NO783202L - PROCEDURES FOR THE PREPARATION OF NEW PHARMACOLOGICAL ACTIVE ESTERS - Google Patents

Description

The present invention relates to new pharmacologically active

esters, methods for their preparation and pharmaceutical compositions containing them.

Analgesics are widely used 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 desirable to use an agent that expands

sees an anti-inflammatory effect in addition to its analgesic activity. A number of anti-inflammatory analgesic agents are known, and it is common practice at present to use one of these known agents to alleviate the symptoms of chronic rheumatism, joint

gout and similar conditions.

Some of the best-known, most effective and widely re-

reversed of the existing anti-inflammatory analgesics are the 4-alkyl-3,5-dioxopyrazolidine derivatives of the general formula:

wherein Alk denotes an n-propyl or n-butyl group, and where one of W and W" denotes a phenyl group, and the other a phenyl or para-hydroxyphenyl group, or where W and W" together with the intervening nitrogen atoms to which they is attached, denotes a -dimethylamino-7-methyl-[1,2,4]-benzotriazine ring system fused with the pyrazolidine ring.

These compounds of general formula I can exist in

the following tautomeric forms:

The following compounds are examples of these known anti-inflammatory analgesics of general formula I: 1,2-diphenyl-3,5-dioxy-4-n-butylpyrazolidine;

1-phenyl-2-(p-hydroxyphenyl)-3,5-dioxo-4-n-butylpyrazolidine (which can also be called 1-p-hydroxyphenyl-2-phenyl-3,5-dioxo-4-n- butylpyrazolidine); and 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo-[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione.

Another class of existing anti-inflammatory analgesics that are quite widely used at present are the well-known aromatic carboxylic acids of the general formula:

in which A denotes a carbon atom or a C-CH^-, C-CHCl-,

C-CH(CH3)- or C-CO-CH2-CH2- group, R denotes a hydrogen atom or a hydroxy, 2,4-dichlorophenoxy or 3-trifluoromethylaniline group, B denotes a nitrogen atom or a C-F,

C-Cl or C-H group; R<4> denotes either a hydrogen atom or a phenylisobutyl, n-prop-2-enyloxy, cyclohexyl, 2-methyl-cyclohexyl, 2-fluorophenyl, l-oxo-2-isoindolinyl or 2,5-dihydropyrrol-l-yl group , and R<5>denotes a hydrogen atom or a

4 5 benzoyl, 2,4-difluorophenyl or phenoxy group; or R and R

together with the intermediate carbon atoms to which they are attached, form a methoxy-substituted benzene ring, a 6-methylbenzo-[e]-(1,4)-thiazine ring or a methoxy-substituted 6-methylbenzo[e]-(1,4 )-thiazine ring, where the benzothiazine rings are each fused to the aromatic ring at their [b] position, or a 5-chloro-indole ring fused to the aromatic ring at its

[b] position. The following compounds are typical of the active compounds of general formula II:

2-(4-isobutyl-phenyl)-propionic acid (a compound in which

2 5

A is ^C-4 CH(CHJ,)-, B is ?C-H, R and R are each hydrogen and R is isobutyl);

2-(3-benzoyl-phenyl)-propionic acid (A is >C-CH(CH_)-,

B is ^C-H, R 2 and R 4 are each hydrogen and R<5> is benzoyl);

2-(6-methoxy-2-naphthyl)-propionic acid (A is ^C-CH(CH~)-,

2 4 5

B is ?C-H, R is hydrogen and R and R form a fused methoxy-substituted benzene ring);

2-(4-cyclohexyl-phenyl)-propionic acid (A is ^C-CH (CH-.) - , B is :?C-H, R and R are each hydrogen and R is cyclohexyl);

2-(4-[2-methyl-cyclohexyl]-phenyl)-propionic acid (A is

_ 2 5

/C-4 CH(CHJo)-, B is ^C-H, R and R are each hydrogen, and R is 2-methyl-cyclohexyl);

2-(2<1->fluoro-4-biphenyl)-propionic acid (A is ^C-CH(CH-),

B is 5"C-H, R 2 and R 5 are each hydrogen and R<4> is 2-fluorophenyl);

2-(4-[1-oxo-2-isoindolinyl]-phenyl)-propionic acid (A is

-» 2 5

>4 C-CH (CHJ-.) -, B is ^C-H, R and R are each hydrogen and R is 1-oxo-2-isoindolinyl);

2-(6-chloro-2-carbazolyl)-propionic acid (A is ^C-CH (CH-,)

B is ^C-H, R is hydrogen and R and R form a [b] fused 5-chloro-indole ring);

2-(7-methoxy-10-methyl-2-phenothiazinyl)-propionic acid (A is ^C-CH(CH3)-, B is ^C-H, R2 is hydrogen and R<4>and R<5> form a [ b] fused 6-methyl-benzo[e]-(1,4)-thiazine ring);

2-(3-phenoxyphenyl)-propionic acid (A is ^C-CH(CH3)-,

B is '/C-H, R2 and R4 are each hydrogen and R^ is phenoxy, 2-(3-fluoro-4-biphenyl)-propionic acid (A is ^C-CH(CH-)-

B is "/C-F, R<2> and R • 5 are each hydrogen and R<4> is phenyl) 2-(3-chloro-4-[2,5-dihydropyrrol-1-yl]-phenyl)-propionic acid (A is ^C-CH(CH-,)-, B is ^C-Cl, R 2 and R 5 are each hydrogen and R is 2,5-dihydropyrrol-1-yl);

3-(4-biphenylcarbonyl)-propionic acid (A is ^C-CO-CH2CH

B is ^C-H, R ? and R 5 is each hydrogen and R 4 is phenyl) 2-(3-trifluoromethyl-aniline)-nicotinic acid (A is carbon,

B is nitrogen, R 4 and R 5 are each hydrogen and R 2 is 3-trifluoromethyl-aniline);

2',4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid (A is

^4 2 5 carbon, B is >C-H, R is hydrogen, R is hydroxy and R is 2,4-difluorophenyl);

Chloro-(3-chloro-4-cyclohexylphenyl)-acetic acid (A is

^C-CHC1-, B is ^C-Cl, R<2>and R<5> are each hydrogen and R<4> is cyclohexyl);

(2-[2,4-dichlorophenoxy]-phenyl)-acetic acid (A is ^C-CH--, B

--4 5 2

is >C-H, R and R are each hydrogen and R is 2,4-dichlorophenoxy);

(3-chloro-4-n-prop-2<1->enyloxyphenyl)-acetic acid (A is ^C-CH2-, B is '/C-Cl, R<2> and R<5> are each hydrogen and R<4>

is n-prop-2-enyloxy);

(4-isobutylphenyl)-acetic acid (A is /C-CH--, B is ^C-H)

2 5 4

R and R are each hydrogen and R is isobutyl);

3-pyridineacetic acid (A is /C-CH-, B is nitrogen and R<2>,

4 5

R and R are hydrogen); and

(10-methyl-2-phenothiazinyl)-acetic acid (A is^C-CH--, .

v. 2 4 5

B is >C-H, R is hydrogen and R and R form a [b] fused 6-methyl-benzo[e]-(1,4)-thiazine ring).

Unfortunately, the desirable anti-inflammatory and analgesic properties of both the compounds of general formula I and the compounds of general formula II suffer from the disadvantage that they tend to give rise to disturbances in the gastrointestinal tract. In the case of the aromatic carboxylic acids of general formula II, it has been suggested that this may be due to the acidic nature of their carboxyl function, but this explanation is not quite correct, as there is little or no attenuation of this tendency when these anti-inflammatory analgesics are administered in the form of their salts, and furthermore there are no acid functions in the 4-alkyl-3,5-dioxopyrazolidine derivatives of general formula I: It is therefore particularly surprising that it has been found that it is not only possible to form an ester bond between the carboxyl group present in the aromatic carboxylic acids of general formula II and the hydroxy group present in the tautomeric forms of the 4-alkyl-3,5-dioxopyrazolidine derivatives shown in general formulas Ia and Ib, but also that the resulting esters, although these are formed between gastrointestinal interfering groups, nevertheless are predominantly or mainly completely free of unwanted side effects on the intestinal tract while being effective e and really excellent anti-inflammatory analgesics.

According to one aspect of the present invention, 4-alkyl-3,5-dioxopyrazolidinyl aromatic carboxylate esters formed between a 4-alkyl-3,5-dioxopyrazolidine derivative of the general formula are thus provided as new compounds with anti-inflammatory and analgesic activity I (as previously defined) on the one hand and an aromatic carboxylic acid of general formula II (as previously defined) on the other hand, and where possible, acid addition salts of the esters.

Esters can be formed with any of the 3-oxo and 5-oxo groups of the compounds of general formula I, since, as previously indicated, these compounds can exist in tautomeric forms in which one or the other of the 3- and 5-positions carries e,n hydroxy group. Furthermore, when W or W" in the compounds of general formula I denotes a para-hydroxyphenyl group, esters can be formed with the phenolic hydroxy group, either in addition to or instead of esters formed at the 3- or 5-position of the pyrazolidine nucleus.

