KR100508156B1 - Cathechol Hydrazide Derivatives - Google Patents

Abstract

The present invention relates to novel catechol hydrazide derivatives. More specifically, it relates to a novel catechol hydrazide derivative having the structure of formula (1). The compound according to the present invention has an inhibitory effect on phosphodiesterase IV or Tumor necrosis factor (TNF), and also has asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease, psoriasis, allergic rhinitis, dermatitis It is also useful in the treatment of diseases including AIDS, HIV, Crohn's disease, sepsis, septic shock, other inflammatory diseases such as fetal odor, and production of TNF.

<Formula 1>

(In the formula, R ₁ to R ₄ and Y are the same as defined in the specification.)

Description

Novel catechol hydrazide derivatives

The present invention relates to novel catechol hydrazide derivatives, pharmaceutically acceptable salts or isomers thereof. More specifically, the present invention relates to novel catechol hydrazide derivatives, pharmaceutically acceptable salts thereof, and isomers that have an inhibitory activity against PDE IV or TNF having the structure of Formula 1.

In the above formula

R ₁ is a (C ₃ -C ₇ ) cycloalkyl, Indan or benzyl group,

R ₂ is or or or or or And

R ₅ and R ₆ are each a (C ₁ -C ₅ ) alkyl group, X is O, S, NR ₇ ,

R ₇ is hydrogen or a (C ₁ -C ₅ ) alkyl group,

R ₃ is hydrogen or a (C ₁ -C ₅ ) alkyl group,

Y is a direct bond or -C (= O)-, or -C (= O) O-,

R ₄ is (C ₁ -C ₇ ) alkyl wherein one or two halogen, hydroxy, phenyl or amine compounds are optionally substituted or unsubstituted; Nitro, nitrile, halogen, (C ₁ -C ₃ ) alkyl or (C ₁ -C ₃ ) alkoxy groups optionally substituted with 1 to 2 substituted or unsubstituted phenyl, and

Halogen is Cl, F, or Br

Phosphodiesterase (hereinafter referred to as PDE) is an enzyme that hydrolyzes cyclic nucleotides as one of the chemical delivery agents. In particular, PDE IV is an enzyme that selectively hydrolyzes cyclic adenosine 3 ', 5'-monophosphate to inactive adenosine 3', 5'-monophosphate and cyclic adenosine 3 ', 5'-monophosphate is an external cellular stimulus. As a second messenger responsible for regulating the response of cells to the body, it relaxes and contracts the bronchial muscles.

Inhibition of PDE IV prevents bronchial spasms by maintaining the concentration of cyclic adenosine 3 ', 5'-monophosphate. Therefore, compounds that inhibit PDE IV are useful as therapeutic agents for asthma.

Tumor necrosis factor (TNF) is known to be associated with many infections, including atherosclerosis, and autoimmune diseases, which are seen as the major mediators of the inflammatory response seen in sepsis and septic shock.

To date, compounds having a structure similar to the present invention have been disclosed as inhibitors for PDE IV or TNF, as follows.

International Publication No. WO00 / 26201, filed by Merck, discloses a material having a structure having a catechol pyridazine nucleus, specifically 3, the mother of cathetchol ethers. A new catechol pyridazine compound having a structure represented by the following formula (2), which introduces a pyridazine structure to the basic structure of 3-methoxy-4-cyclopentoxy, is disclosed.

In the above formula

B comprises an unsubstituted phenyl ring or a phenyl ring substituted with R ³ ,

Q is a C ₁ to C ₄ alkylene group,

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

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

R ⁴ is — (C ₃ to C ₇ ) cycloalkyl, alkylenecycloalkyl of (C ₅ to C ₁₀ ), alkenyl group of (C ₂ to C ₈ ), and halogen is F, Cl, Br or I group .

In the international application WO 00/73280 filed by the present applicant, 3-methoxy-4-cyclopentyloxy, which is a mother core of catechol ether, has a basic structure. It has been disclosed with respect to catechol hydrazone derivatives such as the formula (3).

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 group _,

R ³ and R ⁴ are independently hydrogen, C ₁ -C ₇ alkyl, C (= X) -R ⁵ , or 2-, 3- or 4-pyridyl, pyrimidyl or halogen, (C ₁ -C ₆ ) A phenyl group substituted with alkoxy, nitro, trifluoromethyl, (C ₁ -C ₆ ) alkyl, etc. _,

X is oxygen, sulfur or NH group,

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

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

In addition, Korean Patent Application No. 2001-24139 filed by the present applicant discloses a novel method of 3-methoxy-4-cyclopentyloxy, which is a parent nucleus of catechol ether. A catechol N-methylhydrazide derivative has been disclosed, which is represented by the following Chemical Formula 4.

