KR20180105987A - N-Benzyl-N-phenoxycarbonyl-phenylsulfonamide Derivatives and Pharmaceutical Composition Comprising the Same - Google Patents

Abstract

The present invention relates to N-benzyl-N-phenoxycarbonyl-phenylsulfonamide derivatives having excellent activity to inhibit PGE2 production through inhibition of microcrystalline prostaglandin E2 synthetase-1 (mPGES-1), a manufacturing method thereof and a pharmaceutical composition containing the same as an active ingredient. The N-benzyl-N-phenoxycarbonyl-phenylsulfonamide derivatives of the present invention can be effectively used for treatment or prevention of brain diseases such as inflammation, arthritis, high fever, pain, cancer, stroke or Alzheimer′s disease.

Description

N-benzyl-N-phenoxycarbonyl-phenylsulfonamide derivatives and pharmaceutical compositions containing the same.

The present invention is N-benzyl-N-phenoxycarbonyl-phenyl sulfonamide derivatives, to a method of manufacturing and pharmaceutical compositions containing them, more particularly microsomal prostaglandin E synthase ₂ -1 (microsomal prostaglandin E synthase N -benzyl- N -phenoxycarbonyl-phenylsulfonamide derivatives which block the production of PGE _{2 as} an inflammatory factor through inhibition of mPGES-1: ≪ / RTI >

Prostanoid (prostanoid) is an endocrine substances involved in various physiological action, prostaglandin E _2, one of which (prostaglandin E _2: PGE ₂₎ is known to be involved in inflammation.

COX-2 inhibitors that selectively inhibit only cyclooxygenase-2 (COX-2) enzymes have been developed as therapeutic agents against such inflammation. Representative COX-2 inhibitors include Pfizer's Celecox Celecoxib (Celebrex ^TM ), J. D. Syeolsa (GD Searle & Company) of valdecoxib (valdecoxib; Bextra ^TM) and rofecoxib of Merck (Merck): and the like (rofecoxib Vioxx ^TM). They have been used extensively in arthritis, severe pain, rheumatism and the like.

However, COX-2 inhibitors have been withdrawn from the pharmaceutical market, except for celecoxib, due to cardiovascular side effects, despite reducing gastrointestinal disturbances, the most serious side effects of nonsteroidal anti-inflammatory analgesics (NSAIDs). These cardiovascular side effects have been reported to be due to the inhibition of the production of PGE ₂ (prostacyclin) and TXA ₂ (thromboxane) as well as PGE ₂ by inhibiting the production of intermediate PGH ₂ (prostaglandin H ₂ ).

Thus, by acting on the end stage of the PGH ₂ microsomal prostaglandin E synthase ₂ -1 (microsomal prostaglandin E synthase-1 : mPGES-1) involved in the production of PGE ₂ inhibitor which selectively inhibits the COX-2 inhibitor is of The researchers are currently studying mPGES-1 as a new drug candidate that complements the disadvantages of taking advantage.

In particular, mPGES-1 inhibition has been shown to be as effective as treatment with non-steroidal anti-inflammatory analgesics in pain and inflammatory animal model studies and is effective in treating brain diseases such as inflammation, arthritis, high fever, pain, cancer, stroke, Alzheimer's disease Is expected.

Korean Patent No. 10-1680455 discloses N -phenyl- N' -phenoxycarbonyl-phenylsulfone hydrazide derivatives of formula (I) as inhibitors of mPGES-1. However, there is a problem in that the compound of formula (I) is converted into another regio-isomer having a weak activity when it is stored for a long time in the preparation and solution state [EB Park, KJ Kim, HR Jeong, JK Lee, HJ Kim, HH Lee, JW Lim, J.-S. Shin, A. Koeberle, O. Werz, K.-T. Lee, JY Lee Bioorg . Med . Chem. Lett . 26 (2016), p.5193].

There is also an additional problem of slightly inhibiting the human cytochrome P450 (CYP) enzyme involved in the metabolism of toxic substances in the liver. Therefore, there is a need for the development of selective inhibitors of the novel mPGES-1 of the new skeleton that overcome these drawbacks.

(I)

Korean Patent No. 10-1680455

 E. B. Park, K. J. Kim, H. R. Jeong, J. K. Lee, H.J. Kim, H.H. Lee, J.W. Lim, J.-S. Shin, A. Koeberle, O. Werz, K.-T. Lee, J. Y. Lee Bioorg. Med. Chem. Lett. 26 (2016), p.5193.

It is an object of the present invention to provide an N -benzyl- N -phenoxycarbonyl-phenylsulfonamide derivative of the general formula (II), or a pharmaceutically acceptable salt thereof, which strongly inhibits the production of PGE ₂ .

Another object of the present invention is to provide a process for preparing an N -benzyl- N -phenoxycarbonyl-phenylsulfonamide derivative of the general formula (II) or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical composition for the inhibition of mPGES-1 comprising an N -benzyl- N -phenoxycarbonyl-phenylsulfonamide derivative of the general formula (II) or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention relates to an N -benzyl- N -phenoxycarbonyl-phenylsulfonamide derivative of the general formula (II): or a pharmaceutically acceptable salt thereof.

≪ RTI ID = 0.0 &

In this formula,

R ¹ is hydrogen, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group,

R ² is hydrogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a nitro, a C ₁ -C ₆ haloalkyl group or an aryl group,

R < ¹ > and R < ² > together with the carbon atoms to which they are attached form a 4- to 7-membered hydrocarbon ring or a heterohydrocarbon ring,

R ³ is hydrogen, a C ₁ -C ₆ alkyl group, a halogen, a nitro or a C ₁ -C ₆ alkoxy group,

R ⁴ is hydrogen, a C ₁ -C ₆ alkyl group, a halogen, a nitro or a C ₁ -C ₆ alkoxy group,

R ⁵ is hydrogen, a C ₁ -C ₆ alkyl group, a halogen, a nitro or a C ₁ -C ₆ alkoxy group,

R ⁶ is hydrogen, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group,

R ⁷ is hydrogen, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group,

R ⁸ is hydrogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or an aryloxy group,

R < ⁷ > and R < ⁸ > together with the carbon atoms to which they are attached form a 4- to 7-membered hydrocarbon ring or a heterohydrocarbon ring.

