KR20020037213A - Novel catechol enone derivatives - Google Patents

Abstract

PURPOSE: Provided are novel catechol enone derivatives and their pharmaceutically acceptable salt or solvate. The novel compounds have inhibition effects on tumor necrosis factor(TNF) or phosphodiesterase IV. CONSTITUTION: The novel compounds are represented by the formula(1), wherein R1 is hydrogen, C1-C7 alkyl, C3-C7 cycloalkyl, benzyl or phenyl; R is C1-C6 lower alkyl, C1-C6 lower haloalkyl, C1-C6 lower alkenyl or cycloalkyl, or one of following formulae, in which R2, R and X are as defined in the description.

Description

New Catechol Enone Derivatives {NOVEL CATECHOL ENONE DERIVATIVES}

The present invention relates to a novel catechol enone derivative or a pharmaceutically acceptable salt or solvate thereof, and more particularly, to a novel catechol enone derivative or a pharmaceutically acceptable salt or solvate thereof. One catechol enone derivative or pharmaceutically acceptable salt or solvate thereof. The catechol enone derivatives or pharmaceutically acceptable salts or solvates thereof of the present invention are asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease, psoriasis, allergic rhinitis, dermatitis, AIDS, HIV, Crohn's disease, sepsis, It is useful for the treatment of diseases including shock, etiology, other inflammatory diseases or the production of tumor necrosis factor (TNF) caused by sepsis.

Phosphodiesterases are enzymes that hydrolyze cyclic nucleotides as one of the chemical delivery agents. 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 cell stimuli.

Inhibitory action of phosphodiesterase IV can prevent bronchial spasms by maintaining the concentration of cyclic adenosine 3 ', 5'-monophosphate and in addition have anti-inflammatory action. Thus compounds that inhibit phosphodiesterase IV are useful as therapeutic agents for asthma, inflammatory diseases and the like.

Tumor necrosis factor (TNF) is known to be associated with many infectious diseases including automatism and autoimmune diseases, and TNF has also been shown to be a major mediator of the inflammatory response seen in sepsis and septic shock.

Phosphodiesterase IV inhibitors are generally known to inhibit TNF-α, a tumor necrosis factor, and have been clinically identified (Christian Schudt, Phosphodiesterase Inhibitors).

Several compounds have been known to act as inhibitors of phosphodiesterase IV or tumor necrosis factor (TNF).

For example, the company Rhone Poulenc Rorer reported in WO 94/02465 a compound having various alkenyl or aryloxycarbonyl structures such as the following structural formula (A).

(A)

Where

R ₁ is a lower alkyl group,

R ₂ is alkyl, alkenyl, cycloalkenyl or cyclothioalkyl,

R ₃ is aryl or heteroaryl,

Z, Z ₁ , Z ₂ are oxygen or sulfur,

Z ₃ is -CH = CH-, alkynyl, -CH ₂ -CZ-, -CZ-CZ-, -CH ₂ -NH-, -CH ₂ -O-, or -N = N- and the like.

Celltech also discloses compounds of formula (B) in WO 94/14800.

(B)

Where

Y is halogen or OR ₁ , where R ₁ is a substituted alkyl group,

X is oxygen, sulfur or N (R ₆ ), where R ₆ is hydrogen or alkyl,

R ₂ is alkyl, alkenyl, cycloalkyl or cycloalkenyl,

R ₃ and R ₄ are the same or different — (CH ₂ ) _n Ar, where Ar is a ring structure having one or more heteroatoms,

R ₅ is hydrogen or an alkyl group.

Although the above compounds have been reported, it can be seen that they are structurally different from the compounds of the present invention.

The present inventors have studied over a long period of time to produce a novel catechol enone derivative or a pharmaceutically acceptable salt or solvate thereof that has an inhibitory effect on phosphodiesterase IV or TNF. That is, an object of the present invention is to provide a catechol enone derivative represented by Formula 1 below, or a pharmaceutically acceptable salt or solvate thereof.

The present invention relates to novel catechol enone derivatives or pharmaceutically acceptable salts or solvates thereof. They have an inhibitory effect on phosphodiesterase IV or tumor necrosis factor (TNF) and are asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease, psoriasis, allergic rhinitis, dermatitis, AIDS, HIV, Crohn's It is useful for the treatment of diseases, sepsis, septic shock, other inflammatory diseases such as atherosclerosis or diseases including the production of tumor necrosis factor (TNF).

Specifically, the present invention relates to a compound represented by the following formula (1) or a pharmaceutically acceptable salt or solvate thereof, and a method for preparing the same.

