KR100780934B1 - Cathecol N-methylhydrazide derivatives and the methods of preparing them - Google Patents

Abstract

The present invention relates to novel catechol N-methylhydrazide derivatives having inhibitory action against phosphodiesterase IV or TNF, methods for their preparation and pharmaceutical compositions containing them.

Compounds provided by the present invention have an inhibitory effect on phosphodiesterase IV or Tumor necrosis factor (TNF) to asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease, psoriasis, allergic rhinitis, It is useful for the treatment of dermatitis and other inflammatory diseases such as AIDS, Crohn's disease, sepsis, septic shock, malaria and the production of TNF.

Description

Cathecol N-methylhydrazide derivatives and the methods of preparing them

The present invention provides a novel catechol N-methylhydrazide derivative having an inhibitory effect on phosphodiesteraes (PDE) or Tumor Necrosis Factor (TNF), a preparation method thereof, and a pharmaceutical composition containing the same. It is about.

Phosphodiesterases are enzymes that hydrolyze cyclic nucleotides as one of the chemical transporters. In particular phosphodiesterase IV is an enzyme that selectively hydrolyzes cyclic adenosine 3 ', 5'-monophosphate to inactive adenosine 3', 5'-monophosphate and is a cyclic adenosine 3 ', 5'-monophosphate Is a second messenger responsible for regulating the response of cells to external cellular stimuli. Inhibitory action of phosphodiesterase IV prevents bronchial spasms by maintaining the concentration of cyclic adenosine 3 ', 5'-monophosphate and, in addition, anti-inflammatory action. Therefore, compounds that inhibit phosphodiesterase IV are useful as therapeutic agents for asthma and the like.

TNF has been known to be associated with many infections, including atherosclerosis, and autoimmune diseases, which have been shown to be the major mediators of the inflammatory response seen in sepsis and septic shock. Therefore, compounds that inhibit TNF are useful as inflammatory agents.

As inhibitors for phosphodiesterase IV or TNF, compounds having structures similar to the present invention have been published. For example, a substance with a structure having a catechol pyridazine nucleus has been reported.

Merck uses a new catechol pyridazine compound, such as [Formula A] below, which introduces a pyridazine structure to the basic structure of 3-methoxy-4-cyclopentoxy, the mother core of catechol ether in WO 00-26201. The literature was reported.

[Formula A]

 Where

B includes 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 are 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 -C ₇ ) cycloalkyl, alkylenecycloalkyl of (C ₅ -C ₁₀ ), alkenyl group of (C ₂ -C ₈ ), and halogen is an F, Cl, Br or I group.

Applicant cheiljedang in WO 00/73280 reported the synthesis of catechol hydrazone derivatives such as [formula B] in the basic structure of 3-methoxy-4-cyclopentyloxy, the mother core of cathechol ether.

[Formula B]

Where

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 is independently hydrogen, C ₁ -C ₇ alkyl, C (= X) -R ₅ , or 2-, 3- or 4-pyridyl, pyrimidyl or halogen, (C ₁ -C ₆ ) alkoxy, Phenyl group substituted with 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.

Although a compound having the above structure similar to the present invention has already been reported as an inhibitor for phosphodiesterase IV or TNF, there is a difference in the structure of the compound from the compound provided in the present invention, and in terms of efficacy, It does not show the results, the synthesis process is complicated and it is difficult to separate high purity compounds.

The present invention provides a novel catechol N-methylhydrazide derivative having an inhibitory effect on phosphodiesteraes (PDE) or Tumor necrosis factor (TNF), a preparation method thereof, and a pharmaceutical composition containing the same. There is a purpose.

The present invention relates to catechol N-methylhydrazide derivatives having an inhibitory action on phosphodiesterase IV or TNF, methods for their preparation, and pharmaceutical compositions containing them.

The compound of the present invention is a catechol N-methylhydrazide derivative represented by the following [Formula 1] and salts thereof.

In the above formula

R ₁ is a (C ₃ -C ₇ ) cycloalkyl, indan or benzyl group, R ₂ is a methyl group, Y is an ester bond and means -C (= 0) O-, and R ₃ is halogen or (C ₁ -C ₃ ) (C ₁ -C ₇ ) alkyl wherein 1-2 compounds are optionally substituted or unsubstituted; (C ₁ -C ₃₎ the compound is optionally substituted or unsubstituted (C ₁ -C ₇₎ cyclo-alkyl; Phenyl optionally substituted with one or two nitro, nitrile, halogen, (C ₁ -C ₃ ) alkyl or (C ₁ -C ₃ ) alkoxy groups; Nitro, benzyl, optionally substituted with one or two substituted or unsubstituted halogen groups.

Wherein halogen is Cl, F, or Br.

