AU639043B2

AU639043B2 - Pyridazine derivatives, process for their preparation and pharmaceutical compositions containing them

Info

Publication number: AU639043B2
Application number: AU66672/90A
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: 1989-11-17
Filing date: 1990-11-16
Publication date: 1993-07-15
Anticipated expiration: 2010-11-16
Also published as: IE75697B1; PT95902A; AU6667290A; LV11972B; DK0429344T3; EP0429344A1; CA2030133A1; GR3021933T3; HUT56078A; FI101881B; IL96384A0; DE69028602D1; KR910009672A; EP0429344B1; NZ236107A; FR2663326A2; HK1000597A1; NO178967B; CA2030133C; IE904145A1

Description

4 i(- 639043 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION NAME ADDRESS OF APPLICANT: 0

S

*5 5 5 Sanofi avenue George V Paris 75008 France NAME(S) OF INVENTOR(S): Robert BOIGEGRAIN Roger BRODIN Jean Paul KAN Dominique OLLIERO Camille Georges WERMUTH ADDRESS FOR SERVICE: DAVIES COLLISON Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

*6.

S

*5S* 65* S 50i 5* 9

S

5*

S

0**95e 0 0 COMPLETE SPECIFICATION FOR THE INVENTION ENTITLED: Pyridazine derivatives, process for their preparation and pharmaceutical compositions containing them the best method The following statement is a full description of this invention, including of performing it known to me/us:- 13 I all ~3 :a For many years pyridazine derivatives have been suggested as medicines, in particular medicines active on the cardiovascular system or on the central nervous system.

In particular, French patent 2 510 998 and European patent 72 726 disclose pyridazine derivatives variously substituted on the pyridazine ring and all bearing at position 1X /x 3 an amine substituent of the type -NH-alkylene-N in

Y

which X and Y independently represent hydrogen, alkyl or form together with the nitrogen atom to which they are attached a heterocycle such as morpholine.

All of these compounds exhibit an activity on the central nervous system as antidepressants.

According to the present invention, novel derivatives of pyridazine have now been discovered which have lost their antidepressant activity and acquired a useful activity as 20 ligands of cholinergic receptors, in particular receptors of the M 1 type.

In accordance with a first feature, the object of the present invention is novel derivatives of pyridazine corresponding to the formula: o* 0 00 0 0 0 0 go

R

3 Ar NH-R4

M-N

in which Ar represents a phenyl group substituted by R 1 and R 2 or an optionally substituted heterocycle; R and R 2 each independently denotes hydrogen, halogen, trifluoromethyl, hydroxy, C 1

-C

4 alkoxy or C 1

-C

4 alkyl;

R

3 represents a C 1

-C

4 linear or branched alkyl, C 3

-C

7 cycloalkyl, benzyl, phenethyl or the Ar' radical, Ar' Sbeing phenyl substituted by R 1 and R 2 0 930503,p: oper\dab,66672.spe,l i -2- R4 represents:

CH

2

X

1 a -CH2 C (CH 2 )n N group, with n 0 or 1

CH

2

X

1 R6 in which X 1 represents hydrogen or methyl;

R

5 represents a C 1

-C

6 linear alkyl group;

R

6 represents a C 1

-C

6 linear alkyl group, or R 5 and R 6 also constitute together with the nitrogen atom to which they are attached a heterocycle selected from morpholine, pyrrolidine or piperidine; as well as their salts with organic or mineral acids.

Preferentially, Ar represents phenyl, unsubstituted or mono-substituted at position 2, more particularly Ar represents a group selected from phenyl 2-halo-phenyl, in particular 2-chloro-phenyl, 2-methoxy-phenyl or 2-hydroxyphenyl, R 3 represents a phenyl or n-propyl,

R

5 and R 6 each represents ethyl, n 0 and XI H.

S 20 Ar may also represent an optionally substituted heterocycle, such as, for example, a pyridyl group unsubstituted or substituted by methyl or methoxy or a thienyl group unsubstituted or substituted by chlorine, methyl or methoxy. Preferably, the optionally substituted heterocycle 25 is a 2-thienyl, 5-chloro-2-thienyl, 3-pyridyl, 2-pyridyl or 4-pyridyl group.

The following compounds are particularly preferred: 3-(2-diethylamino-2-methyl-propyl)amino-6-phenyl-5propyl-pyridazine and its salts; 3-(2-diethylamino-2-methyl-propyl)amino-5,6diphenyl-pyridazine and its salts.

