KR20030046086A - Catechol pyrazole derivatives, the methods of preparing them and the pharmaceutical composition comprising them - Google Patents

Abstract

PURPOSE: Catechol pyrazole derivatives, a preparation process thereof and a pharmaceutical composition containing the same are provided, thereby inhibiting phosphodiesterase IV(PDE IV) or tumor necrosis factor(TNF), so that various diseases associated with PDE IV or TNF can be effectively treated. CONSTITUTION: Catechol pyrazole derivatives represented by formula(1) and pharmaceutically acceptable salts thereof are provided, wherein R1 is methyl; R2 is C3-C7 cycloalkyl; R3 is hydrogen or alkyl, C1-C7 cycloalkyl or phenyl; and R4 is alkyl, 1 to 3 halogens substituted methyl, methyl ester or carboxylic acid. A process for preparing catechol pyrazole derivatives comprises the steps of: reacting benzaldehyde(2) of which a hydroxyl group at C3 site is substituted by R1 with R2-A to prepare benzaldehyde(3) of which two hydroxyl groups are substituted by R1 and R2, respectively; reacting the benzaldehyde(3) with a compound selected from trifluoroacetate, ethyl difluoroacetate, ethyl fluoroacetate, diethyloxalate and dimethyloxalate to prepare dicarbonyl compound(4); and reacting the dicarbonyl compound(4) with alkylhydrazine to prepare a compound(1).

Description

Catechol pyrazole derivatives, the methods of preparing them and the pharmaceutical composition comprising them}

The present invention relates to a novel catechol pyrazole derivative having an inhibitory effect on phosphodiesterase (PDE) or Tumor Necrosis Factor (TNF), a preparation method thereof, and a pharmaceutical composition containing the same. will be.

Phosphodiesterases are enzymes that hydrolyze cyclic nucleotides as one of the chemical transporters. In particular phosphodiesterase IV is an enzyme that selectively hydrolyzes cyclic adenosine 3 ′, 5′-monophosphate to inactive adenosine 3 ′, 5′-monophosphate.

Cyclic adenosine 3 ', 5'-monophosphate is a second messenger responsible for regulating cellular response to external cellular stimulation, and also relaxes the bronchial muscles and inhibits the immune and inflammatory responses. It works.

Therefore, compounds that inhibit phosphodiesterase IV, an enzyme that hydrolyzes cyclic adenosine 3 ', 5'-monophosphate to adenosine 3', 5'-monophosphate, are cyclic adenosine 3 ', 5'-monophosphate Maintaining the concentration of bronchial spasms can be prevented and, in addition, anti-inflammatory action. Therefore, compounds that inhibit phosphodiesterase IV are useful as therapeutic agents for asthma or inflammatory agents.

TNF has been known to be associated with many infections, including atherosclerosis, and autoimmune diseases, which have been shown to be the major mediators of the inflammatory response seen in sepsis and septic shock. Therefore, compounds that inhibit TNF are useful as inflammatory agents.

As described above, PDE IV is an enzyme that hydrolyzes cAMP. Inhibition of PDE IV eventually serves to increase intracellular cAMP, and the increase of cAMP eventually inhibits the production of various cytokines. Therefore, TNF, a type of cytokine, is also inhibited by this mechanism of action. Therefore, inhibition of TNF may be effective only by inhibiting PDE IV ( Biochemical Pharmacology, 2000, 59, 1323-1355, J.Med. Chem. 1998, 41, 821-835). . Previously, compounds having an inhibitory effect on phosphodiesterase IV or TNF have been published.

For example, a compound having a structure having a ketchol pyridazine nucleus has been reported.

Merck reported in WO 00-26201 a novel catechol pyridazine compound that introduces a pyridazine structure to the basic structure of 3-methoxy-4-cyclopentoxy, the parent of catechol ethers.

