CN1161692A - Di-tert-butylphenol compounds with heterocyclic moieties as anti-inflammatory agents - Google Patents

Abstract

The subject matter of the present invention relates to a compound of structural formula (I), wherein a) each R is independently an alkyl group containing 1 to about 7 carbon atoms; b) Z is O or NX; c) X is selected from hydrogen, containing 1 to an alkyl group of about 7 carbon atoms, C(O)Y, C(S)Y and _SO2Y ; d) Y is selected from R', OR' and _NR'2 ; and e) R' is selected from hydrogen , Alkyl and phenyl groups containing 1 to about 7 carbon atoms. The invention also relates to pharmaceutical compositions comprising the above compositions, and methods of using such compounds to treat inflammation or pain.

Description

Di-tert-butylphenol compounds with heterocyclic moieties as anti-inflammatory agents

technical field

The present invention relates to non-steroidal anti-inflammatory drugs, in particular to substituted di-tert-butylphenol compounds.

background of the invention

Certain di-tert-butylphenol compounds and others structurally related thereto have been found to possess significant anti-inflammatory and/or analgesic activity; other compounds of this class have also been found to possess other therapeutic activity. Some of these compounds, their methods of preparation, and their uses are disclosed in the following references: U.S. Patent 4,535,165 issued to Moore on August 13, 1985; U.S. Patent 4,724,246 issued to Ravichandran on February 9, 1988; US Patent 4,808,620 issued to Oe, Kawasaki, Terasawa &Yasunaga; US Patent 4,891,374 issued January 2, 1990 to Thorwart, Gebert, Schleyerbach &Bartlett; 4,908,364 issued March 13, 1990 to Thorwart, Gebert, Schleyerbach &Bartlett; 1990 4,940,790 awarded to Thorwart, Gebert, Schleyerbach & Bartlett on July 10; 5,155,122 awarded to Connor, Flynn, Kostlan, Mullican, Shrum, Unangst & Wilson on October 13, 1992; Yamanouchi Pharm.Co announced on September 5, 1983 Patent Application 58-148858 of .; Patent Application 1-180878 of Yoshitomi Pharm. Ind., published July 18, 1989; Patent Application 2-229169 of Takeda Pharmaceutical Co., Ltd., published September 11, 1990; ., S.Sakamoto, N.Ito, H.Homma, T.Abe & K.Kubo, published in Chem.Pharm.Bull Vol. 32 (1984), No. 1, pp. 152-165 "Synthesis of 2,6-di-tert-butylphenols with a heterocyclic group in the para position and their anti-inflammatory activity, III"; Unangst, P.C., G.P. Shrum, D.T. Connor, R.D. Dyer & D.J. Schrier, published in Medicine "New 1,2,4-oxadiazoles and 1,2 , 4-thiadiazole"; Costantino, L., C.Parenti, M.DiBella, P.Zanoli & M.Baraldi, published in Pharmacological Research (Pharmacological Research) vol. 27 (1993) No. 4, pp. 349-358 "Anti-inflammatory activity of newly synthesized 2,6-bis(1,1-dimethylethyl)phenol derivatives"; Mullican, M.D., M.W.Wilson, D.T.Connor, C.R. Kostlan, D.J.Schrier & R.D.Dyer, published In Medicinal Chemistry (J.Med.Chem) 36 volumes (1993) 1090-1099 pages "5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3,4-thiadi Azoles, -1,3,4-oxadiazoles and -1,2,4-triazoles for use as orally active, nonulcerogenic anti-inflammatory agents".

Although some di-tert-butylphenol compounds have been shown to have anti-inflammatory activity, many such compounds have little or no anti-inflammatory activity. It is therefore generally not possible to determine whether such compounds have significant anti-inflammatory activity without an activity test.

It is an object of the present invention to provide compounds having potent anti-inflammatory, analgesic and/or antioxidant activity.

Another object of the present invention is to provide such compounds with few side effects.

Yet another object of the present invention is to provide methods of treating inflammation and/or pain using the compounds of the present invention.

Overview of the invention

The present invention includes compounds of the following structures:

in:

a) each R is independently an alkyl group having 1 to about 7 carbon atoms;

b) Z is O or N-X;

c) X is selected from hydrogen, an alkyl group having 1 to about 7 carbon atoms, C(O)Y, C(S)Y, SO ₂ Y;

d) Y is selected from R', OR' and NR'₂;

e) each R' is selected from hydrogen, alkyl and phenyl having 1 to about 7 carbon atoms.

