FI66353B - ANALOGIFICATION OF THERAPEUTIC FREQUENCY OF THERAPEUTIC ANALYSIS 1-AMINO- (LAEGRE-ALKYL) -3,4-DIPHENYL-1H-PYRAZOLER - Google Patents

Description

g M <"> SÄRÄÄ 6635 3 {51) KvJl / ImXX3 C 07 D 231/12 FINLAND-FINLAND (ϊΐ) 773836 19.12.77 (23) AtoHM-GMgM.hg 19.12.77 (41) TMh> HMwtai» WMi » published 21.06.78,

Pitntti- ja rakbfearihalMM ^ ta hMUrffaim ».

PMMMxoch laglrtarityralwn ”* mUm Mk * a & mLiaem fJuSunt 29.06.84 {32X31K31)> n ** f —9 · φ4ρ * Μ 20.12.76 USA (US) 752316 (71) Sterling Drug Inc., 90 Park Avenue, New York, NY , USA (US) (72) Denis Mahlon Bailey, East Greenbush, New York, USA (US) (74) Oy Koi ster Ab (54) Analogue Method S. Therapeutically useful 1-amino- (alempl-alkyl) -3.4 for the preparation of -diphenyl-1H-pyrazoles - Analog-free form for the preparation of therapeutically active compounds 1-amino - (lactic-alkyl) -3,4-diphenyl-1H-pyrazole

The invention relates to an analogous process for the preparation of therapeutically useful 1-amino- (lower alkyl) -3,4-diphenyl-1H-pyrazoles of the formula I

C6HS | jTC6H5

kN.N

(CH 2) -N = B i n where n is 2 and N = B is diethylamino; or n is 3 and N = B is amino, methylamino, dimethylamino or diethylamino, and their acid addition salts.

The novel 1-amino-lower alkyl-3,4-diphenyl-1H-pyrazoles are useful as antidepressants and analgesics.

S

2 66353

Rosenthal, Arch. Intern. Pharmacodynamie, 9-6 (19 53) 2 20-230 discloses 1- (2-aminoethyl) -3,5-diphenyl-1H-pyrazole having the activity of a topical anesthetic; Grandberg et.ai., Zh. Obsch. Khim. 31 (1961) 3700-3705; C.A. 57 (1957) 9839 disclose 1- (3-aminopropyl) -3,5-diphenyl-1H-pyrazole, for which no use has been shown; Torf et al., Biol. Aktivn. Soedin, Akad. Nauk SSR, 1965, 171-174; C.A. 63 (1965) 16329d disclose 1- (2-diethylaminoethyl) -3,5-diphenyl-1H-pyrazole, for which no use has been described; Jones et al., J.0rg. Chem. 1J3 (1954) 1428-1434 disclose various 1- (2-aminoethyl) -3-phenyl-1H-pyrazoles which have been studied and found to be inactive as gastric secretion stimulants and histamine-like agents; and Biichi et al., Helv. Chim. Acta., 38, (1955) 680-679 discloses 1- (2-dimethylaminoethyl) -2-phenyl-4-methyl-ΙΗ-pyrazole which has been shown to have analgesic activity.

However, none of the known studies disclose the specific class of 1-amino-lower alkyl-3,4-diphenyl-1H-pyrazoles disclosed in this application, whose desired antidepressant and analgesic activities are due to certain precise structural features.

Those compounds of formula I in which n is 3 and N = B is either dimethylamino or methylamino are particularly useful as antidepressants, while compounds in which n is 3 and N = B is amino or diethylamino and those compounds in which n is 2 and N = B is diethylamino, are useful as analgesics.

The method according to the invention is characterized in that

a) reducing with hydrogen in the presence of ammonia, methylamine, dimethylamine or diethylamine with a catalyst a compound of formula III

C6H5 | j-j | -C6HS

HI

(CH 2) n CTN

wherein n 'is n-1;

b) obtaining a compound of formula IV

3

V

66353 CKHr —.- n— CcHr

N Γ 5 IV

I! ι (CH0) OTs. . 1 η wherein Ts is toluenesulfonyloxy, to react with an amine of formula H - N = B;

