MXPA97002941A - Compounds of di-ter-butilfenol that have a heterociclica unaportion, useful as agentesanti-inflamator - Google Patents

Abstract

The present invention relates to compounds having the structure (I), the present invention also relates to pharmaceutical compositions comprising the above compounds, and methods for treating inflammation or pain using the compounds

Description

COMPUFSTOS T) F DI-TER-BUTILFENOL THAT HAS ONE PORTION HFTFROCTCLIC. USEFUL AS ANTI-INFLAMMATORY AGENTS TECHNICAL FIELD The present invention relates to non-steroidal antiinflammatory drugs, particularly to the substituted di-tert-butyl enol compounds.

BACKGROUND PE INVENTION Certain di-tert-butyl phenol compounds and other compounds structurally related thereto have been found to have significant anti-inflammatory and / or analgesic activity; It has been discovered that others have other activities that alter diseases. Some of said compounds, methods for making them, and uses for them are described in the following references: Patents of E. U. A. Nos. 4, 535, 165, issued to Moore on August 13, 1985; 4, 724, 246, issued to Ravichandran on February 9, 1988; 4, 80B, 620, issued to Oe Kawasaki, Terasawa Yasunaga on February 28, 1989; 4, 891, 374, issued to Thorwarr. , Gebert, Schleyerbach to Bartlett on January 2, 1990; 4, 908, 364 issued to Thorwart, Gebert, Schleyerbach to Bartlett on March 13, 1990; 4, 940,790 issued to Thorwart, Gerbert, Schleyerbach Bartlett on July 10, 1990; 5,155,122 issued to Connor, Flynn, Rostian, Mullican, Shrurn, Unangst & iilson on October 13, 1992; Japanese Patent Application Nos. 58-148858 to Ya anouchi Pharrn. Co. published on September 5, 1983; 1-180878 of Yoshitorni Pharrn. Ind. Published on July 18, 1989; 2-229169 of Takeda Chemical Ind. Published on September 11, 1990; Isornura, Y., S. Sakarnoto, N. Ito, H. Homrna, T. Abe to K. Kubo, "Synthesis and Anti-infla matory Activity of 2,6-Di-ter-butylphenols with a Heterocyclic Group at the 4 -Position "III.", Chern. Pharrn,. Bull .. Vol. 32 (1984) No. I, pp. 152-165; Unangst, P. C, G. p. Shrurn, DT Connor, RD Dyer D. 3. Schier, "Novel 1, 2, 4-Oxadiazoles and 1 2 4-Thiadiazules as Dual 5-Lipoxygenase and Cyclooxygenase Inhibitors", 3. Med. Che .. Vol. 35 (1992 ), pp. 3691-3698; Constantino, L., C. Parenti, M. Di Bella, P. Zanoli M. Baraldi, "Anti-inflammatory activity of Newly Synthesized 2 6-Bis-l-Dimethylethyl) Phenol Derivati is". P armacoloqical Research. Vol. 27 (1993) No. 4, pp. 349-358; Mullican, M. D., M. LJ. Uilson, DT Connor, CR Kostlan, D. 3. Schrier to RD Dyer, "Design of 5- (3, 5-Di-tert-butyl-4-hydroxyphenyl) -1, 3, 4-oxadiazoles, and 1, 2 , 4-triazoles as Orally-Active, Nonulcerogenic Anti-inflammatory Agents, "3. Med. Chem. Vol. 36 (1993), p. 1090-1099. Although a number of di-tert-butyl enol compounds have been shown to exhibit anti-inflammatory activity, many of these compounds exhibit little or no anti-inflammatory activity. In this way, it is generally not possible to predict which compounds have substantial anti-inflammatory activity without testing for activity. An object of the present invention is to provide compounds having effective anti-inflammatory, analgesic and / or antioxidant activity. Another object of the present invention is to provide said compounds that cause less adverse side effects. It is also an object of the present invention to provide methods for treating inflammation and / or pain using said compounds.

BRIEF DESCRIPTION OF THE INVENTION The present invention involves the compounds having the structure: wherein a) each R is independently alkyl having from 1 to about 7 carbon atoms; b) Z is 0 or N-X; c) X is selected from hydrogen, alkyl having from 1 to about 7 carbon atoms; C (0) Y, and SOsY; with changes; d) Y is selected from R ', OR' and NR's »; and e) each R 'is selected from hydrogen, alkyl having from 1 to about 7 carbon atoms, and phenyl.