Detailed description of the invention

Herein, unless otherwise specified, "alkyl" refers to a linear, branched or cyclic, saturated or unsaturated, substituted or unsubstituted hydrocarbon chain group. Preferred alkyl groups are straight chain. Preferred branched alkyl groups have 1-2 branches, preferably one branch. Preferred cycloalkyl groups are monocyclic groups or a combination of straight chain and monocyclic, especially straight chain groups with monocyclic end groups. Preferred alkyl groups are saturated. Unsaturated alkyl groups have one or more double bonds and/or one or more triple bonds. Preferred unsaturated alkyl groups have one or two double bonds or one triple bond, most preferably one double bond. Preferred alkyl groups are unsubstituted. Preferred substituted alkyl groups are mono-, di- or tri-substituted, most preferably mono-substituted. Preferred alkyl substituents include halogen, hydroxy, alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentyloxy), aryloxy (e.g. phenoxy, chlorophenoxy, xyloxy, methoxyphenoxy, alkoxycarbonylphenoxy, acyloxyphenoxy), benzyloxy, acyloxy (such as propionyloxy, benzoyloxy, Acetyloxy), carbamoyloxy, carboxyl, mercapto, alkylthio, acylthio, arylthio (such as phenylthio, chlorophenylthio, alkylphenylthio, alkoxyphenylthio, Alkoxycarbonylphenylthio), benzylthio, aryl (such as phenyl, xylyl, alkoxyphenyl, alkoxycarbonylphenyl, carboxyphenyl, halophenyl), heterocyclyl , heteroaryl, amino (such as amino, one and two C ₁ -C ₃ saturated alkylamino, methylphenylamino, methylbenzylamino), amido (such as amido, one and two C ₁ -C ₃ saturated alkylamide group, carbamamido group (carbamamido)), urea group and guanidine group.

Herein, "saturated alkyl" means a saturated alkyl.

Herein, "alkoxy" refers to a substituent having a Q-O structure (wherein Q is an alkyl group).

As used herein, "alkylthio" refers to a substituent having a Q-S structure (wherein Q is an alkyl group).

As used herein, "aryl" means a moiety having an unsubstituted or substituted aromatic ring having 6 to about 10 carbon atoms. Preferred aryl is phenyl or naphthyl; most preferred aryl is phenyl. Preferred aryl groups are unsubstituted. Preferred substituted aryl groups are mono-, di- or tri-substituted, most preferably mono-substituted. Preferred aryl substituents include hydroxy, mercapto, halo, methyl, ethyl and propyl.

As used herein, "heterocyclyl" refers to a substituted or unsubstituted heterocyclyl group with 3 to about 8 ring atoms (including 2 to about 6 carbon atoms and 1 to about 4 heterocyclic rings selected from O, S and N). atom) non-aromatic ring moiety. Preferred heterocyclyl groups have 5 or 6 ring atoms (including 1-3, preferably 1 or 2 heteroatoms). Preferred specific heterocyclic groups include piperidinyl, tetrahydrothiophenyl, pyrrolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxazolidine group, isoxazolidinyl, oxthiazolidinyl, isothiazolidinyl, azepinyl, oxepinyl (oxepinyl), triazolidinyl. The heterocyclic group is unsubstituted or substituted, preferably unsubstituted. Preferred substituted heterocyclic groups are mono-, di- or tri-substituted, most preferably mono-substituted. Preferred heterocyclic substituents include alkyl (including substituted alkyl such as thiomethyl, carboxymethyl, chloromethyl, trifluoromethyl), halo, hydroxy, carboxy, alkoxy, acyloxy, mercapto , Amino (including one and two C ₁ -C ₃ saturated alkylamino, such as methylamino, dimethylamino), amido, formamide, thioformamide, ureido, thiourea, guanidine (including methyl-substituted guanidino, such as methylguanidino, N, N'-dimethylguanidino, N, N-dimethylguanidino).

As used herein, "heteroaryl" refers to an aromatic ring moiety having 5 or 6 ring atoms (including 2-5 carbon atoms and 1-4 heteroatoms selected from O, S and N). Most preferred heteroaryl groups have 1-3 (preferably 1 or 2) heteroatoms. Preferred specific heteroaryl groups include pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, isoxazolyl, pyranyl, thienyl, tetrazolyl, thiazolyl, isothiazolyl , furyl, oxathiazolyl. Heteroaryl is unsubstituted or substituted, preferably unsubstituted. Preferred substituted heterocyclic groups are mono-, di- or tri-substituted, most preferably mono-substituted. Preferred heteroaryl substituents include alkyl (including substituted alkyl such as thiomethyl, carboxymethyl, chloromethyl, trifluoromethyl), halogen, hydroxy, alkoxy, sulfur, amino (including one Or two C ₁ -C ₃ saturated alkylamino, such as methylamino, dimethylamino, methoxymethylamino, carboxymethylamino), amido, cyanoamide, thioformamide, urea group, thioureido group, guanidino group (including methyl substituted guanidino group, such as methyl guanidino group, N, N'-dimethylguanidino group, N, N-dimethylguanidino group), S-methyl Thiocarbamoyl.

