KR19990085815A - Catechol hydrazone derivatives, methods for their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

The present invention provides a catechol hydrazone derivative represented by the following general formula (I) having an inhibitory action on cyclic adenosine 3 ′, 5′-monophosphate phosphodiesterase IV or TNF and pharmaceutically acceptable Salts, methods for their preparation and pharmaceutical compositions containing them:

(I)

Wherein R ¹ is C ₁ -C ₇ alkyl or C ₃ -C ₇ cycloalkyl, R ² is —H, —OH, —C ₁ -C ₅ alkyl or —CH ₂ CH ₂ C (═O) NH ₂ and R ³ or R ⁴ are each independently i) -H, ii) C ₁ -C ₇ alkyl, iii) -C (= X) -R ⁵ , iii) halogen, C ₁ -C ₆ alkoxy, nitrile , 2-, 3- or 4-pyridyl, pyrimidyl or phenyl group optionally substituted with one or two of trifluoromethyl, C ₁ -C ₆ alkyl and carboxylic acid groups, or iii) oxygen, sulfur or nitrogen A cyclic compound connected directly to C ₃ -C ₄ containing X, X is O, S or NR ⁶ , R ⁵ is i) -C ₁ -C ₇ alkyl, ii) -NHR ⁶ or iii) halogen, nitrile, Is a 2-, 3- or 4-pyridyl, pyrimidyl or phenyl group with optionally substituted trifluoromethyl, (C ₁ -C ₆ ) alkyl or carboxylic acid groups, and R ⁶ is —H, —OH, — ( C ₁ -C ₅ ) alkoxy, — (C ₁ -C ₅ ) alkyl, pyridyl or phenyl group.

Description

Catecol Hydrazone Derivatives, Methods for Making the Same, and Pharmaceutical Compositions Containing the Same (Catethcol Hydrazone Derivatives, Process for Preparing the Same and Pharmaceutical Composition Containing the Same)

The present invention is directed to phosphodiesterase IV or tumor necrosis factor (TNF) and to asthma, arthritis, osteoarthritis, bronchitis, chronic airway obstruction, psoriasis, allergic rhinitis, dermatitis and AIDS, HIV, Crohn's disease, Novel catechol hydrazone derivatives useful for the treatment of diseases including sepsis, septic shock, other inflammatory diseases such as atherosclerosis and the production of TNF, and methods for their preparation and pharmaceutical compositions containing them .

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 cellular stimuli, which relaxes and contracts the bronchial muscles.

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

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.

As inhibitors for phosphodiesterase IV or TNF, compounds having structures similar to the present invention have been disclosed. For example, materials having oxime-carbamate and oxime-carbonate structures represented by the following formulas are reported in EP 470,805 (American Home Product):

(A)

Wherein R is C _3-7 alkyl or C _3-7 cycloalkyl, R ¹ is a halogen or lower alkyl group, and R ² is amino, lower alkylamino, arylamino, lower alkoxy or aryloxy.

In addition, phenylalkyl oxamide-based compounds represented by the following formula are described in USP 5,393,788 (SmithKline Beecham Corporation):

(B)

Wherein R 1 is C _4-6 cycloalkyl, X is YR ² halogen or lower alkyl group, Y is oxygen or sulfur, R ₃ or R ₅ are each hydrogen or OR ⁷ , and R ₄ is hydrogen or C _{1 -2} alkyl, R ₆ is OR ₇ or NR ₇ OR ₇ , and R ₇ is hydrogen or C _1-3 alkyl.

The inventors have developed novel compounds which are structurally different from the above known compounds.