The compound of [Formula 1] of the present invention may exist in the form of isomers, and the present invention includes derivatives and salts thereof represented by [Formula 1] and these isomers and mixtures thereof.

The catechol N-methylhydrazide derivative represented by [Formula 1] of the present invention may be prepared through a reaction process such as the following [Scheme 1]. Here, benzaldehyde (1) in which the hydroxy group at position 4 is substituted with R ₂ is reacted with a reaction reagent designated as R ₁ -A so that benzaldehyde (2) in which two hydroxyl groups are substituted with R ₁ and R ₂ , respectively. In the first step of synthesizing, the second step of synthesizing hydrazone (3) by reacting benzaldehyde (2) with methyl hydrazine, the 4-nitrobenzoyl group is introduced by reacting hydrazone (3) with 4-nitrobenzoyl halide 3 steps of synthesizing N'-benzylidene-N-methylhydrazide (4) to reduce the nitro group of N'-benzylidene-N-methylhydrazide (4) to synthesize amine derivative (5) In step 4, the coupling reaction is carried out using the amine derivative (5) and the compound of 3R-YB and consists of five steps of synthesizing the desired compound (6) of [Formula 1].

In Scheme 1, B is halide and halide is Cl.

The reaction scheme described in more detail by dividing [Scheme 1] into three schemes 1 to 3 steps [Scheme 2], 4 steps [Scheme 3], 5 steps to [Scheme 4] as follows. .

In the following Reaction Scheme 2, benzaldehyde (1) in which the hydroxy group at position 4 is substituted with R ₂ is reacted with R ₁ -A in anhydrous N, N-dimethylformamide solvent. Induction of the reaction was carried out to synthesize benzaldehyde (2) in which two hydroxy groups were substituted with each of R ₁ and R ₂ , and methylhydrazine was refluxed under an alcohol solvent for 5 to 10 hours. As the alcohol solvent, methyl alcohol or ethyl alcohol is preferable, of which methyl alcohol is more suitable, and a reaction time of 5 hours is more suitable. In the above reaction, the reaction is generally performed under acid catalyst conditions, but in the present reaction, when the reaction is performed using an acid catalyst, for example, hydrochloric acid, sulfuric acid, or nitric acid, side reactions occur, and the yield is significantly lowered. Therefore, this reaction proceeded without the use of an acid catalyst to synthesize a compound of more than 85% yield.

The synthesized hydrazone (3) was reacted with 4-nitrobenzoyl chloride at 25 ° C. with triethylamine as a base in anhydrous methylene chloride solvent, whereby N'-benzylidene-N- into which 4-nitrobenzoyl group was introduced. Methyl hydrazide (4) is synthesize | combined.                     

In the following [Reaction Scheme 3], the nitro group of N'-benzylidene-N-methylhydrazide (4) to which 4-nitrobenzoic acid was introduced was 10% Pd / under a mixed solvent of methyl alcohol and tetrahydrofuran. The reaction is carried out at 0 ° C. to 70 ° C. using C and ammonium formate. 10% Pd / C uses about 5.0 to 15% of the starting material and about 2 to 5 equivalents of ammonium formate. The optimum reaction conditions were 10% Pd / C 7.5% and 5 molar equivalents of ammonium formate, and the reduction reaction was conducted under these conditions to synthesize an amine derivative compound (5).

In the following [Scheme 4], the amine derivative compound (5) undergoes a coupling reaction with various R ₃ -YB compounds to synthesize the desired compound (6).

The coupling reaction of [Scheme 4] will be described in more detail below.

First, the amine derivative compound undergoes a coupling reaction with various R ₃ -O-CO-B ₁ compounds (Scheme 4-1). Here, B ₁ includes Cl and the like. Preferably, the amine derivative (5) and the aryl acid chloride or the amine derivative (5) and the alkyl acid chloride are reacted by using a base in anhydrous acetonitrile solvent to form a compound of formula (6-). Synthesize 1). Triethylamine or pyridine is used as the base, and pyridine is preferably used to synthesize pure Compound (I) in a yield of 80 to 90% by simple chemical treatment.

Scheme 4-1

Second, after activating the amine derivative (5) and the aryl acid or the amine derivative (5) and the alkyl acid, the reaction was carried out to synthesize compound (6-2) of [Formula 1] [Scheme 4-2]. A method of synthesizing an active ester using an aryl acid or an alkyl acid using 1-hydroxybenzotriazole and dicycloimide, followed by reaction to synthesize compound (6-2) of [Formula 1], and triphenyl There is a method of synthesizing an active substance using phosphine and hexachloroethane and reacting with an amine derivative (5) to synthesize a desired compound (6-2) of [Formula 1]. As the base used in the reaction, triethylamine is preferable.                     

