CH627172A5 - Process for the preparation of 1-(lower aminoalkyl)-3,4-diphenyl-1H-pyrazoles - Google Patents

Abstract

1-[3-(N,N-Dimethylamino)propyl]-3,4-diphenyl-1H-pyrazole is prepared by reductive alkylation, by formaldehyde in combination with formic acid or with hydrogen in the presence of a catalyst, of 1-(3-aminopropyl)-3,4-diphenyl-1H-pyrazole. The compound obtained is an antidepressant agent.

Description

627172

2

Claim 1. Process for the preparation of 1- [3- (N, N-dimethyl-amino) -propyl] -3,4-diphenyl-1H-pyrazole, or one of its acid addition salts, characterized in that which is reduced by formic acid or by hydrogen in the presence of a catalyst a mixture of l- (3-aminopropyl) -3,4-diphenyl-1H-pyrazole and at least two molar equivalents of formaldehyde, and if desired, the free base obtained is converted into one of its acid addition salts.

10

This invention relates to the preparation of diphenyl-1H-pyrazole and its salts, which is useful as an antidepressant and is an analgesic.

Rosenthal, Arch. Intern. Pharmacodynamics, 96, 220-230 (1953) describes 1- (2-aminoethyl) -3,5-diphenyl-1H-pyrazole having local anesthetic activity; Grandberg et al., Zh.

Obsch. Khim. 31, 3700-3705 (1961); C.A. 57, 9839 (1957) describes 1- (3-aminopropyl) -3,5-diphenyl-1H-pyrazole for which no utility is indicated; Torf et al., Biol. Aktivn. Soedin, Adad. Nauk SSR, 1965, 171-174; C.A. 63,16329d (1965) describe 1- (2-diethylaminoethyl) -3,5-diphenyl-1H-pyrazole for which no utility is described; Jones et al., J. 2s Org. Chem. 19, 1428-1434 (1954) describe various l- (2-aminoethyl) -3-phenyl-1H-pyrazoIes which have been tested and found inactive as stimulants of gastric secretion and histamine agents; and Biichi et al., Helv. Chim. Acta., 38, 670-679 (1955) describe 1- (2-dimethyl-aminoethyl) -3- # phenyl-4-methyl-1H-pyrazole for which analgesic activity is indicated.

However, nothing in the prior art suggests the compound described and claimed herein which owes its desired antidepressant activities to certain characteristics of specific structures.

This invention relates to the preparation of the compound of formula:

c c h ii r

(CH.,) -N = B z n

I

or n is 3 and N = B is a dimethylamino group. This compound is particularly useful as an antidepressant agent.

The process for preparing the compound of formula I where n is 3 and N = B is a dimethylamino group, consists in reducing with formic acid or with hydrogen in the presence of a catalyst a mixture of l- (3-aminopropyl ) -3,4-diphenyl-1H-pyrazole and at least two equivalents of formaldehyde. The reaction is preferably carried out in an organic solvent inert under the reaction conditions, for example a lower alkanol such as ethanol. A preferred method is to reduce the reaction mixture with hydrogen on a catalyst to a hydrogen pressure of 3.4 to 6.3 kg / cm2, and a preferred catalyst is platinum oxide.

The starting material, i.e. 1- (3-amino-propyl) -3,4-diphenyl-1H-pyrazole, can be prepared by various methods. One technique comprises the reduction, by an alkali metal and aluminum hydride, of an œ- [1- (3,4-diphenyl-1H-pyrazolyl)] - propionamide of formula II:

C6H5

He he

C6H5

(CH2> 2

2-

nh.

C6H5

T

NOT

-C6H5

I

(CH2) 3-KH2

II

The reaction is preferably carried out in an organic solvent inert under the reaction conditions, for example dioxane, diethyl ether or tetrahydrofuran at temperatures between about -10 ° C and the boiling point of the solvent used. The desired starting material of formula II is prepared by reaction of 3,4-diphenylpyrazole with a lower alkyl acrylate in the presence of a strong base, saponification of the resulting ester, transformation of

C6H5

^ n '

NOT

c m

6 5

so the acid resulting in the corresponding acid chloride and reaction of the latter with ammonia in the presence of an acid acceptor, for example pyridine.

Another method of preparing the starting material consists in reducing, with safe hydrogen, a catalyst of Raney ss nickel in the presence of ammonia the l- (cyanoethyl) -3,4-diphenyl-1H-pyrazole of formula III for obtain the amino compound:

f cat.

nh.

