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Publication numberUS3551571 A
Publication typeGrant
Publication dateDec 29, 1970
Filing dateMay 19, 1967
Priority dateMay 19, 1967
Also published asDE1770459A1
Publication numberUS 3551571 A, US 3551571A, US-A-3551571, US3551571 A, US3551571A
InventorsDavid L Nicholas, Irwin J Pachter
Original AssigneeEndo Lab
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Methods for reducing pain,reducing fever and alleviating inflammatory syndromes with heteroaromatic pyrrol-3-yl ketones
US 3551571 A
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Description  (OCR text may contain errors)

United States Patent Oflice US. Cl. 424274 9 Claims ABSTRACT OF THE DISCLOSURE A method for administering heteroaromatic pyrrol-3-yl ketones to mammals and therapeutic compositions incorporating such compounds and orally, parenterally or rectally administrable pharmaceutical carriers as well as novel heteroaromatic pyrrol-3-yl ketones are disclosed. The heteroaromatic pyrrol-3-yl ketones have antiinflarnmatory, analgetic and antipyretic properties.

BACKGROUND OF THE INVENTION (A) Field of the invention This invention relates to a method for the use of certain chemical compounds having valuable pharmacodynamic activity, and to therapeutic compositions incorporating such compounds. More particularly, the invention relates to a method for administering certain heteroaromatic pyrrol-3-y1 ketones having antiinflammatory, analgetic and antipyretic properties and to therapeutically useful compositions incorporating such materials.

(B) Description of the prior art Various heteroaromatic pyrrol-3-yl ketones have previously been described by Gardner, Wenis and Lee (J. Org. Chem. 23, 823 [1958]). Such compounds were reported to be without pharmacological or chemotherapeutic interest.

SUMMARY OF THE INVENTION It has been found, in accordance with the present invention, that pain may be relieved, fever reduced, and inflammatory syndromes in mammals alleviated, by the administration of compounds of the following formula:

R I C =Het R -L lRa N R may be hydrogen; lower alkyl, lower alkenyl or cycloalkyl having not more than six carbon atoms; or benzyl or phenyl, including halo, lower alkoxyor lower alkylsubstituted benzyl or phenyl groups, the lower alkoxy or lower alkyl substituents of which have not more than four carbon atoms;

R R and R may each be hydrogen; lower alkyl, lower alkenyl, lower alkynyl, or cycloalkyl, having not more than six carbon atoms; halo; or phenyl or phenyl lower alkyl, the alkyl substituent of which has not more than four carbon atoms, and including lower alkoxyor lower alkyl-substituted phenyl or phenyl lower alkyl groups, the lower alkoxy or lower alkyl substituents of which have not more than four carbon atoms; and

Het is a fiveor six-membered heteroaromatic monocyclic radical, viz, a fully unsaturated monocyclic heterocyclic radical wherein the hetero atoms are nitrowherein:

Patented Dec. 29, 1970 gen, oxygen or sulfur or combinations of two or more of such moieties.

Most unexpectedly, and contrary to the teachings of the above cited prior art, it has been discovered in accordance with the present invention that the noted class of compounds has outstanding antiinflammatory, analgetic and antipyretic properties. Such compounds are of particular value in alleviating the symptoms of rheumatic, arthritic, allergic and other inflammatory conditions.

In comparison with other nonsteroidal antiinflammatory compounds known in the art, the compounds employed in accordance with the present invention are remarkable for their potency, for their ability to alleviate deep pain as evidenced by their activity on the hot plate test for analgesia, and for their ability to reverse an experimentally induced inflammatory condition in animals.

The biological activity of one of the preferred compounds of this invention, Z-furyl 2,5-dimethylpyrrol-3-yl ketone (see Example 1 below) may be cited as an illustration of efficacy. This compound is three times as potent as phenylbutazone in the carrageenin edema assay in the rat. As an antipyretic it is equal in potency to indomethacin, ten times as potent as phenylbutazone and 40 times as potent as aspirin. In the hot plate test for analgesia it is approximately equal to codeine phosphate and is much more potent than aspirin, indomethacin or phenylbutazone, which are essentially inactive in this test. Z-furyl 2,5-dimethylpyrrol-3-yl ketone, furthermore, has the ability to reverse an experimentally induced infiammation.

Indomethacin, phenylbutazone and aspirin suppress inflammation, but only the compounds of the present in- "vention reverse inflammations already produced. In the cotton pellet granuloma test, many compounds of this invention are equal in potency to hydrocortisone.

The compounds are therapeutically useful when administered to mammals orally, parenterally or rectally. The oral route is preferred. Although they may be administered as pure compounds, the limited solubility in water of many of the compounds employed in the practice of this invention makes it advantageous to combine them with pharmaceutically acceptable carriers such as starch, sugar, talc and the like to form powder-s which can be used directly or inserted into gelatin capsules or converted into tablets. Suitable lubricants like magnesium stearate, binders such as gelatin and disintegrating agents like sodium carbonate in combination with citric acid can be used to form tablets. They may also be formulated as suspensions or emulsions in suitable liquid carriers.

DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION In this specification, and in the claims appended hereto, all radicals identified are intended to include both the unsubstituted groups and the corresponding substituted moieties. Moreover, all parts and percentages are given by weight, unless otherwise indicated.