The present invention provides novel catechol hydrazone derivatives represented by formula (I) and pharmaceutically acceptable salts thereof:

(I)

In the above formula,

R ¹ is C ₁ -C ₇ alkyl or C ₃ -C ₇ cycloalkyl;

R ² is —H, —OH, —C ₁ -C ₅ alkyl or —CH ₂ CH ₂ C (═O) NH ₂ ;

R ³ or R ⁴ are each independently i) -H, ii) C ₁ -C ₇ alkyl, i) -C (= X) -R ⁵ , i) halogen, C ₁ -C ₆ alkoxy, nitrile, trifluor A 2-, 3- or 4-pyridyl, pyrimidyl or phenyl group optionally substituted with one or two of rommethyl, C ₁ -C ₆ alkyl and carboxylic acid groups, or iii) containing oxygen, sulfur or nitrogen Cyclic compounds directly linked to C ₃ -C ₄ ;

X is O, S or NR ⁵ ;

R ⁵ is 2-, 3- optionally substituted from i) -C ₁ -C ₇ alkyl, ii) -NHR ⁶ or iii) halogen, nitrile, trifluoromethyl, C ₁ -C ₆ alkyl and carboxylic acid groups Or 4-pyridyl, pyrimidyl or phenyl group;

R ⁶ is —H, —OH, —C ₁ -C ₅ alkoxy, —C ₁ -C ₅ alkyl, pyridyl or phenyl group.

Compounds (I) of the present invention may exist in the form of optical isomers or geometric isomers, and the present invention includes these isomers and mixtures thereof.

The present invention also relates to a pharmaceutical composition having an inhibitory effect on phosphodiesterase IV or TNF by containing the compound of formula (I) of the present invention as described above together with a pharmaceutically acceptable carrier.

The compound of formula (I) according to the present invention is prepared by the following scheme (I).

Scheme I

Some derivatives were synthesized by known methods (J. Med. Chem., 1994, 37, 1696) and hydrazine compounds were synthesized in alcoholic solvents in 60-90% yield using acid catalysts (Tetrahedron. Lett. 1994, 35 , 3711).

The present invention is explained in detail by the following examples. However, these examples are only intended to illustrate the invention and should not be understood as limiting the invention to these examples.

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), anhydrous dimethylformamide (650 mL) was stirred at 65 ° C., and the suspension was then cyclopentyl bromide ( 127.3 g, 0.85 mol) was slowly added dropwise for 1 hour, stirred at 65 ° C. for 1 day, and then the temperature was lowered to room temperature. Toluene (2.0 L) was added to the mixed solution and diluted, followed by 1M 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 (CDCl 3, d): 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)

Example 1.

(E) -3-cyclopentyloxy-4-methoxybenzaldehyde isnicotinichydrazone

0.44 g (2.0 mmol) of the compound of Reference Example 1 was diluted in 30 ml of ethanol, and then a catalytic amount of concentrated sulfuric acid was added thereto, followed by stirring at room temperature for 10 minutes. 0.33 g of isonicotinic hydrazide was added to the reaction solution, followed by stirring at 50 ° C. for 4.0 hours. The residue obtained by concentrating the solvent under reduced pressure was diluted with dichloromethane and washed twice with 50 ml of distilled water. The separated organic layer was dried over anhydrous acetic acid, distilled under reduced pressure to obtain white crystals, and then recrystallized from dichloromethane to give 0.67 g (88.450%) of the title compound as white.

Melting Point: 170 ~ 171 ℃

¹ H NMR (DMSO-d6): 1.60 (2H, m) 1.75 (4H, m) 1.92 (2H, m) 3.81 (3H, s) 4.85 (1H, m) 7.04 (1H, d J = 8.4 Hz) 7.24 (1H, dd, J = 8.4, 1.8 Hz) 7.33 (1H, d J = 1.8 Hz) 7.81 (2H, dd, J = 4.5, 1.6 Hz) 8.39 (1H, s) 8.78 (2H, dd, J = 4.5 , 1.6 Hz) 11.92 (1H, s)

Example 2

(E) -ethyl [(3-cyclopentyloxy-4-methoxyphenyl) methylene] carbazate

After diluting 1.00 g (4.54 mmole) of the compound of Reference Example 1 in 80 ml of ethanol, a catalytic amount of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 10 minutes. 0.73 g of ethyl carbazate was added to the reaction solution, followed by stirring at 50 ° C. for 4.0 hours. The residue obtained by concentrating the solvent under reduced pressure was diluted with dichloromethane and washed twice with 50 ml of distilled water. The separated organic layer was dried over anhydrous acetic acid, distilled under reduced pressure to obtain white crystals, and then recrystallized from dichloromethane to obtain 1.25 g (89.87%) of a white title compound.

