Abstract:
The present invention provides novel cathecol hydrazone derivatives of formula (I) or pharmaceutically acceptable salts thereof, wherein R 1  is C 1-7  alkyl or C 3-7  cycloalkyl; R 2  is hydrogen, hydroxy, C 1-5  alkyl or —CH 2 CH 2 C(═O)NH 2 ; R 3  and R 4  are independently hydrogen, C 1-7  alkyl, —C(═X)—R 5 , or 2-, 3- or 4-pyridyl, prymidyl or phenyl substituted with one or two selected from a group consisting of halogen, C 1-6  alkoxy, nitro, trifluoromethyl, C 1-6  alkyl and carboxyl, or R 3  and R 4  are directly bonded by C 3-4  containing oxygen, sulfur or nitrogen to form a heterocyclic ring, X is oxygen, sulfur or NH and R 5  is C 1-7  alkyl, —NHR 6 , CONH 2  or 2-, 3- or 4-pyridyl, prymidyl or phenyl substituted with one selected from a group consisting of halogen, C 1-6  alkoxy, nitrile, trifluoromethyl, C 1-6  alkyl and carboxyl, and R 6  is hydrogen, hydroxy, NH 2 , C 1-5  alkoxy, C 1-5  alkyl, pyridyl or phenyl.

Description:
This application is the national phase under 35 U.S.C. §371 of PCT International Application No. PCT/KR99/00264 which has an International filing date of May 28, 1999, which designated the United States of America and was published in English. 
     FIELD OF THE INVENTION 
     The present invention relates to novel cathecol hydrazone derivatives which inhibit the enzymatic activity of phosphodiesterase IV or tumor necrosis factor. These compounds may be useful in prevention or treatment of bronchial asthma, arthritis, bronchitis, chronic atretic airway, psoriasis, allergic rhinitis, dermatitis, AIDS, Crohn&#39;s disease, septicemia, septic shock, other inflammatory diseases such as cachexia, TNF related diseases, etc. Also, the present invention relates to a method for producing said compounds and a pharmaceutical composition containing said compound. 
     BACKGROUND OF THE INVENTION 
     Phosphodiesterase IV is an enzyme that specifically hydrolyzes cAMP (cyclic adenosine 3′,5′-monophosphate) into inactive adenosine 3′,5′-monophosphate. The cAMP has been shown to be a second messenger mediating the cellular responses to external stimuli and to act as relaxing or contradicting bronchial muscles. 
     The inhibition of phosphodiesterase IV leads to the prevention of broncospasm by maintaining the concentration of cAMP and also induces an anti-inflammation. Therefore, compounds that inhibit phosphodiesterase IV should be effective in treating asthma and the like diseases. 
     It is known that tumor necrosis factor (TNF) is implicated in infectious disease such as cachexia and autoimmune disease. Also, TNF appears to act as a primary mediator for inflammatory reaction such as septicemia and septic shock. 
     Therefore, it is expected that compounds with the inhibitory activity against phosphodiesterase IV or TNF will be pharmaceutically valuable and there is always a need to develop new compounds which inhibit phosphodiesterase IV and TNF. 
     Many compounds have been suggested as inhibitors of phosphodiesterase IV and TNF. For example, EP 470,805 of American Home Product describes oximcarbamate and oximcarbonate of formula:                           
     wherein R is C 3-7  alkyl or C 3-7  cycloalkyl, R 1  is halogen or lower alkyl, and R 2  is amino, lower alkylamino, arylamino, lower alkoxy or aryloxy. 
     U.S. Pat. No. 5,393,798 of SmithKline Beecham Corporation describes phenylalkyl oxamide compound of formula:                           
     wherein R 1  is C 4-6  cycloalkyl, X is YR 2  halogen in which Y is oxgen or sulfur, or lower alkyl, R 3  and R 5  are independently OR 7 , 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. 
     SUMMARY OF THE INVENTION 
     The present invention provides novel cathecol hydrazone derivatives of formula I:                           
     or pharmaceutically acceptable salts thereof, wherein 
     R 1  is C 1-7  alkyl or C 3-7  cycloalkyl; 
     R 2  is hydrogen, hydroxy, C 1-5  alkyl or —CH 2 CH 2 C(═O)NH 2 ; 
     R 3  and R 4  are independently hydrogen, C 1-7  alkyl, —C(═X)—R 5 , or 2-, 3- or 4-pyridyl, prymidyl or phenyl substituted with one or two selected from a group consisting of halogen, C 1-6  alkoxy, nitro, trifluoromethyl, C 1-6  alkyl and carboxyl, or R 3  and R 4  are directly bonded by C 3-4  containing oxygen, sulfur or nitrogen to form a heterocyclic ring, X is oxygen, sulfur or NH, and R 5  is C 1-7  alkyl, —NHR 6 , CONH 2  or 2-, 3- or 4-pyridyl, prymidyl or phenyl substituted with one selected from a group consisting of halogen, C 1-6  alkoxy, nitrile, trifluoromethyl, C 1-6  alkyl and carboxyl, and R 6  is hydrogen, hydroxy, NH 2 , C 1-5  alkoxy, C 1-5  alkyl, pyridyl or phenyl. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The compound of formula I can be present as optical isomers or stereoisomers. Thus, the present invention includes such isomers and mixtures thereof. 
     The present invention provides a pharmaceutical composition for inhibiting phosphodiesterase IV or TNT which comprises a compound of formula I and a pharmaceutically acceptable carrier. 
     The compound of formula I can be prepared by the following reaction scheme I:                           
     wherein R 1 , R 2 , R 3  and R 4  are the same as defined above. 
     Some derivatives were synthesized by a known method (J. Med. Chem., 1994, 37, 1696). Hydrazine compounds were synthesized in yield of 60% to 90% in alcohol solvent using acid catalyst (Tetrahedron Lett. 1994, 35, 3711). 
    
