IE41709B1 - 5-acetyl-4-hydroxy-2h-pyran-2,6(3h)-dione derivatives and pharmaceutical compositions comprising such compounds - Google Patents

Abstract

Compounds of the formula and their tautomers suppress the antigen-antibody response. They are prepared by reacting 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one with an amine of the general formula II R-NH2 (II> in which R has the meaning given in Patent Claim 1, and, if appropriate, converting the product with an alkali metal alcoholate into its mono- or dialkali metal salts.

Description

This invention relates to substituted 2H-pyran-2,6(3H)dione derivatives a process for their preparation, and pharmaceutical compositions comprising such derivatives which inhibit the antigen-antibody reaction. b The substituted 2H-pyran-2,6(3H)-dione derivatives which comprise the active ingredient of the pharmaceutical compositions of this invention, in association with a non-toxic pharmaceutical carrier or diluent, are represented by the following general structural formula: Formula I wherein R represents lower alkyl, straight or branched chain, of from 3 to 6 carbon atoms, phenyl, halophenyl such as chlorophenyl, lb bromophenyl or fluorophenyl, hydroxyphenyl, methoxyphenyl, alkanoyloxyphenyl, the alkanoyl moiety having from 2 to 7 carbon atoms, carbamoyloxyphenyl, N-methylcarbamoyloxyphenyl, N-benzylcarbamoyloxyphenyl, N,N-dimethylcarbamoyl oxyphenyl, p-mercaptophenyl, aminophenyl or ureidophenyl, or a monoor di-alkali metal salt of said compound.

Particular compositions of this invention comprise a compound of Formula I above when R is lower alkyl, straight or branched chain, of from to 6 carbon atoms, phenyl, halophenyl, hydroxyphenyl, methoxyphenyl, p-mercaptophenyl or aminophenyl. 41700 Advantageously the compositions of this invention comprise a compound of formula I above when R is n-propyl, p-mercaptophenyl, hydroxyphenyl, p-acetoxyphenyl, p-pentanoyloxyphenyl, p-aminophenyl or p-ureidophenyl.

Preferably R is p-hydroxymenyl.

In U.S. Patent Application No. 492,640 from which priority is claimed the active ingredient of the pharmaceutical compositions was described as a 5-substituted carbamyldehydroacetic acid. However we also disclosed that Kiang, A.K. et al. J. Chem. Soc (c) pp. 2721 -6 (1971) questioned the structure assigned by previous authors such as Wiley, R.H. etal. J. Org. Chem. 21:686-688 (1956) to the reaction product of acetonedicarboxylic acid and acetic anhydride, designated 5-carboxydehydroacetic acid, and -carbamyl derivatives of dehydroacetic acid. Thus, Kiang et al. supra reported that the reaction of acetonedicarboxylic acid with acetic anhydride gave the compound of structure II and that the latter reacted with aniline to form the compound of structure III: Formula II Formula III In view of these facts we stated in said earlier application that we could not discount that the 5-substituted carbamyldehydroacetic acid could have the isomeric structure indicated by Kiang et al.

Upon subsequent investigation which has included 3 C nuclear magnetic·· resonance spectral and X-ray crystallographic studies, we have now arrived at the following conclusions. The reaction of acetonedicarboxylic acid with acetic anhydride gives a product having the tautomeric structure as shown below; A For convenience this product is designated herein as 3,5-diacetyl~4,6-dihydroxy-2H-pyran-2-one. This agrees with Kiang et al1s gross structure indicated by formula II above.

IS The rate of tautomerization represented by A above is affected, among other factors, by the solvent used in the C spectral study. Accordingly the reaction of this product with an amine, R'NHg gives a product having the tautomeric structures as shown below: Β in which R‘ is lower alkyl, straight or branched chain, of from 3 to 6 carbon atoms, hydroxyphenyl, carbamoyloxyphenyl, N-methylcarbamoyloxyphenyl , N-benzylcarbamoyloxyphenyl, Ν,Ν-dimethylcarbamoyloxyphenyl, p-mercaptophenyl, aminophenyl or ureidophenyl. This also agrees with Kiang et al's gross structure indicated by formula III above.

