DK146624B - ANALOGY PROCEDURE FOR PREPARING 1-AMINOALKYL-3,4-DIPHENYL-1H-PYRAZOLES - Google Patents

Description

β V.

(19) DENMARK

(12) PUBLICATION WRITING (11) 146624 Β

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Patent Application No. 5662/77 (51) Int.CI.3: C 07 D 231/12 (22) Filing Date: 19 Dec 1977 (41) Aim. available: 21 Jun 1978 (44) Submitted: 21 Nov 1983 (86) International Application No: - (30) Priority: 20 Dec1976US752316 (71) Applicant: 'STERLING DRUG INC .; New York, US.

(72) Inventor: Denis Mahlon 'Bailey; US.

(74) Agent: Hofman-Bang & Boutard Patent Office (54) Analogous Process for Preparation of 1-Aminoalkyl-3,4-Diphenyl-1H-Pyrazoles

The present invention relates to an analogous process for the preparation of novel 1-aminoalkyl-3,4-diphenyl-1H-pyrazoles useful as antidepressants, the method being self-3Q judgmental as set forth in the characterizing claim.

N

® Rosenthal, Arch, Intern. Pharmacodynamics,% 6, 220-230 (1953) disclose 1- (2-aminoethyl) -3,5-diphenyl-1H-pyrazole as having local anesthetic effect. Grandberg et al., Zh. Obsch. Khim. 31, 3700- D 3705 (1961), C.A. 57, 9839 (1957), disclose 1- (3-aminopropyl) -3,5-diphenyl-1H-pyrazole, for which no specific use is disclosed. Torf et al., Biol. Aktivn. Sudin, Akad. Nauk SSR, 1965 171-174, C.A. 63, 16329d (1965), discloses 1- (2-diethylaminoethyl) -3,5-diphenyl-1H-pyrazole for which no specific use is indicated. Jones et al., J. Org. Chem. 19, 1428-1434 (1954) disclose various 1- (2-aminoethyl) -3-phenyl-1H-pyrazoles which were tested and found inactive as stimulants for ventricular secretion or as histamine active substances, and Btichi et al, Helv. Chim. Acta., 38, 670-679 (1955) disclose 1- (2-dimethylaminoethyl) -3-phenyl-4-methyl-1H-pyrazole, which is claimed to have an analgesic effect.

However, nowhere in the prior art, the specific group of 1-aminoalkyl-3,4-diphenyl-1H-pyrazoles, herein, has been proposed with desirable antidepressant effects due to certain structural properties.

The present invention thus relates to an analogous process for the preparation of compounds of the formula: C6H5-Π - C6H5

i k I

(CH2) 3-N = B

and with the chemical designation 1- [3- (N = B) -propyl] -3,4-diphenyl-1H-pyrazoles, wherein (N = B) is methylamino or dimethylamino. The present compounds are particularly useful as antidepressants.

The compounds of formula I are prepared by reduction of a) - [1- (3,4-diphenyl-1H-pyrazolyl [] - alkanamide of formula II: C6H5-j- ° 6f5_ ^ C6H5-j-1 | -c6H5

I 0 I

(ch2) 2_c-n = b (CH2) 3-N = B

II I

wherein (N = B) has the meaning given above by means of an all-aluminum-hydride. The reaction is preferably carried out in an organic solvent which is inert under the reaction conditions, e.g. dioxane, diethyl ether or tetrahydrofuran, at temperatures of about -10 ° C to the boiling point of the solvent. The necessary starting materials of formula II are prepared by reacting 3,4-diphenylpyrazole with a lower alkyl acrylate in the presence of a strong base, hydrolyzing the resulting ester, converting the acid thus formed to the corresponding acid chloride and reacting this acid chloride with an appropriate amine under presence of an acid acceptor, e.g. pyridine.

Another method of preparing compounds of formula I consists in reducing a 1- (cyanoethyl) -3,4-diphenyl-1H-pyrazole of formula III with hydrogen over Raney nickel in the presence of methylamine or dimethylamine to prepare the corresponding compounds wherein (N = B) is methylamino or dimethylamino. This method can be described by the following reaction scheme: c6h5 - [- c6h5 c6h5 - J-rr-c6H5 -> n In S /

T I

(CH2) 2C = N (CH2) 3-N = B

III I

wherein (N = B) is methylamino or dimethylamino. 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 hydrogen pressure in the range of 3.5 to 6.3 atm.