C6H5

(CH2) 2 C = N III

(ch2) 3-nh2

627172

The reduction is carried out in an inert organic solvent under the reaction conditions, for example a lower alkanol, at ambient temperature and at hydrogen pressures of between 3.5 and 6.3 kg / cm 2.

The starting material of formula III is prepared by reacting 3,4-diphenylparazole with acrylonitrile in the presence of a strong base.

A third technique for preparing the starting compound consists in reacting an l- [3- (tosyloxy) propyl] -3,4-diphenyl-1H-pyrazole of formula IV, with ammonia, as represented in the reaction next:

? 6H5

C6H5

C6H5

NH-

C6H5

(CH) OTs 3

iv ••

The reaction is carried out by heating a mixture of the compound of formula IV with ammonia in an organic solvent inert under the reaction conditions, for example acetonitrile or a lower alkanol, to a temperature of approximately 100 to approximately 150 ° C. .

The intermediate of formula IV is prepared by condensation of formyldoxybenzoin [Russell et al., J. Am. Chem. Soc. 76, 5714-5718 (1954)] with a 3-hydroxy-propyl-hydrazine, then by reaction of the resulting 1- (3-hydroxy-propyl) -3,4-diphenyl-1H-pyrazole with a toluenesulfonyl halide to

20

25

C6 "5

T

NOT

C6H5

(ch_) -n = b presence of pyridine.

Another process for preparing the starting compound consists in reacting 3,4-diphenyl-1H-pyrazole with a strong base, for example sodium hydride, in an organic solvent inert under the reaction conditions, by example tetrahydrofuran, dioxane or diethyl ether, and reacting the resulting sodium salt with a halopropylamine in the same solvent system at its reflux temperature. The process is illustrated by the following reaction:

C6H5

x- (ch2) 3

-NR ^

•not'

i

H

- nh.

acid acceptor [here called process (b)]; or the introduction of a hydroxypropyl group in position I of 3,4-diphé-nylpyrazole by condensation of formyldoxyoxybenzoin with zole by addition of Michael of a lower alkyl acrylate or <• »a 3-hydroxypropyl- hydrazine [here called process (c)]. These where X represents a halogen.

As indicated above, the preparation of the final product of formula I requires the alkylation of 3,4-diphenylpyra-

acrylonitrile (here called process (a)); the alkylation of 3,4-diphenyl-pyrazole with a halopropylamine in the presence of various transformations are represented schematically in the following diagram:

OR!

x- (ch2) 3NH2

C6H5

coor

C6H5

(ch2) 2

C6H5

c, h

6 5

'cho

+ H2 ^ NH (CH2) 3OH_v ^ 1 ^

(ch2) 3oh

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4

where X has the meaning indicated above. From the previous diagram, it can be seen that the three processes result in the formation of a mixture of the 3, 4-diphenyl and 4,5-diphenyl derivatives. In processes (a) and (b), these mixtures originate from the alkylation of one of the two possible tautomeric forms of the starting diphenyl-pyrazole. In process (c), these mixtures result from a lack of reactive selectivity of the carbonyl, ketone and aldehyde groups of the starting formydeoxybenzoin. Generally speaking, alkylation with a lower alkyl acrylate or with acrylonitrile [process (a)] produces about 85% of the desired 3,4-diphenyl isomer; alkylation with a halopropylamine [process (b)] produces an approximately 50:50 mixture of the isomers; and method (c) appears to promote the formation of the 3,4 isomer. In all cases, it is necessary to separate the 3,4 and 4,5 isomers from each other at some point in the overall synthesis, regardless of the process used.

The structure assignments for the 3,4- and 4,4-diphenyl isomers were made based on their ultraviolet and NMR spectra and their behavior in gas chromatography. Thus, one can see a coherent and unambiguous relationship between the isomers in the ultraviolet spectra. One element of each pair of isomers has absorption maxima at 223 nm and 249 ± 2 nm, while the other has absorption maxima at 227 + 2 and 252 + 1 nm in 95% ethanol . In addition, the extinction coefficients are generally higher for element 227/252 of the couple. Thus, one can use ultraviolet spectra to identify an isomer once a particular structure has been assigned to any particular isomer in the whole series.

Such an assignment can be made using NMR data. Elguero and Jacquier [J. Chim. Phys. 63.1242 (1966)] have shown that in very polar solvents such as hexa-methylphosphortriamide, the proton in position 3 of a series of 1,4-disubstituted pyrazoles is always found in strong fields compared to the proton in position 5. If we apply this to this series, we can attribute the substitution 3,4-diphenyl to the elements of the series having the maxima uv 227/252 and the substitution 4,5,5-diphenyl to the series 233/249 because, in the NMR spectra, the same absorption is obtained in the weak fields for the proton in position 5 for the 3,4-diphenyl isomer, the absorption in the strong fields for position 3 being absent. Conversely, the same absorption is obtained in the strong fields for the proton in position 3 of the 4, 5-diphenyl isomer, while the absorption in the weak fields of the proton in position 5 is absent.

