CS216206B2 - Method of making the derivatives of the diphenylpyrazole - Google Patents

Abstract

New pyrazole derivs. are of formula (I) (where n = 1-4; R1-4 are H, halogen, alkyl, alkoxy, CF3, NO2 or NH2; and X is CN, aminocarbonyl, lower alkoxy, carbonyl or carboxyl). (I) and their salts have low toxicity and do not cause stomach disorders. Typical cpds. include (I; n = 1, X is CN; R1-4 are H). They may be prepd. from (I; X is halogen) by reaction with an alkali metal cyanide, opt. followed by hydrolysis or redn. In an example, 2.81g (I; X is Br; n = 1; R1-4 are H) was treated with 1.17g KCN and 300 mg 18-dibenzo-6-crown (catalyst) in acetonitrile at 40 degrees C to give (I: X is CN; n = 1; R1-4 are H).

Description

Y denotes fluorine, chlorine and bromine atoms, and reacts in the presence of a deprotonating agent with a dialkyl malonic acid ester or with malonic acid ester ester obtained from the reaction. The product is saponified and decarboxylated and optionally present. the nitro groups reduce, the resulting carboxylic acids are converted into their salts, or are esterified with an alcohol having 1 to 6 carbon atoms.

The process according to the invention is carried out in a manner known per se by reacting a malonic acid esteruitry (such as methyl ethyl methitrile; malonic acid or a malonic acid ethyl ester nitrile) or a dialkyl malonic acid (such as dimethylethyl malonate or Maleate zieehyleesteir) in an inert solvent with deprotonation. and then a pyrazole derivative of the formula II (preferably chloride, bromide or iodide).

Suitable inert solvents for this reaction are, for example, hydrocarbons (such as benzene, xylene or toluene) or ethers (such as dioxane, tetrahydrofuran or glycol dimethyl ether). Alkali metal alcoholates (such as sodium methylate or target, potassium buiylate), alkali metal hydrides (such as sodium hydride or potassium hydride), alkali metal amides (such as sodium amide or potassium amide) are used as deprotonating agents for this reaction. Or thalliumalkyl compounds (such as thallium methylate).

Upon completion of the reaction, the esters formed are saponified in a known manner (for example by reaction with bases such as sodium hydroxide, sodium carbonate, sodium hydroxide ^, potassium, potassium carbonate or potassium hydrogen sulphite in the presence of water) and heating · decarboxylates. The decarboxylation may be carried out without solvents or in the presence of a high boiling solvent (such as xylene, chlorobenzene or decalin);

Any subsequent hydrolysis of the cyano compounds of the formula (I) is also carried out under conditions known to those skilled in the art. So, for example, nitrite. They can partially hydrolyze to the corresponding amides with strong mineral acids (such as hydrochloric acid or sulfuric acid) or they can be completely hydrolyzed to the corresponding carboxylic acids under sharpened conditions.

Any subsequent conversion of the carboxylic acids into the corresponding amides or nitriles is also carried out by known working methods.

For example, acid chlorides, mixed anhydrides or esters corresponding to carboxylic acids can be converted into the corresponding amides under known conditions by treatment with ammonia.

The possible subsequent conversion into nitriles is carried out, for example, by treating the corresponding aninocarbonyl compounds under known conditions with water means, such as dicyclohexyl carbodiimide, carbonyidiimidazole, polyphosphoric acid, thionylchioridene or phosphorous oxychloride. .

The possible esterification of the free acids is also carried out by methods known per se. ·. Thus, for example, the acids can be reacted with diazomethyl or diazo-ethane to give the corresponding methyl or ethyl esters. A generally applicable method is the reaction of acids with alcohols in the presence of carbonyidimidazole or dicyclohexylcarbodiimide.

Further, for example possible to let the acid reacted with 11 • ^! ^ ^Βη: ίύι in the presence of carbon or cuprous oxide stříbrnéiho.

Another method is to convert the free acids into the dine: thylpha-α-manidalkylacetals in the corresponding alkyl esters of acids. In addition, the acids can be reacted with alcohols or esters of low aicancarboxylic acids and alcohols in the presence of strongly acidic catalysts such as hydrogen chloride, sulfuric acid, perchloric acid, trifluoromethylsulfonyl acid or p-toluenesulfonic acid.

