GB2168976A - Amides and compositions thereof having anti-inflammatory activity - Google Patents

Abstract

N-(substituted aralkyl) alkanamide and thioamide compounds, and pharmaceutically-acceptable salts thereof, of the formula: <IMAGE> wherein n1 is 1 or 2, R1 is selected from the group consisting of <IMAGE> R2 is selected from the group consisting of OH, OCH3, and OCH2CH3, R3 is H or CH3, R4 is O or S, and R5 is a straight or branched alkyl having from 2 to 24 carbon atoms.

Description

SPECIFICATION Compounds and compositions having anti-inflammatory activity Technical field The present invention relates to certain amides and thioamides and pharmaceutical compositions containing these compounds which exhibit anti-inflammatory activity.

Background of the invention Inflammation, or the "inflammatory response", is the result of complex interconnected physiological events, including increased vascular permeability, fluid accumu-lation, and the migration of a changing population of inflammatory cells into the inflammed area. The clinical manifestations of inflammation include swelling (edema), increased local temperature, erythema, and pain. The inflammatory response can be triggered by any of a number of causative factors, including certain bacteria, radiation, hypersensitivity to chemical agents, arthritis-like conditions, and the like. The inflammatory response is generally believed to be a primary defense mechanism in the body, but, unchecked, can become excessive and can result in functional impairment.

The use of non-steroidal anti-inflammatory, anti-pyretic and analgesic drugs, especially the salicylates, which include aspirin and aspirin derivatives, to combat inflammation and attendant pain is accepted medical practice. The non-steroidals are commonly employed to relieye pain and inflammation associated with, for example, bursitis, arthritis, and the like.

It has been recently discovered that capsaicin, a natural product of certain species of the genus Capsicum, induses analgesia. Capsaicin (8-methyl-N-vanillyl-6-nonen-amide) and "synthetic" capsaicin (N-vanillylnonamide) are disclosed as analgesics in U.S. Patent 4,313,958, LaHann, issued February 2, 1982.

Analgesic activity of capsaicin has also been discussed in the chemical and medical literature, including Yaksh, et al, Science, 206, pp 481-483 (1979); Jancso, et al, Naunyn-Schmiedeberg's Arch. Pharmacol, Vol. 311, pp 285-288 and Holzer et al, Eur. J. Pharm. Vol 58, pp 511-514 (1979). U.S. Patent 4,238,505, Nelson, issued December 9, 1980, discloses 3-hydroxyacetanilide for use in producing analgesia in animals. U.S. Patent 4,424,205, LaHann, et al, issued January 3, 1984, describes hydroxyphenylacetamides with analgesic and anti-irritant activity. Similarly, analgesic and anti-irritant activity is disclosed for Nvanillyl sulfonamides in U.S. Patent 4,401,663, Buckwalter, et al, issued August 30, 1983; N-vanillylureas in U.S. Patent 4,460,602, Buckwalter, et al, issued July 17, 1984; N-(substituted phenyl)methyl alkynamides in U.S.Patent Application Serial No. 514,204,Janusz, et al. filed July 1983; methylene substituted N-(substituted phenyl)methylal-kanamides in U.S. Patent Application Serial No. 514,205, Janusz, et al, filed July 14, 1983; N-(substituted phenyl) methyl-cis-monounsaturated alkenamides, in U.S. Patent Application Serial No. 514,206, LaHann, et al, filed July 14, 1983; and N-(substituted phenyl)methyl diunsaturated amides in U.S. Patent Application Serial No. 514,207, LaHann, et al, filed July 14, 1983. None of these documents suggests in any way that the disclosed compounds have anti-inflammatory activity.

It has now been discovered that certain amides and thioamides have anti-inflammatory activity similar to that of non-steroidals such as aspirin in humans and lower animals. These amides and thioamides are far less toxic than capsaicin.

Summary of the invention The present invention provides compounds useful for reducing inflammation in humans and lower animals, of the formula:

wherein n, is 1 or 2, R, is selected from the group consisting of OH, OCH3,

R2 is selected from the group consisting of OH, OCH3, and OCH3CH3, R3 is H or CH3, R4, is O or S, R5 is a straight or branched alkyl having from 2 to 24 carbon atoms; and pharmaceutically-acceptable salts thereof.

