KR20030055769A - Novel catechol benzamide derivatives and process for preparing the same - Google Patents

Abstract

PURPOSE: A novel catechol benzamide derivative, its preparation method and a pharmaceutical composition containing the derivative are provided, which derivative inhibits the phosphodiesterase IV or the tumor necrosis factor (TNF). CONSTITUTION: The catechol benzamide derivative is represented by the formula 1, wherein R1 is a cycloalkyl group of C3-C7, an indanyl group or a benzyl group; and X and Y are independently H, an alkyl group of C1-C7, an alkoxy group of C1-C7, a nitro group, an amino group or a halogen atom, or X is -NH-Z-R2 and Y is H (wherein R2 is an alkyl group of C1-C7 substituted or unsubstituted with one or two group selected from the group consisting of a halogen atom, OH, an acetoxy group, an alkoxy group of C1-C3 and an amino group, or a phenyl group substituted or unsubstituted with one or two group selected from the group consisting of a nitro group, a cyano group, a halogen atom, an alkyl group of C1-C3 and an alkoxy group of C1-C3, and the halogen atom is F, Cl or Br).

Description

Novel catechol benzamide derivatives and process for preparing the same

The present invention relates to a catechol benzamide derivative of formula (I) having a inhibitory effect on phosphodiesterase IV or Tumor necrosis factor (TNF), a pharmaceutically acceptable salt or isomer thereof:

[Formula 1]

In the above formula

R ¹ represents C ₃ -C ₇ -cycloalkyl, indanyl or benzyl,

X and Y each independently represent hydrogen, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxy, nitro, amino or halogen,

X is , Y represents hydrogen,

From here

Z represents -C (= 0)-or -C (= 0) O-,

R ² represents C ₁ -C ₇ -alkyl unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of halogen, hydroxy, acetoxy, C ₁ -C ₃ -alkoxy and amino; Phenyl substituted or unsubstituted by 1 to 2 substituents selected from the group consisting of nitro, cyano, halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein halogen is fluorine, chlorine or Bromine.

The present invention also provides a method of preparing a compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof, and a phosphodiesterase IV or TNF inhibitory pharmaceutical composition comprising the compound as an active ingredient. It is about. The compounds according to the invention are particularly suitable for asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction, psoriasis, allergic rhinitis, dermatitis, AIDS, HIV, Crohn's disease, sepsis, septic shock, etiology and It is useful for the treatment of such inflammatory diseases and diseases related to the regulation of production of TNF.

Phosphodiesterase is an enzyme that hydrolyzes cyclic nucleotides as one of the chemical transporters, and cyclic adenosine 3 ', 5'-monophosphate is a secondary messenger responsible for regulating the cellular response to external stimuli. (second messenger) involved in the relaxation and contraction of bronchial muscles. Phosphodiesterase IV is an enzyme that selectively hydrolyzes cyclic adenosine 3 ', 5'-monophosphate to inactive adenosine 3', 5'-monophosphate. Therefore, inhibition of phosphodiesterase IV can prevent bronchial spasms by keeping the concentration of cyclic adenosine 3 ', 5'-monophosphate constant, and in addition, anti-inflammatory effect can be obtained. For this reason, compounds that inhibit phosphodiesterase IV are useful as therapeutic agents for asthma and the like.

TNF is known to be associated with many infectious and autoimmune diseases, including atherosclerosis, and is also thought to be a major mediator of the inflammatory response seen in sepsis and septic shock.

As inhibitors for phosphodiesterase IV or TNF, compounds with structures similar to the compounds according to the invention have already been reported.

For example, Smith kline Beecham, in USP 5,393,788, discloses a compound of formula (2) which introduces an oxamide structure into the structure of 3-methoxy-4-cyclopentyloxy, the catechol ether parent nucleus.

In the above formula

R ¹ may be substituted by C ₄ to C ₆ cyclicalkyl (optionally substituted by 1 to 3 methyl or 1 ethyl), C ₁ to C ₇ alkyl (optionally by one or more halogens ),-(CH ₂ ) _n COO- (CH ₂ ) _m CH ₃ ,-(CH ₂ ) _n OCH ₃ , (CH ₂ ) _p OH, -CH ₂ C ₅ H ₉ , CH ₂ C ₃ H ₅ ,- C ₅ H ₉ , or tetrahydrofuranyl,

Where n is 2-4, m is 0-2, p is 2-4,

X is halogen, nitro, amino, C ₁ -C ₂ dialkylamine, C ₁ -C ₂ monoalkylamine, formylamine, or YR ² ,

Wherein Y is oxygen or S (O) _{m '} , m' is 0-2, R ² is methyl or ethyl, which may be optionally substituted by one or more halogens,

R ³ is hydrogen or OR ⁷ ,

Wherein R ⁷ is one or more fluoro, cyano, C ₁ -C ₂ alkyl, or alkyl optionally substituted by C ₁ -C ₂ alkyl substituted by one or more fluoro,

R ⁴ is hydrogen, fluoro, cyano, or the like,

R ¹² is hydrogen, fluoro, cyano, methyl substituted by 1-3 fluoro,

R ³ and R ¹² together may form a ketone group,

R ⁵ is hydrogen, OR ⁷ ,-(CH ₂ ) _m Ar, or C ₁ -C ₆ alkyl,

Wherein Ar is 2-, 3-, 4-pyridyl, pyrimidyl, morpholino, or phenyl,

R ⁶ is or Etc.

Wherein R ⁷ and R ⁸ are independently of each other hydrogen or C ₁ -C ₃ alkyl, and q is 0 or 1.

In addition, Merck reported a new catechol pyridazine compound of the following formula (3) in which a pyridazine structure was introduced in WO 00/26201 into the basic structure of 3-methoxy-4-cyclopentoxy, the parent of catechol ether:

In the above formula

B comprises unsubstituted phenyl or phenyl substituted with R ³ ,

Q is C ₁ -C ₄ alkylene,

R ¹ and R ² are -OR ⁴ , -SR ⁴ , -SO-R ⁴ or -SO ₂ -R ⁴ ,

R³R⁴, Halogen, OH, OR⁴, OPh, NO₂, NHR⁴, N (R⁴)₂, NHCOR⁴, NHSOR⁴Or NHCOOR⁴Is,

R ⁴ is (C ₃ -C ₇ ) cycloalkyl, (C ₅ -C ₁₀ ) alkylenecycloalkyl or (C ₂ -C ₈ ) alkenyl,

Halogen is F, Cl, Br or I.

The present inventors have also reported synthesis of a catechol hydrazone derivative of the following formula (4) based on 3-methoxy-4-cyclopentyloxycatechol (WO 00/73280):

In the above formula

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 ,

R ³ and R ⁴ are independently hydrogen, (C ₁ -C ₇ ) alkyl, -C (= X) -R ⁵ , 2-, 3- or 4-pyridyl, or pyrimidyl, halogen, (C ₁ and ~ C ₆₎ substituted by alkoxy, nitro, methyl, (C ₁ ~ C ₆₎ alkyl, such as trifluoromethyl, phenyl,

X is oxygen, sulfur or NH,

R ⁵ is (C ₁ -C ₇ ) alkyl, -NHR ⁶ , CONH ₂ or 2-, 3- or 4-pyridyl, or pyrimidyl,

R ⁶ is hydrogen, hydroxy, (C ₁ -C ₅ ) alkyl, (C ₁ -C ₆ ) alkoxy, pyridyl, or phenyl.

The present applicant also discloses a novel catechol N-methylhydrazide derivative of the following formula (5) comprising 3-methoxy-4-cyclopentyloxy, the parent of catechol ether, in Korean Patent Application No. 10-2001-0024139 It was initiated.

In the above formula

R ¹ represents C ₃ -C ₇ -cycloalkyl, indanyl or benzyl,

R ² represents nitro or -NH-YR ³ ,

From here

Y represents a direct bond, carbonyl (-CO-) or sulfonyl (-SO _2- ),

R ³ represents hydrogen; C ₁ -C ₇ -alkyl which is mono- or di-substituted or unsubstituted by hydroxy or halogen; C ₁ -C ₂ -alkyl substituted by a substituent selected from the group consisting of phenyl, phenoxy and C ₁ -C ₃ -alkylcarbonyloxy; A 5- or 6-membered heteroaryl comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; Phenyl substituted or unsubstituted by one or two substituents selected from the group consisting of nitro, cyano, halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein halogen is fluorine, chlorine or Bromine.

Under this technical background, the inventors conducted intensive studies to develop compounds which are structurally different from previously reported compounds and exhibit excellent inhibitory activity against phosphodiesterase IV or TNF. The compound was found to meet this purpose and the present invention was completed.

Accordingly, it is an object of the present invention to provide a compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof.

It is also an object of the present invention to provide a new method for preparing a compound of formula (1), a pharmaceutically acceptable salt or isomer thereof.

The present invention also provides a phosphodiesterase IV or TNF inhibitory active pharmaceutical composition characterized by containing a compound of formula 1, a salt thereof, or an isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier. The purpose.

First, the present invention relates to catechol benzamide derivatives of formula (1), pharmaceutically acceptable salts or isomers thereof:

[Formula 1]

In the above formula

R ¹ represents C ₃ -C ₇ -cycloalkyl, indanyl or benzyl,

X and Y each independently represent hydrogen, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxy, nitro, amino or halogen,

X is , Y represents hydrogen,

From here

Z represents -C (= 0)-or -C (= 0) O-,

R ² represents C ₁ -C ₇ -alkyl unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of halogen, hydroxy, acetoxy, C ₁ -C ₃ -alkoxy and amino; Phenyl substituted or unsubstituted by 1 to 2 substituents selected from the group consisting of nitro, cyano, halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein halogen is fluorine, chlorine or Bromine.

Pharmaceutically acceptable salts of the compound of formula 1 according to the present invention include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, formic acid, succinic acid, benzoic acid, tartaric acid and fumaric acid. Organic carboxylic acids such as or salts with sulfonic acids such as methanesulfonic acid, para-toluenesulfonic acid, and salts with other acids known and used in the catechol hydrazide art. These acid addition salts can be prepared according to a conventional conversion method. The compounds of formula (1) may also form salts with bases. Bases that can be used include alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkali metal hydrogencarbonates (e.g. sodium bicarbonate, potassium bicarbonate), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate), alkaline earth metal carbonates ( Examples include inorganic bases such as calcium carbonate, magnesium carbonate) and organic bases such as amino acids.

The compounds according to the invention may have an asymmetric carbon center depending on the kind of substituents, and therefore may exist as mixtures thereof, including R or S isomers, diastereomers, or racemates. Accordingly, the scope of the present invention includes each of these isomers and mixtures thereof.

Among the compounds of formula 1 according to the invention more preferred are R ¹ is C ₃ -C ₇ -cycloalkyl, X and Y are each independently hydrogen, C ₁ -C ₇ -alkoxy, nitro or amino, or X is And Y is hydrogen, where Z is -C (= 0)-or -C (= 0) O- and R ² is C ₁ -C ₇ -alkyl unsubstituted or substituted by acetoxy; And phenyl unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of halogen and C ₁ -C ₃ -alkoxy.

Representative of the compound of formula 1 according to the present invention may be mentioned:

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] benzamide;

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -2,4-dimethoxybenzamide;

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -3,4-dimethoxybenzamide;

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4-nitro-benzamide;

4-amino-N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] benzamide;

{4- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethylcarbamoyl] -phenylcarbamoyl acetic acid methyl ester;

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4-benzamidobenzamide;

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4- (4-methoxybenzamido) -benzamide;

{4- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethylcarbamoyl] -phenyl} -carbamic acid ethyl ester;

{4- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethylcarbamoyl] -phenyl} -carbamic acid phenyl ester;

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4- (2,4-dimethoxybenzamido) -benzamide;

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4- (3,4-dimethoxybenzamido) -benzamide; And

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4- (4-bromobenzamido) -benzamide.

Meanwhile, the compound of formula 1, pharmaceutically acceptable salts and isomers thereof according to the present invention may be prepared by (a) reacting a compound of formula 6 with a compound of formula 7 in the presence of a base in a solvent to obtain a compound of formula 1 ; (b) reducing the compound of formula 1a to yield a compound of formula 1b; (c) The obtained compound of formula 1b may be prepared by coupling reaction with a compound of formula 8 to obtain a compound of formula 1c. Therefore, it is another object of the present invention to provide such a manufacturing method.

In the above formula

R ¹ , X, Y, Z and R ² are as defined above,

L represents hydroxy or halogen.

The methods (a), (b) and (c) according to the present invention are shown in the following schemes 1, 2 and 3, respectively, and will be described in more detail below.

According to Scheme 1, the catechol benzamide derivative of Formula 1 according to the present invention may be synthesized by reacting an amine compound of Formula 6 with various benzoyl chlorides in a solvent such as dichloromethane and acetonitrile.

Reduction from the compound of Formula 1a to the compound of Formula 1b in which X is 4-nitro and Y is hydrogen in the compound of Formula 1 (Scheme 2) is 5 to 10% in a mixed solvent of alcohol (especially methanol) and tetrahydrofuran. Pd / C and ammonium formate are used to proceed at a temperature of about 25 to 70 ℃. 5-10% Pd / C is usually used at 5-15% of the starting material and ammonium formate is used at 2-5 equivalents. The optimum reaction condition is to use 10% Pd / C 5% and 5 equivalents of ammonium formate.

The amine derivative of Formula 1b obtained in Scheme 2 can be coupled to various LZR ² compounds to synthesize the desired compound of Formula 1c. The coupling reaction may vary depending on what L corresponds to the leaving group. For example, where Z is carbonyl and L is halogen, especially chlorine, the amine derivative and acylchloride compound are reacted in the presence of a base in anhydrous acetonitrile solvent. Triethylamine or pyridine can be preferably used as the base. In addition, when Z is carbonyl and L is hydroxy, the target compound can be smoothly obtained by activating the carboxylic acid compound first to proceed with the reaction. That is, the carboxylic acid compound can be converted to the active ester using 1-hydroxybenzotriazole and dicyclodiimide derivatives, and then the reaction can be proceeded. After the reaction can proceed. At this time, triethylamine is preferably used as the base.

On the other hand, the compound of formula 6 used as a starting material in the method according to the invention can be prepared according to the method shown in Scheme 4.

Benzaldehyde of formula 9 is reacted with compound (10) of formula R ¹ -L in the presence of anhydrous potassium carbonate in anhydrous N, N-dimethylformamide solvent, and the benzaldehyde of formula 10 wherein two hydroxy groups are substituted with R ¹ and methyl, respectively Synthesize. The compound of formula 10 is refluxed with ammonium acetate for 4 to 10 hours in a nitromethane solvent to obtain a compound of nitrostyrene structure (11). The compound of formula 11 is reduced with lithium aluminum hydride (LAH) at a temperature of 0 to 40 ° C. in a mixed solvent of diethyl ether and anhydrous tetrahydrofuran to prepare an amine compound of formula 6.

After the reaction is completed, the product can be separated and purified by conventional post-treatment methods such as silica gel column chromatography, recrystallization, iontophoresis, ion exchange resin chromatography, and the like.

As described above, the compound of formula 1 according to the present invention may be usefully used as a phosphodiesterase IV or TNF inhibitor. Accordingly, the present invention provides a phosphodiesterase IV or TNF inhibitory activity characterized in that it contains a compound of formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier. It is another object to provide a pharmaceutical composition. The composition according to the present invention is particularly effective in treating asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction, psoriasis, allergic rhinitis, dermatitis, AIDS, HIV, Crohn's disease, sepsis, septicemia, It is useful for the treatment of such inflammatory diseases and diseases related to the regulation of production of TNF.

The total daily dose to be administered to an adult in a single dose or in separate doses when administering a compound of the present invention for clinical purposes is typically in the range of 10 to 20 mg per kg, but in the case of infection by some strains a higher daily dose is required. Can be. In addition, the specific dose level for a particular patient may vary depending on the particular compound to be used, weight, age, sex, health condition, diet, time of administration, method of administration, rate of excretion, drug mixing and the severity of the disease.

The compounds of the present invention can be administered in injectable and oral formulations as desired.

Injectable preparations, for example sterile injectable aqueous or oily solutions, suspensions or emulsions, can be prepared using suitable dispersing agents, wetting agents, suspending agents or stabilizers according to known techniques. Solvents that can be used include water, Ringer's solution and isotonic NaCl solution, and sterile fixed oils are conventionally employed as a solvent or suspending medium. Any non-irritating fixed oil may be used for this purpose, including mono- and diglycerides, and fatty acids such as oleic acid may be used in the preparation of injectables. Also, for example, it may be in the form of a dry powder for immediate use, which is sterile and deionized with water, which is dissolved before use.

The compounds of the present invention may also be formulated into suppositories using conventional suppository bases such as cocoa butter or other glycerides.

Solid dosage forms for oral administration may be capsules, tablets, pills, powders and granules, and capsules and tablets are particularly useful. Tablets and pills are preferably prepared with enteric agents. Solid dosage forms are prepared by mixing the active compound of formula 1 according to the present invention with a carrier selected from one or more inert diluents such as sucrose, lactose, starch and the like, lubricants such as magnesium stearate, disintegrants and binders.

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

3-cyclopentyloxy-4-methoxybenzaldehyde

A suspension of isovanillin (100 g, 0.66 mol), anhydrous potassium carbonate (136.2 g, 0.99 mol), potassium iodide (3 g) and anhydrous dimethylformamide (650 mL) was stirred at 65 ° C. and then cyclones to the suspension. Pentyl bromide (127.3 g, 0.85 mol) was slowly added dropwise for 1 hour. Stir at 65 ° C. for 1 day and then cool to room temperature. Toluene (2.0 L) was added to the mixed solution, and the mixture was diluted with 1M sodium hydroxide solution (2 × 1.5 L). The aqueous layer was extracted with toluene (0.5 L) and the organic layer obtained was washed with distilled water (2 × 1.5 L). The organic layer was dried and concentrated to give a light brown oily title compound (117 g).

¹ H NMR (400 MHz, CDCl ₃ , δ): 2.1-1.6 (m, 8H), 3.93 (s, 3H), 4.87 (m, 1H), 6.95 (d, 1H), 7.42 (m, 2H), 9.84 (s, 1 H)

Reference Example 2

2-cyclopentyloxy-1-methoxy-4- (2-nitro-vinyl) -benzene

Ammonium acetate (8.7 g) was suspended in nitromethane (50 mL), followed by addition of a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (10 g) synthesized in Reference Example 1 in nitromethane (100 mL). . After reacting at 60 ° C. for 4 hours, distillation under reduced pressure was carried out to remove nitromethane, water (100 mL) and ethyl acetate (100 mL) were added thereto, followed by stirring for 10 minutes. The aqueous layer was separated and extracted with ethyl acetate (50 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed by distillation under reduced pressure. Recrystallization from ethanol gave the title compound (8.6 g).

¹ H NMR (400 MHz, CDCl ₃ , δ): 1.55-1.97 (m, 8H), 3.90 (s, 3H), 4.80 (m, 1H), 6.89 (d, 1H), 7.02 (d, 1H), 7.16 (dd, 1H), 7.49 (d, 1H), 7.97 (d, 1H)

Reference Example 3

2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethylamine

2-cyclopentyloxy-1-methoxy-4- (2-nitro-vinyl) -benzene (5 g) synthesized in Reference Example 2 was added to anhydrous tetrahydrofuran (50 ml) to dissolve, followed by lithium aluminum hydride (2.6 g) was added dropwise to the solution dissolved in diethyl ether (50 mL) under nitrogen atmosphere for 1 hour. After heating under reflux for 2 hours, 20 ml of saturated sodium sulfate solution was added dropwise, cooled to 0 ° C., and stirred for 30 minutes. The resulting solid was filtered, dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure to remove the solvent, and then purified by column chromatography (eluent: ethyl acetate / methanol = 1/3, v / v) to obtain the title compound (1.9). g) was obtained.

¹ H NMR (400 MHz, CDCl ₃ , δ): 1.61-1.91 (m, 8H), 2.66 (t, 2H), 2.94 (t, 2H), 3.81 (s, 3H), 4.76 (m, 1H), 6.79 ~ 6.82 (m, 3H)

Example 1

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] benzamide

2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethylamine (0.3 g) synthesized in Reference Example 3 was added to dichloromethane (10 ml) to dissolve, and anhydrous pyridine (0.3 g) was added thereto for 5 minutes. Stirred. Benzoyl chloride (0.2 g) was added, stirred at room temperature for 5 hours, and then water (10 mL) was added. The reaction solution was stirred for 5 minutes, and the layers were separated. The organic layer was washed with 0.5N hydrochloric acid solution (10 mL). After drying over anhydrous magnesium sulfate and filtration, the solvent was distilled under reduced pressure, and then purified by column chromatography (eluent: ethyl acetate / hexane = 1/2, v / v) to obtain the title compound (0.32 g).

MS, m / e = 340.3

Melting Point: 113 ~ 114 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ): 1.58-1.89 (m, 8H), 2.77 (t, 2H), 3.45 (m, 2H), 3.70 (s, 3H), 4.70 (m, 1H ), 6.78 (m, 2H), 6.87 (d, 1H), 7.45 (m, 3H), 7.82 (d, 2H), 8.49 (t, 1H)

Example 2

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -2,4-dimethoxybenzamide

2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethylamine (0.1 g) synthesized in Reference Example 3 was dissolved in dichloromethane (5 ml), and then anhydrous pyridine (0.1 g) was added thereto for 5 minutes. Stirred. 2,4-Dimethoxybenzoyl chloride (0.095 g) was added, stirred at room temperature for 5 hours, and then water (10 mL) was added. The reaction solution was stirred for 5 minutes, and the layers were separated. The organic layer was washed with 0.5N hydrochloric acid solution (5 mL). After drying over anhydrous magnesium sulfate and filtration, the solvent was distilled under reduced pressure, and then purified by column chromatography (eluent: ethyl acetate / hexane = 1/1, v / v) to obtain the title compound (0.089 g).

MS, m / e = 400.48

Melting Point: 120 ~ 121 ℃

¹ H NMR (400 MHz, CDCl ₃ , δ): 1.57 to 1.83 (m, 8H), 2.85 (t, 2H), 3.68 (q, 2H), 3.83 (s, 3H), 3.90 (s, 3H), 3.99 (s, 3H), 4.72 (m, 1H), 6.70 (m, 2H), 6.83 (m, 2H), 7.13 (dd, 1H), 7.39 (d, 1H)

Example 3

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -3,4-dimethoxybenzamide

2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethylamine (0.1 g) synthesized in Reference Example 3 was dissolved in dichloromethane (5 ml), and then anhydrous pyridine (0.1 g) was added thereto for 5 minutes. Stirred. 3,4-Dimethoxybenzoyl chloride (0.095 g) was added, stirred at room temperature for 5 hours, and then water (10 mL) was added. The reaction solution was stirred for 5 minutes, and the layers were separated. The organic layer was washed with 0.5N hydrochloric acid solution (5 mL). After drying over anhydrous magnesium sulfate and filtration, the solvent was distilled under reduced pressure, and then purified by column chromatography (eluent: ethyl acetate / hexane = 1/1, v / v) to obtain the title compound (0.089 g).

MS, m / e = 400.48

Melting Point: Untested (oil form)

¹ H NMR (400 MHz, CDCl ₃ , δ): 1.56-1.87 (m, 8H), 2.84 (t, 2H), 3.69 (q, 2H), 3.73 (s, 3H), 3.84 (s, 3H), 3.86 (s, 3H), 4.73 (m, 1H), 6.57 (d, 1H), 6.59 (dd, 1H), 6.79 (m, 2H), 6.84 (d, 1H), 7.76 (m, 1H), 8.19 (d, 1H)

Example 4

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4-nitro-benzamide

2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethylamine (1 g) synthesized in Reference Example 3 was dissolved in dichloromethane (10 ml), and then anhydrous pyridine (1.2 g) was added thereto, followed by stirring for 5 minutes. It was. 4-nitrobenzoyl chloride (0.87 g) was added, stirred at room temperature for 5 hours, and then water (20 mL) was added. The reaction solution was stirred for 5 minutes, and the layers were separated. The organic layer was washed with 0.5N hydrochloric acid solution (10 mL). After drying over anhydrous magnesium sulfate and filtration, the solvent was distilled under reduced pressure. The residue was recrystallized from ethanol to give the title compound (0.92 g).

MS, m / e = 385.43

Melting Point: 116 ~ 117 ℃

¹ H NMR (400 MHz, CDCl ₃ , δ): 1.57-1.89 (m, 8H), 2.88 (t, 2H), 3.73 (q, 2H), 3.83 (s, 3H), 4.73 (m, 1H), 6.15 (s, 1H), 6.76 (m, 2H), 6.82 (d, 1H), 7.85 (d, 2H), 8.26 (d, 2H)

Example 5

4-amino-N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] benzamide

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4-nitro-benzamide (0.9 g) synthesized in Example 4 was added to anhydrous tetrahydrofuran (20 mL). After melting, methanol (20 mL) was added. Ammonium formate (2.3 g) was added and then heated to reflux to completely dissolve the ammonium formate. 10% Pd / C (0.1 g) was added and heated to reflux for 1 hour and then cooled to 40 ° C. 10% Pd / C was filtered off with Celite, and then the solvent was removed by distillation under reduced pressure. Water (30 mL) and ethyl acetate (50 mL) were added, followed by stirring for 5 minutes and layer separation. The organic layer was dried over anhydrous magnesium sulfate, filtered, the solvent was distilled under reduced pressure and crystallized with diethyl ether to obtain the title compound (0.59 g).

MS, m / e = 355.42

Melting Point: 104 ~ 105 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ): 1.53-1.88 (m, 8H), 2.74 (t, 2H), 3.40 (m, 2H), 3.70 (s, 3H), 4.70 (m, 1H ), 5.55 (s, 2H), 6.53 (d, 2H), 6.76 (m, 2H), 6.86 (d, 1H), 7.56 (d, 2H), 8.00 (t, 1H)

Example 6

{4- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethylcarbamoyl] -phenylcarbamoyl} acetic acid methyl ester

4-amino-N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] benzamide (0.1 g) synthesized in Example 5 was added to dichloromethane (5 ml) to dissolve, and then dried. Pyridine (0.07 g) was added and stirred for 5 minutes. Acetoxyacetyl chloride (0.043 g) was added thereto, stirred at room temperature for 12 hours, and then water (10 mL) was added thereto. The reaction solution was stirred for 5 minutes, and the layers were separated. The organic layer was washed with 0.5N hydrochloric acid solution (5 mL). Dry over anhydrous magnesium sulfate, filter, distill the solvent under reduced pressure, and then purify with ethanol to give the title compound (0.069 g).

MS, m / e = 455.52

Melting Point: 165 ~ 166 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ): 1.57-1.89 (m, 8H), 2.13 (s, 3H), 2.87 (t, 2H), 3.38 (m, 2H), 3.70 (s, 3H ), 4.67 (s, 2H), 4.73 (m, 1H), 6.72 (m, 2H), 6.87 (d, 1H), 7.62 (d, 2H), 7.81 (d, 2H), 8.41 (t, 1H) , 10.37 (s, 1H)

Example 7

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4-benzamidobenzamide

4-amino-N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] benzamide (0.1 g) synthesized in Example 5 was added to acetonitrile (10 ml) to dissolve, and then dried. Pyridine (0.07 g) was added and stirred for 5 minutes. Benzoyl chloride (0.048 g) was added and stirred at room temperature for 8 hours, then water (20 mL) was added and stirred for 10 minutes. The resulting solid was filtered and washed with excess water to give the title compound (0.084 g).

MS, m / e = 459.55

Melting Point: 212 ~ 213 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ): 1.53-1.81 (m, 8H), 2.87 (t, 2H), 3.41 (m, 2H), 3.70 (s, 3H), 4.70 (m, 1H ), 6.78 (m, 2H), 6.88 (d, 1H), 7.62 (m, 2H), 7.86 (m, 4H), 7.98 (d, 2H), 8.43 (t, 1H), 10.40 (s, 1H)

Example 8

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4- (4-methoxybenzamido) -benzamide

4-amino-N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] benzamide (0.1 g) synthesized in Example 5 was added to acetonitrile (10 ml) to dissolve, and then dried. Pyridine (0.07 g) was added and stirred for 5 minutes. p-anisoyl chloride (0.053 g) was added and stirred at room temperature for 8 hours, then water (20 mL) was added and stirred for 20 minutes. The resulting solid was filtered and washed with excess water to give the title compound (0.11 g).

MS, m / e = 489.58

Melting Point: 224 ~ 225 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ): 1.53-1.82 (m, 8H), 2.87 (t, 2H), 3.41 (m, 2H), 3.70 (s, 3H), 3.86 (s, 3H ), 4.71 (m, 1H), 6.76 (m, 2H), 6.88 (d, 1H), 7.18 (d, 2H), 7.83 (m, 4H), 7.97 (d, 2H), 8.40 (t, 1H) , 10.30 (s, 1H)

Example 9

{4- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethylcarbamoyl] -phenyl} -carbamic acid methyl ester

4-amino-N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] benzamide (0.1 g) synthesized in Example 5 was added to dichloromethane (10 ml) to dissolve, and then dried. Pyridine (0.07 g) was added and stirred for 5 minutes. Methylchloroformate (0.03 g) was added and stirred at room temperature for 6 hours. Water (10 ml) was added, the mixture was stirred for 5 minutes, and the layers were separated, and the organic layer was washed with 0.5 N hydrochloric acid solution (5 ml). Drying over anhydrous magnesium sulfate, filtration, distillation of the solvent under reduced pressure and crystallization with diethyl ether to give the title compound (0.052g).

MS, m / e = 413.48

Melting Point: 121 ~ 122 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ): 1.53-1.88 (m, 8H), 2.74 (t, 2H), 3.40 (m, 2H), 3.67 (s, 3H), 3.70 (s, 3H ), 4.70 (m, 1H), 6.57 (m, 2H), 6.87 (d, 1H), 7.76 (m, 2H), 7.86 (m, 2H), 8.42 (t, 1H), 10.68 (s, 1H)

Example 10

{4- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethylcarbamoyl] -phenyl} -carbamic acid phenyl ester

4-amino-N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] benzamide (0.1 g) synthesized in Example 5 was added to dichloromethane (10 ml) to dissolve, and then dried. Pyridine (0.07 g) was added and stirred for 5 minutes. Phenylchloroformate (0.05 g) was added and stirred at room temperature for 11 hours. Water (10 ml) was added, the mixture was stirred for 5 minutes, and the layers were separated, and the organic layer was washed with 0.5 N hydrochloric acid solution (5 ml). Drying over anhydrous magnesium sulfate, filtration, distillation of the solvent under reduced pressure and recrystallization with ethanol to give the title compound (0.052g).

MS, m / e = 475.55

Melting Point: 133 ~ 134 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ): 1.53-1.88 (m, 8H), 2.74 (t, 2H), 3.40 (m, 2H), 3.70 (s, 3H), 4.70 (m, 1H ), 6.57 (m, 2H), 6.87 (d, 1H), 7.12 (m, 3H), 7.31 (m, 2H), 7.76 (m, 2H), 7.86 (m, 2H), 8.52 (t, 1H) , 10.19 (s, 1H)

Example 11

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4- (2,4-dimethoxybenzamido) -benzamide

4-amino-N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] benzamide (0.1 g) synthesized in Example 5 was added to acetonitrile (10 ml) to dissolve, and then dried. Pyridine (0.07 g) was added and stirred for 5 minutes. 2,4-dimethoxybenzoyl chloride (0.063 g) was added and stirred at room temperature for 12 hours, then water (20 mL) was added and stirred for 5 minutes. The resulting solid was filtered and washed with excess water to give the title compound (0.93 g).

MS, m / e = 519.60

Melting Point: 188 ~ 190 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ): 1.53-1.82 (m, 8H), 2.79 (t, 2H), 3.45 (m, 2H), 3.71 (s, 3H), 3.86 (s, 3H ), 3.97 (s, 3H), 4.69 (m, 1H), 6.73 (m, 4H), 6.86 (d, 1H), 7.79 (m, 5H), 8.41 (t, 1H), 10.09 (s, 1H)

Example 12

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4- (3,4-dimethoxybenzamido) -benzamide

4-amino-N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] benzamide (0.1 g) synthesized in Example 5 was added to acetonitrile (10 ml) to dissolve, and then dried. Pyridine (0.07 g) was added and stirred for 5 minutes. 3,4-dimethoxybenzoyl chloride (0.063 g) was added thereto, stirred at room temperature for 12 hours, and then water (20 mL) was added thereto, and stirred for 5 minutes. The resulting solid was filtered and washed with excess water to give the title compound (0.74 g).

MS, m / e = 519.67

Melting Point: 153 ~ 155 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ): 1.53-1.80 (m, 8H), 2.77 (t, 2H), 3.44 (m, 2H), 3.71 (s, 3H), 3.86 (s, 3H ), 3.97 (s, 3H), 4.70 (m, 1H), 6.70 (m, 4H), 6.86 (d, 1H), 7.81 (m, 5H), 8.41 (t, 1H), 10.10 (s, 1H)

Example 13

N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4- (4-bromobenzamido) -benzamide

4-amino-N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] benzamide (0.1 g) synthesized in Example 5 was added to acetonitrile (10 ml) to dissolve, and then dried. Pyridine (0.07 g) was added and stirred for 5 minutes. 4-Bromobenzoyl chloride (0.068 g) was added and stirred at room temperature for 12 hours, followed by water (20 mL) and stirring for 5 minutes. The resulting solid was filtered and washed with excess water to give the title compound (0.89 g).

MS, m / e = 538.45

Melting Point: 234 ~ 235 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ): 1.48-1.80 (m, 8H), 2.77 (t, 2H), 3.47 (m, 2H), 3.70 (s, 3H), 4.72 (m, 1H ), 6.78 (m, 2H), 6.87 (d, 1H), 7.76 (d, 2H), 7.84 (s, 4H), 7.92 (d, 2H), 8.42 (t, 1H), 10.50 (s, 1H)

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

Subtybe classification- Trends in Endocrinology & Metabolism, Moreland et al (1999) 10, 97-; Mol. Cell. Biol., Bolger G. et al (1993) 13, 6558 PDE IV (final concentration 0.02 mg / mL), the test compound, and 1.0 μM cAMP containing 0.01 μM of [ ³ H] cAMP were incubated at 30 ° C. for 20 minutes. The PDE reaction, in which cAMP was converted to AMP, was completed by boiling for 2 minutes. Snake venom nucleotidase (Sigma V7000; snake venom from Crotalus atrox) was added at a final concentration of 0.2 mg / ml and 30 ° C. AMP was converted to adenosine by incubation for 10 minutes at. Since the non-hydrolyzed cAMP is combined with AG1-X2 resin, the [ ³ H] adenosine remaining in the aqueous solution was quantified by scintillation counting, and the results are shown in Table 1 below. However, SB 207499 used as a comparative material in Table 1 is known from J. Med. Chem. 1998, 41, 821-835 as a compound having the following structure:

Concentration (μM) % Inhibition Concentration (μM) % Inhibition SB 207499 (Comparative) One ND SB 207499 (Comparative) One ND 10 40.9 10 40.9 Example 1 One 39.7 Example 8 One 38.4 10 40.5 10 40.3 Example 2 One 40.5 Example 9 One ND 10 42.8 10 18.9 Example 3 One 38.9 Example 10 One ND 10 41.3 10 15.0 Example 4 One 40.1 Example 11 One 37.7 10 45.4 10 41.5 Example 5 One 38.8 Example 12 One 40.4 10 39.3 10 42.0 Example 6 One 43.6 Example 13 One 37.9 10 42.8 10 40.3 Example 7 One 41.9 10 41.9

As can be seen from the results of Table 1, the compound according to the present invention showed an excellent PDE IV inhibitory activity compared to the control compound SB 207499.

Claims (5)

Catechol benzamide derivatives of Formula 1 below, pharmaceutically acceptable salts or isomers thereof: [Formula 1] In the above formula R ¹ represents C ₃ -C ₇ -cycloalkyl, indanyl or benzyl, X and Y each independently represent hydrogen, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxy, nitro, amino or halogen, X is , Y represents hydrogen, From here Z represents -C (= 0)-or -C (= 0) O-, R ² represents C ₁ -C ₇ -alkyl unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of halogen, hydroxy, acetoxy, C ₁ -C ₃ -alkoxy and amino; Phenyl substituted or unsubstituted by 1 to 2 substituents selected from the group consisting of nitro, cyano, halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein halogen is fluorine, chlorine or Bromine. The compound of claim 1, wherein R ¹ is C ₃ -C ₇ -cycloalkyl, and X and Y are each independently hydrogen, C ₁ -C ₇ -alkoxy, nitro or amino, or X is And Y is hydrogen, where Z is -C (= 0)-or -C (= 0) O- and R ² is C ₁ -C ₇ -alkyl unsubstituted or substituted by acetoxy; A compound which is phenyl unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of halogen and C ₁ -C ₃ -alkoxy. The method of claim 1, N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] benzamide; N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -2,4-dimethoxybenzamide; N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -3,4-dimethoxybenzamide; N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4-nitro-benzamide; 4-amino-N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] benzamide; {4- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethylcarbamoyl] -phenylcarbamoyl acetic acid methyl ester; N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4-benzamidobenzamide; N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4- (4-methoxybenzamido) -benzamide; {4- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethylcarbamoyl] -phenyl} -carbamic acid ethyl ester; {4- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethylcarbamoyl] -phenyl} -carbamic acid phenyl ester; N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4- (2,4-dimethoxybenzamido) -benzamide; N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4- (3,4-dimethoxybenzamido) -benzamide; And N- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -ethyl] -4- (4-bromobenzamido) -benzamide. (a) reacting a compound of formula 6 with a compound of formula 7 in the presence of a base in a solvent to give a compound of formula 1; (b) reducing the compound of formula 1a to yield a compound of formula 1b; (c) a catechol benzamide derivative as defined in claim 1, characterized in that the compound of formula 1b is subjected to a coupling reaction with a compound of formula 8 to give a compound of formula 1c To prepare acceptable salts or isomers thereof: [Formula 6] [Formula 7] [Formula 1a] [Formula 1b] [Formula 8] [Formula 1c] In the above formula R ¹ , X, Y, Z and R ² are as defined in claim 1, L represents hydroxy or halogen. Phosphodiesterase IV or TNF characterized by containing together with a pharmaceutically acceptable carrier an catechol benzamide derivative of formula (I) as defined in claim 1, a pharmaceutically acceptable salt or isomer thereof. Inhibitory pharmaceutical compositions.