NZ236107A

NZ236107A - 3 (substituted amino)-6-phenyl (and heterocyclyl)-1,2-diazine derivatives; preparatory processes and pharmaceutical compositions

Info

Publication number: NZ236107A
Application number: NZ236107A
Authority: NZ
Inventors: Robert Boigegrain; Roger Brodin; Jean Paul Kan; Dominique Olliero; Camille Georges Wermuth
Original assignee: Sanofi Sa
Priority date: 1989-11-17
Filing date: 1990-11-16
Publication date: 1992-10-28
Also published as: FR2663326A2; ATE143010T1; IE904145A1; FI101881B; IE75697B1; DK0429344T3; EP0429344A1; HU207852B; JPH03170465A; HU211351A9; AU6667290A; FI101881B1; CA2030133C; HU907178D0; FI905663A0; IL96384A; KR910009672A; FI905663A; KR0164599B1; NO904984L

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £36107 3 Priority wSri.. 236 j C'-osr!?>*oJs f5p©cjfic<iriO!" :i-» j i C.a.i: (-)CO:20X&l!2.C, XolO^lW, CQ;)i^^/oU CPlowslnsft 5-3?: i 88"0TT TO ■ f"J -1*'-.; r* r s r*'-s«v ;, M'": . •y '■>, ' v ■ > i : .- ■ - •. 4* v f !'■• ,. -: Vs ^ e 71 "Vj Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION PYRIDAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM WE, SANOFI, a French company of 40 Avenue George V, 75008 Paris, FRANCE hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: | 16 HOV - 1 - (followed by page la) 236 la For many years pyridazine derivatives have been suggested as medicines, in particular medicines active on the cardiovascular system or on the central nervous system. Til 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 t'/pe -NH-alkvlene-N in which X and Y independently -\10 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 .20. formula: R3 Ar-/ \—NH-R4 ^ V/ ^ 25 in which - Ar represents a phenyl group substituted by and or a heterocyclic radical such as a pyridyl group, unsubstituted or substituted by methyl or methoxy, or a thienyl group, unsubstituted or substituted "N ' ■ -J 30' by chlorine, methyl or methoxy; - and each independently denotes hydrogen, halogen, trifluoro-nethyl, hydroxy, alkoxy or alkyl; - R0 represents a linear or branched alkyl, cycloalkyl, . : benzyl, phenethyl or the Ar' radical, Ar' being phenyl substituted 35 by and R2; (followed by page 2) 2 3 6 1 0 2 - R^ represents: C»2Xi r5 . a ^ " ^"2)n " N group, with n = 0 or 1 CI,2Xi r6 in which X^ represents hydro3en or methyl; - R,- represents a linear alkyl group; - !v represents a C.-C, linear alkyl '»roup, or Rc and R, also constitute 6 1 16 5 o together with the nitrogen atom to which they are attached a hetero-cycle 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-hydroxy-phenyl, R^ represents phenyl or n-propyl, R^ and R^ each represents ethyl, 11 = 0 and = M. The following compounds are particularly preferred: 3-(2-diethylamino-2-methyl-propyl)amino-6-phenyl-5-propyl-pyridazine and its salts; 3-(2-diethylamino-2-methyl-propy1)amino-5,6-diphenyl-pyridazine 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 pharmaccutically acceptable salts such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydro^en 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 U). 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: 236 1 J -n 5 (in in which Ar and 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) ^ 10 by the aniine 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. 