This invention also provides pharmaceutical compositions comprising a safe and effective amount of these compounds, or mixtures thereof, and a pharmaceutically-acceptable carrier. Also provided are methods for reducing inflammation by administering the compounds and compositions of this invention.

Description of the invention The compositions and methods of this invention incorporate certain N-(substituted aralkyl) alkanamides and thioamides, or pharmaceutically-acceptable salts thereof, of the formula:

wherein n1 is 1 or 2, R, is selected from the group consisting of OH, OCH3,

R3 is selected from the group consisting of OH, OCH3, and OCH2CH3, R3 is H or CH3, R4, is O or S, Rs is a straight or branched alkyl having from 2 to 24 carbon atoms.

Preferably, n1 is 1, Ri is OH or OCH3, R2 is OH or OCH3, R3 is H, R4 is 0, and R5 is either a straight chain alkyl group having from 6 to 10 carbon atoms or a branched chain alkyl having from 12 to 24 carbon atoms. Most preferably, R1 is OH, R2 is OCH3, and R5 is a straight chain alkyl having from 6 to 8 carbon atoms. Amides and thioamides preferred for anti-inflammatory activity, in descending order, are N-vanillyl thiononanamide, N-vanillyl-9-methyloctadecanamide, N-vanillyl thioheptanamide, N-(4-oxypivaloyl-3methoxybenzyl) nonanamide, N-(4-oxypropionyl-3-methoxybenzyl)nonanamide, N-(4-acetoxy-3-methoxybenzyl)-nonanamide, N-(3,4-dihydroxy-phenethyl)octanamide, N-(4-hydroxy-3-ethoxybenzyl )nonanam ide, and N-vanillyl undecanamide.Preferred pharmaceutically-acceptable amide and thioamide salts include the sodium, potassium, calcium, magnesium, and ammonium salts.

The amides described herein can be readily prepared by the following typical synthetic scheme:

The acids used in the synthesis of preferred amides and thioamides are commercially-available or can be readily synthesized by methods described herein.

Compositions The compositions of the present invention comprise: (a) a safe and effective amount of an amide or thioamide defined herein; and (b) a pharmaceutically-acceptable carrier.

A safe,and effective amount of amide or thioamide is that amount which provides anti-inflammatory activity, thereby alleviating or preventing the inflammation being treated at a reasonable benefitirisk ratio, as is intended with any medical treatment Obviously, the amount of amide or thioamide used will vary with such factors as the particular condition that is being treated, the severity of the condition, the duration of the treatment, the physical condition of the patient, the nature of concurrent therapy (if any), the route of administration, the specific formulation and carrier employed, and the solubility and concentration of amide or thioamide therein.

Depending upon the particular route of administration, and compatibility with the active chosen, a variety of pharmaceutically-acceptable carriers, well-known in the art, may be used. These include solid or liquid fillers, diluents, hydrotropes, excipients, surface-active agents, and encapsulating substances. The amount of the carrier employed in conjunction with the amide or thioamide is sufficient to provide a practical quantity of material per unit dose.

Pharmaceutically-acceptable carriers for systemic administration that may be incorporated into the compositions of this invention, include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils; synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Specific pharmaceutically-acceptable carriers are described in the following U.S. Patents and European Patent Applications, all incorporated by reference herein: U.S.

Patent 4,401,663, Buckwalter, et al, issued August 1983; European Patent Application 0089710, La Hann, et al, published September 28, 1983; and European Patent Application 0068592, Buckwalter, et al, published January 5, 1983. Preferred carriers for parenteral adminis-tration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically-acceptable carrier, in compositions for parenteral administration, comprises at least about 90% by weight of the total composi tion.

Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50% of the amide or thioamide. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, preservatives, flow-inducing agents, and melting agents.Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effer-vescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents, and flavoring agents.

Preferred carriers for oral administration include gelatin, propylene glycol, cottonseed oil and sesame oil.

Specific examples of pharmaceutically-acceptable carriers and excipients that may be used to formulate oral dosage forms, which may be used in formulating oral dosage forms containing amides or thioamides, are described in U.S. Patent 3,903,297, Robert, issued September 2, 1975, incorporated by reference herein. Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms", Modern Pharmaceutics, Vol 7, (Banker and Rhodes, editors), 359-427 (1979), incorporated by reference herein.

