CH626067A5 - Process for the preparation of 1-(lower aminoalkyl)-3,4-diphenyl-1H-pyrazoles - Google Patents

Description

This invention relates to the preparation of 1-aminoalkyl-lower-3,4-diphenyl-1 H-pyrazoles, useful as antidepressants and analgesics.

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) describe 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, and“ C.A. ”, 63.16329d (1965) describe 1- (2-diethylaminoethyl) -3,5-diphenyl-1H-pyrazole for which no utility is described; Jones et al., "J. Org. Chem. ", 19,1428-1434

(1954) describe various 1- (2-aminoethyl) -3-phenyl-1 H-pyrazoles which have been tested and found to be inactive as stimulants of gastric secretion and histamine agents; and Büchi et al., "Helv. Chim. Acta. ”, 38,670-679 (1955) describe 1- (2-dimethylaminoethyl) -3-phenyl-4-methyl-1 H-pyrazole for which analgesic activity is indicated.

However, nothing in the prior art suggests the particular group of 1-aminoalkyl-lower-3,4-diphenyl-1H-pyrazoles described and claimed here which owe their desired antidepressant and analgesic activities to certain characteristics of precise structures.

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

(CH2) n-N = B

where n and n have the meanings given above, and N = B is an amino, methylamino, dimethylamino or diethylamino group. The reduction is preferably carried out in an inert organic solvent under the reaction conditions, for example a lower alkanol, at room temperature and at hydrogen pressures of between 3.5 and 6.3 kg / cm 2. The process is particularly advantageous for preparing the compounds where n is 3.

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

As indicated previously, the preparation of the products of formula III requires the alkylation of 3,4-diphenylpyrazole by addition of Michael of acrylonitrile. This transformation is shown schematically in the following diagram;

(Formulas at the top of the next page.

60

where n and N = B have the meanings indicated above. From the previous diagram, it can be seen that the process results in the formation of a mixture of 3,4-diphenyl and 4,5-diphenyl derivatives. These mixtures originate from the alkylation of one of the two possible tautomeric forms of the starting diphenylpyrazole. Generally speaking, alkylation with acrylonitrile [process (a)] produces about 85% of the desired 3,4-diphenyl isomer. In all cases, it is normally necessary to separate the 3,4 and 4,5 isomers

626067

C6H5

C6H5

<>

C6H5

NOT

C6H5

N H

CN

N-II

C6H5

the

C6K5

NOT

'NOT

4

C6H5

M "

C6H5

(CH2) n-N = D

(CH2) n, CN

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 maximums at 223 nm and at 249 + 2nm, while the other has absorption maximums at 227 + 2 and 252 + lnm 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 hexamethylphosphoro-triamide, the proton in position 3 of a series of pyrazoles

1.4-disubstituted is always in the strong fields compared to the proton in position 5. If this is applied to the present series, the substitution of 3,4-diphenyl can be attributed to the elements of the series having the UV 227 maximums / 252 and the substitution 4,5-diphenyl for the 233/249 series 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 of position 3 being absent. Conversely, the same absorption is obtained in the strong fields for the proton in position 3 of the isomer.

4.5-diphenyl, while 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 couple is also obtained for the chemical displacements of the methylenic 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 isomers by gas chromatography reflect the previous dichotomy found in the spectral data, the 3,4-isomer having in all cases the longest retention time.

Due to the presence of a basic amino group, the free base form represented by the preceding formula I reacts with organic and mineral acids by forming 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 a organic solvent and mixing the two solutions, or 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 addition salt as a residue. The acid parts or anions of these salts are not in themselves new or determinative, and therefore may be any acid anion or any acidic substance which can form salts with the base.

Typical acids 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, succinamic acid, tannic acid, glutamic acid, tartaric acid, oxali-30 acid as, pyromucic acid, citric acid, lactic acid, glycolic acid, gluconic acid, 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, l 3-indole-acetic acid, barbituric acid, sulfamic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, butylarsonic acid, methanephosphonic acid, 40 acid resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, nitric acid, sulfuric acid, acid phosphoric, 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 45 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 purposes, the addition salts of relatively non-toxic and pharmaceutically acceptable acids, for example hydrochloric acid, lactic acid, tartaric acid, etc. are obviously used.

As indicated previously, in the procedures 55 of conventional pharmacological tests, the compounds of formula I above where n is 3 and N = B is a methylamino or dimethylamino group and their acid addition salts have been found to be useful as antidepressant agents, while the compounds of formula I above where n is 3 and N = B is an amino group or 60 diethylamino and those where n is 2 and N = B is a diethylamino group have been found to be useful as pain relievers.

