KR20040065438A - Fluorine-Substituted Cathechol N-Methyl Hydrazide Derivatives - Google Patents

Abstract

PURPOSE: Provided is a fluorine-substituted catechol N-methyl hydrazide derivative which has an inhibition effect to phosphodiesterase(PDE) IV or tumor necrosis factor(TNF), and a pharmaceutically acceptable composition comprising the same. CONSTITUTION: The fluorine-substituted catechol N-methyl hydrazide derivative is represented by formula 1. In the formula 1, R1 is (C3-C7)cycloalkyl, cyclopropylmethyl, indane or benzyl group, R2 is hydrogen or (C1-C5)alkyl group, Y is a direct bond or -C(=O)-, or -C(=O)O-, R3 is (C1-C7)alkyl selectively substituted with one or two of halogen, hydroxy, phenyl or amine compound or unsubstituted (C1-C7)alkyl, phenyl selectively substituted with one or two of nitro, nitrile, halogen, (C1-C3)alkyl or (C1-C3)alkoxy group or unsubstituted phenyl, wherein halogen is Cl, F, or Br.

Description

Fluorine-substituted Cathechol N-Methyl Hydrazide Derivatives

The present invention relates to novel catechol N-methylhydrazide derivatives and pharmaceutical compositions containing them. More particularly, the present invention relates to a novel catechol N-methylhydrazide derivative having inhibitory activity against PDE IV or TNF having a structure of Formula 1 and a pharmaceutical composition containing the same.

In Chemical Formula 1

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

R ² is hydrogen or a (C ₁ -C ₅ ) alkyl group,

Y means direct 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; Nitro, nitrile, halogen, (C ₁ -C ₃ ) alkyl or (C ₁ -C ₃ ) alkoxy groups are optionally substituted with one or two substituted or unsubstituted phenyl, wherein halogen is Cl, F, or Br to be

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, and is seen as a major mediator 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 a group 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 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^OneIs (C₃-C₇A 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

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 or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical composition containing a compound of formula 1 or a salt 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 fluorine-substituted catechol N-methylhydrazide derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof.

<Formula 1>

R in Formula 1^OneIs (C₃-C₇Cycloalkyl, cyclopropylmethyl, indane or benzyl group, R²Is hydrogen or (C_One-C₅An alkyl group, Y means a direct bond or -C (= O)-, or -C (= O) O-, and R³(C) wherein one or two halogen, hydroxy, phenyl or amine compounds are optionally substituted or unsubstituted (C_One-C₇Alkyl; Nitro, nitrile, halogen, (C_One-C₃Alkyl or (C)_One-C₃Alkoxy groups are optionally substituted or unsubstituted phenyl, wherein halogen is Cl, F, or Br

In addition, the derivative of Formula 1 is N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl- hydrazinocarbonyl] -phenyl} -2 , 4-dimethoxy-benzamide; N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -3,4-dimethoxy-benzamide ; N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -benzamide; 4-bromo-N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -benzamide; N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -isonicotinamide; Acetic acid {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenylcarbamoyl} -methylester; And N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -2-hydroxy-acetamide ; It may be at least one selected from the group consisting of.

The present invention also provides an inhibitory pharmaceutical composition against phosphodiesterase IV or TNF, which contains a compound of formula 1 or a salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.

The present invention also provides a catechol N-methylhydrazide derivative or a pharmaceutically acceptable salt thereof substituted with fluorine having the structure of Formula 5 below.

In Formula 5, R ¹ is a (C ₃ -C ₇ ) cycloalkyl, cyclopropylmethyl, indan or benzyl group, and R ² is hydrogen or a (C ₁ -C ₅ ) alkyl group.

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) at the top left of Scheme 1 was mixed with sodium hydride at 0 ° C. under anhydrous N, N-dimethylformamide solvent and stirred, and then alkylated with adding bromide, followed by reaction for 6 to 12 hours. Get)

The compound (2) was dissolved in a 1,4-dioxane solvent, 50% aqueous NaOH solution was added, and benzyltrimethylammonium bromide was added as a phase transfer catalyst, followed by stirring for 2 to 5 hours while adding chlorodifluoromethane gas at 4 ° C or lower. To obtain compound (3). Here, as the phase transfer catalyst, benzyltrimethylammonium chloride or benzyltriethylammonium bromide may be used in addition to benzyltrimethylammonium bromide, and the reaction temperature may be in the range of 4 to -10 ° C.