The compositions of the present invention can also be administered topically to a biologic subject, i.e., by the direct laying on or spreading of the composition on epidermal or epithelial tissue. Such compositions include lotions, creams, solutions, gels and solids. These topical compositions comprise a safe and effective amount, usually at least about 0.5%, and preferably from about 1% to about 5%, of the amide or thioamide. Suitable carriers for topical administration of the amide or thioamide preferably remain in place on the skin as a continuous film and resist being washed off easily by perspiration or by immersion in water. Generally, the carrier is either organic in nature or an aqueous emulsion and capable of having the amide or thioamide dispersed or dissolved therein.The carrier may include pharmaceutically-acceptable emollients, coloring agents, fragrances, emulsifiers, thickening agents, and solvents.

Specific systemic and topical formulations useful in this invention are described in the following U.S.

Patents and European Patent Applications, all incorporated by reference herein: U.S. Patent No.

4,401,663, Buckwalter, et al, issued August 30, 1983; and European Patent Application 0089710; LaHann, et al, published September 28, 1983; European Patent Application 0068590, Buckwalter, et al, published January 5, 1983; and European Patent Application 0068592, Buckwalter, et al, published January 5, 1983.

Topical vehicles, useful herein, are disclosed in the following U.S. Patent Applications, incorporated by reference herein: "Improved Penetrating Topical Pharmaceutical Compositions Combining 1-dodecylazacycloheptan-2-one", Serial No. 506,275, Cooper, filed June 21, 1983; and "Penetrating Topical Pharmaceutical Compositions Containing N-(2-hydroxyethyl)-pyrrolidone", Serial No. 506,273, Cooper, filed June 21, 1983. Additional formulations, useful for parenteral, oral, and topical administration of araalkanamides, are disclosed in the following U.S.Patent Appli-cations all incorporated by reference herein: "Compositions Useful for Producing Analgesia", Serial No. 514,206, LaHann and Buckwalter, filed July 14, 1983; "Novel Compounds and Compositions Useful for Producing Analgesia", Serial No. 514,207, LaHann, Janusz, and Buckwalter, filed July 14, 1983; "Novel Compounds Useful for Producing Analgesia", Serial No. 514,204 Janusz and LaHann, filed July 14, 1983 and "Novel Compounds and Compositions Useful for Producing Analgesia", Serial No. 514,205 Janusz, Buckwalter and LaHann, filed July 14, 1983.

Methods for producing anti-inflammatory activity The present invention also encompasses methods of producing anti-inflammatory activity in humans or lower animals through administering, to the human or lower animal, a safe and effective amount, usually from about 1 mg to about 3600 mg per day, preferably from about 200 mg to about 2000 mg per day, of an amide or thioamide. While dosages higher than the foregoing are effective to reduce inflammation, care must be taken in some individuals to prevent adverse side effects.The amide or thioamide and compositions of this invention can be used to reduce inflammation and reduce the pain associated with inflammation in various disorders at the deeper structures, muscles, tendons, bursa and joints associated with disease and trauma, and in various other conditions in which non-steroidal anti-inflammatory, antipyretic and analgesic drugs such as aspirin have heretofore been used to reduce inflammation.

The amides or thioamides and compositions of the instant invention can be administered topically or systemical. Systemic application includes any method of introducing the compound into the tissues of the body, e.g., intrathecal, epidural, intramuscular, transdermal, intra-venous, intraperitoneal, subcutaneous, sublingual, and oral administration.

A preferred method of parenteral administration is through intramuscular injection. As is known and practiced in the art, all formulations for parenteral administration must be sterile. For mammals, especially humans, (assuming an approximate body weight of 70 kg) individual doses of from about 2 mg to about 400 mg of amide or thioamide are acceptable. Individual doses of from about 50 mg to about 200 mg are preferred. Although frequency of administration will be determined by the duration of activity of the particular amide or thioamide administered, which is variable, the amides and thioamides are generally long-acting, and in some cases it may be possible to obtain effective relief by administering the com position as infrequently as once every 1-2 days.

A preferred method of systemic application of the amides or thioamides is through oral administration.

For mammals, especially humans, (assuming an approximate body weight of 70 kg) individual doses of from about 1 mg to about 900 mg of amide or thioamide are acceptable. individual doses of from about 50 mg to about 600 mg are especially preferred.

