HU185383B - Process for preparing pyrazole derivatives - Google Patents

Abstract

The prepn. of 3-pyrazole-acetic acid deris. having formula (I), (where A is -CH2COOH; R1, R2, R3 and R4 are H, halogen, alkyl, alkoxy, CF3, NO2, amino, alkylthio or alkylsulphonyl, in o-, m- or p-positions provided that 1 of R1 to R4 is other than H), and of their salts with non-toxic bases, according to P2633992, is modified. In modification, a 3-acetyl-pyrazole deriv. having formula (I where A is Ac), (II), is reacted with S and an amine HNR5R6, (III), (where R5 and R6 together are -(CH2)4-, -(CH2)5- or ethoxyethylene or R5 is H or 1-4C alkyl and R6 is 1-4C alkyl, Ph or pyridyl). The 3-pyrazolyl-thioacetyl deriv. obtd. having formula (I where A is -CH2CSNR5R6), (IV), is hydrolysed with acids or bases and the acids obtd. are converted to their salts. (I) can be obtd. in good yields.

Description

The present invention relates to novel pyrazole derivatives of the general formula I in which R 1 is hydrogen or halogen in the ortho, potato or meta position, trifluoromethyl or nitro,

R ₂ is hydrogen or halogen ortho, para or meta or trifluoromethyl; and

R ₃ is hydrogen or halogen at the ortho, para or meta position, trifluoromethyl,

C 1-4 alkylthio or alkylsulfinyl, a. with the proviso that at least one of the substituents R _{1 to} R _{3 is} formed with bases other than hydrogen and physiologically tolerable bases.

Partially identical pyrazole derivatives are known a

No. 33,992 from the disclosure document in the Federal Republic of Germany. Alkylthio and alkylsulfinyl derivatives of R ₃ where C 1-4 is present are not new compounds in the literature.

The aforementioned and 25 36 003 are incorporated herein by reference. Disclosure in the Federal Republic of Germany; According to French patent application, pyrazole acetic acid derivatives are prepared by hydrolysis of amide or nitrile.

However, the preparation according to the known processes is very labor intensive and the yields obtained are often unsatisfactory (21-28%), whereas the present invention achieves significantly better values (44-65%).

By the process of the present invention, the pyrazole derivatives of formula I can be prepared by simple synthesis in good yield.

The invention is characterized in that reacting a compound of formula wherein R, R ₂ and R ₃ have the same meanings as given above, with sulfur and an amine of formula III wherein R _s and R ₆ together represent an ethoxy ethyl group - reacting hydrolyzing the resulting compound of formula IV, wherein R 1 -R ₃ , R ₅ and R ₆ are the same as the above-mentioned acids or bases, and if desired, oxidizing the resulting compounds of formula I wherein R ₃ is alkylthio and / or converting the resulting acid to a salt.

The process of the invention is carried out under reaction conditions known per se. [Org. Reactions, 3, 1946, 83- 107; Angew. Chem. 70, 351-367 (1958) and Synthesis, 1975, 358-375],

The process of the invention is carried out in the presence of primary or secondary amines. Suitable amines are, for example, methylamine, ethylamine, dimethylamine, diethylamine, dibutylamine, aniline, α-, β- or γ-picoline, piperidine or especially morpholine and pyrrolidine.

The pyrazole derivatives of formula (I) are pharmacologically active substances that are particularly distinguished for having an pronounced anti-inflammatory activity, are well tolerated by the stomach, and exhibit relatively low toxicity. In addition, these compounds are often distinguished by rapid onset of action, high potency and long duration of action, good absorption, and thus relatively good stability in galenic formulations.

The pyrazole derivatives of the formula I are converted in the body differently from the known anti-inflammatory compounds.

The novel compounds are suitable for use in combination with conventional carriers in galenic pharmaceuticals for the treatment of the following diseases.

(a) topically: contact dermatitis, various eczema, nueurodermatitis, erythrodermatitis, first degree burns, pruritus vulvae et ani, re10 sacea, erythematodes curaneus, psoriasis,

Lichen ruber plans et verruconus,

(b) orally: for the production of acute and chronic polyarthritis, neurodermatitis, bronchial asthma, hay fever and the like.