Although we have not been able to identify by C nmr the exact tautomer represented by (j) in solution, an X-ray crystallographic study in solid form of the compound wherein R1 is p-hydroxyphenyl showed that because of extensive conjugation the carbon-carbon bonds throughout the molecule are hybridized and therefore the bond lengths lie somewhere between the values for double and single bonds. However, since one of the exchangeable hydrogens in this compound is located on the nitrogen, for convenience we have chosen to use one tautomeric form, namely the intermediate enamine pyran-2,6-dione structure, to represent all of the compounds formed by the reaction of (a) with an amine, R'NHg, as indicated by formula I above. It will be apparent however to one skilled in the art that the more complete representation of the compounds of formula I is shown by the tautomerization (Έ). 417 0 9 'j ?.o 2') As indicated above the starting material represented by ζλ) is obtained by reaction of acetonedicarboxylic acid and acetic anhydride, carried out in sulfuric acid at elevated temperature. This material and the amine, R'NHg are usually heated at reflux in an inert organic solvent such as benzene, toluene or methanol for from two to twelve hours to give the products of formula I. Mono-and di-alkali metal salts of the compounds of formula I, such as the mono-and di-sodium or potassium salts are readily obtainable by treatment with the appropriate alkali metal alkoxide, for example methoxide, in an alkanol solvent such as methanol.

Several products of the reaction of 5-carboxydehydroacetic acid, now known to be the structure represented by © , with amines have been reported by Wiley et al. supra and similarly, Kiang et al. supra has disclosed such reaction products as anils. However no biological utility has been described for any of these products.

Certain of the compounds of formula I are novel compounds and as such form a part of this invention. These compounds may be represented by the following formula: wherein R represents lower alkyl, straight or branched chain, of from 3 td 6 carbon atoms, hydroxyphenyl, alkanoyloxyphenyl, the alkanoyl moiety having from 2 to 7 carbon atoms, carbamoyl oxyphenyl, N-methyl carbamoyl oxyphenyl, N-benzylcarbamoyloxyphenyl, N,N-d1methylcarbamoyloxyphenyl, p-mercaptophenyl, p-am1nophenyl or ureldophenyl, and their mono- and di-alkali metal salts.

Particular compounds of this invention ahe those of Formula IV in which R is lower alkyl, straight or branched chain, of from 3 to 6 carbon atoms, p-mercaptophenyl or hydroxyphenyl.

The compounds wherein R is alkanoyloxyphenyl are conveniently prepared from the corresponding hydroxyphenyl derivative by reaction with the appropriate alkanoyl chloride, preferably in an organic base such as triethylamine and a nonreactive solvent such as tetrahydrofuran.

The pharmaceutical compositions of this invention inhibit the release and/or formation of pharmacologically active mediators from effector cells triggered by the interaction of antigen and a specific antibody fixed to the cell surface. Thus the compositions are valuable in the treatment of allergic diseases such as asthma, rhinitis and urticaria.

The inhibitory activity of the compositions of this invention on mediator release in sensitized tissues is measured by the ability of the active medicament to inhibit the passive cutaneous anaphylaxis (PCA) reaction in rats. In this test system, titered and appropriately diluted serum (from rats previously immunized by the intraperitoneal injection of ovalbuminaluminum hydroxide or ovalbumin-i.m.-Bordatella pertussis U.S.P. i.p.-and NBrasiiiensis i.p.) containing reaginic antibodies directed against ovalbumin is injected intradermally at four sites on the shaved backs of normal adult male rats. Forty-eight hours later the animals are injected intravenously with 0.5 ml. of isotonic saline solution containing 5 mg. of the ovalbumin antigen and 5 mg. of Evans blue dye. Chemical mediators such as histamine and serotonin which are released at the sensitized sites as a result of a local cellular anaphylaxis, cause an increase in capillary permeability with resultant leakage of plasma and formation of a wheal.