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

A third process for preparing the compounds of formula I consists in a reaction of 1-C3- (tosyloxy) propyl3-3,4-diphenyl-1H-pyrazole as set forth in formula IV with a suitable amine, HN = B, which indicated in the following reaction scheme: 4 146624 C6H5 -j] c6H5 C6H5 - [] - c6H5

N

\ / \ /

N N

(CH ^ OTg _ϋζϋΐ?> (CH2) 3-N = B

IV I

wherein N = B has the meaning given above. The reaction is carried out by heating the chemical compound of formula XV together with the amine in an organic solvent which is inert under the reaction conditions, e.g. acetonitrile or a lower alkanol, to a temperature of ca. 100 ° C to approx. 150 ° C.

The intermediates of Formula IV can be prepared by condensation of formyl oxybenzoin [Russell et al., J.Am.Chem. Soc. Z6, 5714-5718 (1954) J with 3-hydroxypropylhydrazine, followed by a reaction of the resulting 1- (3-hydroxypropyl) -3,4-diphenyl-1H-pyrazole with a toluene sulfonyl halide in the presence of pyridine.

Another method of preparing chemical compounds of formula I consists of reacting a 3,4-diphenyl-1H-pyrazole with a strong base, e.g. sodium hydride, in an inert organic solvent, the reaction conditions, e.g. tetrahydrofuran, dioxane or diethyl ether, and then react the sodium salt formed with a suitable halopropylamine in the same solvent at its reflux temperature. The process can be illustrated by the following reaction scheme: C5H5 -n-IJ- C6H5 C6H5U Π- C6H5 \ "/ (V)? -? T.

H + X - (CH 2) 3-N = B (CH 2) 3-N = B

wherein (N = B) has the meaning given above and wherein X represents a halogen atom.

Yet another process for preparing chemical compounds of formula I wherein (N = B) is dimethylamino, reduction of 1- (3-aminopropyl) -3,4-diphenyl-1H-pyrazole and at least two equivalents comprises formaldehyde 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 short-chain alkanol such as ethanol. A preferred process consists of reducing the reaction mixture with hydrogen in the presence of a catalyst and at a hydrogen pressure of 3.5 - 6.3 atm., And a preferred catalyst is plation oxide.

Due to the presence of a basic amino group, the free base form, as described by Formula I, will react with organic and inorganic acids to form acid addition salts. The acid addition salts are formed with any organic or inorganic acid. They are available in a traditional way, e.g. either by directly mixing the base with the acid or, when this is not feasible, by dissolving one or both components of water or an organic solvent separately and then mixing the two solutions, or by dissolving both the base and the acid together in one solvent. The acid addition salt thus formed is isolated by filtration if it is insoluble in the reaction medium, or by evaporation of the reaction medium, leaving the acid addition salt as the residue of evaporation. The acid moieties or anions of these salt forms are themselves neither new nor critical to the invention, and therefore can be constituted by any acid anion or acid-like compound capable of forming a salt with the base.

Examples of acids useful for the formation of acid addition salts include formic acid, acetic acid, isobutyric acid, α-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaric acid, succinic acid, monoamidoracetic acid, tannic acid, glutamic acid, tartaric acid, citric acid, mica , penicillin, benzoic acid, phthalic acid, salicylic acid, 3,5-dinitrobenzoic acid, anthranilic acid, cholic acid, 2-pyridinecarboxylic acid, embonic acid, 3-hydroxy-2-naphtolic acid, picric acid, 1,3,4,5-tetrahydroxy-cyclohexane carboxyl 2-acid, 1a-phenyl-β-hydroxy-propionic acid, 3-indole acetic acid, barbituric acid, amidosulfonic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, butanaric acid, methylphosphonic acid, resins with acid characters, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, arsenic acid and the like.

Chemical compounds of formula I may be administered in the same manner as already known antidepressants, e.g. either parenterally or orally in any conventional pharmaceutical form, e.g. in solution, in suspension, in tablets, in capsules or the like.

The useful properties of the chemical compounds of the invention have been demonstrated by standard pharmacological test methods which can be readily performed by highly qualified pharmaceutical personnel so that the relevant determination of the numerical biological data defining a particular compound for testing can be achieved. without the need for extensive experimentation.