As noted hereinabove, the heterocyclic moiety of the therapeutically active compounds utilized in the practice of the present invention may incorporate any suitable 5- or 6-membered heteroaromatic monocyclic radical. Among the preferred heteroaromatic groups which may thus be utilized are furyl, pyrryl, thienyl, oxadiazolyl, pyrazolyl, thiadiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyridyl, imidazolyl, tetrazolyl, isoxazolyl, pyrirnidinyl, triazolyl and isothiazolyl. Such radicals may be unsubstituted or, alternatively, substituted, for example, by halogen, nitro, amino, hydroxy, phenyl, sulfamoyl, carbamoyl, cyano, trifluoromethyl, mercapto, lower alkyl, lower,

alkylthio, lower alkoxy, lower alkylamino, di-lower alkylamino, lower .alkanoylamino, carb-lower alko'xy, and

phenyl lower alkyl, the carbon chains of the aliphatic substituted substituents having not more than six carbon atoms.

Among the most preferred compounds employed in the practice of the present invention are those in which the heteroaromatic monocyclic radical Het is a 2- or 3-furyl group, whether unsubstituted or substituted as aforesaid, the preferred substituents on such radical being selected from the group consisting of halo, nitro, amino, or lower alkyl, lower alkoxy or lower alkylthio having no more than four carbon atoms in their aliphatic chains.

It is further preferred to employ as active compounds those wherein R is hydrogen and R R and R may each be selected from the group of hydrogen, halogen, or lower alkyl or cycloalkyl having not more than six carbon atoms. It is particularly desirable to incorporate such substituents in the active compounds utilized in accordance herewith when the heterocyclic moiety of the compound is constituted of the preferred 2- or 3-furyl; 2- or 3-thienyl; pyrrol-2-yl or pyrrol-3-yl; or 1,2,5-oxadiazol-3- yl or 1,2,4-oxadiazol-3-yl radicals.

Many of the compounds employed in the present method may be prepared by means of the reaction of an acid chloride with a Grignard derivative of an appropriate pyrrole. This reaction may be represented as follows:

+ llet-COCl Ila-W RJ LN/ l ti and may be carried out by reacting the pyrroles having the substituents indicated hereinabove with suitable acid halide derivatives of the desired heteroaromatic moieties, preferably the acid chlorides or acid bromides thereof.

The boron trifluoride catalyst is preferably utilized in the form of a suitable complex such as an etherate complex, which is understood to mean a complex of boron trifluoride with dialkyl ethers such as diethyl ether, dimethyl ether, dipropyl ether, and the like, as well as cyclic ethers such as tetrahydrofuran or dioxan. These complexes are prepared in accordance with methods well known in the art.

In the preferred modifications of the process, the pyrrole which is to form the pyrrole moiety of the ketone, the heteroaromatic acid halide, and the boron trifluoride complex are mixed in an anhydrous reaction-inert organic solvent, suitably a hydrocarbon solvent such as an aliphatic hydrocarbon solvent, for example, hexane, heptane, octane, cyclohexane, cycloheptane or the like, or an aromatic solvent such as benzene or toluene. Benzene is the solvent of choice, since undesirable side reactions are thereby minimized.

While the reaction temperature is not critical, ambient temperatures, say from about to about 30, suitably about are preferred. At the lower temperatures the reaction proceeds too slowly, and at higher temperatures undesirable side reactions will occur.

While it is known to carry out a Friedel-Crafts reaction on compounds similar to the pyrroles utilized in the process of the present invention, using other Friedel- Crafts catalysts, for example, magnesium bromide, boron trifluoride is employed as the catalyst herein. This reagent has many advantages over other Friedel-Crafts catalysts in the process of this invention. Boron trifluoride, particularly in its etherate form, is a far more convenient reagent to employ in large scale syntheses than other Friedel-Crafts catalysts such as magnesium bromide. Furthermore, boron trifluoride is readily purified and does not leave solid residues.

The boron trifluoride Friedel-Crafts process of the present invention is also superior to the Grignard process mentioned hereinabove in that the use of ether or similar solvents required in Grignard reactions is kept to a mini mum, it being well known that the use of large volumes of ether in industrial processes gives rise to problems involving extraordinary precautions against fire and explo- $1011.

The compounds utilized in the present invention, which include both novel and known substances, may, as noted above, be compounded into tablets or capsules. Suitably, such dosage forms contain from about 5 to 500 mg., preferably 15 to mg., of active material per tablet or capsule. Alternatively stated, the therapeutically active compounds are incorporated in such dosage forms in the proportion of therapeutically active material to carrier of between 1:30 and 1:0.33, preferably 1:10 to 121.5. Also within the purview of this invention are solutions, emulsions or suspensions of the active materials containing between 0.1 mg. and 100 mg. per ml. of liquor, preferably 5 to 25 mg. per ml. of liquor.

It is understood that the non-therapeutically active material used in preparing the aforementioned capsules, tablets, solutions, suspensions or emulsions may consist of any of the pharmaceutically acceptable carriers, suspendants, additives and the like usually used in the preparation of the dosage forms specified hereinabove.

The active compounds may also be admixed with cocoa butter or the like to form suppositories containing from 1 mg. to 250 mg., suitably from 10 to 100 mg., of the active compound per suppository, that is to say the ratio of active material to carrier in the suppository falls within the range of from about 1:2000 to about 1:8, preferably from about 1:200 to 1:20.

