DE2312256B2 - 5-PYRAZOLE VINETIC ACID DERIVATIVES, THE PROCESS FOR THEIR PRODUCTION AND THE PHARMACEUTICAL PRODUCTS CONTAINING THEM - Google Patents

Description

in which R is the phenyl, benzyl or 2-methylpropyl group means.

2. Process for the preparation of the compounds according to claim 1, characterized in that one either

a) a compound of the general formula II

H ₅ C ₆

C ₆ H ₅

ZH ₁ C

in which R has the meanings given in claim 1 and Z is an ester, nitrile, amide or is a thioamide group, subjected to hydrolysis in a manner known per se, or

b) a malonic acid derivative of the general formula III

H ₅ C ₆ η π C ₆ H ₅

σι «

HOOC-CH N

/ I

HOOC R

in which R has the meanings given in claim 1, subjected to a decarboxylation 3. Anti-inflammatory, antipyretic and analytically effective agents, containing at least A compound according to claim 1.

The new 5-PyrazoIessigsäHrederivate forming the subject of the invention have a strong antiiaflammatory, antipyretic and analgesic effect - With regard to the three effects mentioned, they are clearly superior to the comparable commercial products with the same direction of action indomethacin, phenylbutazone and aspirin when assessing the overall properties with about the same Tmd quote, d. Length, the superior efficacy of erfino compounds according is not achieved at the expense of higher overall toxicity The compounds of the invention are therefore useful in the Hinnantherapie, particularly in anti-inflammatory, antipyretic and analgesic agents. The doses in which the compounds according to the invention can be administered will of course depend on the type of treatment, the type of administration and the duration of the treatment. The total daily doses for oral or rectal administration, however, are generally 100 to 800 mg of active compound in adult humans.

The compounds according to the invention can be used in the form of pharmaceutical agents which contain at least one of the compounds according to the invention Compounds together with pharmaceutically customary carriers or diluents, if appropriate in combination with suitable customary ones pharmaceutical adjuvants such as coating agents, wetting agents, preservatives, lubricants, dissolving agents, coloring agents and flavoring agents.

Below is an example of making a 500 mg total tablet specified:

1 -BenzyW.'i-diphenyl-S-pyrazole-

acetic acid 250 mg

Strength 190 mg

Colloidal silica 50 mg Magnesium stearate 10 mg

The invention also relates to a process for the preparation of the compounds mentioned at the outset, which is characterized in that one either

a) a compound of the general formula II

H ₅ C ₆ -

ZH ₂ C

C ₆ H ₅

The invention relates to new 5-pyrazole acetic acid

derivatives, processes for their production and they _ _,

containing, anti-inflammatory, antipyretic and 55 and Z an ester, nitrile, amide or thioamide analgesic agent. group means, in a manner known per se, one

The invention relates to new 5-pyrazole acetic acid derivatives of the general formula I

in which R has the meanings given above

Subject to hydrolysis, or
b) a malonic acid derivative of the general formula III

H, C,

HOOC-H ₂ C

C _fi H

6 ⁿ 5

H ₅ C ₆ π η C ₆ H ₅

(ΠΙ)

in which R denotes the phenyl, benzyl or 2-methylpropyl group.

HOOC-CH N

• / ι

HOOC R

in which R has the meanings given above, is subjected to a decarboxylation.

23 121256

3 y 4th

The hydrolysis according to variant (a) of the invention The pharmacological properties of the invention

According to the method, under usual conditions, the compounds according to the invention are made below carried out. One can, for example, be briefly summarized in one

alkaline aqueous medium, optionally in counter- The anti-inflammatory activity of the invention

wart a water-soluble organic solution 5 according to compounds and the comparative compounds, such as ethanol or glycol, work. In general indomethacin, phenylbutazone and aspirin

was examined in rats and guinea pigs after oral administration on the basis of three artificially induced types of inflammation:

1. Carraghenin edema: Winter's method, "Arch, intern. Pharmacod. ^ 112, 174 (1957);

2. "Ultraviolet" edema: Winter's method, “Arch. Intern. Pharmacod. ", 114, 261 (1958);

mine one applies return flow conditions. But you can also work in a strongly acidic aqueous medium, if appropriate in the presence of a water-soluble organic solvent, such as acetic acid or dioxane. The concentration of the acid used and the reaction temperature vary in this case depending on the

3. Formation of a graauioma caused by subcutaneous implantation of cottonseed in a rat: Winter's method, »J. At the. Pharm. Ass. ScL Ε & <ς Volume 46, page 515 (1957).

The analgesic activity on pain exerted in a mouse by subcutaneous injection of Acetic acid was produced according to the modified method of Siegmund, »Pro. Soc. Explt. Biol. Med. ", 95, 729 (19571, determined.

desired products and in particular depending on the type of functional group Z. The Esters are generally concentrated into one acidic medium and hydrolyzed at a slightly elevated temperature, often at ambient temperature The nitriles, amides and thioamides are generally more or less concentrated acidic medium, for example at a concentration of 5 η to 15 n, but generally with re-nut, hydrolyzed

The decarboxylation according to variant (b) des

The method according to the invention is also carried out under conditions typical for fever. For this purpose, use the method of B i a η c h i, »Arzn. For example, the malonic acid derivative of the general research «, 17, 246 (1967), determined mean formula III near or above its In addition, the toxicities of the invention

Melting point or in the medium of an inert compound and the comparison products organic solvent (with a high boiling point 30 as well as its effect on the treatment of a polyp point) heated under reflux. One can also get into arthritis caused by Freund's adjuvant,

examined in a rat (see in particular the following Table II).

For this purpose, a suspension of Mycobacterium butyricum was placed in the tail of the rat injected (method by E. M. G1 e η η and J. G r a y, "At the. J. Vet. Res. ", 1965, 26, 1180, 1194). The compounds to be tested were delivered by the oral route

^ _rj For 3 weeks, 6 days a week, from

azolidines, indazoles and condensed "rings" in "The 40 days of Freund's adjuvant injection. Chemistry of Heterocyclic Compounds «, published administered. The results obtained were on from Interscience, 1967; and F. H. C. Stewart in "Chemical Reviews", 64, 129 [1964]).

The compounds according to the invention can generally by conventional methods, for example by distillation, crystallization or chromatography.

Table I.

work in an alkaline or acidic environment, most often one works under conditions like them for the hydrolysis of nitriles and amides have been given above.

! The implementation of the invention The starting materials used in the process are produced by known methods (cf., for example, L. C. B e h r et al, »Pyrazoles, pyrazolines, pyr-

Hand assessed the following criteria:

1. Frequency of arthritis symptoms (frequency),

2. increase in volume of the rat's hind paws (Δ V),

3. Severity of polyarthritis disease (severity)

attempt Attempt Dose, example 1 Example 2 Example 3 Indometh Phenyl Aspi animal mg / kg / p. 0 acin butazon Toxicity (oral) rat DL, 520 55 40 40 520 mouse DL " 940 280 350 55 750 Pain caused by mouse DE ₅₀ 150 180 90 6.5 110 130 acetic acid Bicr yeast pyrexia rat DE ₅₀ + 1 0.3 0.6 2 40 40 Ultraviolet erythema Sea-
Cf * Vl W (MTI- DE ₅₀ 1.6 1.3 1.7 1.7 6.5 50 OwIl WCIIl
chen Carraghenin edema rat DE ₅₀ 23 25th 13th 13th 75 180 Trefoil seed granuloma rat DE ₅₀ 80 18th 6th 7th > 200 - Polyarthritis caused rat Cans 25th 2 I. 2 100 Freund's adjuvant same (Details in Table II) effect

