KR19980041770A - Catechol derivatives and preparation methods thereof - Google Patents

Abstract

The present invention relates to a novel catechol derivative of the general formula (I) or a pharmaceutically acceptable salt thereof having a inhibitory action against phosphodiesterase IV and a process for preparing the same:

(I)

Wherein R 1 represents C _1-7 alkyl, C _3-7 cycloalkane, phenyl, pyrimidine or pyridine, wherein each of phenyl, pyrimidine or pyridine is substituted by lower alkyl, alkoxy, nitro or halogen; X, Y and Z represent at least one of them oxygen, nitrogen or sulfur and X, Y and Z are each independently unsubstituted or substituted by C ₁ -C ₇ alkyl; W is oxygen or sulfur.

Description

Catechol derivatives and preparation methods thereof

Phosphodiesterases are enzymes that hydrolyze cyclic nucleotides as one of the chemical transfer 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 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 have an inhibitory action on phosphodiesterase IV are useful as therapeutic agents for asthma and the like.

As phosphodiesterase IV inhibitors, European Patent Publication No. 232,199 B1 describes phenyl compounds of the general formula: In the formula, A ₂ represents an anti-inflammatory and / or anti-allergic action as alkyl or polycycliccycloalkyl.

W092 / 12961 describes the following general formula compounds. This compound inhibits cyclic adenosine phosphate phosphodiesterase but does not mention the inhibitory effect of TNF.

Wherein B ₁ is an alkane or mono- or polycyclic cycloalkyl group and B ₂ is bonded to a phenyl group via O or S.

European Patent Publication 497,564 A1 describes the following general formula compounds, which have been found to have an inhibitory effect on cyclic adenosine 3 ', 5'-phosphate phosphodiesterase IV.

In the above formula, D ₁ , D ₂ is a C _1-6 alkyl group including a cyclic group, D ₃ is O or S and D ₄ is a cyclic alkyl group including a substituent.

There is a need for development of materials that are structurally different from conventional phosphodiesterase inhibitors.

The present invention relates to novel catechol derivatives represented by the following general formula (I) and pharmaceutically acceptable salts thereof, which have an inhibitory action on phosphodiesterase IV:

(I)

In the above formula,

R 1 represents C _1-7 alkyl, C _3-7 cycloalkane, phenyl, pyrimidine or pyridine, wherein each of phenyl, pyrimidine or pyridine is substituted by lower alkyl, alkoxy, nitro or halogen;

X, Y and Z represent at least one of them oxygen, nitrogen or sulfur and X, Y and Z are each independently unsubstituted or substituted by C ₁ -C ₇ alkyl;

W is oxygen or sulfur.

Preferred compounds according to the invention indicate that R 1 represents methyl or cyclopentyl, 1) X = CH, Y = CH, Z = S, 2) X = N, Y = CH, Z = NR 2, in X, Y and Z, 3) X = CH, Y = N, Z = NR2, 4) X = NR2, Y = N, Z = N or 5) X = N, Y = N, Z = NR2, where R2 is C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkane or phenyl, where W is oxygen.

Moreover, this invention reacts the compound of the following general formula (III) with the amino carboxyamide derivative of the following general formula (IV), and produces | generates the carboxyamide compound of the following general formula (II).

And a cyclization thereof provides a process for the preparation of compounds of the general formula (I)

(I)

(II)

(III)

(IV)

Wherein R 1, X, Y, Z and W are as defined in claim 1.

Representative method for preparing a compound of formula (I) according to the present invention is as follows:

Scheme (I)

According to the above scheme, the intermediate of the carboxyamide (II) was obtained by reacting the exit chloride synthesized by the known method (J. Med. Chem. 1994, 37, 1696) with the commercialized aminocarboxyamide derivative, and these carboxyl. The amide compound is cyclized by known methods (Bioorg. Med. Chem. Lett., 1996, 6, 1819) to give the target compound (I).

The present invention is explained in detail by the following examples. However, these examples should not be understood as limiting the invention.

Reference Example 1

3-cyclopentyloxy-4-methoxybenzylaldehyde

Isovanillin (50 g) was added dropwise to dimethylformamide (300 ml), and anhydrous potassium carbonate (70 g) and potassium iodide (1.5 g) were added thereto, followed by stirring at 65 ° C for 30 minutes. Cyclopentyl bromide (63 g) was slowly added dropwise to the suspension for 1 hour, stirred at 65 ° C. for 1 day, diluted with toluin (1 L) cooled to room temperature, and washed with 1N sodium hydroxide (2 × 500 ml). And wash with distilled water (2 x 250 ml). The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain the title compound (58 g, 80%).

¹ H NMR (CDCl ₃ , δ): 9.84 (1H, s), 7.42 (2H, m), 6.94 (1H, D, J = 9 Hz), 4.87 (1H, m), 3.93 (3H, s), 2.1 -1.6 (8H, m)

Reference Example 2

3-cyclopentyloxy-4-methoxybenzoic acid

A solution of 80% sodium chloride (30 g) dissolved in distilled water (450 ml) was added to the suspension obtained by dissolving 3-cyclopentyloxy-4-methoxybenzylaldehyde (58 g) in 80% acetic acid (450 ml) and dropping sulfamic acid (35 g) dropwise. Slowly dropwise for 1 hour while maintaining the reaction temperature at 18 ℃ -20 ℃. After stirring the reaction solution at room temperature for 1 hour, distilled water (450 ml) was added dropwise for 30 minutes to dilute. The solution was filtered through distilled water and dried to give the title compound (56 g, 90%) as a white solid.

