DE2031238C3 - i.a-Diphenyl-S.S-dioxo ^ -substituted pyrazolidines, process for their preparation and pharmaceuticals - Google Patents

Description

co

NC ₆ H ₅

C ₆ H ₅

in which R is a 3-methyl-2-butenyl or 4-methyl-3-pentenyl group means and their physiologically acceptable salts.

2. Verfaüiren for the preparation of a compound according to claim 1, characterized in that in known manner either a) hydrazobenzene or a reactive derivative the same with a reactive malomic acid derivative of the general formula II

15th

20th

COX

R-CH
\

(H)

COX

in which R has the meaning given above and X are groups with Hydrazobenzene or a reactive derivative thereof to form a compound of the general formula I react in the presence of a condensing agent under essentially anhydrous conditions is implemented, or

b) 1,2-diphenyl-3,5-dioxopyrazolidine or an alkali metal salt of which with a compound of the general formula R-Hal, in which R is the above Is important and Hai is a halogen atom, especially a bromine atom, in the presence an acid-binding agent is reacted, or

c) a compound of the general formula IV

35

40

45

OH

CH CO (IV)

CO N-CH ₅

N I

in which χ denotes the number 1 or 2, is dehydrated with a dehydrating agent, or

d) a compound of the general formula V.

R —CH ₂ —CO — N — NH — C _r , H _s C “H ₅

(V)

in which R has the above meaning, under practically anhydrous conditions with a reactive carbonic acid derivative in the presence of a basic condensing agent is implemented.

3. Medicines with analytical, anti-inflammatory and antipyretic effects, thereby characterized in that it contains one or more compounds according to claim 1

The invention relates to new 1,2-diphenyl-3,5-dioxo-4-substituted Pyrazolidines. These compounds have valuable pharmacological properties.

In British Patent 6 46 597 there are compounds the general formula

R ¹ -CH

CO

CO

N— Arvl

Aryl

described, in which R ^{1 is} a hydrocarbon radical or substituted hydrocarbon radical with 2 to 10 carbon atoms, which is bonded to the pyrazolidine nucleus via a primary or secondary carbon atom, in particular a saturated or unsaturated aliphatic or cycloaliphatic or a phenyl-substituted aliphatic hydrocarbon or a substituted hydrocarbon radical, and aryl means a phenyl radical which is either unsubstituted or substituted by halogen atoms, alkyl and / or alkoxy groups, such as alkyl groups and alkoxy groups with 1 to 3 carbon atoms. The compounds described in the British patent have analgesic and / or antipyretic properties.

Among the compounds described in the British patent is the substance 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine, known under the name phenylbutazone, which has been widely used, especially for the treatment of rheumatic and arthritic complaints, in terms of its anti-inflammatory analgesic and antipyretic Properties. It should be noted that in the said British patent no references to The anti-inflammatory properties of phenylbutazone are included for those properties were only discovered at a later date

It is known that phenylbutazone has an ulcerogenic effect when used repeatedly, what Gives rise to serious consequences.

The applicant has determined the properties of a number of 1,2-diphenyl-3,5-dioxo-4-substituted pyrazolidine compounds studied that are related to phenylbutazone to find compounds that have the desired therapeutic properties have, in particular the anti-inflammatory effect of phenylbutazone, but with a reduced effect ulcerogenic effect. So were z. B. 1,2-Diphenyl-3,5-dioxo-4- (2'-butenyl) - and 1,2-Diphenyl-3,5-dioxo-4-allylpyrazolidines investigated, which are described in the said British patent specification, it was found that the first of these two compounds is one

Has anti-inflammatory and ulcerogenic effects which are in any case comparable to the effects of phenylbutazone. The 4-ailyl compound has an ulcerogenic effect which is less than that of phenylbutazone, but its anti-inflammatory effect is also less. From this one can conclude that there is a certain connection between the desired pharmacological effect and the ulcerogenic side effect as far as the known straight-chain 4-alkyl and 4-alkenyl, ₀ derivatives of 1,2-diphenyl-3,5-dioxopyrazolidine are concerned

In continuation of the investigations two new compounds were found, which are described in more detail below, which both anti-inflammatory, have _5-inhibiting and analgesic effects which are at least as large as those of phenylbutazone, but their ulcerogenic effects pronounced are lower. The two new compounds also have significant antipyretic effects, but less than that of phenylbutazone. It is known, however, that in the treatment of rheumatic and arthritic conditions, the anti-inflammatory and analgesic properties are of primary concern and the antipyretic effect is useful but of secondary concern. Therefore the new compounds are very effective drugs for the treatment of rheumatic, arthritic and other conditions for which it otherwise used phenylbutazone, but have the important advantage _J0 that they display a markedly reduced ulcerogenic effect.