Also within the scope of the present invention are certain novel compounds Within the class defined hereinabove, having the structural formula:

wherein:

R is hydrogen; lower alkyl, lower alkenyl or cycloalkyl, having not more than six carbon atoms; benzyl; or phenyl;

R R and R are each hydrogen; lower alkyl, lower alkenyl, lower alkynyl or cycloalkyl, having not more than six carbon atoms; phenyl, phenyl lower alkyl in which the alkyl group has not more than four carbon atoms; halo;

H, is furyl, pyrryl, thienyl, oxadiazolyl, pyrazolyl, thiadiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyridyl, imidazolyl, tetrazolyl, isoxazolyl, pyrimidinyl, triazolyl or isothiazolyl;

Z in the group (Z) is hydrogen, halogen, nitro, amino,

hydroxy, phenyl, sulfamoyl, carbamoyl, cyano, trifluoromethyl, mercapto, lower alkyl, lower alkylthio, lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoylamino, lower alkoxycarbonyl, and phenyl lower alkyl, the carbon chains of the aliphatic substituted substituents having from one to six carbon atoms; n is 0,1, 2 or 3;

and the moieties Z may be the same or dillerent;

where R and R are lower alkyl and H, is furyl or thienyl, at least one member of the group (Z) is other than hydrogen and n is other than zero.

It will, therefore, be understood that furyland thienyl- 2,5-di-lower alkyl-pyrrol-3-yl ketones are not within the scope of the novel compounds of this invention.

The following examples are given as non-limiting illustrations of therapeutic compositions prepared in accordance with preferred embodiments of the present invention. In the following examples, as well as hereinabove, all parts and percentages are given by weight and all temperatures in C., unless otherwise indicated.

EXAMPLE 1 Capsules containing 2-puryl 2,5-dimethylpyrrol- 3-yl ketone The indicated compound is prepared by reaction of the Grignard derivative of 2,5-dimethylpyrrol with 2- furoyl chloride. Initially, the Grignard reagent is prepared by placing magnesium (3.6 g.) in a round-bottom flask in an anhydrous system, and the system then flushed with dry nitrogen. Suflicient anhydrous ether to cover the magnesium ml.) is then added.

Two grams of methyl iodide is then added to initiate reaction. Once reaction begins, a solution of 14.3 g. of methyl iodide in ml. of dry ether is added, with stirring, at a rate suflicient to maintain reflux. tAfter addition is complete, reflux and stirring are continued for one hour.

External heating is then discontinued and a solution of 9.5 g. of 2,5-dimethylpyrrole in 10 ml. of dry ether is added dropwise at a rate suflicient to maintain reflux. Stirring is continued for an additional minutes, during which time a heavy precipitate forms.

Dry benzene (30 ml.) is added and the reaction mixture cooled to below -10. While stirring, a solution of 14.3 g. of Z-furoyl chloride in 20 ml. of benzene is slowly added, maintaining the internal temperature between 10 and -50". Stirring is continued an additional two hours while the reaction mixture comes to room temperature.

The reaction mixture is then cooled in an ice bath and 30 ml. of 25% aqueous ammonium chloride is added dropwise, followed by 100 ml. of water. The layers are then separated and the organic layer washed successively with water, two 50 ml. portions of 10% aqueous sodium hydroxide, and again with H O. After drying, the solvent is removed at diminished pressure and the residue triturated with five 20 ml. portions of hexane and then filtered. The product is dissolved in benzene and decolorized by passage through a short column of alumina. Concentration of the benzene eluate aifords 14 g. of pure product, M.P. 9899.

The thus prepared compound is incorporated in the following composition for capsule use:

Ingredient: Mg./capsule 2-furyl 2,5-dimethylpyrrol-3-yl ketone 15 Lactose 150 Cab-O-Sil (colloidal silica) 2.5

The above mixture is well mixed, screened through a #60 mesh sieve and 'filled into two-piece, hard gelatin capsules.

Similar antiinflammatory compounds are prepared employing the procedure of the preceding example by reaction of other appropriate acid halides in place of the 2- furoyl chloride reactant. In such manner the following compounds are prepared for capsule or other mode of administration.

4,5-dibromo-2-furyl 2,5-dimethylpyrrol-3-yl ketone 5-bromo-4-isopropyl-2-furyl 2,5-dimethylpyrrol-3-yl ketone 4-bromo-5-methyl-2-furyl 2,5-dimethylpyrrol-3-yl ketone 3-chloro-2-furyl 2,5-dimethylpyrrol-3-yl ketone 5-methoxy-2-furyl 2,5-dimethylpyrrol-3-yl ketone 3,5-dichloro-2-furyl 2,5-dimethylpyrrol-3-yl ketone 5-acetyl-2-furyl-2-furyl 2,5-dimethylpyrrol-3-yl ketone S-acetyl-Z-furyl 2,5-dimethylpyrrol-3-yl ketone 5-isopropoxy-2-furyl 2,5-dimethylpyrrol-3-yl ketone 5-ethylthio-2-furyl 2,5-dimethylpyrrol-3-yl ketone 2,5-dimethylpyrrol-3-yl 5-piperidino-2-furyl ketone EXAMPLE 2 Tablets containing 5'-bromo-2'fnryl 2,5-dimethylpyrrol- 3-yl ketone The above active compound is prepared by reacting 5-bromo-2-furoyl chloride with the Grignard derivative of 2,5-dimethylpyrrole. In order to form the Grignard reagent 19.02 g. of 2,5-dimethylpyrrole is added dropwise with stirring to a Grignard solution prepared from 5.84 g. of magnesium and 26.4 g. of ethyl bromide in 200 ml. of anhydrous ether. The mixture is stirred for 30 minutes after addition is completed. A solution of 50.3 g. of 5- bromo-2-furoyl chloride in 150 ml. of anhydrous benzene is added and the reaction mixture is stirred for 2 hours, then heated at reflux for 0.5 hour. 35 ml. of 25 aqueous ammonium chloride is added to quench the reaction. The organic layer is separated, washed with water, 10% aqueous sodium bicarbonate and water, and then dried. Upon concentration a solid, M.P. 165-167", is obtained. The product is recrystallized from ethyl acetate/benzene (1:1) to give yellow crystals, M.P. 166- 167.