    
     The invention will now be described with reference to the following illustrative Examples. 
     EXAMPLES 
     Reference Example 1 
     3-cyclopentyloxy-4-methoxybenzaldehyde 
     A solution of 100 g (0.66 mol) of isovanillin, 136.2 g (0.99 mol) of anhydrous potassium carbonate, and 3 g of potassium iodide in 650 ml of anhydrous dimethylformamide was stirred at 65° C. 127.3 g (0.85 mol) of cyclopentyl bromide was slowly added dropwise for 1 hour to the solution. This solution was stirred at 65° C. for 1 day and, then, its temperature was lowered to a room temperature. It was diluted by 2.0 L of toluene and was washed with 1M sodium hydroxide (2×1.5 L). The aqueous layer was extracted with 0.5 L of toluene, and the organic layer was washed with distilled water (2×1.5 L). The organic layer was dried and concentrated to obtain 117 g of light brown oily title compound.  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) 2.1-6(m, 8H) 
     Example 1 
     (E)-3-cyclopentyloxy-4-methoxybenzaldehyde isonicotinic hydrazone 
     
       
                 
         
             
             
         
      
     
     A catalytic amount of concentrated sulfuric acid was added to a solution of 0.44 g (2.0 mmole) of compound prepared by Reference Example 1 in 30 ml of ethanol and the mixture was stirred at room temperature for 10 minutes. 0.33 g of isonicotinic hydrazide was added to the reaction solution. The solution was stirred at 50° C. for 4 hours and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and was washed twice with 50 ml of distilled water. The separated organic layer was dried over anhydrous magnesium sulfate and was distilled under reduced pressure. The resulting white crystal was recrystalized in dichloromethane to obtain 0.67 g (88.45%) of white title compound. m.p. 170-171° C.  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]hydrazinoformate 
     
       
                 
         
             
             
         
      
     
     A catalytic amount of concentrated hydrochloric acid was added to a solution of 1.00 g (4.54 mmole) of compound prepared by Reference Example 1 in 80 ml of ethanol and the mixture was stirred at room temperature for 10 minutes. 0.73 g of ethyl carbazate was added to the reaction solution. The solution was stirred at 50° C. for 4 hours and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and was washed twice with 50 ml of distilled water. The separated organic layer was dried over anhydrous magnesium sulfate and was distilled under reduced pressure. The resulting white crystal was recrystallized in dichloromethane to obtain 1.25 g (89.87%) of white title compound. m.p. 146-147° C.  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(1H, s) 
     Example 3 
     (E)-3-cyclopentyloxy-4-methoxybenzaldehyde phenylhydrazone 
     
       
                 
         
             
             
         
      
     
     A catalytic amount of concentrated hydrochloric acid was added to a solution of 0.50 g (2.27 mmole) of compound prepared by Reference Example 1 in 60 ml of ethanol and the mixture was stirred at room temperature for 10 minutes. 0.34 ml of phenylhydrazine was added to the reaction solution. The solution was stirred 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 white title compound. m.p. 138-140° C.  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 
     