According to the invention, compounds of the general formula I

R-CH CO

I 1

CO N — C “H ₅

(I)

40

created, wherein R is a 3-methyl-2-butenyl or 4-methyl-3-pentenyl group. The invention also includes salts of these compounds with physiologically acceptable cations, e.g. B. the sodium, Calcium, 2-hydroxyethylammonium and tris (2-hydroxyethyl) ammonium salts, as well as other salts analogous to salts of phenylbutazone.

The properties of the new compounds obtained according to the invention are illustrated by the results demonstrated by pharmacological experiments which are given in the table below.

In these experiments, the various substances were administered orally, the doses being in mg / kg are given in parentheses after each result.

R-CH-CO

CO

NC ₁₁ H ₅

R =

Anti-inflammatory
Activity in rats *)

η-butyl 3-methyl-4-methyl-2-butenyl 3-pentenyl

Carragee induced 100 (100) 115 (100) 134 (1 (M)) edema (l)

Analgesic activity
in rats *)

Mechanical
stimulation
the paw (2)

Antipyretic
activity
in rats *)

100 (100) 119 (100) 115 (100)

100 (100) 51.6 (100) -

Yeast Induced 100 (300) 49 (300) 52 (3 (X))

Fever (3)

Ulcerogenic effects 84 (100) 33 (200) 30 (200) in rats

Tumor frequency 95 (200) 50 (400) 50 (400) in percent (4)

R-CH R = CO N ί ₅ CO
\ Anti-inflammatory
Activity in rats *) NC ₁₁ F Q ₁ H ₅ \ Carragee induced
Breath (l) allyl Analgesic activity
in rats *) 2-butenyl Mechanical
Paw stimulation (2) 65 (100) Antipyrclic antivism
in rats *) 94 (100) Yeast Induced Firber (3rd 76.9 (100) Ulcerogenic effect
in rats 104.6 (100) 76.4 (100) 60.8 (100) 60 (200) 82 (200)

_b0 tumor frequency
in percent (4)

100 (400)

100 (400)

CIK

Remarks:

*) The results are expressed on the basis of the action of phenylbeutazone, which is assumed to be 100. These experiments were carried out as essentially described by: ') CA. Winter, "International Symposium on Non Steroid Anti-Inflammatory Drugs," September 1964 - Excerpta Medica Foundation. Amsterdam. P. 190; ² ) LO R a η da 11 and

JJ S e I i 11 o, Arch. InL Pharmacodyn, 111, 409 (1957); ³ ) C. Bianchi, B. Lumachi and LPegrassi, Arzn. Forsch, 17,246 (19571

The ulcerogenic effect *) was determined on male Sprague-Dawley rats (weight 200 to 220 gj). The products were administered per os in single doses to the animals that had not eaten for 9 hours and the animals were also given no food during the entire experiment, except Water. 15 hours after the administration, 2 ml / rat of a 1.5% (w / v) solution of FeCb was administered in order to better determine the lesions. After one hour, the animals were sacrificed Washed with water and immersed in a 2% solution of potassium ferricyanide acidified with 1% hydrochloric acid. After washing with water, the stomachs were examined macroscopically

The new compounds to be prepared according to the invention can be prepared by any customary processes can be produced, for example, using the following methods.

In the following description the term "lower" means in relation to alkyl or alkanoyl groups those groups that contain 1 to 6 carbon atoms.

1. Reaction of hydrazobenzene or a reactive derivative thereof with a reactive one Derivative of malonic acid of the general formula II

COX

R-CH

(II)

COX

(wherein R has the above meaning and the groups X are those with hydrazobenzene or a reactive derivative thereof react to form a compound of general formula I, e.g. B. lower alkyl groups or halogen atoms) in the presence of a condensation agent under essentially anhydrous conditions. Optionally, the reaction can be carried out in two stages by a compound of the general formula

45

COX

R-CH

(IH)

CO-N -NH-C ₁₁ H ₅

5 °

55

! (wherein R and X have the above meaning) by usual methods, preferably a lower alkyl ester (X = O-alkyl) produces, after which the compound of formula general III in the presence ■ *, a condensing agent is cyclised, so that one a Compound of general formula I is obtained.