The thus prepared compound is incorporated in the following composition for tableting:

Ingredient: Mg./tablet 5-bromo-2-furyl 2,5-dimethylpyrrol-3-yl ketone 25 Lactose, USP Magnesium stearate 1.2 Polyvinylpyrrolidone 6 Absolute ethanol, as required The keytone produce is initially blended with the lactose, the mixture screened through a #40 mesh screen and reblended. The PVP is dissolved in the alcohol and used to granulate the powder mass, after which the mixture is screened through a #12 screen, and dried at -120 F. to 1.5% moisture content. The mass is then screened through a #16 screen and magnesium stearate (which has been previously screened through a #40 mesh) added thereto. The composition is mixed and compressed into tablets.

EXAMPLE 3 Suppositories containing S-furyl 2,5-dimethylpyrrol-3-yl ketone The above product is prepared by reaction of 3-furoyl chloride with the Grignard reagent of 2,5-dimethylpyrrole. Initially, the 3-furoyl chloride is prepared by heating a mixture of 20 g. of 3-furoic acid and 30 g. of thionyl chloride on a steam bath for eight hours. The excess thionyl chloride is evaporated and the residue is extracted twice with benzene and then distilled to give the 3-furoyl chloride, B.P. 475 at 15 mm.

3.43 g. of 2,5-dimethylpyrrole is then added to a Grignard solution prepared from 0.9 g. of magnesium and 4.07 g. of ethyl bromide in 30 ml. of ether. The mixture is stirred for 30 minutes after addition is completed. A solution of 4.4 g. of the 3-furoyl chloride in 15 ml. of anhydrous benzene is added and the mixture is stirred under nitorgen for two hours, then heated at a reflux for 0.5 hour. 5 ml. of 25 aqueous ammonium chloride is added to quench the reaction. The organic layer is separated, washed with water, 10% aqueous sodium bicarbonate, and water and then dried. Upon concentration, a solid, M.P. 90-95 is obtained. The product is decolorized on an alumina column, recrystallized twice from benzene and dried in vacuo to give a solid, M.P. 99-100.

The active compound thus prepared is thoroughly admixed with cocoa butter to provide 2 g. suppositories of the following composition:

Ingredient: Mg./suppository 2-fury 2,5-dimethylpyrrol-3-yl ketone 100 Cocoa butter, Q.s.

Similar therapeutically active compounds are prepared by the reaction of other acid halides in place of 3-furoyl chloride employing the procedure of the preceding example. The following are thus prepared:

5-acetyl-3-furyl 2,5-dimethylpyrrol-3-yl ketone 2,5-dimethyl-3-furyl 2,5-dimethylpyrrol-3-yl ketone 2-methyl-5-phenyl-3-furyl 2,5-dimethylpyrrol-3-yl ketone 5-bromo-3-furyl 2,5-dimethylpyrrol-3-yl ketone Suspension of 2,5-dimethylpyrrol-3-yl 2-thienyl ketone EXAMPLE 4 The above active compound is prepared by reaction of 2-thiophenecarboxylic acid chloride with the Grignard derivative of 2,5-dimethylpyrrole.

The Grignard reagent is initially prepared by adding 16.14 g. of 2,5-dimethylpyrrole to a Grignard solution prepared from 4.12 g. of magnesium and 18.7 g. of ethylbromide in 150 ml. of anhydrous ether. The mixture is stirred for 30 minutes after the addition is completed.

A solution of 25 g. of Z-thiophenecarboxylic acid chloride in 100 ml. of anhydrous benzene is then added. The reaction mixture is stirred for two hours and then refluxed for 30 minutes. 30 ml. of aqueous ammonium chloride is added to quench the reaction. The organic layer is separated, washed with water, aqueous sodium bicarbonate, and water, and then dried. On concentration two products are obtained. The second product yields yellow needles, M.P. 124.5-125", after recrystallization from benzene.

The thus prepared compound is dispersed in a PVP solution of the following composition:

Ingredient:

2,5 dimethylpyrrol-3-yl 2 thienyl ketone mg./ml Sodium carboxymethylcellulose 7 MSP percent 1 Polyvinylpyrrolidone (Plasdone) do 1 Tween 80 (sorbitan monooleate) do 0.1-0.5 Methylparaben (methyl p-hydroxybenzoate) percent- 0.18 Propylparaben (propyl p-hydroxy-benzoate) percent 0.02 Water, Q.s.

The dispersion is prepared by initially dissolving the methyl and propylparabens in boiling water, allowing the solution to cool, adding the sorbitan monooleate and mixing well. The PVP and CMC are separately dissolved in water, after which the active ketone product is dispersed in the PVP solution and the two solutions well mixed. Q.s.