Topical administration can be used to reduce inflammation and produce local or systemic analgesia, through directly laying on or spreading a safe and effective amount of the amides or thioamides, or composition containing an amide or thioamide, on epidermal or epithelial tissue, including outer skin and oral, gingival, and nasal tissue The amount of the pharmaceutical composition to be topically administered may vary from about 1 mg/cm2 to 10 mg/cm2, depending upon such factors as the sensitivity, type and location of tissue to be treated, the composition and carrier (if any) to be administered, and the particular amide or thioamide to be administered as well as the particular disorder to be treated. The extent of anti-inflammatory activity also depends upon such factors as the amount of amide or thioamide, the area of tissue to be covered, and the ability of the amide or thioamide composition to penetrate the skin tissues.

The following non-limiting Examples illustrate the compounds, compositions, and methods of treatment of the present invention.

Example I N-vanillyl-9-methyloctadecanamide was synthesized by the following method:

Specifically, 63 ml diethylmaionate were added to 150 ml of sodium ethoxide (prepared using ethanol and 8 g of sodium), warmed to 60"C, and stirred. Bromooctane (71 ml) was added, dropwise, the mixture warmed to 75-800C, and stirred for overnight. The ethanol was evaporated, the mixture mixture taken up in ethyl ether and water, the layers separated, the ether layer washed with water and brine, then dried and evaporated to yield 105 g of C8H 7CH(CO3C2H)3. This product was distilled, collecting 56.8 g, and then added dropwise to 200 ml of a solution of 75 g potassium hydroxide in 400 ml ethanol, which was refluxed overnight. The solution was cooled and ethanol evaporated. The residue was dissolved in 500 ml H2O and acidified with HC1.The product was extracted with ether and the ether phase was washed with water and brine, and then dried, filtered, and evaporated, yielding 43 g of C8H1,CH(CO 2H)2.

In a separate process, 23.9 g of azelaic monomethyl-ester was dissolved in 30 ml chloroform. Oxalyl chloride (15 ml) was added, all at once, and the mixture refluxed 2 hours at 50"C. The mixture was cooled; excess solvent and oxalyl chloride were evaporated. After distillation, 25.8 g of CH3OCO(CH2)7COCI was obtained.

3 grams of the CsH17CH(CO2H)2 product obtained above were added, in small portions, to a mixture of 3.3 ml dihydropyran in 25 ml of benzene and 20 ul sulfuric acid, and stirred at 25"C, for 1 hour. Potassium hydroxide was added to neutralize the sulfuric acid, and the mixture was stirred for an additional 30 minutes. The solvent was then evaporated, and with 25 ml benzene, the mixture was added dropwise to 0.6 g of washed 50% NaH in 30 ml benzene, and stirred for 1 hour. 3 g of the CH3OCO (CH2)7COCI product prepared above was added dropwise in benzene and the mixture stirred overnight. Acetic acid (2.0 ml) was added and the mixture refluxed for 4 hours. The reaction was cooled, washed with water, dried over magnesium sulfate, filtered and evaporated.The residue was taken up in ether, washed with 1 N NaOH, water and brine, and dried to give 4.0 g of crude product. Chromatography on silica gel with 15% ethyl acetate and hexane gave 1.5 g of C8H,7CH2CO(CH2)7COOCH3.

A round bottom flask was cleaned, dried, charged with 3.6 g of 50% NaH, and cleared with pentane washes. The flask was then purged with argon and 75 ml of distilled dimethyl sulfoxide (DMSO) added via syringe, and heated to 70 C for 45 minutes. After hydrogen evolution had stopped, the solution was cooled in a water bath and 26.8 g methyl-triphenylphosphonium bromide, in 10 ml DMSO, was added all at once to the reaction solution and stirred for 20 minutes at room temperature. 18 g of C8H,7CH2CO( CH2)7-COOCH3, prepared as above, was dissolved in 50 ml DMSO, added all at once to the reaction solution, and stirred overnight. The mixture was then poured into 250 ml water and extracted twice with 50/50 toluene and pentane. The organic phase was washed with water, dried and evaporated.

The residue was filtered through silica gel to give 16.7 g of C8H,7CH2C(CH2)CH2(CH2) 6COOCH3.