Scheme 4-2

Third, the amine derivative compound (5) and various sulfonyl halide compounds (R ₃ -SO ₂ -B ₂ ) are reacted with a base using anhydrous acetonitrile in a compound (6-3). Synthesize B ₂ has Cl. Triethylamine or pyridine is used as the base, and pyridine is preferably used to synthesize pure Compound (I) in a yield of 60 to 85% by simple chemical treatment.

Scheme 4-3

Since compound (6) of Formula 1 has a double bond, the present invention includes cis and trans isomers. Thus, the compounds of the present invention include each geometric isomer as well as a mixture of geometric isomers. Geometric isomers are named E and Z according to priority nomenclature.                     

The present invention places more importance on the E-form, and the E isomer can be synthesized by the conventional method described in the following examples, and it is very unstable and difficult to exist even when the Z-form is synthesized.

The invention also provides a pharmaceutical composition having an inhibitory action against phosphodiesterase IV or TNF comprising a therapeutically effective amount of a compound of formula 1, an isomer thereof or a mixture thereof in combination with a pharmaceutically acceptable carrier. It includes.

Because these pharmaceutical compositions contain catechol N-methylhydrazide derivatives, they have an inhibitory effect on phosphodiesterase IV or tumor tract factors, resulting in asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease, psoriasis, allergic It is useful for the treatment of rhinitis, dermatitis and other inflammatory diseases such as AIDS, HIV, Crohn's disease, sepsis, septic shock, malaria and the production of TNF.

The pharmaceutical composition may be in the form of tablets, effervescent tablets, capsules, granules, powders, sustained release tablets, sustained release capsules (alone and complex unit preparations), ampoules for intravenous and intramuscular injection and infusions, suspensions It may be administered in the form of suppositories or in other suitable pharmaceutical forms.

Sustained release pharmaceutical forms may contain the active compound in a complete or partial sustained release form with or without an initial dosage content.

The active compounds may be present together or as part of a formulation that is partly or completely separate from one another, so that separate or timed administration may also be possible.                     

When these completely separate formulations are present, they cooperate with each other and contain each active compound in the dosage unit in the same amount and corresponding weight ratio that may be present in the mixture in which they are combined.

Preferred are oral administrable pharmaceutical compositions containing the indicated combinations.

To prepare pharmaceutical formulations containing such combinations, the active compounds are formulated in the indicated amounts in a preferred manner with physiologically resistant excipients and / or diluents and / or adjuvants.

Examples of excipients and auxiliaries are natural sugars such as gelatin, sucrose or lactose, lecithin, pectin, starch (e.g. corn starch or amylose), cyclodextrins and cyclodextrin derivatives, dextran, polyvinylpyrrolidone, polyvinyl acetate , Gum arabic, alginic acid, tylose, talc, lycopodium, silicic acid, calcium hydrogen phosphate, cellulose, cellulose derivatives such as methoxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, 12 carbon atoms To 22 fatty acids, emulsifiers, oils and fats, in particular also vegetable glycerol esters and polyglycerol esters of saturated fatty acids, polyglycols such as mono or polyhydric alcohols and polyethylene glycols, monohydric aliphatic alcohols having 1 to 20 carbon atoms, or Glycol, glycerol, diethylene Esters of aliphatic saturated or unsaturated fatty acids of 2 to 22 carbon atoms with polyhydric alcohols such as glycols, 1,2-propylene glycol, sorbitol, mannitol.

Further suitable auxiliaries are also substances which cause disintegration (so-called disintegrants), cross-linked polyvinylpyrrolidone, carboxymethyl starch sodium, carboxymethylcellulose sodium, microcrystalline cellulose. Known coating materials can also be used. Polymers and copolymers of acrylic acid and / or methacrylic acid and / or esters thereof, zein, ethylcellulose, ethylcellulose succinate, shellac and the like.

Plasticizers suitable as coating materials can be citric acid esters and tartaric acid esters, glycerol and glycerol esters, polyethylene glycols of various chain lengths. It is suitable for the preparation of water or physiologically acceptable organic solvents such as alcohol and fatty alcohol solutions or suspensions.

In liquid formulations, it may be necessary to use preservatives such as solvate potassium, methyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate, antioxidants such as ascorbic acid and fragrance enhancers such as peppermint oil.

In the preparation of the formulations, known and conventional solubilizers, or emulsifiers, such as polyvinylpyrrolidone and polysorbate 80 can be used.

Further examples of suitable excipients and auxiliaries can be found in the literature [Dr. H.P. Fiedler "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete" [Encyclopaedia of auxiliaries for pharmacy, cosmetics and related fields].

The following examples will specifically illustrate the present invention and the present invention is not limited to these examples.

