GB1597970A - Pharmacologically-active esters processes for their preparation and pharmaceutical compositions incorporating them - Google Patents

Pharmacologically-active esters processes for their preparation and pharmaceutical compositions incorporating them Download PDF

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GB1597970A
GB1597970A GB39609/77A GB3960977A GB1597970A GB 1597970 A GB1597970 A GB 1597970A GB 39609/77 A GB39609/77 A GB 39609/77A GB 3960977 A GB3960977 A GB 3960977A GB 1597970 A GB1597970 A GB 1597970A
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Sterwin AG
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Priority to FR7826146A priority patent/FR2403997A1/en
Priority to DE19782839738 priority patent/DE2839738A1/en
Priority to NL7809303A priority patent/NL7809303A/en
Priority to BE190573A priority patent/BE870589A/en
Priority to LU80259A priority patent/LU80259A1/en
Priority to AT0678478A priority patent/ATA678478A/en
Priority to DK418378A priority patent/DK418378A/en
Priority to NO783202A priority patent/NO783202L/en
Priority to SE7809943A priority patent/SE7809943L/en
Priority to FI782883A priority patent/FI782883A/en
Publication of GB1597970A publication Critical patent/GB1597970A/en
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/54—Preparation of carboxylic acid anhydrides
    • C07C51/56—Preparation of carboxylic acid anhydrides from organic acids, their salts, their esters or their halides, e.g. by carboxylation
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58—Preparation of carboxylic acid halides
    • C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/28—Two oxygen or sulfur atoms
    • C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
    • C07D231/32—Oxygen atoms
    • C07D231/34—Oxygen atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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Description

(54) NEW PHARMACOLOGICALLY-ACTIVE ESTERS, PROCESSES FOR THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS INCORPORATING THEM (71) We, STERWIN A.G., a Swiss Company, of Zeughausgasse 9, Cm4300 Zug, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention concerns new pharmacologically-active esters. processes for their preparation and pharmaceutical compositions incorporating them.
Analgesics are in widespread use today, and many compounds of different types have been proposed and marketed for use as such. For the relief of chronic conditions such as rheumatism and arthritis it is normally desirable to use an agent which displays an anti-inflammatory effect in addition to its analgesic activity. A number of anti-inflammatory analgesic agents are known and it is normal practice at present to use one of these known agents for alleviation of the symptoms of chronic rheumatism, arthritis and similar conditions.
Some of the best-known, most effective and widely-used of the existing antiinflammatory analgesics are the 4-alkyl-3,5-dioxo-pyrazolidine derivatives of the general formula:
wherein Alk represents an n-propyl or n-butyl group, and either one of W' and W" represents a phenyl group and the other represents a phenyl or a parahydroxyphenyl group or W' and W" together with the intervening nitrogen atoms to which they are respectively attached represent a 3-dimethylamino-7-methyl [1 ,2,4]-benzotriazine ring-system fused with the pyrazolidine ring.
These compounds of general formula I may 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-dioxo-4-n-butylpyrazolidine; 1-phenyl-2-(p-hydroxyphenyl)-3,5-dioxo-4-n-butylpyrazolidine (which may also be named 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, quite widely used at present, are the well-known aromatic carboxylic acids of the general formula:
(wherein A represents a carbon atom or a #C-CH2-, #C-CHCl-, #C-CH(CH3)- or #C-CO-CH2-CH2- group; R represents a hydrogen atom, or a hydroxy, 2,4-dichlorophenoxy or 3-trifluoromethyl-anilino group; B represents a nitrogen atom or a #C-F, #C-Cl or #C-H group; either R4 represents a hydrogen atom or a phenyl, isobutyl, n-prop-2-enyloxy, cyclohexyl, 2methyl-cyclohexyl, 2-fluoro-phenyl, 1-oxo-2-isoindolinyl or 2,5-dihydropyrrol-1-yl group, and R5 represents a hydrogen atom or a benzoyl, 2,4-difluoro-phenyl or phenoxy group; or R4 and R5 together with the intervening carbon atoms to which they are respectively attached form a methoxy-substituted benzene ring, a 6 methyl-benzo[e]-(1,4)-thiazine ring or a methoxy-substituted 6-methyl-benzo[e] (1,4)-thiazine ring, the benzothiazine rings each being fused to the aromatic ring at the [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 werein A is #C-CH(CH3)-, B is #C-H, R and R5 are each hydrogen and R4 is isobutyl); 2-(3-benzoyl-phenyl)-propionic acid (A is #C-CH(CH3)-, B is #C-H, R and R4 are each hydrogen and R5 is benzoyl); 2-(6-methoxy-2-naphthyl)-propionic acid (A is #C-CH(CH3)-, B is #C-H, R is hydrogen and R4 and R5 form a fused methoxy-substituted benzene ring); 2-(4-cyclohexyl-phenyl)-propionic acid (A is > \C-C-CH(CH3)-, B is #C-H, R and R5 are each hydrogen and R4 is cyclohexyl); 2-(4-[2-methyl-cyclohexyl]-phenyl)-propionic acid (A is #C-CH(CH3)-, B is #C-H, R and R5 are each hydrogen and R4 is 2-methyl-cyclohexyl); 2-(2'-fluoro-4-biphenyl)-propionic acid (A is #C-CH(CH3)- B is #C-H, R and R5 are each hydrogen and R4 is 2-fluorophenyl); 2-(4-[1-oxo-2-isoindolyl]-phenyl)-propionic acid (A is #C-CH(CH3)-, B is #C-H, R and R5 are each hydrogen and R4 is 1-oxo-2-isoindolinyl); 2-(6-chloro-2-carbazolyl)-propionic acid (A is #C-CH(CH3)- B is #C-H, R is hydrogen and R4 and R5 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 R4 and R5 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 R5 is phenoxy); 2-(3-fluoro-4-biphenyl)-propionic acid (A is > C-CH(CH3)-, B is > \C-F, R2 and R5 are each hydrogen and R4 is phenyl); 2-(3-chloro-4-[2,5-dihydropyrrol-1-yl]-phenyl)-propionic acid (A is #C-CH(CH3)-, B is #C-Cl, R and R5 are each hydrogen and R4 is 2,5 dihydropyrrol-1-yl); 3-(4-biphenylcarbonyl)-propionic acid (A is #C-CO-CH2-CH2- B is #C-H, R and R5 are each hydrogen and R4 is phenyl); 2-(3-trifluoromethyl-anilino)-nicotinic acid (A is carbon, B is nitrogen, R4 and R5 are each hydrogen and R2 is 3-trifluoromethyl-anilino); 2',4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid (A is carbon, B is > C-H, R4 is hydrogen, R2 is hydroxy and R5 is 2,4-difluorophenyl); chloro-(3-chloro-4-cyclohexyl-phenyl)-acetic acid (A is > C-CHCl-, B is #C-Cl, R and R5 are each hydrogen and R4 is cyclohexyl); (2-[2,4-dichlorophenoxy]-phenyl)-acetic acid (A is #C-CH2-, B is #C-H, R4 and R5 are each hydrogen and R2 is 2,4-dichlorophenoxy) ; (3-chloro-4-n-prop-2'-enyloxy-phenyl)-acetic acid (A is > C-CH2-, B is > C-Cl, R2 and R5 are each hydrogen and R4 is n-prop-2-enyloxy); (4-isobutyl-phenyl)-acetic acid (A is > C-CH2, B is > 'C-H, R2 and R5 are each hydrogen and R4 is isobutyl); 3-pyridineacetic acid (A is > 'C-CH2, B is nitrogen and R2, R4 and R5 are hydrogen); and (10-methyl-2-phenothiazinyl)-acetic acid (A is > C-CH2-, B is > C-H, R2 is hydrogen and R4 and R5 form a [b] fused 6-methyl-benzo[e]-(l ,4)-thiazine ring).
Unfortunately, however, the desirable anti-inflammatory and analgesic properties both of these compounds of general formula I and of the compounds of general formula II, are offset by their tendency to give rise to disturbances of the gastric tract. In the case of the aromatic carboxylic acids of general formula II it has been suggested that this may be attributable to the acidic nature of their carboxyl functions; but that explanation is not altogether reliable, since 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 acidic carboxyl functions in the 4-alkyl-3,5-dioxo-pyrazolidine derivatives of general formula I.
It is therefore particularly surprising that we have found not only that it is possible to form an ester linkage 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-dioxo-pyrazolidine derivatives shown in general formulae Ia and Ib, but also that the resultant esters, although formed between gastrically-disturbing moieties, are nevertheless largely or substantially wholly free from unwanted side-effects upon the gut, while being effective and indeed outstanding anti-inflammatory analgesics.
According to one aspect of this invention, there are therefore provided, as new compounds having anti-inflamatory and analgesic activity, the 4-alkyl-3,5-dioxopyrazolidinyl aromatic-carboxylate esters formed between a 4-alkyl-3,5-dioxopyrazolidine derivative of general formula I (as defined hereinbefore) on the one hand and an aromatic carboxylic acid of general formula II (as defined hereinabove) on the other hand, and where feasible the acid addition salts of the esters, provided that W' and W" are not both phenyl when R4 is isobutyl or cyclohexyl and A is #C-CH(CH3)- or #C-CH2-.
Esters may be formed with either of the 3-oxo and 5-oxo groups of the compounds of general formula I, since as indicated hereinbefore these compounds may exist in tautomeric forms in which either one of the 3- and 5-positions bears a hydroxy group. Furthermore, when W' or W" in the compounds of general formula I represents a para-hydroxyphenyl group esters may be formed with the phenolic hydroxy group, either in addition to or instead of esters being formed at the 3- or 5position of the pyrazolidine nucleus.
Thus, the compounds of the invention are the compounds of the general formula:
(wherein Alk is as defined above; either one of B' and B" represents a phenyl group and the other represents a phenyl group or a phenyl group substituted by a group --OZ', or B' and B" together with the intervening nitrogen atoms to which they are respectively attached represent a 3-dimethylamino-7-methyl-[l ,2,4]-benzotriazine ring system fused with the pyrazolidine ring; and at least one of Z and Z' represents an aromatic-carbonyl group:
(wherein A, R2, B, R4 and R5 are as defined hereinbefore and when only one of Z and Z' represents an aromatic-carbonyl group the other represents a hydrogen atom) and where feasible the acid addition salts thereof, provided that B' and B" are not both phenyl when R4 is isobutyl or cyclohexyl and A is C--CH(CH,))- or C-CH2-.
It is to be noted that it is feasible to form acid addition salts with only those 4alkyl-3,5-dioxo-pyrazolidinyl aromatic-carboxylates of general formula III which contain a salifiable moiety - for example, those compounds wherein B is nitrogen and/or B' and B" make up a benzotriazine ring-system.
While any of the acid addition salts which may be formed are useful for preparative purposes, it is naturally only those formed with pharmacologicallyacceptable acids which may be used in human or animal therapy.
A preferred group of compounds falling within general formula III are 4-alkyl3,5-dioxo-pyrazolidinyl acetates of the general formula:
wherein Alk is as defined hereinbefore; either one of B' A and B" A represents a phenyl group and the other represents a phenyl group or a phenyl group substituted by a group OZ'A, or B'A and B"A together with the intervening nitrogen atoms to which they are respectively attached represent a 3-dimethyl-amino-7-methyl [1,2,4]-benzotriazine ring-system fused with the pyrazolidine ring; and at least one of ZA and Z'A represents a substituted 2-phenyl-propionyl group:
in which R4 and R5 are as defined hereinbefore, and when only one of ZA and Z'A represents a substituted 2-phenyl-propionyl group the other represents a hydrogen atom, and where feasible their acid addition salts, again provided that BA' and BA" are not both phenyl when R4 is isobutyl or cyclohexyl.