The wheal is visualized by che plasma protein-bound Evans blue dye. Under conditions of the test, the average control % wheal is approximately 12x12 mm. Thirty minutes following antigen challenge, the animals are killed, the dorsal skin is reflected and the diameter of the wheals recorded. A test compound is administered intravenously, initially at 0.5 minutes prior to antigen challenge (longer pretreatment times and other routes of drug administration, i.e. oral or intraperitoneal, may be employed). Percent inhibition is calculated from the difference in mean average wheal diameter between a treated group and saline or appropriate diluent controls.

The compounds of formula I administered intravenously to rats at doses of from 0.5 to 10 mg/kg produce marked inhibition of the PCA reaction. A preferred compound, 5-acetyl-4-hydroxy-3-[1-(p-hydroxyphenylamino)-ethylidene] 2H-pyran-2,6(3H)-dione, produced 73% inhibition of the rat PCA wheal at 5.0 mg/kg, i.v. Another preferred compound, 5-acetyl-4-hydroxy-3-[l-(p-mercaptophenylamino)-ethylidene]2-H-pyran-2,6(3H)-dione, produced 100% inhibition of the i rat PCA wheal at 5.0 mg/kg, i.v. Similarly 5-acetyl-3-[l(p-aminophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)dione produced 58% inhibition of the rat PCA wheal at 0.5 mg/kg, i.v.

In testing for mechanism of action, the compounds of formula I were found not to provide comparable inhibition of wheals of equal severity produced in rats by the intra8 cutaneous administration of histamine and serotonin following i.v. administration of the test compound at the same dose and pretreatment time which exhibited significant inhibition of the rat 48-hour PCA reaction.

Upon oral administration, 5-acetyl-4-hydroxy-3[1-(p-hydroxyphenylamino)ethylideneJ-2H-pyran-2,6(3H)-dione produced 58% inhibition in the rat 48 hour PCA system at 25 mg/kg and a pretreatment time of 15 minutes. This compound is also active in vitro for inhibition of antigen induced mediator release from monkey lung and skin and rat lung systems at concentrations of 3.3 x 10^M to 3.3 x 10'6M. Similarly 5-acetyl-3-[l-(p-aminophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione upon oral administration produced 32% inhibition in the rat 48 hour PCA system at 25 mg/kg and a pretreatment time of 5 minutes.

The pharmaceutical compositions of this invention comprise an appropriate amount of a substituted 2H-pyran2,6(3H)-dione derivative as set forth in formula I in association with a pharmaceutical carrier or diluent. The nature of the composition and the pharmaceutical carrier or diluent will of course depend upon the intended route of administration, i.e. orally, parenterally or by inhalation. Preferably the active medicament is administered to an animal in a composition comprising an amount sufficient to produce an inhibition of the antigen-antibody reaction.

When employed in this manner, the dosage of composition is such that from 0.5 mg to 500 mg of active ingredient are administered at each administration. Advantageously equal doses will be administered 1 to 4 times daily with the daily dosage regimen being about 0.5 mg to about 2000 mg.

In general, particularly for the prophylactic treatment of asthma, the compositions will be in a form suitable for administration by inhalation. Thus the compositions will comprise a suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer. Alternatively the compositions will comprise a suspension or solution of the active ingredient in a conventional liquified propellant such as dichlorodifluoromethane or chlorotrifluoroethane to be administered from a pressurized container. The compositions may also comprise the solid active ingredient diluted with a solid diluent, e.g. lactose, for administration from a powder inhalation device. In the above compositions, the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid, it may be present in Less, equal or greater amounts than the solid active ingredient.

A wide variety of other pharmaceutical forms can be employed. Thus, if a solid carrier is used the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet, form, or in the form of a troche or lozenge for oral administration. The amount of solid carrier will vary widely but preferably will be about 25 mg to about 1 If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule, or an aqueous or nonaqueous liquid suspension.

Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Exemplary of liquid carriers are syrup, peanut oil, olive oil and water.