The test procedure for determining the antidepressant effect of the compounds of this invention can be described as follows: Male mice (Swiss-Welster from Taconic Farms) weighing from 19 to 24 g were divided into four groups of nine to ten mice per day. group. The first three groups were administered the test compound at doses of 64, 16 and 4 mg / kg dissolved either in water in the form of a water-soluble acid addition salt or in the form of a suspension in 1% tragacanth gum. The fourth group was given the carrier only. Four hours after administration of the drug, both the control animals and the test animals were administered 50 mg / kg (i.p.) of intraperitoneal tetrabenazine and placed in a photocell activity measuring cage / described by Harris et al., Psychon. Sci., 4, 267 (1966)], which was equipped with a digital counter to measure the number of times a light beam hitting the photocell was interrupted during the experimental period. Starting thirty minutes after the dose of the tetrabenazine dose, the photocell units were activated and the photocell counts were recorded over a 50 minute period. The substances were listed as either active or inactive, the activity being defined as having a significant difference (at 0.05 level or less, two-sided) between the photocell count readings on the drug group and the control group according to Kruskal-Wallis's statistical probability test.

7 U6624

The structural composition of the chemical compounds of this invention was determined through the synthesis methods, through elemental analysis, and through spectral analysis using UV, IR and NMR spectra. The course of the reaction and the homogeneity of the prepared substances were determined by thin layer chromatography.

The method and the individual steps for preparing the chemical compounds in accordance with this invention, as well as the most convenient way proposed by the inventor to carry out the process proposed in accordance with this invention, will hereinafter be described so that one skilled in the art can carry out the preparation. The melting points listed are uncorrected, unless otherwise stated.

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 (benzyl-trimethylammonium hydroxide) and solution was then treated dropwise with 26.3 ml (0.4 mol) of acrylonitrile. while maintaining the temperature at 40 - 45 ° C.

The mixture was kept under stirring for an additional twenty minutes at room temperature, then acidified by the addition of 3 ml of acetic acid and poured into 700 ml of ice / water mixture. The mixture was then treated with 200 ml of ethyl acetate and ca. 1 teaspoon of sodium chloride, shaken and filtered to remove an insoluble precipitate. The organic layer was removed from the filter and the aqueous layer was extracted twice with ethyl acetate. The combined organic extract layers were washed with saturated sodium bicarbonate solution, then brine, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to dryness, resulting in a red oil which was crystallized from 60 ml of methanol. In this way 13.82 g of substance were obtained with m.p. 90 - 103 ° C which, by gas-phase chromatographic analysis, showed the presence of two isomers in the ratio 13/87 comprising 13% of the 4,5-diphenyl isomer and 87% of the 3,4-diphenyl isomer of 1- (2-cyanoethyl) - diphenyl-lH-pyrazole.

In another method of preparation, a low-concentration 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 causes vigorous stirring to be treated with 292 ml ( 4.4 moles of acrylonitrile, which was added dropwise over a two hour period. After the entire amount was added, stirring was continued for 2 hours Tinder cooling in an external ice bath and the mixture was then allowed to stand for two days at room temperature. The mixture was then cooled again to 0 ° C and the solid isolated and dried, resulting in 723 gm of m.p. 103 - 108 ° C. Recrystallization from ethanol resulted in 681 g of substance, m.p.

108 - 111 ° C (soft at 106 ° C), and this substance was found by gas chromatography to comprise 92 - 93% of the 3,4-isomer and 6-7% of the 4,5-diphenyl isomer of 1- 2-cyanoethyl) -diphenyl-lH-pyrazole.

PREPARATION 2

To a solution of 28 g (0.127 mol) of 3,4-diphenylpyrazole in 130 ml of dioxane was added 11 ml of Triton B. The solution was then treated at room temperature with 45 ml of methyl acrylate, which was added dropwise over a period of approx. fifteen minutes. The mixture was then stirred for an additional hour and forty-five minutes, acidified to pH 5.5 with acetic acid and then poured over ice. The mixture was processed in the same manner as described in Preparation 1 above, resulting in 40 g of a mixture oil consisting of methyl [1- (3,4-diphenyl-1H-pyrazolyl)] propionate and methyl A (4,5-diphenyl-lH-pyrazolyl) ^ propionate.

