KR100576339B1 - Pyridazine-4-one derivatives, processes for the preparation thereof, and pharmaceutical compositions containing the same - Google Patents

Abstract

The present invention provides a pyridazin-4-one derivative represented by the following formula (1) or a non-toxic salt thereof:

In Chemical Formula 1,

R ¹ is C ₃ -C ₆ cycloalkyl; C ₃ -C ₆ cycloalkenyl; Phenyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, acetoxy, halogen, amino, monoalkylamino, dialkylamino, nitro, and cyano Phenyl substituted with one or more groups selected from the group consisting of; Stillenyl; C ₁ -C ₆ alkoxy stillenyl; Or pyridyl,

R ² is methyl or amino.

Description

Pyridazine-4-one derivatives, processes for the preparation etc, and pharmaceutical compositions containing the same}

The present invention relates to a pyridazin-4-one derivative or a non-toxic salt thereof, a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient.

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. the tricyclic system, which is essentially a sulfonamide or methanesulfone group in one phenyl.

 According to US Pat. No. 5,466,823, a compound of formula 35 (celecoxib) is disclosed. The following celecoxib is a substituted pyrazole benzene sulfonamide derivative.

According to WO 95/00501 a compound (lofecoxib) having the formula 36 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 35 to 37 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 pyridazin-4-one derivatives or non-toxic salts thereof.

It is also an object of the present invention to provide a method for preparing the pyridazin-4-one derivative or non-toxic salt thereof.

It is also an object of the present invention to provide a pharmaceutical composition having an antipyretic, analgesic and anti-inflammatory effect comprising the pyridazin-4-one derivative or a non-toxic salt thereof as an active ingredient.

The present invention provides a pyridazin-4-one derivative represented by the following formula (1) or a non-toxic salt thereof:

[Formula 1]

In Chemical Formula 1,

R ¹ is C ₃ -C ₆ cycloalkyl; C ₃ -C ₆ cycloalkenyl; Phenyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, acetoxy, halogen, amino, monoalkylamino, dialkylamino, nitro, and cyano Phenyl substituted with one or more groups selected from the group consisting of; Stillenyl; C ₁ -C ₆ alkoxy stillenyl; Or pyridyl,

R ² is methyl or amino.

In Formula 1, R ¹ is phenyl; Pyridazin-4-one derivatives or non-toxic salts thereof, wherein C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, or phenyl substituted with halogen, R ² is methyl or amino are preferred.

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, methanesulfonic 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 However, the present invention is not limited thereto, and salts with succinic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, phosphoric acid, sulfuric acid, or tartaric acid are preferable.

The pyridazin-4-one derivatives of the present invention

6- (4-methanesulfonylphenyl) -1-phenyl-1H-pyridazin-4-one;

6- (4-methanesulfonylphenyl) -1-p-tolyl-1H-pyridazin-4-one;

6- (4-methanesulfonylphenyl) -1- (4-methoxyphenyl) -1H-pyridazin-4-one;

1- (4-fluorophenyl) -6- (4-methanesulfonylphenyl) -1H-pyridazin-4-one; And

Preference is given to any one selected from the group consisting of 4- (5-oxo-2-phenyl-2,5-dihydro-pyridazin-3-yl) -benzenesulfonamide.

The present invention provides a pyridazine derivative of the following formula 8 as a synthetic intermediate of the pyridazin-4-one derivative of the formula (1).

In Chemical Formula 8, R ¹ is as defined in Chemical Formula 1.

On the other hand, the compound of Formula 1 provided in the present invention can be prepared according to the same method as in Scheme 1.

However, the method according to Scheme 1 below corresponds to one embodiment of the method for preparing the pyrazin-4-one derivative of Formula 1, and reaction conditions such as, for example, the amount of the reaction solvent, the base, and the amount of the reactant are described below. It is not limited to only. In addition, the pyridazin-4-one derivative of Chemical Formula 1 may be prepared by arbitrarily combining various synthesis methods disclosed in the art, in addition to the method of Scheme 1 below.

In the above scheme, R ¹ is as defined in formula (I).

The reaction is briefly described as follows.