15 The product of formula I thus obtained is isolated in the form of the free base or a salt according to standard techniques. \'hen 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, 20' dissolved for example in an alcohol such as isopropanol, with a solution of the selected acid in the sane solvent, the correspondinj salt is obtained which is isolated according to standard techniques. In this way, the hydrochloride, the hydrobroraide, the sulfate, the hydrogen sulfate, the dihydro^cn phosphate, the methane sulfonate, the methyl . • ^ 25 sulfate, the oxalate, the naleate, the fumarate and the 2-nap'ntnalene 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 30 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. '■.'hen and /'or I?2 represent a hydroxy 1 group, the compound according to th*e invention is obtained starting from compound (I) in 35 which and/or denote alkoxy and all of the other substituents 23 6 1 0 A have the above definitions, by dealkylation using known methods. The 6-chloro pyridnzines (II), used as starting materials, are prepared from the corresponding 2II-pyridazin-3-oncs (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: 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.SC'L'IIDT et al. in 'lelv. Chini. Acta, 1954, L5, 134-140, starting from malonic acid diethyl ester and a hydrazone derivative according to the following reaction scheme: Ar'-CO-C-Ar + CH2-CO2C2H5 N-NH2 CO2C2H5 Ar' CO2C2H5 Ar1 COOH (HI) 5 2 3 6 1 When represents an alkyl or cycloalkyl radical, the compounds (III) are prepared from a ketone Ar-CO-CI^Rg (JJ*: CHO R3 OH COOC2H5 XCH—CH C / \ 5 Ar-C-CH2"R3 > Ar - C C = 0 _ ii ii / 0 1 0 H5C20 2 ^3 OH r3 h NH2NH2 CH-CH c=C ilJ / \ / \ ^ > Ar - C C = 0 > Ar - C C = 0 'J N N N_/ 3 ft (III) J 15 The hydroxy keto ester is obtained from the ketone by heating it with ethyl ^lyoxylate at a temperature between 80 and 14Q°C. The crude reaction mixture is then taken up in an inert solvent such as n-butanol and hydrazine hydrate is added. Cy heatiny at reflux for 24 hours, the 4,5-dihydro 4-hydroxy pyridazin-3-one 3_ is obtained .20 which, when heated in an acidic Medium, leads by dehydration to the 2II-pyridazin-3-one (III/. The amines are known or prepared by known methods. Thus, when n = 0, they may be prepared from a cyano derivative of formula: j 25 X1CH2 OH X (rv) X1CH2 CN By reaction with an amine by heating at a temperature •* 30 between 40 and S0°C, optionally in the presence of a salt of a strong acid such as sodium sulfate or magnesium sulfate, a compound of formula XICH2 NR5R6 (V) 35 XiCH2/ \N * 10 15 20 3 25 0730 236 1 0 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: XICH2 yNR5R6 X CVI) 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^NI^. When n = 0, the amine may also be prepared from a chloronitroso derivative (VII) according to the procedure described in J. Prakt. Chem., 1978, 320 (3), 433-451. X1CH2 X1CH2 1 1 CI - C - CH2NO + R5R6NH2 > R6R5N - C - CH = NOH X1CH2 Xi<^H2 (VII) (VIII) Li A1 H4 X1CH2 > R6R5N - C - CH2 - NH2 X1CH2 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 CH2Xi 0 0 CII2X1 || I T T ' C + N0C1 > CI - C - C»2 - N = N - CH2 - C - CI / \ 1 1 X1CH2 CH2Xi CH2X1 CH2X1 35 (IX) (VII a ) 2 3 6 1 7 Finally, when n = 1, the amine Imay be prepared according to the method described in Heilstein 4_ (3), 596, i.e. by reaction of lithium aluminium hydride on the oxine (X): CH2Xi LiAlH^ CH2X1 HO - N = CH - C - C»2 " NR5R6 > H2N ~ cti2 " C ~ CH2~ NR5R6 CH2X1 CH2X1 (X) The amine "I!? - - C'l^-NfCTU)^ is commercially available. The following examples illustrate the invention without in any way limiting it. The compounds are characterized by their melting point (m.p., expressed in decrees centigrade. EX.V'PLF. 1 3-(2-diethylamino-2-methyl-propyl)amino-6-phenyl-5-propyl-pyridazine sesquifumarate: SR 46559 A. A) 6-chloro-3-phenyl-4-propyl-pyridazine. 1. "thyl 2-hydroxy-4-oxo-4-phenyl-3-propyl-butyrate. A mixture of 43.07 g of valerophenone and 45.94 g of ethyl "lyoxylate is heated at 120°C for 15 hours. The crude reaction product is used as such in the following step. 2. 6-phenyl-5-propyl-2!!-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 cor 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 nnd the product is left to crystallize. The solid is filtered off and dried. '..'eight: 44 3 M.p.: 160°C. 2 3 6 10/ 8 .