KR100736838B1 - Novel catechol N-methylhydrazide derivatives and process for preparation thereof - Google Patents

Abstract

The present invention provides a catechol N-methylhydrazide derivative of Formula 1, a method for preparing the compound of Formula 1, and the compound of Formula 1, which have an inhibitory effect on phosphodiesterase IV or Tumor necrosis factor (TNF). A phosphodiesterase IV or TNF inhibitory pharmaceutical composition characterized in that it contains:

In the above formula

R ¹ and R ² are as defined in the specification.

Description

Novel catechol N-methylhydrazide derivatives and process for preparation

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

[Formula 1]

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.

The present invention also provides a method for preparing the compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof, and a phosphodiesterase IV or TNF inhibitory active 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, a compound of formula 2 having a catechol pyridazine parent nucleus was published by Merck (WO 99/65880):

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.

In addition, the present applicant has also reported to synthesize a catechol hydrazone derivative of the formula (3) 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.

Under this technical background, the present inventors conducted intensive studies to develop compounds exhibiting improved inhibitory activity against phosphodiesterase IV or TNF compared to previously reported compounds, and as a result, The compound has been found to meet this purpose and has been 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 (I), a salt or an isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier. It is done.

First, the present invention relates to catechol N-methylhydrazide 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 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.

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. It may also exist in trans or cis form, depending on the geometry of the double bond site. Accordingly, the scope of the present invention includes each of these isomers and mixtures thereof. Particular preference is given when the compound of formula 1 according to the invention is present in the trans form.

More preferred among the compounds of formula 1 according to the present invention are those wherein R ¹ is C ₃ -C ₇ -cycloalkyl or indanyl; R ² is -NH-YR ³ , wherein Y and R ³ are compounds as defined above.

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

4-nitrobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide;

4-Aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide;

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -4-nitrobenzamide;

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

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} benzamide;

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -4-methylbenzamide;                     

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2-methylbenzamide;

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -4-methoxybenzamide;

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2-methoxybenzamide;

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -3,5-dimethoxybenzamide;

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

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

Furan-2-carboxylic acid {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} amide;

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} isonicotinamide;

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -4-methylbenzenesulfonamide;

4-bromo-N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} benzenesulfonamide;                     

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2,2-dimethylpropionamide;

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

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2-phenylacetamide;

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2-phenoxyacetamide;

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} acetamide;

3-chloro-N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} propionamide;

2-chloro-N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} acetamide;

4-nitrobenzoic acid N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazide;

4-aminobenzoic acid N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazide;

N- (4- {N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazinocarbonyl} phenyl) -2,4-dimethoxybenzamide;                     

N- (4- {N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazinocarbonyl} phenyl) acetamide;

N- (4- {N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazinocarbonyl} phenyl) benzamide;

N- (4- {N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazinocarbonyl} phenyl) -2-methoxybenzamide;

N- (4- {N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazinocarbonyl} phenyl) -4-methoxybenzamide;

4-Aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide hydrochloride; And

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2-hydroxyacetamide.

Meanwhile, the compound of formula 1 according to the present invention, pharmaceutically acceptable salts and isomers thereof may be reacted with (a) the compound of formula 4 with 4-nitrobenzoylchloride in the presence of a base in a solvent to obtain a compound of formula 1a. do or; (b) reducing the obtained compound of formula 1a to yield a compound of formula 1b; (c) The compound of Chemical Formula 1b may be prepared by a coupling reaction with a compound of Chemical Formula 5 to obtain a compound of Chemical Formula 1c. Therefore, it is another object of the present invention to provide such a manufacturing method.                     

In the above formula

R ¹ , Y and R ³ are as defined above,

L represents hydroxy or halogen.

The method according to the present invention will be described in more detail by way of example.

First, any organic solvent which does not adversely affect the reaction may be used as the solvent in the method (a), but anhydrous methylene chloride is preferably used. As the base, triethylamine is preferably used, and the reaction is preferably carried out at a temperature of about 25 ° C.

In method (b) the reduction of the nitro group to the amino group can be carried out using conventional methods known in the art. For example, good results can be obtained by reacting a solvent such as tetrahydrofuran, methylene chloride and acetic acid at 60-70 ° C. using Pd / C and ammonium formate in a mixed solvent mixed with an alcohol solvent. If 10% Pd / C is used, Pd / C is used in an amount of 5 to 15% of the starting material and ammonium formate is used in 2 to 5 equivalents. Depending on the type of compound, the optimal reaction condition is to use 10% Pd / C in an amount of 7.5% and ammonia formate 2.5 equivalents.

The coupling reaction of the method (c) can be obtained by varying the reaction conditions depending on whether the leaving group L is hydroxy or halogen, or whether Y is carbonyl or sulfonyl. For example, when reacting a compound of Formula 5, ie, an acyl halide compound, in which Y is carbonyl or sulfonyl and L is halogen, with an amine derivative of Formula 1b, the reaction proceeds smoothly by using a base in anhydrous acetonitrile solvent. You can. At this time, as the base that can be used may refer to triethylamine or pyridine, and among them, preferably, pyridine may be used to synthesize the pure compound of Formula 1 in a yield of 60 to 90%. Or dicycloimide / 1-hydroxybenzotriazole or triphenylphosphine / hexa when coupling a compound of Formula 5, ie a carboxylic acid compound, with Y being carbonyl and L is hydroxy, i.e. The desired compound of formula 1 is synthesized by proceeding the reaction via an intermediate activated by an additional coupling agent such as chloroethane. In this reaction, triethylamine is preferably used as the base.

On the other hand, the compound of formula 4 used as a starting material in the method (a) can be prepared according to the method shown in Scheme 1.

In the above formula

R ¹ is as defined above,

L 'represents halogen.

Benzaldehyde in which 4-position hydroxy is substituted with methyl is reacted with a compound represented by R ¹ -L 'in a solvent such as anhydrous N, N-dimethylformamide in the presence of a base such as anhydrous potassium carbonate. Benzaldehyde substituted by methyl and R ¹ is synthesized. This compound is refluxed with methylhydrazine in an alcoholic solvent for 5 to 10 hours to obtain the desired compound of formula (4). At this time, methanol or ethanol is preferably used as the alcohol solvent, of which ethanol is suitable and the reaction time is suitable for 5 hours. This reaction is generally carried out under acid catalyst conditions, and the present inventors have performed the reaction with an acid catalyst such as hydrochloric acid, sulfuric acid, nitric acid, or the like to obtain a result of significantly lower side reactions and yields. Therefore, the present inventors proceeded the reaction without using an acid catalyst, thereby synthesizing the compound of Formula 4 with a high yield of 90% or more.