In another embodiment of this reaction, a compound of the general formula I can be made by making a di-lower alkyl ester of malonic acid and hydrazobenzene (or a reactive derivative thereof) with a halide of Has meaning and Hal is a halogen atom) in the general formula R-Hal (where R has the above The presence of a condensing agent reacts. These reactions are further explained as follows:

a) A di-lower alkyl ester of the general formula II (X = O-lower alkyl), preferably the diethyl ester, can be reacted with hydrazobenzene or a lower alkanoyl derivative thereof; z. B. N-acetylhydrazobenzene in the presence of a basic condensing agent, preferably sodium methylate, ethylate or butylate, or sodium amide under essentially anhydrous conditions. The reaction is preferably carried out in the presence of an inert solvent, for example ethanol, butanol, toluene or xylene, at an elevated temperature, e.g. B. carried out the boiling point of the reaction mixture, after which the solvent is distilled off to obtain a solid mass. The reaction can also be carried out by slowly adding a basic condensing agent, e.g. B. one of the above to a mixture of a di-lower-alkyl ester, preferably the diethyl ester, of malonic acid, hydrazobenzene and a halide R-Hal (where R has the above meaning and Hal is a halogen atom, preferably Br _; ), preferably in Presence of an inert solvent: », e.g. B. one of the above. During the addition of the condensing agent, the temperature of the reaction mixture is slowly increased to the boiling point and refluxing is carried out, continuing for about 1 hour. The solvent is then distilled off under mild conditions until a solid mass is obtained

b) Halides of the general formula II (X = halogen), preferably chlorides, can be treated with hydrazobenzene in the presence of an acid-binding agent, preferably tertiary amines, e.g. B. pyridine, quinoline or dimethylaniline, in the presence of an inert solvent such as ether or chloroform, are reacted. If necessary, an excess of tertiary amine can serve as a solvent. The reaction may for example be carried out at a temperature of 0 to 50 ⁰ C.

c) In one embodiment of the reactions described under a) and b), a compound of general formula II, in which X is a lower alkoxy group or a halogen atom as a starting material used and cyclized in the presence of a condensing agent or an acid-binding agent will.

2. Implementation of l, 2-diphenyl-3,5-dioxo-pyrazolidine in the presence of a säurebinder.den means, or one Alkali metal salt of pyrazolidine, with a halide of the general formula R - Hai (where R above Has meaning and Hal is a halogen atom), so that a compound of the general formula I is obtained The reaction is preferably carried out by one of an alkali metal salt, preferably the sodium salt, des l, 2-diphenyl-3,5-dioxopyrazolidine proceeds preferably in an inert solvent, e.g. B. Carbon tetrachloride, benzene or dimethyl sulfoxide, is suspended, the suspension being slowly added Halide R-Hal, preferably the bromide, at room temperature or above. The reaction can be completed by refluxing.

The crude compound of the general formula I obtained can be obtained by crystallization from ether or Ethanol, preferably from ether, or purified by chromatography.

3. Dehydration of a compound of the general Formula IV

OH

C-CH ₂ - (CHj) ₁ -CH CO

(IV)

CO NQ ₁ H ₅ ίο

wherein χ represents 1 or 2, with a dehydrating agent.

The reaction is carried out under anhydrous conditions, e.g. B. phosphorus oxychloride, phosphorus oxybromide or boron trifluoride (preferably phosphorus oxychloride) as a dehydrating agent in Presence of an acid-binding agent, advantageously a tertiary amine, such as. 3. pyridine or quinoline, The reaction can be carried out at temperatures of e.g. 0 to 40 ° C. The thus obtained Crude compound can be purified by recrystallization, e.g. B. from ethanol or ether. Connections of general formula IV can be obtained by customary methods, for example by the Grignard reaction of corresponding ketones with methyl magnesium bromide or iodide; the ketone can be saponified corresponding ketal can be obtained, which in turn from the corresponding malonic acid ester and hydrazobenzene is obtained in the presence of a basic condensing agent.

4. Reaction under essentially anhydrous conditions of a compound of the general formula V

R-CH ₂ -CO-N-NH-C ₆ H ₅

(V)

40

45

(where R has the above meaning) with a reactive derivative of carbonic acid, e.g. B. a lower alkyl chlorocarbonate or a di-lower-alkyl carbonate in the presence of a basic condensing agent.