Example

Example 1 Preparation of Intermediates

Intermediate 1) 1. 3-cyclopentyloxy-4-methoxybenzaldehyde

A suspension of isovanillin (100 g, 0.66 mol), anhydrous potassium carbonate (136.2 g, 0.99 mol), potassium iodide (3 g) and anhydrous dimethylformamide (650 mL) was stirred at 65 ° C. and then cyclopentyl was added to the suspension. Bromide (127.3 g, 0.85 mol) was slowly added dropwise for 1 hour, stirred at 65 ° C. for 1 day, and then cooled to room temperature. Toluene (2.0 L) was added to the mixture, diluted with 1 M sodium hydroxide (2 × 1). .5 L). The obtained aqueous layer solution was extracted with toluene (0.5 L), and the obtained organic layer was washed with distilled water (2 × 1.5 L). The organic layer was dried and concentrated to give a light brown oily title compound (117 g).

¹ H NMR (400 MHz, CDCl ₃ , δ) 9.84 (s, 1H) 7.42 (m, 2H) 6.95 (d, 1H, J = 9 Hz) 4.87 (m, 1H) 3.93 (s, 3H) 2.1-1.6 ( m, 8H)

Intermediate 2. Toluene-4-sulfone acid indan-2-yl ester

2-indanol (5.0 g, 37.3 mmole) was dissolved in 20 ml of anhydrous pyridine, and the reaction solution was cooled to 10 ° C and stirred for 5 minutes. Tosyl chloride (8.53 g, 1.2 equivalents) was added while maintaining the reaction temperature, the mixture was stirred for 30 minutes, and then stored in the refrigerator 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 ethyl ether, and dried under reduced pressure at 40 ° C. to obtain a light brown solid title compound (4.6 g).

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) 2.466 ( s, 3 H)

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

A suspension of isovanillin (25.9 g, 3.47 mmol), anhydrous potassium carbonate (35.1 g, 1.1 equiv), potassium iodide (0.8 g), anhydrous dimethylformamide (160 mL) was stirred at 65 ° C., and then this suspension 2-indanol tosylate (0.4 g, 2.62 equiv) was slowly added dropwise to the mixture, stirred at 65 ° C. for 1 day, and then cooled to room temperature. Toluene (1.50 L) was added to the mixture, diluted with 1 M hydroxide. Washed with sodium (2 × 0.3 L). The obtained aqueous layer was extracted with toluene (0.1 L), and the obtained organic layer 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 = 10 Hz) 7.47 (d, 1H, J = 1.6 Hz) 7.27 (m, 2H) 7.19 (m, 3H ) 5.29 (m, 1H) 3.81 (s, 3H) 3.38 (m, 2H) 3.03 (m, 2H)

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

Dissolve 5.0 g (22.7 mmol) of 3-cyclopentyloxy-4-methoxybenzaldehyde synthesized in Intermediate 1 in 150 ml of anhydrous methyl alcohol, fill with argon gas, and add 1.05 g (1.2 equivalents) of methyl hydrazine. Stirred for 6 h. 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 give a light brown solid title compound (4.6 g).

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)

Intermediate 5. N- [3- (Indan-2-yloxy) -4-methoxybenzylidene] -N'-methylhydrazine

Dissolve 6.3g (23.4mmole) of 3- (Indan-2-yloxy) -4-methoxybenzaldehyde, intermediate 3, in 150ml of anhydrous methyl alcohol, fill with argon gas and add 1.2g (1.1 equiv) of methylhydrazine. And stirred at 70 ° C. for 6 hours. The reaction solution was cooled, distilled under reduced pressure to give an orange oil, diluted with 200 ml of methylene chloride, the reaction solution was diluted, washed three times with 200 ml of distilled water, and the separated solution was dried over anhydrous magnesium sulfate. The filtered solution was distilled under reduced pressure to give a light brown solid title compound (5.9 g).                     

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 (1H, d) 5.19 ( s, 1H) 3.68 (s, 3H) 3.38 (m, 2H) 3.06 (m, 2H) 2.79 (d, 3H, J = 4.8 Hz)

Intermediate 6. 4-nitrobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide

2.0 g (8.05 mmole) of N- (3-cyclopentyloxy-4-methoxybenzylidene) -N'-methylhydrazine, intermediate 4, was dissolved in anhydrous methylene chloride (100 ml), and then charged with argon gas and heated to 20 ° C. 1.80 g (1.2 equivalents) of 4-nitrobenzoyl chloride was added thereto, stirred at the temperature for 10 minutes, and then 1.50 ml (1.3 equivalents) of triethylamine was added thereto at room temperature, 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 (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).                     