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.

Compounds of the invention may be administered in a single dose or in separate doses when administered for clinical purposes, and higher infections may be required for infection with some strains. 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 depyrogenated water 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

Anhydrous dimethylformamide (650 ml) suspension of isovanillin (100 g, 0.66 mol), anhydrous potassium carbonate (136.2 g, 0.99 mol) and potassium iodide (3 g) was stirred at 65 ° C. and then cyclopentyl was added to the suspension. Bromide (127.3 g, 0.85 mol) was slowly added dropwise for 1 hour. Stir at 65 ° C. for 1 day and then lower the temperature to room temperature. Toluene (2.0 L) was added to the mixture and diluted with 1M sodium hydroxide (2 × 1.5 L). The aqueous layer was extracted with toluene (0.5 L) and the organic layer obtained was washed with distilled water (2x1.5 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) 9.84 (s, 1H), 7.42 (m, 2H), 6.95 (d, 1H, J = 9Hz), 4.87 (m, 1H), 3.93 (s, 3H) , 2.1-1.6 (m, 8H)

Reference Example 2

Toluene-4-sulfonic acid indan-2-yl ester

2-indanol (5.0 gr, 37.3 mmol) was dissolved in 20 ml of anhydrous pyridine, and the reaction solution was cooled to 10 DEG C and stirred for 5 minutes. Tosyl chloride (8.53gr, 1.2 equiv) was added while maintaining the reaction temperature, the mixture was stirred for 30 minutes, and then stored in the refrigerating chamber for 3 days. The reaction solution was added dropwise to 300 ml of distilled water and stirred for 30 minutes. The precipitated crystals were filtered, washed with 200 ml of diethyl ether, and dried under reduced pressure at 40 ° C. to obtain a light brown solid title compound (4.6 gr).

¹ H NMR (400 MHz, CDCl ₃ , δ) 7.81 (d, 2H, 8.5 Hz), 7.35 (d, 2H, 8.5 Hz), 7.26 (s, 4H), 5.30 (m, 1H), 3.17 (m, 4H), 2.46 (s, 3H)

Reference Example 3

3- (Indan-2-yloxy) -4-methoxybenzaldehyde

Anhydrous dimethylformamide (160 mL) suspension of isovanillin (25.9 g, 0.17 mol), anhydrous potassium carbonate (35.1 g, 1.1 equiv) and potassium iodide (0.8 g) was stirred at 65 ° C. and then added to the suspension Toluene-4-sulfonic acid indan-2-yl ester (0.4 g, 2.62 equiv) was slowly added dropwise. Stir at 65 ° C. for 1 day and then lower the temperature to room temperature. Toluene (1.50 L) was added to the mixture and diluted with 1M sodium hydroxide (2 × 0.3 L). The aqueous layer was extracted with toluene (0.1 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 (62.9 g).

¹ H NMR (400 MHz, CDCl ₃ , δ) 9.90 (s, 1H), 7.57 (d, 1H, J = 10Hz), 7.47 (d, 1H, J = 1.6Hz), 7.27 (m, 2H), 7.19 (m, 3H), 5.29 (m, 1H), 3.81 (s, 3H), 3.38 (m, 2H), 3.03 (m, 2H)

Reference Example 4

N- (3-cyclopentyloxy-4-methoxybenzylidene) -N'-methylhydrazine

5.0 gr (22.7 mmol) of 3-cyclopentyloxy-4-methoxybenzaldehyde synthesized in Reference Example 1 was dissolved in 150 ml of anhydrous methanol and filled with argon gas. Methylhydrazine 1.05 gr (1.2 equiv) was added and stirred at 70 ° C. for 6 hours. The reaction solution was cooled and distilled under reduced pressure to obtain an orange oil, which was diluted with 150 ml of methylene chloride. After washing three times with 100ml of distilled water, the separated solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to give a light brown solid title compound (4.6 gr).

¹ H NMR (400 MHz, CDCl ₃ , δ) 1.64 (2H, m), 1.91 (4H, m), 2.01 (2H, m), 2.35 (3H, d, J = 1.0 Hz), 7.23 (1H, dd) , J = 1.0, 1.1 Hz), 7.66 (2H, d, J = 1.1 Hz), 7.89 (1H, d, J = 1.0 Hz), 8.60 (1H, brs), 10.05 (1H, s)

Reference Example 5

N- [3- (indan-2-yloxy) -4-methoxybenzylidene] -N'-methylhydrazine

6.3 gr (23.4 mmol) of 3- (indan-2-yloxy) -4-methoxybenzaldehyde synthesized in Reference Example 3 was dissolved in 150 ml of anhydrous methanol and filled with argon gas. 1.2 gr (1.1 equiv) of methylhydrazine were added and stirred at 70 ° C. for 6 hours. The reaction solution was cooled and distilled under reduced pressure to obtain an orange oil, which was then diluted with 200 ml of methylene chloride. After washing three times with 100ml of distilled water, the separated solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to give a light brown solid title compound (5.9 gr).                     

¹ H NMR (400 MHz, CDCl ₃ , δ) 7.41 (s, 1H), 7.30 (m, 2H), 7.21 (m, 1H), 7.20 (m, 2H), 7.00 (m, 2H), 6.91 (d , 1H), 5.19 (s, 1H), 3.68 (s, 3H), 3.38 (m, 2H), 3.06 (m, 2H), 2.79 (d, 3H, J = 4.8 Hz)

Example 1

4-nitrobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide

N- (3-cyclopentyloxy-4-methoxybenzylidene) -N'-methylhydrazine (2.0gr, 8.05mmol) synthesized in Reference Example 4 was dissolved in anhydrous methylene chloride (100ml), followed by argon gas. Filled. 4-nitrobenzoyl chloride (1.80gr, 1.2 equiv) was added at 20 ° C, and the mixture was stirred for 10 minutes at the same temperature. Triethylamine (1.50 mL, 1.3 equiv) was added and stirred at room temperature for 10 hours. The reaction solution was washed successively using 0.1 N sodium hydroxide, 0.1 N hydrochloric acid solution and distilled water (50 mL each), and the organic layer was extracted and separated. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give a pale yellow solid title compound (1.50 gr).