The compound (3) is dissolved in an alcoholic solvent and refluxed with an alkyl hydrazine (specifically, methyl hydrazine or hydrazine) for 5 to 10 hours to obtain a compound (4) in which the alkyl hydrazine is substituted. The alcohol solvent is preferably methyl alcohol or ethyl alcohol, more preferably ethyl alcohol and a reaction time of 5 hours is appropriate. In the above reaction, the reaction is generally carried out under acidic catalyst conditions. However, in the present reaction, side reactions and yields may be remarkably lowered when the reaction is performed using an acid catalyst, for example, hydrochloric acid, sulfuric acid, or nitric acid. The reaction proceeds without using an acid catalyst to synthesize the compound in a yield of 80% or more.

Compound (4) was reacted with 4-nitrobenzoyl chloride at 25 ° C. with triethylamine as a base in anhydrous methylene chloride solvent to synthesize 4-nitrobenzoic acid (5).

The compound (5) to which 4-nitrobenzoic acid was introduced was reacted at 70 ° C. using 10% Pd / C and ammonium formate under a mixed solvent of methyl alcohol and tetrahydrofuran. 10% Pd / C uses 5.0-15% of the starting material and 2-5 equivalents of ammonium formate. The optimum reaction conditions were 10% Pd / C 7.5% and ammonia formate was 5 equivalents. The reduction reaction was carried out under these conditions to synthesize an amine derivative compound (6).

The amine derivative compound (6) (which is the same as Chemical Formula 5) undergoes a coupling reaction with various ³ RYB compounds, and anhydrous acetonitrile is substituted with an amine derivative and an aryl acid chloride or an amine derivative and an alkyl acid chloride. The reaction is carried out using a base in a solvent to synthesize Compound (I) (which is the same as that of Formula 1). The base used is triethylamine or pyridine, preferably pyridine to synthesize pure Compound (I) in a yield of 80 to 90% by simple chemical treatment.

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

As described above, the compound of formula 1 according to the present invention may be usefully used as a PDE IV, or TNF inhibitor, and the present invention is a compound of formula 1, a pharmaceutically acceptable salt thereof, together 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-cyclopropylmethoxy-4-hydroxy-vanzaldehyde [3-Cyclopropylmethox y -4-hydroxy-benzaldehyde]

(Bromomethyl) cyclopropane (3%) 5.0 g, 37 mmol) is added and the mixture is stirred for 6 hours. 300 ml of water and 200 ml of diethyl ether were added to the mixed solution, and the layers were separated. The water layer was washed two more times with 100 ml of diethyl ether, and the organic layers were combined and washed with 200 ml of water. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated solution was purified by column chromatography to obtain the target product (1.8 g) (Formula 6).

¹ H NMR (400 MHz, CDCl ₃ , δ) 9.84 (s, 1H), 7.45 (d, 1H, J = 1.9 Hz), 7.40 (dd, 1H, J = 8.3, 2.0 Hz), 6.92 (d, 1H , J = 8.2 Hz), 5.92 (s, 1H), 3.95 (d, 2H), 1.37 (m, 1H), 0.69 (m, 2H), 0.39 (m, 2H)

Reference Example 2

Preparation of 3-cyclopropylmethoxy-4-difluoromethoxy-benzaldehyde [3-Cyclopropyl methoxy-4-difluoromethoxy-benzaldehyde]

3-cyclopropylmethoxy-4-hydroxy-benzaldehyde (6.0 g, 31.2 mmol) synthesized in Reference Example 1 was dissolved in 1,4-dioxane solvent (60 ml), and a 50% aqueous NaOH solution (30 ml) was added thereto. After adding benzyltrimethylammonium bromide (300mg) as a phase transfer catalyst, the mixture was stirred for 4 hours while bubbling chlorodifluoromethane gas at 4 ° C or lower. The organic layer was separated by 200 ml of water and 100 ml of ethyl acetate, and the separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated solution was purified by column chromatography to obtain the target product (3.8g) (Formula 7).

¹ H NMR (400 MHz, CDCl ₃ , δ) 9.87 (s, 1H), 7.74 (s, 1H), 7.71 (d, 1H), 7.01 (d, 1H), 6.64 (t, 1H, J = 74.7 Hz ), 3.98 (d, 2H), 1.39 (m, 1H), 0.69 (m, 2H), 0.40 (m, 2H)

Reference Example 3

Of N- (3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N'-methyl-hydrazine [N- (3-Cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N'-methyl-hydrazine] Produce

3-cyclopropylmethoxy-4-difluoromethoxy-benzaldehyde 2.1 g (8.6 mmoles) synthesized in Reference Example 2 was dissolved in 50 ml of anhydrous methyl alcohol, filled with argon gas, and 0.48 g (1.2 equivalents) of methyl hydrazine. ) Was added and stirred at 70 ° C. for 5 hours. The reaction solution was cooled, distilled under reduced pressure to give an orange oil, diluted with 50 ml of methylene chloride, the reaction solution was diluted, washed three times with 40 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 (1.8 g), which was applied to the compound synthesis of <Reference Example 4> without a separation step (Formula 8).