       
                 
         
             
             
         
      
     
     A catalytic amount of concentrated hydrochloric acid was added to a solution of 0.50 g (2.27 mmole) of compound prepared by Reference Example 1 in 60 ml of ethanol and the mixture was stirred at room temperature for 10 minutes. 0.26 g of acetic hydrazide was added to the reaction solution. The solution was stirred at 25° C. for 10 hours and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and was washed twice with 50 ml of distilled water. The separated organic layer was dried over anhydrous magnesium sulfate and was distilled under reduced pressure. The resulting white crystal was recrystallized in dichloromethane to obtain 0.59 g (94.06%) of white title compound. m.p. 155-156° C.  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-chloroquinolone-4-ylhydrazone 
     
       
                 
         
             
             
         
      
     
     A catalytic amount of concentrated hydrochloric acid was added to a solution of 0.50 g (2.27 mmole) of compound prepared by Reference Example 1 in 60 ml of ethanol and the mixture was stirred at room temperature for 10 minutes. 0.67 g of 7-chloro-4-hydrazinoquinoline was added to the reaction solution. The solution was stirred at 45° C. for 10 hours. The resulting precipitate was filtered and washed with 20 ml of ethanol to obtain 0.55 g (61.20%) of white title compound. m.p. 210-212° C.  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-imidazolinohydrazone 
     
       
                 
         
             
             
         
      
     
     A catalytic amount of concentrated hydrochloric acid was added to a solution of 0.50 g (2.27 mmole) of compound prepared by Reference Example 1 in 50 ml of ethanol and the mixture was stirred at room temperature for 10 minutes. 0.63 g of hydrozino-2-imidazoline hydrobromide was added to the reaction solution. The solution was stirred at 45° C. for 8 hours and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and was washed twice with 50 ml of distilled water. The separated organic layer was dried over anhydrous magnesium sulfate and was distilled under reduced pressure. The resulting light yellow oil was purified by a flash chromatography (silica gel, 7.5% methanol-dichloromethane as a developing solution) to obtain 0.45 g (65.56%) of white title compound. m.p. 87-90° C.  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 
     
       
                 
         
             
             
         
      
     
     A reaction as in Example 6 was carried out using 0.50 g (2.27 mmole) of compound prepared in Reference Example 1 as a starting material to obtain 0.47 g (74.66%) of white title compound. m.p. 144-146° C.  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-nitrophenylhydrazone 
     
       
                 
         
             
             
         
      
     
     A reaction as in Example 3 was carried out using 0.50 g (2.27 mmole) of compound prepared in Reference Example 1 as a starting material to obtain 0.63 g (78.09%) of red yellow title compound. m.p. 135° C. (decomposed)  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 
     
       
                 
         
             
             
         
      
     
     A reaction as in Example 6 was carried out using 1.00 g (4.54 mmole) of compound prepared in Reference Example 1 as a strating material to obtain 0.94 g (70.57%) of white title compound. m.p. 112-114° C. 1H 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 4chlorophenylhydrazone 
     
       
                 
         
             
             
         
      
     
     A reaction as in Example 6 was carried out using 1.50 g (6.81 mmole) of compound prepared in Reference Example 1 as a starting material to obtain 1.65 g (70.26%) of white title compound. m.p. 133-135° C.  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(1 H, 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(1H, s) 10.27(1H, s) 
     Example 11 
     (E)-2[(3-cyclopentyloxy-4-methoxyphenyl)methylene]hydrazinecarbonylmethyl(trimethyl)ammonium chloride 
     
       
                 
         
             
             
         
      
     
     A reaction as in Example 6 was carried out using 1.50 g (6.81 mmole) of compound prepared in Reference Example 1 and 1.03 g of (carboxymethyl)trimethylammonium chloride hydrazide as starting materials to obtain 1.73 g (68.68%) of white title compound. m.p. 178-179° C.  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-oxazine-4-yl)-3-cyclopentyloxy-4-methoxyphenylmethaneimine 
     
       
                 
         
             
             
         
      
     