(c) subjecting to formula V

• <• ·. i ».ι ···· 1. CcHr I ----- .1 CcHr 6 1 H 6 5 v

... ‘· · I N

\ N / • i

B

a salt of a strong base of a compound of the formula for reacting with a halogen (lower alkyl) amine, X- (CH 2) n -N = B, wherein X is halogen;

d) reducing with a alkali metal aluminum hydride a compound of formula II

CcH5 —--- CKH, 6 5 6 5 0

I H

(CH2) n-N = C B

wherein n * is 2 to give a compound of formula I wherein n is 3, or e) reducing a mixture of 1- (3-aminopropyl) -3,4-diphenyl-ΙΗ-pyrazole with either formic acid or hydrogen in the presence of a catalyst, and at least two molar equivalents of formaldehyde, to give a compound wherein n is 3 and N = B is dimethylamino; • '' * · * '· 5% and, if desired, convert the resulting free base into the acid addition salt.

t 4 66353

In process variant d) an alkali metal aluminum hydride is used to reduce the β · * / 1- (3,4-diphenyl-1H-pyrazolyl) - (lower alkane) amide of the formula II, The reaction is preferably carried out in an organic solvent which is inert under the reaction conditions, e.g. up to the boiling point of the solvent used in dioxane, diethyl ether or tetrahydrofuran at a temperature in the range from -10 [deg.] C. The process is particularly suitable for the preparation of compounds in which n 'is 2 and n is 3. The desired starting materials of formula II are prepared by the diphenylpurazole is reacted with the lower alkyl acrylate in the presence of a strong base, the ester formed is saponified, the acid formed is converted to the corresponding acid chloride and the latter is reacted with the appropriate amine in the presence of an acid acceptor, e.g. pyridine.

According to process variant a), 1- (cyano-lower alkyl) -3,4-diphenyl-1H-pyrazole of formula III is reduced with hydrogen over a Raney nickel catalyst in the presence of ammonia to give the corresponding compounds in which N = B is amino. If compounds in which N = B is methylamino, dimethylamino or diethylamino are desired, then the reaction is 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. lower alkanol, ambient temperature and hydrogen pressure of about 344.5 to 620.1 kPa. The method is particularly suitable for the preparation of compounds where n is 3.

The starting materials of formula III in which n 'is 2 are prepared by reacting 3,4-diphenylpyrazole with acrylonitrile in the presence of a strong base.

In process variant b) 1- (3- (3-tosyloxy) -propyl] - or 1- [2- (tosyloxy) -ethyl] -3,4-diphenyl-1H-pyrazole of the formula IV is reacted with a suitable amine, HN = B The reaction is carried out by heating a mixture of a compound of formula IV with an amine in an organic solvent which is inert under the reaction conditions, e.g. acetonitrile or lower alkanol, at a temperature in the range of about 100-150 ° C.

The intermediates of formula IV are prepared by the condensation reaction of formyl deoxybenzoin (Russell et al., J. Am. Chem. Soc. 7-5, (1954) 5714-5718) with N-hydroxyalkylhydrazine, followed by the formation of 1- (3-hydroxypropyl) Reaction of -3,4-diphenyl-1H-pyrazole or 1- (2-hydroxyethyl) -3,4-diphenyl-1H-pyrazole with toluenesulfonyl halide in the presence of pyridine.

In process variant c), 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, e.g. tetrahydrofuram, dioxane or diethyl ether, and the resulting sodium salt is reacted with a halogen. with an alkylamine in the same solvent system at its reflux temperature.

In process variant e), a mixture of 1- (3-aminopropyl) -3,4-diphenyl-1H-pyrazole and at least two formaldehyde equivalents is reduced with either formic acid or hydrogen in the presence of a catalyst. The reaction is preferably carried out in an organic solvent which is inert under the reaction conditions, e.g. a lower alkanol such as ethanol. In a preferred process, the reaction mixture is reduced over a catalyst at a hydrogen pressure of 344.5-620.1 kPa and the primary catalyst is platinum oxide.

Due to the basic amino group present, the free base form shown in formula I above reacts with organic and inorganic acids to form acid addition salts. Acid addition salt forms are prepared from any organic or inorganic acid. They are prepared in a conventional manner, for example either by mixing the base directly with an acid or, where this is not appropriate, by dissolving one or both acids and the base separately in water or an organic solvent, or by dissolving both the base and the acid together in the solvent. The resulting acid addition salt is isolated by filtration if insoluble in the reaction medium, or by evaporation of the reaction medium, leaving the acid addition salt as a residue. The acidic moieties or amines in these salt forms are not in themselves new or critical, and therefore any acid amine or acid-like substance may be capable of salt formation with a base.