In Scheme 1, the reaction of triflate pyridazine (7) with aryl boronic acid (R ¹ B (OH) ₂ ) is performed in the presence of a base, and the solvent used is dichloromethane, chloroform, tetrahydrofuran, dimethyl. Formamide, benzene, toluene, diethyl ether and the like can be used, of which toluene is most preferred. The reaction temperature is preferably performed at -10 ° C to 110 ° C, and the reaction time requires 10 minutes to 48 hours depending on the substrate.

When the reaction is completed, it is preferable to remove the salts by extraction with an organic solvent such as water and ethyl acetate, dichloromethane, tetrahydrofuran, or ether and then purified by column chromatography on silica gel to obtain the product.

The base used in the reaction includes an organic base or an inorganic base, and the organic base is preferably triethylamine, trimethylamine, tripropylamine, pyridine, or imidazole, and the inorganic base includes sodium acetate, sodium hydroxide, Sodium hydride, potassium hydroxide, sodium carbonate, or potassium carbonate is preferred, and potassium carbonate is most preferred.

By the above reaction, a sulfide intermediate (8) is obtained, and the compound (1a) can be obtained by oxidizing the sulfide intermediate with sulfone, and oxidants used in this process are mainly oxone, hydrogen peroxide, and magnesium monoperoxyphthalate. Hexahydrate, 3-chloroperoxybenzoic acid, and the like, of which 3-chloroperoxybenzoic acid is most preferred.

Thus produced compound (1a) can be amidated to give benzenesulfonamide derivative (1b).

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 present invention provides a pharmaceutical composition having an antipyretic, analgesic and anti-inflammatory effect, which contains a therapeutically effective amount of pyridazin-4-one derivative or 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 1 mg / day to 1000 mg / day based on the compound of Formula 1 or their salts as the active ingredient, it can be increased or decreased depending on the severity of the disease.

The present invention also contains a therapeutically effective amount of the pyridazin-4-one derivative of Formula 1 or a non-toxic salt thereof as an active ingredient and a pharmaceutical composition for treating cancer and the treatment of dementia comprising a pharmaceutically acceptable carrier. It provides a pharmaceutical composition.

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 compositions may be in the form of tablets, effervescent tablets, capsules, granules, powders, sustained release tablets, sustained release capsules (alone and complex unit preparations), intravenous and intramuscular injections and infusions, suspensions, suppositories In the form or other suitable pharmaceutical form.

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 are natural sugars such as gelatin, sucrose or lactose, lecithin, pectin, starch (e.g. corn starch or amylose), cyclodextrins and cyclodextrin derivatives, dextran, polyvinylpyrrolidone, polyvinyl acetate , Gum arabic, alginic acid, tylose, talc, calcium hydrogen phosphate, cellulose, cellulose derivatives such as methoxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, fatty acids of 12 to 22 carbon atoms, emulsions Topical, oils and fats, in particular also vegetable glycerol esters and polyglycerol esters of saturated fatty acids, polyglycols such as monohydric or polyhydric alcohols and polyethylene glycols, monohydric aliphatic alcohols having 1 to 20 carbon atoms, or glycols, glycerol, diethylene Glycol, 1,2-propyl Glycol, a sorbitol carbon atoms, such as polyhydric alcohol having 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 solvate 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 1

4-Chloro-5-methoxy-2H-pyridazin-3-one

Dissolve 1.65 g of 4,5-dichloro-2H-pyridazin-3-one in 15 ml of a 5: 1 methanol / water mixed solvent, add 5.52 g of potassium carbonate, stir and reflux for 24 hours, and then cool to room temperature. And hydrochloric acid was slowly added dropwise to the reaction solution to adjust to pH 5. The resulting white solid was filtered under reduced pressure, washed with diethyl ether at 0 ° C., washed with normal hexane and dried to obtain 1.4 g of 4-chloro-5-methoxy-2H-pyridazin-3-one (yield: 87%).

