AU638858B2

AU638858B2 - 6-alkylpyridazine derivatives, method of preparation and pharmaceutical compositions in which they are present

Info

Publication number: AU638858B2
Application number: AU81476/91A
Authority: AU
Inventors: Robert Boige-Grain; Roger Brodin; Jean-Paul Kan; Dominique Olliero; Camille Georges Wermuth
Original assignee: Sanofi SA
Current assignee: Sanofi SA
Priority date: 1990-07-31
Filing date: 1991-07-31
Publication date: 1993-07-08
Anticipated expiration: 2011-07-31
Also published as: FI913656A0; DE69104155T2; ATE111900T1; FR2665442A1; NZ239181A; IE66376B1; PT98474B; JPH04234369A; EP0469992B1; AU8147691A; HU213392B; IE912658A1; DE69104155D1; KR920002550A; FR2665442B1; NO179905B; HU211645A9; ZA916030B; CA2048162A1; NO179905C

Abstract

Pyridazine derivatives of formula: <IMAGE> in which: - Ar denotes an optionally mono- or disubstituted phenyl group, a pyridyl group or a thienyl group; - R3 denotes a C1-C5 straight or branched alkyl, a -CH2-C6H5 group or a -CH2-CH2-C6H5 group; - R4 denotes the group <IMAGE> in which: - X denotes a C1-C6 straight or branched alkylene - each of R5 and R6 independently denotes hydrogen or a C1-C4 alkyl, or, together with the nitrogen atom to which they are bonded, they form a heterocyclic ring chosen from pyrrolidine, morpholine or piperidine, or else R4 denotes a group chosen from: <IMAGE> in which n is as defined above and R7 denotes H or a C1-C4 alkyl; <IMAGE> in which n is as defined above or <IMAGE> and their salts with inorganic or organic acids. Application: medications useful for the treatment of a cholinergic deficiency.

Description

638858

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION NAME OF APPLICANT(S): Sanofi ADDRESS FOR SERVICE: DAVIES COLLISON Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

INVENTION TITLE: 6-Alkylpyridazine derivatives, method compositions in which they are present of preparation and pharmaceutical The following statement is a full description of this invention, including of performing it known to me/us:the best method

.I

Pyridazine derivatives have been proposed as drugs for many years, especially those which are active on the cardiovascular system or the central nervous system.

In particular, French patent 2 510 998 and European patent 72 726 disclose pyridazine derivatives which are variously substituted on the pyridazine ring and which all carry, in the 3-position, an amine substituent of the type -NH-alkylene-N

Y

in which X and Y are independently hydrogen or an alkyl group or form, with the nitrogen atom to which they are bonded, a heterocycle such as morpholine.

All these compounds are active 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 obtained which have lost their antidepressant activity and acquired a valuable activity as M,-type cholinergic receptor ligands.

The present invention relates to novel pyridazine derivatives of the formula a Ar

(I)

R3 -NH-R4

N-N

in which Ar is a phenyl group of the formula 2 R2 a pyridyl group or a thienyl group; R1 and R 2 are each independently hydrogen, a halogen atom, a hydroxyl group, a C 1

-C

4 alkyl group, a C -C 4 alkoxy or the trifluoromethyl group; R3 is a linear or branched C1C 5 alkyl, a group -CH

CH

5 or a group -CH 2

-CH-C

5 and S- R is the group

R

-X-N

R

6 in which X is a linear or branched C1C 6 alkylene and especially either a group in which n is an integer from 1 to 3; or a group xl

-CH

2 -C-(CH2)nlin which n, is 0 or 1 and X, is a C 1

-C

3 alkyl group; and a R 5 and R 8 are each independently hydrogen or a linear or branched C 1 0C 4 alkyl or form, with the nitrogen atom to which they are bonded, a heterocycle selected from pyrrolidine, morpholine or piperidine; or '6^35 R 4 is a group selected from 3 -(CH2)n~ I7 in which n is as defined above and R 7 is hydrogen or a C 1

-C

4 preferably CT-C 2 alkyl group; -(CH2) n

N

in which n is as defined above, -CH2 N

-N-C

2 or N- (CH2)2and to their salts with mineral or organic acids.