The compounds of formula I can be administered in the same manner as known antidepressant and analgesic agents, i.e. parenterally or orally in any of the conventional pharmaceutical forms, such as, for example, solutions. , suspensions, tablets, capsules, etc.

The useful properties of the compounds of this invention have been demonstrated by standard pharmacological procedures

626067

4

easily implemented by technicians of these procedures, so that the actual determination of the final digital biological data for a particular test compound can be done without any undue experimentation.

The test procedure used to determine the antidepressant activity of the compounds of 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 / kg, in solution in water, in the form of an acid addition salt or in the form of 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 (ip) of tetrabenazine and placed in a photocell activity cage [described by Harris et al., "Psychon . Sci. ”, 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 min after administration of tetrabenazine, the photoelectric cells are activated and the cell counts are recorded over a period of 50 min. The compounds are then classified as being 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 Kruskal-Wallis statistical probability test.

The test procedures used to determine the analgesic activities of the compounds of this invention have been described in detail in the prior art and are as follows: the acetylcholine-induced abdominal constriction test, which is a primary selection test analgesic compounds for measuring the ability of a test agent to suppress abdominal constrictions induced by acetylcholine in mice, described by Collier et al., "Brit. J. Pharmacol. Chemotherap. ”, 32, 295 (1968), and the phenyl-o-quinone-induced convulsion test, which is also a primary screening test for analgesics, designed to measure the ability of a test to prevent convulsions induced by phenyl-p-quinone in mice, described by Pearl and Harris, "J. Pharmacol. Exptl. Therap. ", 154, 319-323 (1966).

The developed formulas of the compounds of this invention were established by the mode of synthesis, by elemental 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

To a solution of 22 g (0.1 mol) of 3,4-diphenylpyrazole in 150 ml of dioxane, 10 ml of triton B (benzyltrimethylammonium hydroxide) is added and the solution is then treated dropwise with 26.3 ml ( 0.4 mol) of acrylonitrile while maintaining the temperature at 40-45 "C. The mixture is stirred for an additional 20 min at room temperature, acidified by the addition of 3 ml of acetic acid and poured into 700 ml of ice and water, then the mixture is 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. of the filtrate and the aqueous layer is extracted twice with ethyl acetate. The combined organic extracts are washed with saturated sodium bicarbonate solution then with brine, dried over magnesium sulphate, treated with carbon, we filter them and evaporate them to dryness, and we get a red oil that we cry tallises in 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-diphenyl isomer and 87% of the isomer

1,2-cyanoethyldiphenyl-1 H-pyrazole 3,4-diphenyl.

In another test, a suspension is stirred quickly

7.7 g (0.14 mol) thick potassium hydroxide and 805 g (3.65 mol) 3,4-diphenylpyrazole in 3.41 ethanol while treating with 292 ml (4.4 mol) of acrylonitrile which is added dropwise over 2 hours. Once the addition is complete, the stirring is continued for 2 h while cooling in an external ice bath, then the mixture is left to stand for 2 d 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 (m.p. 103-108 C). Recrystallization of the latter from ethanol provides 691 g of substance (mp 108-111 C, softening 106 C) which gas chromatography shows that it comprises 92-93% of the isomer 3,4 and 6- 7% of the isomer

4.5- diphenyl of 1- (2-cyanoethyl) diphenyl-1 H-pyrazole.

Preparation of final products

Example 1:

A. To a suspension of 13.8 g (0.05 mol) of 1- (2-cyanoethyl) -

3,4-diphenyl-1H-pyrazole described in the above preparation 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 agitator 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 isopropanol and 30 ml of isopropyl acetate. The solution is treated with 20 ml of 7.5N ethanolic hydrochloric acid, the solid which separates is collected, washed with additional solvent and dried, giving 15.2 g of 1- (3-dihydrochloride) -aminopropyl) -3,4-diphenyl-1 H-pyrazole (mp 177-188 ° C) which gas chromatography shows that it is a 94% pure isomer.

B. Following a procedure similar to that described in part A above, reduction is carried out with hydrogen on a Raney nickel catalyst at 3.5 kg / cm2.27.3 g (0.1 mol ) 97% pure 1- (2-cyanoethyl) -3,4-diphenyl-1H-pyrazole described in the above preparation, in a solution of methylamine in ethanol; after isolation of the product as described in part A, it is transformed into the hydrochloride which is recrystallized from ethanol. 5.9 g of 1- [3- (N-methylamino) propyl] -3,4-diphenyl-1H-pyrazole hydrochloride are thus obtained (mp 124-132 ° C).

