N-PHENYL-N'-PHENOXYCARBONYL-PHENYLSULFONHYDRAZIDE DERIVATIVE AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

Abstract

The present invention relates to a N-phenyl-N-phenoxycarbonyl-phenylsulfonhydrazide derivative with excellent inhibitory activity on PGE.sub.2 production, a method for preparing the same and a pharmaceutical composition comprising the same as an active ingredient. The present N-phenyl-N-phenoxycarbonyl-phenylsulfonhydrazide derivative may be used effectively for preventing or treating inflammation, arthritis, high fever, pain, cancer, stroke or bone disease.

Claims

1. A N-phenyl-N-phenoxycarbonyl-phenylsulfonhydrazide derivative of the following formula (I) or pharmaceutically acceptable salt thereof: ##STR00006## wherein, R.sup.1 is hydrogen, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy, R.sup.2 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, C.sub.1-C.sub.6 haloalkyl or aryl, R.sup.3 is hydrogen, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy, R.sup.4 is hydrogen, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy, R.sup.5 is hydrogen, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy, and R.sup.6 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy or aryloxy, or R.sup.5 and R.sup.6 are taken together with the carbon atom to which they are attached to form a 4 to 7-membered hydrocarbon ring.

2. The N-phenyl-N-phenoxycarbonyl-phenylsulfonhydrazide derivative according to claim 1 or pharmaceutically acceptable salt thereof, wherein, R.sup.1 is hydrogen or C.sub.1-C.sub.6 alkyl, R.sup.2 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, C.sub.1-C.sub.6 haloalkyl or aryl, R.sup.3 is hydrogen or C.sub.1-C.sub.6 alkyl, R.sup.4 is hydrogen or C.sub.1-C.sub.6 alkoxy, R.sup.5 is hydrogen, and R.sup.6 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy or aryloxy, or R.sup.5 and R.sup.6 are taken together with the carbon atom to which they are attached to form a 4 to 7-membered hydrocarbon ring.

3. The N-phenyl-N-phenoxycarbonyl-phenylsulfonhydrazide derivative according to claim 1 or pharmaceutically acceptable salt thereof, wherein, R.sup.1 is hydrogen or methyl, R.sup.2 is methyl, n-propyl, i-propyl, t-butyl, methoxy, chloro, trifluoromethyl or phenyl, R.sup.3 is hydrogen or methyl, R.sup.4 is hydrogen or methoxy, R.sup.5 is hydrogen, and R.sup.6 is hydrogen, methyl, ethyl, methoxy, ethoxy, phenoxy or benzyloxy, or R.sup.5 and R.sup.6 are taken together with the carbon atom to which they are attached to form a 5-membered hydrocarbon ring.

4. The N-phenyl-N-phenoxycarbonyl-phenylsulfonhydrazide derivative according to claim 1 or pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds: N-phenyl-N-(4-methoxyphenoxycarbonyl)-4-methoxyphenylsulfonhydrazide (I-1); N-phenyl-N-(4-methylphenoxycarbonyl)-4-methylphenylsulfonhydrazide (I-2); N-phenyl-N-(2-methoxyphenoxycarbonyl)-4-methylphenylsulfonhydrazide (I-3); N-phenyl-N-(4-benzyloxyphenoxycarbonyl)-4-methoxyphenylsulfonhydrazide (I-4); N-phenyl-N-(4-ethoxyphenoxycarbonyl)-4-methoxyphenylsulfonhydrazide (I-5); N-phenyl-N-(4-phenoxyphenoxycarbonyl)-4-methoxyphenylsulfonhydrazide (I-6); N-phenyl-N-(4-ethylphenoxycarbonyl)-4-methoxyphenylsulfonhydrazide (I-7); N-phenyl-N-(4-benzyloxyphenoxycarbonyl)-4-methylphenylsulfonhydrazide (I-8); N-phenyl-N-(2,3-dihydro-1H-inden-5-oxycarbonyl)-4-methoxyphenylsulfonhydrazide (I-9); N-phenyl-N-phenoxycarbonyl-4-chlorophenylsulfonhydrazide (I-10); N-phenyl-N-(2-methoxyphenoxycarbonyl)-4-chlorophenylsulfonhydrazide (I-11); N-phenyl-N-(4-ethylphenoxycarbonyl)-4-chlorophenylsulfonhydrazide (I-12); N-phenyl-N-(4-ethoxyphenoxycarbonyl)-4-chlorophenylsulfonhydrazide (I-13); N-phenyl-N-(4-phenoxyphenoxycarbonyl)-4-chlorophenylsulfonhydrazide (I-14); N-phenyl-N-(4-benzyloxyphenoxycarbonyl)-4-chlorophenylsulfonhydrazide (I-15); N-phenyl-N-(4-phenoxyphenoxycarbonyl)-2-mesitylenesulfonhydrazide (I-16); N-phenyl-N-(4-benzyloxyphenoxycarbonyl)-2-mesitylenesulfonhydrazide (I-17); N-phenyl-N-(4-phenoxyphenoxycarbonyl)-biphenyl-4-sulfonhydrazide (I-18); N-phenyl-N-(4-benzyloxyphenoxycarbonyl)-biphenyl-4-sulfonhydrazide (I-19); N-phenyl-N-(4-phenoxyphenoxycarbonyl)-4-n-propylphenylsulfonhydrazide (I-20); N-phenyl-N-(4-benzyloxyphenoxycarbonyl)-4-trifluoromethylphenylsulfonhydrazide (I-21); N-phenyl-N-(4-benzyloxyphenoxycarbonyl)-4-t-butylphenylsulfonhydrazide (I-22); N-phenyl-N-(4-phenoxyphenoxycarbonyl)-4-t-butylphenylsulfonhydrazide (I-23); N-phenyl-N-(4-phenoxyphenoxycarbonyl)-4-i-propylphenylsulfonhydrazide (I-24); N-phenyl-N-(2,3-dihydro-1H-inden-5-oxycarbonyl)-4-methylphenylsulfonhydrazide (I-25); N-phenyl-N-(2,3-dihydro-1H-inden-5-oxycarbonyl)-4-chlorophenylsulfonhydrazide (I-26); N-phenyl-N-(2,3-dihydro-1H-inden-5-oxycarbonyl)-4-trifluorophenylsulfonhydrazide (I-27); and N-phenyl-N-(2,3-dihydro-1H-inden-5-oxycarbonyl)-2-mesitylenesulfonhydrazide (I-28).

