NO147108B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITY 1-AMINO-LAVERE-ALKYL-3,4-DIPHENYL-1H-PYRAZOLES - Google Patents

Description

The present invention relates to the production of 1-amino-lower-alkyl-3,4-diphenyl-1H-pyrazoles which can be used as agents against depression and as pain relievers.

Rosenthal, Arch.Intern.Pharmacodynamie, 96, 220-230

(1953) describe that 1-(2-aminoethyl)-3,5-diphenyl-1H-pyrazole has local analgesic activity: Grandberg et al., Zh.Obsch.

Kim. 31, 3700-3705 (1961), CA.57, 9839 (1957) describe that 1-(3-aminopropyl)-3,5-diphenyl-1H-pyrazole has no utility, while Torf et al., Biol. Active. Soedin, Acad. Nauk SSR,

1965, 171-174, CA. 63, 16329d (1965) describes 1-(2-diethylaminoethyl)-3,5-diphenyl-1H-pyrazole, but no applicability is indicated for 1-(2-diethylaminoethyl)-3,5-diphenyl-1H -pyrazole, and Jones et al., J.Org.Chem.19, 1428-1434 (1954) describe that various 1-(2-aminoethyl)-3-phenyl-1H-pyrazoles were tried and found inactive as stimulants for gastric juice and histamine effect, while Biichi et al., Heiv. Chim. Acta., 38, 670-679

(1955) that no analgesic activity has been found for 1-(2-dimethylaminoethyl)-3-phenyl-4-methyl-1H-pyrazole.

To the best of our knowledge, it has not yet been described or suggested that the specific group of 1-amino-lower-alkyl-3,4-diphenyl-1H-pyrazoles described here has a desirable analgesic activity and a desirable activity against depression, something which is due to certain precise structural features.

The present invention thus relates to the preparation of compounds with the following formula

and are chemically designated as 1-/3-(N=B)-propyl7_ and 1-/2-(N=B)-ethyl/-3,4-diphenyl-1H-pyrazoles where n is 2 and N=B is diethylamino , or where n is 3 and N=B is amino, methylamino, dimethylamino or diethylamino. The compounds where n is 3 and N=B is either dimethylamino or methylamino are particularly useful as anti-depressants, while those where n is 3 and N=B is amino or dimethylamino and those where n is 2 and N=B is diethylamino , are usable as pain relievers. The compounds with formula I are prepared according to the invention by (a) reducing with an alkali metal aluminum hydride a compound with the formula: where n<1> is 2, thereby obtaining a compound where n is 3; (b) reducing with hydrogen in the presence of ammonia, methylamine, dimethylamine or diethylamine over a catalyst, a compound of the formula: where n' is n-1; (c) reacts a compound of the formula: where Ts is toluenesulfonyloxy, with an amine, H-N=B; (d) reacts a salt of a strong base of a compound of the formula:

with a halogen-lower-alkylamine, X-(CH2)n-N=B where X represents

teres halogen; or

(e) reducing either with formic acid or with hydrogen in the presence of a catalyst, a mixture of 1-(3-amino-propyl)-3,4-diphenyl-1H-pyrazole and at least two molar equivalents of formaldehyde, thereby obtaining a compound where n is 3 and N=B

is dimethylamino,

and, if desired, converting the free base produced into an acid addition salt thereof.

Because of the beneficial therapeutic effect, it is preferred to prepare a compound of formula I where n is 3 and N=B is dimethylamino.

Method (a) where, with an alkali metal aluminum

hydride reduces an ω-[I-(3,4-diphenyl-1H-pyrazolyl)-7-lower-alkanamide of formula II is preferably carried out in an organic solvent which is inert under the prevailing conditions, e.g. dioxane, diethyl ether or terahydrofuran at temperatures from approx. -10°C to the boiling point of the solvent used.