Specific preferred esters conforming to the general formula III above are, for example: the 1 - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butylpyrazolidine esters of 2 - (4 - isobutyl - phenyl) - propionic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo - [1,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of 2 - (4 - isobutyl - phenyl) - propionic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (3 - benzoylphenyl) - propionate; the I - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butyl - pyrazolidine esters of 2 - (3 - benzoyl - phenyl) - propionic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo - [1,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of 2 - (3 - benzoyl - phenyl) - propionic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (6 - methoxy 2 - naphthyl) - propionate; the 1 - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butyl - pyrazolidine esters of 2 - (6 - methoxy - 2 - naphthyl) - propionic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo[l,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of 2 - (6 - methoxy - 2 - naphthyl)propionic acid; the 1 - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butyl - pyrazolidine esters of 2 - (4 - cyclohexyl - phenyl) - propionic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo - [1,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of 2 - (4 - cyclohexyl - phenyl) - proprionic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2 - (4 - [2 - methylcyclohexyl] - phenyl) - propionate; the 1 - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butyl - pyrazolidine 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) - dione esters of 2 - (4 - [2 - methyl - cyclohexyl]phenyl) - propionic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - [2' - fluoro - 4biphenyl]propionate; the 1 - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butyl - pyrazolidine esters of 2 - [2' - fluoro - 4 - biphenyl] - propionic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo [1,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of 2 - [2' - fluoro - 4 - biphenyl] - propionic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - [4 - (1 - oxo - 2isoindolinyl) - biphenyl] - propionate; the 1 - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butylpyrazolidine esters of 2 - [4 - (1 - oxo - 2 - isoindolinyl) - phenyl] - propionic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo [1,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of 2 - [4 - (1 - oxo - 2 - isoindolinyl)phenyl] - propionic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (6 - chloro - 2carbazolyl) - propionate; the 1 - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butylpyrazolidine esters of 2 - (6 - chloro - 2 - carbazolyl) - propionic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo [1,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters 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; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo [1,2-a][1,2,4]benzotriazine - 1,3(2H) - dione esters 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 6f2 - (7 - methoxy - 10 - methyl - 2 - phenothiazinyl) - propionic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo [1,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of 2 - (7 - methoxy - 10 - methyl - 2phenothiazinyl) - propionic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (3 - phenoxyphenyl) - propionate; the 1 - phenyl - 2 - p - hydroxphenyl - 3,5 - dioxo - 4 - 71 - butylpyrazolidine esters of 2 - (3 - phenoxyphenyl) - propionic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo [1,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of 2 - (3 - phenoxyphenyl) - propionic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (3 - fluoro - 4biphenyl) - propionate; the 1 - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butylpyrazolidine esters of 2 - (3 - fluoro - 4 biphenyl) - propionic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo [1,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of 2 - (3 - fluoro - 4 - biphenyl) - propionic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (3 - chloro - 4 (2,5 - dihydropyrrol - 1 yl) - phenyl - propionate; the 1 - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butyl - pyrazolidine esters of 2 - (3 - chloro - 4 - (2,5 - dihydropyrrol - 1 - yl) - phenyl) - propionic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo [1,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of 2 - (3 - chloro - 4 - (2,5 - dihydropyrrol - 1 - yl) - phenyl) - propionic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (3 - trifluoromethyl - anilino) - nicotinate; the 1 - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butyl - pyrazolidine esters of 2 - (3 - trifluoromethyl - anilino) - nicotinic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo [1,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of 2 - (3 - trifluoromethyl - anilino) - nice tinic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butyl - pyrazolid - 4 - en - 5 - yl 2",4" - di- fluoro - 4' - hydroxy - 3' - biphenylcarboxylate; the 1 - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butylpyrazolidine esters of 2',4' - difluoro - 4 - hydroxy - 3 - biphenylcarboxylic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo[l,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of 2',4' - difluoro - 4 - hydroxy - 3 - biphenylcarboxylic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl chloro - (3 - chloro4 - cyclohexyl - phenyl) - acetate; the 1 - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butyl - pyrazolidine esters of chloro - (3 - chloro - 4 - cyclohexyl - phenyl) - acetic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo [1,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of chloro - (3 - chloro - 4 - cyclohexylphenyl) - acetic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 3' - (4 - biphenylcarbonyl) - propionate; the 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 - pyrazolo [1,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of 3 - (4 - biphenylcarbonyl) - propionic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl [2 - (2A - dichlorophenoxy) - phenyl]acetate; the 1 - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butylpyrazolidine esters of [2 - (2,4 - dichlorophenoxy) - phenyl]acetic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo [1,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of [2](2,4 - dichlorophenoxy)phenyl] - acetic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl (3 - chloro - 4 - nprop - 2' - enyloxy - phenyl) - acetate; the 1 - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butyl - pyrazolidine esters of (3 - chloro - 4 - n - prop - 2' - enyloxy phenyl) - acetic acid; the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo [1,2-a] [1,2,4]benzotriazine - 1,3(2H) - dione esters of (3 - chloro - 4 - n - prop - 2' - enyloxy - phenyl) - acetic acid; 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 3' - pyridineacetate; the 1 - phenyl - 2 - p - hydroxyphenyl - 3,5 - dioxo - 4 - n - butyl - pyrazolidine 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) - dione esters of 3 - pyridineacetic acid.
1 - phenyl - 2 - (p - hydroxyphenyl) - 3,5 - dioxo - 4 - n - butyl - pyrazolidine may form esters with the substituted a-(2-methyl-ind[ene/ol]-3-yl)-acetic acids by means of an ester link formed with the oxygen in the 3-position, with the oxygen in the 5position or with the hydroxy group on the 2-(para-hydroxy-phenyl group. It is also possible to form two ester links, one with the 2-(para-hydroxyphenyl) hydroxy group and one with either the 3- or 5-position oxygen. Thus, there are five 1phenyl-2-(p-hydroxyphenyl)-3,5-dioxo-4-n-butylpyrazolidine esters which may be formed with an acid.
For example the possible 1-phenyl-2-p-hydroxyphenyl)-3,5-dioxo-4-nbutylpyrazolidine esters of 2-(4-isobutyl-phenyl)-propionic acid are the following compounds: a) I - phenyl - 2 - (p - hydroxyphenyl) - 3 - oxo - 4 - n - butylpyrazolid - 4 - en5 - yl 2' - (4 - isobutyl - phenyl) - propionate, of the structural formula:
CIH3 0 9 aOH I ii II isobutyl -C-Oyhlo n-biltyl butyl b) the 5 - oxo - pyrazolid - 3 - en - 3 - yl isomer of a) namely:
OH O)NN~ ~ II I -butyt C-CH- Lsobutyt c) 1 - phenyl - 2 - p - [2' - (4 - isobutyl - phenyl) - propionyl] - phenyl - 3 - oxo4 - n - butylpyrazolid - 4 - en - 5 - yl 2" - (4 - isobutyl - phenyl) - propionate, of the structural formula:
o CH3 CH3 O 0 I II J I but II - -i:H -Q-isobutyl isobutyloCH -C-O n-butyl 0 d) the 5 - oxo - pyrazolid - 3 - en - 3 - yl isomer of c), namely:
o CH3 III 9 yo ll -n- isobutyl 0 Cfl3 n-butfl 0sC-cHt3isobutyl e) 1 - phenyl - 2 - p - [2' - (4 - isobutyl - phenyl) - propionyl] - phenyl - 3 - oxo - 4n - butylpirazolidine of the structural formula:
9 011 I' Cuit3 0 -but:"0-" C-CH7=r ~-butyl 10 The 5-(dimethylamino)-9-methyl-2-n-propyl-l H-pyrazolo-[1,2-a][1 ,2,4]benzotriazine-1,3(2H)-dione esters may be also formed with an ester linkage incorporating the oxygen atom of the 1-oxo group oor the 3-oxo group, and these positions are not equivalent due to the assymmetry of the fused benzotriazine system.
Thus, for example. the possible 5-(dimethylamino)-9-methyl-2-n-propyl-1Hpyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione esters of 2-(4-isobutyl-phenyl) propionic acid are: a) 5 - (dimethylamino) - 9 - methyl - 1 - oxo - 2 - n - propyl - pyrazolid - 2 - eno [1 ,2-a][l,2,4]benzotriazine - 3 - yl 2' - (4 - isobutyl - phenyl) - propionate, of the structural formula:
CH3 fH3 Cit3 011 N ,\ isobutyl CIN CHC-O CH n-butyl O and b) the 3 - oxo - pyrazolid - 1 - eno[l,2-a][l ,2,4]benzotriazine - 1 - yl isomer of a), of the structural formula:
CH39 Cit3 11N isobutyl4CHC2 CH3 CH3 Cit3 It should be pointed out that at present, of the specifically preferred compounds set out hereinbefore, the 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl esters are currently of greatest interest and therefore it is these compounds that are presently highly preferred.
We have moreover found that the 4-alkyl-3,5-dioxo-pyrazolidinyl aromaticcarboxylate esters of general formula III may be prepared conveniently and in good yield by reacting the 4-alkyl-3,5-dioxo-pyrazolidines of general formula I with the appropriate aromatic-carboxylic acid chlorides.
According to another aspect of this invention there is therefore provided a process for the preparation of the 4-alkyl-3,5-dioxo-pyrazolidinyl aromaticcarboxylate esters of general formula III, in which a 4-alkyl-3,5-dioxo-pyrazolidine derivative of general formula I (but effectively in one of its tautomeric forms of general formula Ia or Ib) is reacted with an aromatic-carboxylic acid chloride of the general formula:
(wherein A B, R2, R4 and R5 are as defined hereinbefore) or an acid addition salt thereof to yield the desired corresponding 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic carboxylate ester of general formula III or acid addition salt thereof.
The reaction between the 4-alkyl-3,5-dioxo-pyrazolidine derivative of general formula I and the acid chloride of general formula IV is desirably effected in an anhydrous inert solvent. The inert solvent will normally be an organic solvent, and is advantageously a 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 preferred solvent is dichloromethane.
Being fairly vigorous, the reaction may be carried out at ambient temperature without heating or possjbly, when the reaction is very vigorous as sometimes it is, even with cooling.
The reaction is preferably effected in the presence of a base, which is most conveniently a tertiary amine. The base currently preferred above all others is pyridine.
The process of the invention may also advantageously include the preliminary step of preparing the acid chloride starting materials of general formula IV by reacting a solution or suspension in an anhydrous inert solvent of an aromaticcarboxylic acid of general formula II (as defined hereinbefore) or a salt thereof with thionyl chloride.
The salt of the acid of general formula II preferably employed in this preliminary step is the pyridine salt.
The reaction with thionyl chloride may be conducted at any convenient temperature between ambient and the reflux temperature of the solvent, and usually will be carried out at a temperature within the range of from about 40"C up to about 65"C.
The solvent used may be the same as that used in the above-described subsequent stage of 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 employed is preferably anhydrous dichloromethane, and then the reaction can most conveniently be effected under reflux at a temperature of about 40" AI"C.
The proportions of the reactants will preferably be about 1 mole of thionyl chloride per mole of the acid of general formula II and, w or (b) a sterically-encumbered alkyl, aralkyl, aryl or alkaryl acid chloride of the general formula:
such as pivaloyl chloride or isovaleryl chloride or (c) an alkyl, aralkyl, aryl or alkaryl sulphonyl chloride:
such as methyl sulfonyl chloride, phenyl sulphonyl chloride, benzyl sulphonyl chloride or toluyl sulphonyl chloride in which Ayl represents an alkyl, aralkyl, aryl or alkaryl group having up to 20 carbon atoms therein, as defined hereinbefore.
