CA2048162A1 - 6-alkylpyridazine derivatives, method of preparation and pharmaceutical compositions in which they are present - Google Patents

Abstract

PATENT APPLICATION
entitled: 6-Alkylpyridazine derivatives, method of preparation and pharmaceutical compositions in which they are present in the names of: Robert BOIGEGRAIN
Roger BRODIN
Jean Paul KAN
Dominique OLLIERO
Camille-Georges WERMUTH

Assignee: SANOFI

ABSTRACT OF THE DISCLOSURE

The present invention relates to pyridazine derivatives of formula :

(I) in which - Ar is a phenyl group of the formula a pyridyl group or a thienyl group;
- R1 and R2 are each independently hydrogen, a halogen atom, a hydxoxyl group, a C1-C4 alkyl group, a C1-C4 alkoxy or the trifluoromethyl group;
-R3 is a linear or branched C1-C5 alkyl, a group -CH2-C6H5 or a group -CH2-CH2-C6H5; and -R4 is the group in which ? X is a linear or branched C1-C6 alkylene and ? R5 and R6 are each independently hydrogen or a linear or branched C1-C4 alkyl or form, with the nitrogen atom to which they are bonded, a hetero-cycle selected from pyrrolidine, morpholine or piperidine; or -R4 is a group selected from in which n is as defined above and R7 is hydrogen or a C1-C4, preferably C1-C2, alkyl group;

in which n is as defined above, or and its salts with mineral or organic acids.
The invention compounds have a valuable activity as M1- type cholinergic receptor ligands.

Description

6-Alkylpyridazine derivatives, m~thod o~
preparation and pharmaceutical compositiuns in which they are pre~ent:
Pyridazine derivatives have been proposed as drugs for many years, especially those which are active on the cardiova~cular system or the central nerv~us sys~em.
05 In particular, French patent 2 510 998 and European patent 72 726 disclo,e pyridazine derivative~
which are variously substituted on the pyridazine ring and which all carry, in the 3-position, an amine sub-stituent of the type -NH-alkylene-N \

in which X and Y are independently hy~rogen or an alkyl group or form, with the nitrogen atom to which they are bonded, a heterocycle such as morpholine.
All these compounds are ackive on the central nervous system as antidepressants.
According to the present invention, it has now been found that by modifying the substituents on the pyridazine ring, compounds are ob~ained which have lost their antid~pressant activity and acquired a valuable activity as Ml-t~pe cholinergic receptor ligands.
The presen~ inven~ion relate~ to novel pyrida-zine derivatives of the ~ormula ~ (I) R3~ NH-R4 N~J

in whi~h - Ar is a phe:nyl group o~ the formula .
., , , , :

.:
: : .
- ' . : ' "
'. '' , '. .: ' '.. ~' ' " ', ' . ~ ' ' 2 ~

Rl ~, R2~

05 a pyridyl group or a thienyl group;
~ ~1 and ~ are each indep~nderltly hydrogen, a halogen atom, a hydroxyl group, a C~-C4 alkyl group, a C1-C4 alkoxy or the trifluoromethyl gxoup;
- R3 is a linear or bxanched C1-C5 alkyl, a group -CH2 ~ ~ or a group -CH2-CH~C~5; and - R is the group -X-N

in which X is a linear or branched CrC6 alkylene and ~pecially either a group -(CH~)n~, in which n is an integer from 1 to 3;
or a group Xl -CH2~C~(CH2)nl~
~1 in which n is 0 or 1 and Xl is a CrC3 alkyl group; and ~ R5 and R6 are each independ~ntly hydrogen or a : linear or branched C1-C4 alkyl or form, with the nitrogen ato~ to which they are bonded, a hetero cycle selected from pyrrolidine, morpholine or pipe~idine; or 35 ` - R4 is a group elected Prom , .

:
. .

,~ , .

2~ 2 ~(CH2)n~

05 ~7 in which n is as defined above and R7 is hydrogen or a C1-c~, pref erably C ~C2, alkyl group ;

~tCH2)n ~
N

in which n is as def ined above, -CH2 _ N
\J
~0 {~N-C2H5 or : (~,N-(CH2~2-~:, and to their ~;alts with mineral or organic acids.
The salts of the compounds of formula ( I ) according to the pre~ent invention include both those with mlneral or organic acids which permit appxopriate : ~ 35 separation ox cry~tallizatiorl of the compounds of :

~ : , :: : ' ..... , .. ~., . ~,. .. ..

