KR20060007614A - Isoxazole derivatives, processes for the preparation thereof, and pharmaceutical compositions containing the same - Google Patents

Abstract

The present invention provides an isoxazole derivative represented by the following formula (1) or a nontoxic salt thereof, a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient:

[Formula 1]

In Chemical Formula 1,

R ₁ is phenyl; Or substituted with one or more groups selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, halogen, chlorosulfonyl, and aminosulfonyl Phenyl.

Description

Isoxazole derivatives, processes for the preparation, and pharmaceutical compositions containing the same}

The present invention relates to isoxazole derivatives or non-toxic salts thereof, methods for their preparation, and pharmaceutical compositions comprising them as active ingredients.

Most nonsteroidal anti-inflammatory drugs exhibit their anti-inflammatory, analgesic, and antipyretic effects through inhibition of an enzyme called cyclooxoygenase or prostaglandin G / H synthase, and also inhibits hormonal contractions caused by hormones and some Inhibits the growth of cancer. Initially, only the constitutive enzyme found in cattle, cyclooxygenase-1 (COX-1), was known. Recently, an inducible form of cyclooxygenase-2 (COX-2) has been identified. Cyclooxygenase-2 is clearly different from cyclooxygenase-1 and is easily induced by mitogen, endotoxin, hormones, growth factors and cytokines and the like.

Prostaglandins play a pathological and physiological role. Cyclooxygenase-1, a constitutive enzyme, is involved in the secretion of basic endogenous prostaglandins and plays an important role in physiological aspects such as maintaining the state of the stomach and blood circulation in the kidneys. Cyclooxygenase-2, on the other hand, is caused by inflammatory factors, hormones, growth factors and cytokines and the like, and thus plays a major role in the pathological effects of prostaglandins. Therefore, inhibitors selective for cyclooxygenase-2 are expected to have no side effects due to mechanisms of action, and anti-inflammatory, analgesic and antipyretic effects, compared to conventional nonsteroidal anti-inflammatory drugs. It is expected to inhibit inhibition and some types of cancer growth. In particular, side effects such as gastrointestinal toxicity and kidney toxicity are expected to be low. It is also expected to prevent the synthesis of contractile prostanoids and thus inhibit the contraction of smooth muscles induced by prostanoids, and thus are expected to be useful for diseases related to premature birth, menstrual irregularities, asthma and eosinophils. In addition, it is expected to be useful in the treatment of osteoporosis, glaucoma, colorectal cancer, prostate cancer and dementia. John Vane, "Towards a better aspirin" in the usefulness of inhibitors selective to cyclooxygenase-2 Nature, 367, pp. 215-216, 1994; Bruno Battistini, Regina Botting and YS Bakhle, "COX-1 and COX-2: Toward the Development of More Selective NSAIDs" in Drug News and Perspectives, Vol. 7, 501-512 , 1994; David B. Reitz and Karen Seibert, "Selective Cyclooxygenase Inhibitors" in Annual Reports in Medicinal Chemistry, James A. Bristol, Editor, Vol. 30, pp. 179-188, 1995).

Existing drugs known as inhibitors that selectively act on cyclooxygenase-2 take a wide variety of forms in their structure. The structure most commonly studied and thus designed with the most candidates is the structure of the diaryl heterocycle, i.e., a tricyclic system, which is essentially a sulfonamide or methylsulfone group in one phenyl.

US Pat. No. 5,466,823 discloses a compound of formula 27 (celecoxib). The following celecoxib is a substituted pyrazole benzene sulfonamide derivative.

According to WO 95/00501 a compound (lofecoxib) having the formula (28) is disclosed. Rofecoxib has a diaryl heterocycle structure like celecoxib but has a furanone structure as a heterocycle.

U.S. Patent No. 5,633,272 describes a compound (valdecoxib) such as Valdecoxib has a phenyl sulfonamide structure like celecoxib but has an isoxazole structure as a heterocycle.

The compounds of Formulas 27 to 29 are all selective inhibitors of COX-2 and have anti-inflammatory analgesic effect without side effects compared to conventional nonsteroidal anti-inflammatory agents.

The present invention aims to provide isoxazole derivatives or non-toxic salts thereof.

It is also an object of the present invention to provide a method for preparing the isoxoxazole derivative or non-toxic salt thereof.

It is also an object of the present invention to provide a pharmaceutical composition having an antipyretic, analgesic, anti-inflammatory effect comprising the isoxazole derivative or a non-toxic salt thereof as an active ingredient.

It is also an object of the present invention to provide a pharmaceutical composition for treating cancer or dementia, comprising the alkoxy-substituted isoxazole derivative or non-toxic salt thereof as an active ingredient.

The present invention provides isoxazole derivatives represented by the following general formula (1) or nontoxic salts thereof:

In Chemical Formula 1,

R ₁ is phenyl; Or substituted with one or more groups selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, halogen, chlorosulfonyl, and aminosulfonyl Phenyl.

In Formula 1, R ₁ is phenyl; Or isoxoxazole derivatives or non-toxic salts thereof, which are phenyl substituted with one or more groups selected from the group consisting of C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen, chlorosulfonyl, and aminosulfonyl.

The compound represented by Formula 1 may exist in the form of a non-toxic salt. Non-toxic salts herein means pharmaceutically acceptable non-toxic salts, including organic salts and inorganic salts.

Inorganic salts with the compound of Formula 1 include, but are not limited to, salts with aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, or zinc, ammonium, calcium, magnesium, potassium, Or sodium salt is preferred.

