NO178967B - Analogous Process for Preparing Therapeutically Active Pyridazine Derivatives - Google Patents

Analogous Process for Preparing Therapeutically Active Pyridazine Derivatives Download PDF

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NO178967B
NO178967B NO904984A NO904984A NO178967B NO 178967 B NO178967 B NO 178967B NO 904984 A NO904984 A NO 904984A NO 904984 A NO904984 A NO 904984A NO 178967 B NO178967 B NO 178967B
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phenyl
formula
diethylamino
mixture
pyridazine
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NO904984A
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NO178967C (en
NO904984D0 (en
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Robert Boigegrain
Roger Brodin
Jean-Paul Kan
Dominique Olliero
Camille Georges Wermuth
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Sanofi Sa
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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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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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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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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—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
    • 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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    • C07D487/04—Ortho-condensed systems

Description

I mange år er pyridazin-derivater blitt foreslått som medisiner, spesielt medisiner som er aktive når det gjelder det kardiovaskulære system eller sentralnervesystemet. For many years, pyridazine derivatives have been proposed as drugs, especially drugs that are active on the cardiovascular system or the central nervous system.

Spesielt beskriver fransk patent 2 510 998 og europeisk patent 72 726 pyridazin-derivater som er forskjellig substituert på pyridazinringen, og som alle i stilling 3 bærer en amin- In particular, French patent 2 510 998 and European patent 72 726 describe pyridazine derivatives which are differently substituted on the pyridazine ring, and which all carry an amine in position 3

substituent av typen substituent of the type

hvor X og Y uavhengig av where X and Y are independent of

hverandre representerer hydrogen eller alkyl, eller sammen med det nitrogenatom som de er bundet til, danner en heterocyklisk ring såsom morfolin. each other represent hydrogen or alkyl, or together with the nitrogen atom to which they are attached, form a heterocyclic ring such as morpholine.

Alle disse forbindelser oppviser en aktivitet når det gjelder sentralnervesystemet som antidepressive midler. All these compounds exhibit activity in the central nervous system as antidepressants.

I henhold til den foreliggende oppfinnelse er det nå blitt oppdaget nye derivater av pyridazin som har mistet sin antidepressive aktivitet og erhvervet en nyttig aktivitet som ligander til cholinerge reseptorer, spesielt reseptorer av M^typen. According to the present invention, new derivatives of pyridazine have now been discovered which have lost their antidepressant activity and acquired a useful activity as ligands to cholinergic receptors, especially receptors of the M₂ type.

Det er formålet med den foreliggende oppfinnelse å fremstille nye derivater av pyridazin som svarer til formelen: It is the purpose of the present invention to prepare new derivatives of pyridazine that correspond to the formula:

hvor where

Ar representerer en fenylgruppe substituert med R, og R2; Ar represents a phenyl group substituted with R 1 and R 2 ;

R1 og R2 hver, uavhengig av hverandre, angir hydrogen, R1 and R2 each independently represent hydrogen,

halogen, hydroksyl eller C^-C^-alkoksy; halogen, hydroxyl or C 1 -C 4 alkoxy;

R3 representerer rettkjedet eller forgrenet C.,-CA-alkyl, R 3 represents straight chain or branched C 1 -C 1 -alkyl,

C3-C7-cykloalkyl eller fenyl; C3-C7 cycloalkyl or phenyl;

R4 representerer gruppen R4 represents the group

R5 representerer en rettkjedet C^-C^-alkylgruppe; R 5 represents a straight chain C 1 -C 4 alkyl group;

R6 representerer en rettkjedet C^-C^-alkylgruppe, eller R 6 represents a straight-chain C 1 -C 4 -alkyl group, or

R5 og R6, sammen med det nitrogenatom som de er bundet til, utgjør en heterocyklisk ring valgt blant morfolin og piperidin; R 5 and R 6 , together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from morpholine and piperidine;

såvel som deres salter med organiske eller mineralsyrer. as well as their salts with organic or mineral acids.

Fortrinnsvis representerer Ar fenyl som er usubstituert eller monosubstituert i stilling 2; mer spesielt representerer Ar en gruppe valgt blant fenyl, 2-halogenfenyl, spesielt 2-klorfenyl, 2-metoksyfenyl eller 2-hydroksyfenyl, R3 representerer fenyl eller n-propyl, og R5 og R6 representerer hver etyl. Preferably, Ar represents phenyl which is unsubstituted or monosubstituted in position 2; more particularly, Ar represents a group selected from phenyl, 2-halophenyl, especially 2-chlorophenyl, 2-methoxyphenyl or 2-hydroxyphenyl, R3 represents phenyl or n-propyl, and R5 and R6 each represent ethyl.

Følgende forbindelser er spesielt foretrukket: 3-(2-dietylamino-2-metylpropyl)amino-6-fenyl-5-propyl-pyridazin og dets salter; The following compounds are particularly preferred: 3-(2-diethylamino-2-methylpropyl)amino-6-phenyl-5-propyl-pyridazine and its salts;

3-(2-dietylamino-2-metylpropyl)amino-5,6-difenylpyridazin og dets salter. 3-(2-diethylamino-2-methylpropyl)amino-5,6-diphenylpyridazine and its salts.

Saltene av forbindelsene med formel I som fremstilles ifølge oppfinnelsen innbefatter slike med både mineralsyrer og organiske syrer som muliggjør at forbindelsene med formel I kan separeres eller hensiktsmessig krystalliseres, såsom pikrinsyre eller oksal-syre, slike som danner farmasøytisk tilfredsstillende salter såsom hydroklorid, hydrobromid, sulfat, hydrogensulfat, dihydrogen-fosfat, metansulfonat, metylsulfat, maleat, fumarat og 2-naftalen-sulfonat. The salts of the compounds of formula I that are prepared according to the invention include those with both mineral acids and organic acids which enable the compounds of formula I to be separated or appropriately crystallized, such as picric acid or oxalic acid, such as form pharmaceutically satisfactory salts such as hydrochloride, hydrobromide, sulfate , hydrogen sulphate, dihydrogen phosphate, methane sulphonate, methyl sulphate, maleate, fumarate and 2-naphthalene sulphonate.

Ifølge den foreliggende oppfinnelse er fremgangsmåten karakterisert ved at et amin R4NH2 hvor R4 er som definert ovenfor, omsettes med et 6-klorpyridazin med formel: According to the present invention, the method is characterized in that an amine R4NH2 where R4 is as defined above is reacted with a 6-chloropyridazine of formula:

hvor Ar og R3 har de betydninger som er angitt ovenfor for (I), og at eventuelt den således oppnådde forbindelse omdannes til et salt med en mineralsyre eller en organisk syre. where Ar and R 3 have the meanings indicated above for (I), and that optionally the compound thus obtained is converted into a salt with a mineral acid or an organic acid.