The reaction between the acid of general formula II and the reactive chloride of general formula VI (VIa, VIb or VIc) is most conveniently carried out in an anhydrous inert solvent, which is preferably an organic solvent such as is employed in the subsequent stage in the process.
This reaction must be performed in the presence of a base, which is advantageously a tertiary amine, and most preferably either triethylamine or pyridine.
There is no need 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 secondstage reaction in the same reaction mixture without elimination of the base therefrom, and in the same reaction vessel.
According to a still further aspect of this invention there is also provided a third process for the preparation of the 4-alkyl-3,5-dioxo-pyrazolidinyl aromaticcarboxylate esters of general formula III, in which a 4-alkyl-3,5-dioxo-pyrazolidine derivative of general formula I above (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:
(wherein A, B, R2, R4 and R5 are as defined hereinbefore) in the presence of a strong aqueous base, so that the reaction mixture forms a two-phase system, which is agitated to yield the desired 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic-carboxylate ester.
The reaction between the 4-alkyl-3,5-dioxo-pyrazolidine derivative of general formula I and the acid anhydride of general formula VII produces the corresponding aromatic-carboxylic acid of general formula II as a side-product, and must therefore be effected in the presence of a strong base, which can be an organic base such as triethylamine but preferably will be aqueous sodium hydroxide. The anhydride is somewhat unstable in the presence of water, and is therefore brought to reaction in solution in a water-immiscible solvent and preferably an anhydrous inert organic solvent, conveniently for instance benzene, toluene, chloroform, dichloromethane or ethers such as diethyl ether. The reaction is conducted with agitation in a two-phase reaction system, and thus any breakdown of the anhydride before it has participated in the intended reaction is minimized. This reaction can conveniently be carried out at ambient or nearambient temperatures not exceeding 300 C.
This third process can moreover advantageously include the further preliminary step of preparing the acid anhydride of general formula VII by reacting an aromatic-carboxylic acid of general formula II with a carbodiimide in solution with an anhydrous, non-hydroxylic and otherwise inert organic solvent at ambient or near-ambient temperatures, usually not exceeding 30"C.
In principle any carbodiimide can be employed, but in practice the carbodiimide used must of course be stable, and accordingly we envisage that the carbodiimide used would best be an N,N'-di[alk/ar]yl-carbodiimide of general formula:
wherein Z' and Z" each represent an alkyl, cycloalkyl, alkaryl, aryl or aralkyl group containing from 6 to 20 carbon atoms. Moreover it must be added that at present the only carbodiimide commercially available (at least in Britain) at an economic price is N,N'-dicyclohexyl-carbodiimide, which therefore is preferred for use in this invention.
The 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic-carboxylate esters of general formula III appear to display excellent anti-inflammatory and analgesic activities when tested by generally-accepted tests for anti-inflammatory drugs; and preliminary studies suggest that, when administered orally, these compounds will be substantially free from gastric side-effects.
Naturally, however, for employment in human and veterinary medicine as anti-inflammatory analgesics the 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic carboxylate esters of general formula III should first be properly formulated into appropriate pharmaceutical compositions, by association with suitable pharmaceutical vehicles.
The term "pharmaceutical" is used herein to exclude any possibility that the nature of the vehicle (considered of course in relation to the route by which the composition is intended to be administered) could be harmful. The choice of a suitable vehicle for a chosen route and mode of presentation is believed to be within the competence of those accustomed to the preparation of pharmaceutical compositions.
Accordingly, in yet another aspect of this invention, there are provided pharmaceutical compositions comprising as active ingredient, one or more of the 4alkyl-3,5-dioxo-pyrazolidinyl aromatic-carboxylate esters of general formula III in association with a suitable pharmaceutical vehicle.
Although the compositions of this invention are primarily designed for administration via the digestive tract, including rectally, they can also be administered parenterally. In respect of these various modes of presentation the "pharmaceutical vehicle" is desirably: (a) the ingestible excipient of a tablet, coated tablet, sublingual tablet or pill; the ingestible container of a capsule or cachet; the ingestible pulverulent solid carrier of a powder, or the ingestible liquid medium of a syrup, solution, suspension or elixir; (b) the solid or liquid medium of a paste, lotion, salve, ointment or unguent, or the propellant medium of an aerosol; (c) a sterile injectable liquid solution or suspension medium; or (d) a base material of a suppository.
Whilst the modes of presentation just listed represent those most likely to be employed, they do not necessarily exhaust the possibilities.
The preferred route for administration of the anti-inflammatory analgesics of general formula III, is orally, including perlingually, so that the compositions will most frequently be administered in the form of tablets, capsules and other solid dose forms.
Bearing in mind the presently-contemplated dosage rates, which are indicated below, the compositions will normally be presented in the form of unit doses containing usually from 30 mg to 2.7 g.
Whilst the dosage of these anti-inflammatory analgesics of general formula III will to some degree depend upon the route by which the compositions are to be administered, and of course also upon the condition to be treated and the patient under treatment, as a general indication it may be said that the useful dose ranges from 0.1 g to 5 g (in divided doses) of the active analgesic per day for an adult, a unit dose containing from 30 mg to 2.7 g, preferably 200 mg for the compounds of general formula III in which B' and B" each represent a phenyl or parahydroxyphenyl group and 550 mg for the compounds of general formula III in which B' and B" together with the intervening nitrogen atoms form a 3 dimethylamino-7-methyl-[ ,2,4]-benzotriazine ring system.
In order that the invention may be well understood, the preparation of certain preferred compounds will now be described in more detail, though by way of illustration only, with reference to the following Examples.
Preparation of the compounds of general formula III from the acid chloride, including the preliminary step of preparing the acid chloride (Examples I to 6): Example 1.
Preparation of the 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - IH - pyrazolo[1 2-91- [I,2,4]henzotriazine - 1,3(2H) - dione ester of2 - (4 - isobutyl - phenyl) - propionic acid.
Stage A: Preparation of 2-(4-isobutyl-phenyl)-propionic chloride 6.2 grams of 2-(4-isobutyl-phenyl)-propionic acid were dissolved in 40 ml of dichloromethane. 3.8 grams of thionyl chloride and 0.5 ml of dimethylformamide were added and the mixture was stirred and refluxed until the evolution of gases ceased.
The product thus formed, namely 2-(4-isobutyl-phenyl)-propionyl chloride, was not isolated, but was used directly for preparing the ester as described below.
Stage B: Preparation of the 5-(dimethylamino)-9-methyl-2-n-propyl-lH-pyrazolo- [1,2-a][1,2,4]benzotriazine-1,3(2H)-dione ester of 2-(4-isobutyl-phenyl)-pro- pionic acid.
A mixture of 9.0 grams of 5 -(dimethylamino)-9.methyl-2-n-propyl- 111- pyrazolo-[1,2-a][l ,2,4]benzotriazine-l ,3(2H)-dione and 3.0 grams of pyridine in dichloromethane was added to the product obtained from Stage A above, and the mixture was refluxed for 5 minutes. The dichloromethane solution thus obtained 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 etheral solution was washed twice with 2M aqueous sodium hydroxide solution, once with water, and then dried over MgSO4.
Concentration of the ethereal solution under reduced pressure gave a yellow oil that crystallized from ether-petroleum ether (60--80"C) as 4.5 grams of cream coloured needles of the desired ester which is believed to be 5(dimethylamino)-9 methyl- I-oxo-2-n-propyl- IH-pyrazolid-2-eno-[1 ,2-a] [1 ,2,4]benzotriazine-3-yl 2'-(4 isobutyl-phenyl)-propionate, the melting point of which was 110-112 C.
Example 2.
Preparation of 1.2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid 4 - en - 5 -y12' - (3 - ben zoyl -phenyl) -propionate.
Stage A: Preparation of 2-(3-benzoyl-phenyl)-propionyl chloride.
10.0 grams of 2-(3-benzoyl-phenyl)-propionic acid were dissolved in 100 ml of dichloromethane containing 1 ml of N,N-dimethyl formamide. 7 grams (or 4.6 ml) of thionyl chloride were added and the mixture was refluxed for 2 hours. The lightyellow solution thus obtained was concentrated under reduced pressure to yield the desired product, 2-(3-benzoylphenyl)-propionyl chloride, as an oil.
Stage B: Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3 benzoyl-phenyl)-propionate.
The 2-(3-benzoyl-phenyl)-propionyl chloride prepared in Stage A above was dissolved, together with 12.0 grams of 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine in 100 ml of dichloromethane and 9 ml of pyridine were added to the solution. The orange-coloured solution thus prepared 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 2.5M sodium hydroxide solution and, finally, once more with 100 ml of water. After washing, the solution was dried over MgSO;.
Evaporation of the dichloromethane under reduced pressure gave a yield of 12 grams of the desired 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-benzoylphenyl)-propionate, as a yellow oil.
Example 3.
Preparation of 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (6 methoxy - 2 - naphthy!) -propionate Stage A: Preparation of 2-(6-methoxy-2-naphthyl)-propionyl chloride.
23 grams of 2-(6-methoxy-2-naphthyl)-propionic acid were suspended in 50 ml of chloroform and 1 ml of N,N-dimethylformamide was added thereto. Then 12 grams (or 8 ml) of thionyl chloride were added to the suspension, which was heated and stirred at 40"C for 3 hours.
The product thus obtained, namely 2-(6-methoxy-2-naphtyl)-propionyl chloride, was not isolated but was used directly in the preparation described below.
Stage B B: Preparation of l,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6- methoxy-2-naphthyl)-propionate.
To the solution of 2-(6-methoxy-2-naphthyl)-propionyl chloride obtained in Stage A above, there were added 30 grams of l,2-diphenyl-3,5-dioxo-4-n-butyl- pyrazolidine and 15 grams of pyridine dissolved in 50 ml of chloroform. This reaction mixture was then refluxed for 30 minutes. The resultant chloroform solution was washed first with 100 ml of dilute HCI and then 100 ml of 10% sodium carbonate solution. After washing the solution was dried and the chloroform was removed from it by evaporation.
The product was taken up and recrystallised from methanol/water and acetone/petrol. The melting point of the desired 1,2-diphenyl-3-oxo-4-nbutylpyrazolid-4-en-5-yl 2'-(6-metnoxy-2-naphthyl)-propionate thus obtained in this state of purity was 127"--1280C.
Example 4.
Preparation of 1,2 - dtphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (3 phenoxy - phenyl) - propionate.
Stage A: Preparation of 2-(3-phenoxy-phenyl)-propionyl chloride.
41 grams of 2-(3-phenoxy-phenyl)-propionic acid were dissolved in 200 ml of dichloromethane. 20 grams of thionyl chloride and 1 ml of N,N-dimethylformamide were added to the solution thus obtained, and the mixture was warmed to initiate the reaction. The mixture was stirred at room temperature for 20 minutes, and then refluxed for 2 hours, after which the evolution of hydrogen chloride had ceased.
The product thus formed, namely 2-(3-phenoxy-phenyl)-propionyl chloride, was not isolated, but was used directly for preparing the ester as described below.
Stage B: Preparation of 1,2-diphenyl 3 oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3phenoxy-phenyl)-propionate.
A mixture of 56 grams of l,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 Stage A. After the addition, the mixture was refluxed for 20 minutes and then allowed to cool to room temperature. The dichloromethane solution was washed twice with 100 ml portions of 2M hydrochloric acid and twice with 100 ml portions of 2M sodium hydroxide. After washing, the solution was dried over MgSO4, and the solvent was removed to give 81 grams of a viscous oil of 1 ,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-phenoxy-phenyl)-propionate.