[Formula A]

In the above formula,

B includes an unsubstituted phenyl ring or a phenyl ring substituted with R ₃ , Q is a C ₁ to C ₄ alkylene group, R ₁ and R ₂ are —OR ₄ , -SR ₄ , SO-R ₄ or -SO ₂ -R ₄ , R ₃ are R ₄ , halogen, OH, OR ₄ , OPh, NO ₂ , NHR ₄ , N (R ₄ ) ₂ , NHCOR ₄ , NHSOR ₄ , or NHCOOR ₄ groups, R ₄ is -(C ₃ -C ₇ ) cycloalkyl, alkylenecycloalkyl of (C ₅ -C ₁₀ ), alkenyl group of (C ₂ -C ₈ ), and halogen is F, Cl, Br or I group. Applicant CheilJedang reported the synthesis of catechol hydrazone derivatives such as [Formula B] below with the basic structure of 3-methoxy-4-cyclopentyloxy, the parent nucleus of cathechol ether, in WO 00/73280.

[Formula B]

Where

R ₁ is C ₁ -C ₇ alkyl or C ₃ -C ₇ cycloalkyl, R ₂ is hydrogen, hydroxy, C ₁ -C ₅ alkyl or CH ₂ CH ₂ C (═O) NH ₂ group, R ₃ And R ₄ is independently hydrogen, C ₁ -C ₇ alkyl, C (= X) -R ₅ , or 2-, 3- or 4-pyridyl, pyrimidyl or halogen, (C ₁ -C ₆ ) alkoxy, Phenyl group substituted with nitro, trifluoromethyl, (C ₁ -C ₆ ) alkyl, etc., X is oxygen, sulfur or NH group, R ₅ is (C ₁ -C ₇ ) alkyl, -NHR ₆ , CONH ₂ or 2-, 3- or 4-pyridyl, pyrimidyl group, R ₆ is hydrogen, hydroxy, C ₁ -C ₅ alkyl, (C ₁ -C ₆ ) alkoxy, pyridyl, phenyl group.

As described above, a compound having an inhibitory effect on PDE IV or TNF has already been reported, but as the compound is structurally different from the present invention, in the present invention, the catechol pyrazole derivative has an inhibitory effect on PDE IV or TNF. It was found that the present invention has been completed.

It is an object of the present invention to provide novel catechol pyrazole derivatives and their pharmaceutically acceptable salts.

It is another object of the present invention to provide a method for producing the novel catechol pyrazole derivatives.

In addition, in the present invention by having an inhibitory effect on PDE IV or TNF, asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease, psoriasis, allergic rhinitis, dermatitis and AIDS, HIV, Crohn's disease, sepsis, sepsis shock It is an object of the present invention to provide a pharmaceutical composition containing a catechol pyrazole derivative which is effective for treating diseases including other inflammatory diseases such as atherosclerosis, and production of TNF.

In order to achieve the above object, the present invention provides catechol pyrazole derivatives represented by the following formula (I) and pharmaceutically acceptable salts thereof.

In Chemical Formula 1,

R ₁ is a methyl group;

R ₂ is (C ₃ -C ₇ ) cycloalkyl;

R ₃ is hydrogen or alkyl, (C ₁ -C ₇ ) cycloalkyl or phenyl;

R ₄ is alkyl, methyl, methyl ester or carboxylic acid substituted with 1 to 3 halogens.

In order to achieve another object of the present invention, the present invention provides a method for producing a catechol pyrazole derivative represented by the above [Formula 1] comprising a reaction process as shown in the following [Reaction Scheme 1].

The catechol pyrazole derivatives represented by [Formula 1] of the present invention may be prepared through a reaction process such as the following [Scheme 1]. [Scheme 1] is to react the benzaldehyde (2) in which the hydroxyl group at position 3 is substituted with R ₁ with a reaction reagent designated as R ₂ -A to replace two hydroxyl groups with R ₁ , R ₂ The first step of synthesizing the benzaldehyde (3), the benzaldehyde (3) is selected from the group consisting of ethyl trifluoroacetate, ethyl difluoro acetate, ethyl floroacetate, diethyl oxalate and dimethyl oxalate A second step of synthesizing the dicarbonyl compound (4) by reacting with any one compound and a third step of synthesizing the desired compound (1) by reacting the dicarbonyl compound (4) with alkylhydrazine do.

In Scheme 1,

R ₁ is a methyl group;

R ₂ is (C ₃ -C ₇ ) cycloalkyl;

R ₃ is hydrogen or alkyl, (C ₁ -C ₇ ) cycloalkyl or phenyl;

R ₄ is alkyl, methyl, methyl ester or carboxylic acid substituted with 1 to 3 halogens.