Substitusjonsreaksjonen for 6-klorpyridazinet (II) med aminet R4NH2 utføres ved mellom 100 og 150°C, eventuelt i nærvær av ammoniumklorid. Omsetningen utføres uten løsningsmiddel eller i nærvær av et inert løsningsmiddel såsom n-butanol. Produktet (I) isoleres ved ekstraksjon og renses, f.eks. ved kromatografi. The substitution reaction for the 6-chloropyridazine (II) with the amine R4NH2 is carried out at between 100 and 150°C, optionally in the presence of ammonium chloride. The reaction is carried out without solvent or in the presence of an inert solvent such as n-butanol. The product (I) is isolated by extraction and purified, e.g. by chromatography.

Produktet med formel I oppnådd på denne måte isoleres i form av den frie base eller et salt ifølge standard teknikker. The product of formula I obtained in this way is isolated in the form of the free base or a salt according to standard techniques.

Når forbindelsen med formel I fås i form av den frie base, utføres saltdannelse ved behandling med den utvalgte syre i et organisk løsningsmiddel. Ved behandling av den frie base, oppløst f.eks. i en alkohol såsom isopropanol, med en oppløsning av den utvalgte syre i det samme løsningsmiddel, fås det tilsvarende salt, som isoleres ifølge standard-teknikker. På denne måte fremstilles hydrokloridet, hydrobromidet, sulfatet, hydrogen-sulfatet, dihydrogenfosfatet, metansulfonatet, metylsulfatet, oksalatet, maleatet, fumaratet og 2-naftalensulfonatet. 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. When treating the free base, dissolved e.g. 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, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methane sulfonate, methyl sulfate, oxalate, maleate, fumarate and 2-naphthalene sulfonate are produced.

Ved slutten av reaksjonen kan forbindelsen med formel I isoleres i form av ett av sine salter, f.eks. hydrokloridet; i dette tilfellet kan, hvis nødvendig, den frie base fremstilles ved nøytralisering av saltet med en mineralbase eller en organisk base såsom natriumhydroksyd eller trietylamin, eller et alkalimetall-karbonat eller -bikarbonat såsom natrium- eller kaliumkarbonat eller -bikarbonat. At the end of the reaction, the compound of formula I can be isolated in the form of one of its salts, e.g. the hydrochloride; in this case, if necessary, the free base can be prepared by neutralizing the salt with a mineral base or an organic base such as sodium hydroxide or triethylamine, or an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate.

Når R., og/eller R2 representerer en hydroksylgruppe, fås forbindelsen ved at man går ut fra forbindelse (I) hvor R, og/ eller R2 angir alkoksy, og alle de andre substituenter har ovennevnte definisjoner, ved dealkylering under anvendelse av kjente f remgangsmåter. When R., and/or R.sub.2 represents a hydroxyl group, the compound is obtained by starting from compound (I) where R, and/or R.sub.2 denotes alkoxy, and all the other substituents have the above-mentioned definitions, by dealkylation using known f rem walking ways.

6-klorpyridazinene (II), anvendt som utgangsmaterialer, fremstilles ut fra de tilsvarende 2H-pyridazin-3-oner (III) ved omsetning med et overskudd av varmt fosforoksyklorid i fravær av et løsningsmiddel eller i nærvær av et inert løsningsmiddel såsom acetonitril, i henhold til følgende reaksjonsskjema: The 6-chloropyridazines (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, in according to the following reaction scheme:

2H-pyridazin-3-onene (III) er kjent eller fremstilles ved kj ente f remgangsmåter. The 2H-pyridazin-3-ones (III) are known or are prepared by known methods.

Når R3 representerer et alkyl- eller cykloalkylradikal, fremstilles forbindelsene (III) ut fra et keton Ar-CO-CH2R3 (1) : When R3 represents an alkyl or cycloalkyl radical, the compounds (III) are prepared from a ketone Ar-CO-CH2R3 (1):

Hydroksyketo-esteren (2) fås ut fra ketonet (1) ved oppvarming av det med etylglyoksylat ved en temperatur på mellom 80 og 140°C. Den ubearbeidete reaksjonsblanding opptas så i et inert løsningsmiddel såsom n-butanol, og hydrazinhydrat tilsettes. Ved oppvarming under tilbakeløp i 24 timer fås 4,5-dihydro-4-hydroksypyridazin-3-onet (3), som ved oppvarming i surt miljø ved dehydratisering fører til 2H-pyridazin-3-onet (III). The hydroxyketo ester (2) is obtained from the ketone (1) by heating it with ethyl glyoxylate at a temperature of 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. When heated under reflux for 24 hours, the 4,5-dihydro-4-hydroxypyridazin-3-one (3) is obtained, which on heating in an acidic environment by dehydration leads to the 2H-pyridazin-3-one (III).

Aminene R4NH2 er kjent eller fremstilles ved kjente frem-gangsmåter. De kan således fremstilles ut fra et cyanoderivat med formel: The amines R4NH2 are known or are prepared by known methods. They can thus be prepared from a cyano derivative with the formula:

Ved omsetning med et amin HNR5R6 ved oppvarming ved en temperatur på mellom 40 og 8 0°C, eventuelt i nærvær av et salt av en sterk syre såsom natriumsulfat eller magnesiumsulfat, dannes det først en forbindelse med formel: og deretter hydratiseres denne forbindelse ved omsetting med en sterk syre såsom varm svovelsyre for dannelse av det tilsvarende amin: By reaction with an amine HNR5R6 by heating at a temperature 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 is first formed: and then this compound is hydrated by reaction with a strong acid such as hot sulfuric acid to form the corresponding amine:

Til slutt fører reduksjon ved oppvarming med et metallhydrid såsom borhydrid eller litiumaluminiumhydrid, til dannelse av aminet R4NH2. Finally, reduction by heating with a metal hydride such as borohydride or lithium aluminum hydride leads to the formation of the amine R4NH2.

Videre kan aminet R4NH2 også fremstilles ut fra et klornitroso-derivat (VII) i henhold til fremgangsmåten beskrevet i J. Prakt. Chem., 1978, 320 (3), 433-451. Furthermore, the amine R4NH2 can also be prepared from a chloronitroso derivative (VII) according to the method described in J. Prakt. Chem., 1978, 320 (3), 433-451.

Forbindelsene med formel (VII) kan anvendes i form av en dimer (Vila) som fås ved omsetning av nitrosylklorid med det hensiktsmessige olefin (IX) ifølge fremgangsmåten beskrevet i J. Prakt. Chem., 1965, 29 (4), 123. The compounds of formula (VII) can be used in the form of a dimer (Vila) which is obtained by reacting nitrosyl chloride with the appropriate olefin (IX) according to the method described in J. Prakt. Chem., 1965, 29 (4), 123.

Følgende eksempler illustrerer oppfinnelsen. Forbindelsene er karakterisert ved sitt smeltepunkt (smp.) uttrykt i grader celsius. The following examples illustrate the invention. The compounds are characterized by their melting point (m.p.) expressed in degrees Celsius.