Organic salts with compounds of Formula 1 include, but are not limited to, primary, secondary or tertiary amines, substituted amines, cyclic amines, or salts with basic ion exchange resins present in nature. Examples of salts prepared from basic ion exchange resins and the like include arginine, betaine, caffeine, choline, N, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylene Diamine, N-ethylmorpholine, N-ethylpiperidine, N-methylglucamine, glucamine, glucosamine, histidine, hydramine, N- (2-hydroxyethyl) piperidine, N- (2- Hydroxyethyl) pyrrolidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tro Salts such as metamine, but are not limited thereto.

The compound of Formula 1 may be present in the form of a salt with a pharmaceutically acceptable organic or inorganic acid.

Organic or inorganic acid salts of the compounds of Formula 1 include acetic acid, adipic acid, aspartic acid, 1,5-naphthalenedisulfonic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, Ethylenediaminetetraacetic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, isetionic acid, lactic acid, maleic acid, malic acid, manderic acid, methylsulfonic acid, music acid, 2-naphthalenedisulfonic acid Salts with nitric acid, oxalic acid, parnoic acid, pentothenic acid, phosphoric acid, pivalic acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, or 10-undecenoic acid Although not limited thereto, salts with succinic acid, hydrobromic acid, hydrochloric acid, maleic acid, methylsulfonic acid, phosphoric acid, sulfuric acid, or tartaric acid are preferred.

Ixoxazole derivatives of the present invention

3- (4-methylsulfonylphenyl) -5-methyl-4-phenoxy-isoxazole;

3- (4-methylsulfonylphenyl) -5-methyl-4-p-tolyloxy-isoxazole;

4- (4-chlorophenoxy) -3- (4-methylsulfonylphenyl) -5-methyl-isoxazole;

4- (4-ethoxyphenoxy) -3- (4-methylsulfonylphenyl) -5-methyl-isoxazole;

4- [3- (4-methylsulfonylphenyl) -5-methyl-isoxazol-4-yloxy] -benzenesulfonyl chloride;

4- [3- (4-Methylsulfonyl-phenyl) -5-methyl-isoxazol-4-yloxy] -benzenesulfonamide

3- (4-methylsulfonylphenyl) -4- (4-methoxyphenoxy) -5-methyl-isoxazole; And

It is preferably one selected from the group consisting of 4- (4-bromophenoxy) -3- (4-methylsulfonylphenyl) -5-methyl-isoxazole.

The present invention provides a 2-alkoxyacetophenone derivative represented by the following Chemical Formula 5 as a synthetic intermediate of the isoxoxazole derivative of Chemical Formula 1:

In Formula 5, R ₁ is as defined in Formula 1, n is an integer of 0 to 2.

The present invention also provides a method for preparing an isoxazole derivative of formula 1 or a non-toxic salt thereof comprising reacting an oxime derivative of formula 6a with acetic anhydride in the presence of a base:

In Chemical Formula 6a, R ₁ is as defined in Chemical Formula 1.

The present invention also provides a method for preparing an isoxazole derivative of formula (1) or a non-toxic salt thereof comprising reacting an oxime derivative of formula (6b) with an acetic anhydride in the presence of a base and then oxidizing with an oxidizing agent.

In Formula 6b, R ₁ is as defined in Formula 1, and m is 0 or 1.

The base that can be used for the isoxazole formation reaction includes an organic base or an inorganic base, and as the organic base, triethylamine, trimethylamine, tripropylamine, pyridine, or imidazole is preferable. Acetate, sodium hydroxide, sodium hydride, potassium hydroxide, sodium carbonate, butyllithium, or potassium carbonate is preferred, and butyllithium is most preferred.

A polar solvent may be used as a solvent for the formation reaction of isooxazole, and such a polar solvent may be tetrahydrofuran, dimethylformamide, dioxane, dimethyl sulfoxide, methylpyrrolidinone, or m -xylene. It is not limited to this.

At this time, the reaction temperature is preferably carried out at -10 ℃ to 110 ℃, the reaction time is required 10 minutes to 36 hours depending on the substrate.

When the isoxazole formation reaction is completed, the salts may be removed by extraction using an organic solvent such as water and ethyl acetate, dichloromethane, tetrahydrofuran, or ether, and then purified by column chromatography on silica gel to obtain a product.

The reaction of oxidizing the sulfide group or sulfinyl group with a sulfone group is preferably performed using an oxidizing agent in dichloromethane, and the oxidizing agent may be MMPP (Magnesium monoperoxyphthalate hexahydrate), MCPBA (m-chloroperoxybenzoic acid), or Oxone (Potassium peroxymonosulfate). It is preferable to use etc.

After all the reactions have been completed, the product can be separated and purified by conventional post-treatment methods such as chromatography, recrystallization and the like.

The compound represented by Chemical Formula 6, including Chemical Formulas 6a and 6b, may be prepared by reacting the compound of Chemical Formula 5 with hydroxyamine in the presence of a base.

[Formula 5]

In Chemical Formulas 5 and 6, R ₁ is as defined in Chemical Formula 1, and n is an integer of 0 to 2.

The base that can be used in the reaction of the compound 6 is an organic base or an inorganic base, triethylamine, trimethylamine, tripropylamine, pyridine, or imidazole is preferred as the organic base, sodium as the inorganic base Acetate, sodium hydroxide, sodium hydride, potassium hydroxide, sodium carbonate, butyllithium, or potassium carbonate is preferred, and potassium carbonate is most preferred among them.