Similarly the carrier or diluent can include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

The effects of an antigen-antibody reaction may be inhibited by the prior application of a therapeutically effective amount of a substituted 2H-pyran-2,6(3H)-dione of formula I to the area of antigen-antibody reaction. A particular application is a method of relieving or preventing allergic airway obstruction which comprises administering to an animal a therapeutically effective amount at suitable i ntervals.

The pharmaceutical preparations are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary, or variously mixing and dissolving the ingredients as appropriate to the desired end product.

The accompanying examples illustrate the preparation of compounds of formula I and their incorporation into pharmaceutical compositions of this invention and as such are not to be considered as limiting the invention set forth in the claims appended hereto.

EXAMPLE 1 To a boiling solution of 4.2 g. (0.02m.) of 3,5diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml. of benzene/methanol is added 1.2g (0.02m.) of n-propylamine and the resulting mixture is refluxed overnight. The 417 0 9 reaction mixture is concentrated, filtered and the solid treated with wafer to give pure 5-acetyl-4-hydroxy-3-[l(n-propylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 145-148°C.

Similarly, 1.8 g. (0.025 m.) of n-butylamine and .3 g. (0.025 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2one are refluxed overnight in 50 ml. of benzene and the resulting solid filtered to give 5-acetyi-3-[l-(n-butylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 112-114°C.

EXAMPLE 2 To a boiling solution of 4.2 g. (0.02 m.) of ,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml. of benzene is added 2.0 g. (0.02 m.) of n-hexylamine and the mixture is concentrated and the oily residue is triturated with petroleum-ether to give 5-acetyl-3-[l-(n-hexylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 80-82°C.

EXAMPLE 3 3,5-Diacetyl-4,6-dihydroxy-2H-pyran-2-one (5.3 g.) is dissolved in 200 ml. of boiling toluene and an equimolar amount of p-chloroaniline is added. The mixture is refluxed for 12 hours, cooled and filtered to yield 5-acetyl-3[l-(p-chlorophenylamino)ethylidene]-4-hydroxy-2H-pyran2,6(3H)-dione, m.p. 205-206°C.

EXAMPLE 4 o-Chloroaniline (2.55 g., 0.02 m.) is added to 4.24 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2one in 150 ml. of methanol and the mixture is refluxed overnight. The reaction mixture is concentrated, cooled and filtered to give 5-acetyl-3-[l-(o-chlorophenylamino)ethylidene]-4-hydroxy-2U-pyran-2,6(3H)-dione, m.p. 143-145°C Similarly, equimolar amounts of tn-chloroaniline anti 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one are refluxed in methanol to afford, after workup, 5-acetyl-3-[l-(m-chloro phenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 163-164°C.

EXAMPLE 5 To a boiling solution of 4.24 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 200 ml. of methanol is added 2.18 g. (0.02 m.) of p-hydroxyaniline.

The resulting mixture is refluxed overnight and filtered to yield 5-acetyl-4-hydroxy-3-[l-(p-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 223-225°C. Both the mono-and di-sodium salts are prepared upon treatment of the dione with sodium methoxide in methanol.

Similarly, m-hydroxyaniline and o-hydroxyaniline are reacted with an equimolar amount of 3,5-diacetyl-4,6dihydroxy-2H-pyran-2-one in methanol to give the respective products, 5-acetyl-4-hydroxy-3-[l-(m-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 213-216°C., and 5-acetyl-4-hydroxy-3-[l-(o-hydroxyphenylamino)ethylidene]2H-pyran-2,6(3H)-dione, m.p. 210-212°C.

EXAMPLE 6 p-Fluoroaniline (2.2 g., 0.02 m.) is added to a hot solution of 4.24 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml. of methanol. The mixture is refluxed overnight and filtered to give 5-acetyl-3-[l(p-fluorophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 199-201°C. j EXAMPLE Ί A mixture of 2.12 g. of 3,5-diacetyl-4,6-dihyilroxy-2H-pyran-2-one, 1.25 g. of p-aminothiophenol and 75 m3 . of methanol is refluxed for two hours, cooled and filtered to yield 5-acetyl-4-hydroxy-3-[l-(p-mercaptophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 207-210°C.