¹ H-NMR (400 MHz, DMSO) δ 13.36 (s, 1H), 8.23 (s, 1H), 4.09 (s, 3H)

Reference Example 2

4-Chloro-5-methoxy-2-phenyl-2H-pyridazin-3-one

1.6 g of 4-chloro-5-methoxy-2H-pyridazin-3-one prepared in Reference Example 1 was dissolved in 20 ml of dichloromethane, and 2.44 g of phenylboronic acid, 2.72 g of kappaacetate and 1.6 ml of pyridine were added thereto. . After adding a small amount of molecular sieve (molecular sieve) to the drying tube and the reaction solution was stirred for 48 hours at room temperature. After completion of the reaction, the solvent was removed by distillation under reduced pressure, purified by flash column chromatography (developing solvent: normal hexane / ethyl acetate = 2/1), and 4-chloro-5-methoxy-2-phenyl-2H-pyridazine- 1.47 g of 3-one were obtained (yield: 62%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.58 (m, 2H), 7.50 (m, 3H), 4.15 (s, 3H)

MS (EI, M ⁺ ) 236

Reference Example 3

4-Chloro-5-methoxy-2-p-tolyl-2H-pyridazin-3-one

The title compound 4-chloro-5-methoxy-2- was reacted in the same manner as in Reference Example 2, except that 1.36 g of p-tolylboronic acid was used instead of phenylboronic acid in Reference Example 2. 1.89 g of p-tolyl-2H-pyridazin-3-one were obtained (yield: 73%).

MS (EI, M ⁺ ) 250

Reference Example 4

4-Chloro-5-methoxy-2- (4-methoxyphenyl) -2H-pyridazin-3-one

The title compound 4-chloro-5-methoxy- was reacted in the same manner as in Reference Example 2, except that 1.52 g of 4-methoxyphenylboronic acid was used instead of phenylboronic acid in Reference Example 2. 1.55 g of 2- (4-methoxyphenyl) -2H-pyridazin-3-one were obtained (yield: 58%). It was used for the next reaction without further confirmation.

Reference Example 5

4-Chloro-2- (4-fluorophenyl) -5-methoxy-2H-pyridazin-3-one

The title compound 4-chloro-2- (4- was reacted in the same manner as in Reference Example 2, except that 1.40 g of 4-fluorophenylboronic acid was used instead of phenylboronic acid in Reference Example 2. 1.63 g of fluorophenyl) -5-methoxy-2H-pyridazin-3-one were obtained (yield: 64%). It was used for the next reaction without further confirmation.

Reference Example 6

5-chloro-6-hydroxy-1-phenyl-1H-pyridazin-4-one

2.37 g of 4-chloro-5-methoxy-2-phenyl-2H-pyridazin-3-one prepared in Reference Example 2 was dissolved in 13 ml of morpholine and stirred at 100 ° C. for 3 hours. After completion of the reaction, morpholine was removed under reduced pressure. The reaction was adjusted to pH 13 with 1N aqueous sodium hydroxide solution, washed with dichloromethane to remove impurities, and the water layer was adjusted to pH 3 with 1N hydrochloric acid. After extraction with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.67 g of 5-chloro-6-hydroxy-1-phenyl-1H-pyridazin-4-one (yield: 75%).

¹ H-NMR (300 MHz, MeOD) δ 7.89 (s, 1 H), 7.48-7.53 (m, 5 H)

Reference Example 7

5-Chloro-6-hydroxy-1-p-tolyl-1 H-pyridazin-4-one

4-Chloro-5-methoxy-2-p-tolyl- prepared in Reference Example 3 instead of 4-chloro-5-methoxy-2-phenyl-2H-pyridazin-3-one in Reference Example 6 above The title compound 5-chloro-6-hydroxy-1-p-tolyl-1H-pyri was reacted in the same manner as in Reference Example 6 except that 2.51 g of 2H-pyridazin-3-one was used. 1.71 g of dazin-4-one were obtained (yield: 72%).