DETAILED DESCRIPTION OF THE INVENTION As used herein, unless otherwise indicated, "alkyl" means straight, branched or cyclic, saturated or unsaturated hydrocarbon chain., replaced or unsubstituted. The preferred alkyl is straight chain. The preferred branched alkyl has one or two branches, preferably one branching. The preferred cyclic alkyl is monocyclic or straight chain and a monocyclic combination, especially a straight chain with a monocyclic terminal. The preferred alkyl is saturated. The unsaturated alkyl has one or more double bonds and / or one or more triple bonds. The preferred unsaturated alkyl has one or two double bonds or a triple bond, more preferably a double ligation. The preferred alkyl is unsubstituted. The preferred substituted alkyl is mono-, di-, or trisubstituted, most preferably unsubstituted. Preferred alkyl substituents include halogen, hydroxy, alkoxy (for example, rhetoxy, ethoxy, propoxy, b-toxy, pentoxy), aryloxy (e.g., phenoxy, chlorophenoxy, tolyloxy, ethoxy enoxi, alkyloxycarbonyl phenoxy, acyloxyphenoxy), benzyloxy acyloxy (for example, propionyloxy, benzoyloxy, acetoxy), carbamoyloxy, carboxy, mercapto, alkylthio, acylthio, arylthio (for example, phenylthio, chlorophenylthio, alkynylthio, alkoxyphenylthio, alkyloxycarbonylphenyl), benzylthio, aryl (for example, phenyl, tolyl, alkyloxyphenyl) , alkyloxycarbonylphenyl, carboxyphenyl, allophenyls), heterocyclyl, heteroaryl, amino (for example, amino, mono- and di-alkanyl of C-C3, rnethylphenylamino, rnethylbenzylamine), amido (for example, arni, mono- and di- gone alkylene of C-C3, carbarnamido), ureido and guanidino. As used herein, "alkanyl" means a saturated alkyl. As used herein, "alkoxy" means a substituent having the structure 0-0-, wherein 0 is alkyl. As used herein, "alkylthios" means a substituent having the structure 0-S-, wherein 0 is alkyl. As used herein, "aryls" means a portion having an unsubstituted or substituted aromatic ring having from 6 to about 10 carbon atoms. The preferred aryl is phenyl and naphthyl; the most erred aryl is phenyl. The erred aryl is not substituted. The erred substituted aryl is mono-, di-, or trisubstituted, more erably monosubstituted. erred aryl substituents include hydroxy, mercapto, halogen, methyl, ethyl and propyl. As used herein, "hete ocicyl" means a portion having a non-aromatic saturated or unsaturated ring having from 3 to about 8 ring atoms, including from 2 to about 6 carbon atoms and from 1 to about 4 heteroatoms selected from 0, 5, and N. erred heterocycles are saturated. erred heterocycles have 5 or 6 ring atoms including 1 to 3 heteroatoms in the ring, also erably 1 or 2 heteroatoms in the ring. erred erred heterocycles include piperidinyl, tetrahydrothienyl, pyrrolidinyl, piperazinyl, orpholinyl, tetrahydropyranyl, tetrahydrofuranyl, imidazolirinyl, pyrazolidinyl, oxazolidinyl, isoxazolirinyl, oxathiazotilidinyl, ixothiazolidinyl, acetinyl, oxepinyl, triazolidinyl. The heterocycles are unsubstituted or substituted, erably not substituted. erred substituted heterocycles are mono-, di-, or trisubstituted, more erably monosubstituted. erred heterocyclic substituents include alkyl (including substituted alkyl, eg, ethyl thio, carboxymethyl, chloro-ethyl, trifluoromethyl), halogen, hydroxy, carboxy, alkoxy, acyloxy, mercapto, amino (including mono- and di-alkylamino of CX ~ C3, for example, methylamino, direthylamino), amido, carba amido, thiocarba amido, ureido, thioureido, guanidino (including substituted guanidino rnetil, eg, rnethylguanidino, N, N '-dimethylguanidino, N, N-dimethylguanidino). As used herein, "heteroaryls" means a portion having an aromatic ring having 5 or 6 ring atoms including from 2 to 5 carbon atoms and from 1 to 4 heteroatoms selected from 0, S and N. The most erred heteroaryls have from 1 to 3 heteroatoms in the ring, also erably 1 or 2 heteroatoms in the ring. erred specific heteroaryls include pyrrolyl, imidazolyl, pyridyl, pyrimidimyl, pyracimyl, oxazolyl, isoxazolyl, pyranyl, thienyl, tetrazolyl, thiazolyl, isothiazolyl, fyl, oxathiazolyl. Heteroalyls are unsubstituted or substituted, erably not substituted. erred substituted heterocycles are mono-, di-, or trisubstituted, more erably substituted. erred heteroaryl substituents include alkyl, (including substituted alkyl, eg, thioromethyl, carboxymethyl, chloromethyl, trifluoromethyl), halogen, hydroxy, alkoxy, thio, amino, (including mono- and dialkanoylamino of C -Ca, for example, methylated ino, direthylamino, methoxymethyl amino, carboxymethylamino), aido, cyanamido, thiocarba amido, ureido, thioureido, guanidino (including methyl substituted guanidinos, for example, methylguanidi.no, N, N'-dimethylguanidino, N, N-dimethylguanidino), S-methylthiocarba oyl.