The following studies were conducted regarding the therapeutic efficacy of the compounds of the present invention.

1. Carrageinin paw edema assay (see Proc.

_2θ Soc., Exptl. Biol. Med. 111, 1962, 544).

In rats, acute exudative inflammation was induced by injection of Carragenin solution. This inflammation can be inhibited by anti-inflammatory agents. The volume of edema was measured.

The assays used ₂₅ male weighing 120-140 g (SPF) Wistar rats. 16 hours prior to oral administration of the compounds, the animals were deprived of food and given water as desired.

Carragenin was used as the proinflammatory agent. Carragenin 10 mg / L was added to 0.9% saline solution, of which! 0.1 ml was injected into the rat paws.

^Three doses of the test compounds were administered once per experimental animal at 0.5 hour / hour before the induction of edema with 0.5 ml vehicle / 100 g body weight. .

Five animals were used for each dose group. After instrumental measurement of the right hind paw volume, the compounds were administered orally; One hour later, injection of 0.1 ml of an anti-inflammatory agent into the foot caused inflammation. After a further 3 hours, the paw volume was again measured and the degree of suppression of inflammation ^J calculated. The evaluation was as follows:

% inhibition = 100 - z

Y = mean paw volume difference in the treated groups,

Z = mean paw volume difference in control groups.

2. Adjuvant-Arthritis Study (see Brit. J. Pharmacoh, 21, 1963, 127).

After injection of Freundschem Adjuvans (M. Butyricum), the rats were exposed for approx. Within two weeks, polyarticular inflammation (polyarthritis) develops in several joints, which can be inhibited by an anti-inflammatory agent.

Female and male rats of the Lewis (LEW) breed weighing 110-190 g were used for the experiment. The animals were also provided with drinking water and food.

For each dose group, 10 rats were used65.

185,383

Mycrobacterium butyricum (Difko, Detroit) was used as the inflammatory agent. A suspension of 0.5 mg of M. butyricum in 0.1 ml of clear running paraffin (DAB 7) was injected into the right hind paw by foot injection. 5

The test compounds were administered orally daily from day 11 of the experiment for 4 days. The compounds were administered as a clear aqueous solution or as a crystalline suspension in isotonic sodium chloride solution.

For the experiments, the rats were divided into different groups according to their body weight, preferably including animals of the same weight. The volume of the right and left hind paws was instrumentally measured, followed by an injection of 0.1 ml of adjuvant into the right hind paw. The right hind paws were measured from day 14 of the experiment until the end of the trial period. The left hind paws in which no anti-inflammatory agent was injected were also measured from day 14 of the experiment. The duration of the experiment was 3 weeks. 20

The results were evaluated as follows:

% inhibition = 100 - ——θZ 25 y = mean difference in paw volume between animals in the treated group.

z - mean difference in paw volume between control animals.

3. External examination (see Arc. Int. Pharmacodys. 192, 1971,370 ff.).

Gastric ulcer is a common complication with NSAID therapy. This side effect can be demonstrated in animal experiments.

Male Wistar rats (SPF) were used for the experiment. The animals weighed 130 ± 10 g. 16 hours before the start of the experiment, the animals were deprived of food and provided with drinking water as desired.

Five to five animals were tested per dose. The compounds were administered once orally, dissolved in sodium chloride, or as a crystalline suspension.

Three hours after the administration of the compounds, 1 in 1 of a 3% solution of diphenyl blue dye was administered by intravenous injection and the animals were sacrificed. The stomach was excised and the number and size of epithelial cell lesions and ulcers, which were conspicuous by the dye, were determined under a microscope.

The results of the experiments are summarized in Table I below.

