GB2168974A - Compounds and compositions having anti-inflammatory activity - Google Patents

Abstract

Substituted phenylacetic acid esters, and pharmaceutically-acceptable salts thereof, of the formula: <IMAGE> wherein n is an integer between 1 and 14, R1 is selected from the group consisting of H, OH, and a short-chain ester, R2 is selected from the group consisting of H, OH, and OCH3 and R3 is CH3 or phenyl.

Description

SPECIFICATION Compounds and compositions having anti-inflammatory activity Technical field The present invention relates to certain substituted phenylacetic acid esters 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 accummulation, 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 derivatives, to combat inflammation and attendant pain is accepted medical practice. Thenon-sternidals are commonly employed to relieve 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 Capsicium, induces 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, issed January 3, 1984, describes hydroxyphenylacetamides with analgesic and anti-irritant activity. Similarly, analgesic and anti-irritant activity is disclosed for Nvanilly 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, 1983; N-(substituted phenyl)-methyl alkynamides in U.S.Patent Application Serial No. 514,204, Janusz, et al, filed 1984; methylene substituted N-(substituted phenyl)methylalkanamides 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 phenylacetic acid esters have anti-inflammatory activity similar to that of non-steroidal anti-inflammatories such as aspirin in humans and lower animals. These esters 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 an integer between 1 and 14, R1 is selected from the group consisting of H, OH, and a shortchain ester, R2 is selected from the group consisting of H, OH, and OCH3, and R3 is CH3 or phenyl; and pharmaceutical ly-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 substituted phenylacetic acid esters, or pharmaceutically-acceptable salts thereof, of the formula:

wherein n is an integer between 1 and 14, R1 is selected from the group consisting of H, OH, and a shortchain ester R2 is selected from the group consisting of H, OH, and MOCHA, and Ra is CH3 or phenyl.

Preferably, n is an integer between 1 and 9, R1 is OH or a short-chain ester, R2 is OH or MOCHA, and Ra is CHa. Most preferably, R1 is OH, R2 is MOCHA, and n is an integer between 6 and 9. The preferred value of n for anti-inflammatory activity, is 7. Esters preferred for anti-inflammatory activity, in decending order, areoctyl homovanillate, decyl homovanillate, 3-phenylpropyl homovanillate, benzyl homovanillate, and hexyl homovanillate.

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

The acid and alkyl bromides used in the synthesis of preferred esters are commercially-available.

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

A safe and effective amount of ester is that amount which provides anti-inflammatory activity, thereby alleviating or preventing the inflammation being treated at a reasonable benefitlrisk ratio, as is intended with any medical treatment. Obviously, the amount of ester 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 ester 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 ester 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 30, 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 administration include pr-opylene 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 composition.

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 ester. Tablets can be compressed, tablet triturates, en- teric-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-effervescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, sus pending 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 ester, 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 10%, of the ester.

Suitable carriers for topical administration of the ester 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 ester 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 references 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 Applications 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, La Hann, 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 ester. While dosages higher than the foregoing are effective to reduce inflammation, care must be taken in some individuals to prevent adverse side effects.The esters and compositions of this invention can be used to reduce 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 alleviate pain and discomfort caused by inflammation.

The esters and compositions of the instant invention can be administered topically or systemically.

Systemic application includes any method of introducing the ester compound into the tissues of the body, e.g., intrathecal, epidural, intramuscular, transdermal, intravenous, 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 formulatios 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 ester 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 ester administration, which is variable, the esters are generally long-acting, and in some cases it may be possible to obtain effective relief by administering the composition as infrequently as once a day.

A preferred method of systemic application of the esters 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 ester are acceptable. Individual doses of from about 50 mg to about 600 mg are especially preferred.

Topical administration can be used to reduce inflammation, through directly laying on or spreading a safe and effective amount of the ester, or composition containing an ester, 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 5 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 ester to be administered as well as the particular disorder to be treated. The extent of the reduction of inflammation also depends upon such factors as the amount of ester, the area of tissue to be covered, and the ability of the ester 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 Octyl homovanillate was synthesized by the following method:

Specifically, 2 g of homovanillic acid was dissolved in 11 ml of 1N sodium hydroxide. The water was then evaporated, and the residue-was dried under high vacuum. The resulting solid was suspended in 50 ml of N,N-dimethyl-formamide (DMF) and heated to 900C. 2.3 g of 8-bromooctane was added, and the mixture was stirred overnight at 90"C. The DMF was removed under vacuum, and the residue partitioned between ether and water. The ether layer was then washed with saturated sodium bicarbonate, water, and brine, dried over magnesium sulfate, filtered and evaporated. 2.9 g of crude product was obtained.

This material was chromatographed on silica gel with 20% ethyl acetate/hexane and then Kugelbrohr distilled at 120"C to provide the analytically pure product as a colorless oil.

In the above example, decyl homovanillate and hexyl homovanillate were made by substituting, respectively, 10-bromodecane and 6-bromohexane for 8-bromooctane.

