IE904145A1 - Pyridazine derivatives, process for their preparation and pharmaceutical compositions containing them - Google Patents

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

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IE904145A1
IE904145A1 IE414590A IE414590A IE904145A1 IE 904145 A1 IE904145 A1 IE 904145A1 IE 414590 A IE414590 A IE 414590A IE 414590 A IE414590 A IE 414590A IE 904145 A1 IE904145 A1 IE 904145A1
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phenyl
methyl
compound
substituted
formula
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IE414590A
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IE75697B1 (en
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Robert Boigegrain
Roger Brodin
Jean Paul Kan
Dominique Olliero
Camille Georges Wetmuth
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Sanofi Sa
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Priority claimed from FR8915137A external-priority patent/FR2654727B1/en
Application filed by Sanofi Sa filed Critical Sanofi Sa
Publication of IE904145A1 publication Critical patent/IE904145A1/en
Publication of IE75697B1 publication Critical patent/IE75697B1/en

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    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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Abstract

The invention relates to pyridazine derivatives of the formula: in which: - Ar represents a phenyl substituted with R1 and R2 or a heterocyclic radical such as pyridyl, unsubstituted or substituted with a methyl or a methoxy, or thienyl unsubstituted or substituted with a chlorine, a methyl or a methoxy; - R1 and R2 each independently denote hydrogen, a halogen atom, a trifluoromethyl group, a hydroxyl group, a C1-C4 alkoxy group or a C1-C4 alkyl group; - R3 represents a linear or branched C1-C4 alkyl group, a C3-C7 cycloalkyl, a benzyl, a phenethyl or a radical Ar', Ar' being a phenyl substituted with R1 and R2; - R4 represents a group: with n = 0 or 1, in which X1 represents hydrogen or a methyl; - R5 represents a linear C1-C6 alkyl group; - R6 represents a linear C1-C6 alkyl group, or alternatively R5 and R6, with the nitrogen atom to which they are linked, form a heterocycle chosen from morpholine, pyrrolidine or piperidine; as well as its salts with inorganic or organic acids. Application: medicaments which are active with respect to type M1 cholinergic receptors.

Description

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 2 510 993 and European 5 patent 72 726 disclose pyridazine derivatives variously substituted on the pyridazine ring and all bearing at position 3 an amine /X substituent of the type -NH-alkylene-λ^ in 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 15 pyridazine have now been discovered which have lost their antidepressant activity and acquired a useful activity as ligands of cholinergic receptors, in particular receptors of the type.
In accordance with a first feature, the object of the present invention is novel derivatives of pyridazine corresponding to the formula: R3 Ar-Z \-NH-R4 XN_NZ (I) in which - Ar represents a phenyl group substituted by R^ and Rg or a heterocyclic radical such as a pyridyl group, unsubstituted or substituted by methyl or methoxy, or a thienyl group, unsubstituted or substituted by chlorine, methyl or methoxy; - 7^ and 7? each independently denotes hydrogen, halogen, trifluoromethyl, hydroxy, C^-C^ alkoxy or C^-C^ alkyl; - 7q represents a linear or branched alkyl, C^-Cy cycloalkyl, benzyl, phenethyl or the Ar' radical, Ar’ being phenyl substituted by and 7?; - R^ represents: C»2Xl R5a CH2 C (CH2)n - N group, with n - 0 or 1 Cfl2*l R6 in which represents hydrogen or methyl; - Rg represents a C^-Cg linear alkyl group; - Rg represents a C^-Cg linear alkyl group, or Rg and Rg 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 monosubstituted 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-hydroxy-phenyl, Rg represents phenyl or n-propyl, Rg and Rg each represents ethyl, 11 = 0 and X^ = H.
The following compounds are particularly preferred: 3-(2-diethylamino-2-methyl-propyl)amino-6-phenyl-5-propyl20 pyridazine and its salts; 3-(2-diethylamino-2-methyl-propyl)amino-5,6-diphenylpyridazine and its salts.
