NZ515213A - Cathecol hydrazone derivatives and pharmaceuticals thereof - Google Patents

Abstract

A compound of formula I, where: R1 is C3-7cycloalkyl R2 is H, hydroxy, C1-5alkyl or ûCH2CH2C(=O)NH2 R3 and R4 and independently H, C1-7alkyl, -C(=X)-R5, or 2-, 3- or 4-pyridyl, pyrimidyl or phenyl substituted with one or two substituents selected from a group consisting of halogen, C1-6alkoxy, nitro, trifluoromethyl, C1-6alkyl and carboxyl, or R3 and R4 are directly bonded by C3-4 optionally containing oxygen, sulfur or nitrogen to form a heterocyclic ring. Also described is a pharmaceutical composition for inhibiting phosphodiesterase IV or TNF which comprises a pharmaceutically effective amount of the compound described above and a pharmaceutically acceptable carrier.

Description

New Zealand Paient Spedficaiion for Paient Number 515213 Intellectual Property Office of New Zealand IP Summary Report Page: 2 of 2 Date: 23 April 2003 Time: 09:04:37 (iprip02 3.00.07) (11) NZ Patent number:. 515213 (57) Abstract: Patent 515213 A compound of formula I, where: R1 is C3.7cycloalkyl R2 is H, hydroxy, Ci-5alkyl or-CH2CH2C(=0)NH2 R3 and R4 and independently H, Chalky!, -C(=X)-R5, or 2-, 3- or 4-pyridyl, pyrimidyl or phenyl substituted with one or two substituents selected from a group consisting of halogen, Ci_6alkoxy, nitro, trifluoromethyl, Chalky! and carboxyl, or R3 and R4 are directly bonded by C3.4 optionally containing oxygen, sulfur or nitrogen to form a heterocyclic ring.

Also described is a pharmaceutical composition for inhibiting phosphodiesterase IV orTNF which comprises a pharmaceutical^ effective amount of the compound described above and a pharmaceutically acceptable carrier.

Drawing: R2 R3 CH3 * End of report * CATHECOL HYDRAZONE DERIVATIVES, PROCESS FOR PREPARING THE SAME AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME 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 10 compounds may be useful in prevention or treatment of bronchial asthma, arthritis, bronchitis, chronic atretic airway, psoriasis, allergic rhinitis, dermatitis, AIDS, Crohn'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 20 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. 25 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 30 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 pharmaceutical^ 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 5 TNF. For example, EP 470,805 of American Home Product describes oximcarbamate and oximcarbonate of formula: O JD—IJ— R2 N wherein R is C3.7 alkyl or C3.7 cycloalkyl, R1 is halogen or lower alkyl, and R2 is amino, lower alkylamino, arylamino, lower alkoxy or aryloxy.

US Patent No. 5,393,788 of SmithKline Beecham Corporation describes phenylalkyl oxamide compound of formula: wherein R1 is C4_6 cycloalkyl, X is YR2 halogen in which Y is oxgen or sulfur, or lower alkyl, R3 and R5 are independently OR7, R4 is hydrogen or CU2 alkyl, R6 is OR7 or NR7OR7, and R7 is hydrogen or C,_3 alkyl. c SUMMARY OF THE INVENTION PI iSCEJ The present invention provides novel cathecol hydrazone derivatives of formula or pharmaceutical^ acceptable salts thereof, wherein R' is C,.7alkyl or C3.7 cycloalkyl; R2 is hydrogen, hydroxy, CM alkyl or -CH?CH2C(=0)NH2; R3 and R4 are independently hydrogen, C,.7 alkyl, -C(=X)-R5, or 2-, 3- or 4-pyridyl, pyrimidyl or phenyl substituted with one or two selected from a group consisting of halogen, C|.6alkoxy, nitro, trifluoromethyl, C|.6alkyl and carboxyl, or R3 and R4are directly bonded by C3.4 optionally containing oxygen, sulfur or nitrogen to form a heterocyclic ring, X is oxygen, sulfur or NH, and R5 is C,.7 alkyl, -NHR6, CONH2 or 2-, 3- or 4-pyridyl, pyrimidyl or phenyl substituted with one selected from a group consisting of halogen, C|.6 alkoxy, nitrile, trifluoromethyl, C|.6 alkyl and carboxyl, and R6 is hydrogen, hydroxy, NH2, alkoxy, C|_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 TNF 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, R, R and R 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 20 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-cycIopentyloxy-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 (2x1.5 L). The aqueous layer was extracted with 0.5 L of toluene, and the organic layer was washed with distilled 5 water (2 x 1.5 L). The organic layer was dried and concentrated to obtain 117 g of light brown oily title compound.