5.5 g of methyl-9-methyleneoctadecanoate in 100 ml of ethyl acetate was hydrogenated in a Parr hydrogenation apparatus over 200 mg of 5% palladium on charcoal for 2 1/2 hours. The catalyst was filtered off and the solvent evaporated to give 4.9 g of methyl-9-methyloctadecanoate. This was then dissolved in 50 ml of ethanol. 0.88g of potassium hydroxide was dissolved in 10 ml of water and added to the ethanol solution. The mixture was refluxed for 2 1/2 hours, cooled and the solvent was evaporated.

The residue was dissolved in aqueous sodium hydroxide and extracted with ether. The aqueous phase was acidified with concentrated hydrochloric acid and extracted twice with ether. The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered and evaporated to give 4.8 g of 9-methyloctadecanoic acid. The 9-methyloctadecanoic acid and 30 ml of oxalyl chloride were refluxed for 1 hour. The excess oxalyl chloride was then removed under vacuum.

In a separate flask, 3.1 g of vanillylamine hydrochloride was suspended in 25 ml of dimethylformamide (DMF). 6.5 ml of 5N sodium hydroxide was added and the mixture was stirred for 15 minutes. The acid chloride prepared above was dissolved in 20 ml of ether and added dropwise to the vanillylamine solution, which has been cooled to 0"C. The reaction mixture was stirred for 3 hours, during which time it was allowed to warm to room temperature. The reaction mixture was then poured into water and extracted twice with ether. The combined extracts were washed with 1N HC1, saturated sodium bicarbonate, water and brine and dried over sodium sulfate, filtered and evaporated to give 5.6 g of crude product. Chromatography on silica gel with 45% ethyl acetate/hexane gave 2.5 g of pure product as a colorless oil.

Example II N-(3,4-dihydroxyphenethyl)octanamide was synthesized by the following method:

Following the procedure used for combining vanillylamine hydrochloride with the acid chloride in Example 1, 7.0 g of 3-hydroxytyramine hydrochloride was reacted with 6.0 g of octanoyl chloride to give 8.95 g of crude product. The crude product was recrystallized from methylene chloride/pentane to give 6.1 g of pure product having a melting point of 66"-68"C.

Example Ill N-(4-acetoxy-3-methoxybenzyl)nonanamide was synthesized by the following method:

o zoo 2 (cur2) 7cur3 + on HOOCR (3c) 20 3 pyridiness CHC13 0 CB2NEC (CB2) 7CE3 o Q B3cc Specifically, 7.6 g of vanillyl nonanamide (capsaicin) and 2.5 g of pyridine were dissolved in 100 ml of chloroform. 2.9 g of acetic anhydride were added in one portion. The mixture was stirred at room temperature for 3 days. The solvent was evaporated and the residue partitioned between ether and saturated sodium bicarbonate. The ether phase was washed with 1N HC1, water, and brine, dried over magnesium sulfate, filtered and evaporated to give 8.6 g of crude product.This was then recrystalized from 1:3 ethyl acetate/hexane to give 4.0 g of pure product having a melting point of 69"-70"C.

Example IV N-(4-oxypropionyl-3-methoxybenzyl)nonanamide was synthesized by the following method:

CE2WC(CE2)7cB3 + C2X5 aof3 + c2Hcc1 OCE3 pyridine CHC13 0 E5C2C CE2NBC (cur2) 7CR3 OCH3 Specifically, 3.0 g of vanillyl nonanamide (capsaicin) and 1.6 ml of pyridine were dissolved in 50 ml of chloroform. Propionyl chloride was prepared from propionic acid and oxalyl chloride as in Example I, and then distilled from 76 -80 c. 1.5 g was added dropwise, to the above solution and the reaction mixture was refluxed overnight. The solvent was evaporat.ed and the residue partitioned between ether and water. The ether layer was washed with 1 N sodium hydroxide, water, and brine, dried over magnesium sulfate, filtered and evaporated to give 3.2 g of crude product, which was then Kugelrohr distilled at 0.025 mm at 180to give 2.6 g of pure product having a melting point of 60"-61"C.

In the above example, N-(4-oxypivaloyl-3-methoxybenzyl)nonanamide was prepared by substituting the appropriate chloride.