As used herein, a C ₁ -C ₆ alkyl group means a linear or branched hydrocarbon group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, Butyl, t-butyl, and the like.

As used herein, the C ₁ -C ₆ alkoxy group means a straight or branched alkoxy group having 1 to 6 carbon atoms, and includes, but is not limited to, methoxy, ethoxy, n-propaneoxy, and the like.

As used herein, a C ₁ -C ₆ haloalkyl group means a straight or branched hydrocarbon of 1 to 6 carbon atoms substituted with at least one halogen selected from the group consisting of fluorine, chlorine, bromine and iodine, But are not limited to, trifluoromethyl, trichloromethyl, and the like.

As used herein, an aryl group includes both an aromatic group and a heteroaromatic group and a partially reduced derivative thereof. The arromatic group is a simple or fused ring of 5 to 15 members, and the heteroaromatic group means an aromatic group containing at least one of oxygen, sulfur or nitrogen. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, pyridinyl, furanyl, thiophenyl, indolyl, quinolinyl, But are not limited to, imidazolinyl, oxazolyl, thiazolyl, tetrahydronaphthyl, and the like.

As used herein, the term " 4- to 7-membered hydrocarbon ring " means a 4- to 7-membered hydrocarbon ring including, but not limited to, cyclobutane, cyclopentane, cyclohexane and the like.

As used herein, the term " 4- to 7-membered heterohydrocarbon ring " means a functional group in which at least one of the ring carbon atoms of the 4- to 7-membered hydrocarbon ring is substituted with oxygen, sulfur or nitrogen, and examples thereof include oxolane, And the like, but are not limited thereto.

In the present specification, an aryloxy group means an oxygen functional group mono-bonded to an aryl group, and includes, but is not limited to, phenoxy, benzyloxy, and the like.

The C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkoxy group, the C ₁ -C ₆ haloalkyl group, the aryl group, the 4 to 7-membered hydrocarbon ring, the 4 to 7-membered heterohydrocarbon ring and the aryloxy group Or more hydrogen is replaced by a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, a C ₃ -C ₁₀ cycloalkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ thioalkoxy group of -C ₆ alkoxy group, C ₁ -C _6, the group of aryl, acyl, hydroxy, thio (thio), halogen, amino, alkoxycarbonyl, carboxy, carbamoyl, cyano, nitro And the like.

In one embodiment of the present invention, the N -benzyl- N -phenoxycarbonyl-phenylsulfonamide derivative is N-

R < ¹ > is hydrogen,

R ² is hydrogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen or a nitro group,

R ¹ and R ² together with the carbon atom to which they are attached form a 4- to 7-membered heterohydrocarbon ring,

R < ³ > is hydrogen or halogen,

R ⁴ is hydrogen or a C ₁ -C ₆ alkyl group,

R ⁵ is hydrogen, nitro or a C ₁ -C ₆ alkoxy group,

R ⁶ is an alkoxy group of hydrogen or C ₁ -C _6,

R < ⁷ > is hydrogen,

R ⁸ is hydrogen or an aryloxy group,

R < ⁷ > and R < ⁸ > together with the carbon atoms to which they are attached form a 4- to 7-membered hydrocarbon ring.

In one embodiment of the present invention, the N -benzyl- N -phenoxycarbonyl-phenylsulfonamide derivative is N-

R < ¹ > is hydrogen,

R ² is hydrogen, i-propyl, t-butyl, methoxy, chloro or nitro,

R < ¹ > and R < ² > together with the carbon atoms to which they are attached form a pentagonal oxoolefin,

R < ³ > is hydrogen or chloro,

R < ⁴ > is hydrogen or methyl,

R < ⁵ > is hydrogen, nitro or methoxy,

R < ⁶ > is hydrogen or methoxy,

R < ⁷ > is hydrogen,

R < ⁸ > is hydrogen, phenoxy or benzyloxy,

R < ⁷ > and R < ⁸ > together with the carbon atoms to which they are attached form a pentagonal hydrocarbon ring.

Pharmaceutically acceptable salts herein include both non-toxic inorganic acid salts and organic acid salts and include, for example, hydrochloride, sulfate, nitrate, phosphate, acetate, adipate, aspartate, benzoate, benzenesulfonate A salt of at least one compound selected from the group consisting of an acid salt, a citrate, a camphorate, a camphorsulfonate, a diphosphate, an ethanesulfonate, a fumerate, a glutamate, a maleate, a lactate, Acid salts, polycarboxylates, tosylate salts, and the like.

Representative compounds among the compounds of the present invention are selected from the following groups.

N - (2- chlorobenzyl) - N - (4- benzyloxy-phenoxycarbonyl) phenyl-4-chloro-sulfonamide (II-1);

N -benzyl- N- (4-phenoxyphenoxycarbonyl) -4- t -butylphenylsulfonamide (II-2);

N -benzyl- N- (4-phenoxyphenoxycarbonyl) -4- i -propylphenylsulfonamide (II-3);

N -benzyl- N- (2,3-dihydro- 1H -indene-5-oxycarbonyl) -4-chlorophenylsulfonamide (II-4);

N -benzyl- N- (4-benzyloxyphenoxycarbonyl) - (2,3-dihydrobenzofuran-5-yl) sulfonamide (II-5);

N - (3- methylbenzyl) - N - (4- phenoxy phenoxycarbonyl) - (2,3-dihydro-benzofuran-5-yl) sulfonamide (II-6);

N - (2- chlorobenzyl) - N - (4- benzyloxy-phenoxycarbonyl) - (2,3-dihydro-benzofuran-5-yl) sulfonamide (II-7);

