl melting
po;nt 260C (decompos;t;on)~
14. 3-(4-Chlorophenylamino)-6-phenyl-TP HCl meltin~
point 258C tdecompos;tion).
15. 3-(3-Trifluoromethylphenylamino~-6~phenyl-TP HCl~
melting point 245C.
16. 3-Propylamino-6-(4-fluorophenyl~-TP HCl melt;ng
po;nt 241C.
170 3-Cyclohexylamino-6-t4-fluorophenyl)-TP HCl melt;ng
po;nt 262C (decomposition).
15 18. 3-~3 Chlorophenylamino)-6-~4-fluorophenyl)-TP HCl
melting point 250C.
19 3-(3 4-D;chlorophenylam;no)-6-(4-fluorophenyl)-TP HCl
melt;ng point 289-290C.
20. 3-(2-Fluorophenylam;no)-6-(4-fluorophenyl)-TP HCl
melt;ng point 242C.
21 3~(3-Fluor~ophenylamino)-6~(4-fluorophenyl)-TP HCl
meltins po;nt 260-262C.
- 22. 3-(4-Fluorophenylam;no)-6-(4-fluorophenyl~ TP HCl~
melt;rlg pOt nt 282 284C.
25 23. 3 (4 Methylphenylamino)-6-(4-fluorophenyl~ TP HCl
melt;ng point 263C.
24. 3-~3-Cyanophenylamirlo)-6-(4 fluorophenyl)-TP HCl
melting point 321C.
2S. 3-(3-Trifluoromethylplenylam;no)-6-(4-fluorophenyl)-

- 22 ~ 56~ `
TP HCl, melt;ng point 286C~
26r 3 PhenylaMino-6 (3-fluorophenyl)-TP HCl, melting
point Z66C ~decomposition~.
27. 3-(4-Chlorophenylam;no)-6-(3-fluorophenyl)-TP,
5 melt;ng po;nt 258C.
28. 3-(3-Fluorophenylam;no)-6-~3-~fluorophenyl)-TP,
melting po;nt 23 6C.
29. 3-(4~Fluorophenylamino)-o-(3-fluorophenyl)~TP,
melt;ng point 241C.
10 30 3-Phenylamino-6-(3-tr;fluoromethylphenyl)-TP,
melt;ng po;nt 206C.
31. 3-(3-Chlorophenylam;no)-6-~3-tr;fluoromethylphenyl)-
TP melt;ng po;nt 212C.
32. 3-(4-Chlorophenylamino)-6-(3 trifluoromethylphenyl)-
TP, melt;ng point 208C.
33O 3-(3,4 D;chlorophenylam;rIo)-6-(3-tr;fluoromethyl
phenyl)-TP, melt;ng po;nt 198C.
34. 3-(2-Fluorophenylam;no)-6-(3-tr;fluorome~hylphenyl~-
TP, melt;ng po;nt 198C.
20 35. 3-(3-Fluorophenylam;no)-6 (3-trifluoromethylphenyl)-
TPr rnelt;ng point 209C
36 3 (4-Fluorophenylam;no~-6 t3-trifluoromethylphenyl)-
TP, melting po;nt 234C.
37. 3-Phenylam;no-6-(4-tr;fluoromethylphenyl)-TP HCl,
melt;ng po;n 271C.
38. 3-(3-Fluorophenylamino)-6-(4-phenoxyphenyl~-TP,
melting point 211C.
- 39. 3-Phenylam;no~ 4-phenylthiophenyl~-rP HCl, mel ing
point 247C.
,
.