Example V N-vanillyl thioheptanamide was synthesized by the following method:

o HO (ca2) 5ca3 I SOCH3 CR3oPK\ -OCH3 toluene S II o))Q3CR2NH (CR2) 5CR3 bca3 Specifically, 5.0 g of N-vanillyl heptanamide was prepared from vanillylamine hydrochloride and heptanoyl chloride as described in Example I, and dissolved in 100 ml of toluene. 4.0 g of Lawesson's reagent ([2,4-bis(4-methoxyphenyl)-1 ,3-dithia-2,4-diphosphetane-2,4-disulfidej was added in one portion.

The reaction was refluxed for 3 hours and stirred at room temperature overnight. The solvent was evaporated and the residue was flash chromatographed twice on silica gel with 60% ethyl acetate hexane to give 2.0 g of product.

In the above example, N-vanillyl thiononanamide was prepared by substituting the appropriate vanillylamide.

Example Vl N-(4-hydroxy-3-ethoxybenzyl) nonanamide was synthesized by the following method:

Specifically, 5.0 g of 4-hydroxy-3-ethoxybenzaldehyde and 17 g of diammonium hydrogen phosphate were added to a solution consisting of 75 ml of nitropropane and 25 ml of glacial acetic acid. The mixture was refluxed for 16 hours and the solvent was then removed under vacuum. The residue was partitioned between water and ether and the aqueous layer was then extracted twice with ether. The combined extracts were washed with saturated sodium bicarbonate, water, and brine, then dried over magnesium sulfate, filtered and evaporated. The crude 4-hydroxy-3-ethoxybenzonitrile was recrystallized from benzene/hexane to give 3.4 g of pure 4-hydroxy-3-ethoxybenzonitrile.This material was dissolved in 50 ml of ethanol and 6 ml of chloroform and was hydrogenated overnight on the Parr apparatus over 50 mg of platinum oxide. Filtration of the catalyst and evaporation of the solvent gave 3.3 g of 4-hydroxy-3-ethoxybenzylamine hydrochloride. Following the procedure for reacting vanillylamine hydrochloride with the acid chloride described in Example I, 3.0 g of 4-hydroxy-3- ethoxybenzylamine hydrochloride and 2.9 g of nonanoyl chloride were reacted to give 4.8 g of crude product. The crude product was then recrystallized from benzene/hexane to give 3.3 g of pure product.

Example VIl A composition for parenternal administration is prepared by combining the following ingredients: N-vanillyl-9-methyloctadecanamide 300 g Ethyl oleate 980 ml Benzyl alcohol 20 ml The octadecanamide is dissolved in the solution combining ethyl oleate and benzyl alcohol, sealed into air-tight 5 ml ampoules, and sterilized by autoclaving. Injection of 1.5 ml of the contents of one of these ampoules intramuscularly into a 65 kg human reduces inflammation.

A substantially similar effect is obtained when N-vanillyl-9-methyloctadecanamide is replaced by Nvanillyl thioheptanamide, N-(4-oxypropionyl-3-methoxybenzyl) nonanamide, N-(4-acetoxy-3-methoxybenzyl)nonanamide, N-(3,4-dihydroxyphenethyl)octanamide, N-(4-hydroxy-3-ethoxy-benzyl)nonanamide, or N-vanillyl undecanamide.

Example Vlil A composition for oral administration is prepared by combining the following ingredients: N-vanillyl-9-methyloctadecanamide 1.10 kg Sesame oil 3.25 litres The octadecanamide is dissolved in the sesame oil with the aid of sonication and is packaged in soft gelatin capsules using methods known in the art. Two of the resulting capsules, each containing 225 mg of the composition, are administered to a 60 kg human, reducing inflammation.

A substantially similar effect is obtained when N-vanillyl-9-methyloctadecanamide is replaced by Nvanillyl thioheptanamide, N-(4-oxypropionyl-3-methoxybenzyl)nonan-amide, N-(3,4-dihydroxyphenethyl)octanamide, N-(4-hydroxy-3-ethoxybenzyl)nonanamide, or N-vanillyl undecanamide.- Example IX A composition for oral administration is prepared by combining the following ingredients: N-vanillyl-9-methyloctadecanamide 360 g Propylene glycol 1800 ml Ethyl alcohol 175 ml Distilled water 75 ml Artificial Strawberry flavor 10 ml FD & Red #40 0.2 g The above ingredients are combined to produce a syrup and are packaged under sterile conditions in 6 oz. bottles. One teaspoon of this formulation is administered to a 70 kg adult human, reducing inflammation.