. . , ~ ' ' , . ' ' " ' ~ ' ' ' ' ' . ' ,' ' ' ' ' ' ', ~ ' . ' " '"' ' ' ' 81~2 formula (I), such as picric acid or oxalic acid, and those with mineral or organic acids which form pharma-ceutically acceptable salts such as khe hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogen-05 phosphate, methanesul~onate, methylsulfate, maleate, ~umarate or naphthale~e-2-sul~onate.
According to another feature, the pre~enk invention relates to a methoal of preparing the co~-pounds oE formula (I), which comprises reacting a 3w chloropyridazine of the formula Ar ~ (II) R~ Cl N_N

in which Ar and R3 are as defined above, with an amine o~ the ~ormula ~NH2 in which R4 is as defined above, to yive tha compounds (I) according to the invention and, if desired, conver-ting the resulting compound ~o a salt with a mineral or organic acid.
The substitution reaction of the 3-chloropyri-dazine (II) with the amine ~NH2 is carried out at a temperature of between 100 and 150C, in the absence of a solvent or in the presence o~ an inert solven~ such as n-butanol.
The resulting product of formula (I) is isola ted, in the form of the ~ree base or a salt, by the conventional techni~ues.
when the compound of formula (I) is obtained in the ~orm of the free base, conversion to a salt is .
. , .
'. '` ' ' ` `' `

.

5~ 2~48h62 e~fected hy treatment with the chosen acid in an orga-nic solvent. Treatment of the free base, for example dissolved in an alcohol ~uch as i~opropanol, with a solution of the chosen acid in the sam~ solvent gives 05 the corresponding salt, which is isolated by the con-ventional techniques. The hydrochlori.de, hydrobromide, sul~ate, hydrogensulfate/ dihydrogenphosphate, mekhane-sulfonate, methylsulfate, oxalate, maleate, fumarate or naphthalene-2 sul~onate, for example, is prepared in this way.
When the reaction is complete, the compound of formula (I) can be isolated in the ~orm of one of its salts, for example the hydrochloride, oxalate or fumarata. In this case, if necessary, the free ba~e can be prepared by neutralization of sai.d salt with a mineral or organic base such as sodium hydroxide or triethylamine, or with an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate~
When Rl and/or R2 are a hydroxyl group, the compound according to the inv~ntion is obtained ~rom the compound (I) in which Rl and/or R2 are an alkoxy, all the other substituents being as de~ined above, by dealkylation using known methods.
The 3-chloropyrida~ines (II) used as starting materials are prepared from the 2H-pyridazin-3-ones (III) of the formula Ar R3~O ( III ) N.rN~
N

by reaction with exaess phosphorus oxychloride under , ~ .

~ 6 - 2~

the action of heat, without a solvent or in the pre-~ence of an inert solvent such as acetonitrile.
The 2H-pyridazin-3-one:s ~ L3 above are obtai~
ned by dehydrogenation of th4 compounds o~ ~ormula 05 tIV):

Ar R3~=0 N_ ~or example by reaction with bromine in acetic acid.
The 2,3,4,5-tetrahydropyridazin 3-ones o~ the formula Ar R3 ~ - (IV) N_ H

and the 2,3-dihydropyridazin-3-one~ of ~ormula (III) which are novel and form part o~ the invention, ar~
prepared by the methods described by SUT~ et al., J.
Am. Chem. Soc., 1942, 64, 533-536, MUKHIRJI D., Science and Culture, 1948, 13, 426, and PINNA G. et al., Il Farmaco, Ed. Sci., 1988, ~, 539-549.
The intermediates o~ the ~ormulae : , ,~, .
` .