Melting Point: 146 ~ 147 ℃

¹ H NMR (DMSO-d6): 1.23 (3H, t, J = 7.1 Hz) 1.58 (2H, m) 1.73 (4H, m) 1.88 (2H, m) 3.77 (3H, s) 4.13 (2H, q, J = 7.1 Hz) 4.80 (1H, m) 6.98 (1H, d J = 8.4 Hz) 7.07 (1H, dd, J = 8.4, 1.9 Hz) 7.20 (1H, d J = 1.9 Hz) 7.93 (1H, s) 10.92 (1 H, s)

Example 3

(E) -3-cyclopentyloxy-4-methoxybenzaldehyde phenylhydrazone

0.50 g (2.27 mmole) of the compound of Reference Example 1 was diluted in 60 ml of ethanol, and then a catalytic amount of concentrated hydrochloric acid was added, followed by stirring at room temperature for 10 minutes. 0.34 ml of phenylhydrazine was added to the reaction solution, followed by stirring at 50 ° C. for 10 hours. The resulting precipitate was filtered and washed with 20 ml of ethanol to obtain 0.63 g (89.41%) of the title compound as white.

Melting Point: 138 ~ 140 ℃

¹ H NMR (DMSO-d6): 1.60 (2H, m) 1.75 (4H, m) 1.92 (2H, m) 3.77 (3H, s) 4.85 (1H, m)

6.72 (1H, m) 6.95 (1H, d J = 8.2 Hz) 7.03 (2H, d, J = 7.6 Hz) 7.09 (1H, dd, J = 8.2, 1.8 Hz) 7.20 (2H, t) 7.26 (1H, d J = 1.8 Hz) 7.78 (1H, s) 10.12 (1H, s)

Example 4

(E) -3-cyclopentyloxy-4-methoxybenzaldehyde acetic hydrazone

0.50 g (2.27 mmole) of the compound of Reference Example 1 was diluted in 60 ml of ethanol, and then a catalytic amount of concentrated hydrochloric acid was added, followed by stirring at room temperature for 10 minutes. 0.26 g of acetic hydrazide was added to the reaction solution, followed by stirring at 25 ° C. for 10 hours. The residue obtained by concentrating the solvent under reduced pressure was diluted with dichloromethane and washed twice with 50 ml of distilled water. The separated organic layer was dried over anhydrous acetic acid, distilled under reduced pressure to obtain white crystals, and then recrystallized from dichloromethane to obtain 0.59 g (94.06%) of the title compound as white.

Melting Point: 155 ~ 156 ℃

¹ H NMR (DMSO-d6): 1.58 (2H, m) 1.71 (4H, m) 1.88 (2H, m) 2.18 (3H, s) 3.78 (3H, s)

4.81 (1H, m) 6.99 (1H, d J = 8.4 Hz) 7.14 (1H, dd, J = 8.4, 1.8 Hz) 7.24 (1H, d J = 1.8 Hz) 7.88 (1H, s) 11.12 (1H, s )

Example 5

(E) -3-cyclopentyloxy-4-methoxybenzaldehyde (7-chloroquinolin-4-yl) hydrazone

0.50 g (2.27 mmole) of the compound of Reference Example 1 was diluted in 60 ml of ethanol, and then a catalytic amount of concentrated hydrochloric acid was added, followed by stirring at room temperature for 10 minutes. 0.67 g of 7-chloro-4-hydrazinoquinoline was added to the reaction solution, stirred at 45 ° C. for 10 hours, and the resulting precipitate was filtered and washed with 20 ml of ethanol to obtain 0.55 g (61.20%) of the title compound. .