¹ H-NMR (300 MHz, MeOD) δ 7.89 (s, 1H), 7.39 (d, 2H, J = 9.0 Hz), 7.31 (d, 2H, J = 9.0 Hz), 2.41 (s, 3H)

Reference Example 8

5-chloro-6-hydroxy-1- (4-methoxyphenyl) -1H-pyridazin-4-one

4-chloro-5-methoxy-2- (4-methoxy) prepared in Reference Example 4 instead of 4-chloro-5-methoxy-2-phenyl-2H-pyridazin-3-one in Reference Example 6 Reaction in the same manner as in Reference Example 6, except that 2.67 g of methoxyphenyl) -2H-pyridazin-3-one was used to give the title compound 5-chloro-6-hydroxy-1- (4- 1.85 g of methoxyphenyl) -1H-pyridazin-4-one were obtained (yield: 73%).

¹ H-NMR (300 MHz, MeOD) δ 7.89 (s, 1H), 7.43 (d, 2H, J = 9.0 Hz), 7.04 (d, 2H, J = 9.0 Hz), 3.87 (s, 3H)

Reference Example 9

5-chloro-1- (4-fluorophenyl) -6-hydroxy-1H-pyridazin-4-one

4-Chloro-2- (4-fluorophenyl) -5 prepared in Reference Example 5 instead of 4-chloro-5-methoxy-2-phenyl-2H-pyridazin-3-one in Reference Example 6 The title compound 5-chloro-1- (4-fluorophenyl)-in solid phase was reacted in the same manner as in Reference Example 6, except that 2.55 g of methoxy-2H-pyridazin-3-one was used. 1.88 g of 6-hydroxy-1H-pyridazin-4-one were obtained (yield: 78%).

¹ H-NMR (300 MHz, MeOD) δ 7.91 (s, 1 H), 7.57-7.59 (m, 2 H), 7.23-7.26 (m, 2 H)

Reference Example 10

6-hydroxy-1-phenyl-1H-pyridazin-4-one

2.23 g of 5-chloro-6-hydroxy-1-phenyl-1H-pyridazin-4-one prepared in Reference Example 6 was dissolved in 30 ml of ethanol, and 0.53 g of 10% Pd / C and 2.8 ml of TEA were added thereto. High pressure (10 psig) hydrogenation was performed at room temperature for 18 hours. After completion of the reaction, the reaction solution was filtered through Celite to remove Pd / C, and distilled under reduced pressure to remove the solvent. 1N hydrochloric acid was added and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and distilled under reduced pressure to obtain 1.65 g of 6-hydroxy-1-phenyl-1H-pyridazin-4-one (yield: 88%).

¹ H-NMR (300 MHz, MeOD) δ 8.10 (s, 1H), 7.51 (m, 5H), 6.93 (s, 1H)

Reference Example 11

6-hydroxy-1-p-tolyl-1H-pyridazin-4-one

5-Chloro-6-hydroxy-1-p-tolyl- produced in Reference Example 7 instead of 5-chloro-6-hydroxy-1-phenyl-1H-pyridazin-4-one in Reference Example 10 above The title compound 6-hydroxy-1-p-tolyl-1H-pyridazine-4- in solid phase was reacted in the same manner as in Reference Example 10 except that 2.37 g of 1H-pyridazin-4-one was used. One obtained 1.86 g (yield: 92%).

¹ H-NMR (300 MHz, MeOD) δ 7.82 (s, 1H), 7.36 (d, 2H, J = 9.0 Hz), 7.29 (d, 2H, J = 9.0 Hz), 6.18 (s, 1H), 2.40 ( s, 3 H)

Reference Example 12

6-hydroxy-1- (4-methoxyphenyl) -1H-pyridazin-4-one

5-Chloro-6-hydroxy-1- (4-meth) prepared in Reference Example 8 instead of 5-chloro-6-hydroxy-1-phenyl-1H-pyridazin-4-one in Reference Example 10 The title compound 6-hydroxy-1- (4-methoxyphenyl) was reacted in the same manner as in Reference Example 10, except that 2.52 g of methoxyphenyl) -1H-pyridazin-4-one was used. 1.85 g of -1H-pyridazin-4-one were obtained (yield: 85%).