As used herein, "halogens" means fluorine, chlorine, bromine or iodine; the preferred halogens are fluorine, chlorine and bromine; more preferred is chlorine and also fluorine.

CQflPUESTQS The present invention involves the particular di-tert-butyl phenol compounds having the following structure: In the above structure, each R is independently alkyl having 1 to about 7 carbon atoms, preferably 1 to about 4 carbon atoms. Each R is preferably saturated. Each R is preferably not replaced. Each R is preferably straight or branched chain alkanyl from Cx to about Ca, or cyclic alkanyl of C3 at about c. Each R is preferably methyl, ethyl, n-propyl, or i-propyl; more preferably methyl or ethyl, most preferred methyl. Each R is preferably also cyclopropyl. Preferably, both R's are the same portion.

In the previous structure, Z is 0 or N-X; Preferred Z is oxygen. X is selected from hydrogen, alkyl having from 1 to about 7 carbon atoms, C (0) Y, C (S) Y, and SOa-Y. Preferred X is hydrogen. Also the preferred X is SOs, and. And it is selected from R ', OR' and NR's ». The preferred Y is R '. Also the preferred Y is NR'a. The preferred R 'is hydrogen or alkyl of Ca.-CA. The most preferred R 'is selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, and cyclopropyl; more preferred is hydrogen or methyl. Preferred compounds of the present invention include those having the above structure with R, Z, X, Y and R 'as indicated in the following table: COMPOSITE No. R z XYR '1 Me, Me 0 2 Me, Me NX H - - 3 Me, Me NX SOaY R' Me 4 Me, Me NX C (0) and NR'a, HH 5 c - Pr, c - PR NX H - _ To determine and ensure pharmacological activity, the testing of said compounds in animals is carried out using various tests known to those skilled in the art. The anti-inflammatory activity of the present compounds can be conveniently demonstrated using a test designed to test the ability of said compounds to antagonize the local ademe that is characterized by the inflammatory response. Examples of such known tests include the test of carrageenan edema in rats, the oxasolone-induced inflamed mouse ear test, and the induced inflammatory test of mouse arachidonic acid. Analgesic activity can be tested in models known in the art such as the phenylbenzoquinone-induced test in mice, and the Randall-Selitto test in rats. Another useful test known in the art is the rat adjuvant arthritis test which is a useful model for ensuring antiinflammatory activity, antiarthritic activity and antiresorptive activity in a chronic rather than an acute model. These and other tests appropriate for pharmacological activity are described and / or referred to in the Patent of E. U. A. No. 4, 130, 666, issued to Moore on December 19, 1978; Patent of E. U. A. No. 4, 431, 656 issued on February 14, 1984 to Katsu i, and others; Patent of E. U. A. No. 4, 440, 784 issued to Katsumi, et al., April 3, 1984; Patent Application 3a? onea 95/54315 of Katsumi, et al., published March 28, 1985; European Patent Application No. 0.59, 090, of Yamanuchi Pharmaceutical Co pany Ltd., published September 1, 1982; Opas, E. V., R. 3. Bonney to 3. L. Humes, "Prostaglandin and Leukotriene Synthesis in Mouse Ears Infla ed by Arachadonic Acid", The 3ournal of Inv s i a * ive Denna-rolooi. Vol. 84, No. 4 (1985), pp. 253-256; Bwingle, K. F., R.L. Bell to G.G. I. moore, "Anti-inflammatory Activity of Antioxidants", phynti-inflammation and Antirheumatic Drugs. Vol. III, Charpert 4, K. D. Rainsford, ed., CRC Press, Inc., (1985), p. 105-126; Adarnkiewicz, V. U., U. B. Rice to 3. D. McColl, "Antiphilogistic Effect of Trypsin in Normally in Adrenalectized Rats," Canadian Journal of Biochemistry Phvsioloq. Vol. 33 (1955), pp. 3 * 32-339; Sellye, H., "Further Studi.es Concerning the Participation of the Adrenal Cortex in the Pathogenesis of Arthritis", Briti h Medical Journal. Vol. 2 (1949), pp. 1129-1135; and Uinter, C. A., E. A. Risley G. U. Nuss, "Carrageenan-lnduced Edema in Hind Paw of the Rats as an Assay for Anti-inflammatory Drugs" Proceedings Qf Socje of Experiment to Bioloqv and Medicine. Vol. 111 (1962), pp. 544-547; Otterness, I., 8 M. L. Bliven, "Laboratory Methods for Testing Nonsteroidal Anti-inflammatorial Drugs", Nonstdroidal Anti- inflamtorv Druis. Chapter 3, 3. G. Lornbardino, ed., 3 John Sons, Inc. (1985), pp. 111-252. Hitchens, 3. T., S. Goldstein, L. She ano 3. M. Beiler, "Analgesic Effects of Irritants in Three Models of Experirnentally-lnduced Pain", Arch. Tnt. Pharmacodvn .. Vol.169, No. 2 (1967), pp. 384-393; Milne, G. M. T. Twimey, "The Analgetic Properties of Piroxica in Animáis and Correlation with Experimentally determined Plasma Levéis", Aqents and Action. Vol. 10, No. 1/2 (1980), pp. 31-37; Randall, L. O. to 3. 3. Selitto, "A Method for Measurement of Analgesic Activity on Inflamed Tissue", rch. Int. Pharrnacodvn .. Vol. 111, No. 4 (1957), pp. 409-419; winter, C. A. to L. Faltaker, "Nociceptive Thresholds as Affected by Parenteral Administration of Irritants and of Various Antinociceptive Drugs", i. Phar acol. Exo. Ther .. Vol. 148, No. 3 (1965), pp. 373-379; the description 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 asymptotic, can be serious enough to require hospitalization and still be lethal. The compounds of the present invention generally cause less gastrointestinal side effects compared to other NSAIDs, even compared to many other di-tert.-butyl phenol derivatives. Some compounds of the present invention are gastroprotective, which protect the stomach from ulcers and erosions, particularly those caused by ethanol or other NSAIDs. Certain NSAIDs, including certain di-tert-butylphenol derivatives, when dosed systemically, cause an undesirable increase in the systemic levels of certain liver enzymes. The compounds of the present invention generally cause little or no side effect of liver enzyme. The compounds useful in the present invention can be made using the following general reaction schemes: III A general method for the preparation of the compounds with the general structure III, when Z is 0, is the reaction of cyclocondensation with hydroxyl amine of an appropriate (3-chloroketone in the general structure II. performed by slow treatment of an alcoholic solution of the appropriate β-chloroketone and hydroxylahydrohalide salt with a stoichiometric amount of aqueous NaOH The compounds of the general structure III, when Z is NH, can be prepared by cyclocondensation The α, β-unsaturated ketones of the general structure and with hydrazine For example, this reaction can be carried out by heating an alcohol solution of an appropriate α-unsaturated ketone and a stoichiometric amount of hydrazine hydrate at temperatures between 30 ° C and 60 ° C. C. If higher reaction temperatures are desired, the reaction can be carried out in a sealed flask.The required ß-chloroketones and the ketones α, β-unsaturated are conveniently prepared by means of the Friedel-Crafts reaction of 2,6-di-tert-butyl enol with an appropriate α, β-unsaturated acid chloride followed by exposure to excess hydrochloric acid, or by condensation of aldol of 3,5-di-tert-butyl-4-hydroxyacetophenone silylated with an appropriate acetone under the influence of TiCl *. The following non-limiting examples provide more information regarding the synthesis of the present compounds.