A substantially similar effect is obtained when N-vanillyl-9-methyloctadecanamide is replaced by Nvanillyl thioheptanamide, N-(4-oxypropionyl-3-methoxybenzyl) nonanamide, N-(4-acetoxy-3-methoxybenzyl)nonanamide, N-(3,4-dihydroxyphenethyl)octanamide, N-(4-hydroxy-3-ethoxy-benzyl)nonanamide, or N-vanillyl undecanamide.

Example V A composition for topical administration is prepared by combining the following ingredients: N-vanillyl-9-methyloctadecanamide 4 9 Propylene glycol 100 ml Ethyl alcohol 100 ml The liquid octadecanamide is combined with the other ingredients. Application of 0.4 ml of the resulting liquid to a 80 cm2 portion of the forearm of a 60 kg human reduces inflammation.

A substantially similar effect is obtained when N-vanillyl-9-methyloctadecanamide is replaced by Nvanillyl thioheptanamide, N-(4-oxypropionyl-3-methoxybenzyl) nonanamide, N-(4-acetoxy-3-methoxybenzyl)nonanamide, N-3,4-dihydroxyphenethyl)octanamide, N-(4-hydroxy-3-ethoxy-benzyl)nonanamide, or Nvanillyl undecanamide.

Effectiveness in reducing inflammation Example XI Seven amide and thioamide compositions were tested for anti-inflammatory activity using the croton oil induced mouse ear inflammation test.

Adult male Cdx ICR mice, 20-30 g, were treated on the left ear at 20-28 hours prior to sacrifice and a second time 5-6 hours prior to sacrifice with 25 lli of a 1% ethanolic solution of the test compound. Four hours prior to sacrifice both ears were treated with 25 Wl of a 2% solution of croton oil in acetone. Each animal was then placed in individual cages and given food and water ad lib. Animals were sacrificed by cervical dislocation and both ears removed. From these ears, 0.38 cm2 punch biopsies were taken from the central portion and each biopsy weighed on a Cahn electrobalance.

For each test substance, a group of 10 animals was used. Control groups either had both ears treated with croton oil or just the right ear. It was experimentally determined that a value of 11.0 mg could be assumed for a punch biopsy from a normal untreated ear and still be within the experimental error of the test. Therefore, for the calculation of percent inhibition, a value of 11.0 mg was used.

Weight Right Ear - Weight Left Ear Weight Right Ear-Weight Control Ear (11.0 mg) x 100 This calculation is valid only when no systemic effects are noted as evidenced by comparison of right ears of treated and control groups.

Statistical significance at the 95% confidence level was determined by the paired t test.

Compound % Inhibition N-vanillyl thiononanamide 96.2 +18.3 N-vanillyl-9-methyloctadecanamide 88.3 + 15.6 N-vanillyl-thioheptanamide 82.0 +31.3 N-(4-oxypivaloyl-3-methoxybenzyl) 73.4 + 13.0 nonanamide N-(4-oxypropionyl-3-methoxybenzyl) 69.7 +16.8 nonamide N-(4-acetoxy-3-methoxybenzyl) 69.6 t21.8 nonanamide N-(3,4-dihydroxyphenethyl)octanamide 31.8 +24.4 N-(4-hydroxy-3-ethoxy benzyl) 31.7 + 17.4 nonanamide N-vanillyl undecanamide 29.6 It39.6 These results show that the amide and thioamide compositions tested do in fact have statistically significant anti-inflammatory activity.

Claims (33)

1. Amide and thioamide compounds, and pharmaceutically-acceptable salts thereof, of the formula:

wherein n1 is 1 or 2, R, is selected from the group consisting of OH, OCH3,

R2 is selected from the group consisting of OH, OCH3, and OCH2CH3, R3 is H or CH3, R4 is O or S, and R5 is a straight or branched alkyl having from 2 to 24 carbon atoms.

2. Amide and thioamide compounds, and pharmaceutically-acceptable salts thereof, according to Claim 1 wherein n1 is 1.

3. Amide and thioamide compounds, -and pharmaceutically-acceptable salts thereof, according to Claim 2, wherein R3 is H.

4. Amide and thioamide compounds, and pharmaceutically-acceptable salts thereof, according to Claim 3, wherein R4 is O.

5. Amide and thioamide compounds, and pharmaceutically-acceptable salts thereof, according to Claim 4, wherein R1 is OH or OCH3 and R2 is OH or OCH3.