Melting Point: 210 ~ 212 ℃

¹ H NMR (DMSO-d6): 1.61 (2H, m) 1.78 (4H, m) 1.94 (2H, m) 3.81 (3H, s) 4.89 (1H, m)

7.04 (1H, d J = 8.3 Hz) 7.28 (1H, dd, J = 8.3, 1.8 Hz) 7.36 (1H, d J = 5.2 Hz) 7.42 (1H, d J = 1.8 Hz) 7.61 (1H, d) 7.86 (1H, s) 8.39 (1H, s) 8.44 (2H, d J = 9.1 Hz)

Example 6

(E) -3-cyclopentyloxy-4-methoxybenzaldehyde (2-imidazolino) hydrazone

0.50 g (2.27 mmole) of the compound of Reference Example 1 was diluted in 50 ml of ethanol, and then a catalytic amount of concentrated hydrochloric acid was added, followed by stirring at room temperature for 10 minutes. 0.63 g of hydrazino-2-imidazoline hydrobromide was added to the reaction solution, followed by stirring at 45 ° C. for 8.0 hours. The residue obtained by concentrating the solvent under reduced pressure was diluted with dichloromethane and washed twice with 50 ml of distilled water. The separated organic layer was dried over anhydrous acetic acid and distilled under reduced pressure to give a pale yellow oily product. The residue was purified by flash chromatography (silica gel: developing solution 7.5% methanol-dichloromethane) to give 0.45 g (65.56%) of the title compound as white. Got it.

Melting Point: 87 ~ 90 ℃

¹ H NMR (DMSO-d6): 1.61 (2H, m) 1.72 (4H, m) 1.89 (2H, m) 3.70 (4H, s) 3.79 (3H, s)

4.89 (1H, m) 7.01 (1H, d J = 8.4 Hz) 7.24 (1H, dd, J = 8.4, 1.8 Hz) 7.44 (1H, d J = 1.8 Hz) 8.06 (1H, s)

Example 7

(E) -2-[(3-cyclopentyloxy-4-methoxyphenyl) methylene] hydrazinecarboxamide

The reaction was carried out in the same manner as in Example 6, using 0.50 g (2.27 mmole) of the compound of Reference Example 1 as a starting material to obtain 0.47 g (74.66%) of a white title compound.

Melting Point: 144 ~ 146 ℃

¹ H NMR (DMSO-d6): 1.58 (2H, m) 1.71 (4H, m) 1.89 (2H, m) 3.76 (3H, s) 4.92 (1H, m)

6.44 (2H, brs) 6.93 (1H, d J = 8.3 Hz) 7.09 (1H, dd, J = 8.3, 1.9 Hz) 7.36 (1H, d J = 1.9 Hz) 7.75 (1H, s) 10.08 (1H, s )

Example 8

(E) -3-cyclopentyloxy-4-methoxybenzaldehyde (2-nitrophenyl) hydrazone

The reaction was carried out in the same manner as in Example 3 using 0.50 g (2.27 mmole) of the compound of Reference Example 1 to obtain 0.63 g (78.09%) of the title compound in red yellow color.

Melting Point: 135 ℃ Decomposition

¹ H NMR (DMSO-d6): 1.61 (2H, m) 1.77 (4H, m) 1.94 (2H, m) 3.80 (3H, s) 4.88 (1H, m)

6.89 (1H, m) 7.03 (1H, d J = 8.4 Hz) 7.22 (1H, dd, J = 8.4, 1.9 Hz) 7.35 (1H, d J = 1.9 Hz) 7.66 (1H, t J = 1.6 Hz) 7.95 (1H, d J = 8.7 Hz) 8.11 (1H, dd J = 8.5, 1.4 Hz) 8.39 (1H, s) 11.15 (1H, s)

Example 9

(E) -2-[(3-cyclopentyloxy-4-methoxyphenyl) methylene] hydrazinecarbothioamide

Reaction was carried out in the same manner as in Example 6, using 1.00 g (4.54 mmole) of the compound of Reference Example 1 to obtain 0.94 g (70.57%) of the white title compound.