Mass Spectrum, m / e = 397

M.P = 173 ~ 174 ℃

¹ H NMR (400 MHz, CDCl ₃ , δ) 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)

Intermediate 7. 4-Aminobenzoic Acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide

0.90 g of solid obtained from intermediate 6, 4-nitrobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide, was treated with tetrahydrofuran (50 ml) and methyl. After dissolving at 50 ° C. in a mixed solvent of alcohol (100 ml), ammonium formate (1.0 g) was added and dissolved, and then palladium / activated carbon (5%, dry) was carefully added at 60 ° C. 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).

Mass Spectrum, m / e = 367

M.P = 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) 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)

Intermediate 8. 4-nitrobenzoic acid N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazide

Argon gas after dissolving 5.9 g (20.2 mmole) of N- [3- (indan-2-yloxy) -4-methoxybenzylidene] -N'-methylhydrazine as intermediate 5 in anhydrous methylene chloride (250 ml) 4.50 g (1.2 equivalents) of 4-nitrobenzoyl chloride was added thereto at 20 ° C., followed by stirring for 10 minutes at this temperature, followed by 4.3 ml (1.5 equivalents) of triethylamine, 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 (150 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 (3.53 g).

Mass Spectrum, m / e = 445

M.P = 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)

Intermediate 9. 4-Aminobenzoic Acid N '-[3- (Indan-2-yloxy) -4-methoxybenzylidene] -N-methyl-hydrazide

2.4 g (5.39 mmole) of 4-nitrobenzoic acid N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methylhydrazide as intermediate 8 was dissolved in anhydrous methylene chloride (200 ml), 50 ml of acetic acid and 10 ml of methyl alcohol and then stirred for 10 minutes. Palladium / activated carbon 80mg was added to the reaction solution, filled with nitrogen gas, stirred at 20 ° C for 20 minutes, and washed five times with 200 ml of saturated sodium bicarbonate. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (1.9 g) of light yellow color.

Mass Spectrum, m / e = 415

M.P = 76 ~ 78 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 7.89 (s, 1 H) 7.53 (d, 2H, J = 8.6 Hz) 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 2. {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid methyl ester

4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbony] phenyl} -carbamic acid methyl ester

0.2 g (0.54 mmol) of 4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide, intermediate 7, was dissolved in 40 ml of anhydrous acetonitrile. 0.09 ml (2.0 equiv) was added thereto, followed by stirring at 20 ° C. for 30 minutes. 0.07 g (1.2 equivalents) of methylchloroformate was added and stirred at room temperature for 10 hours. 40 ml of distilled water was added to the reaction mixture, and the acetonitrile was distilled off under reduced pressure. Then, 40 ml of ethyl acetate was added to separate layers. The organic layer was separated, dried over MgSO ₄ , concentrated, and re-crystallized by adding 10 ml of ethyl acetate and 20 ml of hexane again for 12 hours in a refrigerator. 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 the desired product (0.10 g).

Mass Spectrum, m / e = 425

M.P = 144 ~ 146 ℃

¹ H NMR (400 MHz, CDCl ₃ , δ) 7.76 (2H, d, J = 8.8 Hz), 7.68 (1H, s), 7.44 (2H, d, J = 8.7 Hz), 7.12 (1H. D, J = 1.9 Hz) 7.00 (1H, dd, J = 8.2, 1.9 Hz), 6.83 (1H, d, J = 8.3 Hz), 6.71 (1H, brs), 4.65 (1H, m), 3.86 (3H, s) , 3.79 (3H, s), 3.54 (3H, s), 1.82 (6H, m)

Example 3. {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid 5-isopropyl-2-methylcyclohexyl ester

{4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} -carbamic acid 5-isopropyl-2-methylcyclohexyl ester

  0.2 g (0.54 mmoles) of 4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide as intermediate 7 and 0.15 g of (-)-mentylchloroformate The reaction was carried out in the same manner as in Example 2 using (1.2 equivalents) as a starting material to obtain the target product (0.09 g).

   Mass Spectrum, m / e = 550

   M.P = 104 ~ 106 ℃

¹ H NMR (400 MHz, CDCl ₃ , δ) 7.75 (2H, d, J = 8.7 Hz), 7.67 (1H, s), 7.45 (2H, d, J = 8.6 Hz), 7.14 (1H. D, J = 1.9 Hz) 6.99 (1H, dd, J = 8.2, 1.9 Hz), 6.83 (1H, d, J = 8.2 Hz), 6.67 (1H, brs), 4.66 (2H, m), 3.86 (3H, s) , 3.54 (3H, s), 2.10 (1H, m), 1.92 (1H, m), 1.78 (8H, m), 1.56 (4H, m), 1.38 (1H, m), 1.03 (2H, m), 0.92 (6H, dd), 0.82 (3H, d)

Example 4. {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid phenylmethyl ester

{4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methyl hydrazinocarbonyl] phenyl} carbamic acid phenylmethyl ester

4-aminobenzoic acid intermediate N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide 0.2 g (0.54 mmol) and 0.11 g (1.2 equiv) phenylchloroformate The reaction was carried out in the same manner as in Example 2, using the starting material to obtain the target product (0.11 g).

