NL9002188A - PROCESS FOR THE PREPARATION OF PHARMACEUTICAL PREPARATIONS WITH AN Analgesic Effects, Thus Formulated Preparations Obtained, And Process For The Preparation Of New Pyrazole Derivatives To Be Used In These Preparations. - Google Patents

Description

Brief designation: Process for the preparation of pharmaceutical preparations with analgesic effect, thus obtained shaped preparation, as well as a process for the preparation of new pyrazole derivatives to be used in these preparations.

Division of patent application 7713811

The invention relates to the preparation and use of 1-aminoalkyl-3,4-diphenyl-1H-pyrazoles, which are suitable as anti-depressants.

In an article by S.R. Rosenthal, Arch. Internal. Pharmacodynamics, 96, 220-230 (1953), it is reported that 1- (2-aminoethyl) -3,5-diphenyl-1 H -pyrazole has local anesthetic activity. In an article by I.I. Grandberg et al., Zh. Obshch. Khim. 31, 3700-3705 (1961), Chem. Abstr. 57, 9839a (1962) disclose 1- (3-aminopropyl) -3,5-diphenyl-1H-pyrazole, for which compound no use is given. In an article by S.F. Torf et al., Biol. Aktivn. Sudin, Akad. Nauk SSR, 1965. 171-174, Chem. Abstr. 63, 16329d (1965) disclose 1- (2-diethylaminoethyl) -3,5-diphenyl-1H-pyrazole, for which compound no use is given. R.G. Jones et al., J. Qrg. Chem. 19, 1428-1434 (1954) discloses several 1- (2-aminoethyl) -3-phenyl-1H-pyrazoles which have been tested and found to be ineffective as stimulants of gastric secretion and histamine agents. The article by J. Büchi et al., Helv. Chim. Acta 38, 670-679 (1955) mentions 1- (2-dimethylaminoethyl) -3-phenyl-4-methyl-1H-pyrazole, which compound was found to have an analgesic effect.

Two new 1-aminoalkylpyrazole derivatives with a desired analgesic effect have now been found.

The invention relates to a process for the preparation of pharmaceutical preparations with analgesic action, which is characterized in that a compound of the formula (1) of the formula sheet, wherein n = 3 and N = Q represents an amino or diethylamino group, or n = 2 and n = Q represents a diethylamino group or an addition salt thereof with an acid, in a dosage form suitable for therapeutic purposes.

The invention also relates to shaped pharmaceutical preparations thus obtained.

The invention further relates to the preparation of the aforementioned new 1-aminoalkylpyrazole derivatives and their pharmaceutically acceptable salts in a manner known per se for analogous compounds.

According to a preparation method, the compounds of formula (1) can be obtained by reducing a w- [1- (3,4-diphenyl-1H-pyrazolyl)] -alkanamide of formula (2) with an alkali metal aluminum hydride according to reaction scheme A of the formula sheet, wherein n '= -1. This conversion is preferably carried out in an organic solvent which is inert under the reaction conditions, such as dioxane, diethyl ether or tetrahydrofuran and at temperatures of about -10 ° C to the boiling point of the solvent used. The starting materials of the formula (2) can be prepared by reacting 3,4-diphenylpyrazole with a layer of alkyl acrylate in the presence of a strong base, saponification of the resulting ester, conversion of the acid obtained to the corresponding acid chloride and conversion of this acid chloride with methyl or dimethylamine in the presence of an acid acceptor such as pyridine. This method is particularly advantageous for the preparation of compounds in which n = 3.

According to another method of preparing compounds of formula (1), a 1- (cyanoalkyl) -3,4-diphenyl-1H-pyrazole of formula (3) is reduced with hydrogen over Raney nickel as a catalyst in the presence of methylamine or dimethylamine. This method is shown in reaction scheme B, where n '= 2. The reduction is carried out in an organic solvent which is inert under the reaction conditions, such as a low alkanol, at ambient temperature and at a hydrogen pressure of 345-620 kPa. The starting materials of formula (3) can be prepared by reacting 3,4-diphenylpyrazole with acrylonitrile in the presence of a strong base. This method is also particularly advantageous for the preparation of compounds in which n = 3.

