DE2304977A1 - 3-Aminoaryl-5-alkyl-4,5-dihydro-6(1H)-pyridazones - prepd. by reacting 2-alkyl-3-aminoaroyl-propionic acids with hydrazines - Google Patents

Abstract

Cpds. of formula (I): (where R1 is lower alkyl; R2 is H or lower alkyl; and R3 is H or acyl) have valuable pharmaceutical (e.g., cardiovascular and antiphlogistic) props. They are prepd. by cyclising a cpd. of formula (II) with R2NHNH2 and opt. exchanging a halogen atom present in an acyl gp. R3 for an amino gp. so as to give a cpd. in which R3 is aminoacyl. Prodts. in which R3 is H may be N-acylated to give prodts. in which R3 is acyl.

Description

New Dihydropyridazinones The invention relates to dihydropyridazinones of the formula I. their acid addition salts and processes for their preparation.

In the formula I, the individual radicals have the following meanings: R1 is lower Alkyl, R2 is hydrogen or lower alkyl and R3 is a hydrogen atom or a Acyl residue.

For R1 and R2, the lower alkyl radicals are saturated straight-chain or branched alkyl radicals having 1 to 6 carbon atoms are expedient.

Examples of these are: methyl, ethyl, isopropyl, propyl, Butyl, Amyl and Isoamyl The particularly preferred alkyl radicals for R1 are methyl and propyl. The particularly preferred alkyl radical for R2 is methyl.

Suitable acyl radicals for R5 are acyl radicals of saturated aliphatic straight-chain or branched carboxylic acids with 1 to 7 carbon atoms, which optionally can be substituted, or cycloaliphatic carboxylic acids with 5 to 7 carbon atoms in the ring.

Examples of acyl radicals are: formyl, carbethoxy, acetyl, propionyl, Butyroyl, valeroyl, caproyl, hexahydrobenzoyl.

The acyl radicals can additionally be substituted, with as substituents Halogen, such as chlorine, bromine, or NH2, alkylamino, dialkylamino, cycloaliphatic Amino groups or amines in which the amine nitrogen is part of a saturated heterocyclic Ring is to be highlighted.

in the amino groups The alkyl radicals X can also contain double bonds or Triple bonds or additionally contain phenyl radicals. The amino groups can are derived from cyclic amines, which contain further heteroatoms, such as oxygen, nitrogen or sulfur, contained in the ring.

Examples of amino groups as substituents on the acyl radicals are.

Methylamino, ethylamino, n-propylamino, isopropylamino, sec.

Butylamino, cyclohexylamino, cyclopentylamino, 2-thylphenylamino, Benzylamino, ß Hydroxyäthylamino, Allylamino, Butyn- (1) -yl -) - amino, Dimethylamino, Diethylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, N-methylpiperazino.

As acyl radicals RS that contain halogen, the following may be mentioned: chloroacetyl, Chloropropionyl, chlorobutyryl, bromovaleroyl.

The preferred acylamino radicals are derived from acetic acid, propionic acid, Valeric acid from and are optionally substituted.

The compounds according to the invention have the 4-position of the dihydropyridazinone ring an asymmetric carbon atom and can therefore exist in stereoisomeric forms. The stereoisomers or their racemates are expressly included in the invention.