EXAMPLE 8 To a boiling solution of 3.0 g. (0.014 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 25 ml. of benzene is added 1.4 g. (0.015 m.) of aniline and the resulting mixture is refluxed overnight. The reaction mixture is cooled and filtered to give 5-acetyl-4-hydroxy-3-[lphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 184-186°C Similarly, equimolar amounts of p-methoxyaniline and 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one are refluxed in methanol to give, upon workup, 5-acetyl-4-hydroxy-3-[l(p-methoxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 212-214°C.

EXAMPLE 9 o-Phenylenediamine (2.1 g., 0.02 m.) is added to a hot solution of 4.2 g. (0.02 m.) of 3,5-diacetyl-4,6dihydroxy-2H-pyran-2-one in methanol and the resulting mixture is refluxed for two hours. The reaction mixture is cooled and filtered to yield 5-acetyl-3-[l-(o-amihophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 179-181°C.

Similarly, reaction of an equimolar amount of p-phenylenediamine as described above gives the corresponding 5-acetyl-3-[l-(p-aminophenylamino)ethylidene]-4-hydrox_v2H-pyran-2,6(3H)-dione, m.p. 215-218°C.

EXAMPLE 10 To a solution of 3.03 g. (0.01 m.) of 5-acetyl4-hydroxy-3-[l-(p-hydroxyphenylamino)ethylidene]-2H-pyran2,6(3H)-dione, 1.0 g. (0.01 m.) of triethylamine in 150 ml. of tetrahydrofuran is added 0.78 g. (0.01 m.) of acetyl chloride. The resulting mixture is refluxed for two hours, cooled and filtered. The solid is recrystallized to give 3-[l-(p-acetoxyphenylamino)ethylidene]-5-acetyl-4-hydroxy2H-pyran-2,6(3H)-dione, m.p. 199-201°C.

Similarly, equimolar amounts of 5-acetyl-4-hydroxy-3-[l-(p-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione and an appropriate alkanoyl chloride are reacted as described above to give the following alkanoyloxy derivatives : ι -acetyl-4-hydroxy-3-[l-(p-propionyloxypheny1amino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 168-170°C; -acetyl-3-[l-(p-butyryloxyphenylamino)ethylidene] -4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 158-160°C.; -acetyl-4-hydroxy-3 -[1-(p-pentanoyloxypheny1amino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 155-157°C: -acetyl-3 -[1-(p-hexanoyloxyphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 148-149°C.; -ace ty1-3-(1-(p-hep tanoyloxyphenylamino)e thylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 147-148°C.

EXAMPLE 11 To a boiling solution of 2.1 g. (0.01 m.) of -,5 diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml. of methane is added 2.4 g. (0.01 m.) of p-(N-benzylcarbamoyloxy)aniline and the resulting mixture is refluxed for one hour.

The cooled reaction mixture is filtered and the solid is recrystallized to furnish 5-acetyl-3~[l-(p-N-benzylcarbamoyloxyphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 195-197°C.

EXAMPLE 12 A solution of 1.88 g. (0.01 ra.) of p-carbamoyloxyaniline hydrochloride and 1.0 g. (0.01 m.) of triethylamine in 50 ml. of methanol is added to a hot solution of 2.21 g. (0.01 m.) of 3,5-diacetyl-4,6-dihydroxy-2H«pyran-2one in 150 ml. of methanol. The resulting mixture is refluxed for two hours, cooled and the filtered solid recrystallized to give 5-acetyl-3-il-(p-carbamoyloxyphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 213-215°C.

Similarly, reaction with p-(N-methylcarbamoyloxy)aniline or p-(N,N-dimethylcarbamoyloxy)-aniline as described above or in Example 11 yields the corresponding products, namely 5-acety1-4-hydroxy-3-[1-(ρ-N-methylcarbamoyloxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione and 5-acetyl3-[l-(p-N,N-dimethylcarbamoyloxyphenylamino)ethylidene]-4hydroxy-2H-pyran-2,5(3H)-dione.