Table I

Carrageuin's paw edema test

Adjuvant-Arthritis Study

Ulceration test

Song i Compound Dose, mg / kg animal- body weight %ancestor inhibition Dose, mg / kg animal- body weight % OS inhibition, right paw % OS inhibition, left paw Dose, mg / kg animal- body weight song surface in mm First 1-Phenyl-4- (4-chlorophenyl) - 15 39 4X3 20 35 30 1.4 0.8 3-yl-acetic acid 30 46 4x10 36 42 60 1.2 0.6 75 52 4x30 45 50 100 2.6 1.9 Second 1- (4-Fluorophenyl) -4- (4- 15 42 4X3 41 35. 30 0.2 0.1 chlorophenyl) -3-pyrazolyl) - 30 ' 53 4x10 45 39 60 3.2 1.6 acetic acid 75 67 4x30 49 81 100 1.3 9.9 Third 1-Phenyl-4- (4-chlorophenyl) - 15 0 4X3 0 1 3-yl-oxy-acetic acid 30 0 4x10 7 18 75 ' 39 4x30 9 17 4th l-Phenyl-3- (4-chlorophenyl) - 15 37 4X3 14 17 30 9.0 6.5 Pyrazol-4-acetic acid 30 43 4x10 0 18 60 10.6 8.0 . 75 54 4x30 33 29 100 20.3 22.4 5th 1-Phenyl-3- (4-chlorophenyl) - 15 9 4X3 2 5 Pyrazolyl-5-acetic acid 30 14 4x10 6 75 41 4x30 22 36

From the table it can be seen that the compounds 1 and 2 according to the invention outperform the known structural analogs 3, 4 and 5 in that they have a stronger anti-inflammatory effect and / or less gastric ulcer.

-3185383

The following Examples illustrate the process of the present invention.

Example 1

a) 28.9 g of 4-fluoroaniline are mixed with 260 ml of 15% hydrochloric acid and 260 g of ice, cooled to -5 ° C and diazotized with a solution of 19.7 g of sodium nitrite in 50 ml of water. Add dropwise while stirring and cooling

A solution of 38.4 g of 3-chloro-2,4-pentanedione in 260 ml of ethanol, 260 g of ice water and 350 g of sodium acetate hydrate was added. The reaction mixture was stirred at 0 ° C for a further 3 hours and then diluted with water until the material crystallized. The crystalline residue was recrystallized from ethanol to give 50 g of 1-chloro-1- (4-fluorophenylhydrazono) -2-propanone, m.p. 148 ° C.

b) A solution of 19.6 g of 4-bromobenzyl cyanide in 100 ml of toluene was added dropwise at -10 ° C under nitrogen to 108 ml of 20% toluene diisobutylaluminum hydride (Dibah) solution and finally for 15 minutes. stirred. Carefully add 35 ml of ethanol, then add about 20 ml of concentrated sulfuric acid and 250 ml of water (to pH 2) and stir for 15 minutes at 0 ° C. The toluene phase is then separated, the aqueous phase is extracted with toluene and the combined toluene solution is washed with water and dried over magnesium sulfate. After filtration, the toluene solution of (4-bromophenyl) acetaldehyde in toluene (87 g) was slowly concentrated in vacuo to half volume and allowed to stand overnight. After evaporation of the solution, the residue is triturated with α-cyclohexane and crystallization begins. The crystallized material is finally recrystallized from diisopropyl ether; 12 g of 4- (4-bromostyryl) -morfollnt having a melting point of 142 ^e C.

c) a solution of 7.2 g of 4- (4-bromo-styryl) -morpholine in 30 ml of chloroform successively with 2.7 g of triethylamine; and

A solution of 5.3 g of 1-chloro-1- (4-fluorophenylhydrazono) -2-propanone in 30 ml of chloroform is added and the mixture is stirred overnight at room temperature (or refluxed for 4 hours). The reaction mixture was washed with 2N hydrochloric acid, sodium bicarbonate solution and water, then the chloroform layer was dried over magnesium sulfate and evaporated. The residue (10.5 g) crystallized from hexane / cyclohexane was either used as such or recrystallized from ethanol once more; There was thus obtained 3-acetyl-4- (4-bromophenyl) -1- (4-fluorophenyl) -5-morpholino-4,5-dihydropyrazole, m.p. 148 ° C.