Model acids that form acid addition salts include formic acid, acetic acid, isobutyric acid, ct-merkaptopropio-acid, trifluoroacetic acid, maleic acid, fumaric acid, succinic acid, succinic as half, tannic acid, glutamic j 66353 acid, tartaric acid, oxalic acid, mucic acid, citric acid, lactic acid, glycolic acid , gluconic acid, sugar acid, ascorbic acid, penicillin, benzoic acid, phthalic acid, salicylic acid, 3,5-di-nitrobenzoic acid, anthranilic acid, bile acid, 2-pyridinecarboxylic acid, naphthoic acid, pamoic acid, 2-hydroxy acid, 3-hydroxy acid, 3-hydroxy -indolietikkahappo, barbituric acid, sulfamic acid, methanesulfonic acid, ethanesulfonic acid, isotio-sulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, butyl arsonilic acid, methane phosphoric acid, acidic resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, arsenic acid and the like.

All acid addition salts are useful sources of the free base forms when reacting with an inorganic base. Thus, it is appreciated that if one or more properties of a particular base or acid addition salt formed therefrom, such as solubility, molecular weight, physical state, toxicity, or the like, make the form unsuitable for the present purpose, it can be readily converted to another more suitable form. For pharmaceutical purposes, of course, relatively non-toxic, pharmaceutically acceptable acids are used, for example, hydrochloric acid, lactic acid, tartaric acid or the like.

The compounds of formula I can be administered as a medicament in the same way as known antidepressant or analgesic agents, i. either parenterally or orally in any conventional pharmaceutical form, such as, for example, solutions, suspensions, tablets, capsules or the like.

The beneficial properties of the compounds of this invention were demonstrated by easy-to-perform, standard pharmacological standard methods, so that the actual determination of numerous biological measurements accurate for a particular test compound could be performed without extensive experimentation.

The experimental method used to determine the antidepressant activity of the compounds of the invention is described as follows: Swiss-Webster male mice (Taconic Farms) weighing 19-24 g were divided into four groups of 9-10 mice. The first three groups were administered the following doses of test compound, 64, 16, and 4 mg / kg, respectively, dissolved in water as a water-soluble acid addition salt or as a suspension in 1% tramp gum. The fourth group received only the solvent. Four hours after drug administration, all control and experimental animals were treated with 50 mg / kg (i.p.) tetrabenazine and placed in a photocell activity device / Harris et al. have described the device as a Psychon. Sci., 4 ^ (1966) 2677, which was equipped with a digital counter which registers the number of times the light beam hitting the photocell is interrupted during the experiment. The experiment was started 30 minutes after tetrabenazine administration, the photocell units were activated, and the number of photocell disconnections was recorded over a period of more than 50 minutes. Compounds were recorded as either active or inactive, activity was determined as the significant difference (0.05 level or less, two-part) between the number of photocells in the drug and control groups, according to the Kruskal-Wallis probability test.

The test methods used to determine the analgesic activity of the compounds of the invention have been described in detail in a previous study and are as follows: Acetylcholine-induced abdominal cramping assay, the primary analgesic screening assay to measure acetylcholine-induced abdominal contraction in mice described by Collier et al., Brit. J. Pharmacol. Chemotherap. 32 (1968) 295, and phenyl β-quinone induced pain test / Pearl and Harris, J. Pharmacol. Exptl. Therap. 154 319-323 (1966) 7, including an analgesic screening assay designed to measure the ability of a test substance to inhibit phenyl β-quinone-induced pain in mice.

The structures of the compounds of this invention have been elucidated by syntheses, elemental analyzes, UV, infrared and NMR spectra. The progress of the reactions and the homogeneity of the products were monitored by thin layer chromatography.