SThe salts of the compounds of formula I according to the present invention includes those with both mineral and organic acids which enable the compounds of formula I to be separated or suitably crystallized, such as picric acid or oxalic acid, those which form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, .930503,p:\oper\dab,66672.spe,2 I I 1- _I C r- 2a dihydrogen phosphate, methane sulfonate, methyl sulfate, maleate, fumarate, 2-naphthalene sulfonate.

In accordance with a second feature, the present invention relates to a process for the preparation of the compounds of formula According to the present invention, the process for the preparation of the compounds of formula is characterized in that an amine R 4

NH

2 is reacted with a 6-chloro pyridazine of formula: 5

OS

0 0

S

0 S. 0 0 6

S..

0

S

0O S

SO..

S

0 00 S 0 930503,p:\operdab,66672.spe,3 3 R3 Ar Cl (II)

N-N

in which Ar and R 3 have the meanings indicated above for and, optionally, the compound thus obtained is converted into a salt with a mineral or organic acid.

The substitution reaction of the 6-chloro pyridazine (II) by the amine R 4

NH

2 is carried out between 1000 and 150°C, optionally in the presence of ammonium chloride. The reaction is performed without solvent or in the presence of an inert solvent such as n-butanol. The product is isolated by extraction and purified, for example, by chromatography.

The product of formula I thus obtained is isolated in the form of the free base or a salt according to standard techniques.

When the compound of fotmula I is obtained in the form of the free base, salt formation is carried out by treatment with the selected acid in an organic solvent. By treatment of the free base, dissolved for example in an alcohol such as isopropanol, with a solution of the selected acid in the same solvent, the corresponding salt is obtained which is isolated according to standard techniques. In this S way, the hydrochloride, the hydrobromide, the sulfate, the hydrogen sulfate, the dihydrogen phosphate, the methane sulfonate, the methyl sulfate, the oxalate, the maleate, the fumarate and the 2-naphthalene sulfonate are prepared.

At the end of the reaction, the compound of formula I may be isolated in the form of one of its salts, for example the hydrochloride; in this case, if necessary, the free base may be prepared by neutralization of the said salt with a mineral or organic base such as sodium hydroxide or triethylamine or an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate.

When R 1 and/or R 2 represent a hydroxyl group, the compound according to the invention is obtained starting from compound in which R 1 and/or R 2 denote alkoxy and all of the other substituents 1 have the above definitions, by dealkylation using known methods.

The 6-chloro pyridazines used as starting materials, are prepared from the corresponding 211-pyridazin-3-ones (III) by reaction with an excess of hot phosphorus oxychioride in the absence of a solvent or in the presence of an inert solvent such as acetonitrile, according to the following reaction scheme: R3 Ar -0 POC 13 (11)

H

0 se .15 The 211-pyridazin-3-ones (IT) are known or prepared by known methods.

Thus, when R, is a Ar' radical, the 211-pyridazin-3-ones are obtained according to the method described by P.SCIMT1DT et al. in 1holy.

Chim. Acta, 1954, 15, 134-140, starting from maloiiic acid ditethyl ester and a hydrazone derivative according to the following, reaction scheme: -CO-C-Ar C112-CO2C 2

N-NH

2 C02G 2 115 a 0 S Ar- 0 Ar -0 H H Ar'

-N

When R 3 represents an alkyl or cycloalkyl radical, the compounds (III) are prepared from a ketone Ar-C0-C1 2 R 3 CHio

R

3 oHl

COOC

2 1f 5 Ci /l 5Ar-C-C11 2

-R

3 Ar C C= 0 0I 1i 0 15C20 2 R3 off

R

3 Hf NH2NH 2 /l CHCH

/C=C

S> Ar -C C 0 Ar -C C 0 N -N' 0 0 1!5The hydroxy Iceto ester 2 is obtained from the ketone 1 by heating it with ethyl olyoxylate at a temporati,,e between 80 and 140'C.

The crude reaction mixture is then taken up in an inert solvent such as n-hutanol and hydrazine hydrate is added. By heating at reflux for 24 hours, the 4,5-dihydro 4-hydroxy pyridazin-3-one 3 is obtained which, when heated in an acidic medium, leads by dehydration to thle 2 11-pyridazin-3-one

(III).

S The amines R 112 are known or prepared by known methods.