The crude mixture obtained by the above reaction was dissolved in ca. 80 ml of methanol and the solution were treated with 130 ml of 2 N potassium hydroxide solution in methanol and then refluxed for two hours. The majority of the solvent was then removed under vacuum and the remaining portion treated with dilute hydrochloric acid and ethyl acetate. After cooling, the mixture solidified to a white mass which was powdered by water and adjusted to pH 2 with hydrochloric acid. The solid was isolated by filtration and resulted in a 40.1 g mixture consisting essentially of ca. 85% O- [1- (3,4-diphenyl-1H-pyrazolyl)] propionic acid and 15% [1- (4,5-diphenyl-1H-pyrazolyl)] propionic acid.

The crude mixture was slurried with acetonitrile and filtered, resulting in 30.1 g as 3,4-diphenyl isomer with m.p. 184.5 -187 ° C.

9 146624

The mixture was refluxed and stirred for approx. one hour, treated with charcoal and filtered. The solvent was evaporated from the filtrate under vacuum. The residue was dissolved in 50 ml of tetrahydrofuran, and this solution was added drop by drop with stirring to a solution of 25 ml of 6N dimethylamine in tetrahydrofuran, maintaining a temperature of approx. 0-10 ° C.

After the addition was complete, the mixture was allowed to rise to room temperature, and then refluxed for one hour and poured into 150 ml of ice water and extracted into three mls of 50 ml of ethyl acetate. The combined ethyl acetate extracts were washed with water, then with 10% potassium carbonate solution, then with brine, dried over sodium sulfate, filtered and dried to give 6 g of pale yellow oil.

This oil was chromatographed on 500 g of silica gel in ethyl acetate and eluted with ethyl acetate. After removing approx. 750 mg of substance was eluted to 5% methanol in ethanol resulting in 3.50 g of substance with R f + 0.31 and consisting of 1- (3,4-diphenyl-1H-pyrazolyl)] - N, N-dimethylpropionamide in the form of a yellow rubbery substance.

EXAMPLE 1 A. 27.3 g (0.1 mole) of 87% pure 1- (2-cyanoethyl) -3,4-diphenyl-1H-pyrazole, prepared as described in Preparation 1 above, were suspended in a solution of methylamine in ethanol and reduced in a Parr shaking autoclave at a hydrogen pressure of 3.5 atm. in the presence of catalytic Raney nickel. After 3 days, the mixture was filtered and the filtrate dried and evaporated. The residue was dissolved in 40 ml of isopropanol and 30 ml of isopropyl acetate and the obtained solution was treated with 20 ml of 5.7 N HCl in ethanol.

The precipitated solid was recrystallized from ethanol to give 5.9 g of 1- [3- (N-methylamino) -propyl] -3,4-diphenyl-1H-pyrazole hydrochloride, m.p. 124-132 ° C.

B. Analogously to Section A, in three separate syntheses, portions of 100 g (0.35 mol) of 92-93% pure 1- (2-cyanoethyl) -3,4-diphenyl-1H-pyrazole were prepared as described in Preparation 1 above and in a solution containing 110-120 g of methylamine in 960 ml of ethanol reduced over 5 g of 10% palladium precipitated on charcoal. The reacitant was first converted to the oxalic acid salt (m.p.

140 - 143 ° C) which was returned to the free base and then converted to the dihydrochloride salt, which was recrystallized from isopropanol, resulting in a total yield of the three syntheses of 262 g of 1- N-dimethylamino) propyl] -3,4-diphenyl-1H-pyrazole dihydrochloride 183 - 185 ° C (soft at 175 ° C). This substance was estimated to contain 1-2% impurities on the basis of thin layer chromatography. (See Example 2 below).

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- [1- (3,4-diphenyl-1H-pyrazolyl)] N, N-dimethylpropionamide and the mixture was boiled under stirring and reflux for approx. 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 solution and another 1 ml of water. The mixture was stirred for one hour and filtered and the filtrate was evaporated to dryness under vacuum. The residue of 3.0 g of yellow oil was dissolved in isopropyl acetate and treated with 4 ml of 6N hydrogen chloride in ethanol. The solid which was separated was isolated and recrystallized from isopropanol containing an additional amount of hydrogen chloride in ethanol. 1.2 g of 1 - [] 3- (N, N-dimethylamino) -propyl] -3,4-diphenyl-1H-pyrazole dihydrochloride, m.p. 170 - 174 ° C.