Reference Example 4

4-nitrobenzoic acid N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N'-methyl-hydrazide [4-Nitro-benzoic acid N'-(3-cyclopropylmethoxy- 4-difluoromethoxy-benzylidene) -N-methyl-hydrazide]

N- (3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N'-methyl-hydrazine (2.0 g, 7.4 mmole) synthesized in Reference Example 3 was added to anhydrous methylene chloride (30 ml). After dissolving, the mixture was filled with argon gas, and 1.6 g (1.2 equivalents) of 4-nitrobenzoyl chloride was added at 20 ° C., stirred at the temperature for 10 minutes, and then 1.34 ml (1.3 equivalents) of triethylamine was added to the room temperature. And stirred 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 (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 g) (Formula 9).

Mass Spectrum, m / e = 420

¹ H NMR (400 MHz, CDCl ₃ , δ) 8.29 (d, 2H), 7.83 (d, 2H), 7.70 (s, 1H), 7.26 (s, 1H), 7.23 (d, 1H), 6.91 (d , 1H), 6.56 (t, 1H), 3.88 (d, 2H), 3.57 (s, 3H), 1.26 (m, 1H), 0.65 (m, 2H), 0.35 (m, 2H)

The compound of Example 1 was prepared using the compound obtained in Reference Example 4 (Formula 9).

Example 1

4-aminobenzoic acid N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N'-methyl-hydrazide [4-Amino-benzoic acid N'-(3-cyclopropylmethoxy- 4-difluoromethoxy-benzylidene) -N-methyl-hydrazide]

1.5 g of 4-nitrobenzoic acid N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N'-methyl-hydrazide obtained in Reference Example 4 was added to tetrahydrofurantan ( 10 ml) and methyl alcohol (10 ml), and then mixed with Ammonium Formate (1.0 g) at 60 ° C to dissolve, and carefully watch for palladium / activated carbon (Pd / c 5%, dry) at 60 ° C. Was added at a time. After stirring the reaction solution for 10 minutes, the solid obtained by cooling, filtration and distillation under reduced pressure 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 a white title solid (0.52 g) (Formula 10).

¹ H NMR (400 MHz, CDCl ₃ , δ) 7.65 (d, 2H), 7.61 (s, 1H), 7.39 (d, 1H, J = 2.0 Hz), 7.30 (dd, 1H, J = 8.5, 2.0 Hz ), 6.88 (d, 1H, J = 8.5 Hz), 6.63 (d, 2H), 4.06 (d, 2H), 3.48 (s, 3H), 1.23 (m, 1H), 0.63 (m, 2H), 0.33 (m, 2H)

The material prepared in Example 1 is the same as that of Chemical Formula 10, which was used as a starting material of Examples 2 to 8.

Example 2

N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -2,4-dimethoxy-benzamide Preparation of [N- {4- [N '-(3-Cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -2,4-dimethox y-benzamide]

4-aminobenzoic acid N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N'-methyl-hydrazide 0.2 g (0.52 mmol) obtained in Example 1 It was dissolved in 40 ml of nitrile and 0.09 ml (2.0 equiv) of pyridine was added thereto, followed by stirring at 20 ° C. for 30 minutes.

0.16 g (1.5 equivalents) of 2,4-dimethoxybenzoyl chloride was added and stirred at room temperature for 3 hours. 60 ml of distilled water was added to the reaction solution, and the acetonitrile was distilled off under reduced pressure, and 20 ml of ethyl acetate was added to separate the layers. The organic layer was separated, dried over MgSO ₄ , concentrated, and re-crystallized at room temperature with 10 ml of ethyl acetate and 20 ml of hexane. The resulting solid was filtered, washed with ethyl acetate and 100 ml of hexane (volume ratio 1: 6), and dried under reduced pressure at 40 ° C. to obtain a target compound (0.15 g).

