AU7255700A - Sulfur containing di-tert-butylphenol compounds useful as anti-inflammatory agents - Google Patents

Description

Pm.

r/UUlU I I L.IuI I Regulation 3.2(2)

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: Invention Title: SULFUR CONTAINING DI-TERT-BUTYLPHENOL COMPOUNDS USEFUL AS ANTI-INFLAMMATORY AGENTS *o The following statement is a full description of this invention, including the best method of performing it known to us SULFUR CONTAINING DI-TERT-BUTYLPHENOL

COMPOUNDS

USEFUL AS ANTI-INFLAMMATORY

AGENTS

TECHNICAL

FIELD

The subject invention relates to nonsteroidal anti-inflammatory drugs, particularly to substituted sulfur containing di-tert-butylphenol compounds.

BACKGROUND OF THE INVENTION Di-tert-butylphenol compounds are a class of compounds known for their use as stabilizers for plastics, oils and fats; see, U.S. Patent No. 3,711,544 issued to Engelhardt, Fruhstorfer, Hesse, Dennier Baumer on January 16, 1973.

Certain di-tert-butylphenol compounds and other compounds structurally related thereto have been found to have significant anti-inflammatory and/or analgesic activity. Such compounds, processes for making them, and uses for them are disclosed in the following references: U.S. Patent Nos. 3,784,701 issued to Tomcufcik, Grassing Sloboda on January 8, 1974; 3,917,672 issued to Schmidt on November 4, 1975; 4,124,725 issued to Moore on November 7, 1978; 4,130,666 issued to Moore on December 19, 1978; 4,165,383 issued to Moore on August 21, 1979; 4,172,082 issued to Moore on October 23, 1979; 4,357,345 issued to Moore on November2, 1982; 4,418,074 issued to Moore on November 29, 1983; 4,440,784 issued to Katsumi, Kondo, Yamashita, Hidaka, Hosoe, Ariki, Yamashita Watanobe on April 3, 1984; 4,535,165 issued to Moore on August 13, 1985; 4,677,113 issued to Bell Moore on June 30, 1987; 4,708,966 issued to Loomans, Matthews Miller on November 24, 1987; 4,714,776 issued to Bell Moore on December 22, 1987; 4,833,155 issued to Muchowski, Greenhouse, Young Murthy on May 23, 1989; 4,968,710 issued to Rustad on November 6, 1990; 4,982,006 issued to Hudec on January 1, 1991; 5,086,064 issued to Capris, Conner Sircar on February 4, 1992; 5,102,897 issued to Boschelli, Conner, Kostlan, Kramer, Mullican Sircar on April 7 1992; European Patent Application No. 0,212,848 of Riker Laboratories, published March 4, 1987; PCT Patent Application Nos. WO 83/01774 and WO 83/91775 of Riker Laboratories, both published May 26, 1983; WO 93/07865 of The Procter Gamble Company, published April 29, 1993; Kaffenberger, T.H. Eichhold M.J. Doyle, "Determination of Tebufelone (A New Anti-Inflammatory Drug) Strength and Stability in Bulk Drug, Dosage Formulations and Feed Admixtures by Reversed-Phase High-Performance Liquid Chromatography", Journal ofChromatography, Vol. 505 (1990), pp. 349-356. Such compounds are also disclosed and reviewed in Batt, Inhibitors and Their Anti-inflammatory Activities", Progress in Medicinal Chemistry, Vol. 29 (1992), pp. 1-15, 45-50, and references disclosed therein.

Although a number of di-tert-butylphenol compounds have been demonstrated to exhibit anti-inflammatory activity, many such compounds exhibit little or no antiinflammatory activity. Thus it is generally not possible to predict whether such compounds have substantial anti-inflammatory activity without testing for the activity.

It is an object of the subject invention to provide compounds which have effective anti-inflammatory, analgesic and/or anti-oxidant activity.

It is a further object of the subject invention to provide such compounds which cause few adverse side effects.

It is yet another object of the subject invention to provide such compounds which exhibit gastroprotective effects.

It is also an object of the subject invention to provide methods for treating inflammation and/or pain using the subject compounds.

SUMMARY OF THE INVENTION The subject invention involves compounds having the structure: H CH3 0 wherein xis from 1 to y is from I to 2; and z is from 0 to Preferably x is from I to 3; more preferably from 1 to 2. Preferably z is from 0 to 3; more preferably from 0 to 1. When x is 1 and z is 1, y is preferably 2.