The 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, 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 (I)· According to the present invention, the process for the preparation of the compounds of formula (I) is characterized in that an amine is reacted with a 6-chloro pyridazine of formula: in which Ar and Rg have the meanings indicated above for (I) 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^NHg is carried out between 100° 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 (I) 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 formula 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 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 and/or Rg represent a hydroxyl group, the compound according to the invention is obtained starting from compound (I) in which and/or Rg denote alkoxy and all of the other substituents have the above definitions, by dealkylation using known methods.
The ό-chloro pyridazines (II), used as starting materials, are prepared from the corresponding 2H-pyridazin-3-ones (III) by reaction with an excess of hot phosphorus oxychloride in the absence of a solvent or in the presence of an inert solvent such as acetonitrile, according to the following reaction scheme: H (III) POC13 (II) The 2H-pyridazin-3-ones (III) are known or prepared by known methods.
Thus, when Is a Ar' radical, the 2!I-pyridazin-3-ones are obtained according to the method described by P.SCHMIDT et al. in llelv. Chim. Acta, 1954, 15, 134-140, starting from malonic acid diethyl ester and a hydrazone derivative according to the following reaction scheme: Ar'-CO-C-Ar + CH2-CO2C2H5 NNH2 CO2C2H5 (III) When Rg represents an alkyl or cycloalkyl radical, the compounds (III) are prepared from a ketone Ar-CO-CHgRg (1.): OH Ar-C-CHv-Ra ll NH2NH2 CHO I COOC2H5 Ar - C il 0 R3 \ / CH-CH / H5C2O R3 OH \ / CH —CH A / \ Ar - C C = 0 R3 H \ / C=C / \ Ar - C C N-t/' I (in: The hydroxy keto ester 2_ is obtained from the ketone by heating it with ethyl glyoxylate at a temperature between 80 and 140°C. The crude reaction mixture is then taken up in an inert solvent such as n-butanol 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 the 2ΓΙ—pyridazin-3-one (III).
The amines R^NHg are known or prepared by known methods.
Thus, when n = 0, they may be prepared from a cyano derivative of formula; XlCH2 OH (IV> X1CH2 CN By reaction with an amine HNRgR^ by heating at a temperature 30 between 40 and 80°C, optionally in the presence of a salt of a strong acid such as sodium sulfate or magnesium sulfate, a compound of formula X1CH2 NR5R6 C ΧΐΟΗ2Ζ cn (V) is first prepared, then this compound is hydrated by reaction with a strong acid such as hot sulfuric acid in order to produce the corresponding amide: X1CH2 nr5r6 c (VI) / \ X1CH2 CONH2 Finally, reduction by heating with a metal hydride such as boron hydride or lithium aluminium hydride leads to the formation of the amine R.NIL.
Z When n = 0, the chloronitroso derivative in J. Prakt. Chem., 1978, X1CH2 Cl - C - CH2NO X1CH2 (VII) amine may also be prepared from a VII) according to the procedure described 320 (3), 433-451.
XlCH2 I + R5R6NH2 -> R6R5N - c - CH = NOH Xl^H2 (VIII) Li Al H4 XiCH2 -> R6R5N - C - CH2 - nh2 XlCH2 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 olefin (IX) according to the procedure described in J. Prakt. Chem., 1965, 29 (4), 123.
CH2 |l CH2X1 1 0 A 0 T CH2Xi 1 C + NOCI - —> Cl - C - CH2 - N = N - CH2 - C - Cl / \ 1 1 X1CH2 CHgXl CH2X1 CH2Xi (IX) (VII a ) Finally, when n = 1, the amine may be prepared according to the method described in Eeilstein 4_ (3), 596, i.e. by reaction of lithium aluminium hydride on the oxime (X): CH2X1 LiAlH4 CH2X1 HO - N = CH - C - CH2 - NR5R6 -> h2nCH2 c CH2~ NR5R6 CH2Xi (X) CH2X1 amine 'Jilg - CHgCXCHgYg CHg-NCCHgjg Is commercially following exaniDles illustrate the invention without in The available.