The desired starting materials of formula II can be prepared by

to react 3,4-diphenylpyrazole with a lower alkyl acrylate in near-

weather of a strong base, after which one saponifies the resulting ester, converts the resulting acid into the corresponding acid chloride, after which one reacts the latter compound with a suitable amine in the presence of an acid acceptor, e.g. pyridine.

Method (b) consists in reducing a 1-(cyano-lower-alkyl)-3,4-diphenyl-1H-pyrazole of formula III with hydrogen over a Raney nickel catalyst in the presence of ammonia, whereby the corresponding compounds are prepared where N =B is amino, If it is desired with compounds where N=B is methylamino, dimethyl-

amino or diethylamino, then the reaction can be carried out in the presence of methylamine, dimethylamine or diethylamine, respectively. The reduction is carried out in an organic solvent which is inert under the reaction conditions, e.g. a lower alkanol, at room temperature and at a hydrogen pressure varying from 3.5 to 7 kg/cm 2 .

the procedure is particularly advantageous for the preparation of compounds where n is 3• The starting compounds of formula III where n<1>is 2 can be prepared by reacting 3,4-diphenylpyrazole with acrylonitrile in the presence of a strong base.

In method (c), a 1-[3-(tosyloxy)-propyl?-or 1-[2-(tosyloxy)ethyl]-3,4-diphenyl-1H-pyrazole of formula IV is reacted with a suitable amine, H-N=B. The reaction is carried out by heating a mixture of the compound of formula IV with the amine in an organic solvent, e.g. acetonitrile or a lower alkanol, at temperatures in the range 100-150°C.

The intermediate of formula IV can be prepared by condensing formyldeoxybenzoin (Russel et al., J.Am. Chem.Soc. 76, 5714-5718 (1954) with a w-nyhydroxyalkylhydrazine, after which reacting the resulting 1-(3-hydroxy- propyl)-3,4-diphenyl-1H-pyrazole or 1(2-hydroxyethyl)-3,4-diphenyl-1H-pyrazole with a toluenesulfonyl halide in the presence of pyridine.

Method (d) where a 3,4-diphenyl-1H-pyrazole of formula V is reacted with a strong base, e.g. sodium hydride, is carried out in an organic solvent, e.g. tetrahydrofuran, dioxane or diethyl ether, and the resulting sodium salt is reacted with an appropriate halogen-lower alkylamine in the same solvent system at the boiling point of these solvents.

Method (e), which consists in reducing with formic acid or with hydrogen in the presence of a catalyst, a mixture of 1-(3-aminopropyl)-3,4-diphenyl-1H-pyrazole and at least two equivalents of formaldehyde, is preferably carried out in an organic solvent, e.g. a lower alkanol such as ethanol. A preferred method consists in reducing the reaction mixture with hydrogen over a catalyst at a hydrogen pressure of 3.5-7 kg/cm 2 , and a preferred catalyst is platinum oxide.

Due to the presence of a basic amino group, the free base form of the compounds as represented in formula I will react with organic and inorganic acids to form acid addition salts. Such salts can be prepared from any organic or inorganic acid. They can be prepared in the usual way, either by directly mixing the base with the acid, or when this is not possible, either by dissolving the base separately in water or an organic solvent and then mixing the two solutions, or by dissolving both the base and the acid together in a solvent. The resulting acid addition salt can be isolated by filtration if it is insoluble in the reaction medium, or by evaporation of the medium, so that a residue of the acid addition salt is obtained. The acid parts or the anions in these salts are not new or critical in themselves, and any acid anion or acid-like substance can thus form a salt with the base.