Mass Spectrum, m / e = 488

M.P = 123 ~ 125 ℃

¹ H NMR (400 MHz, CDCl ₃ , δ) 7.75 (2H, d, J = 8.7 Hz), 7.67 (1H, s), 7.39 (6H, m), 7.11 (1H. D, J = 1.8 Hz), 6.99 (1H, dd, J = 8.2, 1.9 Hz), 6.82 (1H, d, J = 8.3 Hz), 6.76 (1H, brs), 5.21 (1H, s), 4.63 (1H, m), 3.85 (3H , s), 3.53 (3H, s), 1.79 (6H, m), 1.51 (2H, m)

Example 5. {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid phenyl ester

{4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid phenyl ester                     

4-aminobenzoic acid intermediate N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide 0.2 g (0.54 mmole) and benzyl chloroformate 0.17 g (1.2 equiv) Using the product as a starting material, the reaction was carried out as in Example 2 to obtain the target product (0.09 g).

Mass Spectrum, m / e = 502

M.P = 188 ~ 189 ℃

¹ H NMR (400 MHz, CDCl ₃ , δ) 7.77 (2H, d, J = 8.8 Hz), 7.68 (1H, s), 7.51 (2H, d, J = 8.7 Hz), 7.40 (1H, d, J = 8.5 Hz), 7.39 (1H, m), 7.25 (1H, m), 7.18 (1H, dd, J = 8.8, 1.3 Hz), 7.11 (1H, d, J = 2.0 Hz), 7.06 (1H, brs ), 7.00 (1H, dd, J = 8.2, 2.0 Hz), 6.82 (1H, d, J = 8.3 Hz), 4.64 (1H, m), 3.85 (3H, s), 3.54 (3H, s), 1.81 (6H, m), 1.56 (2H, m)

Example 6. {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid ethyl ester

{4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid ethyl ester                     

4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide 0.2 g (0.54 mmol) and 0.08 g (1.2 equivalents) of ethylchloroformate, intermediate 7 The reaction was carried out in the same manner as in Example 2, using the starting material to obtain the target product (0.12 g).

Mass Spectrum, m / e = 440

M.P = 165 ~ 166 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 9.88 (s, 1H) 7.89 (s, 1H), 7.58 (m, 4H), 7.56 (m, 2H), 7.07 (m, 2H), 6.96 ( d, 1H, J = 8.2 Hz, 4.55 (m, 1H), 4.16 (m, 2H) 3.76 (s, 3H), 3.46 (s, 3H), 1.79 (m, 2H) 1.63 (m, 6H), 1.27 (t, 3 H),

Example 7. {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid butyl ester

{4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid butyl ester

4-aminobenzoic acid intermediate N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide 0.2 g (0.54 mmoles) and 0.10 g (1.2 equiv) butylchloroformate The reaction was carried out as in Example 2 using the starting material to obtain the target product (0.14g).

Mass Spectrum, m / e = 468

M.P = 85 ~ 87 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 9.87 (s, 1H) 7.89 (s, 1H), 7.59 (m, 2H), 7.56 (m, 2H), 7.07 (m, 2H), 6.96 ( d, 1H, J = 8.2 Hz) 4.56 (m, 1H), 4.12 (t, 2H) 3.76 (s, 3H), 3.45 (s, 3H), 1.78 (m, 2H), 1.61 (m, 8H), 1.41 (m, 2 H), 0.94 (t, 3 H)

Example 8. {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid propyl ester

{4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid propyl ester

4-aminobenzoic acid intermediate N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide 0.2 g (0.54 mmole) and propylchloroformate 0.09 g (1.2 equiv) The reaction was carried out in the same manner as in Example 2, using the starting material to obtain the target product (0.18 g).

Mass Spectrum, m / e = 454

M.P = 121 ~ 122 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 9.88 (s, 1H), 7.89 (s, 1H), 7.58 (m, 4H), 7 (m, 2H), 6.96 (d, 1H, J = 8.1 Hz), 4.56 (m, 1H), 4.08 (t, 2H), 3.76 (s, 3H), 3.46 (s, 3H), 1.78 (m, 2H) 1.63 (m, 8H), 0.96 (t, 3H )

Example 9. {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid 4-chlorophenyl ester

{4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid 4-chlorophenyl ester

0.2 g (0.54 mmoles) of 4-aminobenzoic acid N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide as intermediate 7 and 0.13 g of 4-chlorophenylchloroformate ( 1.2 equivalents) as a starting material, the reaction was carried out as in Example 2 to obtain the target product (0.20 g).