¹ H-NMR (300 MHz, MeOD) δ 7.81 (s, 1H), 7.39 (d, 2H, J = 9.0 Hz), 7.02 (d, 2H, J = 9.0 Hz), 6.18 (s, 1H), 3.85 ( s, 3 H)

Reference Example 13

1- (4-fluorophenyl) -6-hydroxy-1H-pyridazin-4-one

5-Chloro-1- (4-fluorophenyl) -6 prepared in Reference Example 9 instead of 5-chloro-6-hydroxy-1-phenyl-1H-pyridazin-4-one in Reference Example 10 The title compound 1- (4-fluorophenyl) -6-hydroxy in solid phase was reacted in the same manner as in Reference Example 10, except that 2.41 g of -hydroxy-1H-pyridazin-4-one was used. 1.87 g of -1H-pyridazin-4-one were obtained (yield: 91%).

¹ H-NMR (300 MHz, MeOD) δ 7.83 (s, 1 H), 7.53-7.55 (m, 2 H), 7.20-7.24 (m, 2H), 6.18 (s, 1 H).

Reference Example 14

Trifluoromethanesulfonic acid 5-oxo-2-phenyl-2,5-dihydro-pyridazin-3-yl ether

1.88 g of 6-hydroxy-1-phenyl-1H-pyridazin-4-one prepared in Reference Example 10 was dissolved in 30 ml of dichloromethane under nitrogen atmosphere and cooled to 0 ° C. 1.83 g of 4-dimethylaminopyridine and 3.52 g of tricyclic anhydride were slowly added dropwise under a nitrogen atmosphere, and then the reaction temperature was raised to room temperature and stirred for 1 hour. The organic layer was washed with 1N aqueous sodium hydroxide solution and 1N hydrochloric acid, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give trifluoromethanesulfonic acid trifluoro-methanesulfonic acid 5-oxo-2-phenyl-2,5- 2.98 g of dihydro-pyridazin-3-yl ether were obtained (yield: 93%). It was used for the next reaction without any other confirmation.

Reference Example 15

Trifluoromethanesulfonic acid 5-oxo-2-p-tolyl-2,5-dihydro-pyridazin-3-yl ether

6-hydroxy-1-p-tolyl-1H-pyridazin-4-one prepared in Reference Example 11 instead of 6-hydroxy-1-phenyl-1H-pyridazin-4-one in Reference Example 14 The reaction was carried out in the same manner as in Reference Example 14 except that 2.02 g was used to give the title compound trifluoro-methanesulfonic acid 5-oxo-2-p-tolyl-2,5-dihydro-pyridazine- in solid phase. 3.04 g of 3-day ether were obtained (yield: 91%). It was used for the next reaction without any other confirmation.

Reference Example 16

Trifluoromethanesulfonic acid 5-oxo-2- (4-methoxyphenyl) -2,5-dihydro-pyridazin-3-yl ether

6-hydroxy-1- (4-methoxyphenyl) -1H-pyridazine prepared in Reference Example 12 instead of 6-hydroxy-1-phenyl-1H-pyridazin-4-one in Reference Example 14 Reaction was carried out in the same manner as in Reference Example 14, except that 2.18 g of 4-one was used to give the title compound trifluoromethanesulfonic acid 5-oxo-2- (4-methoxyphenyl) -2 as a solid, 3.04 g of 5-dihydro-pyridazin-3-yl ether were obtained (yield: 90%). It was used for the next reaction without any other confirmation.

Reference Example 17

Trifluoromethanesulfonic acid 5-oxo-2- (4-fluorophenyl) -2,5-dihydro-pyridazin-3-yl ether

1- (4-fluoro-phenyl) -6-hydroxy-1H-pyri prepared in Reference Example 13 instead of 6-hydroxy-1-phenyl-1H-pyridazin-4-one in Reference Example 14 The reaction was carried out in the same manner as in Reference Example 14, except that 2.06 g of dazin-4-one was used to give the title compound trifluoromethanesulfonic acid 5-oxo-2- (4-fluorophenyl) -2 as a solid, 3.14 g of 5-dihydro-pyridazin-3-yl ether were obtained (yield: 93%). It was used for the next reaction without any other confirmation.