Where

R 1 is hydrogen, (C 1 -C 7) alkyl group, (C 3 -C 7) cycloalkyl group, benzyl or phenyl,

R is C1-C6 lower alkyl, C1-C6 lower haloalkyl, C1-C6 lower alkenyl or cycloalkyl, or

or or Is

here,

R2 is hydrogen or 1-5 chloro, fluorine or bromo, or lower alkyl of C1-C6, lower haloalkyl of C1-C6, nitro, hydroxy, lower alkoxy of C1-C6 or C1-C6 Lower alkenyl or NR4R5 or NC (O) R6 wherein R4 and R5 are the same or different from each other and are hydrogen or lower alkyl of C1-C6, R6 is lower alkyl of C1-C6,

R3 is hydrogen or 1-3 chloro, fluorine or bromo, or lower alkyl of C1-C6, lower haloalkyl of C1-C6, nitro, hydroxy, lower alkoxy of C1-C6 or C1-C6 Is lower alkenyl of or is NR 4 R 5 or NC (O) R 6, wherein R 4 and R 5 are the same or different from each other and are hydrogen or lower alkyl of C 1 to C 6, R 6 is lower alkyl of C 1 to C 6,

X is oxygen or sulfur.

In Formula 1, the alkyl group includes straight chain and branched chain.

Preferred compounds of formula (I) that fall within the scope of the present invention are as follows:

1- (3-cyclopentyloxy-4-methoxyphenyl) -3-phenyl- (E) -2-propen-1-one,

1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (4-pyridyl)-(E) -2-propen-1-one,

1N- {4- [3- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxo- (E) -1-propenyl] phenyl} acetamide,

1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (2,6-dichlorophenyl)-(E) -2-propen-1-one,

1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (3-nitrophenyl)-(E) -2-propen-1-one,

1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (4-nitrophenyl)-(E) -2-propen-1-one,

1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (3-thienyl)-(E) -2-propen-1-one,

1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (3-furyl)-(E) -2-propen-1-one,

1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (4-nitro-3-furyl)-(E) -2-propen-1-one, and

1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (2-fluorophenyl)-(E) -2-propen-1-one.

The present invention also relates to a pharmaceutical composition for inhibiting phosphodiesterase IV or tumor necrosis factor, comprising an effective amount of the compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable carrier. will be. In addition, the present invention comprises asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease, psoriasis, allergic reaction, comprising an effective amount of the compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable carrier Pharmaceuticals useful for the treatment of diseases including rhinitis, dermatitis, AIDS, HIV, Crohn's disease, sepsis, sepsis shock, etiology, other inflammatory diseases or the production of tumor necrosis factor (TNF) It relates to a composition.

The following reaction schemes exemplify the preparation method of the novel compounds represented by the general formula (1) of the present invention, and the preparation method of the compounds of the present invention is not limited to the following schemes. Many variations of the following preparation methods will be apparent to those skilled in the art. Unless stated otherwise, in the following R 1 and R are the same as defined above for Formula (1).

The reaction scheme 1 is described in detail as follows.

First, an alkyl bromide or cycloalkyl bromide is introduced to isovanillin as a starting material to synthesize a benzaldehyde compound represented by the following Chemical Formula 2.

Formula 2

Benzaldehyde compound of Chemical Formula 2 is oxidized and esterified to form methyl catecholbenzoate of Chemical Formula 3 below. Preferably, an ester of the benzaldehyde compound represented by the formula (2) using sulfamic acid and sodium chlorite at 80 ° C. in acetic acid and water at 0-25 ° C., followed by methanol as a solvent and sulfuric acid as an acid catalyst. Through methylation reaction, it is made of methyl catechol benzoate of Chemical Formula 3 below.

Formula 2 Formula 3

Methyl catechol benzoate of Formula 3 is reacted with dimethyl methyl phosphonate of Formula 4 in the presence of a base such as butyllithium and then reacted with various aldehydes in the presence of acid Enone derivatives or pharmaceutically acceptable salts or solvates thereof are synthesized. Preferably, the reaction of methyl catechol benzoate of Formula 3 with dimethyl methyl phosphonate of Formula 4 in tetrahydrofuran in the presence of a base such as butyllithium at -72 ° C as a solvent and then in the presence of an acid By reacting with an aldehyde, a catechol enone derivative of Formula 1 or a pharmaceutically acceptable salt or solvate thereof is synthesized.

Formula 3 Formula 4 Formula 1

Since the compound of Formula 1 has a double bond, it has an E / Z isomer, but is almost (E) -formed through the preparation method.

In each reaction herein, the product can be separated and / or purified from the reaction system by conventional methods known in the art. Examples of separation and purification methods include distillation (including distillation under atmospheric pressure and distillation under reduced pressure), recrystallization, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, thin layer chromatography, phase separation, solvent extraction, Washing and the like can be used. Purification can be carried out after each reaction or after a series of reactions.