In the above formula

R ^{1 is a} (C ₃ -C ₇ ) cycloalkyl, indan or benzyl group,

R ² is a methyl group,

Y means a bond and is a -C = O or -SO ₂ group,

R ³ is (C ₁ -C ₇ ) alkyl, or a heterocyclic compound containing 1 or 2 (C ₁ -C ₇ ) alkyl optionally substituted with 1 to 2 halogens, nitrogen, oxygen or sulfur, or Nitro, nitrile, halogen, (C ₁ -C ₃ ) alkyl or (C ₁ -C ₃ ) alkoxy groups, optionally with 1 to 2 substituted phenyl groups.

Wherein halogen is Cl, F, or Br

In addition, Korean Patent Application No. 2002-019747 discloses a novel catechol N-methylhydrazide derivative as shown in Formula 5 below.

In the above formula

R ¹ is a (C ₃ -C ₇ ) cycloalkyl, indan or benzyl group,

R ² is a methyl group,

Y means a bond or -C (= O)-, or -C (= O) O-,

R ³ is (C ₁ -C ₇ ) alkyl wherein one or two halogen, hydroxy, phenyl or amine compounds are optionally substituted or unsubstituted; Phenyl optionally substituted with 1 to 2 substituted nitro, nitrile, halogen, (C ₁ -C ₃ ) alkyl or (C ₁ -C ₃ ) alkoxy groups,

R ⁴ is hydrogen or a (C ₁ -C ₅ ) alkyl group

Wherein halogen is Cl, F, or Br

Although the compounds as described above are similar in purpose to the present invention, it can be seen that the compounds are structurally different from the present invention.

Therefore, the present inventors have diligently studied the problems of the prior art, and have found a novel compound of Chemical Formula 1, which can be expected to inhibit the action of PDE IV or TNF, thus completing the present invention.

It is therefore an object of the present invention to provide a compound of formula 1, a pharmaceutically acceptable salt or isomer thereof.

Another object of the present invention is to provide a method of preparing a compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof.

Another object of the present invention is to provide a pharmaceutical composition containing a compound of formula 1, a salt thereof or an isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier.

The above and other objects of the present invention can be achieved by the present invention described below.

In order to achieve the above object, the present invention provides a derivative represented by the following formula (1) and salts thereof.

<Formula 1>

In the above formula

R ₁ is a (C ₃ -C ₇ ) cycloalkyl, indan or benzyl group,

R ₂ is or or or or or And

Wherein R ₅ and R ₆ are each a (C ₁ -C ₅ ) alkyl group, X is O, S, NR ₇ ,

Wherein R ₇ is hydrogen or a (C ₁ -C ₅ ) alkyl group,

R ₃ is hydrogen or a (C ₁ -C ₅ ) alkyl group,

Y means a direct bond or -C (= O)-, or -C (= O) O-

R ₄ is (C ₁ -C ₇ ) alkyl wherein one or two halogen, hydroxy, phenyl or amine compounds are optionally substituted or unsubstituted; Nitro, nitrile, halogen, (C ₁ -C ₃ ) alkyl or (C ₁ -C ₃ ) alkoxy groups are optionally substituted or unsubstituted phenyl.

Wherein halogen is Cl, F, or Br

The compound of Formula 1 may exist in the form of optical isomers, geometric isomers, and the present invention includes these isomers and mixtures thereof.

In addition, the compound of Formula 1 is (4-methylpiperazin-1-yl) -acetic acid N '-(4-benzyloxycarbonylamino-benzoyl) -N- (3-cyclopentyloxy-4-methoxy Benzyl) -N'-methylhydrazinocarbonyloxymethyl ester;

Pyrrolidin-1-yl acetic acid N '-(4-benzoyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methylhydrazinocarbonyloxymethyl ester ;

Morpholin-4-yl acetic acid N '-(4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methylhydrazinocarbonyloxymethyl ester ;

4-morpholin-4-yl-4-oxobutyric acid N '-(4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methylhydra Genocarbonyloxymethyl ester;

4- (4-Methylpiperazin-1-yl) -4-oxo-butyric acid N '-(4-benzyloxycarbonylamino-benzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl ) -N'-methylhydrazinocarbonyloxymethyl ester;

4-oxo-4-pyrrolidin-1-yl butyric acid N '-(4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methyl Hydrazinocarbonyloxymethyl esters;

N, N-dimethylsuccinamic acid N '-(4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methylhydrazinocarbonyloxymethyl One or more of the esters may be selected.