Reference Example 18

6- (4-methylthiophenyl) -1-phenyl-1H-pyridazin-4-one

3.20 g of trifluoromethanesulfonic acid 5-oxo-2-phenyl-2,5-dihydro-pyridazin-3-yl ether prepared in Reference Example 14 was dissolved in 60 ml of toluene under a nitrogen atmosphere, and 4-methylthio 2.52 g of phenyl boronic acid, 0.35 g of tetrakis triphenylphosphine palladium and 2.07 g of potassium carbonate were added thereto, followed by stirring and refluxing for 2 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate and washed sequentially with saturated sodium bicarbonate, 10% aqueous citric acid solution and water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, purified by flash column chromatography (developing solvent: normal hexane / ethyl acetate = 2/1), and purified with 6- (4-methylthiophenyl) -1-phenyl-1H-pyridine. 1.79 g of dazin-4-one were obtained (yield: 61%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.21 (s, 1H), 7.67 (d, 2H, J = 9.0 Hz), 7.53 (d, 2H, J = 9.0 Hz), 7.50-7.52 (m, 2H) , 7.40-7.42 (m, 3H), 7.19 (s, 1H), 2.56 (s, 3H)

Reference Example 19

6- (4-methylthiophenyl) -1-p-tolyl-1H-pyridazin-4-one

Trifluoromethanesulfonic acid 5-oxo-prepared in Reference Example 15 instead of trifluoromethanesulfonic acid 5-oxo-2-phenyl-2,5-dihydro-pyridazin-3-yl ether in Reference Example 18 The title compound 6- (4-methyl in solid phase was reacted in the same manner as in Reference Example 18, except that 3.34 g of 2-p-tolyl-2,5-dihydro-pyridazin-3-yl ether was used. 1.94 g of thiophenyl) -1-p-tolyl-1H-pyridazin-4-one were obtained (yield: 63%).

MS (EI, M ⁺ ) 308

Reference Example 20

6- (4-methylthiophenyl) -1- (4-methoxyphenyl) -1H-pyridazin-4-one

Trifluoromethanesulfonic acid 5-oxo-prepared in Reference Example 16 instead of trifluoromethanesulfonic acid 5-oxo-2-phenyl-2,5-dihydro-pyridazin-3-yl ether in Reference Example 18 The title compound 6- in solid phase was reacted in the same manner as in Reference Example 18, except that 3.50 g of 2- (4-methoxyphenyl) -2,5-dihydro-pyridazin-3-yl ether was used. 1.91 g of (4-methylthiophenyl) -1- (4-methoxyphenyl) -1H-pyridazin-4-one were obtained (yield: 59%).

MS (EI, M ⁺ ) 324

Reference Example 21

6- (4-methylthiophenyl) -1- (4-fluorophenyl) -1H-pyridazin-4-one

Trifluoromethanesulfonic acid 5-oxo-prepared in Reference Example 17 instead of trifluoromethanesulfonic acid 5-oxo-2-phenyl-2,5-dihydro-pyridazin-3-yl ether in Reference Example 18 The title compound 6- in solid phase was reacted in the same manner as in Reference Example 18, except that 3.38 g of 2- (4-fluorophenyl) -2,5-dihydro-pyridazin-3-yl ether was used. 2.15 g of (4-methylthiophenyl) -1- (4-fluorophenyl) -1H-pyridazin-4-one were obtained (yield: 69%).

MS (EI, M ⁺ ) 312

Example 1

6- (4-methanesulfonylphenyl) -1-phenyl-1H-pyridazin-4-one

320 mg (1.0 mmol) of 6- (4-methylthiophenyl) -1-phenyl-1H-pyridazin-4-one prepared in Reference Example 18 was dissolved in 10 ml of dichloromethane, and 3-chloroperbenzoic acid was added thereto. 690 mg was added under a nitrogen atmosphere and then stirred at room temperature for 8 hours. After completion of the reaction, the reaction solution was washed three times with 1 N aqueous sodium hydroxide solution and then completely removed with anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure, followed by flash column chromatography (developing solvent: dichloromethane / methanol = 30/1). ), 220 mg of a white solid 6- (4-methanesulfonylphenyl) -1-phenyl-1H-pyridazin-4-one was obtained (yield: 68%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.19 (s, 1H), 8.12 (d, 2H, J = 9.0 Hz), 7.84 (m, 2H), 7.65 (m, 2H), 7.48 (m, 3H) , 7.26 (s, 1 H), 3.12 (s, 3 H).