Mass Spectrum, m / e = 522

M.P = 177 ~ 179 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 7.86 (s, 1H), 7.51 (d, 4H, J = 8.7 Hz), 7.20 (m, 3H), 7.10 (m, 1H), 6.98 (d , 1H, J = 8.3 Hz, 6.78 (d, 1H, J = 8.6 Hz), 6.55 (d, 2H, J = 8.6 Hz), 5.61 (s, 1H), 4.67 (m, 1H), 3.77 (s , 3H), 3.42 (s, 3H), 1.87 (m, 2H) 1.67 (m, 6H)

Example 10. {4- [N '-(3-cyclopentyloxy-4-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid 2-bromoethyl ester

{4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid 2-bromoethyl ester

4-aminobenzoic acid intermediate N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazide 0.2 g (0.54 mmole) and 2-bromoethylchloroformate 0.13 g The reaction was carried out in the same manner as in Example 2 using (1.2 equivalents) as a starting material to obtain the target product (0.21 g).

Mass Spectrum, m / e = 518

M.P = 153 ~ 154 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 10.88 (s, 1H), 7.90 (s, 1H), 7.59 (d, 4H, J = 8.7 Hz), 7.07 (m, 2H), 6.96 (d , 1H, J = 8.2 Hz), 4.56 (m, 1H), 4.45 (t, 2H), 3.76 (m, 5H), 3.45 (s, 3H), 1.78 (m, 2H) 1.62 (m, 6H)

Example 11. {4- [N '-(3- (Indan-2-yloxy) -4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid methyl ester

{4- [N '-(3- (Indan-2-yloxy) -4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid methyl ester

4-aminobenzoic acid N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methyl-hydrazide 0.2 g (0.48 mmole) with intermediate 9, methylchloroformate The reaction product was carried out in the same manner as in Example 2, using 0.06 g (1.2 equivalents) as a starting material to obtain the target product (0.09 g).

Mass Spectrum, m / e = 474

M.P = 127 ~ 129 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 9.85 (s, 1H), 7.94 (s, 1H), 7.60 (dd, 4H, J = 28.3, 8.8 Hz), 7.25 (m, 2H), 7.15 (m, 4H), 6.98 (d, 1H, J = 8.3 Hz), 5.00 (m, 1H), 3.71 (s, 3H), 3.55 (s, 3H), 3.48 (s, 3H), 3.25 (m, 2H), 2.96 (d, 2H)

Example 12. {4- [N '-(3- (Indan-2-yloxy) -4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid ethyl ester

{4- [N '-(3- (Indan-2-yloxy) -4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid ethyl ester

4-aminobenzoic acid intermediate N '-[3- (indan-2-yloxy) -4-methoxybenzylidene] -N-methyl-hydrazide 0.2 g (0.48 mmole) as intermediate 9 and ethylchloroformate The reaction product was carried out in the same manner as in Example 2, using 0.07 g (1.2 equivalents) as a starting material to obtain the target product (0.08 g).

Mass Spectrum, m / e = 488

M.P = 126 ~ 128 ℃

¹ H NMR (400 MHz, DMSO-d ₆ , δ) 9.81 (s, 1H), 7.94 (s, 1H), 7.61 (dd, 4H, J = 21.9, 8.9 Hz), 7.25 (m, 2H), 7.15 (m, 4H), 6.98 (d, 1H, J = 8.3 Hz), 4.99 (m, 1H), 4.01 (q, 2H), 3.71 (s, 3H), 3.48 (s, 3H), 3.24 (m, 2H), 2.96 (d, 2H), 1.15 (t, 3H)

Pharmacological Experimental Example

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

Subtybe classification- Trends in Endocrinology & Metabolism, Moreland et al (1999) 10, 97-; Mol. Cell. Biol., Bolger G. et al (1993) 13, Partially purified PDE IV, test compound, and 1.0 μM cAMP containing 0.01 μM [ ³ H] cAMP were incubated at 30 ° C. for 20 minutes according to 6558-6571). Phosphodiesterase (PDE) reaction in which cAMP is changed to AMP was completed by boiling for 2 minutes. Snake venom nucleotidase was added and incubated at 30 ° C. for 10 minutes to change AMP to adenosine. Unhydrolyzed cAMP was combined with AG1-X2 resin and the remaining [ ³ H] adenosine in aqueous solution was quantified by scintillation counting. SB 207499 used as a comparative in Table 1 is known from J. Med. Chem. 1998, 41, 821-835 as a compound of the structure:

The experimental results are as follows.