d) A solution of 10 g of the above dihydropyrazole derivative in 110 ml of dioxane is refluxed with 30 ml of 2N hydrochloric acid for 60-90 minutes. After evaporation in vacuo, the residue is dissolved in ethyl acetate, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from methanol to give 7.5 g of 3-acetyl-4- (4-bromophenyl) -1- (4-fluorophenyl) pyrazole, m.p. 185 ° C.

e) A mixture of 7 2 g of 3-acetylpyrazole derivative and 0.84 g of sulfur in 9 ml of morpholine is heated at 135 ° C for 3-4 hours, then poured into 150 ml of ice water and stirred well. The filtered and well-drained precipitate was crystallized from ethyl acetate and dioxane; 7.8 g of 4- [4- (4-bromophenyl) 1- (4-fluorophenyl) -3-pyrazolylthioacetyl] -morpholine are obtained, m.p. 211 ° C.

f) A mixture of 7.4 g of the thioacetylmorpholine derivative prepared in Example 4 and 20 ml of dimethylsulfoxide.

It is mixed with a solution of 6.4 g of sodium hydroxide in 30 ml of water and refluxed for 5 hours. After pouring the reaction mixture into ice water, the sodium salt crystallizes, is filtered off, washed with dichloromethane and suspended in 2N hydrochloric acid. 5 g of sodium salt of 4- (4-bromophenyl) -1- (4-fluorophenyl) -3-pyrazole acetic acid are obtained, m.p. 175 ° C.

Example 2

4- (4-Chlorophenyl) -1- (4-fluorophenyl) -3-pyrazole acetic acid, m.p. 148 ° C (from ethanol / water) was prepared as in Example 1.

The following intermediates are used:

4- (4-chlorostyryl) -morpholine; mp 102 ^e C (diisopropyl ether); (Prepared from 4-chlorobenzyl cyanide according to Example 1b).

3-acetyl-l- (4-fluorophenyl) -4- (4-chlorophenyl) -5-morfolmo4,5-dihydro-pyrazole; 137 DEG C. (ethanol). _

3-acetyl-1- (4-fluorophenyl) -4- (4-chlorophenyl) pyrazole; mp 181 ° C (from isopropanol).

4- [1- (4-Fluoro-phenyl) -4- (4-chloro-phenyl) -3-pyrazolyl-thioacetyl-morpholine; mp 213 ° C (from dioxane).

- (4-Fluorophenyl) -4- (4-chlorophenyl) -3-pyrazole acetic acid, sodium salt; 299 ° C (from water).

Preparation of 3-acetyl-4- (4-chlorophenyl) -1- (4-fluorophenyl) pyrazole, as in Example 1a, from α- (dimethylamino) 4-chloro-styrene and 1- (4-fluoro) -phenylhydrazono) -1-chloro-2-propanol.

The α-dimethylamino-4-chloro-styrene used as starting material can be prepared as follows:

A solution of 4-chlorobenzyl chloride (g) in diethyl ether (50 ml) was added dropwise (under argon) to 1.5 g of magnesium turnings and then stirred for 30 minutes. The solution was then cooled to -15 ° C and a mixture of 11 g of pure dimethylformamide and 30 ml of tetrahydrofuran was added dropwise. The reaction mixture was stirred for 3 hours at -15 ° C, then carefully concentrated in vacuo and mixed with 50 ml of 2N ammonium chloride solution and ethyl acetate. The organic residue was crystallized from methanol to give 5 g of α- (dimethylamino) -4-chloro-styrene, m.p. 77 ° C.

Example 3

Similarly to Example 1, 1,4-bis (4-chlorophenyl) -3-pyrazole-1-acetic acid was obtained, m.p. 184 DEG C. (from toluene).

The following intermediates are used:

-Chloro-1- (4-chlorophenylhydrazono) -2-propanone; mp 175 ° C (from ethanol); (prepared from 4-chloroaniline according to Example 1a).

acetyl-1,4-bis (4-chlorophenyl) pyrazole; 190 DEG C. (from dioxane).