The salts of the compounds of formula (I) according to the present invention include both those with mineral or organic acids which permit appropriate separation or crystallization of the compounds of 4 formula such as picric acid or oxalic acid, and those with mineral or organic acids which form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, maleate, fumarate or naphthalene-2-sulfonate.

According to another feature, the present invention relates to a method of preparing the compounds of formula which comprises reacting a 3chloropyridazine of the formula Ar

R

3 Cl (II)

N

in which Ar and R, are as defined above, with an amine of the formula

R

4

NH

2 in which R4 is as defined above, to give the compounds according to the invention and, if desired, converting the resulting compound to a salt with a mineral or organic acid.

I The substitution reaction of the 3-chloropyridazine (II) with the amine PINH 2 is carried out at a temperature of between 100 and 150°C, in the absence of a solvent or in the presence of an inert solvent such as n-butanol.

The resulting product of formula is isolated, in the form of the free base or a salt, by the conventional techniques.

When the compound of formula is obtained in the form of the free base, conversion to a salt is 5 effected by treatment with the chosen acid in an organic solvent. Treatment of the free base, for example dissolved in an alcohol such as isopropanol, with a solution of the chosen acid in the same solvent gives the corresponding salt, which is isolated by the conventional techniques. The hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, oxalate, maleate, fumarate or naphthalene-2-sulfonate, for example, is prepared in this way.

When the reaction is complete, the compound of formula can be isolated in the form of one of its salts, for example the hydrochloride, oxalate or fumarate. In this case, if necessary, the free base can be prepared by neutralization of said 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 R, are a hydroxyl group, the compound according to the invention is obtained from the compound in which R, and/or R, are an alkoxy, all the other substituents being as defined above, by dealkylation using known methods.

The 3-chloropyridazines (II) used as starting materials are prepared from the 2H-pyridazin-3-ones (III) of the formula Ar R3 0 (Ill)

H

by reaction with excess phosphorus oxychloride under -6 the action of heat, without a solvent or in the presence of an inert solvent such as acetonitrile.

The 2H-pyridaz in- 3-ones (III) above are obtained by deh',drotc'enation of the compounds of formula Ar R3\ 0

N

for example by reaction with bromine in acetic acidL.

The 2,3,4, 5-tetrahydropyridaz in-3 -ones if the formula Ar R3 0 (IV)

N_.

H

*and the 2,3 -dihydropyridaz in- 3-ones of formula (III), which are novel and form part of the invention, are prepared by the methods described by SUiTTER et al., J.

too***Am. Chem. Soc., 1942, LAI 533-536, MUKHIRJI Science *and Culture, 1948, 12, 426, and PINNA G. et al., I I Farmaco, Ed. Sci., 1988, AJ, 539-549.

The intermediates of the formulae 7 Ar Ar R3 0 R3 0 H

H

(IV) (III) in which Ar and R 3 are as defined above, which are useful for the preparation of are novel and form part of th- invention with the exception of the compounds in which Ar is an unsubstituted phenyl and R 3 is a methyl group. By way of example, compounds of formulae (IV) and (III) are described in Tables 1 and 2 below.

The chlorinated compounds of formula (II): Ar

R

3 C1

N-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 described in Table 3 below.

Substitution of these chlorinated compounds (II) with an amine makes it possible to obtain the compounds the preparation of which is illustrated by the reaction scheme below.

8- SCHEME 1 1) EtONa EtOll Ar-CH 2

CN

2) R 3

CO

2 Et Ar-CH-CN

IOR

2

,,H

2 S04,H20 Ar-CH2-,O-fl3 0

N-N

H

1) i-PrONa 2) BrCH2CO2Et 3) NH 2 NH2 .H 2 0

(IV)

POC13 0 Ar R3 l

N=N

S

5 0# B S S S

(III)

j'H2N -R4 -9 Heating a nitrile 1 in the presence of a base and a carboxylic acid ester derivative RCO 2 Et gives the f-ketonitrile 2, which is converted to the corresponding ketone derivative 1 in an acidic medium.