EXAMPLE 1 Synthesis of 3- (3,5-di-tert-butyl-4-hydroxyphen.i.l) -4,5-dihydro-5, 5-d.irnet.-isoxazole: 3-Chloro-l- (3,5-di-tert-butyl-4-hydroxyphenyl) -3-me-r -ylbutan-1-one. In a round bottle at the bottom of 12 L, equipped with an internal thermometer, stirred at the mechanical, funnel inlet and addition septum, it is placed to a solution of 3,3-dimethylaminylchloride (146 g, 1.23 mol) in CHßCla (1000 mL). The stirred solution is cooled in a dry ice bath of CHaCla at -10 ° C, and then TiCl * (1M in H ^ Cla) 1476 rnL, 1.47 moles, 1.2 eq) is added via cannula at a rate of so that the reaction mixture is not heated above -5 ° C. The solution is stirred for 10 minutes after the addition is complete, and then a solution of 2,6-di-tert-butylphenol (253.4 g, 1.23 moles, 1.0 eq.) In HaCl-a (500 mL) is added. in the form of drops by funnel addition. The rate of addition is adjusted to keep the reaction temperature below 0 ° C. After the addition is complete, the cold bath is removed, and the mixture is allowed to stir at room temperature for 4 hours. Analysis of TLC (EtOAc: hexane, 1: 9) indicates that the reaction is complete. Hs »0 (2L) is carefully added, and the mixture is transferred to a 6 L extraction tunnel. The organic phase is separated, washed with additional HaO (2 x 1000 rnL), dried over aa-SO ^. , filtered, and returned to the reaction bottle of 12 L .. Ethereal HCl (1M, Aldrich, 2000 mL) is added .. After stirring for 2 hours, the solution is transferred to the 6 L separating tunnel, and washed with H 0 (3 x ID) The organic phase on a-aSO * filtered in a flask with the bottom round of 10-L, and evaporated by rotation, in the residue it is absorbed in iL of pentane, and maintained at -4 C. During the night, the resulting crystalline solid is filtered and dried to give 3-chloro-l- (3,5-di-tert-butyl-4-hydroxyphenyl) -3-methylbu + al-l-one. (3.5-P-er-l? U l - ^ - i rQ? Ifenil) -, 5- «JifiidrQ-5.5-diptethylisoxazole In a bottle with the lower part of 5 L round, equipped with magnetic stirrer and an Ar input. It is placed in a solution of 3-chloro-l- (3,5-di-tert-butyl-4-hydroxyphenyl) ) -3-rnethylbutan-1-one (77.1 g, 0.24 moles) and hydroxylane hydrochloride (20.1 g, 0.28 moles) in EtOH (2.2L). To the stirred solution is added 2 L of NaOH (119 ml, 0.24 mol, 1.0 eq) in the form of drops for 15 minutes. A yellow color that fade quickly is observed in contact of the two solutions. After the addition is complete the reaction is heated to 50 ° C. The reaction is followed by TLC (EtOAC: hexane, 1: 4). After 3 hours, approximately 50% of the conversion is achieved. The crude product is precipitated by the addition of Hs.0 (750 rnL), and is filtered. The filtrate is separated. An individual recrystallization of the solids from hexane gives 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -4,5-dihydro-5,5-dirnethyldylisoxazole as a light yellow solid. The Ha0 / Et0H filtrate is concentrated on a rotary evaporator to remove EtOH, and the resulting suspension is extracted with CHC12 (3 x 200 mL). The aqueous phase is discarded, and the organic phase is dried (MgSO.sub.0), filtered, combined with the mother liquors of hexane from the previous crystallization, and evaporated in an oily solid. Recrystallization from hexane 3- (3,5-di-tert-butyl-4-hydroxyphenyl) ~ 4,5-dihydro-5,5-dimethyixosazole as a yellow solid slightly less pure than the first charge.

