CN1161692A - Di-tert-butylphenol compound with heterocyclic moiety, useful as anti-inflammatory agent - Google Patents

Abstract

The subject of the invention relates to compounds having structure (I), wherein: a) each R is independently alkyl having from 1 to about 7 carbon atoms; b) Z is O or N-X; c) X is selected from hydrogen, alkyl having from 1 to 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 having from 1 to about 7 carbon atoms, and phenyl. The subject invention also relates to pharmaceutical compositions comprising the above compounds, and methods of treating inflammation or pain using the compounds.

Description

The di-tert-butylphenol compound that has heterocyclic moiety, useful as anti-inflammatory agent

Technical field

The present invention relates to nonsteroidal anti-inflammatory, the di-tert-butylphenol compound that is specifically related to replace.

The background of invention

Have found that some di-tert-butylphenol compounds and have tangible anti-inflammatory and/or analgesic activities with other compound of its structurally associated; Other this compounds has also found to have other activity of curing the disease.Some this compounds, its preparation method and its purposes are disclosed in the following reference: authorized the United States Patent (USP) 4,535,165 of Moore on August 13rd, 1985; Authorized the United States Patent (USP) 4,724,246 of Ravichandran on February 9th, 1988; On February 28th, 1989 was authorized Oe, Kawasaki, Terasawa; The United States Patent (USP) 4,808,620 of Yasunaga; Authorize Thorwart, Gebert, Schleyerbach January 2 nineteen ninety; The United States Patent (USP) 4,891,374 of Bartlett; Authorize Thorwart, Gebert, Schleyerbach March 13 nineteen ninety; 4,908,364 of Bartlett; Authorize Thorwart, Gebert, Schleyerbach July 10 nineteen ninety; 4,940,790 of Bartlett; On October 13rd, 1992 was authorized Connor, Flynn, Kostlan, Mullican, Shrum, Unangst; 5,155,122 of Wilson; The patent application 58-148858 of the Yamanouchi Pharm.Co. that announce September 5 nineteen eighty-three; The patent application 1-180878 of the Yoshitomi Pharm.Ind. that on July 18th, 1989 announced; The patent application 2-229169 of Takede Chemical Industries Ltd that announce September 11 nineteen ninety; Isomura, Y., S.Sakamoto, N.Ito, H.Homma, T.Abe ﹠amp; K.Kubo is published in pharmaceutical chemicals circular (Chem.Pharm.Bull) 32 volumes (1984), the first phase, " being with 2 of heterocyclic group in the contraposition, the synthetic and anti-inflammatory activity of 6-di-t-butyl phenols, III " on the 152-165 page or leaf; Unangst, P.C., G.P.Shrum, D.T.Connor, R.D.Dyer ﹠amp; D.J.Schrier is published in medicinal chemistry (J.Med.Chem) 35 volume (1992), " as 5-lipoxygenase and the epoxidase double inhibitor new 1,2,4-oxadiazole and 1,2,4-thiadiazoles " on the 3691-3698; Costantino, L., C.Parenti, M.DiBella, P.Zanoli ﹠amp; M.Baraldi is published in " new synthetic 2,6-two (1, the 1-dimethyl ethyl) amphyl anti-inflammatory activity " on drug research (Pharmacological Research) 27 volume (1993) fourth phase 349-358 pages or leaves; Mullican, M.D., M.W.Wilson, D.T.Connor, C.R.Kostlan, D.J.Schrier ﹠amp; R.D.Dyer is published in " with 5-(3,5-di-t-butyl-4-hydroxyphenyl)-1; 3,4-thiadiazole ,-1,3; 4-oxadiazole class and-1,2, the 4-triazole species is used as the anti-inflammatory agent of Orally active, unlikely ulcer " on medical chemistry (J.Med.Chem) 36 volume (1993) 1090-1099 pages or leaves.

Have anti-inflammatory activity although confirmed some di-tert-butylphenol compounds, many this compounds seldom or do not have an anti-inflammatory activity.Therefore in general can not determine without activity test whether this compound has significant anti-inflammatory activity.

The purpose of this invention is to provide compound with effective anti-inflammatory, analgesia and/or antioxidant activity.

Another object of the present invention provides this compounds with few side effects.

A further object of the present invention provides the method for using The compounds of this invention treatment inflammation and/or pain.

The general introduction of invention

The present invention includes down the compound of array structure:

Wherein:

A) each R is respectively the alkyl with about 7 carbon atoms of 1-;

B) Z is O or N-X;

C) X is selected from hydrogen, has the alkyl of about 7 carbon atoms of 1-, C (O) Y, C (S) Y, SO ₂Y;

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

E) each R ' is selected from hydrogen, has the alkyl and the phenyl of about 7 carbon atoms of 1-.