5. A method for preparing a N-phenyl-N-phenoxycarbonyl-phenylsulfonhydrazide derivative of the following formula (I) comprising a step of reacting a compound of the following formula (II) with a compound of the following formula (III): ##STR00007## wherein, R.sup.1 is hydrogen, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy, R.sup.2 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, C.sub.1-C.sub.6 haloalkyl or aryl, R.sup.3 is hydrogen, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy, R.sup.4 is hydrogen, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy, R.sup.5 is hydrogen, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy, and R.sup.6 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy or aryloxy, or R.sup.5 and R.sup.6 are taken together with the carbon atom to which they are attached to form a 4 to 7-membered hydrocarbon ring.

6. The method according to claim 5, wherein the compound of formula (II) is reacted with the compound of formula (III) in the presence of a base.

7. The method according to claim 6, wherein the base is triethylamine.

8. The method according to claim 5, wherein the reaction is performed without any additional reaction solvent.

9. A pharmaceutical composition for inhibiting microsomal prostaglandin E.sub.2 synthase-1 (mPGES-1) comprising the N-phenyl-N-phenoxycarbonyl-phenylsulfonhydrazide derivative according to claim 1 or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9 for preventing or treating inflammation, arthritis, high fever, pain, cancer, stroke or bone disease.

11. A method for preventing or treating inflammation, arthritis, high fever, pain, cancer, stroke or bone disease, comprising administering the pharmaceutical composition of claim 9 to a subject in need thereof.

Description

BEST MODE

[0092] The present invention is further illustrated by the following examples, which are not to be construed to limit the scope of the invention.

Preparation Example 1: Preparation of a Compound of Formula II

Preparation Example 1-1: N-phenyl-4-toluenesulfonhydrazide (II-1)

[0093] Phenyl hydrazine (2.29 g, 21.26 mmol, 1.0 eq) was dissolved in dichloromethane solvent at room temperature. To the resulting solution were added 4-toluenesulfonyl chloride (6.05 g, 31.73 mmol, 1.5 eq) and triethylamine (TEA) (4.43 ml, 31.73 mmol, 1.5 eq) at 0 C. and the resulting mixture was stirred at room temperature for 1.5 hrs. After the reaction was completed, dichloromethane solvent was removed using a rotary evaporator and the resulting residue was extracted with ethyl acetate and distilled water. Distilled water remaining in ethyl acetate was removed with anhydrous magnesium sulfate and ethyl acetate solvent was removed using a rotary evaporator. The resulting residue was recrystallized with methanol to produce a white solid which was solidified using n-hexane to give the title compound (II-1) (1.29 g, 4.90 mmol, 23%).

[0094] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.45 (1H, s), 7.74 (2H, m), 7.58 (1H, s), 7.42 (2H, d, J=7.6 Hz), 7.09 (2H, t, J=7.2 Hz), 6.80 (2H, d, J=8.0 Hz), 6.93 (1H, t, J=6.8 Hz).

Preparation Example 1-2: N-phenyl-4-methoxyphenylsulfonhydrazide (II-2)

[0095] The title compound (II-2) (37%) was obtained according to the same procedure as Preparation Example 1-1, except for using 4-methoxyphenylsulfonyl chloride instead of 4-toluenesulfonyl chloride.

[0096] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.36 (1H, s), 7.76 (2H, d, J=8.8 Hz), 7.57 (1H, s), 7.14-7.06 (4H, m), 6.79 (2H, d, J=8.0 Hz), 6.68 (1H, t, J=7.2 Hz), 3.84 (3H, s).

Preparation Example 1-3: N-phenyl-phenylsulfonhydrazide (II-3)

[0097] The title compound as a white solid (II-3) (50%) was obtained according to the same procedure as Preparation Example 1-1, except for using phenylsulfonyl chloride instead of 4-toluenesulfonyl chloride.

[0098] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.56 (1H, s), 7.85 (2H, d, J=7.2 Hz), 7.84-7.59 (4H, m), 7.09 (2H, t, J=7.6 Hz), 6.81-6.71 (2H, m), 6.69 (1H, t, J=7.2 Hz).

Preparation Example 1-4: N-phenyl-4-chlorophenylsulfonhydrazide (II-4)

[0099] The title compound (II-4) (48%) was obtained according to the same procedure as Preparation Example 1-1, except for using 4-chlorophenylsulfonyl chloride instead of 4-toluenesulfonyl chloride.

[0100] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.64 (1H, s), 7.83 (2H, d, J=8.8 Hz), 7.69 (2H, d, J=8.4 Hz), 7.10 (2H, t, J=8.4 Hz), 6.78 (2H, d, J=8.4 Hz), 6.711 (1H, t, J=7.2 Hz).

Preparation Example 1-5: N-phenyl-4-trifluoromethylphenylsulfonhydrazide (II-5)

[0101] The title compound (II-5) (62%) was obtained according to the same procedure as Preparation Example 1-1, except for using 4-trifluoromethylphenylsulfonyl chloride instead of 4-toluenesulfonyl chloride.

[0102] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.01 (2H, d, J=8 Hz), 7.72 (2H, d, J=8 Hz), 7.14-7.10 (2H, m), 6.86 (1H, t, J=7.6 Hz), 6.71 (2H, d, J=8.6 Hz), 6.42 (1H, s).