N -Benzyl- N- (4-phenoxyphenoxycarbonyl) - (2,3-dihydrobenzofuran-5-yl) sulfonamide (II-8);

N - (3- methylbenzyl) - N - (4- benzyloxy-phenoxycarbonyl) - (2,3-dihydro-benzofuran-5-yl) sulfonamide (II-9);

N -benzyl- N- (2,3-dihydro- 1H -indene-5-oxycarbonyl) - (2,3-dihydrobenzofuran-5-yl) sulfonamide (II-10);

N - (2- chlorobenzyl) - N - (2,3-dihydro -1 H-inden-5-butyloxycarbonyl) - (2,3-dihydro-benzofuran-5-yl) sulfonamide (II- 11);

N - benzyl - N - (2,3- dihydro -1 H - inden-5-oxy-carbonyl) -4-methoxy phenyl sulfonamide (II-12);

N -benzyl- N- (2-methoxyphenoxycarbonyl) -4-chlorophenylsulfonamide (II-13);

N - (benzyl-4-nitro) - N - (4-benzyloxy-phenoxycarbonyl) -4-methoxy phenyl sulfonamide (II-14);

N - (benzyl-4-nitro) - N - (4-phenoxy phenoxycarbonyl) -4-methoxy phenyl sulfonamide (II-15);

N - (benzyl-4-nitro) - N - (2,3- dihydro -1 H - inden-5-oxy-carbonyl) -4-methoxy phenyl sulfonamide (II-16);

N - (2- chlorobenzyl) - N - (4- phenoxy phenoxycarbonyl) - (2,3-dihydro-benzofuran-5-yl) sulfonamide (II-17);

N - (3- methylbenzyl) - N - (2,3-dihydro -1 H-inden-5-butyloxycarbonyl) - (2,3-dihydro-benzofuran-5-yl) sulfonamide (II- 18);

N - (4- methoxybenzyl) - N - (4- phenoxy phenoxycarbonyl) -4-chlorophenyl sulfonamide (II-19);

N - (4- methoxybenzyl) - N - (2,3- dihydro -1 H - inden-5-oxy-carbonyl) -4-chlorophenyl sulfonamide (II-20);

N -benzyl- N- (4-benzyloxyphenoxycarbonyl) -4-chlorophenylsulfonamide (II-21);

N - (4-nitro-benzyl) - N - (4-phenoxy phenoxycarbonyl) -4-chlorophenyl sulfonamide (II-22);

N - (benzyl-4-nitro) - N - (4-benzyloxy-phenoxycarbonyl) phenyl-4-chloro-sulfonamide (II-23);

N - (benzyl-4-nitro) - N - (4-benzyloxy-phenoxycarbonyl) -phenyl-sulfonamide (II-24);

N - (4- methoxybenzyl) - N - (4- benzyloxy-phenoxycarbonyl) phenyl-sulfonamide (II-25) 4-nitro; And

N - (benzyl-4-nitro) - N - (4-benzyloxy-phenoxycarbonyl) phenyl-sulfonamide (II-26) 4-nitro.

On the other hand, the present invention relates to a process for the preparation of the N -benzyl- N -phenoxycarbonyl-phenylsulfonamide derivative of formula II, which comprises the step of reacting a compound of formula III:

(III)

(IV)

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined in Formula II.

In one embodiment of the present invention, the compound of formula (III) and the compound of formula (IV) are reacted in the presence of a base.

As the base, triethylamine (TEA), pyridine, N, N -diisopropylethylamine and the like can be used, and triethylamine is preferably used.

The reaction may be carried out in the absence of a separate reaction solvent, or using tetrahydrofuran (THF), 1,4-dioxane, diethyl ether or the like as a reaction solvent. The reaction temperature is preferably room temperature.

The compound of formula (III) and the compound of formula (IV) are commercially available or can be easily prepared by known methods.

Specifically, the compound of formula (III) may be prepared by reacting a compound of formula (V) with a compound of formula (VI).

(V)

(VI)

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in Formula II above.

The reaction can be carried out in the presence of a base. Examples of the base include triethylamine (TEA), pyridine, N , N -diisopropylethylamine and the like, preferably triethylamine.

As the reaction solvent, tetrahydrofuran (THF), 1,4-dioxane, diethyl ether and the like can be used, and the reaction temperature is preferably room temperature.

The compound of formula (IV) may be prepared by reacting a compound of formula (VII) with a triphosgene of formula (VIII):

(VII)

(VIII)

Wherein R ⁶ , R ^7, and R ⁸ are as defined in Formula II above.

The reaction can be carried out in the presence of a base, and the base include triethylamine (TEA), pyridine, N, N - is the may be used diisopropylethylamine (DIPEA), etc., preferably N, N - Diisopropylethylamine is used.

As the reaction solvent, tetrahydrofuran (THF), 1,4-dioxane, diethyl ether and the like can be used, and the reaction temperature is preferably 0 to 10 ° C.

The compound of formula (II) or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent PGE ₂ production inhibitory activity through inhibition of microsomal prostaglandin E ₂ synthetase-1 (mPGES-1) (see Test Example 2) .

In addition, the compound of formula (II) or a pharmaceutically acceptable salt thereof according to the present invention exhibits an efficacy of suppressing foot-edema and ear-edema in an animal model experiment (see Test Example 3).

In addition, the compound of formula (II) or a pharmaceutically acceptable salt thereof according to the present invention exhibits an effect of improving memory in an animal model experiment (see Test Example 4).

Accordingly, the present invention relates to a pharmaceutical composition for inhibiting microsomal prostaglandin E ₂ synthetase-1 (mPGES-1) comprising the compound of formula (II) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, Relates to a pharmaceutical composition for the treatment or prevention of brain diseases such as inflammation, arthritis, high fever, pain, cancer, stroke or Alzheimer's disease.