As used herein, "halogen" means fluorine, chlorine, bromine or iodine; preferred halogens are fluorine, chlorine and bromine; most preferred halogens are chlorine and fluorine.

compound

The present invention specifically includes di-tert-butylphenol compounds having the following structure:

In the above structures, each R is independently an alkyl group having 1 to about 7 carbon atoms, preferably 1 to about 4 carbon atoms. Each R is preferably saturated. Preferably each R is unsubstituted. Each R is preferably a C ₁ -C ₃ saturated linear or branched chain saturated alkyl group, or a C ₃ -about C ₄ saturated cycloalkyl group. Each R is preferably methyl, ethyl, n-propyl or isopropyl; most preferably methyl or ethyl; preferably methyl. Each R is also preferably cyclopropyl. Preferably both R are the same.

In the above structures, Z is O or NX; preferably Z is oxygen. X is selected from hydrogen, alkyl having 1 to about 7 carbon atoms, C(O)Y, C(S)Y, _SO2Y ; preferably X is hydrogen. Preferred X is also SO ₂ Y.

Y is selected from R', OR' and _NR'2 ; preferably Y is R'. Preferred Y is also XR' ₂ . R' is selected from hydrogen, alkyl having 1 to about 7 carbon atoms, and phenyl. Preferred R' is hydrogen or C ₁ -C ₄ alkyl. Most preferably R' is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and cyclopropyl; preferably hydrogen or methyl.

The preferred compound of the present invention is a compound having the above structure as shown in the table below for R, Z, X, Y and R': Compound No. R Z X X Y Y R'

1 Methyl, Methyl O - - - -

2 methyl, methyl N-X H - -

3 methyl, methyl NX SO ₂ Y R' methyl

4 methyl, methyl NX C(O)Y NR' ₂ H, H

5 Cyclopropyl, cyclopropyl N-X H - -

To determine and evaluate pharmaceutical activity, these compounds were subjected to animal experiments using various assay methods known to those skilled in the art. The anti-inflammatory activity of these compounds is conveniently confirmed by assays using these compounds against local edema, which is characteristic of inflammatory responses. Examples of such known tests include the rat carrageenan edema test, the oxazolone-induced inflamed mouse ear test, and the mouse arachadonic acid-induced inflamed ear test. The analgesic activity can be tested by known methods such as the phenylbenzoquinone-induced writhing test in mice and the Randall & Selitto rat test. Other useful assays known in the art are the rat adjuvant arthritis assay, which is a useful means of assessing anti-inflammatory, anti-arthritic and anti-resorptive activity in a chronic rather than acute manner.

These and other suitable assays for pharmaceutical activity are disclosed and/or referred to in U.S. Patent 4,130,666, Moore, published December 19, 1978; Katsumi et al., published February 14, 1984; U.S. Patent 4,431,656; U.S. Patent 4,440,784, Katsumi et al., published April 3, 1984; Japanese Patent Application 85/54315, Katsumi et al., published March 28, 1985; published September 1, 1982 Yamanuchi Pharmaceutical Company Ltd., Published European Patent Application 0,059,090; Opas, E.V., 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, K.F., R.L.Bell & G.G.I.Moore, "Anti- Anti-inflammatory activity of oxidants", Anti-inflammatory and Antirheumatic Drugs, Vol.III, Chapter 4, K.D.Rainsford, ed., CRC Press, Inc., (1985), pp.105 -126; Adamkiewicz, V.W., W.B.Rice & J.D.McColl, "Anti-inflammatory effects of trypsin in normal and adrenalectomized mice", Canadian Journal of Biochemistry & Physiology, Vol.33(1955) , pp.332-339; Sellye, H., "Further studies on the involvement of the adrenal cortex in the pathogenesis of arthritis", British Medical Journal.Vol.2(1949), pp.1129-1135 and Winter, C.A., E.A. Risley & G.W. Nuss, "Carrageenan-Induced Edema in Rat Hindpaw Identified as an Anti-Inflammatory Drug," Proceedings of Society of Experimental Biology and Medicine , Vol.111(1962), pp.544-547; Otterness, I., & M.L.Bliven, "Laboratory Methods for Testing Nonsteroidal Antiinflammatory Drugs", Nonsteroidal Antiinflammatory Drugs , Chapter 3, J.G. Lombardino, ed., John Wiley & Sons, Inc. (1985), pp.111-252; Hitchens, J.T., S. Goldstein, L. Shemano & J.M. Beiler, "Stimulants in three types Analgesic effect in experimentally induced pain", Arch. Int. Pharmacodvn., Vol. 169, No. 2 (1967) pp. 384-393; Milne, G.M. & T.M. Twomey, "Analgesic properties of Piroxicam in animals and its relation to experimentally determined plasma volume", Reagents and Actions (Agents and Actions), Vol.10, No.1/2 (1980), pp.31-37; Randall, L.O. & J.J.Selitto, "in Methods for Measuring Analgesic Activity on Inflamed Tissue", Arch.Int.Pharmacodyn., Vol.111, No.4(1957), pp.409-419; Pain Thresholds Induced by Parenteral Administration of Pain Drugs", J. Pharmacol. Exp. Ther., Vol. 148, No. 3 (1965), pp. 373-379; all of which references are incorporated herein by reference.

