KR810000469B1 - Process for preparing 1-amino lower alkyl 3,4 diphenyl-1h-pyrazoles - Google Patents

Abstract

Title compds.(I; n = 2, 3; N=B is diethylamino, amino, methylamino, dimethylamino) and their acid salts, useful as antidepressants or anodynes, were prepd. by reduction of compound II(n' = 2). Thus, 0.42 g lithium aluminium hydride and 3.5 gβ -[1-(3,4-diphenyl-1H-pyrazolyl) -N,N-dimethylpropionamide were stirred and refluxed in 50 ml THF for 18 hr. The obtained products were separated by adding 10.4 ml H2O, 0.6 ml 10 % NaOH and 1 ml H2O successively, to give 1.2 g 1-[3-(N,N-dimethylamino)propyl -3,4-diphenyl-1H-pyrazol dihydrochloride.

Description

[Name of invention]

Method for preparing 1-amino-lower alkyl-3,4-diphenyl-1H-pyrazoles

Detailed description of the invention

The present invention relates to 1-amino-lower alkyl-3,4-diphenyl-1H-pyrazoles useful as antidepressants and analgesics.

et al., Helv. Chim. Acta., 38, 670-679(1955)에 공지되어 있다.1- (2-aminoethyl) -3,5-diphenyl-1H-pyrazole with local anesthetic activity was found in Rosenthal, Arch. Intern. Pharmacodynamie, 96, 220-230 (1953); 1- (3-aminopropyl) -3,5-diphenyl-1H-pyrazole is disclosed in Grandberg et al., Ih. Obsch. khim. 31, 3700-3705 (1961) CA 57, 9839 (1957), but their usefulness is not mentioned. 1- (2-diethylaminoethyl) -3,5-diphenyl-1H-pyrazole-Torf et al., Biol. Aktivn. Soedin. Akad. Nauk SSR, 1965, 171-174; Known in CA 63, 16329d (1965), but its usefulness is not mentioned. As a result, various 1- (2-aminoethyl) -3-phenyl-1H-pyrazoles which were found to be inert as gastric juice secretion accelerators and histamines were described by Jones et al., J. Org. Chem. 19, 1428-1434 (1954); And 1- (2-dimethylaminoethyl) -3-phenyl-4-methyl-1H-pyrazole, whose analgesic activity is mentioned

et al., Helv. Chim. Acta., 38, 670-679 (1955).

However, any known technique, due to any particular aspect of the invention described and claimed herein, is a 1-amino-lower alkyl-3,4-diphenyl-1H-pyra of desired antidepressant and analgesic activity. No special group of sols was presented.

The present invention has the following structural formula (I) and chemically 1- [3- (N = B) -propyl]-and 1- [2- (N = B) -ethyl] -3,4-diphenyl- It relates to a compound represented by 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. Compounds in which n is 3 and N = B is amino or diethylamino and compounds in which n is 2 and N = B is diethylamino are also useful as analgesics, but compounds in which n is 3 and N = B is dimethylamino or methylamino It is particularly useful as a treatment for depression.

Compounds of formula (I) are prepared by reducing W- [1- (3,4-diphenyl-1H-pyrazolyl)]-lower-alkanamides of formula (II) with alkali metal aluminum hydride.

Where n and N = B are as above and n 'is n-1. Preferably the reaction is carried out in an inert organic solvent under the reaction conditions. For example, it is carried out in dioxane, dimethyl ether at a temperature up to the boiling point of the solvent used at about −10 ° C. This method is particularly advantageous when preparing compounds in which n 'is 2 and n is 3. Preferred starting materials of formula (II) are those reacting 3,4-diphenylpyrazole with lower-alkyl acrylates in the presence of strong bases and saponifying the resulting esters to convert the resulting acid to the corresponding acid chloride, which then acidifies the acid chloride. Prepared by reaction with a suitable amine in the presence of a receptor, for example pyridine.