The pharmaceutical composition according to the present invention may be administered orally (e.g., by taking or inhalation) or parenterally (e.g., by injection, sedation, implantation, suppository), and the injection may be, for example, , Subcutaneous injection, intramuscular injection or intraperitoneal injection. The pharmaceutical composition according to the present invention may be formulated into tablets, capsules, granules, fine subtilae, powders, sublingual tablets, suppositories, ointments, injections, emulsions, suspensions, syrups, Can be formulated. The various forms of the pharmaceutical composition according to the present invention can be prepared by a known technique using a pharmaceutically acceptable carrier commonly used in each formulation. Examples of pharmaceutically acceptable carriers are excipients such as excipients, binders, disintegrating agents, lubricants, preservatives, antioxidants, isotonic agents, buffers, encapsulating agents, sweeteners, solubilizers, bases, , Suspending agents, stabilizers, coloring agents and the like.

The pharmaceutical composition according to the present invention varies depending on the form of the medicament, but it includes about 0.01 to 95% by weight of the compound of the present invention or a pharmaceutically acceptable salt thereof.

The specific dosage of the pharmaceutical composition of the present invention may vary depending on the kind of mammal including the person to be treated, body weight, sex, degree of disease, judgment of a doctor, and the like. Preferably, 0.01 to 50 mg of active ingredient per kilogram of body weight per day is administered per day for oral administration, and 0.01 to 10 mg of active ingredient per kilogram of body weight per day for parenteral administration. The total daily dose may be administered once or several times depending on the severity of the disease, the judgment of the physician, and the like.

The compounds of the present invention are excellent in stability in the course of preparation and storage and can be used as a microsomal prostaglandin E ₂ synthetase-1 (mPGES-1) without inhibiting the enzyme of human cytochrome P450 (CYP) ) exhibit excellent inhibitory activity through inhibiting PGE ₂ generation. In addition, the compounds of the present invention exhibit efficacy and cognitive potency in suppressing edema in animal model experiments. Accordingly, the compounds of the present invention can be effectively used in pharmaceutical compositions for the treatment or prevention of brain diseases such as inflammation, arthritis, high fever, pain, cancer, stroke or Alzheimer's disease.

1A shows the results of inhibition of foot edema of the compound (MPO-0112) of Example 21 of the present invention.
Fig. 1B shows the experimental results of inhibition of ear edema of the compound (MPO-0112) of Example 21 of the present invention.
FIG. 2 shows the effect of the compound (MPO-0112) of Example 21 of the present invention on the decline of memory power in the passive avoidance experiment.
3 shows the mPGES-1 inhibition experiment result of the compound (MPO-0112) of Example 21 of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are for illustrative purpose only and that the scope of the present invention is not limited to these embodiments.

Manufacturing example  1: III ≪ / RTI >

Manufacturing example  1-1: N -(2- Chlorobenzyl )-4- Chlorophenylsulfonamide ( III -One)

2-Chlorobenzylamine (0.30 g, 2.15 mmol, 1.0 eq) was dissolved in a tetrahydrofuran solvent at room temperature, and then 4-chlorophenylsulfonyl chloride (0.50 g, 2.37 mmol, 1.1 eq) and triethylamine TEA) (0.30 ml, 2.80 mmol, 1.3 eq) at 0 < 0 > C and then stirred for 2 hours at room temperature. After completion of the reaction, the tetrahydrofuran solvent was removed using a rotary evaporator, and the mixture was extracted with ethyl acetate and distilled water. The residual distilled water was removed from ethyl acetate using anhydrous magnesium sulfate, and the residue was purified by using a rotary evaporator To remove the ethyl acetate solvent. Recrystallization from dichloromethane and n-hexane gave the title compound (III-1) (0.56 g, 1.78 mmol, 83%) as a white solid.

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 8.38 (1H, s), 7.79 (2H, d, J = 8.4 Hz), 7.65 (2 H, d, J = 8.8 Hz), 7.41-7.37 (2H, m), 7.30-7.26 (2H, m), 4.08 (1H, s).

Manufacturing example  1-2: N -Benzyl-4- t - Butyl phenyl sulfonamide ( III -2)

The procedure of Production Example 1-1 was repeated except that benzylamine was used instead of 2-chlorobenzylamine and 4- t -butylphenylsulfonyl chloride was used instead of 4-chlorophenylsulfonylchloride to obtain the title compound (III-2) (50%).

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 8.11 (1H, s), 7.72-7.70 (2H, d, J = 8.4 Hz), 7.59-7.57 (2 H, d, J = 8.4 Hz) , 7.28-7.21 (5 H, m), 3.97 (2 H, s), 1.31 (9 H, s).

Manufacturing example  1-3: N -Benzyl-4- i - Propyl phenyl sulfonamide ( III -3)

The procedure of Production Example 1-1 was repeated except that benzylamine was used instead of 2-chlorobenzylamine and 4- i -propylphenylsulfonylchloride was used instead of 4-chlorophenylsulfonylchloride to obtain the title compound (III-3) (80%).

^{1 H NMR (400 MHz, DMSO-} d 6) δ: 8.11 (1H, t, J = 6.4 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.43 (2H, d, J = 8.4 Hz), 7.24 (5H, m), 3.97 (2H, d, J = 6.4 Hz), 2.97 (1H, q, J = 7.2 Hz), 1.21 (6H, d, J = 7.2 Hz).

Manufacturing example  1-4: N -Benzyl-4- Chlorophenylsulfonamide ( III -4)

(III-4) (75%) was obtained in the same manner as in PREPARATION 1-1, except that benzylamine was used in place of 2-chlorobenzylamine.

^{1 H-NMR (400 MHz,} CDCl 3) δ: 7.81 (2H, d, J = 6.8 Hz), 7.50 (2H, d, J = 8.8 Hz), 7.32-7.28 (3H, m), 7.21 (2H, d, J = 7.6, Hz), 4.69 (1H, s), 4.186 (2H, d, J = 6.4 Hz).