Examples of compounds according to the invention include: 6- (p-aminophenyl) ° 4-methyl-4,5-d-hydropyridazinone- (3) 6- (p-formylaminophenyl) -4-methyl-4,5-d-hydropyridazinone- (3) 6- (p-Carbethoxyaminophenyl) 4-meth l-4,5-dihydropyridazinone- (5) 6- (p-acetaminophenyl) -6- (p-hexahydrobenzoylaminophenyl) - "6- (p-chloroacetaminophenyl) -6- (p -ocPchloropropionylaminophenyl) -6- (p - # - Bromvaleroylaminophenyl) - "6- (p-Ethylaminoacetylaminophenyl) -" 6- (pn-Propylaminoacetylaminophenyl) -4-methyl-4,5-dihydropyridazinone- (3) 6- (p- Isopropylaminoacetylaminophenyl) -4-methyl-4,5-dihydropyridazinone- (3) 6- (p-sec-Butylaminoacetylaminophenyl) -4-methyl-4,5-dihydropyridazinone- (3) 6- (p -cyclohexylaminoacetylaminophenyl) -4 -methyl-4,5-dihydropyridazinone- (3) 6- (p-β-hydroxyethylaminoacetylaminophenyl) -4-methyl-4,5-dihydropyridazinone- (5) 6- (p-allylaminoacetylaminophenyl) -4-methyl-4,5 -dihydropyrida zinon- (5) 6- (p-butyn- (1) -yl- (3) -aminoacetylaminophenyl) -4-methyl-4,5-dihydropyridazinone- (3) 6- (p-2-phenylethylaminoacety laminophenyl) -4-methyl-4,5-dihydropyridazinone- (3) 6- (p-dimethylaminoacetylaminophenyl) -4-methyl-4,5-dihydropyridazinone- (3) 6- (p-diethylaminoacetylaminophenyl) -4-methyl- 4,5-dihydropyridazinone- (3) 6- (p-pyrrolidinoacetylaminophenyl) -4-methyl-4,5-dihydropyridazinone- (3) 6- (p-morpholinoacetylaminophenyl) -4-methyl-4,5-dihydropyridazinone- ( 3) 6- (p-Hexamethyleneiminoacetylaminophenyl) -4-methyl-4,5-dihydro pyridazinone- (5) 6- (p-N'-Mthylpiperazinoacetylaminoheny pyridazinone- (3) 6- (p-aminophenyl) -2,4- dimethyl 4,5-dthydro-3 (2H) pyridazinone 6- (p-acetaminophenyl) -4-propyl-4,5-dihydro-3 (2H) pyridazinone 6- (p-aminophenyl) -4-propyl 4,5- dthydro-3 (2H) pyridazinonO The new compounds can be obtained by converting acylanilides of the formula II with a 2-alkylsuccinic anhydride of the formula III under the conditions of a Friedel-Crafts reaction to give the corresponding 2-alkyl-3- (p-acylaminobenzoyl) -propionic acid derivative of the formula IV.

In the formula scheme given, R1 have the meaning given above and R3 is an acyl radical of a saturated straight-chain or branched one, Carboxylic acid with 1 to 7 carbon atoms which is optionally substituted by halogen or a cycloaliphatic carboxylic acid with 5 to 7 carbon atoms in the ring.

For example, when using acetanilide (R3 = CH3-CO-) and methylsuccinic anhydride (R1 = CH3) according to the formula IV, 2-methyl-3- (p-acetaminobenzoyl) propionic acid is obtained.

The position of the methyl group can be determined from the mass spectrum prove.

The compounds of the formula IV can be combined with hydrazines of the formula R2NHNH2J, in which R2 has the meaning given for the compounds of the formula I, to give the dihydropyridazinones of the formula Ia in a manner known per se are cyclized in which R3 is the acyl radical of a saturated straight-chain or branched, optionally halogen-substituted carboxylic acid with 1 to 7 carbon atoms or a cycloaliphatic carboxylic acid with 5 to 7 carbon atoms in the ring.

The hydrolysis of compounds of the formula IV by conventional methods, for example with aqueous hydrochloric acid, gives 2-alkyl -) - (p-aminobenzoyl) propionic acids of the formula V, which according to the following equation with hydrazines of the formula R2NHNH 2 to dihydropyridazinones of the formula Ib can be cyclized with an unsubstituted amino group, where R1 and R2 have the meanings given above.

The dihydropyridazinones of the formula Ib can also be attached to the amino group subsequently with the appropriate acylating agents, such as carboxylic acids, carboxylic acid anhydrides, Carboxylic acid chlorides, carboxylic acid esters or the corresponding substituted by halogen functional acid derivatives are acylated to give compounds of the formula Ia.

Dihydropyridazinones in which the acyl radical R3 is a halogen-substituted acyl radical having 1 to 7 carbon atoms can be mixed with primary or secondary amines of the formula are reacted, with an exchange reaction forming the corresponding dihydropyridazinones of the formula Ic which are substituted in the acyl radical by amino groups. R4 and R5 are hydrogen or straight-chain or branched alkyl radicals up to 6 carbon atoms, which can also contain further substituents or double bonds and triple bonds. R3 and R5 can also form a heterocyclic ring together with the nitrogen atom connecting them, optionally with the participation of further heteroatoms, such as nitrogen, oxygen, sulfur.