The following examples illustrate the invention. Melting points are uncorrected unless otherwise indicated. , Manufacture of intermediates

Method of preparation 1

To a solution of 22 g (0.1 mol) of 3,4-diphenylpyrazole in 150 ml of dioxane was added 10 ml of Triton B (Benzyltriamonium hydroxide) and 26.3 ml (0.4 mol) of carylonitrile was added dropwise to the solution. while the temperature remained at 40-45 ° C The mixture was further stirred for 20 minutes at ambient temperature, acidified by adding 3 ml of acetic acid and poured into 700 ml of an ice-water mixture. The mixture was then treated with 200 mL of ethyl acetate and about one tablespoon of sodium chloride, shaken and filtered to remove insoluble precipitate. The organic layer was isolated from the filtrate and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, then brine, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to dryness to give a red oil which was crystallized from 60 ml of methanol. This gave 13.82 g of material, m.p. 90-103 ° C, of which gas chromatographic analysis showed the presence of two isomers in a ratio of 13/87, with 13% being the 4,5-diphenyl isomer of 1- (2-cyanoethyl) -diphenyl-1H-pyrazole and 87% 3, 4-diphenyl-isomer.

In the second run, a lean suspension of 7.7 g (10.14 moles) of potassium hydroxide and 805 g (3.65 moles) of 3,4-diphenylpyrazole in 3.4 L of ethanol was stirred rapidly with simultaneous treatment with 292 mL (4.4 moles) of acrylonitrile added dropwise over a period of more than two hours. After the addition was complete, stirring was continued for two hours while cooling in an external ice bath, and the mixture was then allowed to stand for two days at ambient temperature. The mixture was cooled once more to 0 ° C and the solid product was collected and dried to give 723 g of material with a melting point of 103-108 ° C. Recrystallization of the latter from ethanol gave 681 g of material, m.p. 108-111 ° C (softening point 106 ° C), which according to gas chromatography analysis appeared to be 92-93% of the 3,4-isomer of 1- (2-cyanoethyl) -diphenyl-1H-pyrazole and 6-7% of 4, 5-diphenyl isomer.

Method of preparation 2

To a solution of 28 g (0.127 moles) of 3,4-diphenylpyrazole in 130 mL of dioxane was added 11 mL of Triton B. To the solution was added dropwise at ambient temperature 45 ml of methyl acrylate over 15 minutes. The mixture was stirred for one hour and 45 minutes, acidified to pH 5 with acetic acid and then poured onto ice. The mixture was treated as described in Preparation 1 to give 40 g of methyl [3- [1- (3,4-diphenyl-1H-pyrazolyl)] propionate and methyl p- [1- (4,5-diphenyl-1H-pyrazolyl). ) _7 A mixture of propionate which was an oil. This crude mixture was dissolved in about 80 ml of methanol, the solution was treated with 130 ml of 2N methanolic potassium hydroxide solution and then the reflux was cooled for two hours. Most of the solvent was then removed in vacuo and treated with dilute hydrochloric acid and ethyl acetate. Upon cooling, the mixture formed a white mass which was triturated with water to a powder and adjusted to pH 2 with hydrochloric acid. The solid was collected by filtration to give 40.1 g of a mixture consisting essentially of about 85% of N- [1- (3,4-diphenyl-1H-pyrazolyl) -7-propionic acid and 15% of β-β- (4,5-diphenyl-1H Pyrazolyl X7-propionic acid The crude material was slurried with acetonitrile and filtered to give 30.1 g of pure 3,4-diphenyl isomer, mp 184.5-187 ° C.

The latter (7.0 g, 0.024 mol) was slurried in 50 ml of chloroform, and the slurry was added to 3.22 g (0.027 mol) of thionyl chloride. The mixture was refluxed with stirring for about an hour, then carbon was added and filtered and the solvent was removed in vacuo from the filtrate. The residue was dissolved in 50 ml of tetrahydrofuran, and the solution was added dropwise while stirring to 25 ml of 6N dimethylamine in tetrahydrofuran, while maintaining the temperature between 0-10 ° C. When the addition was complete, the mixture was allowed to warm to ambient temperature, then refluxed for one hour and poured into 150 ml of ice water and extracted with three 50 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with water, then 10% potassium carbonate and then brine, dried over sodium sulfate, filtered and evaporated to dryness to give 6 g of a pale yellow oil. The latter was chromatographed on silica gel in ethyl acetate eluting with ethyl acetate. After removal of 750 mg of material, the elution was converted to elution in 5% methanol-ethanol to give 3.5 g of a material having Rf = 0.31 and comprising β- [1- (3-diphenyl-1H-). pyrazolyl lead-NjN-dimethylpropionamide as a yellow resin.

