NO831614L - 3-AMINO-6-ARYL-1,2,4-TRIAZOLO (4,3-B) PYRIDAZINES, THEIR PREPARATION AND THEIR USE - Google Patents

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE Amino-6-aryl-1,2,4-triazolo[4,3-b]pyridazines of the general formula I see diagramm : EP0094038,P8,F2 and their salts with a physiologically tolerated acid, wherein R**1 and R**2 are identical or different and represent hydrogen, alkyl groups having 1-6 carbon atoms, phenyl or chlorine and Ar represents phenyl, biphenyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, 1- or 2-naphtyl, 2- or 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 2-, 3- or 4-pyridyl, which radicals can optionally be substituted by one, two, three, four or five fluorine, chlorine, bromine, iodine, alkyl groups having 1-6 carbon atoms, cycloalkyl groups having 3-8 carbon atoms, phenylalkyl groups having 1-4 alkyl carbon atoms, alkoxy or alkylthio groups each having 1-6 carbon atoms, hydroxyl, nitro, cyano, trifluormethyl, carboxyl groups, their esters with C1 -C6 -alcohols, aminocarbonyl, amino, acetamino or alkoxycarbonylamino having 1-6 carbon atoms in the alkyl radical. 1. Claims for the Contracting State : AT Processes for the preparation of 3-amino-6-aryl-1,2,4-triazolo[4,3-b]pyridazines of the general formula I see diagramm : EP0094038,P9,F1 and of their salts with a physiologically tolerated acid, wherein R**1 and R**2 are identical or different and represent hydrogen, alkyl groups having 1-6 carbon atoms, phenyl or chlorine and Ar represents phenyl, biphenyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, 1- or 2-naphtyl, 2- or 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 2-, 3- or 4-pyridyl, which radicals can optionally be substituted by one, two, three, four or five fluorine, chlorine, bromine, iodine, alkyl groups having 1-6 carbon atoms, cycloalkyl groups having 3-8 carbon atoms, phenylalkyl groups having 1-4 alkyl carbon atoms, alkoxy or alkylthio groups each having 1-6 carbon atoms, hydroxyl, nitro, cyano, trifluormethyl, carboxyl groups, their esters with C1 -C6 -alcohols, aminocarbonyl, amino, acetamino or alkoxycarbonylamino having 1-6 carbon atoms in the alkyl radical which comprise a) reacting an arylhydrazinopyridazine of the formula II see diagramm : EP0094038,P9,F4 wherein R**1 , R**2 and Ar have the meanings indicated for formula I, with cyanogen chloride, cyanogen bromide, O-methylisourea or S-methylisothiourea, guanidine or their salts, chloroformamidine hydrochloride or cyanamide as cyclization reagent, or b) reacting an arylhydrazinopyridazine of the formula II with a N-(R**3 -oxy)carbonyl-O-methylisourea, to give a compound of the formula III see diagramm : EP0094038,P9,F6 wherein Ar, R**1 and R**2 have the meanings indicated for formula I and R**3 denotes alkyl having 1-10 carbon atoms, benzyl or phenyl, and then hydrolyzing the compound thus obtained, or c) reacting a compound of the formula IV see diagramm : EP0094038,P9,F2 wherein R**4 denotes chlorine, bromine or methylthio, and Ar, R**1 and R**2 have the meanings indicated for formula I, with ammonia or d) cyclizing a compound of the formula V see diagramm : EP0094038,P9,F3 wherein Ar, R**1 and R**2 have the meanings indicated for formula I and Z represents O, S or NH, by heating, optionally with the addition of a condensing agent, to give a compound of the formula I, and optionally converting the compound thus obtained into the salt with a physiologically tolerated acid.

Description

The object of the invention is new 3-amino-6-aryl-1,2,4-triazolo[4,3-b]pyridazines of the general formula. In - -

and their salts with a physiologically tolerable acid, and in which R 1 and R 2 are the same or different and mean hydrogen, alkyl groups with 1-6 C atoms, phenyl or chlorine and Ar means aromatic residues such as phenyl, biphenyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, 1- or 2-naphthyl, 2- or 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 2-, 3- or 4-pyridyl, which may optionally be substituted with one two Three. four or five residues such as fluorine, chlorine, bromine, iodine, alkyl groups with 1-6 C atoms, cycloalkyl groups with 3-8 C atoms, phenylalkyl groups with 1-4 alkyl C atoms, alkoxy or alkylthio groups with each time 1 -6 C atoms, hydroxy. nitro, cyano, trifluoromethyl, carboxy groups, their esters with C₁-C₂ alcohols, aminocarbonyl, amino, acetamino, alkoxycarbonylamino with 1-6 C atoms in the alkyl residue.