Manufacturing example  1-5: N -Benzyl- (2,3- Dihydrobenzofuran -5 days) Sulfonamide ( III -5)

Was prepared in the same manner as in Preparation Example 1 (1), except that benzylamine was used instead of 2-chlorobenzylamine and (2,3-dihydrobenzofuran-5-yl) sulfonyl chloride was used in place of 4-chlorophenylsulfonylchloride. (85%) of the title compound (III-5).

^{1 H-NMR (400 MHz,} DMSO-d 6) δ: 7.94 (1H, t, J = 6.4 Hz), 7.61 (1H, s), 7.56 (1H, d, J = 8.4 Hz), 7.48-7.21 ( 5H, m), 6.90 (1H , d, J = 8.4 Hz), 4.64 (2H, t, J = 8.8 Hz), 3.93 (2H, d, J = 6.4 Hz), 3.23 (2H, t, J = 8.8 Hz).

Manufacturing example  1-6: N - (3- Methylbenzyl ) - (2,3- Dihydrobenzofuran -5 days) Sulfonamay De ( III -6)

Except that 3-methylbenzylamine was used instead of 2-chlorobenzylamine and (2,3-dihydrobenzofuran-5-yl) sulfonyl chloride was used instead of 4-chlorophenylsulfonyl chloride. (97%) of the title compound (III-6) was obtained in the same manner as in PREPARATION 1-1.

^{1 H-NMR (400 MHz,} CDCl 3) δ: 7.55 (2H, s), 7.05 (1H, t, J = 7.6 Hz), 6.94 (1H, d, J = 7.6 Hz), 6.89 (2H, s) , 6.70 (1H, d, J = 8.8 Hz), 4.57 (2H, t, J = 9.2 Hz), 3.96 (2H, d, J = 5.6 Hz), 3.12 (2H, t, J = 8.8 Hz), 2.18 (3H, s).

Manufacturing example  1-7: N -(2- Chlorobenzyl ) - (2,3- Dihydrobenzofuran -5 days) Sulfonamay De ( III -7)

(III-7) was obtained in the same manner as in PREPARATION 1-1, except that (2,3-dihydrobenzofuran-5-yl) sulfonyl chloride was used in place of 4-chlorophenylsulfonyl chloride. (80%).

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 8.03 (1H, t, J = 6.0 Hz), 7.63 (1H, s), 7.57 (1H, d, J = 8.0 Hz), 7.44-7.42 ( 1H, m), 7.39-7.37 (1H , m), 7.32-7.25 (2H, m), 6.90 (1H, d, J = 8.4 Hz), 4.63 (2H, t, J = 8.8 Hz), 4.02 (2H , d, J = 6.4 Hz), 3.23 (2H, t, J = 8.8 Hz).

Manufacturing example  1-8: N -Benzyl-4- Methoxyphenylsulfonamide ( III -8)

In the same manner as in PREPARATION 1-1, except that benzylamine was used instead of 2-chlorobenzylamine and 4-methoxyphenylsulfonyl chloride was used instead of 4-chlorophenylsulfonylchloride, the title compound ( III-8) (90%).

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 7.98 (1H, s), 7.73 (2H, d, J = 9.2 Hz), 7.30-7.26 (2H, m), 7.09 (2H, d, J = 8.8 Hz), 3.92 (2H, s), 3.83 (3H, s).

Manufacturing example  1-9: N -(4- Nitrobenzyl )-4- Methoxyphenylsulfonamide ( III -9)

The procedure of Production Example 1-1 was repeated except that 4-nitrobenzylamine was used instead of 2-chlorobenzylamine and 4-methoxyphenylsulfonyl chloride was used instead of 4-chlorophenylsulfonylchloride To give the title compound (III-9) (93%).

^{1 H-NMR (400 MHz,} CDCl 3) δ: 8.23 (1H, t, J = 6.4 Hz), 8.15 (2H, d, J = 8.8 Hz), 7.73-7.70 (2H, m), 7.52 (2H, d, J = 8.8Hz), 7.10-7.07 (2H, m), 4.10 (2H, d, J = 6.4Hz), 3.82 (3H, s).

Manufacturing example  1-10: N - (4-methoxybenzyl) -4- Chlorophenylsulfonamide ( III -10)

(89%) of the title compound (III-10) was obtained in the same manner as in PREPARATION 1-1, except that 4-methoxybenzylamine was used instead of 2-chlorobenzylamine.

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 8.19 (1H, s), 7.75 (2H, d, J = 8.8 Hz), 7.62 (2H, d, J = 8.8 Hz), 7.11 (2H, d, J = 8.8 Hz), 6.81 (2H, d, J = 6.4 Hz), 3.92 (2H, s), 3.71 (3H, s).

Manufacturing example  1-11: N -(4- Nitrobenzyl )-4- Chlorophenylsulfonamide ( III -11)

The title compound (III-11) (69%) was obtained in the same manner as in PREPARATION 1-1, except that 4-nitrobenzylamine was used instead of 2-chlorobenzylamine.

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 8.79 (1H, s), 8.15 (2H, d, J = 7.2 Hz), 7.79 (2H, d, J = 8.8 Hz), 7.65 (2H, d, J = 8.8Hz), 7.51 (2H, d, J = 8.8Hz), 4.09 (2H, s).

Manufacturing example  1-12: N -(4- Nitrobenzyl ) - Phenyl sulfonamide ( III -12)

According to the same manner as in PREPARATION 1-1, except that 4-nitrobenzylamine was used instead of 2-chlorobenzylamine and benzenesulfonyl chloride was used instead of 4-chlorophenylsulfonylchloride, the title compound ( III-12) (86%).

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 8.40 (1 H, s), 8.15 (2 H, d, J = 8.8 Hz), 7.80 (2 H, d, J = 8.4 Hz), 7.66 -7.56 (3 H, m), 7.53 (2 H, d, J = 8.8 Hz), 4.15 (2 H, d, s).

Manufacturing example  1-13: N - (4-methoxybenzyl) -4- Nitrophenylsulfonamide ( III -13)

The procedure of Production Example 1-1 was repeated except that 4-methoxybenzylamine was used instead of 2-chlorobenzylamine and 4-nitrophenylsulfonyl chloride was used instead of 4-chlorophenylsulfonylchloride To give the title compound (III-13) (90%).