In the NMR spectra, a predictable and very regular relationship between the elements of a pair is also obtained for the chemical displacements of methylene protons close to the hydrogen atom in position 1 of the pyrazole ring. The 3,4-diphenyl isomer is always found in weak fields compared to the 4,5-diphenyl isomer.

Finally, the retention times of the siomers by gas chromatography reflect the previous dichotomy found in the spectral data, the isomer 3,4 having in all cases the longest retention time.

Due to the presence of a basic amino group, the free base form represented by the above formula I reacts with organic and mineral acids to form acid addition salts. The acid addition salts are prepared from any organic or mineral acid. They are obtained in a conventional manner for example by direct mixing of the base with the acid or, when this is not appropriate, by dissolving either the base or the acid or both separately in water or in an organic solvent and by mixing the two solutions, or by simultaneously dissolving the base and the acid in a solvent. The resulting acid addition salt is isolated by filtration if it is insoluble in the reaction medium, or by

evaporating the reaction mixture to leave the acid additive salt as a residue. The acid parts or anions of these salts are in themselves neither new nor determinative and it can therefore be any acid anion or any acid substance capable of forming salts with the base.

Typical acids for the formation of acid addition salts include acetic acid, isobutyric acid, α-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaric acid, acid succinic, succinamic acid, tannic acid, glutamic acid, tartaric acid, oxalic acid, pyromucic acid, citric acid, lactic acid, glycolic acid, acid gluconic, saccharic 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-indole-acetic acid, barbituric acid, sulfamic acid, methanesulfonic acid, ethane-sulfonic acid, isethionic acid, benzenesulfonic acid, p-acid -toluenesulfonic, butylarsonic acid, methanephosphonic acid, acid resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, nitric acid, l sulfuric acid, phosphoric acid, arsenic acid, etc.

All the acid addition salts can be used as sources of the free base forms by reaction with an inorganic base. It will thus be seen that if one or more of the characteristics of a given base or of its acid addition salt, such as solubility, molecular weight, physical appearance, toxicity, etc., make this form unsuitable for end use, it can easily be transformed into another more suitable form. For pharmaceutical needs, the addition salts of relatively non-toxic and pharmaceutically acceptable acids are obviously used, for example hydrochloric acid, lactic acid, tartaric acid, etc.

As indicated previously, in the procedures of conventional pharmacological tests, the compound of formula I above where n is 3 and N = B is a dimethylamino group, and its acid addition salts have proved to be useful as antidepressant agents.

The compound of formula I can be administered in the same way as the known antidepressant and analgesic agents, that is to say parenterally or orally in any of the conventional pharmaceutical forms such as, for example, solutions, suspensions, tablets, capsules, etc.

The useful properties of the compound obtained according to the invention have been demonstrated by conventional pharmacological procedures easily implemented by technicians of these procedures, so that the actual determination of the digital biological data for a particular test compound can be do without any too important experimentation.

The test procedure used to determine the antidepressant activity of the compound obtained according to the invention is described below below: male Swiss-Webster mice (Taconic Farms) weighing 19 to 24 g are divided into four groups of 9 or 10 mice per group. The first three groups are administered the test compound at respective doses of 64.16 and 4 mg per kg, in solution in water as an acid addition salt or as a suspension in tragacanth at 1%. The fourth group receives only the vehicle. Four hours after administration, all control and test animals are treated with 50 mg / kg (i.p.) of tetrabenazine and placed in a photocell activity cage [described by Harris et al., Psychon. Sci.,

s

10

15

20

25

30

35

40

45

50

55

"0

65

4, 267 (1966)] equipped with a digital counter to record the number of times a light beam falling on a photocell is interrupted during the test period. Starting 30 minutes after administration of tetrabenazine, the photoelectric cells are activated and the cell counts are recorded over a period of 50 minutes. The compounds are then classified as active or inactive, the activity being defined as a significant difference (threshold 0.05 at least, with two limits) between the counts of the photoelectric cells for the control group and for the group treated according to the statistical probability of Kruskal- "Waüis.