According to a third method of preparing the present compounds, 1- [3- (tosyloxy) propyl] -3,4-diphenyl-1H-pyrazole of the formula (4) is reacted with an ammonia or diethylamine. This conversion is shown in reaction scheme C, where Ts represents a tosyl group. The reaction is carried out by mixing a mixture of the compound of the formula (4) and the amine in an organic solvent, which is inert under the reaction conditions, such as acetonitrile or a lower alkanol, at a temperature of 100-150 ° C. heating.

The starting compound of the formula (4) can be prepared by condensation of formyl deoxybenzoin [P.B. Russell et al., J. Am. Chem. Soc. 76, 5714-5718 (1954)] with .alpha.-hydroxypropylhydrazine, followed by reaction of the obtained 1- (3-hydroxypropyl) -3,4-diphenyl-1H-pyrazole with a toluenesulfonyl halide in the presence of pyridine.

According to yet another preparation method for the compounds of formula (1), 3,4-diphenyl-1H-pyrazole is reacted with a strong base, e.g. sodium hydride, in an organic solvent which is inert under the reaction conditions, such as tetrahydrofuran, dioxane or diethyl ether, after which the sodium salt obtained is reacted with an appropriate haloalkylamine in the same solvent system and at its boiling temperature. This method is shown in Reaction Scheme D, where X represents a halogen atom.

As can be seen from the above, one can choose as starting material for the preparation of the present compounds 3,4-diphenylpyrazole and subject it to a Michael addition with a layer of alkyl acrylate or acrylonitrile [method (a)] or to an alkylation with a haloalkyl amine in the presence of an acid acceptor [method (b)] or one can form an 1-hydroxypropyl-3,4-diphenylpyrazole by condensation of formyl-deoxybenzoin with -hydroxyalkylhydrazine [method (c)]. These conversions are summarized in reaction scheme E. From this scheme it appears that all three methods lead to the formation of a mixture of the 3,4-diphenyl and 4,5-diphenyl product. In general, method (a) gives a mixture containing about 85% of the desired 3,4-diphenyl isomer; method (b) gives an isomer mixture with a ratio of about 50:50 and method (c) appears to favor the formation of the 3,4-isomer. In all cases, it is necessary to separate the two isomers at some stage of the total synthesis, regardless of which method is used.

The structure of the 3,4- and 4,5-diphenyl isomers was determined on the basis of the ultraviolet spectrum, the NMR spectrum and the behavior in gas chromatography. Thus, in the ultraviolet spectrum, one of each set of isomers in 95% ethanol exhibits absorption maxima at 223 and 249 ± 2 nm, while the other isomer absorptive maxima at 227 ± 2 and 252 ± 1 nm. The extinction coefficients for the isomer with absorption maxima at 227 and 252 nm are generally higher. Thus, the ultraviolet spectrum can serve to identify an isomer once the structure of a given isomer of the entire series has been established.

This structure determination can take place on the basis of NMR data. From an article by Elguero and Jacquier J. Chim. Phys. 63, 1242 (1966), it appears that in highly polar solvents, such as hexamethylphosphorotriamide, the proton in position 3 of a series of 1,4-disubstituted pyrazoles always falls above the proton in position 5. Applied to the present compounds this leads to the attribution of the 3,4-diphenyl structure to the isomers with UV maxima at 227 and 252 nm and the 4,5-diphenyl structure to the isomers with UV maxima at 223 and 249 nm, since in the NMR spectrum the same absorption below that of the proton in the 5-position for the 3,4-diphenyl isomer is obtained, the absorption above that of the proton in the 3-position being absent. The same absorption above that of the proton in the 3-position is obtained for the 4,5-diphenyl isomer, with the absorption below that of the proton in the 5-position being absent.

In the NMR spectrum, a completely regular and predictable relationship between the two isomers is also obtained for the chemical shifts of the protons of the methylene group bound to the nitrogen atom at the position 1 of the pyrazole ring. The 3,4-diphenyl isomer is always below the 4,5-diphenyl isomer.