'HNMR(CDCl3,d): 9.84(s, lH)7.42(m,2H)6.95(d, 1H, J=9Hz)4.87(m, lH)3.93(s,3H) 2.1-1.6(m, 8H) EXAMPLE 1 (E)-3-cyclopentyIoxy-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 25 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 0.67 g (88.45%) of white title compound, m.p. 170 - 17TC 'H NMR(DMSO-d6): 1.60(2H, m) 1.75(4H, m) 1.92(2H, m) 3.81(3H, s) 4.85(1H, m) 30 7.04(1H, d J=8.4Hz) 7.24(1H, dd, J=8.4, 1.8Hz) 7.33(1H, d J=1.8Hz) 7.81(2H, dd, J=4.5,1.6Hz) 8.39(1H, s) 8.78(2H, dd, J=4.5, 1.6Hz) 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 'H NMR(DMSO-d6): 1.23(3H, t, J=7.1Hz) 1.58(2H, m) 1.73(4H, m) 1.88(2H, m) 3.77(3H, s) 4.13(2H, q, J=7.1Hz) 4.80(1H, m) 6.98(1H, d J=8.4Hz) 7.07(1H, dd, J=8.4, 1.9Hz) 7.20(1H, d J=1.9Hz) 7.93(1H, s) 10.92(1H, s) EXAMPLE 3 (E)-3-cyclopentyloxy-4-methoxybenzaldehyde phenylhydrazone H CH 3 H CH 3 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 5 obtain 0.63 g (89.4 l%)ofwhite title compound, m.p. 138- 140°C 'HNMR(DMSO-d6): 1.60(2H, m) 1.75(4H, m) 1.92(2H, m) 3.77(3H, s) 4.85(1H, m) 6.72(1 H, m) 6.95(1H, d J=8.2Hz) 7.03(2H, d, J=7.6Hz) 7.09(1H, dd, J=8.2, 1.8Hz) 7.20(2H,t) 7.26(1H, d J=1.8Hz) 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 20 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 25 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 '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=8.4Hz) 7.14(1H, dd, J=8.4, 1.8Hz) 7.24(1H, d J=1.8Hz) 30 7.88(1H, s) 11.12(1H, s) EXAMPLE 5 (E)-3-cycIopentyloxy-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 '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=8.3Hz) 7.28(1H, dd, J=8.3, 1.8Hz) 7.36(1H, d J=5.2Hz) 7.42(1H, d J=1.8Hz) 7.61(1H, d) 7.86(1H, s) 8.39(1H, s) 8.44(2H, d J=9.1Hz) EXAMPLE 6 (E)-3-cycIopentyloxy-4-methoxybenzaldehyde 2-imidazolinohydrazone OX^ „ I CH3 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 5 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 '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=8.4Hz) 7.24(1H, dd, J=8.4, 1.8Hz) 7.44(1H, d J=1.8Hz) 8.06(1 H, 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 '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=8.3Hz) 7.09(1H, dd, J-8.3, 1.9Hz) 7.36(1H, d J=1.9Hz) 25 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) '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=8.4Hz) 7.22(1H, dd, J=8.4, 1.9Hz) 7.35(1H, d J=1.9Hz) 7.66(1H, t J=1.6Hz) 7.95(1H, d J=8.7Hz) 8.11(1H, dd J=8.5, 1.4Hz) 8.39(1H, s) 11.15(1H, s) EXAMPLE 9 (E)-2-[(3-cyclopentyIoxy-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 '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=8.4Hz) 7.09(1H, dd, J=8.4, 1.9Hz) 7.36(1H, d J=1.9Hz) 7.74(1H, s) 10.06(1H, s) EXAMPLE 10 (E)-3-cyclopentyloxy-4-methoxybenzaldehyde4-chlorophenylhydrazone H 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 '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(1 H, d J=8.4Hz) 7.04(2H, dd J=6.8,2.1Hz) 7.12(1H, dd, J=8.4,1.9Hz) 7.24(2H, dd J=6.8, 2.1Hz) 7.27(1H, d J=1.9Hz) 7.87(1H, s) 10.27(1H, s) EXAMPLE 11 (E)-2-[(3-cycIopentyloxy-4-methoxyphenyI)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 '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=8.4Hz) 7.23(1H, dd, J=8.4,1.8Hz) WO 00/73280 PCT/KR99/00264 7.29(1H, d J=1.8Hz) 8.01(lHa',s) 8.26(lHa', s) 12.05(1H, brs) EXAMPLE 12 (E)-N-(l,4-oxazine-4-yI)-3-cyclopentyloxy-4-methoxyphenylmethaneimine .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 '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 WO 00/73280 PCT/KR99/00264 starting materials to obtain 0.65 g (94.68%) of white title compound, m.p. 81 - 82°C '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 .N^NH2 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 1HNMR(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=8.4Hz) 7.33(1H, dd, J=8.4, 2.0Hz) 7.54(1H, d J=1.9Hz) 7.7(1H, brs) 8.36(1H, s) 11.69(1H, s) EXAMPLE 15 (E)-3-cyclopentyloxy-4-methoxybenzaidehyde 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 1H 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=8.3Hz) 7.10(1H, dd, J=8.3,1.8Hz) 7.20(1 H, d J=8.4Hz)7.27(lH, d J=1.8Hz) 7.62~7.63(1H, m) 7.94(1H, s) 8.09(1H, dd J=4.9, l.OHz) 10.67(1H, s) EXAMPLE 16 (E)-3-cyclopentyloxy-4-methoxybenzaIdehyde 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 '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, l.OHz) 6.99(1H, d J=8.4Hz) 7.20(1H, dd, J=8.4, 1.9Hz) 7.32(1H, d J=1.9Hz) 7.50(1H, dd J=7.0, 1.6Hz) 7.68(1H, dd J=8.5, 0.8Hz) 7.84(1H, dd J=8.0, 1.4Hz) 8.05(1H, s) 8.79(1H, d J=4.9Hz) 11.17(1H, s) EXAMPLE 17 (E)-3-cyclopentyloxy-4-methoxybenzaIdehyde 4-trifluoromethylpyrimidin-2-ylhydrazone CH CH 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 '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=8.4Hz) 7.19(1H, dd, J=8.4,2.0Hz) 7.21(1H, d J=4.9Hz) 7.27(1H, d J=2.0Hz) 8.11(1H, s) 8.79(1H, d J =4.9Hz) 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 'H NMR(DMSO-d6): 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(1 H, d J=8.3Hz) 7.07(1H, dd, J=8.3, 1.7Hz) 7.42(1H, d J=1.6Hz) 7.74(1H, s) 8.03(lH,s) 10.23(lH,s) EXAMPLE 19 (E)-2-[(3-cyclopentyloxy-4-methoxyphenyl)methylene]hydrazinedicarboxamide H H CH 3 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 10 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 'H NMR(DMSO-d6): 1.57(2H, m) 1.71(4H, m) 1.87(2H, m) 3.76(3H, s) 4.11(2H, brs) 15 4.95(lH,m) 6.91(1H, d J=8.5Hz) 7.28(1H, dd, J=8.5, 2.2Hz) 7.42(1H, d J=2.1Hz) 7.83(1H, s) 9.32(lH,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 30 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) 'H NMR(DMSO-d6): 1.59(2H, m) 1.71(4H, m) 1.87(2H, m) 3.74(3H, s) 3.83(2H, brs) 4.77(lH,m) 6.90(1 H, d J=8.5Hz) 6.96(1H, dd, J=8.3, 1.7Hz) 7.09(1H, d J=1.7Hz) 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[3H]cAMP were incubated at 30°C for 20 minutes. 15 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 [3H]adenosine in the aqueous solution was quantified by scintillation counting. The results are shown in Table I below, 20 in which the values indicate inhibition (%) of the PDE IV by each test compound.