Mass Spectrum, m / e = 554

M.P = 195 to 196 ° C

¹ H NMR (400 MHz, DMSO-d6): 10.1 (s, 1H), 7.96 (s, 1H), 7.78 (m, 3H), 7.67 (d, 2H), 7.51 (d, 1H), 7.48 (s , 1H), 7.17 (d, 1H), 7.01 (t, 1H), 6.71 (m, 3H), 3.96 (s, 3H), 3.88 (d, 2H), 3.85 (s, 3H), 3.64 (s, 3H), 1.22 (m, 1H), 0.55 (m, 2H), 0.32 (m, 2H)

Example 3

N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -3,4-dimethoxy-benzamide Preparation of [N- {4- [N '-(3-Cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -3,4-dimethox y-benzamide]

4-aminobenzoic acid N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N'-methyl-hydrazide 0.2g (0.52mmole) obtained in Example 1, 3, 0.16 g (1.5 equivalents) of 4-dimethoxybenzoyl chloride was used as a starting material, and the reaction was carried out as in Example 2 to obtain the target product (0.10 g).

Mass Spectrum, m / e = 554

M.P = 98 to 100 ° C

¹ H NMR (400 MHz, DMSO-d6): 10.3 (s, 1H), 7.97 (s, 1H), 7.85 (m, 2H), 7.66 (m, 3H), 7.55 (d, 1H), 7.47 (d , 1H), 7.21 (s, 1H), 7.09 (m, 3H), 7.01 (t, 1H), 3.93 (d, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.65 (s, 3H), 1.23 (m, 1H), 0.55 (m, 2H), 0.32 (m, 2H)

Example 4

N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -benzamide [N- {4- [ Preparation of N '-(3-Cyclopropylmethoxy-4-difluorometho xy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -benzamide]

4-aminobenzoic acid N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N'-methyl-hydrazide 0.2 g (0.52 mmol) and benzoyl chloride obtained in Example 1 above The reaction was carried out in the same manner as in Example 2, using 0.10 g (1.3 equivalents) as a starting material to obtain a target compound (0.11 g) (Formula 13).

Mass Spectrum, m / e = 494

M.P = 161-162 degreeC

¹ H NMR (400 MHz, DMSO-d6): 10.5 (s, 1H), 7.97 (m, 4H), 7.88 (d, 2H), 7.68 (d, 2H), 7.57 (d, 2H), 7.46 (d , 1H), 7.22 (s, 1H), 7.17 (d, 1H), 7.01 (t, 1H), 3.89 (d, 2H), 3.63 (s, 3H), 1.23 (m, 1H), 0.56 (m, 2H), 0.33 (m, 2H)

Example 5

4-Bromo-N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -benzamide [4 Preparation of -Bromo-N- {4- [N '-(3-cyclopropylmetho xy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -benzami de]

4-aminobenzoic acid N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N'-methyl-hydrazide 0.2 g (0.52 mmol) and 4- obtained in Example 1 0.15 g (1.3 equivalents) of bromobenzoyl chloride was used as a starting material, and the reaction was carried out as in Example 2 to obtain the target product (0.14 g) (Formula 14).

Mass Spectrum, m / e = 573

M.P = 157-159 ° C.

¹ H NMR (400 MHz, DMSO-d6): 10.5 (s, 1H), 7.97 (s, 1H), 7.93 (d, 2H), 7.84 (d, 2H), 7.76 (d, 2H), 7.64 (d , 2H), 7.45 (d, 1H), 7.39 (s, 1H), 7.15 (d, 1H), 7.01 (t, 1H), 3.91 (d, 2H), 3.63 (s, 3H), 1.23 (m, 1H), 0.56 (m, 2H), 0.33 (m, 2H)

Example 6

N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -isonicotinamide [N- {4- Preparation of [N '-(3-Cyclopropylmethoxy-4-di fluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -isonicotinami de]

4-aminobenzoic acid N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N'-methyl-hydrazide 0.2 g (0.52 mmole) obtained in Example 1 and isico The reaction was carried out in the same manner as in Example 2, using 0.12 g (1.3 equivalents) of thynoyl chloride hydrochloride as a starting material (0.15 g).

Mass Spectrum, m / e = 495

M.P = 195-196 degreeC

¹ H NMR (400 MHz, DMSO-d6): 10.7 (s, 1H), 8.80 (d, 2H), 7.97 (s, 1H), 7.87 (m, 4H), 7.71 (d, 2H), 7.41 (d , 1H), 7.35 (s, 1H), 7.15 (d, 1H), 7.01 (t, 1H), 3.91 (d, 2H), 3.61 (s, 3H), 1.23 (m, 1H), 0.56 (m, 2H), 0.33 (m, 2H)

Example 7

Acetic acid {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenylcarbamoyl} -methyl ester [Acetic acid { Preparation of 4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbon yl] -phenylcarbamoyl} -methyl ester]

4-aminobenzoic acid N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N'-methyl-hydrazide 0.34g (0.89mmole) and acetoxy obtained in Example 1 above 0.18 g (1.5 equivalents) of acetyl chloride was used as a starting material, and the reaction was carried out as in Example 2 to obtain the target product (0.50 g) (Formula 16).