Eksempel 1 Example 1

3-(2-dietylamino-2-metylpropyl)amino-6-fenyl-5-propylpyridazin-seskvifumarat: SR 46559 A. 3-(2-Diethylamino-2-methylpropyl)amino-6-phenyl-5-propylpyridazine sesquifumarate: SR 46559 A.

A) 6-klor-3-fenyl-4-propyl-pyridazin. A) 6-chloro-3-phenyl-4-propyl-pyridazine.

1. Etyl-2-hydroksy-4-okso-4-fenyl-3-propylbutyrat. 1. Ethyl 2-hydroxy-4-oxo-4-phenyl-3-propyl butyrate.

En blanding av 48,67 g valerofenon og 45,94 g etylglyoksylat oppvarmes ved 120°C i 15 timer. A mixture of 48.67 g of valerophenone and 45.94 g of ethyl glyoxylate is heated at 120°C for 15 hours.

Det rå reaksjonsprodukt anvendes som det er i følgende trinn. The crude reaction product is used as is in the following step.

2. 6-fenyl-5-propyl-2H-pyridazin-3-on. 2. 6-Phenyl-5-propyl-2H-pyridazin-3-one.

Råproduktet oppnådd ovenfor oppløses i 450 ml n-butanol, og deretter tilsettes 30 g hydrazinhydrat, og blandingen oppvarmes under tilbakeløp i 24 timer. The crude product obtained above is dissolved in 450 ml of n-butanol, and then 30 g of hydrazine hydrate are added, and the mixture is heated under reflux for 24 hours.

n-butanolen inndampes under vakuum. Residuet opptas i en blanding av 3 00 ml eddiksyre og 3 0 ml konsentrert saltsyre. Blandingen oppvarmes ved 100°C i 3 timer. Oppløsningen helles i kaldt vann, og produktet får utkrystalliseres. 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 allowed to crystallize.

Faststoffet filtreres fra og tørkes. The solid is filtered off and dried.

Vekt: 44 g. Smp.: 160°C. Weight: 44 g. Melting point: 160°C.

Utbytte: 69%. Yield: 69%.

3. 6-klor-3-fenyl-4-propyl-pyridazin. 3. 6-chloro-3-phenyl-4-propyl-pyridazine.

250 ml fosforoksyklorid tilsettes til 44 g pyridazinon oppnådd ovenfor, og blandingen oppvarmes ved 8 0°C i 4 timer. Etter at reaksjonsblandingen har fått stå over natten ved romtemperatur, konsentreres den til 3/4 og helles så langsomt på is. Blandingen ekstraheres to ganger med 3 00 ml diklormetan, og ekstraktene tørkes over natriumsulfat og konsentreres. Kromatografi på silika utføres så ved eluering med en etylacetat-metylenklorid-blanding (50/50 på volumbasis). 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 the reaction mixture has been allowed to stand overnight at room temperature, it is concentrated to 3/4 and then slowly poured onto ice. The mixture is extracted twice with 300 ml of dichloromethane, and the extracts are dried over sodium sulfate and concentrated. Chromatography on silica is then carried out by elution with an ethyl acetate-methylene chloride mixture (50/50 by volume).

Etter omkrystallisering fra isopropyleter fås 43,7 g av det ventete produkt. After recrystallization from isopropyl ether, 43.7 g of the expected product are obtained.

Smp.: 60 °C. Melting point: 60 °C.

Utbytte: 92%. Yield: 92%.

B) Fremstilling av 2-dietylamino-2-metyl-propylamin. B) Preparation of 2-diethylamino-2-methyl-propylamine.

1. 2-dietylamino-2-metyl-propionitril. 1. 2-Diethylamino-2-methyl-propionitrile.

85,1 g av cyanohydrinet av destillert aceton og 73,1 g dietylamin blandes, 85,7 g magnesiumsulfat tilsettes, og blandingen oppvarmes under forsiktig tilbakeløp i 2 0 timer under omrøring. Sulfatmassen som dannes, filtreres fra og vaskes med' eter. Filtratet konsentreres og destilleres deretter. 85.1 g of the cyanohydrin of distilled acetone and 73.1 g of diethylamine are mixed, 85.7 g of magnesium sulfate is added, and the mixture is heated under gentle reflux for 20 hours with stirring. The sulphate mass that forms is filtered off and washed with ether. The filtrate is then concentrated and distilled.

86,6 g av det ventete produkt utvinnes. 86.6 g of the expected product is recovered.

Utbytte: 62%. Yield: 62%.

Kp. = 68-70°C ved 15 mm kvikksølv. Kp. = 68-70°C at 15 mm of mercury.

2. 2-dietylamino-2-metylpropionamid. 2. 2-diethylamino-2-methylpropionamide.

Til 95,9 g av nitrilet fremstilt i det foregående trinn tilsettes 450 ml svovelsyre og 70 ml vann under omrøring, og blandingen oppvarmes på oljebad ved 100-110°C i 2 timer. Reaksjonsblandingen helles langsomt i løpet av 1 time i 1,4 1 av en 2 0% ammoniakkoppløsning og 4 00 ml vann avkjølt på et tørris/- aceton-bad. Blandingen ekstraheres tre ganger med 600 ml metylenklorid, og ekstraktene tørkes over natriumsulfat og konsentreres. To 95.9 g of the nitrile prepared in the previous step, 450 ml of sulfuric acid and 70 ml of water are added while stirring, and the mixture is heated in an oil bath at 100-110°C for 2 hours. The reaction mixture is poured slowly over 1 hour into 1.4 1 of a 20% ammonia solution and 400 ml of water cooled on a dry ice/acetone bath. The mixture is extracted three times with 600 ml of methylene chloride, and the extracts are dried over sodium sulfate and concentrated.

Det ventete produkt fås ved destillasjon. The expected product is obtained by distillation.

Vekt: 102,5 g Weight: 102.5 g

Utbytte: 9 5% Yield: 9 5%

Kp. = 134-139°C ved 15 mm kvikksølv. Kp. = 134-139°C at 15 mm of mercury.

3. 2-dietylamino-2-metylpropylamin. 3. 2-diethylamino-2-methylpropylamine.

En blanding som inneholder 52,4 g av amidet fremstilt i det foregående trinn og 60 ml tetrahydrofuran oppvarmes ved 45-50°C. 86 ml av boran-dimetylsulfid-komplekset tilsettes under en atmosfære av nitrogen i løpet av 1 time, og oppvarming fortsettes i 3 timer på oljebad ved 80-85°C. A mixture containing 52.4 g of the amide prepared in the previous step and 60 ml of tetrahydrofuran is heated at 45-50°C. 86 ml of the borane-dimethyl sulphide complex is added under an atmosphere of nitrogen over the course of 1 hour, and heating is continued for 3 hours in an oil bath at 80-85°C.