Table U

product

Dose, effect on

Day

frequency

Δ V

Heaviness

example 1
Example 2
Example 3
Indomethacin

Phenylbutazone

IO line product is dissolved in 1000 τηΐ water, and the aqueous phase is washed three times with a total of 600 ml of ether. The aqueous phase is acidified with 50 ml of concentrated CM> rhydrophobic acid. The precipitate obtained is filtered off with suction on a glass frit and washed three times with a total of 1500 ml of water. After crystallization from 7 parts by volume of acetonitrile, 87 g of 1- {2-methylpropyl) -3,4-diphenyl-5-pyrazcledgic acid, mp 181 ° C., are obtained.

Example 3
1,3,4-triphenyl-5-pyrazole acetic acid

• 5

The invention is illustrated in more detail by the following examples.

example 1

1-Benzyl-3,4-diphenyl-5-pyrazolyl-acetic acid

2 g of l-benzyl-S. ^ - diphenyl-S-pyrazole-acetonitrile be dissolved in 4 ml of concentrated sulfuric acid and 4 ml of water. Heat under for 30 minutes The mixture is refluxed and then cooled to ambient temperature and 8.7 ml of water are added. The one that fails Resin is extracted with 50 ml of warm chloroform. The organic phase is used twice in total Washed 60 ml of water. It is dried over magnesium sulphate and the chloroform is evaporated under reduced pressure Pressure a. The residue is taken up in 15 ml of 1N NaOH, and the aqueous phase is washed twice with a total of 40 ml of ether. The aqueous phase is mixed with 2 ml of concentrated hydrochloric acid acidified, the resulting precipitate is filtered off with suction, twice with a total of 20 ml Water and then washed twice with a total of 40 ml of isopropyl ether. 1.9 g of product are obtained which is recrystallized from 13 parts by volume of acetonitrile, after which 1.5 g of 1-benzyl -3,4-diphenyl-5-pyrazole-acetic acid received, F. 181-182 "C.

Example 2

1- (2-methylpropyl) -3,4-diphenyl-5-pyrazole acetic acid

28.5 g of sodium hydroxide, dissolved in 100 ml of water, are added to 102.5 g of 1- (2-methylpropyl) -3 ₎ 4-diphenyl-5-pyrazole acetonitrile, dissolved in 1000 ml of ethanol. The mixture is refluxed and stirred for 20 hours. It is cooled to ambient temperature and the methanol is evaporated under reduced pressure. The resulting crystal

-CH ₂ COOH

To 19 g of! ^, + • triphenyl-S-pyrazole acetonitrile, dissolved in 200 ml of ethanol, 4.6 g of sodium hydroxide dissolved in 19 ml of water are added. Heat 20 Under reflux for hours with stirring. Cool to ambient temperature and evaporate the ethanol under reduced pressure, the product obtained is taken up with 1000 ml of water, and the oil which separates out is extracted with 200 ml of ether. The aqueous phase is with 8 ml of concentrated hydrochloric acid acidified, the precipitate obtained is dissolved in 300 ml of chloroform, the chloroform solution is over magnesium sulfate dried and evaporated under reduced pressure. A crystallized product is obtained, which is recrystallized in 6 parts by volume of acetonitrile to form 7 g of l ^^ triphenyl-S-pyrazole acetic acid, F. 200 ° C.

9.3 g of aniline and 10.1 g of triethylamine, dissolved in 60 ml of benzene and cooled to 0 ° C., are added within of 30 minutes with stirring 11.2 ml of bromoethyl acetate, stirred for 3 hours at ambient temperature and sucks off the triethylamine hydrobromide formed. The organic phase is washed with 100 ml of water and dry them over magnesium sulfate. The benzene is evaporated under reduced pressure Pressure and thus receives 15.5 g of phenylaminoethyl acetate in the form of a yellow oil.

Claims (1)

Patent claims: 1. 5-pyrazole acetic acid derivatives of the general Formula I. QH ₅ Ä /
HOOC