MS, m / e = 397

Melting Point = 173 ~ 174 ℃                     

¹ H NMR (400 MHz, CDCl ₃ , δ) 8.27 (dd, 2H, J = 1.9, 6.7 Hz), 7.83 (dd, 2H, J = 1.8, 6.8 Hz), 7.71 (s, 1H), 6.97 (m , 2H), 6.81 (m, 2H), 4.53 (m, 1H), 3.85 (s, 3H), 3.57 (s, 3H), 1.88 (m, 6H), 1.54 (m, 2H)

Example 2

4-Aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide

The 4-nitrobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.90gr) obtained in Example 1 was added with tetrahydrofuran (50 mL) and methanol (100 mL). After dissolving at 50 ° C in a mixed solvent of ammonium formate (1.0gr) was added to dissolve. At 60 ° C., 0.09 gr of palladium / activated carbon (5%, dry) was carefully added at once. The reaction solution was stirred for 10 minutes, cooled, filtered and distilled under reduced pressure. The obtained solid was dissolved in methylene chloride, and the insoluble solid was removed by washing with distilled water. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (0.52gr) as a white solid.

MS, m / e = 367                     

Melting Point = 80 ~ 82 ℃

¹ H NMR (400 MHz, CDCl ₃ , δ) 7.68 (m, 3H), 7.20 (d, 2H, J = 1.9 Hz), 7.01 (dd, 1H, J = 1.9, 8.3 Hz), 6.81 (d, 2H , J = 8.3 Hz), 6.61 (d, 1H, J = 8.6 Hz), 4.68 (m, 1H), 3.95 (brs, 2H), 3.86 (s, 3H), 3.50 (s, 3H), 1.84 (m , 6H), 1.59 (m, 2H)

Example 3

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -4-nitrobenzamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.2gr, 0.54mmol) synthesized in Example 2 was dissolved in anhydrous acetonitrile (30ml). After filling with argon gas. Pyridine (0.09 ml, 2.0 equiv) was added thereto, followed by stirring at 20 ° C. for 10 minutes. 4-nitrobenzoyl chloride (0.12gr, 1.2 equiv) was added and stirred at room temperature for 10 hours. Distilled water (20 mL) was added to the reaction solution, and the precipitated crystals were filtered by stirring for 1 hour. The mixture was washed with 100 ml (volume ratio 1/3) of ethyl acetate and hexane, and dried under reduced pressure at 40 ° C. to obtain the title compound (0.19 gr) as a pale yellow solid.                     

MS, m / e = 516

Melting Point = 237 ~ 238 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.75 (s, 1H), 8.30 (d, 2H, J = 8.7 Hz), 8.19 (d, 2H, J = 8.7 Hz), 7.91 (m, 3H ), 7.66 (d, 2H, J = 8.6 Hz), 7.07 (m, 2H), 6.94 (d, 1H, J = 8.2 Hz), 4.56 (m, 1H), 3.74 (s, 3H), 3.47 (s , 3H), 1.75 (m, 2H), 1.72 (m, 4H), 1.59 (m, 2H)

Example 4

4-bromo-N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} benzamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.2gr, 0.54mmol) synthesized in Example 2 was dissolved in 30 ml of anhydrous acetonitrile. Filled with argon gas. Pyridine (0.09 ml, 2.0 equiv) was added thereto, followed by stirring at 20 ° C. for 10 minutes. 4-Bromobenzoyl chloride (0.14 gr, 1.2 equiv) was added and stirred at room temperature for 10 hours. 20 ml of distilled water was added to the reaction solution, and the precipitated crystals were filtered by stirring for 1 hour. The mixture was washed with 100 ml (volume ratio 1: 4) of ethyl acetate and hexane, and dried under reduced pressure at 40 ° C. to obtain the title compound (0.21 gr) as a white solid.

MS, m / e = 550

Melting Point = 200 ~ 201 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.51 (s, 1H), 7.91 (m, 5H), 7.79 (d, 2H, J = 8.5 Hz), 7.65 (d, 2H, J = 8.6 Hz ), 7.08 (m, 2H), 6.96 (d, 1H, J = 8.2 Hz), 4.57 (m, 1H), 3.75 (s, 3H), 3.48 (s, 3H), 1.75 (m, 2H), 1.59 (m, 4H), 1.44 (m, 2H)

Example 5

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} benzamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.2gr, 0.54mmol) synthesized in Example 2 was dissolved in 30 ml of anhydrous acetonitrile. Filled with argon gas. Pyridine (0.09 ml, 2.0 equiv) was added thereto, followed by stirring at 20 ° C. for 10 minutes. Benzoyl chloride (0.10 mL, 1.5 equiv) was added and stirred at room temperature for 12 hours. 20 ml of distilled water was added to the reaction solution, and the precipitated crystals were filtered by stirring for 1 hour. The mixture was washed with 100 ml of ethyl acetate and hexane (volume ratio 1: 5), and dried under reduced pressure at 40 ° C. to obtain the title compound (0.15 gr) as a white solid.

MS, m / e = 471

Melting Point = 196 ~ 198 ℃

¹ H NMR (400 MHz, CDCl ₃ , δ) 7.79 (m, 7H), 7.51 (m, 3H), 7.14 (d, 2H, J = 1.8 Hz), 7.02 (dd, 1H, J = 1.9, 8.3 Hz ), 6.83 (d, 1H, J = 8.3 Hz), 4.67 (m, 1H), 3.85 (s, 3H), 3.55 (s, 3H), 1.81 (m, 6H), 1.54 (m, 2H)

Example 6

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -4-methylbenzamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.30gr, 0.82mmol) synthesized in Example 2 was dissolved in 30 ml of anhydrous acetonitrile. Filled with argon gas. Pyridine (0.14 mL, 2.1 equiv) was added thereto, followed by stirring at 20 ° C. for 10 minutes. p-Toluoyl chloride (0.16 gr, 1.3 equiv) was added and stirred at room temperature for 10 hours. 20 ml of distilled water was added to the reaction solution, and the precipitated crystals were filtered by stirring for 1 hour. The mixture was washed with 100 ml (volume ratio 1: 3) of ethyl acetate and hexane, and dried under reduced pressure at 40 ° C. to obtain the title compound (0.16 gr) as a white solid.