The compounds according to the invention are thus compounds of the general formula: in which Alk is as indicated above, where either one of B' and B" denotes *a phenyl group, and the other denotes a phenyl group or a phenyl group substituted with a group -OZ', or B ' and B" together with the intervening nitrogen atoms to which they are attached, denote a 3-dimethylamino-7-methyl-[1,2,4]-benzotriazine ring system fused with the pyrazolidine ring; and where at least one of Z and Z<1> denotes an aromatic carbonyl group: ; (wherein A, R<2>, B, R<4>and R^ are as previously defined, and when only one of Z and Z<1> denotes an aromatic carbonyl group, the other denotes a hydrogen atom) and where possible, acid addition salts hence. ;It should be noted that it is possible to form acid addition salts with only the 4-alkyl-3,5-dioxopyrazolidinyl aromatic carboxylates of general formula III which contain a saltable group - e.g. those compounds in which B is nitrogen and/or B' and B" form a benzotriazine ring system. Although any of the acid addition salts which can be formed are useful for preparative purposes, naturally only those formed with pharmacologically acceptable acids which can be used in human therapy or in veterinary therapy, A preferred group of compounds falling within general formula III are 4-alkyl-3,5-dioxopyrazolidinyl acetates of general formula: in which Alk is as previously indicated, where either one of B' and B"^ denotes a phenyl group, and the other denotes a phenyl group or a phenyl group substituted with a group 0Z'A, or B'A and B" together with the intervening nitrogen atoms to which they are attached, denotes a 3-dimethylamino-7 -methyl-[1,2,4]-benzotriazine ring system fused with the pyrazolidine ring, and where at least one of Z and Z' denotes a substituted 2-phenylpropionyl group: ; wherein R 4 and R 5 are as previously indicated, and when only one of Z^ and Z' denotes a substituted 2-phenyl-propionyl group, the other denotes a hydrogen atom, and where possible, their acid addition salts. ;Specifically preferred esters of general formula III are e.g. : ;1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(4-isobutylphenyl)-propionate; 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(4-isobutylphenyl)-propionic acid; 5-(dimethylamino)-9-methyl-2-n-propyo-1H-pyrazolo-[1,2-a][1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(4- isobutyl-phenyl)-propionic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-benzoylphenyl)-propionate; 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(3-benzoylphenyl)-propionic acid; 5-(dimethylaraino)-9-methyl-2-n-propyl-1H-pyrazolo-[1,2-a][1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(3- benzoyl-phenyl)-propionic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 21-(6-methoxy-2-naphthyl)-propionate; The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(6-methoxy-2-naphthyl)-propionic acid; 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo-[1,2-a][1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(6- methoxy-2-naphthyl)-propionic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2-(4-cyclohexylphenyl)-propionate; 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(4-cyclohexylphenyl)-propionic acid; 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo [1,2-a][1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(4-cyclo -hexylphenyl)-propionic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2-(4-[2-methyl-cyclohexyl]-phenyl)-propionate; 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(4-[2-methyl-cyclohexyl]-phenyl)-propionic acid; The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(4-[ 2-methyl-cyclohexyl]-phenyl)-propionic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2<1->[2'-fluoro-4-biphenyl]propionate; 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-[2'-fluoro-4-biphenyl]-propionic acid; 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazole [1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2-[2<1 ->fluoro-4-'biphenyl]-propionic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-[4-(1-oxo-2-isoindolinyl)-phenyl]-propionate; 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-[4-(1-oxo-2-isoindolinyl)-phenyl]-propionic acid; 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazole [1,2-a][1,2,4]benzotriazine-1,3(2H)-dionesters of 2-[4-( 1-oxo-2-isoindolinyl)-phenyl]-propionic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2<1-(6-chloro-2-carbazolyl)-propionate; . 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(6-chloro-2-carbazolyl)-propionic acid; 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazole [1,2-a][1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(6-chloro -2-carbazolyl)-propionic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl (10-methyl-2-phenothiazinyl)acetate; The 1-phenyl-2-p-hydroxyphenyl-3-oxo-4-n-butylpyrazolidine esters of (10-methyl-2-phenothiazinyl)-acetic acid; 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazole thi,2-a][1,2,4]benzotriazine-1,3(2H)-dionesters of (10-methyl-2- phenothiazinyl)-acetic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(7-methoxy-10-methyl-2-phenothiazinyl)-propionate; The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(7-methoxy-10-methyl-2-phenothiazinyl)-propionic acid; 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazole [1,2-a][1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(7-methoxy -10-methyl-2-phenothiazinyl)-propionic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-4n-5-yl 2'-(3-phenoxyphenyl)-propionate; 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(3-phenoxyphenyl)-propionic acid; 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazole [1,2-a][1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(3-phenoxyphen -yl)-propionic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-fluoro-4-biphenyl)-propionate; The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(3-fluoro-4-biphenyl)-propionic acid; 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(3-fluoro -4-biphenyl)-propionic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl-21-(3-chloro-4-(2,5-dihydropyrrol-1-yl)-phenyl)-propionate; The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(3-chloro-4-(2,5-dihydropyrrol-1-yl)-phenyl)-propionic acid; 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazole. The [1,2-a][1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(3-chloro-4-(2,5-dihydropyrrol-1-yl)-phenyl)-propionic acid ; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-4n-5-yl 2 1 -(3-trifluoromethylaniline)-nicotinate; 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(3-trifluoromethylaniline)-nicotinic acid; 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(3-trifluoromethyl -aniline) -nicotinic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-4n-5-yl 2",4"-difluoro-4'-hydroxy-3'-biphenylcarboxylate; 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2<1>,4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid; 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2<1>,4 <1->difluoro-4-hydroxy-3-biphenylcarboxylic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl chloro-(3-chloro-4-cyclohexylphenyl)-acetate; 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of chloro-(3-chloro-4-cyclohexylphenyl)-acetic acid; The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of chloro-(3-chloro -4-cyclohexylphenyl)-acetic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 3'-(4-biphenylcarbonyl)-propionate; 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 3-(4-biphenylcarbonyl)-propionic acid; The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-porazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 3-(4-biphenylcarbonyl )-propionic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl [2-(2,4-dichlorophenoxy)-phenyl]acetate; 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine-[2-(2,4-dichlorophenoxy)-phenyl]acetic acid; 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of [2-(2, 4-dichlorophenoxy)-phenyl]-acetic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl (3-chloro-4-n-prop-2<1->enyloxyphenyl)-acetate; The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of (3-chloro-4-n-prop-2'-enyloxyphenyl)-acetic acid; 5-(Dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4] benzotriazine-,1,3(2H)-dionesters of (3- chloro-4-n-prop-2'-enyloxyphenyl)-acetic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl (4-iso-butylphenyl)-acetate; The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of (4-isobutylphenyl)-acetic acid; 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of (4-isobutylphenyl)- acetic acid; 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 3'-pyridineacetate; 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 3-pyridineacetic acid; and the 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dioesters of 3-pyridineacetic acid. 1-phenyl-2-(p-hydroxyphenyl)-3,5-dioxo-4-n-butylpyrazolidine can form esters with the substituted α-(2-methyl-ind[ene/ol]-3-yl) -acetic acids by means of an ester bond formed with the oxygen in the 3-position, with the oxygen in the 5-position or with the hydroxy group on the 2-(para-hydroxyphenyl) group. It is also possible to form two ester bonds, one with the 2-(para-hydroxyphenyl)hydroxy group and one with either the 3- or 5-position oxygen. Thus there are five 1-phenyl-2-(p-hydroxyphenyl)-3,5-dioxo-4-n-butylpyrazolidine esters which can be formed with an acid. e.g. the possible 1-phenyl-2-p-hydroxyphenyl)-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(4-isobutylphenyl)-propionic acid are the following compounds: a) 1-phenyl-2-(p -hydroxyphenyl)-3-oxo-4-n-butylpyrazolid-4-en-5-yl 21 -(4-isobutylphenyl)-propionate of the structural formula: b) the 5-oxo-pyrazolid-3-en-3-yl isomer of a), namely: ; c), 1-phenyl-2-p-[21-(4-isobutylphenyl)-propionyl]-phenyl-3-oxo-4-n-butylpyrazolid-4-5-yl 2"-(4-isobutylphenyl)-propionate of the structural formula: d) the 5-oxo-pyrazolid-3-en-3-yl isomer of c), namely: e) 1-phenyl-2-p-[2'-(4-isobutylphenyl)-propionyl] -phenyl-3-oxo-4-n-butylpyrazolidine of the structural formula: ; The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a];[1,2,4]benzotriazine-1,3(2H)-dionesters can also be formed with an ester bond which includes the oxygen atom of the 1-oxo group or the 3-oxo group, and these positions are not equivalent due to the asymmetry of the condensed benzotriazine system. Thus, e.g. the possible 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a][1,2,4]benzitriazine-1,3(2H)-dionesters of 2-(4 -isobutylphenyl)-propionic acid: a) 5-(dimethylamino)-9-methyl-1-oxo-2-n-propylpyrazolid-2-eno[1,2-a][1,2,4]benzitriazin-3-yl 2'-(4-isobutylphenyl)-propionate ;of the structural formula:; ; and ;b) the 3-oxo-pyrazolid-l-eno[1,2-a][1, 2,4]benzitriazin-l-yl isomer of a) of the structural formula: ; It should be noted that currently the 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl esters are most frequently of greatest interest among the specifically preferred compounds listed, and therefore these compounds which are currently strongly preferred. It has further been found that the 4-alkyl-3,5-dioxopyrazole-idinylaromatic-carboxylates of general formula III can be prepared in an appropriate manner and in good yield by reacting the 4-alkyl-3,5-dioxopyrazolidines of general formula I and the appropriate aromatic carboxylic acid chlorides. Another aspect of the invention thus relates to a process for the production of 4-alkyl-3,5-dioxopyrazolidinyl aromatic carboxyl esters of general formula III, in which a 4-alkyl-3,5-dioxopyrazolidine derivative of general formula I (but ef- effectively in one of its tautomeric forms of general formula Ia or Ib) is reacted with an aromatic carboxylic acid chloride of general formula: ; 2 4 5 ; in which A, B, R , R and R are as previously indicated, or an acid addition salt thereof, forming the desired corresponding 4-alkyl-3,5-dioxopyrazolidinyl aromatic carboxylate ester of general formula III or acid addition salt thereof . The reaction between the 4-alkyl-3,5-dioxopyrazolidine derivative of general formula I and the acid chloride of general formula IV is preferably carried out in an anhydrous inert solvent. The inert solvent will. normally be an organic solvent, and is advantageously a substituted aromatic hydrocarbon such as Voluen, one of the many halogenated aromatic solvents, an aliphatic hydrocarbon or a halogenated aliphatic hydrocarbon such as chloroform or dichloromethane. The preferred solvent is dichloromethane. As the reaction is relatively vigorous, it can be carried out at ambient temperature without heating, or possibly, when the reaction is very vigorous, which it sometimes is, even during cooling. The reaction is preferably carried out in the presence of a base which is suitably a tertiary amine. The base that is frequently preferred over all others is pyridine. The method according to the invention can also advantageously include a preliminary step, namely the production of the acid chloride starting materials of general formula IV by reacting a solution or suspension in an anhydrous, inert solvent of an aromatic carboxylic acid of general formula II (as previously defined) or a salt thereof and thionyl chloride. The salt of the acid of general formula II which is preferably used in this preliminary step is the pyridine salt. The reaction with thionyl chloride can be carried out at any suitable temperature between ambient temperature and the reflux temperature of the solvent, and will usually be carried out at a temperature in the range from 40 to 65°C. The solvent used can be the same as that used in the above-described subsequent step in the preparation. It will normally be an organic solvent, and is advantageously a relatively low-boiling substituted aromatic hydrocarbon such as toluene, one of the many halogenated aromatic solvents, an aliphatic hydrocarbon or a halogenated aliphatic hydrocarbon such as chloroform or dichloromethane. The solvent used is preferably anhydrous dichloromethane, and the reaction can then suitably be carried out under reflux cooling at a temperature of 40 - 41°C. The quantity of the reactants will preferably be approx. 1 mol of thionyl chloride per mol of acid of general formula II, and when the acid is used in the form of the preferred pyridine salt, per moles of pyridine. It has been found advantageous to carry out the reaction between the acid of general formula II and the thionyl chloride in the presence of a catalytic amount of N,N-dimethylformamide. Another side of the invention thus relates to an alternative process for the production of 4-alkyl-3,5-dioxopyrazolidinylaromatic carboxyl esters of general formula III, in which *a mixed anhydride of the general formula:

2 4 5

where A, B, R , R and -R are as previously indicated, "Ayl" denotes an alkyl group containing from 1 to 20 carbon atoms, an aryl group containing from 6 to 20 carbon atoms, an alkaryl group containing from 7 to 20 carbon atoms or a aralkyl group containing from 7 to 20 carbon atoms; m is 0 or 1; and Q denotes a carbon atom, or when m is 0, a sulfinyl group, is reacted with a 4-alkyl-3,5-dioxopyrazolidine derivative of general formula

I while forming the desired corresponding 4-alkyl-3,5-dioxopyra-zolidinyl aromatic carboxylate ester of general formula III.