The compound of the general formula V can be obtained by customary methods, for example from the Chloride of the corresponding acid and hydrazobenzene.

If desired, the reaction can also be carried out in a single stage by one of Mixture of a lower alkyl ester of the general formula V

R-CH, -COOAIk

(VI)

60

(where R has the above meaning and AUc is a lower alkyl group), hydrazobenzene and a reactive Derived from carbonic acid in the presence of a basic condensing agent

These reactions are explained in more detail as follows: a) Reaction under essentially anhydrous Conditions of a compound of the general formula V with a lower alkyl chlorocarbonate are advantageous Ethyl chlorocarbonate, in the presence of a basic condensing agent, advantageously sodium hydride or crushed sodium.

The reaction is preferably carried out by using the compound of general formula V with heated to an excess of ethyl chlorocarbonate to the boiling point of the reaction mixture, e.g. B. for 1 to 5 hours. The excess ethyl chlorocarbonate is then distilled off and the residue in a solvent, e.g. B. benzene, dissolved, whereupon in the presence of the basic condensing agent for the purpose Completion of the reaction heated e.g. B. reflux for 8 to 16 hours in the presence of a 50% suspension of sodium hydride in mineral oil.

b) reaction under essentially anhydrous conditions of a compound of the general formula V with an excess of a di-lower-alkyl carbonate, preferably diethyl carbonate., In the presence a condensing agent such as sodium amide, sodium hydride, or crushed sodium. The reaction mixture is z. B. refluxed for 12 to 24 hours.

c) reaction under essentially anhydrous conditions of a compound of the general formula Vl, such as the ethyl ester, hydrazobenzene, a di-lower alkyl carbonate, e.g. B. diethyl carbonate and a condensing agent such as sodium hydride or crushed sodium metal. The reaction is z. B. carried out by a mixture of a compound of the general formula VI and the di-lower-alkyl carbonate to a mixture (kept at 50 to 100 ° C) of hydrazobenzene and a 50% suspension of Sodium hydride in mineral oil, in the presence of an inert solvent, preferably toluene, or xylene, adds the reaction being completed by refluxing the reaction mixture for 6 to 18 hours heated

The '.' Compounds obtained as described above of the general formula I can from the reaction medium as aqueous solutions of the corresponding Alkali metal (e.g. sodium) salts can be isolated by acidifying the solution e.g. B. with Hydrochloric acid, whereupon the compound of general formula I obtained in this way by crystallization from a suitable solvent, e.g. B. ethanol, ether, hexane or cyclohexane, or purified by chromatography will.

In pure form, the new compounds obtained according to the invention are generally white, crystalline Solids that are insoluble in water, which dissolve in aqueous alkaline solutions (with the formation of the corresponding salts), and in ethanol, methanol, Benzene and ether are soluble.

Salts of compounds of the general formula I can be obtained by treating them with a Equivalent of the corresponding base neutralized in the customary manner. For example, the alkali metal salts are obtained the compound of general formula 1 by treatment with an alkali metal in water or aqueous alcohol or with an alkali metal alcoholate in alcohol. The alkali metal salts of the compounds of general formula I are soluble in water. the Alkaline earth metal salts, e.g. the calcium salts, are im generally insoluble in water and can, for example, be caused by a double decomposition reaction between one aqueous solution of a soluble salt, preferably the Na salt, a compound of the general formula I and a water-soluble alkaline earth metal salt. Examples of salts of compounds of

709 607M71

Formula I according to the invention are the sodium, calcium, ethanolamine and triethanolamine salts.

From the compounds obtained according to the invention, pharmaceutical preparations with analytical, anti-inflammatory and anti-pyretic effects create that as an active ingredient at least one compound of general formula I or contain at least one salt thereof and at least one pharmaceutical carrier or excipient included, with at least one further customary therapeutic in the preparations if desired active substance may be included.

Pharmaceutical preparations can be produced by methods customary in the relevant technology will. For internal applications, dosage units are generally preferred, each dosage unit 20 to 1000 mg, preferably 50 to 500 mg, of the active ingredient

For oral administration, the compounds of general formula I are preferably used as Packaged tablets, coated tablets or capsules

For rectal administration, the compounds are preferably used as suppositories with conventional Excipients such as cocoa butter, glycerides of fatty acids and / or polyoxyethylene glycols are prepared

For parenteral administration are preferred soluble salts of the compounds of general formula I used preferably in the form of Ampoules or bottles containing a lyophilized mass of the salt.