Starting materials and reagents necessary for the synthesis of the compounds of the present invention are readily prepared or commercially available by the methods of the literature or by the methods exemplified above and in the Examples below.

Although the present invention will be described in more detail with reference to the following examples, the following examples are provided for illustrative purposes only and are not intended to limit the scope and scope of the present invention.

Reference Example 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 bromide was added to the suspension. (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. Then, diluted with toluene (2.0 L) was added to the mixture, followed by diluting with 1 M sodium hydroxide (2 × 1.5 L). The organic layer was dried and concentrated to give a light brown oily title compound (117 g).

¹ H NMR (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)

Reference Example 2. 3-cyclopentyloxy-4-methoxybenzoic acid

3-cyclopentyloxy-4-methoxybenzaldehyde (41g, 0.186mole) and sulfamic acid (24.4g, 0.251mole) synthesized in Reference Example 1 were dissolved in 80% acetic acid and then heated to 0 ° C. Cooled. To this was added dropwise a solution of sodium chlorite (21.9 g, 0.193 mole) in 90 ml of water over 1 hour. At this time, the internal temperature was maintained at 15 to 20 ° C. After stirring for 1 h at 20 ° C., 320 ml of water was added, followed by stirring for 1 h, and the resulting solid was filtered and dried to yield an off-white solid title compound (36.2 g).

¹ H NMR (CDCl ₃ , δ): 12.35 (s, 1H) 7.42 (m, 2H) 6.95 (d, 1H, J = 9 Hz) 4.87 (m,

1H) 3.93 (s, 3H) 2.1 to 1.6 (m, 8H)

Reference Example 3. Methyl 3-cyclopentyloxy-4-methoxybenzoate

After cooling 450 ml of methanol to 0 ° C., acetyl chloride (42 ml, 0.592 mol) was added dropwise over 30 minutes. After stirring for 10 minutes, 3-cyclopentyloxy-4-methoxybenzoic acid (46.7 g, 0.197 mole) synthesized in Reference Example 2 was added. After refluxing for 5 hours, the mixture was cooled to room temperature. The solvent was removed under reduced pressure and recrystallized with 80% methanol to give the title compound (44.5 g) as a white color.

¹ H NMR (CDCl ₃ ): 7.74 (m, 1 H) 7.55 (d, 1 H) 6.87 (d, 1 H) 4.83 (m, 1 H)

3.89 (s, 3H) 3.87 (s, 3H) 1.57-1.97 (m, 8H)

Example 1. 1- (3-cyclopentyloxy-4-methoxyphenyl) -3-phenyl- (E) -2-propen-1-one

To the reactor was added dimethylmethylphosphonate (2.16 ml, 20 mmol) followed by 20 ml of anhydrous tetrahydrofuran. After cooling this to -78 degreeC, n-butyllithium 1.6 M hexane solution (12.5 ml, 20 mmol) was slowly added dropwise over 20 minutes. To this reaction solution was added dropwise a solution of methyl 3-cyclopentyloxy-4-methoxybenzoate (2 g, 8 mmoles) synthesized in Reference Example 3 in 5 ml of tetrahydrofuran dropwise for 5 minutes. After stirring for 10 minutes, 10 ml of saturated ammonium chloride solution was added at -30 ° C, stirred for 5 minutes, 20 ml of ethyl acetate was added, and stirred for 5 minutes. The layers were separated and the aqueous layer was removed. The organic layer was washed with 10 ml of water, washed with saturated brine, dried and the solvent was distilled off under reduced pressure. 2 ml of tetrahydrofuran was added to the obtained oily compound, benzylaldehyde (1.2 g, 11 mmoles) and lithium chloride (0.69 g, 16 mmoles) were added, followed by cooling to 0 ° C. To this was slowly added dropwise 1,8-diazabicyclo [5.4.0] -7-cene (1.3 g, 8.8 mmole). After stirring for 5 hours, 0.5N hydrochloric acid solution was added, stirred for 5 minutes, and extracted by adding 5 ml of ethyl acetate. The organic layer was washed with water and saturated brine, dried, the solvent was distilled off under reduced pressure, and crystallized with 80% methanol to obtain a white title compound (2.35 g).