However, it is also possible to convert carboxylic acids into chlorides. acids or mixed acid anhydrides and these are reacted with alcohols in the presence of basic catalysts such as pyridine, collidine, lutidine or 4-diaminocylamino-pyridine.

Salts of carboxylic acids are formed, for example, by the saponification of esters with basic catalysts or by neutralizing acids with physiologically acceptable bases.

The following pyrazole derivatives of the general formula (I) can be prepared by the process according to the invention:

(1,4-diphenyl-3-pyrazolyl) -acetic acid, 3- (1,4-diphenyl-3-pyrazidyl) -propionic acid, 4- (1,4-diphenyl-3-pyrazolyl) butyric acid, 5- (1,4-diphenyl-3-pyrazolyl) -valeric acid and their amides, nitriles, sodium salts, methyl esters, ethyl esters, propyl esters and butyl esters.

The novel 1,4-diphenylpyrazole derivatives of formula (I) are fan-pharmacologically active substances which are characterized in particular by having significant anti-inflammatory activity, good tolerance to the stomach and only relatively low toxicity . In addition, these compounds are characterized by a rapid onset of action, a high intensity of action, and a long duration of 1622 hours. effect, have a favorable. resorbability-t.a. in galenic formulations ... reia- tively. good stability. ''

The pyrazole derivatives of general formula (I) are:. . in the body metabolize other way than known anti-inflammatory substances ..... ...................

Novel compounds in combination with conventional carriers. v. gaienic pharmacy are suitable for c ...

(a) locally:

contact dermatides, eczema of different species, neurodermitis,. erythrodermia, 1st degree burns, PrurituS vulvae et ani, Rosacea, Erythematodes curaneus ,. ... Psoriasi ^ ,. Lichen 'rúber planus et verrucošus; '

(b) orally:

acute and chronic polyarthritis, neurodermitis, bronchial asthma, hay fever and others.

The preparation of the medicaments is carried out in the usual manner by converting the active ingredient, with suitable additives, carriers and flavoring agents, into the desired dosage forms, such as tablets, dragees, capsules, solutions, ointments, mahogany agents, etc.

Especially suitable for oral use are tablets, dragees and capsules which contain, for example, 1 to -2'510-mg of active ingredient and 50 mg to 2 g of pharmacologically inactive. carriers such as lactose, amytose, talc, gelatin, magnesium stearate and the like, as well as conventional additives. Powders, ointments, aerosols and the like, which preferably contain 0.01 to 2% by weight of the active ingredient, are suitable for topical use.

The efficacy of the compounds according to the invention results from the following experimental results and from the attached table.

First Cairrageninový odor edema test (cf., Proc. Soc. Exptl. Biol. Med. 111, 1962, 544) ^V

Acar-exudative inflammation was induced in the rat paw by injection of Caaragenine. This inflammation is suppressible by anti-inflammatory agents. Edema. is measured voiumetrically.

Male Wistar rats (SPF) are used. in the range of 120 to 140 g. 16 hours before oral administration of the substances. the animals are excluded from feeding, they receive water ad libat.

Carragenine is the edema-inducing agent. 10 mg / ml Carragemn is taken in 0.9% sodium chloride solution, 0.1 ml is injected. into a rat paw.

Individual. a dose of test substance is administered to the test animal an hour before edema induction in 0.5 ml binder for 100 g body weight. It serves as a binder physiological. table salt solution; for water-insoluble substances, a microsuspension is made up of physiological saline solution. with Myr. 53 (85 mg / 100 ml).

Experimental Handle:

5 animals are taken for each dosing group. After plethysmographic volumetric measurement of the right hind paw, the substance was taken. administered orally; After one hour, inflammation was induced by intraplantic injection of 0.1. ml of edema-inducing substance. After another 3 hours. se. measured again. and the suppression of inflammation is calculated. '...,

Evaluation:

% Wrap = 1 () 0-- ^Y100 . ...........

Y = mean difference in volume of the levers in the treatment group

Z = mean difference in volume of levers in the control group

2 ·. Adjuvant arthritis test (cf. Brit. J. Pharmacol., 21, 1963, 12.7)

After Freund's injection. adjuvant (M. butyricum). rats develop in about. two weeks of polyarthritis, which can be suppressed by anti-inflammatory agents.