The preparation of the final product of formula (I) involves the alkylation of 3,4-diphenylpyrazole by the addition of lower-alkyl acrylates or acrylonitrile to Michael (here referred to as method (a)); Alkylation of 3,4-diphenylpyrazole with halo-lower-alkylamine in the presence of an acid acceptor, represented by method (b); Or introducing a hydroxy-lower-alkyl group at the 1-position of 3,4-diphenylpyrazole by condensing formyl deoxyoxybenzoin with W-hydroxy-lower-alkyl-hydrazine, wherein method (c) is indicated. It is necessary. These various conversions are outlined in the following process diagram.

Where n and N = B are as defined above and X is halogen.

From the process diagram, it can be seen that the result of all three methods results in a mixture of 3,4-diphenyl and 4,5-diphenyl products. In methods (a) and (b), these mixtures result from alkylation of one of two possible tautomers of diphenylpyrazole starting materials.

In process (c), the mixtures are produced by the lack of reaction selectivity of ketone and aldehyde carbonyl groups of formyldecoxy benzoin starting material. Generally speaking, alkylation with lower-alkyl acrylates or acrylonitrile [method (a)] yields about 85% of the desired 3,4-diphenyl isomers; Alkylation with halo-lower-alkylamine [method (b)] yields an isomeric mixture of about 50:50; And method (c) appears to favorably produce 3,4-isomers. In all cases, regardless of the method used, the 3,4- and 4,5-isomers need to be separated from each other at any time in any synthesis.

Structural assignment of the 3,4- and 4,5-diphenyl isomers was made based on their ultraviolet and NMR spectra and their behavior on gas chromatography. Thus, a consistent and reliable relationship between isomers can be seen within the ultraviolet spectrum. One of the isomeric pairs shows an absorption maximum at 223 nm and 249 ± 2 nm in 95% ethanol and the other shows an absorption maximum at 227 ± 2 nm and 252 ± 1 nm. Moreover, the extinction coefficient is generally higher for the pair of 227/252 members. As such, once a particular structure is assigned to a particular isomer of the entire series, the ultraviolet spectrum can be used to identify the isomer. Such assignments can be made using NMR data. Elguero and Jacquier [J. Chim. Phys. 63, 1242 (1966)], in highly polar solvents, such as hexamethylphosphoramide, have always shown that the proton at the 3-position of the series of 1,4-disubstituted parasols is always higher than the 5-position quantum. Showed in the hush. In the NMR spectrum, the same low magnetic absorption from the 5-position quantum is obtained for the 3,4-diphenyl isomer and there is no high magnetic absorption from the 3-position, so applying this to this series results in the 227 / 252uv maximum series. 3,4-diphenyl substitution of the submaterial and 4,5-diphenyl substitution to the 233/247 series were formed. In contrast, for 4,5-diphenyl isomers the same high magnetic absorption from the 3-position quantum is obtained while there is no low magnetic absorption from the 5-position quantum.

In the NMR spectrum, a completely regular and predictable relationship between a pair of members is obtained by chemical shifts of methylene protons adjacent to the nitrogen atom at the 1-position of the pyrazole ring. 3,4-diphenyl isomers are always found in a lower magnetic field than 4,5-diphenyl isomers.

Finally, the retention time of isomers on gas chromatography reflects the dichotomy found above in the spectral data and reflects that the 3,4-isomer has a long holding time in all cases.

Because of the presence of basic amino groups, the free base type represented by formula (I) reacts with organic and inorganic acids to form acid addition salts. Acid addition salts are prepared from all organic or inorganic acids. They are obtained by conventional methods, for example by mixing the base directly with an acid, or when it is not suitable, by dissolving the acid and base together or in water or an organic solvent and mixing the two solutions together, or by dissolving the acid and base together in a solvent. . The acid addition salts produced are either isolated by filtration if they are insoluble in the reaction medium or the reaction medium is evaporated to obtain acid addition salts as a residue.

Since acid components or anions in the di- salt form are not new or important in themselves, any acid anion or acid-like substance capable of forming a salt with a base is possible.