Preparation Example 1-6: N-phenyl-2-mesitylenesulfonhydrazide (II-6)

[0103] The title compound (II-6) (35%) was obtained according to the same procedure as Preparation Example 1-1, except for using 2-mesitylenesulfonyl chloride instead of 4-toluenesulfonyl chloride.

[0104] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.10-7.06 (2H, m), 6.90 (2H, s), 6.81-6.77 (1H, m), 6.71-6.69 (2H, m), 6.21 (1H, s), 2.64 (6H, s), 2.29 (3H, s).

Preparation Example 1-7: N-phenyl-biphenyl-4-sulfonhydrazide (II-7)

[0105] The title compound (II-7) (42%) was obtained according to the same procedure as Preparation Example 1-1, except for using biphenyl-4-sulfonyl chloride instead of 4-toluenesulfonyl chloride.

[0106] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.94-7.92 (2H, m), 7.67-7.62 (2H, m), 7.58-7.56 (2H, m), 7.50-7.42 (3H, m), 7.12-7.08 (2H, m), 6.84-6.80 (1H, m), 6.76-6.74 (2H, m), 6.35 (1H, s).

Preparation Example 1-8: N-phenyl-4-n-propylphenylsulfonhydrazide (II-8)

[0107] The title compound (II-8) (59%) was obtained according to the same procedure as Preparation Example 1-1, except for using 4-n-propylphenylsulfonyl chloride instead of 4-toluenesulfonyl chloride.

[0108] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.71 (2H, d, J=8.4 Hz), 7.17 (2H, d, J=8.4 Hz), 7.04-7.00 (2H, m), 6.75-6.71 (1H, m), 6.65-6.63 (2H, m), 6.14 (1H, s), 2.55 (2H, t, J=7.2 Hz), 1.56 (2H, m), 0.85 (3H, t, J=7.2 Hz).

Preparation Example 1-9: N-phenyl-4-t-butylphenylsulfonhydrazide (II-9)

[0109] The title compound (II-9) (45%) was obtained according to the same procedure as Preparation Example 1-1, except for using 4-t-butylphenylsulfonyl chloride instead of 4-toluenesulfonyl chloride.

[0110] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.48 (1H, s), 7.76 (2H, d, J=8.4 Hz), 7.64-7.62 (3H, m), 7.08 (2H, t, J=8 Hz), 6.79 (2H, d, J=8 Hz), 6.68 (1H, t, J=7.2 Hz), 1.34 (9H, s).

Preparation Example 1-10: N-phenyl-4-i-propylphenylsulfonhydrazide (II-10)

[0111] The title compound (II-10) (23%) was obtained according to the same procedure as Preparation Example 1-1, except for using 4-i-propylphenylsulfonyl chloride instead of 4-toluenesulfonyl chloride.

[0112] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 7.81 (2H, d, J=8.4 Hz), 7.30 (2H, t, J=8.4 Hz), 7.10 (2H, d, J=7.6 Hz), 6.83 (1H, t, J=7.2 Hz), 6.73 (2H, d, J=8.4 Hz), 6.23 (1H, s), 5.70 (3H, s), 2.97 (1H, m), 1.29 (6H, d, J=15.2 Hz).

Preparation Example 2: Preparation of a Compound of Formula III

Preparation Example 2-1: 4-(Benzyloxy)phenyl chloroformate (III-1)

[0113] Triphosgene (2.37 g, 7.99 mmol, 0.8 eq) was dissolved in anhydrous THF solvent at anhydrous condition. To the resulting solution was added 4-(benzyloxy)phenol (2.00 g, 9.99 mmol, 1.0 eq) dissolved in anhydrous THF solvent. To the resulting mixture was slowly added diisopropylethylamine (DIPEA) (1.74 ml, 9.99 mmol, 1.0 eq) and the resulting mixture was stirred at 0 r for 16 hrs. And then, the mixture was extracted with ethyl acetate and distilled water, and the distilled water was removed from the resulting ethyl acetate solution using anhydrous magnesium sulfate. The ethyl acetate solvent was removed using a rotary evaporator to give the title compound as a white solid (III-1) (2.667 g, 10.15 mmol, >99%).

[0114] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.46-7.34 (5H, m), 7.18-7.13 (2H, m), 7.02-6.68 (2H, m).

Preparation Example 2-2: 4-(Ethoxy)phenyl chloroformate (III-2)

[0115] The title compound (III-2) (98%) was obtained according to the same procedure as Preparation Example 2-1, except for using 4-ethoxyphenol instead of 4-(benzyloxy)phenol.

[0116] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.06-7.01 (2H, m), 6.82-6.78 (2H, m), 3.93 (2H, q, J=6.8 Hz), 1.33 (3H, t, J=6.8 Hz).

Preparation Example 2-3: 4-(Phenoxy)phenyl chloroformate (III-3)

[0117] The title compound (III-3) (99%) was obtained according to the same procedure as Preparation Example 2-1, except for using 4-phenoxyphenol instead of 4-(benzyloxy)phenol.

[0118] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.41-7.36 (2H, m), 7.22-7.15 (3H, m), 7.06-7.03 (4H, m).

Preparation Example 2-4: 4-(Ethyl)phenyl chloroformate (III-4)

[0119] The title compound (III-4) (98%) was obtained according to the same procedure as Preparation Example 2-1, except for using 4-ethylphenol instead of 4-(benzyloxy)phenol.

[0120] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.19-7.15 (2H, m), 7.06-7.04 (2H, m), 2.59 (2H, q, J=7.2 Hz), 1.17 (3H, t, J=7.2 Hz).

Preparation Example 2-5: 2,3-Dihydro-1H-inden-5-yl chloroformate (III-5)

[0121] The title compound (III-5) (98%) was obtained according to the same procedure as Preparation Example 2-1, except for using 2,3-dihydro-1H-inden-5-ol instead of 4-(benzyloxy)phenol.