Representative acids for the formation of acid addition salts include formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tannic acid, glutamic acid, tartaric acid and oxalic acid, pyromucinic acid, citric acid, lactic acid, glycolic acid, gluconic acid, saccharinic acid, ascorbic acid, penicillin / benzoic acid, phthalic acid, salicylic acid, 3,5-dinitrobenzoic acid, anthranilic acid, cholic acid, 2-pyridinecarboxylic acid, pamoic acid, 3-hydroxy-2-naphthoic acid, picric acid, quinic acid, tropic acid, 3-indoleacetic acid, barbituric acid, sulfamic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid , benzenesulfonic acid, p-toluenesulfonic acid, butylarsonic acid, methanephosphinic acid, acid resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, nitric acid, sulfuric acid, forphoric acid, arsenic acid and the like.

All these acid addition salts can be used as a starting point for the formation of the free base, e.g. by a reaction with an inorganic base. It is thus obvious that if one or more properties, such as solubility, molecular weight, physical appearance, toxicity or the like of a given acid addition salt make this form unsuitable for one purpose or another, then it can easily be converted into another and more suitable form. For pharmaceutical purposes, one will of course use acid addition salts of relatively non-toxic, pharmaceutically acceptable acids, such as hydrochloric acid, lactic acid or tartaric acid.

As mentioned above, compounds of formula I are wherein

n = 3 and N=B are methylamino or dimethylamino and acid addition salts of such compounds, useful as anti-depressants, while compounds of formula I where n = 3 and N=B are amino or diethylamino and those where n = 2 and N= ;B are diethylamino useful as pain relievers.

Compounds of formula I can be administered in the same way as known anti-depressants and painkillers, i.e. either parenterally or orally in any known manner and in any commonly known pharmaceutical form, e.g. in the form of solutions, suspensions, tablets, capsules and the like.

The valuable properties of compounds of formula

I was shown by standard pharmacological methods well known to one skilled in the art, so that a determination of the numerical bioligical data required for a particular compound can be readily established without the necessary use of expensive and lengthy experimentation.

The method used to determine the anti-depressant activity of the compounds of formula I can be described as follows: Male Swiss-Webster mice (Taconic Farms)

which weighed from 19-24 g were divided into four groups with from nine to ten mice in each group. The first three groups were given the test compound in doses of 64, 16 and 4 mg/kg body weight respectively, either in water as an aqueous acid addition salt or as a suspension in 1% gum tragacanth. The fourth group received only the tragacanth solution. Four hours after administration, the control group and test animals were administered 50/kg (i.p.) of tetrabenzine and were placed in a photocell activity cage (described by Harris et al., Psychon, Sei., 4, 267 (1966)) equipped with a counter to determine the number of times that a light beam that hits a photocell is interrupted during the test period. Thirty minutes after the introduction of tetrabenzine, the photocell units were activated, and the number of interruptions of the light beam was measured during a 50 minute test. The compounds were then considered to be either active or inactive, and activity was defined as a significant difference (0.50 level or less) between the two mentioned groups, according to the Kruskal-Wallis statistical probability test.

try.

The methods used to determine the analgesic activity of the present invention have been described in detail in previously known literature and are as follows: It is an acetylcholine-induced abdominal constriction test, which is a primary test of analgesics for the agent's ability to suppress acetylcholine -induced abdominal compression in mice, and it is described by Collier et al., Brit. J. Pharmacol. Chemotherapy. 32, 295 (1968), in addition to the known phenyl-p-quinone-induced convulsion test also a primary test designed to examine analgesics for their ability to prevent a phenyl-p-quinone-induced writhing or convulsion in mice, and it is described by Pearl and Harris, J. Pharmacol. Exptl. Therapy. 154, 319-323 (1966).

The structure of the compounds was determined by means of the synthesis routes, by elemental analysis and by ultraviolet, infrared and nuclear magnetic resonance spectra. The reaction pathways and the homogeneity of the products were determined by thin-layer chromatography.

The following examples illustrate the invention. Melting points are uncorrected unless otherwise stated. Production of_ intermediate products.

Production 1.