Example 5.
Preparation of 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl [2 - (2,4 dichlorophenoxy)phenyll - acetate Stage A: Preparation of [2-(2,4-dichlorophenoxy)phenyl]-acetyl chloride 9.9 grams of [2-(2,4-dichlorophenoxy)phenyl]acetic acid were dissolved in 100 ml of dichloromethane. 4 grams of thionyl chloride and 0.5 ml of dimethylformamide were added to the solution obtained, and the mixture was refluxed for 30 minutes.
The product thus obtained, namely [2-(2,4-dichlorophenoxy)phenyl]-acetyl chloride, was not isolated, but was used directly in the preparation of the ester, as described below.
Stage 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 grams of l,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine and 3 ml of pyridine in 25 ml of dichloromethane was added to the product obtained from Stage A, and the mixture was refluxed for 30 minutes. The dichloromethane solution was washed twice with 100 ml portions of 2M hydrochloric acid and twice with 100 ml portions of a 2M sodium hydroxide solution, After washingf, the solution was dried over MgSO4 and evaporated to dryness to give 14.7 grams of 1,2diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl [2-(2,4-dichlorophenoxy)phenyl] -acet- ate, as a viscous oil.
Example 6.
Preparation of 1,2 - diphenyl -3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl (3 - chloro 4 - prop -2' - enyloxy - phenyl) - acetate Stage A: Preparation of (3-chloro-4-prop-2'-enyloxy-phenyl) acetyl chloride 22.6 grams of (3-chloro-4-prop-2'-enyloxy-phenyl)-acetic acid were dissolved in 150 ml of dichloromethane. 12 grams of thionyl chloride and I ml of N,Ndimethylformamide were added to the solution formed and the mixture was stirred at room temperature for 40 minutes before being refluxed for 30 minutes. The mixture was then allowed to cool.
The product thus formed, namely (3-chloro-4-prop-2'-enyloxy-phenyl)-acetyl chloride, was not isolated, but was used directly for preparing the ester, as described below.
Stage B: Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl (3-chloro 4-prop-2'-enyloxy-phenyl)-acetate A solution of 30.8 grams of 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine and 9.0 grams of pyridine in 100 ml of dichloromethane was added to the product obtained from Stage A and the mixture was refluxed for 20 minutes. The solution was washed with 200 ml 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 MgSO4 and then evaporated to dryness to give 30 grams of l,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl (3-chloro-4-prop-2'-enyloxyphenyl)-acetate as a pale yellow viscous oil.
Preparation of compounds of general formula III by the symmetrical anhydride route (Example 7).
Example 7.
Preparation of 1,2 - diphenyt - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (6 methoxy - 2- naphthyl) -propionate Stage A: Preparation of 2-(6-methoxy-2-naphthyl)-propionic acid 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'-dicyclohexyl-carbodiimide was added and the formed mixture was left at room temperature overnight. After filtration, the filtrate was evaporated to dryness and the residue recrystallised from ethanol to give 2-(6methoxy-2-naphthyl)-propionic acid anhydride.
Stage B: Preparation of the desired ester 3.08 g of l,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine was dissolved in 20 ml of 1 M sodium hydroxide and a solution of 4.42 g of 2-(6-methoxy-2-naphthyl)propionic acid anhydride in 20 ml of benzene was added. The mixture was shaken vigorously for 30 minutes and then filtered to yield 1,2-diphenyl-3-oxo-4-nbutylpyrazolid-4-en-5-yl 2'-(6-methoxy-2-naphthyl)-propionate, which was indistinguishable from the product of Example 4.
Further Examples of preparations using the acid chloride route (Examples 8-13).
Example 8.
Preparation of 1,2 - diphenvl -3 - oxo -4 - n - butylpyrazolid -4 - en -5 -y12' -(4 -1- oxo - 2 - isoindolinyll -phenyl) -propionate Stage A: Preparation of 2-(4-[1 -oxo-2isoindolinyl] -phenyl)-propionyl chloride 28.1 g of 2-(4-[l-oxo-2-isoindolinyl]-phenyl)-propionic acid were dissolved in 150 ml of chloroform containing 1 ml of N,N-dimethylformamide. 12 g (or 8 ml) of thionyl chloride were added and the mixture was stirred at 400C for three hours.
The product obtained, namely 2-(4-[ 1 -oxo-2-isoindolinyl]-phenyl)-propionyl chloride was not isolated, but was used directly for preparing the ester as described below.
Stage B: Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(4-[1oxo-2-isoindolinyl]-phenyl)-propionate.
To the solution of 2-(4-[l-oxo-2-isoindolinyflphenyl)-propionyl chloride obtained from Stage A above there was added a mixture of 30.8 g of 1,2-diphenyl3,5-dioxo-4-n-butyl-pyrazolidine and 15 g of pyridine in 200 ml of chloroform. The mixture became warm and was refluxed for 30 minutes. The resultant 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 sulphate and the solvent 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 ethereal layer was separated, washed with 100 ml of water and dried.
On evaporation of the ether, the desired 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4en-5-yl 2'-(4-[l-oxo-2-isoindolinyl]-phenyl)-propionate was obtained. This was crystallised from ether-petroleum ether.
Example 9.
Preparation of 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid4 - en - 5 -y12' - (6 - chloro 2 - carbazolyl) - propionate Stage A: Preparation of 2-(6-chloro-2-carbazolyl)-propionyl chloride 22.4 g of 2-(6-chloro-2-carbazolyl)-propionic acid were dissolved in 150 ml of chloroform containing 1 ml of N,N-dimethylformamide. 12 g (or 8 ml) of thionyl chloride were added and the mixture was stirred at 400C for three hours.
The product obtained, namely 2-(6-chloro-2-carbozolyl)-propionyl chloride, was not isolated, but was used directly for preparing the ester as described below.
Stage B: Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6chloro-2-carbazolyl)-propionate To the solution of 2-(6-chloro-2-carbazolyl)-propionyl chloride obtained from Stage A above there was added a mixture of 30.8 g of 1,2-diphenyl-3,5-dioxo-4-nbutylpyrazolidine and 15 g of pyridine in 200 ml of chloroform. The mixture became warm and was refluxed for 30 minutes.
The resultant chloroform solution was washed with 100 ml of dilute hydrochloric acid, then with 10% sodium carbonate solution. The chloroform layer was dried over MgSO4 and solvent 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 ethereal layer was separated, washed with 100 ml of water and dried. On evaporation of the ether, the desired 1 ,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5- yl 2'-(6-chloro-2-carbazolyl)-propionate was obtained. This was crystallised from ether-petroleum ether, Example 10.
Preparation of 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (3 chloro - 4 - (2,5 - dihydropyrrol - 1 -yl) -phenyl) -propionate Stage 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 were dissolved in 150 ml of chloroform containing 1 ml of N,N-dimethylformamide. 12 g (or 8 ml) of thionyl chloride were added and the mixture was stirred at 40 C for three hours.
The product obtained, namely 2-(3-chloro-4-[2,5-dihydro-pyrrol- 1 -yl]-phenyl)- propionyl chloride was not isolated, but was used directly for preparing the ester as described below.
Stage B: Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3chloro-4-(2,5-dihydropyrrol-1-yl)-phenyl)-propionate To the solution of 2-(3-chloro-4-[2,5-dihydropyrrol-1-yl]-phenyl propionyl chloride obtained from Stage A above there was added a mixture of 30.8 g of 1,2diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine and 15 g of pyridine in 175 ml of chloroform. The mixture became warm and was refluxed for 30 minutes.
The resultant chloroform solution was washed with 100 ml of dilute hydrochloric acid, then with 10% sodium carbonate solution. The chloroform layer was dried over MgSO4 and solvent 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 ethereal layer was separated, washed with 100 ml of water and dried. On evaporation of the ether, the desired 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5yl 2'-(3-chloro-4-(2,5-dihydropyrrol- 1 -yl)-phenyl)-propionate was obtained. This was crystallised from ether-petroleum ether.
Example 11.
Preparation of 1,2 - diphenyl - 3 - oxo - 4 - n - butyl -pyrazolid - 4 - en - 5 -y12' - (3 trifluoromethyl - anilino) - nicotinate.
Stage A: Preparation of 2-(3-trifluoromethyl-anilino)-nicotinoyl chloride 28.2 g of 2-(3-trifluoromethyl-anilino)-nicotinic acid were dissolved in 150 ml of chloroform containing 1 ml of N,N-dimethylformamide. 12 g (or 8 ml) of thionyl chloride were added and the mixture was stirred at 400C for three hours.
The product obtained, namely 2-(3-trifluoromethylanilino)-nicotinoyl chloride, was not isolated, but was used directly for preparing the ester as described below.
Stage B: Preparation of 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-tri fluoromethyl-anilino)-nicotinate To the solution of 2-(3-trifluoromethyl-anilino)-nicotinoyl chloride obtained from Stage A above there was added a mixture of 30.8 g of 1 ,2-diphenyl-3,5-dioxo4-n-butylpyrazolidine and 15 g of pyridine in 200 ml of chloroform. The mixture became warm and was refluxed for 30 minutes.
The resultant chloroform solution was washed with 100 ml of dilute hydrochloric acid, then with 10% sodium carbonate solution. The chloroform layer was dried over MgSO4 and solvent 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 ethereal layer was separated, washed with 100 ml of water and dried. On evaporation of the ether, the desired 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5- yl 2'-(3-trifluoromethyl-anilino)-nicotinate was obtained. This was crystallised from ether-petroleum ether.
Example 12.
Preparation of 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (3 fluoro -4- biphenylyl)propionate Stage A: Preparation of 2-(3-fluoro-4-biphenylyl-propionic acid chloride 24.4 g of 2(3-fluoro-4-biphenylyl)propionic acid were dissolved in 150 ml of chloroform containing 1 ml of N,N-dimethylformamide. 12 g (or 8 ml) of thionyl chloride were added and the mixture was stirred at 400C for three hours.
The product obtained, namely 2-(3-fluoro-4-biphenylyl)propionic acid chloride, was not isolated, but was used directly for preparing the ester as described below.
Stage 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 Stage A above there was added a mixture of 30.8 g of 1 ,2-diphenyl-3,5-dioxo4-n-butylpyrazolidine and 15 g of pyridine in 175 ml of chloroform. The mixture became warm and was refluxed for 30 minutes.
The resultant chloroform solution was washed with 100 ml of dilute hydrochloric acid, then with 10% sodium carbonate solution. The chloroform layer was dried over magnesium sulphate and the solvent 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 hydroxide. A further 100 ml of ether was added and the ethereal layer was separated, washed with 100 ml of water and dried. On evaporation of the ether, the desired 1,2diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(2-fluoro-4-biphenylyl)propionate was obtained. This was cry chloroform containing 2 ml of N,N-dimethylformamide, 24 g (or 16 ml) of thionyl chloride were added and the mixture was stirred at 40"C for three hours.
The product obtained, namely 2-(4-isobutyl-phenyl)-propionyl chloride, was not isolated, but was used directly for preparing the ester as described below.
Stage B: Preparation of the diester To the solution of 2-(4-isobutyl-phenyl)-propionyl chloride obtained from Stage A above there was added a mixture of 32.4 g of l-(p-hydroxyphenyl)-2- phenyl-3,5-dioxo-4-n-butylpyrazolidine and 15 g of pyridine in 200 ml of chloroform. The mixture became warm and was refluxed for 30 minutes.
The resultant chloroform solution was washed with 100 ml of dilute hydrochloric acid, then with 10% sodium carbonate solution. The chloroform layer was dried over MgSO4 and solvent 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 ethereal layer was separated, washed with 100 ml of water and dried. On evaporation of the ether, the desired diester was obtained. This was crystallised from ether-petroleum ether.