The any way limiting it. The compounds are characterized by their melting point (m.p.) expressed in degrees centigrade.
EXAMPLE 1 3-(2-diethylamino-2-methyl-propyl)amino-6-phenyl-5-propylpyridazine sesquifumarate: SR 46559 A.
A) 6-chloro-3-phenyl-4-propy1-pyridazine. 1. Ethyl 2-hydroxy-4-oxo-4-phenyl-3-propyl-butyrate.
A mixture of 43.67 g of valerophenone and 45.94 g of ethyl glyoxylate is heated at 120°C for 15 hours.
The crude reaction product is used as such in the following step. 2. 6-pheny1-5-propyl-2M-pyridazin-3-one.
The crude product obtained above is dissolved in 450 ml of n-butanol, then 30 g of hydrazine hydrate are added and the mixture is heated at reflux for 24 hours.
The n-butanol is evaporated under vacuum. The residue is taken up in a mixture of 300 ml of acetic acid and 30 ml of concentrated hydrochloric acid. The mixture is heated at 100°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. ’’’eight: 44 g M.p.: 160°C.
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°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. : 60°C Yield: 92%.
B) Preparation of 2-diethylamino-2-methyl-propylamine. 1. 2-diethylamino-2-methyl-propionitrile. 85.1 g of the cyanohydrin of distilled acetone and 73.1 g of diethylamine are mixed, 35.7 g of magnesium sulfate are added and the mixture is heated under gentle reflux for 20 hours with stirring.
The sulfate mass which is formed is filtered off and washed with ethe The filtrate is concentrated and then distilled. 86.6 g of the expected product are recovered.
Yield : 62% 3.p. = 63-70°C 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 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 20% 30 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 : 95% B.p. : 134-139°C at 15 mm of mercury. 3. 2-diethylamino-2-methyl—propylamine.
A mixture containing 52.4 g of the amide prepared in the preceding step and 60 ml of tetrahydrofuran are heated at 45-50°C. 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 mixture is cooled whilst 200 ml of 301( sodium hydroxide are added.
The mixture is extracted 3 times with 250 ml of ether, the extracts are dried over sodium sulfate and concentrated.
The expected product is obtained by distillation.
Weight: 23 g Yield : 43/( 3.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 the mixture is extracted twice with 50 ml of hydrochloric acid. The mixture is then made alkaline by the addition of 50 ml of 30M sodium hydroxide 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°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 (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 = 74,5 M.p. = 151 °C EXAMPLE 2 SE 46559 A A) 6-chloro-3-phenyl-4-propyl-pyridazine, described in example 1.
B) 2-diethylamino-2-methyl-propylamine. 1. Preparation of the compound of formula (VII a) with = 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 rise(+5°C) during one and a half hours, then the temperature is brought to between °C 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.
M.p. = 102-104°C m = 64 g 2. Preparation of the compound of formula VIII: = H; - „6 - b2.._ 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°C for 6 hours. An oil is obtained which solidifies. m = 19.5 g M.p. < 50°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°C and -10°C, 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 temperature, the solution is filtered, the precipitate is washed with anhydrous ether, the filtrate is dried over sodium sulfate and the solvents are removed under vacuum. The product is distilled: B.p. = 72-75°C at 15 mm of mercury. m = 4.2 g C) SR 46559 is then prepared as described in example 1.
EXAMPLE 3 3-(2-diethylamino-2-methyl-propyl)amino-6-(2-chloro-phenyl)10 5-propyl-pyridazine sesquifumarate. SR 47863 A. 1.7 g of 3-chloro 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 16 dichloromethane and washed with a solution of sodium bicarbonate. The organic phase is decanted, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is chromatographed on silica gel, eluant: dichloroncthane/methanol 98/2.
The concentration of the pure fractions gives an oil which 20 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°C.