A solution of 22g (0.1 mol) of 3,4-diphenyl-pyrazole i

150 ml of dioxane was added to 10 ml of Triton B (benzyl trimethyl ammonium hydroxide), and the solution was treated dropwise with 26.3 ml (0.4 mol) of acrylonitrile while the temperature was 40-45°C. The mixture was stirred for a further 2 minutes at room temperature, acidified by the addition of 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 approx. 1 teaspoon sodium chloride, shaken and filtered to remove an insoluble precipitate. The organic layer was separated and the aqueous layer extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, where

after with sodium chloride solution, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to dryness, where-

by a red oil was obtained, which was crystallized from 60 ml of methanol. One thus obtained 13.82 g of a substance, melting point 90-103°C, which, by gas chromatographic analysis, showed the presence of two isomers in a ratio of 13/87, and which consisted of 13% of the 4,5-diphenyl isomer and 87% of the 3,4-diphenyl isomer of 1-(2-cyanoethyl)-diphenyl-1H-pyrazole.

In another experiment, a thin suspension of 7.7 g

(0.14 mol) potassium hydroxide and 805 g (3.65 mol) 3,4-diphenyl-pyrazole in 3.4 1 ethanol stirred rapidly while treating with 292 ml (4.4 mol) acrylonitrile added dropwise over two hours After the addition, stirring was continued for two hours with cooling in an external ice bath, and the mixture was then left for two days at room temperature. It was then cooled again to 0°C and a solid product was filtered off and dried, and 723 g of product was obtained, melting point 103-108°C. Recrystallization of the latter from ethanol gave 681 g, mp 108-111°C (softening 106°C), and this product showed

by vapor phase chromatography and be 92-93% of the 3,4-isomer and 6-7% of the 4,5-diphenyl isomer of 1-(2-cyanoethyl)-diphenyl-1H-pyrazole.

Manufacturing 2.

A solution of 28 g (0.127 mol) of 3,4-diphenyl-pyrazole

11 ml of Triton B was added to 130 ml of dioxane. The solution was then treated dropwise at room temperature with 45 ml of methyl acrylate over the course of 15 minutes. The mixture was stirred for a further 1 hour and 35 minutes, acidified to pH 5.5 with acetic acid and then poured into ice. The mixture was worked up as described above under preparation no. 1, and gave 40 g of a mixture of methyl 3 ~ 0-~

(3,4-diphenyl-1H-pyrazolyl-7-propionate and methyl 3-£\ (4,5-diphenyl-1H-pyrazolyl)-7-propionate as an oil.

The mixture obtained above was dissolved in

80 ml of methanol, the solution was treated with 130 ml of a 2N solution of potassium hydroxide in methanol and then refluxed for two hours. The bulk of the solvent was removed in vacuo and the residue was treated with dilute hydrochloric acid and ethyl acetate. On cooling, the mixture became a white mass which was treated with water and adjusted to pH 2 with hydrochloric acid. The solid was filtered off and 40.1 g of a mixture consisting of all essentials was obtained. 85% 3-^1-(3,4-diphenyl-1H-pyrazolyl)ypropionic acid and 15% of , 5-diphenyl-1H-pyrazolyl)-7-propionic acid. This raw material was stirred with acetonitrile and filtered and 30.1 g of the pure 3,4-diphenyl isomer was obtained, melting point 184.5-187°C.

The latter product (7.0 g, 0.024 mol) was stirred in

50 ml of chloroform and to the suspension added 3.22 g (0.027 mol) of thionyl chloride. The mixture was refluxed for one hour with stirring, then treated with charcoal, filtered and the solvent removed in vacuo. The residue was dissolved in 50 ml of tetrahydrofuran and the solution was added dropwise with stirring to a solution of 25 ml of 6N dimethylamine in tetrahydrofuran, while the temperature was kept between 0-10°C. The mixture was then slowly warmed to room temperature, then refluxed for 1 hour and poured into 150 ml of ice water and extracted with three 50 ml portions of ethyl acetate. The combined ethyl acetate extract was washed with water, then with 10% potassium carbonate and then with sodium chloride solution and dried over sodium sulfate, filtered and evaporated to dryness to give 6 g of a pale yellow oil. This was chromatographed on 500 g of silica gel in ethyl acetate with ethyl acetate elution. After removing approx. 750 g of compound, the elution was transferred to

5% methanol in ethanol and this gave 3.50 g of material with R^=0.31,

and consisted of 6-(1-(3,4-diphenyl-1H-pyrazolyl)-N,N-dimethylpropionamide as a yellow gum).