In the above example, 3-phenylpropyl homovanillate was made by substituting 1-phenyl-3.bromopro- pane for 8-bromooctane. The crude product was purified by silica gel chromatography with 30% ethyl acetate/hexane and then Kugelbrohr distilled to provide the analytically pure product as a pale yellow oii.

Example II A composition for parenteral administration is prepared by combining the following ingredients: Octyl homovanillate 300 g Ethyl oleate 980 ml Benzyl alcohol 20 ml The octyl homovanillate 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 the octyl homovanillate is replaced with hexyl homovan hate, decyl homovanillate, benzyl homovanillate, or 3-phenyl-propyl homovanillate.

Example III A composition for oral administration is prepared by combining the following ingredients: Octyl homovanillate 1.10 kg Sesame oil 3.25 liters The octyl homovanillate 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 the octyl homovanillate is replaced with hexyl homovan ii late, decyl homovanillate, benzyl homovanillate, or 3-phenyl-propyl homovanillate.

Example IV A composition for oral administration is prepared by combining the following ingredients: Octyl homovanillate 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 the octyl homovanillate is replaced with hexyl homovanillate, decyl homovanillate, benzyl homovanillate, or 3-phenyl-propyl homovanillate.

Example V A composition for topical administration is prepared by combining the following ingredients: Octyl homovanillate 4g Propylene glycol 100 ml Ethyl alcohol 100 ml The above ingredients are combined to give a clear solution. 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 the octyl homovanillate is replaced with hexyl homovanillate, decyl homovanillate, benzyl homovanillate, or 3-phenyl-propyl homovanillate.

Effectiveness in reducing inflammation Example Vl Five ester compositions were tested for anti-inflammatory activity using the croton oil induced mouse ear inflammation test.

Adult male Cox 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 al of a 1% ethanolic solution of the test compound. Four hours prior to sacrifice both ears were treated with 25 al 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) 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 Octyl homovanillate 62.0+26.1 Decyl homovanillate 31.5t15.7 3-phenylpropyl homovanillate 28.3+14.5 Benzyl homovanillate 25.527.6 Hexyl homovanillate 24.4+26.1 These results show that the ester compositions tested do in fact have statistically significant anti-inflammatory activity.

Claims (19)

1. Substituted phenylacetic acid ester compounds, and pharmaceutically-acceptable salts thereof, of the formula:

wherein n is an integer between 1 and 14, R1 is selected from the group consisting of H, OH, and a shortchain ester, R2 is selected from the group consisting of H, OH and OCH3, and R3 is CH3 or phenyl.

2. Substituted phenylacetic acid ester compounds, and pharmaceutically-acceptable salts thereof, according to Claim 1, wherein R3 is CH3.

3. Substituted phenylacetic acid ester compounds, and pharmaceutically-acceptable salts thereof, according to Claim 1, wherein R, is OH or a short-chain ester and R2 is OH or SOCH3

4. Substituted phenylacetic acid ester compounds, and pharmaceutically-acceptable salts thereof, according to Claim 3, wherein R1 is OH and R2 is OCH3.

5. Substituted phenylacetic acid ester compounds, and pharmaceutically-acceptable salts thereof, according to Claim 4, wherein R3 is-CH3.

6. Substituted phenylacetic acid ester compounds, and pharmaceutically-acceptable salts thereof, according to Claim 3, wherein n is an integer between 1 and 9.

7. Substituted phenylacetic acid ester compounds, and pharmaceutically-acceptable salts thereof, according to Claim 6, wherein n is an integer between 6 and 9.

8. Substituted phenylacetic acid ester compounds, and pharmaceutically-acceptable salts thereof, according to Claim 8, wherein n is 7.

9. A composition for reducing inflammation in humans or lower animals comprising: (a) a safe and effective amount of substituted phenylacetic acid ester compound of the formula:

wherein n is an integer between 1 and 14, R1 is selected from the group consisting of H, OH, and a shortchain ester, R2 is selected from the group consisting of H, OH, and OCH3, and R3 is CH3 or phenyl, or a pharmaceutically-acceptable salt thereof, or mixtures thereof; and (b) a pharmaceutically-acceptable carrier.

10. A composition, according to Claim 9, wherein R3 is CH3.

11. A composition, according to Claim 9, wherein R1 is OH or a short-chain ester and R2 is OH or OCH3.

12. A composition, according to Claim 11, wherein R, is OH and R2 is OCH3.

13. A composition, according to Claim 12, wherein R3 is CH3.

14. A composition, according to Claim 12, wherein n is an integer between 1 and 9.

15. A composition, according to Claim 14, wherein n is an integer between 6 and 9.

16. A composition, according to Claim 15, wherein n is 7.

17. A composition, according to Claim 9, for parenteral administration, comprising at least about 90%, by weight, of said pharmaceutically-acceptable carrier.

18. A composition, according to Claim 9, for oral administration, comprising from about 25% to about 50%, by weight, of said phenylacetic acid esters.

19. A composition, according to Claim 9, for topical administration, comprising from about 1% to about 5%, by weight, of said phenylacetic acid esters.