Preparation 3 105 g (0.47 mol) of formyl deoxybenzoline and an equimolar amount of 2-hydroxyethylhydrazine in 450 ml of absolute ethanol were refluxed for 2.5-3 hours, then cooled and the solid which precipitated was collected by filtration. . The filtrate was evaporated to dryness to give a brown oil which was dissolved in chloroform, washed with water and evaporated to dryness to give a white solid with a melting point of 99-105 ° C. The latter was recrystallized from a solution of 40 ml of ethylene dichloride and 100 ml of pentane to give 46.5 g of 1- (2-hydroxyethyl) -3,4-diphenyl-1H-pyrazole, m.p. 102-! 10 66353 103, which according to gas chromatographic analysis was about 97-98% pure 3,4-diphenyl isomer.

32.6 g (0.12 moles) of the latter in 130 ml of pyridine were mixed with 24.5 g (0.13 moles) of p-toluenesulfonyl chloride in 75 ml of pyridine and the solution was stored in a refrigerator for about 18 hours. The solid that had separated was collected by filtration and the filtrate was poured into about five times the ice / water mixture. The mixture was allowed to stand at about 0 ° C for two hours. The liquid was decanted from a gummy solid which was slurried in cold methanol to give 15 g of a white solid, 1-Z * 2- (4-toluenesulfonyloxyethyl) -3,4-diphenyl-1H-pyrazole, m.p.

109-110 ° C.

Manufacture of the final product

Example 1 A. To a slurry of 13.8 g (0.05 moles) of 1- (2-cyanoethyl) -3,4-diphenyl-1H-pyrazole as described in Preparation 1, 100 mL of methanol, containing anhydrous ammonia, a small amount of Raney nickel catalyst was added and the mixture was reduced on a Parr shaker under a hydrogen pressure of 34.45 kPa. After three days, the mixture was filtered and the filtrate was evaporated to dryness and the remaining residue was dissolved in 40 ml of isopropanol and 30 ml of any isopropyl acetate. The solution was treated with 20 ml of 5.7N hydrogen chloride in ethanol and the solid which separated was washed, washed with an additional amount of solvent to give 15.2 g of 1- (3-aminopropyl) -3,4-diphenyl-1H-pyrazolidine hydrochloride, m.p. . 177-188 ° C, which was 94% pure isomer by gas chromatographic analysis.

B. Following the procedure described in Part A, 27.3 g (0.1 mol) of 87% pure 1- (2-P} methylethyl> -3,4-diphenyl-1H-pyrazole, described in Preparation 1, methylamine, wherein was ethanol, reduced with Raney nickel catalyst under 344.5 kPa hydrogen pressure, and the product, after isolation as described in A, was converted to the hydrochloride salt, which was recrystallized from ethanol to give 5.9 g of 1-Z "3- (N-methylamino) -propyl7- 3,4-diphenyl-1H-pyrazole hydrochloride, mp 124-132 ° C.

C. Following the procedure described in Part A, in three separate runs of 11,635,353 in portions of 100 g (0.36 moles) of 92-93% pure 1- (2-cyanoethyl) -3,4-diphenyl-1H-pyrazole, described in Preparation 1 , in a solution of 110-120 g of dimethylamine in 960 ml of ethanol, was reduced with 5 g of 10% palladium-on-carbon catalyst and the product was first converted to the oxalate salt (m.p. 140-143 ° C), which was again was converted to the free base and the latter was converted to the dihydrochloride salt which was recrystallized from isopropanol to give 262 g of 1- [3- (N, N-dimethylamino) propyl] -3,4-diphenyl-1H-pyrazolidihydrochloride in total yield from all three runs, m.p. 183-185 ° C (softening point 175 ° C) The latter was estimated to contain 1-2% of impurities by thin layer chromatography (see Example 2).

Example 2

To a stirred slurry 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 β-Π- (3,4-diphenyl-1H-pyrazolylX7-N, N-dimethylpropionate). The reaction mixture was then quenched by the careful addition of 0.4 mL of water and then 0.6 mL of 10% sodium hydroxide, followed by an additional 1 mL of water, and the mixture was stirred for 1 hour, then filtered and refluxed. the filtrate was evaporated to dryness in vacuo The residue, comprising 3.0 g of a yellow oil, was dissolved in isopropyl acetate and the solution was treated with 4 ml of 6N hydrogen chloride in ethanol The solid which separated was isolated and recrystallized from isopropanol containing additional hydrogen chloride in ethanol. , 2 g of 1-Z "3- (N, N-dimethylamino) propyl-3,4-diphenyl-1H-pyrazole dihydrochloride, mp 170-174 ° C.