Finally, the retention times of the isomers in gas chromatography reflect the above twofold of the spectral data; the 3,4 isomer has a longer retention time in all cases.

Due to the presence of a basic amino group, the compounds of formula (1) can be converted into addition salts with organic and inorganic acids. This conversion can be carried out in a conventional manner, e.g. by mixing the base directly with the acid or, if not suitable, by dissolving the base and / or acid separately in water or an organic solvent and the two solutions with by mixing together or by dissolving the base and the acid together in a solvent. The addition salt is isolated by filtration, if it is insoluble in the reaction medium or by evaporation of the reaction medium, whereby it is obtained as a residue.

All acid addition salts are suitable as sources of the free base form, by reaction with an inorganic base. If one or more properties, such as the solubility, molecular weight, physical appearance or toxicity of the base or addition salt thereof with an acid make this form unsuitable for the intended purpose, the form in question can easily be converted to another, more suitable form . For pharmaceutical purposes, of course, addition salts with relatively non-toxic, pharmaceutically acceptable acids, such as hydrochloric, lactic or tartaric acid, are used.

As mentioned, the present compounds and their addition salts are suitable as analgesics according to conventional pharmacological tests. They can be administered in the same manner as known analgesics, namely parenterally or orally in any conventional pharmaceutical form, such as solutions, suspensions, tablets and capsules.

The methods used to determine the analgesic activity of the present compounds were the following: A primary test for assessing the analgesic activity, determining the ability of a test substance to suppress abdominal contraction caused by acetylcholine in mice which test has been described by Collier et al., Brit. J. Eharmacol. Chemothe rap. 32, 295 (1968); and another primary assay for assessing the analgesic activity, determining the ability to prevent phenyl p-quinone-induced floundering in mice, described by Pearl and Harris, J. Fharmacol. Expt. Therap. 154, 319-323 (1966).

The results listed in the table below were achieved. Where does ED50 mean the value at which the analgesic effect occurs in 50% of the animals examined? the doses are expressed in mg / kg.

1-Substituent Acetylcholine Fenvl p.quinone

Aminoprolyl (Example 1) ED50 = 11 (s.c.)

Diethylaminoethyl (Example 2) 60% / 100 (s.c.) ED5o = 90 (p.o.) 67% / 50 (s.c.) 53% / 10 (s.c.) ED5o = 2 ° (p.o.)

Diethylaminopropyl (Example 3) ED50 = 2.2 (s.c.)

The structure of the compounds of the invention was determined by the preparation methods, the elemental analysis, the ultraviolet spectrum, the infrared spectrum and the nuclear magnetic resonance spectrum. The progress of the reactions and the homogeneity of the products were determined by thin layer chromatography.

In the preparations and examples below, unless otherwise stated, the melting points are not corrected.

Preparation of intermediate compounds Preparation 1

To a solution of 22 g (0.1 mol) of 3,4-diphenylpyrazole in 150 ml of dioxane, 10 ml of Triton B (benzyl trimethyl ammonium hydroxide) were added. The solution was then treated dropwise with 26.3 ml (0.4 mole (acetonitrile, keeping the temperature at 40-45 ° C. The mixture was stirred at ambient temperature for an additional 20 min., Acidified by adding 3 ml of acetic acid and poured into 700 ml of ice / water The mixture was then treated with 200 ml of ethyl acetate and about 1 teaspoon of sodium chloride, shaken and filtered to remove an insoluble precipitate The organic layer was separated from the filtrate and the aqueous layer twice extracted with ethyl acetate The combined organic extracts were washed with saturated sodium hydrogen carbonate solution and then with brine, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to give a red oil which was crystallized from 60 ml of methanol to give 13 82 g material, mp 90-103 ° C. This material showed the presence in gas chromatographic analysis Two isomers in a ratio of 13/87, 13% of the 4,5-diphenyl isomer and 87% of the 3,4-diphenyl isomer of 1- (2-cyanoethyl) diphenyl-1H-pyrazole.