4- [l, 4-bis (4-chlorophenyl) -3-pyrazolyl thioacetyl] -morpholine; mp 204 ° C (from dioxane).

Example 4

Similarly to Example 1, 4- (4-chlorophenyl) -1- (4-methylthiophenyl) -3-pyrazole acetic acid, m.p. 169 ° C (from methanol), is prepared.

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The following intermediates are used:

l- (4-Methylthio-phenyl-hydrazono) -l-chloro-2-propanone; 110 ° C (from carbon tetrachloride); (prepared from 4-methylthioaniline in Example 1a).

3-Acetyl-1- (4-methylthiophenyl) -4- (4-chlorophenyl) pyrazole; 85 ° C (from methanol).

4- [1- (4-Methylthio-phenyl) -4- (4-chloro-phenyl) -3-pyrazolyl-thioacetyl] -morpholine; mp 248 ° C (from ethyl acetate).

Example 5

A solution of 1.8 g of 1- (4-methylthiophenyl) -4- (4-chlorophenyl) -3-pyrazole acetic acid (prepared as in Example 4) in 20 ml of chloroform and 20 ml of acetic acid was treated with aqueous hydrogen peroxide solution and stirred at room temperature for 1 hour. It is then diluted with water until the material crystallizes. The crystalline material is filtered off, washed with spinning water and recrystallized from methanol; 1.4 g of 1- (4-methylsulfinylphenyl) -4- (4-chlorophenyl) -3-pyrazole acetic acid are obtained, m.p. 193 ° C.

Example 6

1-Phenyl-4- (4-chlorophenyl) -3-pyrazole acetic acid, m.p. 169 DEG C. (from toluene) was prepared in a similar manner to Example 1.

The following intermediates are used:

1-Phenylhydrazono-1-chloro-2-propanone; 136 DEG C. (from ethanol).

3-Acetyl-1-phenyl-4- (4-chlorophenyl) pyrazole; 101 ° C (from methanol).

4- [1-Phenyl-4- (4-chlorophenyl) -3-pyrazolylthioacetyl] morpholine, m.p. 205 DEG C. (from dioxane).

Example 7 A solution of 1- (4-fluorophenyl) -4- (4-chlorophenyl) -3-pyrazole acetic acid (prepared in Example 2) in 30 ml of dimethylformamide was treated with 600 mg of copper II-. diacetate in 35 ml of dimethylformamide and stirred at room temperature for 8 hours. The solvent was evaporated in vacuo, the oily residue was dissolved in acetone and filtered from the insoluble material. After acetone distillation, the salt residue is crystallized from methanol. so

1.7 g of 1- (4-fluorophenyl) -4- (4-chlorophenyl) -3-pyrazole-acetic acid copper II monohydrate are obtained, m.p. 171 ° C.

Example 8

Similarly to Example 1, 1,4-bis (4-fluorophenyl) -3-pyrazole acetic acid (m.p. 116 ° C; from carbon tetrachloride) was prepared.

Example 9

Similarly to Example 1, 4- (2,4-dichlorophenyl) -1- (4-fluorophenyl) -3-pyrazole acetic acid (m.p. 135 ° C; from toluene) was prepared.

Example 10

Similarly to Example 1, 1- (2-fluorophenyl) -4- (4-nitrophenyl) -3-pyrazole acetic acid (m.p. 208 ° C; from ethyl acetate) was prepared.

Example 11

As in Example 1 was prepared the 4- l- (2-fluorophenyl) (4-chlorophenyl) -3-pyrazol acid (melting point 187 C. ^c; ethyl acetate).

Example 72

Similarly to Example 1, 1- (4-fluorophenyl) -4- (4-nitrophenyl) -3-pyrazole acetic acid (m.p. 254 ° C; from acetonitrile) was prepared.

Example 13

Similarly to Example 1, 4- (3,4-dichlorophenyl) -1-fluorophenyl] -5-pyrazole acetic acid was obtained (m.p. 178 ° C; from toluene).