Detailed description of the present invention

In this article, except as otherwise noted, otherwise " alkyl " is meant straight chain, side chain or cyclic, saturated or undersaturated, replacement or unsubstituted hydrocarbon chain group.Alkyl is a straight chain preferably.Branched-chain alkyl has 1-2 root side chain preferably, preferably has a side chain.Cycloalkyl is monocyclic groups or straight chain and monocyclic combination preferably, particularly has the straight chain group of monocycle end group.Alkyl is saturated preferably.Undersaturated alkyl has one or more pair key and/or one or more triple bond.Unsaturated alkyl has one or two two keys or a triple bond preferably, is preferably a two key.Alkyl is unsubstituted preferably.Substituted alkyl is one, two or trisubstituted preferably, and is preferably monobasic.Alkyl substituent comprises halogen preferably, hydroxyl, alkoxyl group is (as methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy), aryloxy is (as phenoxy group, chlorophenoxy, xylyloxy, the methoxyl group phenoxy group, the alkoxy carbonyl phenoxy group, the acyloxy phenoxy group), benzyloxy, acyloxy is (as propionyloxy, benzoyloxy, acetoxyl group), carbamoyloxy, carboxyl, sulfydryl, alkylthio, the acyl sulfenyl, arylthio is (as thiophenyl, the chlorobenzene sulfenyl, alkyl sulfur-base, the alkoxy benzene sulfenyl, the alkoxy carbonyl thiophenyl), benzylthio-, aryl is (as phenyl, xylyl, alkoxyl phenyl, alkoxycarbonylphenyl, carboxyl phenyl, halogenophenyl), heterocyclic radical, heteroaryl, amino (as amino, one and two C ₁-C ₃Saturated alkyl amino, aminomethyl phenyl amino, methyl-benzyl amino), amide group is (as amide group, one and two C ₁-C ₃Saturated alkyl amide group, formamido-(carbamamido)), urea groups and guanidine radicals.

In this article, " saturated alkyl (alkanyl) " is meant saturated alkyl (alkyl).

In this article, " alkoxyl group " is meant have the Q-O structure substituting group of (wherein Q is an alkyl).

In this article, " alkylthio " is meant have the Q-S structure substituting group of (wherein Q is an alkyl).

In this article, " aryl " is meant and has parts that do not replace or replace, about 10 the carbon atom aromatic rings of band 6-.Aryl is a phenyl or naphthyl preferably; Best aryl is a phenyl.Aryl is unsubstituted preferably.Substituted aryl is one, two or trisubstituted preferably, and is preferably mono-substituted.Aryl substituent comprises hydroxyl, sulfydryl, halogen, methyl, ethyl and propyl group preferably.

In this article, " heterocyclic radical " is meant to have and replaces or loop section unsubstituted, that be with the non-aromatics of about 8 annular atomses of 3-(comprising about 6 carbon atoms of 2-and about 4 heteroatomss that are selected from O, S and N of 1-).Heterocyclic radical has 5 or 6 annular atomses (comprising 1-3, best 1 or 2 heterocyclic atom) preferably.Concrete preferably heterocyclic radical comprises piperidyl, tetrahydro-thienyl, pyrrolidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, tetrahydrofuran base, imidazolidyl, pyrazolidyl, oxazolidinyl, isoxazole alkyl, Evil thiazolidyl, isothiazole alkyl, azepines base, oxepin base (oxepinyl), triazolidinge.Heterocyclic radical is not replace or replace, and better is unsubstituted.Substituted heterocyclic radical is one, two or trisubstituted preferably, and is preferably mono-substituted.Heterocyclic substituent comprises that alkyl (comprising substituted alkyl, as thiomethyl, carboxyl methyl, chloromethyl, trifluoromethyl), halogen, hydroxyl, carboxyl, alkoxyl group, acyloxy, sulfydryl, amino (comprise one and two C preferably ₁-C ₃Saturated alkyl amino,, dimethylamino), amide group, formamido-, thioformamide base, urea groups, sulfo-urea groups, guanidine radicals (comprise methyl substituted guanidine radicals, as methyl guanidine radicals, N, N '-dimethyl guanidine radicals, N, N-dimethyl guanidine radicals) as methylamino.

In this article, " heteroaryl " is meant and has 5 or 6 annular atomses the aromatic nucleus part of (comprising 2-5 carbon atom and 1-4 heteroatoms that is selected from O, S and N).Best heteroaryl has 1-3 (best 1 or 2) heterocyclic atom.Concrete preferably heteroaryl comprises pyrryl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, oxazolyl, isoxazolyl, pyranyl, thienyl, tetrazyl, thiazolyl, isothiazolyl, furyl, Evil thiazolyl.Heteroaryl is unsubstituted or replaces, better is unsubstituted.Substituted heterocyclic radical is one, two or trisubstituted preferably, and is preferably mono-substituted.The heteroaryl substituting group comprises that alkyl (comprising substituted alkyl, as thiomethyl, carboxyl methyl, chloromethyl, trifluoromethyl), halogen, hydroxyl, alkoxyl group, sulphur, amino (comprise one or two C preferably ₁-C ₃Saturated alkyl amino; as methylamino; dimethylamino, methoxymethyl amino, carboxyl methylamino), amide group, cyano group amide group, thioformamide base, urea groups, sulfo-urea groups, guanidine radicals (comprise methyl substituted guanidine radicals; as methyl guanidine radicals, N; N '-dimethyl guanidine radicals, N; N-dimethyl guanidine radicals), S-methyl thiocarbamoyl.