The diester is believed to comprise both l-phenyl-2-p-[2'-(4-isobutyl-phenyl) propionyloxy]-phenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2"-(4-isobutyl-phenyl)propionate and its 5-oxo-pyrazolid-3-en-3-yl isomer, which may also be named l-p [2'-(4-isobutyl-phenyl)-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 attempted.
So as to show another aspect of this invention, details of the formulation of one of the 3-oxo-5-pyrazolidinyl aromatic-carboxylate ester derivatives of the invention into several forms of pharmaceutical compositions will now be given, though again only for purposes of illustration.
Formulation 1.
Composition in the form of Tablets A tabletting mixture was made up by intimately mixing together the following ingredients: 1 ,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6-methoxy 2-naphthyl)-propionate 400 grams dicalcium phosphate 300 grams lactose, spray dried 254 grams granular microcrystalline cellulose 40 grams magnesium stearate 6 grams 1000 grams The mixture was then compressed by conventional tabletting machinery to form 500 mg tablets, each containing 200 milligrams of 1,2-diphenyl-3-oxo-4-nbutylpyrazolid-4-en-5-yl 2'-(6-methoxy-2-naphthyl)-propionate.
Formulation 2.
Composition in the form of Capsules A mixture was made up by intimately mixing together the following ingredients: 1 ,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6-methoxy 2-naphthyl)-propionate 500 grams maize starch 240 grams lactose 250 grams magnesium stearate 10 grams 1000 grams The mixture was then filled into capsules in an amount of 400 milligrams per capsule, corresponding to 200 milligrams of 1 ,2-diphenyl-3-oxo-4-n-butylpyrazolid4-en-5-yl 2'-(6-methoxy-2-naphthyl)-propionate per capsule.
Formulation 3.
Composition in the form oflnjectable Suspension 1 ,2-diphenyl-3 -oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6-methoxy 2-naphthyl)-propionate 5.00% w/v polysorbate 80 0.15% w/v thiomersal 0.005% w/v sodium chloride 0.07% w/v disodium phosphate 1.00% w/v phosphoric acid qs to pH 6.O7.0 water for injection to 100% w/v The 1 ,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6-methoxy-2naphthyl)-propionate was suspended in the injection vehicle and the pH was adjusted (if necessary) with phosphoric acid. The suspension was made up to volume, autoclaved under predetermined conditions and asceptically transferred into presterilised multi-dose ampoules.
Formulation 4.
Composition in the form of Suppositories 1 ,2-diphenyl-3-oxo-4-n-butyopyrazolid-4-en-5-yl 2'-(6-methoxy 2-naphthyl)-propionate 125.0 grams suppository base* 937.5 grams 1062.5 grams *Artificial wax, formed of mono-, di- and triglycerides, trade name "Suppocire AM" and available from Arthur Chemicals Limited of Staines, England.
The suppository base was melted and the 1,2-diphenyl-3-oxo-4-n-butyl pyrazolid-4-en-5-yl 2'-(6-methoxy-2-naphthyl)-propionate was added in a finely divided form. The mixture was stirred until evenly dispersed, poured into 2 gram suppository moulds, left to solidify and then demoulded. Each suppository contained 250 milligrams of 1 ,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6 methoxy-2-naphthyl)-propionate.
Finally, certain evaluations will be given below which indicate the freedom from undesirable side-effects of some of the 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic-carboxylate ester derivatives of this invention and their excellent antiinflammatory and/or analgesic properties.
EVALUATION OF STABILITY OF THE ANALGESIC & C ESTERS In order first to evaluate the stability (or otherwise) of l,2-diphenyl-3-oxo-4-n- butylpyrazo-4-en-5-yl 2'-(3-benzoyl-phenyl)-propionate and 1,2-diphenyl-3-oxo-4n-butylpyrazolid-4-en-5-yl 2'-(6-methoxy-2-naphthyl)-propionate in the gastrointestinal tract, simulated gastric and intestinal fluids were prepared as follows: Preparation ofsimulated gas tric flu id 2 grams of sodium chloride were mixed with 7.0 ml of conc. hydrochloric acid and the mixture was then made up to a volume of 100 ml with distilled water, yielding a simulated gastric fluid with a pH value of about 1.2.
Preparation ofsimulated intestinalfluid 6.8 grams of monobasic potassium phosphate were dissolved in 250 ml of water and to this was added a mixture of 190 ml of 0.2M 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, yielding a simulated intestinal fluid.
Method ofevaluation 100 milligrams of the 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic-carboxylate ester under test were suspended in 5 mls of each of the simulated fluids and shaken for 16 hours at 37"C. After this, the mixture was allowed to stand and the supernatant liquid was spotted onto silica t.l.c. plates and developed in 90:10 chloroform/methanol. The mixture was then extracted with 5 mls of chloroform and the chloroform-containing mixture was filtered through phase-separating papers which only allow the chloroform solution to pass through. The chloroform solution was also spotted onto silica t.l.c. plates and developed in 90:10 chloroform/methanol.
The results of this procedure, carried out for both the simulated gastric and simulated intestinal fluids for each of the above esters, show that negligible breakdown occurs in either of these fluids.
This indicates that all of the 4-alkyl-3,5-dioxo-pyrazolidinyl aromaticcarboxylic esters of the invention should be largely or wholly free from gastric disturbance effects when administered orally.
EVALUATION 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 major problem concerned in the oral administration of the class of compound possessing analgesic and anti-inflammatory properties.
Accordingly, certain of the compounds of this invention were tested for their acute (4 or 6 hours) gastric tolerance in rats, following 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 novel ester was formed.
So that the experiments could be performed in conditions which allow the differences between the new compounds and the known compounds used as the standard of comparison to be reproducibly and unequivocally observed, the effect of reference drugs, namely the component acids and alcohols of the ester, in relation to their dose was also examined in a series of preliminary experiments, which allowed suitable dosages to be established before testing of the compounds of this invention was commenced.
Test Procedure Groups of 10 male rats (Charles River, 180--250 grams bodyweight) were fasted overnight and until sacrifice (about 21 hours). The drugs were administered orally, as a suspension in 1% gum 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 pinned flat on a board for examination.
In the examination, superficial mucosal haemorrhages were classified in increasing severity, according to their size and number as: pinpoint, spots, or larger zones. Haemorrhagic lesions penetrating the mucosa (submucosal lesions) were considered as ulcers and also graded in severity according to their size and number: spots (1--2 mm in size), grooves (having a longitudinal dimension). Perforations were not usually observed.
The animals were then ranked in order, according to the most severe symptom each one showed, the ulcers (submucosal lesions) being as a rule considered more severe than mucosal haemorrhages (superficial). Control animals regularly showed some degree of "hyperaemia", which in fact corresponds to a congestive state of the vasculature at the moment of sacrifice and not to a persising functional hyperaemia -- it was therefore not considered as a sign of gastric irritation.
The results were expressed in simplified terms and tabulated as the percentage of rats showing either mucosal (superficial) haemorrhages alone, or submucosal (penetrating) lesions (ulcers) generally associated with mucosal haemorrhages.
Statistical comparisons between specified groups were performed by the Mann and Whitney U-test, based on the graded severities of the observations. The results are tabulated as percentage of rats showing either mucosal (superficial) haemorrhages alone, or submucosal (penetrating) lesions (ulcers) generally associated with mucosal haemorrhages.
RESULTS a) Table I sets out the results for 5-(dimethylamino)-9-methyl-1-oxo-2-npropyl-pyrazolid-2-eno[1,2-a][1,2,4]benzotriazine-3-yl 2'-(4-isobutyl-phenyl)propionate (Compound B) as compared to 5-(dimethylamino)-9-methyl-2-n-propyl1H-pyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione (Compound Az) in a 6 hour test.
TABLE I: Acute (6 hour) gastric tolerance in Rats.
Number of rats with Number of gastric lesions normal + Dose Number of hyperemic Haemorrhage Ulcer Total incidence Substance mg/kg rats used stomachs (mucose) (Submucosa) of lesions (%) Control - 8 3 + 5 - - Nil Compound Az 336 8 3 + 2 2 + 1 - 37% (dihydrate) Compound B 476 1 1 - - Nil As indicated in Table I, gastric lesions were observed in a proportion of animals treated with Compound Az at 1 mole/kg. And although only a very small number of animals could be dosed with compound B, there is an indication that the gastric irritancy is not increased or even may have been improved, comparatively to the reference Compound Az. b) Table II sets out the results for a test of acute (4 hour) gastric tolerance in rats comparing 1,2-diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl (3-chloro-4-n-prop2'-enyloxy-phenyl)-acetate (Compound C) with Compound Ph and (3-chloro-4-nprop-2'-enyloxy-phenyl)-acetic acid (Compound Al).
Compound C has some haemorrhagic effect on the gastric mucosa, but as shown in Table II its gastric tolerance is significantly better than the equivalent mixture of Compound Ph and Compound Al at the higher dosage rate tested. It should also be noted that there was no increase in the incidence of gastric lesions in the test with Compound C when the dose was doubled.
TABLE II: Acute gastric tolerance in rats.
* The position (from left to right) in these columns refers to increasing severity of the specified symptom.
Number of rats with Number of gastric lesions Total U-test Number mormal + incidence versus the U-test Dose of hyperemic Hemorrhage Ulcer of lesions control versus the Substance mg/kg rats used stomachs (mucosa) * (submucosa) * (%) group mixture Control group - 12 1 + 11 0% - Compound 80 # 12 3 1 + 5 + 1 1 + 1 75% p < 0.01 Copound Al 59 Compound C 134 12 2 + 5 2 + 2 + 1 42% NS p < 0.05 (F-twst:p = 0.025) Control group - 12 5 + 6 1 8% - Compound Ph 61 + # 12 5 + 4 2 + 1 25% NS Compound Al 45 Compound C 103 12 2 + 6 3 + 1 33% NS NS c) Table III shows the acute (4 hour) gastric tolerance results in rats for 1,2diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-phenoxy-phenyl)-propionate (Compound D) as compared with Compound Ph. These results show that Compound D has remarkably improved gastric tolerance compared to an equimolar amount of Compound Ph. It appears that Compound D is non-irritant to the gastric mucosa.
TABLE III * The position (from left to right) in these columns refers to increasing severity of the specified symptom.
Number of rats with Number of gastric lesions Total U-test Number mormal + incidence U-test versus Dose of rats hyperemic Hemorrhage Ulcer of lesions control versus the equimolar Substance mg/kg used stomachs (mucosa) * (submucosa) * (%) control group phenylbutazene CONTROL GROUP (g. tragacanth - 10 1 + 9 0% - + Labrafil*) Compound Ph 120 10 2 + 1 3 + 4 70% p < 0.01 Compound D 210 10 5 + 5 0% N.S. p < 0.01 * Labrafil" is a Registered Trade Mark.
EVALUATION OF DESIRED PHARMACOLOGICAL EFFECTS Three tests are conventionally employed to evaluate the efficacy of analgesic and anti-inflammatory drugs, and these three tests were used in evaluating compounds of the invention in comparison with their parent compounds, as reported below.
Test I A) Adjuvant Arthritis Test (Inclined Screen) in Rats Method Adjuvant disease was induced in several groups of rats. When adjuvant arthritis is induced in rats (normally with mycobacterial adjuvant) the adjuvant produces inflamed lesions in areas of the body remote from the injection site, after a delay of 10 to 15 days; though the inflammation starts to subside by the 30th day.
One group of rats were left untreated as controls; other groups were treated by oral administration, once per day for 18 days, with various amounts of the parent compound used as the standard of comparison, and of the compound to be evaluated.