Concentration (μM) % Suppression Concentration (μM) % Suppression SB 207499 (Comparative) One 50.9 SB 207499 (Comparative) One 50.9 0.3 40.8 0.3 40.8 Example 1 One 61.4 Example 8 One Untested 0.3 56.9 0.3 Untested Example 2 One Untested Example 9 One 49.5 0.3 Untested 0.3 43.1 Example 3 One 49.1 Example 10 One Untested 0.3 44.4 0.3 Untested Example 4 One 47.4 Example 11 One Untested 0.3 46.4 0.3 Untested Example 5 One 51.6 0.3 51.8 Example 6 One 50.3 0.3 43.7 Example 7 One Untested 0.3 Untested

The present invention relates to a catechol N-methylhydrazide derivative represented by [Formula 1], a method for preparing the same, and a pharmaceutical composition containing the same, wherein the compound is used in phosphodiesterase IV or Tumor necrosis factor (TNF). It has inhibitory effects such as asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases such as AIDS, HIV, Crohn's disease, sepsis, septic disease, fetal odor and TNF It is useful for the treatment of diseases involving the production of.

Claims (5)

The catechol N-methylhydrazide carbamic ester 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, indan or benzyl group, R ₂ is a methyl group, Y is an ester bond and means -C (= O) O-, and R ₃ is (C ₁ -C ₇ ) alkyl wherein one or two halogen or (C ₁ -C ₃ ) compounds are optionally substituted or unsubstituted; (C ₁ -C ₃₎ the compound is optionally substituted or unsubstituted (C ₁ -C ₇₎ cyclo-alkyl; Phenyl optionally substituted with one or two nitro, nitrile, halogen, (C ₁ -C ₃ ) alkyl or (C ₁ -C ₃ ) alkoxy groups; Nitro, a nitrile or a halogen group optionally substituted with one or two substituted halogen groups, wherein the halogen is Cl, F or Br. 2. A compound according to claim 1, wherein {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid methyl ester, {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid 5-isopropyl-2-methylcyclohexyl ester, {4- [N'- (3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid phenylmethyl ester, {4- [N '-(3-cyclopentyloxy-4-meth Oxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid phenyl ester, {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocar Carbonyl] phenyl} carbamic acid ethyl ester, {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid butyl ester, {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N- Ylhydrazinocarbonyl] phenyl} carbamic acid propyl ester, {4- [N '-(3-cyclopentyloxy-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic liquid Seed 4-chlorophenyl ester, {4- [N '-(3-cyclopentyloxy-4-4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid 2-bromoethyl Ester, {4- [N '-(3- (indan-2-yloxy) -4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid methyl ester, {4- [ N '-(3- (indan-2-yloxy) -4-methoxybenzylidene) -N-methylhydrazinocarbonyl] phenyl} carbamic acid ethyl ester, characterized in that any one of N -Methylhydrazide carbamic ester derivatives or pharmaceutically acceptable salts thereof. The isomer of the compound or mixture thereof. delete As shown in [Scheme 1], benzaldehyde in which the hydroxy group at position 4 is substituted with R ₂ is reacted with a reaction reagent designated as R ₁ -A, and two benz is substituted with R ₁ and R ₂ , respectively. Step 1 of synthesizing aldehyde (a), step 2 of synthesizing hydrazone (b) by reacting benzaldehyde (a) with methylhydrazine, 4-nit by reacting hydrazone (b) with 4-nitrobenzoyl chloride 3 steps of synthesizing N'-benzylidene-N-methylhydrazide (c) in which robenzoic acid is introduced, and reducing the nitro group of N'-benzylidene-N-methylhydrazide (c) to reduce the amine derivative The catechol N-methyl of claim 1 consisting of a four step of synthesizing (d) and a five step of synthesizing the compound of the structural formula (I) by carrying out a coupling reaction with the amine derivative (d) and the compound of 3R-YB Process for preparing hydrazide carbamic ester derivatives: Scheme 1

Wherein R ₁ is a (C ₃ -C ₇ ) cycloalkyl, indan or benzyl group, R ₂ is a methyl group, Y is an ester bond and means —C (═O) O—, and R ₃ is halogen or (C ₁ -C ₇ ) alkyl in which _one or two (C ₁ -C ₃ ) compounds are optionally substituted or unsubstituted; (C ₁ -C ₃₎ the compound is optionally substituted or unsubstituted (C ₁ -C ₇₎ cyclo-alkyl; Phenyl optionally substituted with one or two nitro, nitrile, halogen, (C ₁ -C ₃ ) alkyl or (C ₁ -C ₃ ) alkoxy groups; Nitro, a nitrile or a halogen group optionally substituted with one or two halogen groups, wherein halogen is Cl, F, or Br and B is Cl.