C. Following a procedure similar to that described in part A above, in three separate tests, 100 g (0.36 mol) portions of l- are reduced to 5 g of 10% palladium on carbon. 92-93% pure (2-cyanoethyl) -3,4-diphenyl-1H-pyrazole, described in preparation A above, in a solution containing

110-120 g of methylamine in 960 ml of ethanol; first the product is transformed into its Oxalate (mp 140-143 ° C) which is again transformed into the free base and the latter is transformed into the dihydrochloride which is recrystallized from isopropanol in order to obtain a yield total of the three trials of 262 g of 1- [3- (N, N-dimethylamino) propyl] -3,4-diphenyl-1H-pyrazole dihydrochloride (mp 183-185 ° C, softening 175 ° C). It is estimated, by thin layer chromatography, that the latter contains from 1 to 2% of total impurities.

Bioassay results

The results obtained in convulsion trials induced by antitetrabenazine (TB), acetylcholine (Ach) and phenylquinone (PPQ) for the 3,4-diphenyl compounds of the invention are given in the table. All the 3,4-diphenyl compounds are identified by the numbers of the preceding examples describing their preparation, and all the doses are expressed in milligrams per kilogram (mg / kg).

5

10

15

20

25

30

35

40

45

50

55

60

65

5

626067

Examples

TB

Ach

PPQ

1A

Inact. (at)

ED50 = 11 (s.c.)

-

1B

Act / 16.64

-

-

Inact./4

-

-

1E *

Inact. (at)

60% / 100 (s.c.)

DE5O = 90 (p.o.)

67% / 50 (s.c.)

53% / 10 (s.c.)

DES0 = 29 (p.o.)

ip **

Inact. (at)

ED50 = 2.2 (s.c.)

(a) Tested at 4.16 and 64 mg / kg (p.o.)

* 1E = 1- [2- (N, N-diethylamino) ethyl] -3,4-diphenyl-1 H-pyrazole hydrochloride, m.p. 147-148 "C.

** 1F = 1- [3- (N, N-diethylamino) propyl] -3,4-diphenyl-1 H-pyrazole hydrochloride, m.p. 165-166'C.

Claims (6)

626067 2. Method according to claim 1, characterized in that the starting materials are chosen to prepare a compound in which n is 3 and N = B is a dimethylamino or methylamino group. 2 Process for the preparation of a compound of formula I: C6H5 " C6V -C6H5 ï 6 O (I) (I) (CH-) -N = B 2 n where n is 2 and N = B is a diethylamino group; or n is 3 and N = B is an amino, methylamino, dimethylamino or diethylamino group, or one of its acid addition salts, characterized in that reduced by hydrogen in the presence of ammonia, methyl -amine, dimethylamine or diethylamine, respectively, on a catalyst, a compound of formula III: CcH ~ 6 r> C6H5 • NOT (III) NOT I (CH2) n, C = N where n 'is n - 1; and if desired, convert the free base to one of its acid addition salts. 3. Method according to claim 1, characterized in that the starting materials are chosen to prepare a compound in which n is 3 and N = B is an amino or diethylamino group, where n is 2 and N = B is a group diethylamino. 25 (CH.) -N = B zn and chemically called l- [3- (N = B) -propyl] -and l- [2- (N = B) -ethyl] -3,4-diphenyl-1 H- pyrazoles, where either n is 2 and N = B is a diethylamino group, or n is 3 and N = B is an amino, methylamino, dimethylamino or diethylamino group. Compounds where n is 3 and N = B is a dimethylamino or methylamino group are particularly useful as antidepressant agents, while those where n is 2 and N = B is a diethylamino group are useful as analgesic agents. The process for preparing the compounds of formula I consists in reducing with hydrogen over a catalyst, for example Raney nickel, in the presence of ammonia, a 1- (cyanoalkyl-lower) -3,4-diphenyl-1 H -pyrazole of formula III to obtain the corresponding compounds where N = B is an amino group. If the compounds in which N = B is a methylamino, dimethylamino or diethylamino group are desired, the reaction is then carried out in the presence of methylamine, dimethylamine or diethylamine, respectively. The process is illustrated by the following reaction: C6H5 C, H- 6 D (ili) -NOT <CH2) n, C = N C6H5 (n '= n — 1) C6H5 (I)