Representative acids for forming acid addition salts are formic acid, acetic acid, isobutyric acid, α-mercaptopropionic acid, trifluoroacetic acid, unggeum acid, fumaric acid, succinic acid, succinic acid, tannic acid, glutamic acid, tartaric acid, oxalic acid, pyromus acid, citric acid , Lactic acid, glycolic acid, gluconic acid, sakaric 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, acethionic acid, benzenesulfonic acid, P-toluenesulfonic acid, butylarsonic acid, methane Phosphonic acid, acidic resin, hydrofluoric acid, hydrochloric acid, bromic acid, iodide, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, arsenic acid and the like.

All acid addition salts are useful as a source of free base form by reaction with an inorganic base. A given base or its acid addition salt can easily be converted to another, more suitable form if the form is inappropriate for the purpose due to one or more of its characteristics such as solubility, molecular weight, physical shape, toxicity, and the like. For pharmaceutical purposes, acid addition salts of relatively non-toxic and pharmaceutically acceptable acids such as hydrochloric acid, lactic acid, tartaric acid and the like are of course used.

As indicated above, in the standard pharmacological test procedures, compounds of formula (I) and acid addition salts thereof, wherein n is 3 and N = B is methylamino or dimethylamino, have been found to be useful as antidepressants. On the other hand, it has been found that compounds of the above formula wherein n is 3, N = B is amino or diethylamino and n is 2 and N = B is diethylamino are useful as analgesics.

The compound of formula (I) can be administered parenterally or orally in the same manner as known antidepressants and analgesics, ie in the form of all conventional pharmaceutical forms such as solutions, suspensions, tablets, capsules and the like. .

The useful properties of the compounds of the present invention are shown by standard pharmacological processes that can be easily performed by those skilled in the pharmacological test process, so that the actual determination of various biological data, which is a definition for a particular test, can lead to extensive experiments. You can be sure without having to.

The test procedure used to determine the antidepressant activity of the present invention is described below. 19-24 grams of male Swiss-Webster rats (Tagonic kennels) were divided into 4 groups with 9-10 digits per group. The first three groups received 64., 10 and 4 mg / kg of test compound, respectively, in water-soluble acid addition salts in water or in the form of a suspension in 1% tragacanth rubber. The fourth group received only excipients. Four hours after dosing, a photovoltaic cage equipped with a digital counter to record and time 50 mg / kg (i.p) tetrabenazine to all control and test animals [Harrs et al., Psychon. Sci., 4, 267 (1966)], placed above, the light beams colliding with the photocells are suspended during the test period. Starting 30 minutes after tetrabenazine administration the photovoltaic unit was activated and the photocell count was recorded over 30 minutes. It is then recorded whether the compound is active or inactive, and activity is defined as a significant difference (0.05 or less, two tails) between drug and control photocell counts according to the Kruskal-wallis statistical prediction test. do.

The test procedure used to determine the analgesic activity of the compounds of the present invention is as follows: acetylcholine-derived abdomen, a primary analgesic sample for determining the ability of test compounds to suppress acetylcholine-induced abdominal contraction in rats. Shrinkage tests were performed by Collier et al., Brit. J. Pharmacol. chemotherap. 32, 295 (1968), and phenyl P-quinone-induced trials and primary analgesic assays, designed to determine the ability of test compounds to inhibit phenylP-quinone-induced trials in rats, were described in Pearl and Harris, J. Pharmacol. Exptl, Therap. 154, 319-323 (1966).

The structure of the compound of the present invention was established by synthetic method, elemental analysis and ultraviolet, infrared and nuclear magnetic resonance spectra. The reaction path and homogeneity of the product was confirmed by thin layer chromatography.

The manners and methods of making and using the present invention and the best mode of carrying out the present invention contemplated by the inventors are described to enable those skilled in the art to make and use. Melting points were not corrected unless otherwise indicated.

[Production of Intermediate Product]

11 ml of Triton B was added to a solution of 28 g (0.127 mol) of 3,4-diphenyl-pyrazole in 130 ml of dioxane. 45 ml of methyl acrylate was added dropwise to the solution over about 15 minutes at ambient temperature. The mixture is stirred for 1 hour 45 minutes, acidified with acetic acid to pH5.5 and poured onto ice. The mixture was treated in the same manner as in Preparation 1 to prepare methyl β- [1- (3,4-dimethyl-1H-pyrazolyl)] propionate and methyl β- [1- (4,5-diphenyl-1H- 40 g of a mixture of pyrazolyl)]-propionate was obtained in oil form.

