DE19521822A1 - New 4-substd. 3-amino-pyrazole derivs. have anticonvulsant and anti-epileptic activity - Google Patents

Abstract

3-Amino-4-(phenyl or benzyl)-pyrazoles of formula (I) and their acid addn. salts are new, with the exception of 3-amino-4-(2-methyl- or 2-chloro-phenyl)-pyrazole. n = 0 or 1 ; R = H or Me; X = Me, CF3, F or Cl; Y = H, F or Cl.

Description

The invention relates to new, pharmaceutically applicable, in particular anticonvulsant 3-aminopyrazoles, which are in the 4-position an orthosubstituted Ar (alk) yl radical contain and process for their preparation and use.

3-Aminopyrazoles with an ortho-substituted benzyl radical in the 4-position were bis not described here. The preparation of a diaminopyrazole, the 3,5-diamino-4- benzylpyrazole, has recently been reported (Synth. Commun. 23 (1993), 7, 925-930).

The synthesis of the intermediates in the process according to the invention set α-benzyl-β-amino-crotonic acid nitriles from β-amino-crotonic acid nitrile and the corresponding benzyl halides using phase transfer catalysis was just if not described.

Merely the benzylation of β-amino-crotonitrile with benzyl chloride in Ge The presence of sodium in the presence of α-benzyl-β-crotonic acid nitrile has so far become known (J. Prakt. Ch. [2] 90 (1914) 189 ff.).

Of the 3-aminopyrazoles with an ortho-substituted phenyl ring in the 4-position only 3-amino-4- (2-chlorophenyl) pyrazole and 3-amino-4- (2-me thylphenyl) -pyrazole and examined for their muscle relaxant effect (J. Med. Chem. 7 (1964), 259).

Analogous compounds with a para or meta substituted phenyl ring in 4- Position as intermediates for pyrazolo [1,5-a] pyrimidines (J. Med. Chem. 1976, 19 (2), 291) or triazole compounds (J. Heterocyclic Chem., 14, (1977), 65).

The representation of the 3-amino-4-phenyl-pyrazoles is based on the corresponding Ben cyclic cyanides. From these are in the presence of sodium methylate with Amei Sen or ethyl acetate 2-formyl or 2-acetyl-benzyl-cyanide obtained with Hy Drazinhydrat be cyclized in acetic acid to the 3-amino-4-phenyl-pyrazoles.

An anticonvulsant effect is not mentioned for any of these compounds or na set.

The compounds according to the invention are pharmacologically active. In particular, the compounds of the invention have a strong one anticonvulsant effect on.

The invention is therefore based on the object, connections with cheap phar to provide macological properties, for example, as an medicinal products with a deep epileptic effect can be used, as well as corresponding ones To specify manufacturing processes for this.

The following explanations are examples of important information:
The radical R occurring in formula 1 can be hydrogen or methyl. The number of CH₂ groups is either 1 (3-amino-4-benzylpyrazole) or 0 (3-amino-4-phenylpyrazole).

The radical X can be methyl, trifluoromethyl, fluorine or chlorine, while Y Can mean hydrogen, fluorine or chlorine.

Accordingly, the 3-aminopyrazoles according to the invention can, for example, fol containing substituents in the 4-position: o-methylphenyl- or -benzyl-, o- Trifluoromethylphenyl or benzyl, o-chlorophenyl or benzyl, o-fluorophenyl or -benzyl-, 2,6-dichlorophenyl- or -benzyl-, 2,6-difluorophenyl- or -benzyl- or 2-chloro-6-fluorophenyl or benzyl.

Depending on the process conditions and starting materials, the end products are obtained of formula 1 in free form or in the form of its salts.

The process for the preparation of the compounds of formula 1 is in a Lö carried out at temperatures between 80 and 120 ° C. As a solution aromatic hydrocarbons are preferred, for example benzene or Toluene in question. However, the reaction can also take place in an organic acid as a solvent, for example formic or acetic acid. When working in aromatic hydrocarbons, it is necessary to use the reak tion mixture an organic acid, for example formic or acetic acid to add. In these cases the reaction is carried out with water separation leads.

The process for the preparation of the starting materials of formula 2 goes either from β-amino-crotonitrile or appropriately substituted benzyl cyanides.  