Example 3

A mixture of 29.5 g (0.073 moles) of 1- [2- (4-β-toluenesulfonyloxy) ethyl] -3,4-diphenyl-1H-pyrazole and 103 ml of diethylamine in 400 ml of acetonitrile was heated in an autoclave for nine minutes. hours at 120-130 ° C. The reaction mixture was washed from the autoclave with acetonitrile and the mixture was evaporated to dryness in vacuo. The residue was suspended in 800 ml of ethyl acetate and the 12 66353 suspension was washed with water containing a small amount of sodium hydroxide. The organic layer was then washed with brine, dried and evaporated to dryness to give 28 g of a brown oil which was distilled in vacuo. The fraction distilled at 81-100 ° C / 0.01 mm (15.3 g) was collected and dissolved in diethyl ether and treated with hydrogen chloride-methanol solution. The solid that separated was recrystallized from acetone to give 10.5 g of 1-Z 2 - (N, N-diethylamino) ethyl-3,4-diphenyl-1H-pyrazole hydrochloride, mp 147-148 ° C.

Example 4

A mixture of 4.2 g (0.1 mol) of sodium hydride in 100 ml of tetrahydrofuran and 220 g (0.1 mol) 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 hours, then filtered and distilled to dryness in vacuo. The residue was taken up in ethyl acetate, extracted into dilute hydrochloric acid and the acidic solution was washed once with ethyl acetate and neutralized with potassium carbonate. The aqueous mixture was then extracted with ethyl acetate and the organic extracts were washed twice with brine, dried and evaporated to dryness to give 20.4 g of a yellow oil. The latter was dissolved in diethyl ether, treated with an equimolar amount of methanolic hydrogen chloride, and the solid which separated after cooling was isolated and dried to give 20.2 g of crude hydrochloride. The latter was reconverted to the free base, which was dissolved in chloroform, and the chloroform solution was washed four times with a 125 ml portion of water. The organic layer was then dried and evaporated to dryness and the residue was redissolved in diethyl ether and treated again with excess methanolic hydrogen chloride. There was thus obtained 16.5 g of a 1: 1 mixture of 1 - Z - 3- (N, N-diethylamino) propyl] -3,4-diphenyl-1H-pyrazole hydrochloride and the corresponding 4,5-diphenyl isomer compound, m.p. 143-146 ° C.

The latter (800 mg) was dissolved in methanol and fed to four 20 x 40 cm silica gel thin layer chromatography plates. The plates were eluted with a 19: 1 solution of 95% ethanol / concentrated ammonium hydroxide and the upper third of the plate containing the higher R 1 material was excised from the lower 2/3 and both parts were extracted separately with a solution containing 1: 1 chloroform / methanol. Gas chromatographic analysis of the higher R 1 fraction showed 97-99% pure 4,5-diphenyl isomer and the lower R 2 fraction was found to be a 82/18 ratio mixture of 3,4 / 4,5 isomers. The higher R 2 fraction, originally obtained as an oil, was crystallized from acetone / hexane to give 75 mg of 1-Z'S (N (N-N-diethylamino) propyl] -4,5-diphenyl-1H-pyrazole hydrochloride, m.p. 148-149 ° C, gas chromatographic analysis showed it to be 99.8% pure 4.5-isomer.

The lower R 2 fraction repeatedly recrystallized from acetone / hexane gave 103 mg of 1- [3 - (N, N-diethylamino) propyl] -3,4-diphenyl-1H-pyrazole hydrochloride, m.p. 165-166 ° C, gas chromatographic analysis showed it to be 98% pure 3,4-isomer. (Note: the hydrochloride salts of both osimers were chromatographed and isolated despite the use of concentrated ammonium hydroxide in the elution.)