The reaction between the mixed anhydride of general formula V and the 4-alkyl-3,5-dioxopyrazolidine derivative of general formula I can and should preferably be carried out in an anhydrous, inert solvent. This solvent is generally organic, and preferably one of the solvents previously indicated as preferred for use in the first method according to the invention.

Furthermore, the reaction can be carried out without injury in the presence of a base such as a tertiary amine such as triethylamine or pyridine.

The mixed anhydride of general formula V is conveniently prepared by reacting an aromatic carboxylic acid of general formula II or a salt thereof with a reactive organic chloride of general formula:

wherein Ayl, m and Q are as previously indicated, in the presence of a base.

The reactive organic chloride of general formula VI can e.g. be: (a) an alkyl, aralkyl, aryl or alkaryl chloroformate of general formula:

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

or (c) an alkyl, aralkyl, aryl or alkarylsulfonyl chloride:

wherein Ayl denotes an alkyl, aralkyl, aryl or alkaryl group of up to 20 carbon atoms as previously defined.

The reaction between the acid of general formula II and the reactive chloride of general formula VI (Via, VIb or VIc) is conveniently carried out in an anhydrous, inert solvent, which is preferably an organic solvent such as that used in the subsequent step of the process.

This reaction must be carried out in the presence of a base which is advantageously a tertiary amine, and preferably is either triethylamine or pyridine.

It is not necessary to isolate the mixed anhydride of general formula V from the reaction mixture in which it was prepared. Instead, the solution of the mixed anhydride obtained from the first stage reaction can be subjected to the second stage reaction in the same reaction mixture without removing the base, and in the same reaction vessel.

Another aspect of the invention relates to a third method for producing 4-alkyl-3,5-dioxopyrazolidinyl aromatic carboxyl esters of general formula III in which a 4-alkyl-3,5-dioxopyrazolidine derivative of general formula I (but effectively in one of its tautomeric forms Ia or Ib) is reacted with a solution in a water-immiscible solvent of a symmetrical aromatic carboxylic acid anhydride of the general formula:

2 4 5

wherein A, B, R , R and R are as previously indicated, in the presence of a strong aqueous base, so that the reaction mixture forms a two-phase system which is stirred to form the desired 4-alkyl-3,5-di-oxopyrazolidinyl aromatic carboxylate ester .

The reaction between the 4-alkyl-3,5-dioxopyrazolidine derivative of general formula I and the acid anhydride of general formula VII gives the corresponding aromatic carboxylic acid of general formula II as a by-product, and must therefore be carried out in the presence of a strong base, which can be an organic base such as triethylamine, but which will preferably be aqueous sodium hydroxide. The anhydride is somewhat unstable in the presence of water, and is therefore brought to the reaction in solution in a water-immiscible solvent, and preferably an anhydrous, inert, organic solvent, suitably e.g. benzene, toluene, chloroform, dichloromethane or ethers such as diethyl ether. The reaction is carried out with stirring in a two-phase reaction system so that the chance of any breakdown of the anhydride before it has taken part in the calculated reaction is reduced to a minimum. This reaction can conveniently be carried out at an ambient or near-ambient temperature that does not exceed 30°C.

This third process can further advantageously include

a further preliminary step, namely the preparation of the acid anhydride of general formula VII by reacting an aromatic carboxylic acid of general formula II with a carbodiimide in solution in an anhydrous, non-hydroxylic or otherwise inert organic solvent at ambient or near-ambient temperature, usually not above 30°C.

In principle, any carbodiimide can be used, but in practice the carbodiimide used must of course be stable, and consequently it is recommended that the carbodiimide used should be an N,N<1->di[alk/ar]yl-carbodiimide of general formula:

wherein Z' and Z" each denote an alkyl, cycloalkyl, alkaryl, aryl or aralkyl group containing from 6 to 20 carbon atoms. Furthermore, it must be added that at present the only commercially available carbodiimide (at least in Great Britain) of a economic price is N,N<1->dicyclohexylcarbodiimide, which is therefore preferred for use according to the present invention.

The present invention of course also relates to intermediate products for the first-mentioned process, namely the aromatic carboxylic acid chlorides of general formula VI, the intermediate products in the second process, namely the mixed anhydrides of general formula V, and the intermediate products in the third process, namely the symmetrical anhydrides of general formula VII, as well as the desired end product of general formula II produced by a pre-

4-Alkyl-3,5-dioxopyrazolidinyl aromatic carboxyl esters of general formula III appear to exhibit excellent anti-inflammatory and analgesic activity when tested by generally accepted tests for anti-inflammatory drugs, and preliminary studies show that when administered orally, they will be mainly free of gastrointestinal side effects.

However, for use in human and veterinary medicine as anti-inflammatory analgesics, the 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic carboxylate esters of general formula III must first be carefully formulated into suitable pharmaceutical compositions by association with suitable pharmaceutical carriers.

The term "pharmaceutical" is used here to exclude any possibility that the nature of the carrier (obviously considered in relation to the mode of administration for which the composition is intended) could be harmful. The choice of a suitable carrier for a chosen method of administration is believed to be a matter of skill for the person skilled in the art.

A further aspect of the present invention is thus pharmaceutical compositions comprising as active ingredient Sn or several of 4-alkyl-3,5-dioxopyrazolidinyl aromatic carboxyl esters of general formula III in connection with a suitable pharmaceutical carrier.

Although the compositions according to the invention are primarily intended for administration by means of the gastrointestinal tract, including rectally, they can also be administered parenterally. In terms of these various routes of administration, the "pharmaceutical carrier" is preferably: (a) the swallowable excipient in a tablet, coated tablet, sublingual tablet or pill; the ingestible container in a capsule, the ingestible powdery solid carrier in a powder, or the ingestible liquid medium in a syrup, solution, suspension or elixir; (b) the solid or liquid medium in a paste, lotion, salve or propellant in an aerosol; (c) a sterile injectable liquid solution or suspension medium; or

(d) a base material for a suppository.

Although the formulation types indicated above represent those that are most likely to be used, they do not necessarily exclude other possibilities.

The preferred mode of administration for the anti-inflammatory analgesics of general formula III is oral, including oral, so that the compositions will most often be administered in the form of tablets, capsules and other solid dosage forms.

Taking into account the dosage concentrations indicated below, the compositions will normally be presented in the form of unit doses containing usually from 30 mg to 2.7 g.

Although the dose of these anti-inflammatory analgesics

of general formula III will to a certain extent depend on the method of administration, and of course also on the patient's condition, it can be said as a general indication that the applicable dose varies from 0.1g to 5g (in divided doses) of the active analgesic per . day for an adult patient, a unit dose containing from 30 mg to 2.7 g, preferably 200 mg for the compound of general formula III in which B' and B" each represent a phenyl or para-hydroxyphenyl group and 550 mg for the compounds of general formula formula III in which B' and B" together with the intervening nitrogen atoms form a 3-dimethylamino-7-methyl-[1,2,4]-benzotriazine ring system.

The following examples illustrate the invention.

Preparation of compounds of general formula III from the acid chloride, including the preliminary step for the preparation of the acid chloride (Examples 1 - 8): Example 1 Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyra- Zolid-4-en-5-yl 2'-(4-isobutylphenyl)-propionate Step A: Preparation of 2-(4-isobutylphenyl)-propionyl chloride

20.6 g of 2-(4-isobutylphenyl)-propionic acid were dissolved in

50 ml of chloroform containing 1 ml of N,N-dimethylformamide. 12 g (or 8 ml) of thionyl chloride was added and the mixture was stirred at 40°C for 3 hours.

The product thus obtained, namely 2-(4-isobutylphenyl)-propionyl chloride, was not isolated, but used directly for the preparation of the ester described below.

Step B: Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(4-isobutylphenyl)-propionate To a solution of 2-(4-isobutylphenyl)- propionyl chloride obtained from step A was added to a mixture of 30 g of 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine and 15 g of pyridine in 75 ml of chloroform. The mixture became warm and was boiled under reflux for 30 minutes.

The resulting chloroform solution was washed with 100 ml of dilute hydrochloric acid, then with 10% sodium carbonate solution. The chloroform layer was dried over MgSO 4 , and the solvent was removed under reduced pressure. The oil thus obtained was dissolved in 75 ml of ether, and the solution was shaken vigorously for 10 minutes with 75 ml of 2M NaOH. A further 100 ml of ether was added and the ether layer was separated, washed with 100 ml of water and dried. Evaporation of the ether gave the desired 1,2-diphenyl-3-oxo-4-n-but-ylpyrazolid-4-en-5-yl 21-(4-isobutylphenyl)-propionate, first as an oil which crystallized from ether-petroleum ether to give 26.4 g of a pale red solid with a melting point of 82 - 84°C.

Example 2 Preparation of 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dionester of 2- (4-isobutylphenyl)-propionic acid

Step A: Preparation of 2-(4-isobutylphenyl)-propionyl chloride

6.2 g of 2-(4-isobutylphenyl)-propionic acid was dissolved in 40 ml of dichloromethane. 3.8 g of thionyl chloride and 0.5 ml of dimethylformamide were added, and the mixture was stirred and refluxed until the evolution of gas subsided.

The product thus formed, namely 2-(4-isobutylphenyl)-propionyl chloride, was not isolated, but used directly for the preparation of the ester as described below.

Step B: Preparation of the 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a][1,2,4]benzitriazine-1,3(2H)-dionester of 2 -(4-isobutylphenyl)-propionic acid

A mixture of 9.0 g of 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazole-[1,2-a][1,2,4]benzotriazine-1,3(2H)- dione and 3.0 g of pyridine in dichloromethane were added to the product obtained from step A, and the mixture was refluxed for 5 minutes. The dichloromethane solution was washed with 100 ml of 2M hydrochloric acid and then concentrated under reduced pressure to give a residual oil. This was dissolved in 200 ml of ether containing 5% ethyl acetate, and the ether solution was washed twice with 2M aqueous sodium hydroxide solution, once with water, and then dried over MgSO 4 . Concentration of the ether solution under reduced pressure gave a yellow oil which crystallized from ether-petroleum ether (60 - 80°) as 4.5 g of cream-colored needles of the desired ester which is believed to be 5(dimethylamino)-9-methyl-l-oxo -2-n-propyl-1H-pyrazolid-2-eno-[1,2-a] [1,2,4]benzotriazin-3-yl 21 -(4-isobutyl-phenyl)-propionate with melting point 110 - 112 °C.