Example 2

6- (4-methanesulfonylphenyl) -1-p-tolyl-1H-pyridazin-4-one

6- (4-methylthiophenyl) -1-p- prepared in Reference Example 19 instead of 6- (4-methylthiophenyl) -1-phenyl-1H-pyridazin-4-one in Example 1 The reaction was carried out in the same manner as in Example 1, except that 308 mg (1.0 mmol) of tolyl-1H-pyridazin-4-one was used to obtain 210 mg (yield 62%) of the title compound as a solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 8.07 (d, 2H, J = 9.0 Hz), 8.04 (d, 2H, J = 9.0 Hz), 7.46 (d, 2H, J = 9.0 Hz), 7.23 (d, 2H, J = 9.0 Hz), 7.15 (s, 1H), 3.05 (s, 3H), 2.35 (s, 3H)

Example 3

6- (4-methanesulfonylphenyl) -1- (4-methoxyphenyl) -1H-pyridazin-4-one

6- (4-methylthiophenyl) -1- (4 prepared in Reference Example 20 instead of 6- (4-methylthiophenyl) -1-phenyl-1H-pyridazin-4-one in Example 1 206 mg (yield 58%) of the title compound in the solid phase were reacted in the same manner as in Example 1 except that 324 mg (1.0 mmol) of -methoxyphenyl) -1H-pyridazin-4-one was used. Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.80 (d, 2H, J = 9.0 Hz), 7.69 (d, 2H, J = 9.0 Hz), 7.65 (d, 2H, J = 9.0 Hz), 7.47 (d, 2H, J = 9.0 Hz), 7.03 (s, 1H), 3.86 (s, 3H), 3.12 (s, 3H)

Example 4

6- (4-methanesulfonylphenyl) -1- (4-fluorophenyl) -1H-pyridazin-4-one

6- (4-methylthiophenyl) -1- (4 prepared in Reference Example 21 instead of 6- (4-methylthiophenyl) -1-phenyl-1H-pyridazin-4-one in Example 1 The title compound 6- (4-methanesulfonyl in solid phase was reacted in the same manner as in Example 1 except that 312 mg (1.0 mmol) of -fluorophenyl) -1H-pyridazin-4-one was used. 203 mg (59% yield) of phenyl) -1- (4-fluorophenyl) -1H-pyridazin-4-one were obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.18 (s, 1H), 8.11 (d, 2H, J = 9.0 Hz), 8.82 (d, 2H, J = 9.0 Hz), 7.65-7.66 (m, 2H) , 7.21-7.23 (m, 2H), 7.18 (s, 1H), 3.14 (s, 3H)

Example 5

4- (5-Oxo-2-phenyl-2,5-dihydro-pyridazin-3-yl) -benzenesulfonamide

326 mg (1.0 mmol) of 6- (4-methanesulfonylphenyl) -1-phenyl-1H-pyridazin-4-one prepared in Example 1 was dissolved in 15 ml of tetrahydrofuran under a nitrogen atmosphere, and the reaction solution was Cooled to -78 ° C. After 1.5 ml of 2.0 mol lithium diisopropylamine tetrahydrofuran solution was slowly added dropwise, the reaction temperature was raised to 0 ° C. and 0.22 ml of methyl iodide trimethylsilane was added. The reaction temperature was slowly raised to room temperature and stirred for 24 hours. The reaction solution was diluted with ethyl acetate and washed with 1N hydrochloric acid. The mixture was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, purified by flash column chromatography (developing solvent: normal hexane / ethyl acetate = 1/1), and dried in vacuo. The intermediate thus obtained was dissolved in 15 ml of tetrahydrofuran, and 3 ml of 1.0 mol tetrahydrofuran solution of tetrabutylammonium fluoride was added dropwise, followed by heating to reflux for 1 hour. After the reaction temperature was lowered to room temperature, 410 mg of sodium acetate was dissolved in 3 ml of water, and 555 mg of hydroxyamine-O-sulfonic acid was added thereto, followed by stirring for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with sodium bicarbonate, water and saturated brine in that order. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure and purified by flash column chromatography (developing solvent: ethyl acetate / methanol = 1/1) to give a white solid 4- (5-oxo-2-phenyl-2,5-di. 141 mg of hydro-pyridazin-3-yl) -benzenesulfonamide were obtained (yield: 43%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.19 (s, 1H), 8.12 (d, 2H, J = 9.0 Hz), 7.84 (m, 2H), 7.65 (m, 2H), 7.48 (m, 3H) , 7.26 (s, 1 H), 7.24 (s, 2 H, br)