~41~`56~3
- 23 - .
40. 3-(4 Chlorophenylamino)-6-(4-phenylth;ophenyl)-TP HCl,
melting Po;nt 274C.
41. 3-(3~Fluorophenylamino)-6-(4-phenylth;ophenyl~TP HCl,
melt;ng point 253C.
42. 3~t4-Fluorophenylam;no)-6-(4-phenylthiophenyl)-TP HCl,
melting point 263C.
43. 3-PhenyLamino-6-(5-chloro-2-thienyl)-TP HCl, meltin0
po;nt 271C.
44. 3-(4-Chlorophenylam;no)-6-(S-chloro~2~thienyl)-TPr
melting point 246C
45. 3-(3-Fluorophenylamino)-6-(S-chloro-2-thienyl)-TPO
melting point 287C.
46. 3~(2-Fluorophenylamino)-6~(5-chloro 2-thienyl)-TP,
melting point 232C.
47. 6-~4~(4~Fluorophenoxy)phenyl3-3-phenylamino-TPr
melt;ng point 235C.
48. 6-c4-~4-Fluorophenoxy)phenyl]-3-(3-fluorophenylam;no?
TP, melt;ng po;nt 233C.
49. 3-(4~Chlorophenylam;no)-6~C4-(4-fluorophenoxy)phenyl~-
TP, melting point 267C.
50. 3 t3-Fluorophenylamino)-6 (2-furyl)-TP, melting point
2'l7 - 218C.
51~ 3 (4-Chlorophenylamino)-6-52-furyl)-TP, melting po;nt
201 - 202C
52O 3-Phenylamino-6-t2-th;enyl)~TP, melt;ng po;nt 204C.
53~ 3-(3-Fluorophenylamino)-6-t2-thienyl)-TP, melt;ng
po;nt 212C~

- 24 - '~ 5~
Example 54, process b)
3-Cyclohexylamino 6-p_enyl~1,2 4-triazolo~4~3-b~pyrida-
zine ~y~
_. ,
3 g of 3-bromo-6-phenyl-1,2,4~triazoloL'4,3-b]-
5 pyridaz;ne in 10 ml of cyclohexylamine are heated atreflux temperature for five hours`. After cooling, the
product is stirred w;th diisopropyl ether, and the
sol;d ;s f;ltered off w;th suct;on and recrystall;zed
from isopropanol~ Ethanolic hydrogen chloride gives the
hydrochloride~ melt;ng point 258C.
The compounds, according to the invention, of
Examples 2 to 53 are obtained by an analogous procedure.
In th;s procedure, a 6 aryl-3-bromo-1~2,4-tri-
azolo~4,3-b~pyridazine (general formula IV) wh;ch has
been prepared ;n analo~y w;th the literature process and
wh;ch carries the same 6-substituent as the compound of
the corresponding example is reacted with the amine
tgeneral formula V) which forms the basis of the 3-sub
stituent of the example.
Example 55, process c)
3-Benzylamino-6-phe~y~ ~4-triazolo~ b]pyridaz;ne
hydrochlor;de
5 9 of 3-am;no-6-phenyl-1,2,4-tr;azolo~4,3-b~
pyr;daz;ne and 3 g of benzyl chlor;de ;n 2S ml of
d;methylformam;de are heated under reflux w;th 5 g of
potassium carbonate for 10 hours. After cooling, ~Jater
;s addedr and the product is f;ltered off with suct;on,
' treated with ethanolic hydrogen chlor;de and evaporated~
The residue ;s recrystallized from giacial acetic acidr

- 25 - ~2~56~
~ashed w;th diisopropyl ether and dr;ed, meLt;ng poinc
236C (decomposit;on~.
The compounds, accord;ng to the ;nvent;on~ of
Examples 1 and 3 to 53 are obta;ned by an anaLogous pro--
cedure
In this procedure the 3-am;no-6-aryl-1,2,4-
triazolo~4,3-b}pyr1ddzine ~general formula VI, described
in German Offenlegungsschr;ft 3,217,325) on which the
example concerned ;s based ;s reacted with the R4-Y
compound (general formula VII) the alkyl or aryl rad;cal
of wh;ch forms the bas;s of the 3-substituent of the
corresponding example~