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 hydrate under the action of heat.

Dehydrogenation of the compound (IV) by reaction with bromine in acetic acid makes it possible to prepare the 2,3-dihydropyridazin-3-one (III).

In the case where n 1 0, the amines 1 5

H

2

N-X-N

6 in which X is a group

X

1 in which X. is as defined above, are prepared from a cyano derivative of the formula

CN

(X1)-C-OH by reaction with an amine of the formula HNRR,, if appropriata in the presence of a salt of a strong acid, such as sodium or magnesium sulfate, at a temaperature of between 40 and 80°C, to give the aminonitrile of the formula 10 CN R

S

which is hydrated under the customary conditions, in an acidic medium, to give the corresponding amide of the formula CONH, 2 R 2

-N

which is then reduced by reaction with a metal hydride, such as lithium aluminum hydride or boron hydride, to give the expected amine HN-CH,- -N R 1 6 The following Examples illustrate tLe invention without however implying a limitation.

EXAMPLE 1 3-(2-Diethylamino-2-methylprop-l-yl)amino-5-(4-fluorophenyl)-6-propylpyridazine a A) a-Butyryl-4-fluorophenylacetonitrile 10.9 g of sodium are added to 150 ml of absolute ethanol. While maintaining reflux, a solution of 49.5 g of 4-fluorophenylacetonitrile in 65.2 g of ethyl butyrate is added. The reaction mixture is refluxed for 4 hours and then left to stand overnight at room temperature. The solvents are concentrated under vacuum and the residue is taken up in water and washed with ether. The aqueous phase is cooled in an ice bath 11 and acidified to pH 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 MgSO,, filtered and concentrated under vacuum.

m 50 g M.p. 53-54'C B) 1-(4-Fluoi -)phenyl)pentan-2-one g of the product obtained above are treated with 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 80 0 C for hour and cooled, 534 ml of water are then added and the mixture is refluxed overnight.

The mixture is extracted with methylene chloride and the organic phase is decanted, dried over NaSO,, filtered and concentrated under vacuum.

The residue is chromatographed on silica gel using 50/50 cyclohexane/methylene chloride as the eluent.

m 39.2 g C) 5-(4-Fluorophenyl)-6-propyl-2,3,4,5-tetrahydropyridazin-3-one 2.76 g of sodium ,re dissolved in 115 ml of isopropanol. A solution of 21.56 g of the product obtained above in 30 ml of isopropanol is added, with cooling in an ice bath. The mixture is stirred for one hour at room temperature, a solution of 15 ml of ethyl bromoacetate in 20 ml of isopropanol is then added dropwise and the mixture is left to stand at room temperature for 24 hours.

The residue is taken up in acidified water (HC1 pH 2) and extracted with methylene chloride.

The organic phase is decanted and dried over MgSO,. It is filterec\ and concentrated under vacuuma. The residue 12 is taken up in 75 ml of butanol, 11.25 ml of hydrazine hydrate are added and the reaction mixture is refluxed for 4 hours.

The mixture is concentrated under vacuum and the residue is taken up in water and extracted with methylene chloride. The organic phase is decanted, dried over MgSO,, filtered and concentrated under vacuum.

m =13.7 g M.p. 78-79°C S. D) 2,3-Dihydro-5-(4-fluorophenyl)-6-propylpyridazin-3one 9.37 g of the product obtained above are dissolved in 40 ml of acetic acid and heated to 80°C. A solution of 7.6 g of bromine in 70 ml of acetic acid is then added dropwise and the reaction mixture is refluxed for 4 hours. It is cooled to 15°C and a precipitate is filtered off.

m 6.6 g M.p. 193-194'C E) 3-Chloro-5-(4-fluorophenyl)-6-propylpyridazine 4.64 g of the product obtained above are dissolved in 28 ml of acetonitrile and 8.6 ml of phosphorus oxychloride and the reaction mixture is refluxed for 4 hours and then concentrated under vacuum. The residue is taken up in icea water, aqueous ammonia is S.o, added and the mixture is then extracted with methylene chloride. The organic phases are decanted, dried over MgSO,, filtered and concentrated under vacuum. The residue is chromatographed on silica gel using 95/5 methylene chloride/ethyl acetate as the eluent.

m 4.35 g M.p. 640C 13 F) Compound 1 1 g of the product obtained above and 3 g of 1amino-2-diethylamino-2-methylpropane are heated at 120°C, under nitrogen, for 48 hours.