Example 5

A solution of 11.5 g (0.04 mol) of 1- (3-aminopropyl) -3,4-diphenyl-1H-pyrazole and 60 ml of 35% aqueous formaldehyde in 125 ml of ethanol was reduced by Parr 500 V platinum oxide catalyst at 345 kPa hydrogen pressure. The reduction was stopped after a hydrogen pressure of 200 kPa was applied, another 500 mg of catalyst was added and the reduction was continued until a hydrogen pressure of 269 kPa was used. The reduction was stopped once more and formaldehyde and catalyst were added and the reduction was continued until a final hydrogen pressure of 214 kPa was used. The mixture was treated as described in Example 1A and the product was converted to the hydrochloride salt to give two different products totaling 6.6 g of 1- [3- (N, N-dimethylamino) propyl] -3,4-diphenyl-1H-pyrazole dihydrochloride, 4.0 g , mp 178-191 ° C and 2.6 g, mp 185-191 ° C.

i m 66353

Biological test results

The results obtained in anti-tetrabenazine (TB) acetylcholine (AsK) and phenylquinone pain tests (PPQ) with the 3,4-diphenyl compounds of the invention are shown in the table below. All 3,4-diphenyl compounds are identified by the above example numbers, where the preparation methods are described and all doses are expressed in milligrams per kilogram (mg / kg).

Example TB AsK PPQ

1 ~ Ä Inakt (a) ED ^ Q = 11 (s.c.) 1 1 B Akt / 16.64

Inakt / 4 2 Akt / 4,8,16 Inakt / 2 3 Inakt (a) 60% / 100 (sc) ED5Q = 90 (po) 67% / 50 (sc) 53% / 10 (sc) ED50 = 29 ( po) 4 Inact (a) ED 2 q = 2.2 (sc) (a) tested 4, 16, 64 mg / kg (po)

Claims (4)

Claims 6635 An analogous process for the preparation of therapeutically useful 1-amino- (lower alkyl) -3,4-diphenyl-1H-pyrazoles of the formula IM, -1 CKHr 1 Γ 6 5 i IL (CH 2) -N = B cn wherein n is 2 and N = B is diethylamino; or n is 3 and N = B is amino, methylamino, dimethylamino or diethylamino, and for the preparation of their acid addition salts, characterized in that a) a compound of formula is reduced with hydrogen in the presence of ammonia, methylamine, dimethylamine or diethylamine III CeH5 ~ [j [Γ C6H5 k / N 111 (CH2) n, CiN where n * is n-1; b) reacting a compound of formula IV caHs T-if ce «s (CH 2) OTs 2 n wherein Ts is toluenesulfonyloxy with an amine of formula H - N = B; c) reacting a strong base salt of a compound of formula V 16 66353 1 if B with a halo (lower alkyl) amine, X- (CH 2) -N = B, wherein X is halogen; d) reducing with a alkali metal aluminum hydride a compound of formula II C6H5 "Tj Γ" C6H5 IL Ji 11 I μ (CH2) n, CN = B where n * is 2 to give a compound of formula I wherein n is 3, or e) reducing with either formic acid or hydrogen in the presence of a mixture of 1- (3-aminopropyl) -3,4-diphenyl-1H-pyrazole and at least two molar equivalents of formaldehyde to give a compound wherein n is 3 and N = B is dimethylamino and, if desired, converting the resulting free base into an acid addition salt. Process for the preparation of 1- [3- (N, N-dimethylamino) propyl] -3,4-diphenyl-1H-pyrazole hydrochloride according to Claim 1, characterized in that β- [1- (3,4-diphenyl-1H -pyrazolyl) N-N, N-Dimethylpropionamide is reduced with lithium aluminum hydride and converted into the hydrochloride salt. „. .v 17 66353 1. An analogue of the formulation of a therapeutically active bar-1-amino (carbon-alkyl) -3,4-diphenyl-1H-pyrazole with the formula I C6H5 -Π-Γ C6H5 K '* <CH,> -N = B 2 n color n är 2 and N = B är diethylamino; or n is 3 and N = B is amino, methylamino, dimethylamino or diethylamino, and a hydrogenation moiety which is preferred for the preparation of a) reducing a mixture of formula III C6H5 "Ti j" C6H5 1. m (CH2 ) n, C = N color n 'är n-1, mediated by ammonia, methylamine, dimethylamine or diethylamine over a catalyst; (b) a mixture of compounds of formula IV C6H5 ~ jj ["C6H5 kN-N CV (CH0 ) OTs 2 n color Ts är toluenesulfonloxi, med Amin med formuleln HN = B; c) omsätter ett sait av en Stark bas av förening med formuleln V cKHc -r-rr CrH, 6 5 (| 6 5 VL and i H with a halogenated alkyl, X- (CH2) RN = B, color X is halogen;