Thus, when n 0, they may be prepared from a cyano derivative of 0 formula: 2:XICH 2

OH

,C

(IV)

6 0XICH 2

CN

S By reaction with an amine HNR R 6 by heating at a temperature between 40 and 80'C, optionally in the presence o' a salt of a strong acid such as sodium sulfate or magnesium sulfate, a coapound of formula: XlCC1 2

NR

5

R

6

C

j12 C r 6 is first prepared, then this compound is hydrated by reaction with a strong acid such as hot sulfuric acid in o:der to produce the corresponding amide:

X

1

CH

2

NR

5

R

6

C

X

1 CF1 2 CONHi 2

(VI)

Finally, reduction by heating with a metal hydride such as boron hydride or lithium aluminium hydride leads to the formation of the amine R 4 NTi 2 When n the amine R 4 N111 2 nay also be prepared from a a* chloronitroso derivative (VII) according to the procedure described in J. Prakt. Chem., 1978, 320 433-451.

St .00:: *6 SO 15 XjCH 2 CI C CH 2

NO

i 1

H

X

1 C11 2 R5R6NH 2 R6R 5 N C CH= NOH

(VIII)

(VII)

SOSS

a 0.00

SO

S* S a a .e

S

S0

S

OS SO S S

S

Li 41 H4

X

1

CH

2

>ROO

5 C CH 2

NH

2

X

1

CH

2 The compound of formula (VII) may be used in the form of a dimer (VIla) which is obtained by reaction of nitrosyl chloride with the appropriate olef in (IX) according to the procedure described in J. Prakt. Chem., 1965, 29 123.

C11 2

C

XjCH 2 C11 2

X

1 CiH 2

X

1 0 0 C11 2

XI

OI >Cl'

I

OI- l-C C11 2 N =N C11 2 -C C1 CH1 2 X 1 C11 2

X

1

(IX)

(VII a 7 Finally, when n 1, the amine R 4

NH

2 may be prepared according to the method described in Beilstein 4 596, i.e. by reaction of lithiumin aluminium hydride on the oxime CHZX1 LiA1H4 CH 2

XI

110 N CH C CH2 NR5R6 H 2 N CH2 C CH2- NRSR6 CH2X1

CH

2 X1

(X)

The amine NiH CIH 2

C(CH

3 2 C2-N(Cil 3 2 is commercially available.

The following examples illustrate the invention without in any way limiting it. The compounds are characterizcI by their melting point (mni.p.) expressed in degrees centigrade.

EXAMPL. 1 3-(2-diethylamino-2-methyl-propyl)amino-6-phenyl-5-propylpyridazine sesquifumarate: SR 46559 A.

A) 6-chloro-3-phenyl-4-propyl-pyridaine.

1. Ethyl 2-hydroxy-4-oxo-4-phenyl-3-propy butyrate.

6 mixture of 48.67 g of valerophenone and 45.94 g of ethyl 0aO@ to glyoxylate is heated at 120 0 C for 15 hours.

The crude reaction product is used as such in the following step.

i2 2. (-phenyl-5-propyl-2H-pyridazin-3-one.

The crude product obtained above is dissolved in 450 ml of n-butanol, then 30 Q oE hydrazine hydrate are added and the mixture is heated at reflux for 24 houra.

The n-butanol is evaporatedunder vacuum. The residue is taken up in a mixture of 300 ml of acetic acid and 30 ml of concentrated hydrochlotic acid. The mixture is heated at 100 0 C for 3 hours. The solution is poured into cold water and the product is left to crystallize.

The solid! is filtered off and dried.

tdeAg'tit: 44 Ip.: 160'C.

E21 A i 8 Yield 69% 3. 6-chloro-3-phenyl-4-propyl-pyridazine.

250 ml of phosphorus oxychloride are added to 44 g of pyridazinone obtained above and the mixture is heated at 80 0 C for 4 hours. After being left to stand overnight at room temperature, the reaction mixture is concentrated to 3/4 and then poured slowly onto ice. The mixture is extracted twice with 300 ml of dichloromethane, the extracts are dried over sodium sulfate and concentrated.

Chromatography on silica is then carried out by eluting with an ethyl acetate-methylene chloride mixture (50/50 v/v).

After recrystallization from isopropyl ether, 43.7 g of the expected product are obtained.

M.p. Yield: 92%.

B) Preparation of 2-diethylamino-2-methyl-propylamine.

S, 1. 2-diethylamino-2-methyl-propionitrile.

",oo 85.1 g of the cyanohydrin of distilled acetone and 73.1 g of diethylamine are mixed, 85.7 g of magnesium sulfate are added and mixture is heated under gentle reflux for 20 hours with stirring.

The sulfate mass which is formed is filtered off and washed with ether.

The filtrate is concentrated and then distilled.

86.6 g of the expected product are recovered.

SYield 62% B.p. 68-700C at 15 mm of mercury.