-W Yield : 69% 3. 6-chloro-3-phenyl-4-propyl—pyridazine. 250 nil of phosphorus oxychloride are added to 44 g of pyridazinone obtained above and the mixture is heated at 80°C for 4 5 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 10 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". 15 B) Preparation of 2-diQthylamino-2-methyl-propylar.iine. 1. 2-dicthylamino-2-methyl—propionitrile. S5.1 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. 20 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. Yield : 62% 3.p. = 63-70°C at 15 mm of mercury. 25 2. 2-diet'nylamino 2-nethyl 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. ''eight : 102.5 3 35 Yield : 95% 236 9 B.p. : 134-139°C at 15 mm of mercury. 3. 2-diethylamino-2-methy 1—propylamine. A mixture containing 52.4 g of the amide prepared in the preceding step and 60 nl of tetrahydrofuran are heated at 45-50°C. 86 ml of the borane-dinethylsulfide complex are added under an atmosphere of nitrogen during one hour and heating is continued for 3 hours on an oil bath at 30-85°C. After being left overnight at room temperature, the mixture is cooled in an ice bath, then 315 ml of 6!I 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 30^ 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 : 43/1 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 T, 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 30;" 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 10 (175 ml) is concentrated to 130 ml. The product is allowed to crystallize, the crystals are filtered off and then washed v/ith acetone. 4.1 3 of the expected product are obtained. Overall yield of step C = 7UY, 5 M.p. = 151"C EXAMPLE 2 SR 46559 A A) 6-chloro-3-phenyl-4-propyl-pyridazine, described in example 1. 10 B) 2-diethylanino-2-:iethyl-propylamine. 1. Preparation of the compound of fornula ^VII a) with X^ = II. 47.14 » oE isobutylenc are dissolved in 150 ml of n-'neptane, the mixture is cooled to a temperature between -10° and -20°C and 50 3 of nitrosyl chloride are added. The temperature is allowed to rise(+5°C) 15 during one and a half hours, then the temperature is brought to between 10°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. :i.p. = 102-104GC in = 64 3 '20 2. Preparation of the compound of formula VIII: = H; rL = ? - P T1 o 2D 21.7 3 of the compound prepared in the preceding step are suspended in 150 ml of absolute alcohol, 39.17 3 of diethylamine are added and the mixture is heated at 60°C for 6 hours. An oil is obtained 25 which solidifies. m = 19.5 g :>.P. < 500c 3. 2-diethylamino-2-methyl-propylamine 7.01 3 of lithium aluminium hydride arc added to 50 inl of 30 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, '-.'bile 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 '35 water during 30 minutes. After being stirred for 2 hours at room 11 t f* A L 3 0 1 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. ;n = 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-chloro 6-(2-chloro-phenyl) 5-propyl pyridazine and 6 ml of 2-diethyla:nino 2-methyl propylamine arc heated at 110°C under nitrogen for 20 hours. After evaporation under vacuum, the mixture is taken up in 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: dichloromethane/methanol 93/2. 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°C. EXAMPLE 4 3-(2-diethylamino-2-methyl-propyl)amino-6-(2-methoxy-phenyl)-5-methyl-pyridazine. 1.6 g of 3-chloro-o-(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. S6 1 07 "A 12 The organic phase is separated, dried over .''gSO, . filtered and evaporated to dryness in a vacuum. The residue is chromatographed on alumina, eluent: ethyl acetate +2% of triethylamine. 5 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-methy1-6-(2-hydroxy-10 phenyl)-pyridazine. SR 96376. 