In this article, " halogen " is meant fluorine, chlorine, bromine or iodine; Halogen is fluorine, chlorine and bromine preferably; Best halogen is chlorine and fluorine.

Compound

The present invention specifically comprises the di-tert-butylphenol compound with following array structure:

In said structure, each R has about 7 carbon atoms of 1-, preferably has the alkyl of about 4 carbon atoms of 1-.Each R is preferably saturated.Each R is preferably unsubstituted.Each R is C preferably ₁-C ₃Saturated straight or branched saturated alkyl, or C ₃-Yue C ₄Saturated cyclic alkyls.Each R better is methyl, ethyl, n-propyl or sec.-propyl; Preferably methyl or ethyl; Be preferably methyl.Each R also better is a cyclopropyl.It is identical to be preferably two R.

In said structure, Z is O or N-X; Z is an oxygen preferably.X is selected from hydrogen, has the alkyl of about 7 carbon atoms of 1-, C (O) Y, C (S) Y, SO ₂Y; X is a hydrogen preferably.X also can be SO preferably ₂Y.

Y is selected from R ', OR ' and NR ' ₂Y is R ' preferably.Y also can be XR ' preferably ₂R ' is selected from hydrogen, has the alkyl and the phenyl of about 7 carbon atoms of 1-.R ' is hydrogen or C preferably ₁-C ₄Alkyl.Best R ' is selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl and cyclopropyl; Preferably hydrogen or methyl.

The compounds of this invention is R, Z, X, Y and the R ' compound with said structure as shown in the table preferably: compound sequence number R Z X Y R '

1 methyl, methyl O---

2 methyl, methyl N-X H--

3 methyl, methyl N-X SO ₂Y R ' methyl

4 methyl, methyl N-X C (O) Y NR ' ₂H, H

5 cyclopropyl, cyclopropyl N-X H--

In order to determine and to estimate pharmaceutical activity, use the known various test methods of those of skill in the art in this area that these compounds have been carried out animal experiment.Use the anti-local edema of these compounds (it is that inflammatory reaction is peculiar) test can prove conclusively the anti-inflammatory activity of these compounds easily.The example of these known tests comprises the inflammation mouse ear test that big white mouse carrageenin (carrageenan) oedema Shi Yan, azolactone brings out, and the inflammation ear that mouse arachadonic acid is brought out is tested.Can be in a known manner, the mouse of bringing out as the phenyl benzoquinones is because of painful test and the Randall that twists health; The big hundred mouse test of Selitto, the test analgesic activities.Other useful test as known in the art has big white mouse adjuvant arthritis test, and it is a kind of in chronic mode but not acute mode is estimated anti-inflammatory activity, arthritis and the anti-useful mode of assimilating activity again.

These and other suitable pharmaceutical activity test has disclosure and/or mentions in following patent and document, in the United States Patent (USP) 4,130,666 of disclosed Moore on the 19th December in 1978; United States Patent (USP) 4,431,656 in people such as disclosed Katsumi on the 14th February in 1984; United States Patent (USP) 4,440,784 in people such as disclosed Katsumi on the 3rd April in 1984; The people's such as Katsumi that announce on March 28th, 1985 Japanese patent application 85/54315; The Yamanuchi Phamaceutical Company Ltd. that announces September 1 nineteen eighty-two, the european patent application of delivering 0,059,090; Opas, E.V., R.J.Bonney ﹠amp; J.L.Humes, " cause synthetic (the Prostaglandin and LeukotrieneSynthesis in Mouse Ears Inflamed by Arachadonic Acid) of prostaglandin(PG) and Leukotriene in the mouse ear of inflammation " at arachidonic acid, the investigation dermatoses is learned magazine (The Journal of Investigative Dermatology), Vol.84, No.4 (1985), pp.253-256; Swingle, K.F., R.L.Bell ﹠amp; G.G.I.Moore, " anti-inflammatory activity of antioxidant ", anti-inflammatory and antirheumatic thing (Anti-inflammatory and Antirheumatic Drugs), Vol.III, the 4th chapter, K.D.Rainsford, ed., CRC Press, Inc., (1985), pp.105-126; Adamkiewicz, V.W., W.B.Rice ﹠amp; J.D.McColl, " antiphlogistic effects that trypsinase is merely hit common and adrenalectomized mouse ", Canadian biological chemistry and physiology magazine (Canadian JournalofBiochemistry ﹠amp; Physiology), Vol.33 (1955), pp.332-339; Sellye, H., " about the further research of the participation of adrenal cortex in the sacroiliitis pathogeny ", BMJ (British Medical Journal) .Vol.2 (1949), pp.1129-1135; And Winter, C.A., E.A.Risley ﹠amp; G.W.Nuss, " edema of bringing out by carrageenin as the rear solid end that the anti-inflammatory medicine is identified " SEBM's communique (Proceedings of Society ofExperimental Biology and Medicine) mouse, Vol.111 (1962), pp.544-547; Otterness, I. ， ﹠amp; M.L.Bliven, " laboratory method of test non-steroidal anti-inflammatory drugs ", non-steroidal anti-inflammatory drugs (Nonsteroidal Antiinflammatory Drugs), the 3rd chapter, J.G.Lombardino, ed., John Wiley ﹠amp; Sons, Inc. (1985), pp.111-252; Hitchens, J.T., S.Goldstein, L.Shemano ﹠amp; J.M.Beiler, " stimulant is three types of experimental analgesic effects of bringing out in the pain ", Arch.Int.Pharmacodvn., Vol.169, No.2 (1967) pp.384-393; Milne, G.M.﹠amp; T.M.Twomey, " Piroxicam in animal analgesia character and with the relation of the plasma volume of experimental mensuration ", reagent and effect (Agents and Actions), Vol.10, No.1/2 (1980), pp.31-37; Randall, L.O.﹠amp; J.J.Selitto, " in Inflamed tissue, measuring the method for analgesic activities ", Arch.Int.Pharmacodyn., Vol.111, No.4 (1957), pp.409-419; Winter, C.A.﹠amp; L.Faltaker, " stimulant and various anti-pain medicine are without the pain threshold due to the stomach administration ", J.Pharmacol.Exp.Ther., Vol.148, No.3 (1965), pp.373-379; All these reference are quoted in conjunction with reference at this.