2. 2-diethylamino 2-methyl propionamide.

To 95.9 g of the nitrile prepared in the preceding step 450 ml of sulfuric acid and 70 ml of water are added with stirring and S the mixture is heated on an oil bath at 100-110°C for 2 hours. The reaction mixture is poured slowly during one hour into 1.4 1 of a ammonia solution and 400 ml of water cooled in a Dry Ice/acetone bath. The mixture is extracted 3 times with 600 ml of methylene chloride, the extracts are dried over sodium sulfate and concentrated.

The expected product is obtained by distillation.

Weight 102.5 g Yield ii 9 B.p. 134-139 0 C at 15 mm of mercury.

3. 2-diethylamino-2-methyl--propylamiiie.

A mixture containing 52.4 g of the amide prepared in the preceding step and 60 ml of tetrahydrofuran are heated at 45-50 0

C.

86 ml of the borane-dimethylsulfide complex are added under an atmosphere of nitrogen during one hour and heating is continued for 3 hours on an oil bath at 80-85°C.

After being left overnight at room temperature, the mixture is cooled in an ice bath, then 315 ml of 6N hydrochloric acid are added slowly during 3 hours and the mixture is heated again at 135'C for 3 hours. After being left overnight at room temperature, the reaction a *e mixture is cooled whilst 200 ml of 30% sodium hydroxide are added.

S The mixture is extracted 3 times with 250 ml of ether, the extracts are dried over sodium sulfate and concentrated.

15 The expected product is obtained by distillation.

Weight: 23 g Yield 48% B.p. 71-73°C at 15 mm of mercury.

C) SR 46559 A A mixture of 2.5 g of the chloro derivative obtained above in step A and 4.6 g of the diamine obtained in step B are heated at 120°C overnight. 150 ml of ethyl acetate are added, then mixture is extracted twice with 50 ml of hydrochloric acid. The mixture is then made alkaline by the addition of 50 ml of 30% sodium hydroxide p and then extracted with ethyl acetate. The extracts are washed with dilute salt solution, dried over sodium sulfate and concentrated.

Chromatography on alumina is carried out by eluting with a methylene chloride-ethyl acetate mixture (70/30, v/v).

3.2 g of an oil is obtained which crystallizes.

M.p. 75-77 0

C

Yield: 87% Sesquifumarate 3.1 g of the base obtained in the preceding step are taken up in 50 ml of acetone and 1.6 g of fumaric acid in 150 ml of acetone are added. The mixture is filtered hot. The total volume recovered i_ (175 ml) is concentrated to 130 ml. The product is allowed to crystallize, the crystals are filtered off and then washed with acetone.

4.1 g of the expected product are obtained.

Overall yield of step C 74% M.p. 151°C EXAMPLE 2 SR 46559 A A) 6-chloro-3-phenyl-4-propyl-pyridazine, described in example 1.

B) 2-diethylamino-2-methyl-propylamline.

1. Preparation of the compound of formula (VII a) with X 1

H.

47.14 g of isobutylene are dissolved in 150 ml of n-heptane, the mixture is cooled to a temperature between -10° and -20°C and 50 g of nitrosyl chloride are added. The temperature is allowed to Sdurin3 one and a half hours, then the temperature is brought to between 1000 and 20°C and the mixture is stirred for one and a half hours. The precipitate formed is filtered off, washed with heptane and then dried.

MI.p. 102-1040C m 64 g 2. Preparation of the compound of formula VIII: X 1

R

6 C2 21.7 g of the compound prepared in the preceding step are suspended in 150 ml of absolute alcohol, 39.17 g of diethylamine are added and the mixture is heated at 60 0 C for 6 hours. An oil is obtained which solidifies.

:m 19.5 g 1.p. 50 0

°C

3. 2-diethylamino-2-methyl-propylamine 7.01 g of lithium aluminium hydride are added to 50 ml of an ethereal solution of the compound obtained in the preceding step during 1 hour. After being stirred for one and a half hours at room temperature, the mixture is refluxed for 4 hours. While the mixture is maintained between 0 0 C and -100C, 7.1 ml of water are added during 1 hour, 7.1 ml of sodium hydroxide during 30 minutes and 21.3 ml of water during 30 minutes. After being stirred for 2 hours at room i ;j

CH

2

X

1 CH2 C (CH2)n N

CH

2

XI

group, with n 0 or 1 in which X 1 represents hydrogen or methyl; ./2 I I I i i: temperature, the solution is filtered, the precipitate is washed with anhydrous ether, the filtrate is dried over sodium sulfate and the solvents are removed undervacuum. The product is distilled: B.p. 72-75 0 C at 15 mm of mercury.

m 4.2 g C) SR 46559 A is then prepared as described in example 1.