Table I Test Compounds Concentration (uM) Inhibition (%) Rolipram (Control) 70.1 2 62.5 EXAMPLE 1 66.7 2 38.4 EXAMPLE 2 63.7 2 46.7 EXAMPLE 3 80.4 2 46.6

Claims (5)

WO 00/73280 PCT/KR99/00264 5 10 15 20 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 25 30 -18- WHAT l/WE CLAIM IS:

1. A compound of formula I: or pharmaceutically acceptable salts thereof, wherein R1 is C3.7 cycloalkyl; R2 is hydrogen, hydroxy, C,.5 alkyl or -CH2CH2C(=0)NH2; R3 and R4 are independently hydrogen, C,.7 alkyl, -C(=X)-R5, or 2-, 3- or 4-pyridyl, pyrimidyl or phenyl substituted with one or two selected from a group consisting of halogen, C|_6alkoxy, nitro, trifluoromethyl, Ci_6alkyl and carboxyl, or R3 and R4are directly bonded by C3.4 optionally containing oxygen, sulfur or nitrogen to form a heterocyclic ring, X is oxygen, sulfur or NH, and R5 is C|_7 alkyl, -NHR6, CONH2 or 2-, 3- or 4-pyridyl, pyrimidyl or phenyl substituted with one selected from a group consisting of halogen, C|_6 alkoxy, nitrile, trifluoromethyl, Ct.6 alkyl and carboxyl, and R6 is hydrogen, hydroxy, NH2, C[_5 alkoxy, C|.5 alkyl, pyridyl or phenyl.