Melting Point: 112 ~ 114 ℃

¹ H NMR (DMSO-d6): 1.57 (2H, m) 1.71 (4H, m) 1.88 (2H, m) 3.76 (3H, s) 4.91 (1H, m)

6.44 (2H, brs) 6.93 (1H, d J = 8.4 Hz) 7.09 (1H, dd, J = 8.4, 1.9 Hz) 7.36 (1H, d J = 1.9 Hz) 7.74 (1H, s) 10.06 (1H, s )

Example 10

(E) -3-cyclopentyloxy-4-methoxybenzaldehyde (4-chlorophenyl) hydrazone

The reaction was carried out in the same manner as in Example 6, using 1.50 g (6.81 mmole) of the compound of Reference Example 1 as a starting material to obtain 1.65 g (70.26%) of a white title compound.

Melting Point: 133 ~ 135 ℃

¹ H NMR (DMSO-d6): 1.60 (2H, m) 1.76 (4H, m) 1.91 (2H, m) 3.78 (3H, s) 4.86 (1H, m)

6.97 (1H, d J = 8.4 Hz) 7.04 (2H, dd J = 6.8, 2.1 Hz) 7.12 (1H, dd, J = 8.4, 1.9 Hz) 7.24 (2H, dd J = 6.8, 2.1 Hz) 7.27 (1H , d J = 1.9 Hz) 7.87 (1 H, s) 10.27 (1 H, s)

Example 11

(E) -2-[(3-cyclopentyloxy-4-methoxyphenyl) methylene] hydrazinecarbonylmethyl (trimethyl) ammonium chloride

The reaction was carried out in the same manner as in Example 3, using 1.50 g (6.81 mmole) of the compound of Reference Example 1 and 1.03 g of (carboxymethyl) trimethylammonium chloride hydrazide as starting materials to obtain 1.73 g (68.68%) of a white title compound. .

Melting Point: 178 ~ 179 ℃

¹ H NMR (DMSO-d6): 1.60 (2H, m) 1.73 (4H, m) 1.90 (2H, m) 3.30 (9H, s) 3.79 (3H, s)

4.33 (2Ha, s) 4.79 (2Ha, s) 4.84 (1H, m) 7.03 (1H, d J = 8.4 Hz) 7.23 (1H, dd, J = 8.4, 1.8 Hz) 7.29 (1H, d J = 1.8 Hz ) 8.01 (1Ha ', s) 8.26 (1Ha', s) 12.05 (1H, brs)

Example 12

(E) -N- (1,4-oxazin-4-yl) -3-cyclopentyloxy-4-methoxyphenylmethaneimine

After diluting 5.0 g (22.7 mmole) of the compound of Reference Example 1 in 50 ml of ethanol and stirring at room temperature for 10 minutes, 2.91 ml of N-aminomorpholine was added to the reaction solution. The reaction solution was stirred at 25 ° C. for 14 hours, the resulting precipitate was filtered, washed with 20 ml of ethanol and the white solid was recrystallized from isopropyl ether to give 6.37 g (92.19%) of the title compound.

Melting Point: 108 ~ 109 ℃

¹ H NMR (DMSO-d6): 1.56 (m, 2H) 1.70 (m, 4H) 1.88 (m, 2H) 3.03 (m, 4H) 3.67 (m, 7H)

4.77 (m, 1H) 6.88 (d, 1H) 7.04 (dd, 1H) 7.18 (d, 1H) 7.62 (s, 1H)

Example 13

(E) -N-piperidino-3-cyclopentyloxy-4-methoxyphenylmethaneimine

In the same manner as in Example 12, using 0.50 g (2.27 mmole) of the compound of Reference Example 1 and 0.31 ml of N-aminopiperidine as a starting material, 0.65 g (94.68%) of the title compound was obtained.

