IL99013A - 3,5,6-substituted pyridazines method of preparation and pharmaceutical compositions containing them - Google Patents

3,5,6-substituted pyridazines method of preparation and pharmaceutical compositions containing them

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IL99013A
IL99013A IL9901391A IL9901391A IL99013A IL 99013 A IL99013 A IL 99013A IL 9901391 A IL9901391 A IL 9901391A IL 9901391 A IL9901391 A IL 9901391A IL 99013 A IL99013 A IL 99013A
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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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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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
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    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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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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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

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

Description

αηΐΝ n^ann ηιηρπ ·η>¾;:πι ηηαπ^ nv 6,5,3-onnmn DW . 3,5,6-Substituted pyridaz nes, method of preparation and pharmaceutical compositions containing them.
SANOFI C: 84153/6 Pyridazine derivatives have been proposed as drugs for many year;s , especially those which are active on the cardiovascular system or the central nervous system.
In particular, French Patent 2,510,998 and European. Patent 72,726 corresponding to Israel Patent 66408 and U.S. 4,508,720 disclose pyridazine derivatives which are variously substituted on the pyridazine ring and which all carry, in the 3-position, an amine substituent of the type X — NH-(C3-C3)alkylene N \ H in which X is hydrogen or (Ci-Cjjalkyl.
All these compounds are active on the central nervous system as antidepressants.
According to the present invention, it has now been found that by modifying the substituents , compounds are obtained which have lost their antidepressant activity and acquired a valuable activity as M^type cholinergic receptor ligands.
The present invention relates to novel pyridazine derivatives of the formula in which - Ar is a phenyl group of the formula a pyridyl' group or a thienyl group; R^ and are each independently hydrogen, a halogen atom, a hydroxyl group, a C^-C^ alkyl group, a Cj-C4 alkoxy or the trifluoromethyl group; C^-C,. alkyl, a group -CH - and ^ is the group in which ^ X is a linear or branched cfcQ alkylene and especially either a group -(CH9) -, in which n is an integer from 1 to 3; or a group -CH2-c-(CH2)nl- 1 in which n is 0 or 1 and Xx is a 0^-03 alkyl group ; and .» 5 and Rg are each independently hydrogen or a linear or branched C^-Cq alkyl or form, with the nitrogen atom to which they are bonded, a hetero- cycle selected from pyrrolidine, or piperidine; or R. is a group selected from in which n is an integer from 1 to 3 and R7 is hydrogen or a C1-C4, preferably C1-C2, alkyl group ; in which n is as defined above, and their salts with mineral or organic salts.
The salts of the compounds of formula (I) according to the present invention include both those with mineral or organic acids which permit appropriate separation or crystallization of the compounds of formula (I), such as picric acid or oxalic acid, and those with mineral or organic acids which form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide , sulfate, hydrogensulfate, dihydrogen-phosphate, methanesulfonate, methylsulfate, maleate, fumarate or naphthalene-2-sulfonate.
According to another feature, the present invention relates to a method of preparing the compounds of formula (I), which comprises reacting a 3-chloropyridazine of the formula in which Ar and R3 are as defined above, with an amine of the formula ¾NH2 in which is as defined above, to give the compounds (I) according to the invention and, if desired, converting the resulting compound to a salt with a mineral or organic acid.
The substitution reaction of the 3-chloropyri-dazine (II) with the amine R4NH2 is carried out at a temperature of between 100 and 150 °C, in the absence of a solvent or in the presence of an inert solvent such as n-butanol.
The resulting product of formula (I) is isolated, in the form of the free base or a salt, by the conventional techniques .
When the compound of formula (I) is obtained in the form of the free' base, conversion to a salt is effected by treatment with the chosen acid in an organic solvent. Treatment of the free base, for example dissolved in an alcohol such as isopropanol, with a solution of the chosen acid in the same solvent gives the corresponding salt, which is isolated by the conventional techniques. The hydrochloride, hydrobromide , sulfate, hydrogensulfate, dihydrogenphosphate , methane-sulfonate, methylsulfate, oxalate, maleate, fumarate or naphthalene-2-sulfonate, for example, is prepared in this way.
When the reaction is complete, the compound of formula (I) can be isolated in the form of one of its salts, for example the hydrochloride, oxalate or fumarate. In this case, if necessary, the free base can be prepared by neutralization of said salt with a mineral or organic base such as sodium hydroxide or triethylamine , or with an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate.
When Ra and/or R2 are a hydroxy1 group, the compound according to the invention is obtained from the compound (I) in which Rx and/or Ra are an alkoxy, all the other substituents being as defined above, by dealkylation using known methods.
The 3-chloropyridazines (II) used as starting materials are prepared from the 2H-pyridazin-3-ones (III) of the formula Ar reaction with excess phosphorus oxychloride under 99013/2 - 6 - the action of heat, without a solvent or in the presence of an inert solvent such as acetonitrile .
The 2H-pyridazin-3-ones (III) above are obtained by dejydrogenation of the compounds of formula (IV): for example by reaction with bromine in acetic acid.
The 2,3,4,5-tetrahydropyridazin-3-ones of the formula and the 2 , 3-dihydropyridazin-3-ones of formula (III), are prepared by the" methods described by SUTTER et al., J.