A polar solvent may be used as a solvent for forming the compound 6, and such a polar solvent may be tetrahydrofuran, dimethylformamide, dioxane, dimethyl sulfoxide, methylpyrrolidinone, or alcohol, but is not limited thereto. Does not.

At this time, the reaction temperature is preferably carried out at -10 ℃ to 110 ℃, the reaction time is required 10 minutes to 36 hours depending on the substrate.

The compound of Formula 5 may be prepared by reacting a compound of Formula 4 with an alcohol of Formula 3 in the presence of a base:

R ₁ OH

In Chemical Formulas 3 and 4, R ₁ is as defined in Chemical Formula 1, and n is an integer of 0 to 2.

The base that can be used for the reaction of the compound 5 is an organic base or an inorganic base, the organic base is preferably triethylamine, trimethylamine, tripropylamine, pyridine, or imidazole, and the inorganic base is sodium Acetate, sodium hydroxide, sodium hydride, potassium hydroxide, sodium carbonate, butyllithium, or potassium carbonate is preferred, and potassium carbonate is most preferred among them.

Various polar or nonpolar organic solvents may be used as a solvent for the formation of Compound 5, and such various polar or nonpolar organic solvents may include tetrahydrofuran, acetone, dichloromethane, dioxane, toluene, or alcohols. It is not limited.

At this time, the reaction temperature is preferably carried out at -10 ℃ to 110 ℃, the reaction time is required 10 minutes to 36 hours depending on the substrate.

A preferred embodiment of the process for preparing the compound of Formula 1 described above is shown in Scheme 1 below.

In Scheme 1, R ₁ and n are as defined above.

Method for preparing a compound according to the present invention, for example, reaction conditions, such as the amount of the reaction solvent, the base, the amount of the reactant is not limited to those described above, but various as described herein or disclosed in the publicly known literature Synthetic methods can be readily prepared by any combination, and such combinations are conventional techniques that are generalized to those skilled in the art.

The present invention provides a pharmaceutical composition having an antipyretic, analgesic and anti-inflammatory effect, which contains a therapeutically effective amount of the isoxazole derivative of Formula 1 or a non-toxic salt thereof as an active ingredient and a pharmaceutically acceptable carrier. .

Such pharmaceutical compositions include the compounds of Formula 1 or their pharmaceutically acceptable salts with selective inhibitory activity against cyclooxygenase-2, and thus can be used as antipyretic, analgesic, anti-inflammatory agents with minimal side effects. have.

Conventional nonsteroidal anti-inflammatory agents are not only cyclooxygenase-2 involved in the synthesis of pathological prostaglandins, but also cyclos, which participate in the secretion of basic endogenous prostaglandins and play important roles in physiological aspects such as maintaining the state of the stomach and blood circulation of the kidneys. Oxygenase-1 was inhibited indiscriminately and had various side effects.

In contrast, the compounds of Formula 1 and their pharmaceutically acceptable salts have a selective inhibitory activity on cyclooxygenase-2, so that conventional nonsteroidal antipyretics that indiscriminately inhibit cyclooxygenase-1, It can minimize the side effects of analgesic and anti-inflammatory drugs.

Therefore, pharmaceutical compositions comprising a compound of formula 1 and / or their pharmaceutically acceptable salts and pharmaceutically acceptable carriers or excipients can be used as a substitute for typical nonsteroidal anti-inflammatory agents, in particular existing nonsteroidal As an alternative drug with improved side effects of antipyretic, analgesic and anti-inflammatory drugs, it is useful for patients with peptic ulcer, gastritis, partial enteritis, ulcerative colitis, diverticulitis, gastrointestinal bleeding, hypoprothrombinemia.

The pharmaceutical compositions of the present invention can be used for both pathological prostaglandin related inflammatory diseases, and are particularly useful for osteoarthritis and rheumatoid arthritis requiring high doses of administration.

The pharmaceutical composition may be administered to the adult 1mg / day to 1000mg / day based on the compound of formula (1) or salts thereof as the active ingredient, it can be increased or decreased depending on the severity of the disease.

The present invention also provides a pharmaceutical composition for treating cancer and dementia treatment, comprising a therapeutically effective amount of the isoxoxazole derivative of Formula 1 or a non-toxic salt thereof as an active ingredient and a pharmaceutically acceptable carrier. To provide.

Recently, nonsteroidal anti-inflammatory drugs have been described as colorectal cancer (European Journal of Cancer, Vol 37, p2302, 2001), prostate cancer (Urology, Vol 58, p127, 2001) or dementia (Exp.Opin. Invest. Drugs, Vol 9, p671). , 2000). Accordingly, the pharmaceutical composition including the compound of Formula 1 or a pharmaceutically acceptable salt thereof, which is a nonsteroidal anti-inflammatory agent, may be used as a composition for treating colorectal cancer or dementia.

The pharmaceutical composition may be administered to the adult 1mg / day to 1000mg / day based on the compound of formula (1) or salts thereof as the active ingredient, it can be increased or decreased depending on the severity of the disease.

The pharmaceutical composition may be used in the form of tablets, effervescent tablets, capsules, granules, powders, sustained release tablets, sustained release capsules (alone and complex unit preparations), ampoules for intravenous and intramuscular injection, suspensions, suppositories, Or in other suitable pharmaceutical forms.

Sustained release pharmaceutical forms may contain the active compound in a complete or partial sustained release form with or without an initial dosage content.

The active compounds may be present together or as part of a formulation that is partly or completely separate from one another, so that separate or timed administration may also be possible.