Mass Spectrum, m / e = 490

M.P = 138 to 140 ° C

400 M-NMR (DMSO-d6): 10.3 (s, 1H), 7.96 (s, 1H), 7.65 (m, 4H), 7.38 (d, 1H), 7.34 (s, 1H), 7.16 (d, 1H) , 7.01 (t, 1H, J = 74.6 Hz), 4.68 (s, 3H), 3.90 (d, 2H), 3.48 (s, 3H), 2.13 (s, 3H), 1.24 (m.1H), 0.56 ( m.2H), 0.33 (m, 2H)

Example 8

N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -2-hydroxy-acetamide [ Preparation of N- {4- [N '-(3-Cyclopropylmethox y-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -2-hydrox y-acetamide]

Acetic acid {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl- hydrazinocarbonyl] -phenylcamamoyl} obtained in Example 1 above- 0.38 g of methyl ester was dissolved in methyl alcohol (10 ml), and 1.2 ml of 1N KOH aqueous solution was added thereto, followed by stirring for 2 hours. 20 ml of 1N HCl aqueous solution and 50 ml of methylene chloride were added to the reaction solution, and the separated organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to give a white title solid (0.19 g).

Mass Spectrum, m / e = 448

M.P = 142-144 ° C.

400M-NMR (DMSO-d6): 9.87 (s, 1H), 7.97 (s, 1H), 7.79 (d, 2H), 7.64 (d, 2H), 7.40 (d, 1H), 7.36 (s, 1H) , 7.17 (d, 1H), 7.03 (t, 1H), 5.68 (s, 1H), 4.04 (d, 2H), 3.92 (d, 2H), 3.46 (s, 3H), 1.18 (m, 1H), 0.57 (m, 2H), 0.34 (m, 2H)

In order to evaluate the pharmacological effects of the compounds of the present invention obtained in Examples 2 to 8, 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 32.8 30 12.4 Example 2 100 67.5 30 33.4 Example 3 100 65.9 30 31.2 Example 4 100 49.3 30 24.2 Example 5 100 33.6 30 19.6 Example 6 100 41.8 30 20.5 Example 7 100 69.6 30 39.5 Example 8 100 75.2 30 45.1

As can be seen in Table 1, the compounds of Examples 2 to 8 of the present invention were found to have a very small amount of adenosine remaining as compared to the SB 207499, which is a comparative substance, thereby significantly inhibiting the effect of PDE. 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 N-methylhydrazide derivatives with fluorine substitutions that are useful for the treatment of diseases including Crohn's disease, sepsis, septic shock, other inflammatory diseases such as atherosclerosis, and production of TNF And pharmaceutical compositions containing the same.

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 (4)

A fluorine-substituted catechol N-methylhydrazide 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, cyclopropylmethyl, indane or benzyl group, R ² is hydrogen or a (C ₁ -C ₅ ) alkyl group, Y means direct 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; Nitro, nitrile, halogen, (C ₁ -C ₃ ) alkyl or (C ₁ -C ₃ ) alkoxy groups are optionally substituted with one or two substituted or unsubstituted phenyl, wherein halogen is Cl, F, or Br to be The method of claim 1, The derivative is N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -2,4-dimethoxy-benzamide ; N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -3,4-dimethoxy-benzamide ; N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -benzamide; 4-bromo-N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -benzamide; N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -isonicotinamide; Acetic acid {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenylcarbamoyl} -methylester; And N- {4- [N '-(3-cyclopropylmethoxy-4-difluoromethoxy-benzylidene) -N-methyl-hydrazinocarbonyl] -phenyl} -2-hydroxy-acetamide; A fluorine-substituted catechol N-methylhydrazide derivative, characterized in that at least one member selected from the group consisting of. An inhibitory pharmaceutical composition against phosphodiesterase IV or TNF, which contains as an active ingredient a compound of formula (1) or a salt thereof as an active ingredient with a pharmaceutically acceptable carrier. A fluorine-substituted catechol N-methylhydrazide derivative represented by the following Formula 5 or a pharmaceutically acceptable salt thereof. <Formula 5> In the above formula R ¹ is a (C ₃ -C ₇ ) cycloalkyl, cyclopropylmethyl, indane or benzyl group, R ² is hydrogen or a (C ₁ -C ₅ ) alkyl group.