EXAMPLE 4 3- (2-diethylamino-2-methyl-propyl)amino-6-(2-methoxy-phenyl)5-methyl-pyridazine. 1.6 g of 3-chloro-6-(2-methoxy-phenyl)-5-methyl pyridazine, 30 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.
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 +2% of triethylamine.
The concentration of the pure fractions gives the expected product. The structure is confirmed by NMR spectral analysis.
EXAMPLE 5 3- (2-diethylamino-2-methyl-propyl)amino-5-methyl-6-(2-hydroxy10 phenyl)-pyridazine. SR 96376. 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 evaporated to dryness under vacuum, the residue is made alkaline with an aqueous solution of potassium carbonate and the solution is extracted with dichloromethane. The organic phase is decanted, dried over MgSO^. 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 EXAMPLES 6 TO 35 A) 3y using the procedure indicated in example 1Λ, but by varying the starting ketone, the 6-chloro-pyridazines assembled in the tables 1 and 2 are obtained.
TABLE 1 : Ri :r2 : r3 : Physical : : constants : : H : H : -CH2CH2CH3 :M.p.: 52-53°C : : Cl (4) : H : -CH3 :M.p; 178-180°C : : Cl (4) : H : -CH2CH2CH3 :M.P; 95°C : : OCH3 (4): H : -CH2CH2CH3 =M.pt 68-69°C : : H : H ch3 : M.p'·: 123-124°C : H : H : phenyl : M.pt U5°C : : H : H : cyclopropyl •'M.p. H9°C : : F (4) : H : isopropyl : M.p. 89-90°C : : Cl (2) : H : CH2CH2CH3 : oil, NMR : : OCH3(2) : H : CH3 : NMR ' : : H : H : benzyl :m.P; 92°C : Cl (4) H : Cl-4 phenyl •m . p : 118-119°C : H : H : Cl-4 phenyl :M. p c 130°C 05 : Cl (4) : H : phenyl : M. n'» 125°C : Cl (2) : Cl (4) : ch2ch2ch3 ••M.p: 71-72°C 10 : Cl (3) : H : CH2CH2CH3 :M.p; 48°C : CH3 (4) : H : Cl-4 phenyl :M.p. 140°C : OCII3(2) : H : CII2CH2CH3 : oil, nmr 15 : OCH3(3) : H : CH2CH2CH3 : oi 1, nmr : F (4) H : Cl-4 phenyl : M. p . 139°C NMR : NMR spectral analysis enaoles the structure of the above compounds to be confirmed.
TABLE 2 Cl Ar R3 Physical constants 2-thienyl phenyl M.p: 148°C 2-C1 5-thienyl phenyl NMR 3-pyridyl phenyl M.p: 184°C 2-pyridyl pheny1 M.p. 138°C 4-pyridyl phenyl M.p 193^0 B) Starting from 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„R, used. 4 TABLE 3 47068 12 OCH3(4) H nC3H7 47069A 0H(4) H nC3H7 13 47097A H H cyclo- 14 propyl 47098A : 15 : F(4) : H : iPr 47138A : 16 : H : H : nC3H7 47153A : 17 : H : H : phenyl 47227A : 18 H : H : benzyl 47297A : 19 : Cl (4) : H : Cl-4 : phenyl 47608A : 20 : H : H II ft ft ft If If If 11 ίΚ3/Λ ch2-c-n 0 ϋΗ3\Ζ CH3 ch3 ch2-c-ch2-n ι ' CH3 CH3 CH3 c2h5 I / CH2-C-N\ 0h3 C2H5 65-66°C base hydrobromide 179-181°C sesquifumarate 158-160°C sesquifumarate hemihydrate 143-145°C sesquifumarate 149-151°C 164°C sesquifumarate fumarate 163°C dihydrochlaride 138°C hydrate dihydrochloride 147°C 47609A 21 Cl (4) : H : phenyl »1 ft : dehydro . chleride^yOc 47655A Cl (2) Cl-(4): nC3H7 tt tt : sesquifuma- 22 : rate : 165-166°C C2H5 ch3 ' / ch2-c-n 1 \ C2H5 ch3 : base 47673 23 H H : nC3H7 : oi 1 : NMR* ch3 1 / ch2-c-n 1 \ ch3 C2H5 : sesquifuma- 47878Λ 24 Cl (3) H : nC3H7 c2h5 : rate 146°C 47890A 25 CH3 (4) H : Cl-4 : phenyl ft If; dihydrochloride „ : 138 C 47967 F (4) H : Cl-4 tf ft : 98°C 26 : phenyl : base 48079A OCH3 (2) 1 H : nC3H7 ft tt : sesquifuma- 27 : rate 95°C 48080 OH (2) H : nC3H7 ft tt : 159,5°C 28 : base 48081A 29 OCH3 (3) H : nC3H7 tf II: dihydrochloride : NMR 48082 OH (3) H : nC3H7 t« ft : 166°C 30 : base NMR spectrum of SR 47673 (DMSO d<; 200 MHz) 0.70 (t : 3 II); 0.30 (t ; 611); 1.30 (q ; 2II); 1.50 (m ; 4H); 2.30 (s ; 6H); 2.40 (m ; 211); 3,40 (m ; 211); 6.20 (tn ; HI); 6.30 (s ; 1H); 7.35 (s ; 511).