Example 3 Preparation of 1,2-diphenyl-3-oxo-4-n-butyl-pyrazolid-4-en-5-yl 2'-(3-benzoylphenyl)-propionate Step A: Preparation of 2-(3-benzoylphenyl) )- propionyl chloride

10.0 g of 2-(3-benzoylphenyl)-propionic acid was dissolved in 100 ml of dichloromethane containing 1 ml of N,N-dimethylformamide. 7 g (or 4.6 ml) of thionyl chloride was added and the mixture was refluxed for 2 hours. The pale yellow solution thus obtained was concentrated under reduced pressure to give the desired product, 2-(3-benzoylphenyl)-propionyl chloride as an oil.

Step B: Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-benzoylphenyl)-propionate

2-(3-benzoylphenyl)-propionyl chloride prepared in step A was dissolved together with 12.0 g of 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine in 100 ml of dichloromethane, and 9 ml of pyridine was added to the solution. The orange colored solution was allowed to stand for 15 minutes.

The reaction mixture was then washed, first with 100 ml of water, then 3 times with 50 ml each time of 2.5 M sodium hydroxide solution, and finally once with 100 ml of water. After washing, the solution was dried over MgSO 4 .

Evaporation of the dichloromethane under reduced pressure gave a yield of 12 g of the desired 1,2-diphenyl-5-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-benzoylphenyl)-propionate as a yellow oil.

Example 4 Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6-methoxy-2-naphthyl)-propionate

Step A: Preparation of 2-(6-methoxy-2-naphthyl)-propionyl chloride

23 g of 2-(6-methoxy-2-naphthyl)-propionic acid were suspended

in 50 ml of chloroform, and 1 ml of N,N-dimethylformamide was added. Then 12 g (or 8 ml) of thionyl chloride was added to the suspension which was heated and stirred at 40°C.

The product thus obtained, namely 2-(6-methoxy-2-naphthyl)-propionyl chloride, was not isolated, but used directly in the preparation described below.

Step B: Preparation of 1,2-diphenyl-3-oxo-4-n-butyl 1-pyrazo-lid-4-en-5-yl 2'-(6-methoxy-2-naphthyl)-propionate

To the solution of 2-(6-methoxy-2-naphthyl)-propionyl chloride obtained in step A were added 30 g of 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine and 15 g of pyridine dissolved in 50 ml of chloroform . This reaction mixture was then boiled under reflux for 30 minutes. The resulting chloroform solution was washed first with 100 mL of dilute HCl and then with 100 mL of 10% sodium carbonate solution. After washing, the solution was dried and the chloroform was removed by evaporation.

The product was taken up and crystallized from methanol/water and acetone/petroleum ether. The melting point of the desired 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6-methoxy-2-naphthyl)-propionate obtained in this state of purity was 127 - 128°C.

Example 5 Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazo-1-yl-4-en-5-yl 2'-(3-phenoxyphenyl)-propionate

Step A: Preparation of 2-(3-phenoxyphenyl)-propionyl chloride

41 g of 2-(3-phenoxyphenyl)-propionic acid were dissolved in 200 ml of dichloromethane. 20 g of thionyl chloride and 1 ml of N,N-dimethylformamide were added to the solution thus obtained, and the mixture was heated to initiate the reaction. The mixture was stirred at room temperature for 20 minutes, and then boiled under reflux for 2 hours, after which the evolution of hydrogen chloride had subsided.

The product thus formed, namely 2-(3-phenoxyphenyl)-propionyl chloride, was not isolated, but used directly for the preparation of the ester as described below.

Step B: Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-phenoxyphenyl)-propionate

A mixture of 56 g of 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine and 18 ml of pyridine in 100 ml of dichloromethane was added dropwise with stirring to the product obtained from step A. After the addition, the mixture was boiled under reflux 20 minutes and then allowed to cool to room temperature. The dichloromethane solution was washed 2 times with 100 ml portions of 2M hydrochloric acid and 2 times with 100 ml portions of 2M sodium hydroxide. After washing, the solution was dried over MgSO 4 , and the solvent was removed to give 81 g of a viscous oil of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-( 3-phenoxyphenyl)-propionate.

Example 6 Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl [2-(2,4-dichlorophenoxy)phenyl]-acetate Step A: Preparation of [2 -(2,4-dichlorophenoxy)phenyl]-acetyl chloride

9.9 g of [2-(2,4-dichlorophenoxy)phenyl]acetic acid was dissolved

1 100 ml of dichloromethane. 4 g of thionyl chloride and 0.5 ml of dimethylformamide were added to the resulting solution, and the mixture was refluxed for 30 minutes.

The product thus obtained, namely [2-(2,4-dichlorophenoxy)phenyl]-acetyl chloride, was not isolated, but used directly in the preparation of the ester as described below.

Step B: Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl [2-(2,4-dichlorophenoxy)phenyl]-acetate A mixture of 10.3 g of 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine and 3 ml of pyridine in 25 ml of dichloromethane were added to the product obtained from step A, and the mixture was refluxed for 30 minutes. The dichloromethane solution was washed 2 times with 100 ml portions of 2M hydrochloric acid and 2 times with 100 ml portions of a 2M sodium hydroxide solution. After washing, the solution was dried over MgSO4 and evaporated to dryness to give 14.7 g of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl [2-(2,4- dichlorophenoxy)phenyl]acetate as a viscous oil.

Example 7 Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl (3-chloro-4-prop-2'-enyloxyphenyl)-acetate

Step A: Preparation of (3-chloro-4-prop-2'-enyloxyphenyl)-acetyl chloride

22.6 g of (3-chloro-4-prop-2<1->enyloxyphenyl)-acetic acid was dissolved in 150 ml of dichloromethane. 12 g of thionyl chloride and 1 ml of N,N-dimethylformamide were added to the resulting solution, and the mixture was stirred at room temperature for 40 minutes, after which it was refluxed for 30 minutes. The mixture was then allowed to cool.

The product thus formed, namely (3-chloro-4-prop-2<1->enyloxyphenyl)-acetyl chloride, was not isolated, but used directly for the preparation of the ester, as described below.

Step B: Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl (3-chloro-4-prop-2<1->enyloxyphenyl)-acetate

A solution of 30.8 g of 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine and 9.0 g of pyridine in 100 ml of dichloromethane was added to the product obtained from step A, and the mixture was boiled under reflux cooling 20 minutes. The solution was washed with 200 ml of hydrochloric acid and then with 4,250 ml portions of a 2M sodium hydroxide solution and finally with 200 ml of water. After washing, the solution was dried over MgSO 4 and then evaporated to dryness to give 30 g of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl (3-chloro-4-prop-2< 1->enyloxyphenyl)-acetate as a pale yellow viscous oil.

Example 8 Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl (4-isobutylphenyl)-acetate

Step A: Preparation of (4-isobutylphenyl)-acetyl chloride

38.4 g of (4-isobutylphenyl)-acetic acid was dissolved in 100 ml of dichloromethane, and the solution was stirred.

24.5 g of thionyl chloride and 1 ml of N,N-dimethylformamide were

added to the stirred solution, and when the evolution of gas had decreased (after about 1 hour), the mixture was boiled under reflux cooling until the evolution of gas had stopped (about 15 minutes). The product thus formed, namely (4-isobutylphenyl)-acetyl chloride, was not isolated, but used directly for the preparation of the ester, as described below.

Step B: Preparation of 1,2-diphenyl-3-oxo-4-n-butyl-pyrazolid-4-en-5-yl 4-isobutylphenyl)-acetate

A solution of 61.9 g of 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine in 100 ml of dichloromethane and 22 ml of pyridine was carefully added to the stirred solution of (4-isobutylphenyl)-acetyl chloride prepared in step A. The mixture was refluxed for 30 minutes and then cooled; the resulting solution was washed 2 times with 2M hydrochloric acid, 2 times with 240 ml portions

of a 2M aqueous sodium hydroxide solution and then dried over MgSO 4 . After drying, the solution was concentrated under reduced pressure to give 72.0 g of 1,2-diphenyl-3-oxo-4-n-but-ylpyrazolid-4-en-5-yl (4-isobutylphenyl)-acetate as a lysegyl oJ.je with a solubility in water of less than 0.2 mg/ml.

Alternative preparation of the compounds of general formula III via the mixed anhydride (example 9): Example 9 Preparation of 1,2-diphenyl-3-oxo-4-n-butyl- pyrazolid-4-en-5-yl 2'-(4-isobutylphenyl)-propionate Step A: Preparation of mixed anhydride of general formula

VII

2.06 g (0.01 mol) of 2-(4-isobutylphenyl)-propionic acid was dissolved in 25 ml of dichloromethane, and cooled to below 10°C. 1.17 g (0.01 mol) of pivaloyl chloride was added with stirring and cooling to maintain the temperature below 10°C. While stirring and cooling was continued, 1.01 g (0.01 mol) of triethylamine was then slowly added. When the addition was complete, the reaction mixture was allowed to assume room temperature, it contained the desired mixed anhydride of general formula VII, which was not isolated, however, but used directly in the next step of the process.

Instead of using pivaloyl chloride in the above process, it is possible to use an equimolar amount of another sterically hindered acid chloride such as isovaleryl chloride.

Alternatively, instead of a sterically hindered acid chloride, an equimolar amount of either a chloroformate such as ethyl chloroformate, phenyl chloroformate, benzyl chloroformate or tolyl chloroformate, or a sulfonyl chloride such as methylsulfonyl chloride, phenylsulfonyl chloride, benzylsulfonyl chloride or toluylsulfonyl chloride can be used.

Step B: Preparation of 1,2-diphenyl-3-oxo-4-n-butyl-pyrazolid-4-en-5-yl 2'-(4-isobutylphenyl)-propionate To the reaction product from step A was added

3.08 g (0.01 mol) of 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine and 1.01 g (0.01 mol) of triethylamine. This reaction mixture was heated to approx. 40°C for 20 minutes, and after cooling the organic solution was washed with 2M hydrochloric acid and then with either 20% sodium carbonate solution or 2M sodium hydroxide solution. The organic solution was finally dried over magnesium sulfate, and the solvent was then removed under reduced pressure.

The residue is the desired product which, after recrystallization from the suitable solvents, is indistinguishable from the product according to example 1.

If the mixed anhydride starting material is prepared from either another sterically hindered acid chloride or a sulfonyl chloride in step A, the procedures described in step B can be followed. If, however, the starting material in step B is derived from the use of chloroformate in step A, the triethylamine used in step B (or any other base) must be omitted.

Preparation of compounds of general formula III by the symmetrical anhydride route (Example 10)

Example 10 Preparation of 1,2-diphenyl-3-oxo-4-n-butyl-pyrazolid-4-en-5-yl 2'-(6-methoxy-2-naphthyl)-, propionate

Step A: Preparation of 2-(6-methoxy-2-naphthyl)-propionic anhydride

To a solution of 18.42 g of 2-(6-methoxy-2-naphthyl)-propionic acid in 150 ml of tetrahydrofuran, 16.5 g of N,N<1->dicyclohex-yl-carbodiimide was added, and the resulting mixture was allowed to stand at room temperature overnight. After filtration, the filtrate was evaporated to dryness, and the residue recrystallized from ethanol to form 2-(6-methoxy-2-naphthyl)-propionic anhydride.