[0122] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.10 (1H, d, J=8.0 Hz), 6.93 (1H, s), 6.83 (1H, d, J=8.0 Hz), 2.79 (4H. t, J=7.0 Hz), 1.99 (2H, p, J=7.0 Hz).

Example 1: N-phenyl-N-(4-methoxyphenoxycarbonyl)-4-methoxyphenylsulfonhydrazide (I-1: MPO-0047)

[0123] The compound (II-2) (0.50 g, 1.80 mmol, 1.0 eq) obtained in Preparation Example 1-2 was dissolved in a small amount of 4-methoxyphenyl chloroformate (0.34 g, 2.17 mmol, 1.2 eq). To the resulting solution was added TEA (0.180 ml, 1.29 mmol, 1.2 eq) and the resulting mixture was stirred under reflux at 50 C. for 0.5 hr. And then, the mixture was extracted with ethyl acetate and distilled water, and the distilled water was removed from the resulting ethyl acetate solution using anhydrous magnesium sulfate. The ethyl acetate solvent was removed using a rotary evaporator. And then, the resulting residue was purified using a flash column chromatography with a mixed solvent of ethyl acetate and n-hexane (1:3) and then recrystallized with diethylether and n-hexane to give the title compound as a white solid (I-1) (0.2260 g, 0.527 mmol, 49%).

[0124] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.90-7.88 (2H, m), 7.28-7.21 (2H, m), 7.01-6.93 (5H, m), 6.86-6.74 (4H, m), 3.90 (3H, s), 3.78 (3H, s).

Example 2: N-phenyl-N-(4-methylphenoxycarbonyl)-4-methylphenylsulfonhydrazide (I-2: MPO-0048)

[0125] The title compound as a white solid (I-2) (63%) was obtained according to the same procedure as Example 1, using the compound (II-1) obtained in Preparation Example 1-1 and 4-methylphenyl chloroformate.

[0126] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.85-7.81 (2H, m), 7.43 (1H, d, J=8.4 Hz), 7.29-7.22 (3H, m), 7.11 (2H, d, J=8.4 Hz), 6.98 (1H, t, J=7.6 Hz), 6.90-6.87 (2H, m), 6.81-6.79 (2H, m), 6.53 (1H, s), 2.44 (3H, s), 2.30 (3H, s).

Example 3: N-phenyl-N-(2-methoxyphenoxycarbonyl)-4-methylphenylsulfonhydrazide (I-3: MPO-0049)

[0127] The title compound as a white solid (I-3) (48%) was obtained according to the same procedure as Example 1, using the compound (II-1) obtained in Preparation Example 1-1 and 2-methoxyphenyl chloroformate.

[0128] .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.83-7.81 (2H, m), 7.28-7.22 (4H, m), 7.20-7.16 (1H, m), 7.01-6.95 (2H, m), 6.91-6.87 (4H, m), 3.65 (3H, s), 2.43 (3H, s).

Example 4: N-phenyl-N-(4-benzyloxyphenoxycarbonyl)-4-methoxyphenylsulfonhydrazide (I-4: MPO-0050)

[0129] The title compound as a white solid (I-4) (75%) was obtained according to the same procedure as Example 1, using the compound (II-2) obtained in Preparation

Example 1-2 and the Compound (III-1) Obtained in Preparation Example 2-1

[0130] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.16 (1H, s), 7.93 (2H, d, J=8.8 Hz), 7.43-7.19 (9H, m), 7.00-6.98 (2H, m), 6.90-6.85 (3H, m), 6.87 (2H, d, J=8.0 Hz), 5.07 (2H, s), 3.88 (3H, s).

Example 5: N-phenyl-N-(4-ethoxyphenoxycarbonyl)-4-methoxyphenylsulfonhydrazide (I-5: MPO-0051)

[0131] The title compound as a white solid (I-5) (52%) was obtained according to the same procedure as Example 1, using the compound (II-2) obtained in Preparation Example 1-2 and the compound (III-2) obtained in Preparation Example 2-2.

[0132] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.17 (1H, s), 7.93 (2H, d, J=8.8 Hz), 7.27-7.19 (4H, m), 6.91-6.83 (5H, m), 6.78 (2H, d, J=8.0 Hz), 3.98 (2H, q, J=6.8 Hz), 1.29 (3H, t, J=6.8 Hz).

Example 6: N-phenyl-N-(4-phenoxyphenoxycarbonyl)-4-methoxyphenylsulfonhydrazide (I-6: MPO-0052)

[0133] The title compound as a white solid (I-6) (81%) was obtained according to the same procedure as Example 1, using the compound (II-2) obtained in Preparation Example 1-2 and the compound (III-3) obtained in Preparation Example 2-3.

[0134] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.17 (1H, s), 7.94 (2H, d, J=9.2 Hz), 7.39 (2H, t, J=7.2 Hz), 7.27-7.20 (4H, m), 7.15 (1H, t, J=7.2 Hz), 7.00-6.99 (6H, m), 6.85 (1H, t, J=7.2 Hz), 6.80 (2H, t, J=8.0 Hz), 3.88 (3H, s).

Example 7: N-phenyl-N-(4-ethylphenoxycarbonyl)-4-methoxyphenylsulfonhydrazide (I-7: MPO-0053)

[0135] The title compound as a white solid (I-7) (44%) was obtained according to the same procedure as Example 1, using the compound (II-2) obtained in Preparation Example 1-2 and the compound (III-4) obtained in Preparation Example 2-4.

[0136] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.18 (1H, s), 7.94-7.92 (2H, m), 7.27-7.20 (6H, m), 6.88-6.78 (5H, m), 3.89 (3H, s), 2.57 (2H, q, J=7.6 Hz), 1.14 (3H, t, J=7.6 Hz).