DETAILED DESCRIPTION OF THE INVENTION As used herein, "alkyl" means a saturated hydrocarbon substituent, straight, branched or cyclic chain, unsubstituted or substituted. Preferred alkyl are Cl to C12; more preferred are C1-C6; more preferred still are C1-C3; especially preferred are C2 and Cl.

As used herein, "alkanyl" means a saturated alkyl.

3 As used herein, "alkanoxy" means a substituent having the structure Q-O-, where Q is alkanyl.

As used herein, "alkanylthiol" means a substituent having the structure Q-S-, where Q is alkanyl.

As used herein, "halo" means fluoro, chloro, bromo or iodo.

Compounds The subject invention involves particular di-tert-butylphenol compounds having the following structure:

H

S CH 2 )x S(O)y -(CH2)zCH 3 wherein x is from 1 to y is from 1 to 2; and zisfrom 0 Preferably x is from I to 3; more preferably from I to 2. Preferably z is from 0 to 3; more preferably from I to 3. When x is 1 and z is 1, y is preferably 2.

Preferred compounds of the subject invention include those having the above structure with x, y and z as indicated in the following table: Compound No. x y z 1 2 0 2 1 1 o 3 2 1 0 4 1 1 1 5 2 2 0 6 1 2 1 In order to determine and assess pharmacological activity, testing of the subject compounds in animals is carried out using various assays known to those skilled in the art. The anti-inflammatory activity of the subject compounds can be conveniently demonstrated using an assay designed to test the ability of the subject compounds to antagonize the local edema which is characteristic of the inflammatory response.

Examples of such known tests include the rat carrageenan edema test, the oxazoloneinduced inflamed mouse ear test, and the mouse arachadonic acid-induced inflamed ear test. Analgesic activity may be tested in art-known models such as the phenylbenzoquinone-induced writhing test in mice, and the Randall Selitto test in rats. Another useful art-known test is the rat adjuvant arthritis test which is a useful model for assessing anti-inflammatory activity, anti-arthritic and anti-resorptive activity in a chronic, rather than an acute, model.

These and other appropriate tests for pharmacological activity are disclosed and/or referred to in U.S. Patent No. 4,130,666 issued to Moore on December 19, 1978; U.S. Patent No. 4,431,656 issued February 14, 1984 to Katsumi, et al.; U.S.

Patent No. 4,440,784 issued to Katsumi, et al. on April 3, 1984; Japanese Patent Application 85/54315 of Katsumi, et al., published March 28, 1985; European Patent Application No. 0,059,090 of Yamanuchi Pharmaceutical Company Ltd., published September 1, 1982; Opas, R.J. Bonney J.L. Humes, "Prostaglandin and Leukotriene Synthesis in Mouse Ears Inflamed by Arachadonic Acid", The Journal of Investigative Dermatology, Vol. 84, No. 4 (1985), pp. 253-256; Swingle,

R.L.

Bell G.G.I. Moore, "Anti-inflammatory Activity of Antioxidants", Antiinflammatory and Antirheumatic Drugs, Vol. III, Chapter 4, K.D. Rainsford, ed., CRC Press, Inc., (1985), pp. 105-126; Adamkiewicz, W.B. Rice J.D.

McColl, "Antiphlogistic Effect f Trypsin in Normal and in Adrenalectomized Rats", Canadian Journal of Biochemistry Physiology, Vol. 33 (1955), pp. 332-339; Sellye, "Further Studies Concerning the Participation of the Adrenal Cortex in the Pathogenesis of Arthritis", British Medical Journal, Vol. 2 (1949), pp. 1129-1135; and Winter, E.A. Risley G.W. Nuss, "Carrageenan-Induced Edema in Hind Paw of the Rats as an Assay for Antiinflammatory Drugs" Proceedings of Society of Experimental Biology and Medicine, Vol. 111 (1962), pp. 544-547; Otterness, M. L. Bliven, "Laboratory Methods for Testing Nonsteroidal Antiinflammatory Drugs", Nonsteroidal Antiinflammatorv Drugs. Chapter 3, J. G. Lombardino, ed., John Wiley Sons, Inc. (1985), pp. 111-252. Hitchens, J. S. Goldstein, L.

Shemano J. M. Beiler, "Analgesic Effects of Irritants in Three Models of Experimentally-Induced Pain", Arch. Int. Pharmacodyn. Vol. 169, No. 2 (1967) pp. 384-393; Milne, G. M. T. M. Twomey, "The Analgetic Properties of Piroxicam in Animals and Correlation with Experimentally Determined Plasma Levels", Agents and Actions, Vol. 10, No. 1/2 (1980), pp. 31-37; Randall, L. O. J.