Among the compounds of the general formula I are such fore-1 2

drawn in which R and R are the same or different and mean hydrogen, methyl, ethyl, phenyl or chlorine and in which Ar means phenyl, biphenyl, 2- or 3-thienyl, 2-furyl, 2-, 3- or 4-pyridyl, which may optionally be substituted with one, two or three fluorine, chlorine, bromine, alkyl groups with 1-6 C atoms, cycloalkyl groups with 3-6 C atoms or trifluoromethyl.

Particularly preferred are such compounds of formula I

1 2

wherein R and R are the same or different and mean hydrogen,

methyl or ethyl and Ar means phenyl, 2- or 3-thienyl, 2-,

3- or 4-pyridyl, optionally substituted by one or two fluoro, chloro, methyl, ethyl or trifluoromethyl.

The subject of the invention is also a method for producing these compounds as well as pharmaceutical preparations of these compounds and their use as medicine.

The process for the preparation of the compounds of formula I is characterized by an aryl-hydrazino-pyridazine of formula

II

in which R 1 and R 2 and Ar have the meaning given under formula I, a) is reacted with a cyclization reagent such as cyanogen chloride, cyanogen bromine, O-methylisourea or S-methylisothiourea,

guanidine or their salts, chloroformamidine hydrochloride or cyanamide, or

b) is reacted with N-(R 3-oxy)-carbonyl-O-methylisourea

to a compound of formula III

1 2

in which Ar, R and R have the meaning given under formula I and R 3 means alkyl with 1-10 C atoms, benzyl or phenyl and then the compound thus formed is saponified or,

c) that a compound of formula IV,

4 12

R means chlorine bromine or methylthio, and Ar, R and R have the meaning given under formula I react with ammonia, or

d) that a compound of formula V

12 in which Ar, R and R have the meaning given under formula I and that Z means 0, S or NH, is optionally cyclized with the addition of a condensing agent to a compound of formula I. Compounds of formula II are e.g. known from J. Heterocyclic Chem. 15_, 881 (1978) and can be prepared from chlorine compounds of formula VI with hydrazine hydrate

according to methods known in the literature (The Chemistry of Heterocyclic Compounds, Vol 28 Pyridazines, Editors A. Weissberger and E.C. Taylor, John Wiley, New York 1973). Both literature citations also refer to the production of the chlorine compounds VI and their precursors.

Method a) is carried out in a suitable solvent in a temperature range from 0°C to the boiling point of the solvent used, preferably at 50 to 100°C.

As a solvent for method a) there is e.g.

in particular water, acetic acid, aliphatic alcohols such as methanol, ethanol, isopropanol, dioxane, DMF, toluene, chlorinated hydrocarbons such as methylene chloride, chloroform, dichloroethane, carbon tetrachloride.

Method b) is carried out in a suitable solvent

in the presence of an acid. For example, you work in a mixture of methanol/glacial vinegar in a volume ratio of e.g. 10:1 at flow-return temperature. The saponification of the carbamate III occurs

proceeds under alkaline conditions by heating with an alkali or alkaline earth metal hydroxide such as e.g. NaOH, KOH, Ca(OH)2, Ba(OH)2 in a solvent or solvent mixture to 60-180°C, preferably to 100-140°C . Solvents include water and aliphatic alcohols and diols such as ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, glycol.

For method c) starting materials of formula IV are reacted by heating arylhydrazinopyridazines II with formic acid or its esters (when r<4>= H), chloroformic acid esters or a dialkyl carbonate (when R 4= OH) or with carbon disulfide and alkali

(where R 4 = SH), optionally with the addition of a solvent or diluent such as chloroform, toluene, dioxane, water, ethanol to a compound of formula IV<1>, in which R 4 = H, OH or SH. When heated with bromine in glacial acetic acid/sodium acetate (where R 4= H), phosphorus oxychloride (where R 4= OH) or methyl iodide or dimethyl sulfate (where R = SH) are obtained, the corresponding compounds IV with R 4= Br, Cl, SCH3.

According to procedure c), the turnover of the compounds takes place

of formula IV with liquid aqueous or alcoholic ammonia or in an inert solvent such as methanol, dioxane,

or toluene with gaseous ammonia by introduction or under pressure. The temperature range extends from the temperature for liquid ammonia up to 20 0°C.