', 2~4~
-- 7 ~

Ar Ar R3 _~= 0 R3 ~ ~0 N_N~ N_N
05 }I ~H

(IV) (III) in which Ar and R3 are a~ de~ined above, which are use-~ul ~or the preparation o~ (I), are novel and form part of the invention with the exception oP the compounds in which Ar is an un~ubstituted phenyl and R3 is a methyl group. By way o~ example, compounds of formulae (IV) and (III) are described in rrables 1 and 2 below.
The chlorinated compounds of ~ormula (II):

Ar ~ (II) R3 ~\ ~ 51 ~N

which are novel and form part of the invention, are prepared by the customary methods. By way of example, compounds of formula (II) are de~cri~ed in Table 3 below.
Substitution of these chlorinated compounds (II) with an amine makes it possible to v~tain the compounds (I), ~he preparation o~ which is illustrated by the reaction scheme below.
: 30 :
.

:! :

, SC~ME 1 1) EtONa EtOH
Ar-CH2CN ~-~ Ar-CH-CN
2) R3Co2Et Co-R3 H2S04, H20 Ar 1) i-PrONa ~ /
R3~ ~ o ~ CH2-CO-R3 N N 2~ BrCH~C02Et H 3) NH2N~l2 . H20 ~IV~

~r2 AcOI{
~9r ~ POC13 --<N~N>= ---~ Ar H R3~ Cl N~N

(III) (II) H2N~R4 ~ /
(I) ,:

.

20~62 Heating a nitrile 1 in the presence of a base and a carboxylic acid ester derivative R3CO2Et gives the ~-ketonitrile 2, which is ~onver~ed to the corre~-ponding ketone derivative 3 in an acidic medium.
05 Cyclization to the 2,3,4,5-tetrahydropyridazin-3-one is effected by reaction with ethyl bromoacetate in an alcoholic solvent at room temperature, followed by reaction with hydrazine hyd:rate under the action of heat.
Dehydrogenation of the compound (IV) by reac-tion with bromine in acetic ac:id makes it possible to prepare the 2,3-dihydropyridazin-3-one (III).
In the case where n1 = I the amines ~ R5 H2N-X-N ~
~6 in which X is a group ~1 CH2 (~

in which Xl is a~ defined above, are prepared ~rom a cyano derivative of the formula CN
(X1)2 ~ OH
by reaction with an amine o~ the formula HNR5R6, if appropriate in the presence of a salt of a strong acid, such as sodium or magnesium suIfat~, at a temperature of between 40 and 80 C, to give the aminonitrile of the formula :

, .: : ' . ~ , . ~ .

CN ~ Rs ( Xl ) 2~C~M~R

05 which is hy~rated under the customary conditions, in an acidic medium, to give the corresponding amide of the formula CO~H2 / R5 ( ~1 ) 2 - ~ - N \
R~

which is then reduced by reaction with a metal hydride, such as lithium aluminum hydride or boron hydride, to give the expected amine H 2N-CH2~-N
\R6 The following Examples illustrate the invention without howeYer implying a limitation.

25 3-(2-Diethylamino-2-methylprop-1-yl) amino-5- ( 4 -f luoro-phenyl)-6-propylpyridazine A) ~-Butyryl-4-fluorophenylacetonitrile 10.9 g of sodium are added to 150 ml of abso-lute ethanol. While maintaining re~lux, a solution Q~
30 49.5 g of 4--fluoroph*nylacetoni~rile in 65.2 g of e~hyl butyrate is adde~. The reaction mixture is re~luxed Por ~ hours and then left to ætand overnight at room temperature. The solvents are concentrated under vacuum and the residue is taken up in water and washed with ether. The aqueous ph~se is cooled in an ice bath .