Melting Point: 81 ~ 82 ℃

¹ H NMR (DMSO-d6): 1.52 (m, 4H) 1.67 (m, 8H) 1.90 (m, 2H) 3.04 (m, 4H) 3.70 (s, 3H)

4.76 (m, 1H) 6.89 (d, 1H) 7.04 (dd, 1H) 7.18 (d, 1H) 7.57 (s, 1H)

Example 14

(E) -2-[(3-cyclopentyloxy-4-methoxyphenyl) methylene] hydrazinecarboximidamide

The reaction was carried out in the same manner as in Example 6, using 1.50 g (6.81 mmole) of the compound of Reference Example 1 and 0.73 g of aminoguanidine hydrochloride as a starting material to obtain 1.60 g (85.02%) of the white title compound.

Melting Point: 100 ~ 103 ℃

¹ H NMR (DMSO-d6): 1.62-1.64 (2H, m) 1.74-1.78 (4H, m) 1.94-1.97 (2H, m) 3.84 (3H, s) 4.95-4.98 (1H, m) 7.05 (1H , d J = 8.4 Hz) 7.33 (1H, dd, J = 8.4, 2.0 Hz) 7.54 (1H, d J = 1.9 Hz) 7.7 (1H, brs) 8.36 (1H, s) 11.69 (1H, s)

Example 15

(E) -3-cyclopentyloxy-4-methoxybenzaldehyde (2-pyridinyl) hydrazone

The reaction was carried out in the same manner as in Example 6, using 0.80 g (3.63 mmole) of the compound of Reference Example 1 and 0.39 g of 2-hydrazinopyridine as starting materials to obtain 0.96 g (84.89%) of the white title compound.

Melting Point: 142 ~ 143 ℃

¹ H NMR (DMSO-d6): 1.58-1.61 (2H, m) 1.71-1.76 (4H, m) 1.89-1.94 (2H, m) 3.77 (3H, s) 4.84-4.87 (1H, m) 6.73-6.74 (1H, m) 6.97 (1H, d J = 8.3 Hz) 7.10 (1H, dd, J = 8.3, 1.8 Hz) 7.20 (1H, d J = 8.4 Hz) 7.27 (1H, d J = 1.8 Hz) 7.62 to 7.63 (1H, m) 7.94 (1H, s) 8.09 (1H, dd J = 4.9, 1.0 Hz) 10.67 (1H, s)

Example 16

(E) -3-cyclopentyloxy-4-methoxybenzaldehyde (2-carboxyphenyl) hydrazone

The reaction was carried out in the same manner as in Example 6, using 0.80 g (3.63 mmole) of the compound of Reference Example 1 and 0.66 g of 2-hydrazinobenzoic acid hydrochloride as a starting material to obtain 1.05 g (81.57%) of a white title compound.

Melting Point: 174 ~ 176 ℃

¹ H NMR (DMSO-d6): 1.59-1.60 (2H, m) 1.71-1.76 (4H, m) 1.92-1.93 (2H, m) 3.78 (3H, s) 4.85 (1H, m) 6.78 (1H, dd) J = 7.0, 1.0 Hz) 6.99 (1H, d J = 8.4 Hz) 7.20 (1H, dd, J = 8.4, 1.9 Hz) 7.32 (1H, d J = 1.9 Hz) 7.50 (1H, dd J = 7.0, 1.6 Hz) 7.68 (1H, dd J = 8.5, 0.8 Hz) 7.84 (1H, dd J = 8.0, 1.4 Hz) 8.05 (1H, s) 8.79 (1H, d J = 4.9 Hz) 11.17 (1H, s)

Example 17

(E) -3-cyclopentyloxy-4-methoxybenzaldehyde (4-trifluoromethylpyrimidin-2-yl) hydrazone

In the same manner as in Example 6, 0.80 g (3.63 mmole) of the compound of Reference Example 1 and 0.63 g of 2-hydrazino-4- (trifluoromethyl) pyrimidine were used as starting materials. 79.62%).