Claims (12)

A process for the preparation of Irish azole derivatives of the formula I in the formula Rj is hydrogen or halogen at the ortho, meta or para position, trifluoromethyl or nitro, R ₂ is hydrogen or halogen at the ortho, meta or para position or trifluoromethyl; and R ₃ is hydrogen or halogen at the ortho, meta or para position, trifluoromethyl, C 1-4 -alkylthio or C 1-4 -alkylsulfinyl, provided that at least one of R 1 -R _{3 is} substituted with non-hydrogen and physiologically acceptable bases, characterized in that: a compound of formula II wherein R 1. R ₂ and R ₃ have the same meanings as given above, with sulfur and a primary amtnnal formula III wherein R _s and R ₆ together represent an ethoxyethyl group is reacted to IV resulting compound of the formula wherein _R-R3, R5 and _R6 are the hydrolyzing with the same acids or bases as described above and, if desired, oxidizing the resulting compound of formula I wherein R ₃ is alkylthio and / or converting the resulting acid to a salt. Process for the preparation of 4- (4-bromophenyl) -1- (4-fluorophenyl) -3-pyrazole acetic acid according to claim 1, characterized in that the starting material is 3-acetyl-4- (4-bromophenyl). ) -I- (4-fluorophenyl) pyrazole is used. The process for the preparation of 1,4-bis (4-chlorophenyl) -3-pyrazole acetic acid according to claim 1, characterized in that: -5185 383 using 3-acetyl-1,4-bis (4-chlorophenyl) pyrazole as starting material. A process for the preparation of 4- (4-chlorophenyl) 1- (4-methylthiophenyl) -3-pyrazole acetic acid according to claim 1, wherein the starting material is 3-acetyl-4- (4-chlorophenyl). ) -1- (4-methylthiophenyl) pyrazole is used. 5. A process for the preparation of 4- (4-chlorophenyl) -1-phenyl-3-pyrazole acetic acid according to claim 1, wherein the starting material is 3-acetyl-4- (4-chlorophenyl) -. Phenylpyrazole is used. 6. A process for the preparation of 1,4-bis (4-fluorophenyl) -3-pyrazole acetic acid according to claim 1, wherein the starting material is 3-acetyl-1,4-bis (4-fluorophenyl) pyrazole. . 7. A process according to claim 1 for the preparation of 4- (2,4-dichlorophenyl) 1- (4-fluorophenyl) -3-pyrazole acetic acid, wherein the starting material is 3-acetyl-4- (2 , 4-dichlorophenyl) -1- (4-fluorophenyl) pyrazole is used. 8. A process for the preparation of 1- (2-fluorophenyl) 4- (4-nitrophenyl) -3-pyrazole acetic acid according to claim 1, wherein the starting material is 3-acetyl-1- (2-fluorophenyl). ) -4- (4-nitrophenyl) pyrazole is used. 9. A process according to claim 1 for the preparation of 4- (4-chlorophenyl) -5- (2-fluorophenyl) -3-pyrazole acetic acid, wherein the starting material is 3-acetyl-4- (4- chlorophenyl) -1- (2-fluorophenyl) pyrazole is used. The process according to claim 1, for preparing the sodium salt of 4- (4-chlorophenyl) 1- (4-fluorophenyl) -3-pyrazole acetic acid, 10 wherein the starting material is 3-acetyl-4- (4-chlorophenyl) -1- (4-fluorophenyl) pyrazole. 11. A process according to claim 1 for the preparation of the copper (H) salt of 4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazole acetic acid, wherein the starting material is 3-acetyl. -415 (4-chlorophenyl) -1- (4-fluorophenyl) pyrazole was used. 12. A process according to claim 1 for the preparation of 4- (4-chlorophenyl) 1- (4-methylsulfonylphenyl) -3-pyrazole acetic acid, wherein the starting material is 4- (4-chlorophenyl) -. 1- (4-methylthiophenyl) -3-pyrazole acetic acid is used.