2. The compound according to claim 1 wherein R1 is cyclopentyl, R2 is hydrogen, R3 and R4 are independently C|.5 alkyl, -C(=X)-R5, or 2-, 3- or 4-pyridyl, pyrimidyl or phenyl substituted with one selected from a group consisting of halogen, nitro, trifluoromethyl and carboxyl, or R3 and R4 are directly bonded by C3.4 optionally containing oxygen or nitrogen to form a heterocyclic ring, X is oxygen, sulfur or NH, and R5 is -NHR6 or 4-pyridyl and R6 is hydrogen, hydroxy or 4-pyridyl.

3. The compound according to claim 1 which is selected from a group consisting of - 19- WO 00/73280 PCT/KR99/00264 (E)-3-cyclopentyloxy-4-methoxybenzaldehyde isonicotinic hydrazone, (E)-ethyl [(3-cyclopentyloxy-4-methoxyphenyl)methylene]hydrazinoformate, (E)-3-cyclopentyloxy-4-methoxybenzaldehyde phenylhydrazone, (E)-3-cyclopentyloxy-4-methoxybenzaldehyde acetic hydrazone, (E)-3-cyclopentyloxy-4-methoxybenzaldehyde 7-chloroquinolone-4-ylhydrazone, (E)-3-cyclopentyloxy-4-methoxybenzaldehyde 2-imidazolinohydrazone, (E)-2-[(3-cyclopentyloxy-4-methoxyphenyl)methylene]hydrazine carboxamide, (E)-3-cyclopentyloxy-4-methoxybenzaldehyde 2-nitrophenylhydrazone, (E)-2-[(3-cyclopentyloxy-4-methoxyphenyl)methylene]hydrazinecarbothioamide, (E)-3-cyclopentyloxy-4-methoxybenzaldehyde 4-chlorophenylhydrazone, (E)-2-[(3-cyclopentyloxy-4-methoxyphenyl)methylene]hydrazinecarbonylmethyl (trimethyl) ammonium chloride, (E)-N-(l,4-oxazine-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-pyridinylhydrazone, (E)-3-cyclopentyloxy-4-methoxybenzaldehyde 2-carboxyphenylhydrazone, (E)-3-cyclopentyloxy-4-methoxybenzaldehyde 4-trifluoromethylpyrimidin-2-ylhydrazone, (E)-2-[(3-cyclopentyloxy-4-methoxyphenyl)methylene]hydrazinecarbohydrazine, (E)-2-[(3-cyclopentyloxy-4-methoxyphenyl)methylene]hydrazinedicarboxamide, and (E)-2-[(3-cyclopentyloxy-4-methoxyphenyl)methylene]hydrazinoacetic acid.

4. A process for producing a compound of formula I: R2 R3 0 1 CH 3 or pharmaceutical^ acceptable salts thereof, wherein -20- WO 00/73280 tj'-x £/~j) <£} L"y j a i ^ PCT/KR99/00264 R1 is C37 cycloalkyl; R2 is hydrogen, hydroxy, C,.5 alkyl or -CH2CH2C(=0)NH2; R3 and R4 are independently hydrogen, C,.7 alkyl, -C(=X)-R5, or 2-, 3- or 4-pyridyl, pyrimidyl or phenyl substituted with one or two selected from a group consisting of halogen, 5 C\.balkoxy, nitro, trifluoromethyl, C|.6 alkyl and carboxyl, or R3 and R4 are directly bonded by C3.4 optionally containing oxygen, sulfur or nitrogen to form a heterocyclic ring, X is oxygen, sulfur or NH, and R5 is C,.7 alkyl, -NHR6, CONH2 or 2-, 3- or 4-pyridyl, pyrimidyl or phenyl substituted with one selected from a group consisting of halogen, C[.6 alkoxy, nitrile, trifluoromethyl, C,.6 alkyl and carboxyl, and R6 is hydrogen, hydroxy, NH2, 10 Ci_5 alkoxy, C|.5 alkyl, pyridyl or phenyl, which comprises reacting C3_7 cycloalkyl with a compound of formula II: 15 HO to produce a compound of formula III: 20 O I CH wherein R1 is the same as defined above, and reacting the compound of formula III with a compound of formula IV: WO 00/73280 PCT/KR99/00264 wherein R2, R3 and R4 are the same as defined above. v ~ \ ' /

5. A pharmaceutical composition for inhibiting phosphodiesterase IV or TNF which comprises a pharmaceutically effective amount of the compound of claim 1 and a 5 pharmaceutically acceptable carrier. 10 15 20 25 (sj(Is 1)0 rat J. D. h'ARDlE & CO. Paten'- Attorneys for 30 th3 Appiicant(s).