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 8.48 (1H, t, J = 6.4 Hz), 8.35 (2H, d, J = 8.8 Hz), 7.97 (2 H, d, J = 8.8 Hz ), 7.10 (2H, d, J = 8.8 Hz), 6.79 (2H, d, J = 8.8 Hz), 3.99 (2H, d, J = 6.4 Hz), 3.69 (3H, s).

Manufacturing example  1-14: N -(4- Nitrobenzyl )-4- Nitrophenylsulfonamide ( III -14)

The procedure of Preparation Example 1-1 was repeated except that 4-nitrobenzylamine was used instead of 2-chlorobenzylamine and 4-nitrophenylsulfonyl chloride was used instead of 4-chlorophenylsulfonylchloride To give the title compound (III-14) (93%).

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 8.79 (1H, s), 8.38 (2H, d, J = 8.8 Hz), 8.15 (2H, d, J = 8.8 Hz), 8.02 (2H, d, J = 8.8 Hz), 7.51 (2H, d, J = 8.8 Hz), 4.24 (2H, s).

Manufacturing example  2: IV ≪ / RTI >

Manufacturing example  2-1: 4- ( Benzyloxy ) Phenyl Chloroformate ( IV -One)

(2.00 g, 7.99 mmol, 0.8 eq) was dissolved in anhydrous THF solvent under anhydrous conditions and then 4- (benzyloxy) phenol (2.00 g, 9.99 mmol, 1.0 eq) was dissolved in anhydrous THF solvent and diisopropylethylamine (DIPEA) (1.74 ml, 9.99 mmol, 1.0 eq) was slowly added and stirred at 0 ° C for 16 h. Thereafter, the mixture was extracted with ethyl acetate and distilled water. The extracted ethyl acetate solution was treated with anhydrous magnesium sulfate to remove the remaining distilled water, and the ethyl acetate solvent was removed using a rotary evaporator to obtain the title compound as a white solid IV-1) (2.667 g, 10.15 mmol, > 99%).

¹ H-NMR (400 MHz, CDCl ₃ )?: 7.46-7.34 (5 H, m), 7.18-7.13 (2 H, m), 7.02-6.68 (2 H, m).

Manufacturing example  2-2: 4- ( Phenoxy ) Phenyl Chloroformate ( IV -2)

The title compound (IV-2) (99%) was obtained in the same manner as in Production Example 2-1, except that 4-phenoxyphenol was used instead of 4- (benzyloxy) phenol.

¹ H-NMR (400 MHz, CDCl ₃ )?: 7.41-7.36 (2 H, m), 7.22-7.15 (3 H, m), 7.06-7.03 (4 H, m).

Manufacturing example  2-3: 2,3- Dihydro -One H - Inden -5 days Chloroformate ( IV -3)

(IV-3) (98) was obtained in the same manner as in Production Example 2-1, except that 2,3-dihydro- 1H -inden-5-ol was used instead of 4- (benzyloxy) %).

^{1 H-NMR (400 MHz,} CDCl 3) δ:. 7.10 (1 H, d, J = 8.0 Hz), 6.93 (1H, s), 6.83 (1H, d, J = 8.0 Hz), 2.79 (4H t , J = 7.0Hz), 1.99 (2H, p, J = 7.0Hz).

Example  One: N -(2- Chlorobenzyl ) - N -(4- Benzyloxyphenoxycarbonyl ) -4-chlorophenylsulfonamide ( II -One: MPO -0120)

Compound (IV-1) (0.61 g, 2.32 mmol, 1.5 eq) obtained in Preparative Example 2-1 was added to the compound (III-1) (0.49 g, 1.55 mmol, 1.0 eq) After dissolution, TEA (0.28 ml, 2.01 mmol, 1.3 eq) was added and stirred at ambient temperature for 2 hours. Thereafter, the mixture was extracted with ethyl acetate and distilled water. The extracted ethyl acetate solution was treated with anhydrous magnesium sulfate to remove the remaining distilled water, and then the ethyl acetate solvent was removed using a rotary evaporator. Subsequently, recrystallization using dichloromethane and n-hexane gave the title compound (II-1) as a white solid (0.50 g, 0.93 mmol, 60%).

^{1 H-NMR (400 MHz,} CDCl 3) δ: 7.84 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.39-7.29 (9H, m), 6.93-6.86 ( 4H, m), 5.31 (2H, s), 5.04 (2H, s).

Example  2: N -benzyl- N -(4- Phenoxyphenoxycarbonyl )-4- t -Butyl phenyl sulfonamide ( II -2: MPO -0121)

The title compound (II-2) was obtained as a white solid in the same manner as in Example 1, using the compound (III-2) obtained in Production Example 1-2 and the compound (IV- (17%).

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 7.86-7.84 (2H, d, J = 8.8 Hz), 7.68-7.65 (2H, d, J = 8.8 Hz), 7.44-7.34 (7H, m ), 7.17-7.137 (1H, t, J = 7.4 Hz), 7.00-6.98 (4H, m), 6.92-6.89 (2H, d, J = 8.8 Hz), 5.21-5.17 (2H, d, J = 16.8 Hz), 1.31 (9H, s).

Example  3: N -benzyl- N -(4- Phenoxyphenoxycarbonyl )-4- i - propyl phenyl sulfonamide ( II -3: MPO -0122)

The title compound (II-3) was obtained as a white solid in the same manner as in Example 1, using the compound (III-3) obtained in Preparation Example 1-3 and the compound (IV- (70%).

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 7.83 (2H, d, J = 8.4 Hz), 7.51 (2H, d, J = 8.8 Hz), 7.42 (4H, d, J = 4.8 Hz) , 7.37 (4H, m), 7.15 (1H, t, J = 7.6 Hz), 6.99 (4H, m), 6.91 (2H, d, J = 6.8 Hz), 5.17 (2H, s), 3.01 (1H, q, J = 6.8 Hz), 1.20 (6H, d, J = 6.8 Hz).