For topical applications, the compounds obtained according to the invention are used, for example, as ointments, Creams or dermatological solutions made up, taking the compounds of the general Shape! I in concentrations of 1 to 10 percent by weight, preferably 5 percent by weight

The daily dose of the compound obtained according to the invention to be administered is in the adult with internal administration about 50 to 1000 mg, depending on the nature of the disease to be treated For topical Applications are the topical preparations on the affected area several times a day, if necessary, upset.

The following examples serve to explain the process according to the invention in more detail.

example 1

43.8 g (0.237 mol) of hydrazobenzene are obtained by dissolving a solution of sodium ethylate 6.55 g (0.285 mole) sodium in 125 ml anhydrous Ethanol, added 59.6 g (0.2612 mol) of diethyl 3-methyl-2-butenyl malonate are then added with stirring Reflux temperature added

The reaction mixture is refluxed for 1 hour, after which the solvent is slowly distilled off and the distillation is completed in vacuo. The solid residue obtained in this way is dissolved in 400 ml of water and washed with ether. The solution is acidified with 10% HQ and the 1,2-diphenyl-3,5-dioxo-4- {3'-methyl-2'-butenyl) pyrazolidine which separates out is purified by crystallization from ethanol (melting point 155 up to 156 ⁰ C).

Analysis for C20H20N2O2:
Found: C 75.04, H 632, N 8.65%; calculated: C 74.97. H 6.29. N 8.74%.

55

60 If you work in an analogous manner, but starting from diethyl 4-methyl-3-pentenyl malonate, then 1,2-diphenyl-3,5-dioxo-4- (4'-methyl-3'- pentenyl) pyrazolidine from mp 136 to 137 ° C.

Analysis for C21H22N2O2:
Found: C 75.72, H 6.65, N 8.48%; Calculated: C 75.42, H 6.63, N 8.38%.

Example 2

4.1 g (0.019 mol) of 3-methyl-2-butenyl-malonyl chloride are added to a solution of 3.41 g (0.043 mol) of pyridine in 34 ml of chloroform added, the temperature being kept at 0 to 5 ° C. 3.61 g (0.019 mol) of hydrazobenzene, dissolved in 19 ml of chloroform are then added

The reaction mixture is stirred at room temperature for 12 hours, after which it is diluted with ether Water then washes with 10% hydrochloric acid and finally with water until the wash waters are opposite Phenolphthalein react neutrally. The organic layer is dried over sodium sulfate and used for Evaporated to dryness. The remaining 1,2-diphenyl-3,5-dioxo-4- (3'-methyl-2'-butenyl) -pyrazolidine is recrystallized from ethanol, melting point 155 to 156 ° C).

Example 3

14.5 g (0.097 mol) of l-bromo-3-methyl-2-butene are added to a suspension of 19 g (0.069 mol) of des Sodium salt of 1,2-diphenyl-3,5-dioxopyrazolidine in 120 ml of carbon tetrachloride dripped

The reaction mixture is stirred at room temperature for 1 hour and then under reflux for 4 hours The precipitate is filtered off and the Fütrat is evaporated to dryness The residue is washed thoroughly with ether and redissolved in aqueous sodium hydroxide.

After washing with ether, the alkaline solution is acidified with 10% hydrochloric acid and the precipitated U-Diphenyl-3,5-dioxo-4- (3'-methyl-2'-buter.yl) -pyrazolidine recrystallized from ether; M.p. 155 to 156 "C).

Example 4

3.87 g (0.0237 mol) of l-bromo-4-methyl-3-pentene are added to a solution of 5 g (0.0182 mol) with stirring. of the sodium salt of 1-4 -diphenyl-S.S-dioxopyrazolidine added dropwise to 40 ml of dimethyl sulfoxide, the temperature being kept at 50 to 60.degree.

The reaction mixture is then be six hours 6O ⁰ C stirred The solvent is distilled off in Vakuun and the residue is treated simultaneously mi 100 ml ether and 10 ml of 10% hydrochloric acid

The ethereal layer is separated using water washed, dried over magnesium sulfate and evaporated

The tarry product obtained in this way is purified by chromatography on silica gel (solvent medium Benzene, 9: 1 benzene-ethyl acetate mixture).