Step B: Preparation of the desired ester

3.08 g of 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine was dissolved in 20 ml of 1M sodium hydroxide, and a solution of 4.4 2 g of 2-(6-methoxy-2-naphthyl)- propionic anhydride in 20 ml of benzene was added. The mixture was shaken vigorously for 30 minutes and thereafter

filtered to form 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6-methoxy-2-naphthyl)-propionate which could not be distinguished from the product according to example 4.

Further examples of preparations using the acid-chloride route (examples 11 - 16)

Example 11 Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(4-[1-oxo-2-isoindolinyl]-phenyl)-propionate

Step A: Preparation of 2-(4-[1-oxo-2-isoindolinyl]-phenyl)-propionyl chloride

28.1 g of 2-(4-[1-oxo-2-isoindolinyl]-phenyl)-propionic acid was dissolved in 150 ml of chloroform containing 1 ml of N,N-dimethylformamide. 12 g (or 8 ml) of thionyl chloride was added and the mixture was stirred at 40°C for 3 hours.

The product obtained, namely 2-(4-[1-oxo-2-isoindolinyl] phenyl)-propionyl chloride was not isolated, but used directly for the preparation of the ester as described below.

Step B: Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(4-[1-oxo-2-isoindolinyl]-phenyl)-propionate

A mixture of 30.8 g of 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine and 15 g pyridine in 200 ml chloroform. The mixture was heated and refluxed for 30 minutes. The resulting chloroform solution was washed with 100 ml of 2M hydrochloric acid, then with 100 ml of saturated sodium bicarbonate solution. The chloroform layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The oil thus obtained was dissolved in 200 ml of ether, and the solution was shaken vigorously for 10 minutes with 75 ml of 2M sodium carbonate. A further 100 ml of ether was added and the ether layer was separated, washed with 100 ml of water and dried. Evaporation of the ether gave the desired 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(4-[1-oxo-2-isoindolinyl]-phenyl)-propionate obtained. This was crystallized from ether-petroleum ether.

Example 12 Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6-chloro-2-carbazolyl)-propionate

Step A: Preparation of 2-(6-chloro-2-carbazolyl)-propionyl chloride

22.4 g of 2-(6-chloro-2-carbazolyl)-propionic acid was dissolved in 150 ml of chloroform containing 1 ml of N,N-dimethylformamide. 12 g (or 8 ml) of thionyl chloride was added and the mixture was stirred at 40°C for 3 hours.

The product obtained, namely 2-(6-chloro-2-carbazolyl)-propionyl chloride, was not isolated, but used directly for the preparation of the ester as described below.

Step B: Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazo-1id-4-en-5-yl 2'-(6-chloro-2-carbazolyl)-propionate For the dissolution of 2-( 6-chloro-2-carbazolyl)-propionyl chloride obtained from step A was added to a mixture of 30.8 g of 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine and 15 g of pyridine in 200 ml of chloroform. The mixture was heated and boiled under reflux for 30 minutes.

The resulting chloroform solution was washed with 100 ml of dilute hydrochloric acid, then with 10% sodium carbonate solution. The chloroform layer was dried over MgSO 4 , and the solvent was removed under reduced pressure. The oil thus obtained was dissolved in 200 ml of ether, and the solution was shaken vigorously for 10 minutes with 75 ml of 2M NaOH. A further 100 ml of ether was added, and the ether layer was separated, washed with 100 ml of water and dried. By evaporation of the ether, the desired 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 21-(6-chloro-2-carbazolyl)-propionate was obtained. This was crystallized from ether-petroleum ether.

Example 13 Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 21 -(3-chloro-4-(2,5-dihydropyrrol-1-yl)- phenyl)- propionate

Step A: Preparation of 2-(3-chloro-4-[2,5-dihydropyrrol-1-yl]-phenyl)-propionyl chloride

19.2 g of 2-(3-chloro-4-[2,5-dihydropyrrol-1-yl]-phenyl)-propionic acid was dissolved in 150 ml of chloroform containing 1 ml of N,N-dimethylformamide. 12 g (or 8 ml) of thionyl chloride was added and the mixture was stirred at 40°C for 3 hours.

The product obtained, namely 2-(3-chloro-4-[2,5-dihydropyrrol-1-yl]-phenyl)-propionyl chloride, was not isolated, but used directly for the preparation of the ester as described below.

Step B; Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 21 -(3-chloro-4-(2,5-dihydropyrrol-1-yl)-phenyl) - propionate

To the solution of 2-(3-chloro-4-[2,5-dihydropyrrol-1-yl]-phenylpropionyl chloride obtained from step A was added a mixture of 30.8 g of 1,2-diphenyl-3,5-dioxo -4-n-butylpyrazolidine and 15 g of pyridine in 175 ml of chloroform The mixture was warmed and refluxed for 30 minutes.

The resulting chloroform solution was washed with 100 ml of dilute hydrochloric acid, then with 10% sodium carbonate solution. The chloroform layer was dried over MgSO 4 , and the solvent was removed under reduced pressure. The oil thus obtained was dissolved in 200 ml of ether, and the solution was shaken vigorously for 10 minutes with 75 ml of 2M NaOH. A further 100 ml of ether was added, and the ether layer was separated, washed with 100 ml of water and dried. Evaporation of the ether gave the desired 1,2-diphenyl-4-oxo-4-n-butylpyrazolid-4-en-5-yl 21 -(3-chloro-4-(2,5-dihydropyrrol-1-yl) -phenyl)-propionate obtained. This was crystallized from ether-petroleum ether.

Example 14 Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazo-1id-4-en-5-yl 2'-(3-trifluoromethylaniline)-nicotinate

Step A: Preparation of 2-(3-trifluoromethylaniline)-nicotinoyl chloride

28.2 g of 2-(3-trifluoromethylaniline)-nicotinic acid were dissolved in 150 ml of chloroform containing 1 ml of N,N-dimethylformamide. 12 g (or 8 ml) of thionyl chloride was added and the mixture was stirred at 40°C for 3 hours.

The product obtained, namely 2-(3-trifluoromethylaniline)-nicotinoyl chloride, was not isolated, but used directly for the preparation of the ester as described below.

Step B: Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-trifluoromethylaniline)-nicotinate To the solution of 2-(3-trifluoromethylaniline) -nicotin-oyl chloride obtained from step A was added to a mixture of 30.8 g

1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine and 15 g pyridine in 200

ml of chloroform. The mixture was heated and boiled under reflux for 30 minutes.

The resulting chloroform solution was washed with 100

ml of dilute hydrochloric acid, then with 10% sodium carbonate solution. The chloroform layer was dried over MgSO 4 , and the solvent was removed under reduced pressure. The oil thus obtained was dissolved in 200 ml of ether, and the solution was shaken vigorously for 10 minutes with 75 ml of 2M NaOH. A further 100 ml of ether was added and the ether layer was separated, washed with 100 ml of water and dried.

Evaporation of the ether gave the desired 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-trifluoromethylaniline)-nicotinate. This was crystallized from ether-petroleum ether.

Example. 15 Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-fluoro-4-biphenylyl)propionate

Step A: Preparation of 2-(3-fluoro-4-biphenylyl)-propionic acid chloride

1.70 g of 2-(3-fluoro-4-biphenylyl)-propionic acid, 2 drops of dimethylformamide and 0.90 g of thionyl chloride were added to 15 ml of dichloromethane. The mixture was stirred at ambient temperature for 90 minutes, then refluxed for 5 minutes and cooled to 0°C in an ice bath.

The product obtained, namely 2-(3-fluoro-4-biphenylyl)-propionic acid chloride, was not isolated, but used directly for the preparation of the ester as described below.

Step B: Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-fluoro-4-biphenylyl) propionate

To the solution of 2-(3-fluoro-4-biphenylyl)propionic acid chloride obtained from step A was slowly added a mixture of 2.15 g of 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine and 0.6 g pyridine in 10 ml chloroform. The mixture was refluxed for 30 minutes, then cooled to room temperature.

The resulting chloroform solution was washed twice

ger with 100 ml of 2M sodium hydroxide, twice with 100 ml of 2M saline

acid and once with water. The chloroform layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The oil thus obtained was chromatographed on silica

gel and eluted with chloroform, and the resulting ester was washed

twice with 300 ml of 10% sodium carbonate solution. 1.5 g of the desired 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(2-fluoro-4-biphenylyl)propionate was obtained as a colorless oil. This was recrystallized from ether-petroleum ether.

Example 16 Preparation of the di-[2-(4-isobutylphenyl))propionate] ester of 1-phenyl-2-p-hydroxyphenyl-3,5-dione-4-n-butylpyrazolidine

Step A; Preparation of 2-(4-isobutylphenyl)-propionyl chloride

41.2 g of 2-(4-isobutylphenyl)-propionic acid was dissolved in 250 ml of chloroform containing 2 ml of N,N-dimethylformamide, 24 g (or 16 ml) of thionyl chloride was added, and the mixture was stirred at 40°C for 3 hours .

The product obtained, namely 2-(4-isobutylphenyl)-propionyl chloride, was not isolated, but used directly for the preparation of the ester as described below.

Step B: Preparation of the diester

To the solution of 2-(4-isobutylphenyl)-propionyl chloride obtained from step A was added a mixture of 32.4 g of 1-(p-hydroxyphenyl)-2-phenyl-3,5-dioxo-4-n-butylpyrazolidine and 15 g pyridine in 200 ml chloroform. The mixture became hot and was boiled under reflux for 30 minutes.

The resulting chloroform solution was washed with 100 ml of dilute hydrochloric acid, then with 10% sodium carbonate solution. The chloroform layer was dried over MgSO 4 , and the solvent was removed under reduced pressure. The oil thus obtained was dissolved in 75 ml of ether, and the solution was shaken vigorously for 10 minutes with 75 ml of 2M NaOH. A further 100 ml of ether was added and the ether layer was separated, washed with 100 ml of water and dried. Evaporation of the ether gave the desired diester. This was recrystallized from ether-petroleum ether.

The diester is believed to include both 1-phenyl-2-p-[2<1->(4-isobutylphenyl)-propionyloxy]-phenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2" -(4-isobutylphenyl)-propionate and its 5-oxo-pyrazolid-3-en-3-yl isomer which can also be designated as 1-p-[2'-(4-isobutylphenyl)-propionyloxy]-phenyl-2-phenyl- 3-oxo-4-n-butylpyrazolid-4-en-5-yl 2"-(4-isobutyl-phenyl)-propionate. The mixture could be separated into the individual isomers, but this has not yet been done.

To show another side of the invention, details for formulating one of the 3-oxo-5-pyrazolidinyl aromatic carboxylate ester derivatives according to the invention in several forms of pharmaceutical compositions are illustrated in the following.

Formulation 1: Composition in the form of tablets

A tablet mixture was prepared by intimately mixing the following ingredients:

The mixture was then compressed with conventional tableting machinery to form 500 ml<1>s tablets, each containing 200 mg of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'- (6-methoxy-2-naphthyl)-propionate.