The solution obtained by dissolving the crude mixture obtained above in about 80 ml of methanol was refluxed for 2 hours after treatment with 130 ml of a 2N solution in which potassium hydroxide was dissolved in methanol. Most solvent was removed in vacuo and the residue was treated with dilute hydrochloric acid and ethyl acetate. The mixture is cooled to soften the resulting white mass with water and adjusted to pH 2 with hydrochloric acid. The solids were collected by filtration, mainly about 85% β- [1- (3,4-diphenyl-1H-pyrazolyl)]-propionic acid and 15% β- [1- (4,5-diphenyl- 1H-pyrazolyl)] 40.1 g of a mixture consisting of propionic acid was obtained. The crude material was slurried with acetonitrile and filtered to give 30.1 g of pure 3,4-diphenyl isomer at m.P 184.5-187 ° C. The latter (7.0 g, 0.024 mole) was slurried in 50 ml of chloroform and the slurry was added to 3.22 g (0.027 mole) thionyl chloride. The mixture was refluxed for about 1 hour with stirring and then filtered through charcoal and the solvent was removed from the filtrate in vacuo. The solution in which the residue was dissolved in 50 ml of tetrahydrofuran was added dropwise while stirring to a solution of 25 ml of 6N dimethylamine dissolved in tetrahydrofuran while maintaining a temperature of about 0-10 ° C. After the addition was completed, the mixture was heated to ambient temperature, refluxed for 1 hour, poured into 150 ml of ice water, and extracted into 50 ml portions of three ethyl acetate. The combined ethyl acetate extracts were washed with water, washed with 10% potassium dehydrate, washed again with brine, dried over sodium sulfate and filtered to give 6 g of pale yellow oil. The latter was eluted with ethyl acetate and chromatographed on 500 g of silica gel in ethyl acetate. After removal of about 750 mg of material, the elution was changed to 5% methanol in ethanol to yield Rf = 0.31 consisting of β- [1- (3,4-diphenyl-1H-pyrazolyl)]-N, N-dimethylpropionamide. 3.50 g of phosphorus was obtained in the form of a yellow rubber.

[Example of Preparation of Final Product]

3.5 g (0.011 moles) of β- (1- (3,4-diphenyl-1H-pyrazolyl)]-N in a slurry obtained by stirring 0.42 g (0.011 moles) of lithium aluminum halide in 50 ml of tetrahydrofuran. , N-dimethylpropionamide was added and the mixture was stirred and refluxed for about 18 hours The reaction mixture was decomposed by carefully adding 10.4 ml of water, 0.6 ml of 10% sodium hydroxide, and 1 ml of water in order. The mixture was stirred for 1 hour, filtered, and the filtrate was dried in vacuo.The residue, consisting of 3.0 g of yellow oil, was dissolved in isopropyl acetate and the solution was treated with 4 ml of a 6N hydrogen chloride solution in ethanol. It was recrystallized from isopropanol containing addition amount, so 1- [3- (N, N-dimethylamino) propyl] -3,4-diphenyl-1H-pyrazole dihydrochlorolide 1.2, which is mp 170-174 ° C. g was obtained.

[Results of biological tests]

The results obtained in the induced writhing test with anti-tetrabenazine (TB), acetylcholine (Ach) and phenylquinone on the 3,4-diphenyl compound of the present invention are shown in the following table. All 3,4-diphenyl compound doses are expressed in mg / kg.

(a) Test at 4, 16 and 64 mg / kg (P.O)

Claims (1)

Reducing the compound of formula (II) with n 'to 2 with an alkali metal aluminum hydride to produce a compound with n is 3 and converting the free base obtained if desired to its acid addition salt, wherein n is 2 and N B is diethylamino, or n is 3 and N = B is amino, methylamino, dimethylamino or diethylamino.