Example 8: N-phenyl-N-(4-benzyloxyphenoxycarbonyl)-4-methylphenylsulfonhydrazide (I-8: MPO-0055)

[0137] The title compound as a white solid (I-8) (36%) was obtained according to the same procedure as Example 1, using the compound (II-1) obtained in Preparation Example 1-1 and the compound (III-1) obtained in Preparation Example 2-1.

[0138] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.18 (1H, s), 7.89 (2H, d, J=8.4 Hz), 7.58 (2H, d, J=8.4 Hz), 7.51-7.23 (7H, m), 7.00-6.98 (2H, m), 6.97-6.79 (5H, m), 5.07 (2H, s), 2.44 (3H, s).

Example 9: N-phenyl-N-(2,3-dihydro-1H-inden-5-oxycarbonyl)-4-methoxyphenylsulfonhydrazide (I-9: MPO-0057)

[0139] The title compound (I-9) (10%) was obtained according to the same procedure as Example 1, using the compound (II-2) obtained in Preparation Example 1-2 and the compound (III-5) obtained in Preparation Example 2-5.

[0140] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 9.16 (1H, s), 7.94-7.91 (1H, m), 7.27-7.23 (2H, m), 7.22-7.18 (3H, m), 6.85 (1H, t, J=7.2 Hz), 6.81-6.77 (3H, m), 6.72 (1H, dd, J.sub.1=8.0 Hz, J=2.4 Hz,), 3.89 (3H, s), 2.81 (2H, t, J=7.2 Hz), 2.80 (2H, t, J=7.2 Hz), 2.00 (2H, p, J=7.6 Hz).

Example 10: N-phenyl-N-phenoxycarbonyl-4-chlorophenylsulfonhydrazide (I-10: MPO-0058)

[0141] The title compound (I-10) (76%) was obtained according to the same procedure as Example 1, using the compound (II-4) obtained in Preparation Example 1-4 and phenyl chloroformate.

[0142] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.24 (1H, s), 8.02 (2H, d, J=8.8 Hz), 7.80 (2H, d, J=8.4 Hz), 7.39 (2H, t, J=8 Hz), 7.27 (3H, t, J=8 Hz), 7.00 (2H, d, J=7.6 Hz), 6.88 (1H, q), 6.82 (2H, d, J=7.6 Hz).

Example 11: N-phenyl-N-(2-methoxyphenoxycarbonyl)-4-chlorophenylsulfonhydrazide (I-11: MPO-0059)

[0143] The title compound (I-11) (92%) was obtained according to the same procedure as Example 1, using the compound (II-4) obtained in Preparation Example 1-4 and 2-methoxyphenyl chloroformate.

[0144] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.30 (1H, s), 7.99 (2H, d, J=8.8 Hz), 7.79 (2H, d, J=8.8 Hz), 7.29-7.21 (3H, m), 7.08 (1H, t, J=8 Hz), 7.01 (1H, q, J=8 Hz), 6.94-6.83 (4H, m), 3.61 (3H, s).

Example 12: N-phenyl-N-(4-ethylphenoxycarbonyl)-4-chlorophenylsulfonhydrazide (I-12: MPO-0060)

[0145] The title compound (I-12) (75%) was obtained according to the same procedure as Example 1, using the compound (II-4) obtained in Preparation Example 1-4 and the compound (III-4) obtained in Preparation Example 2-4.

[0146] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.23 (1H, s), 8.01 (2H, d, J=8.8 Hz), 7.79 (2H, d, J=8.8 Hz), 7.26 (2H, t, J=8 Hz), 7.21 (2H, d, J=8.8 Hz), 6.88 (3H, t, J=8.4 Hz), 6.80 (2H, d, J=7.6 Hz), 2.57 (2H, q, J=7.6 Hz), 1.13 (3H, t, J=7.6 Hz).

Example 13: N-phenyl-N-(4-ethoxyphenoxycarbonyl)-4-chlorophenylsulfonhydrazide (I-13: MPO-0061)

[0147] The title compound (I-13) (78%) was obtained according to the same procedure as Example 1, using the compound (II-4) obtained in Preparation Example 1-4 and the compound (III-2) obtained in Preparation Example 2-2.

[0148] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.21 (1H, s), 8.01 (2H, d, J=8.4 Hz), 7.79 (2H, d, J=8.8 Hz), 7.26 (2H, t, J=8.0 Hz), 6.87 (5H, m), 6.81 (2H, d, J=8 Hz), 6.80 (2H, d, J=8.0 Hz), 2.57 (2H, q), 1.29 (3H, t, J=6.8 Hz).

Example 14: N-phenyl-N-(4-phenoxyphenoxycarbonyl)-4-chlorophenylsulfonhydrazide (I-14: MPO-0062)

[0149] The title compound (I-14) (75%) was obtained according to the same procedure as Example 1, using the compound (II-4) obtained in Preparation Example 1-4 and the compound (III-3) obtained in Preparation Example 2-3.

[0150] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.23 (1H, s), 8.03-8.00 (2H, m), 7.82-7.79 (2H, m), 7.41-7.37 (2H, m), 7.27 (2H, t, J=7.6 Hz), 7.15 (1H, t, J=7.6 Hz), 7.06-6.97 (6H, m), 6.89-6.81 (3H, m).

Example 15: N-phenyl-N-(4-benzyloxyphenoxycarbonyl)-4-chlorophenylsulfonhydrazide (I-15: MPO-0063)

[0151] The title compound (I-15) (54%) was obtained according to the same procedure as Example 1, using the compound (II-4) obtained in Preparation Example 1-4 and the compound (III-1) obtained in Preparation Example 2-1.

[0152] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.22 (1H, s), 8.11 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.4 Hz), 7.43-7.25 (7H, m), 7.01-6.98 (2H, m), 6.93-6.85 (3H, m), 6.82-6.80 (2H, d, J=8.4 Hz), 5.07 (2H, s).