NMR spectrum of SR 48081 Λ (DMSO dr; 200 MHz) o 0.30 (t ; 3H); 1.40 (tn ; 8H); 1.5 (s ; 611); 2.56 (q ; 2H); 3.40 (b.s. ; 4H); 3.30 (s ; 3H); 4.00 (d ; 2Π) ; 7.02 (in ; 3H); 7.40 (t ; HI); 7.83 (b.s. ; HI).
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 NILR, used. 4 IE 90414b TABLE 4 NH R4 SR No.
Ex. No. 47674 A 31 Ar R3 R4 Salt or base: 2-thienyl phenyl 47675 A 32 5-C1 2-thienyl phenyl 47802 A 33 47803 A 34 47804 A 35 3-pyridyl 2-pyridyl 4-pyridyl phenyl phenyl phenyl CH3 C2H5 I / CH2-C-N ' \ CH3 C2H5 ii ii dihydrochloride „ 133 C dihydrochlaride 130°C decomposition trihydrochlaride 225°C trihydrochloride 233°C trihydrochloride 239°C The compounds according to the invention were studied with respect to their pharmacological properties and in particular with respect to their affinity for the muscarinic cholinergic receptors of type Mj and Mg.
In vitro, the compounds (I) were assayed according to the technique described by Watson J.D. et al. (Life Sciences, 1982, 31, 2019-2029) as far as their affinity for the receptors of type M^ is concerned and according to the technique described by Hammer R. et al. (Mature, 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 Mg type is concerned.
The compounds according to the invention exhibit good affinity for the receptors of type M^ and a marked specificity for the central receptors of type M^ as opposed to receptors of type Mg.
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 Mj and Mg receptors.
Similarly, the compound SR 47047 A showed inhibiting concentrations 50 of 0.04 and 0.9, respectively, on the Mj and Mg receptors.
In vivo, the compounds according to the invention were assayed for their effect on the rotations induced by intrastriatal pirenzepine in the test described by Worms P, et al. (Psychopharmacology, 1987, 93, 439-493) 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 pirenzepine.
At a dose of 3 mg per kg of body weight, the compounds according 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 73M.
Furthermore, the compounds according to the invention were shown to be active in the passive avoidance tests in the rat described by Jarvik M.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 administered 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 ing/kg, respectively,in each of these tests.
Moreover, some compounds according to the invention were studied in several predictive models of 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. (J. Pharmacol. (Paris), 1977, 3., 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 (I) 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 pirenzcpine. They allow the use of the products according to the invention to be contemplated in all cases in which a cholinergic deficit is indicated and particularly for the treatment of cognitive and memory disorders, and degenerative syndromes associated with senescence and senile dementia.