Etter at blandingen har fått stå over natten ved romtemperatur, avkjøles den på isbad, deretter tilsettes 315 ml 6 N saltsyre langsomt i løpet av 3 timer, og blandingen oppvarmes igjen ved 135°C i 3 timer. Etter at reaksjonsblandingen har fått stå over natten ved romtemperatur, avkjøles den mens 2 00 ml 3 0% natriumhydroksyd tilsettes. Blandingen ekstraheres tre ganger med 250 ml eter, og ekstraktene tørkes over natriumsulfat og konsentreres. After the mixture has been allowed to stand overnight at room temperature, it is cooled in an ice bath, then 315 ml of 6 N hydrochloric acid is added slowly over 3 hours, and the mixture is heated again at 135°C for 3 hours. After the reaction mixture has been allowed to stand overnight at room temperature, it is cooled while 200 ml of 30% sodium hydroxide is added. The mixture is extracted three times with 250 ml of ether, and the extracts are dried over sodium sulfate and concentrated.

Det ventete produkt fås ved destillasjon. The expected product is obtained by distillation.

Vekt: 23 g Weight: 23 g

Utbytte: 48% Yield: 48%

Kp. = 71-73°C ved 15 mm kvikksølv. Kp. = 71-73°C at 15 mm of mercury.

C) SR 46559 A C) SR 46559 A

En blanding av 2,5 g av klorderivatet oppnådd ovenfor i trinn A og 4,6 g av diaminet oppnådd i trinn B oppvarmes ved 120°C over natten. 150 ml etylacetat tilsettes, og deretter ekstraheres blandingen to ganger med 50 ml saltsyre. Blandingen gjøres så alkalisk ved tilsetting av 50 ml 3 0% natriumhydroksyd og ekstraheres så med etylacetat. Ekstraktene vaskes med fortynnet saltoppløsning, tørkes over natriumsulfat og konsentreres. Kromatografi på aluminiumoksyd utføres ved eluering med en metylenklorid/etylacetat-blanding (70/30, på vektbasis). A mixture of 2.5 g of the chlorine derivative obtained above in step A and 4.6 g of the diamine obtained in step B is heated at 120°C overnight. 150 ml of ethyl acetate are added, and 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 saline, dried over sodium sulfate and concentrated. Chromatography on alumina is carried out by elution with a methylene chloride/ethyl acetate mixture (70/30, by weight).

3,2 g av en olje fås, som utkrystalliseres. 3.2 g of an oil are obtained, which crystallizes out.

Smp. = 75-77°C Temp. = 75-77°C

Utbytte: 87% Yield: 87%

Seskvifumarat Sesquifumarate

3,1 g av basen oppnådd i det foregående trinn opptas i 50 ml aceton, og 1,6 g fumarsyre i 150 ml aceton tilsettes. Blandingen filtreres varm. Det totale utvunnete volum (17 5 ml) konsentreres 3.1 g of the base obtained in the previous step is taken up in 50 ml of acetone, and 1.6 g of fumaric acid in 150 ml of acetone is added. The mixture is filtered hot. The total recovered volume (175 ml) is concentrated

til 130 ml. Produktet får utkrystalliseres, krystallene filtreres fra og vaskes så med aceton. to 130 ml. The product is allowed to crystallize, the crystals are filtered off and then washed with acetone.

4,1 g av det ventete produkt oppnås. 4.1 g of the expected product is obtained.

Totalt utbytte fra trinn C = 74% Total yield from step C = 74%

Smp. = 151°C. Temp. = 151°C.

Eksempel 2 Example 2

SR 46559 A SR 46559 A

A) 6-klor-3-fenyl-4-propyl-pyridazin, beskrevet i eksempel 1. A) 6-chloro-3-phenyl-4-propyl-pyridazine, described in example 1.

B) 2-dietylamino-2-metyl-propylamin. B) 2-diethylamino-2-methyl-propylamine.

1. Fremstilling av forbindelsen med formel (Vila) med X1 = H. 1. Preparation of the compound of formula (Vila) with X1 = H.

47,14 g isobutylen oppløses i 150 ml n-heptan, blandingen avkjøles til en temperatur mellom -10 og -20°C, og 50 g nitrosylklorid tilsettes. Temperaturen får stige (+5°C) i løpet av 1,5 time, og deretter bringes temperaturen til mellom 10 og 2 0"C og blandingen omrøres i 1,5 time. Den dannete utfeining filtreres fra, vaskes med heptan og tørkes. 47.14 g of isobutylene is 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 is added. The temperature is allowed to rise (+5°C) over 1.5 hours, and then the temperature is brought to between 10 and 20°C and the mixture is stirred for 1.5 hours. The precipitate formed is filtered off, washed with heptane and dried.

Smp. = 102-104°C Temp. = 102-104°C

m = 64 g m = 64 g

2. Fremstilling av forbindelsen med formel VIII: X., = H; 2. Preparation of the compound of formula VIII: X., = H;

<R>5<=><R>6<=C>2<H>5. <R>5<=><R>6<=C>2<H>5.

21,7 g av forbindelsen fremstilt i det foregående trinn suspenderes i 150 ml absolutt alkohol, 39,17 g dietylamin tilsettes, og blandingen oppvarmes ved 60°C i 6 timer. Det fås en olje som størkner. 21.7 g of the compound prepared in the previous step is suspended in 150 ml of absolute alcohol, 39.17 g of diethylamine is added, and the mixture is heated at 60°C for 6 hours. An oil is obtained which solidifies.

m = 19,5 g m = 19.5 g

Smp. <50°C Temp. <50°C

3. 2-dietylamino-2-metyl-propylamin. 3. 2-diethylamino-2-methyl-propylamine.

7,01 g litiumaluminiumhydrid tilsettes til 50 ml av en eterisk oppløsning av forbindelsen oppnådd i det foregående trinn, i løpet av 1 time. Etter at blandingen er blitt omrørt i 1,5 time ved romtemperatur, kokes den under tilbakeløp i 4 timer. Mens blandingen holdes mellom 0 og -10°C, tilsettes 7,1 ml vann i løpet av 1 time, 7,1 ml natriumhydroksyd i løpet av 3 0 minutter og 7.01 g of lithium aluminum hydride is added to 50 ml of an ethereal solution of the compound obtained in the previous step, over the course of 1 hour. After the mixture has been stirred for 1.5 hours at room temperature, it is refluxed for 4 hours. While the mixture is kept between 0 and -10°C, 7.1 ml of water are added over 1 hour, 7.1 ml of sodium hydroxide over 30 minutes and

21,3 ml vann i løpet av 3 0 minutter. Etter at oppløsningen er blitt omrørt i 2 timer ved romtemperatur, filtreres den, utfel-ningen vaskes med vannfri eter, filtratet tørkes over natrium-sulf at og løsningsmiddelet fjernes under vakuum. Produktet destilleres: 21.3 ml of water in 30 minutes. After the solution has been stirred for 2 hours at room temperature, it is filtered, the precipitate is washed with anhydrous ether, the filtrate is dried over sodium sulfate and the solvent is removed under vacuum. The product is distilled:

Kp. = 72-75°C ved 15 mm kvikksølv. Kp. = 72-75°C at 15 mm of mercury.

m = 4 , 2 g m = 4, 2 g

C) SR 46559 A fremstilles så som beskrevet i eksempel 1. C) SR 46559 A is produced as described in example 1.