M.P: 101-102 ° C

¹ H NMR (CDCl ₃ ): 7.97 (d, 1 H) 7.64 (m, 4 H) 7.56 (d, 1 H) 7.41 (m, 3 H)

6.92 (d, 1H) 4.89 (m, 1H) 3.91 (s, 3H) 1.26 to 2.00 (m, 8H)

Example 2. 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (4-pyridyl)-(E) -2-propen-1-one

To the reactor was added dimethylmethylphosphonate (2.16 ml, 20 mmol) followed by 20 ml of anhydrous tetrahydrofuran. This was cooled to -78 ° C and n-butyllithium 1.6M hexane solution (12.5 ml, 20 mmol) was slowly added dropwise over 20 minutes. To this reaction solution was added dropwise a solution of methyl 3-cyclopentyloxy-4-methoxybenzoate (2 g, 8 mmol) synthesized in Reference Example 3 in 5 ml of tetrahydrofuran dropwise. After stirring for 10 minutes, 10 ml of saturated ammonium chloride solution was added at -30 ° C, stirred for 5 minutes, 20 ml of ethyl acetate was added, followed by stirring for 5 minutes. The layers were separated and the aqueous layer was removed. The organic layer was washed with 10 ml of water, washed with saturated brine, dried and the solvent was distilled off under reduced pressure. 2 ml of tetrahydrofuran was added to the obtained oily compound, 4-pyridinecarboxaldehyde (1.17 g, 11 mmoles) and lithium chloride (0.69 g, 16 mmoles) were added, followed by cooling to 0 ° C. To this was slowly added dropwise 1,8-diazabicyclo [5.4.0] -7-cene (1.3 g, 8.8 mmole). After stirring for 5 hours, 0.5N hydrochloric acid solution was added, stirred for 5 minutes, and extracted by adding 5 ml of ethyl acetate. The organic layer was washed with water and saturated brine, dried, the solvent was distilled off under reduced pressure, and then crystallized with 80% methanol to obtain a pale yellow title compound (1.96 g).

M.P: 123-125 ℃

¹ H NMR (CDCl ₃ ): 8.49 (d, 2H) 7.62 (m, 4H) 7.50 (d, 2H) 6.93 (d, 1H)

4.82 (m, 1H) 3.90 (s, 3H) 1.64 to 2.06 (m, 8H)

Example 3. 1N- {4- [3- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxo- (E) -1-propenyl] phenyl} acetamide

To the reactor was added dimethylmethylphosphonate (2.16 ml, 20 mmol) followed by 20 ml of anhydrous tetrahydrofuran. This was cooled to -78 ° C and n-butyllithium 1.6M hexane solution (12.5 ml, 20 mmol) was slowly added dropwise over 20 minutes. To this reaction solution was added dropwise a solution of methyl 3-cyclopentyloxy-4-methoxybenzoate (2 g, 8 mmol) synthesized in Reference Example 3 in 5 ml of tetrahydrofuran dropwise. After stirring for 10 minutes, 10 ml of saturated ammonium chloride solution was added at -30 ° C, stirred for 5 minutes, 20 ml of ethyl acetate was added, followed by stirring for 5 minutes. The layers were separated and the aqueous layer was removed. The organic layer was washed with 10 ml of water, washed with saturated brine, dried and the solvent was distilled off under reduced pressure. 2 ml of tetrahydrofuran was added to the obtained oily compound, 4-acetamidobenzaldehyde (1.78 g, 11 mmoles) and lithium chloride (0.69 g, 16 mmoles) were added, followed by cooling to 0 ° C. To this was slowly added dropwise 1,8-diazabicyclo [5.4.0] -7-cene (1.3 g, 8.8 mmole). After stirring for 5 hours, 0.5N hydrochloric acid solution was added, stirred for 5 minutes, and extracted by adding 5 ml of ethyl acetate. The organic layer was washed with water and saturated brine, dried, the solvent was distilled off under reduced pressure, and then crystallized with 80% methanol to obtain a pale yellow title compound (2.36 g).

M.P: 204 to 205 ° C

¹ H NMR (CDCl ₃ ): 7.92 (s, 1 H), 7.61-77.7 (m, 7 H) 7.48 (d, 1 H) 6.94 (d, 1 H)

4.88 (m, 1H) 3.93 (s, 3H) 2.20 (s, 3H) 1.62 to 1.97 (m, 8H)

Example 4. 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (2,6-dichlorophenyl)-(E) -2-propen-1-one