1 g of the product obtained previously in exanple A is dissolved in 50 ml of 40% hydrobromic acid and the mixture is heated at reflux for AG hours. After this time, the reaction mixture is evaporated to dryness under vacuum, the residue is made alkaline with 15 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/nethanol 9/1 + 2% of triethylamine. 20 The concentration of the pure fractions gives a residue which is crystallized from isopropanol. m = 200 mg ■I.p. = 159.2°C 125 EXAMPLES 6 TO 35 A) 3y 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. ^30 35. - 13 - 236 10 7 -j 05 10 ; 15 ; 20 i 25 30 TABLE 1 3 2 r1 R2 R3 : Physical : constants h h -ch2ch2ch3 :M.p.: 52-53°c ci (4) h -ch3 : m. p; 178-180°c ci (4) h -CH2CH2CH3 :m.p; 95°c 0ch3 (4) h -CH2CH2CH3 :m.p; 68-69°c h h ch3 :M.p:; 123- 124°c H h phenyl : M.p:. 115°c h h cyclopropyl : M.p:. h9°c f c«) h isopropyl *• M.p. s9-90°c ci (2) h ch2ch2ch3 : oil, NMR 0ch3(2) H ch3 - NMR H H benzy] :M.p; 92°c - 14 - CI (4) : H ; Cl-4 phenyl :M>p: 118-119°C H : H : Cl-4 phenyl :M.p~ 130°C CI (4) : H : phenyl :M.p! 125°C CI (2) : CI (4) : CH2CH2CH3 :M.P; 71-72°C CI (3) : H : CII2CH2CII3 :M.p; 48°C CH3 (4) : H : Cl-4 phenyl :M.p. 140°C OCII3C2) : H : CH2CH2CH3 toil, NMR" OCH3(3) : H : CH2CH2CH3 :oil, NMR" F (4) : H : Cl-4 phenyl :M.p. 139°C NMR : NHH spectral analysis enaoles the structure of the above compounds to be confirmed. 15 TABLE 2 236 1 0 o R3 Ar-0-ci N-N 10 15 Ar 2-thienyl 3-pyridyl : Physical R3 : constants phenyl :M.p: 148°C 2-C1 5-thienyl : phenyl phenyl NMR M.p: 184 °C 20 O 25 2-pyridyl 4-pyridyl pheny1 M.p: 138°C phenyl :M.p. 193 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 ^^R^ used. U30 35 - 16 - 236 1 0 TABLE 3 —> 5 6 r3 05 R2. 4 rl f\ 3 2 ~V V N-N NH-r4 : SR No. : : salt or base: : Ex. No. : rl : r2 : r3 : R4 : M.p. : 10 : 46729A : Cl(4) : H : CH3 : C„3 : CH2C-N \ : aihydro- : chloride : 6 : : in3\y : 240-242°C : 15 : - : sesqui- : : 46732A : H : H : nC3H7 ,r 11 : fumarate : : 7 ; : 159-161°C 20 : 46733A : Cl(4) rh : CH3 CH3/C2H5 : ch2-C-N ' \ : CH3 C2H5 : Fumarate : : 138-140°C : 8 : : 47020A : : 9 : H : H : CH3 " 11 : sesquifuma- : : rate 161°C : 25 : 47047A : : 10 : H : H : phenyl " " : fumarate : : 193°C : S w', ...... , : 47054A : : 11 : C1C4) : H : nC3H7 " " : sesqui- : : fumarate : : 152-154°C : - 17 - £ n 47068 12 47069A 13 47097A 14 47098A 15 47138A 16 47153A 17 47227A 18 47297A 19 47608A 20 ocil3(4): h oh(4) f(4) CI (4) H H 11c3h7 nc3h 7 cyclopropyl iPr 11C3H7 phenyl benzyl Cl-4 phenyl TVn -CH2-c-n 0 CH3V/ CH3 CH3 CH2-c-CH2-n I \ ch3 ch3 ch3 .c2h5 l / ch2-c-n^ £H3 C2H5 65-66°C base hydrobromide1 179-181°c sesquifumarate 158-160°c sesquifumarate hemihydrate 143-145°c sesquifumarate 149-151°c 164°C sesquifumarate fumarate 163°C dihydro-chlaride 138°C hydrate dihydro-chlaride 147°C - 18 - 23 47609A 21 CI (4) : H phenyl : 47655A 22 CI (2) :Cl-(4) nC3H7 : 47673 23 H : H nC3»7 : 47878A 24 CI (3) : II nC3H7 : 47890A 25 CH3 (4) : H Cl-4 : phenyl : 47967 26 F (4) : H Cl-4 : phenyl : 48079A 27 0CH3 (2) H nC3H7 : 48080 28 OH (2) : H nC3H7 48081A 29 0CH3 (3) : H nC3H7 48082 30 OH (3) : H nC3H7 : : dJiycL-o chlcri c2hs ch3 ch2-C-n > \ c2h5 ch3 ch3 c2h5 I / ch2-c-n ch3 c2h5 ideur sesquifumarate 165-166°G base oil :imr" sesquifumarate 146°C dihydro- chloride a 138 C 98°C base sesquifumarate 95°C 159,5°C base dihydro-chloride NMR 166°C : base 19 NMR spectrum of SR 47673 fDMSO d,; 200 MHz) u 0.70 (t : 3 !I); 0.80 (t ; 611); 1.30 (q ; 2H); 1.50 (in ; 411); 2.30 (s ; 611); 2.40 (m ; 2!1); 3,40 (m ; 211); 6.20 (:n ; 1H); 6.30 (s ; 1H); 7.35 (s ; 511). NMR spectrum of SR 48081 A (DMSO d6; 200 MHz) 0.80 (t ; 3H); 1.40 (m ; 811); 1.5 (s ; 6H>; 2.56 (q ; 211); 3.40 (b.s. ; 4)1); 3.30 (s ; 3!I); 4.00 (d ; 2'I); 7.02 (m ; 3:1); 7.40 (t ; 111); 7.83 (b.s. ; 1!!). The following abbreviations are used for the analysis of a NMR spectrum. s = singlet ; b.s. : broad sin«let; <1 : doublet; t : triplet q : quadruplet; ;n : multiplet. C) Starting from the chloro derivatives of table 2 and by following the procedure described in example 1, the compounds accordin3 to the invention assembled in table 4 below are obtained by varying the amines NH^R^ used. 236 20 TABLE 4 R3 : SR No. Ar R3 R4 : Salt or base: 10 : Ex. No. : 47674 A 2-thienyl phenyl CH2- CH3 C2H5 ■hY • \ CH3 C2H5 : dihydro- : chloride _ : 133 C : : 31 15 : 47675 A : 32 5-C1 2-thienyl phenyl ff ft : dihydro- : . chloride 130°C . : decomposi- : : tion : ^ : 20 : 47802 A : 33 3-pyridyl phenyl It It : trihydro- : . chloride 225°C . : 47803 A : 34 2-pyridyl phenyl It It : trihydro- : ; chloride 233°C ; 0.;:25 : 47804 A : 35 4-pyridyl phenyl It It : trihydro- : . chloride : 239°C : The compounds accordin3 to the invention were studied with respect to their pharmacological properties and in particular with respect to their affinity for the nuscarinic cholinergic receptors of type Mj and In vitro, the compounds (I) were assayed according to the technique described by Watson J.D. et al. (Life Scienccs, 19S2, 31, u,30 .35 236 1 21 2019-2029) as far as their affinity for the receptors of type is concerncd and according to the technique described by Hammer R. et al. O'ature, 19S0, 283, 90-92) and Hulme F..C. et al. ..Molecular Pharmacology, 1978, 14, 737-750) as far as their affinity for the 5 receptors of the M9 type is concerned. The compounds according to the invention exhibit 3ood affinity for the receptors of type M^ and a marked specificity for the central receptors of type as opposed to receptors of type '! As an example, the compound SR 46559 A showed an inhibiting 10 concentration 50 expressed in micromoles of 0.11 and 2.2, respectively, on the and receptors. Similarly, the compound SR 47047 A showed inhibiting concentrations 50 of 0.04 and 0.9, respectively, on the M^ and 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, 20 the injection of pirenzepine. At a dose of 3 rn_j 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 4G559 A inhibits the rotations induced by pirenzepine by 73%. ) 25 Further more, 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,, 1939, 98, 236-283. Thus, according to the results of these tests, the compounds 30 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 mg/kg, respectively,in each of these tests. 35 Moreover, some compounds according to the invention were 22 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, 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 (.1) 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 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 rug per day. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> n 236 1 n 23 Each unit dose may contain Erom 0.1 to 100 mg of active ingredient in combination with a pharmaceutical vehicle. This unit dose may be administered 1 to 5 ti:nes per day. '.'hen a solid composition is prepared in the form of tablets, 5 the principal activo ingredient is mixed with a pharmaceutical vehicle such as 3elatine, starch, lactose, magnesium stearate, talc, 311m 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 10 a predetermined amount of active ingredient. A 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 v/ith 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 v/ith binders melting at the rectal temperature, 20 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. 25 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: SH 46559 A 0.010 3 30 Lactose 0.050 g Magnesium stearate 0.005 g by mixing the above ingredients intimately and pouring the mixture into gelules of hard gelatine. 35 236 1 0 CLAff* WHATX^WE CLAIM IS:-