EXAMPLE 13 A solution of 1.5 g. (0.01 m.) of p-ureidoaniline in 50 ml. of methanol is added to a solution of 2.1 g. (0.01 m.) of 3,5-diacetyl-4,6-dihydroxy 2H-pyran-2-one in 150 mi. of methanol. A solid is formed immediately and the mixture is refluxed for 12 hours. The filtered solid is recrystallized to give 5-acetyl-4-hydroxy-3-[l-(pureidophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 250-253°C.

As a specific embodiment of a useful composition of this invention, an active ingredient such as 5-acetyl-4hydroxj—3-[1-(n-propylamino)ethylidene]-2H-pyran-2,6(3H)dione is dissolved in sterile water at a concentration of 0.5% and aerosolized from a nebulizer operating at an air flow adjusted to deliver the desired aerosolized weight of drug.

For oral administration, compositions such as those in the following examples can be prepared.

EXAMPLE 14 Ingredients Mg./Tablet -Acetyl-4-hydroxy-3*[l-(p- 10 hydroxyphenylamino)ethylidene] -2H-pyran-2,6(3H)-dione Calcium sulfate, dihydrate 150 Sucrose, 25 Starch 15 Talc 5 Stearic acid 3 The sucrose, calcium sulfate and active ingredient are thoroughly mixed and granulated with hot 10% gelatin solution. The wetted mass is passed through a #6 mesh screen directly onto drying trays. The granules are dried at 120°F. and passed through a #20 mesh screen, mixed with the starch, talc and stearic acid, and compressed into tablets.

EXAMPLE 15 Ingredients Mg./Capsule -Acetyl-4-hydroxy-3-[l-(p- 50 hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione Ingredients EXAMPLE 15 (cont'd) Mg./Capsule Magnesium stearate Lactose 350 The above ingredients are screened through a #40 mesh screen, mixed and filled into #0 hard gelatin capsules.

It will be understood that the applicant makes no claim to a preparation or composition consisting merely of a compound of Formula I in solution or suspension in non-sterile water or a common organic solvent.

Claims (32)

1. A pharmaceutical composition which inhibits the antigen-antibody reaction comprising a pharmaceutical carrier or diluent and a compound represented by the formula: wherein R is lower alkyl, straight or branched chain, of from 3 to 6 carbon atoms, phenyl, halophenyl, hydroxyphenyl, methoxyphenyl, alkanoyloxyphenyl, the alkanoyl moiety having from 2 to 7 carbon atoms, carbamoyloxyphenyl, N-methylcarbamoyloxyphenyl, N-benzylcarbamoyloxyphenyl, Ν,Ν-dimethylcarbamoyloxyphenyl, p-mercaptophenyl, aminophenyl or ureidophenyl, or a mono-or di-alkali metal salt of said compound.

2. A pharmaceutical composition according to claim 1 in a form suitable for administration by inhalation.

3. A pharmaceutical composition according to claim 1 comprising a solution or suspension of the active ingredient in sterile water.

4. A pharmaceutical composition according to claim 1 in the form of an aerosol formulation.

5. A pharmaceutical composition according to claim 1 comprising the solid active ingredient diluted with a solid diluent.

6. A pharmaceutical composition according to claim 1 in which R is n-propyl, p-mercaptophenyl, hydroxyphenyl, p-acetoxyphenyl, p-pentanoyloxyphenyl, p-aminophenyl or p-ureidophenyl. A pharmaceutical composition in which R is p-hydroxyphenyl.

7. 8. A pharmaceutical composition 5 in which R is p-aminophenyl.

8. 9. A pharmaceutical composition 1 in dosage unit form. according accordi ng accord ing to Claim 6 to claim to claim

9. 10. A pharmaceutical composition according to claim 9 in which the active ingredient is in an amount of 0.5 mg to 500 mg. per dosage unit.

10. 11. A pharmaceutical composition according to claim 9 in which R is n-propyl, p-mercaptophenyl, hydroxypheny!, p-acetoxyphenyl, p-pentanoyloxyphenyl, p-aminophenyl or p-ureidophenyl.