In another aspect, the present invention provides a method for preparing a compound of Formula 1 by reacting a compound of Formula 11 or a salt thereof in the presence of 18-crown-6 as a phase transition catalyst with potassium carbonate, specifically, a compound of Formula 11 Or (a) (4-) methylpiperazine1-yl) acetic acid, potassium iodide, potassium carbonate, 18-crown-6 ether, and a salt thereof to give a compound of formula 12 b) adding 1-pyrrolidinylacetic acid, potassium iodide, potassium carbonate, 18-crown-6 ether to react to obtain a compound of formula (13), or (c) 4-morpholinylacetic acid, Potassium iodide, potassium carbonate, 18-crown-6 ether to react to give a compound of formula 14, or (d) 4-morpholin-4-yl-4-oxobutyric acid, potassium iodide , Potassium carbonet Or 18-crown-6 ether to give a compound of formula 15, or (e) 4- (4-methylpiperazin-1-yl) -4-oxobutyric acid, potassium iodide, Potassium carbonate, 18-crown-6 ether is added to give a compound of formula 16, or (f) 4-oxo-4-pyrrolidin-1-yl butyric acid, potassium iodide, potassium carbonate, 18 -Crown-6 ether is added to give a compound of formula 17, or (g) N, N-dimethylsuccinamic acid, potassium iodide, potassium carbonate, 18-crown-6 ether is added to react To provide a compound of formula 1 to obtain a compound of formula 18 .

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

Hereinafter, the present invention will be described in detail.

The novel compounds represented by Formula 1 of the present invention may be prepared by the same method as in Scheme 1 below.

The reaction scheme 1 will be described in detail as follows.

Compound (1) was reacted with a reaction reagent designated R ¹ -A in anhydrous N, N-dimethylformamide solvent in the presence of anhydrous potassium carbonate to obtain compound (2), and methylhydrazine was refluxed in an alcoholic solvent. The reaction proceeds for 10 hours to synthesize compound (3). 4-nitrobenzoylchloride was reacted in the presence of a base in methylene chloride solvent to obtain compound (4), and 50 ^° C. using 10% Pd / C and ammonium formate in a mixed solvent of methyl alcohol and tetrahydrofuran. The reaction proceeds at from 70 ^o C. 10% Pd / C uses 5.0-15% of the starting material and 2-5 equivalents of ammonium formate.

Optimum reaction conditions were 10% Pd / C 7.5% and ammonia formate was 5 equivalents, and a reduction reaction was conducted under these conditions to synthesize an amine derivative compound (5). Compound (6) was synthesized by carrying out a coupling reaction with various ³ RYB compounds ^.

Compound (7) was synthesized by reaction with chloroformic acid chloromethyl ester in anhydrous methylene chloride solvent. Compound (7) and compound (8) were reacted with potassium carbonate in the presence of 18-crown-6 as a phase transfer catalyst in the presence of a benzene solvent to obtain the desired compound (I) (compound of formula 1).

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

As described above, the compound of formula 1 according to the present invention may be usefully used as a PDE IV, or TNF inhibitor, and the present invention provides a compound of formula I, a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. Or a PDE IV or TNF inhibitory active pharmaceutical composition containing an isomer thereof as an active ingredient.

The composition according to the invention is particularly effective for asthma, arthritis, bronchitis, chronic airway obstruction, psoriasis, allergic rhinitis, dermatitis, AIDS, HIV, Crohn's disease, sepsis, septic shock, inflammation It is useful for the treatment of gland diseases and diseases associated with the regulation of production of TNF.

The total daily dose to be administered to adults in single or separate doses when administering a compound of the present invention for clinical purposes is typically in the range of 1 to 10 mg per kg, although higher daily doses are required for infection by some strains. Can be. In addition, the specific dosage 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, excretion, drug mixture and severity of the disease.

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

Injectable solutions, 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-, 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

Preparation of 3-cyclopentyloxy-4-methoxybenzaldehyde

A suspension of 100 g of isovaniline, 136.2 g of anhydrous potassium carbonate, 3 g of potassium iodide, and 650 mL of anhydrous dimethylformamide was stirred at 65 ^° C., and then 127.3 g of cyclopentyl bromide was slowly added dropwise to the suspension for 1 hour, and 65 ^{o After} stirring for 1 day at C and lowering the temperature to room temperature, 2.0L of toluene was added to the mixture and diluted with 1M sodium hydroxide (2x1.5L). After extracting the obtained aqueous layer with 0.5L of toluene, the obtained organic layer was washed with distilled water (2x1.5L). The organic layer was dried and concentrated to give a light brown oily title compound (117 g) (Formula 6).