J. Selitto, "A Method for Measurement of Analgesic Activity on Inflamed Tissue", Arch. Int. Pharmacodvn., Vol. 111, No. 4 (1957), pp. 409-419; Winter, C. A. L.

Faltaker, "Nociceptive Thresholds as Affected by Parenteral Administration of Irritants and of Various Antinociceptive Drugs", J. Pharmacol. Exp. Ther., Vol. 148, No- 3 (1965), pp. 3 73-379; the disclosure of all these references are incorporated herein by reference.

Many anti-inflammatory drugs, particularly non-steroidal anti-inflammatory drugs (NSAIDs) cause undesirable gastrointestinal side effects,' especially when dosed perorally; such side effects may include ulcers and erosions. These side effects,- which are often asymptomnatic, can become serious enough to require hospitalization and can even be lethal. Compounds of the subject invention generally .cause fewer such gastrointestinal side effects compared to other NSAIDs, even compared to many other di-tert-butyiphenol derivatives. Some compounds of the subject invention are even gastroprotective, protecting the stomach from ulcers and erosions, particularly those caused by ethanol or other NSAIDs.

Certain NSAJ)Ds, including certain di-tert-butyiphenol derivatives, when dosed systemically, cause an undesirable increase in systemic levels of certain liver enzymes.

Compounds of the subject invention generally cause less of such liver enzyme side effects compared to other di-teit-butyiphenol compounds.

Compounds useful in the. subject invention can be made using the following general reaction schemes: (A)OH 0 W (CH 2

)S(CHD

2 )C2{ 3 weeW02=lOR haid etc.

(riedeLCsAfis Reation)

OH

rTCPBA) L -I (CH) S0y (CH) ClH 3 The following non-limiting examples provide fu~rther information regarding :synthesis of the subject compounds.

Example I I 3 ,5-di-t-butyl-4-hydroxyphenyl)-2-(rnethylsulfanyl)ethanone. 2,6-di-tbutylphenol (1.7680 g, 8.66mniol) is- placed in a flame dried RBF, and 2- (methylthio)acetic acid (O.8OmiL, 9.19 mmol) is then added- This is then blanketed with argon and TFAA (1.30 mL, 9.20 mnmol) is added via syringe at a fast rate. A small amount of CH2C12 is added to aid in mixing. The reaction quickly turns violet and darkens. It is followed by TLC using 10% EtOAc in hexanes. After 5 h, the reaction is carefully poured into 70mL saturated bicarbonate and extracted with 2 portions of Et20. The combined organics are washed with brine, filtered through cotton, dried over molecular sieves, then concentrated on a rotavap and dried under vacuum. This gives a white solid which can be crystallized from EtOAc/hexanes to give orange crystals, mp 108.5-109.5oC.

Example 2 1-(3,5-di-t-butyl-4-hydroxyphenyl)-2-(methylsulfnyl)ethanone. 1-(3,5-di-tbutyl-4-hydroxyphenyl)-2-(methylsulfanyl)ethanone (15.00 g, 50.94 mmol) is dissolved in CH2Cl2 (100 mL) in a flame-dried flask under argon then cooled in an bath. mCPBA 10.45 g, 51.47 mmol) is added carefully, generating some gas evolution of H2. The reaction is stirred for 1.75 h while maintaining the bath temperature until the last 20 minutes when the bath is allowed to warm. The reaction is then poured into saturated bicarbonate, separated and extracted with 2 x CH2C12. The organics are concentrated on a rotavap then dried under vacuum (being careful of foaming). This gives a light tan foam which is purified by flash chromatography on silica with 1.6 L 27.5% acetone in hexanes then 100% acetone.

A white solid is obtained which can be crystallized with EtOAc/hexanes with refrigeration to give white crystals, mp 143.6-144.9oC.