Hereinafter, the reaction scheme 1, which is a method of preparing the compound of [Formula 1], will be described in detail.

The reaction reagent specified in R ₂ -A a benzaldehyde (2) substituted by a hydroxy group R ₁ of the first-step reaction, the 3-position under anhydrous N, N- dimethylformamide solvent in the presence of anhydrous potassium carbonate carbon By inducing the reaction, benzaldehyde (3) having two hydroxyl groups substituted with R ₁ and R ₂ is synthesized.

In the reaction, A means halogen such as chloro, bromo, iodo and the like. In the second stage reaction, benzaldehyde (3) in which the hydroxyl group prepared in the first stage is substituted with R ₁ and R ₂ is replaced with ethyl trifluoroacetate, ethyl difluoro acetate, ethyl fluoroacetate, and diethyl oxalate. And refluxing for 3 to 24 hours in the presence of a base in an alcohol solvent with any one compound selected from the group consisting of dimethyl oxalate to synthesize dicarbonyl compound (4).

As the alcohol solvent in the second step reaction, methanol or ethanol is preferable, methanol is most suitable, and the reaction time is preferably 7 to 12 hours. As the base used in the reaction, other bases can generally be used, but 25% sodium methoxide methanol solution has obtained the best yield.

In the third stage reaction, the dicarbonyl compound (4) synthesized in the second stage reaction is refluxed for 5 to 20 hours in the presence of alkylhydrazine in an alcohol solvent to obtain the target compound (1).

Ethanol is preferred as the alcohol solvent in the third reaction.

In order to achieve another object of the present invention, the present invention provides a PDE IV comprising a therapeutically effective amount of a compound of Formula 1, a pharmaceutically acceptable salt thereof or a mixture thereof in combination with a pharmaceutically acceptable carrier or Provided is a pharmaceutical composition having an inhibitory effect on TNF.

Since these pharmaceutical compositions contain the above catechol pyrazole derivatives, they have an inhibitory effect on phosphodiesterase IV or tumor tract factors, thereby asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease, psoriasis and allergic rhinitis. , Dermatitis and other inflammatory diseases such as AIDS, HIV, Crohn's disease, sepsis, septic shock, ecstasy and the production of TNF.

The pharmaceutical composition is generally administered to the adult 1mg / kg to 10mg / kg based on the compound of formula (1) or salts thereof as the active ingredient, can be increased or decreased depending on the severity of the disease.

The pharmaceutical composition may be 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 and infusions, suspensions It may be administered in the form of 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 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, lycopodium, silicic acid, calcium hydrogen phosphate, cellulose, cellulose derivatives such as methoxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose 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, diethylene Esters of aliphatic saturated or unsaturated fatty acids having 2 to 22 carbon atoms with polyhydric alcohols such as glycols, 1,2-propylene glycol, sorbitol, mannitol.

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].

The present invention will be described in detail with reference to the following examples, which should not be construed as limiting the invention thereto.

(Example)

Example 1 Preparation of Intermediates

Intermediate 1

1- (4-cyclopentyloxy-3-methoxy-phenyl) -ethanone

10 g of 1- (4-hydroxy-3-methoxy-phenyl) ethanone is added to 100 ml of N, N-dimethylformamide and dissolved. 12.5 g of anhydrous potassium carbonate and 0.5 g of potassium iodide were added and stirred at 65 ° C. for 5 minutes, and then 8.4 ml of cyclophenyl bromide was added dropwise for 1 hour, followed by stirring at 65 ° C. for 1 day. After the temperature was lowered to room temperature, toluene (500 ml) was added to the mixed solution, and the mixture was diluted, and then washed with 1 M sodium hydroxide (2 × 0.5 L). The obtained aqueous layer solution was extracted with toluene (200 ml), and the obtained organic layer was washed with distilled water (2 × 0.5 L). The organic layer was dried and concentrated to give a light brown oily title compound (12 g).