When these completely separate formulations are present, they cooperate with each other and contain each active compound in the dosage unit in the same amount and corresponding weight ratio that may be present in the mixture in which they are combined.

Preferred are orally administrable pharmaceutical compositions containing the indicated combinations.

To prepare pharmaceutical formulations containing such combinations, the active compounds are formulated in the indicated amounts in a preferred manner with physiologically resistant excipients and / or diluents and / or adjuvants.

Examples of excipients and auxiliaries include natural sugars such as gelatin, sucrose or lactose, lecithin, pectin, starch (eg corn starch or amylose), cyclodextrins and cyclodextrin derivatives, dextran, polyvinylpyrrolidone, polyvinyl acetate , Gum arabic, alginic acid, tylose, talc, lycopodium, silicic acid, calcium hydrogen phosphate, cellulose, cellulose derivatives such as methoxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, 12 carbon atoms To 22 fatty acids, emulsifiers, oils and fats, in particular also vegetable glycerol esters and polyglycerol esters of saturated fatty acids, polyglycols such as mono or polyhydric alcohols and polyethylene glycols, monohydric aliphatic alcohols having 1 to 20 carbon atoms, or Glycol, glycerol, diethyl Glycol, the 1,2-propylene glycol, sorbitol, mannitol, such as a polyhydric alcohol having a number of C atoms from 2 to 22 aliphatic saturated or unsaturated fatty acid ester.

Further suitable auxiliaries are also substances which cause disintegration (so-called disintegrants), crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethylcellulose, microcrystalline cellulose. Known coating materials can also be used. Polymers and copolymers of acrylic acid and / or methacrylic acid and / or esters thereof, zein, ethylcellulose, ethylcellulose succinate, shellac and the like.

Plasticizers suitable as coating materials can be citric acid esters and tartaric acid esters, glycerol and glycerol esters, polyethylene glycols of various chain lengths. It is suitable for the preparation of water or physiologically acceptable organic solvents such as alcohol and fatty alcohol solutions or suspensions.

In liquid formulations, it may be necessary to use preservatives such as sorbate potassium, methyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate, antioxidants such as ascorbic acid and fragrance enhancers such as peppermint oil.

In the preparation of the formulations, known and conventional solubilizers, or emulsifiers, such as polyvinylpyrrolidone and polysorbate 80 can be used.

Additional examples of suitable excipients and auxiliaries can be found in the literature (Dr. H. P. Fiedler "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete" [Encyclopaedia of auxiliaries for pharmacy, cosmetics and related fields].

Hereinafter, the present invention will be described in more detail with reference to the following Examples and Experimental Examples. However, these Examples and Experimental Examples are only for better understanding of the present invention, and the scope of the present invention is not limited by them in any sense.

Reference Example  One

2- Bromo -1- (4- Methylthiophenyl )- Ethanon

2.0 g (12.03 mmole) of 4-methylthioacetophenone was dissolved in 30 ml of dichloromethane, and then 0.69 ml (12.03 mmole) of acetic acid was added dropwise. Bromine 1.92 g (12.03 mmole) was added dropwise at room temperature, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane. The reaction solution was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The reaction product obtained under reduced pressure was purified by flash column chromatography (ethyl acetate: n-hexane = 2: 8) to give 2.09 g (yield 71%) of the titled compound as an oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ 2.50 (s, 3H), 4.55 (s, 2H), 7.30 (d, 2H, J = 6.8Hz), 7.75 (d, 2H, J = 6.8Hz)

Reference Example  2

1- (4- Methylthiophenyl )-2- Phenoxy - Ethanon

1.0 g (4.08 mmole) of 2-bromo-1- (4-methylthiophenyl) -ethanone prepared in Reference Example 1 was dissolved in 20 ml of acetone, followed by 0.62 g (4.49 mmole) of 0.42 g of potassium carbonate ( 4.49 mmole) and 0.45 g (4.49 mmole) of phenol were added sequentially, followed by stirring at room temperature for 3 hours. After the reaction was completed, the reaction solution was diluted with water and ethyl acetate and extracted twice with ethyl acetate. The extracted organic layer was washed once with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The reaction product obtained under reduced pressure was purified by flash column chromatography (ethyl acetate: n-hexane = 2: 8) to give 0.70 g (yield 66%) of the title compound in an oil phase.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.50 (s, 3H), 5.25 (s, 2H), 6.88-6.92 (m, 3H), 7.25-7.35 (m, 4H), 7.60 (d, 2H, J = 6.8 Hz)

Reference Example  3

1- (4- Methylthiophenyl ) -2-p- Tolyloxy - Ethanon

The reaction was carried out in the same manner as in Reference Example 2, except that 0.49 g (4.49 mmole) of 4-methylphenol was used instead of phenol in Reference Example 2 to obtain 0.81 g (yield 73%) of the title compound in oil form. .

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.50 (s, 3H), 3.05 (s, 3H), 5.25 (s, 2H), 7.10 (d, 2H, J = 8.0Hz), 7.25 (d, 2H, J = 8.0 Hz), 7.40 (d, 2H, J = 6.8 Hz), 7.60 (d, 2H, J = 6.8 Hz)

Reference Example  4

2- (4- Chlorophenoxy ) -1- (4- Methylthiophenyl )- Ethanon

 The reaction was carried out in the same manner as in Reference Example 2, except that 0.58 g (4.49 mmole) of 4-chlorophenol was used instead of phenol in Reference Example 2 to obtain 0.73 g (yield 61%) of the title compound in oil. .

¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.05 (s, 3H), 5.25 (s, 2H), 7.15 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J = 8.0 Hz), 7.40 (d, 2H, J = 6.8 Hz), 7.60 (d, 2H, J = 6.8 Hz)

Reference Example  5

2- (4- Ethoxyphenoxy ) -1- (4- Methylthiophenyl )- Ethanon

The reaction was carried out in the same manner as in Reference Example 2, except that 0.56 g (4.49 mmole) of 4-ethoxyphenol was used instead of phenol in Reference Example 2 to obtain 0.81 g (yield 69%) of the title compound in oil form. It was.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.45 (t, 3H, J = 6.9), 3.05 (s, 3H), 4.10 (q, 2H, J = 6.9), 5.25 (s, 2H), 7.20 (d , 2H, J = 8.0 Hz, 7.30 (d, 2H, J = 8.0 Hz), 7.40 (d, 2H, J = 6.8 Hz), 7.60 (d, 2H, J = 6.8 Hz)

Reference Example  6

1- (4- Methylthiophenyl )-2- Phenoxy -ethane Oxime

1.0 g (3.87 mmole) of 1- (4-methylthiophenyl) -2-phenoxy-ethanone prepared in Reference Example 2 was dissolved in 15 ml of ethanol, followed by 0.69 g (5.03 mmole) of potassium carbonate, and hydroxy. 0.35 g (5.03 mmole) of ammonium chloride were added sequentially. The reaction solution was stirred at reflux for 12 hours. After the reaction was completed, the temperature of the reaction solution was lowered to room temperature, water and ethyl acetate were added to the reaction solution, the aqueous layer was extracted twice with ethyl acetate, and the obtained organic layer was washed once with saturated brine and dried over anhydrous magnesium sulfate. After filtration. The filtrate was concentrated under reduced pressure, and the resulting reaction was purified by flash column chromatography (ethyl acetate: n-hexane = 2: 8) to give 0.76 g (yield 72%) of the title compound on oil. After briefly checking by mass spectrometry, the next reaction proceeded.

Mass (EI) 273

Reference Example  7

1- (4- Methylthiophenyl ) -2-p- Tolyloxy -ethane Oxime

1- (4-methylthiophenyl) -2-p-tolyloxy-ethanone 1.05 prepared in Reference Example 3 instead of 1- (4-methylthiophenyl) -2-phenoxy-ethanone in Reference Example 6 above The reaction was carried out in the same manner as in Reference Example 6, except that g (3.87 mmole) was used, to obtain 0.76 g (yield 75%) of the title compound in the oil phase. After briefly checking by mass, the next reaction was carried out.

Mass (EI) 287

Reference Example  8

2- (4- Chlorophenoxy ) -1- (4- Methylthiophenyl )-ethane Oxime

2- (4-chlorophenoxy) -1- (4-methylthiophenyl) prepared in Reference Example 4 instead of 1- (4-methylthiophenyl) -2-phenoxy-ethanone in Reference Example 6 above Reaction was carried out in the same manner as in Reference Example 6, except that 1.13 g (3.87 mmole) of ethanone was obtained, thereby obtaining 0.82 g (yield 69%) of the title compound in oil form. After briefly checking by mass, the next reaction was carried out.

Mass (EI) 308

Reference Example  9

2- (4- Ethoxyphenoxy ) -1- (4- Methylthiophenyl )-ethane Oxime

1.13 g of 2- (4-ethoxyphenoxy) -1- (4-methylthiophenyl) -ethanone instead of 1- (4-methylthiophenyl) -2-phenoxy-ethanone in Reference Example 6 The reaction was carried out in the same manner as in Reference Example 6, except that 3.87 mmole) was used, to obtain 0.70 g (yield 63%) of the title compound in the oil phase. After briefly checking by mass, the next reaction was carried out.

Mass (EI) 317

Reference Example  10

5- methyl -3- (4- Methylthiophenyl )-4- Phenoxy - Ixoxazole

After dissolving 790 mg (2.89 mmole) of 1- (4-methylthiophenyl) -2-phenoxy-ethane oxime prepared in Reference Example 6 in 10 ml of anhydrous tetrahydrofuran, the temperature of the reaction solution was -40 ° C or lower. Lowered. 2.9 ml (7.23 mmole) of n-BuLi 2.5M solution using hexane was added dropwise, followed by stirring at −40 ° C. or lower for 30 minutes. The reaction solution was heated to 0 ° C. and stirred for another 30 minutes, and then a solution of 0.33 ml (3.47 mmole) of acetic anhydride in 4 ml of tetrahydrofuran was slowly added dropwise. The reaction solution was stirred at 0 ° C. for 30 minutes and then stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water and ethyl acetate, extracted twice with ethyl acetate, and the organic layer was washed with saturated brine. Then, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The reaction mixture was concentrated under reduced pressure and dissolved in 10 ml of dichloromethane. Three drops of sulfuric acid were added. Then, the reaction solution was heated to reflux for 2 hours. After the reaction was completed, the organic layer obtained by diluting with water and ethyl acetate and extracting twice with ethyl acetate was washed with saturated brine. Then, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. After concentration under reduced pressure, the reaction product was purified by flash column chromatography (ethyl acetate: n-hexane = 2: 8) to give 370 mg (yield 43%) of the title compound as an oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.35 (s, 3H), 2.50 (s, 3H), 6.88-6.92 (m, 2H), 7.10 (d, 1H, J = 7.4Hz), 7.30-7.40 ( m, 4H), 7.80 (d, 2H, J = 8.7 Hz)