Example 3 S1-(3,5,-di-t-butyl-4-hydroxyphenyl)--(methysulfonyl)ethanone. 1-(3,5-di-tbutyl-4-hydroxyphenyl)-2-(methylsulfanyl)ethanone (2.7422 g, 9.31 mmol) is dissolved in CH2C2 (30 mL) in an RBF under argon then cooled in an ice/H20 bath.

mCPBA 4.35 g, 21.4 mmol) is carefully added. A white precipitate forms making stirring difficult so more CH2C12 is added. The reaction is stirred overnight, allowing the cooling bath to warm. The next morning, it is transferred to a S. separatory funnel, diluted to -125 mL and washed with 2 x dilute sodium bisulfite then 2x 0.5N bicarbonate. The combined organics are filtered through cotton, dried over mol sieves, concentrated on a rotavap then dried under vacuum being careful of foaming. This gives a yellow foam which can be crystallized from EtOAc/hexanes to give white crystals, mp 138.6-139.5oC.

Example 4 1-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(methylsulfinyl)propan-1-one. This material is obtained from 1-(3,5,-di-t-butyl-4-hydroxyphenyl)-3- (methylsulfanyl)propan- 1-one following the (method of 1-(3,5-di-t-butyl-4hydroxyphenyl)-2- (methylsulfinyl)ethanone). The product is purified by flash chromatography With 3 acetone in hexanes and recrystallized from EtOAc/hexanes, mp 15 8 8 15 Example 1 -(3,5-di-t-butyl4hydroxyphenyl)2{ethliyjj)taoe This material is obtained from 1( 3 ,5di-tbutyI-4.hydroyphenyl) 2 (thllfanlehnn following (the method .of 1(,,d--uyl-yrxpey)2 (methylsulflnyl)ethanone). The material is purified by flash chromatography with acetone. in hexanes followed by crystallization. from EtOAc/hexanes with refigeration giving white crystals, mg 13 3 134oC.

Example 6 1I35d -uyl-yrxpey -one. This material was prepared from J 3,,d--uy4hdrxpel)- (miethylsiulfanyl)propan- 1-one following._ .(the method of, -35-i-uy4 hyaroxyphenyl)2(methylsulfanyl)propan-I A flash choagrp wt 100% acetone followed by recrystallization from wt~/etn ie w ith f osolid, mp 6 1: 9 168.5oC..- 1'4 3 ,5 di-t-.butlhyl ypExamp-(t~sle oy~~hnn~ i7te -i prepared4fro impure I- (t oolowg the method Of J 05-. -btl-yrxpey)2 (mnetiy'lsul'fbnyl)et~one) Crystallization (of the,, crude. product).-, from tOAdhexne followed by a second..c~ysta11izatipoi.,then: a flash crmtgah wit by 9.-205c a third crystallization with refrigeration gives- White crystals, Compoitions of the subject invention comprise. a. safe and effective amount of the subject compounds, and a pharmaceutically-.acceptable carrier. As- used, herein, "safe and effective amount" means .an- amount of a .compound -sufficient to significantly induce a positive modification in the condition to be treated, but low enough to, avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. A safe and effective amount of a compound will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severi ty of the. condition, the duration of the. treatment, the nature of concurrent therapy, the particular pharmaceutically-.acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.

0* Compositions of the subject invention preferably comprise from about 0.1% to about 99.9% by weight of a compound, more preferably from about 20% to about and most preferably from about 40% to about In addition to the compound, the compositions of the subject invention contain a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal. The term "compatible", as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations.

Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated.

Some examples of substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as cornstarchand potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; powdered .tragacanth;: malt; gelatin; talc; solid lubricants, such as stearic acid, magnesium stearate; calcium sulfate; triglycerides and derivatives; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycolf'glycin, sorbitol, ianniol, and iolyethylene glycol; alginic acid; emulsifiers, such as the Tweens®; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents, excipients; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

The choice of a pharmaceutically-acceptable carrier to be used in conjunction with a subject compound is basically determined by the way the compound is to be administered.

If the subject compound is to be injected, it is preferably injected nonintravenously, the preferred pharmaceutically-acceptable carrier is sterile, physiological saline, with blood compatible suspending agent, the pH of which has been adjusted to about 7.4. Such injectable compositions preferably comprise from about 1% to about 50% of the subject compound, more preferably from about 5% to about 25%, also preferably from about 10 mg to about 600 mg of the subject compound per dose.

Suitable pharmaceutically-acceptable carriers for topical application include those suited for use in lotions, creams, gels and the like. Topical compositions preferably contain from about 1% to about 50% of an emollient, more preferably from about 5% to about 25% of an emollient. Such topical compositions preferably comprise from about 0.1% to about 50%, of the subject compound, more preferably from about 0.5% to about 10%, also preferably from about 5 mg to about 3500 mg per dose.