Melting Point: 73 ~ 75 ℃

¹ H NMR (DMSO-d6): 1.58-1.59 (2H, m) 1.72-1.76 (4H, m) 1.89 (2H, m) 3.79 (3H, s)

4.81 to 4.84 (1H, m) 7.01 (1H, d J = 8.4 Hz) 7.19 (1H, dd, J = 8.4, 2.0 Hz) 7.21 (1H, d J = 4.9 Hz) 7.27 (1H, d J = 2.0 Hz ) 8.11 (1H, s) 8.79 (1H, d J = 4.9 Hz) 1.67 (1H, s)

The following experiments were conducted to evaluate the pharmacological effects induced by the compounds of the present invention.

A. Experimental Method

PDE IV partially purified from human U 937 cells, the test compound, and 1.0 μM cAMP containing 0.01 μM [3H] cAMP were incubated at 30 ° C. for 20 minutes. The PDE reaction, in which cAMP was changed to AMP, was completed by boiling for 2 minutes. Toxic nucleotidase was added and incubated at 30 ° C. for 10 minutes to change AMP to adenosine. Unhydrolyzed cAMP was bound to AG1-X2 resin and the remaining [3H] adenosine in aqueous solution was quantified by scintillation counting. The results are shown in Table 1 below.

Test compound Concentration (μM) % Inhibition Test compound Concentration (μM) % Inhibition Rolipram (Comparative) 202 70.162.5 Example 9 202 81.069.0 Example 1 202 66.738.4 Example 10 202 70.739.3 Example 2 202 63.746.7 Example 11 202 45.143.3 Example 3 202 80.446.6 Example 12 202 79.462.9 Example 4 202 72.151.7 Example 13 202 73.331.4 Example 5 202 64.937.9 Example 14 202 57.714.7 Example 6 202 58.331.7 Example 15 202 63.649.4 Example 7 202 89.766.2 Example 16 202 76.642.3

Claims (5)

