GB1589816A - Pharmacologically active esters of alkyl-dioxo-pyrazotidine derivatives - Google Patents

Description

(54) NEW PHARMACOLOGICALLY ACTIVE ESTERS OF ALKYL-DIOXO-PYRAZOLIDINE DERIVATIVES (71) We, STERWIN A.G., a Swiss Company, of Zeughausgasse 9, CH6300 Zug, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention concerns new pharmacologically-active esters of alkyl-dioxopyrazolidine derivatives.

Analgesics are in widespread use today, and many compounds of different types have been proposed and marketed for use as such. For the relief of chronic conditions such as rheumatism and arthritis it is normally desired to use an agent which displays an anti-inflammatory effect in addition to its analgesic activity. Thus for the alleviation of chronic arthritic and rheumatic conditions it is at present normal to employ one of the known anti-inflammatory analgesic agents.

Some of the best-known, most effective and widely-used of the existing antiinflammatory analgesics can be regarded as 4-alkyl-3,5-dioxo-pyrazolidone derivatives most conveniently represented by the general formula:

but which can be assumed to exist also in the following alternative tautomeric forms: -

in all of which general formulae I, Ia and Ib either X is phenyl and Y is phenyl or para-hydroxyphenyl, or else X and Y together with the intervening nitrogen atoms to which they are respectively attached represent a 3-dimethylamino-7-metbyl- [1,2,4] - benzotriazine ring-system fused with the pyrazolidine ring, and Alk represents either an n-butyl or an n-propyl group.

It should be noted that hereinafter any reference to the compounds of general formula I should be assumed to include reference to the tautomeric forms Ia and Ib thereof.

The following compounds are typical of the known anti-inflammatory, analgesic pyrazolidine derivatives of general formula I above, namely: - 1 ,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine; l-phenyl-2-(p-hydroxyphenyl)-3,5-dioxo-4-n-butyl-pyrazolidine; and 5-dimethylamino-9-methyl-2-n-propyl-lH-pyrazolo [1,2-a] [1,2,4] benzotriazine 1,3(2H)-dione.

Even better known as an analgesic is the compound of structural formula:

namely 2-acetoxy-benzoic acid.

Unfortunately however the desirable anti-inflammatory and analgesic properties of the pyrazolidine derivatives of the general formula I above and the desirable analgesic properties of 2-acetoxy-benzoic acid of structural formula II are, in each case, offset by their tendency to give rise to disturbances of the gastric tract. Moreover when both are administered simultaneously to the patient they have been found to be mutually antagonistic, each hindering assimilation of the other.

It is therefore particularly surprising that we have found not only that it is possible to form esters between the carboxyl group present in 2-acetoxy-benzoic acid of structural formula II above and the hydroxy group(s) present in the pyrazolidine derivatives of general formula I above (or at least in the tautomeric forms Ia and Ib thereof) but also that the resultant esters, although formed between gastricallydisturbing and mutually-antagonistic moieties, are nevertheless largely or indeed almost wholly free from unwanted side-effects upon the gastric tract, while being effective and indeed outstanding anti-inflammatory analgesics, satisfactorily assimilated by the patient.

According to one aspect of this invention there are therefore provided the 2acetoxy-benzoic acid esters of the 4allryl-3,5-dioxo-pyrazolidine derivatives of general formula I above, and (where feasible) their acid addition salts when formed with pharmacologically-acceptable mineral and organic acids.

Specific preferred 2-acetoxy-benzoic acid esters or 4-alkyl-3,5-dioxo-pyrazolidine derivatives in accordance with this invention are for instance: 1,2 - diphenyl - 3 - oxo - 4 - n - butyl - 5 (2' - acetoxy - benzoyloxy) - pyrazolid - 4 - ene of structural formula:

n-butyl 1 - phenyl - 2 - (para - hydroxy - phenyl) - 3 - oxo - 4 - n - butyl- 5 - (2'acetoxy - benzoyloxy) - pyrazolid - 4 - ene of structural formula:

UN (B) CH3CO-O sCûO U O n - butyl or its 3 - (2' - acetoxy - benzoyloxy) - 5 - oxo - isomer, namely 1 - phenyl - 2 (para - hydroxy - phenyl) - 3 - (2' - acetoxy - benzoyloxy) - 4 - n - butyl - 5 - oxopyrazolid - 3 - ene which however may alternatively and more conveniently be called 1 - (para - hydroxy - phenyl) - 2 - phenyl - 3 - oxo - 4 - n - butyl - 5 - (2' - acetoxybenzoyloxy) - pyrazolid - 4 - ene, of structural formula:

HO tsNN X3 (B') CH3 -CO -- 0 ,CO -0-6 n-butyl 1 - phenyl - 2 - (para - [2' - acetoxy - benzoyloxy] - phenyl) - 3,5 - dioxo - 4n - butyl - pyrazolidine of structural formula:

o-co .O-CO-CH3 (c) onto n- butyl or either of its tautomeric 5 - hydroxy - 4 - en - 3 - one and 3 - hydroxy - 3 - en5 - one forms, which are to be regarded as encompassed by the name and structural formula C just given above, 1 - phenyl - 2 - (para - [2' - acetoxy - benzoyloxy] - phenyl) - 3 - oxo - 4 - nbutyl - 5 - (2' - acetoxy - benzoyloxy) - pyrazolid - 4 - ene of structural formula:

I,n-Qo-,, CD- CH3 CH3-CD-D OUCO-O 9 (D) n- butyl D-CD or its 3 - (2' - acetoxy - benzoyloxy) - 5 - oxo - isomer, namely 1 - phenyl - 2 - (para [2' - acetoxy - benzoyloxy] - phenyl) - 3 - (2' - acetoxy - benzoyloxy) - 4 - n - butyl5 - oxo - pyrazolid - 3 - ene, which however may alternatively and more conveniently be called 1 - (para - [2' - acetoxy - benzoyloxy] - phenyl) - 2 - phenyl - 3 - oxo4 - n - butyl - 5 - (2' - acetoxy - benzoyloxy) - pyrazolid - 4 - ene of structural formula:

I D-CU 0- CU-CH3 - (D') "- butyl O- CO - CH3 n- butyl 1 - (2' - acetoxy - benzoyloxy) - 2 - n - propyl - 3 - oxo - 5 - dimethylamino9 - methyl - pyrazolid - 2 - eno[1,2 - a] [1,2,4]benzotriazine of structural formula:

CH3 q N(Cit3 (E) N-N CH3 CH3-CO- OX XCO-O n- % propyl and acid addition salts thereof formed with pharmacologically - acceptable acids; or its 1 - oxo - 3 - hydroxy isomer, namely - 1 - oxo - 2 - n - propyl - 3 - (2' - acetoxybenzoyloxy) - 5 - dimethylamino - 9 - methyl - pyrazolid - 3 - eno[1,2 - a] [1,2,4]benzotriazine of structural formula:

CH3 - N(H3 (E') CH3 \CH3 0 /D-CO 0-CD-Cit3 n - propyl and acid addition salts thereof formed with pharmacologically - acceptable acids.

We have moreover found that these 2-acetoxy-benzoic acid esters of 4-alkyl3,5-dioxo-pyrazolidine derivatives in accordance with this invention may be prepared quite conveniently and usually in fairly good yield by various preparative processes, as follows.

According to another aspect of this invention there is therefore provided a first process for the preparation of the 2-acetoxy-benzoic acid esters of 4-alkyl-3,5-dioxopyrazolidine derivatives in accordance with this invention, in which a 4-alkyl-3,5dioxo-pyrazolidine derivative of general formula I above (but in one of its tautomeric forms Ia or Ib) is reacted in the presence of a base with 2-acetoxy-benzoic acid chloride of the structural formula:

to yield the desired 2-acetoxy-benzoic acid esters of the corresponding 4-alkyl-3,5dioxo-pyrazolidine derivative or (where feasible) an acid addition salt thereof.

The reaction between the pyrazolidine derivative of general formula I and the 2-acetoxy-benzoic acid chloride is desirably effected in an anhydrous inert solvent.

Being fairly vigorous, it may be carried out without heating at ambient temperature; or it may even be necessary or at least desirable when the reaction is very vigorous (as sometimes it is) to employ cooling.

The inert solvent may advantageously be an organic solvent, such as especially (a) substituted aromatic hydrocarbons (including halogenated hydrocarbons) for example toluene, (b) aliphatic hydrocarbons (including halogenated hydrocarbons) for example chloroform (trichloromethane) and dichloromethane, and (c) aliphatic ethers, for example diethyl-ether. The preferred solvents are chloroform and dichloromethane.

The reaction must be effected in the presence of a base, which can most con veniently be a tertiary amine. The base currently preferred above all others is pyridine.

This first process of the invention may also advantageously include the preliminary step of preparing the 2-acetoxy-benzoic acid chloride starting material, of structural formula III above, by reacting 2-acetoxy-benzoic acid of structural formula II, in solution and/or suspension in an anhydrous inert solvent, with thionyl chloride.

The reaction with thionyl chloride may be conducted at any convenient temperature between ambient and the reflux temperature of the solvent, and usually within the range of from room temperature up to about 65 0C.

The solvent can with obvious advantage be the same as that used in the abovedescribed subsequent stage of the preparation, since then the 2-acetoxy-benzoic acid chloride obtained need not be isolated from the reaction product, and thus for instance may desirably be a relatively low-boiling organic solvent, such as (a) a substituted aromatic hydrocarbon (including halogenated hydrocarbons) for example toluene, (b) an aliphatic hydrocarbon (including halogenated aliphatic hydrocarbons) for example chloroform (trichloromethane) or dichloromethane or (c) an aliphatic ether for example diethylether. The specific preferred solvents are chloroform and dichloromethane.