Example 3 A. A mixture of 1- {] 3- (4-toluenesulfonyloxy) propyl] -3,4-diphenyl-1H-pyrazole and a solution of a molar excess of methylamine in acetonitrile was heated in an autoclave. The reaction mixture was washed out of the acetonitrile autoclave and the mixture was evaporated to dryness under vacuum. The product was converted to the corresponding hydrochloride salt by treatment with a solution of hydrogen chloride in methanol. The salt was recrystallized from ethanol to give 1- [3- (N-methylamino) propyl] -3,4-diphenyl-1H-pyrazole hydrochloride, mp 124-132 ° C.

Following a procedure as described above (A), 1- [3- (4-toluenesulfonyloxy) propyl] -3,4-diphenyl-1H-pyrazole was heated in a solution containing a molar excess of dimethylamine in acetonitrile in an autoclave and the product was converted to dihydrochloride salt. This salt was recrystallized from isopropanol to give 1- [3- (N, N-dimethylamino) propyl] -3,4-diphenyl-1H-pyrazole dihydrochloride, mp 183-185 ° C (soft at 175 ° C).

EXAMPLE 4

A solution of 3,4-diphenylpyrazole in tetrahydrofuran was treated with a molar equivalent of sodium hydride in tetrahydrofuran and the resulting sodium salt was treated with a molar equivalent of N- (3-chloropropyl) -N-methylamine. The product was converted to the corresponding hydrochloride salt by treatment with a molar equivalent amount of methanolic hydrogen chloride. After recrystallization from ethanol, 1- [3- (N-methylamino) propyl] -3,4-diphenyl-1H-pyrazole hydrochloride was obtained, mp 124-132 ° C.

EXAMPLE 5

A solution of 11.5 g (0.04 mol) of 1- (3-aminopropyl) -3,4-diphenyl-ΙΗ-pyrazole and 60 ml of 35% aqueous formaldehyde in 125 ml of ethanol was reduced in a Parr shaking autoclave over 500 mg of platinum oxide at 3.5 atm. hydrogen pressure. The reduction was discontinued after consumption of 2.0 atm. hydrogen pressure, an additional 500 mg of catalyst was added and the reduction was continued until an additional 2.75 atm. hydrogen pressure had been consumed. The reduction was then discontinued again, additional formaldehyde and catalyst were added, and the reduction was continued until the last 2.2 atm. hydrogen pressure had been consumed. The mixture was worked up in the same manner as described in Example 1A above, and the resulting substance was converted to the hydrochloride salt, resulting in two yield portions totaling 6.6 g of 1- [3- (N, N-dimethylamino) propyl] - 3,4-diphenyl-1H-pyrazole dihydrochloride, 4.0 g of m.p. 178 - 191 ° C and 2.6 g with m.p. 185 - 191 ° C.

12 146624

Biological test results

The results obtained through anti-tetrabenzazine (TB), acetylcholine (Ach) and phenylquinone-induced convulsion (PPQ) tests with the 3,4-diphenyl compounds prepared according to the present invention are listed. in the table below. All the 3,4-diphenyl compounds are marked with the number of the above example in which the method of preparation of the substance in question is described and all dosages are given in milligrams per minute. kilogram (mg / kg).

Example TB _; _ Ach_PPQ__ 1 A Active / 16.64

Inactive / 4 2 Active / 4,8.16 Inactive / 2 3 Inactive (a) 60% / 100 (sc) ED5q = 90 (po) 67% / 50 (sc) 53% / 10 (sc) ED50 = 29 ( po) 4 Inactive (a) ED 50 = 2.2 (sc) (a) tested at 4, 16 and 64 mg / kg (po)

Claims (1)

13_66624 P_a_t_e_n_t_k_r_a_y__: Analogous process for the preparation of 1-aminoalkyl-3,4-diphenyl-1H-pyrazoles of the general formula C6V | -jp ^ S Τ Ι 1 (CH2) 3-N = B where (N = B) is methylamino or dimethylamino, or acid addition salts thereof, characterized in that: a) reducing a compound of formula III 6.j 6 6 \ h / N 111, 1> (CH2) 2CSN with hydrogen over a catalyst in the presence of methylamine or dimethylamine, or b) converts a compound of formula IV 65. 1 [65 V "(ch reacting a salt of a strong base of a compound of formula V C6H5 -Tj-jp C6H5 INVH with a haloalkylamine, X- (CHg) 3 ~ N = B, wherein X is a halogen atom and N = B has the meaning given above. , or