In another run, a thin suspension of 7.7 g (0.14 mole) of potassium hydroxide and 805 g (3.65 mole) of 3,4-diphenylpyrazole in 3.4 L of ethanol was stirred rapidly and simultaneously treated with 292 ml (4 .4 mol) acrylonitrile; the acrylonitrile was added dropwise over 2 h. After completion of this addition, stirring was continued for an additional 2 hours while cooling in an external ice bath. The mixture was then allowed to stand at ambient temperature for 2 d. After this, the mixture was again cooled to 0 ° C and the solid product collected and dried, yielding 723 g of material, mp 103-108 ° C. This material was recrystallized from ethanol to give 681 g of material having a melting point of 108-111 ° C (softening point 106 ° C), which material was 92-93% of the 3,4-diphenyl isomer by 6-phase chromatography. -7% of the 4,5-diphenyl isomer of 1- (2-cyanoethyl) diphenyl-1H-pyrazole.

Preparation 2

A solution of 105 g (0.47 mol) of forrcyldesoxybenzoin and a molar equivalent amount of 2-hydroxyethylhydrazine in 450 ml of absolute ethanol was refluxed for 2.5-3 h and then cooled; the precipitated solid was collected by filtration. The filtrate was evaporated to dryness to obtain a brown oil which was dissolved in chloroform, washed with water and then evaporated to dryness to obtain 53 g of off-white material, m.p. 99-105 ° C. The latter material was crystallized from a solution of about 40 ml of didiloreethane and 100 ml of pentane to obtain 46.5 g of 1- (2-hydroxyethyl) -3,4-diphenyl-1H-pyrazole, mp 102-103 ° C which material was found to be about 97-98% pure 3,4-diphenyl isomer according to gas chromatographic analysis.

A solution of 32.6 g (0.12 mol) of the latter compound in 130 ml of pyridine was mixed with a solution of 24.5 g (0.13 mol) of p-toluenesulfonyl chloride in 75 ml of pyridine; the resulting solution was kept in a refrigerator for about 18 hours. The solid which had separated was collected by filtration and the filtrate was poured into about five times the volume of ice / water. The mixture was allowed to stand at about 0 ° C for 2 h; then the liquid was decanted from the gummy solid slurried with ether to leave a solid slurried with cold methanol to give 15 g of 1- [2- (4-toluenesulfonyloxy) ethyl] -3,4-diphenyl -1H-pyrazole, mp 109-110 ° C, in the form of a white solid.

Example I

To a slurry of 13.8 g (0.05 mol) of 1- (2-cyanoethyl) -3,4-diphenyl-1H-pyrazole (Preparation 1) in a solution of 100 ml of anhydrous ammonia containing methanol, a small amount was added Raney nickel added as a catalyst; the mixture was reduced in a Parr shaker at a hydrogen pressure of about 3.5 kg / cm2. After 3 days, the mixture was filtered and the filtrate evaporated to dryness, leaving a residue which was dissolved in 40 ml of isopropanol and 30 ml of isopropyl acetate. The solution was treated with 20 ml of 5.7N hydrochloric acid in ethanol; the separated solid was collected, rinsed with a further amount of solvent and dried, yielding 15.2 g of 1- (3-aminopropyl) -3,4-diphenyl-1H-pyrazole dihydrochloride, mp 177-188 ° C, which material contained 94% pure isomer according to gas chromatography.

Example II

A mixture of 29.5 g (0.073 mol) of 1- [2- (4-toluenesulfonyloxy) -ethyl] -3,4-diphenyl-1H-pyrazole and 103 ml of dimethylamine in 400 ml of acetonitrile was left in a autoclave heated to 120-130eC. The reaction mixture was washed with autoclave with acetoniril and evaporated to dryness under reduced pressure. The residue was suspended in 800 ml of ethyl acetate and the suspension washed with water containing a small amount of sodium hydroxide. Then the organic layer was washed with brine, dried and evaporated to dryness to obtain 28 g of brown oil which was distilled under reduced pressure. The fraction (15.3 g) collected at 81-100 ° C / 0.01 mmHg was dissolved in diethyl ether and treated with a solution of hydrogen chloride in methanol. The separated solid was recrystallized from acetone to obtain 10.5 g of 1- [2- (N, N-diethylamino) ethyl] -3,4-diphenyl-1H-pyrazole hydrochloride, mp 147-148-fC.