When the solvent employed is anhydrous dichloromethane, the reaction can most conveniently be effected under reflux at a temperature of about 40"C. The proportions of the reactants will preferably be about 1 mole of thionyl chloride per mole of 2acetoxy-benzoic acid.

It has been found advantageous to effect the reaction between the 2-acetoxybenzoic acid and the thionyl chloride in the presence of a catalytic amount of N,Ndimethylformamide.

According to another aspect of the invention there is also provided an alternative, second process for the preparation of the 2-acetoxy-benzoic acid esters of 4-alkyl-3,5 dioxo-pyrazolidene derivatives in accordance with this invention, in which a mixed anhydride of general formula:

(in which "Ayl" represents an alkyl group with 1 - 20 carbon atoms, an aryl group with 6 - 20 carbon atoms, an alkaryl group with 7 - 20 carbon atoms or an aralkyl group with 7 - 20 carbon atoms; m is 0 (zero) or 1; and Q represents a carbon atom C or when m is zero a sulphinyl group S = 0) is reacted with a 4-alkyl-3,5dioxo-pyrazolidine derivative of general formula I above (but in one of its tautomeric forms Ia or Ib) to yield the desired 2-acetoxy-benzoic acid ester of the corresponding 4-aLkyl-3,5-dioxo-pyrazolidine derivative.

This reaction between the mixed anhydride of general formula IV and the 4alkyl-3,5-dioxo-pyrazolidine derivative of general formula I can and desirably should be carried out in an anhydous inert and usually organic solvent, which may for instance be a substituted aromatic solvent, for example toluene, or any conventionalIyemployed halogenated aromatic hydrocarbon solvent, or halogenated aliphatic hydrocarbon solvent for example chloroform (trichloromethane).

For reasons which will appear below, it should be noted that this reaction can moreover be conducted without detriment in the presence of a base, such as a tertiary amine like triethylamine or pyridine.

The mixed anhyrides of general IV above are believed to be novel compounds, which of course are useful as intermediates in the synthesis of the 2-acetoxy-benzoic acid esters of 4-alkyl-3,S-dioxo-pyrazolidine derivatives in accordance with this invention.

The mixed anhydrides of general formula IV above may advantageously be prepared in a preliminary stage of this overall second process in which a reactive organic chloride of general formula:

(in which "Ayl", m and Q all have the same meanings as before) is reacted with 2 acetoxy-benzoic acid of structural formula II above or a salt thereof in the presence of a base, to yield the desired corresponding mixed anhydride.

The reactive organic chloride of general formula V above can for instance be: (a) an alkyl or aralkyl or aryl or alkaryl chloroformate, of general formula:

or (b) a sterically-encumbered alkyl or aralkyl or aryl or alkaryl acid chloride, of general formula:

or (c) an alkyl or aralkyl or aryl or alkaryl sulphonyl chloride, of general formula:

in all of which, as in general formula V, "Ayl" represents an alkyl, aralkyl, aryl or alkaryl group having the previously-defined number of carbon atoms therein.

The reaction (sometimes hereinafter called the "first-stage reaction") between the 2-acetoxy-benzoic acid of structural formula II above and the reactive organic chloride of general formula V (or specifically Va, Vb or Vc) is most conveniently carried out in an anhydrous, inert and usually organic solvent, which may for instance be a substituted aromatic solvent, for example toluene, or any conventionallyemployed halogenated aromatic hydrocarbon solvent or halogenated aliphatic hydrocarbon solvent, for example chloroform (trichloromethane).

This first-stage reaction must be performed in the presence of a base, which advantageously will be a tertiary amine, and preferably either triethylamine or pyridine.

As previously indicated, the subsequent reaction between the mixed anhydride IV and the 4-alkyl-3,5-dioxo-pyrazolidine derivative I (sometimes hereinafter called the "second-stage reaction") is advantageously performed in the same kind of anhydrous, inert organic solvent as that in which the first-stage reaction is performed, and furthermore the second-stage reaction suffers no detriment from the presence of a base. It is therefore possible and indeed dcsirable to carry out both the first-stage reaction and the second-stage reaction in the same anhydrous inert organic solvent, without intervening isolation of the first-stage reaction product, and usually in the same reaction vessel.

According to a still further aspect of this invention there is also provided a third process for the preparation of the 2-acetoxy-benzoic acid esters of the 4-alkyl3,5-dioxo-pyrazolidine derivatives in accordance with this invention, in which a 4alkyl-3,5-dioxo-pyrazolidine derivative of general formula I above (but in one of its tautomeric forms Ia or Ib) is reacted with a solution in a water-immiscible solvent of 2-acetoxy-benzoic acid anhydride, of structural formula:

in the presence of a strong aqueous base so that the reaction mixture forms a twophase reaction system which is agitated to yield the desired 2-acetoxy-benzoic acid ester of the corresponding 4-alkyl-3,5-dioxo-pyrazolidine derivative.

The refection between the 4-alkyl-3,S-dioxo-pyrazolidine derivative of general formula I above and the 2-acetoxy-benzoic acid anhydride of structural formula VI produces 2-acetoxy-benzoic acid as a side-product, and must therefore be effected in the presence of a strong base, which can for instance be an organic base such as triethylamine but preferably will be aqueous sodium hydroxide. Since the anhydride is somewhat unstable in the presence of water, it must be brought to reaction in solution in an anhydrous inert water-immiscible organic solvent, convenient benzene, toluene, chloroform, dichloromethane or an aliphatic ether such as diethylether, so that the reaction can then be conducted with strong agitation in a two-Dhase reaction system, thus minimizing any breakdown of the anhydride before it has participat in the intended reaction. This reaction can conveniently be carried out at ambient or near-ambient temperatures not exceeding 300C.

2-Acetoxy-benzoic acid anhydride of structural formula VI above is believed to be a novel compound, which of course is useful as an intermediate in the synthesis of the 2-acetoxy-benzoic acid esters of 4-alkyl-3,5-dioxo-pyrazolidine derivatives in accordance with this invention.

This third process can moreover advantageously include the further preliminary step of preparing the 2-acetoxy-benzoic acid anhydride of structural formula VI above by reacting 2-acetoxy-benzoic acid of structural formula II with a carbodiimide in solution in an anhydrous, non-hydroxylic and otherwise inert organic solvent at ambrent or near-ambient temperatures, usually not exceeding 30"C.

In principle any carbodiimide can be employed, but in practice the carbodiimide used must of course be stable, and accordingly we envisage that the carbodiimide used would best be an N,N'-di[alk/ar]yl-carbodiimide of general formula:

wherein Z' and Z" each represents an alkyl or cycloalkyl or alkarvi or aryl or aralkyl group containing from 6 to 20 carbon atoms. Moreover it must be added that at present the only carbodiimide commercially available (at least in Britain) at an economic price is N,N'-dicyclohexyl-carbodiimide, which therefore is preferred for use in this invention.

The solvent used in the process will advantageously be tetrahydrofuran.

This invention of course extends to the 2-acetoxyqbenzoic acid esters of the 4-alkyl-3,5-dioxo-pyrazolidine derivatives of general formula I, whenever prepared in or by any of the first, second or third processes outlined above and further described in the subsequent Examples.

The 2-acetoxy-benzoic acid esters of 4-alkyl-3,5-dioxo-pyrazolidine derivatives according to this invention, whether prepared by any of the processes herein described or in any other manner, appear to display excellent anti-inflammatory and analgesic activities when tested by generally-accepted tests for anti-inflammatory and analgesic drugs; and preliminary studies suggest that when administered orally the preferred compounds herein identified will be substantially free from gastric side-effects.

For employment in human and veterinary medicine as antizinflammatory analgesics the 2-acetoxy-benzoic acid esters of the 4-alkyl-3,5-dioxo-pyrazolidine derivatives of general formula I above, and specifically the preferred compounds of formulae A, B and B', C, D and D' as well as E and E' above, should however naturally be suitably formulated into appropriate pharmaceutical compositions, by association with suitable pharmaceutical vehicles.

The term "pharmaceutical" is used herein to exclude any possibility that the nature of the vehicle (considered of course in relation to the route by which the composition is intended to be administered) could be harmful rather than beneficial.

The choice of a suitable vehicle for any chosen route and mode of presentation is believed to be within the competence of those accustomed to the preparation of pharmaceutical compositions.

Accordingly in yet another aspect of this invention there are provided pharmaceutical compositions wherein the active ingredient is or includes one or more of the 2-acetoxy-benzoic acid esters of the 4-alkyl-3,5-dioxo-pyrazolidine derivatives of general formula I above, said active ingredient being associated with a suitable pharmaceutical vehicle as herein defined.

Although the compositions of this invention are primarily designed for administration via the digestive tract, including rectally, they can also be administered parenterally. The preferred route of administration is however orally, including per lingually. In respect of these various modes of presentation the "pharmaceutical vehicle" is desirably: (a) the ingestible excipient of a tablet, coated tablet, sublingual tablet or pill; the ingestible container of a capsule or catchet; the ingestible pulverulent solid carrier of a powder, or the ingestible liquid medium of a syrup, solution, suspension or elixir; (b) the solid or liquid medium of a paste, lotion, salve, ointment or unguent; (c) a sterile injectable liquid solution or suspension medium; or (d) a base material of low melting point capable of releasing the active ingredient to perform its pharmacological function, which base material when appropriately shaped forms a suppository.

Whilst the modes of presentation just listed represent those most likely to be employed, they do not necessarily exhaust the possibilities.