The mixture is concentrated under vacuum and the residue is taken up in a 5% solution of sodium carbonate and extracted with methylene chloride. The organic phase is decanted, dried over MgSO,, filtered and concentrated under vacuum. The residue is chromatographed on Merck H silica gel using 96/4 methylene chloride/methanol as the eluent.

The pure product fractions are concentrated under vacuum, the residue is taken up in ether and the addition of a solution of hydrogen chloride in ether makes it possible to prepare the hydrochloride, which is filtered off.

m 1.4 g M.p. 100-115'C EXAMPLES 2 TO 19 A) The 2,3,4,5-tetrahydropyridazin-3-ones listed in Table 1 below are obtained 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 carboxylic acid ester is varied.

14 TABLE 1

R.R

3 M 0C Recrystallization solvent H -CH 2

CH

3 131-132 hexane H n-C 3

H

7 104-105 hexane H i-C3H, 137-138 heptane H i-C 4

H

9 92-93 hexane H neopentyl 155-156 hexane HI -C1 2

-C

6

H

5 114-115 hexane, H -C11 2

-CH

2

-C

6

H

5 142-143 Et 2 o F n-O3H 7 78-79 heptane F i-C 4

H

9 106.5-107.5 heptane Cl -CH3 160-161 Et 2

O

Cl -CH 2

CH

3 121-122 hexane Cl n-C 3

H

7 118-119 heptane B) The 2, 3-dihydropyridaz in-3 -ones listed in Table 2 below are obtained from the derivatives in Table 1 in the manner described in Example step D, by reaction with bromine followed by dehydrohalogenation. These compounds were all recrystallized from a methylene chloride/hexane mixture.

15 TABLE 2

RI

R3 R1R 3

'C

H -CHI 3 123-124 H n-CAH 162-163 H i-CAH 178-179 H i-C 4 H 9 154-155 H neopentyl 181-182 H -CH 2 -CH 140-141 H -CH 2

-CH

2

-CGH

5 169-7 Fn-C 3 11 7 193-194 F i-C 4 11 9 194-195 Cl -CH 3 212-214 Cl n-C 3H7 187-188 a C) The chlorinated derivatives are prepared from the derivatives in Table 2 by reaction with phosphorus oxychloride in the manner described in Example 1, step E.

These chlorine derivatives, which are listed in Table 3 below, were all recrystallized from methylene chloride.

16 TABLE 3

I

R 3 *C HC 2H3 4 H n-C 3

H

7 58 H i-C 3

H

7 86-87 H i-C 4 H 9 70-71 H neopentyl. 99-100 H -CH 2

-C

6

H

5 99 H -Cf 2 -Cf 2 -C11 94-95 F n-C 3

H

7 64 F i-C 4

H

9 oil Cl -CH3 127-128 Cl _C2H3 84-85 Cl n-C 3 HX 63 'I.e.

I. *s

I

U

D) Substitution of the chlorinated derivatives with an amine, according to Example 1, step F, makes it possible to prepare the compounds according to the invention, which are listed in Tables 4, 5 and 6 below.

17 R5 MI R3 /NH-(CH 2 N-N 6 1 i -NR Exalpe R, 3 _NRecrystalli s 2 H CL 3 2 -N( 2 2 8 hexane 3 H n-C 3

H.

7 2 N'(Y 2 5 2 129 EtOR H -CH 3 2 -N 0 93 bexane 6 Cl D-0 3

H

7 3 (CA) 2 h58 hexane 18 e.

19- TABLE 5_ (Cont I d)

(I)

P14) to tee.