Example III

A mixture of 4.2 g (0.1 mole) of sodium hydride in 100 ml of tetrahydrofuran and 22.0 g (0.1 mole) of 3,4-diphenylpyrazole in 150 ml of tetrahydrofuran was heated with stirring until a clear solution was obtained. The mixture was then treated with 14.9 g of N- (3-chloropropyl) -N, N-diethylamine. The solution was refluxed for 30 h, then filtered and evaporated to dryness under reduced pressure. The residue was taken up in ethyl acetate and taken up in dilute hydrochloric acid by extraction; the acidic solution was washed once with ethyl acetate and neutralized with potassium carbonate. The aqueous mixture was then extracted with ethyl acetate; the organic extracts were washed twice with brine, dried and evaporated to dryness, yielding 20.4 g of yellow oil. The latter material was dissolved in diethyl ether and treated with a molar equivalent amount of methanolic hydrogen chloride; the solid, which separated after cooling, was collected and dried, yielding 20.2 g of crude hydrochloride. The latter material was converted into the free base, which was dissolved in chloroform; the chloroform solution was washed four times with 125 ml portions of water. Then the organic layer was dried and evaporated to dryness; the residue was redissolved in diethyl ether and treated again with excess methanolic hydrogen chloride. There was thus obtained 16.5 g of a mixture of 1- [3- (Ν, Ν-diethylamino) propyl] -3,4-diphenyl-1H-pyrazole hydrochloride and the corresponding isomeric 4,5-diphenyl compound in a ratio of 1: 1; the melting point was 143-146 ° C.

800 mg of the latter material were dissolved in methanol. The solution was applied to 4 silica gel containing 20 by 40 cm thin layer chromatography plates. The plates were eluted with a solution of 95% ethanol / concentrated ammonium hydroxide (19: 1); the top third of the plate, containing material with the highest Rf value, was cut from the plate and the middle third and the bottom third of the plate were extracted separately with chloroform / meuol (1: 1). The highest Rf fraction was, by gas chromatography, 97-99% pure 4,5-diphenyl isomer, and the lowest Rf fraction was found to be a mixture of the 3,4 isomer and the 4.5 isomer in to be a ratio of 82/18. The fraction with the largest Rf value, originally obtained as an oil, was crystallized from acetone / hexane to obtain 75 mg of 1- [3- (N, N-diethylamino) propyl] -4,5-diphenyl-1H pyrazole hydrochloride, m.p. 148-149 ° C, according to gas chromatography, 99.8% pure 4.5 isamer.

The fraction with the lowest Rf value, after repeated recrystallization from acetone / hexane, gave 103 mg of 1- [3- (NN-diethylamino) propyl] -3,4-diphenyl-1H-pyrazole hydrochloride, melting point 165- 166 ° C, according to gas chromatography, 98% pure 3,4 isomer. (It is noted that the hydrochloride salts of both isomers persisted during the chromatography and separation, despite the use of concentrated ammonium hydroxide in the elution).

Claims (3)

A process for the preparation of pharmaceutical preparations with analgesic effect, characterized in that a compound of the formula (1) of the formula sheet, wherein n = 3 and N = Q represents an amino or diethylamino group or n = 2 and N = Q represents a diethylamino group, or brings an addition salt thereof with an acid, into a dosage form suitable for therapeutic purpose. A molded pharmaceutical preparation obtained by the method of claim 1. Process for the preparation of medicinal compounds for use in the process according to claim 1, characterized in that a compound of the formula (1), wherein n = 3 and N = Q represents an amino or diethylamino group or n = 2 and N = Q represents a diethylamino group, or prepares a pharmaceutically acceptable addition salt thereof with an acid, in a manner known per se for analogous compounds.