Similar active ketones are prepared in the manner described in Example 4, utilizing other thiophenecarboxylic acid chloride reactants. In this manner, the following ketones are prepared:

2,5-dimethylpyrrol-3-yl 3-(methylthio)-2-thienyl ketone 2,5-dimethylpyrrol-3-yl 4-methyl-2-thienyl ketone 2,5-dimethylpyrrol-3-yl 5-methoxy-2-thienyl ketone 2,5-dimethylpyrrol-3-yl 3-thienyl ketone 2,4,5-trimethylpyrrol-3-yl 5-nitro-3-thienyl ketone 2,5-dimethylpyrrol-3-yl 2,5-di-tert-butyl-3-thienyl ketone EXAMPLE 5 Emulsions containing 2,5-dimethylpyrrol-1-methylpyrrol- 2-yl ketone The above active compound is prepared by reaction of l-methylpyrrole-Z-carbonyl chloride with the Grignard derivative of 2,5-dimethylpyrrole. The acid chloride reactant is initially obtained by adding 60 g. of thionyl chloride with stirring to a solution of 58 g. of l-methylpyrrole-Z-carboxylic acid and 102 g. of triethylamine in ml. of anhydrous benzene. The mixture is refluxed for one hour and then is filtered and evaporated to remove solvents. On distillation, 40 g. of l-methylpyrrole-Z- carbonyl chloride, -B.P. 7274, at 1.0 mm., is obtained.

10.03 g. of 2,5-dimethylpyrrole is then added dropwise, with stirring, to a Grignard solution prepared from 5.84 g. of magnesium and 26.4 g. of ethylbromide in 200 ml. of anhydrous ether. The mixture is stirred for 30 minutes after addition is completed. A solution of 31 g. of 1- methylpyrrole-Z-carbonyl chloride in 100 ml. of anhydrous benzene is added and the reaction mixture is stirred for two hours, then heated at reflux for 0.5 hour. 35 ml. of 25% aqueous ammonium chloride is added to quench the reaction. The organic layer is separated, washed with water, 10% aqueous sodium bicarbonate, and water, and then dried. Upon concentration, 32 g. of a product, M.P. 12S, is obtained in two crops. The product is recrystallized from benzene two times and then dried in vacuo to give 31 g. (80%) of a solid, M.P. 1385-.

The compound thus prepared is emulsified in the following composition:

Ingredient: Grams/liter 2,5-dimethylpyrrol l-methylpyrrol-Z-yl ketone 10.0 Corn oil 500 Polyoxyethylene sorbitan monostearate 50 Sorbitan monooleate 50 Sucrose, USP 50 Methylparaben, USP 1.8 Propylparaben, USP 0.2 Sorbitol solution 5.0 Flavor Q.s. Color Q.s.

Water, q.s. ad 1000 ml.

The active drug is initially dissolved in the corn oil with the aid of gentle heat. The oil is then mixed with the polyoxyethylene sorbitan monostearate and the sorbitan monooleate and warmed to 50 C. The sucrose and paraben mixture is dissolved in water heated to 60 C; and the resulting water phase added to the oil phase with stirring. The sorbitol solution is then added and the emulsion allowed to cool, after which the flavor is added. Q.s. and mix well.

0.05% butylated hydroxyanisole may be added to the corn oil as an antioxidant.

The following examples illustrate the preparation of other heteroaromatic pyrrol-3-yl ketones which exhibit therapeutic activity in accordance with the present inven- -tion. Such materials may be administered in mammals in various of the formulations described hereinabove or, alternatively, incorporated in other suitable pharmaceutically acceptable carriers for oral, parenteral or rectal administration:

EXAMPLE 6 3,4,5-trichloro-2-furyl 2,5-dimethyl-pyrrol-3-yl ketone Chlorine gas is passed into rapidly stirred methyl 2- furoate for three hours. The material which is distilled from the reaction mixture at 137l47 at 14 mm. is hydrolyzed with 40% aqueous sodium hydroxide. The reaction is exothermic and the sodium salt of 3,4,5-trichloro-Z-furoic acid precipitates. The mixture is acidified and extracted with ether. The ether solution is evaporated to give 3,4,5-trichloro-2-furoic acid, M.P. l76177. 10 g. of the acid and 50 ml. of thionyl chloride are heated on a steam bath until sulfur dioxide and hydrochloric acid are no longer evolved. The mixture is evaporated twice from benzene and the residue is distilled to give 3,4,5-trichloro-2-furoyl chloride, B.P. 112-116 at 14 6.34 g. of 2,5-dimethylpyrrole is added to a Grignard solution prepared from 1.7 g. of magnesium and 7.7 g.

of ethyl bromide in 70 ml. of anhydrous ether. The mixture is stirred for 30 minutes after addition is completed. A solution of 11.2 g, of 3,4,5-trichloro-2-furoyl chloride in 70 ml. of anhydrous benzene is added and the reaction mixture is stirred for two hours and then refluxed for 0.5 hour. 12 ml. of 25% aqueous ammonium chloride is added to quench the reaction. The organic layer is separated, washed with water, 10% aqueous sodium bicarbonate, and water, and then dried. Upon concentration, 5 g. of solid, M.P. 195200 is obtained. The product is chromatographed on alumina and recrystallized twice from benzene to give yellow platelets which melt at 202- 203 after drying in vacuo.