..
, 6$~, ~- 11 n~

and acidi~ied to p~ 5 6 by the addition of concentrated acetic acid to give crystals, which are filtered off, washed with water and dissolved in methylene chloride.
The organic phase is decanted, dried over 05 ~gS04~ filtered and concentxated under vacuum.
m = 50 g M.p. = 53-54 C
B) 1-(4 Fluorophenyl)pentan-2-one 50 g of the product obtained above are treated 10with 36 ml of water and 148 ml of concentrated sulfuric acid, which is added dropwise at 4 C, with stirring.
The mixture is then heated at 80C for ~ hour and cooled, 534 ml of water are then added and the mixture is refluxed overnight.
15The mixture is extrac-ted with methylene chlo-ride and the organic phase is decanted, dried over Na250~, ~iltered and concentrate~ under vacuum.
The residue is chromatographed on silica gel using 50/50 cyclohexane/methylene chloride aæ the eluent.
m = 39.2 g C) 5-(4-Fluorophenyl)-6-propyl-2,3,4,5-tetrahydro-pyridazin-3-one 2O76 g o~ sodium are dissolved in 115 ml o~
isopropanol. A solution of 21.56 g o~ the prcduct obtained above in 30 ml of isopropanol is added, with cooling in an ice bath. The mixture is st.irred ~or one hour at room temperature, a ~olution o~ 1~ ml of ethyl ~romoacetate in 20 ml of isopropanol is then added dropwise and the mixture is le~t to stand at roam tem-perature ~or 24 hours.
The residue is taken up in acidi~ied water (HCl - pH = 2) and extracted with methylene chloride~
The organic phase is decanted and dri~d over ~gS04. It is filtered and concentrated under vacuum~ The residue , -~
' ' ' ~:, .

2 ~ 2 is taken up in 75 ml of butanol, 11.25 ml o~ hydrazine hydrate are added and the reaction mixture is refluxed for 4 hours.
The mix~ure is concentra~ed under vacuum and 05 the residue is taken up in wiater ancl extracted with methylene chloride. The organic phase is decanted, dried over MgS04, filtered and concentrated under vacuum.
m = 13~7 g M.p. = 78-79 C
D) 2,3-Dihydro-5-( 4-fluorophenyl)-6~propylpyridazin-3-one 9.37 g of the product obtained above are di~-solved in 40 ml of acetic acid and heate~ to 80 C.
solution o~ 7. 6 g of bromine in 70 ml o~ acetic acid is then added dropwise and the reaction mixture is re~luxed for 4 hours. It is cooled to 15C and a pre-cipitate is filtered o~fO
m = 6.6 g M.p. = 193-194 C
E) 3 Chloro-5-(4-~luorophenyl)-6-propylpyridazine 4.64 g of the product obtained above are dis-solved in 28 ml of acetonitrile and g.6 ml of phos-phorus oxychloride and ~he reaction mix~ure is re~luxed for 4 hours and then concentrated under vacuum. ~he residue i~ taken up in iced water, aqueou~ ammonia i~
added and the mi~ture is then extracted with methylene chloride. The organic phases are decanted~ dried over MgS04, filtered and concentrated under vacuum. The residue iB chromatographed on silica gel using 95/5 methylene chloride~ethyl ~cetate as the eluent.
m = 4.35 g M.p. - 64 C

~~ 13 --F) Compound l 1 g of the product obtained above and 3 g of 1-amino-2-diethylamino-2-methylpropane are heated at 120 C, under nitrogen, for 48 hours.
05 The mixture is concent:rated under vacuum and the residue is taken up in a 5% solution o~ sodium carbonate and extrac~d with methylene chloride. The organic phase is decant~d, dried over MgS0~, ~iltered and concentrated under vacuum. The residue is chroma tographed on Merck H silica gel uslng 96/4 methylene chloride/methallol as the eluent.
The pure product ~ractions are concantrated under vacuum, the residue is taken up in ether and the addition of a solution of hydrogen chlori~e in ether makes it possible to prepare the hydrochloride, which is filtered of~.
m = 1.4 g M.p. = 100 115~C

EXP~PLES 2 T0 19 A) The 2,3,4,5~tetrahydropyridazin-3-ones lis~ed in Table 1 below are obtainPd by following the procedure described in Example 1, steps A~ B and C, except that the starting nitrile is replaced with another nitrile derivative, where appropriate, and the carboxylie acid ester is varied~

, : .

TABLE

Rl (rv R3 ~ -O
N \
}I

._ _ ~_~
1 _ ~ 3 _. M.p.; C Recrystallization sol~ent IEI ~C~C~3 131-132 hexane n-C~7 104-105 hexane lEI i-~3~7 137-138 heptane H i-C4~19 ~2-93 he~ane neopentyl 155-156 hexane -C6H5 114-115 hexane -CH2-~2-C6~5 1~2-143 ~t20 ~ n-C3~7 78_7g heptane J~i-C4E[9 106.5-107.5 heptane Cl CE13 160-161 Et20 Cl-C~2CH3 121-122 hexane .
ClIl-C,I(, ~

.
: B) The 2,3-dihydropyridazin-3 ones listed in Table 2 below are obtained ~rom the derivatives in Table 1 i~
~:25 ths manner described in Example 1, step D, by r~aGtiOn with bromine followed ~y dehydrohalogenation. These compounds were all :recrystallized ~rom a methylene chloride~hexane mixture.
: : :
; ~ 3 ~ ::

.