Am. Chem. Soc, 1942, 64/ 533-536, MUKHIRJI D. , Science and Culture, 1948, 13, 426, and PINNA G. et al., II Farmaco, Ed. Sci., 1988, 42, 539-549.
The intermediates of the formulae (IV) (III) in which Ar and R3 are as defined above, which are use- ful for the preparation of (I), are novel with the exception of the compounds in which Ar is an unsubstituted phenyl and R3 is a methyl group. By way of example, compounds of formulae (IV) and (III) are described in Tables 1 and 2 below.
The chlorinated compounds of formula (II): which are novel/ are prepared by the customary methods. By way of example, compounds of formula (II) are described in Table 3 below.
Substitution of these chlorinated compounds (II) with an amine makes it possible to obtain the compounds (I), the preparation of which is illustrated by the reaction scheme below.
SCHEME 1 1) EtONa EtOH Ar-CH2CN Ar-CH-CN 2) R3C02Et CO-R3 (IV) (HI) (II) H2N-R4 (I) Heating a nitrile i in the presence of a base and a carboxylic acid ester derivative R3C02Et gives the /3-ketonitrile 2, which is converted to the corresponding ketone derivative 3_ in an acidic medium.
Cyclization to the 2,3,4,5-tetrahydropyridazin- 3-one is effected by reaction with ethyl bromoacetate in an alcoholic solvent at room temperature, followed by reaction with hydrazine hydrate under the action of heat.
Dehydrogenation of the compound (IV) by reaction with bromine in acetic acid makes it possible to prepare the 2,3-dihydropyridazin-3-one (III).
In the case where n^ = 0, the amines in which X is a group in which Xx is as defined above, are prepared from a cyano derivative of the formula CN (X^-C-OH by reaction with an amine of the formula HNRBR6/ if appropriate in the presence of a salt of a strong acid, such as sodium or magnesium sulfate, at a temperature of between 40 and 80 " C , to give the aminonitrile of the formula which is hydrated under the customary conditions, in an acidic medium, to give the corresponding amide of the formula which is then reduced by reaction with a metal hydride , such as lithium aluminum hydride or borori hydride, to give the expected amine The following Examples illustrate the invention without however implying a limitation.
EXAMPLE 1 3- ( 2-Diethylamino-2-methylprop-l-yl ) amino-5- ( 4-fluoro-phenyl ) -6-propylpyridazine A) a-Butyryl-4-fluorophenylacetonitrile 10.9 g of sodium are added to 150 ml of absolute ethanol. While maintaining reflux, a solution of 49.5 g of 4-fluorophenylacetonitrile in 65.2 g of ethyl butyrate is added. The reaction mixture is refluxed for 4 hours and then left to stand overnight at room temperature. The solvents are concentrated under vacuum and the residue is taken up in water and washed with ether. The aqueous phase is cooled in an ice bath and acidified to pH 5-6 by the addition of concentrated acetic acid to give crystals, which are filtered off, washed with water and dissolved in methylene chloride.
The organic phase is decanted, dried over MgS04, filtered arid concentrated under vacuum. m = 50 g M.p. = 53-54°C B) l-(4-Fluorophenyl)pentan-2-one 50 g of the product obtained above are treated with 36 ml of water and 148 ml of concentrated sulfuric acid, which is added dropwise at 4°C, with stirring. The mixture is then heated at 80 °C for ½ hour and cooled, 534 ml of water are then added and the mixture is refluxed overnight.
The mixture is extracted with methylene chloride and the organic phase is decanted, dried over Na2S04, filtered and concentrated under vacuum.
The residue is chromatographed on silica gel using 50/50 cyclohexane/methylene chloride as the eluent. m = 39.2 g C) 5-(4-Fluorophenyl)-6-propyl-2,3,4,5-tetrahydro- pyridazin-3-one 2.76 g of sodium are dissolved in 115 ml of isopropanol. A solution of 21.56 g of the product obtained above in 30 ml of isopropanol is added, with cooling in an ice bath. The mixture is stirred for one hour at room temperature, a solution of 15 ml of ethyl bromoacetate in 20 ml of isopropanol is then added dropwise and the mixture is left to stand at room temperature for 24 hours.
The residue is taken up in acidified water (HC1 - pH = 2) and extracted with methylene chloride. The organic phase is decanted and dried over MgS04. It is filtered and concentrated under vacuum. The residue is taken up in 75 ml of butanol, 11.25 ml of hydrazine hydrate are added and the reaction mixture is refluxed for 4 hours.
The mixture is concentrated under vacuum and the residue is taken up in water and extracted with methylene chloride. The organic phase is decanted, dried over MgS04, filtered and concentrated under vacuum. m = 13.7 g M.p. = 78-79°C D) 2 , 3-Dihydro-5- ( 4-fluorophenyl ) -6-propylpyridazin-3- one 9.37 g of the product obtained above are dissolved in 40 ml of acetic acid and heated to 80 eC. A solution of 7.6 g of bromine in 70 ml of acetic acid is then added dropwise and the reaction mixture is refluxed for 4 hours. It is cooled to 15 °C and a precipitate is filtered off. m = 6.6 g M.p. = 193-194°C E) 3-Chloro-5- (4-fluorophenyl )-6-propylpyridazine 4.64 g of the product obtained above are dissolved in 28 ml of acetonitrile and 8.6 ml of phosphorus oxychloride and the reaction mixture is refluxed for 4 hours and then concentrated under vacuum. The residue is taken up in iced water, aqueous ammonia is added and the mixture is then extracted with methylene chloride. The organic phases are decanted, dried over MgS04, filtered and concentrated under vacuum. The residue is chromatographed on silica gel using 95/5 methylene chloride/ethyl acetate as the eluent. m = 4.35 g M.p. = 64°C F) Compound 1 1 g of the product obtained above and 3 g of 1-amino-2-diethylamino-2-methylpropane are heated at 120eC, under nitrogen, for 48 hours.
The mixture is concentrated under vacuum and the residue is taken up in a 5% solution of sodium carbonate and extracted with methylene chloride. The organic phase is decanted, dried over MgS04, filtered and concentrated under vacuum. The residue is chroma-tographed on Merck H silica gel using 96/4 methylene chloride/methanol as the eluent.