The anti-inflammatory analgesics of this invention, and especially the preferred 2-acetoxy-benzoic acid esters of 4-alkyl-3,S-dioxo-pyrazolidine derivatives identified previously herein and having the structural formulae A, B and B', C, D and D' as well as E and E' above, will most frequently be administered in the form of tablets, capsules and other solid dosage forms.

Whilst the dosage of these anti-inflammatory analgesics may depend to some degree upon the particular compound used, the route by which the compositions are to be administered, and of course also upon the condition to be treated, as a general indication it may be said that the useful dose will usually range from 400 mg up to 5 g (in divided doses) of the active analgesic per day for an adult, a unit dose containing usually from 150 mg to 400 mg of the active analgesic.

In order that the invention may be well understood some preparations of certain of the preferred 2-acetoxy-benzoic acid esters of 4-alkyl-3,5-dioxo-pyrazolidine derivatives in accordance with the invention will now be described in more detail, though by way of illustration only, with reference to the following Examples: GROUP I.

Preparations by the "First" Process, via 2-Acetoxy-Benzoic Acid Chloride.

EXAMPLE 1.

Preparation of 1,2 - diphenyl - 3 - oxo - 4 - n - butyl - 5 - (2' - acetoxy - benzoyloxyf pyrazolid - 4 - ene (A).

Stage A.

Preparation of 2-acetoxy-benzoic acid chloride (III).

100 Grams of 2-acetoxy-benzoic acid were suspended in 27 ml of chloroform containing 1 ml of N,N-dimethylformamide. 42 M1 (or 68.9 grams) of thionyl chloride were added, and the mixture was stirred at room temperature for two hours. Then a further 5 ml of thionyl chloride were added, and the mixture was warmed to 35"C for 20 minutes. By this time the reaction mixture had become clear. The solvent was removed on the rotary evaporator, and the residue was pumped out under a high vacuum for 2 hours.

The acid chloride thus prepared, namely 2-acetoxy-benzoic acid chloride of formula III above, was obtained in this way as an oil, in a yield of about 100 grams, which was used without further purification in the following Stage B.

However, when taken up in a mixture (20:1) of petroleum ether (40--60") and chloroform, the desired 2-acetoxy-benzoic acid chloride can be recovered in crystalline form. Yield 80 grams, m. pt. = 48-500C.

Stage B.

Preparation of 1,2 - diphenyl - 3 - oxo - 4 - n - butyl - 5 - (2' - acetoxy - benzoyloxy) pyrazolid - 4 - ene (A).

20 Grams of 2-acetoxy-benzoic acid chloride, obtained as described in Stage A above, were dissolved in 300 ml of ether, and to that solution there were added 9.0 grams of pyridine. Then 30.8 grams of 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazoli- dine were added, and this reaction mixture was vigorously stirred for 20 minutes and thereafter refluxed for 1 hour.

The mixture was filtered to remove pyridine hydrochloride, then the ether was removed and the residue dissolved in 100 ml of dichloromethane. This solution was washed with dilute hydrochloric acid, then with 5 , sodium carbonate solution. The dichloromethane solution was dried, and evaporated to dryness under reduced pressure.

TLC (chloroform) indicated the presence of unreacted pyrazolidine derivative.

This could be completely removed by dissolving the product in 75 ml of ether, and shaking vigorously with 100 ml of 2.5 M sodium hydroxide solution for 20 minutes.

A further 100 ml of ether was added to the mixture to extract the product. The ether layer was dried, and evaporated to give an almost colourless oil, which quickly solidified on standing. TLC (chloroform) indicated that the product was pure.

A yield of 30 grams of the desired 1,2-diphenyl-3-oxo-4-n-butyl-5-(2'-acetoxy- benzoyloxy)-pyrazolid-4-ene was thus obtained. M.pt. = 9v99 C.

EXAMPLE 2.

Preparation of 1 - (2' - acetoxy - benzoyloxy) - 2 - n - propyl - 3 - oxo - 5 - dimethyl amino - 9 - methyl - pyrazolid - 2 - eno [1,2 - a] [1,2,4] - benzotriazine (E).

Stage A.

Preparation of 2-acetoxybenzoic acid chloride.

This was similar to Stage A of Example 1.

Stage B.

Preparation of 1 - (2' - acetoxy - benzoyloxy) - 2 - n - propyl - 3 - oxo - 5 - dimethyl amino - 9 - methyl - pyrazolid - 2 - eno [1,2 - a] [1,2,4] - benzotriazine (E).

A mixture of 9.0 grams of 5-dimethylamino-9-methyl-2-nwpropyl-lH-pyrazolo [1,2-a] [1,2,4] benzotriazine-1,3(2H)-dione and 3.0 grams of pyridine in 50 ml of dichloromethane was added to a stirred solution in 100 ml of dichloromethane of 60 grams of 2-acetoxywbenzoic acid chloride, prepared as indicated in Stage A above.

This reaction mixture was refluxed for 10 minutes, cooled, and washed with 100 ml of 2M hydrochloric acid. The dichloromethane solution was then concentrated under reduced pressure, and the residual oil was dissolved in 200 ml of ether containing 5% ethyl acetate, and washed twice with 100 ml of 2M aqueous sodium hydroxide solution, and then with 100 ml of water, and dried over magnesium sulphate. Concentration of the ether solution under reduced pressure gave a yellow oil.

Addition of an ether/petroleum - ether mixture (60--80") caused the desired 1 - (2' - acetoxy - benzoyloxy) - 2 - n - propyl - 3 - oxo - 5 - dimethylamino - 9methyl - pyrazolid - 2 - eno [1,2 - a] [1,2,4] - benzotriazine (E) to crystallise out, in a yield 6.4 grams of creamy - coloured needles. M.pt. = 1380-1400C.

GROUP II.

Preparation by the "Second" Process, via the Mixed Anhydride of the General Formula IV.

EXAMPLE 3.

Preparation of 1-phenyl-2-(psra-[2'-acetoxyHbenzoyloxy]-phenyl)-3,5-dioxo-4-n-butyl- pyrazolidine (C).

Stage A.

Preparation of the mixed anhydride of 2-acetoxy-benzoic acid and ethoxy-formic acid (IV, where Ayl = Et, m = 1, Q = C).

3.6 Grams (0.02 mole) of 2-acetoxy-benzoic acid and 2.18 grams (0.02 mole) of ethoxy-formic acid chloride were stirred together in 50 ml of dichloromethane at 5"C. A solution of 2.02 grams (0.02 mole) of triethylamine in 25 ml of dichioro- methane was added dropwise, while maintaining a temperature of less than 10 Cb and the mixture was subsequently stirred at room temperature for 30 minutes.

A solution was thus obtained of the desired mixed anhydride of 2-acetoxy-benzoic acid and formic acid of general formula IV where Ayl represents an ethyl group, m is 1 and Q represents a carbon atom. That solution was used, without intervening isolation of the mixed anhydride, in Stage B below.

Stage B.

Preparation of l-phenyl-2-(para- [2'-acetoxy-benzoyloxy] -phenyl)-3,5-dioxo-4-n-butyl- pyrazolidine (C).

To the solution obtained from Stage A above there was slowly added a solution of 3.24 grams (0.01 mole) of 1 - phenyl - 2 - (para - hydroxyphenyl) - 3,5 - dioxo4 - n - butyl - pyrazolidine and 2.02 grams (0.02 mole) of triethylamine in 25 ml dichlorom

GROUP III.

Preparation by the "Third" Process, via 2-Acetoxy-Benzoic Acid Anhydride.

EXAMPLE 4.

Preparation of 1-phenyl-2-(para [2'-acetoxy-benzoyloxy] -phenyl-3,Sdioxo-4-n-butyl- pyrazolidine (C).

Stage A.

Preparation of 2-acetoxy-benzoic acid anhydride (VI).

16.5 Grams (0.08 mole) of N,N'-dicyclohexyl-carbodiimide were added to a solution of 14.4 grams (0.08 mole) of 2-acetoxy-benzoic acid in 150 ml of tetrahydrofuran. The resultant mixture was left at room temperature overnight. It was then filtered, the filtrate was evaporated to dryness, and the residue taken up in ethanol and recrystallised to yield 6.5 grams of the desired 2-acetoxy-benzoic acid anhydride. M.pt. = 830 - 850C.

Stage B.

Preparation of l-phenyl-2-(para- [2 '-acetoxy-benzoyloxy] -phenyl-3,5-dioxo-4-n-butyl pyrazolidine (C).

3.24 Grams (0.01 mole) of l-phenyl-2 -(para-hydroxy-pheny1)-3 ,5-dioxo4-n-butyl- pyrazolidine were dissolved in 20 ml of 1M sodium hydroxide. To this solution there was then added a solution of 6.84 grams (0.02 mole) of 2-acetoxy-benzoic acid anhydride, obtained as described in Stage A above, in 20 ml of benzene. The twophase mixture was shaken vigorously for 30 minutes, and then filtered to give the desired product, M.pt. = 1560 - 1570C.

-0-0-0-0-0-0- It will be noted that whatever method may be employed, the esterification by 2 - acetoxy - benzoic acid of 1 - phenyl - 2 - (para - hydroxy - phenyl) - 3,5 - dioxo4 - n - butyl - pyrazolidine results preferentially in the mono - ester 1 - phenyl - 2 (para - [2' - acetoxy - benzoyloxy] - phenyl) - 3,5 - dioxo - 4 - n - butyl - pyrazolidine (C) rather than the possible alternative isomeric mono - esters (B) or (B') at least under the reaction conditions employed in the foregoing Examples 3 and 4.