¹ H NMR (CDCl ₃ , δ): 7.73 (1H, dd, J = 9,1 Hz), 7.24 (2H, d, J = 1 Hz), 6.92 (1H, d, J = 9 Hz), 4.84 (1H, m ), 3.93 (3H, s), 2.1-1.6 (8H, m)

Reference Example 3

3-cyclopentyloxy-4-methoxybenzoic acid chloride

3-cyclopentyloxy-4-methoxybenzoic acid (54 g) was refluxed for 5 hours with the addition of dichloride (30 ml). Toluine (50 ml) was added to the reaction solution and distilled under reduced pressure to obtain a dark brown title compound (58 g, 98%).

¹ H NMR (CDCl ₃ , δ): 7.82 (1H, dd, J = 9,1 Hz), 7.53 (1H, d, J = 1 Hz), 6.92 (1H, d, J = 9 Hz), 4.9-4.8 (1H , m), 3.87 (3H, s), 2.1-1.9 (2H, m), 1.9-1.7 (4H, m), 1.7-1.5 (2H, m)

Reference Example 4

3,4-dimethoxybenzylaldehyde

Isovanillin (5 g) was added dropwise to dimethylformamide (30 ml), anhydrous potassium carbonate (7 g) and potassium iodide (0.7 g) were added thereto, and the suspension obtained was stirred at 65 ° C for 30 minutes. Methyl bromide (g) was slowly added dropwise to the suspension for 1 hour, stirred at 65 ° C for 1 day, diluted with toluin (1 L) cooled to room temperature, washed with 1N sodium hydroxide (2 x 500 ml). Wash with distilled water (2 x 250 ml). The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain the title compound (g).

¹ HNMR (CDCl ₃ , δ): 7.87 (1H, dd, J = 9, 1 Hz), 7.58 (1H, d, J = 1 Hz), 6.95 (1H, d, J = 9 Hz), 3.94 (3H, s) , 3.82 (3H, s)

Reference Example 5

3- (exo-bicycle [2,2,1] hexyl-2-oxy) -4-methoxybenzylaldehyde

Isovanillin (5 g), endo-2-norbonol (2.5 g) and triphenylphosphate (8.8 g) are dissolved in tetrahydrofuran and then disopropyl azocarboxylate (6.8 g) is added dropwise. The reaction solution was refluxed for 48 hours and then cooled to room temperature and added dropwise to distilled water (250 ml). Extraction with ether (3 x 50 ml) is followed by successive washings with distilled water (2 x 50 ml), 1N sodium hydroxide (2 x 50 ml) and sodium chloride (50 ml). The organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure and separated by column chromatography to obtain the title compound (4.2 g, 75%).

¹ H NMR (CDCl ₃ , δ): 9.83 (1H, s), 7.43 (1H, dd, J = 9, 1 Hz), 7.35 (1H, d, J = 1 Hz), 6.96 (1H, d, J = 9 Hz ), 4.28 (1H, d, J = 6 Hz), 3.93 (3H, s), 2.54 (1H, d, J = 5 Hz), 2.34 (1H, t, J = 3 Hz), 1.9-1.1 (8H, m)

Reference Example 6

3- (3-cyclopentyloxy-4-methoxyphenylcarboxyamide) -2-diophenylcarboxyamide

3-cyclopentyloxy-4-methoxybenzoic acid chloride (1.5 g) was added dropwise to the suspension obtained by dropwise addition of pyridine (10 ml) to 3-amino-2-diophenylcarboxyamide (700 mg). Stirred. The reaction solution was distilled under reduced pressure, diluted with chloroform and washed with 1N hydrochloric acid, saturated sodium bicarbonate and sodium chloride. The obtained organic layer was dried and evaporated under reduced pressure, and then separated by column chromatography to obtain the title compound (1.1 g).

¹ H NMR (DMSO-d ₆ , δ): 12.42 (1H, brs), 8.11 (1H, d, J = 5.5Hz), 7.84 (1H, d, J = 5.5Hz), 7.51 (1H, dd, J = 8.5,2 Hz), 7.45 (1H, d, J = 2 Hz), 7.14 (1H, d, J = 8.5 Hz), 5.0-4.8 (1H, m), 3.84 (3H, s), 2.1-1.9 (2H , m), 1.9-1.7 (4H, m), 1.7-1.6 (2H, m)

Example 1

2- (3-cyclopentyloxy-4-methoxyphenyl) -3,4-dihydrodienono [3,4-d] pyrimidin-4-one

1N sodium chloride (25ml) and ethyl alcohol (5ml) were added dropwise and refluxed for 4 hours, followed by distillation under reduced pressure. 1N hydrochloric acid was added dropwise to the reaction, followed by acidification, followed by filtration with distilled water to obtain the title compound (390 mg).