The fraction obtained is evaporated to dryness and the residue is triturated with ether U-Diphenyl-3 ^ -dioxo-4- (4'-methyl-3'-pei tenyO-pyrazolidine, mp 136-137 ° C

Example 5

a) a solution of 0.4 mol of methylmagnesim iodide 200 ml of dry ether is in a solution of 253 (0.080 moles) U-diphenyl-3 ^ -dioxo-4- (3'-oxo-butyl) -p

razolidine was added dropwise to 400 ml of dry benzene, the temperature being kept at 0 to 10 ° C.

The reaction mixture is stirred for 16 hours at room temperature and then under external Cooling decomposes by carefully adding a saturated ammonium chloride solution.

The aqueous layer is washed with ether and acidified with 10% hydrochloric acid.

l, 2-diphenyl-3,5-dioxo-4- (3'-methyl-3'-hydroxy-butyl) -pyrazolidine separates as a tarry substance which solidifies (mp. 145-146 ⁰ C).

b) 10.15 g (0.03 mol) of 1,2-diphenyl-3,5-dioxo-4- (3'-methyl ^ '- hydroxy-butyO-pyrazolidine, dissolved in 50 ml of pyridine, are added dropwise to a A solution of 7.2 g (0.047 mol) of POCb in 13.8 ml of pyridine is added, the temperature being kept at 0 to 5 ° C. The reaction mixture is stirred for 24 hours at room temperature and then poured into 40 ml of water adjusted to pH 5.4 using 15% hydrochloric acid A tarry substance separates out, which is collected and crystallized from ethanol, 1,2-diphenyl-3,5-dioxo-4- (3'-methyl-2 '-butenyI) pyrazolidine has a melting point of 155 ° to 156 ° C. The procedure is analogous, except that 1,2-diphenyl-3,5-dioxo-4- (4'-methyl-4'-hydroxy pentyl) pyrazolidine , then 1,2-diphenyl-3 ₁ 5-dioxo-4- (4'- methyl-3'-pentenyl) pyrazolidine is obtained.

Example 6

9.2 g (0.063 mol) of a solution of 5-methyl-4-hexanoyl chloride in 10 ml of benzene are added with stirring to a mixture of 10.55 g (0.057 mol) of hydrazobenzene, 50 ml of benzene, 2.47 g (0.068 mol) of sodium hydroxide and 20 ml of water are added, while maintaining at 10 ° C. The yellow, thick suspension obtained is stirred for 45 minutes at room temperature and then filtered

The solid obtained is washed with benzene and crystallized from methanol, 5-methyl-4-hexenoyl-N, N'-diphenylhydrazine receives

5 g (0.017 mol) of 5-methyl-4-hexenoyl-N, N'-diphenylhydrazine and 9.22 g (0.085 mol) of ethyl chlorocarbonate are refluxed for 5 hours and then the excess of ethyl chlorocarbonate is distilled off. The oily residue thus obtained is dissolved in 50 ml of dry benzene and refluxed for 12 hours in the presence of 1.23 g (0.025 mol) of a 50% suspension of sodium hydride in mineral oil. The reaction mixture is then decomposed by careful addition of water with external cooling. The aqueous solution is washed with ether and acidified with 10% hydrochloric acid, whereupon the precipitated l ^ -diphenyl-3 ^ -dioxo-4- (3'-methyl- 2'-butenyl) pyrazolidine crystallized from ethanol (melting point 155 ° to 156 ° C.).

Example 7

2 g (0.0068 mol): ~ methyl-4-hexenoyl-N, N'-diphenylhydrazine and 1.21 g (0.0102 mol) of diethyl carbonate in 30 ml of benzene for 18 hours in the presence of 0.4 g (0.0102 mol) of sodium amide heated under reflux. After cooling, the reaction mixture is decomposed by the careful addition of water, and the aqueous layer is washed with ether and acidified with 10% hydrochloric acid

55

60

65

Example 8

A mixture of 7.19 g (0.046 mol) of ethyl 5-methyl-4-hexenoate and 5.76 g (0.048 mol) of diethyl carbonate is added to a mixture of 7.36 g (0.040 mol) of hydrazobenzene, 8 g (0.167 mol ) a 50% suspension of sodium hydride in mineral oil and 120 ml of dry xylene which ^{is heated to 75 °} C. is added. The reaction mixture is refluxed for 12 hours and, after cooling, it is carefully treated with water. The aqueous layer is washed with ether and acidified with 10% hydrochloric acid.