The β-aminocrotonitrile is at temperatures between 20 and 50 ° C, before preferably at 35 ° C, in a suitable solvent mixture in the presence of a Catalyst with an appropriately substituted benzyl halide under phase Alkylated transfer conditions. For example, 50 % sodium hydroxide solution and an aromatic hydrocarbon such as benzene or toluene to serve. The catalyst is, for example, TEBA (triethylbenzylammonium chloride) well suited.

The substituted benzyl cyanides are preferably at room temperature a carboxylic acid ester, for example ethyl acetate or formic acid reethylester in a suitable solvent in the presence of a condensate implemented by means. Aliphatic alcohols, for example serve ethanol or methanol or aliphatic ethers such as diethyl ether. As a con Sealants are alcoholates, for example sodium methylate or sodium amide suitable.

The compounds according to the invention are for the preparation of pharmaceutical additives suitable compositions. The pharmaceutical compositions drugs can one or more of the Ver bindings included. For the preparation of the pharmaceutical preparations the usual pharmaceutical carriers and auxiliaries are used. The Arz drugs can be parenteral (e.g. intravenous, intramuscular subcutaneous) or can be used orally.

The following examples serve to illustrate the invention.

Examples General regulations for the preparation of the compounds of formula 1 according to Ta belle 1, examples 1-13 option A

0.086 mol of 100% hydrazine hydrate, 8.2 ml, are added in succession to 90 ml of toluene Glacial acetic acid and 0.0645 mol of compound of formula 2 and heated for 4.5 hours Water separator. After cooling, the solution with 12 ml and then twice shaken with 5.5 ml of 1: 1 dilute hydrochloric acid.

The combined aqueous extracts are heated under reflux and alkali for 3 hours then siert up to pH 11 with sodium hydroxide solution. The precipitate is suctioned off.  

Variant B

0.03 mol of compound of formula 2 are added dropwise in 4.2 ml of glacial acetic acid Hydrazine hydrate 100% added and heated under reflux for 2 hours. After that there the solution in 100 ml of water is made with conc. Hydrochloric acid pH 2-3 and heated another 30 minutes under reflux. After cooling with conc. Ammonia pH 9 set and the oily separation in ethyl acetate. To Drying the ethyl acetate, the solvent is distilled off and the residue mixed with ether. The gradually crystallizing product is suctioned off.

Table 1

General regulations for the preparation of the compounds of formula 2 according to Table 2, Examples 14-29 option A

At 3 g (0.055 mol) of sodium methylate in 100 ml of dry ether at room temperature a mixture of 0.043 mol substituted benzyl cyanide and 4.74 g (0.064 Mol) dropped formic acid ethyl ester. The mixture is stirred for 6 hours at room temperature and lets stand overnight. Then it is mixed with 100 ml of ethyl acetate and the Suction filtered. The solid is dissolved in 80 ml of water and at 0 ° C with 5.2 ml of glacial acetic acid. The solution is shaken twice with ethyl acetate.  

After drying over sodium sulfate, the solvent is stripped off and obtained yellowish oil that solidifies after a while.

Variant B

3.93 g (0.171 mol) of sodium are dissolved in 48 ml of abs. Ethanol, heated to boiling and For this purpose, a mixture of 0.134 mol of substituted benzyl cyanide drips in 30 minutes and 14.65 g (0.198 mol) of ethyl formate. After dropping has ended is heated under reflux for 4 hours, then cooled and with 55 ml of Essi yesterday moved. The precipitate is filtered off, dissolved in 240 ml of water and acidified the solution at 0 ° C with 160 ml of glacial acetic acid. It is stirred for 1 hour and then aspirated.

Variant C

A mixture of 5.69 g (0.083 mol) of sodium methylate and 100 ml of ether is added dropwise slowly at room temperature a solution of 0.066 mol substituted benzylcya nid in 9.6 ml (0.098 mol) of ethyl acetate. It is stirred for 7.5 hours and then over Let stand at night, the approach solidifies into a thick paste. You suck the precipitate, dissolve it in 120 ml of water and add 8 ml of ice at 0 ° C vinegar. The oil that separates is taken up in ethyl acetate. To Drying over sodium sulfate, the solvent is removed. As a backlog obtained a pale yellowish oil.