MS, m / e = 485

Melting Point = 182 ~ 183 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.28 (s, 1H), 7.98 (d, 2H, J = 8.8Hz), 7.91 (m, 3H), 7.64 (d, 2H, J = 8.6Hz ), 7.09 (m, 4H), 6.96 (d, 1H, J = 8.1 Hz), 4.57 (m, 1H), 3.86 (s, 3H), 3.75 (s, 3H), 3.48 (s, 3H), 1.77 (m, 2H), 1.58 (m, 4H), 1.45 (m, 2H)

Example 7

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2-methylbenzamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.30gr, 0.82mmol) synthesized in Example 2 was dissolved in 30 ml of anhydrous acetonitrile. Filled with argon gas. Pyridine (0.14 mL, 2.1 equiv) was added thereto, followed by stirring at 20 ° C. for 10 minutes. o-Toluoyl chloride (0.16 gr, 1.3 equiv) was added and stirred at room temperature for 10 hours. 20 ml of distilled water was added to the reaction solution, and the precipitated crystals were filtered by stirring for 1 hour. The mixture was washed with 100 ml (volume ratio 1: 3) of ethyl acetate and hexane, and dried under reduced pressure at 40 ° C. to obtain the title compound (0.19 gr) as a white solid.

MS, m / e = 485

Melting Point = 184 ~ 185 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.26 (s, 1H), 7.91 (m, 3H), 7.65 (d, 3H, J = 8.2 Hz), 7.55 (s, 1H), 7.11 (m , 3H), 6.96 (d, 1H, J = 7.8 Hz), 4.58 (m, 1H), 3.87 (s, 6H), 3.76 (s, 3H), 3.48 (s, 3H), 1.79 (m, 2H) , 1.60 (m, 4H), 1.46 (m, 2H)

Example 8

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -4-methoxybenzamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.20gr, 0.54mmol) synthesized in Example 2 was dissolved in 30 ml of anhydrous acetonitrile. Filled with argon gas. Pyridine (0.09 ml, 2.0 equiv) was added thereto, followed by stirring at 20 ° C. for 10 minutes. 4-anisoyl chloride (0.12gr, 1.3 equiv) was added thereto, and the mixture was stirred at room temperature for 10 hours. 20 ml of distilled water was added to the reaction solution, and the precipitated crystals were filtered by stirring for 1 hour. The mixture was washed with 100 ml of a mixture of ethyl acetate and hexane (volume ratio 1: 4) and dried under reduced pressure at 40 ° C. to obtain the title compound (0.185 gr) as a white solid.

MS, m / e = 501

Melting Point = 180 ~ 181 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.28 (s, 1H), 7.98 (d, 2H, J = 8.8Hz), 7.91 (m, 3H), 7.64 (d, 2H, J = 8.6Hz ), 7.09 (m, 4H), 6.96 (d, 1H, J = 8.1 Hz), 4.57 (m, 1H), 3.86 (s, 3H), 3.75 (s, 3H), 3.48 (s, 3H), 1.77 (m, 2H), 1.58 (m, 4H), 1.45 (m, 2H)

Example 9

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2-methoxybenzamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.20gr, 0.54mmol) and o-anisoyl chloride (0.11ml, synthesized in Example 2) 1.3 equivalents) was reacted in the same manner as in Example 8 to obtain the title compound (0.17gr) as a white solid.                     

MS, m / e = 501

Melting Point = 178 ~ 179 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.36 (s, 1H), 7.92 (s, 1H), 7.86 (d, 2H, J = 8.5 Hz), 7.65 (m, 3H), 7.54 (m , 1H), 7.21 (d, 1H, J = 8.5 Hz), 7.10 (m, 3H), 6.97 (d, 1H, 8.7 Hz), 4.59 (m, 1H), 3.93 (s, 3H), 3.76 (s , 3H), 3.48 (s, 3H), 1.79 (m, 2H), 1.63 (m, 4H), 1.53 (m, 2H)

Example 10

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -3,5-dimethoxybenzamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.20gr, 0.54mmol) and 3,5-dimethoxybenzoyl chloride synthesized in Example 2 ( 0.13 gr, 1.2 equivalents) was reacted in the same manner as in Example 8, to obtain the title compound (0.18 gr) as a white solid.

MS, m / e = 531                     

Melting Point = 207 ~ 208 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.37 (s, 1H), 7.91 (m, 3H), 7.64 (d, 2H, J = 8.5 Hz), 7.08 (m, 4H), 6.96 (d , 1H, J = 8.4Hz), 6.75 (s, 1H), 4.57 (m, 1H), 3.84 (s, 6H), 3.75 (s, 3H), 3.41 (s, 3H), 1.78 (m, 2H) , 1.61 (m, 4H), 1.47 (m, 2H)

Example 11

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2,4-dimethoxybenzamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.20gr, 0.54mmol) and 2,4-dimethoxybenzoyl chloride synthesized in Example 2 ( 0.13 gr, 1.2 equiv) was reacted in the same manner as in Example 8 to obtain the title compound (0.16 gr) as a white solid.

MS, m / e = 531

Melting Point = 163 ~ 165 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.09 (s, 1H), 7.90 (s, 1H), 7.84 (d, 2H, J = 8.7Hz), 7.76 (d, 1H, J = 8.6Hz ), 7.63 (d, 2H, J = 8.7 Hz), 7.09 (m, 2H), 6.95 (d, 1H, J = 8.8 Hz), 6.70 (m, 2H), 4.57 (m, 1H), 3.97 (s , 3H), 3.85 (s, 3H), 3.74 (s, 3H), 3.46 (s, 3H), 1.78 (m, 2H), 1.59 (m, 4H), 1.46 (m, 2H)

Example 12

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -3,4-dimethoxybenzamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.30gr, 0.82mmol) synthesized in Example 2 and 3,4-dimethoxybenzoyl chloride ( 0.21 gr, 1.3 equiv) was reacted in the same manner as in Example 8 to obtain the title compound (0.25 gr) as a white solid.