Many anti-inflammatory drugs, especially non-steroidal anti-inflammatory drugs (NSAIDs), can cause unwanted gastrointestinal side effects, especially when administered orally; these side effects include ulceration and erosion. These side effects, which are often asymptomatic, can be severe enough to require hospitalization and even death. Compared to other NSAIDs, even compared to many other di-tert-butylphenol derivatives, the compounds of the present invention generally cause less gastrointestinal side effects of this kind. Some compounds of the present invention are even gastroprotective, protecting the stomach from ulceration and corrosion, especially ulceration and corrosion caused by ethanol and other NSAIDs.

Some NSAIDs, including some di-tert-butylphenol derivatives, can cause undesired increases in systemic concentrations of certain liver enzymes when administered systemically. The compounds of the invention generally cause little or no liver enzyme side effects.

Compounds useful in this invention can be prepared using the general reaction schemes described below.

A general method for the preparation of compounds of general formula III (when Z is O) is to subject a suitable β-chloroketone of general formula II to a ring-forming condensation reaction with hydroxylamine. For example, the reaction can be accomplished by slowly treating an alcoholic solution of the appropriate β-chloroketone and hydroxylamine hydrogenhalide salt with a stoichiometric amount of aqueous NaOH. Compounds of general formula III (when Z is NH) can be prepared by ring condensation of an α,β-unsaturated ketone of general formula I with a hydrazino. For example, the reaction can be carried out by heating an alcoholic solution of the appropriate α,β-unsaturated ketone and a stoichiometric amount of hydrazine hydrate at a temperature of 30-60°C. If higher reaction temperatures are desired, the reaction can be carried out in a sealed flask. The desired β-chloroketones and α,β-unsaturated ketones can generally be prepared by the Friedel-Craft reaction of 2,6-di-tert-butylphenol with the appropriate α,β-unsaturated acid chloride Friedel-Crafts reaction followed by contact with excess hydrochloric acid or aldol condensation of silylated 3,5-di-tert-butyl- ₄ -hydroxyacetophenone with the appropriate ketone in the presence of TiCl reaction.

The following non-limiting examples provide further details on the synthesis of compounds of the invention.

Example 1

Synthesis of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-4,5-dihydro-5,5-dimethylisoxazole

3-Chloro-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methylbutan-1-one. A solution of 3,3-dimethylacryloyl chloride (146 g, 1.23 mol) in CH ₂ Cl ₂ (1000 mL) was placed in a 12 liter round bottom flask equipped with an internal thermometer, mechanical stirrer, addition funnel and septum inlet . The stirred solution was cooled to -10°C in a _CH2Cl2 -dry ice bath, then _{TiCl4 ( 1M} solution in _CH2Cl2 , 1476 mL , 1.47mol, 1.2eq). After the addition was complete, the solution was stirred for 10 minutes, then a solution of 2,6-di-tert-butylphenol (253.4 g, 1.23 mol, 1.0 eq) dissolved in _CH2Cl2 ( ₅₀₀ mL) was added dropwise via the addition funnel. The rate of addition was adjusted to keep the reaction temperature below 0°C. After the addition was complete, the cooling bath was removed and the mixture was stirred at room temperature for 4 hours. TLC analysis (EtOAc:hexane, 1:9) indicated the reaction was complete. _H2O (2L) was added carefully and the mixture was transferred to a 6L extraction funnel. The organic phase was separated, _washed with additional _H2O (2 x 1000 mL), dried over _Na2SO4 , filtered, and returned to the 12 L reaction vessel. A solution of HCl in ether (1M, Aldrich, 2000 mL) was added. After stirring for 2 hours, the solution was transferred to a 6 L separatory funnel and washed with _H2O (3 x 1 L). The organic phase was dried over _Na2SO4 , filtered into _a 10 L round bottom flask, and rotovaped. The residue was dissolved in 1 L of pentane and kept at -4°C overnight. The resulting crystalline solid was filtered and dried to obtain 3-chloro-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methylbutan-1-one.