^{1H NMR (400 MHz, CDC l} 3, d) 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

Preparation of N- (3-cyclopentyloxy-4-methoxybenzylidene) -N'-methylhydrazine [N- (3-Cyclopentyloxy-4-methoxy-benzylidene) -N'-methyl-hydrazine]

Dissolve 5.0 g of 3-cyclopentyloxy-4-methoxybenzaldehyde synthesized in Reference Example 1 in 150 ml of anhydrous methyl alcohol, fill with argon gas, add 1.05 g of methylhydrazine, and stir at 70 ^° C. for 6 hours. It was. The reaction solution was cooled, distilled under reduced pressure to give an orange oil, diluted with 150 ml of methylene chloride, the reaction solution was diluted, washed three times with 100 ml of distilled water, and the separated solution was dried over anhydrous magnesium sulfate. The filtered solution was distilled under reduced pressure to obtain a light brown solid title compound (4.6 gr) (Formula 7).

¹ H NMR (400 MHz, CDCl ₃ , d) 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 3

4-nitrobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide [4-Nitro-benzoic acid N'-(3-cyclopentyloxy-4-methoxy-benzylidene) -N-methyl-hydrazide]

Synthesized in Reference Example 2 N- (3- cyclo pentyloxy-4-methoxy-benzylidene) -N'- methyl hydrazine to 2.0 g in dry methylene chloride were dissolved in 100 ml filled with argon gas and 20 ^o C 1.80 g of 4-nitrobenzoyl chloride was added thereto, followed by stirring for 10 minutes at the above temperature. Then, 1.50 ml of triethylamine was added thereto, followed by stirring at room temperature for 10 hours. The application solution was washed successively with 0.1 N sodium hydroxide, 0.1 N hydrochloric acid solution and distilled water in 50 ml each, and the organic solution layer was extracted and separated. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give a pale yellow solid (1.50 gr) (Formula 8).

Mass Spectrum, m / e = 397

M.P = ℃

¹ H NMR (400 MHz, CDCl ₃ , d) 8.27 (dd, 2H, J = 1.9,6.7) 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)

Reference Example 4

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazide [4-Amino-benzoic acid N'-(3-cyclopentyloxy-4-methoxy-benzyl)- N-methyl-hydrazide]

25 g of 4-nitrobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide synthesized in Reference Example 3 was dissolved in 250 ml of methanol and 250 ml of tetrahydrofuran. After adding 25 g of ammonium formate, the mixture was heated to reflux to completely dissolve, cooled to 35 ^° C., and 3 g of 10% palladium / activated carbon was added and heated to reflux for 5 hours. The remaining palladium was filtered off and distilled under reduced pressure to remove the solvent.

300 ml of ethyl acetate and 300 ml of water were added and stirred for 30 minutes, and then the organic solution layer was extracted and separated. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give the target compound (19.5 g) as a colorless oil (Formula 9).

 Mass Spectrum, m / e = 370

 M.P = 103 to 104 ° C

¹ H NMR (400 MHz, DMSO-d ₆ , d) 7.31 (d, 2H) 6.81 (d, 1H, J = 8.6 Hz), 6.73 (d, 2H), 6.50 (d, 2H J = 8.6 Hz), 5.43 (s, 2H), 4.54 (brs, 1H), 3.81 (d, 2H), 3.70 (s, 3H), 3.09 (s, 3H), 1.82 (m, 2H), 1.63 (m, 6H)

Reference Example 5

{4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinocarbonyl] phenyl} carbamic acid benzyl ester [{4- [N'-(3-Cyclopentyloxy-4 -methoxy-benzyl) -N-methyl-hydrazinocarbonyl] -phenyl} -carbamic acid benzyl ester]

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazide 36g synthesized in Reference Example 4 was dissolved in 120 ml of acetonitrile, and then cooled to 5 ° C., followed by sodium A solution of 12.3 g of bicarbonate in 60 ml of water was added dropwise for 30 minutes. 20 g of benzylchloroformate was added dropwise for 30 minutes, followed by stirring at room temperature for 12 hours.

After 300 ml of ethyl acetate was added and stirred for 10 minutes, the organic layer was separated, the aqueous layer was extracted with 100 ml of ethyl acetate, and the organic layers were combined and washed once with water. 50 ml of methanol was added to the oily compound obtained by drying over anhydrous magnesium sulfate, filtration, and then concentrated under reduced pressure, and recrystallized to obtain a target compound (15 g) as a white solid (Formula 10).

Mass Spectrum, m / e = 504

M.P = 151-153 ° C.