Male and female Lewis rats (LEW) weighing 110-190 g are used. The animals receive drinking water and compressed feed Altromin'ad libitum.

10 rats are used for each dosing group. As edema-inducing agent, it is used. Mycobacterium butyricum of Difko, Detroit. A suspension of mg5 mg M. butyricum is injected into the right hind paw. in 0.1 ml of thinly liquid paraffin (DAB 7).

The test substances were administered orally daily for 4 days from day 11. The substances are applied as a clear aqueous solution or suspension. crystals' for. of Myrj 53. (85 mg '%) in isotonic sodium chloride solution.

Experimental Handle:

The rats are divided into groups of groups as evenly as possible with respect to body weight. After a plethysmographic 'measurement' of the volume of the right and left hind paws is. the right hind paw will give a subplantar injection of 0.1 mil adjuvant. . The right hind paws were measured on day 14 of the test day to the end. attempt.

Also, the measurement of the non-irritated left hind paws is taken from the 14th experimental ¹ day. The duration of the experiment is 3 weeks.

% suppression = 1GO— y. 100 · z

Evaluation:

218206 y == mean volume difference of the levers. treatment group z = mean difference in volume of the control group levers

3. Gastric wall damage test (cf. Arch. Int. Pharmacodys. '192, 1971, 370' ff.)

A common complication in therapy with non-steroidal inflammatory suppressants is the development of gastric ulcers. This side effect can be demonstrated by animal experiments.

Male Wi-star (SPF) rats were used. The animals are within the weight range. 13O + 10O. g. 10 hours prior to the start of the experiment, the animals are removed from feeding; receive water ad libitum.

5 animals are used per dose. The substances are applied once orally dissolved in sodium chloride or as a crystal suspension with the addition of 85 mg% Myrj 53.

3 hours after administration of the substances, 1 ml of a 3% diphenyl blue dye solution is injected intravenously and the animal is killed. The stomach is resected and the number and size of forests in the epithelium and ulcer exiting the dye enrichment are examined microscopically.

Evaluation of experiments:

The table below shows that the substances 1 and 2 according to the invention are stronger than the previously known structurally analogous compounds 3, 4 and 5, since they have a stronger anti-inflammatory effect and / or induce smaller gastric ulcers.

Substance Carragenrn test Ad-juvant airthritis test Stone damage test for stone edema and gastric wall

Dose in% Suppression- Dose in% Suppression-% Suppression- Dose in No. Area mg / kg Reading mg / kg Reading Reading mg / kg in animal animal right paw left animal paw mm

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-Obecného starting compound of the formula II can be ^one prepared from the corresponding carboxylic acid by ,, that this acid is reduced, for example lithiumaluminiumihydr-ideas in the corresponding carbinol · as TTO example as described in the synthesis of '3-'lbnom ^ i ^^ ethyl-l 1,4-diphenylpyrazole:

(a) To 5,67 g of α-moofolinostyrene in 35 ml of dry, ethanol-free ethanol, at room temperature, 3 g of triethylamine and a solution of 6,78 g of ethyl (2-chloro-2-phenylhydrazoicioacetic acid) in 20 ml The reaction mixture was stirred at 40 ° C for 1 hour and at room temperature for 16 hours, washed with dilute hydrochloric acid, dilute, sodium carbonate solution and water, dried and concentrated in vacuo, digested with hexane, recrystallized from hexane. of ethanol-hexane to give 4-morpholino-3-phenyl-2-phenyl-hydro-3-butenoic acid ethyl ester, m.p. 130-131 ° C.

b). To 33 g of 4-morpholino-S-phenyl-4-phenyl-hydrazono-S-butenoic acid ethyl ester was added 330 mL of dloxane and 100 mL of 2 N hydrochloric acid and heated at reflux for 46 min. The reaction mixture is concentrated in vacuo, the residue is dissolved in chloroform, the chloroform solution is washed, dried and concentrated in vacuo. The residue is recrystallized. from ethanol-hexane to give 21.15 g of 1,4-ethyl-3-carboxylic acid ethyl ester of melting point 103-104 ° C.