Eksempel 3 Example 3

3-(2-dietylamino-2-metylpropyl)amino-6-(2-klorfenyl)-5-propyl-pyridazin-seskvifumarat. SR 47863 A. 3-(2-diethylamino-2-methylpropyl)amino-6-(2-chlorophenyl)-5-propyl-pyridazine-sesquifumarate. SR 47863 A.

1,7 g 3-klor-6-(2-klorfenyl)-5-propyl-pyridazin og 6 ml 2-dietylamino-2-metyl-propylamin oppvarmes ved 110"C under nitrogen i 2 0 timer. 1.7 g of 3-chloro-6-(2-chlorophenyl)-5-propyl-pyridazine and 6 ml of 2-diethylamino-2-methyl-propylamine are heated at 110°C under nitrogen for 20 hours.

Etter inndamping under vakuum, opptas blandingen i diklormetan og vaskes med en oppløsning av natriumbikarbonat. Den organiske fase dekanteres, tørkes over magnesiumsulfat, filtreres og konsentreres under vakuum. Residuet kromatograferes på silika-gel, elueringsmiddel: diklormetan/metanol 98/2. 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 sulphate, filtered and concentrated under vacuum. The residue is chromatographed on silica gel, eluent: dichloromethane/methanol 98/2.

Konsentrering av de rene fraksjoner gir en olje, som oppløses i 10 ml metanol. Fumarsyre tilsettes, metanolen inndampes under vakuum og seskvifumaratet utkrystalliseres fra eter. 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 is crystallized from ether.

m = 1,6 g m = 1.6 g

Smp. = 144°C Temp. = 144°C

Eksempel 4 Example 4

3-(2-dietylamino-2-metylpropyl)amino-6-(2-metoksyfenyl)-5-metyl-pyridazin. 3-(2-diethylamino-2-methylpropyl)amino-6-(2-methoxyphenyl)-5-methyl-pyridazine.

1,6 g 3-klor-6-(2-metoksyfenyl)-5-metylpyridazin, 4 g 2-dietylamino-2-metylpropylamin og 0,3 6 g ammoniumklorid smeltes sammen ved 120°C, og reaksjonsblandingen får stå ved denne temperatur i 24 timer. 1.6 g of 3-chloro-6-(2-methoxyphenyl)-5-methylpyridazine, 4 g of 2-diethylamino-2-methylpropylamine and 0.36 g of ammonium chloride are fused together at 120°C, and the reaction mixture is allowed to stand at this temperature for 24 hours.

Blandingen avkjøles til romtemperatur, ekstraheres med etylacetat og vaskes med en mettet vandig oppløsning av natrium-klorid. The mixture is cooled to room temperature, extracted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride.

Den organiske fase fraskilles, tørkes over MgS04, filtreres og inndampes til tørrhet i vakuum. The organic phase is separated, dried over MgSO 4 , filtered and evaporated to dryness in vacuo.

Residuet kromatograferes på aluminiumoksyd, elueringsmiddel: etylacetat +2% trietylamin. The residue is chromatographed on aluminum oxide, eluent: ethyl acetate + 2% triethylamine.

Konsentreringen av de rene fraksjoner gir det ventete produkt. Strukturen bekreftes ved NMR-spektralanalyse. The concentration of the pure fractions gives the expected product. The structure is confirmed by NMR spectral analysis.

Eksempel 5 Example 5

3-(2-dietylamino-2-metylpropyl)amino-5-metyl-6-(2-hydroksyfenyl)-pyridazin. SR 96376. 1 g av produktet oppnådd tidligere i eksempel 4 oppløses i 50 ml 48% hydrobromsyre, og blandingen oppvarmes under tilbakeløp i 48 timer. Etter denne tid inndampes reaksjonsblandingen til tørrhet under vakuum, residuet gjøres alkalisk med en vandig oppløsning av kaliumkarbonat, og oppløsningen ekstraheres med diklormetan. Den organiske fase dekanteres, tørkes over MgS04, filtreres og inndampes til tørrhet under vakuum. 3-(2-diethylamino-2-methylpropyl)amino-5-methyl-6-(2-hydroxyphenyl)-pyridazine. SR 96376. 1 g of the product obtained previously in example 4 is dissolved in 50 ml of 48% hydrobromic acid, and the mixture is heated under 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 4 , filtered and evaporated to dryness under vacuum.

Residuet kromatograferes på aluminiumoksyd, elueringsmiddel: etylacetat/metanol 9/1 + 2% trietylamin. The residue is chromatographed on aluminum oxide, eluent: ethyl acetate/methanol 9/1 + 2% triethylamine.

Konsentreringen av de rene fraksjoner gir et residuum, som krystalliseres fra isopropanol. The concentration of the pure fractions gives a residue, which is crystallized from isopropanol.

m = 2 00 mg m = 200 mg

Smp. = 159,2°C. Temp. = 159.2°C.

Eksempler 6- 3 5 . Examples 6- 3 5 .

A) Ved anvendelse av fremgangsmåten angitt i eksempel IA, men ved variasjon av utgangs-ketonet, fås 6-klorpyridazinene som er samlet i tabellene 1 og 2. B) Ved å gå ut fra klorderivatene i tabell 1 og følge fremgangsmåten anvendt i eksempel 1 fås forbindelsene som kan fremstilles ifølge oppfinnelsen oppført i tabell 3 nedenfor ved at man varierer de anvendte aminer NH2R4. A) By applying the method indicated in example IA, but by varying the starting ketone, the 6-chloropyridazines collected in tables 1 and 2 are obtained. B) By starting from the chlorine derivatives in table 1 and following the method used in example 1 the compounds which can be prepared according to the invention are obtained listed in table 3 below by varying the amines NH2R4 used.

NMR-spektrum av SR 47673. NMR spectrum of SR 47673.

(DMSO d6; 200 MHz) (DMSO d6; 200 MHz)

0,70 (t; 3H); 0,80 (t; 6H); 1,30 (q; 2H); 1,50 (m; 4H); 2,30 (s; 6H); 2,40 (m; 2H); 3,40 (m; 2H) ; 6,20 (m; 1H); 6,80 (s; 1H); 7,35 (s; 5H). 0.70 (t; 3H); 0.80 (t; 6H); 1.30 (q; 2H); 1.50 (m; 4H); 2.30 (s; 6H); 2.40 (m; 2H); 3.40 (m; 2H); 6.20 (m; 1H); 6.80 (s; 1H); 7.35 (s; 5H).