EXAMPLE 7 2,5-dimethylpyrrol-3-yl 5-nitro-2-furyl ketone 13.3 g. of 2,5-dimethylpyrrole is added to a solution of 32 g, of boron trifiuoride etherate and 26 g. of 5-nitro-2- furoyl chloride in 50 ml. of benzene. After remaining at room temperature for 72 hours, the reaction mixture is poured onto 60 ml. of ice and water and the solid is collected by filtration. Upon purification, it melts at 209- 210.

EXAMPLE 8 2-furyl 1,2,5-trimethylpyrrol-3-yl ketone A mixture of 56.8 g. of boron trifiuoride etherate, 26.0 g. of 2-furoyl chloride, 21.8 g. of 1,2,5-trimethylpyrrole and 50 ml. of anhydrous benzene is allowed to stand for 72 hours in the absence of moisture. It is then stirred into 150 g. of ice and water. The organic layer is collected and concentrated. The residue is stirred for 30 minutes with aqueous sodium hydroxide to remove 2-furoic acid. Organic material is extracted into benzene. The benzene solution is distilled to afford the product.

EXAMPLE 9 2-furyl 2,5-dimethyl-1 phenylpyrrol-3-yl ketone 2,5-dimethyl-l-phenylpyrrole, M.P. 60-51 is allowed to react with 2-furoyl chloride under conditions of Example 10 to produce the product, M.P. 154-155 in 54% yield.

Similarly, 1-cyclohexyl-2,5-dimethylpyrrole, M.P. 47- 48 is converted into 1-cyclohexyl-2,S-dimethylpyrrole- 3-y1 Z-furyl ketone; 1-benzyl-2,5-dimethylpyrrole M.P. 48-49 is converted into l-benzyl-Z,5-dimethylpyrrol-3- yl 2-furyl ketone; and 1-allyl-2,S-dimethylpyrrole is converted into 1-allyl-2,5-dimethylpyrrol-3-yl 2-furyl ketone by related procedures.

EXAMPLE 10 4-isobutyl-2,5-dimethylp-yrrol-3-yl 2-furyl ketone 33g. of 3-isobuty1-2,S-dimethylpyrrole is added to a Grignard solution prepared from 5.7 g. of magnesium and 34 g. of methyliodide in 100 ml. of anhydrous ether. The mixture is stirred for 30 minutes after addition is complete. 31 g. of Z-furyol chloride, dissolved in 100 ml. of benzene, is added and the mixture is stirred for two hours. 75 ml. of aqueous ammonium chloride is added to quench the reaction. The layers are separated and the organic layer is washed with water and sodium hydroxide. The organic layer is dried over calcium carbonate and evaporated to give g. of solid M.P. 220- 224". After two recrystallizations from ethanol the product melts at 224-225".

By the procedure of Example 12, using appropriate pyrroles in place of 3-isobutyl-2,5-dimethylpyrrole and appropriate acid halides in place of 2-furoyl chloride, the following are prepared:

3-butyl-2,5-dimethylpyrrol-3-yl 5-methyl-2-furyl ketone 3-isopropyl-2,S-dimethylpyrrol-3-yl 2,4,5-trimethyl-3- furyl ketone 4-bromo-5-methoxy-2-furyl 2,5-diethylpyrrol-3-yl ketone S-tert-butyl-Z-furyl EXAMPLE l1 2,5-dimethylpyrrol-3-yl pyrrol-2-yl ketone A solution of 44.4 g. of pyrroIe-Z-carboxylic acid and 40.8 g. of triethylamine in ml. of anhydrous benzene is added dropwise, over 20 minutes, to a solution of 43.2 g. of ethyl chloroforrnate in 100 ml. of anhydrous benzene at 0 C. The mixture is filtered after standing 20 minutes longer at 0. The collected 2-pyrrole carboxylic acid carbonic acid anhydride, ethyl ester is dissolved in 50 ml. of anhydrous benzene containing 113.6 g. of boron trifiuoride etherate. 38.1 g. of 2,5-dimethylpyrrole is added to the solution which is kept at room temperature for 72 hours. The reaction mixture is poured in 100 ml. of ice water.

The organic layer is separated, washed two times with water, dried and evaporated to give an oil which is treated with 40% aqueous sodium hydroxide for one hour. The mixture is diluted with water and extracted with ether two times. Upon evaporation of the dried ether fractions an oil is obtained which crystallizes, after trituration with cyclohexane/benzene to give a solid M.P. -147 which is recrystallized two times from 'benzene and dried in vacuo to give crystals, M.P. 156-157".

By the procedure of Example 11, using appropriate acids, the following are prepared:

5-methyl-2-pyrazolin-5-yl 2,5-dimethylpyrrol-3-yl ketone 3-osobutyl-4-methyl-2-pyrazolin-4-yl 2,5-dimethylpyrrol- 3-yl ketone Di (2,5-dirnethylpyrrol-3-yl ketone 2,5-dimethylpyrrol-3-yl 4-benzyl-2,5-dimethylpyrrol-3-y1 ketone EXAMPLE 12 2,5-dimethylpyrrol-3-yl 4-pyridyl ketone A solution of 59.50 g. of ethyl chloroformate in 100 ml. of anyhdrous benzene at 0 is added, with stirring, to a solution of 67.65 g. of isonicotinic acid and 56.1 g. of triethylamine in 100 ml. of anhydrous benzene. The mixture is stirred at 0 for 20 minutes and then filtered. The collected pyridine-4-carboxylic acid carbonic acid anhydride, ethyl ester is dissolved in 15 ml. of anhydrous benzene and reserved.