¹ H NMR (400 MHz, DMSO-d ₆ , d) 9.93 (s, 1H), 7.45 to 7.39 (m, 9H), 7.78 (m, 1H), 6.76 (m, 1H), 6.42 (m, 1H) , 5.17 (s, 2H), 4.32 (m, 1H), 3.79 (s, 2H), 3.68 (s, 3H), 3.14 (s, 3H), 1.71-1.46 (m, 8H)

Reference Example 6

N- (4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N-methyl hydrazinecarboxylic acid chloromethyl ester [N '-(4-Benzyloxycarbonylamino-benzoyl ) -N- (3-cyclopentyloxy-4-methoxy-benzyl) -N'-methyl-hydrazinecarboxylic acid chloromethyl ester]

0.5 g of {4- [N '-(3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinocarbonyl] phenyl} synthesized in Reference Example 5 was dissolved in 10 ml of methylene chloride. 0.14 g of chloroformic acid chloromethyl ester was added slowly and stirred for 12 hours. Using thin layer chromatography (solvent condition: ethyl acetate / hexane = 1/1), the starting material disappeared. The reaction solution was used in the next step without purification.

The material prepared in Reference Example 6 was the same as that of Formula 11, and used as a starting material of Examples 1 to 7 below.

Example 1

(4-Methylpiperazin-1-yl) -acetic acid N '-(4-benzyloxycarbonylamino-benzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methylhigh Drazinocarbonyloxymethyl ester [(4-Methyl-piperazin-1-yl) -acetic acid N '-(4-benzyloxycarbonylamino-benzoyl) -N- (3-cyclopentyloxy-4-methoxy-benzyl) -N'- Preparation of methyl-hydrazinocarbonyloxymethyl ester]

A solution of N- (4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinecarboxylic acid methyl ester obtained in Reference Example 6 (0.589 g) , 0.99 mmol) was distilled under reduced pressure to remove methylene chloride. 10 ml of anhydrous benzene was dissolved in it.

0.156 g of (4-methylpiperazin1-yl) acetic acid was added, 0.49 g of potassium iodide, 0.684 g of potassium carbonate, and 0.26 g of 18-crown-6 ether were added, and the mixture was heated to reflux for 12 hours. After cooling to room temperature, 10 ml of water and 10 ml of ethyl acetate were added, followed by stirring for 30 minutes, followed by layer separation to obtain an organic layer solvent, and the aqueous layer was extracted with 10 ml of ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled under reduced pressure. The mixture of the oily phase was column separated to obtain a target compound (0.53 g) (Formula 12).

(Methylene chloride: methanol = 10: 1)

Mass Spectrum, m / e = 717

¹ H NMR (400 MHz, DMSO-d ₆ , d) 9.53 (s, 1H), 7.45 to 7.19 (m, 9H), 6.87 (m, 2H), 6.78 (m, 1H), 6.76 (m, 1H) , 6.42 (m, 1H), 5.34 (s, 2H), 4.32 (m, 2H), 4.23 (m, 1H), 3.78 (s, 3H), 3.32 (m, 2H), 2.74 (s, 3H), 2.74-2.62 (m, 8H), 2.27 (m, 3H), 1.71-1.46 (m, 8H)

Example 2

Pyrrolidin-1-yl acetic acid N '-(4-benzoyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methylhydrazinocarbonyloxymethyl ester Preparation of [Pyrrolidin-1-yl acetic acid N '-(4-benzoyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methylhydrazinocarbonyloxymethylester]

A solution of N- (4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinecarboxylic acid methyl ester obtained in Reference Example 6 (0.589 g) , 0.99 mmol) was distilled under reduced pressure to remove methylene chloride. 10 ml of anhydrous benzene was dissolved in it.

0.127 g of 1-pyrrolidinylacetic acid was added, 0.49 g of potassium iodide, 0.684 g of potassium carbonate, and 0.26 g of 18-crown-6 ether were added thereto, and the mixture was heated to reflux for 12 hours. After cooling to room temperature, 10 ml of water and 10 ml of ethyl acetate were added, followed by stirring for 30 minutes, followed by layer separation to obtain an organic layer solvent, and the aqueous layer was extracted with 10 ml of ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled under reduced pressure. The resulting oily mixture was separated by column to obtain the target compound (0.53 g) (Formula 13).