Reference Example  11

5- methyl -3- (4- Methylthiophenyl ) -4-p- Tolyloxy - Ixoxazole

1- (4-methylthiophenyl) -2-p-tolyloxy-ethane oxime prepared in Reference Example 7 instead of 1- (4-methylthiophenyl) -2-phenoxy-ethane oxime in Reference Example 10 The reaction was carried out in the same manner as in Reference Example 10, except that 830 mg (2.89 mmol) was used, to obtain 370 mg (yield 41%) of the title compound in oil form.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.30 (s, 3H), 2.40 (s, 3H), 2.50 (s, 3H), 6.85 (d, 2H, J = 8.7Hz), 7.10 (d, 2H, J = 8.7 Hz), 7.30 (d, 2H, J = 6.8 Hz), 7.80 (d, 2H, J = 6.8 Hz)

Reference Example  12

4- (4- Chlorophenoxy ) -5- methyl -3- (4- Methylthiophenyl )- Ixoxazole

2- (4-chlorophenoxy) -1- (4-methylthiophenyl) -ethane prepared in Reference Example 8 instead of 1- (4-methylthiophenyl) -2-phenoxy-ethane oxime in Reference Example 10 above The reaction was carried out in the same manner as in Reference Example 10, except that 890 mg (2.89 mmol) of oxime was used to obtain 350 mg (yield 37%) of the title compound in oil form.

¹ H-NMR (400MHz, CDCl ₃ ) δ 2.35 (s, 3H), 2.50 (s, 3H), 6.85 (d, 2H, J = 6.5Hz), 7.25 (d, 2H, J = 6.5Hz), 7.30 (d, 2H, J = 8.2 Hz), 7.80 (d, 2H, J = 8.2 Hz)

Reference Example  13

4- (4- Ethoxyphenoxy ) -5- methyl -3- (4- Methylthiophenyl )- Ixoxazole

2- (4-ethoxyphenoxy) -1- (4-methylthiophenyl) prepared in Reference Example 9 instead of 1- (4-methylthiophenyl) -2-phenoxy-ethane oxime in Reference Example 10; 370 mg (yield 39%) of the title compound was obtained in the same manner as in Reference Example 10, except that 870 mg (2.89 mmol) of) -ethane oxime was used.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.45 (t, 3H, J = 6.9), 2.40 (s, 3H), 2.50 (s, 3H), 4.10 (q, 2H, J = 6.9), 6.85 (d , 2H, J = 8.7Hz, 7.10 (d, 2H, J = 8.7Hz), 7.30 (d, 2H, J = 6.8Hz), 7.80 (d, 2H, J = 6.8Hz)

Reference Example  14

4- [5- methyl -3- (4- Methylthiophenyl )- Ixoxazole -4- Iloxy ]- Benzenesulfonyl Chloride

790 mg (2.89 mmole) of 1- (4-methylthiophenyl) -2-phenoxy-ethane oxime prepared in Reference Example 6 was dissolved in 10 ml of anhydrous tetrahydrofuran, and the temperature of the reaction solution was lowered to -40 ° C or lower. . 2.9 ml (7.23 mmole) of n-BuLi 2.5 M solution using hexane as a solvent was added dropwise, followed by stirring at −40 ° C. or lower for 30 minutes. The reaction solution was heated to 0 ° C. and stirred for another 30 minutes. A solution of 0.33 ml (3.47 mmole) of acetic anhydride in 4 ml of tetrahydrofuran was slowly added dropwise. The reaction solution was stirred at 0 ° C. for 30 minutes and then stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water and ethyl acetate and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. 2.5 ml of chlorosulfonic acid was slowly added dropwise at room temperature with stirring under reduced pressure. After stirring for 30 minutes, the mixture was diluted with ethyl acetate and water was added slowly. After extraction twice with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. It was then concentrated under reduced pressure, and the resulting reaction was purified by flash column chromatography (ethyl acetate: n-hexane = 2: 8) to give 340 mg (yield 30%) of the titled compound as an oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.40 (s, 3H), 2.50 (s, 3H), 7.05 (d, 2H, J = 8.7Hz), 7.25 (d, 2H, J = 8.7Hz), 7.70 (d, 2H, J = 6.8 Hz), 7.95 (d, 2H, J = 6.8 Hz)

Example  One

3- (4- Methylsulfonylphenyl ) -5- methyl -4- Phenoxy - Ixoxazole

100 mg (0.34 mmole) of 5-methyl-3- (4-methylthiophenyl) -4-phenoxy-isoxazole prepared in Reference Example 10 was dissolved in a mixed solvent of 2.5 ml of dichloromethane and 0.5 ml of methanol. MMPP 273 mg (0.44 mmole) was added little by little at room temperature. The reaction solution was stirred for 5 hours, filtered, and the filtrate was washed once with sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered under reduced pressure. The reaction obtained by filtration under reduced pressure was purified by flash column chromatography (ethyl acetate: n-hexane = 1: 2) to give 100 mg (yield 89%) of the title compound in oil form.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.35 (s, 3H), 3.05 (s, 3H), 6.88-6.92 (m, 2H), 7.10 (d, 1H, J = 7.4Hz), 7.30-7.40 ( m, 2H), 7.95 (d, 2H, J = 8.7 Hz), 8.05 (d, 2H, J = 8.7 Hz)