Formulation 2: Composition in the form of capsules

A mixture was prepared by intimate mixing of the following ingredients:

The mixture was then filled into capsules in an amount of 400 mg per capsule, corresponding to 200 mg of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6-methoxy-2-naphthyl)-propionate per capsule.

Formulation 3: Composition in the form of injectable suspension

The 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2 1 -(6-methoxy-2-naphthyl)-propionate was suspended in the injection vehicle, and the pH was adjusted (if necessary) with phosphoric acid. The suspension was made up to the required volume, autoclaved under pre-determined conditions and aseptically transferred into pre-sterilised multi-dose vials.

Formulation 4: Composition in the form of suppositories

The suppository base was melted and 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6-methoxy-2-naphthyl)-propionate was added in finely divided form. The mixture was stirred until evenly dispersed, poured into 2 g suppository molds, allowed to solidify, and then removed from the molds. Each suppository contained 250 mg of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 21-(6-methoxy-2-naphthyl)-propionate.

In what follows, certain provisions such as

shows that some of the 4-alkyl-3,5-dioxopyrazolidinyl aromatic carboxylate ester derivatives according to the invention are free of unwanted side effects, and which furthermore show their excellent anti-inflammatory and/or analgesic properties.

Assessment of stability of analgesics and esters

To first determine the stability of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5^yl 2'-(4-isobutylphenyl)-propionate, 1,2-diphenyl-3-oxo- 4-n-butylpyrazolid-4-en-5-yl 21-(3-benzoylphenyl)-propionate and 1,2-diphenyl-3-oxo-4-n-butylporazolid-4-en-5-yl 2'-( 6-methoxy-2-naphthyl)-propionate in the gastrointestinal tract, simulated stomach and intestinal fluids were prepared as follows:

Preparation of simulated gastric fluid

2 g of sodium chloride was mixed with 7.0 ml of concentrated hydrochloric acid, and the mixture was then made up to a volume of 100 ml with distilled water, forming a simulated gastric fluid with a pH value of approx. 1.2.

Preparation of simulated intestinal fluid

6.8 g of monobasic potassium phosphate was 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 0.2M sodium hydroxide, and the solution was then diluted to 1000 ml with distilled water to form a simulated intestinal fluid.

Assessment method

100 mg of the 4-alkyl-3,5-dioxopyrazolidinyl aromatic carboxylate ester to be tested was suspended in 5 ml of each of the simulated liquids and shaken for 16 hours at 37°C. The mixture was then allowed to stand, and the supernatant was placed on silica thin layer chromatography 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 paper allowing only the chloroform solution to pass through. The chloroform solution was also placed on silica thin-layer chromatograph plates and developed in 90:10 chloroform/methanol.

The results of this procedure, carried out for both the simulated gastric and simulated intestinal fluid for each of the three above-mentioned esters, show that negligible degradation occurred in both of these fluids.

This indicates that all the 4-alkyl-3,5-dioxopyrazolidinylaromatic carboxylic acid esters according to the invention will be predominantly or completely free of stomach-disturbing effects when administered orally.

Assessment of acute gastric tolerance in rats

In relation to anti-inflammatory, analgesic compounds, the therapeutic index (or safety factor) is best demonstrated by the gastric tolerance test in rats. Gastric intolerance is the main problem associated with oral administration of the class of compounds exhibiting analgesic and anti-inflammatory properties.

Accordingly, these compounds of the invention were tested for their acute (4 or 6 hour) gastric tolerance in rats after oral administration at two or more dose levels, each compound being compared with an equimolar mixture of the two anti-inflammatory drugs from which the new ester is formed.

In order for the experiments to be carried out under conditions that allowed the difference between the new compounds and the known compounds used as a comparison standard to be reproducible and unequivocal, the effect of the reference drugs, namely the acid component and the alcohol component of the ester, in relation to the dose was also examined in a series of preliminary tor searches, which enabled suitable doses to be determined before testing of the compounds according to the invention began.

Test procedure

Groups of 10 male rats (Charles River, 180 - 250 g body weight) were fasted overnight and until sacrifice (approximately 21 hours). The drugs were administered orally as a suspension in 1% tragacanth.

Four or six hours (as specified in the results) after administration, the animals were killed by bleeding from the neck, then their stomachs were removed, opened, gently washed with saline, and stretched flat for examination.

During the examination, superficial mucosal bleeding was classified according to increased severity according to their size and number as: dots, spots or large zones. Bleeding lesions penetrating the mucosa (submucosal lesions) were considered ulcers, and also graded in severity according to their size and number: spots (1 - 2 mm in size), channels with a longitudinal dimension). Perforations were not usually observed.

The animals were then ranked according to the most serious symptoms each one showed, and where the wounds (submucosal lesions) were as a rule considered more serious than mucosal bleeding (superficial). The control animals uniformly showed some degree of "hyperemia," which corresponds to a congestive state of the blood vessels at the point of sacrifice, and not a persistent functional hyperemia. It was therefore not considered a sign of stomach irritation.

The results are expressed in simplified terms and tabulated as the percentage of rats that exhibited either muco-sal (superficial) bleeding alone, or submucosal (penetrating) lesions (ulcers) generally associated with mucosal bleeding.

i Statistical comparisons between specified groups were performed by the Mann and Whitney U test, based on the graded severity of the observations. The results are listed as the percentage of rats that exhibited either superficial mucosal bleeding alone, or ulceration (submucosal lesion) generally associated with mucosal bleeding.

Results

a) Table I shows the results for 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(4-isobutylphenyl)-propionate (Compound A) compared to 1,2- diphenyl-3,5-dioxo-4-n-butylpyrazolidine and 2-(4-isobutylphenyl)-propionic acid in a 4 hour test.

From the results listed in Table I, it is possible to derive the relative gastric toxicity compared to 1,2-diphenyl-3,5-di-oxo-4-n-butylpyrazolidine (hereafter compound Ph), and this is shown in Table II which also includes results with respect to relative inflammatory activity (oblique vision test) as follows:

Compared with the equivalent amount of an equimolar mixture of 2-(4-isobutylphenyl)-propionic acid and compound pH, the new ester, compound A, is completely tolerated by the gastric mucosa, it has the same effect as the widely used anti-inflammatory analgesics 4-acetamidophenyl-2-acetoxybenzoate.

It appears from Table II that, in comparison with compound Ph on a molar basis, the gastric tolerance of compound A is improved by a factor of at least 2.

There is also a two-fold increase in the anti-inflammatory activity compared to compound Ph. Thus, the therapeutic index for compound A shows a 4-fold improvement compared to compound Ph by molar comparison.

b) Table III gives the results for 5-(dimethylamino)-9-methyl-1-oxo-2-n-propylpyrazolid-2-eno[1,2-a]benzotriazin-3-yl

21 -(4-isobutylphenyl)-propionate (compound B) compared to 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a][1,2,4]-benzotriazine -1,3(2H)-dione (compound Az) in a 6 hour test.

As indicated in Table III, gastric lesions were observed in a certain proportion of animals treated with compound Az at 1 mol/kg. And although only a very small number of animals could be dosed with compound B, it is an indication that gastric irritation is not increased or may even have been improved compared to the reference compound Az. c) Table IV sets forth the results of an acute (4 hour) gastric tolerance test in rats comparing 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl (3-chloro -4-n-prop-21-enyloxyphenyl)-acetate (compound C) with compound Ph and 3-chloro-4-n-prop-2'-enyloxyphenyl)-acetic acid (compound A1).

Compound C has some bleeding effect on the gastric mucosa, but as shown in Table IV, its gastric tolerance is significantly better than the equivalent mixture of compound Ph and compound Al at higher dose concentrations. It should also be noted that there was no increase in the appearance of gastric lesions in the compound C test when the dose was doubled.

d) Table V shows the results from acute (4 hours) gastric tolerance test in rats for 1-2-diphenyl-3-oxo-4-n-butulpyrazolid-4-en-5-yl 2'-(3-phenoxyphenyl)- propionate (compound D) compared to compound Ph. These results show that compound D has remarkably improved gastric tolerance compared to an equimolar amount of Ph. It seems that compound D is non-irritating to the stomach lining.

Assessment of desired pharmacological effects

Three tests are commonly used to determine the efficacy of analgesic and anti-inflammatory drugs, and these three tests were used to evaluate compounds of the invention with their parent compounds as indicated below.

Test I

A) Provoked arthritis test (oblique view) in rats

Method

Provoked disease was induced in several groups of rats. When provoked arthritis was induced in rats (normally with a mycobacterial provocateur), the provocateur induces inflamed lesions in areas of the body distant from the injection site, after a period of 10 - 15 days, although the inflammation begins to subside by the 30th day.

One group of rats was left untreated as a control; other groups were treated by oral administration once a day for 18 days with different amounts of the parent compound used as a comparison standard and with the compound to be evaluated.

In each case, the compound was administered to the rat in solution in 1 part polyoxyethylene oleic acid glyceride filled up to 5 parts with 1% aqueous gum tragacanth, to which 1% ethanol was also added when this was necessary to effect dissolution. The amount of this solvent carrier administered was generally 5 ml per kg rat. The same vehicle (but without active ingredient) was also administered to the control group of rats.

Treatment was continued for 18 days, during which time the rats were tested at intervals using the standard oblique vision test. Briefly stated, this grasping function of the rat is assessed by placing it on a steel wire sieve which is turned up over an angle of 90° from the horizontal to the vertical, and if necessary further. The angle at which the rat loses its grip and falls from view is recorded. The greater the angle of inclination at which the rat falls out of sight, the stronger is its grip on it, and thus the less its grasping function is affected by the arthritis-like provoked disease, or in other words the better relief of the pain exhibited by the tested compound.

Results

i) 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(4-isobutylphenyl)-propionate (compound A)

A group of rats that acted as control animals only received vehicle in the appropriate amount per day from day 0 to 18

(17 doses). Another group of rats received 40 mg/kg per day of compound Ph for 18 days. A third group received 80 mg/kg per day of connection Ph. A fourth group of rats received 64 mg/kg of compound A. The molar equivalent of a dose concentration of 64 mg/kg of compound IV is a dose concentration of approximately 40 mg/kg of compound Ph, and to the extent that compound A proves to be superior to compound Ph, its use is thereby established.

The results obtained are shown graphically in fig. 1 in the accompanying drawings, where the line of gradual weakening of the grasping function expressed in the oblique angle of the sight against time is shown for each of the different compounds tested, and fer the controls.

From fig. 1, it can be concluded that compound A is approximately as active as the double molar amount of compound Ph in the gripping function test. In a separate test, compound A was found to be as active as three times the molar amount of 2-(4-isobutylphenyl)-propionic acid (compound Ib).

ii) 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl (3-chloro-4-n-prop-2'-enyloxyphenyl)-acetate (compound C)

Compound C was tested at a concentration of 67 mg/kg/day, and to provide a basis for comparison, separate groups of rats received the parent compound, compound Ph, at concentrations of 40 mg/kg and 80 mg/kg/day. The molar equivalent of a dose concentration of 67 mg/kg of compound C is 40 mg/kg of compound Ph.