Mass Spectrum, m / e = 688

¹ H NMR (400 MHz, DMSO-d ₆ , d) 9.51 (s, 1H), 7.43 ~ 7.23 (m, 9H), 6.87 (m, 2H), 6.78 (m, 1H), 6.73 (m, 1H) , 6.41 (m, 1H), 5.32 (m, 2H), 4.22 (m, 2H), 4.12 (m, 1H), 3.78 (s, 3H), 3.30 (m, 2H), 2.95 (s, 3H), 2.25 (m, 4H), 1.65 (m, 4H), 1.71-1.46 (m, 8H)

Example 3

Morpholin-4-yl acetic acid N '-(4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methylhydrazinocarbonyloxymethyl ester Preparation of [Morpholin-4-yl-acetic acid N '-(4-benzyloxycarbonylamino-benzoyl) -N- (3-cyclopentyloxy-4-methoxy-benzyl) -N'-methyl-hydrazinocarbonyloxymethyl ester]

A solution of N- (4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinecarboxylic acid methyl ester obtained in Reference Example 6 (0.589 g) , 0.99 mmol) was distilled under reduced pressure to remove methylene chloride. 10 ml of anhydrous benzene was dissolved in it.

0.143 g of 4-morpholinylacetic acid was added, 0.49 g of potassium iodide, 0.684 g of potassium carbonate, and 0.26 g of 18-crown-6 ether were added, and the mixture was heated to reflux for 12 hours. After cooling to room temperature, 10 ml of water and 10 ml of ethyl acetate were added, followed by stirring for 30 minutes, followed by layer separation to obtain an organic layer solvent, and the aqueous layer was extracted with 10 ml of ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled under reduced pressure. The resulting oily mixture was separated by column to obtain the target compound (0.53 g) (Formula 14).

(Methylene chloride: methanol = 10: 1)

Mass Spectrum, m / e = 704

¹ H NMR (400 MHz, DMSO-d ₆ , d) 9.62 (s, 1H), 7.48 ~ 7.19 (m, 9H), 6.97 (m, 2H), 6.76 (m, 1H), 6.71 (m, 1H) , 6.41 (m, 1H), 5.32 (m, 2H), 4.22 (m, 2H), 4.12 (m, 1H), 3.78 (s, 3H), 3.30 (m, 2H), 3.28 (m, 4H), 2.98 (s, 3H), 2.37 (m, 4H), 1.71-1.46 (m, 8H)

Example 4

4-morpholin-4-yl-4-oxobutyric acid N '-(4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methylhydra Zinocarbonyloxymethyl ester [4-Morpholin-4-yl-4-oxo-butyric acid N '-(4-benzyloxycarbonylamino-benzoyl) -N- (3-cyclopentyloxy-4-methoxy-benzyl) -N'-methyl -hydrazinocarbonyloxymethyl ester]

A solution of N- (4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinecarboxylic acid methyl ester obtained in Reference Example 6 (0.589 g) , 0.99 mmol) was distilled under reduced pressure to remove methylene chloride. 10 ml of anhydrous benzene was dissolved in it.

0.185 g of 4-morpholin-4-yl-4-oxobutyric acid was added, 0.49 g of potassium iodide, 0.684 g of potassium carbonate, and 0.26 g of 18-crown-6 ether were added and heated to reflux for 12 hours. After cooling to room temperature, 10 ml of water and 10 ml of ethyl acetate were added, followed by stirring for 30 minutes, followed by layer separation to obtain an organic layer solvent, and the aqueous layer was extracted with 10 ml of ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled under reduced pressure. The resulting oily mixture was separated by column to obtain the target compound (0.53 g) (Formula 15).

(Methylene chloride: methanol = 10: 1)

Mass Spectrum, m / e = 746

¹ H NMR (400 MHz, DMSO-d ₆ , d) 9.58 (s, 1H), 7.52 to 7.20 (m, 9H), 7.12 (m, 2H), 6.82 (m, 1H), 6.73 (m, 1H) , 6.41 (m, 1H), 5.32 (m, 2H), 4.31 (m, 2H), 3.98 (m, 1H), 3.78 (s, 3H), 3.58 (m, 4H), 3.47 (m, 4H), 2.98 (s, 3H), 2.56-2.59 (m, 4H), 1.71-1.46 (m, 8H)

Example 5

4- (4-Methylpiperazin-1-yl) -4-oxo-butyric acid N '-(4-benzyloxycarbonyl amino-benzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl ) -N'-methylhydrazinocarbonyl oxymethyl ester [4- (4-Methyl-piperazin-1-yl) -4-oxo-butyric acid N '-(4-benzyloxycarbonylamino-benzoyl) -N- (3 -cyclopentyloxy-4-methoxy-benzyl) -N'-methyl-hydrazinocarbonyloxymethyl ester]

A solution of N- (4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinecarboxylic acid methyl ester obtained in Reference Example 6 (0.589 g) , 0.99 mmol) was distilled under reduced pressure to remove methylene chloride. 10 ml of anhydrous benzene was dissolved in it.