Example  2

3- (4- Methylsulfonylphenyl ) -5- methyl -4-p- Tolyloxy - Ixoxazole

3- (4-methylthiophenyl) -5-methyl-4 prepared in Reference Example 11 instead of 5-methyl-3- (4-methylthiophenyl) -4-phenoxy-isoxazole in Example 1 The reaction was carried out in the same manner as in Example 1, except that 106 mg (0.34 mmol) of -p-tolyloxy-isoxazole was used to obtain 100 mg (yield 86%) of the title compound as an oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.30 (s, 3H), 2.40 (s, 3H), 3.05 (s, 3H), 6.85 (d, 2H, J = 8.7Hz), 7.10 (d, 2H, J = 8.7 Hz), 7.90 (d, 2H, J = 6.8 Hz), 8.05 (d, 2H, J = 6.8 Hz)

Example  3

4- (4- Chlorophenoxy ) -3- (4- Methylsulfonylphenyl ) -5- methyl - Ixoxazole

4- (4-chlorophenoxy) -5-methyl-3 prepared in Reference Example 12 instead of 5-methyl-3- (4-methylthiophenyl) -4-phenoxy-isoxazole in Example 1 above The reaction was carried out in the same manner as in Example 1, except that 112 mg (0.34 mmol) of-(4-methylthiophenyl) -isoxazole was used to obtain 104 mg (yield 84%) of the title compound in oil form. .

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.35 (s, 3H), 3.05 (s, 3H), 6.85 (d, 2H, J = 6.5Hz), 7.25 (d, 2H, J = 6.5Hz), 7.95 (d, 2H, J = 8.2 Hz), 8.05 (d, 2H, J = 8.2 Hz)

Example  4

4- (4- Ethoxyphenoxy ) -3- (4- Methylsulfonylphenyl ) -5- methyl - Ixoxazole

4- (4-ethoxyphenoxy) -5-methyl prepared in Reference Example 13 instead of 5-methyl-3- (4-methylthiophenyl) -4-phenoxy-isoxazole in Example 1 The reaction was carried out in the same manner as in Example 1, except that 111 mg (0.34 mmol) of 3- (4-methylthiophenyl) -isoxazole was used to obtain 99 mg (yield 81%) of the title compound in oil. Obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.45 (t, 3H, j = 6.9), 2.40 (s, 3H), 3.05 (s, 3H), 4.10 (q, 2H, J = 6.9), 6.85 (d , 2H, J = 8.7Hz, 7.10 (d, 2H, J = 8.7Hz), 7.90 (d, 2H, J = 6.8Hz), 8.05 (d, 2H, J = 6.8Hz)

Example  5

4- [3- (4-methylsulfonylphenyl) -5-methyl-isoxazol-4-yloxy] -benzenesulfonyl chloride

4- [5-methyl-3- (4-methylthio) prepared in Reference Example 14 instead of 5-methyl-3- (4-methylthiophenyl) -4-phenoxy-isoxazole in Example 1 119 mg (yield 82) of the title compound as a solid was reacted in the same manner as in Example 1 except that 135 mg (0.34 mmol) of phenyl) -isoxazol-4-yloxy] -benzenesulfonyl chloride is used. %) Was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.40 (s, 3H), 3.05 (s, 3H), 7.10 (d, 2H, J = 12.2 Hz), 7.95-8.05 (m, 6H)

Mass (EI) 428

m.p. 162 ~ 163 ℃

Example  6

4- [3- (4- Methylsulfonylphenyl ) -5- methyl - Ixoxazole -4- Iloxy ]- Benzenesulfonamide

100 ml (0.23 mmole) of 4- [3- (4-methylsulfonylphenyl) -5-methyl-isoxazol-4-yloxy] -benzenesulfonyl chloride prepared in Example 5 was added to 4 ml of dichloromethane. After dissolving in 2 ml of saturated ammonia water was added. Then stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was diluted with water and dichloromethane and extracted twice with dichloromethane. Thus obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. After concentration under reduced pressure, the reaction product was purified by flash column chromatography (ethyl acetate: n-hexane = 1: 1) to obtain 65 mg (yield 69%) of the title compound in the solid phase.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.40 (s, 3H), 3.05 (s, 3H), 4.70 (s, br, 2H), 7.03 (d, 2H, J = 6.9Hz), 7.90 (d, 2H, J = 6.9 Hz), 7.95-8.05 (m, 4H)

Mass (EI) 408

M.P. 118 ~ 119C

Pharmacological Experimental Example

Cyclooxygenase Selective inhibitory activity against -2

1. Experiment Method

In order to pharmacologically verify the selective inhibitory activity of the cyclooxygenase-2 enzyme of the compound according to the present invention, the enzyme inhibitory activity on cyclooxygenase-1 and cyclooxygenase-2 was respectively as follows. Measured by.

1) Using U-937 Cyclooxygenase -1 suppression effect search

The cultured U-937 (Human lymphoma cell) (obtained from Korea Cell Line Bank, Accession No .: 21593) was collected by centrifugation and diluted to 1x10 ⁶ cells / ml using 1xHBSS (Hank's balanced salt solution). 1 ml was dispensed for each well of the well plate. 5 μl each of the sample solution dissolved in DMSO and diluted to 1 μM and DMSO as a control was mixed and incubated at 37 ° C. for 15 minutes in a CO ₂ incubator. A stock solution prepared by dissolving arachidonic acid used as a substrate in ethanol at a concentration of 10 mM was diluted 10-fold with 1 × HBSS to prepare a 1 mM solution. 10 μl of 1 mM arachidonic acid solution was added to each well treated with the material, followed by incubation at 37 ° C. for 30 minutes in a CO ₂ incubator. The cell solution of each well was collected in a centrifuge test tube, and then centrifuged at 4 ° C. and 10,000 rpm for 5 minutes. The concentration of PGE2 in the supernatant separated from the cells collected by centrifugation was determined using a monoclonal kit (Cayman Chemicals), and the concentration of PGE2 of each substance was compared with that of the DMSO group. The inhibitory effect of the substance on the cyclooxygenase-1 enzyme was determined by determining the production inhibition rate.