In method d), they are transferred, for example, by turnover

of the chlorine compounds VI with semicarbazide, -thiosemicarbazide or aminoguanidine in a solvent such as e.g. methanol, ethanol, isopropanol, DMF, tetrahydrofuran. toluene, chloroform or dichloroethane formed compounds V by heating e.g.

in one of the aforementioned solvents to 40 - 150°C, possibly with the addition of a condensing agent such as glacial acetic acid, cyclohexylcarbodiimide, 1-hydroxybenztriazole to compounds of formula I. When the compounds of formula I are obtained according to the methods mentioned as salts, it can with ammonia, amines and hydroxides, the corresponding bases are released.

The four bases of formula I are transferred with physiologically tolerable acids to the corresponding salts. As acids, inorganic or organic acids such as hydrochloric or hydrobromic acid come into consideration. phosphoric acid, acetic acid, benzoic acid, citric acid, maleic acid, fumaric acid, lactic acid, tartaric acid, succinic acid, acetylglycine. The hydrochlorides of formula I are preferred.

The compounds according to the invention with formula I are suitable for the production of pharmaceuticals. The medicines may contain one or more of the compounds according to the invention or also mixtures of these with other pharmaceutically active substances. For the production of medicinal products, the usual pharmaceutical carriers and excipients and known gelling methods can be used. The drugs can be used enterally, parenterally, orally or perlingually. For example, the administration can take place in the form of tablets, capsules, pills, dragees, drops, gels, creams, powders, liquids, stick powders or aerosols. Liquids include, for example: oily or aqueous solutions or suspensions, emulsions, injectable aqueous solutions or suspensions.

The compounds according to the invention can also be used as intermediates for the production of other medicinal products. As compounds according to the invention, the following should be mentioned: 3-amino-6-(2-bromophenyl)-1,2,4-triazolo[4,3-b]pyridazine, 3-amino-6-(2-trifluoromethylphenyl)-1, 2,4-triazolo[4,3-b]pyridazine, 3-amino-6-(4-chloro-3-trifluoromethylphenyl)-1,2,4-triazolo[4,3-b]~pyridazine, ,3- amino-6-(3-ethylphenyl)-1,2,4-triazolo[4,3-b]-pyridazine, 3-amino-6-(2-methylphenyl)-1,2,4-triazolo[4,3 -b]-pyridazine, 3-amino-6-(2-ethylphenyl)-1,2,4-triazolo[4,3-b]-pyridazine, 3-amino-6-(3-methoxyphenyl)-1,2 ,4-triazolo[4,3-b]-pyridazine, 3-amino-6-(4-propylthiophenyl)-1,2,4-triazolo[4,3-b]-pyridazine, 3-amino-6-( 4-acetamidophenyl)-1,2,4-triazolo[4-3-b]-pyridazine, 3-amino-6-(4-aminophenyl)-1,2,4-triazolo[4,3-b]-pyridazine , 3-amino-6-(4-methoxycarbonylaminophenyl-1,2,4-triazolo-[4,3-b]pyridazine, 3-amino-6-(4-nitrophenyl)-1,2,4-triazolo[4 ,3-b]-pyridazine, 3-amino-6-(3-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine, 3-amino-6-(2-nitrophenyl)-1, 2,4-triazolo[4,3-b]pyridazine, 3-amino-6-(4-cyanophenyl)-1,2,4-triazolo[4,3-b]pyridazine, 3-amino-6-(3 -cyanophenyl)-1,2,4-triaz olo[4,3-b]pyridazine, 3-amino-6-(2-cyanophenyl)-1,2,4-triazolo[4,3-b]pyridazine, 3-amino-6-(4-phenylsulfinylphenyl)- 1,2,4-triazolo[4,3-b]pyridazine, 3-amino-6-(4-phenylsulfonylphenyl)-1,2,4-triazolo[4,3-b]pyridazine, 3-amino-6- (4-hydroxyphenyl)-1,2,4-triazolo[4,3-b]pyridazine, 3-amino-6-(3-hydroxyphenyl)-1,2,4-triazolo[4,3-b]pyridazine, 3-amino-6-(3,4-dihydroxyphenyl)-1,2,4-triazolo[4,3-b]pyridazine, 3-amino-6-(1-naphthyl)-1,2,4-triazolo[ 4,3-b]pyridazine, 3-amino-6-(2-naphthyl)-1,2,4-triazolo[4,3-b]pyridazine, 3-amino-6-(3-thienyl)-1, 2,4-triazolo[4,3-b]pyridazine, 3-amino-6-(4-chloro-2-thienyl)-1,2,4-triazolo[4,3-b]pyridazine, 3-amino- 6-(3-methyl-2-thienyl)-1,2,4-triazolo[4,3-b]pyridazine, 3-amino-6-(4-methyl-2-thienyl)-1,2,4- triazolo[4,3-b]pyridazine, 3-amino-6-(2-furyl)-1,2,4-triazolof 4,3-b]pyridazine, 3-amino-6-(5-methyl-2- furyl)-1,2,4-triazolo[4,3-b]pyridazine, 3-amino-6-(4-pyridyl)-1,2,4-triazolo-[4,3-b]pyridazine, 3- amino-6-(3-pyridyl)-1,2,4-triazolo[4,3-b]-pyridazine, 3-amino-6-(2-pyridyl-1,2,4-triazolo[4,3- b]py ridazine, 3-amino-6-(2-pyrrolyl)-1,2,4-triazolo[4,3-b]pyridazine and 3-amino-6-(1-methyl-2-pyrrolyl)-1,2, 4-triazolo[4,3-b]pyridazine. The compounds according to the invention with formula I have pharmacological properties, in particular they act as anxiolytic and anticonvulsant. Insomnia, agitation and vegetative depression are therefore taken into consideration as indications.