47.5 g. of 2,5-dimethylpyrrole is added dropwise, with stiriring, to a Grignard solution prepared from 13.4 g. of magnesium and 60.53 g. of ethyl bromide in 500 ml. of anhydrous ether. The mixture is stirred for 30 minutes after addition is completed. The benzene solution of pyridine-4-carboxylic acid carbonic acid anhydride, ethyl ester is added and the mixture is refluxed for three hours. The reaction is quenched with water. The organic layer is separated and treated with dilute hydrochloric acid, then extracted with ether. The aqueous layer is treated with 40% aqueous sodium hydroxide, then extracted with ether. The ether extract is dried and evaporated to give a solid, M.P. 192-193", which is chromatographed on alumina with benzene and then recrystallized from benzene twice and dried in vacuo to give crystals, M.P. 197-198".

In similar fashion, pyrazinoic acid produces 2,5-dimethylpyrrol-3-yl pyrazinyl ketone, 3-pyridinecarboxylic acid and produces 2,5-dimethylpyrrol-3-yl 3-pyridyl ketone and pyrimidine-Z-carboxylic acid produces, 2,5- dimethylpyrrol-3-yl pyrimidin-Z-yl ketone.

EXAMPLE 13 2-methyl-5-phenylpyrrol-3-yl 3-thienyl ketone 2-methyl-5-phenylpyrrole is treated with boron trifiuoride and 3-thiophenecarboxylic acid chloride in benzene 1 1 by the procedure of Example 8 to yield the desired product.

In similar fashion 2-(4-chloropheny1)-5-methylpyrrole, M.P. 125-126, leads to -(4-chlorophenyl)-2-methylpyrrol-3-yl 3-thienyl ketone and 2,4-dimethy1-5-phenylpyrrole, M.P. 74, produces 2,4-dimethyl-S-phenylpyrrol- 3-yl 3-thienyl ketone.

EXAMPLE 14 3-(2-chlorophenyl)-5-methyl-4-isoxazolyl 2,5-dimethylpyrrol-3-yl ketone 28.5 g. of 2,5-dimethylpyrrole is added to a Grignard solution prepared from 8.5 g. of magnesium and 38.5 g. of ethyl bromide in 300 ml. of anhydrous ether. The mixture is stirred for 30 minutes after the addition is completed. 87 g. of 3 -(2 chlorophenyl) 5-methyl-4- isoxazole carbonyl chloride is added and the reaction mixture is stirred for two hours, then refluxed for 30 minutes. 50 ml. of 25% aqueous ammonium chloride is added to quench the reaction. The organic layer is separated, washed with water, aqueous sodium bicarbonate, and water and then dried. On concentration, the product crystallizes. After decolorization on a short alumina column, recrystallization from benzene and drying in vacuo, a solid, M.P. l78.5l79, is obtained.

By the procedure of Example 14, using appropriate acids, the following are prepared:

2-benzyl-5-methyl-4-oxazolyl 2,5-dimethylpyrrol-3-yl ketone 5-methyl-2-phenyl-4-oxazolyl 2,5-dimethylpyrrol-3-yl ketone 4-methyl-5-oxazolyl 2,5-dimethylpyrrol-3-yl ketone 3-isoxazolyl 2,4,5-trimethylpyrrol-3-yl ketone 5-methyl-4-isoxazolyl 2,5-dimethylpyrrol-3-yl ketone Z-mercapto-l-methylimidazol-S-yl 2,5-dimethylpyrrol-3- yl ketone 1-benzylimidazol-2-yl 2,5-dimethylpyrrol-3-yl ketone 3-methyl-5-isothiazolyl 2,5-dimethylpyrrol-3-yl ketone 2,5-dimethylpyrrol-3-yl tetrazol-S-yl ketone 5-acetamido-2-thiazolyl 2,5-dimethylpyrrol-3-yl ketone 2-hydroxy-4-methyl-5-thiazolyl 2,5 dimethylpyrrol-3-yl ketone EXAMPLE l5 4-methyl-l ,2,5-oxadiazol-3-yl 2,5-dimethylpyrrol-3-yl ketone 14.6 g. of 4-methyl-l,2,5-oxadiazole-3-carboxylic acid monohydrate is azeotropically distilled with benzene to remove one mole of water, 20.4 g. of triethylamine is i added and the mixture is cooled. 23.6 g. of thionyl chloride is added and the mixture is stirred for two hours, then filtered. The filtrate is diluted with benzene and evaporated twice to give 4-methyl-1,2,5-oxadiazole-3-carbonyl chloride.

8.07 g. of 2,5-dimethylpyrrole is added to a Grignard solution prepared from 2.06 g. of magnesium and 9.35 g. of ethylbromide in 75 ml. of anhydrous ether. The mixture is stirred for 30 minutes after addition is complete. A solution of 11.9 g. of 4-methyl-1,2,5-oxadiazole-3-carbonyl chloride in 40 ml. of anhydrous benzene is added. The mixture is stirred for two hours and then refluxed for 30 minutes. ml. of aqueous ammonium chloride is added to quench the reaction. The organic layer is separated, washed with water, 10% aqueous sodium bicarbonate, and water, and then dried. Upon concentration a total of 14.2 g. (83%) of solid, M.P. 130143, is obtained. The product is decolorized on an alumina column, recrystallized from benzene twice and dried in vacuo to give yellow plates, M.P. 144145.