Many antiphlogistons, especially nonsteroidal anti-inflammatory (NSAIDs) can cause undesirable stomach side effect, particularly when oral administration; These side effects comprise ulcer and corrosion.Usually be that asymptomatic these side effect meetings reach and are enough to that needs are in hospital and or even lethal severity.Compare with other NSAIDs, even compare with many other di-t-butyl amphyls, compound of the present invention seldom causes this stomach side effect usually.Compounds more of the present invention or even protection stomach, the protection stomach avoids ulcer and corrosion, especially by ethanol and caused ulcer of other NSAIDs and corrosion.

When being administered systemically, comprise that some di-t-butyl amphyls can make the systemic concentrations of some liver enzyme that undesirable increase is arranged some interior NSAIDs.Compound of the present invention seldom or not can cause the liver enzyme side effect usually.

Can use following popular response schema to prepare the useful compound of the present invention.

The logical method of preparation general formula III (when Z is O) compound is that suitable β-chlorine ketone and the azanol with general formula I I is carried out to ring-closing condensation reaction.For example, this reaction can be finished by the alcoholic solution of slowly handling suitable β-chlorine ketone and azanol halogenation hydrogen salt with the NaOH aqueous solution of stoichiometric quantity.General formula III (when Z is NH) compound can prepare by alpha, beta-unsaturated ketone and the hydrazine generation cyclic condensation with general formula I.For example, this reaction can be finished by the alcoholic solution of suitable alpha, beta-unsaturated ketone of heating and stoichiometric quantity hydrazine hydrate under 30-60 ℃ of temperature.If wish higher temperature of reaction, then this reaction can be carried out in sealed flask.Required β-chlorine ketone and α; alpha, beta-unsaturated ketone usually can be by following prepared in reaction: make 2,6-di-tert-butylphenol and suitable α, beta-unsaturated acyl base chlorine carry out friedel-crafts (Friedel-Crafts) reaction; contact with excessive hydrochloric acid subsequently, perhaps at TiCl ₄Make silylatedly 3 under existing, 5-di-t-butyl-4-hydroxy acetophenone and suitable ketone carry out aldolisation.

Following unrestricted embodiment further provides the detailed description of synthetic The compounds of this invention.

Embodiment 1

3-(3,5-di-t-butyl-4-hydroxyphenyl)-4,5-dihydro-5,5-dimethyl isoxazole synthetic

3-chloro-1-(3,5-di-t-butyl-4-hydroxyphenyl)-3-methyl fourth-1-ketone.Put into 3 in 12 liters of round-bottomed flasks that interior thermometer, mechanical stirrer, feed hopper and barrier film import be housed, (146g 1.23mol) is dissolved in CH to the 3-dimethyl acryloyl chloride ₂Cl ₂Solution (1000mL).At CH ₂Cl ₂In-the dry ice bath stirred solution is chilled to-10 ℃, adds TiCl so that the temperature of reaction mixture is no more than-5 ℃ speed through sleeve pipe then ₄(at CH ₂Cl ₂In 1M solution, 1476mL, 1.47mol, 1.2eq).Add finish after, with solution stirring 10 minutes, be added dropwise to 2 through feed hopper then, (253.4g, 1.23mol 1.0eq) are dissolved in CH to the 6-di-tert-butylphenol ₂Cl ₂Solution (500mL).Interpolation speed is adjusted to and makes temperature of reaction keep below 0 ℃.After interpolation finishes, remove cryostat, mixture was at room temperature stirred 4 hours.TLC analyzes (EtOAc: hexane, 1: 9) and shows and react completely.Add H carefully ₂O (2L) transfers to mixture in the 6L extraction funnel.Separate organic phase, with other H ₂(Na is used in 2 * 1000mL) washings to O ₂SO ₄Drying is filtered, and is put back in the 12L reaction vessel again.Adding HCl diethyl ether solution (1M, Aldrich, 2000mL).Stir after 2 hours, solution is transferred in the 6L separating funnel, use H ₂O (3 * 1L) washings.Organic phase Na ₂SO ₄Drying is filled in the 10L round-bottomed flask, is rotated evaporation.Residuum is dissolved in the 1L pentane, and remains under-4 ℃ and spend the night.Filter the crystalline solid of gained, dry 3-chloro-1-(3,5-di-t-butyl _ 4-the hydroxyphenyl)-3-methyl fourth-1-ketone that obtains.