In accordance with another of its features, the present application thus relates to pharmaceutical compositions containing at least one of the compounds of formula (I) or one of their salts as active ingredient.
In the pharmaceutical compositions of the present invention for oral, sublingual, transdermal or rectal administration, 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.
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. Λ preparation of capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.
The powders or granules dispersible in water may contain the 15 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.
The active ingredient may also be formulated in the form of microcapsules, with or without one or more additives or supports.
As an example of a galenic preparation, capsules may be prepared containing: SE 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 (11)

1. Compound of formula: N.N in which : - Ar represents a phenyl group substituted by R^ and Rg or a hetero10 cyclic radical such as a pyridyl group, unsubstituted or substituted by methyl or methoxy, or a thienyl group, unsubstituted or substituted by chlorine, methyl or methoxy. - and R ? each independently denotes hydrogen, halogen, trifluoromethyl, hydroxyl, C^-C^ alkoxy or C^-C^ alkyl; 15 - represents linear or branched C^-C^ alkyl, Cg-Cg cycloalkyl, benzyl, phenethyl or the Ar' radical, Ar' being phenyl substituted by and Rg; - R^ represents: 20 ™ 2 Χΐ /5 a - CH 2 - C - (CH 2 ) n a ι x group, with n = 0 or 1 CK 2 Xl r 6 in which represents hydrogen or methyl; - Rg represents a C^-C, linear alkyl group; 25 - R reoresents a C.-C< linear alkyl I’roup, or R r and R- also constitute with the nitrogen atom to which they are attached a heterocycle selected from morpholine, pyrrolidine or piperidine; as well as its salts with mineral or organic acids.
2. Compound according to Claim 1 in which: 30 - Ar represents phenyl, unsubstituted or substituted at position 2 by chlorine, hydroxyl or methoxy; - Rg represents phenyl or n-propyl; - Rg and Rg each represents ethyl; n = 0 and Xj = Π 55 as well as its salts with mineral or organic acids.
3. 3-N-(2-diethylamino 2-methyl propyl) 6-phenyl 5-propyl pyridazinamine and its salts.
4. 3-M-(2-diethylamino 2-methyl propyl) 5,6-diphenyl pyridazinamine and its salts.
5. Process for the preparation of a compound according to Claim 1, characterized in that an amine R^NHg reacts with a 6-chloro pyridazine of formula: (II) in which Ar and Rg 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.
6. Pharmaceutical composition characterized in that it contains as active ingredient one compound according to any one of the Claims 1 to 4.
7. Pharmaceutical composition according to Claim 6, characterized in that it contains from 0.5 to 100 mg of active ingredient per dosage unit.
8. A compound of formula (I) given and defined in Claim 1 or a salt thereof, substantially as hereinbefore described and exemplified.
9. A process for the preparation of a compound of formula (I) given and defined in Claim 1 or a salt thereof, substantially as hereinbefore described and exemplified.
10. A compound of formula (I) given and defined in Claim 1 or a salt thereof, whenever prepared by a process claimed in a preceding claim.
11. A pharmaceutical composition according to Claim 6, substantially as hereinbefore described and exemplified.
IE414590A 1989-11-17 1990-11-16 Pyridazine derivatives process for their preparation and pharmaceutical compositions containing them IE75697B1 (en)

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WO1997026258A1 (en) * 1996-01-15 1997-07-24 Janssen Pharmaceutica N.V. Angiogenesis inhibiting pyridazinamines
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US6528529B1 (en) 1998-03-31 2003-03-04 Acadia Pharmaceuticals Inc. Compounds with activity on muscarinic receptors
AU2002255851B2 (en) 2001-03-23 2008-03-06 Advanced Bionutrition Microbial feeds for aquaculture and agriculture
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CA2620333A1 (en) 2005-08-26 2007-03-01 Braincells, Inc. Neurogenesis by muscarinic receptor modulation
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