The pure product fractions are concentrated under vacuum, the residue is taken up in ether and the addition of a solution of hydrogen chloride in ether makes it possible to prepare the hydrochloride, which is filtered off. m = 1.4 g M.p. = 100-115°C EXAMPLES 2 TO 19 A) The 2,3,4,5-tetrahydropyridazin-3-ones listed in Table 1 below are obtained by following the procedure described in Example 1, steps A, B and C, except that the starting nitrile is replaced with another nitrile derivative, where appropriate, and the carboxylic acid ester is varied.
TABLE 1 B) The 2,3-dihydropyridazin-3-ones listed in Table 2 below are obtained from the derivatives in Table 1 in the manner described in Example 1 , step D , by reaction with bromine followed by dehydrohalogenation. These compounds were all recrystallized from a methylene chloride/hexane mixture.
C) The chlorinated derivatives are prepared from the derivatives in Table 2 by reaction with phosphorus oxy-chloride in the manner described in Example 1, step E. These chlorine derivatives, which are listed in Table 3 below, were all recrystallized from methylene chloride.
TABLE 3 D) Substitution of the chlorinated derivatives with an amine, according to Example 1, step F, makes it possible to prepare the compounds (I) according to the invention, which are listed in Tables 4, 5 and 6 below. 99013/2 - 17 - TABLE 4 TABLE 5 (Cont'd) TABLE 6 The compounds according to the invention were studied for their pharmacological properties and in particular for their affinity for the Mt-type and M2-type muscarinic cholinergic receptors.
In vitro, the compounds (I) were tested according to the technique described by L. POTTER et al., J. Pharmacol. Exp. Ther., 1989, 284. 974-978, for their affinity for the Mx-type receptors, and according to the technique described by HAMMER R. et al., Life Science, 1986, 38, 1653-1662, for their affinity for the M2-type receptors.
The compounds according to the invention have a good affinity for the Mx-type receptors and a marked specificity for the Mx-type central receptors compared with the M2-type receptors.
By way of example, compound 6 showed 50% inhibitory concentrations, expressed in micromol, of 0.16 and 1.5 on the Mx and M2 receptors respectively.
Likewise, compound 25 showed 50% inhibitory concentrations of 0.04 and 0.9 on the Mx and M2 receptors respectively.
In vivo, the compounds according to the invention were subjected to the test for the rotations induced by intrastriatal pirenzepine, described by Worms P. et al., Psychopharmacology, 1987, 93, 489-493.
At a dose of 3 mg per kg of body weight, administered orally, the products according to the inven- tion strongly inhibit the number of rotations induced by pirenzepine. Thus, by way of example, compound 6 causes a 71% inhibition of the rotations induced by pirenzepine.
Furthermore, the compounds according to the invention have proved to be active on the memory deficiency induced by scopolamine and pentetrazole in the passive avoidance test on rats, described by WORMS P. et al., Psychopharmacol . , 1989, 9JL, 286-288.
Thus the results of this test show that compound 6 according to the invention opposes the amnesia induced by pirenzepine administered intraperitoneally at a dose of 75 mg/kg, with an ED50 of 0.47 mg/kg, administered orally.
Finally, the compounds according to the invention showed no signs of toxicity at the doses at which they are active.
Consequently, the compounds (I) can be used as drugs .
The results indicated show that the compounds according to the invention have a good affinity for the muscarinic receptors and a good activity in the tests for amnesia induced by scopolamine or pirenzepine. They make it possible to consider using the products according to the invention in all cases where a cholinergic deficiency is evident, especially for the treatment of cognitive memory disorders and degenerative syndromes associated with senescence and with senile dementia .
According to another feature, the present patent application therefore relates to the pharmaceutical compositions in which at least one of the compounds of formula (I) or one of their salts is present as the active principle.
In the pharmaceutical compositions of the present invention for oral, sublingual, transdermal or rectal administration, the active principles of formula (I) above can be administered to humans in unit forms of administration, mixed with the conventional pharma-ceutical- carriers, especially for the treatment of cognitive memory disorders or degenerative syndromes. Appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspen-sions to be taken orally, forms for sublingual and buccal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration.
To obtain the desired effect, the dose of active principle can vary between 5 and 1000 mg per day .
Each unit dose can contain from 5 to 200 mg of active ingredient in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times a day.
If a solid composition in the form of tablets is prepared, the main active principle is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other appropriate substances or they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.
A preparation in the form of gelatin capsules is obtained by mixing the active principle with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
Water-dispersible granules or powders can contain the active principle mixed with dispersants or wetting agents or with suspending agents such as poly- vinylpyrrolidone, as well as with sweeteners or taste correctors .
Rectal administration is effected using suppositories which are prepared with binders melting at the rectal temperature, for example cacao butter or polyethylene glycols.
Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharma-ceutically compatible dispersants and/or wetting agents, for example propylene glycol and butylene glycol .
The active principle can also be formulated as microcapsules, if appropriate with one or more carriers or additives.
As a pharmaceutical preparation, it is possible to prepare gelatin capsules containing Compound 6 0.010 g Lactose 0.050 g Magnesium stearate 0.005 g by intimately mixing the above ingredients and pouring the mixture into hard gelatin capsules . 99013/2 25