The l, 2-diphenyl-3,5-dioxo-4- (3'-methyl-2'-butenyl) pyrazolidine which separates out is crystallized from ethanol, melting point 155 to 156 ° C. If you work in a similar manner Way, but starting from ethyl 6-methyl-5-heptenoate, then 1,2-diphenyl-3,5-dioxo-4- (4'-methyl-3'-pentenyl) -pyrazolidine is obtained.

Example 9

12.5 g (0.039 mole) 1,2-diphenyl-3,5-dioxo-4- (3'-methyl-2'-butenyl) pyrazolidine are dissolved by heating in a solution of sodium ethylate, which is obtained from 0.89 g (0.039 mol) of sodium and 90 ml of dry Received ethanol. The solvent is distilled off under reduced pressure and the sodium salt des 1,2-diphenyl-3,5-dioxo-4- (3'-methyl-2'-butenyl) -py razoüüins is obtained as an ivory white solid.

Example 10

10 g of the sodium salt of l, 2-diphenyl-3,5-dioxo-4 · (3'-methyl-2'-butenyl) pyrazolidine, dissolved in 150 ml of water are stirred with a saturated aqueous solution of calcium chloride r treated for a long time until no more precipitate forms Da; precipitated calcium salt is filtered off, washed with water and dried under reduced pressure

The following examples explain the production of pharmaceutical preparations from the invention obtained compounds.

Example 11

Tablets A. B. B. C. C. (mg) (mg) (mg) (mg) (mg) l, 2-diphenyl-3,5-dioxo- 200 300 400 4- (3'-methyl-2'-butenyl) - pyrazolidine Microcrystalline cellulose 50 50 50 Cornstarch 77 115 115 Talc and magnesium stearate 3 5 5 Example 12 A. (mg)

^^ y ^ iy ^ yJpy Lidine is purified by crystallization from ethanol

Hard gelatine capsules
Each capsule contains:

l, 2-diphenyl-3,5-dioxo-

4- (3'-methyl-2'-butenyl) -

pyrazolidine

200

300

400 5

20 31 13

Example 13

ABC

(mg) (mg) (mg)

. — ___ j Coated tablets,
K.?rn:

1,2-diphenyl-3,5-dioxo-200 300 400

4- (3'-methyl-2'-butenyl) -

pyrazolidine ^l0

Microcrystalline cellulose 130 170 210 corn starch, talc and

Magnesium stearate

Cover " ⁵

Sugar, gum arabic, coloring and titanium dioxide.

ABC (mg) (mg) (mg)

20th

Final weight 550 700 850

Example 14
Dermatological solution _2S

1,2-diphenyl-3,5-dioxo-4- (3'-methyl-

2'-butenyl) pyrazolidine 5 g

Dimethyl sulfoxide 85 g

Distilled water 10 g .v>

Example 15
ointment

1,2-Diphenyl-3,5-dioxo-4- (3'-methyl-35

2'-butenyl) pyrazolidine 5 g

Methyl p-hydroxybenzoate 0.1 g

Propyl p-hydroxybenzoate 0.02 g

Lanolin 5.88 g

White Vaseline 89 g 40

238 /

6th ^M.

Example 16 creams

1,2-diphenyl-3,5-dioxo-4- (3'-methyl-

2'-butenyl) pyrazolidine 5 g

Cetyl alcohol 7.5 g

Glyceryl monostearate 3.75 g

Lanolin 230 g

White Vaseline 27.00 g

Methyl p-hydroxybenzoate 0.09 g

Propyl p-hydroxybenzoate 0.05 g

Distilled water qs to 100 g

Example 17

Suppositories A B

1,2-piphenyl-3,5-dioxo-300 mg 400 mg

4- (3'-methyl-2'-butenyl) -

pyrazolidine

Glycerides of fatty acid q. s.

Weight of the suppositories 2 g 2 g

Example 18 vials containing a lyophilized mass

1,2-diphenyl-3,5-dioxo-4- (3'-methyl-

2'-butenyl) pyrazolidine Na salt 250 mg

N atrium Glycollate 250 mg

Distilled water q. see for a lyophilized solution to obtain a solid one Dimensions

Solvent vial, 5 ml distilled water twice

Claims (1)

Patent claims: i. l ^ -Diphenyl-3 ^ -diox (v4-substituted pyrazolidines of the general formula I. R-CH CO (D