6. Amide and thioamide compounds, and pharmaceutically-acceptable salts thereof, according to Claim 5, wherein R1 is OH and R2 is OCH3.

7. Amide and thioamide compounds, and pharmaceutically-acceptable salts thereof, according to Claim 6, wherein Rs is a straight chain alkyl having from 6 to 10 carbon atoms.

8. Amide and thioamide compounds, and pharmaceutically-acceptable salts thereof, according to Claim 6, wherein R5 is a branched chain alkyl having from 12 to 24 carbon atoms.

9. Amide and thioamide compounds, and pharmaceutically-acceptable salts thereof, according to Claim 7, wherein R5 is a straight chain alkyl having from 6 to 8 carbon atoms.

10. Amide and thioamide compounds, and pharmaceutically-acceptable salts thereof, according to Claim 3, wherein said thioamide is N-vanillyl thiononanamide

11. Amide and thioamide compounds, and pharmaceutically-acceptable salts thereof, according to Claim 8, wherein said amide is N-vanillyl-9-methyloctadecanamide.

12. Amide and thioamide compounds and pharmaceutically-acceptable salts thereof, according to Claim 9, wherein said thioamide is N-vanillyl thioheptanamide.

13. Amide and thioamide compounds, and pharmaceutically-acceptable salts thereof, according to Claim 9, wherein said amide is N-(4-oxypivaloyl-3-methoxybenzyl) nonanamide.

14. Amide and thioamide compounds, and pharmaceutically-acceptable salts thereof, according to Claim 4, wherein said amide is N-(4-oxypropionyl-3-methoxybenzyl)-nonanamide.

15. Amide and thioamide compounds, and pharmaceutically-acceptable salts thereof, according to Claim 4, wherein said amide is N-(4-acetoxy-3-methoxybenzyl) nonanamide.

16. A composition for reducing inflammation in humans or lower animals comprising: a) a safe and effective amount of amide or thioamide compound of the formula

wherein n, is 1 or 2, R, is selected from the group consisting of OH, OCH3,

R3 is selected from the group consisting of OH, OCH3, and OCH3CH3, R3 is H or CH3, R4, is O or S, R5 is a straight or branched alkyl having from 2 to 24 carbon atoms, or a pharmaceutically-acceptable salt thereof, or mixtures thereof; and b) a pharmaceutically-acceptable carrier.

17. A composition according to Claim 16. wherein n1 is 1.

18. A composition, according to Claim 17, wherein R3 is H.

19. A composition, according to Claim 18, wherein R4 is O.

20. A composition, according to Claim 19, wherein R1 is OH or OCH3 and R2 is OH or OCH3.

21. A composition, according to Claim 20, wherein R1 is OH and R2 is SOCH3.

22. A composition, according to Claim 21, wherein R5 is a straight chain alkyl having from 6 to 10 carbon atoms.

23. A composition, according to Claim 21, wherein R is a branched chain alkyl having from 12 to 24 carbon atoms.

24. A composition, according to Claim 22, wherein R is a straight chain alkyl having from 6 to 8 carbon atoms.

25. A composition, according to Claim 16, wherein said compound is N-vanillyl thiononanamide.

26. A composition, according to Claim 16, wherein said compound is N-vanillyl-9-methyloctadecanamide.

27. A composition, according to Claim 16, wherein said compound is N-vanillyl thioheptanamide.

28. A composition according to Claim 16, wherein said compound is N-(4-oxypivaloyl-3-methoxybenzyl)nonan-amide.

29. A composition, according to Claim 16, wherein said compound is N-(4-oxypropionyl-3-methoxybenzyl)nonanamide.

30. A composition according to Claim 16, wherein said compound is N-(4-acetoxy-3-methoxybenzyl)nonanamide.

31. A composition, according to Claim 16, for parenteral administration, comprising at least about 90%, by weight, of said pharmaceutically-acceptable carrier.

32. A composition, according to Claim 16, for oral administration, comprising from about 25% to about 50%, by weight, of said amide or thioamide.

33. A composition, according to Claim 16, for topical administration, comprising from about 1% to about 10% by weight, of said amide or thioamide.