11. 12. A pharmaceutical composition according to claim 11 in which R is p-hydroxyphenyl.

12. 13. A pharmaceutical composition according to claim 12 in a form suitable for oral administration. 4ί 70S

13. 14. A pharmaceutical composition according to claim 13 in the form of a tablet or capsule.

14. 15. A pharmaceutical composition according to claim 11 in which R is p-aminophenyl.

15. 16. A compound represented by the formula: CH. wherein R ie lower alkyl, straight or branched chain, of from 3 to 6 carbon atoms, hydroxyphenyl, alkanoyloxyphenyl, the alkanoyl moiety having from 2 to 7 carbon atoms, carbamoyloxyphenyl, N-methylcarbamoyloxyphenyl, N-benzylcarbamoyloxyphenyl, Ν,Ν-dimethylcarbamoyloxyphenyl, p-mercapto phenyl, aminophenyl or ureidophenyl, or a mono-or di-alkali metal salt of said compound.

16. 17. A compound according to claim 16 in which R is hydroxyphenyl.

17. 18. A compound according to claim 17 in which R is p-hydroxyphenyl.

18. 19. A compound according to claim 18 in the form of a disodium salt.

19. 20. A compound according to claim 16 in which R is p-aminophenyl.

20. 21. The product hereinbefore referred to as a compound of Formula IV formed by the process wherein acetonedicarboxylic acid is reacted with acetic anhydride an^L.the resulting product is reacted with an amine, KNH 2 , in which R is lower alkyl, straight or branched chain, of from 3 to 6 carbon atoms, hydroxyphenyl, . 21 carbamoyloxyphenyl, n-methyTcarbamoyloxyphenyl, N-benzylcarbamoyloxyphenyl, Ν,Ν-dimethylcarbamoyloxyphenyl, p-mercaptophenyl, aminophenyl or ureidophenyl.

21. 22. The product according to claim 21 in which R is p-hydroxyphenyl.

22. 23. A process for the preparation of compounds according to Claim 16 wherein R is lower alkyl, straight or branched chain, of from 3 to 6 carbon atoms, hydroxyphenyl, carbamoyloxyphenyl, N-methylcarbamoyloxyphenyl, N-benzylcarbamoyloxyphenyl, Ν,Ν-dimethylcarbamoyloxyphenyl, p-mercaptophenyl, aminophenyl or ureidophenyl, which comprises reacting 3,5-diacetyl-4,5-dihydroxy-2H-pyran2-one with an amine, RNHg, in which R is as defined above.

23. 24. The process of claim 23 in which the reactants are heated at reflux in an inert organic solvent for from two to twelve hours.

24. 25. The process of claim 23 in which the products are treated with an alkali metal alkoxide to give the corresponding mono- and di-alkali metal salts.

25. 26. The process of claim 23 in which the amine is p-hydroxyaniline.

26. 27. A pharmaceutical composition according to Claim 1 or Claim 9 in which R is lower alkyl, straight or branched chain, of from 3 to 6 carbon atoms, phenyl, halophenyl, hydroxyphenyl, methoxyphenyl, p-mercaptophenyl or aminophenyl.

27. 28. A compound according to Claim 16 in which R is lower alkyl, straight or branched chain, of from 3 to 6 carbon atoms, p-mercaptophenyl or hydroxyphenyl.

28. 29. A pharmaceutical composition according to Claim 1 or Claim 9 in which the active ingredient is a compound as hereinbefore described in any one of Examples 1 to 13.

29.

30. A process for the preparation of compounds 5 according to Claim 16 wherein R is alkanoyloxyphenyl, the alkanoyl moiety having from 2 to 7 carbon atoms, which comprises treating a compound according to Claim 16 wherein R is hydroxyphenyl with the appropriate alkanoyl chloride. 10

31. A process according to Claim 30 wherein the reaction is carried out with triethylamine in tetrahydrofuran.

32. A compound according to Claim 16 whenever prepared by a process according to any one of claims 23-26, 30 and 31.