Small amounts of 1 - phenyl - 2 - (para - hydroxy - phenyl) - 3 - oxo - 4 - n - butyl5 - (2' - acetoxy - benzoyloxy) - pyrazolid - 4 - ene (B) and of 1 - (para - hydroxyphenyl) - 2 - phenyl - 3 - oxo - 4 - n - butyl 5 - (2' - acetoxy - benzoyloxy) - pyrazolid - 4 - ene (B') are however formed in the course of these reactions, and so too are certain amounts of the diesters, 1 - phenyl - 2 - (para - [2' - acetoxy - benzoyloxy] phenyl) - 3 - oxo - 4 - n - butyl - 5 - (2' - acetoxy - benzoyloxy) - pyrazolid - 4 - ene (D) and 1 - (para - [2' - acetoxy - benzoyloxy] - phenyl) - 2 - phenyl - 3 - oxo - 4n - butyl - 5 - (2' - acetoxy - benzoyloxy) - pyrazolid - 4 - ene (D'), all of which can be recovered and isolated if the reactions are performed on an appropriate scale and with suitable operating conditions. The recovery and isolation of these various alternative compounds B, B', D and D' is not however here further described, since we cannot recommend striving to make any of B, B', D and D' with difficulty when C is readily prepared and so far as our evaluations have shown possesses essentially the same pharmacoligical activity as its isomers.

It will also be noted that essentially the same comments apply to the esterification by 2 - acetoxy - benzoic acid of 5 - dimethylamino - 9 - methyl - 2 - n - propyl1H - pyrazolo [1,2 - a] [1,2,4] benzotriazine - 1,3(2H) - dione which, presumably due to steric hindrance, results preferentially in 1 - (2' - acetoxy - benzoyloxy) - 2n - propyl - 3 - oxo - 5 - dimethylamino - 9 - methyl - pyrazolid - 2 - eno [1,2 - a] [1,2,4] benzotriazine (E) rather than its isomer 1 - oxo - 2 - n - propyl - 3 - (2'acetoxy - benzoyloxy) - 5 - dimethylamino - 9 - methyl - pyrazolid - 3 - eno [1,2 - a] [1,2,4] benzotriazine (E'), at least under the reaction conditions employed in the foregoing Example 2. Small amounts of the isomer E' are however formed in the course of the reaction, and can be recovered and isolated if the reaction is performed on an appropriate scale and with suitable operating conditions - but again, this is not here described since we cannot recommend an attempt to make isomer E' with difficulty when E is readily prepared and seems to possess essentially the same activity.

-0-0-0-0-0-0- So as to illustrate another aspect of this invention details will now be given, though only by way of example, of the formulation of the preferred 2-acetoxy-benzoic acid esters of 4-alkyl-3,5aioxo-pyrazolidine derivatives of structural formulae A, C and E into pharmaceutical compositions, as follows: Formulation 1.

Tablets containing 1-(2 '-acetoxy-benzoyloxy)-2-n-propyl-3 -oxo-5 -dimethyiamino-9 methyl-pyrazolid-2-eno [1,2-a] [1,2,4]-benzotriazine (E).

A tabletting mixture was made up by intimately mixing together the following ingredients: 1 - (2' - acetoxy - benzoyloxy) - 2 - n - propyl - 3 - oxo - 5 - dimethylamino2 - eno [1,2 - a] [1,2,4] benzotriazine. benzotriazine 400 mg/tablet 0.800 kg spray dried lactose 100 mg/tablet 0.200 kg microcrystalline cellulose 25 mg/tablet 0.050 kg stearic acid 5 mg/tablet 0.010 kg 530 mg/tablet 1.060 kg The mixture was then compressed by conventional tabletting machinery to form 2000 tablets, each weighing 530 mg and containing 400 mg of 1 - (2' - acetoxybenzoyloxy) - 2 - n - propyl - 3 - oxo - 5 - dimethylamino - 9 - methyl - pyrazolid2 - eno [1,2 - a] [1,2,4] benzotriazine.

Formulation 2.

Tablets containing 1,2-diphenyl-3-oxo-4-n-butyl-5-(2'-acetoxy-benzoyloxy)-pyrazolid 4-ene (A).

1,2-diphenyl-3-oxo-4-n-butyl-5-(2' acetoxy-benzoyloxy)-pyrazolid-4-ene 150 mg/tablet 0.600 kg microcrystalline cellulose 32 mg/tablet 0.128 kg spray dried lactose 150 mg/tablet 0.600 kg stearic acid 3 mg/tablet 0.012 kg 335 mg/tablet 1.340 kg The ingredients were prescreened via a BS 16 mesh sieve and then intimately mixed. The mixture was then compressed by conventional tabletting machinery to form 4000 tablets, each weighing 335 mg and containing 150 mg of 1,2 - diphenyl 3 - oxo - 4 - n - butyl - 5 - (2' - acetoxy - benzoyloxy) - pyrazolid - 4 - ene.

Formulation 3.

Capsules containing 1 (2'-acetoxy-benzoyloxy)-2-n-propyl-3-oxo-5-dimethylamino-9- methyl-pyrazolid-2-eno [1,2-a] [1,2,4] benzotriazine (E).

A mixture was made by intimately mixing together the following ingredients: 1 (2,-acetoxy-benzoyloxy)-2-n-propyl 3-oxo-5-dimethylamino-9-methyl pyrazolid-2-eno[1,2-a] [1,2,4] benzotriazine 400 mg/capsule 0.800 kg starch 192 mg/capsule 0.384 kg lactose 192 mg/capsule 0.384 kg stearic acid 8 mg/capsule 0.016 kg talc 8 mg/capsule 0.016 kg 800 1.600 Granules were formed from this mixture and the granules were filled into 2000 size O capsules each containing 800 mg of mix and thus 400 mg of 1 - (2' - acetoxybenzoyloxy) - 2 - n - propyl - 3 - oxo - 5 - dimethylamino - 9 - methyl - pyrazolid2 - eno [1,2 - a] [1,2,4] benzotriazine.

Formulation 4.

Capsules containing 1,2-diphenyl-3-oxo-4-n-butyl-5-(2'-acetoxy-benzoyloxy)-pyrazolid- 4-ene (A).

A mixture was made by intimately mixing together the following ingredients: 1,2-diphenyl-3-oxo-4-n-butyl-5-(2' acetoxy-benzoyloxy)-pyrazolid-4-ene 150. mg/capsule 0.600 kg lactose 76.4 mg/capsule 0.3056 kg maize starch 76.4 mg/capsule 0.3056 kg stearic acid 3.6 mg/capsule 0.0144 kg talc 3.6 mg/capsule 0.0144 kg 310. mg/capsule 1.2400 kg After mixing the above ingredients intimately in a suitable blender, granules were formed therefrom. The granules were filled into 4000 size 1 capsule shells on a suitable capsule filling machine, each capsule thus containing 310 mg of mix and thus 150 mg of 1,2-diphenyl-3-oxo-4-n-butyl-5-(2'-acetoxy-benzoyloxy)-pyrazolid-4- ene per capsule.

Formulation 5.

Suppositories containing 12 '-acetoxy-benzoyloxy)-2-n-propyl-3-oxos-dimethylamino- 9-methyl-pyrazolid-2-eno [1,2-a] [1,2,4] benzotriazine (E).

The ingredients were as follows: Active material: 1-(2'-acetoxy-benzoyloxy) 2-n-propyl-3 -oxo-5-dimethylamino-9-methyl pyrazolid-2-eno [1,2-a] [1,2,4j-benzotriazine 1.6 kg Artificial wax (formed of mono-, di- and tri-glycerides) 6.4 kg The active material was milled, the wax was melted in a suitable vessel, and the active material was incorporated therein. The molten mixture was then filled into suitably-shaped moulds, and upon solidification 4000 suppositories were thus obtained, each weighing 2 grams and containing 400 mg of the active material.

Formulation 6.

Suppositories containing 1,2-diphenyl-3-oxo-4-n-butyl-5-(2'-acetoxy-benzoyloxy)-pyra- zolid-4-ene (A).

The ingredients were as follows Active material: 1 ,2-diphenyl-3 -oxo-4-n-butyl- 5-(2'-acetoxy-benzoyloxy)-pyrazolid-4-ene 0.3 kg Artificial wax (formed of mono-, di and tri-glycerides) 3.7 kg The active material was milled, the wax was melted in a suitable vessel, and the active material was incorporated therein. The molten mixture was then filled into suitably-shaped moulds, and upon solidification 2000 suppositories were thus obtained, each weighing 2 grams and containing 150 mg of the active material.

Formulation 7.

Injectable Suspension of 1-(2'-acetoxy-benzoyloxy)-2-n-propyl-3-oxo-5-dimethylamino 9-methyl-pyrazolid-2-eno [1,2-a] [1,2,4] benzotriazine (E).

The active compound was ground and suspended in a suitable isotonic injection medium, using normal pharmaceutical practices, then autoclaved in bulk and filled under aseptic conditions into single - dose ampoules, each containing 400 mg of 1 - (2' - acetoxy - benzoyloxy) - 2 - n - propyl - 3 - oxo - 5 - dimethylamino - 9methyl - pyrazolid - 2 - eno [1,2 - a] [1,2,4] benzotriazine.

Formulation 8.

Injectable Suspension of 1,2-diphenyl-3-oxo-4-n-butyl-5-(2'-acetoxy-benzoyloxy)-pyra- zolid-4-ene (A).