The pharmaceutical preparations usually contain between 1 and 10% of the active component(s) according to the invention.

The anxiolytic effect of the compound of formula I is followed by very little sedation and good tolerability (Ld^Qi.a. over 300 mg/kg i.p. in mice). This is evident from studies where the impact of the compounds according to the invention was measured on the motor activity, hexobarbital narcosis and cardiazole convulsions in mice. In addition, the Beller anxiolysis test was used as well as the Lick-Shock test on rats.

ten

The lowest already effective dose in the indicated trials is, for example, 5 mg/kg orally, 2.5 mg/kg sublingually, 1 mg/kg intravenously. As a general dose range for the effect (animal experiments as above), the following are for example: 5 to 50 mg/kg orally, 2.5 - 25 mg/kg sublingually, 1 to 10 mg/kg intravenously.

For example, it can be applied 3 times a day 1 to 3

tablets with a content of 10 to 100 mg of active substance or, for example, by intravenous injection 1 to 3 times a day, an ampoule of 2 to 4 mg content with 0.5 to 5 mg of substance.

Example 1: Procedure a)

3-Amini-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine hydrochloride 25 g of 3-hydrazino-6-phenylpyridazine and 17.1 g of cyanogen bromide are stirred

in 150 ml of ethanol for 3 hours under reflux and then evaporated in vacuo. The residue is dissolved hot in water, filtered and made alkaline with excess ammonia. The free base is suctioned off, washed neutrally and dried, suspended in ethanol, mixed with ethanolic hydrochloric acid and evaporated in vacuo.

The precipitated hydrochloride is suctioned off, washed with ethanol and dried, melting point 280°C during decomposition.

Example 2: Procedure a)

3-Amino-6-(4-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine hydrochloride

In a solution of 5 g of 3-(4-fluorophenyl)-6-hydrazino-pyridazine in 50 ml of ethanol, a small excess of cyanogen chloride is introduced at 0 - 10°C and further stirred at room temperature until complete reaction (DC control).

The precipitated hydrochloride is suctioned off, washed with isopropanol and dried, melting point 284°C during decomposition.

Example 3: Procedure b)

3-amino-6-(3,4-dichlorophenyl)-1,2,4-triazolo[4,3-b]pyridazine

3 g of 6-(3,4-dichlorophenyl)-3-methoxycarbonylamino-1,2,4-tri-azolo[*4 ^3-b]pyridazine and 3 g of potassium hydroxide are heated in 10 ml of water and 20 ml of 2-methoxyethanol in 16 hours to the return run.

The precipitated product is filtered off, washed neutrally and recrystallized from isopropanol, melting point 281°C.

Example 3: Procedure c)

6-(4-methylphenyl)-1,2,4-triazolo[4,3-b]pyridazine

5 g of 3-hydrazino-6-(4-methylphenyl)-pyridazine are stirred in 10 ml of formic acid for 2 hours under reflux. After cooling, dilute with water and the precipitated product is filtered off with suction and washed neutrally and dried, melting point 186°C.