C

4e 0 e 20 CH3 R R3 -H2-Cr,,Ie RI R 3 Recrystaliation solvent Salt 10 15 B -CH3 2

H

5 2 132-~134 furaarate H 2 0 acetone 16 R -C2Hc -N-(0 2 11 5 2 95 difumarate Et 2

O

1517 B n .C -N-(C 2

B

5 2 121 difumarate Et 2 o 18 B i-C 3

H

7

-N(C

2

H

5 2 164-165 sesquifunarate 4* i-POH 19 H1 i- 4 -N(C 2 148-149 difumiarate IEt 2 0 CH2 u -N-(C 2

HS)

2 115 2HC1 .:/Et 2 O0 21 H1 -CH 2 -11(C215)2 114-115 21101 t-Bu Et 2

O

22 B -(qH2)2 -N(C 2

B

5 2 110 21101 US Et 2

O

23 F i-C 4 HA 2

H

5 l) 2 161-162 sesquifumarate Et 2

O

21 24 Cl -CH 5 2 100-105 2HC1 Et,0 Cl -C, 2 s (C 2

H

5 2 95-100 2BC1 Et 2

O

26 Cl n-C 3 H, -N-(C 2 Hs) 2 134-135 difumarate 2t 2 0 The compounds according to the invention were 10 studied for their pharmacological properties and in particular for their affinity for the M,-type and M,type muscarinic cholinergic receptors.

In vitro, the compounds were tested according to the technique described by L. POTTER et al., J.

1 Pharmacol. Exp. Ther., 1989, 284, 974-978, for their affinity for the M 1 -type receptors, and according to the technique described by HAMMER R. et al., Life Science, 1986, 38, 1653-1662, for their affinity for the M 2 -type receptors.

The compounds according to the invention have a good affinity for the M,-type receptors and a marked specificity for the M,-type central receptors compared with the M 2 -type receptors.

By way of example, compound 6 showed 50% inhi- 25 bitory concentrations, expressed in micromol, of 0.16 and 1.5 on the M and M, receptors respectively.

Likewise, compound 25 showed 50% inhibitory concentrations of 0.04 and 0.9 on the M. and M, receptors respectively.

In vivo, the compounds according to the invention were subjected to the test for the rotations inducec by intrastriatal pirenzepine, described by Worms P. et al., Psychopharmacology, 1987, 93, 489-493.

At a dose of 3 mg per kg of body weight, administered orally, the products according to the inven- 22 tion strongly inhibit the number of rotations induced by pirenzepine. Thus, by way of example, compound 6 causes a 71% inhibition of the rotations induced by pirenzepine.

Furthermore, the compounds according to the invention have proved to be active on thet Temory deficiency induced by scopolamine and pentetrazole in the passive avoidance test on rats, described by WORMS P.

et al., Psychopharmacol., 1989, 286-288.

10 Thus the results of this test show that comia pound 6 according to the invention opposes the amnesia induced by pirenzepine administered intraperitoneally at a dose of 75 mg/kg, with an ED, of 0.47 mg/kg, administered orally.

Finally, the compounds according to the invenges tion showed no signs of toxicity at the doses at which they are active.

Consequently, the compounds can be used as drugs.

The results indicated show that the compounds according 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 cholinergic deficiency is evident, especially for the treatment of cognitive memory disorders and degenerative syndromes associated with senescence and with senile dementia.

According to another feature, the present patent application therefore relates to the pharmaceutical compositions in which at least one of the compounds of formula or one of their salts is present as the active principle.

In the pharmaceutical compositions of the 23 present invention for oral, sublingual, transdermal or rectal administration, the active principles of formula above can be administered to humans in unit forms of administration, mixed with the conventional pharmaceutical carriers, especially for the treatment of cognitive memory disorders or degenerative syndromes.

Appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual and buccal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for 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 combination with a pharmaceutical carrier. This unit dose can be administered 1 to times a day.

If a solid composition in the form of tablets is prepared, the main active principle is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.

The tablets can be coated with sucrose or other appropriate substances or they can be treated so as to have a prolonged 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 contain the active principle mixed with dispersants or wetting agents or with suspending agents such as poly- 24 vinylpyrrolidone, as well as with sweeteners or taste correctors.