The preferred mode of administering the subject compound is perorally. The preferred unit dosage form is therefore tablets, capsules and the like, comprising a safe and effective amount of the compound, .which is preferably from about 5 mg to about 3500 mg, more preferably from about 10 mg to about 1000 mg, and most preferably from about 25 mg to about 600 mg. The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well-known in the art. Their selection will depend on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be made without difficulty by a person skilled in the art.

Many of the subject compounds are hydrophobic. If it is desired to provide an aqueous-based composition or a composition soluble in or miscible with aqueous media, a solubilizing agent may be included in the cfrilbsition. Non-limiting examples pfsuch solubilizing'agents include polyethylene glycol, propylene glycol, *.ethano!, and polyoxyethylene (35) castor oil. Particularly preferred oral composition carriers suitable for compositions of the subject invention are disclosed in U.S. Patent Nos. 5,189,066 of Kelm Bruns, Oo- issued February 23, 1993, entitled "Pharmaceutical Compositions of Tebufelone", and 5,281,420 of Kelm Dobrozsi, issued January 25, 1994, entitled "Solid Dispersion Compositions of Tebufelone", hereby incorporated herein by reference.

The preferred mode of administration of the subject compounds is peroral, but other known methods of administration are contemplated as well, e.g., dermatomucosally (for example, dermally, rectally and the like), and parenterally (for example, by subcutaneous injection, intramuscular injection, intraarticular injection, intravenous injection and the like). Ocular administration and inhalation are also included. Thus specific modes of administration include, without limitation, peroral, transdermal, mucosal, sublingual, intranasal, intramuscular, intravenous, intraperitoneal, subcutaneous, and topical administration.

Preferred doses of the subject compounds range from about 0.2 mg/kg to about mg/kg, more preferably from about 0.5 mg/kg to about 12 mg/kg. Preferred injectable doses comprise from about 0.1 mg/kg to about 10 mg/kg of the subject compound. Preferred topical doses comprise from about 1 mg/cm2 to about 200 mg/cm2 of the subject compound applied to the skin surface. Preferred peroral doses comprise from about 0.5 mg/kg to about 50 mg/kg, more preferably from about 1 mg/kg to about 10 mg/kg, of the subject compound. Such doses are preferably administered from about once to about six times daily, more preferably from about twice to about four times daily. Such daily doses are preferably administered for at least one week, also preferably for at least two weeks, also preferably at least one month, also preferably for at least 2 months, also preferably for at least 6 months, 1 year, 2 years, or more.

The following non-limiting examples illustrate the subject invention.

Example A Pharmaceutical compositions in the form of tablets are prepared by conventional methods, such as mixing and direct compaction, formulated as follows: Ingredient uantity (mg per tablet) Compound 1 200 Microcrystalline Cellulose 100 Sodium Starch Glycollate Magnesium Stearate 3, 3 When administered orally two times daily,: the above'composition significantly reduces the inflammation in a patient suffering: from rheumatoid arthritis. A significant benefit is also achieved by twice .daily administration of this composition to a patient suffering from osteoarthritis. Example B A pharmaceutical composition in capsule form is prepared by conventional methods, formulated as follows: IngredientOuantity (mg per capsule) Compound 2 200 Lactose To fill to volume of capsule The above capsule administered orally once a day substantially reduces the symptomology of a patient afflicted with rheumatoid arthritis or osteoarthritis.

Example C Aoral solid dosage pharmaceutical composition is prepared by conventional methods, formulated as follows: Ingredient Quantity weight) Compound 6 Pluronic F108 Tween® Example D An oral solid dosage pharmaceutical compositon is prepared by conventional methods, formulated as follows: Ingredient Quantity weight) Compound 6 Triglycerides and Derivatives Cremaphor EL Another aspect of the subject invention is methods for treating or preventing diseases characterized by inflammation by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment. The term "diseases characterized by inflammation",, as used herein, means conditions which are known to involve inflammation, and may include conditions such as arthritis rheumatoid arthritis, osteoarthritis, psoriatic arthritis, juvenile arthritis, Reiter's syndrome, infectious arthritis, and ankylosing spondylitis, systemic lupus, erythematosus and gout), as well as the presence of inflammation whether or not it is associated with an identifiable disease. Diseases characterized by inflammation further may include inflammation in theoral cavity inflammation associated with gingit or periodontal disease); inflammation nthe, gastrointestinal tract, mflanmmation associated ith ulcers and irritable bowel disease); inflammation associated with dermatological. diseases, psoriasis, acne, and other skin inflammation); inflamaon associated with, the respiratqry -tract (e.g.,-asthma, bronchitis, and allergies); and inflammation in the central nervous system Alzheimer's disease).