NMR-spektrum av SR 4808IA. NMR spectrum of SR 4808IA.

(DMSO d6; 200 MHz) (DMSO d6; 200 MHz)

0,80 (t; 3H); 1,40 (m; 8H); 1,5 (s; 6H); 2,56 (q; 2H); 3,40 (b.s.; 4H); 3,80 (s; 3H); 4,00 (d; 2H) ; 7,02 (m; 3H); 7,40 (t; 1H); 7,83 (b.s.; 1H). 0.80 (t; 3H); 1.40 (m; 8H); 1.5 (s; 6H); 2.56 (q; 2H); 3.40 (b.s.; 4H); 3.80 (s; 3H); 4.00 (d; 2H); 7.02 (m; 3H); 7.40 (t; 1H); 7.83 (b.s.; 1H).

Følgende forkortelser er anvendt for analyse av et NMR-spektrum : s = singlett; b.s.: bred singlett; The following abbreviations are used for analysis of an NMR spectrum: s = singlet; b.s.: wide singlet;

d: dublett; t: triplett; d: doublet; t: triplet;

q: kvadruplett; m: multiplett. q: quadruple; m: multiplet.

C) Idet man går ut fra klorderivatene ifølge tabell 2 og følger . fremgangsmåten beskrevet i eksempel 1, fås forbindelsene som kan fremstilles ifølge oppfinnelsen oppført i tabell 4 ved at man varierer de anvendte aminer NH2R4. C) Starting from the chlorine derivatives according to table 2 and following . the method described in example 1, the compounds which can be produced according to the invention listed in table 4 are obtained by varying the amines NH2R4 used.

Forbindelsene fremstilt ifølge oppfinnelsen ble undersøkt med hensyn til farmakologiske egenskaper og spesielt med hensyn til affinitet overfor de muskarine cholinerge reseptorer av typen M1 og M2. The compounds produced according to the invention were examined with regard to pharmacological properties and especially with regard to affinity towards the muscarinic cholinergic receptors of the type M1 and M2.

In vitro ble forbindelsene (I) analysert ifølge teknikken beskrevet av J.D. Watson et al. (Life Sciences, 1982, 31, 2019-2029) når det gjelder deres affinitet overfor reseptorene av type M1, og ifølge teknikken beskrevet av R. Hammer et al. (Nature, 1980, 283, 90-92) og E.C. Hulme et al. (Molecylar Pharmacology, 1978, 14, 737-750) når det gjelder deres affinitet overfor reseptorene av M2-typen. In vitro, the compounds (I) were analyzed according to the technique described by J.D. Watson et al. (Life Sciences, 1982, 31, 2019-2029) in terms of their affinity towards the receptors of type M1, and according to the technique described by R. Hammer et al. (Nature, 1980, 283, 90-92) and E.C. Hulme et al. (Molecylar Pharmacology, 1978, 14, 737-750) in terms of their affinity for the M2-type receptors.

Forbindelsene fremstilt ifølge oppfinnelsen oppviser god affinitet for reseptorene av type M1 og en markert spesifisitet for de sentrale reseptorer av type M1, i motsetning til reseptorer av type M2. The compounds produced according to the invention show good affinity for the receptors of type M1 and a marked specificity for the central receptors of type M1, in contrast to receptors of type M2.

Som et eksempel viste forbindelsen SR 46559A en inhiberende konsentrasjon 50 uttrykt i mikromol av henholdsvis 0,11 og 2,2 på M,- og M2-reseptorene. As an example, the compound SR 46559A showed an inhibitory concentration expressed in micromoles of 0.11 and 2.2 on the M 1 and M 2 receptors, respectively.

Likeledes viste forbindelsen SR 47047A inhiberende konsentra-sjoner 50 på henholdsvis 0,04 og 0,9, på M.,- og M2-reseptorene. Likewise, the compound SR 47047A showed inhibitory concentrations 50 of 0.04 and 0.9, respectively, on the M1 and M2 receptors.

In vivo ble forbindelsene fremstilt ifølge oppfinnelsen analysert med hensyn til sin effekt på rotasjonene bevirket ved intrastripe- ("intrastriatal") pirenzepin ved forsøket beskrevet av P. Worms et al. (Psychopharmacology, 1987, 93, 489-493), modifisert på den måte at administreringen av forbindelsene oralt fant sted 4 timer før, istedenfor 30 minutter før, injeksjonen av pirenzepin. In vivo, the compounds prepared according to the invention were analyzed with respect to their effect on the rotations caused by intrastripe ("intrastriatal") pirenzepine in the experiment described by P. Worms et al. (Psychopharmacology, 1987, 93, 489-493), modified in such a way that the administration of the compounds orally took place 4 hours before, instead of 30 minutes before, the injection of pirenzepine.

Ved en dose på 3 mg pr. kg kroppsvekt inhiberer forbindelsene fremstilt ifølge oppfinnelsen sterkt antallet rotasjoner bevirket ved pirenzepin. Som et eksempel inhiberer således forbindelsen SR 46559A rotasjonene bevirket ved pirenzepin med 78%. At a dose of 3 mg per kg body weight, the compounds produced according to the invention strongly inhibit the number of rotations effected by pirenzepine. As an example, the compound SR 46559A thus inhibits the rotations caused by pirenzepine by 78%.

Videre ble det vist at forbindelsene fremstilt ifølge oppfinnelsen var aktive ved de passive unngåelsestester i rotte beskrevet av M.E. Jarvik et al. i Psychol. Med., 1967, 21, 221-224 og P. Worms et al. i Psychopharmacol., 1989, 98, 286-288. Furthermore, it was shown that the compounds produced according to the invention were active in the passive avoidance tests in rats described by M.E. Jarvik et al. in Psychol. Med., 1967, 21, 221-224 and P. Worms et al. in Psychopharmacol., 1989, 98, 286-288.

I henhold til resultatene av disse forsøk motvirker følgelig forbindelsene fremstilt ifølge oppfinnelsen hukommelsestap som bevirkes ved skopolamin administrert intraperitonealt med 0,5 mg/kg, og hukommelsestap bevirket ved pirenzepin administrert intraperitonealt med 75 mg/kg. F.eks. oppviser SR 46559A en oral effektiv dose 50 på henholdsvis 0,25 mg/kg og 0,027 mg/kg i hvert av disse forsøk. Accordingly, according to the results of these experiments, the compounds produced according to the invention counteract amnesia caused by scopolamine administered intraperitoneally at 0.5 mg/kg, and amnesia caused by pirenzepine administered intraperitoneally at 75 mg/kg. E.g. SR 46559A exhibits an oral effective dose 50 of 0.25 mg/kg and 0.027 mg/kg, respectively, in each of these trials.

Videre ble en del forbindelser fremstilt ifølge oppfinnelsen undersøkt ved flere forutsigbare modeller av antidepressiv-aktivitet såsom den tvungne svømmetest beskrevet av Porsolt et al. Furthermore, a number of compounds produced according to the invention were examined by several predictable models of antidepressant activity such as the forced swimming test described by Porsolt et al.