By the procedure of Example 15, using appropriate acids, the following are prepared:

S-methyl-l,2,4-oxadiazol-3-yl 2,5-dimcthylpyrrol-3-yl ketone S-benzyl-1,2,4-oxadiazol-3-yl 2,4,S-trimethylpyrrol-3-yl ketone 4-carbamoyl-l,2,5-thiadiazol-3-yl 2,5-dimethylpyrrol-3-yl ketone S-acetamido-1,3,4-thiadiazol-2-yl 2,5-dimethylpyrrol-3-yl ketone 5-cyano-v-triazol-4-yl 2,5-dimethy1pyrrol-3-yl ketone 1-benzyl-5-mercapto-1H-l,2,3-triazol-4-yl 2,5-dimethylpyrrol-3-yl ketone It will be apparent that various changes may be made in the preferred embodiment described hereinabove without departing from the scope of the methods and compositions of the present invention. Accordingly, it is intended that the preceding description be construed as illustrative and not in a limiting sense.

We claim:

1. A method for relieving pain, reducing fever and alleviating inflammatory syndromes in a mammal, which comprises administering to a mammal in need of such treatment an effective amount of a compound of the formula:

wherein R represents hydrogen; lower alkyl, lower alkenyl or cycloalkyl, having not more than six carbon atoms; benzyl or phenyl;

R R and R individually represent hydrogen; lower alkyl, lower alkenyl, lower alkynyl or cycloalkyl, having not more than six carbon atoms; phenyl, phenyl lower alkyl in which the alkyl group has not more than four carbon atoms or halo; and

Het represents furyl, thienyl, or pyrrolyl.

2. The method of claim 1 wherein Het represents furyl. 3. The method of claim 2 wherein R is hydrogen; R

R and R individually are hydrogen, halogen, lower alkyl of not more than six carbon atoms, or cycloalkyl of not more than six carbon atoms; and Het is a 2-furyl or 3- 4. The method of claim 3 wherein said compound is 2- furyl 2,5-dimethylpyrrol-3-yl ketone.

5. The method of claim 3 wherein said compound is 3- furyl 2,5-dimethylpyrrol-3-yl ketone.

6. The method of claim 3 wherein said compound is 5- bromo-2-furyl 2,5-dimethylpyrrol-3-yl ketone 7. The method of claim 1 wherein said compound is 2,5-dimethylpyrrol-3-yl 2-thienyl ketone.

8. The method of claim 1 wherein said compound is 2,5-dimethylpyrrol-3-yl l-methylpyrrol-Z-yl ketone.

9. The method of claim 1 wherein said compound is 2,5-dimethylpyrrol-3-yl pyrrol-2-yl ketone.

References Cited UNITED STATES PATENTS 7/1968 Preau 424274 9/1968 Pachter 424274 STANLEY J. FRIEDMAN, Primary Examiner US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent 510. 3,551,571 Dated December 29, 1970 lnventor(s) J. PaChteI et a].

It is certified that error appears in the above-identified patent and .that said Letters Patent are hereby corrected as shown below:

Column 1, line SU, in the upper right-hand corner of the formula,

' n n for "-C=Het" read -C-Het Column 2, line 72, for "carb-lower alko read lc :wer alkoxy carbonyl Column 3, line for the mtial formula read --R o l lineOHO, in the upper rlght comer f t la f mul f r "--Het" read C-Het Column 5, 1 1'4, for "2-puryl" read 2-furyl line 17, for "2,5-dimethylpyrrol" r 2,5-dzunethylpyrrole Column 6, delete line 2; between lines 3 and mead S-ethoxymethyl-Z-fmyl 2,5-dimethylpyrrol-3-yl ketone between hnes I and Bread S-nethyl-H-sulfannyl-Z-furyl 2,5-dimethylpyrml-3-y1 keton llne 39, for "keytone produce" read ketone product lit for "rutorgen" read nitrogen Column 7, invert lines 16 and 17.

Column 10, lme 33, for "3-osobuty1-" read 3-isobutylline 35, i "D:|.(2,5-d1methylpyrrol-3-yDketone" read Di(2,5-dimethylpyrml-3-yl) ke r- Column 12, line 25, for the formula read Signed and sealed this 7th day of September 1971 (SEAL) Attest:

EDWARD M.FLETCHER, I ROBERT GOTTSCHALK Attes lng Officer Acting Commissioner of Pa

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Classifications
U.S. Classification514/422, 548/134, 548/253, 548/236, 548/195, 548/518, 548/214, 548/255, 548/131, 548/188, 548/517, 548/527, 546/279.1, 548/314.7, 544/333, 548/247, 548/139
International ClassificationC07D207/333, C07D405/06, C07D413/06, C07D409/06, C07D401/06, C07D207/32
Cooperative ClassificationC07D401/06, C07D207/333, C07D405/06, C07D413/06, C07D409/06
European ClassificationC07D207/333, C07D409/06, C07D413/06, C07D401/06, C07D405/06
Legal Events
DateCodeEventDescription
Nov 22, 1982ASAssignment
Owner name: E.I. DU PONT DE NEMOURS AND COMPANY, 1007 MARKET S
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:ENDO LABORATORIES, INC., A CORP. OF DEL.;REEL/FRAME:004063/0107
Effective date: 19821110