EXAMPLE 3 3-( 2 -diethylamino-2-methyl-propyl)amino-6-(2-chloro-phenyl)- 5-propyl-pyridazine sesquifumarate. SR 47863 A.

1.7 g of 3-chlor3 6-(2-chloro-phenyl) 5-propyl pyridazine and 6 ml of 2-diethylamino 2-methyl propylamine are heated at 110°C under nitrogen for 20 hours.

After evaporation under vacuum, the mixture is taken up in 15 dichloromethane and washed with a solution of sodium bicarbonate. The S organic phase is decanted, dried over magnesium sulfate, filtered and concentrated undervacuum. The residue is chromatographed on silica gel, eluant: dichloromethane/methanol 98/2.

The concentration of the pure fractions gives an oil which is dissolved in 10 ml of methanol. Fumaric acid is added, the methanol is evaporated under vacuum and the sesquifumarate crystallizes from ether.

m 1.6 g M.p. 144 0

C.

S.

C.

S.,

I

0S~ oo• o.. EXAMPLE 4 .00 3-(2-diethylamino-2-methyl-propyl)amino-6-(2-methoxy-phenyl)- 1.6 g of 3-chloro-6-(2-methoxy-phenyl)-5-methyl pyridazine, 4 g of 2-diethylamino-2-methyl-propylamine and 0.36 g of ammonium chloride are melted together at 120'C and the reaction mixture is left at this temperature for 24 hours.

The mixture is cooled to room temperature, extracted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride.

I i 12 The organic phase is separated, dried over MgSO. filtered and evaporated to dryness in a vacuum.

The residue is chromatographed on alumina, eluent: ethyl acetate of triethylamine.

The concentration of the pure fractions gives the expected product. The structure is confirmed by NMR spectral analysis.

EXAMPLE 3-(2-diethylamino-2-methyl-propyl)amino-5-methyl-6-(2-hydroxyphenyl)-pyridazine. SR 96376.

1 g of the product obtained previously in example 4 is dissolved in 50 ml of 48% hydrobromic acid and the mixture is heated at reflux for 48 hours. After this time, the reaction mixture is 0O evaporated to dryness under vacuum, the residue is made alkaline with

S

1 an aqueous solution of potassium carbonate and the solution is extracted with dichloromethane. The organic phase is decanted, dried over MgSO 4 filtered and evaporated to dryness under vacuum.

The residue is chromatographed on alumina, eluent: ethyl acetate/methanol 9/1 2% of triethylamine.

The concentration of the pure fractions gives a residue which is crystallized from isopropanol.

m 200 mg M.p. 159.2 C p 25. EXAMPLES 6 TO A) By using the procedure indicated in example 1A, but by varying the starting ketone, the 6-chloro-pyridazines assembled in the tables 1 and 2 are obtained.

3* 13 TABLE 1 6 R3

R

2 3 2

RI

of 0 *0 0 0 0 *0@ 0O 300 C 1 (4) C 1 (4) OCf1 3

H

F (4) C1 (2) OCH3 (2)

H

1<2 R<3 :Physical :constants H -CI12CH 2 CH3 52-53 0

C

H -CH 3 178-180 0

C

If -C11 2 CHf 2

CH

3 H -CH 2 CH1 2

CI

3 -6 -19 0

C

H CH 3 m. 123-1240'C H phenyl 115 0

C

If cyclopropyl 119 0

C

H isopropyl fv.g;. 89-90 0

C

H CH 2 CHf 2

CH

3 oil, NMR H CH3 NR H benzy] 92 0

C

ONE[

14 *Ci If C1-4 phenyl 118-119"C H H C1-4 phenyl :M.pz- 130 0

C

C1 H phenyl 125 0

C

*C1 C1 CH2CH 2

CII

3 :mI.p: 71-72 0

C

*Ci H C112CIH 2

CH

3 48 0

C

*Cl! 3 H Ci-4 phenyl. :M 1400C *.OCllj(2) H CHI 2 CEI2CH3 oil, NMR* FC H C1-4Cphenyl :oil, 1390 NMR :NMR spectral analysis enables the structure of the above compounds to be confirmed.

C*

C.