3-(3,5-di-tert-butyl-4-hydroxyphenyl)-4,5-dihydro-5,5-dimethylisoxazole.

Add 3-chloro-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methylbutan-1-one (77.1 g, 0.24 mol) and carbane hydrochloride (20.1 g, 0.28 mol) in EtOH (2.2 L). 2N NaOH (119 mL, 0.24 mol, 1.0 eq) was added dropwise to the stirred solution over 15 minutes. When the two solutions were in contact, a rapidly diffuse yellow color was observed. After the addition was complete, the reaction was heated at 50°C. Followed by TLC (EtOAc:Hexane, 1:4). After 3 hours, about 50% conversion was reached. _H2O (750 mL) was added to precipitate the crude product, which was filtered. Set the filtrate aside. The solid was recrystallized once from hexane to obtain 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-4,5-dihydro-5,5-dimethylisoxazole as a pale yellow solid. The _H2O /EtOH filtrate was concentrated in a rotary evaporator to remove _EtOH and the resulting suspension was extracted with _CH2Cl2 (3 x 200 mL). The aqueous phase was discarded and the organic phase dried ( _MgSO4 ), filtered, combined with the hexane mother liquor from the above crystallization and evaporated to an oily solid. 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-4,5-dihydro-5,5-dimethyl was crystallized from hexane as a yellow solid of slightly lower purity than the first batch isoxazole.

Example 2

Synthesis of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,5-dimethyl-1H-dihydropyrazole:

Stir 3-chloro-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methylbutan-1-one (Example 1) (3.45 g, 10.1 mmol) and hydrate at 50° C. A solution of hydrazine (0.8 mL, 14 mmol) was dissolved in anhydrous EtOH (50 mL) for 1 h. Additional hydrazine hydrate (1 mL, 18 mmol) was added in two equal portions over 2 hours. The reaction was complete after stirring at 50 °C for 18 h, followed by TLC (Hex:EtOAc, 9:1). Evaporation of the solvent gave a yellow solid which crystallized from EtOH: _H2O to give 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,5-dimethyl-1H as a white prism - dihydropyrazole.

Example 3

Synthesis of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,5-dimethyl-1-methylsulfonyl-1H-dihydropyrazole:

In 650mg 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,5-dimethyl-1H-dihydropyrazole (Example 2) cooled to 0°C, 360 μl triethylamine , 50mg N,N-dimethylaminopyridine dissolved in 20ml dichloromethane stirred solution was added 182μl methanesulfonyl chloride. After stirring at 0°C for 30 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (10% ethyl acetate in hexane) to obtain 3-(3,5-di-tert-butyl-4-hydroxyphenyl) as a colorless solid -5,5-Dimethyl-1-methanesulfonyl-1H-dihydropyrazole.

Example 4

Synthesis of 1-carbamoyl (carboxamido)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,5-dimethyl-1H-dihydropyrazole:

At 35°C, 600mg of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,5-dimethyl-1H-dihydropyrazole (Example 2) was dissolved in 9ml of acetic acid, 6.5 To a stirred solution in a mixture of ml tetrahydrofuran and 18.6 ml water was added 260 mg potassium cyanate. After stirring at 35°C for 30 minutes, the mixture was stirred at 55°C for 5 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in 50 ml of dichloromethane. The solution was washed 3 times with 15 ml of 0.1N aqueous sodium hydroxide solution and dried over sodium sulfate. The solvent was evaporated and the residue was purified by flash chromatography (20% ethyl acetate in hexanes) to give 1-carbamoyl-3-(3,5-di-tert-butyl-4-hydroxyl as a colorless solid phenyl)-5,5-dimethyl-1H-dihydropyrazole.