Another aspect of the subject invention is methods for treating or preventing pain by administering a safe and effective amount of a subject compound to a human Sor lower animal in need of such treatment. Pain which can be treated or prevented by administering the subject compounds may include peripheral pain, menstrual pain, dental pain, and lower back pain.

Another aspect of the subject invention is methods for protecting against free radical damage resulting from oxidative stress and ischemic conditions by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment. Such treatment may include protecting against ischemic heart disease, atherosclerosis, stroke, and ischemic cell damage of heart.

Another aspect of the subject invention is methods for treating or preventing gastric or duodenal ulcers or erosions by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment. In 12 particular, such ulcers or erosions caused by ethanol or non-steroidal antiinflammatory drugs (NSAIDs) can be treated and/or prevented by administration of preferred subject compounds.

Appropriate tests for determining the gastrointestinal safety or gastroprotective or gastric healing properties of the subject compounds are known.

Methods for determining acute gastrointestinal safety are disclosed and/or referred to in the following references: Unangst, G.P. Shrum, D.T. Connor, R.D. Dyer, and D.J. Schrier, "Novel 1,2,4-Oxadiazoles and 1,2,4-Thiadiazoles as Dual 5-Lipoxygenase and Cyclooxygenase Inhibitors", J. Med. Chem. Vol. (1992), pp. 3691-3698; and SegawaY, 0. Ohya, T. Abe, T. Omata, et al., "Antiinflammatory, Analgesic, and Antipyretic Effects and Gastrointestinal Toxicity of the New Anti-inflammatory 'Drug N-{ 3 3 -(piperidinylmethyl)phenoxy] propyl}carbamoylmethylthio]ethyl -(p-chlorobenzoyl) 5-Methoxy-2methyl-3indolylacetate", Arzneim.-Forsch./Drug Res., Vol. 42 (1992), pp. 954-992. In the methods disclosed therein, stomachs of the animals are typically examined two hours after dosing a compound.

Methods for determining subchronic gastrointestinal safety are disclosed and/or T i S. referred.t in the'following references: Melarange, R, C. Genty, et al., "Anti- Sinflammatory and 'Gatrointestinal Effects ofNabumtione or Its Active Metabolite 6-Methoxy-2-naphthylacetic Acid (6MNA", Dig. is. Sc Vol. 37 (1992), pp.

,i 1847-1852; and Wong;.S., S.J. Lee, et al., "Antiarthritic Profile ofBF-389 A Novel Anti-inflammatory Agent With Low Ulcerogenic Liability", Agents Actions, Vol. 37 (1992), pp. 90-91.

Methods for determining acute gastroprotection are disclosed and/or referred to in the following reference: Playford, D.A. Versey, S. Haldane, M.R. Alison, and J. Calan, "Dose-dependent Effects of Fentanyl on Indomethacin-induced Gastric Damage", Digestion Vol. 49 (1991), pp. 198-203. In the method disclosed therein, female Lewis rats (130-175 g) are dosed perorally with the subject compound mg/kg or vehicle at 2 hours and immediately before administration of a gastric damaging dose of indomethacin. The rats are sacrificed 4 hours later by C02 asphyxiation. Gastric corpus damage (millimeters of hemorrhagic lesions) is measured by digitized imaging.

While particular embodiments of the subject invention have been described, it would be obvious to those skilled in the art that various changes and modifications to the compositions disclosed herein can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention.

Claims (5)

1. 2. The compound of Claim I wherein x is from I to 3, preferably from I to 2.
2. 3. The compound of Claim I or 2 wherein z is from 0 to 3, preferably from 0 to
3. 4. Tecmon fayO h reeigcam hri s1 The compound of any of the preceding claims wherein y is 2.
4. 6. The compound of any of the preceding claims wherein y is I 2. 6. The compound of any or the preceding claims wherein z is 1 T aeadefctv mutohe compound of any one of the peeigcam hri s0 Thcopudoanoftepreceding claims whainnisd
5. 9. A pehrmaceutain m sitiomaio ran comprisingtepeoa adiitrto of(a a saf e and effective amount of the compound of any one ofe 0th preceding claims;.n DAT) ahi p8harmac euia-c ceptabl carrier TH PRCE 0AML OPN WAE*4R PAEN RDCAKTONY 29 BUWODRA HATHRN VI.32