(Arch. Intern. Pharmacodyn., 1977, 229, 327-336) og testen angående antagonisme av reserpin-bevirket ptose beskrevet av (Arch. Intern. Pharmacodyn., 1977, 229, 327-336) and the test regarding antagonism of reserpine-induced ptosis described by

Gouret et al. (J. Pharmacol. (Paris), 1977, 8, 333-350). SR 46559A ble spesielt vist å være inaktivt ved disse tester i orale doser fra 0,1 til 10 mg/kg. Gouret et al. (J. Pharmacol. (Paris), 1977, 8, 333-350). In particular, SR 46559A was shown to be inactive in these tests at oral doses from 0.1 to 10 mg/kg.

Endelig viste ikke forbindelsene fremstilt ifølge oppfinnelsen noe tegn til toksisitet ved de doser hvor de er aktive. Finally, the compounds produced according to the invention did not show any signs of toxicity at the doses where they are active.

Følgelig kan forbindelsene (I) anvendes som medisiner. Consequently, the compounds (I) can be used as medicines.

De angitte resultater viser at forbindelsene fremstilt ifølge oppfinnelsen oppviser god affinitet for muskarin-reseptorene og god aktivitet ved testene som gjelder hukommelsestap bevirket ved skopolamin eller pirenzepin. De gjør det mulig å anvende produktene fremstilt av forbindelser fremstilt ifølge oppfinnelsen i alle slike tilfeller hvor en cholinerg-mangel er påvist og spesielt for behandling av kunnskaps- og hukommelsesforstyrrelser, og degenerative syndromer forbundet med alderdom og alderdoms-sløvsinn. The stated results show that the compounds prepared according to the invention show good affinity for the muscarinic receptors and good activity in the tests concerning memory loss caused by scopolamine or pirenzepine. They make it possible to use the products made from compounds made according to the invention in all such cases where a cholinergic deficiency has been demonstrated and especially for the treatment of knowledge and memory disorders, and degenerative syndromes associated with old age and senile lethargy.

Det kan således fremstilles farmasøytiske blandinger som inneholder minst én av forbindelsene med formel (I) eller ett av deres salter som aktiv bestanddel. Pharmaceutical mixtures containing at least one of the compounds of formula (I) or one of their salts as active ingredient can thus be prepared.

I farmasøytiske blandinger for oral, sublingval, transdermal eller rektal administrering kan de aktive bestanddeler med formel I ovenfor administreres til mennesker i spesifikke administreringsformer, i kombinasjon med de farmasøytiske standard-bærerstoffer, særlig for behandling av kunnskaps- eller hukommelsesforstyrrelser eller degenerative syndromer. De hensiktsmessige spesifikke administreringsformer omfatter de former som anvendes for oral administrering såsom tabletter, kapsler, pulvere, granuler og oppløsninger eller oral-suspensjoner, de former som anvendes for administrering under tunge og i munnhulen, formene for subkutan, intramuskulær eller intravenøs administrering og formene for rektal administrering. In pharmaceutical compositions for oral, sublingual, transdermal or rectal administration, the active ingredients of formula I above can be administered to humans in specific administration forms, in combination with the standard pharmaceutical carriers, in particular for the treatment of cognitive or memory disorders or degenerative syndromes. The suitable specific forms of administration include the forms used for oral administration such as tablets, capsules, powders, granules and solutions or oral suspensions, the forms used for administration under the tongue and in the oral cavity, the forms for subcutaneous, intramuscular or intravenous administration and the forms for rectal administration.

For oppnåelse av den ønskete effekt kan dosen av den aktive bestanddel variere mellom 0,5 og 500 mg pr. dag. To achieve the desired effect, the dose of the active ingredient can vary between 0.5 and 500 mg per day.

Hver enhetsdose kan inneholde fra 0,1 til 100 mg aktiv bestanddel i kombinasjon med et farmasøytisk bærerstoff. Denne enhetsdose kan administreres 1-5 ganger pr. dag. Each unit dose may contain from 0.1 to 100 mg of active ingredient in combination with a pharmaceutical carrier substance. This unit dose can be administered 1-5 times per day.

Når en fast blanding fremstilles i form av tabletter, blandes den aktive hovedbestanddel med et farmasøytisk bærerstoff såsom gelatin, stivelse, laktose, magnesiumstearat, talk, gummi arabicum eller liknende substanser. Tablettene kan belegges med sakkarose eller andre egnete materialer, eller de kan behandles slik at de har vedvarende eller forsinket aktivitet og således at de kontinuerlig frigjør en forutbestemt mengde aktiv bestanddel. When a solid mixture is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or similar substances. The tablets can be coated with sucrose or other suitable materials, or they can be treated so that they have sustained or delayed activity and so that they continuously release a predetermined amount of active ingredient.

Et preparat av kapsler fås ved blanding av den aktive bestanddel med et fortynningsmiddel og ved at den oppnådde blanding helles i myke eller harde kapsler. A preparation of capsules is obtained by mixing the active ingredient with a diluent and by pouring the resulting mixture into soft or hard capsules.

Pulverne eller granulene som er dispergerbare i vann, kan inneholde den aktive bestanddel blandet med dispergeringsmidler eller fuktemidler eller suspenderingsmidler såsom polyvinylpyrro-lidon, såvel som med søtningsstoffer eller smaksmodifiserings-midler. The powders or granules which are dispersible in water may contain the active ingredient mixed with dispersing agents or wetting agents or suspending agents such as polyvinylpyrrolidone, as well as with sweetening agents or taste modifying agents.

Når det gjelder rektal administrering, anvendes det stikk-piller som fremstilles med bindemidler som smelter ved temperaturen i endetarmen, f.eks. kakaosmør eller polyetylenglykoler. When it comes to rectal administration, suppositories are used that are made with binders that melt at the temperature in the rectum, e.g. cocoa butter or polyethylene glycols.

For parenteral administrering anvendes vandige suspensjoner, isotoniske saltoppløsninger eller sterile og injiserbare opp-løsninger som inneholder farmakologisk forlikelige fukte- og/eller dispergeringsmidler, f.eks. propylenglykol eller butylenglykol. For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing pharmacologically compatible wetting and/or dispersing agents are used, e.g. propylene glycol or butylene glycol.

Den aktive bestanddel kan også utformes som mikrokapsler, med eller uten ett eller flere additiver eller bærerstoffer. The active ingredient can also be designed as microcapsules, with or without one or more additives or carriers.

Som et eksempel på et galenisk preparat kan det fremstilles kapsler som inneholder: As an example of a galenic preparation, capsules containing:

ved intim blanding av ovennevnte bestanddeler og ved at blandingen helles i gelkuler av hard gelatin. by intimate mixing of the above-mentioned ingredients and by pouring the mixture into gel balls of hard gelatin.