Example  4: N -benzyl- N - (2,3- Dihydro -One H - Inden -5- Oxycarbonyl ) -4-chlorophenylsulfonamide ( II -4: MPO -0123)

(II-4) (84) was obtained in the same manner as in Example 1, using the compound (III-4) obtained in Preparation Example 1-4 and the compound (IV- %).

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 7.91 (2H, d, J = 8.8 Hz), 7.73 (2H, d, J = 8.8 Hz), 7.45-7.40 (4H, m), 7.37- 7.33 (1H, m), 6.80 (1H, s), 6.66 (1H, dd, J = 6.0 and 2.4 Hz), 5.17 (2H, s), 2.80 (4H, d, J = 7.2 Hz), 2.00 (2H , q, J = 7.2 Hz).

Example  5: N -benzyl- N -(4- Benzyloxyphenoxycarbonyl ) - (2,3- Dihydrobenzofuran -5 days) Sulfonamide ( II -5: MPO -0124)

Using the compound (III-5) obtained in Production Example 1-5 and the compound (IV-1) obtained in Production Example 2-1, the title compound (II-5) %).

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 7.67-7.65 (2H, m), 7.44-7.32 (10H, m), 7.00 (2H, d, J = 9.2 Hz), 6.94 (2H, d , J = 8.0 Hz), 6.86 (2H, d, J = 9.2 Hz), 4.68 (2H, d, J = 8.2 Hz), 2.50 (2H, d, J = 8.8 Hz).

Example  6: N - (3- Methylbenzyl ) - N -(4- Phenoxyphenoxycarbonyl ) - (2,3- Dihydrobenzofuran -5 days) Sulfonamide ( II -6: MPO -0125)

The title compound (II-6) was obtained as a white solid in the same manner as in Example 1, using the compound (III-6) obtained in Production Example 1-6 and the compound (IV-2) (14%).

^{1 H-NMR (400 MHz,} CDCl 3) δ: 7.63 (1H, d, J = 8.8 Hz), 7.55 (1H, s), 7.35 (2H, t, J = 7.6 Hz), 7.26 (3H, m) , 7.15 (2H, m), 6.97 (4H, m), 6.91 (2H, m), 7.78 (1H, d, J = 8.8 Hz), 5.16 (2H, s), 4.68 (2H, t, J = 8.8 Hz), 3.20 (2H, t, J = 8.8 Hz), 2.37 (3H, s).

Example  7: N -(2- Chlorobenzyl ) - N -(4- Benzyloxyphenoxycarbonyl ) - (2,3- Dihyde Lt; RTI ID = 0.0 > 5-yl) Sulfonamide ( II -7: MPO -0126)

The title compound (II-7) was obtained as a white solid in the same manner as in Example 1, using the compound (III-7) obtained in Production Example 1-7 and the compound (IV- (13%).

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 7.77-7.74 (2H, m), 7.52-7.32 (9H, m), 6.98 (3H, t, J = 9.9 Hz), 6.90 (2H, d , J = 9.0 Hz), 5.21 (2H, s), 5.07 (2H, s), 4.70 (2H, t, J = 8.8 Hz), 3.25 (2H, t, J = 9.0 Hz).

Example  8: N -benzyl- N -(4- Phenoxyphenoxycarbonyl ) - (2,3- Dihydrobenzofuran -5 days) Sulfonamide ( II -8: MPO -0127)

The title compound (II-8) was obtained as a white solid in the same manner as in Example 1, using the compound (III-5) obtained in Production Example 1-5 and the compound (IV- (22%).

^{1 H-NMR (400 MHz,} CDCl 3) δ: 7.61 (1H, dd, J = 8.8 Hz), 7.54 (1H, s), 7.47 (2H, dd, J = 8.0 Hz), 7.37 (5H, m) , 7.13 (1H, t, J = 7.6 Hz), 7.00 (2H, d, J = 8.8 Hz), 6.96 (2H, d, J = 9.2 Hz), 6.90 (2H, d, J = 6.8 Hz), 6.77 (1H, d, J = 8.4 Hz), 5.20 (2H, s), 4.69 (2H, t, J = 8.8 Hz), 3.19 (2H, t, J = 8.8 Hz).

Example  9: N - (3- Methylbenzyl ) - N -(4- Benzyloxyphenoxycarbonyl ) - (2,3- Dihydro Benzofuran-5-yl) Sulfonamide ( II -9: MPO -0128)

(58%) of the title compound (II-9) was obtained in the same manner as in Example 1, using the compound (III-6) obtained in Production Example 1-6 and the compound (IV- .

^{1 H-NMR (400 MHz,} CDCl 3) δ: 7.52 (1H, dd, J = 8.0 and 2.0 Hz), 7.45 (1H, t, J = 0.8 Hz), 7.41-7.33 (5H, m), 7.28- 7.21 (3H, m), 7.16 (1H, s), 6.91 (2H, d, J = 8.8 Hz), 6.85 (2H, d, J = 9.2 Hz), 6.77 (1H, d, J = 4.0 Hz), 5.15 (2H, s), 5.04 (2H, s), 4.68 (2H, t, J = 8.8 Hz), 3.18 (2H, t, J = 8.8 Hz), 2.27 (3H, s).

Example  10: N -benzyl- N - (2,3- Dihydro -One H - Inden -5- Oxycarbonyl ) - (2,3- die Hydrobenfuran-5-yl) Sulfonamide ( II -10: MPO -0129)

(43%) of the title compound (II-10) was obtained in the same manner as in Example 1, using the compound (III-5) obtained in Preparation Example 1-5 and the compound (IV- .

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 7.94 (1H, t, J = 6.4 Hz), 7.61 (1H, s), 7.56 (1H, d, J = 6.0 Hz), 7.31-7.21 ( 5H, m), 6.90 (1H , d, J = 8.4 Hz), 4.64 (2H, t, J = 8.8 Hz), 3.93 (2H, d, J = 6.4 Hz), 3.34 (1H, s), 3.23 ( 2H, J = 8.8 Hz).