Example 5

Synthesis of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,5-dicyclopropyl-1H-dihydropyrazole: 1-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3,3-dicyclopropylprop-2-en-1-one. A stirred solution of 4 g of 3,5-di-tert-butyl-4-hydroxyacetophenone dissolved in 250 ml of dry dichloromethane was cooled to -78°C, and 7.3 ml of diisopropylethylamine (i-Pr ₂ EtN) was added, Then 8.1 ml of trimethylsilyl trifluoromethanesulfonate (TMSOTf) were added. The mixture was stirred at -78°C for 10 minutes, then allowed to warm to room temperature over 1 hour. The mixture was then cooled to -78°C and 3.6 ml of dicyclopropyl ketone was added, followed by 32 ml of a 1M solution of titanium tetrachloride in dichloromethane. After stirring for 1 hour, the mixture was washed with 1N aqueous hydrochloric acid, and the solvent was removed under reduced pressure. The residue was dissolved in 50 ml of methanol-1N aqueous hydrochloric acid and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and partitioned between dichloromethane and water. The organic phase was washed with aqueous sodium bicarbonate, brine and dried over sodium sulfate. The solvent was evaporated, the residue was purified by flash chromatography (10% ethyl acetate in hexane), and the product was recrystallized from hexane to give 1-(3,5-di-tert-butyl-4- hydroxyphenyl)-3,3-dicyclopropylprop-2-en-1-one.

3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-5,5-dicyclopropyl-1H-dihydropyrazole. Add 350mg 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3,3-dicyclopropylprop-2-en-1-one, 0.2ml hydrazine hydrate and 15ml ethanol. The vessel was closed and the homogeneous mixture was heated at 80°C for 15 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane, washed with water, and dried over sodium sulfate. The solvent was evaporated and the crude product was purified by crystallization from hexane to obtain 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,5-dicyclopropyl-1H-dihydropyrazole as a yellow solid .

combination

The composition of the present invention comprises a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable carrier. As used herein, "safe and effective amount" means, within normal medical judgment, that amount of the compound that is large enough to produce a positive improvement in the condition being treated, but low enough to avoid serious side effects. (reasonable benefit/risk ratio). The safe and effective amount of the compound depends on 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 concomitant therapies, the particular pharmaceutically acceptable carrier used, and the nursing It depends on a variety of similar factors within the common sense and experience of the physician.

The compositions of the present invention preferably comprise from about 0.1% to about 99.9% by weight compound, more preferably from about 20% to about 80% compound, most preferably from about 40% to about 70% compound.

In addition to the compound, the compositions of the present invention comprise a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as used herein means one or more compatible solid or liquid fill diluents or encapsulating substances suitable for administration to humans or lower animals. As used herein, the term "compatible" means that the components of the composition are intermixed with the compounds of the present invention under normal conditions of use in such a way that no interaction occurs which would significantly reduce the pharmaceutical efficacy of the composition. Pharmaceutically acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to therapeutic humans or lower animals.

Some examples of substances that can serve as pharmaceutically acceptable carriers or components are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose , ethyl cellulose, cellulose acetate; powdered gum tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid, magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oils, corn oil, and cocoa butter; polyols, such as propylene glycol, glycerol, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as Tweens®; humectants, such as lauryl coloring agent; flavoring agent; excipient; tableting; stabilizer; antioxidant; preservative; pyrogen-free water; isotonic saline; and phosphate buffer.

The choice of pharmaceutically acceptable carrier for use with a compound of the invention is essentially determined by the form of administration of the compound.

If the compound of the present invention is injected, it is advisable to use non-intravenous injection; the preferred pharmaceutically acceptable carrier is sterile physiological saline containing a blood-compatible suspending agent, the pH of which has been adjusted to about 7.4 . Such injectable compositions preferably contain from about 1% to about 50%, more preferably from about 5% to about 25%, and likewise preferably from about 10 mg to about 600 mg of the compound of the invention 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% emollients, more preferably from about 5% to about 25% emollients. Such topical compositions preferably contain from about 0.1% to about 50%, more preferably from about 0.5% to about 10%, and likewise preferably from about 5 mg to about 1000 mg of the compounds of the invention per dosage.

The preferred form of administration of the compounds of this invention is oral. Thus preferred unit dosage forms are tablets, capsules, etc. containing a safe and effective amount of the compound, preferably from about 5 mg to about 3500 mg, more preferably from about 10 mg to about 1000 mg, most preferably From about 25 mg to about 600 mg.

Many of the compounds of the invention are hydrophobic. If it is desired to obtain a water-based composition or a composition which is compatible or miscible with an aqueous medium, a solubilizing agent may be added to the composition. Non-limiting examples of such solubilizers include polyethylene glycol, propylene glycol, ethanol and polyethylene oxide (35) castor oil.