Experimental Example

Determination of Selective Inhibitory Activity on Cyclooxygenase-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.

end. Screening of Inhibitory Effect of Cyclooxygenase-1 Using U-937

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 (Hanks balanced salt solution). Dispense 1 ml for each well of the well plate. 5 μl of DMSO and 5 μl each of the sample solution diluted in 1 μM and dissolved in DMSO were 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 tube and 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.

I. Screening of Cyclooxygenase-2 Inhibitory Effect Using Raw 264.7 Cell Line

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) Experiment result

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%

Cyclooxygenase (COX) Inhibitory Effect (% inhibition) compound COX-1 (1 μM) COX-2 (1 nM) Reference substance (Valdecoxib) 28.8 5.47 Example 1 26.7 5.83 Example 2 17.8 6.37 Example 3 21.3 4.19 Example 4 18.6 16.8 Example 5 39.6 16.3

3) Evaluation

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

The ratio of percent inhibition of cyclooxygenase-2 to percent inhibition of cyclooxygenase-1 in Examples 1-5 was found to be nearly equal or significantly better than the valdecoxib. This indicates that the selective inhibitory effect of cyclooxygenase-2 on cyclooxygenase-1 is about the same or significantly better than the reference material. In particular, in the case of 6- (4-chlorophenyl) -5- (4-methanesulfonylphenyl) -1H-pyridazin-4-one of Example 4, the inhibitory effect of cyclooxygenase-2 was shown as a reference substance (valdecoxib). At the same time, the inhibitory effect of cyclooxygenase-1 was significantly lower than that of, and proved to be excellent in selectivity.

In addition, except for Example 3, all of the cyclooxygenase-2 showed a significantly higher inhibitory effect than the reference material. These results indicate that the improved selectivity not only improved side effects than the reference material, but also improved antipyretic analgesic effect.

According to the present invention, the side effects of the conventional nonsteroidal anti-inflammatory drugs have been improved, and thus can be usefully used in patients with peptic ulcer, gastritis, partial enteritis, ulcerative colitis, diverticulitis, gastrointestinal bleeding or hypothrombinemia, etc. A pyridazin-4-one derivative having an analgesic and anti-inflammatory effect, or a non-toxic salt thereof, a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient can be provided.

Claims (7)

A pyridazin-4-one derivative represented by the following formula (1) or a nontoxic salt thereof: [Formula 1]

In Chemical Formula 1, R ¹ is phenyl; Phenyl substituted with C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, or halogen, R ² is methyl or amino. delete The method of claim 1, 6- (4-methanesulfonylphenyl) -1-phenyl-1H-pyridazin-4-one; 6- (4-methanesulfonylphenyl) -1-p-tolyl-1H-pyridazin-4-one; 6- (4-methanesulfonylphenyl) -1- (4-methoxyphenyl) -1H-pyridazin-4-one; 1- (4-fluorophenyl) -6- (4-methanesulfonylphenyl) -1H-pyridazin-4-one; And A pyridazin-4-one derivative or non-toxic salt thereof selected from the group consisting of 4- (5-oxo-2-phenyl-2,5-dihydro-pyridazin-3-yl) -benzenesulfonamide. A pyridazine derivative represented by the following formula (8): [Formula 8]

In the above, R ¹ is as defined in claim 1. A pharmaceutical composition having an antipyretic, analgesic, anti-inflammatory effect, containing a therapeutically effective amount of a pyridazin-4-one derivative according to claim 1 or a non-toxic salt thereof as an active ingredient and a pharmaceutically acceptable carrier. delete delete