The compound was in each case administered to the rat in solution in 1 part of polyoxyethylene oleic glyceride, made up to 5 part with 1% aqueous gum tragacanth, to which 1% ethanol was also added when required to bring about dissolution. The amount of this solvent vehicle administered was general 5 ml per kg of rat. The same vehicle (but without the active ingredient) was also administered to the control group of rats.
Treatment was continued for 18 days, during which time the rats were intermittently tested by means of the conventional Inclined Screen Test. Briefly stated, this evaluates the grip function of the rat, by placing it upon a wire-mesh screen which is pivoted up through an angle of 90" from the horizontal to the vertical, and if necessary then indeed beyond. The angle at which the rat being tested loses its grip and drops off the screen is recorded. Other things being equal, the larger the angle of inclination at which the rat drops off the screen the more powerful is its grip upon it - and thus the less its grip-function has suffered from the arthritis-like adjuvant disease; or, perhaps more strictly the greater the alleviation of the pain of that disease by the compound under test.
Results i) I,Z- diphenyl -3- oxo -4-n- butylpyrazolid -4-en-5- yl (3- chloro -4-n- prop - 2' - enyloxy -phenyl) - actate (Compound C) Compound C was tested at a rate of 67 mg/kg per day, and to provide a comparison separate groups of rats received the parent compound, Compound Ph, at rates of 40 mg/kg and 80 mg/kg per day. The molar equivalent of a dosage rate of 67 mg/kg of Compound C is 40 mg/kg of Compound Ph. One group of rats to serve as controls received only vehicle in the appropriate amount per day.
The results are shown graphically in Figure 1 of the accompanying drawings, where the angle of screen inclination is plotted against time for the various compounds tested and for the controls.
From Figure lit may be concluded that Compound C has approximately the same level of activity as the equimolar quantity of Compound Ph. However, as shown previously, Compound C has a higher gastric tolerance than Compound Ph so that its overall therapeutic performance is better. ii) 1,2 - diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (3 phenoxy- phenyl) -propionate (CompoundD).
Compound D was tested at dosage levels of 35 and 70 mg/kg, and compared with the respective equimolar amounts of 20 and 40 mg/kg of Compound Ph. The results are shown in the following table, Table IV, which indicates Compound D is equiactive to 0.5 molar equivalents of Compound Ph. However, in a separate assessment it has been found that Compound D is equiactive with 2-(3-phenoxyphenyl)-propionic acid at rates of 40 mg/kg for both drugs.
TABLE IV
Diameter mm (mean # SEM) DOSE LEVEL Stastics: t-test vs the control group SUBSTANCE mg/kg mole/kg Right foot Left foot CONTROL GROUP - - 15.3 # 0.6 15.7 # 0.5 12.1 # 0.5 12.3 # 0.6 20 65 p &alpha; 0.01 p &alpha; 0.001 COMPOUND Ph 11.8 # 0.3 11.3 # 0.2 40 130 p < 0.001 p < 0.001 12.1 # 0.3 12.0 # 0.4 35 66 P < 0.001 P < 0.001 COMPOUND D 12.2 # 0.4 11.6 # 0.4 70 132 P < 0.01 P < 0.001 B) AdjuvantArthritis Test (Body weight) in Rats The experimental detection of unknown side-effects is more difficult than the detection of gastric irritation; but their existence can be suggested by a decrease in body weight. Therefore in order to ensure that the results secured in the Inclined Screen Tests were not rendered unreliable by other side-effects of the compound under test, the bodyweights of the rats suffering from the experimentally-induced adjuvant disease were also determined each day.
The results for Compound C are recorded in Figure 2, and these are consistent with the results for the grip function test, in that Compound C is of comparable activity to Compound Ph.
C) Adjuvant Arthritis Test (Acute Phase) - Compound B The anti-inflammatory activity of Compound B was studied by a subacute assay involving 3-dose medication in rats, using the following procedure: Groups of non-fasted female (Charles River) rats of uniform bodyweight were given a subplantar injection of 0.5 mg (per animal) Mvcobacterium butyr. in 0.1 ml sterile paraffin oil into the right hindpaw (the opposite paw being left uninjected), and the oedema which later ensued was measured at the intervals indicated below by differential plethysmometry of injected and non-injected paws using an Ugo Basile apparatus. The following treatment schedule was applied: Day O - 0900 h : 1st drug dose (oral medication) 10.00 h : mycobacterial adjuvant, s.c. injection 15.00 h : oedema volume determination Day 1 0900 h : 2nd drug dose 14.00 h : oedemavolume Day 2 0900 h : 3rd drug dose 14.00 h : oedema volume Day 3 0900 h : oedema volume (no prior medication) In a preliminary experiment, Compound Az was tested at rates of 0.1, 0.2 and 0.4 mmole/kg and was found to have a statistically significant effect at the level of 0.2 mmole/kg.
Compound B was therefore also tested at a dose level of 0.2 mmole/kg, and the results obtained are shown in Table V below.
Compound Az itself showed clearcut dose-related effects in the range of 0.14.24.4 mmole/kg: the total effects (i.e. the sum of % inhibition of oedema observed on Days 0 to 3) amounted to 53-87-160% for the respective dose levels mentioned. Compound B was more effective in that its total effect amounted to 124 , and thus its activity was approximately 1.5 times that of its molar equivalent of Compound Az.
TABLE V
Mean oedema volume (ml) Dose level Percentage reduction of the oedema, and Statistics (t-test) compared to the control group Treatment Day 3 mmole/kg mg/kg Day 0 Day 1 Day 2 (no medication) Control group - - 0.43 # 0.03 0.75 # 0.08 0.87 # 0.14 1.00 # 0.19 0.41 # 0.04 0.70 # 0.06 0.68 # 0.06 0.81 # 0.04 0.1 33.6 5% 7% 22% 19% Compound Az 0.33 # 0.04 0.65 # 0.08 0.62 # 0.09 0.78 # 0.12 (dihydrate) 0.2 67.2 23% 13% 29% 22% 0.27 # 0.04 0.46 # 0.08 0.48 # 0.09 0.61 # 0.10 0.4 134.4 37% 39% 45% 39% P < 0.01 P < 0.05 P < 0.05 0.35 # 0.03 0.57 # 0.09 0.48 # 0.07 0.64 # 0.08 Compound B 0.2 95.3 19% 24% 45% 36% P < 0.05 Test II Antipyretic Test Against Yeast-induced Hyperthermia in rats i) Compound B Using the conventional procedure, groups of rats were injected with yeast.
Immediately after injection various dosages of Compound B, and of Compond A2 were administered orally to a different groups of rats, apart from the control group who received only the vehicle.
The body temperature of all the rats was carefully monitored for a period of 8 hours following oral administration of the compound under study.
The antipyretic test was carried out on Compound B using dosage rates of 23.8 mg/kg and 47.6 mg/kg (corresponding respectively to 0.05 mmole/kg and 0.1 mmole/kg), and Compound Az was used to provide a comparison at a dosage rate of 67.2 mg/kg (0.2 mmole/kg). The results obtained are shown in Figure 3 of the accompanying drawings.
Compound Az showed a strikingly weak antipyretic action in this test.
Compound B had a statistically significant effect at the low dose levels of 0.05 and 0.1 mmole/kg, whilst Compound Az was substantially ineffective at 0.2 mmole/kg.
It is estimated that Compound B was in the region of 10 times more effective, on an equimolar basis, than Compound Az. ii) Compound C The results for the antipyretic test carried out on Compound C are shown in Figure 4 of the accompanying drawings. A dosage rate of 51 mg/kg of Compound C was employed, and a comparison was provided by Compound Ph used at a rate of 30 mg/kg and a mixture of Compound Ph and Compound Al applied at a rate of 30 mg/kg of Compound Ph and 22 mg/kg of Compound Al.
Compound C is equiactive with Compound Ph alone, and virtually as active as the mixture. iv) Compound The results for Compound D in the antipyretic test are shown in Figure 5 of the accompanying drawings. Compound D was administered at 35 and 70 mg/kg, and compared with Compound Ph administered at 40 mg/kg. The Controls were treated with the vehicle alone - containing 1% gum tragacanth and 10% Labrafil.
The results indicate that Compound D is equiactive as an antipyretic with twice the molar amount of Compound Ph. Moreover Compound D acted more quickly and its duration of action was longer than Compound Ph.
TestIlI Randall-selitto Test in Rats Method The tests were conducted upon male rats with an average weight of 135-200 g. Using the conventional techniques, the various compounds under test, as identified below, were administered orally to the rats in each group (except a control group, which received only the vehicle) and, 30 minutes later, each of the rats was injected in one hind-paw with yeast.
In order to evaluate the effect of the treatment upon pain thresholds, pressure was applied both to the injected hind-paw and to the other, non-injected hind-paw.
The pain threshold was noted as the pressure at which the rat flinched; and the readings taken for each rat were expressed as the percentage of the pain threshold pressure for the injected hind-paw as against the pain threshold pressure for the non-injected hind-paw.
These pain threshold percentages were determined at intervals of 3 hours, 5 hours and 24 hours after the injection. Statistics: t-test versus the control group.
Results The results obtained in testing are set out in the following Tables VI-VIl.
TABLE VI
3 h 5 h 7 h Dose Normal Inflamed Normal Inflamed Normal Inflamed Substance mmole/kg paw paw % paw paw % paw paw % 12.8 5.5 45 12.7 5.2 42 12.9 5.3 43 Control group - #1.9 #0.7 #2.0 #1.7 #0.6 #2.6 #1.9 #0.7 #2.5 17.2 9.3 54 13.9 7.0 51 12.9 7.2 56 0.1 #2.0 #1.3 #3.7 #1.9 #1.2 #4.6 #1.5 #1.1 #4.1 Compound Az P < 0.05 P < 0.05 P < 0.02 (dihydrate) 13.8 10.0 67 16.4 10.7 66 11.7 6.8 58 0.2 #2.0 #2.4 #5.1 #1.9 #1.1 #4.6 #1.1 #0.7 #3.6 P < 0.001 P < 0.001 P < 0.001 P < 0.01 12.5 6.9 55 12.4 6.6 55 15.0 7.7 52 Compound B 0.2 #1.0 #0.9 #4.5 #1.1 #0.5 #4.0 #1.4 #0.7 #3.1 P < 0.02 P < 0.05 P < 0.05 TABLE VII
Time afte yeast injeotion (3 =/2hh) (5 5h 17/2hh) 24 h Substance(drug 1/2 1) (7 dose ake dose t Control group 35 c 6.9 43 + 7.0 36 4;9 46 f 4.8 Control group 35 + 6.5 43 + 7.0 36 ~ 4.9 46 4.8 Compound Ph 15 mg/kg 40 + 6.6 45 + 6.9 43 + 5.2 55 + 5.3 Compound Ph 30 mg/kg 58 + 5.7 37 + 5.7 - 56 + 4.7 62 + 6.6 p < 0.02 p < 0.01 p < 0.05 Compound Ph 60 mgAcg 55 + 6.0 65 + 3.3 62 + 5.5 59- + 5.0 p < 0.01 p < 0.01 p + 0.01 Compound C 51 mghcg 57 + 6.2 51 + 3.1 69+ 3.1 65 * 2.9 p < 0.05 p p < 0.001 p < 0.01 TABLE VIII
Time from yeast Time from yeas t injection 3h 5h 7h 24h Time z (drug (3 1/2 h) (5 from yeast Substance (dEUg (3 3 h S 1/2 h 7 h 24'h Dose 1/2 intake) CONTROL GROUP 1% g. tragancanth + 40 + 3.3 40 * 2.9 41 * 2.1 48 + 1.7 10% Labrafil, 5 mlAg) Compound Ph 56 + 3.6 53 + 1.6 49 + 2.1 52 * 1.9 40 mgAg p < 0.01 p < 0.001 p < 0.02 Compound Ph 59 * 4.0 63 + 2.5 61 * 2.4 60 + 2.8 80 mg/kg p < 0.01 p < 0.001 p < 0.001 p < 0.01 55+3.9 55+1.4 562.3 59~+2.1 Compound D 70 mg/g 55 P < 0.001 P < 0.001 P < 0;001 Conclusions The Randall-Sellito test results in the above Tables show that Compound B has the activity of 0.5 times the equimolar amount of Compound Ph. However, as illustrated elsewhere herein, the other properties of Compound B, and particularly its anti-inflammatory and antipyretic properties, make it a highly advantageous therapeutic compound.