AXIS? PLQ 2 Synthesis of 3- (3,5-di-tert-butyl-4-hydroxyphenyl) ~ 5,5-dimethyl-lH-di-hydropi razóla A solution of 3-chloro-1- (3-, 5-di-tert-butyl-4-hydroxyphenyl) -3-methylbutan-1-one (Example .1.) (3.45 g, 10.1 nmrn) and hydrazine hydrate (0.8 ml, 14 mrnols) in absolute EtOH (50 ml) is stirred at 50 ° C for one hour. The additional hydrazine hydrate (1 ml, 18 min) is added in two equal portions in two hours. The reaction is followed by TLC (hexane: EtOAC, 9: 1) and is complete after stirring at 50 ° C for 18 hours. The solvent is evaporated leaving a yellow solid, which is crystallized from EtOH: H30 to give 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -5,5-dirnethyl-IH-dihydro-hirazyl as white prism.

AXIS? PLQ 3 Synthesis of 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -5,5-dimethyl-1-methyl-sulphonyl-1-dihydropy radical: To a stirred solution of 650 mg of 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -5,5-dimethyl-lH-dihydropi reason (Example 2), 360 μl of trityl ina, 50 g of N, N-dimethylamini-iridine in 20 ml of methylene chloride, cooled to 0 ° C is added 182 uL of chloride of sulfonyl chloride. After stirring at 0 ° C for 30 minutes, the cold bath is removed and the mixture is stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure and the residue is purified by means of flash chromatography (10% ethyl acetate in hexane) to give 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -5, 5-dimethyl-1-methylsulfonyl-1H-dihydropyrazol as a colorless solid. EXAMPLE Synthesis of 1-c rboxamido-3- (3, 5-di-tert-butyl-4-hydroxy-phenyl) -5,5-dirnet.-lH-dihydro-yl reason: To a stirred solution of 600 mg of 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -5,5-dimethyl-1H-dihydropyrazol (Example 2), in a mixture of 9 ml of acetic acid, 6.5 ml of tetrahydrofuran and 18.6 ml of water at 35 ° C, 260 mg of potassium cyanate were added. After stirring at 35 ° C for 30 minutes, the mixture is stirred at 55 ° C for 5 hours. The solvents are evaporated under reduced pressure and the residue is absorbed in 50 ml of methylene chloride. The solution is washed 3 times with 15 ml of 0.1 N aqueous sodium hydroxide and dried over sodium sulfate. The solvents are evaporated and the residue is purified by means of flash chromatography (20% ethyl acetate in hexane) to give l -carboxamido -3- (3,5-di-tert-butyl-4-hydroxy phenyl). ) -5, 5-d.yrnethyl-1H-dihydropi was reacted as a colorless solid.