Claims (4)

1. Analogifremgangsmåte for fremstilling av terapeutisk virksomme pyridazin-derivater med følgende generelle formel: hvor Ar representerer en fenylgruppe substituert med R1 og R2; R1 og R2 hver, uavhengig av hverandre, angir hydrogen, halogen, hydroksyl, eller C^-C^-alkoksy; R3 representerer rettkjedet eller forgrenet C^-C^-alkyl, C3-C7-cykloalkyl eller fenyl; R4 representerer en gruppe R5 representerer en rettkjedet CpC^-alkylgruppe; R6 representerer en rettkjedet C^-C^-alkylgruppe, eller R5 og R6, sammen med det nitrogenatom som de er bundet til, utgjør en heterocyklisk ring valgt blant morfolin og piperidin; såvel som deres salter med mineral- eller organiske syrer, karakterisert ved at et amin med formel R4NH2 hvor R4 er som definert ovenfor, omsettes med et 6-klorpyridazin med formel: hvor Ar og R3 har samme betydninger som ovenfor, og forbindelsen oppnådd på denne måte eventuelt omdannes til et salt med en mineral- eller organisk syre.1. Analogy method for the preparation of therapeutically active pyridazine derivatives with the following general formula: where Ar represents a phenyl group substituted with R 1 and R 2 ; R1 and R2 each independently represent hydrogen, halogen, hydroxyl, or C₁-C₁-alkoxy; R3 represents straight-chain or branched C₁-C₁-alkyl, C3-C7 cycloalkyl or phenyl; R4 represents a group R 5 represents a straight chain C 1 -C 6 -alkyl group; R 6 represents a straight-chain C 1 -C 4 -alkyl group, or R 5 and R 6 , together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from morpholine and piperidine; as well as their salts with mineral or organic acids, characterized in that an amine of formula R4NH2 where R4 is as defined above, is reacted with a 6-chloropyridazine of formula: where Ar and R3 have the same meanings as above, and the compound obtained in this way is optionally converted into a salt with a mineral or organic acid. 2. Fremgangsmåte som angitt i krav 1, karakterisert ved at (i) et 6-klorpyridazin med formel (II) hvor: Ar representerer fenyl, usubstituert eller substituert i stilling 2 med klor, hydroksyl eller metoksy; - R3 representerer fenyl eller n-propyl, omsettes med (ii) et amin med formel R4NH2 hvor R4 er gruppen hvor R5 og R6 hver representerer etyl.2. Process as stated in claim 1, characterized in that (i) a 6-chloropyridazine of formula (II) where: Ar represents phenyl, unsubstituted or substituted in position 2 with chlorine, hydroxyl or methoxy; - R3 represents phenyl or n-propyl, reacts with (ii) an amine of formula R4NH2 where R4 is the group where R 5 and R 6 each represent ethyl. 3. Fremgangsmåte som angitt i krav 1 eller 2, karakterisert ved at det anvendes et 6-klorpyridazin med formel (II) hvor Ar er fenyl og R3 er propyl, som omsettes med 2-dietylamino-2-metylpropylamin for å danne 3-(2-dietylamino-2-metylpropyl)amino-6-fenyl-5-propyl-pyridazin eller ett av dets salter.3. Method as stated in claim 1 or 2, characterized in that a 6-chloropyridazine of formula (II) is used where Ar is phenyl and R3 is propyl, which is reacted with 2-diethylamino-2-methylpropylamine to form 3-( 2-diethylamino-2-methylpropyl)amino-6-phenyl-5-propyl-pyridazine or one of its salts. 4. Fremgangsmåte som angitt i krav 1 eller 2, karakterisert ved at 6-klorpyridazin med formel (II) hvor Ar og R3 hver er fenyl, omsettes med 2-dietylamino-2-metylpropylamin for å danne 3-(2-dietylamino-2-metylpropyl)amino-5,6-difenyl-pyridazin eller ett av dets salter.4. Process as stated in claim 1 or 2, characterized in that 6-chloropyridazine of formula (II) where Ar and R3 are each phenyl, is reacted with 2-diethylamino-2-methylpropylamine to form 3-(2-diethylamino-2 -methylpropyl)amino-5,6-diphenyl-pyridazine or one of its salts.
NO904984A 1989-11-17 1990-11-16 Analogous Process for Preparing Therapeutically Active Pyridazine Derivatives NO178967C (en)

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FR909007533A FR2663326B2 (en) 1989-11-17 1990-06-15 PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.

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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.
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JP2009506069A (en) 2005-08-26 2009-02-12 ブレインセルス，インコーポレイティド Neurogenesis through modulation of muscarinic receptors
WO2007066601A1 (en) * 2005-12-07 2007-06-14 Sumitomo Chemical Company, Limited Pyridazine compound and use thereof
FR2904314A1 (en) * 2006-07-26 2008-02-01 Centre Nat Rech Scient LINEAR PYRIDAZINIC AND PYRROLIC COMPOUNDS, METHODS OF OBTAINING AND APPLICATIONS
AR081331A1 (en) 2010-04-23 2012-08-08 Cytokinetics Inc AMINO- PYRIMIDINES COMPOSITIONS OF THE SAME AND METHODS FOR THE USE OF THE SAME
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AR081626A1 (en) * 2010-04-23 2012-10-10 Cytokinetics Inc AMINO-PYRIDAZINIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USE OF THE SAME TO TREAT CARDIAC AND SKELETIC MUSCULAR DISORDERS
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DE69028602D1 (en) 1996-10-24
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AR247557A1 (en) 1995-01-31
FI905663A (en) 1991-05-18
KR0164599B1 (en) 1999-01-15
HUT56078A (en) 1991-07-29
FI101881B1 (en) 1998-09-15
FR2663326B2 (en) 1992-10-16
NO178967C (en) 1996-07-10
HU211351A9 (en) 1995-11-28
EP0429344A1 (en) 1991-05-29
LV11972B (en) 1998-04-20
GR3021933T3 (en) 1997-03-31
PT95902A (en) 1991-09-13
IE904145A1 (en) 1991-05-22
LV11972A (en) 1998-02-20
PT95902B (en) 1998-01-30
ATE143010T1 (en) 1996-10-15
ES2094146T3 (en) 1997-01-16
IL96384A (en) 1995-10-31
CA2030133C (en) 1991-05-18
NO904984D0 (en) 1990-11-16
DK0429344T3 (en) 1997-03-03
EP0429344B1 (en) 1996-09-18
CA2030133A1 (en) 1991-05-18
IL96384A0 (en) 1991-08-16
FI905663A0 (en) 1990-11-15
AU6667290A (en) 1991-05-23
FR2663326A2 (en) 1991-12-20
AU639043B2 (en) 1993-07-15
KR910009672A (en) 1991-06-28
IE75697B1 (en) 1997-09-10
FI101881B (en) 1998-09-15
HU207852B (en) 1993-06-28
JPH03170465A (en) 1991-07-24
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