     5.0 g (22.7 mmole) of compound prepared by Reference Example 1 was dissolved in 60 ml of ethanol and the resulting solution was stirred at room temperature for 10 minutes. 2.91 ml of N-aminomorpholine was added to the reaction solution. The solution was stirred at 5° C. for 14 hours. The resulting precipitate was filtered and washed with 20 ml of ethanol to obtain a while solid. This solid was recrystallized in isopropylether to obtain 6.37 g (92.19%) of title compound. m.p. 108-109° C.  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 
     
       
                 
         
             
             
         
      
     
     A reaction as in Example 12 was carried out using 0.50 g (2.27 mmole) of compound prepared in Reference Example 1 and 0.31 ml of N-aminopiperidine as starting materials to obtain 0.65 g (94.68%) of white title compound. m.p. 81-82° C.  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.i8(d, 1H) 7.57(s, 1H) 
     Example 14 
     (E)-2-[(3-cyclopentyloxy-4-methoxyphenyl)methylene]hydrazinecarboximidamide 
     
       
                 
         
             
             
         
      
     
     A reaction as in Example 6 was carried out using 1.50 g (6.81 mmole) of compound prepared in Reference Example 1 and 0.73 g of aminoguanidine hydrochloride as starting materials to obtain 1.60 g (85.02%) of white title compound. m.p. 100-103° C.  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-pyridinylhydrazone 
     
       
                 
         
             
             
         
      
     
     A reaction as in Example 6 was carried out using 0.80 g (3.63 mmole) of compound prepared in Reference Example 1 and 0.39 g of 2-hydrazinopyrimidine as starting materials to obtain 0.96 g (84.89%) of white title compound. m.p. 142-143 ° C.  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˜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-carboxyphenylhydrazone 
     
       
                 
         
             
             
         
      
     
     A reaction as in Example 6 was carried out using 0.80 g (3.63 mmole) of compound prepared in Reference Example 1 and 0.66 g of 2-hydrazinobenzoic hydrochloride as starting materials to obtain 1.05 g (81.57%) of white title compound. m.p. 174-176° C.  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-ylhydrazone 
     
       
                 
         
             
             
         
      
     
     A reaction as in Example 6 was carried out using 0.80 g (3.63 mmole) of compound prepared in Reference Example 1 and 0.63 g of 2-hydrazino-4-(trifluoromethyl)pyrimidine as starting materials to obtain 1.10 g (79.62%) of white title compound. m.p. 73-75° C.  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˜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) 
     Example 18 
     (E)-2-[(3-cyclopentyloxy-4-methoxyphenyl)methylene]hydrazinecarbohydrazine 
     
       
                 
         
             
             
         
      
     
     A catalytic amount of glacial acetic acid was added to a solution of 1.0 g (4.54 mmol) of compound prepared in Reference Example 1 in 50 ml of methanol and the mixture was stirred at room temperature for 10 minutes and added dropwise over 20 minutes to a solution of 1.0 g of carbohydrazine in 50 ml of distilled water. The reaction mixture was stirred at room temperature for 1 hour and the precipitated solids were filtered to obtain 0.89 g (67.06%) of white title compound. m.p. 179-181° C.  1 H NMR(DMSO-d 6 ): 1.61(2H, m) 1.72(4H, m) 1.89(2H, m) 3.76(3H, s) 4.05(2H, brs) 4.94(1 H,m) 6.92(1H, d J=8.3 Hz) 7.07(1H, dd, J=8.3, 1.7 Hz) 7.42(1H, d J=1.6 Hz) 7.74(1H, s) 8.03(1H,s) 10.23(1H,s) 
     Example 19 
     (E)-2-[(3-cyclopentyloxy-4-methoxyphenyl)methylene]hydrazinedicarboxamide 
     
       
                 
         
             
             
         
      
     
     A catalytic amount of glacial acetic acid was added to a solution of 1.0 g (4.54 mmol) of compound prepared in Reference Example 1 in 50 ml of methanol and the mixture was stirred at room temperature for 10 minutes and added dropwise over 30 minutes to a solution of 1.17 g of oxamic hydrazide in 60 ml of distilled water. The reaction mixture was stirred at room temperature for 2 hours and the precipitated solids were filtered to obtain 1.12 g (80.80%) of white title compound. m.p. 233-235° C.  1 H NMR(DMSO-d 6 ): 1.57(2H, m) 1.71(4H, m) 1.87(2H, m) 3.76(3H, s) 4.11(2H, brs) 4.95(1H,m) 6.91(1H, d J=8.5 Hz) 7.28(1H, dd, J=8.5, 2.2 Hz) 7.42(1H, d J=2.1 Hz) 7.83(1H, s) 9.32(1H,s) 
     Example 20 
     (E)-2-[(3-cyclopentyloxy-4-methoxyphenyl)methylene]hydrazinoacetic acid 
     