In the compounds of the formula Ic, R1, R2, R4 and R5 are as indicated Meanings, where C nH2n is a saturated straight-chain or branched alkylene radical with 1 to 6 carbon atoms means.

General reaction conditions of the process steps leading to the compounds according to the invention are explained in more detail below: Compounds results in Ibo As a rule, the compounds of the formula IV or V are cyclized to dihydropyridazinones of the formula Ia or Ib with 1 to 6 times the amount of the corresponding hydrazine of the formula R2NHNH or using the corresponding amount of a 2 hydrazinium salt in one Solvents which are inert under the reaction conditions, for example water, methanol, ethanol, isopropanol, dioxane, glycol, dimethyl ether, dimethylformamide, at temperatures from about 60 to 150.degree. C., preferably from 80 to 1200.degree.

links The acylation of dihydropyridazinones of the formula Ib to dihydropyridazinones of the formula Ia with carboxylic acids, carboxylic acid anhydrides, carboxylic acid esters, carboxylic acid chlorides can be carried out using at least one mole of the acylating agent with or without a solvent, with or without an auxiliary base at temperatures between 0 ° C and the boiling temperatures of the acylating agent or solvent used, if appropriate with the application of pressure.

links The reactions of the compounds of the general formula la to Ic are carried out in the presence of an agent which binds hydrogen halide. It is advantageous to work in the presence of an inert organic solvent at temperatures between 50 and 15,000. An inorganic or organic base can be used as an agent which binds hydrogen halide. However, an at least molar excess of the corresponding amine, which can also serve as a solvent, is also suitable. Further routes for the preparation of dihydropyridazinones of the formula 1 can be found in the following scheme: In the formula scheme, the substituents R1 to R5 and (CnH2n) have the meanings given. The starting compound is an ester, lower alkyl esters, a compound of the formula V which is acylated on the aromatic amino group by a functional carboxylic acid derivative RSY, where Y can be Cl, OH, NOCH5, OC2H5 or OR3, is then cyclized with hydrazine or a hydrazine derivative to the compounds Ia. If R3 is an acyl radical substituted by halogen, the halogen atom can also be exchanged for an amino group before the cyclization to the dihydropyridazinone Ic. In the formula scheme given, R can also be hydrogen in the starting compound.

The compounds of the formula I can, if appropriate, be known per se Way with physiologically compatible inorganic or organic acids in acid addition salts be transferred. As such, for example, hydrochloric acid, sulfuric acid, phosphoric acid, Acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid or malic acid in Consideration.

The compounds of this invention have valuable pharmaceutical properties Properties, in particular, are, for example, cardiovascular and anti-inflammatory Features to highlight.

Particularly noteworthy connections are, for example, to name: 6- (p-aminophenyl) -4-methyl-4,5-d-hydropyridazinone- (3), 6- (p-formylaminophenyl) -4-methyl-4,5-d-hydropyridazinone u 6- (p-Acetaminophenyl) -4-methyl-4,5-dShydropyridazinone preparations with the new Compounds as active ingredients can be prepared according to methods known per se to the person skilled in the art the desired type of application can be obtained.

The following examples describe the preparation of starting compounds and the preparation of compounds of the invention.

Example 1 2-methyl -) - (p-acetylaminobenzoyl) -propionic acid To 1,2 kg of anhydrous aluminum chloride are 180 ml of dimethylformamide within 50 minutes added dropwise, with a strongly exothermic reaction occurs. One then carries within for 10 minutes 155 g (1 mol) of acetanilide at 60 to 650C. Then be 114 g (1 mol) of 2-methylsuccinic anhydride within 25 minutes at the same temperature added dropwise. The mixture is heated to 70 ° C. over a period of 25 minutes and stirred afterward 1.5 hours at this temperature and carries the melt then put in 6 kg of ice. The mixture is mixed with 600 ml of hydrochloric acid, it is suctioned off, washed neutral with ice water and dried in vacuo at 100.degree. The raw booty is 187 g (75% of theory). Recrystallization from 2.7 liters gives 99.5 g (40 ß of theory) from the melting point 205 to 2060C.