To the reactor was added dimethylmethylphosphonate (2.16 ml, 20 mmol) followed by 20 ml of anhydrous tetrahydrofuran. This was cooled to -78 ° C and n-butyllithium 1.6M hexane solution (12.5 ml, 20 mmol) was slowly added dropwise over 20 minutes. To this reaction solution was added dropwise a solution of methyl 3-cyclopentyloxy-4-methoxybenzoate (2 g, 8 mmol) synthesized in Reference Example 3 in 5 ml of tetrahydrofuran dropwise. After stirring for 10 minutes, 10 ml of saturated ammonium chloride solution was added at -30 ° C, stirred for 5 minutes, 20 ml of ethyl acetate was added, followed by stirring for 5 minutes. The layers were separated and the aqueous layer was removed. The organic layer was washed with 10 ml of water, washed with saturated brine, dried and the solvent was distilled off under reduced pressure. 2 ml of tetrahydrofuran was added to the obtained oily compound, 2,6-dichlorobenzaldehyde (1.93 g, 11 mmole) and lithium chloride (0.69 g, 16 mmole) were added, followed by cooling to 0 ° C. To this was slowly added dropwise 1,8-diazabicyclo [5.4.0] -7-cene (1.3 g, 8.8 mmole). After stirring for 5 hours, 0.5N hydrochloric acid solution was added, stirred for 5 minutes, and extracted by adding 5 ml of ethyl acetate. The organic layer was washed with water and saturated brine, dried, the solvent was distilled off under reduced pressure, and crystallized with 80% methanol to obtain a white title compound (2.48 g).

M.P: 82 ~ 83 ℃

¹ H NMR (CDCl ₃ ): 7.98 (d, 1H), 7.66 (s, 1H) 7.64 (d, 2H) 7.41 (d, 2H)

7.23 (t, 1 H) 6.95 (d, 1 H) 4.82 (m, 1 H) 3.94 (s, 3 H)

1.60 to 2.01 (m, 8H)

Example 5. 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (3-nitrophenyl)-(E) -2-propen-1-one

To the reactor was added dimethylmethylphosphonate (2.16 ml, 20 mmol) followed by 20 ml of anhydrous tetrahydrofuran. This was cooled to -78 ° C and n-butyllithium 1.6M hexane solution (12.5 ml, 20 mmol) was slowly added dropwise over 20 minutes. To this reaction solution was added dropwise a solution of methyl 3-cyclopentyloxy-4-methoxybenzoate (2 g, 8 mmol) synthesized in Reference Example 3 in 5 ml of tetrahydrofuran dropwise. After stirring for 10 minutes, 10 ml of saturated ammonium chloride solution was added at -30 ° C, stirred for 5 minutes, 20 ml of ethyl acetate was added, and stirred for 5 minutes. The layers were separated and the aqueous layer was removed. The organic layer was washed with 10 ml of water, washed with saturated brine, dried and the solvent was distilled off under reduced pressure. 2 ml of tetrahydrofuran was added to the obtained oily compound, 3-nitrobensaldede (1.66 g, 11 mmoles) and lithium chloride (0.69 g, 16 mmoles) were added, followed by cooling to 0 ° C. To this was slowly added dropwise 1,8-diazabicyclo [5.4.0] -7-cene (1.3 g, 8.8 mmole). After stirring for 5 hours, 0.5N hydrochloric acid solution was added, stirred for 5 minutes, and extracted by adding 5 ml of ethyl acetate. The organic layer was washed with water and saturated brine, dried, the solvent was distilled off under reduced pressure, and then crystallized with 80% methanol to obtain the title compound (2.52 g), which was slightly yellow.

M.P: 122-124 ℃

¹ H NMR (CDCl ₃ ): 8.72 (s, 1H) 8.52 (d, 1H) 7.92 (d, 1H) 7.80 (d, 1H)

7.64 (m, 4H) 6.96 (d, 1H) 4.91 (m, 1H) 3.95 (s, 3H)

1.64 to 2.01 (m, 8H)

Example 6. 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (4-nitrophenyl)-(E) -2-propen-1-one

To the reactor was added dimethylmethylphosphonate (2.16 ml, 20 mmol) followed by 20 ml of anhydrous tetrahydrofuran. This was cooled to -78 ° C and n-butyllithium 1.6M hexane solution (12.5 ml, 20 mmol) was slowly added dropwise over 20 minutes. To this reaction solution was added dropwise a solution of methyl 3-cyclopentyloxy-4-methoxybenzoate (2 g, 8 mmol) synthesized in Reference Example 3 in 5 ml of tetrahydrofuran dropwise. After stirring for 10 minutes, 10 ml of saturated ammonium chloride solution was added at -30 ° C, stirred for 5 minutes, 20 ml of ethyl acetate was added, followed by stirring for 5 minutes. The layers were separated and the aqueous layer was removed. The organic layer was washed with 10 ml of water, washed with saturated brine, dried and the solvent was distilled off under reduced pressure. 2 ml of tetrahydrofuran was added to the obtained oily compound, 4-nitrobensaldede (1.66 g, 11 mmoles) and lithium chloride (0.69 g, 16 mmoles) were added, followed by cooling to 0 ° C. To this was slowly added dropwise 1,8-diazabicyclo [5.4.0] -7-cene (1.3 g, 8.8 mmole). After stirring for 5 hours, 0.5N hydrochloric acid solution was added, stirred for 5 minutes, and extracted with 5 ml of ethyl acetate. The organic layer was washed with water and saturated brine, dried, the solvent was distilled off under reduced pressure, and then crystallized with 80% methanol to obtain a pale yellow title compound (2.68 g).