3-(3,5-di-t-butyl-4-hydroxyphenyl)-4,5-dihydro-5,5-dimethyl isoxazole.

5L be equipped with add in the round-bottomed flask of magnetic stirring apparatus and Ar import 3-chloro-1-(3,5-di-t-butyl-4-hydroxyphenyl)-3-methyl fourth-1-ketone (77.1g, 0.24mol) and hydroxyl hydrochloride (20.1g 0.28mol) is dissolved in the solution of EtOH (2.2L).In 15 minutes, in the solution that stirs, be added dropwise to 2N NaOH (119mL, 0.24mol, 1.0eq).During two kinds of solution contacts, observe the yellow of rapid diffusion.After interpolation finishes, 50 ℃ of reacting by heating.Follow the tracks of with TLC (EtOAc: hexane, 1: 4).After 3 hours, reach about 50% transformation efficiency.Add H ₂O (750mL) precipitates crude product, filters.Filtrate is put aside.With hexane recrystallization solid once, obtain faint yellow solid shape 3-(3,5-di-t-butyl-4-hydroxyphenyl)-4,5-dihydro-5,5-dimethyl isoxazole.In rotatory evaporator, concentrate H ₂O/EtOH filtrate is removed EtOH, gained suspension CH ₂Cl ₂(3 * 200mL) extractions.Aqueous phase discarded, dry (MgSO ₄) organic phase, filtering, the hexane mother liquor with from above-mentioned crystallization the time merges, and flashes to the oily solid.Go out the yellow solid shape 3-(3,5-di-t-butyl-4-hydroxyphenyl)-4 of somewhat lower purity in first batch of material, 5-dihydro-5,5-dimethyl isoxazole with the hexane crystallization.

Embodiment 2

3-(3,5-di-t-butyl-4-hydroxyphenyl)-5,5-dimethyl-1H-pyrazoline synthetic:

50 ℃ stir 3-chloro-1-(3,5-di-t-butyl-4-hydroxyphenyl)-3-methyl fourth-1-ketone (embodiment 1) (3.45g, 10.1mmol) and hydrazine hydrate (0.8mL 14mmol) is dissolved in the solution 1 hour of anhydrous EtOH (50mL).In 2 hours, divide two same sections add other hydrazine hydrate (1mL, 18mmol).Follow the tracks of with TLC (hexane: EtOAc, 9: 1), this is reflected at 50 ℃ and stirs 18 hours down afterwards fully.Evaporating solvent obtains a yellow solid, and this solid is from EtOH: H ₂The O crystallization obtains the 3-(3,5-di-t-butyl-4-hydroxyphenyl)-5 of white rib shape, 5-dimethyl-1H-pyrazoline.

Embodiment 3

3-(3,5-di-t-butyl-4-hydroxyphenyl)-5,5-dimethyl-1-methylsulfonyl-1H-pyrazoline synthetic:

At the 650mg 3-(3,5-di-t-butyl-4-hydroxyphenyl)-5 that is chilled to 0 ℃, 5-dimethyl-1H-pyrazoline (embodiment 2), 360 μ l triethylamines, 50mg N, N-Dimethylamino pyridine are dissolved in and add 182 μ l methylsulfonyl chlorides in the stirred solution of 20ml methylene dichloride.After 0 ℃ is stirred 30 minutes, remove cryostat, at room temperature stirred the mixture 2 hours.The vapourisation under reduced pressure solvent, residuum is purified through flash chromatography (being dissolved in 10% ethyl acetate of hexane), obtains colorless solid shape 3-(3,5-di-t-butyl-4-hydroxyphenyl)-5,5-dimethyl-1-methylsulfonyl-1H-pyrazoline.

Embodiment 4

1-formamyl (carboxamido)-3-(3,5-di-t-butyl-4-hydroxyphenyl)-5,5-dimethyl-1H-pyrazoline synthetic:

At 35 ℃, at 600mg 3-(3,5-di-t-butyl-4-hydroxyphenyl)-5,5-dimethyl-1H-pyrazoline (embodiment 2) is dissolved in the stirred solution in the mixture of 9ml acetate, 6.5ml tetrahydrofuran (THF) and 18.6ml water and adds the 260mg potassium cyanate.In the time of 35 ℃, stir after 30 minutes, mixture was stirred 5 hours 55 ℃ the time.Vapourisation under reduced pressure solvent, residuum are dissolved in the 50ml methylene dichloride.Wash solution 3 times with the aqueous sodium hydroxide washes of 15ml0.1N, use dried over sodium sulfate.Evaporating solvent, residuum is purified through flash chromatography (being dissolved in 20% ethyl acetate in the hexane), obtains colorless solid shape 1-formamyl-3-(3,5-di-t-butyl-4-hydroxyphenyl)-5,5-dimethyl-1H-pyrazoline.

Embodiment 5

3-(3,5-di-t-butyl-4-hydroxyphenyl)-5,5-two cyclopropyl-1H-pyrazoline synthetic: 1-(3,5-di-t-butyl-4-hydroxyphenyl)-3,3-two cyclopropyl third-2-alkene-1-ketone.With 4g3, the stirred solution that 5-di-t-butyl-4-hydroxy acetophenone is dissolved in the 250ml dry dichloromethane is chilled to-78 ℃, adds 7.3ml diisopropylethylamine (i-Pr ₂EtN), add 8.1ml trifluoromethanesulfonic acid trimethylammonium first estersil (TMSOTf) subsequently.Stirred the mixture 10 minutes at-78 ℃, in 1 hour, be warmed to room temperature subsequently.Again mixture is chilled to-78 ℃, adds 3.6ml two cyclopropyl ketone, add the solution that the 32ml1M titanium tetrachloride is dissolved in methylene dichloride subsequently.Stir after 1 hour,, under reduced pressure remove and desolvate with 1N aqueous hydrochloric acid purging compound.Residuum is dissolved in 50ml methyl alcohol-1N aqueous hydrochloric acid, at room temperature stirs 1 hour.Mixture under reduced pressure is concentrated, and distributes between methylene dichloride and water.The organic phase sodium bicarbonate aqueous solution, dried over sodium sulfate is used in the salt water washing.Evaporating solvent, residuum is purified through flash chromatography (being dissolved in 10% ethyl acetate in the hexane), and product recrystallization from hexane obtains orange/yellow solid shape 1-(3,5-di-t-butyl-4-hydroxyphenyl)-3,3-two cyclopropyl third-2-alkene-1-ketone.

3-(3,5-di-t-butyl-4-hydroxyphenyl)-5,5-two cyclopropyl-1H-pyrazoline.In withstand voltage Glass Containers, add 350mg 1-(3,5-di-t-butyl-4-hydroxyphenyl)-3,3-two cyclopropyl third-2-alkene-1-ketone, 0.2ml hydrazine hydrate and 15ml ethanol.Closing containers heats uniform mixture 15 hours at 80 ℃.Vapourisation under reduced pressure solvent, residuum are dissolved in the methylene dichloride, wash with water, use dried over sodium sulfate.Evaporating solvent, crude product is crystallization and purification from hexane, obtains yellow solid shape 3-(3,5-di-t-butyl-4-hydroxyphenyl)-5,5-two cyclopropyl-1H-pyrazoline.

Composition

Composition of the present invention comprises acceptable carrier on the The compounds of this invention of safety and significant quantity and the pharmacology.Be meant in normal medical judgment scope in this used " safety and significant quantity ", big with being enough to the amount that under condition to be treated, can produce the positive compound that improves effect, but low to being enough to avoid severe side effect (reasonably benefit/danger ratio).The safety of compound is effectively measured the specified conditions of looking treatment again, treatment patient's age and physical condition, the severity of situation, the time length of treatment, and deposit the characteristic of therapy, various types of on the used specific pharmacology in acceptable carrier and nursing doctor's general knowledge and the experience scope decided like factor.

Composition of the present invention comprises the compound of about 0.1%-about 99.9% (weight) preferably, and the compound of about 20%-about 80% is then better, and about 40%-is about, and 70% compound is then best.

Except compound, composition of the present invention comprises acceptable carrier on a kind of pharmacology.Be meant one or more compatible solids or liquid filling thinner or the encapsulated material that is suitable for human or low etc. animals administer at this used term " acceptable carrier on the pharmacology ".Be meant under common working conditions the composition component that mixes mutually with the interactional mode of curative effect of medication that composition does not take place significantly to reduce and The compounds of this invention at this used term " compatible ".Certainly, acceptable carrier must have sufficiently high purity and enough low toxicity on the pharmacology, so that they are suitable for the human of treatment or the animals administer that hangs down etc.

Can as some examples of the material of acceptable carrier on the pharmacology or component sugar, as lactose, dextrose plus saccharose; Starch is as W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof, as Xylo-Mucine, ethyl cellulose, rhodia; Powdered tragacanth gum; Fructus Hordei Germinatus; Gelatin; Talcum; Solid lubricant, as stearic acid, Magnesium Stearate; Calcium sulfate; Vegetables oil, as peanut oil, Oleum Gossypii semen, sesame oil, sweet oil, Semen Maydis oil and theobroma oil; How pure, as propylene glycol, glycerol, sorbyl alcohol, mannitol, and polyoxyethylene glycol; Alginic acid; Emulsifying agent is as tween (Tweens ); Wetting agent is as Sodium Lauryl Sulphate BP/USP; Tinting material; Flavouring agent; Vehicle; Become tablet; Stablizer; Antioxidant; Sanitas; The water that does not contain pyrogen; Isotonic saline solution; And phosphate buffer.

Selection to acceptable carrier on the pharmacology that uses with The compounds of this invention is determined by the form of medication of compound basically.

If injection compound of the present invention is advisable with injection in the non-vein; Acceptable carrier is the stroke-physiological saline solution that contains suspension agent that can be compatible with blood on the pharmacology preferably, and its pH value has been adjusted to about 7.4.This injectable composition is better with the The compounds of this invention that every dosage comprises about 1%-about 50%, about 5%-about 25% better, the The compounds of this invention that comprises the about 600mg of about 10mg-is better equally.

Acceptable carrier comprises that those are suitable for the carrier that uses in lotion, emulsion, gel etc. on the suitable pharmacology of topical application.The composition of local usefulness comprises the tenderizer of about 1%-about 50% preferably, comprises the lubricant of about 5%-about 25% better.The every dosage of the composition of this local usefulness is better with the The compounds of this invention that comprises about 0.1%-about 50%, about 0.5%-about 10% better, the The compounds of this invention that comprises the about 1000mg of about 5mg-is better equally.

The form of medication preferably of The compounds of this invention is oral.Therefore unit dosage form is the tablet that comprises safety and significant quantity compound preferably, capsule etc., and described safety is effectively measured again and is preferably to be the about 1000mg of about 10mg-better by the about 3500mg of about 5mg-, is the about 600mg of about 25mg-best.

Many The compounds of this invention all are hydrophobic.If wish to obtain with water to be the composition of base or to mix or miscible composition, then in composition, can add solubilizing agent with water medium.The nonrestrictive example of this solubilizing agent comprises polyoxyethylene glycol, propylene glycol, ethanol and polyethylene oxide (35) Viscotrol C.

The good especially oral compositions carrier that is applicable to the present composition is disclosed Kelm on February 23rd, 1993; The United States Patent (USP) that is entitled as " pharmaceutical composition of Tebufelone " 5,189,066 of Bruns and in disclosed Kelm on January 25th, 1994; In the United States Patent (USP) that is entitled as " solid dispersion compositions of Tebufelone " 5,281,420 of Dobrozsi disclosure is arranged, these patents are quoted in conjunction with reference at this.

Method

Another aspect of the present invention is the method for disease that treatment or prevention have the inflammation feature, and it is to take safely the The compounds of this invention of significant quantity again to the people of this treatment of needs or the low animal of waiting.Be meant the known state that comprises inflammation at this used term " disease " with inflammation feature, it can comprise as sacroiliitis (rheumatoid arthritis for example, osteoarthritis, psoriatic arthritis, child's sacroiliitis, wright's syndrome, infectious arthritis, and ankylosing spondylitis, systemic lupus erythematous and gout) and no matter whether with the inflammatory conditions of the existence of identifiable disease-related.Disease with inflammation feature also can comprise intraoral inflammation (for example relevant inflammation of gingivitis or periodontal disease); Inflammation (for example relevant with supersensitivity intestines disease inflammation) in the gi tract with ulcer; The inflammation relevant (psoriasis for example, acne and other skin inflammation) with dermatosis; The inflammation relevant (for example asthma, bronchitis and allergy) with respiratory tract; With the inflammation (for example alzheimer's disease) in the central nervous system.

Another aspect of the present invention is the treatment or the method for prevent irritation, and it is to take the safe The compounds of this invention of significant quantity again to the people of this treatment of needs or the low animal of waiting.Can The compounds of this invention be treated or the pain of preventing comprises appearance pain, cramp, toothache and back pain by taking.

Another aspect of the present invention is to prevent because the free radical that oxidation stress and ischemia condition cause damages, and its way is to take safely the The compounds of this invention of significant quantity again to the people of this treatment of needs or the low animal of waiting.This treatment can comprise and prevents ischemic heart disease, atherosclerosis, apoplexy and the damage of heart ischemia sexual cell.

Another aspect of the present invention is treatment or prevention stomach or duodenal ulcer or corroding method, and its way is to take safely the The compounds of this invention of significant quantity again to the people of this treatment of needs or the low animal of waiting.Especially, this ulcer that causes by ethanol or nonsteroidal anti-inflammatory (NSAIDs) or corrosion can The compounds of this invention obtains medical treatment and/or prevents by taking preferably.

The stomach and intestine security of test The compounds of this invention or the suitable test of stomach protective nature are known.

The method of testing acute stomach and intestine security has in following document and discloses and/or mention: Unangst, P.C., G.P.Shrum, D.T.Connor, R.D.Dyer and D.J.Schrier, " as 1,2 of the novelty of 5-lipoxidase and cyclooxygenase double inhibitor; 4-oxadiazole and 1; 2,4-thiadiazoles ", J.Med.Chem., Vol.35 (1992), pp.3691-3698; And Segawa; Y; O.Ohya; T.Abe; people such as T.Omata " novel antiphlogiston N-{3-(3-(piperidine methyl) phenoxy group) propyl group }-the carbamyl methylthiol) anti-inflammatory of ethyl-1-(to chlorobenzene formacyl)-5-methoxyl group-2-methyl-3-indoleacetic acid ester, ease pain and bring down a fever effect and gastrointestinal toxicity ", Arzneim.-Forsch./Drug Res.; Vol.42 (1992), pp.954-992.In the disclosed method of this article, generally take compound and the stomach of animal is checked after 2 hours.