Example 16: N-phenyl-N-(4-phenoxyphenoxycarbonyl)-2-mesitylenesulfonhydrazide (I-16: MPO-0064)

[0153] The title compound (I-16) (56%) was obtained according to the same procedure as Example 1, using the compound (II-6) obtained in Preparation Example 1-6 and the compound (III-3) obtained in Preparation Example 2-3.

[0154] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.03 (1H, s), 7.38 (2H, t, J=6.8 Hz), 7.28 (2H, t, J=8.4 Hz), 7.14 (3H, t, J=7.6 Hz), 6.99-6.95 (6H, m), 6.88-6.85 (3H, m), 2.61 (6H, s), 2.30 (3H, s).

Example 17: N-phenyl-N-(4-benzyloxyphenoxycarbonyl)-2-mesitylenesulfonhydrazide (I-17: MPO-0065)

[0155] The title compound (I-17) (56%) was obtained according to the same procedure as Example 1, using the compound (II-6) obtained in Preparation Example 1-6 and the compound (III-1) obtained in Preparation Example 2-1.

[0156] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.00 (1H, s), 7.42-7.26 (7H, m), 7.14 (2H, s), 6.96 (2H, d, J=8.8 Hz), 6.86 (1H, t, J=7.2 Hz), 6.74 (2H, d, J=7.2 Hz), 5.05 (2H, s), 2.60 (6H, s), 2.30 (3H, s).

Example 18: N-phenyl-N-(4-phenoxyphenoxycarbonyl)-biphenyl-4-sulfonhydrazide (I-18: MPO-0066)

[0157] The title compound (I-18) (56%) was obtained according to the same procedure as Example 1, using the compound (II-7) obtained in Preparation Example 1-7 and the compound (III-3) obtained in Preparation Example 2-3.

[0158] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.28 (1H, s), 8.09 (2H, d, J=8.8 Hz), 8.01 (2H, d, J=8.8 Hz), 7.79 (2H, d, J=8 Hz), 7.55 (2H, t, J=6.4 Hz), 7.52-7.46 (1H, m), 7.37 (2H, t, J=8 Hz), 7.27 (2H, t, J=8 Hz), 7.14 (1H, t, J=7.2 Hz), 7.04-6.98 (6H, m), 6.89-6.85 (3H, m).

Example 19: N-phenyl-N-(4-benzyloxyphenoxycarbonyl)-biphenyl-4-sulfonhydrazide (I-19: MPO-0067)

[0159] The title compound (I-19) (56%) was obtained according to the same procedure as Example 1, using the compound (II-7) obtained in Preparation Example 1-7 and the compound (III-1) obtained in Preparation Example 2-1.

[0160] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.26 (1H, s), 8.08 (2H, d, J=6.8 Hz), 8.00 (2H, d, J=6.8 Hz), 7.81-7.79 (2H, m), 7.57-7.53 (2H, m), 7.50-7.48 (1H, m), 7.43-7.25 (7H, m), 7.00-6.97 (2H, m), 6.92-6.83 (5H, m), 5.06 (2H, s).

Example 20: N-phenyl-N-(4-phenoxyphenoxycarbonyl)-4-n-propylphenylsulfonhydrazide (I-20: MPO-0068)

[0161] The title compound (I-20) (56%) was obtained according to the same procedure as Example 1, using the compound (II-8) obtained in Preparation Example 1-8 and the compound (III-3) obtained in Preparation Example 2-3.

[0162] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.04 (1H, s), 7.40-7.36 (2H, m), 7.30-7.26 (2H, m), 7.17-7.12 (3H, m), 7.00-6.95 (6H, m), 6.89-6.85 (3H, m), 2.62 (6H, s), 2.31 (3H, s).

Example 21: N-phenyl-N-(4-benzyloxyphenoxycarbonyl)-4-trifluoromethylphenylsulfonhydrazide (I-21: MPO-0078)

[0163] The title compound (I-21) (56%) was obtained according to the same procedure as Example 1, using the compound (II-5) obtained in Preparation Example 1-5 and the compound (III-1) obtained in Preparation Example 2-1.

[0164] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.25 (1H, s), 8.24 (2H, d, J=8.0 Hz), 8.11 (2H, d, J=8.0 Hz), 7.43-7.31 (5H, m), 7.30-7.25 (2H, m), 7.00-6.97 (2H, m), 6.94-6.82 (7H, m), 5.07 (2H, s), 3.51 (1H, s).

Example 22: N-phenyl-N-(4-benzyloxyphenoxycarbonyl)-4-t-butylphenylsulfonhydrazide (I-22: MPO-0081)

[0165] The title compound (I-22) (78%) was obtained according to the same procedure as Example 1, using the compound (II-9) obtained in Preparation Example 1-9 and the compound (III-1) obtained in Preparation Example 2-1.

[0166] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 7.93 (2H, d, J=2.0 Hz), 7.73 (2H, d, J=1.6 Hz), 7.40 (4H, m), 7.34 (1H, t, J=2.0 Hz), 7.25 (2H, m), 6.97 (2H, m), 6.83 (5H, m), 5.07 (2H, s), 1.33 (9H, s).

Example 23: N-phenyl-N-(4-phenoxyphenoxycarbonyl)-4-t-butylphenylsulfonhydrazide (I-23: MPO-0084)

[0167] The title compound (I-23) (33%) was obtained according to the same procedure as Example 1, using the compound (II-9) obtained in Preparation Example 1-9 and the compound (III-3) obtained in Preparation Example 2-3.

[0168] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.21 (1H, s), 7.95 (2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.4 Hz), 7.39 (2H, t, J=7.6 Hz), 7.26 (2H, t, J=7.6 Hz), 7.15 (1H, t, J=7.2 Hz), 6.98 (6H, m), 6.83 (3H, m), 1.33 (9H, s).