M.P: 134 ~ 135 ℃

¹ H NMR (CDCl ₃ ): 8.28 (d, 2H) 7.78 (m, 3H), 7.63 (m, 3H) 6.95 (d, 1H)

4.90 (m, 1H) 3.95 (s, 3H) 1.64-1.99 (m, 8H)

Example 7. 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (3-thienyl)-(E) -2-propen-1-one

To the reactor was added dimethylmethylphosphonate (2.16 ml, 20 mmol) followed by 20 ml of anhydrous tetrahydrofuran. This was cooled to -78 ° C and n-butyllithium 1.6M hexane solution (12.5 ml, 20 mmol) was slowly added dropwise over 20 minutes. To this reaction solution was added dropwise a solution of methyl 3-cyclopentyloxy-4-methoxybenzoate (2 g, 8 mmol) synthesized in Reference Example 3 in 5 ml of tetrahydrofuran dropwise. After stirring for 10 minutes, 10 ml of saturated ammonium chloride solution was added at -30 ° C, stirred for 5 minutes, 20 ml of ethyl acetate was added, and stirred for 5 minutes. The layers were separated and the aqueous layer was removed. The organic layer was washed with 10 ml of water, washed with saturated brine, dried and the solvent was distilled off under reduced pressure. 2 ml of tetrahydrofuran was added to the obtained oily compound, 3-thiophene carboxaldehyde (1.23 g, 11 mmoles) and lithium chloride (0.69 g, 16 mmoles) were added, followed by cooling to 0 ° C. To this was slowly added dropwise 1,8-diazabicyclo [5.4.0] -7-cene (1.3 g, 8.8 mmole). After stirring for 5 hours, 0.5N hydrochloric acid solution was added, stirred for 5 minutes, and extracted with 5 ml of ethyl acetate. The organic layer was washed with water and saturated brine, dried and the solvent was distilled off under reduced pressure, and then crystallized with an ethyl ether / hexane = 1/1 solution to obtain a white compound (1.76 g).

M.P: 118 ~ 119 ℃

¹ H NMR (CDCl ₃ ): 7.81 (d, 1H), 7.60-7.7.6 (m, 3H) 7.38-7.42 (m, 3H)

6.93 (d, 1H) 4.89 (m, 1H) 3.93 (s, 3H) 1.62 to 2.03 (m, 8H)

Example 8. 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (3-furyl)-(E) -2-propen-1-one

To the reactor was added dimethylmethylphosphonate (2.16 ml, 20 mmol) followed by 20 ml of anhydrous tetrahydrofuran. This was cooled to -78 ° C and n-butyllithium 1.6M hexane solution (12.5 ml, 20 mmol) was slowly added dropwise over 20 minutes. To this reaction solution was added dropwise a solution of methyl 3-cyclopentyloxy-4-methoxybenzoate (2 g, 8 mmol) synthesized in Reference Example 3 in 5 ml of tetrahydrofuran dropwise. After stirring for 10 minutes, 10 ml of saturated ammonium chloride solution was added at -30 ° C, stirred for 5 minutes, 20 ml of ethyl acetate was added, and stirred for 5 minutes. The layers were separated and the aqueous layer was removed. The organic layer was washed with 10 ml of water, washed with saturated brine, dried and the solvent was distilled off under reduced pressure. 2 ml of tetrahydrofuran was added to the obtained oily compound, 3-furalaldehyde (1.06 g, 11 mmoles) and lithium chloride (0.69 g, 16 mmoles) were added, followed by cooling to 0 ° C. To this was slowly added dropwise 1,8-diazabicyclo [5.4.0] -7-cene (1.3 g, 8.8 mmole). After stirring for 5 hours, 0.5N hydrochloric acid solution was added, stirred for 5 minutes, and extracted by adding 5 ml of ethyl acetate. The organic layer was washed with water and saturated brine, dried and the solvent was distilled off under reduced pressure, and then crystallized with ethyl ether / hexane = 1/1 solution to give a white title compound (1.62 g).