AXIS? PLQ 5 Synthesis of 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -5,5-dicyclopropyl-1H-dihydropyrazol: l- (3,5-di-tert-butyl-4-hydroxyphenyl) -3-dicyclole-3-en-l-one. A stirred solution of 4 g of 3,5-di-tert-butyl-4-hydroxyacetophenone in 250 ml of dry methylene chloride is cooled to -78 ° C and 7.3 ml of di-iso-propylethylamine (i) is added. -PrasEtN) followed by 8.1 ml of tri-ethylsulphonate of tri-ethylsilyl (TMSOTf). The mixture is stirred at ~78 ° C for 10 minutes and allowed to warm to room temperature for more than 1 hour. The mixture is again cooled to -78 ° C, and 3.6 ml of dicyclopropyl ketone is added followed by 32 ml of 1 M titanium tetrachloride solution in rnetylene chloride. After stirring for 1 hour, the mixture is washed with 1 N of aqueous hydrochloric acid and the solvents are removed under reduced pressure. The residue is dissolved in 50 ml of 1N aqueous methanolic hydrochloric acid and stirred for 1 hour at room temperature. The mixture is concentrated under reduced pressure and divided between methylene chloride and water. The organic phase is washed with aqueous sodium bicarbonate, brine and dried over sodium sulfate. The solvents are evaporated and the residue is purified by means of flash chromatography (10% ethyl acetate in hexane) and the product is recrystallized from hexane to give .1,5-di-tert-butyl- 4-hydroxyphenyl) -3,3-dicyclopropyl? Rop-2-en-l-one as an orange solid. 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -5,5-dicyclolethyl-1H-dihydropyrole. A pressure resistant glass container is loaded with 350 rng of 1- (3, 5-di-tert-butyl-4-hydroxy-phenyl) -3,3-dicyclopripylprop-2-en-l-one, 0.2 ml of hydrazine hydrate and 15 ml of ethanol. The container is closed and the homogenous mixture is heated at 80 ° C for 15 hours. The solvents are evaporated under reduced pressure and the residue is taken up in methylene chloride, washed with water and dried over sodium sulfate. The solvents are evaporated and the crude product is purified by recrystallization from hexane to give 3 ~ (3,5-di-tert-butyl-4-hydroxypheniD-5,5-dicyclopropyl-1H-dihydropyrazol as a solid). yellow. 29 CQ? PQSICIQN The compositions of the present invention comprise a safe and effective amount of the present 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 (to a benefit ratio). / reasonable risk), within the scope of the 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 severity of the condition, the duration of the treatment, the nature of the concurrent therapy, the pharmaceutically acceptable carrier particularly used, and similar factors within the knowledge and experience of the attending physician. The compositions of the present invention preferably comprise from about 0.1% to about 99.9% by weight of a compound, more preferably from about 20% to about 80%, and most preferred from about 40% to about 70%. In addition to the compound, the compositions of the present invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier", as used herein, means 1 or more solid or liquid fillers or encapsulating substances that are suitable for administration to a human being to a lower animal. The term "compatible", as used herein, means that the components of the composition are capable of being mixed with the present compound, and with each other, such that there is no interaction that would substantially reduce the pharmaceutical efficacy of the composition. the composition under ordinary use situations. Of course, pharmaceutically acceptable carriers should be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to a human or lower animal being treated. Some examples of substances that can serve as vehicles or pharmaceutically acceptable components thereof are sugars, such as lactose, glucose and sucrose; starches, such as wheat starch and potato starch; cellulose and its derivatives, such as sodium carboxylmethylcellulose, ethylcellulose, cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; solid lubricants, such as stearic acid, magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, wheat oil and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, rnanitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TweensR; humidifying agents such as sodium lauryl sulfate; coloring agents; flavoring agents; excipients, agents in tablet; stabilizers; antioxidants; conservatives; pyrogen-free water; Isotonic saline and phosphate buffer solutions. The choice of a pharmaceutically acceptable carrier to be used together with a compound is basically determined by the compound to be administered. If the present compound is going to be injected, it is preferable to inject it not intravenously; the preferred pharmaceutically acceptable carrier is sterile physiological saline, with a compatible blood suspension agent, the PH of which has been adjusted to about 7.4. Said injectable compositions preferably comprise from about 1% to about 50% of the present compound, more preferably from about 5% to about 25%, also preferably from about 10 mg to about 600 mg of the present compound per dose. Suitable pharmaceutically acceptable carriers for topical application include those suitable 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. Said topical compositions preferably comprise from about 0.1% to about 50%, of the present 2R compound, more preferably from about 0.5% to about 10%, also preferably from about 5 mg to about 100 mg per dose. The preferred way of administering the present compound is, in particular. The preferred unit dosage form is therefore tablets, capsules and the like comprising a safe and effective amount of the compound, which preferably is from about 5 mg to about 3500 mg, more preferably from about 10 mg to about 100 mg, and very preferable around 25rng to about 600mg. Many of the present compounds are hydrophobic. It is desirable to provide an aqueous-based composition or a composition soluble in miscible with an aqueous medium, a solubilizing agent can be included in the composition. Non-limiting examples of such solubilizing agents include polyethylene licol, propylene licol, ethanol, and polyoxyallylene almond oil (35). Particularly preferred oral composition vehicles for the compositions of the present invention are described in the U.S. Patents. 5,189,066 from Kelrn to Bruns, issued on February 23, 1993, entitled "Phar aceutical Co-positions of Tebufelone", and 5,281,420 from Kelrn Dobrozsi, issued on January 25, 1994, entitled "Solid Dispersion Compositions of Tebufelone", incorporated at present by reference.