-s's those which form pharmaceutically acceptable salts such as the hydrochloride, hydrobronjde, sulfate, hydrogen sulfate, 9 30.503p: \oper~dab,66672.spe,2 TABLE 2 R3 Ar- Cl

N-N

:Physical Ar R3 :constants 2-thienyl phenyl M-p: 148 0

C

00 0 00 00 0* 0 00 0 0 0000 00 0 0 @000 00 00 0 0 :2-Cl 5-thienyl :phenyl NMR 3 -pyridyl 2-pyridyl phenyl M.p- 184 0

C

pheny 1 138 0

C

0000 0 0000 0000 @0 00 0 0 *00000 00 00 0 0000 000000 4 -pyridyl phdnyl 1939t B) Starting fromn the chloro derivatives of table 1 and by following the procedure employed in example 1, the compounds according to the invention assembled in table 3 below are obtained by varying the amines NH 2

R

4 used.

16 TABLE 3 6 R 3 R2 4 /NHf-R4 3 2 :SR No. salt or base: :Ex. NC.: R1 R2 :46729A :C1(4) IfH R3 R4 CH3 :CH2C-N If&3 5 0 '.55 *0 5 9 Z.s 055e 6 M. P.

dihydrochloride 240-242 0

C

sesquifumarate 159-161 0

C

H nC3H7 467 32A 7 It I If

S

5* 5 5

S

*5550 S 467 33A 8 47020A 9 47047A 10 47054A C1(4) j

H

CH

3

CI-

3 pheny'i C113 C 2

HI

5

CH

2 4

-&N

ICH3 C21-1 Fumarate 138- 140 0

C

sesquifumarate 161 0

C

fumarate 1930C If 11 nC 3 H7 C1(4) It sesquifu ma rate 152- 1540C -17 47068 12 470 69A 13 OCHi 3 0OHM4

H

nC:3Hf7 it If :65-66 0 C base: nC:3H7 t It hydrabromi de: 179- 18 1 0

C

47097A 14 :cyclo- :propyl it sesquifumarate 158- 160 0

C

se 20*5

TOO;:

S

.00.

a* 47098A 47138A 16 F(4)

H

it it GH3/-\ nC:3H7 CH 2 0 CH3 C113 phenyl UnC 2 -CL-C11 2

-N

CH3 CID sesquifumarate hemihydrate 143- 145 0

C

sesquifumarate 149- 151 0

C

164 0

C

sesquifumarate fumarate 163 0

C

H 47153A 17 47227A -18 H H 47297A C1 (4) 19 benzyl C1-4 phenyl CH:3 C,2115 H dH3 C 2 11 It it ii It dihydrochloride 138 0

C

hydrate dihydrochloride 147-C 47608A H -18 4760 9A 21 CI (4) H phenyl chlcrid el 4 7

OC

sesquifumarate 165- 166 0

C

47655A C1 (2) 22 nC 3 fH7 H nCJHf7 *fee 0G 47673 23 C 2 1 5 CH3 CH /C-

IH--

C211 5 CH3 base oil

NMR

47878A Cl (3) 24 47 890OA 25 47967 26 480 79A 27 48080 28 48081A 29 48082

CH

3 (4) F (4)

H

*CH3 C2H5 nC3H 7 C112C-N

CH

3

C

2 1-1 sesquifumarate 146 0

C

di hydrochilori de 0 OC11 3

I:H

:Off(2) H

OCH

3 If OH IH C1-4 phenyl :C1-4 phenyl nC3fH7 nC3H7 I 98 0

C

base s;esquifumarate 950C if 159 ,5 0

C

base it nC3H 7 dihydrochlor'ide

NMR

:nC3H7 U It 166 0

C

base :3 i: I I NM.R spectrum of SR 47673 (DSO d 6 200 MHz) 0.70 (t 3 0.80 (t 611); 1.30 (q 211); 1.50 (mi 4H1); 2.30 (s 611); 2.40 (m 2H); 3,40 (m 211); 6.20 (in 111); 6.80 (s 1H); 7.35 (s 511).

NMR spectrum of SR 48081 A (DMISO dl6; 200 NHz) 0.80 (t 3H); 1.40 (in 8H); 1.5 (s 6H); 2.56 (q 2H); 3.40 4H); 3.80 (s 3H); 4.00 (d 211); 7.02 (m 7.40 (t 111); 7.83 1H).

6S S on

S.

fe*

S

*see* The following abbreviations are used for the analysis of a NMR spectrum.

s singlet b.s. broad singlet; d doublet; t triplet; q quadruplet; m multiplet.

C) Starting from the chloro derivatives of table 2 and by following the procedure described in example 1, the compounds according to the invention assembled in table 4 below are obtained by varying the amines NH 2

R

4 used.