¹ H NMR (400 MHz, CDCl ₃ ,)

1.60 ~ 1.96 (m, 8H), 2.5 (s, 3H), 3.89 (s, 3H), 4.84 (m, 1H), 6.89 (d, 1H), 7.51 (m, 2H)

Intermediate 2

1- (4-cyclopentyloxy-3-methoxy-phenyl) -4,4,4-trifluoro-3-hydroxy-buten-2-one

Dissolve 1 g of 1- (4-cyclopentyloxy-3-methoxy-phenyl) -ethanone synthesized in Reference Example 1 in 10 ml of methanol, add 2.1 ml of 25% sodium methoxide methanol solution, stir for 5 minutes, and then 0.3 ml of low acetate was added and then refluxed for 1 day. The solvent was removed by distilling under reduced pressure to room temperature. 5 ml of 10% hydrochloric acid solution was added, followed by extraction with 10 ml of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure and recrystallized with ethanol to obtain the title compound (0.87 g) as yellow.

¹ H NMR (400 MHz, DMSO-d ₆ , δ)

: 1.58 ~ 1.92 (m, 8H), 3.79 (s, 3H), 5.02 (m, 1H), 6.22 (s, 1H), 6.95 (d, 1H), 7.48 (s, 1H), 7.58 (d, 1H )

Intermediate 3

4- (4-cyclopentyloxy-3-methoxy-phenyl) -2-hydroxy-4-oxo-buten-2-non

6 g of 1- (4-cyclopentyloxy-3-methoxy-phenyl) -ethanone synthesized in Reference Example 1 was added to 60 ml of methanol and dissolved. 8.3 ml of 25% sodium methoxide methanol solution was added thereto, stirred for 5 minutes, and 3.6 g of dimethyl oxalate was added thereto, followed by refluxing for 1 day. The solvent was removed by distilling under reduced pressure to room temperature. 30 ml of 10% hydrochloric acid solution was added, followed by extraction with 100 ml of ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure and recrystallized with ethanol to obtain a white title compound (4.8 g).

¹ H NMR (400 MHz, CDCl ₃ , δ)

: 1.64 ~ 1.99 (m, 8H), 3.92 (s, 3H), 3.94 (s, 3H), 4.88 (m, 1H), 6.91 (d, 1H), 7.04 (s, 1H), 7.61 (s, 1H ), 7.82 (d, 1 H)

Example 2

3- (4-cyclopentyloxy-3-methoxy-phenyl) -5-trifluoromethyl-1H-pyrazole

10 ml of 1 g of 1- (4-cyclopentyloxy-3-methoxy-phenyl) -4,4,4-trifluoro-3-hydroxy-buten-2-one as intermediate 2 synthesized in Example 1 After dissolving in, 0.18 ml of hydrazine was added and stirred for 15 hours. The solvent was removed by distilling under reduced pressure to room temperature. 10 ml of ethyl acetate was added, washed with 5 ml of water, dried over anhydrous magnesium sulfate, filtered, the solvent was distilled off under reduced pressure, and then crystallized with 80% ethanol to give 3- (4-cyclopentyloxy-3-methoxy. -Phenyl) -5-trifluoromethyl-1H-pyrazole (0.79 g) was obtained.

Mass Spectrum, m / e = 327

Melting Point (M.P.) = 150 ~ 151 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ)

: 1.55 ~ 1.92 (m, 8H), 3.77 (s, 3H), 4.82 (m, 1H), 6.93 (d, 1H), 7.1 (d, 1H), 7.19 (s, 1H), 7.25 (s, 1H ), 7.60 (s, 1 H)

Example 3

3- (4-cyclopentyloxy-3-methoxy-phenyl) -1-methyl-5-trifluoromethyl-1H-pyrazole

10 ml of 1 g of 1- (4-cyclopentyloxy-3-methoxy-phenyl) -4,4,4-trifluoro-3-hydroxy-buten-2-one as intermediate 2 synthesized in Example 1 It was dissolved in and then 0.16 ml of methylhydrazine was added and stirred for 24 hours. The solvent was removed by distilling under reduced pressure to room temperature. 10 ml of ethyl acetate was added, washed with 5 ml of water, dried over anhydrous magnesium sulfate, filtered, the solvent was distilled off under reduced pressure, and then crystallized with 80% ethanol to give 3- (4-cyclopentyloxy-3-methoxy. -Phenyl) -1-methyl-5-trifluoromethyl-1H-pyrazole (0.84 g) was obtained.