2) Raw 264.7 Cell lines  Used Cyclooxygenase -2 suppression effect search

Raw 264.7 cells (obtained from Korea Cell Line Bank, Accession No .: 40071) were inoculated with 2 × 10 ⁶ cells per well of a 12 well plate, treated with 250 μM of aspirin, and incubated at 37 ° C. for 2 hours. After changing to fresh medium, each sample was treated (10 nM concentration) and incubated for 30 minutes. Each well was treated with interferon γ (100 units / ml) and lipopolysaccharide (LPS, 100ng / ml), followed by incubation for 18 hours. Then, the medium was transferred to another test tube, and PGE2 was quantified using an EIA kit (Cayman Chemicals).

2. Experimental Results

The experimental results are shown in Table 1 below.

% Inhibition = (PGE2 concentration in untreated test substance-PGE2 concentration in untreated test substance) / (PGE2 concentration in untreated test substance) X 100

TABLE 1

Cyclooxygenase (COX) inhibitory effect (% inhibition)

compound COX-1 (1 μM) COX-2 (10 nM) Reference substance (Valdecoxib) 28.8 5.47 Example 1 19.3 5.51 Example 2 20.6 5.49 Example 3 17.3 8.76 Example 4 23.6 12.43 Example 5 12.1 4.32 Example 6 16.9 5.33

Looking at the results of in vitro experiments on the inhibition of the cyclooxygenase-1 and cyclooxygenase-2 are as follows.

The ratio of% inhibition of cyclooxygenase-2 to% inhibition of cyclooxygenase-1 of the test compound was found to be significantly better than the reference material (vladecoxib). This indicates that the selective inhibitory effect of cyclooxygenase-2 on cyclooxygenase-1 is significantly better than the reference material.

In addition, the test compound showed that the absolute inhibitory effect on COX-2 was higher than the reference material except the compound of Example 5. These results indicate that the improved selectivity not only improved side effects than the reference material, but also was superior in terms of antipyretic analgesic effect.

According to the present invention, the side effects of the conventional nonsteroidal anti-inflammatory drugs are improved, and thus can be usefully used in patients with peptic ulcer, gastritis, partial enteritis, ulcerative colitis, diverticulitis, gastrointestinal bleeding, low prothrombinemia, and the like. Isoxazole derivatives or non-toxic salts thereof having antipyretic analgesic anti-inflammatory effect, methods for their preparation, and pharmaceutical compositions containing them as active ingredients can be provided.

Claims (7)

Ixoxazole derivative represented by the following formula (1) or a non-toxic salt thereof: [Formula 1]

In Chemical Formula 1, R ₁ is phenyl; Or substituted with one or more groups selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, halogen, chlorosulfonyl, and aminosulfonyl Phenyl. The compound of claim 1, wherein R ₁ is phenyl; Or phenyl substituted with at least one phenyl substituted with a group selected from the group consisting of C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen, chlorosulfonyl, and aminosulfonyl. The method of claim 1, 3- (4-methylsulfonylphenyl) -5-methyl-4-phenoxy-isoxazole; 3- (4-methylsulfonylphenyl) -5-methyl-4-p-tolyloxy-isoxazole; 4- (4-chlorophenoxy) -3- (4-methylsulfonylphenyl) -5-methyl-isoxazole; 4- (4-ethoxyphenoxy) -3- (4-methylsulfonylphenyl) -5-methyl-isoxazole; 4- [3- (4-methylsulfonylphenyl) -5-methyl-isoxazol-4-yloxy] -benzenesulfonyl chloride; 4- [3- (4-Methylsulfonyl-phenyl) -5-methyl-isoxazol-4-yloxy] -benzenesulfonamide 3- (4-methylsulfonylphenyl) -4- (4-methoxyphenoxy) -5-methyl-isoxazole; And Ixoxazole derivatives selected from the group consisting of 4- (4-bromophenoxy) -3- (4-methylsulfonylphenyl) -5-methyl-isoxazole or nontoxic salts thereof. 2-alkoxy acetophenone derivative represented by the following formula (5): [Formula 5]

In Formula 5, R ₁ is as defined in claim 1, n is an integer of 0 to 2. A therapeutically effective amount of the isoxoxazole derivative according to any one of claims 1 to 3 or a nontoxic salt thereof as an active ingredient and having an antipyretic, analgesic, anti-inflammatory effect comprising a pharmaceutically acceptable carrier. Pharmaceutical compositions. A pharmaceutical composition for treating cancer, comprising a therapeutically effective amount of the isoxoxazole derivative according to any one of claims 1 to 3 or a non-toxic salt thereof as an active ingredient and a pharmaceutically acceptable carrier. A pharmaceutical composition for treating dementia, comprising a therapeutically effective amount of the isoxazole derivative according to any one of claims 1 to 3 or a nontoxic salt thereof as an active ingredient and a pharmaceutically acceptable carrier.