TABLE 4 R3 Ar Nil R4 N NZ SR No. Ar R3 R4 :Salt or base: Ex. No.: CE{13 C21-5 :dihydro- I chloride 47674 A :2-thienyl phenyl CH2I-C;-N 133 0

C

31 CH13 C21-5 477 -lphenyl ::dihydro- 32 :2-thienyl ::chloride 130'C :decomposi- 0 seetion 47802 A :3-pyridyl phenyl :trihydro- 33 see* :47803 A :2-pyridyl p pht~y u n y trihydro- 34 ::chloride 233'C 0: T47804 A 4 -pyridyl :phenyl ":trihydro- 35 .chloride 239 0

C

The compounds according to the invention were studied with respect to their pharmacological 0properties and in particular with respect to their affinity for the MUscaririic cholinergic receptors of type MI and l2 In vitro, the compounds were assayed according to the technique described by Watson J.D. et al. (Life Sciences, 1982, 31, Ii:- I nX4U i 21 2019-2029) as far as their affinity for the receptors of type MI is concerned and according to the technique described by Hammer R. et al. (Nature, 1980, 283, 90-92) and Hulme E.C. et al. (Molecular Pharmacology, 1978, 14, 737-750) as far as their affinity for the receptors of the M.2 cype is concerned.

The compounds according to the invention exhibit good affinity for the receptors of type M 1 and a marked specificity for the central receptors of type M 1 as opposed to receptors of type M 2 As an example, the compound SR 46559 A showed an inhibiting concentration 50 expressed in micromoles of 0.11 and 2.2, respectively, on the M 1 and 12 receptors.

Similarly, the compound SR 47047 A showed inhibiting concentrations 50 of 0.04 and 0.9, respectively, on the M1 and 12 *e receptors.

In vivo, the compounds according to the invention were assayed for their effect on the rotations induced by intrastriatal pirenzepine in the test desc -bed by Worms P, et al. (Psychopharmacology, 1987, 93, 4u9-493) modified in that the administration of the compounds by the oral route took place 4 hours before, instead of 30 minutes before, the injection of pironzepine.

At a dose of 3 mg per kg of body weight, the compounds accordin to the invention strongly inhibit the number of rotations induced by pirenzepine. Thus, as an example, the compound SR 46559 A inhibits the rotations induced by pirenzepine by 73%.

Furthermore, the compounds according to the invention were shown to be active in the passive avoidance tests in the rat described by Jarvik I.E. et al. in Psychol. Med., 1967, 21, 221-224 and by Worms P. et al. in Psychopharmacol., 1989, 98, 286-288.

Thus, according to the results of these tests, the compounds according to the invention counteract the amnesia induced by scopolamine a\ -nistered by the intraperitoneal route at 0.5 mg/kg and the amnesia induced by pirenzepine administered intraperitoneally at 75 mg/kg.

For example, SR 46559 A exhibits an oral efficient dose 50 of 0.25 mg/kg and 0.027 mg/kg, respectively,in each of these tests.

Moreover, some compounds according to the invention were I L

I

i r studied in several predictive models or antidepressant activity such as the forced swimming test described by Porsolt et al. (Arch. Intern.

Pharmacodyn., 1977, 229, 327-336) and the test of antagonism of reserpine-induced ptosis described by Gouret et al. Pharmacol.

(Paris), 1977, 8, 333-350). SR 46559 A in particular was shown to be inactive in these tests at oral doses varying from 0.1 to 10 mg/kg.

Finally,the compounds according to the invention did not show any sign of toxicity at the doses at which they are active.

Consequently, the compounds may be used as medicines.

The results indicated show that the compounds according to the invention exhibit good affinity for the muscarinic receptors and good activity in the tests of amnesia induced by scopolamine or pirenzepine. They allow the use of the products according to the invention to be contemplated in all cases in which a cholinergic dericit is indicated and particularly for the treatment of cognitive and memory disorders, and degenerative syndromes associated with senescence and senile de. 'tia.

In accordance wit another of its features, the present application thus relates to pharmaceutical compositions containing at least one of the compounds of formula or one of their salts as active ingredient.

In the pharmaceutical compositions of the present invention for oral, sublingual, transdermal or rectal administracion, the active ingredients of formula I above may be administered in specific forms of administration, in combination with the standard pharmaceutical vehicles, to humans especially for the treatment of cognitive or memory disorders or degenerative syndromes. The appropriate specific forms of administration comprise the forms used for the oral route such as tablets, capsules, powders, granules and solutions or oral suspensions, the forms used for sublingual and buccal administration, the forms for subcutaneous, intramuscular or intravenous administration and the forms for rectal administration.