MS, m / e = 531

Melting Point = 191 ~ 192 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.26 (s, 1H), 7.91 (m, 3H), 7.65 (d, 3H, J = 8.2 Hz), 7.55 (s, 1H), 7.11 (m , 3H), 6.96 (d, 1H, J = 7.8 Hz), 4.58 (m, 1H), 3.87 (s, 6H), 3.76 (s, 3H), 3.48 (s, 3H), 1.79 (m, 2H) , 1.60 (m, 4H), 1.46 (m, 2H)

Example 13

Furan-2-carboxylic acid {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} amide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.20gr, 0.54mmol) synthesized in Example 2 and 2-peroylchloride (0.07ml, 1.3 equivalents) was reacted in the same manner as in Example 8, to obtain the title compound (0.145 gr) as a white solid.

MS, m / e = 461

Melting Point = 185 ~ 187 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.35 (s, 1H), 7.97 (m, 1H), 7.91 (s, 1H), 7.89 (d, 2H, J = 8.8Hz), 7.63 (d , 2H, J = 8.6 Hz), 7.39 (dd, 1H, J = 3.4, 1.7 Hz), 7.09 (dd, 1H, J = 8.2, 1.9 Hz), 7.05 (d, 1H, J = 1.9 Hz), 6.96 (d, 1H, J = 8.3 Hz), 6.74 (dd, 1H, J = 3.5, 1.7 Hz), 4.57 (m, 1H), 3.75 (s, 3H), 3.47 (s, 3H), 1.75 (m, 2H), 1.58 (m, 4H), 1.44 (m, 2H)

Example 14

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} isonicotinamide

Dissolve triphenylphosphine (1.3gr, 4.90mmol) and hexachloroethane (1.15gr, 4.90mmol) in 50ml of methylene chloride, stir at 20 ° C for 1 hour, and add isonicotinic acid (0.5gr, 4.1mmol). It was. The reaction solution was stirred at 20 ° C. for 1 hour. 4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.5gr, 1.36mmol) synthesized in Example 2 was dissolved in 50 ml of methylene chloride and 30 minutes The reaction mixture was added dropwise and stirred for 10 hours. The reaction mixture was concentrated under reduced pressure to dissolve the liquid substance in 100 ml of dichloromethane, and the organic layer was washed with distilled water 100 ml (twice). The separated organic layer was distilled under reduced pressure to obtain a solid substance obtained by silica gel column chromatography (eluent: dichloromethane / hexane = 1/1, v / v) to give the title compound (0.36 gr) as a pale yellow solid.

MS, m / e = 472

Melting Point = 209 ~ 211 ℃                     

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.79 (s, 1H), 8.89 (d, 2H, J = 6.0 Hz), 7.79 (d, 2H, J = 5.9 Hz), 7.93 (s, 1H ), 7.92 (d, 2H, J = 8.6 Hz), 7.68 (d, 2H, J = 8.6 Hz), 7.09 (m, 2H), 6.96 (d, 1H, J = 8.2 Hz), 4.58 (m, 1H ), 3.76 (s, 3H), 3.48 (s, 3H), 1.76 (m, 2H), 1.61 (m, 4H), 1.46 (m, 2H)

Example 15

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -4-methylbenzenesulfonamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.20gr, 0.54mmol) and p-toluenesulfonylchloride synthesized in Example 2 (0.13gr) , 1.2 equivalents) was reacted in the same manner as in Example 8, to obtain the title compound (0.19 gr) as a white solid.

MS, m / e = 521

Melting Point = 145 ~ 147 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.51 (s, 1H), 7.91 (m, 5H), 7.79 (d, 2H, J = 8.5 Hz), 7.65 (d, 2H, J = 8.6 Hz ), 7.08 (m, 2H), 6.96 (d, 1H, J = 8.2 Hz), 4.57 (m, 1H), 3.75 (s, 3H), 3.48 (s, 3H), 1.75 (m, 2H), 1.59 (m, 4H), 1.44 (m, 2H)

Example 16

4-bromo-N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} benzenesulfonamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.20gr, 0.54mmol) and 4-bromobenzenesulfonylchloride synthesized in Example 2 ( 0.17 gr, 1.2 equiv) was reacted in the same manner as in Example 8 to obtain the title compound (0.21gr) as a white solid.

MS, m / e = 586

Melting Point = 150 ~ 151 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.37 (s, 1H), 7.91 (m, 3H), 7.64 (d, 2H, J = 8.5 Hz), 7.08 (m, 4H), 6.96 (d , 1H, J = 8.4Hz), 6.75 (s, 1H), 4.57 (m, 1H), 3.84 (s, 6H), 3.75 (s, 3H), 3.41 (s, 3H), 1.78 (m, 2H) , 1.61 (m, 4H), 1.47 (m, 2H)

Example 17

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2,2-dimethylpropionamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.20gr, 0.54mmol) and pivaloylchloride (0.09ml, 1.3) synthesized in Example 2 Equivalent weight) was reacted in the same manner as in Example 8, to obtain the title compound (0.18 gr) as a white solid.

MS, m / e = 451

Melting Point = 161 ~ 162 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 9.37 (s, 1H), 7.90 (s, 1H), 7.78 (d, 2H, J = 8.6 Hz), 7.60 (d, 2H, J = 8.6 Hz ), 7.08 (m, 2H), 6.96 (d, 1H, 8.7 Hz), 4.57 (m, 1H), 3.76 (s, 3H), 3.46 (s, 3H), 1.76 (m, 2H), 1.65 (m , 4H), 1.51 (m, 2H), 1.25 (s, 9H)

Example 18

Acetic acid {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenylcarbamoyl} methyl ester

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.20gr, 0.54mmol) synthesized in Example 2 and acetoxyacetylchloride (0.08ml, 1.3) Equivalent weight) was reacted in the same manner as in Example 8, to obtain the title compound (0.19 gr) as a white solid.