Example 24: N-phenyl-N-(4-phenoxyphenoxycarbonyl)-4-i-propylphenylsulfonhydrazide (I-24: MPO-0085)

[0169] The title compound (I-24) (45%) was obtained according to the same procedure as Example 1, using the compound (II-10) obtained in Preparation Example 1-10 and the compound (III-3) obtained in Preparation Example 2-3.

[0170] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.20 (1H, s), 7.94 (2H, d, J=8.4 Hz), 7.58 (2H, d, J=8.4 Hz), 7.40 (2H, d, J=2.4 Hz), 7.38 (2H, t, J=7.6 Hz), 7.25 (1H, t, J=7.2 Hz), 6.98 (6H, m), 6.83 (3H, m), 3.30 (1H, m) 1.24 (6H, d, J=6.8 Hz).

Example 25: N-phenyl-N-(2,3-dihydro-1H-inden-5-oxycarbonyl)-4-methylphenylsulfonhydrazide (I-25: MPO-0086)

[0171] The title compound (I-25) (43%) was obtained according to the same procedure as Example 1, using the compound (II-1) obtained in Preparation Example 1-1 and the compound (III-5) obtained in Preparation Example 2-5.

[0172] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.19 (1H, s), 7.88 (2H, d, J=8.4 Hz), 7.50 (2H, d, J=8.4 Hz), 7.25 (2H, t, J=8.0 Hz), 7.18 (1H, d, J=8.4 Hz), 6.85 (1H, t, J=7.2 Hz), 6.79 (3H, d, J=7.6 Hz), 6.65 (1H, dd, J=8.0 and 2.4 Hz), 2.80 (4H, t, J=7.6 Hz), 2.50 (3H, m), 1.99 (2H, p. J=2 Hz).

Example 26: N-phenyl-N-(2,3-dihydro-1H-inden-5-oxycarbonyl)-4-chlorophenylsulfonhydrazide (I-26: MPO-0087)

[0173] The title compound (I-26) (57%) was obtained according to the same procedure as Example 1, using the compound (II-4) obtained in Preparation Example 1-4 and the compound (III-5) obtained in Preparation Example 2-5.

[0174] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.23 (1H, s), 8.01 (2H, dt, J=9.2 and 2.8 Hz), 7.80 (2H, dt, J=9.2 and 2.4 Hz), 7.26 (2H, t, J=8 Hz), 7.19 (1H, d, J=8 Hz), 6.88-6.80 (4H, m), 6.69 (1H, dd, J=8.0 and 2.4 Hz), 2.83-2.78 (4H, m), 2.04-1.63 (2H, m).

Example 27: N-phenyl-N-(2,3-dihydro-1H-inden-5-oxycarbonyl)-4-trifluorophenylsulfonhydrazide (I-27: MPO-0088)

[0175] The title compound (I-27) (23%) was obtained according to the same procedure as Example 1, using the compound (II-5) obtained in Preparation Example 1-5 and the compound (III-5) obtained in Preparation Example 2-5.

[0176] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.26 (1H, s), 8.23 (2H, d, J=8.4 Hz), 8.12 (2H, d, J=8.4 Hz), 7.27 (2H, t, J=7.8 Hz), 7.19 (1H, d, J=8.4 Hz), 6.89-6.81 (4H, m), 6.70 (1H, dd, J=8, 2 Hz), 2.80 (4H, t, J=7.6 Hz), 1.99 (2H, p, J=7.6 Hz).

Example 28: N-phenyl-N-(2,3-dihydro-1H-inden-5-oxycarbonyl)-2-mesitylenesulfonhydrazide (I-28: MPO-0089)

[0177] The title compound (I-28) (48%) was obtained according to the same procedure as Example 1, using the compound (II-6) obtained in Preparation Example 1-6 and the compound (III-5) obtained in Preparation Example 2-5.

[0178] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.01 (1H, s), 7.28 (2H, t, J=7.6 Hz), 7.14 (3H, s), 6.96 (2H, d, J=7.6 Hz), 6.86 (1H, t, J=7.2 Hz), 6.45 (1H, s), 6.52 (1H, d, J=7.2 Hz), 2.78 (4H, t, J=6.8 Hz), 2.60 (6H, s), 2.30 (3H, s), 1.98 (2H, p, J=6.8 Hz).

Comparative Example 1: N-phenyl-N-(phenoxycarbonyl)-phenylsulfonhydrazide (1: MPO-0046)

[0179] The compound (II-3) (0.450 g, 1.81 mmol, 1.0 eq) obtained in Preparation Example 1-3 was dissolved in phenyl chloroformate. To the resulting solution was added TEA (0.455 ml, 3.27 mmol, 1.8 eq) and the resulting mixture was stirred under reflux at 50 C. for 0.5 hr. And then, the mixture was extracted with ethyl acetate and distilled water, and the distilled water was removed from the resulting ethyl acetate solvent using anhydrous magnesium sulfate. The ethyl acetate solvent was removed using a rotary evaporator. And then, the resulting residue was recrystallized with methanol and solidified using n-hexane to give the title compound (1) as a white solid (0.560 g, 1.52 mmol, 82%).