0.198 g of 4- (4-methylpiperazin-1-yl) -4-oxobutyric acid was added, 0.49 g of potassium iodide, 0.684 g of potassium carbonate, and 0.26 g of 18-crown-6 ether were added for 12 hours. Heated to reflux. After cooling to room temperature, 10 ml of water and 10 ml of ethyl acetate were added, followed by stirring for 30 minutes, followed by layer separation to obtain an organic layer solvent, and the aqueous layer was extracted with 10 ml of ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled under reduced pressure. The resulting oily mixture was separated by column to obtain the target compound (0.53 g) (Formula 16).

(Methylene chloride: methanol = 10: 1)

Mass Spectrum, m / e = 759

¹ H NMR (400 MHz, DMSO-d ₆ , d) 9.58 (s, 1H), 7.52 to 7.20 (m, 9H), 7.12 (m, 2H), 6.82 (m, 1H), 6.73 (m, 1H) , 6.41 (m, 1H), 5.32 (m, 2H), 4.31 (m, 2H), 3.98 (m, 1H), 3.78 (s, 3H), 3.32 (m, 4H), 2.98 (s, 3H), 3.82 (m, 4H), 2.52-2.59 (m, 4H), 2.27 (s, 3H), 1.71-1.46 (m, 8H)

Example 6

4-oxo-4-pyrrolidin-1-yl butyric acid N '-(4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methyl Hydrazinocarbonyloxymethyl ester [4-Oxo-4-pyrrolidin-1-yl-butyric acid N '-(4-benzyloxycarbonylamino-benzoyl) -N- (3-cyclopentyloxy-4-methoxy-benzyl) -N' -methyl-hydrazinocarbonyloxymethyl ester]

A solution of N- (4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinecarboxylic acid methyl ester obtained in Reference Example 6 (0.589 g) , 0.99 mmol) was distilled under reduced pressure to remove methylene chloride. 10 ml of anhydrous benzene was dissolved in it.

0.169 g of 4-oxo-4-pyrrolidin-1-ylbutyric acid was added, 0.49 g of potassium iodide, 0.684 g of potassium carbonate, and 0.26 g of 18-crown-6 ether were added and heated to reflux for 12 hours. . After cooling to room temperature, 10 ml of water and 10 ml of ethyl acetate were added, followed by stirring for 30 minutes, followed by layer separation to obtain an organic layer solvent, and the aqueous layer was extracted with 10 ml of ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled under reduced pressure. The resulting oily mixture was separated by column to obtain the target compound (0.53 g) (Formula 17).

(Methylene chloride: methanol = 10: 1)

Mass Spectrum, m / e = 730

¹ H NMR (400 MHz, DMSO-d ₆ , d) 9.58 (s, 1H), 7.52 to 7.20 (m, 9H), 7.12 (m, 2H), 6.82 (m, 1H), 6.73 (m, 1H) , 6.41 (m, 1H), 5.32 (m, 2H), 4.31 (m, 2H), 3.98 (m, 1H), 3.78 (s, 3H), 3.32 (m, 4H), 2.98 (s, 3H), 2.52-2.59 (m, 4H), 1.97 (m, 4H), 1.71-1.46 (m, 8H)

Example 7

N, N-dimethylsuccinamic acid N '-(4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methylhydrazinocarbonyloxymethyl Preparation of ester [N, N-Dimethyl-succinamic acid N '-(4-benzyloxycarbonylamino-benzoyl) -N- (3-cyclopentyloxy-4-methoxy-benzyl) -N'-methyl-hydrazinocarbonyloxymethyl ester]

A solution of N- (4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N-methylhydrazinecarboxylic acid methyl ester obtained in Reference Example 6 (0.589 g) , 0.99 mmol) was distilled under reduced pressure to remove methylene chloride. 10 ml of anhydrous benzene was dissolved in it.

0.143 g of N, N-dimethylsuccinamic acid was added, 0.49 g of potassium iodide, 0.684 g of potassium carbonate, and 0.26 g of 18-crown-6 ether were added, and the mixture was heated to reflux for 12 hours. After cooling to room temperature, 10 ml of water and 10 ml of ethyl acetate were added, followed by stirring for 30 minutes, followed by layer separation to obtain an organic layer solvent, and the aqueous layer was extracted with 10 ml of ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled under reduced pressure. The mixture of the oily phase was column separated to obtain a target compound (0.53 g) (Formula 18).