1. Compound of formula: R3 o ar_^/==\^n'h-r4 (i) N_N in which : - Ar represents a phenyl group substituted by R^ and or a hetero-10 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 R7 each independently denotes h/droyen, halogen, trifluoro-iiiethyl, hydroxyL, C^-CA alkoxy or C^-C^ alkyl; 15 - R,, represents linear or branched C,-C, alley 1, Cn-C-, cycloalkyl, 1 *4 Of benzyl, phenethyl or the Ar' radical, Ar' bein;> phenyl substituted by Rj and R^; _ p R^ represents: ',20 CH2X1 - CH2 " C - (CH2)n " N\ a x N group, with n = 0 or 1 CH2X1 R6 . - , , ' in which Xj represents hydrogen or methyl; - R^ represents a 0^-C, linear alkyl group; U" 25 - R, reoresents a C.-C. linear alkyl 'toud, or R_ and R, also -^0/ 0 • 1 o 3 u * ' -j 6 constitute with the nitrogen atom to which they are attached a heterocycle selected fron morpholine, pyrrolidine or piperidine; as well as its salts with mineral or organic acids.

2. Compound according to Claim 1 in which: ^ 'j 30 - Ar represents phenyl, unsubstituted or substituted at position 2 by chlorine, hydroxyl or methoxy; - R^ represents phenyl or n-propyl; - Rg and Rq each represents ethyl; n = 0 and Xj = 35 as well as its salts with mineral or organic acids. 7:26) 07 25

3. 3-M-(2-diethylamino 2-met'nyl propyl) 6-phenyl 5-propyl pyridazinamine and its salts.

4. 3-?'-(2-diethylamino 2-inethyl propyl) 5,6-diphenyl pyridazinamine and its salts. 5 5.

Process for the preparation of a compound according to Claim 1, characterized in that an amine R-MIL reacts v/ith a 6-chloro 4 2 pyridazine of formula: R3 10 . •• i (II) in which Ar and R„ have the sa:ne meanings as in Claim 1 and. optionally, the compound thus obtained is converted into a salt 15 with a mineral or orsanic acid. o.

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 20 that it contains from 0.5 to 100 of active ingredient per dosage unit.

8. Compound of claim 1/ substantially as herein described.

9. Compound of claim 1, substantially as herein described with reference to any one of the Examples.

10.Process of claim 5, substantially as herein described.

11 .Pharmaceutical composition of claim 6, substantially as herein described. J SANOFI / ■; l >/v1 .' By Their Attorneys BALDWIN SON & CAREY ^ ^ ^ */> #0 F * •' 35 </div>