MS, m / e = 467

Melting Point = 187 ~ 188 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.28 (s, 1H), 7.91 (s, 1H), 7.68 (d, 2H, J = 8.7 Hz), 7.62 (d, 2H, J = 8.7 Hz ), 7.10 (m, 2H), 6.96 (d, 1H, J = 8.1 Hz), 4.68 (s, 2H), 4.57 (m, 1H), 3.76 (s, 3H), 3.46 (s, 3H), 2.14 (s, 3H), 1.78 (m, 2H), 1.61 (m, 4H), 1.55 (m, 2H)

Example 19

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2-phenylacetamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.30gr, 0.82mmol) synthesized in Example 2 and phenylacetylchloride (0.10ml, 1.3equivalent) ) Was reacted in the same manner as in Example 8 to obtain the title compound (0.16 gr) as a white solid.

MS, m / e = 485

Melting Point = 179 ~ 180 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.36 (s, 1H), 7.90 (s, 1H), 7.71 (d, 2H, J = 8.8 Hz), 7.61 (d, 2H, J = 8.8 Hz ), 7.35 (m, 4H), 7.28 (m, 1H), 7.06 (m, 2H), 6.95 (d, 1H, J = 8.2 Hz), 4.52 (m, 1H), 3.75 (s, 3H), 3.68 (s, 2H), 3.45 (s, 3H), 1.68 (m, 2H), 1.56 (m, 4H), 1.41 (m, 2H)

Example 20

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2-phenoxyacetamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.30gr, 0.82mmol) synthesized in Example 2 and phenoxyacetyl chloride (0.10ml, 1.3 Equivalent weight) was reacted in the same manner as in Example 8, to obtain the title compound (0.18 gr) as a white solid.

MS, m / e = 501

Melting Point = 169 ~ 170 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.22 (s, 1H), 7.92 (s, 1H), 7.76 (d, 2H, J = 8.7Hz), 7.64 (d, 2H, J = 8.7Hz ), 7.34 (m, 2H), 7.08 (m, 2H), 7.02 (m, 3H), 6.97 (m, 1H), 4.73 (s, 2H), 4.57 (m, 1H), 3.76 (s, 3H) , 3.47 (s, 3H), 1.75 (m, 2H), 1.63 (m, 4H), 1.49 (m, 2H)

Example 21

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} acetamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.30gr, 0.82mmol) synthesized in Example 2 and acetyl chloride (0.05ml, 1.3equivalent) Was reacted in the same manner as in Example 8 to obtain the title compound (0.16 gr) as a white solid.

MS, m / e = 409

Melting Point = 208 ~ 209 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.14 (s, 1H), 7.89 (s, 1H), 7.68 (d, 2H, J = 8.7 Hz), 7.60 (d, 2H, J = 8.7 Hz ), 7.07 (m, 2H), 6.96 (d, 1H, J = 8.1 Hz), 4.56 (m, 1H), 3.76 (s, 3H), 3.46 (s, 3H), 2.08 (s, 3H), 1.78 (m, 2H), 1.65 (m, 4H), 1.53 (m, 2H)

Example 22

3-chloro-N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} propionamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.30gr, 0.82mmol) synthesized in Example 2 and 3-chloropropionyl chloride (0.07ml , 1.3 equivalents) was reacted in the same manner as in Example 8, to obtain the title compound (0.16 gr) as a white solid.

MS, m / e = 457

Melting Point = 176 ~ 177 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.34 (s, 1H), 7.84 (s, 1H), 7.71 (d, 2H, J = 8.7 Hz), 7.63 (d, 2H, J = 8.7 Hz ), 7.09 (m, 2H), 6.96 (d, 1H, J = 8.6 Hz), 4.57 (m, 1H), 3.91 (t, 2H, J = 6.1 Hz), 3.76 (s, 3H), 3.47 (s , 3H), 2.86 (t, 2H, J = 6.1 Hz), 1.76 (m, 2H), 1.64 (m, 4H), 1.54 (m, 2H)

Example 23

2-chloro-N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} acetamide

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide (0.30gr, 0.82mmol) synthesized in Example 2 and chloroacetyl chloride (0.06ml, 1.3equivalent) ) Was reacted in the same manner as in Example 8 to obtain the title compound (0.17gr) as a white solid.

MS, m / e = 443

Melting Point = 183 ~ 184 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.50 (s, 1H), 7.91 (s, 1H), 7.70 (d, 2H, J = 8.7 Hz), 7.64 (d, 2H, J = 8.7 Hz ), 7.07 (m, 2H), 6.96 (d, 1H, J = 8.2 Hz), 4.56 (m, 1H), 4.28 (s, 2H), 3.76 (s, 3H), 3.47 (s, 3H), 1.77 (m, 2H), 1.63 (m, 4H), 1.54 (m, 2H)

Example 24

4-nitrobenzoic acid N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazide

N- [3- (indan-2-yloxy) -4-methoxybenzylidene] -N'-methylhydrazine (5.9 gr, 20.2 mmol) synthesized in Reference Example 5 was dissolved in 250 ml of anhydrous methylene chloride, and Filled with argon gas. 4-nitrobenzoyl chloride (4.50gr, 1.2 equiv) was added at 20 ° C, and the mixture was stirred for 10 minutes at the same temperature. Triethylamine (4.3 mL, 1.5 equiv) was added and stirred at room temperature for 10 hours. The reaction solution was washed successively using 0.1 N sodium hydroxide, 0.1 N hydrochloric acid solution and distilled water (150 mL each), and the organic layer was extracted and separated. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (3.53gr) as a pale yellow solid.

MS, m / e = 445

Melting Point = 230 ~ 232 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 8.28 (d, 2H, J = 8.4 Hz), 7.96 (s, 1H), 7.84 (d, 2H, J = 8.4 Hz), 7.18 (m, 2H ), 7.14 (m, 2H), 7.06 (m, 1H), 6.99 (d, 1H, J = 1.0 Hz), 6.90 (d, 1H, J = 8.4 Hz), 4.91 (m, 1H), 3.70 (s , 3H), 3.52 (s, 3H), 3.10 (m, 2H), 2.98 (m, 2H)

Example 25

4-Aminobenzoic acid N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazide

4-nitrobenzoic acid N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazide (2.4gr, 5.39mmol) synthesized in Example 24 was dissolved in anhydrous methylene chloride ( 200 ml), dissolved in a mixture of acetic acid (40 ml) and methanol (10 ml) and stirred for 10 minutes. 80 mg of palladium / activated carbon (5%) was added to the reaction solution and charged with hydrogen gas. Stirred at 20 ° C. for 20 minutes and washed five times with 200 ml of saturated sodium bicarbonate solution. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give the pale yellow title compound (1.9 gr).