Manufacturing 3.

A solution of 105 g (0.47 mole) of formyldeoxybenzoin and a molar equivalent amount of 2-hydroxyethylhydrazine in 450 ml of absolute ethanol was heated under reflux for 2.1/2 hours to 3 hours, cooled and the solid filtered off. The filtrate was evaporated to dryness and a brown oil was obtained

which was dissolved in chloroform, washed with water which evaporated to dryness after which 53 g of a white substance with a melting point of 99-105°C was obtained. The latter product was recrystallized from a solution of approx. 40 ml of ethylene dichloride and 100 ml of pentane and 46.5 g of 1-(2-hydroxyethyl)-3,4-diphenyl-1H-pyrazole was obtained, melting point 102-103°C, and by gas chromatography the substance proved to

be approx. 97-98% pure 3,4-diphenyl isomer.

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, and the mixture stored in a refrigerator for about. 18 hours. The separated solid was filtered off and the filtrate poured into five volumes of ice/water. The mixture was left at 0° for two hours, after which the liquid was decanted from a gummy solid which was stirred with ether and this gave a solid which was stirred with cold methanol to give 15 g of 1-/2-(4- toluenesulfonyloxy)-ethyl!7~3,4-diphenyl-1H-pyrazole, mp 109-110°C as a white solid. Production of the final products.

Example 1

A. A suspension of 13.8 g (0.05 mol) 1-(2-cyanoethyl)-3,4-diphenyl-1H-pyrazole prepared as described under preparation 1 above, in a solution of 100 ml of methanol containing water free ammonia, a small amount of Raney nickel catalyst was added, and the mixture reduced in a Parr apparatus at a hydrogen pressure of 3.5 kg/cm 2. After three days, the mixture was filtered off and the filtrate evaporated to dryness, and a residue was obtained which was dissolved in 40 ml isopropanol and 30 ml isopropyl acetate. The solution was treated with 20 ml of 5.7 N hydrogen chloride in ethanol, and the solid was collected, purified with additional solvent and dried to give 15.2 g of 1-(3-aminopropyl)-3,4 -diphenyl-1H-pyrazole dihydrochloride, melting point 177-188°C, and proved by gas chromatography to be 94% pure isomer.

B. Using the same procedure as described under A above, 27.3 g (0.1 mol) of the 87% pure 1-(2-cyanoethyl)-3,4-diphenyl-1H-pyrazole described under preparation < 1>/ in a solution of methylamine in ethanol reduced with hydrogen over a Raney nickel catalyst at 3.5 kg/cm 2 , and the product, after isolation as described above, converted to the hydrochloride salt which was recrystallized from ethanol. 5.9 g of 1-[3-(N-methylamino)-propyl]-3,4-diphenyl-1H-pyrazole hydrochloride were thus obtained, melting point 124-132°C. C. Using the same procedure as described above under part A, in three separate experiments 100 g (0.36 mol) portions of 92-93% pure 1-(2-cyanoethyl)-3,4-diphenyl-1H- pyrazole described under preparation 1 above, in a solution containing 110-. 120 g of dimethylamine in 960 ml of ethanol, reduced over 5 g of 10% palladium on charcoal catalyst, and the product was first converted to the oxalate salt (melting point 140-143°C), which was converted to the free base again and then this base again converted to the dihydrochloride salt which was recrystallized from isopropanol, so that a total yield from all three trials of 262 g of 1-(N^-dimethylamino)propyl 17-3,4-diphenyl-1H-pyrazole dihydrochloride was obtained, softening point 175°C. The latter product was shown by thin-layer chromatography to contain from 1-2% of total impurities (see example 2). Example 2.