Example 2 2-methyl -) - (p-aminobenzoyl-propionic acid: 84.7 g (0.4) Mol) 3- (p-aminobenzoyl) -2-methylpropionic acid are in 250 ml hydrochloric acid for 50 minutes heated to boiling. Then at 0 to 50C with sodium carbonate solution The pH is adjusted to 5, it is filtered off with suction, washed with ice water and in vacuo at 1000C dried. The yield is 65 g (71 ß of theory) with a melting point of 150 to 1510C.

Example 3 6- (p-Acetaminophenyl) -4-methyl-4,5-dihydropyridazinon-3: 5 g (0.02 mol) of 3- (p-acetaminobenzoyl) -2-methylpropionic acid are dissolved in 50 ml of water heated to boiling with 1.25 g (0.025 mol) of hydrazine hydrate for 3 hours. After cooling down is suctioned off at OOC, washed with ice water and dried in vacuo at 1000C.

Yield: 4.7 g (96% of theory), melting point 214 to 2150C (from Ethanol).

In a corresponding manner, 3- (p-acetaminobenzoyl) -2-propylpropionic acid is converted 6- (p-Acetaminophenyl) -4-propyl-4,5-dihydropyridazinone-5 from melting point 158 to 160 ° C obtained.

Example 4 6- (p-Formylaminophenyl) -4-methyl-4,5-dihydropyridazinone- 3: 8 g (0.04 mol) of 6- (p-aminophenyl) -4-methyl-4,5-dihydropyridazinon-3 are mixed with Heat 20 ml of formic acid to the boil for 4 hours.

It is poured into 400 ml of water, filtered off with suction, washed with water and dried in a vacuum at 100 ° C.

AusueuWe; 3.1 g (88 g of theory), crude melting point 199-2050C.

Melting point after recrystallization from dimethylformamide / water 196 up to 200 ° C.

Example 5 6- (p-Aminophenyl) -4-methyl-4,5-dihydropyridazinone-3 20.7 g (0.1 mol) 3- (p-aminobenzoyl) -2-methylpropionic acid are dissolved in 150 ml of water with 7 g (0.14 mol) of hydrazine hydrate heated to boiling for 4 hours. You suck at OOC off, washed with water and dried at 1000C in vacuo Yield 18.2 g (89% der Theory), melting point from dimethylformamide watera 256 to 2390C.

Example 6 6- (p-Aminophenyl) -2,4-dimethyl-4,5-dihydropyridazinono3 0 7.25 g (0.0) 5 mol) 3- (p-aminobenzoyl) -2-methylpropionic acid are dissolved in 50 ml of water heated to boiling with 1.95 g (0.042 mol) of methylhydrazine for 20 hours the solution to dryness and the residue crystallized from 30 ml of isopropanol around.

Yield: 4.8 g (65 μ of theory); Melting point 100 to 101 ° C.

Example 7 6- (p-Ethylaminoacetylaminophenyl) -4-methyl-4,5-dihydropyridazi non-5 5.6 g (0.02 mole) 6- (p-chloroacetylaminophenyl) -4-methyl-4,5-dihydropyridazinone-3 are with 5.4 g of 60 Xiger alcoholic ethylamine solution (0.06 mol) in 50 ml of ethanol Heated to boiling temperature for 2 hours. The solution is concentrated and the crystallized Residue from 50 ml of water.

Yield: 30.) g of hydrochloride (99% of theory); Melting point 2780C.

Example 8 6- (p-N-Methylpiperazinoacetylaminophenyl) -4-methyl-4,5-dihydropyridazinone- 3: 5.6 g (0.02 mole) 6- (p-chloroacetaminophenyl) -4-methyl-4,5-dihydro pyridazinone-5 are with 6 g (0.06 mol) of N-methylpiperazine in 50 ml of ethanol for 2 hours Boiling temperature heated. The solution is concentrated and the residue is slurried in water up, sucks off the precipitate and dries in vacuo at 80.degree.

Yield: 5.3 g (92 β of theory); Melting point from dimethylformamide water o 207 to 209 ° C.

Example 9 6- (p-Isopropylaminoacetylaminophenyl) -4-methyl-4,5-dihydropyridazinone-3 : 11.2 g (0.04 mol) 6- (p-chloroacetaminophenyl) -4-methyl-4,5-dihydro pyridazinone ») and 11.8 g (0.2 mol) of isopropylamine are dissolved in 110 ml of ethanol for 12 hours Boiling temperature heated. The solution is concentrated in vacuo and the residue is suspended in 100 ml of water and adjusts the pH to 10 with 2N sodium hydroxide solution. The residue is filtered off with suction, washed neutral with water and dried in vacuo at 80.degree.