Particularly preferred oral composition carriers for use in the compositions of the present invention are found in Kelm & Bruns, U.S. Patent No. 5,189,066, published February 23, 1993, entitled "Pharmaceutical Compositions of Tebufelone," and in U.S. Patent No. 5,189,066, published January 25, 1994. Disclosed in U.S. Patent 5,281,420 entitled "Solid Dispersion Compositions of Tebufelone" by Kelm & Dobrozsi, which patents are incorporated herein by reference.

method

Another aspect of the invention is a method of treating or preventing diseases characterized by inflammation by administering to a human or lower animal in need of such treatment a safe and effective amount of a compound of the invention. As used herein, the term "disease characterized by inflammation" refers to a condition known to include inflammation, which may include, for example, arthritis (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis, juvenile arthritis, lysitis, syndrome, infectious arthritis, and ankylosing spondylitis, systemic lupus erythematosus, and gout) and the presence of inflammatory states whether or not associated with identifiable diseases. Diseases with inflammatory features can also include inflammation within the oral cavity (eg, associated with gingivitis or periodontal disease); inflammation within the gastrointestinal tract (eg, associated with ulcers and allergic bowel disease); inflammation associated with skin disorders (such as psoriasis, acne, and other skin inflammations); inflammation associated with the respiratory tract (such as asthma, bronchitis, and allergies); and inflammation in the central nervous system (such as Alzheimer's disease).

A further aspect of the invention is a method of treating or preventing pain by administering to a human or lower animal in need of such treatment a safe and effective amount of a compound of the invention. Pain that can be treated or prevented by administering the compounds of the present invention includes external pain, menstrual pain, toothache and lower back pain.

A further aspect of this invention is the prevention of free radical damage due to oxidative stress and ischemic conditions by administering a safe and effective amount of a compound of this invention to a human or lower animal in need of such treatment. Such treatment may include protection against ischemic heart disease, atherosclerosis, stroke and ischemic cell damage in the heart.

A further aspect of the invention is a method of treating or preventing gastric or duodenal ulcers or erosions by administering to a human or lower animal in need of such treatment a safe and effective amount of a compound of the invention. In particular, such ulcers or erosions caused by alcohol or non-steroidal anti-inflammatory drugs (NSAIDs) can be treated and/or prevented by administering the preferred compounds of the present invention.

Suitable assays for testing the gastrointestinal safety or gastroprotective properties of the compounds of the invention are known.

Methods for testing acute gastrointestinal safety are disclosed and/or referred to in: Unangst, P.C., G.P. Shrum, D.T. Connor, R.D. Dyer, and D.J. Schrier, "As a dual inhibitor of 5-lipoxygenase and cyclooxygenase Novel 1,2,4-oxadiazoles and 1,2,4-thiadiazoles", J.Med.Chem., Vol.35(1992), pp.3691-3698; and Segawa, Y, O.Ohya, T.Abe, T.Omata et al. "Novel anti-inflammatory drug N-{3-[3-(piperidinylmethyl)phenoxy]propyl}-carbamoylmethylthio]ethyl Anti-inflammatory, analgesic and antipyretic effects and gastrointestinal toxicity of 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetate", Arzneim.- Forsch./Drug Res., Vol. 42 (1992), pp. 954-992. In the methods disclosed therein, the stomach of the animal is typically examined 2 hours after administration of the compound.

The method for testing subchronic gastrointestinal safety is disclosed and/or referred to in the following documents: Melarange, R., C.Gentry et al. "Nabumetone or its active metabolite, 6-methoxy-2-naphthyl Anti-inflammatory and gastrointestinal effects of acetic acid (6MNA), ", Dig.Dis.Sci., Vol.37(1992), pp.1847-1852; and "BF-389-a Antiarthritic Profile of BF-389-A Novel Anti-inflammatory Agent With Low Ulcerogenic Liability", Reagents and Effects, Vol.37(1992), pp.90 -91.

Methods for testing acute gastroprotection are disclosed and/or referred to in: Playford, R.J., D.A. Versey, S. Haldane, M.R. Alison and J. Calan, "Fentanyl in indomethacin-induced gastric injury dependent Effects of Dose", Digestion, Vol.49(1991), pp.198-203. In the method disclosed therein, female Lewis rats (130-175 g) were orally administered a compound of the present invention (40 mg/kg b.i.d.) or vehicle, immediately and 2 hours thereafter a gastric lesion dose of indomethacin. After 4 hours the mouse was asphyxiated by CO2. Gastric body damage (mm of bleeding damage) was measured using digitized images.

The preferred mode of administration of the compound of the present invention is oral administration, but other known administration methods have also been studied, as well as percutaneous and mucosal administration (such as transdermal administration, rectal administration, etc.), and parenteral administration ( For example, subcutaneous injection, intramuscular injection, intra-articular injection, intravenous injection, etc.). Also included are ocular administration and inhalation administration. These particular modes of administration include, but are not limited to, oral, transdermal, mucosal, sublingual, intranasal, intramuscular, intravenous, intraperitoneal, subcutaneous administration, and topical administration.