¹ H NMR (DMSO-d ₆ , δ): 12.56 (1H, brs), 8.19 (1H, d, J = 5 Hz), 7.81 (1H, dd, J = 8.5,

2 Hz), 7.75 (1H, d, J = 2 Hz), 7.44 (1H, d, J = 5 Hz), 7.10 (1H, d, J = 8.5 Hz), 5.0-4.8 (1H, m), 3.83 (3H, s), 2.0-1.8 (2H, m), 1.8-1.6 (4H, m), 1.6-1.5 (2H, m)

Example 2

2- (3-cyclopentyloxy-4-methoxyphenyl) -6,7-dihydro-1H-6-purinone

4- (3-cyclopentyloxy-4-methoxyphenylcarboxyamide) -1N-imidazole 5-carboxyamide (500 mg) obtained by the method of Reference Example 6 was reacted in the same manner as in Example 1 to obtain the title compound. (380 mg) was obtained.

¹ H NMR (DMSO-d ₆ , δ): 12.60 (1H, brs), 8.61 (1H, s), 7.78 (1H, dd, J = 8.5, 2 Hz), 7.72 (1H, d, J = 2 Hz), 7.11 (1H, d, J = 8.5 Hz), 5.1-4.9 (1H, M), 3.84 (3H, s), 2.1-1.9 (2H, m), 1.9-1.7 (4H, m), 1.7-1.5 ( 2H, m)

Example 3

In the same manner as in Example 1 obtained by the method of Reference Example 6, the title compound (300 mg) was obtained.

¹ HNMR (DMSO-d ₆ , δ): 12.62 (1H, brs), 8.63 (1H, s), 7.77 (1H, dd, J = 8.5,2Hz), 7.73 (1H, d, J = 2Hz), 7.18 (1H, d, J = 8.5Hz), 5.1-4.9 (1H, m), 3.85 (3H, s), 2.1-1.9 (2H, m), 1.9-1.7 (4H, m), 1.7-1.5 (2H , m)

Example 4

2- (3-cyclopentyloxy-4-methoxyphenyl) -3,4-dihydro-4-quinazolinone

(3-cyclopentyloxy-4-methoxyphenylcarboxyamide) benzylamide (500 mg) obtained in the method of Reference Example 6 was reacted in the same manner as in Example 1 to obtain the title compound (410 mg).

¹ HNMR (DMSO-d ₆ , δ): 12.45 (1H, brs), 8.13 (1H, d, J = 7 Hz), 8.0-7.8 (3H, m), 7.70 (1H, dd, J = 8.5 Hz), 7.48 (1H, dd, J = 7, 7 Hz), 7.10 (1H, d, J = 8.5 Hz), 5.0-4.9 (1H, m), 3.83 (3H, s), 2.1-1.9 (2H, m), 1.9-1.7 (4H, m), 1.7-1.5 (2H, m)

Example 5

3- (3,4-dimethoxyphenylcarboxyamide) -3,4-dihydro-4-quinazolinone

(3,4-dimethoxyphenylcarboxyamide) (500 mg) obtained in the method of Reference Example 6 was reacted in the same manner as in Example 1 to obtain the title compound (400 mg).

¹ H-NMR (CDCl ₃ , δ): 12.40 (1H, brs), 8.10 (1H, d, J = 7 Hz), 8.0-7.8 (3H, m), 7.67 (1H, dd, J = 8.5 Hz), 7.42 (1H, dd, J = 7, 7 Hz), 7.05 (1H, d, J = 8.5 Hz), 3.92 (3H, s), 3.80 (3H, s).

An object of the present invention is to provide a novel drug that can be useful for preventing or treating respiratory diseases by inhibiting phosphodiesterase IV and a method for efficiently preparing the same.

Claims (3)

A compound of formula (I) or a pharmaceutically acceptable salt thereof: (I) In the above formula, R 1 represents C _1-7 alkyl, C _3-7 cycloalkane, phenyl, pyrimidine or pyridine, wherein each of phenyl, pyrimidine or pyridine is substituted by lower alkyl, alkoxy, nitro or halogen; X, Y and Z represent at least one of them oxygen, nitrogen or sulfur and X, Y and Z are each independently unsubstituted or substituted by C ₁ -C ₇ alkyl; W is oxygen or sulfur. The compound of claim 1, wherein R 1 represents methyl or cyclopentyl, and in X, Y and Z 1) X = CH, Y = CH, Z = S, 2) X = N, Y = CH, Z = NR 2, 3 ) X = CH, Y = N, Z = NR 2, 4) X = NR 2, Y = N, Z = N or 5) X = N, Y = N, Z = NR 2, where R 2 is C ₁ -C ₆ Alkyl, C ₃ -C ₆ cycloalkane or phenyl, where W is oxygen. The compound of formula (III) is reacted with an amino carboxyamide derivative of formula (IV) to produce a carboxyamide compound of formula (II), which is cyclized, Method for preparing the compound of I): (I) (II) (III) (IV) Wherein R 1, X, Y, Z and W are as defined in claim 1.