The active compound was ground and suspended in a suitable isotonic injection medium, using normal pharmaceutical practices, then autoclaved in bulk and filled under aseptic conditions into single - dose ampoules, each containing 150 mg of 1,2 - diphenyl - 3 - oxo - 4 - n - butyl - 5 - (2' - acetoxy - benzoyloxy) - pyrazolid4 - ene.

--00--00--0-0- Finally some evaluations will be given below which indicate the freedom from undesirable side-effects of certain of the preferred 2-acetoxy-benzoic acid esters of 4-alkyl-3,5-dioxo-pyrazolidine derivatives of this invention, and their excellent antiinflammatory and/or analgesic properties.

EVALUATION OF STABILITY.

In order first to evaluate the stability (or otherwise) of the compounds of this invention in the gastro-intestinal tract, simulated gastric and intestinal fluids were prepared as follows: Preparation of Simulated Gastric Fluid.

2 Grams of sodium chloride were mixed with 7.0 ml of concentrated hydrochloric acid, and the mixture was then made up to a volume of 1000 ml with distilled water, yielding a simulated gastric fluid with a pH value of about 1.2.

Preparation of Simulated Intestinal Fluid.

6.8 Grams of monobasic potassium phosphate were dissolved in 250 ml of water, and to this was added a mixture of 190 ml of 0.2 M sodium hydroxide solution and 400 ml of water. The pH of the resulting solution was adjusted to 7.5 with 0.2 M sodium hydroxide, and the solution was then diluted to 1000 ml with distilled water, yielding a simulated intestinal fluid.

Method of Evaluation.

100 Mg of the compounds under test were suspended in 5 ml of each of the simulated fluids, and shaken for 16 hours at 37"C. After this, the mixture was allowed to stand; and the supernatant liquid was spotted onto silica TLC plates, and developed in 90: 10 chloroform/methanol. The mixture was then extracted with 5 ml of chloroform, and the chloroform-containing mixture was filtered through phase-separating papers, which only allow the chloroform solution to pass through. The chloroform solution was also spotted onto silica TLC plates and developed in 90: 10 chloroform/ methanol.

The results of this procedure, carried out for both the simulated gastric and simulated intestinal fluids, show that negligible breakdown occurs in either of these fluids. This indicates that all of the compounds tested should be largely or wholly free from gastric disturbance effects when administered per os.

EVALUATION OF THE GASTRIC TOLERANCE IN RATS.

Gastric intolerance being the major problem encountered in the oral adminstra tioa of the class of compounds possessing analgesic and anti-inflammatory properties, the therapeutic index (or safety factor) of such compounds is best demonstrated via the gastric tolerance test in rats.

Accordingly one of the preferred but essentially typical compounds of this invention was tested for its acute (4 hours) gastric tolerance in rats, following oral administration at two or more dose levels, simultaneously being compared with an equimolar mixture of the two anti-inflammatory drugs which are the moieties forming the analgesic ester under test.

So that the experiments could be performed in conditions which allow the differences between the new compounds and the known compounds used as the standard of comparison to be reproducibly and unequivocally observed, the effect of the reference drugs in relation to their dose was also examined in a series of preliminary experiments, which allowed suitable dosages to be established before testing of the compounds of this invention was commenced.

Test Procedure.

Groups of 10 male rats (Charles River, 180-250 g body-weight) were fasted overnight and until sacrifice (about 21 hours). The drugs were administered orally, as a suspension in 1 % gum tragacanth. Four hours after administration, the animals were killed by bleeding from the neck; then their stomachs were removed, opened, gently washed with saline and pinned flat on a board for examination.

On examination superficial mucosal haemorrhages were classified in order of increasing severity, according to their size and number, as: pinpoints, spots or larger zones. Haemorrhagic lesions penetrating the mucosa (submucosal lesions) were considered as ulcers, and also graded in severity according to their size and number: spots (1-2 mm in size); grooves (having a longitudinal dimension). Perforations were not usually observed.

The animals were then ranked in order, according to the most severe symptom each one showed, the ulcers (submucosal lesions) being as a rule considered more severe than mucosal haemorrhages (superfirial). Control animals regularly showed some degree of "hyperaemia", which in fact corresponds to a congestive state of the vasculature at the moment of sacrifice, and not to a persisting functional hyperaemia.

It was therefore not considered as a sign of gastric irritation.

Statistical comparisons between specified groups were performed by the Mann and Whitey U-test, based on the graded severities of the observations. The results, tabulated as percentage of rats showing either mucosal (superficial) haemorrhages alone, or submucosal (penetrating) lesions (ulcers) generally associated with mucosal haemorrhages are set out in simplified form in Table I below: - TABLE I

Number of normal stomachs Number of rats with + gastric lesions U. test Number of Total U. test versus Dose Number of hyperaemic *Haemorrhage *Ulcer incidence v. control Compound Ph Substance mg/kg rats used stomachs (mucosa) (submucosa) of lesions group of mixt. & c.

Control Group 8 4 + 4 0% Compound Ph 80 8 1 + 1 2 + 1 + 1 1 + 1 75% P = 0.005 Compound Ph 120 8 1 2 + 1 1 + 3 87% P = 0.002 Compound A 122 8 3 + 5 0% NS P = 0.007 Compound A 183 8 1 + 7 0% NS P < 0.005 Control Group - 12 12 0% - Compound Ph 60 + # 12 2 1 + 5 + 1 1 + 2 83% P < 0.001 Aspirin Mixt. 36 Compound A 91.6 12 4 + 8 0% NS P < 0.001 Control Group 14 14 0% Aspirin 180 18 6 2 + 6 + 1 1 + 2 67% P < 0.001 * The position from left to right in each column indicates increasing severity of the specified symptoms.

[Notes. (a) Compound Ph = 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine.

(b) Compound A = 1,2-diphenyl-3-oxo-4-n-butyl-5-(2'-acetoxy-benzoyloxy)-pyrazolid-4-ene.

(c) Aspirin = 2-acetoxy-benzoic acid.

The results set out in Table I above show that, as compared, with 1,2-diphenyl3,5-dioxo-4-n-butyl-pyrazolidine alone, with a mixture of 1,2-diphenyl-3,5-dioxo-4-nbutyl-pyrazolidine and aspirin, or even with aspirin alone, Compound A - that is to say, 1,2-diphenyl-3-oXo-4-n-butyl-5-(2'-acetoxy-benzoyloxy)-pyrazolidin-4-ene - is remarkably non-irritant to the gastric mucosa, at doses up to 183 mg/kg, and far better tolerated than aspirin administered at similar dose levels by weight.

--00--00--00-0-0- Similar tests conducted with other compounds of the invention confirm their gastric tolerance already predicted by the Stability Evaluation given previously herein.

Specifically, for instance, acute gastric tolerance tests have been carried out, comparing the effects of 1 -(2 '-acetoxy-benzoyloxy)-2-n-propyl-3 -oxo-5 dimethylamin 9-methyl-pyrazolid-2-eno [1,2-a] [1,2,4] benzotriazine (E) with that of one of its parent compounds, namely 5-(dimethylamino)-9-methyl-2-n-propyl-lH-pyrazolo-[1,2- a] [1,2,4]-benzotriazine-1,3(2H)-dione (hereinafter referred to as "Compound Az").

In these tests, after preliminary experiments to determine the appropriate interval between dosage and sacrifice (finally chosen as 6 hours) the compounds to be tested were ground and suspended in a 1U/" gum tragacanth vehicle, and a single dose was administered orally to groups of fasted rats at a rate of 1 mmole/kg and in a volume of 10 ml/kg body-weight. A control group received only the vehicle. The results are shown (somewhat condensed) in Table II below: - TABLE II

Number of rats with Number of gastric lesions normal + Total Dose Number of hyperemic Haemorrhage incidence Substance mg/kg rats used stomachs (mucosa) * of lesions Control group - 8 3 + 5 Nil Compound Az 336 8 3 + 2 2 + 1 37% Compound E ~L 462 S 3 + 2 Nil [Notes: * The position (from left to right) in this column refers to increasing severity of the specified symptom.] It can be seen from the results given in Table II above that the gastric irritancy of compound E, in accordance with the invention, is reduced as compared with that of the well-known parent compound Az.

EVALUATION OF DESIRED PHARMACOLOGICAL EFFECTS.

Three kinds of tests are conventionally employed to evaluate the efficacy of analgesic and anti-inflammatory drugs, and all three kinds of these tests have been used in evaluating firstly Compound A, 1,2 - diphenyl - 3 - oxo - 4 - n - butyl - 5 (2' - acetoxy - benzoyloxy) - pyrazolid - 4 - ene, in comparison with one of its parent compounds, namely 1,2 - diphenyl - 3,5 - dioxo - 4 - n - butyl - pyrazolidine (Com pound Ph) and also secondly Compound E, 1 - (2' - acetoxy - benzoyloxy) - 2 propyl - 3 - oxo - 5 - dimethylamino - 9 - methyl - pyrazolid - 2 - eno [1,2 - a] [1,2,4] benzotriazine, in comparison with one of its parent compounds, namely 5 dimethylamino - 9 - methyl - 2 - n - propyl - 1H - pyrazolo [1,2 - a] [1,2,4] benzo triazine (Compound Az). la) Adjuvant Arthritis Test (Inclined Screen) in Rats (Compound A).

Adjuvant disease was induced in several groups of rats.

When adjuvant arthritis is induced in rats (normally with mycobacterial adjuvant) the adjuvant produces inflamed lesions in areas of the body remote from the injection site, after a delay of 10 to 15 days; though the inflammation has started to subside by the 30th day.