Compound C is shown in Table VII to have a greater analgesic effect than Compound Ph, comparable to, or slightly less than, the effect of twice the equimolar quantity of Compound Ph.
Table VIII shows that Compound D is equiactive to approximately 1.5 molar equivalents of Compound Ph, and thus favoured in its analgesic activity with respect to Compound Ph.
* Finally, in relation to Compound B, a further test was carried out to evaluate the analgesic activity of the compound of the invention in mice.
Test IV Acetylcholine-induced writhing in Mice - Compound B Groups of 10 female mice, weighing from 27-30 g, were administered orally with the compound under investigation in the amounts set out hereinafter. A further control group of similar mice were not administered with any compound. 60 minutes later the mice, including the control group mice were injected with 3.5 mg/kg of acetylcholine chloride, which tends to induce writhing.
The mice were observed, and the number of mice showing at least one writhing between 25 and 120 seconds after the injection were noted.
Compound B was tested at rates ranging from 0.05 mmole/kg -0.4 mmole/kg and compared with Compound Ph administered at rates ranging from 0.1 mmole/kg -0.8 mmole/kg. The results obtained are set out in Table IX below.
It may be seen that Compound B is remarkably more effective in inhibiting the induced writhing, being of the order of 6 times more effective than Compound Ph for equimolar doses. This demonstrates the excellent analgesic properties of Compound B.
TABLE IX
Compound Az (dihydrate) Compound B Treatment P.O. - 60 minutes Incidence % Incidence of writhing protection of writhing protection Control group 9/10 - 10/10 0.05 9it10 0% 5/10 50% Dose levels 0.1 9it10 0 1/10 90 0.2 7/10 22 1/10 90 mmole/kg 0.4 5/10 44 0/5 100 0.8 0/10 100 -

Claims (97)

WHAT WE CLAIM IS:
1. The 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic-carboxylate esters of the gcneral formula:
wherein Alk represents an n-propyl or n-butyl group; either one of B' and B" represents a phenyl group and the other represents a phenyl group or a phenyl group substituted by a group -OZ', or B' and B" together with the intervening nitrogen atoms to which they are respectively attached represent a 3dimethylamino-7-methy-[1,2,4]-benzotriaine ring system fused with the pyrazolidine ring; and at least one of Z and Z' represents oa aromatic-carbonyl group:
wherein A represents a carbon atom or a #C-CH2, #C-CHCl-, > \C-CH(CH3)- or > C-CO-CH2-CH2- group; R2 represents a hydrogen atom, or a hydroxy, 2,4-dichlorophenoxy or 3-trifluoromethyl-anilino group; B represents a nitrogen atom or a C-, CCl or CH group; either R4 represents a hydrogen atom or a phenyl, isobutyl, n-prop-2-enyloxy, cyclohexyl, 2methyl-cyclohexyl, 2-fluoro-phenyl, l-oxo-2-isoindolinyl or 2,5-dihydropyrrol-l-yl group, and R5 represents a hydrogen atom or a benzoyl, 2,4-difluoro-phenyl or phenoxy group; or R4 and R5 together with the intervening carbon atoms to which they are respectively attached form a methoxy-substituted benzene ring, a 6 methyl-benzo[e]-(l,4)-thiazine ring or a methoxy-substituted 6-methyl-benzo[e] (1,4)-thiazine ring, the benzothiazine rings each being fused to the aromatic ring at the [b] position, or a 5-chloro-indole ring fused to the aromatic ring at its [b] position and when only one of Z and Z' represents an aromatic-carbonyl group the other represents a hydrogen atom) and where feasible the acid addition salts thereof, provided that B' and B" are not both phenyl when R4 is isobutyl or cyclohexyl and A is #C-CH(CH3)- or #C-CH2-
2. An acid addition salt as claimed in Claim 1, formed with a pharmacologically-acceptable acid which maybe used in human or animal therapy.
3. A compound as claimed in Claim 1, falling within the general formula:
wherein Alk is as defined in Claim 1; either one of B'A and B"A represents a phenyl group and the other represents a phenyl group or a phenyl group substituted by a group -OZ'A, or B'A and B"A together with the intervening nitrogen atoms to which they are respectively attached represent a 3-dimethylamino-7-methyl-[1,2,4]benzotriazine ring-system fused with the pyrazolidine ring; and at least one of ZA and Z'A represents a substituted 2-phenyl-propionyl group:
in which R4 and R5 are as defined in Claim 1, and when only one of ZA and Z'A represents a substituted 2-phenyl-propionyl group the other represents a hydrogen atom, and where feasible their acid addition salts.
4. The l-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(4-isobutyl-phenyl)-propionic acid.
5. The 5-(dimethylamino)-9-methyl-2-n-propy-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione esters of 2-(4-isobutyl-phenyl)-propionic acid.
6. 1 ,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(3-benzoyl-phenyl)-propionate.
7. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butyl-pyrazolidine ester of 2-(3-benzoyl-phenyl)-propionic acid.
8. The 5-(dimethylamino)-9-methyl-2-n-propyl- 1H-pyrazolo[1,2-1][1,2,4]benzo- triazine-l ,3(2H)-dione esters of 2-(3-benzoyl-phenyl)-propionic acid.
9. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2'-(6-methoxy-2-naphthyl)propionate.
10. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-nbutylpyrazolidine esters of 2-(6-methoxy-2-naphthyl)-propionic acid.
II. The 5 - (dimethylamino) - 9 - methyl - 2 - n - propyl - 1H - pyrazolo[l,2-a]- [1 ,2,4jbenzotriazine - 1,3(2H) - dione esters of 2 - (6 - methoxy - 2 - naphthyl) - propionic acid.
12. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(4-cyclohexyl-phenyl)-propionic acid.
13. The t-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione esters of 2-(4-cyclohexyl-phenyl)-propionic acid.
14. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2-(4-[2-methyl-cyclohexyl]phenyl)-propionate.
15. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioyo-4-n-butylpyrazolidine esters of 2-(4-[2-methyl-cyclohexyl]-phenyl-propionic acid.
16. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione esters of 2-(4-[2-methyl-cyclohexyl]-phenyl)-propionic acid.
17. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-yl 2-[2'-fluoro-4-biphenyl)]propionate.
18. The l-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-[2'-fluoro-4-biphenyl]-propionic acid.
19. The 5-(dimethylamino)-9-methyl-2-n-propyl- 1 H-pyrazolo[l,2-a][l ,2,4]ben- zotriazine-l ,3(2H)-dione esters of 2-[2'-fluoro-4-biphenyl]-propionic acid.
20. 1,2-Diphenyl-3-oxo-4-n-butylpyrazolid-4-en-5-y12'-[4-(1 - oxo- 2- isoindolinyl) - phenyl] - propionate.
21. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazoiidine esters of 2-[4-(1 -oxo-2-isoindolinyl)-phenyl]-propionic acid.
22. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2a][1,2,4]ben zotriazine- 1 ,3(2H)-dione esters of 2-[4-(1-oxo-2-isoindolinyl)-phenyl]-propionic acid.
23. 1,2 - Diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (6 - chloro 2- carbazolyl) - propionate.
24. The 1 -phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(6-chloro-2-carbazolyl)-propionic acid.
25. The 5-(dimethylamino)-9-methyl-2-n-propyl- 1 H-pyrazolo [1,2-a] [1,2,4]ben- zotriazine-1,3(2H)-dione esters of 2-(6-chloro-2-carbazolyl)-propionic acid.
26. 1,2 - Diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl (10 - methyl - 2phenothiazinyl) - acetate.
27. The 1 -phenyl-2-p-hydroxyphenyl-3-oxo-4-n-butylpyrazolidine esters of (1 0-methyl-2-phenothiazinyl)-acetic acid.
28. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione esters of (10-methyl-2-phenothiazinyl)-acetic acid.
29. 1,2 - Diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (7 - methoxy - 10 - methyl - 2 - phenothiazinyl) - propionate.
30. The l-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(7-methoxy- 1 0-methyl-2-phenothiazinyl)-propionic acid.
31. The 5-(dimethylamino)-9-methyl-2-n-propyl- 1 H-pyrazolo[1,2-a] [1,2,4] ben- zotriazine- 1 ,3(2H)-dione esters of 2-(7-methoxy- 1 0-methyl-2-phenothiazinyl)-pro- pionic acid.
32. 1,2 - Diphenyl- 3-oxo-4-n-butylpyrazolid-4-en-5 -y12'-(3-phen- oxyphenyl) - propionate.
33. The l-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(3-phenoxyphenyl)-propionic acid.
34. The 5-(dimethylamino)-9-methyl-2-n-propyl- 1 H-pyrazolo[l,2-a][l ,2,4]ben- zotriazine-1,3(2H)-dione esters of 2-(3-phenoxyphenyl)-propionic-acid.
35. 1,2 - Diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2'(3 - fluoro 4- biphenyl) - propionate.
36. The l-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(3-fluoro-4-biphenyl)-propionic acid.
37. The 5-(dimethylamino)-9-methyl-2-n-propyl- 1 H-pyrazolo[ 1,2-a] [1 ,2,4]ben- zotriazine-1 ,3(2H)-dione esters of 2-(3-fluoro-4-biphenyl)-propionic acid.
38. 1,2 - Diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2'(3 - chloro 4- (2,5 - dihydropyrrol - 1 - yI) - phenyl) - propionate.
39. 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.
40. The 5-(dimethylamino)-9-methyl-2-n-propyl- 1 H-pyrazolo[l,2-a][l ,2,4]ben- zotriazine- 1 ,3(2H)-dione esters of 2-(3-chloro-4-(2,5-dihydropyrrol- 1 -yl)-phenyl)- propionic acid.
41. 1,2 - Diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2' - (3 - trifluoromethyl - anilino) - nicotinate.
42. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2-(3-trifluoromethyl-anilino)-nicotinic acid.
43. The 5-(dimethylamino)-9-methyl-2-n-propyl- 1 H-pyrazolo[ 1,2-a] [1,2,4] ben- zotriazine- 1 ,3(2H)-dione esters of 2-(3-trifluoromethyl-anilino)-nicotinic acid.
44. 1,2 - Diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl 2",4" - di- fluoro - 4' - hydroxy - 3' - biphenylcarboxylate.
45. The l-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 2',4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid.
46. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione esters of 2',4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid.
47. 1,2 - Diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - yl chloro - (3chloro - 4 - cyclohexyl - phenyl) - acetate.
48. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of chloro-(3-chloro-4-cyclohexyl-phenyl)-acetic acid.
49. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione esters of chloro-(3-chloro-4-cyclohexyl-phenyl)-acetic acid.
50. 1,2 - Dipheny1 - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - y1 3'(4 - biphenylcarbonyl) - propionate.
51. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 3-(4-biphenylcarbonyl)-propionic acid.
52. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione esters of 3-(4-biphenylcarbonyl)-propionic acid.
53. 1,2 - Diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - y1 [2 - (2,4 - di- chloro phenoxy) - phenyl]acetate.
54. The 1 -phenyl-2-p-hydroxyphenyl-3 ,5-dioxo-4-n-butylpyrazolidine esters of [2-(2,4-dichlorophenoxy)-phenyl]acetic acid.
55. The 5-(dimethylamino)-9-methyl-2-n-propyl- 1 H-pyrazolo[1,2-a] [1 ,2,4]ben- zotriazine- 1 ,3(2H)-dione esters of [2-(2,4-dichlorophenoxy)-phenyl]-acetic acid.
56. 1,2 - Diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - y1 (3 - chlord - 4n - prop - 2' - enyloxy - phenyl) - acetate.
57. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of (3-chloro-4-n-prop-2'-enyloxy-phenyl)-acetic acid.
58. The 5-(dimethylamino)-9-methyl-2-n-propyl-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione esters of (3-chloro-4-n-prop-2'-enyloxy-phenyl)-acetic acid.
59. The 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of (4-isobutyl-phenyl)-acetic acid.
60. The 5-(dimethylamino)-9-methyl-2-n-propyl- 1 H-pyrazolo [1.2-a] [1 ,2,4]ben- zotriazine- 1 ,3(2H)-dione esters of (4-isobutyl-phenyl)-acetic acid.
61. 1,2 - Diphenyl - 3 - oxo - 4 - n - butylpyrazolid - 4 - en - 5 - y1 3'-pyridine- acetate.
62. The 1 -phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butylpyrazolidine esters of 3-pyridineacetic acid.
63. The 5-(dimethylamino)-9-methyl-2-n-propyl- 1 H-pyrazolo [1,2-a] [1,2,4] ben- zotriazine-1 ,3(2H)-dione esters of 3-pyridine-acetic acid.
64. A process for the preparation of the 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic-carboxylate esters of general formula III as claimed in Claim 1, in which a 4-alkyl-3,5-dioxo-pyrazolidine derivative of the general formula:
(wherein Alk is as defined in Claim 1, and either one of W' and W" represents a phenyl group and the other represents a phenyl or a para-hydroxyphenyl group or W' and W" together with the intervening nitrogen atoms to which they are respectively attached represent a 3-dimethylamino-7-methyl-[1,2,4]-benzotriazine ring-system fused with the pyrazolidine nucleus) is reacted with an aromatic carboxylic acid chloride of the general formula:
(wherein A, B, R2, R4 and R5 are as defined in Claim 1) or an acid addition salt thereof to yield the desired corresponding 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic-carboxylate ester of general formula III or acid addition salt thereof.
65. A process as claimed in Claim 64, which is effected in an anhydrous inert solvent.
66. A process as claimed in Claim 65, in which the inert solvent is a substituted aromatic hydrocarbon, a halogenated aromatic solvent, an aliphatic hydrocarbon or a halogenated aliphatic hydrocarbon.
67. A process as claimed in Claim 66, in which the solvent is dichloromethane.
68. A process as claimed in any of Claims 64 to 67, which is carried out at ambient temperature without heating or with cooling to maintain ambient temperature.
69. A process as claimed in any of Claims 64 to 68, in which the reaction is effected in the presence of a base.
70. A process as claimed in Claim 69, in which the base is a tertiary amine.
71. A process as claimed in any of Claims 64 to 70, in which 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 the general formula:
(wherein A, B, R2, R4 and R5 are as defined in Claim 1) or a salt thereof with thionyl chloride.
72. A process as claimed in Claim 71, in which a pyridine salt of the acid of general formula II is employed.
73. A process as claimed in Claim 71 or Claim 72, in which the reaction with thionyl chloride is carried out at a temperature within the range of from 40"C to 650C.
74. A process as claimed in any of Claims 71 to 73, in which the solvent used is as defined in Claim 65 or Claim 66.
75. A process as claimed in Claim 74, in which the solvent is anhydrous dichloromethane, and the reaction is effected under reflux at a temperature of 400 C.
76. A process as claimed in any of Claims 71 to 75, in which the reaction with thionyl chloride is effected in the presence of a catalytic amount of N,Ndimethylformamide.
77. A process for the preparation of the 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic-carboxylate esters of general formula III as claimed in Claim 1, in which a mixed anhydride of the general formula:
(wherein A, B, R2, R4 and R5 are as defined in Claim 1, "Ayl" represents an alkyl group containing from I 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 represents a carbon atom or when m is zero a sulphinyl group) is reacted with a 4-alkyl-3,5-dioxopyrazolidine derivative of general formula I (as defined in Claim 64) to yield the desired corresponding 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic-carboxylate ester of general formula III.
78. A process as claimed in Claim 77, in which the reaction is carried out in an anhydrous inert solvent.
79. A process as claimed in Claim 78, in which the solvent is as defined in Claim 66.
80. A process as claimed in any of Claims 77 to 79, in which the reaction is conducted in the presence of a base.
81. A process as claimed in Claim 80, in which the base is a tertiary amine.
82. A process as claimed in any of Claims 77 to 81, in which the mixed anhydride of general formula V is prepared by reacting an aromatic-carboxylic acid of general formula II (as defined in Claim 71) or a salt thereof with a reactive organic chloride of general formula:
(wherein Ayl, m and Q are as defined in Claim 77) in the presence of a base.
83. A process as claimed in Claim 82, in which 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.
84. A process as claimed in Claim 83, in which the solvent is as defined in Claim 66.
85. A process as claimed in any of Claims 82 to 84, in which the base is a tertiary amine.
86. A process as claimed in Claim 85, in which the base is triethylamine or pyridine.
87. A process for the preparation of the 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic-carboxylate esters of general formula III as claimed in Claim 1, in which a 4-alkyl-3,5-dioxo-pyrazolidine derivative of general formula I (as defined in Claim 64) is reacted with a solution in a water-immiscible solvent of a symmetrical aromatic-carboxylic acid anhydride of the general formula:
(wherein A, B, R2, R4 and R5 are as defined in Claim 64) in the presence of a strong aqueous base, so that the reaction mixture forms a two-phase system, which is agitated to yield the desired 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic-carboxylate ester of general formula III.
88. A process as claimed in Claim 87, in which the strong aqueous base is aqueous sodium hydroxide.
89. A process as claimed in Claim 87 or Claim 88, in which the waterimmiscible solvent is benzene, toluene, chloroform, dichloromethane or an ether.
90. A process as claimed in any of Claims 87 to 89, in which the reaction is carried out at a temperature not exceeding 300 C.
91. A process as claimed in any of Claims 87 to 90, in which the acid anhydride of general formula VII is prepared by reacting an aromatic-carboxylic acid of general formula II (as defined in Claim 71) with a carbodiimide in solution in an anhydrous, non-hydroxylic and otherwise inert organic solvent at a temperature not exceeding 30"C.
92. A process as claimed in Claim 91, in which the carbodiimide is N,N' dicyclohexyl-carbodiimide.
93. A process for the preparation of a compound of general formula III as claimed in Claim 1, substantially as described herein with reference to any one of the Examples.
94. A compound of general formula III as claimed in Claim 1 whenever prepared by a process as claimed in any of Claims 64 to 93.
95. A pharmaceutical composition comprising, as active ingredient, one or more of the 4-alkyl-3,5-dioxo-pyrazolidinyl aromatic-carboxylate esters of general formula III as claimed in Claim 1, in association with a suitable pharmaceutical vehicle.
96. A composition as claimed in Claim 95, in the form of a unit dose containing from 30 mg to 2.7 g of active ingredient.
97. A composition as claimed in Claim 95 and substantially as described herein with reference to any one of the Formulations.
GB39609/77A 1977-09-22 1977-09-22 Pharmacologically-active esters processes for their preparation and pharmaceutical compositions incorporating them Expired GB1597970A (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
GB39609/77A GB1597970A (en) 1977-09-22 1977-09-22 Pharmacologically-active esters processes for their preparation and pharmaceutical compositions incorporating them
FR7826146A FR2403997A1 (en) 1977-09-22 1978-09-12 NEW DERIVATIVES OF 3,5-DIOXO-PYRAZOLIDINE, THEIR PREPARATION AND MEDICINAL PRODUCTS CONTAINING THEM
DE19782839738 DE2839738A1 (en) 1977-09-22 1978-09-13 4-ALKYL-3,5-DIOXO-PYRAZOLIDINYL DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND THERAPEUTIC PREPARATIONS CONTAINING THESE COMPOUNDS
NL7809303A NL7809303A (en) 1977-09-22 1978-09-13 PYRAZOLIDINE DERIVATIVES, PHARMACEUTICAL PREPARATIONS THEREOF, AND METHODS FOR PREPARING ANY OTHER.
BE190573A BE870589A (en) 1977-09-22 1978-09-19 NEW DERIVATIVES OF 3,5-DIOXO-PYRAZOLIDINE, THEIR PREPARATION AND MEDICINAL PRODUCTS CONTAINING THEM
LU80259A LU80259A1 (en) 1977-09-22 1978-09-19 4-ALKYL-3,5-DIOXO-PYRAZOLIDINYL DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND THERAPEUTIC PREPARATIONS CONTAINING THESE COMPOUNDS
AT0678478A ATA678478A (en) 1977-09-22 1978-09-20 METHOD FOR PRODUCING NEW 4-ALKYL-3,5-DIOXO-PYRAZOLIDINYL DERIVATIVES AND THEIR SALTS
DK418378A DK418378A (en) 1977-09-22 1978-09-21 PROCEDURE FOR THE PREPARATION OF 4-ALKYL-3,5-DIOXO-PYRAZOLIDINE DERIVATIVES
NO783202A NO783202L (en) 1977-09-22 1978-09-21 PROCEDURES FOR THE PREPARATION OF NEW PHARMACOLOGICAL ACTIVE ESTERS
SE7809943A SE7809943L (en) 1977-09-22 1978-09-21 PHARMACOLOGICAL ACTIVE ESTERS, PREPARATIONS FOR PRODUCTS THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING SUCH ASSOCIATIONS
FI782883A FI782883A (en) 1977-09-22 1978-09-21 NYA PHARMACOLOGICAL ACTIVITIES ESTRAR PHARMACEUTICALS FOR FRAMSTAELLNING AV DEM SAMT PHARMACEUTICAL COMPOSITION INNEHAOLLANDE DEM

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB39609/77A GB1597970A (en) 1977-09-22 1977-09-22 Pharmacologically-active esters processes for their preparation and pharmaceutical compositions incorporating them

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GB1597970A true GB1597970A (en) 1981-09-16

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Country Status (11)

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AT (1) ATA678478A (en)
BE (1) BE870589A (en)
DE (1) DE2839738A1 (en)
DK (1) DK418378A (en)
FI (1) FI782883A (en)
FR (1) FR2403997A1 (en)
GB (1) GB1597970A (en)
LU (1) LU80259A1 (en)
NL (1) NL7809303A (en)
NO (1) NO783202L (en)
SE (1) SE7809943L (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1589816A (en) * 1977-06-02 1981-05-20 Sterwin Ag Pharmacologically active esters of alkyl-dioxo-pyrazotidine derivatives

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LU80259A1 (en) 1979-03-16
NO783202L (en) 1979-03-23
BE870589A (en) 1979-01-15
DE2839738A1 (en) 1979-04-05
DK418378A (en) 1979-03-23
NL7809303A (en) 1979-03-26
FI782883A (en) 1979-03-23
ATA678478A (en) 1982-06-15
FR2403997A1 (en) 1979-04-20
SE7809943L (en) 1979-05-10

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