The structural formula of the compound obtained according to the invention was established by the mode of synthesis, by elementary analysis and by the ultraviolet, infrared, and nuclear magnetic resonance spectra. The course of the reactions is followed and the homogeneity of the products is checked by thin layer chromatography. The manner and method of making and using the invention, and the best embodiment of the invention will now be described to enable those skilled in the art to use it. Melting points are not corrected unless otherwise indicated.

Preparation of intermediaries Preparation 1

To a solution of 22 g (0.1 mole) of 3,4-diphenylpyrazole in 150 ml of dioxane, 10 ml of Triton B (benzyltrimethylammonium hydroxide) is added and then the solution is treated dropwise with 26.3 ml ( 0.4 mole) of acrylonitrile while maintaining the temperature at 40-45 ° C. The mixture is stirred for a further 20 minutes at room temperature, acidified by the addition of 3 ml of acetic acid and poured into 700 ml of ice and water. The mixture is then treated with 200 ml of ethyl acetate and approximately one tablespoon of sodium chloride, the mixture is stirred and filtered to remove an insoluble precipitate. The organic layer is separated from the filtrate and the aqueous layer is extracted twice with ethyl acetate. The combined organic extracts are washed with a saturated sodium bicarbonate solution and then with brine, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to dryness, and a red oil which is crystallized from 60 ml of methanol. 13.82 g of a substance are thus obtained, mp 90-103 ° C, the gas chromatographic analysis of which indicates the presence of two isomers in a 13/87 ratio comprising 13% of the 4,5- isomer. diphenyl and 87% of the 3,4-diphenyl isomer of 1,2-cyanoethyldiphenal-1H-pyrazole.

In another test, a thin suspension of 7.7 g (0.14 mole) of potassium hydroxide and 805 g (3.65 moles) of 3,4-diphenylpyrazole in 3.41 ml is rapidly stirred. ethanol while treating with 292 ml (4.4 moles) of acrylonitrile

627172

trile which is added dropwise over two hours. Once the addition is complete, stirring is continued for two hours while cooling in an external ice bath, then the mixture is left to stand for 2 days at room temperature. The mixture is then cooled once again to 0 ° C and the solid product is collected and dried, which gives 723 g of substance, mp 103-108 ° C. Recrystallization of the latter in the ethanol provides 691 g of substance, mp 108-111 ° C (softening 106 ° C) which gas chromatography shows that it comprises 92-93% of the 3,4-isomer and 6-7% of the isomer 1- (2-cyanoethyl) -diphenyl-1H-pyrazole 4,5-diphenyl.

Preparation 2

To a suspension of 13.8 g (0.05 mole) of 1- (2-cyano-ethyl) -3,4-diphenyl-1H-pyrazole described in preparation 1 above in a solution of 100 ml of methanol containing anhydrous ammonia, a small amount of Raney nickel catalyst is added and the mixture is reduced in a Parr stirrer at a hydrogen pressure of 3.5 kg / cm2. After 3 days, the mixture is filtered, the filtrate is brought to dryness which leaves a residue which is dissolved in 40 ml of isopro-panol and 30 ml of isopropyl acetate. The solution is treated with 20 ml of 7.5N ethanolic hydrochloric acid, and the solid which separates is collected, washed with additional solvent and dried, giving 15.2 g of 1- (dihydrochloride). 3-aminopropyl) -3,4-diphenyl-1H-pyrazole, mp 177-188 ° C, of which gas chromatography shows that it is a 94% pure isomer.

Example

A solution of 11.5 g (0.04 mole) of 1- (3-aminopropyl) is reduced in a Parr stirrer on 500 mg of platinum oxide at a hydrogen pressure of 3.5 kg / cm 2 -3,4-diphenyl-1H-pyrazole and 60 ml of 35% aqueous formaldehyde in 125 ml of ethanol. The reduction is stopped after taking 2 kg / cm 2, an additional 500 mg of catalyst is added and the reduction is continued until an additional 2.7 kg / cm 2 is taken. The reduction is stopped once again, formaldehyde and additional catalyst are added again and the reduction is continued until absorption of 2.2 kg / cm 2. The mixture is treated as described in Example 1A above and the product is transformed into the hydrochloride, which gives two crops totaling 6.6 g of 1- [3- (N, N-dimethyl) hydrochloride. -amino) propyl)] - 3,4-diphenyl-1H-pyrazole, 4.0 g, mp 178-101 ° C, and 2.6 g, mp 185-191 ° C.

Bioassay results

The results given in tests for convulsion induced by antitetrabenazine (TB) for the 3,4-diphenyl compound obtained according to the invention are given in the table below. All doses are expressed in milligrams per kilogram (mg / kg).

5

5

10

1S

20

25

30

35

40

45

50

B