One group were left untreated as controls; other groups were treated by oral administration, once per day for 18 days, with various amounts of the parent compound, namely 1,2-diphenyl-3,5-dioxoA-n-butyl-pyrazdidine used as the standard of comparison, and of the compound to be evaluated, namely 1,2-diphenyl-3-oxo-4-n butyl-5-(2'-acetoxy-benzoyloxy) pyrazolid-4-ene. The compound was in each case administered to the rat in solution in 1 part of polyoxyethylene oleic glyceride, made up to 5 parts with 1% aqueous gum tragacanth, to which 1 % ethanol was also added when required to bring about dissolution. The amount of this solvent vehicle administered was generally 5 ml per kilogram of rat. The same vehicle (but without the active ingredient) was also administered to the control group of rats.

Treatment was continued for 18 days, during which time the rats were intermittently tested by means of the conventional Inclined Screen Test. Briefly stated, this evaluates the grip function of the rat, by placing it upon a wire-mesh screen which then is pivoted up through an angle of 900 from the horizontal to the vertical, and if necessary then indeed beyond 90". The angle at which the rat being tested loses its grip and drops off the screen is recorded. Other things being equal, the larger the angle of inclination at which the rat drops off the screen the more powerful is its grip upon it - and thus the less its grip-function has suffered from the arthritislike adjuvant disease; or, perhaps more strictly, the greater the alleviation of the pain of that disease by the compound under test.

One group of rats, intended to serve as controls, received only vehicle in the appropriate amount per day from day Q18 (17 doses). A second group of rats received 40 mg/kg per day of 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine, for 18 days; of this group one out of ten was dead by day 9. A third group received 80 mg/kg per day of 1,2"diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine; but none cf therm died, showing that the death in the second group was a freak result without significance.

A fourth group of rats received 61 mg/kg of the compound to be evaluated, namely 1,2-diphenyl-3-oxo-4-n-butyl-5-(2'-acetoxy-benzoyloxy)-pyrazolid-4-ene. The molar equivalent of a dosage rate of 61 mg/kg of 1,2-diphenyl-3-oxo-4-n-butyl-5-(2'-acetoxy- lbenzoyloxy)-pyrazolid-4-ene is a dosage rate of approximately 40 mg/kg of 1,2-di- phenyl-3,5-dioxo-4-ebutyl-pyrazolidine; and therefore to the extent that the former shows itself superior to the latter, its use is thereby indicated.

The results obtained in this way are shown graphically in Figure 1 of the accompanying drawings, where the line of progressive deterioration of the grip function in terms of the angle of inclination of the screen against time is shown for each of the various compounds tested and for the controls.

From Figure 1 it may be concluded that Compound A, 1,2-diphenyl-3oxo-4-n- ibuty1-5-(2'-acetoxy-benzoyloxyfpyrazolid-4-ene, when tested at the 61 mg/kg level, is equiactive to 1.5 times its molar amount of 1,2diphenyl-3,5-dioxo-4-n-butyl-pyra- zolidine in the grip function test. No death occurred in the rats treated with 1,2-di phenyl-3-oxot-n-butyl-5-(2'-acetoxy-benzoyloxy)-pyrazolid-4-ene, but one rat died in the group treated with 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine. lb) Adjuvant Arthritis Test (Body Weight) in Rats (Compound A).

The experimental detection of unknown side-effects is more difficult than the detection of gastric irritation; but their existence can be suggested by a decrease in body weight. Therefore in order to ensure that the results secured in the Inclined Screen Tests were not rendered unreliable by other side-effects of the compound under test, the body-weights of the rats suffering from the experimentally-induced adjuvant disease were also determined each day, and the average weight of each group of rats was recorded in Figure 2 of the accompanying drawings.

From Figure 2 it may be concluded that the systemic effect upon bodyweight of 1,2-diphenyl-3-oXo-4-n-butyl-5-(2'-acetoxy-benzoyloxy)-pyrazolid-4-ene is still greater than 2x molar 1 ,2-diphenyl-3,5 -dioxo-4-n-butyl-pyrazolidine. lc) Adjuvant Arthritis (acute phase) in Rats (Compound E).

The anti-inflammatory activity was studied by a subacute assay involving 3-dose medication in rats, using the following procedure: Groups of non-fasted female (Charles River) rats of uniform 170 grams body weight, each group consisting of 6 animals, were given a subplantar injection of 0.5 mg (per animal) Mycobactenurn butyr. in 0.1 ml sterile paraflin oil into the right hindpaw (the opposite paw being left uninjected); and the oedema which later ensued was measured at the intervals indicated below by differential plethysmometry of injected and non-injected paws using an Ugo-Basile apparatus. The following treatment schedule was applied: Day 0 - 09.00 h : 1st drug dose.

10.00 h @ mycobacterial adjuvant, s.c. injection.

15.00 h oedema volume determination.

Day 1 - 09.00 h 2nd drug dose.

14.00 h oedema volume.

Day 2 - 09.00 h 3rd drug dose.

14.00 h oedema volume.

Day 3 - 09.00 h @ oedema volume (no prior medication).

The drugs tested were: Compound E = 1 - (2' - acetoxy - benzoyloxy) - 2 - n - propyl - 3 - oxo - 5dimethylamino - 9 - pyrazolid - 2 - eno [1,2 - a] [1,2,4] benzotriazine.

Compound Az = 5 - dimethylamino - 9 - methyl - 2 - n - propyl - 1H - pyrazolo [1,2 - a] [1,2,4] benzotriazine - 1,3(2H) - dione.

They were administered orally to the animals. The rates of adiminstration were 0.1 mmole/kg, 0.2 mmole/kg and 0.4 mmole/kg in the case of Compound From the results given in Table III, it can be seen that Compound Az showed clearcut dose-related effects in the range of 0.1 - 0.2 - 0.4 mmole/kg : the total effects (i.e. sum of % inhibition of oedema observed on Days 0 to 3) amounted to 53 - 87 - 160 % for the respective dose levels mentioned. Compound E, with a total effect of 59%, was somewhat less active, being approximately equivalent in its effect to that of a 0.5 molar equivalent of Compound Az.

2a) Antipyretic Test against Yeast-induced Hyperthermia in Rats (Compound A).

Using the conventional procedure, groups of rats (each group consisting of 10 animals) were injected with yeast. Immediately after injection various dosages of Compound A, 1,2-diphenyl-3-oXo-4-n-butyl-5-(2'-acetoxy-benzoyloxy)-pyrazolid-4-ene, as well for purposes of comparison dosages of aspirin and of a mixture of aspirin with 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine, were administered orally to different groups of rats, apart from the control group who received only the vehicle.

The body temperature of all the rats was carefully monitored for a period of 8 hours following oral adiminstration of the compound under study. The results are shown in Figures 3 and 4 of the accompanying drawings.

It will be noted that 1,2-diphenyl-3-oxo-4-n-butyl-5-(2'-acetoxy-benzoyloxy)- pyrazolid-4-ene was tested at 30.5, 61, 122 and 244 mg/kg, and compared with aspirin at 61 mg/kg, with 1,2-diphenyl-3,5-dioxo4-n-butyl-pyrazolidine at 20 and 40 mg/kg, and with a mixture of aspirin (12 mg/kg) and 1,2-diphenyl-3,5-dioxo-4-nbutyl-pyrazolidine (20 mg/kg). Compound A is thus shown as having a dose-dependent action in the range of 30 to 120 mg/kg, which is of a relatively slow onset compared to the effects of aspirin or of a mixture of aspirin and 1,2-diphenyl-3,5-dioxo-4-nbutyl-pyrazolidine.

2b) Antipyretic Test against Yeast-Induced Hyperthermia in Rats (Compound E).

Using essentially the same procedure as in Evaluation 2a) above, upon groups of male rats of 215g - 235g body-weight (each group consisting of 7 rats) the results obtained comparing Compound E with Compound Az were as shown in Table IV below: - TABLE IV

Mean body temperature ( C) # SEM Dose level Degrees reduction of fever (in parenthesis) and statistics (t-test) compared to the control group Treatment mmole/kg mg/kg 0 h 1 h 2 h 3 h 4 h 5 h 6 h 7 h Control group - - 39.5 # 0.10 39.7 # 0.11 39.5 # 0.2 39.5 # 0.14 39.6 # 0.13 39.7 # 0.07 39.8 # 0.07 39.9 # 0.12 39.6 # 0.13 39.4 # 0.15 39.0 # 0.16 39.1 # 0.13 39.2 # 0.22 39.1 # 0.09 39.0 # 0.16 39.2 # 0.13 0.25 84.1 (+ 0.1) (- 0.3) (- 0.5) (- 0.4) (- 0.4) (- 0.6) (- 0.8) (- 0.7) Compound Az p < 0.001 p < 0.001 p < 0.01 (dihydrate) 39.5 # 0.11 39.4 # 0.19 39.0 # 0.28 39.1 # 0.21 39.0 # 0.10 39.1 # 0.12 39.3 # 0.12 39.3 # 0.11 0.5 168.2 (0) (- 0.3) (- 0.5) (- 0.4 ) (- 0.6) (- 0.6) (- 0.5) (- 0.6) P < 0.01 P < 0.001 P < 0.01 P < 0.01 39.6 # 0.11 39.4 # 0.11 39.2 # 0.15 39.0 # 0.12 39.0 # 0.08 39.3 # 0.13 39.4 # 0.17 39.5 # 0.18 Compound E 0.5 231.2 (+ 0.1) (- 0.3) (- 0.3) (- 0.5) (- 0.6) (- 0.4) (- 0.4) (- 0.4) P < 0.05 P < 0.01 P < 0.02 P < 0.05) From the results given in Table IV above it can be seen that at a dosage level of 0.5 mmole/kg Compound E has an antipyretic activity comparable with but slightly less than that of Compound Az.