M.P: 94 ~ 95 ℃

¹ H NMR (CDCl ₃ ): 7.59 to 7.73 (m, 4H), 7.47 (s, 1H) 7.26 (m, 1H) 6.90 (d, 1H)

6.71 (s, 1H) 4.89 (m, 1H) 3.92 (s, 3H) 1.61 to 2.01 (m, 8H)

Example 9. 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (4-nitro-3-furyl)-(E) -2-propen-1-one

To the reactor was added dimethylmethylphosphonate (2.16 ml, 20 mmol) followed by 20 ml of anhydrous tetrahydrofuran. This was cooled to -78 ° C and n-butyllithium 1.6M hexane solution (12.5 ml, 20 mmol) was slowly added dropwise over 20 minutes. To this reaction solution was added dropwise a solution of methyl 3-cyclopentyloxy-4-methoxybenzoate (2 g, 8 mmoles) synthesized in Reference Example 3 in 5 ml of tetrahydrofuran dropwise for 5 minutes. After stirring for 10 minutes, 10 ml of saturated ammonium chloride solution was added at -30 ° C, stirred for 5 minutes, 20 ml of ethyl acetate was added, followed by stirring for 5 minutes. The layers were separated and the aqueous layer was removed. The organic layer was washed with 10 ml of water, washed with saturated brine, dried and the solvent was distilled off under reduced pressure. 2 ml of tetrahydrofuran was added to the obtained oily compound, 4-nitro-3-furalaldehyde (1.55 g, 11 mmoles) and lithium chloride (0.69 g, 16 mmoles) were added, followed by cooling to 0 ° C. To this was slowly added dropwise 1,8-diazabicyclo [5.4.0] -7-cene (1.3 g, 8.8 mmole). After stirring for 5 hours, 0.5N hydrochloric acid solution was added, stirred for 5 minutes, and extracted with 5 ml of ethyl acetate. The organic layer was washed with water and saturated brine, dried and the solvent was distilled off under reduced pressure, and then crystallized with ethyl ether / hexane = 1/1 solution to give a yellow title compound (2.03 g).

M.P: 160 ~ 161 ℃

¹ H NMR (CDCl ₃ ): 7.94 (d, 1 H), 7.74 (m, 1 H) 7.61 (d, 1 H) 7.50 (d, 1 H)

7.37 (d, 1H) 6.95 (d, 1H) 6.74 (d, 1H) 4.89 (m, 1H)

3.94 (s, 3H) 1.27 to 2.14 (m, 8H)

Example 10. 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (2-fluorophenyl)-(E) -2-propen-1-one

To the reactor was added dimethylmethylphosphonate (2.16 ml, 20 mmol) followed by 20 ml of anhydrous tetrahydrofuran. This was cooled to -78 ° C and n-butyllithium 1.6M hexane solution (12.5 ml, 20 mmol) was slowly added dropwise over 20 minutes. To this reaction solution was added dropwise a solution of methyl 3-cyclopentyloxy-4-methoxybenzoate (2 g, 8 mmol) synthesized in Reference Example 3 in 5 ml of tetrahydrofuran dropwise. After stirring for 10 minutes, 10 ml of saturated ammonium chloride solution was added at -30 ° C, stirred for 5 minutes, 20 ml of ethyl acetate was added, followed by stirring for 5 minutes. The layers were separated and the aqueous layer was removed. The organic layer was washed with 10 ml of water, washed with saturated brine, dried and the solvent was distilled off under reduced pressure. 2 ml of tetrahydrofuran was added to the obtained oily compound, 2-fluorobenzylaldehyde (1.36 g, 11 mmoles) and lithium chloride (0.69 g, 16 mmoles) were added, followed by cooling to 0 ° C. To this was slowly added dropwise 1,8-diazabicyclo [5.4.0] -7-cene (1.3 g, 8.8 mmole). After stirring for 5 hours, 0.5N hydrochloric acid solution was added, stirred for 5 minutes, and extracted with 5 ml of ethyl acetate. The organic layer was washed with water and saturated brine, dried, the solvent was distilled off under reduced pressure, and then crystallized with 80% methanol to obtain the title compound (2.4 g), which was slightly yellow.

M.P: 93-95 ℃

¹ H NMR (CDCl ₃ ): 8.04 (d, 1 H), 7.63 (m, 4 H) 7.35 (m, 1 H) 7.19 (m, 2 H)

6.90 (d, 1H) 4.88 (m, 1H) 3.91 (s, 3H) 1.25-1.99 (m, 8H)

Experimental Example

Compounds of the present invention or pharmaceutically acceptable salts or solvates thereof inhibit phosphodiesterase IV or tumor necrosis factor, thus asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease, psoriasis, allergic rhinitis, dermatitis, The effect of treating AIDS, HIV, Crohn's disease, sepsis, septic shock, malaria, other inflammatory diseases or diseases including the production of tumor necrosis factor (TNF) was shown by the following experiments: .