Mass spectrum, m / e = 341.4

M.P. = 77 ~ 78 ℃

¹ H NMR (400 MHz, CDCl ₃ , δ)

: 1.64 ~ 2.16 (m, 8H), 3.87 (s, 3H), 3.96 (s, 3H), 4.82 (m, 1H), 6.50 (s, 1H), 6.87 ~ 6.99 (m, 3H)

Example 4

3- (4-cyclopentyloxy-3-methoxy-phenyl) -1-phenyl-5-trifluoromethyl-1H-pyrazole

10 ml of 1 g of 1- (4-cyclopentyloxy-3-methoxy-phenyl) -4,4,4-trifluoro-3-hydroxy-buten-2-one as intermediate 2 synthesized in Example 1 It was dissolved in and 0.37 ml of phenylhydrazine was added and stirred for 16 hours. The solvent was removed by distilling under reduced pressure to room temperature. 10 ml of ethyl acetate was added, washed with 5 ml of water, dried over anhydrous magnesium sulfate, filtered, the solvent was distilled off under reduced pressure, and then crystallized with 80% ethanol to give 3- (4-cyclopentyloxy-3-methoxy. -Phenyl) -1-phenyl-5-trifluoromethyl-1H-pyrazole (0.81 g) was obtained.

Mass spectrum, m / e = 403.4

M.P. = 132 ~ 134 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ)

: 1.59 ~ 1.93 (m, 8H), 3.83 (s, 3H), 5.16 (m, 1H), 7.21 (m, 2H), 7.29 ~ 7.63 (m, 6H), 8.18 (s, 1H)

Example 5

5- (4-cyclopentyloxy-3-methoxy-phenyl) -2H-pyrazole-3-carboxylic acid methyl ester

1 g of 4- (4-cyclopentyloxy-3-methoxy-phenyl) -2-hydroxy-4-oxo-buten-2-one, the intermediate 3 synthesized in Example 1, was dissolved in 10 ml of ethanol, and 0.18 ml of hydrazine. Was added and stirred for 8 hours. The solvent was removed by distilling under reduced pressure to room temperature. 10 ml of ethyl acetate was added, washed with 5 ml of water, dried over anhydrous magnesium sulfate, filtered, the solvent was distilled off under reduced pressure, and then crystallized with 80% ethanol to give the desired compound, 5- (4-cyclopentyloxy-3-methoxy. -Phenyl) -2H-pyrazole-3-carboxylic acid methyl ester (0.87 g) was obtained.

Mass Spectrum, m / e = 317.3

M.P. = 134 ~ 135 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ)

: 1.58 ~ 1.92 (m, 8H), 3.82 (d, 6H), 4.83 (m, 1H), 6.99 (d, 1H), 7.15 (s, 1H), 7.41 (m, 2H)

Example 6

5- (4-Cyclopentyloxy-3-methoxy-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid methyl ester

1 g of 4- (4-cyclopentyloxy-3-methoxy-phenyl) -2-hydroxy-4-oxo-buten-2-one, the intermediate 3 synthesized in Example 1 was dissolved in 10 ml of ethanol, and then 0.17 methylhydrazine. ml was added and stirred for 8 h. The solvent was removed by distilling under reduced pressure to room temperature. 10 ml of ethyl acetate was added, washed with 5 ml of water, dried over anhydrous magnesium sulfate, filtered, the solvent was distilled off under reduced pressure, and then crystallized with 80% ethanol to give the desired compound, 5- (4-cyclopentyloxy-3-methoxy. -Phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (1.03) g was obtained.