The method of testing inferior chronic stomach and intestine security has in following document and discloses and/or mention: Melarange, R., people's such as C.Gentry " Nabumetone or its active metabolite; the anti-inflammatory and the gastrointestinal effects of 6-methoxyl group-2-naphthyl acetic acid (6MNA) ", Dig.Dis.Sci., Vol.37 (1992), pp.1847-1852; And Wong, S., " BF-389-arthritis performance (Antiarthritic Profile of BF-389-A Novel Anti-inflammatory Agent With Low Ulcerogenic Liability) with novel anti-inflammatory agent of low ulcer tendency " of people such as S.J.Lee, reagent and effect, Vol.37 (1992), pp.90-91.

The method of testing the protection of acute stomach has in following document and discloses and/or mention: Playford; R.J.; D.A.Versey; S.Haldane; " fentanyl depends on the effect of dosage in the gastric injury that INDOMETHACIN causes " of M.R.Alison and J.Calan; Digestion, Vol.49 (1991), pp.198-203.In the disclosed method of this article, give oral The compounds of this invention of female Lewis mouse (130-175g) (40mg/kgb.i.d.) or vehicle, at once and the INDOMETHACIN of taking gastric injury dosage afterwards in 2 hours.This mouse is choked to death by CO2 after 4 hours.Measure body of stomach damage (millimeter of hemorrhage damage) with digitized picture.

The compounds of this invention administering mode preferably is oral, but has also studied other known medication, and as through the mucocutaneous membrane administration (for example through the epidermis medication, per rectum medication etc.) with without stomach administration (for example subcutaneous injection, intramuscular injection, intra-articular injection, intravenous injection etc.).Also comprise through ophthalmic administration and inhalation.These special administering modes include, but are not limited to, and are oral, transdermal administration, mucosa delivery, sublingual administration, intranasal administration, intramuscular administration, intravenous administration, intraperitoneal administration, subcutaneous administration, and topical.

The compounds of this invention dosage preferably is the about 70mg/kg of about 0.2mg/kg-, is the about 12mg/kg of about 0.5mg/kg-better.Injectable dosage comprises the The compounds of this invention of the about 10mg/kg of about 0.1mg/kg-preferably.Local dose comprises and is applied to about 1mg/cm on the skin surface preferably ²-Yue 200mg/cm ²The compounds of this invention.Oral dosage comprises the about 50mg/kg of about 0.5mg/kg-preferably, the about 20mg/kg of about better 1mg/kg-, the The compounds of this invention of the about 10mg/kg of about best 2mg/kg-.These dosage take every day about 1 to 6 time better, every day about 2 to 4 times then better.It is better that these per daily doses are taken at least one week, takes fortnight at least, at least one month, at least 2 months, at least 6 months, 1 year, 2 years or longer time.

With unrestricted embodiment the present invention is described below.

Embodiment A

By ordinary method, prepare the tablet medicine composition as mixed and direct compression, its prescription is as follows: group component (mg/ sheet) compound 1 200 Microcrystalline Celluloses 100 Explotabs 30 Magnesium Stearates 3

Oral 2 times of every day, above-mentioned composition has reduced rheumatoid arthritis people's inflammation significantly.Take twice this composition for every day the osteoarthritis patient and also reached obvious effects.

Embodiment B

Prepare the capsule formulation pharmaceutical composition by ordinary method, its prescription is as follows: group component (mg/ capsule) compound 5 200 lactose fill up capsular volume

Every day, oral above-mentioned capsule once reduced rheumatoid arthritis or osteoarthritis patient's symptom significantly.

Embodiment C

Prepare the liquid dosage form pharmaceutical composition by ordinary method, its prescription is as follows: group component compound 2 200mgEtOH 4ml methylcellulose gum 0.4mg distilled water 76ml tweens (Tween) 80 1.6ml

Every day, oral 50ml above-mentioned composition once reduced rheumatoid arthritis or osteoarthritis patient's symptom significantly.

Embodiment D

Prepare the liquid dosage form pharmaceutical composition by ordinary method, its prescription is as follows: group component crystallite (micronized) compound 3 200mgAvicel (Microcrystalline Cellulose) 50mg tweens (Tween) 80 1.6ml methylcellulose gum 0.4mg deionized water 80ml

Every day, oral 100ml above-mentioned composition secondary reduced rheumatoid arthritis or osteoarthritis patient's symptom significantly.

After specific embodiments of the present invention having been done description, it is evident that concerning the art technology expert can be to making various changes and improvements at this disclosed composition under the situation that does not depart from marrow of the present invention and scope.In appending claims, attempt to cover all these improvement in the scope of the 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.