To a stirred suspension of 0.42 g (0.011 mol) of lithium aluminum hydride in 50 ml of tetrahydrofuran was added 3.5 g (0.011 mol) of 3-(1-(3,4-diphenyl-1H-pyrazolyl7-N,N-dimethylpropionamide) and the mixture was stirred and refluxed for about 18 hours.The reaction mixture was then decomposed by careful addition

of 0.4 ml of water followed by 0.6 ml of 10% sodium hydroxide and a further 1 ml of water. The mixture was stirred for 1 hour, then filtered, after which the filtrate was evaporated in vacuo. The residual which consisted of 3.0

g of a yellow oil was dissolved in isopropyl acetate and the solution treated with 4 ml of a 6N solution of hydrogen chloride in ethanol. The solid was filtered off, and then recrystallized from isopropanol containing a further amount of hydrogen chloride

in ethanol. 1.2 g of 1-[3-(N,N-dimethylamino)propyl]-3,4-diphenyl-1H-pyrazole dihydrochloride were thus obtained, melting point 170-174°C. Example 3.

A mixture of 29.5 g (0.073 mol) 1-(4-toluenesulfonyloxy)ethyl7~3,4-diphenyl-1H-pyrazole and 103 ml of dimethylamine in 400 ml of acetonitrile was heated in an autoclave for nine hours at 120 -130°C. The mixture was washed out of the autoclave with acetonitrile, after which it was evaporated in vacuo. The residue was suspended in 800 ml of ethyl acetate, and the suspension became. washed with water containing a small amount of sodium hydroxide. The organic layer was then washed with sodium chloride solution, dried and evaporated to dryness to give 28 g of a brown oil which was distilled in vacuo. The fraction collected at 81-100°C/0.01 mm (15.3 g) was dissolved in diethyl ether and treated with a solution of hydrogen chloride in methanol. A solid was obtained which was recrystallized from acetone, and this gave 10.5 g of 1-(N,N-diethylamino)ethyl7-3,4-diphenyl-1H-pyrazole hydrochloride, melting point 147-148°C .

Example 4.

A mixture of 4.2 g (0.1 mol) of sodium hydride in 100 ml of tetrahydrofuran and 22.0 g (0.1 mol) of 3,4-diphenylpyrazole in 150 ml of tetrahydrofuran was heated 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 hours, filtered and evaporated in vacuo to dryness. The residue was dissolved in ethyl acetate, extracted into dilute hydrochloric acid, and the acid solution was washed once with ethyl acetate and neutralized with potassium carbonate. The aqueous mixture was then extracted with ethyl acetate and the organic extract washed twice with sodium chloride solution, dried and then evaporated to dryness to give 20.4 g of a yellow oil. The latter was dissolved in diethyl ether, treated with a molar equivalent amount of methanolic hydrogen chloride, and the solid which separated after cooling was collected and dried to give 20.2 g of an impure hydrochloride. The latter was converted to the free base which was then dissolved in chloroform, after which the chloroform solution was washed 4 times with 125 ml portions of water. The organic layer was then dried, evaporated to dryness after which the residue was redissolved in diethyl ether and again treated with an excess of methanolic hydrogen chloride. 16.5 g of a 1:1 mixture of 1-(N,N-diethylamino)-propyl7~3,4-diphenyl-1H-pyrazole hydrochloride and the corresponding isomeric 4,5-diphenyl- compound, melting point 143-146°C.