Mass spectrum, m / e = 331.4

M.P. = 88 ~ 89 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ)

: 1.58 ~ 1.89 (m, 8H), 3.80 (s, 3H), 3.87 (s, 3H), 4.12 (s, 3H), 4.80 (m, 1H), 3.96 (d, 1H), 7.29 (s, 1H ), 7.36 (d, 1H), 7.54 (s, 1H)

Example 7

5- (4-Cyclopentyloxy-3-methoxy-phenyl) -2-phenyl-2H-pyrazole-3-carboxylic acid methyl ester

1 g of 4- (4-cyclopentyloxy-3-methoxy-phenyl) -2-hydroxy-4-oxo-buten-2-one, the intermediate 3 synthesized in Example 1, was dissolved in 10 ml of ethanol, followed by phenylhydrazine 0.61 ml was added and stirred for 8 h. The solvent was removed by distilling under reduced pressure to room temperature. 10 ml of ethyl acetate was added, washed with 5 ml of water, dried over anhydrous magnesium sulfate, filtered, the solvent was distilled off under reduced pressure, and then crystallized with 80% ethanol to give the desired compound, 5- (4-cyclopentyloxy-3-methoxy. -Phenyl) -2-phenyl-2H-pyrazole-3-carboxylic acid methyl ester (1.2 g) was obtained.

Mass spectrum, m / e = 393.5

M.P. = 92 ~ 93 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ)

: 1.54 ~ 1.92 (m, 8H), 3.54 (s, 3H), 3.86 (s, 3H), 4.77 (m, 1H), 6.75 (dd, 1H), 6.77 (s, 1H), 6.88 (dd, 1H ), 7.12 (s, 1H), 7.36 (m, 2H), 7.49 (m, 3H)

Example 8

5- (4-Cyclopentyloxy-3-methoxy-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid

0.5 g of 5- (4-cyclopentyloxy-3-methoxy-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid methyl ester synthesized in Example 6 was dissolved in 5 ml of methanol, and then sodium hydroxide. A solution of 0.1 g of the hydroxide was dissolved in 5 ml of water, and stirred at 50 ° C. for 2 hours. Cooled to 5 ℃ and adjusted to pH 5.5 ~ 6.0 with 1N hydrochloric acid solution and extracted with ethyl acetate (2 X 10ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure and recrystallized with ethanol to give the desired compound, 5- (4-cyclopentyloxy-3-methoxy-phenyl) -2-methyl-2H-pyrazole-. 3-carboxylic acid (0.35 g) was obtained.

Mass spectrum, m / e = 317.4

M.P. = 142 ~ 143 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ): 1.20-1.89 (m, 8H), 3.80 (s, 3H), 4.11 (s, 3H), 4.81 (m, 1H), 6.93 (d, 1H) ), 7.32 (s, 1H), 7.37 (m, 2H)

Example 9

5- (4-Cyclopentyloxy-3-methoxy-phenyl) -2-phenyl-2H-pyrazole-3-carboxylic acid

0.4 g of 5- (4-cyclopentyloxy-3-methoxy-phenyl) -2-phenyl-2H-pyrazole-3-carboxylic acid methyl ester synthesized in Example 7 was dissolved in 5 ml of methanol, and then sodium hydroxide. A solution of 0.06 g of the hydroxide was dissolved in 5 ml of water, and stirred at 50 ° C. for 2 hours. Cooled to 5 ℃ and adjusted to pH 5.5 ~ 6.0 with 1N hydrochloric acid solution and extracted with ethyl acetate (2 X 10ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure and recrystallized with ethanol to give the desired compound, 5- (4-cyclopentyloxy-3-methoxy-phenyl) -2-phenyl-2H-pyrazole-. 3-carboxylic acid (0.24 g) was obtained.

Mass spectrum, m / e = 379.4

M.P. = 176 ~ 177 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ)

: 1.54 ~ 1.89 (m, 8H), 3.53 (s, 3H), 4.76 (m, 1H), 6.75 (d, 2H), 6.87 (d, 1H), 7.04 (s, 1H), 7.35 (m, 2H ), 7.48 (m, 3H)

Pharmacological Experimental Example

In order to evaluate the pharmacological effects of the compounds of the present invention, the following experiments were conducted.

Subtybe classification- Trends in Endocrinology & Metabolism, Moreland et al (1999) 10, 97-; Mol. Cell. Biol., Bolger G. et al (1993) 13, Partially purified PDE IV, test compound, and 1.0 μM cAMP containing 0.01 μM [ ³ H] cAMP were incubated at 30 ° C. for 20 minutes according to 6558-6571). Phosphodiesterase (PDE) reaction in which cAMP is changed to AMP was completed by boiling for 2 minutes. Snake venom nucleotidase was added and incubated at 30 ° C. for 10 minutes to change AMP to adenosine. Unhydrolyzed cAMP was combined with AG1-X2 resin and the remaining [3H] adenosine in aqueous solution was quantified by scintillation counting. First, DPM for each blank test (substrate only), control group (enzyme + substrate), and test group (enzyme + substrate + each compound of Example) were obtained by Liquid Scintillation counter (Packard TR ₁ 600 model). It was.