Preferred doses of the compounds of this invention are from about 0.2 mg/kg to about 70 mg/kg, more preferably from about 0.5 mg/kg to about 12 mg/kg. A preferred injectable dose contains from about 0.1 mg/kg to about 10 mg/kg of the compound of this invention. A preferred topical dose comprises from about 1 mg/ ^cm2 to about 200 mg/ ^cm2 of the compound of the invention applied to the skin surface. Preferred oral dosages contain from about 0.5 mg/kg to about 50 mg/kg, more preferably from about 1 mg/kg to about 20 mg/kg, most preferably from about 2 mg/kg to about 10 mg/kg of the compound of the invention. These dosages are preferably administered about 1 to 6 times a day, more preferably about 2 to 4 times a day. These daily doses are preferably administered for at least one week, preferably for at least two weeks, preferably for at least one month, preferably for at least 2 months, preferably for at least 6 months, 1 year, 2 years or more.

The invention is illustrated below by means of non-limiting examples.

Example A

The tablet pharmaceutical composition is prepared by conventional methods, such as mixing and direct compression, and its formula is as follows: Component Quantity (mg/tablet) Compound 1 200 Microcrystalline Cellulose 100 Sodium Starch Glycolate 30 Magnesium Stearate 3

Orally administered twice a day, the above composition significantly reduces inflammation in patients with rheumatoid arthritis. Significant results were also achieved by administering the composition twice a day to osteoarthritis patients.

Example B

Capsule dosage form pharmaceutical composition is prepared by conventional method, and its formula is as follows: Component Amount (mg/capsule) Compound 5 200 lactose Fill the volume of capsule

Oral administration of the above-mentioned capsules once a day significantly reduces symptoms in patients with rheumatoid arthritis or osteoarthritis.

Example C

A liquid dosage form pharmaceutical composition is prepared by a conventional method, and its formula is as follows: Components Quantity Compound 2 200mgEtOH 4ml methylcellulose 0.4mg distilled water 76ml Tween (Tween) 80 1.6ml

Oral administration of 50 ml of the above composition once a day significantly reduces the symptoms of patients with rheumatoid arthritis or osteoarthritis.

Example D

A liquid dosage form pharmaceutical composition is prepared by a conventional method, and its formula is as follows: Components Amount of microcrystalline (micronized) compound 3 200mg Avicel (microcrystalline cellulose) 50mg Tween (Tween) 80 1.6ml methylcellulose 0.4 mg Ionized water 80ml

Oral administration of 100 ml of the above composition twice a day significantly reduced the symptoms of rheumatoid arthritis or osteoarthritis patients.

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

Claims (14)

1. compound, it has following structure:

Wherein

A) each R is independently for containing the alkyl of 1-7 carbon atom;

B) Z is O or N-X;

C) X is selected from hydrogen, contains the alkyl of 1-7 carbon atom, C (O) Y, C (S) Y and SO ₂Y;

D) Y is selected from R ', OR ' and NR ' ₂With

E) R ' is selected from hydrogen, contains the alkyl and the phenyl of 1-7 carbon atom.

2. compound as claimed in claim 1, wherein Z is an oxygen.

3. compound as claimed in claim 1, wherein each R is unsubstituted C ₁-C ₃Alkyl.

4. compound as claimed in claim 3, wherein Z is an oxygen.

5. compound as claimed in claim 3, wherein two R are same section.

6. compound as claimed in claim 5, wherein two R are methyl, Z is an oxygen.

7. compound as claimed in claim 3, wherein Z is N-X.

8. compound as claimed in claim 7, wherein X is hydrogen or unsubstituted C ₁-C ₃Alkyl, two R are same section.

9. compound as claimed in claim 7, wherein X is selected from C (O) Y, C (S) Y and SO ₂Y; R ' is hydrogen or unsubstituted C ₁-C ₃Alkyl; Two R are same section.

10. compound as claimed in claim 9, wherein X is SO ₂Y, Y are unsubstituted C ₁-C ₃Alkyl.

11. compound as claimed in claim 10, wherein Y is a methyl, and two R are methyl.

12. compound as claimed in claim 8, wherein two R are methyl.

13. a pharmaceutical composition, it comprises:

(a) safety again significant quantity as claim 1,4,6,8 or 9 described compounds and

(b) acceptable carrier on a kind of pharmacology.

14. a method for the treatment of inflammation or pain, it comprise oral safety again significant quantity as claim 1,4,6,8 or 9 described compounds.