The latter compound (800 mg) was dissolved in methanol

and four 20x40 cm silica gel thin-layer chromatography plates applied. The plates were eluted with a 19:1 solution of 95% ethanol/concentrated ammonium hydroxide, and the upper third of the plate containing material with a higher R^ value was cut away from the lower two-thirds, and both sections were separately extracted. with a 1:1 solution of chloroform/methanol. The fraction with a higher R^ value was shown by gas chromatography to

to be 97-99% pure 4,5-diphenyl isomer, while the lower R^ fraction was found to be an 82/18 mixture of the 3,4- and 4,5-isomer. The higher R^ fraction originally obtained as an oil was crystallized from acetone/hexane and 75 mg of 1-(n,N-diethylamino)propyl/~4,5-diphenyl-1H-pyrazole hydrochloride was obtained, melting point 14 8-149°C, and this proved to be 99.8% pure 4,5-isomer by gas chromatography.

The lower R^ fraction gave, by repeated recrystallization from acetone and hexane, 103 mg of 1-(N,N-diethylamino)propyl/-3,4-diphenyl-1H-pyrazole hydrochloride, melting point 165-166° C, and was shown by gas chromatography to be 98% pure 3,4-isomer. (Note that the hydrochloride salts of both isomers were chromatographed and separated despite the use of concentrated ammonium hydroxide during the elution.)

Example 5.

A solution of 11.5 g (0.04 mol) 1-(3-aminopropyl)-3,4-diphenyl-1H-pyrazole and 60 ml of 35% aqueous formaldehyde in 125 ml of ethanol was reduced in a Parr apparatus over 500 mg of platinum oxide at a hydrogen pressure of 3.5 kg/cm 2. The reduction was interrupted after the pressure had been reduced to 1.5 kg/cm 2, and a further 500 ml of catalyst was added and reduction continued until the pressure had dropped to approx. 1 kg/cm 2. The reduction was again interrupted, further formaldehyde and catalyst were added, and the reduction continued until the final pressure was 1.5 kg/cm 2. The mixture was worked up as described above in example IA and the product converted to the hydrochloride salt and man gave two yields totaling 6.6 g of 1-(3-(N,N-dimethylamino)propyl7-3,4-diphenyl-1H-pyrazole-dihydrochloride, 4.0 g, mp 178-191°C and 2.6 g, melting point 185-191°C.

Biological test results.

Results obtained in the aforementioned anti-tetrabenazine (TB) and acetylcholine (Ach) and phenylquinone induced writhing or convulsion test (PPQ) for the present 3,4-diphenyl compounds are set forth in the table below. All 3,4-diphenyl compounds were identified by the above example numbers, and all doses are given in milligrams per kilogram (mg/kg).

Claims (2)

1. Analogous method for the preparation of therapeutically effective 1-amino-lower-alkyl-3,4-diphenyl-1H-pyrazoles with general formula: where n is 2 and N=B is diethylamino, or n is 3 and N=B is amino, methylamino, dimethylamino or diethylamino, as well as pharmaceutically acceptable acid addition salts thereof, characterized by (a) reducing with an alkali metal aluminum hydride a compound with the formula: where n' is 2, thereby obtaining a compound where n is 3; (b) reducing with hydrogen in the presence of ammonia, methylamine, dimethylamine or diethylamine over a catalyst, a compound of the formula: where n<1> is n-1; (c) reacts a compound of the formula: where Ts is toluenesulfonyloxy, with an amine, H-N=B; (d) reacts a salt of a strong base of a compound of the formula: with a halogen-lower alkylamine, X-(CH 2 )n~N=B where X represents halogen; or (e) reduces either with formic acid or with hydrogen in the presence of a catalyst, a mixture of 1-(3-amino-propyl)-3,4-diphenyl-1H-pyrazole and at least two molar equivalents of formaldehyde, thereby obtaining the compound where n is 3 and N=B is dimethylamino, and, if desired, converts the produced free base to an acid addition salt thereof. 2. Analogy method according to claim 1, characterized in that a compound of formula I is prepared where n is 3 and N=B is dimethylamino.