The results are shown graphically in fig. 2 in the accompanying drawings where the slant angle of sight versus time is shown for the various compounds tested and for the controls.

From fig. 2, it can be concluded that compound C has approximately the same level of activity as the equimolar amount of compound Ph. However, as previously shown, compound C has a greater gastric tolerance than compound Ph, so that its overall therapeutic performance is better.

iii) 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2 ' — (3 —

phenoxyphenyl)- propionate (compound D)

Compound D was tested at dose concentrations of 35 and 70 mg/kg, and compared to the respective equimolar amounts of

20 and 40 mg/kg of compound Ph. The results are shown in the following Table VI which indicates that compound D is as active as 0.5 molar equivalents of compound Ph. In a separate determination, however, compound D was found to be as active as 2-(3-phenoxyphenyl)-propionic acid in concentrations of 40 mg/kg for both drugs.

B) Provoked arthritis test (body weight) in rats

The experimental determination of unknown side effects is more difficult than the determination of stomach irritation, but their presence can be determined by a reduction in body weight. To ensure that the results of the oblique vision test were not unreliable due to other side effects of the compound being tested,

the body weight of the rats suffering from the induced disease was then determined each day.

The results for compound A are shown in fig. 3 in the accompanying drawings, from which it can be concluded that the systemic effect on body weight of compound A is mainly that of the double molar amount of compound Ph. Compound Ib has no beneficial effect on body weight.

The results for compound C are shown in fig. 4, and these are in agreement with the results of the gripping function test in that compound C has comparable activity to compound pH.

C) Provoked arthritis test (acute phase) - Compound B

The anti-inflammatory activity of compound B was investigated in a subacute test involving 3-dose administrations in rats using the following procedure: Groups of non-fasted female (Charles River) rats of equal body weight were given a subplantar injection of 0, 5 mg (per animal) Mycobacterium butyr. in 0.1 ml of sterile paraffin oil in the right hind paw (the opposite paw remained untreated), and the edema that subsequently developed was measured at the intervals indicated below by differential plethysmometry of injected and non-injected paws under application of enUgo-Basile apparatus. The following treatment schedule was used:

In a preliminary experiment, compound Az was tested at concentrations of 0.1, 0.2 and 0.4 mmol/kg and was found to have a statistically significant effect at a concentration of 0.2 mmol/kg.

Compound B was therefore also tested at a dose concentration of 0.2 mmol/kg, and the results obtained are shown in Table VII.

Compound Az exhibited sharp dose-dependent effects-in the range of 0.1 - 0.2 - 0.4 mmol/kg: The total effects (ie the sum of % inhibition of edema observed at days 0-3) amounted to 53 - 87 - 160% for the respective dose concentrations. Compound B was more effective in that its total effect was 124%, thus its activity was approximately 1.5 times the molar equivalent of compound Az.

Test II Antipyretic test against yeast-induced

hyperthermia in rats'

i) Compound A

By applying the conventional procedure, groups were formed

of rats injected with yeast. Immediately after the injection, varying doses of compound A, compound Ib and compound Ph were administered orally to different groups of rats, except

from the control group that received only the vehicle.

The body temperature of all rats was carefully monitored for a period of 8 hours after oral administration of the test compound. The results are shown in fig. 5 in the accompanying drawings.

Compound A was tested at 24 mg/kg and found to have the same activity as the equimolar concentration (10 mg/kg) of compound Ib, and of the same activity as 30 mg/kg of compound Ph, which is twice the equimolar concentration of the parent compound . Compound A is as rapid in its action as each of the parent compounds.

ii) Compound B

The antipyretic test was performed with compound B using dose concentrations of 23.8 and 47.6 mg/kg (corresponding to 0.05 and 0.1 mmol/kg, respectively), and compound Az was used as a comparison compound in a dose concentration of 67.2 mg/kg (0.2 mmol/kg). The results obtained are shown in fig. 6 in the accompanying drawings.

Compound Az exhibited a strikingly weak antipyretic effect in this test. Compound B had a statistically significant effect at the low dose concentrations of 0.05 and 0.1 mmol/kg, while compound Az was mainly ineffective at 0.2 mmol/kg. It was determined that compound B was 10 times more effective on an equimolar basis than compound Az.

iii) Compound C

The results for the antipyretic test performed with compound C are shown in fig. 7 in the accompanying drawings. A dose concentration of 51 mg/kg of compound C was used, and a comparison was made with compound Ph used at a concentration of 30 mg/kg and a mixture of compound Ph and compound

Al used in a concentration of 30 mg/kg of compound pH and

22 mg/kg of compound Al.

Compound C is as active as compound pH alone,

and really as active as the mixture.

iv) Compound D

The results for compound D in the antipyretic test are shown in fig. 8 in the accompanying drawings. Compound D was administered at 35 and 70 mg/kg, and compared to compound Ph administered at 40 mg/kg. The results indicate that compound D is as active as antipyretic agent with twice the molar amount of compound Ph. Furthermore, compound D acted faster, and its duration of action was longer than that of compound Ph.

Test III Randall-Selitto test in rats

Method

The tests were carried out on male rats with an average weight of 135 - 200 g. Using conventional methods, the various compounds to be tested, as identified in the following, were administered orally to the rats in each group (except a control group which only received the vehicle), and 30 minutes later each of the rats was injected into a hindpaw with yeast.

To assess the effect of the treatment on pain thresholds, pressure was applied to both the injected hindpaw and the other non-injected hindpaw. The pain thresholds were observed as the pressure that the rat did not receive, the readings for each rat being expressed as the percentage of the pain threshold pressure of the injected hindpaw to the pain threshold pressure of the non-injected hindpaw.

These pain threshold percentages were determined at intervals of 3, 5, 7 and 24 hours after the injection. Statistical: t-test against the control group.

Results

The results obtained during the testing are listed in the subsequent tables VIII - XI.

Conclusions

The results from the Randall-Sellito test in the tables indicated above show that compound A has the same activity as the double equimolar amount of compound Ib.

Compound B has an activity of 0.5 times the equimolar amount of compound Ph. However, as shown earlier, the other properties of compound B, and particularly its anti-inflammatory and antipyretic properties, make it a very advantageous therapeutic compound.

Compound C is shown in Table X to have a greater analgesic effect than compound Ph, comparable to, or slightly less than, the effect of the double equimolar amount of compound Ph.

Table XI shows that compound D is as active as approx. 1.5 molar equivalents of compound Ph, and thus advantageous in analgesic activity compared to compound Ph.

As regards compound B, a further test was carried out to assess the analgesic activity of the compound according to the invention in mice.

Test IV

Acetylcholine-induced writhing in mice - Compound B

Groups of 10 female mice, weighing 27-30 g, were administered orally with the compound to be tested in the amounts indicated below. A control group of similar mice was not administered any other compound. 60 minutes later, the mice, including the control group, were injected with 3.5 mg/kg acetylcholine chloride, which induces writhing.

The mice were observed, and the number of mice exhibiting at least one writhing between 25 and 120 seconds after injection was recorded.

Compound B was tested at concentrations ranging from 0.05 mmol/kg - 0.4 mmol/kg and compared to compound Ph administered at concentrations ranging from 0.1 mmol/kg to 0.8 mmol/kg. The results are listed in the following table XII.

It appears that compound B is remarkably more effective in inhibiting the induced torsion, and is in the order of 6 times more effective than compound Ph in equimolar doses. This demonstrates the excellent analgesic properties of compound B.

Claims (103)