From 60 ml of isopropanol, 8.4 g (79 ß of theory) of the melting point are obtained 1450C.

Example 10 6- (p-sec -Butylaminoacetylaminophenyl) -4-methyl-4,5-dihydropyri dazinon-) [11.2 g (0.04 mol) 6- (p-chloroacetaminophenyl) -4-methyl-4,5-dihydropyridazinone-) and 14 g (0.2 mol) of sec-butylamine are refluxed in 110 ml of ethanol for 12 hours cooked. The solution is concentrated in vacuo at 80.degree. The residue is in water Slurried and adjusted to pH 10 with 2N sodium hydroxide solution. The residue is sucked off, washed neutral with water and dried in vacuo at 800C.

Yield: 11.9 g (94% of theory); Melting point 106 to 1070 C.

Recrystallized from 150 ml of isopropanol, 6.4 g (50 μ of the Theory) from melting point 112 to 1150C.

Example 11 6- (p-Pyrrolidinoacetylaminophenyl) -4-methyl-4,5-dihydropyridazinone-5: 5.6 g- (0.02 mol) 6- (p-chloroacetaminophenyl) -4-methyl-4,5-dihydropyridazinone-3 and 4.5 g (0.06 mol) of pyrrolidine are in 50 ml Ethanol for 2 hours Boiling temperature heated. The solution is concentrated, taken up with water, then sucked up Precipitate is washed off with water and dried in vacuo at 80.degree.

Yield: 5.7 g (90% of theory); Melting point 185 to 1850C.

Claims (12)

Claims U dihydropyridazinones of the formula I in which R1 is lower alkyl, R2 is hydrogen or lower alkyl and R3 is a hydrogen atom or an acyl radical. 2. Dihydropyridazinone of the formula given in claim 1, in which R1 is a saturated straight-chain or branched alkyl radical with 1 to 6 carbon atoms, R2 is hydrogen or a saturated straight-chain or branched alkyl radical with 1 to 6 carbon atoms and R5 is hydrogen or an acyl radical of an optionally substituted one saturated aliphatic straight-chain or branched carboxylic acid with 1 to 7 C atoms or a cycloaliphatic carboxylic acid with 5 to 7 C atoms in the ring mean. 3. Dihydropyridazinone of the formula given in claim 1, in which R1 is methyl or propyl, R2 is hydrogen or methyl and R3 is hydrogen or one Acyl radical of an optionally substituted saturated aliphatic straight-chain or branched carboxylic acid with 1 to 5 carbon atoms. 4. 6- (p-Aminophenyl) -4-methyl-4,5-dihydropyridazinone- (3). 5. 6- (p-Formylaminophenyl) -4-methyl-4,5-d-hydropyridazinone- (3). 6. 6- (p-Acetaminophenyl) -4-methyl-4,5-dihydropyridazinone- (5). 7. Process for the preparation of dihydropyridazinones of the formula given in claim 1, characterized in that a compound of the formula in which R1 is a lower alkyl radical and R5 is hydrogen or an acyl radical of a saturated straight-chain or branched, optionally halogen-substituted carboxylic acid with 1 to 7 carbon atoms or a cycloaliphatic carboxylic acid with 5 to 7 carbon atoms in the ring, with a hydrazine of the formula R2NHNH2, in which R2 denotes hydrogen or a lower alkyl radical, is cyclized and, if appropriate, the halogen in the acyl radical is exchanged for amine. 8. A process for the preparation of dihydropyridazinones of claim 1, characterized in that a dihydropyridazinone is used Formula I, in which R5 is hydrogen, acylated on the amino group. 9. Process for the preparation of 6- (p-aminophenyl) -4-methyl-4,5-dihydropyridazinone- (5). 10. Process for the preparation of 6- (p-formylaminophenyl) -4-methyl-4, -dihydropyridazinone- (3) -, 11. Process for the preparation of 6- (p-acetaminophenyl) -4-methyl-4,5-dihydropyridazinone- (3), 12. Preparations containing one or more of those characterized in claim 1 Compounds or their physiologically acceptable acid addition salts as active ingredients.