Compounds of formula (I) and pharmaceutically acceptable salts thereof (I) In the above formula, R ¹ is C ₁ -C ₇ alkyl or C ₃ -C ₇ cycloalkyl; R ² is —H, —OH, —C ₁ -C ₅ alkyl or —CH ₂ CH ₂ C (═O) NH ₂ ; R ³ or R ⁴ are each independently i) -H, ii) C ₁ -C ₇ alkyl, i) -C (= X) -R ⁵ , i) halogen, C ₁ -C ₆ alkoxy, nitrile, trifluor A 2-, 3- or 4-pyridyl, pyrimidyl or phenyl group optionally substituted with one or two of rommethyl, C ₁ -C ₆ alkyl and carboxylic acid groups, or iii) containing oxygen, sulfur or nitrogen Cyclic compounds directly linked to C ₃ -C ₄ ; X is O, S or NR ⁵ ; R ⁵ is i, -C ₁ -C ₇ alkyl, ii) -NHR ⁶ or iii) 2-, 3- optionally substituted with halogen, nitrile, trifluoromethyl, C ₁ -C ₆ alkyl or carboxylic acid groups Or 4-pyridyl, pyrimidyl or phenyl group; R ⁶ is —H, —OH, —C ₁ -C ₅ alkoxy, —C ₁ -C ₅ alkyl, pyridyl or phenyl group. The compound of claim 1, wherein R ¹ is cyclopentyl, R ² is -H, and R ³ and R ⁴ are each independently i) -C ₁ -C ₅ alkyl, ii) -C (= X) -R ⁵ iii) a 2-, 3- or 4-pyridyl, pyrimidyl or phenyl group optionally substituted by halogen, nitrile, trifluoromethyl, carboxylic acid group, i ') with C ₃ -C ₄ containing oxygen or nitrogen A directly linked cyclic compound, X is O, S or NR ⁵ , R ⁵ is -NHR ⁶ , 4-pyridyl and R ⁶ is -H, -OH or 4-pyridyl group. The compound of claim 1 selected from the group of compounds: (E) -3-cyclopentyloxy-4-methoxybenzaldehyde isiconicotinhydrazone; (E) -3-cyclopentyloxy-4-methoxybenzaldehyde acetic hydrazone; (E) -3-cyclopentyloxy-4-methoxybenzaldehyde (7-chloroquinolin-4-yl) hydrazone; (E) -3-cyclopentyloxy-4-methoxybenzaldehyde (2-imidazolino) hydrazone; (E) -2-[(3-cyclopentyloxy-4-methoxyphenyl) methylene] hydrazinecarboxamide; (E) -3-cyclopentyloxy-4-methoxybenzaldehyde (2-nitrophenyl) hydrazone; (E) -2-[(3-cyclopentyloxy-4-methoxyphenyl) methylene] hydrazinecarbothioamide; (E) -3-cyclopentyloxy-4-methoxybenzaldehyde (4-chlorophenyl) hydrazone; (E) -2-[(3-cyclopentyloxy-4-methoxyphenyl) methylene] hydrazinecarbonylmethyl- (trimethyl) ammonium chloride; (E) -N- (1,4-oxazin-4-yl) -3-cyclopentyloxy-4-methoxyphenylmethaneimine; (E) -N-piperidino-3-cyclopentyloxy-4-methoxyphenylmethaneimine; (E) -2-[(3-cyclopentyloxy-4-methoxyphenyl) methylene] hydrazinecarboximidamide; (E) -3-cyclopentyloxy-4-methoxybenzaldehyde (2-pyridinyl) hydrazone; (E) -3-cyclopentyloxy-4-methoxybenzaldehyde (2-carboxyphenyl) hydrazone; And (E) -3-cyclopentyloxy-4-methoxybenzaldehyde (4-trifluoromethylpyrimidin-2-yl) hydrazone C ₁ -C ₇ alkyl or C ₃ -C ₇ cycloalkyl represented by R ¹ is reacted with a compound of formula (II) to give a compound of formula (III), the product of which is a compound of formula (IV) A process for preparing a compound of formula (I) characterized by reacting with: (I) (II) (III) (IV) Wherein R ¹ is C ₁ -C ₇ alkyl or C ₃ -C ₇ cycloalkyl; R ² is —H, —OH, —C ₁ -C ₅ alkyl or —CH ₂ CH ₂ C (═O) NH ₂ ; R ³ or R ⁴ are each independently i) -H, ii) C ₁ -C ₇ alkyl, i) -C (= X) -R ⁵ , i) halogen, C ₁ -C ₆ alkoxy, nitrile, trifluor A 2-, 3- or 4-pyridyl, pyrimidyl or phenyl group optionally substituted with one or two of rommethyl, C ₁ -C ₆ alkyl and carboxylic acid groups, or iii) containing oxygen, sulfur or nitrogen Cyclic compounds directly linked to C ₃ -C ₄ ; X is O, S or NR ⁵ ; R ⁵ is i, -C ₁ -C ₇ alkyl, ii) -NHR ⁶ or iii) 2-, 3- optionally substituted with halogen, nitrile, trifluoromethyl, C ₁ -C ₆ alkyl or carboxylic acid groups Or 4-pyridyl, pyrimidyl or phenyl group; R ⁶ is —H, —OH, —C ₁ -C ₅ alkoxy, —C ₁ -C ₅ alkyl, pyridyl or phenyl group. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 together with a pharmaceutically acceptable carrier to have an inhibitory action against phosphodiesterase IV or TNF.