1. The 4-alkyl-3,5-dioxopyrazolidinyl aromatic carboxylate esters of general formula: wherein Alk denotes an n-propyl or n-butyl group, where either one of B' and B" denotes a phenyl group, and the other denotes a phenyl group or a phenyl group substituted with a group -OZ<1> , or B' and B" together with the intervening nitrogen atoms to which they are attached, denotes a 3-dimethylamino-7-methyl-[1,2,4]-benzotriazine ring system fused with the pyrazolidine ring, and where at least one of Z and Z <1> denotes an aromatic carbonyl group : in which A denotes a carbon atom or e2 n ^C-CH9 -, ^C-CHCl-, ^C-CHtCH^ )- or >C-CO-Cl^ group, R denotes a hydrogen atom, or a hydroxy, 2,4 -dichlorophenoxy or 3-trifluoromethylaniline group, B denotes a nitrogen atom or a ^C-F, >C-C1 or* 5C-H group, R 4 denotes a hydrogen atom or a phenyl, isobutyl, n-prop-2-enyloxy-cyclohexyl, 2 -methyl-cycl :6hexyl, 2-fluorophenyl, l-oxo-2-isoindolinyl or 2,5-dihydropyrrol-l-yl group, and R 5 denotes a hydrogen atom or a benzoyl, 2,4-difluorophenyl or phenoxy group, or R <4> and R <5> together with the intermediate carbon atoms to which they are attached form a methoxy-substituted benzene ring, a 6-methylbenzo[e]-(1,4)-thiazine ring or a methoxy-substituted 6-methylbenzo [ e] -(1, 4 )-thiazine ring, the benzothiazine rings each being fused to the aromatic ring at their [b] position, or a 5-chloroindole ring fused to the aromatic ring at their [d] position, and when only one of Z and Z' denotes an aromatic carbonyl group, the other denotes a hydrogen atom, and where possible, acid addition salts thereof. 2. Acid addition salts according to claim 1, formed with a pharmacologically acceptable acid which can be used in human or veterinary therapy. 3. Compound according to claim 1, of general formula: wherein Alk is as defined in claim 1, where either one of B' and B" denotes a phenyl group, and the other denotes a phenyl group or a phenyl group substituted with a group -OZ', orB <1>^ and B" <A> together with the intervening nitrogen atoms to which they are attached, denotes a 3-dimethylamino-7-methyl-[1,2,4]-benzotriazine ring system fused with the pyrazolidine ring, and where at least one of Z^ and Z'A denotes a substituted 2-phenylpropionyl group: 4 -5 etc wherein R and R are as defined in claim 1, and when only one of Z^ and Z'^ represents a substituted 2-phenylpropionyl group, the other represents a hydrogen atom, and where possible, their acid addition salts. 4. 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(4-isobutylphenyl)-propionate. 5. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(4-isobutylphenyl)-propionic acid. 6. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazole-[1,2-a][1,2,4]benzotriazine-1,3(2H)-dionesters of 2-( 4-isobutyl-phenyl)-propionic acid. 7. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-benzoylphenyl)-propionate. 8. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(3-benzoylphenyl)-propionic acid. 9. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazole-[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2-( 3-benzoylphenyl)-propionic acid. 10. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6-methoxy-2-naphthyl)-propionate. 11. The 1-phenyl-2-p-hydroxydenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(6-methoxy-2-naphthyl)-propionic acid. 12. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(6 -methoxy-2-naphthyl>-propionic acid. 13. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2-(4-cyclohexylphenyl)-propionate. 14. 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine 2-(4-cyclohexylphenyl)-propionic acid. 15. 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(4 -cyclohexylphenyl)-propionic acid. 16. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2-(4-[2-methyl-cyclohexyl]-phenyl)-propionate. 17. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(4-[ 2-methyl-cyclohexyl ]-phenyl)-propionic acid:: - 18. 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(4 -[2-methyl-cyclohexyl]-phenyl)-propionic acid. 19. 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 21 — [2' — fluoro-4-biphenyl]propionate. 20. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-[2'-fluoro-4-biphenyl]-propionic acid. 21. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzitriazine-1,3(2H)-dionesters of 2-[2 '-Fluoro-4-biphen-y]-propionic acid. 22. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-[4-(1-oxo-2-isoindolinyl)-phenyl]-propionate. 23. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-[4-(1-oxo-2-isoindolinyl)-phenyl]-propionic acid. 24. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazole-[1,2a-] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2-[4 -(1-oxo-2-isoindo-linyl)-phenyl]-propionic acid. 25. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6-chloro-2-carbazolyl)-propionate. 26. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(6-chloro-2-carbazolyl)-propionic acid. 27. 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(6 -chloro-2-carbazol-yl)-propionic acid. 28. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl (10-methyl-2-phenothiazinyl)-acetate. 29. The 1-phenyl-2-p-hydroxyphenyl-3-oxo-4-n-butylpyrazolidine esters of (10-methyl-2-phenothiazinyl)-acetic acid. 30. 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of (10-methyl -2-phenothia-zinyl)-acetic acid. 31. 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 21 — (7 — methoxy-10-methyl-2-phenothiazinyl)-propionate. 32. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butyl-pyrazolidinesters of 2-(7-methoxy-10-methyl-2-phenothiazinyl)-propionic acid. 33. 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(7 -methoxy-10-methyl-2-phenothiazinyl)-propionic acid. 34. 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-phenoxyphenyl)-propionate. 35. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(3-phenoxyphenyl)-propionic acid. 36. 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(3 -phenoxyphenyl)-propionic acid . 37. 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2' (3-fluoro-4-biphenyl)-propionate. 38. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(3-fluoro-4-biphenyl)-propionic acid. 39• 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(3 -fluoro-4-biphenyl)-propionic acid. 40. 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-chloro-4-(2,5-dihydropyrrol-1-yl)-phenyl)- propionate. 41. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(3-chloro-4-(2,5-dihydropyrrol-1-yl)-phenyl)- propionic acid. 4 2. 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2-( 3-Chloro-4-(2,5-dihydropyrrol-1-yl)-phenyl)-propionic acid. 43. 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-trifluoromethylaniline)-nicotinate. 44. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(3-trifluoromethylaniline)-nicotinic acid. 45. 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2-(3 -trifluoromethyl-aniline) -nicotinic acid. 46. 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2",4"-difluoro-4 <1-> hydroxy-3 <1-> biphenylcarboxylate. 47. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2',4 <1-> difluoro-4-hydroxy-3-biphenylcarboxylic acid. 48. 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of 2',4 '-difluoro-4-hydroxy-3-biphenylcarbozylic acid. 49. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl chloro-(3-chloro-4-cyclohexylphenyl)-acetate. 50. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of chloro-(3-chloro-4-cyclohexylphenyl)-acetic acid. 51.. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of chloro-( 3-chloro-4-cyclohexylphenyl)-acetic acid. 52. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 3'(4-bi-phenylcarbonyl)-propionate. 53. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 3-^(4-biphenylcarbonyl)-propionic acid. 54. 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1, 2 , 4 ] benzotriazine-1, 3 ( 2H)-dionesters of 3-(4 -bif enylcarbonyl).-propionic acid. 55. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl [2-(2,4-dichlorophenoxy)-phenyl]acetate. 56. 1-Phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine [2-(2,4-dichlorophenoxy)-phenyl]acetic acid. 57. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of [2-( 2,4-dichlorophenoxy)-phenyl]-acetic acid. 58. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl (3-chloro-4-n-prop-2'-enyloxyphenyl)-acetate. 59. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of (3-chloro-4-n-prop-2'-enyloxyphenyl)-acetic acid. 60. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of (3-chloro -4-n-prop-2 <1-> enyloxyphenyl)-acetic acid. 61. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl (4-iso-butylphenyl)-acetate. 62. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of (4-isobutylphenyl)-acetic acid. 63. 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dionesters of (4-isobutylphenyl )-acetic acid. 64. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 3'-pyridine acetate. 65. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 3-pyridine-acetic acid. 66. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2a][1,2,4]benzotriazine-1,3(2H)-dionesters of 3-pyridine-acetic acid. 67. Process for the production of 4-alkyl-3,5-dioxopyr-azolidinyl aromatic carboxylate esters of general formula III according to claim 1, characterized in that a 4-alkyl-3,5-dioxopyrazolidine derivative of general formula; wherein Alk is as defined in claim 1, and one of W and W" denotes a phenyl group, and the other denotes a phenyl or para-hydroxyphenyl group or W and W" together with the intervening nitrogen atoms to which they are attached, denote a 3-dimethyl- <1-> amino-7-methyl-[1,2,4]-benzotriazine ring system condensed with the pyrazolidine core, is reacted with an aromatic carboxylic acid chloride of general formula: wherein A, B, R 2 , R 4 and R 5 are as defined in claim 1, or an acid addition salt thereof, forming the desired corresponding 4-alkyl-3,5-dioxopyrazolidinyl aromatic carboxylate ester of general formula III or acid addition salt hence. 68. Method according to claim 67, characterized in that it is carried out in an anhydrous, inert solvent. 69. Method according to claim 68, characterized in that the inert solvent is a substituted aromatic hydrocarbon, a halogenated aromatic solvent, an aliphatic hydrocarbon or a halogenated aliphatic hydrocarbon. 70. Method according to claim 69, characterized in that the solvent is dichloromethane. 71. Method according to any one of claims 67 - 70, characterized in that it is carried out at ambient temperature without heating or by cooling to maintain ambient temperature. 72. Method according to any one of claims 67 - 71, characterized in that the reaction is carried out in the presence of a base. 73. Method according to claim 72, characterized in that the base is a tertiary amine. 74. Process according to any one of claims 67 - 73, characterized in that the acid chloride of general formula IV is prepared by reacting a solution or suspension in an anhydrous, inert solvent of an aromatic carboxylic acid of general formula: 2 4 5 wherein A, B, R , R and R are as defined in claim 1, or a salt thereof, with thionyl chloride. 75. Method according to claim 74, characterized in that a pyridine salt of the acid of general formula II is used. 76. Method according to claim 74 or 75, characterized in that the reaction with thionyl chloride is carried out at a temperature within the range from 40 to 65°C. 77. Method according to any one of claims 74 - 76, characterized in that the solvent used is as defined in claim 68 or 69. 78. Method according to claim 77, characterized in that the solvent is anhydrous in chloromethane, and that the reaction is carried out under reflux cooling at a temperature of 40 - 41°C. 79. Method according to any one of claims 74 - 78, characterized in that the reaction with thionyl chloride is carried out in the presence of a catalytic amount of N,N-dimethylformamide. 80. Process for the production of 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic carboxyl esters of general formula III according to claim 1, characterized in that a mixed anhydride of general formula: wherein A, B, R 2 , R 4 and R 5 are as defined in claim 1, "Ayl" denotes an alkyl group containing from 1 to 20 carbon atoms, an aryl group containing from 6 to 20 carbon atoms, an alkaryl group containing from 7 to 20 carbon atoms, or an aralkyl group containing from 7 to 20 carbon atoms, m is 0 or 1, and Q denotes a carbon atom or when m is 0, a sulfinyl group, is reacted with a 4-alkyl-3,5-dioxopyrazolidine derivative of general formula I which defined in claim 67, forming the desired corresponding 4-alkyl-3,5-dioxopyrazolidinyl aromatic carboxylate esters of general formula III. 81. Method according to claim 80, characterized in that the reaction is carried out in an anhydrous, inert solvent. 82. Method according to claim 81, characterized in that the solvent is as defined in claim 69. 83. Method according to any one of claims 80 - 82, characterized in that the reaction is carried out in the presence of a base. 84. Method according to claim 83, characterized in that the base is a tertiary amine. 85. Process according to any one of claims 80 - 84, characterized in that the mixed anhydride of general formula V is prepared by reacting an aromatic carboxylic acid of general formula II as defined in claim 74, or a salt thereof, with a reactive organic chloride of general formula: wherein Ayl, m and Q are as defined in claim 80, in the presence of a base. 86. Method according to claim 85, characterized in that the reaction between the acid of general formula II and the reactive chloride of general formula VI is carried out in an anhydrous, inert solvent. 87. Method according to claim 86, characterized in that the solvent is as defined in claim 69. 88. Method according to any one of claims 85 - 87, characterized in that the base is a tertiary amine. 89. Method according to claim 88, characterized in that the base is triethylamine or pyridine. 90. Process for the production of 4-alkyl-3,5-dioxopyrazolidine aromatic carboxyl esters of general formula III according to claim 1, characterized in that a 4-alkyl-3,5-dioxonr pyrazolidine derivative of general formula I as defined in claim 67, is reacted with a solution in a water-immiscible solvent of a symmetrical, aromatic carboxylic acid anhydride of general formula: wherein A, B, R 2 , R 4 and R 5 are as defined in claim 67, in the presence of a strong aqueous base, so that the reaction mixture forms a two-phase system which is stirred to form the desired 4-alkyl-3,5 -dioxopyrazolidinyl aromatic carboxylate esters of general formula III. 91. Method according to claim 90, characterized in that the strong aqueous base is aqueous sodium hydroxide. 92. Method according to claim 90 or 91, characterized in that the water-immiscible solvent is benzene, toluene, chloroform, dichloromethane or an ether. 93. Method according to any one of claims 90 - 92, characterized in that the reaction is carried out at a temperature that does not exceed 30°C. 94.. Process according to any one of claims 90 - 93, characterized in that the acid anhydride of general formula VII is prepared by reacting an aromatic carboxylic acid of general formula II as defined in claim 74, with a carbodiimide in solution in an anhydrous, non- hydroxylic and otherwise inert organic solvent at a temperature not exceeding 30°C. 95. Method according to claim 94, characterized in that the carbodiimide is N,N'-dicyclohexylcarbodiimide. 96. A process for preparing a compound of general formula III according to claim 1, essentially as described with reference to any of the examples. 97. Aromatic carboxylic acid chlorides of general formula IV defining ten claims 67. 98. Mixed anhydrides of general formula V as defined in claim 80. 99. Symmetrical anhydrides of general formula VII as defined in claim 90. 100. Compound of general formula III prepared by a process according to any one of claims 67 - 96. 101. Pharmaceutical composition comprising as active ingredient one or more of 4-alkyl-3,5-dioxopyrazolidinyl aromatic carboxyl esters of general formula III according to claim 1, in connection with a suitable pharmaceutical carrier. 102. Composition according to claim 101, in the form of a unit dose containing from 30 mg to 2.7 g of active ingredient. 103. A composition according to claim 101, and substantially as described" with reference to any of the formulations.