MS, m / e = 415

Melting point = 76 ~ 78 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 7.89 (s, 1H), 7.53 (d, 2H, J = 8.6Hz), 7.29 (m, 3H), 7.18 (m, 3H), 6.98 (d , 2H, J = 8.3 Hz, 6.57 (d, 2H, J = 9.0 Hz), 5.56 (brs, 2H), 5.07 (m, 1H), 3.70 (s, 3H), 3.42 (s, 3H), 3.32 (m, 2H), 3.02 (m, 2H)

Example 26

N- (4- {N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazinocarbonyl} phenyl) -2,4-dimethoxybenzamide

4-aminobenzoic acid N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazide (0.2gr, 0.48mmol) synthesized in Example 25 and 2,4- Dimethoxybenzoyl chloride (0.12 gr, 1.2 equiv) was reacted in the same manner as in Example 8 to obtain the title compound (0.13 gr) as a white solid.                     

MS, m / e = 579

Melting Point = 173 ~ 175 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.02 (s, 1H), 7.95 (s, 1H), 7.85 (d, 2H, J = 8.7Hz), 7.67 (d, 2H, J = 8.6Hz ), 7.54 (d, 1H, J = 8.6 Hz), 7.19 (m, 6H), 7.06 (d, 1H, J = 8.3 Hz), 6.64 (d, 1H, J = 2.2 Hz), 6.59 (dd, 1H) , J = 2.3, 8.6Hz), 5.01 (m, 1H), 3.83 (d, 6H, J = 2.3Hz), 3.69 (s, 3H), 3.32 (s, 3H), 3.19 (dd, 2H, J = 6.0, 17.1 Hz), 2.94 (d, 2H, J = 16.9 Hz)

Example 27

N- (4- {N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazinocarbonyl} phenyl) acetamide

4-aminobenzoic acid N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazide (0.2gr, 0.48mmol) synthesized in Example 25 with acetylchloride (0.04) ML, 1.2 equivalents) was reacted in the same manner as in Example 8, to obtain the title compound (0.14 gr) as a white solid.

MS, m / e = 457                     

Melting Point = 191 ~ 193 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.04 (s, 1H), 7.93 (s, 1H), 7.68 (d, 2H, J = 8.7Hz), 7.62 (d, 2H, J = 8.6Hz ), 7.24 (m, 2H), 7.14 (m, 4H), 6.96 (d, 1H, J = 8.2 Hz), 4.98 (m, 1H), 3.69 (s, 3H), 3.47 (s, 3H), 3.20 (dd, 2H, J = 6.0, 17.1 Hz), 2.94 (d, 2H, J = 16.9 Hz)

Example 28

N- (4- {N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazinocarbonyl} phenyl) benzamide

4-Aminobenzoic acid N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazide (0.15 gr, 0.36 mmol) and benzoyl chloride (0.05) synthesized in Example 25 ML, 1.2 equivalents) was reacted in the same manner as in Example 8, to obtain the title compound (0.14 gr) as a white solid.

MS, m / e = 519

Melting Point = 226 ~ 228 ℃                     

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.38 (s, 1H), 7.96 (s, 1H), 7.92 (d, 2H, J = 8.6Hz), 7.75 (d, 2H, J = 7.3Hz ), 7.69 (d, 2H, J = 8.7 Hz), 7.57 (m, 1H), 7.46 (m, 2H), 7.21 (m, 4H), 7.15 (m, 2H), 6.98 (d, 1H, J = 8.2 Hz), 5.02 (m, 1H), 3.71 (s, 3H), 3.50 (s, 3H), 3.25 (dd, 2H, J = 6.1, 16.9 Hz), 2.96 (d, 2H, J = 16.9 Hz)

Example 29

N- (4- {N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazinocarbonyl} phenyl) -2-methoxybenzamide

4-aminobenzoic acid N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazide (0.15gr, 0.36mmol) synthesized in Example 25 and 2-methoxy Benzoyl chloride (0.07 mL, 1.2 equiv) was reacted in the same manner as in Example 8 to obtain the title compound (0.13 gr) as a white solid.

MS, m / e = 549

Melting Point = 148 ~ 150 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.25 (s, 1H), 7.96 (s, 1H), 7.87 (d, 2H, J = 8.6Hz), 7.69 (d, 2H, J = 8.6Hz ), 7.48 (m, 1H), 7.33 (dd, 1H, J = 8.5, 1.6 Hz), 7.22 (m, 3H), 7.10 (m, 4H), 6.98 (d, 1H, J = 8.4 Hz), 6.97 (m, 1H), 5.03 (m, 1H), 3.78 (s, 3H), 3.70 (s, 3H), 3.50 (s, 3H), 3.24 (dd, 2H, J = 5.9, 16.9 Hz), 2.96 ( d, 2H, J = 16.8 Hz)

Example 30

N- (4- {N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazinocarbonyl} phenyl) -4-methoxybenzamide

4-aminobenzoic acid N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazide (0.15gr, 0.36mmol) synthesized in Example 25 and 4-methoxy Benzoyl chloride (0.074 gr, 1.2 equiv) was reacted in the same manner as in Example 8 to obtain the title compound (0.13 gr) as a white solid.

MS, m / e = 549

Melting Point = 205 ~ 207 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.22 (s, 1H), 7.96 (s, 1H), 7.91 (d, 2H, J = 8.7Hz), 7.79 (d, 2H, J = 8.8Hz ), 7.68 (d, 2H, J = 8.7 Hz), 7.21 (m, 4H), 7.07 (m, 2H), 6.97 (m, 3H), 5.03 (m, 1H), 3.84 (s, 3H), 3.71 (s, 3H), 3.50 (s, 3H), 3.24 (dd, 2H, J = 6.0, 17.1 Hz), 2.96 (d, 2H, J = 16.8 Hz)

Example 31

4-Aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide hydrochloride

The compound (0.2gr, 0.54mmol) synthesized in Example 2 was dissolved in ethyl acetate (20ml) at room temperature, and 0.1N hydrochloric acid solution (1.5ml) dissolved in ethanol was slowly added dropwise. The crystals formed were stirred at room temperature for 30 minutes, filtered and dried to afford the title compound (0.18 gr) as a white solid.