,~ , - . .
,.

15- 20~

TABL~3 2 R
05 ,~
\~< (~II) R3 ~\~0 \H

Rl R3 lI.p., C
-C~2C~3 123-124 H n-C3~ 162-163 ~1 i-'C3E17 1'78-17g H i~C~,~g 154-155 ~neopentyl 181-182 -CH -C ~ 140-141 -C~2-C}I2~C~H5 169-170 F n~c3~7 1~3~194 ~ i~ g 194-195 Cl -C~3 212-214 Cl -C~2CH3 206~207 Cl "-C,~7 187-1B8 C) The chlorinated derivatives ara prepared from the derivatives in: Table 2 by reaction with phosphorus oxy-25 chloride in the manner described in Example 1, step E.These chlorine derivatives, which are listed in Table 3 :; below, were all ~ccrys~allized ~rom me~hylene chloride.

~,: :: :

:
'' ' , 8 ~

~ABLE 3 R
05 ~
~< (II) R3~_ Cl N_ __ _ _ _.
Rl R3 M.p.; C
__ -C~2C~3 49 ~1 n-C3~7 58 H i-C31I7 86-87 i-C4~9 ï0-71 neopentyl 99~100 -~ -C ~ 99 H-C~2-~2-C6H5 ~4-~5 F n-C3~7 64 F i-Ca~g oil Cl -C~3 127-ï28 Cl -C~2C~3 84-85 C~ Il-C,I~, 63 1)~ Substi~ution o~ the chlorinated deriYatiVeS with an amine, acc::ording to Bxample 1, step F, makes it pOB-~5 sible to prepare thP compounds ( I ) according to t}leinvention, which are listed in Table~s 4, 5 and 6 below.

~.

- . -, : :

2 ~

R~
OS ~ /~
R5 ( I ) R3~ NH- (CH ) N /
N_N ~ 6 . ., _ . _ ~ U.p.; 'C
Exa~ple Rl R3 n -~R6 Salt .. _ ___ .. ~

1 5 2 ~-C~ 2 -N-(C~ 5) 2 88 base 3 ~n-c3~ 7 2 -N-(~n5)2 Eton fu~arate 4 H -CH 2 -N ~ 241 2~Cl 2 0 3 ~ EtO~

R -CR3 2 -N O 93 base hexane B Cl ~ B7 3-I-(Cz ~ )z ~ ~s~
_.

:
: :

:. : ~ ' : ~ ' : :
:

~ 18 - 2~4~ 2 ~5 R~

k~
R3~ NH R4 (I) .. _ - . ~
Exa~ple Rl R2 R4 Recrystalllzation sol~ent _. _ __ _- ~ . .... ~__ 7 ~ -cl,~3 ~1 154 sesquifunarate ~ a~r acetone . CH~-CH3 ~ 3 n I ~N2-cs3 2~ 9 n ~ n-c~n7 nt ~ 5 Etz,O 2~Cl ~13 : .

:
:: :
.

:-, .

34g~J

TABLE_ 5 ( Cont ' d ) R~:~
05 ~
R3~ ,~N~-( R4) (I) __ _, . _ _ . _~_ EYa~ple Rl R2 R4 Recrystalilziat;on solvent _. ___ _ __. __ ~ ¦ C ~ ~ ¦ Et ¦ 12 ~ b ¦ ~ -C~ 1i690~ tri~u arate 13 1~ i-C4~g M 99 difu~arate ¦ ~ t,o~i oC beoil Idrate 1~ ~ i~c4~ 9 ~ 151 difu~arate 30 ~L~ t~o _ _ .... . . .