c) To 4.63 g of lithium aluminum hydride in 100 ml of absolute tetrahydrofuran under nitrogen at 0 ° C was added dropwise a solution of 17.2 g of ethyl N-diphenylpyrazole-3-carboxylic acid ethyl ester in 80 ml of absolute tetrahydrofuran . The reaction mixture was stirred for a further 30 minutes, 40 ml of saturated aqueous sodium chloride solution were added thereto, acidified with dilute hydrochloric acid and extracted with ether. The organic phase is concentrated, digested with hexane to give 14.65 g of 3-hydroxy-1,4-diphenyl-pyrazole as a crude product, m.p. 104-106 ° C.

d) To 13i, 2i -surového- g of 3-hydroxymethyl-l-ethyl ^í "4difenγlpγrazolu added 6'3i -130 ml ° / o hydrobromic acid and 4 hours -zahřívá at 90 ° C. Thereafter, the reaction mixture is concentrated in vacuo, excess hydrogen bromide is removed several times by removing the residue in toluene and concentrating in vacuo. The residue was recrystallized from isopropanol to give 10.8 g of 3-bromomethyl-1,4-diphenyl-pyrazole, m.p. 99 ° C.

Example

(a) To a solution of 5,6 g of thallium eithylate in 120 ml of -absolute benzene shall be added successively 3.04 g of di-acid ester of mialonic acid and

4.7 g of 3-bromomethyl-1,4-diphenyl-pyrazole are added and the mixture is stirred at room temperature for 16 hours. The reaction mixture was then diluted with diethyl ether and 100 mL of ice water was added. The organic phase is separated, washed, dried and concentrated in vacuo. To give 5.3 g · ru -diathγl'este 2- (1,4-diphenyl-S-pyrazolylmethyl] malonate as crude _product.; '

b) 6.9 g of the thus obtained crude diethyl 2- (1,4-diphenyl-3-pyrazolylmethyl) malonate were dissolved in 30 ml of water with

2.7 g of sodium hydroxide, 30 ml of dioxane are added and the mixture is refluxed for 3 hours.

The reaction mixture is then concentrated in vacuo as much as possible, the residue is diluted with 100 ml of water, extracted with diethyl ether, the aqueous phase is acidified with concentrated hydrochloric acid up to ρ Ή 1 and the separated oily product is collected.

The crude product thus obtained is dissolved in diethylleither, washed with water, dried and concentrated in vacuo. Thus 4.25 g of 2- (14'-diphenyl-3'-pyrazazolylmethyl) -malonic acid are obtained, m.p. 172 DEG. ;

c) 4.1 g of 2- (1,4-diphenyl-3H-pyrazolylmethyl) -malonate were slowly warmed to 200 ° C. The reaction temperature was maintained at -200 ° C for a further 20 minutes, - allowed to cool, the product obtained was allowed to cool. Crystallization from toluene gave 2.9 g of 3- (1,4-diphenyl-3-pyrazolyl) -propioic acid, m.p. 128-129 ° C.

(d) 2010 mg of 3- (1,4-diphenyl-3-pyrazolyl) -propionic acid is dissolved in 10 ml of absolute ethanol, and 7.0 ml of 0.1 N aqueous sodium hydroxide solution are added to the solution. the vacuum is concentrated.

The residue is once more - is removed -do · 10 ml of absolute ethanol and concentrated again -with ^one in vacuo. The crude product obtained is dissolved in a small amount of absolute ethanol, dieithyl ether is added to the solution, and sodium amorphous 3- (1,4-diphenyl-3,4-pyrazolyl) -propionate is obtained.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of 1,4-diphenylpyrazole derivatives of the general formula (I) of non-toxic salts, characterized in that the pyrazole derivative of the general formula (II): R 1, R 2, R 5 and R 1 are substituents in the ortho, meta or para position and denote hydrogen, fluorine, chlorine and bromine, methyl, inethoxy, trifluoromethyl, nitro or amino, X is cyano, aminocarbonyl, C 1 -C 6 alkoxycarbonyl, carboxyl, n is 1, 2, 3 or 4, or their phy in which: R 1, R 2, R 3, R 1 and n are as previously defined and a Y · denotes an atom. Reacting fluorine, chlorine and bromine in the presence of a deprotoinising agent with dialkyl malonic acid or with malonic eisterinitrile, the reaction product obtained is saponified and decanboxylated and, where appropriate, the nitro groups present are reduced, the resulting carboxylic acids are converted into their salts, or are esterified with an alcohol having 1 to 6 carbon atoms.