J3 JTJ 2QS.

Another aspect of the present invention are methods for treating or preventing diseases characterized by inflammation by administering a safe and effective amount of a compound to a human or lower animal in need of such treatment. The term "diseases characterized by inflammation," as used herein, means conditions that are known to be inflammable, and may include conditions such as arthritis (e.g., reurnatoid arthritis, osteorarthritis, psoriatic arthritis, juvenile arthritis, syndrome of Reiter, infectious arthritis, and spondylitis ankylosis, 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 may also include inflammation in the oral cavity (eg, inflammation associated with gingivitis or peritoneal disease); inflammation in the gastrointestinal tract, for example, inflammation associated with ulcers and irritable bowel disease); inflammation associated with dermatological diseases (eg, suriasis, acne, and other skin inflammation); inflammation associated with the respiratory tract (eg, asthma, bronchitis, and allergies); and inflammation in the central nervous system (e.g., eifner disease) - Another aspect of the present invention are methods for treating or preventing pain by administering a safe and effective amount of a compound to a human or lower animal in need. of said treatment. Pain that can be treated or avoided by administering the present compounds may include peripheral pain, menstrual pain, dental pain, and pain in the lower back. Another aspect of the present invention are methods for protecting against free radical damage resulting from oxidative stress and ischemic conditions by administering a safe and effective amount of a present compound to a human or lower animal in need of such treatment. Such treatment may include protecting against ischemic heart disease, astereosclerosis, embolism, and ischemic heart damage of the heart. Another aspect of the present invention are methods for treating or preventing gastric or duodenal ulcers or erosions by administering a safe and effective amount of a present compound to a human or lower animal in need of such treatment. In particular, said ulcers or erosions caused by ethanol or non-steroidal anti-inflammatory drugs (in NSAIDS) can be treated and / or prevented by the administration of the present preferred compounds. Appropriate tests to determine gastrointestinal safety or gastroprotective properties of the present compounds are known. The methods to determine acute gastrointestinal safety are described and / or referred to in the following references: [Unangst, P, C, G.P. Shrurn, D.T. Connor, R: D. Dyer and D.3. Schrier, "Novel 1,2,4-Oxadiazoles and i, 2,4-Thiadiazoles as Dual 5-Li? Oxygenase and Cyclooxygenase inhibitors", 3. Med. Chern. , Vol. 35 (1992), pp. 3691-3698 and segawa, Y, 0. Ohya, T.Abe, T. Omata et al., "Anti ~ .inflarnrnat.iry, Analgesic, and Antipyretic Effects and Gastrointestinal Toxicity of the New Anti-Inflate Atory Drug N- { 3- [3- (piperidinylmethyl) phenox]? ropyl.}. -carbamoylmethylthio] ethyi l- (p-chlorobenzoyl) 5-Methoxy-2methyl-3 ~ indolylacetate ", Rr-neim-Foch / Drua Res., Vol. 42 (1992), pp. 954-9921. in the methods described herein, the stomachs of the animals are typically examined two hours after the dosing of a compound. Methods for determining subchronic gastrointestinal safety are described and / or referred to in the following references Melarange, R., C. Gentry et al. "Anti-inflammatory and Gastrointestinal Effects Nabumetone or SCi., Vol. 37 (1992), pp. 1847-1852 and Uong, S., S.3.Lee et al., "Antiarthritic Profile of BF-389 - A Novel Anti-inflammatory Agent Uith Low Ulcerogenic Liability," Agnostics Vol. 37 (1992), pp. 90-91 The methods for determining acute gastroprotection are described and / or referenced in the following reference: Playford, R, J-, DA Versey, S Haldane, MR Alison and 3. Calan, "dose-dependent Effects of Fentanyl on Indomet harin-induced Gastric Da age, Vol., 49 (1991), pp. 198-203 In the method described here, Le is female rats (139-175 g) are dosed but orally with the present compound 40mg / Kg bid) or vehicle at two hours and immediately before the administration of a harmful dose of indornetasin gastric. The rats are sacrificed four hours later by means of asphyxia CO3. Damage to the gastric body (millimeters of hemorrhagic lesions) is measured by digitized training. The preferred mode of administration of the present compounds is peroral, but other known methods of administration are likewise contemplated, for example, methyl dermal (e.g. dermaInvent, rectally and the like), and parenterally (e.g., by subcutaneous injection, intramuscular injection. , intra-articular injection, intravenous injection and the like). Ocular administration and inhalation are also included. Thus, specific modes of administration include, without limitation, per-oral, transver al, mucosal, sublingual, intranasal, intramuscular, intravenous, intraperitonal, subcutaneous, and topical administration. Preferred doses of the present compounds range from about 0.2 mg / kg to about 70 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 10ng / kg of the present compound. The preferred topical doses comprise from about lrng / crn2 to about 200 mg / cm2 of the present compound applied to the surface of the skin. Preferred oral doses comprise from about 0.5 mg / kg to about 50 mg / kg, more preferably from about lrng / kg to about 20 mg / kg, more preferably still from about 2 mg / kg to about 10 mg / kg, of the present compound. Said doses are preferably administered from about one to about six times a day, more preferably from about two to about four times a day. Said daily doses are preferably administered for at least one week, also preferably for at least two weeks, also preferably for at least one month, also preferably for at least two months, also preferably for at least six months, a year, two years, or more. The following non-limiting examples illustrate the present invention.