MS, m / e = 403

Melting point = 204 ° C., decomposition

¹ H NMR (400 MHz, CDCl ₃ , δ) 7.73 (m, 3H), 7.24 (d, 2H, J = 1.9 Hz), 7.08 (dd, 1H, J = 1.9, 8.3 Hz), 6.82 (d, 2H , J = 8.3 Hz), 6.63 (d, 1H, J = 8.6 Hz), 4.68 (m, 1H), 3.95 (brs, 2H), 3.86 (s, 3H), 3.50 (s, 3H), 1.84 (m , 6H), 1.59 (m, 2H)

Example 32

N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2-hydroxyacetamide

The compound (0.30 gr, 6.4 mmol) synthesized in Example 18 was dissolved in methanol (20 mL) and 1.0 N potassium hydroxide solution (8.0 mL) dissolved in methanol was slowly added dropwise at room temperature. The reaction solution was stirred at room temperature for 20 minutes, and the oily product obtained by distillation under reduced pressure was dissolved in ethyl acetate (100 mL) and washed twice with distilled water (100 mL). The separated organic layer was dried over magnesium sulfate and distilled under reduced pressure to obtain a white title compound (0.21 gr).

MS, m / e = 425

Melting Point = 157 ~ 158 ℃

¹ H NMR (400 MHz, DMSO, δ) 9.84 (s, 1H), 7.91 (s, 1H), 7.81 (dd, 2H, J = 1.7, 7.0 Hz), 7.61 (dd, 2H, J = 1.7, 7.0 Hz), 7.07 (m, 2H), 6.96 (d, 1H, J = 8.1 Hz), 5.68 (t, 2H, J = 5.9 Hz), 4.56 (m, 1H), 4.02 (d, 2H, 6.0 Hz) , 3.76 (s, 3H), 3.46 (s, 3H), 1.79 (m, 2H), 1.65 (m, 4H), 1.53 (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 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) 0.3 56.0 SB 207499 (Comparative) 0.3 56.0 0.1 43.1 0.1 43.1 Example 1 0.3 76.3 Example 16 0.3 72.9 0.1 63.2 0.1 60.9 Example 2 0.3 73.2 Example 17 0.3 73.6 0.1 66.6 0.1 67.8 Example 3 0.3 73.8 Example 18 0.3 81.2 0.1 56.6 0.1 76.3 Example 4 0.3 78.4 Example 19 0.3 82.9 0.1 75.9 0.1 81.5 Example 5 0.3 80.4 Example 20 0.3 N.T. 0.1 78.1 0.1 N.T. Example 6 0.3 72.5 Example 21 0.3 N.T. 0.1 65.1 0.1 N.T. Example 7 0.3 76.6 Example 22 0.3 N.T. 0.1 75.3 0.1 N.T. Example 8 0.3 76.6 Example 23 0.3 N.T. 0.1 75.5 0.1 N.T. Example 9 0.3 78.8 Example 24 0.3 N.T. 0.1 76.7 0.1 N.T. Example 10 0.3 76.4 Example 25 0.3 N.T. 0.1 74.3 0.1 N.T. Example 11 0.3 83.6 Example 26 0.3 N.T. 0.1 83.1 0.1 N.T. Example 12 0.3 78.7 Example 27 0.3 N.T. 0.1 76.3 0.1 N.T. Example 13 0.3 N.T. Example 28 0.3 N.T. 0.1 N.T. 0.1 N.T. Example 14 0.3 N.T. Example 29 0.3 N.T. 0.1 N.T. 0.1 N.T. Example 15 0.3 78.9 Example 30 0.3 N.T. 0.1 73.5 0.1 N.T.

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 (6)

Catechol N-methylhydrazide derivative of Formula 1 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 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. The compound of claim 1, wherein R ¹ is C ₃ -C ₇ -cycloalkyl or indanyl; R ² is -NH-YR ³ , wherein Y and R ³ are as defined in claim 1. The method of claim 1, 4-nitrobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide; 4-Aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -4-nitrobenzamide; 4-bromo-N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} benzamide; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} benzamide; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -4-methylbenzamide; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2-methylbenzamide; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -4-methoxybenzamide; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2-methoxybenzamide; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -3,5-dimethoxybenzamide; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2,4-dimethoxybenzamide; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -3,4-dimethoxybenzamide; Furan-2-carboxylic acid {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} amide; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} isonicotinamide; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -4-methylbenzenesulfonamide; 4-bromo-N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} benzenesulfonamide; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2,2-dimethylpropionamide; Acetic acid {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenylcarbamoyl} methylester; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2-phenylacetamide; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2-phenoxyacetamide; N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} acetamide; 3-chloro-N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} propionamide; 2-chloro-N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} acetamide; 4-nitrobenzoic acid N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazide; 4-aminobenzoic acid N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazide; N- (4- {N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazinocarbonyl} phenyl) -2,4-dimethoxybenzamide; N- (4- {N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazinocarbonyl} phenyl) acetamide; N- (4- {N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazinocarbonyl} phenyl) benzamide; N- (4- {N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazinocarbonyl} phenyl) -2-methoxybenzamide; N- (4- {N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazinocarbonyl} phenyl) -4-methoxybenzamide; 4-Aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide hydrochloride; And N- {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -2-hydroxyacetamide. The compound according to claim 1, which is present in trans form. (a) reacting a compound of formula 4 with 4-nitrobenzoylchloride in the presence of a base in a solvent to give a compound of formula 1a; (b) reducing the obtained compound of formula 1a to yield a compound of formula 1b; (c) the compound of formula 1 or a pharmaceutically acceptable salt thereof as defined in claim 1, characterized in that the obtained compound of formula 1b is subjected to a coupling reaction with a compound of formula 5 to give a compound of formula 1c How to manufacture: [Formula 4]

[Formula 1a]

[Formula 1b]

[Formula 5]

[Formula 1c]

In the above formula R ¹ , Y and R ³ are as defined in claim 1, L represents hydroxy or halogen. Asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction, psoriasis, allergic rhinitis containing as an active ingredient a compound of formula f1 or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier A pharmaceutical composition for treating or preventing a disease associated with phosphodiesterase IV or TNF selected from the group consisting of, dermatitis, AIDS, HIV, Crohn's disease, sepsis, septic shock and etiology.