Claims (5)

1. A compound in which - Ar is a phenyl group of the formula a pyridyl group or a thienyl group ; - and R2 are each independently hydrogen, a halogen atom, a hydroxyl group, a C1-C4 alkyl group, a C1 -C4 alkoxy or the trifluoromethyl group ; - - R3 is a linear or branched C1-C5 alkyl, a group -CH2-C5H5 or a group -0¾- CH2-C6H5 ; and - R4 is the group /*' X— N \ R. in which " X is a linear or branched C\-C alkylene and R5 and Rg are each independently hydrogen or a linear or branched C1-C4 alkyl or form, with the nitrogen atom to which they are bonded, a heterocycle selected from pyrrolidine or piperidine ; or R4 is a group selected from 1 99013/3 26 in which n is an integer from 1 to 3 and R7 is hydrogen or a C1-C4, preferably C1-C2, alkyl group ; in which n is as defined above, and their salts with mineral or organic salts.
2. A compound according to claim 1, wherein R4 represents the group -X- R5R5 in which : ; X represents either a group -(CH^n- ™ which n is an integer from 1 to 3 ; 99013/2 27 * or a group CHLj- C — ( Hj) - — ln which is 0 or 1 and *i X^ . is a (Ci-C3)alk l, the total number of carbon atoms of said group riot exceeding 6 ; and * R-5 and R are as defined in claim 1.
3. A method of preparing a compound of formula (I) according to claim 1, which comprises : (a) cyclizing the ketone of formula Ar-CH2-CO-R3 3 in which Ar and R3 are as defined for (I) in claim 1, by reaction with ethyl bromoacetate in an alcoholic solvent at room temperature, followed by reaction with hydrazine hydrate under the action of heat ; (b) dehydrogenating th in which Ar and R3 are as defined for (I) in claim 1, by reaction with bromine in acetic acid ; (c) treating the resulting . in which Ar and R3 are as defined for (I) in claim 1, with excess phosphorus oxychloride under the action of heat, without a solvent or in the presence of an inert solvent such as acetonitrile ; (d) reacting the resulting compound, of formula 99013/2 28 in which Ar and R3 are as defined for (I) in claim 1, with an amine of the formula H2 -R4 in which R4 is as defined for (I) in claim 1 ; and (e) optionally, converting the resulting compound to a salt with a mineral or organic acid
4. A pharmaceutical composition in which a compound of formula (I) according to claim 1 is present as the active principle.
5. A pharmaceutical composition according to claim 4 in the form of a dosage unit in which the active principle is mixed with at least one pharmaceutical excipient. For the Applicants, DR. R¾rNH(¾LD COHN AND PARTNERS By:
IL9901391A 1990-07-31 1991-07-30 3,5,6-substituted pyridazines method of preparation and pharmaceutical compositions containing them IL99013A (en)