EXAMPLE A The pharmaceutical compositions in the form of tablets are prepared by means of conventional methods, such as mixing and direct inoculation, formulated in the following manner: Ingredients Can io d, (mg per able as? Compound 1 200 Microcrystalline Cellulose 100 Starch Glycolate of Sodium 30 Magnesium Stearate 3 When administered orally twice a day, the above composition sufficiently reduces 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 osteoratritis.

EXAMPLE B A pharmaceutical composition in the form of a capsule is prepared by conventional methods, formulated as follows: Ingredient Amount (q per capsule) Compound 5 200 Lactose To fill the capsule volume The anterior capsule administered orally once a day, substantially reduces the symptomology of a patient afflicted with reunatoid arthritis or osteoarthritis.

EXAMPLE C A pharmaceutical composition in liquid form is prepared by conventional methods, formulated as follows: Ingredient amount Compound 2 200rng ETOH 4rnl Methyl Cellulose 0.4rng Distilled Water 76ml Tween 89 l, 6ml 50 ml of the above composition administered once per day substantially reduces the symptoms of a patient afflicted with arthritis reu atoide or osteoarthritis.

EXAMPLE P A pharmaceutical composition in liquid form is prepared by means of conventional methods, formulated in the following manner: Ingredients Quantity Compound 3 Microcrystalline 200 rng (micronized). Avicel (Microcrystalline Cellulose) 50 rng Tween 80 1.6 ml Methyl Cellulose 0.4 rng Deionized Water 80 ml 100 inl of the above composition administered perorally twice a day substantially reduces the symptoms of a patient afflicted with rheumatoid arthritis or osteoarthritis. While the particular embodiments of the present invention have been described, it would be obvious to those skilled in the art that various changes and modifications to the compositions described herein can be made without departing from the spirit and scope of the invention. In all the appended claims, it is intended to cover such modifications that are within the scope of this invention.

Claims (14)

NQVEPRP PE Lñ INVENTION CLAIMS

1 . - A compound that has the structure: wherein a) each R is independently alkyl having from 1 to about 7 carbon atoms; b) Z is 0 or N-X; c) X is selected from the group consisting of hydrogen, alkyl having from 1 to 7 carbon atoms, C (0) Y, C (S) Y, and SOaY; d) Y is selected from the group consisting of R ', OR' and NR'2; and e) R 'is selected from the group consisting of hydrogen, alkyl having from 1 to 7 carbon atoms, and phenyl.

2. The compound in accordance with the claim 1, further characterized in that Z is oxygen.

3. The compound according to claim 1, further characterized in that each R is unsubstituted C3 alkanyl.

4. The compound in accordance with the claim 3, further characterized in that Z is oxygen.

5. - The compound according to claim 3, further characterized in that both R are the same portion.

6. The compound according to claim 5, further characterized in that both R are methyl and Z is oxygen.

7. The compound according to claim 3, further characterized in that Z is N-X.

8. The compound according to claim 7, further characterized in that X is hydrogen or C-unsubstituted alkanyl, and both R are the same portion.

9. The compound in accordance with the claim 7, further characterized in that X is selected from the group consisting of C (0) Y, C (S) Y, and SOaY; R 'is hydrogen or alkanyl unsubstituted from C -Ca; and both R are the same portion.

10. The compound according to claim 9, further characterized in that X is S02Y, and Y is unsubstituted alkanyl of Cx-C3.

11. The compound according to claim 10, further characterized in that Y is methyl and both R are methyl.

12. The compound according to claim 8, further characterized in that both R are methyl.

13. A pharmaceutical composition comprising: (a) a safe and effective amount of the compound of 3b claim 1, 4, 6, 8 or 9; and (b) a pharmaceutically acceptable carrier.

14. The use of a safe and effective amount of the compound of claim 1, 4, 6, 8 or 9, in the preparation of compositions for the treatment of inflammation or pain by means of peroral administration.