3a) Randal-Selitto Test in Rats (Compound A).

Using the conventional techniques, the various compounds under test, as identified below, were administered orally to groups of rats (each group consisting of 10 rats) and, 30 minutes later, each of the rats was injected in one bind-paw with yeast. A control group of rats received only the vehicle.

In order to evaluate the effect of the treatment upon pain thresholds, pressure was applied both to the injected hind-paw and to the other, non-injected, hind-paw.

The pain threshold was noted as the pressure at which the rat flinched; and the readings taken for each rat were expressed as the percentage of the pain threshold pressure for the injected hind-paw as against the pain threshold pressure for the noninjected hind-paw.

These pain threshold percentages were determined at intervals of 3 hours, 5 hours, 7 hours and 24 hours after the injection. The results are summarized in Table V below: TABLE V Percentage Pain-Thresholds in the Randall-Selitto Test in Rats

TZME FROM INJECTION OF YEAST (Time from Administration of Compound Tested Compound Amount in 3 hr. 5 hrs. 7 hrs. 24 hrs.

Administered mg/kg (3.5 hrs.) (5.5 hrs.) (7.5 hrs.) (24.5 hrs.) Control - 35 # 4.5 37 * 4.1 43 * 2.4 52 * 4.0 "Ph" 30 47 # 4.4 55 # 6.5 46 # 4.1 58 # 4.3 P < 0.05 "Ph" 60 54 # 4.7 60 # 5.1 64 # 3.7 61 # 4.1 P < 0.01 P P < 0.01 P < 0.001 "A" 23 43 s 4.7 42 * 4.1 51 + 5.2 53 * 4.7 "A" 46 53 t 2.6 49 # 5.0 47 + 3.8 49 + 4.2 P < 0.01 "A" 91 46 # 6.2 54 # 5.7 58 # 3.6 52 # 2.5 P < 0.05 P < 0.01 It will be seen from Table V above that Compound A, 1,2-diphenyl-3-oxo-4-nbutyl-5-(2'-acetoxy-benzoyloxy)-pyrazolid-4-ene, was tested at 23 mg/kg, 46 mg/kg and 91 mg/kg per day, and compared with 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine at 30 mg/kg and 60 mg/kg per day. From the results thus obtained it appears to have the same analgesic effect as 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine at the lower doses tested, e.g. 46 mg/kg of Compound A which is equimolar to 30 mg/kg of 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine. At the highest dosages administered, namely 91 mg/kg of Compound A, it is less active than the equimolar dosage of 60 mg/kg of 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine at the 3-hour reading, which suggests a very slow onset of action by 1,2-diphenyl-3-oxo-4-n-butyl5-(2'-acetoxy-benzoyloxy)-pyrazolid-4-ene.

3b) Randall-Selitto Test in Rats (Compound E).

Using essentially the same technique as in Evaluation 3a) above, upon groups of female rats of 135g - 155g bodyweight (each group consisting of 10 animals) the analgesic properties of Compound E were compared with those of its parent Compound Az, and gave the results set out in Table VI below: TABLE VI

3 hours 5 hours 7 hours Dose Normal Inflamed Normal Inflamed Normal Inflamed Substance mmole/kg paw paw % paw paw % paw paw % - 12.8 5.5 45 12.7 5.2 42 12.9 5.3 43 Control group # 1.9 # 0.7 # 2.0 # 1.7 # 0.6 # 2.6 # 1.9 # 0.7 # 2.5 17.2 9.3 54 13.9 7.0 51 12.9 7.2 56 0.1 # 2.0 # 1.3 # 3.7 # 1.9 # 1.2 # 4.6 # 1.5 # 1.1 # 4.1 Compound Az P < 0.05 P < 0.05 P < 0.02 (dihydrate) 13.8 10.0 67 16.4 10.7 66 11.7 6.8 58 0.2 # 2.0 # 2.4 # 5.1 # 1.9 # 1.1 # 4.6 # 1.1 # 0.7 # 3.6 P < 0.001 P < 0.001 P < 0.001 P < 0.01 15.7 8.8 59 12.4 6.5 55 11.1 6.6 60 Compound E 0.2 # 1.9 # 1.1 # 5.2 # 1.4 # 0.7 # 3.5 # 1.2 # 0.9 # 3.3 P < 0.05 P < 0.05 P < 0.01 P < 0.001 From the results in Table VI above it can be seen that Compound E is slightly less active than Compound Az, equivalent to about 0.5 times at the 0.2 mmole/kg dosage level.

EVALUATION OF THERAPEUTIC INDEX.

From the relative gastric tolerances appearing from Table I and the relative anti-inflammatory activities deduced from Figure 1 it is possible to deduce the relative separation of the anti-inflammatory activity from the gastric toxicity of 1,2-diphenyl3-oxo-4-n-butyl-5-(2'-acetoxy-benzoyloxy)-pyrazolid-4-ene (A) as compared with 1,2diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine (Ph) as shown in Table VII below:- TABLE VII

Relative gain in safety versus the reference drug Reference drug to Relative anti- relative activity which the substance is inflammatory Relative gastric Substance compared activity (a) toxicity (b) relative gastric toxicity 1,2-diphenyl-3-oxo- 1,2 -diphenyl-3,54-n-butyl-5-(2'- dioxo-4-n-butyl- = 1.5 x molar 1/4 molar 6 acetoxy-benzoyloxy)- pyrazolidine pyrazolid-4-ene (a) Rat adjuvant arthritis: 17 daily oral doses (b) acute (4 hour, single, oral dose) gastric tolerance is rats.

In can thus be seen that 1,2-diphenyl-4-n-butyl-5-(2'-acetoxy-benzoyloxy)-pyrazolid-4-ene (Compound A) is significantly improved as compared with 1,2-diphenyl3,5-dioxo-4-n-butyl-pyrazolidine (Compound Ph), not only because it has somewhat stronger anti-inflammatory and analgesic effects (when compared on a molar basis) but also because it has a much reduced gastric toxicity, these factors together giving it an improved therapeutic index perhaps 6 times better than that of 1,2-diphenyl3,5-dioxo-4-n-butyl-pyrazolidine.

The other compounds of this invention have not so far been evaluated in the same degree of detail, but preliminary pharmacological testing indicates that qualitatively similar results are secured with these other compounds. Specifically it will be noted from the previously-given results that 1-(2'-acetoxy-bensoyloxy)2-n-propyl3-oxo-5-dimethylamino-9-methyl-pyrazolid-2-eno [1,2-a] [1,2,4] benzotriazine (Compound E) although somewhat less active also has a distinctly greater gastric tolerance as compared with 5-dimethylamino-9-methyl-2-n-propyl-1H-pyrazolo [1,2-a] [1,2,4] benzotriazine-1,3(2H)-dione, and its therapeutic index is thus at least as good and believed to be better.

Claims (49)

1. WHAT WE CLAIM IS:1. 2-Acetoxy-benzoic acid esters of the 4-alkyl-3,5-dioxo-pyrazolidine derivatives of general formula:

   (in which either X is phenyl and Y is phenyl or para-hydroxy-phenyl, or else X and Y together with the intervening nitrogen atoms to which they are respectively attached represent a 3-dimethylamino-7-methyl- [1,2,4] -benzotriazine ring-system fused with the pyrazolidine ring; and 'Alk' represents an n-propyl or an n-butyl group) as well as (where feasible) their acid addition salts formed with pharmacologically-acceptable mineral and organic acids.
2. 2. 1,2-Diphenyl-3-oxo-4-n-butyl-5-(2 '-acetoxy-benzoyloxy)-pyrazolid-4-ene.
3. 3. 1 Phenyl-2-(para-hydroxy-phenyl)-3-oxo-4-n-butyl-5-(2 '-acetoxy-benzoyloxy)- pyrazolid-4-ene.
4. 4. lgparaFHydroxy-phenyl)-2-phenyl-3-oxo-4-n-butyl-5-(2'-acetoxy-benzoyloxy)- pyrazolidA-ene.
5. 5. l-Phenyl-2-(para- [2'-acetoxy-benzoyloxyl -phenyl)-3,5-dioxo-4-n-butyl-pyrazoli- dine.
6. 6. 1 Phenyl-2-(para- [2 '-acetoxy-benzoyloxy] -phenyl)-3-oxo-4-n-butyl-5-(2'-ace- toxy-benzoyloxy)-pyrazolid-4-ene.
7. 7. 1para- [2'-Acetoxy-benzoyloxy]-phenyl)-2-phenyl-3-oxo-4-n-butyl-5-(2'-ace- toxy-benzoyloxy)-pyrazolid4-ene.
8. 8. 12 '-Acetoxy-benzoyloxy)-2-n-propyl-3 oxc5imethylamino-9-methyl-pyra- zolid-2-eno [1,2-a] [1,2,4] benzotriazine and acid addition salts thereof formed with pharmacologically-acceptable acids.
9. 9. 1-Oxo-2-n-propyl-3-(2 '-acetoxy-benzoyloxy)-5-dimethylamino-9-methyl-pyra zolid-3-eno [1,2-a] [1,2,4] benzotriazine and acid addition salts thereof formed with pharmacologically-acceptable acids.
10. 10. A process for the preparation of the 2-acetoxy-benzoic acid esters of 4-alkyl3,5-dioxo-pyrazolidine derivatives claimed in any of the preceding claims, in which a 4-alkyl-3,5-dioxo-pyrazolidine derivative of general formula