Experimental Method

Partially purified phosphodiesterase IV from human U 937 cells, 1.0 μM cAMP containing the test compound and 0.01 μM [ ³ H] cAMP were incubated at 30 ° C. for 20 minutes. The mixture was then boiled for 2 minutes to complete the phosphodiesterase reaction in which cAMP was changed to AMP. Snamp venom nucleotidase was added thereto and incubated at 30 ° C. for 10 minutes to change AMP to adenosine. Unhydrolyzed cAMP was bound to AG1-X2 resin and the remaining [ ³ H] adenosine in aqueous solution was quantified by scintillation counting. As a comparative group, SB-207499 having a compound name cis- 4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid was used. The pharmacological mechanism of SB-207499 is to inhibit phosphodiesterase IV in the mechanism of cAMP metabolism by phosphodiesterase IV, thereby reducing the metabolism of cAMP. The same [see J. Med.chem., 1998, 41, pp 821-835].

[Pharmacological Results]

The results are shown in Table 1 below.

Table 1

% Inhibition against phosphodiesterase IV

compound Concentration (μM) Suppression% SB-207499 (Comparative) 101 88.081.7 Example 1 101 71.253.9 Example 2 101 64.644.3 Example 3 101 61.744.5 Example 4 101 77.650.8 Example 5 101 61.952.1 Example 6 101 45.333.8 Example 7 101 70.345.5 Example 8 101 71.652.3 Example 9 101 45.442.7 Example 10 101 70.646.4

The compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof of the present invention has an inhibitory effect on phosphodiesterase IV or tumor necrosis factor, and thus, asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction disease , Diseases including psoriasis, allergic rhinitis, dermatitis, AIDS, HIV, Crohn's disease, sepsis, septic shock, malaria, other inflammatory diseases or production of tumor necrosis factor (TNF) It is useful for the treatment.

Although 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 (12)

A compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof: Formula 1 Where R 1 is hydrogen, (C 1 -C 7) alkyl group, (C 3 -C 7) cycloalkyl group, benzyl or phenyl, R is C1-C6 lower alkyl, C1-C6 lower haloalkyl, C1-C6 lower alkenyl or cycloalkyl, or or or Is here, R2 is hydrogen or 1-5 chloro, fluorine or bromo, or lower alkyl of C1-C6, lower haloalkyl of C1-C6, nitro, hydroxy, lower alkoxy of C1-C6 or C1-C6 Lower alkenyl or NR4R5 or NC (O) R6 wherein R4 and R5 are the same or different from each other and are hydrogen or lower alkyl of C1-C6, R6 is lower alkyl of C1-C6, R3 is hydrogen or 1-3 chloro, fluorine or bromo, or lower alkyl of C1-C6, lower haloalkyl of C1-C6, nitro, hydroxy, lower alkoxy of C1-C6 or C1-C6 Or is lower alkenyl of NR4R5 or NC (O) R6, wherein R4 and R5 are the same or different from each other and are hydrogen or lower alkyl of C1-C6, R6 is lower alkyl of C1-C6, X is oxygen or sulfur. The compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein the compound of formula 1 is in (E) -form. The method of claim 1, wherein the compound of Formula 1 is 1- (3-cyclopentyloxy-4-methoxyphenyl) -3-phenyl- (E) -2-propen-1-one, A compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof. According to claim 1, wherein the compound of formula 1 is 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (4-pyridyl)-(E) -2-propen-1-one Characterized in that the compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof. The compound of formula 1, wherein the compound of formula 1 is 1N- {4- [3- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxo- (E) -1-propenyl] phenyl} acet It is an amide, characterized in that the compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof. The compound of formula 1, wherein the compound of formula 1 is 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (2,6-dichlorophenyl)-(E) -2-propene-1 -On, characterized in that the compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof. According to claim 1, wherein the compound of formula 1 is 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (3-nitrophenyl)-(E) -2-propen-1-one Characterized in that the compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof. According to claim 1, wherein the compound of formula 1 is 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (4-nitrophenyl)-(E) -2-propen-1-one Characterized in that the compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof. According to claim 1, wherein the compound of formula 1 is 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (3-thienyl)-(E) -2-propen-1-one Characterized in that the compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof. According to claim 1, wherein the compound of formula 1 is 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (3-furyl)-(E) -2-propen-1-one To the compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof. The compound of formula 1, wherein the compound of formula 1 is 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (4-nitro-3-furyl)-(E) -2-propene-1 -On, characterized in that the compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof. According to claim 1, wherein the compound of formula 1 is 1- (3-cyclopentyloxy-4-methoxyphenyl) -3- (2-fluorophenyl)-(E) -2-propen-1-one Characterized in that the compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof.