KR100866285B1 - Novel catechol hydrazide derivatives and process for preparation thereof - Google Patents

Abstract

The present invention contains a catechol hydrazide derivative of Formula 1 below, a method for preparing the compound of Formula 1, and a compound of Formula 1, which have an inhibitory effect on phosphodiesterase IV or Tumor necrosis factor (TNF). A phosphodiesterase IV or TNF inhibitory agonistic pharmaceutical composition characterized by:

In the above formula

R ¹ , R ² , R ³ and Y are as defined in the specification.

Description

Novel catechol hydrazide derivatives and process for preparation

The present invention relates to a catechol hydrazide derivative of Formula 1, a pharmaceutically acceptable salt or isomer thereof having an inhibitory effect on phosphodiesterase IV or Tumor necrosis factor (TNF):

[Formula 1]

In the above formula

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

R ² represents hydrogen or C ₁ -C ₅ -alkyl,

Y represents a direct bond, or represents carbonyl (-CO-) or carbonyloxy [-C (= O) O-],

R ³ represents C ₁ -C ₇ -alkyl unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, hydroxy, phenyl, acetyloxy and amino; 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, or pyridyl, 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, Merck reported in WO 00/26201 a new catechol pyridazine compound of formula (2) which introduced a pyridazine structure to the basic structure of 3-methoxy-4-cyclopentoxy, the parent of catechol ethers. :

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 ,

R ³ is R ⁴ , Halogen, OH, OR ⁴ , OPh, NO ₂ , NHR ⁴ , N (R ⁴ ) ₂ , NHCOR ⁴ , NHSOR ⁴ or NHCOOR ⁴ ,

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 applicant has also reported the synthesis of a catechol hydrazone derivative of the following Chemical Formula 3 based on 4-methoxy-3-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, trifluoromethyl, (C ₁ ~ C ₆₎ al Kills such as 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 (4) comprising 3-methoxy-4-cyclopentyloxy, which is the parent of catechol ether in Korean Patent Application No. 10-2001-0024139. On the other hand, Korean Patent Application No. 10-2002-0019747 also discloses a novel catechol hydrazide derivative of the formula (5).

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.

In the above formula

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

R ² represents hydrogen or C ₁ -C ₅ -alkyl or carbonyl substituted by C ₁ -C ₅ -alkoxy, phenyl, phenoxy or benzyloxy,

R ³ and R ⁴ each independently represent hydrogen or C ₁ -C ₅ -alkyl,

Y represents a direct bond or carbonyl (-CO-) or carbonyloxy [-C (= 0) O-],

R ⁵ represents hydrogen or C ₁ -C ₅ -alkoxy; C ₁ -C ₇ -alkyl unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, phenyl, pyridine and hydroxy; 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, or pyridyl, 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 hydrazide 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,

R ² represents hydrogen or C ₁ -C ₅ -alkyl,

Y represents a direct bond or carbonyl (-CO-) or carbonyloxy [-C (= 0) O-],

R ³ represents C ₁ -C ₇ -alkyl unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, hydroxy, phenyl, acetyloxy and amino; 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, or pyridyl, 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 bicarbonates (e.g. sodium bicarbonate, potassium bicarbonate), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate), alkaline earth metal carbonates (e.g. 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.                     

More preferred among the compounds of formula 1 according to the present invention are those wherein R ¹ is C ₃ -C ₇ -cycloalkyl; R ² is C ₁ -C ₅ -alkyl; Y is carbonyl (-CO-) or carbonyloxy [-C (= 0) O-]; R ³ is C ₁ -C ₇ -alkyl unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, hydroxy, phenyl and acetyloxy, or a group consisting of halogen and C ₁ -C ₃ -alkoxy Or a phenyl unsubstituted or substituted by one or two substituents selected from among the above.

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

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -2,4-dimethoxybenzamide;

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -3,4-dimethoxybenzamide;

{4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -carbamic acid benzyl ester;

{4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -carbamic acid methyl ester;

{4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -carbamic acid ethyl ester;                     

{4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -carbamic acid phenylester;

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -benzamide;

4-bromo-N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -benzamide;

Acetic acid {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] -phenylcarbamoyl} -methylester;

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -2-hydroxy-acetamide; And

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -isonicotinamide.

On the other hand, the compound of formula 1 according to the present invention, pharmaceutically acceptable salts and isomers thereof can be prepared according to the method shown in Scheme 1 below.                     

In the above formula

R ¹ , R ² , R ³ and Y are as defined above,

B represents a leaving group, preferably halogen.

Referring to the production method according to the invention shown in Scheme 1 in more detail.

Compound (6) having bromomethyl and nitro substituents is reacted with methylhydrazine in a methylene chloride solvent at room temperature for 10 to 24 hours to obtain compound (7) having hydrazino group introduced therein. The obtained compound (7) was subjected to a hydrogenation reaction at room temperature using 10% Pd / C in ethanol solvent to reduce the nitro group to convert to an amino group, thereby preparing compound (8). In this case, 10% Pd / C is preferably used in 5.0 to 15% by weight based on the compound (7) as a starting material. Compound (9) synthesized according to a known method (J. Med. Chem. 1988, 41, 821-835) was reacted with a compound (8) obtained in the previous step by stirring in a methylene chloride solvent for 12 hours to give a compound (10 ) Can be obtained. Finally, compound (10) is reacted with compound (11), such as acyl chloride or chloroformate, in the presence of a base in anhydrous acetonitrile solvent to give the desired compound of formula (1). In this case, the compound (11) is preferably used in an amount of 1.0 to 2.0 equivalents based on the compound (10), and triethylamine or pyridine is preferably used as the base. In particular, when pyridine is used, pure target compound (1) can be obtained in a yield of 70 to 90% by simple chemical treatment.

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 for treating asthma, arthritis, osteoarthritis, bronchitis, chronic obstructive obesity, 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 typically ranges from 1 to 10 mg per kilogram, 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. In addition, it may be in the form of dry powder for immediate use, which is, for example, sterile and deionized, and used before being dissolved with water.

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

Synthesis of N-methyl-N- (4-nitrobenzyl) hydrazine

A mixture of methyl hydrazine (4.2 g, 92 mmol), 4-nitrobenzyl bromide (10.0 g, 18 mmol), methanol (10 mL) and methylene chloride (100 mL) was stirred at 20 ° C. for 16 hours. To the suspension was added 100 ml of saturated aqueous NaHCO ₃ solution and the layers were separated. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated to give a reddish brown title compound (6.4 gr).

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 8.35 (d, 2H), 8.04 (d, 2H), 6.10 (s, 1H), 5.10 (s, 2H), 3.35 (s, 3H)

Reference Example 2

Synthesis of 4- (N-methylhydrazinomethyl) phenylamine

After dissolving 6.4 gr of N-methyl-N- (4-nitrobenzyl) hydrazine synthesized in Reference Example 1 in ethanol (50 ml), 500 mg of palladium / activated carbon (5%, dry) was carefully added at once to hydrogenate. The reaction was advanced. After confirming that the pressure of hydrogen did not drop any more, the reaction solution was filtered and distilled under reduced pressure to obtain the title compound (4.6 gr) as a light brown liquid, which was used immediately in the next reaction.

Reference Example 3

Synthesis of 4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenylamine hydrobromide

4.6 gr (30.4 mmol) of 4- (N-methylhydrazinomethyl) phenylamine synthesized in Reference Example 2 was dissolved in anhydrous methylene chloride (40 mL) and charged with argon gas. Methylene chloride (50 mL) in which 4-bromomethyl-2-cyclopentyloxy-1-methoxy-benzene 8.6gr (30.4mmole) was dissolved at 20 ° C was added thereto, followed by stirring at the same temperature for 12 hours. As the starting material disappears, a solid forms and precipitates. After confirming that the starting material disappeared by TLC, the resulting solid was filtered and washed twice with 20 ml of methylene chloride. A yellow solid title compound (8.7 gr) was obtained.

Mass Spectrum, m / e = 356

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 7.21 (m, 3H), 7.11 (d, 1H), 7.04 (d, 1H), 6.63 (d, 2H), 5.48 (s, 3H), 4.79 (m, 1H), 4.50 (m, 4H), 3.79 (s, 3H), 2.83 (s, 3H), 1.91 (m, 2H), 1.74 (m, 4H), 1.58 (m, 2H)

Example 1

Synthesis of N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -2,4-dimethoxybenzamide

40 ml of anhydrous acetonitrile in 0.5 g (1.15 mmol) of 4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] -phenylamine hydrobromide obtained in Reference Example 3 It was dissolved in, 0.20 ml (2.0 equivalent) of pyridine was added and stirred at 20 ° C. for 30 minutes. 0.23 gr (1.0 equiv) of 2,4-dimethoxybenzoyl chloride was added and stirred at room temperature for 6 hours. 60 ml of distilled water was added to the reaction solution, acetonitrile was distilled off under reduced pressure, and 30 ml of methylene chloride was added thereto, and the layers were separated. The organic layer was separated, dried over MgSO ₄ and concentrated. The residue was separated and purified by column chromatography (eluent: methylene chloride / methanol = 30/1 to 10/1) to give the title compound (0.40 gr) as a white solid.