    (in which either X is phenyl and Y is phenyl or para-hydroxy-phenyl, or else X and Y together with the intervening nitrogen atoms to which they are respectively attached represent a 3-dimethylamino-7-methyl-[1,2,4] benzotriazine ring-system fused with the pyrazolidine ring; and 'Alk' represents an n-propyl or an n-butyl group) is reacted in the presence of a base with 2-acetoxy-benzoic acid chloride to yield the desired 2-acetoxy-benzoic acid ester of the corresponding 4-alkyl-3,5-dioxo-pyrazolidine derivative or (where feasible) an acid addition salt thereof.
11. 11. A process as claimed in claim 10, in which the reaction between the pyrazolidine derivative and the 2-acetoxy-benzoic acid chloride is effected in an anhydrous inert organic solvent without heating.
12. 12. A process as claimed in claim 11, in which the inert solvent is one or a mixture of the following organic solvents, namely substituted aromatic hydrocarbons (including halogenated hydrocarbons), aliphatic hydrocarbons (including halogenated hydrocarbons) and aliphatic ethers.
13. 13. A process as claimed in claim 12 in which the solvent used is chloroform or dichloromethane.
14. 14. A process as claimed in any of claims 10 to 12, in which the base is a tertiary amine.
15. 15. A process as claimed in claim 14 in which the base is pyridine.
16. 16. A process as claimed in any of claims 10 to 15 and substantially as herein described with reference to Stage B of Example 1 or Example 2.
17. 17. A process as claimed in any of claims 10 to 16, which includes the preliminary step of preparing the 2-acetoxy-benzoic acid chloride starting material by reacting 2-acetoxy-benzoic acid, in solution and/or suspension in an anhydrous inert solvent, with thionyl chloride.
18. 18. A process as claimed in claim 17, in which the reaction with thionyl chloride is conducted at a temperature within the range of from room temperature up to 65 0C.
19. 19. A process as claimed in claim 17 or claim 18, in which the solvent employed is the same as that used in the subsequent stage of the preparation as claimed in any of claims 10 to 16, and the 2-acetoxy-benzoic acid chloride obtained is not isolated from the reaction product before the subsequent stage is carried out.
20. 20. A process as claimed in any of claims 17 to 19, in which the solvent employed is anhydrous dichloromethane, and the reaction is effected under reflux.
21. 21. A process as claimed in any of claims 17 to 20, in which the proportions of the reactants are substantially in the ratio of 1 mole of thionyl chloride per mole of 2-acetoxy-benzoic acid.
22. 22. A process as claimed in any of claims 17 to 21, in which the reaction between the 2-acetoxy-benzoic acid and the thionyl chloride is effected in the presence of a catalytic amount of N,N-di,methylformamide.
23. 23. A process as claimed in any of claims 17 to 22 and substantially as herein described with reference to Stage A of Example 1 or Example 2.
24. 24. A process for the preparation of the 2-acetoxy-benzoic acid esters of 4-alkyl3,5-dioxo-pyrazolidine derivatives as claimed in any of claims 1 to 9, in which a mixed anhydride of general formula:

    (in which 'Ayl' represents an alkyl group with 1-20 carbon atoms, an aryl group with 6-20 carbon atoms, an alkaryl group with 7-20 carbon atoms or an aralkyl group with 7-20 carbon atoms; m is 0 (zero) or 1; and Q represents a carbon atom C or when m is zero a sulphinyl group S=O) is reacted with a 4-alkyl-3,5-dioxo-pyrazolidine derivative of general formula:

    (in which either X is phenyl and Y is phenyl or para-hydroxy-phenyl, or else X and Y together with the intervening nitrogen atoms to which they are respectively attached represent a 3-dimethylamino-7-methyl-[1,2,4] benzotriazine ring-system fused with the pyrazolidine ring; and 'Alk' represents an n-propyl or an butyl group) to yield the desired 2-acetoxy benzoic acid ester of the corresponding 4-alkyl-3,5-dioxopyrazolidine derivative.
25. 25. A process as claimed in claim 24, in which the reaction between the mixed anhydride and the 4-alkyl-3,5-dioxo-pyrazolidine derivative is carried out in an anhydrous inert organic solvent.
26. 26. A process as claimed in claim 25, in which the solvent used is one or a mixture of the following, namely toluene and chloroform (trichloromethane).
27. 27. A process as claimed in any of claims 24 to 26 and substantially as herein described with reference to Stage B of Example 3.
28. 28. A process as claimed in any of claims 24 to 27, which includes the preliminary stage of preparing the mixed anhydride starting material by reacting 2-acetoxy-benzoic acid with a reactive organic chloride of general formula:

    (in which 'Ayl', m and Q all have the same meanings as before) with 2-acetoxy-benzoic acid or a salt thereof, in the presence of a base, to yield the desired corresponding mixed anhydride.
29. 29. A process as claimed in claim 28, in which the reactive organic chloride is: (a) an alkyl or aralkyl or aryl or alkaryl chloroformate, of general formula:

    or (b) a sterically-encumbered alkyl or aralkyl or aryl or alkaryl acid chloride, of general formula:

    or (c) an alkyl or aralkyl or aryl or alkaryl sulphonyl chloride, of general formula:

    in all of which 'Ayl' represents an alkyl, aralkyl, aryl or alkaryl group having the number of carbon atoms therein specified in claim 28.
30. 30. A process as claimed in claim 28 or 29, in which the first-stage reaction between the 2-acetoxy-benzoic acid and the reactive organic chloride is carried out in an anhydrous, inert, organic solvent.
31. 31. A process as claimed in claim 30, in which the solvent is a substituted aromatic solvent, a halogenated aromatic hydrocarbon solvent or a halogenated aliphatic hydrocarbon solvent.
32. 32. A process as claimed in claim 31 in which the solvent is chloroform (tri chloromethane).
33. 33. A process as claimed in any of claims 28 to 32, in which the base used is a tertiary amine.
34. 34. A process as claimed in claim 33, in which the base is triethylamine or pyridine.
35. 35. A process as claimed in any of claims 28 to 34, in which both the first-stage reaction and the second-stage reaction are carried out in the same anhydrous inert organic solvent, without intervening isolation of the first-stage reaction product.
36. 36. A process for the preparation of the 2-acetoxy-benzoic acid esters of the 4 allyl-3,5-dioxopyrazolidine derivatives claimed in any of claims 1 to 9, in which a 4-alkyl-3,5-dioxo-pyrazolidine derivative of general formula

    (in which either X is phenyl and Y is phenyl or pora-hydroxy-phenyl, or else X and Y together with the intervening nitrogen atoms to which they are respectively attached represent a 3-dimethylamino-7-methyl-[1,2,4] benzotriazine ring-system fused with the pyrazolidine ring; and 'Alk' represents an n-propyl or an n-butyl group) is reacted with a solution in a water-immiscible solvent of 2-acetoxy-benzoic acid anhydride in the presence of a strong aqueous base so that the reaction mixture forms a two-phase reaction system which is agitated to yield the desired 2-acetoxy-benzoic acid ester of the corresponding 4-alkyl-3,5-dioxo-pyrazolidine derivative.
37. 37. A process as claimed in claim 36, in which the base used is aqueous sodium hydroxide.
38. 38. A process as claimed in claim 36 or claim 37, in which the water-immiscible organic solvent used is benzene, toluene, chloroform, dichloromethane or diethylether.
39. 39. A process as claimed in any of claims 36 to 38, in which the reaction is carried out at an ambient or near-ambient temperature not exceeding 30"C.
40. 40. A process as claimed in any of claims 36 to 39 and substantially as herein described with reference to Stage B of Example 4.
41. 41. A process as claimed in any of claims 36 to 40, which includes the preliminary step of preparing the 2-acetoxy-benzoic acid anhydride there used as starting material by reacting 2-acetoxy-benzoic acid with a carbodiimide in solution in an anhydrous, non-hydroxylic and otherwise inert organic solvent at an ambient or nearambient temperature not exceeding 30"C.
42. 42. A process as claimed in claim 41, in which the carbodiimide used is an N,N'-di [alk/arlyl-carbodiimide of general formula:

    wherein Z' and Z" each represents an alkyl or cycloalkyl or alkaryl or aryl or arallyl group containing from 6 to 20 carbon atoms.
43. 43. A process as claimed in claim 41 or claim 42 in which the carbodiimide used is N,N'-dicyclohexylsarbodiimide.
44. 44. A process as claimed in any of claims 41 to 43 in which the solvent used is tetrahydrofuran.
45. 45. A process as claimed in any of claims 41 to 44 and substantially as herein described with reference to Stage A of Example 4.
46. 46. The 2-acetoxy-benzoic acid esters of the 4-alkyl-3,5-dioxo-pyrazolidine derivatives of general formula I as defined in claim 1, whenever prepared in or by any of the processes claimed respectively in any of claims 10 to 23, in any of claims 24-27 and 28-35 or in any of claims 36--40 and 41--45.
47. 47. Pharmaceutical compositions wherein the active ingredient is or includes one or more of the 2-acetoxy-benzoic add esters of the 4-alkyl-3,5-dioxo-pyrazolidine derivatives as claimed in any of claims 1 to 9 and/or claim 46, said active ingredient being associated with a suitable pharmaceutical vehicle as herein defined.
48. 48. A composition as claimed in claim 47, in which the pharmaceutical vehicle is the ingestible excipient of a tablet, coated tablet, sublingual tablet or pill, or the ingestible container of a capsule or cachet, or the ingestible pulverulent solid carrier of a powder.
49. 49. A composition as claimed in claim 47 or claim 48, presented in the form of solid unit-doses wherein each solid unftdose contains from 150 mg to 400 mg of said active ingredient.