Variant D

0.15 g is added to 50% sodium hydroxide solution (from 7.5 g caustic soda and 7.5 ml water) TEBA, 50 ml of benzene and 4.05 g (0.05 mol) of β-aminocrotonitrile. To do this 9.3 g (0.05 mol) of substituted benzyl halide in 45 with good stirring at 35 ° C. Minutes dripped. The mixture is stirred at 35 ° C for 2 hours and at 40 ° C for 30 minutes. Then the batch is mixed with 100 ml of water and the solid is suctioned off Cooling off.

Variant E

To 50% sodium hydroxide solution (made from 30 g caustic soda and 30 ml water) 0.5 g of TEBA, 50 ml of benzene and 16.4 g (0.2 mol) of β-aminocrotonitrile. To is at 35 ° C with vigorous stirring a solution of 0.2 mol of substituted Ben drop of cyl halide in 50 ml of benzene within 1 hour. It will be at 2 hours Stirred at 35 ° C and 30 minutes at 40 ° C. Then add the approach 100 ml of water and cools down. The organic phase is separated off with water  washed and dried over sodium sulfate. The after distilling off the The oily residue obtained from benzene is reacted without further purification.

Variant F

To 50% sodium hydroxide solution (made from 30 g caustic soda and 30 ml water) 0.5 g of TEBA, 50 ml of benzene and 16.4 g (0.2 mol) of β-aminocrotonitrile. To is at 35 ° C with vigorous stirring a solution of 0.2 mol of substituted Ben drop of cyl halide in 50 ml of benzene within 1 hour. It will be at 2 hours Stirred at 35 ° C and 30 minutes at 40 ° C. Then add the approach 100 ml of water and cools down. The organic phase is separated off with water washed and dried over sodium sulfate. The after distilling off the Benzene obtained oily residue is treated with 40 ml at room temperature for 1 hour conc. Stirred hydrochloric acid. Then 100 ml of water are added and the oil is taken in Ethyl acetate and distilled the solvent after drying over sodium sulfate.

Table 2

The compounds according to the invention were applied in vivo after i.p. application Mice according to the international standard (Pharmac. Weekblad, Sc. Ed. 14,  132 (1992) and Antiepileptic Drugs, Third. Ed., Raven Press, New York 1989) on their anticonvulsant effect tested (Tab. 3).

Analogous results were obtained for the oral effect. For example, for the compound 2 (3-amino-4- (2-fluorophenyl) pyrazole) in the mouse for the ma ximal electric shock the ED₅₀ (p.o.) at 42.8 mg / kg, in subacute pentrazole Cramp (PTZ) at 51.5 mg / kg and for neurotoxicity the NT₅₀ (p.o.) at 210 mg / kg certainly.

Table 3

Claims (4)

1. 3-aminopyrazoles of the general formula 1 where R is hydrogen or methyl and X is methyl, trifluoromethyl, fluorine or chlorine and Y is hydrogen, fluorine or chlorine and their physiologically tolerable acid addition salts, with the exception of 3-amino-4- (2-methylphenyl) pyrazole and 3-amino-4- ( 2-chlorophenyl) pyrazole. 2. Process for the preparation of 3-aminopyrazoles of the general formula 1 where R is hydrogen or methyl and X is methyl, trifluoromethyl, fluorine or chlorine and Y is hydrogen, fluorine or chlorine and their physiologically tolerable acid addition salts, with the exception of 3-amino-4- (2-methylphenyl) pyrazole and 3-amino-4- ( 2-chlorophenyl) pyrazole, characterized in that a compound of general formula 2 reacted with hydrazine, where R, X and Y have the meaning given and Z is oxygen or the NH group. 3. Medicaments with an anti-epileptic effect which contain at least one compound of the general formula 1 as active ingredient where R is hydrogen or methyl and X is methyl, trifluoromethyl, fluorine or chlorine and Y is hydrogen, fluorine or chlorine and their physiologically tolerable acid addition salts, with the exception of 3-amino-4- (2-methylphenyl) pyrazole and 3-amino-4- ( 2-chlorophenyl) pyrazole. 4. Use of 3-aminopyrazoles according to formula 1 for the preparation of Medicines with an anti-epileptic effect.