In order to obtain the desired effect, the dose of the active ingredient may vary between 0.5 and 500 mg per day.

I .L I ~nnrrrr 23 Each unit dose may contain from 0.1 to 100 mg of active ingredient in combination with a pharmaceutical vehicle. This unit dose may be administered 1 to 5 times per day.

When a solid composition is prepared in the form of tablets, the principal active ingredient is mixed with a pharmaceutical vehicle such as gelatine, starch, lactose, magnesium stearate, talc, gum arabic, or similar substances. The tablets may be coated with sucrose or other suitable materials or they may be treated so that they have sustained or delayed activity and so that they release continuously a predetermined amount of active ingredient.

A preparation of capsules is obtained by mixing the active ingredient witlh diluent and by pouring the mixture obtained into soft or hard capsules.

The powders or granules dispersible in water may contain the active ingredient mixed with dispersing agents or wetting agents or suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste modifiers.

In the case of rectal administration, suppositories are used which are prepared with binders melting at the rectal temperature: for example cocoa butter or polyethylene glycols.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible wetting and/or dispersing agents, for example propylene glycol or butylene glycol, are used.

5 The active ingredient may also be formulated in the form S of microcapsules, with or without one or more additives or supports.

As an example of a galenic preparation, capsules may be prepared containing: SR 46559 A 0.010 g Lactose 0.050 g Magnesium stearate 0.005 g by mixing the above ingredients intimately and pouring the mixture into gelules of hard gelatine.

Claims

1. Compound of formula: R 3 Ar- NH-R4 (I) N.N in which: Ar represents a phenyl group substituted by R 1 and R 2 or an optionally substituted heterocycle; S R 1 and R 2 each independently denotes hydrogen, halogen, trifluoromethyl, hydroxyl, C 1 -C 4 alkoxy or C 1 -C 4 alkyl; S R 3 represents linear or branched C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, benzyl, phenethyl or the Ar' radical, Ar' being phenyl substituted by R 1 and R 2 R 4 represents SCH2X1 RS Sa CH2 C (CH2)n N group, with n 0 or 1 CH2X1 R6 Sin which X 1 represents hydrogen or methyl; R 5 represents a C 1 -C 6 linear alkyl group; R 6 represents a C 1 -C 6 linear alkyl group, or R 5 and R 6 also constitute together with the nitrogen atom to which C they are attached a heterocycle selected from morpholine, pyrrolidine or piperidine; as well as their salts with organic or mineral acids.

2. Compound according to Claim 1 in which: Ar represents phenyl, unsubstituted or substituted at 0 position 2 by chlorine, hydroxyl or methoxy; R 3 represents phenyl or n-propyl; R 5 and R 6 each represents ethyl; n 0 and X 1 H; as well as its salts with mineral or organic acids. 930503,p:\oper\dab,66672.spe,24 I

3. Compound according to Claim 1 in which: Ar represents a 2-thienyl, 5-chloro-2-thienyl, 3- pyridyl, 2-pyridyl or 4-pyridyl group.

4. 3-N-(2-diethylamino 2 -methyl propyl) 6-phenyl pyridazinamine and its salts.

5. 3-N-(2-diethylamino 2-methyl pyridazinamine and its salts. propyl) 5,6-diphenyl

6. Process for the preparation of a compound according to Claim 1, characterized in that an amine R 4 NH 2 reacts with a 6-chloro pyridazine of formula: S 5@ 0 0O S OS.. SO S 0 0 S 5O 00 0 Ar Cl N .N (II) in which Ar and R3 have the same meanings as in Claim 1 and, optionally, the compound thus obtained is converted into a salt with a mineral or organic acid.

7. Pharmaceutical composition characterized in that it contains as an active ingredient one compound according to any one of the Claims 1 to 5, in combination with a pharmaceutically acceptable carrier.

8. Pharmaceutical composition according to Claim 7, characterized in that it contains from 0.5 to 100 mg of active ingredient per dosage unit. i>. WXL 930503,p:\oper\dab66672spe,25 26

9. A compound according to Claim 1, a process for the preparation thereof, or a pharmaceutical composition comprising a said compound, substantially as hereinbefore described with reference to the Examples. DATED this 3rd day of May, 1993 Sanofi By Its Patent Attorneys DAVTIES COLLISON CAVE *see 0 00 00 So0 0 0 00 a 0 o g*0 00 0 00 0 930503,p:\oper\dab,66672-spe,26