`, . ,' ;
'" ' ' ' ' . ' ,:

J

TA~,E 6 R~

~ C~13 ~5 05 ~3~ NH-CH2-C-N~
N_N dH3 R6 .. _ __ .~ -~ p.; C
~xa~ple R1 R3 ~R Recrystalllzation solvent . __ 6 _ ~o 15 11 -c~3 -N-(C2~;)2 13~-134 fu~arate ~120 acetone 16 11 -C2~5 -N-(C2~,j)2 95 diPu~arate 17 H n-C3117 ~N-tC2~5)2 121 difumarate 18 ~ i-C3~7 -~1(C2ll5)2 164rlH5 SesquifuDarat;e 19 ~ c-Hc2~, -N(C2~5)2 148-149 difuDarate ~ ~ (c2lls)2 1 5 21 Cl 21 H -C~2 -N(C2~5)2 114-115 2~Cl ~BIl Et20 22 ~ (~B~)2 -N(c2~)2 ~t20 23 F i-C4~!~ -N~C2~5)2 161-162 sesquifu~arat~

.
' ' .
-. . .

- 21 ~ 2~ 2 24 Cl -CH3 -N-(C2~5)~ 100-l05 2~Cl Cl ~C2~s -N~lC2~l532 95-100 2~Cl 05 26 Cl n-C,R7 -N-(C,Rs), _ _._ _ _ The compounds according to the invention were studied for their pharmacological pxoperties and in particular for their affinity for the Ml-type and M~-type muscarinic cholinergic receptors.
In vitro, the compounds (I) were tested accor-ding to the technique described by L. POTTER et al., J.
Pharmacol. Exp. Ther., 1989, 28~, 974-97~, ~or their af~inity for the M1-type receptors, and according to the technique described by HAMMER R. et al., Life Science, 1986, 38, 1653-1662, for their af~inity for the M2-typ~ receptors.
~O The compounds according to the invention have ~
good affinity for the M~-type receptors and a mar]ced specificity ~or the ML-type central receptors compared with the ~a-type receptors.
By way of example, compound 6 showed 50% inhi-bitory conGentrations~ expressed in micromol, of 0.16and 1.5 on the Mi and M2 receptors respectively.
Likewis~, compound 25 showed 50% inhibitory concentrations of 0.04 and 0.9 on the ~ and M2 recep-tors respectively.

In vivo, the compounds according to the inven-tion were su~jected to the test for the rotations induced by .intrastriatal pirenzepine, described by Worms P. et al., P~ychopharmacology, 1987, 93, 489-493.
At a dose of 3 mg per kg of body weight, admi-nistered orally, the products according to the inven-:
" .
" , . . .
.. .

: ~ ~ : ';.' . ' '' ' ~ : ' '. ' .. . . .

2 ~

tion strongly inhibit the number of rotations induced by pirenzepine. Thu~" by way of example, compound 6 causes a 71~ inhibition of the rotations induced by pirenzepine.
05 Furthermore, the compounds according to the invention have proved to be active on the memory de~i~
ciency induced by scopolamine and pentetrazole in the passive avoidance test on rats, described by WORMS P.
et al., Psychopharmacol., 1989, 98, 286-288.
Thus the results of this test show that com-pound 6 according to the invention opposes the amnesia induced by pirenzepine administered intraperitoneally at a dose o~ 75 mg~kg, with an EDso of 0.47 mg/kg, administered orally.
F'inally, the compou~ds according to the invan-tion showed no signs of toxicity at the doses at which they are active.
Consequently, the compounds (I) can be used as drugs.
The results indicated show that the compounds accordin~ to the invention have a good affinity for the muscarinic receptors and a good activity in the tests for amnesia induced by scopolamine or pirenzepine.
They make it possible to consider using the products according to the invention in all cases where a choli-nergic deficiency is evident, especially ~or the treat-ment o~ cognitive memvry disorders and degenerative syndromss a~sociated with senescence and with senile dementia~
According to another feature, the present patent application therefore relates to the pharmaceu-tical compositions in ~hich at least one of the com-pounds of formula (I) or one of their salts is present as tke active principle.
In the pharmaceutical compositions of the ;. . : ,. - . :. . - , , . ~
:, . , , ~. . ~ .: .
:' -, , ~