[0180] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.25 (1H, s), 8.02 (2H, t, J=8 Hz), 7.82 (1H, t, J=7.6 Hz), 7.70 (2H, t, J=8.4 Hz), 7.38 (2H, t, J=6.4 Hz), 7.26 (3H, t, J=8 Hz), 6.94 (2H, d, J=7.6 Hz), 6.84 (3H, m)

Experiment Example 1: Inhibitory Activity on PGE2 Production

[0181] Raw264.7 cells (macrophage cell line from mouse) were obtained from Korean Cell Line Bank (KCLB) and cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% Fetal Bovine Serum (FBS), penicillin (100 units/mL), streptomycin sulfate (100 g/mL) at 37 C. and 5% CO.sub.2 in humidified environment. RAW264.7 cells at 510.sup.5 cells/mL were seeded at 1 mL/well in 24 wells using DMEM, left overnight, replaced with a fresh medium and then treated with a test compound of an appropriate concentration. The cells were incubated for 1 hr and then treated with LPS at 1 g/mL and incubated for 24 hrs (or proper period). A supernatant was taken and diluted five times. 150 L of an analysis buffer was added to Non Specific Binding (NSB) well, and 100 L of an analysis buffer was added to zero point standard (B0) well. 100 L of a standard sample was added to the other wells and 50 L of PGE.sub.2 conjugate was added (excluding NSB). 50 L of PGE.sub.2 antibody solution was added and wells were shaken for 2 hrs. Each well was suctioned and washed with a wash buffer five times. Each 200 L of para-Nitrophenyl phosphate (pNPP) substrate was added to the all wells and the wells were stored in a bench at room temperature for 1 hr. 50 L of stop solution was added and an absorbance was measured at 405 nm. The amount of PGE.sub.2 was quantified using the measured absorbance and a standard curve and compared to a group treated with LPS only to obtain a concentration inhibiting 50% (IC.sub.50). The results are shown in the following Table 1 and the presented values are means of three measurements.

TABLE-US-00001 TABLE 1 Inhibition of PGE.sub.2 Cell production Substituent viability % IC.sub.50 R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 (M) (M).sup.a (nM) Example 1 H MeO H H H MeO >10 85.6 (1).sup. 490 Example 2 H Me H H H Me >10 49.7 (1).sup. 1010 Example 3 H Me H MeO H H >0.1 91.9 (0.1) 34.05 Example 4 H MeO H H H BnO >1 62.8 (0.1) 50.00 Example 5 H MeO H H H EtO >0.1 94.1 (0.1) 20.52 Example 6 H MeO H H H PhO >0.1 93.4 (0.1) 17.06 Example 7 H MeO H H H Et >0.1 90.9 (0.1) 28.49 Example 8 H Me H H H BnO >0.1 66.6 (0.1) 32.62 Example 9 H MeO H H CH.sub.2CH.sub.2CH.sub.2 >0.1 79.5 (0.01) 4.50 Example 10 H Cl H H H H >10 81.8 (0.01) 5.42 Example 11 H Cl H MeO H H >10 85.9 (0.01) 3.52 Example 12 H Cl H H H Et >10 80.5 (0.01) 3.70 Example 13 H Cl H H H EtO >10 74.8 (0.01) 5.02 Example 14 H Cl H H H PhO >10 67.8 (0.01) 5.09 Example 15 H Cl H H H BnO >10 84.5 (0.01) 3.42 Example 16 Me Me Me H H PhO >1 39.8 (0.1) 176.92 Example 17 Me Me Me H H BnO >1 60.0 (0.1) 81.51 Example 18 H Ph H H H PhO >1 39.3 (0.1) 160.71 Example 19 H Ph H H H BnO >1 68.1 (0.1) 93.04 Example 20 H n-Pr H H H PhO >10 45.4 (0.1) 133.83 Example 21 H CF.sub.3 H H H BnO >0.1 65.5 (0.1) 47.10 Example 22 H t-Bu H H H BnO >0.1 69.8 (0.1) 56.89 Example 23 H t-Bu H H H PhO >1 67.9 (0.1) 99.60 Example 24 H i-Pr H H H PhO >1 65.4 (0.1) 130.30 Example 25 H Me H H CH.sub.2CH.sub.2CH.sub.2 >1 40.4 (0.1) 66.72 Example 26 H Cl H H CH.sub.2CH.sub.2CH.sub.2 >1 45.8 (0.1) 70.46 Example 27 H CF.sub.3 H H CH.sub.2CH.sub.2CH.sub.2 >1 51.1 (0.1) 55.77 Example 28 Me Me Me H CH.sub.2CH.sub.2CH.sub.2 >1 57.2 (0.1) 58.58 Comparative H H H H H H >10 84.4 (10) 5700 Example 1 .sup.aInhibition of PGE.sub.2 production (%) when treated with the concentration in parentheses

[0182] As shown in Table 1, N-phenyl-N-phenoxycarbonyl-phenylsulfonhydrazide compounds according to the present invention have IC.sub.50 of 3.42 to 1010 nM showing an excellent inhibitory activity on PGE.sub.2 production compared to the compound of Comparative Example 1 with IC.sub.50 of 5,700 nM.

Experiment Example 2: Measurement of Cell Viability

[0183] Raw264.7 cells (macrophage cell line from mouse) were obtained from Korean Cell Line Bank (KCLB) and cultured in Dulbecco's modified Eagle's medium containing 10% FBS, penicillin (100 units/ml), streptomycin sulfate (100 g/ml) at 37 C. and 5% CO.sub.2 in humidified environment.

[0184] Cells were collected by centrifugation and scraping, and seeded at 110.sup.5 cells/well in a 96 well plate containing 100 l of RPMI 1640 medium with 10% FBS. 3, 4-epoxy-8-isobutyryloxyguaia-1(10), 11, (13)-diene-12.6-olide was dissolved in dimethylsulfoxide (DMSO) solvent and the concentration of DMSO was not more than 0.1% in all experiments. Next day, test compounds and LPS (1 g/mL) were added and the plate were cultured for 24 hrs. After washing cells once, 50 l of the medium containing 5 mg/ml MTT but without FBS was added and cells were cultured at 37 C. for 4 hrs. And then, the medium was removed, formazan blue formed in the cells was dissolved in 100 l of DMSO, and an absorbance was measured at 540 nm to obtain IC.sub.50 values for cell toxicity. IC.sub.50 means a concentration exhibiting 50% reduction of cell number compared to no treatment with a compound. The results are shown in the above Table 1 and the values are means of three measurements.