Example 4: -~Procedure c)

3-bromo-6-(4-methylphenyl)-1,2,4-triazolo[4,3-b]pyridazine

4 g of 6-(4-methylphenyl)-1,2,4-triazolo[4,3-b]pyridazine and 3 g of sodium acetate are suspended in 20 ml of glacial acetic acid. 1 ml of bromine in 5 ml of glacial acetic acid is added dropwise to the solution and heated to reflux for 5 hours. Evaporate to dryness, mix with water and suction off the<*>product. After recrystallization from isopropanol and drying, melting point 211°C.

Example 5: Procedure c)

3-amino-6-(4-methylphenyl)-1,2,4-triazolo[4,3-b]pyridazine

3 g of 3-bromo-6-(4-methylphenyl)-1,2,4-triazolo[4,3-b]pyridazine is treated with 25 ml of methanol and 25 ml of concentrated ammonia solution at 100°C in an autoclave. After cooling, dilute with water, remove with suction, wash neutrally and dry, melting point 261°C.

Example 6: Procedure d)

3-phenyl-6-thiosemicarbazidopyridazine

6 g of 3-chloro-6-phenylpyridazine and 6 g of thiosemicarbazide are heated in 60 ml of ethanol for 3 hours to reflux. The formed precipitate is filtered off with suction, washed with ethanol and water and dried in a vacuum, melting point 213°C during cleavage.

Example 7: Procedure d)

3-amino-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine

2 g of 3-phenyl-6-thiosemicarbazidopyridazine are heated in 20 ml of glacial acetic acid for 6 hours under reflux. After evaporation of the reaction solution, it is stirred with aqueous ammonia, filtered off with suction, washed neutrally with water, dried and recrystallized from isopropanol, melting point 212°C.

Analogous to examples 1-7, the following compounds can be prepared:

Claims (1)

1. 3-amino-6-aryl-1,2/4-triazolo[4,3-b]pyridazines of the general formula I and their salts with a physiologically tolerable acid in which R and R 2 are the same or different and mean hydrogen, alkyl groups with 1-6 C atoms, "phenyl or chlorine and Ar means aromatic residues such as phenyl, biphenyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinyl, phenylsulfonyl, 1- or 2-naphthyl, 2- or 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 2-, 3- or 4-pyridyl which may optionally be substituted with two, three, four or five residues such as fluorine , chlorine, bromine, iodine, alkyl groups with 1-6 C atoms, cycloalkyl groups with 3-8 C atoms, phenylalkyl groups with 1-4 alkyl C atoms, alkoxy or alkylthio groups with each 1-6 C atoms, hydroxy, nitro, cyano, trifluoromethyl, carboxy groups, their esters with C^ -Cg- alcohols, aminocarbonyl, amino, acetamino, alkoxycarbonylamino with 1-6 C atoms in the alkyl residue. 1 2 2. Compounds according to claim 1, in which R and R are the same or different and mean hydrogen, methyl, ethyl, phenyl or chlorine, and in which Ar means phenyl, biphenyl, 2- or 3-thienyl, 2-furyl, 2- , 3- or 4-pyridyl which may optionally be substituted with one, two or three fluorine, chlorine, bromine alkyl groups with 1-6 C atoms, cycloalkyl groups with 3-6 C atoms or trifluoromethyl. 3. Process for preparing compounds of formula I in claim 1, characterized in that an aryl-hydrazinopyridazine of formula II 1 2 in which R , R and Ar have the meaning given in formula I, a) is reacted with a cyclization reagent, or b) is reacted with an N-(R 3-oxy)-carbonyl-O-methylisourea to a compound of formula III 1 2 in which Ar, R and R have the meaning given in formula I and R 3 means alkyl with 1-10 C atoms, benzyl or phenyl and then the compound thus formed is saponified, orc) that a compound of formula IV 4 12 in which R means chlorine, bromine or methylthio and Ar, R and R have the meaning given in formula I, reacted with ammonia or d) that a compound of formula V 12- in which Ar, R and R have the meaning specified for formula I that Z means 0, S or NH, is cyclized by heating optionally with the addition of a condensing agent to a compound of formula I, and optionally the compound thus formed is transferred to the salt with a physiologically tolerable acid. 4. Pharmaceutical preparations with anxiolytic and anticonvulsant action, characterized by a content of a compound with the general formula I in claim 1 / 5. Use of a compound of the general formula I in claim 1 for the treatment of states of agitation, insomnia, convulsive states and vegetative dystonia.