       
                 
         
             
             
         
      
     
     A reaction as in Example 6 was carried out using 0.80 g (3.63 mmole) of compound prepared in Reference Example 1 and 0.63 g of ethylhydrazinoacetate as starting materials to obtain 0.98 g of white ethyl (E)-2-[3-cyclopentyloxy-4-methoxyphenylmethylene]hydrazinoacetate. The prepared ester compound was hydrolysed in the mixture of methanol and 1.0 N aqueous sodium hydroxide solution to afford 0.75 g (70.77%) of white title solid. m.p. 165° C. (decomposed)  1 H NMR(DMSO-d 6 ): 1.59(2H, m) 1.71(4H, m) 1.87(2H, m) 3.74(3H, s) 3.83(2H, brs) 4.77(1H,m) 6.90(1H, d J=8.5 Hz) 6.96(1H, dd, J=8.3, 1.7 Hz) 7.09(1H, d J=1.7 Hz) 7.57(1H, s) 
     Experimental Example 
     Inhibition of Phosphodiesterase IV Activity 
     Compounds prepared by Examples 1 through 16 and Rolipram as control were tested on the inhibition of phosphodiesterase IV. 
     Phosphodiesterase IV partially purified from human U937 cells, test compound and 1.0 uM cAMP including 0.01 uM[ 3 H]cAMP were incubated at 30° C. for 20 minutes. The PDE reaction to convert cAMP into AMP was completed by boiling the reaction solution for 2 minutes. AMP was converted into adenosine by adding snake venom nucleotidase and incubating the reaction solution at 30° C. for 10 minutes. While unhydrolyzed cAMPs were bonded to AG1-X2 resin, the [ 3 H]adenosine in the aqueous solution was quantified by scintillation counting. The results are shown in Table I below, in which the values indicate inhibition (%) of the PDE IV by each test compound. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE I 
               
               
                   
                   
               
               
                   
                 Test Compounds 
                 Concentration (uM) 
                 Inhibition (%) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Rolipram (Control) 
                 20 
                 70.1 
               
               
                   
                   
                 2 
                 62.5 
               
               
                   
                 EXAMPLE 1 
                 20 
                 66.7 
               
               
                   
                   
                 2 
                 38.4 
               
               
                   
                 EXAMPLE 2 
                 20 
                 63.7 
               
               
                   
                   
                 2 
                 46.7 
               
               
                   
                 EXAMPLE 3 
                 20 
                 80.4 
               
               
                   
                   
                 2 
                 46.6 
               
               
                   
                 EXAMPLE 4 
                 20 
                 72.1 
               
               
                   
                   
                 2 
                 51.7 
               
               
                   
                 EXAMPLE 5 
                 20 
                 64.9 
               
               
                   
                   
                 2 
                 37.9 
               
               
                   
                 EXAMPLE 6 
                 20 
                 58.3 
               
               
                   
                   
                 2 
                 31.7 
               
               
                   
                 EXAMPLE 7 
                 20 
                 89.7 
               
               
                   
                   
                 2 
                 66.2 
               
               
                   
                 EXAMPLE 9 
                 20 
                 81.0 
               
               
                   
                   
                 2 
                 69.0 
               
               
                   
                 EXAMPLE 10 
                 20 
                 70.7 
               
               
                   
                   
                 2 
                 39.3 
               
               
                   
                 EXAMPLE 11 
                 20 
                 45.1 
               
               
                   
                   
                 2 
                 43.3 
               
               
                   
                 EXAMPLE 12 
                 20 
                 79.4 
               
               
                   
                   
                 2 
                 62.9 
               
               
                   
                 EXAMPLE 13 
                 20 
                 73.3 
               
               
                   
                   
                 2 
                 31.4 
               
               
                   
                 EXAMPLE 14 
                 20 
                 57.7 
               
               
                   
                   
                 2 
                 14.7 
               
               
                   
                 EXAMPLE 15 
                 20 
                 63.6 
               
               
                   
                   
                 2 
                 49.4 
               
               
                   
                 EXAMPLE 16 
                 20 
                 76.6 
               
               
                   
                   
                 2 
                 42.3