(Methylene chloride: methanol = 10: 1)

Mass Spectrum, m / e = 704

¹ H NMR (400 MHz, DMSO-d ₆ , d) 9.58 (s, 1H), 7.52 to 7.20 (m, 9H), 7.12 (m, 2H), 6.82 (m, 1H), 6.73 (m, 1H) , 6.41 (m, 1H), 5.32 (m, 2H), 4.31 (m, 2H), 3.98 (m, 1H), 3.78 (s, 3H), 3.02 (s, 6H), 2.98 (s, 3H), 2.52-2.59 (m, 4H), 1.71-1.46 (m, 8H)

In order to evaluate the pharmacological effects of the compounds of the present invention obtained in the above examples, the following experiment was conducted.

Pharmacological Effect Evaluation Experiment

Partially purified PDE IV from Human U 1.0 μM937 cells, test compound and cAMP containing 0.01 μM [ ³ H] cAMP are incubated at 30 ° C. for 20 minutes. The PDE reaction, where cAMP is changed to AMP, is completed by boiling for 2 minutes. Snake venom nucleotidase is added and incubated at 30 ° C. for 10 minutes to change the AMP to adenosine. Unhydrolyzed cAMP is combined with AG1-X2 resin and the remaining [ ³ H] adenosine in aqueous solution is quantified by scintillation counting and the results are shown in Table 1 below. Shown in

conc. (nM) % Inhibition SB 207499 (Comparative) 100 41.6 10 27.7 Example 1 100 24.4 10 5.9 Example 2 100 25.2 10 12.3 Example 3 100 41.7 10 21.4 Example 4 100 30.3 10 18.9 Example 5 100 45.6 10 28.0 Example 6 100 32.6 10 22.8 Example 7 100 28.0 10 5.9

As can be seen in Table 1, the compounds of Examples 1 to 7 of the present invention were found to have a very small amount of adenosine remaining as compared to SB 207499, which is a comparative substance, whereby the inhibitory effect of PDE is remarkable. And it was found.

As can be seen from the above, the present invention has an inhibitory effect on PDE IV or Tumor necrosis factor (TNF), as well as asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease, psoriasis, allergic rhinitis, dermatitis and AIDS, HIV , Novel catechol hydrazide derivatives and methods for their preparation, which have useful effects in the treatment of diseases including Crohn's disease, sepsis, septic shock, other inflammatory diseases such as fetal disorders and production of TNF, and their preparation It is a useful invention to provide one pharmaceutical composition.

While the invention has been described in detail above with reference to the described embodiments, it will be apparent to those skilled in the art that various modifications and variations are possible within the scope and spirit of the invention, and such variations and modifications are within the scope of the appended claims. It is natural to belong.

Claims (2)

The catechol hydrazide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof. <Formula 1> In the above formula R ₁ is a (C ₃ -C ₇ ) cycloalkyl or benzyl group, R ₂ is or or or or or And R ₅ and R ₆ are each a (C ₁ -C ₅ ) alkyl group, X is O, S, NR ₇ , R ₇ is hydrogen or a (C ₁ -C ₅ ) alkyl group, R ₃ is hydrogen or a (C ₁ -C ₅ ) alkyl group, Y is a direct bond or -C (= O) O-, R ₄ is (C ₁ -C ₇ ) alkyl wherein one or two halogen, hydroxy, phenyl or amine compounds are optionally substituted or unsubstituted; Nitro, nitrile, halogen, (C ₁ -C ₃ ) alkyl or (C ₁ -C ₃ ) alkoxy groups optionally substituted with 1 to 2 substituted or unsubstituted phenyl, and Halogen is Cl, F, or Br The method of claim 1, The derivative is (4-Methylpiperazin-1-yl) -acetic acid N '-(4-benzyloxycarbonylamino-benzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methylhigh Draginocarbonyloxymethyl esters;   Pyrrolidin-1-yl acetic acid N '-(4-benzoyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methylhydrazinocarbonyloxymethyl ester ; Morpholin-4-yl acetic acid N '-(4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methylhydrazinocarbonyloxymethyl ester ;   4-morpholin-4-yl-4-oxobutyric acid N '-(4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methylhydra Genocarbonyloxymethyl ester;   4- (4-Methylpiperazin-1-yl) -4-oxo-butyric acid N '-(4-benzyloxycarbonylamino-benzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl ) -N'-methylhydrazinocarbonyloxymethyl ester;  4-oxo-4-pyrrolidin-1-yl butyric acid N '-(4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methyl Hydrazinocarbonyloxymethyl esters; And N, N-dimethylsuccinamic acid N '-(4-benzyloxycarbonylaminobenzoyl) -N- (3-cyclopentyloxy-4-methoxybenzyl) -N'-methylhydrazinocarbonyloxymethyl ester; A catechol hydrazide derivative, characterized in that at least one selected from the group consisting of.