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FR9009777A FR2665442B1 (en) 1990-07-31 1990-07-31 ALKYL-6 PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.

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CA (1) CA2048162A1 (en)
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FR2676444B1 (en) * 1991-05-16 1995-03-10 Sanofi Elf NOVEL AMINO-3 PYRIDAZINE DERIVATIVES ACTIVE IN THE CENTRAL NERVOUS SYSTEM, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.
JP2983141B2 (en) * 1993-10-06 1999-11-29 株式会社三和化学研究所 Novel compound and brain function improving agent containing the compound as active ingredient
JP4017214B2 (en) * 1996-06-11 2007-12-05 興和創薬株式会社 5-Phenyl-3-pyridazinone derivatives

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FR2510998B1 (en) * 1981-08-07 1986-01-10 Sanofi Sa NOVEL AMINO DERIVATIVES OF PYRIDAZINE, PROCESS FOR THEIR PREPARATION AND DRINKING ACTS THEREOF
FR2539742B1 (en) * 1983-01-24 1986-09-05 Sanofi Sa AMINO DERIVATIVES OF PYRIDAZINE SUBSTITUTED IN POSITION 6 BY A HETEROCYCLE OR ALICYCLE, SAID DERIVATIVES Being ACTIVE ON THE CENTRAL NERVOUS SYSTEM
FR2663326B2 (en) * 1989-11-17 1992-10-16 Sanofi Sa PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.

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NO179905C (en) 1997-01-08
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FR2665442A1 (en) 1992-02-07
IL99013A0 (en) 1992-07-15
IE66376B1 (en) 1995-12-27
PT98474A (en) 1992-05-29
KR920002550A (en) 1992-02-28
FI913656A (en) 1992-02-01
ZA916030B (en) 1992-04-29
FR2665442B1 (en) 1992-12-04
CA2048162A1 (en) 1992-02-01
NO912972L (en) 1992-02-03
NZ239181A (en) 1993-09-27
HU211645A9 (en) 1995-12-28
EP0469992A1 (en) 1992-02-05
HUT58706A (en) 1992-03-30
NO179905B (en) 1996-09-30
EP0469992B1 (en) 1994-09-21
JPH04234369A (en) 1992-08-24
AU8147691A (en) 1992-02-06
DE69104155D1 (en) 1994-10-27
AU638858B2 (en) 1993-07-08
HU213392B (en) 1997-06-30
NO912972D0 (en) 1991-07-30
ATE111900T1 (en) 1994-10-15
HU912555D0 (en) 1992-01-28
PT98474B (en) 1997-10-31
DE69104155T2 (en) 1995-05-04

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