% Inhibition = [(DPM _{test group} -DPM _{control group} ) / (DPM _{blank test} -DPM _{control group} )] × 100

SB 207499 used as a comparative in Table 1 is known from J. Med. Chem. 1998, 41, 821-835 as a compound of the structure:

The experimental results are as follows.

TABLE 1

According to the present invention, by inhibiting PDE IV or TNF, asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction, psoriasis, allergic rhinitis, dermatitis and AIDS, HIV, Crohn's disease, sepsis, sepsis Catechol pyrazole derivatives and methods for preparing the same, and pharmaceutical compositions containing the same, which are effective in treating other inflammatory diseases such as shock and atherosclerosis and diseases including the production of TNF.

Claims (4)

Catechol pyrazole derivatives represented by Formula 1 and their pharmaceutically acceptable salts: [Formula 1] In Chemical Formula 1, R ₁ is a methyl group; R ₂ is (C ₃ -C ₇ ) cycloalkyl; R ₃ is hydrogen or alkyl, (C ₁ -C ₇ ) cycloalkyl or phenyl; R ₄ is alkyl, methyl, methyl ester or carboxylic acid substituted with 1 to 3 halogens. The method of claim 1, wherein the catechol pyrazole derivatives are 3- (4-cyclopentyloxy-3-methoxy-phenyl) -5-trifluoromethyl-1H-pyrazole, 3- (4-cyclopentyloxy 3-methoxy-phenyl) -1-methyl-5-trifluoromethyl-1H-pyrazole, 3- (4-cyclopentyloxy-3-methoxy-phenyl) -1-phenyl-5-triflo Romethyl-1H-pyrazole, 5- (4-cyclopentyloxy-3-methoxy-phenyl) -2H-pyrazole-3-carboxylic acid methyl ester, 5- (4-cyclopentyloxy-3-meth Methoxy-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid methyl ester, 5- (4-cyclopentyloxy-3-methoxy-phenyl) -2-phenyl-2H-pyrazole-3- Carboxylic acid methyl ester, 5- (4-cyclopentyloxy-3-methoxy-phenyl) -2-methyl-2H-pyrazole-3-carboxylic acid and 5- (4-cyclopentyloxy-3-meth Catechol pyrazole derivatives and their pharmaceuticals, characterized in that any one selected from the group consisting of oxy-phenyl) -2-phenyl-2H-pyrazole-3-carboxylic acid Salts for. As shown in the following [Reaction Scheme 1], benzaldehyde (2) in which the hydroxyl group at position 3 is substituted with R ₁ is reacted with the reaction reagent designated as R ₂ -A so that the two hydroxyl groups are each R _1. , A first step of synthesizing benzaldehyde (3) substituted with R ₂ , benzaldehyde (3) to ethyl trifluoroacetate, ethyl difluoroacetate, ethyl fluoroacetate, diethyl oxalate and dimethyl oxalate A second step of synthesizing the dicarbonyl compound (4) by reaction with any one compound selected from the group consisting of and a third step of synthesizing the desired compound (1) by reacting the dicarbonyl compound (4) with alkylhydrazine A process for preparing the compound of claims 1 to 3 comprising the step. Scheme 1 In Scheme 1, R ₁ is a methyl group; R ₂ is (C ₃ -C ₇ ) cycloalkyl; R ₃ is hydrogen or alkyl, (C ₁ -C ₇ ) cycloalkyl or phenyl; R ₄ is alkyl, methyl, methyl ester or carboxylic acid substituted with 1 to 3 halogens. A pharmaceutical composition having an inhibitory effect on phosphodiesterase IV or TNF in combination with a therapeutically effective amount of the compound of any one of claims 1 to 3 and a pharmaceutically acceptable carrier.