Rectal administration is effected using suppositories which are prepared wlLn binders melting at the rectal temperature, for example cacao butter or polyethylene glycols.

Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmaceutically compatible dispersants and/or wetting agents, for example propylene glycol and butylene .glycol.

The active principle can also be formulated 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 g Lactose 0.050 g Magnesium stearate 0.005 g by intimately mixing the above ingredients and pouring the mixture into hard gelatin capsules.

t 3 3

Claims

1. A compound of the formula Ar R3/ NH-R4 NN in which Ar is a phenyl group of t's-e formula R2i a pyridyl group or a thienyl group; and R. are each independently hydrogen, a 41alogen atom, a hydroxyl group, a alkyl. group, a C,-C, alk.oxy or the trifluoromethyl group; R 3 is a linear or branched alkyl, a group -CH,- 6H.or a group and R. is the group R -X-N in which 0X is a linear or branched Cl-C. alkylene md 26 *R 5 and R. are each independently hydrogen or a linear or branched C 1 C, alkyl or form, with the nitrogen atom to which they are bonded, a hetero- cycle se~ected from pyrrolidine, morpholine or piperidine; or R. is a group selected f rom (CH 2 )l7 N K7 in which n is-kft dei and R. i's hydrogen or a preferably alkyl group; -(2CH 2 )n N in which n is as defined above, N I~, I *1 4 44* I ~.gg a I. a -KZ N-C2115 O

14- (CH2) 2 and its salts with mineral or organic acids. 27 A compound according to claim 1, wherein R 4represents -X N R 5 R 6 in which: *X represents either a group -(CH 2 in which n is an integer from 1 to 3 *or a group X1 -CH 2 (CH2)ni- ain which n 1 is 0 or 1 end X 1 is a C 3.C 3 alkyl -group; and *R 5and R 6 are as defined in claim 1. formula Ar R3\ 0 N\ H *in which Ar and R 3 are as de ned in claim 1, with the *a 9~ excention of the compound V) in which =R =Ha nd1 CH 3 4. An intermediate r formula 1 ~2 reparation of of the (III) -28- 3. A method of preparing a compound according to claim 1, which comprises reacting an amine of the formula H 2 N-R 4 in which R 4 is as defined in claim 1, with a 3-chloro-pyridazine derivative of the formula Ar (II) R3 /C1 in which Ar and R 3 are as defined in claim 1, and, if desired, converting the resulting compound to a salt with a mineral or organic acid. 4. A pharmaceutical composition in which a compound of formula according to claim 1 or claim 2 is present as the active principle, together with a pharmaceutically acceptable carrier. A pharmaceutical composition according to claim 4 in the form of a dosage unit in which the active principle is mixed with at least one pharmaceutically acceptable carrier. 6. A compound according to claim 1 or claim 2, a method for the preparation or use thereof, or a pharmaceutical composition comprising a said compound, substantially as hereinbefore described with reference to the Examples. S we DATED this 3rd day of May, 1993. SANOFI By Its Patent Attorneys DAVIES COLLISON CAVE 930503,p:\operdab,81476san5p,28 ABSTRACT-OF THE DISCLOSURE The present invention relates to pyridezine derivatives of formula Ar R3 -NIXNH-R4 in which Ar is a phenyl group of the formula R2 a pyridyl. group or a thienyl group; R. and R 2 are each independently h~~drogen., a halogen atom, a hydroxyl group, a C,.-C 4 alkyl. group, a CC a.lkoxy or the trifluoromethyl group; R. is a linear or branch~ed alkyl, a, group -CH 2 CAH or a group -C H an R 4 is the group in which X is a linear or branched alkylene and R, and R. are each independently hydrogen or a linear or branched alkyl or form, with the nitrogen atom to which they are bonded, a hetero- cycle selected from pyrrolidine, morpholine or piperidine; or R. is a group selected from -(CH 2 )n i 17 in which n is as defined above and R, is hydrogen or a preferably C 1 alkyl group; -(CH2)n in which n is as defined above, -CH 2 N -5 or (CH2)2" and its salts with mineral or organic acids. The invention compounds have a valuable activity as Mi- type cholinergic receptor ligands.