.. ~ , s~48~2 ~ 23 ~

present invsntion for oral~ sublingual, transdermal or rectal administration, the active principles of formula ( I ) above can be administered to humans in unit ~orms of administration, mixed with the conventional pharma-05 ceutical carriers, especially for the treatment ofcognitive memory disorders or degenerative syndromes.
Appropriate unit Porms of administration include ~orms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspen-sions to be taken orally, ~orms ~or ~ublingu~l andbuccal administration, ~orms for subcutaneous, intra-muscular or intravenous administration and ~orms ~or rectal administration.
To obtain the desired effect, the dose of active principle can vary between 5 and 1000 mg per day.
Each unit dose can contain from 5 to 200 mg of active ingredient in combinatlon with a pharmaceutical carrier~ This unit dose can be administered 1 to 5 times a day.
If a solid composition in the ~orm of tablets i5 prepared, the main active principle is mixed with a pharmaceutical vehicle such as gelatin t starch, lac-tose, magnesium stearate, talc, gum arabic or the like.
The tablets can be coated with sucrose or other appro-priate substances or they can be treated so as to have a prolong~d or delayed activity and so as to release a predetermined amount of active principle continuously.
A preparation in the form of gelatin capsules is obtained by mixing the active principle with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
Water~dispersible granules or powders can con-tain the activ~ principle mixed with dispersants or wetting agents or with suspendinq agents such as poly-~8:~ ~2 - 2~ -vinylpyrrolidone, as well as with sweeteners or taste ~orrectors.
Rectal adminiætration is e~fected using 8Up-positories which are prepared with binder~ melting at 05 the rectal tPmperature, for example cacao butter or polyethylene glycols.
Parenteral administration is ef~ected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharma ceutically compatible dispersants and/or wetting agents, for example propylene glycol and butylene ~lycol.
The active principle can also be ~ormulated as microcapsules, if appropriate with one or more carriers or additives.
As a pharmaceutical preparation, it is possible to prepare gelatin capsules containing Compound 6 0.010 ~
Lactose 0.050 g Magne~ium stearate 0.005 g by intimately mixing the above ingredients and pouri~g the mixture into hard gelatin capsules~

- ~, .
,. , ~ . :

Claims (8)

1. A compound of the formula (I) in which - Ar is a phenyl group of the formula a pyridyl group or a thienyl group;
- R1 and R2 are each independently hydrogen, a halogen atom, a hydroxyl group, a C1-C4 alkyl group, a C1-C4 alkoxy or the trifluoromethyl group;
- R3 is a linear or branched C1-C5 alkyl, a group -CH2-C6H5 or a group -CH2-CH2-C6H5; and - R4 is the group in which ? X is a linear or branched C1-C6 alkylene and ? R5 and R6 are each independently hydrogen or a linear or branched C1-C4 alkyl or form, with the nitrogen atom to which they are bonded, a hetero-cycle selected from pyrrolidine, morpholine or piperidine; or - R4 is a group selected from in which n is as defined above and R7 is hydrogen or a C1-C4, preferably C1-C2, alkyl group;

in which n is as defined above, or and its salts with mineral or organic acids.

2. A compound according to claim 1, wherain R4 represents - X - N R5R6 in which :
? X represents either a group -(CH2)n- , in which n is an integer from 1 to 3 ;
? or a group in which n1 is 0 or 1 and Xl is a C1-C3 alkyl group; and R5 and R6 are as defined in claim 1.

3. An intermediate for the preparation of (I), of the formula (IV) in which Ar and R3 are as defined in claim 1, with the exception of the compound (IV) in which R1 = R2 = H and R3 = CH3.

4. An intermediate for the preparation of (I), of the formula (III) in which Ar and R3 are as defined in claim 1, with the exception of the compound (III) in which R1 = R2 = H
and R3 = CH3.

5. An intermediate for the preparation of (I), of the formula (II) in which Ar and R3 are as defined in claim 1.

6. A method of preparing a compound according to claim 1, which comprises reacting an amine of the formula in which R4 is as defined in claim 1, with a 3-chloro-pyridazine derivative of the formula (II) in which Ar and R3 are as defined in claim 1, and, if desired, converting the resulting compound to a salt with a mineral or organic acid.

7. A pharmaceutical composition in whih a compound of formula (I) according to claim 1 is present as the active principle.

8. A pharmaceutical composition according to claim 6 in the form of a dosage unit in which the active principle is mixed with at least one pharmaceutical excipient.