Mass Spectrum, m / e = 520

Melting Point = 72 ~ 74 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.1 (s, 1H), 7.85 (d, 2H, J = 8.6 Hz), 7.74 (d, 1H, J = 8.6 Hz), 7.57 (d, 2H , J = 8.6 Hz), 7.18 (d, 1H, J = 1.4 Hz), 7.13 (dd, 1H, J = 1.9 Hz, 8.3 Hz), 7.10 (d, 1H, J = 8.3 Hz), 6.74 (d, 1H, J = 2.3Hz, 6.69 (dd, 1H, J = 2.3Hz, 8.7Hz), 5.60 (s, 1H), 4.81 (m, 1H), 4.40 (m, 4H), 3.97 (s, 3H) , 3.86 (s, 3H), 3.81 (s, 3H), 2.90 (s, 3H), 1.91 (m, 2H), 1.75 (m, 4H), 1.58 (m, 2H)

Example 2

Synthesis of N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -3,4-dimethoxybenzamide

4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] -phenylamine hydrobromide 0.5gr (1.15mmole) and 3,4-dimethol obtained by the reference example 3 The title compound (0.21 gr) was obtained in the same manner as in Example 1, except that 0.23 gr (1.0 equivalent) of oxybenzoyl chloride was used as a starting material.

Mass Spectrum, m / e = 520

Melting Point = 136 ~ 137 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.3 (s, 1H), 7.91 (d, 2H), 7.63 (d, 1H), 7.54 (m, 3H), 7.10 (m, 4H), 5.60 (s, 1H), 4.80 (m, 1H), 4.60 (m, 4H), 3.86 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 2.91 (s, 3H), 1.90 ( m, 2H), 1.74 (m, 4H), 1.59 (m, 2H)

Example 3

Synthesis of {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -carbamic acid benzyl ester

4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] -phenylamine hydrobromide 0.5gr (1.15mmole) and benzylchloroformate 0.34 obtained in the reference example 3 The title compound (0.30 gr) was obtained by reaction in the same manner as in Example 1 except that gr (1.7 equiv) was used as the starting material.

Mass Spectrum, m / e = 490

Melting Point = 89 ~ 91 ℃

¹ H NMR (400 MHz, CDCl ₃ , δ) 10.2 (s, 1H), 7.59 (d, 2H), 7.52 (d, 2H), 7.35 (m, 6H), 7.11 (d, 1H), 6.89 (d , 1H), 5.75 (s, 1H), 5.18 (m, 3H), 4.84 (m, 3H), 3.86 (s, 3H), 3.48 (s, 2H), 2.99 (s, 3H), 2.01 (m, 2H), 1.80 (m, 4H), 1.60 (m, 2H)

Example 4

Synthesis of {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -carbamic acid methyl ester

4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] -phenylamine hydrobromide 0.5gr (1.15mmole) and methylchloroformate 0.16 obtained by the reference example 3. The title compound (0.10 gr) was obtained in the same manner as in Example 1 except that gr (1.5 equivalent) was used as a starting material.

Mass Spectrum, m / e = 414

Melting Point = 74 ~ 75 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 9.90 (s, 1H), 7.55 (d, 2H), 7.48 (d, 2H), 7.15 (s, 1H), 7.04 (m, 2H), 5.56 (s, 1H), 4.77 (m, 1H), 4.56 (m, 4H), 3.77 (s, 3H), 3.67 (s, 3H), 2.84 (s, 3H), 1.87 (m, 2H), 1.70 ( m, 4H), 1.55 (m, 2H)

Example 5

Synthesis of {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -carbamic acid ethyl ester

4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] -phenylamine hydrobromide obtained in Reference Example 3 with 0.3gr (0.68mmole) and ethylchloroformate 0.089 The title compound (0.15 gr) was obtained in the same manner as in Example 1, except that gr (1.2 equivalents) was used as a starting material.

Mass Spectrum, m / e = 428

Melting point = 77 ~ 78 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 9.86 (s, 1H), 7.55 (d, 2H), 7.47 (d, 2H), 7.14 (s, 1H), 7.05 (m, 2H), 5.54 (s, 1H), 4.77 (m, 1H), 4.53 (m, 4H), 4.11 (m, 2H), 3.77 (s, 3H), 3.30 (s, 3H), 2.84 (s, 3H), 1.87 ( m, 2H), 1.70 (m, 4H), 1.55 (m, 2H)

Example 6

Synthesis of {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -carbamic acid phenylester

4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] -phenylamine hydrobromide 0.2gr (0.46mmole) and phenylchloroformate 0.086 obtained by the reference example 3. The title compound (0.04 gr) was obtained in the same manner as in Example 1, except that gr (1.2 equivalents) was used as a starting material.

Mass Spectrum, m / e = 476

Melting Point = 96 ~ 98 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 9.38 (s, 1H), 7.23 ~ 7.05 (m, 6H), 6.76 (m, 2H), 6.63 (m, 2H), 5.75 (s, 1H) , 5.48 (m, 2H), 4.79 (m, 1H), 4.48 (m, 4H), 3.79 (s, 3H), 2.82 (s, 3H), 1.91 (m, 2H), 1.72 (m, 4H), 1.58 (m, 2 H)

Example 7

Synthesis of N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -benzamide

0.2 g (0.46 mmole) of 4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] -phenylamine hydrobromide obtained in Reference Example 3 and 0.084 gr of benzoyl chloride ( 1.2 equivalent) was used in the same manner as in Example 1 except that the title compound (0.14 gr) was obtained.

Mass Spectrum, m / e = 460

Melting Point = 74 ~ 76 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.47 (s, 1H), 7.97 (m, 4H), 7.61 (m, 5H), 7.24 (d, 1H), 7.10 (m, 2H), 5.66 (s, 1H), 4.80 (m, 1H), 4.66 (m, 4H), 3.80 (s, 3H), 2.91 (s, 3H), 1.92 (m, 2H), 1.73 (m, 4H), 1.58 ( m, 2H)

Example 8

Synthesis of 4-bromo-N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -benzamide

4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] -phenylamine hydrobromide 0.2gr (0.46mmole) and 4-bromobenzoyl obtained in the reference example 3 The title compound (0.05gr) was obtained by the same method as in Example 1, except that 0.13 gr (1.3 equivalent) of chloride was used as a starting material.

Mass Spectrum, m / e = 539

Melting Point = 61 ~ 63 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.55 (s, 1H), 7.93 (m, 4H), 7.77 (d, 2H, J = 8.5Hz), 7.61 (d, 2H, J = 8.6Hz ), 7.23 (d, 1H), 7.12 (m, 2H), 5.68 (s, 1H), 4.80 (m, 1H), 4.66 (m, 4H), 3.80 (s, 3H), 2.91 (s, 3H) , 1.92 (m, 2H), 1.74 (m, 4H), 1.58 (m, 2H)

Example 9

Synthesis of acetic acid {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] -phenylcarbamoyl} -methylester

4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] -phenylamine hydrobromide 0.5gr (1.15mmole) and acetoxyacetylchloride 0.19 obtained by the reference example 3. The title compound (0.40gr) was obtained in the same manner as in Example 1, except that gr (1.3 equiv) was used as the starting material.

Mass Spectrum, m / e = 456

Melting Point = 73 ~ 75 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.37 (s, 1H), 7.71 (d, 2H, J = 8.6 Hz), 7.54 (d, 2H, J = 8.6 Hz), 7.17 (s, 1H ), 7.12 (d, 1H, J = 8.2 Hz), 7.06 (d, 1H, J = 8.2 Hz), 5.59 (s, 1H), 4.80 (m, 1H), 4.68 (s, 2H), 4.56 (m , 4H), 3.79 (s, 3H), 2.87 (s, 3H), 2.13 (s, 3H), 2.02 (m, 2H), 1.73 (m, 4H), 1.57 (m, 2H)

Example 10

Synthesis of N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -2-hydroxy-acetamide

0.30 gr of acetic acid {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] -phenylcarbamoyl} -methyl ester obtained in Example 9 10 ml), and 1.1 ml of 1N KOH aqueous solution was added thereto, followed by stirring for 2 hours. 20 ml of 1N HCl aqueous solution and 50 ml of methylene chloride were added to the reaction solution. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (0.15 gr) as a white solid.

Mass Spectrum, m / e = 414

Melting Point = 70 ~ 71 ℃

¹ H NMR (400 MHz, DMSO, δ) 10.03 (s, 1H), 7.83 (d, 2H, J = 8.6Hz), 7.56 (d, 2H, J = 8.6Hz), 7.24 (d, 1H, J = 1.9 Hz), 7.13 (dd, 1H, J = 1.9 Hz, 8.3 Hz), 7.04 (d, 1H, J = 8.4 Hz), 5.76 (s, 1H), 4.81 (m, 1H), 4.66 (m, 4H ), 4.02 (s, 2H), 3.79 (s, 3H), 2.87 (s, 3H), 2.13 (s, 3H), 1.90 (m, 2H), 1.71 (m, 4H), 1.57 (m, 2H)

Example 11

Synthesis of N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -isonicotinamide

4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] -phenylamine hydrobromide 0.2gr (0.46mmole) and isicotinoyl chloride obtained in the reference example 3 The title compound (0.10gr) was obtained in the same manner as in Example 1, except that 0.10 gr (1.2 equivalent) of hydrochloride was used as a starting material.

Mass Spectrum, m / e = 461

Melting Point = 110 ~ 111 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.73 (s, 1H), 8.81 (d, 2H), 7.91 (d, 2H), 7.88 (d, 2H), 7.62 (d, 2H), 7.21 (s, 1H), 7.13 (dd, 1H), 7.07 (d, 1H), 5.65 (s, 1H), 4.81 (m, 1H), 4.63 (m, 4H), 3.80 (s, 3H), 2.90 ( s, 3H), 1.90 (m, 2H), 1.72 (m, 4H), 1.59 (m, 2H)

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 [ ³ H] cAMP were incubated at 30 ° C. for 20 min. The PDE reaction, in which cAMP was converted to AMP, was completed by boiling for 2 minutes. Snake venom nucleotidase (Snake venom nucleotidase) (Sigma V7000; snake venom from Crotalus atrox) was added at a final concentration of 0.2 mg / ml and incubated at 30 ° C. for 10 minutes to convert AMP to adenosine. 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 (nM) % Inhibition Concentration (nM) % Inhibition SB 207499 (Comparative) 100 39.4 SB 207499 (Comparative) 100 39.4 10 12.4 10 12.4 Example 1 100 35.6 Example 7 100 18.3 10 31.5 10 11.4 Example 2 100 39.2 Example 8 100 12.4 10 30.1 10  9.2 Example 3 100 33.8 Example 9 100 22.0 10 29.8 10 10.7 Example 4 100 16.0 Example 10 100  9.4 10 15.1 10  5.2 Example 5 100 17.9 Example 11 100  6.1 10 16.3 10  3.2 Example 6 100 21.1 10 13.4

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

Claims (4)

Catechol hydrazide derivatives of formula (I) or a pharmaceutically acceptable salt thereof: [Formula 1]

In the above formula R ¹ represents C ₃ -C ₇ -cycloalkyl, indanyl or benzyl, R ² represents hydrogen or C ₁ -C ₅ -alkyl, Y represents a direct bond or carbonyl (-CO-) or carbonyloxy [-C (= 0) O-], R ³ represents C ₁ -C ₇ -alkyl unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, hydroxy, phenyl, acetyloxy and amino; 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, or pyridyl, wherein Halogen is fluorine, chlorine or bromine. The compound of claim 1, wherein R ¹ is C ₃ -C ₇ -cycloalkyl; R ² is C ₁ -C ₅ -alkyl; Y is carbonyl (-CO-) or carbonyloxy [-C (= 0) O-]; R ³ is C ₁ -C ₇ -alkyl unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, hydroxy, phenyl and acetyloxy, or a group consisting of halogen and C ₁ -C ₃ -alkoxy Or phenyl unsubstituted or substituted by one or two substituents selected from the group consisting of pyridyl. The method of claim 1, N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -2,4-dimethoxybenzamide; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -3,4-dimethoxybenzamide; {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -carbamic acid benzyl ester; {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -carbamic acid methyl ester; {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -carbamic acid ethyl ester; {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -carbamic acid phenylester; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -benzamide; 4-bromo-N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -benzamide; Acetic acid {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] -phenylcarbamoyl} -methylester; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -2-hydroxy-acetamide; And N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinomethyl] phenyl} -isonicotinamide. Asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease, psoriasis, allergy, containing as an active ingredient a compound of formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, together with a pharmaceutically acceptable carrier For the treatment of diseases associated with phosphodiesterase IV or tumor necrosis factor (TNF) selected from the group consisting of sexual rhinitis, dermatitis, AIDS, HIV, Crohn's disease, sepsis, septic shock and etiology Pharmaceutical compositions.