Example  11: N -(2- Chlorobenzyl ) - N - (2,3- Dihydro -1H- Inden -5- Oxycarbo Yl) - (2,3- Dihydrobenzofuran -5 days) Sulfonamide ( II -11: MPO -0130)

(II-11) (47%) was obtained by using the compound (III-7) obtained in Production Example 1-7 and the compound (IV-3) obtained in Production Example 2-3, .

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 7.77-7.78 (2H, m), 7.52-7.37 (4H, m), 7.19 (1H, d, J = 8.0 Hz), 6.82 (1H, s ), 6.6 (1H, dd, J = 8.0 and 2.0 Hz), 5.21 (2H, s), 4.697 (2H, t, J = 8.8 Hz), 3.34 (2H, s), 3.26 (2H, t, J = 8.4 Hz), 2.83-2.78 (4H, m), 2.00 (2H, q, J = 7.6 Hz).

Example  12: N -benzyl- N - (2,3- Dihydro -1H- Inden -5- Oxycarbonyl ) -4-methoxyphenylsulfonamide ( II -12: MPO -0131)

(45%) of the title compound (II-12) was obtained in the same manner as in Example 1, using the compound (III-8) obtained in Production Example 1-8 and the compound (IV- .

^{1 H-NMR (400 MHz,} CDCl 3) δ: 7.72 (2H, d, J = 8.8 Hz), 7.49 (2H, d, J = 6.8 Hz), 7.40-7.35 (3H, m), 7.14 (1H, d, J = 8.4 Hz), 6.89 (2H, d, J = 8.8 Hz), 6.80 (1 H, s), 6.66 (1H, d, J = 7.2 Hz), 5.20 (2H, s), 3.87 (3H , s), 2.89-2.85 (4 H, m), 2.08 (2H, q, J = 7.2 Hz).

Example  13: N -benzyl- N -(2- Methoxyphenoxycarbonyl ) -4-chlorophenylsulfonamide ( II -13: MPO -0132)

The title compound (II-13) (62%) was obtained in the same manner as in Example 1, using the compound (III-4) obtained in Preparation Example 1-4 and 2-methoxyphenyl chloroformate.

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 7.82 (2H, d, J = 8.8 Hz), 7.69 (2H, d, J = 8.8 Hz), 7.43 (4H, d, J = 4.4 Hz) , 7.359 (1H, m), 7.23 (1H, t, J = 7.1 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.00 (1H, d, J = 8.4 Hz), 6.91 (1H, m) , 5.17 (2H, s), 3.54 (3H, s).

Example  14: N -(4- Nitrobenzyl ) - N -(4- Benzyloxyphenoxycarbonyl ) -4-methoxyphenylsulfonamide ( II -14: MPO -0133)

(46%) of the title compound (II-14) was obtained in the same manner as in Example 1, using the compound (III-9) obtained in Production Example 1-9 and the compound (IV- .

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 8.30 (2H, d, J = 8.4 Hz), 7.89 (2H, d, J = 12.0 Hz), 7.67 (2H, d, J = 8.0 Hz) , 7.43-7.30 (5H, m), 7.17 (2H, d, J = 8.0 Hz), 6.98 (2H, d, J = 12.0 Hz), 6.90 (2H, d, J = 8.0 Hz), 5.27 (2H, s), 5.07 (2H, s), 3.87 (3H, s).

Example  15: N -(4- Nitrobenzyl ) - N -(4- Phenoxyphenoxycarbonyl ) -4-methoxyphenylsulfonamide ( II -15: MPO -0134)

(84%) of the title compound (II-15) was obtained in the same manner as in Example 1, using the compound (III-9) obtained in Production Example 1-9 and the compound (IV- .

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 8.31 (2H, d, J = 8.8 Hz), 7.92 (2H, d, J = 9.2 Hz), 7.69 (2H, d, J = 8.8 Hz) , 7.39 (2H, t, J = 8.0 Hz), 7.20-7.13 (3H, m), 7.04-6.98 (6H, m), 5.30 (2H, s), 3.88 (3H, s).

Example  16: N -(4- Nitrobenzyl ) - N - (2,3- Dihydro -One H - Inden -5- Oxycarbo Yl) -4- Methoxyphenylsulfonamide ( II -16: MPO -0135)

(80%) of the title compound (II-16) was obtained in the same manner as in Example 1, using the compound (III-9) obtained in Production Example 1-9 and the compound (IV- .

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 8.31 (2H, d, J = 8.8 Hz), 7.89 (2H, d, J = 8.8 Hz), 7.69 (2H, d, J = 8.8 Hz) , 7.20-7.17 (3H, s), 6.83 (1H, s), 6.6 (1H, dd, J = 6.4 and 2.0 Hz), 5.28 , J = 6.8Hz), 2.00 (2H, q, J = 7.6Hz).

Example  17: N -(2- Chlorobenzyl ) - N -(4- Phenoxyphenoxycarbonyl ) - (2,3- Dihyde Lt; RTI ID = 0.0 > 5-yl) Sulfonamide ( II -17: MPO -0136)

(53%) of the title compound (II-17) was obtained in the same manner as in Example 1, using the compound (III-7) obtained in Production Example 1-7 and the compound (VI- .

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 7.77 (2H, d, J = 11.6 Hz), 7.52 (1H, d, J = 8.0 Hz), 7.46 (2H, d, J = 6.4 Hz) , 7.39 (3H, t, J = 4.4 Hz), 7.15 (1H, t, J = 7.6 Hz), 7.03-6.97 (7H, m), 5.23 (2H, s), 4.70 (2H, t, J = 8.8 Hz), 3.26 (2H, t, J = 8.4 Hz).

Example  18: N - (3- Methylbenzyl ) - N - (2,3- Dihydro -One H - Inden -5- Oxycarbonyl ) - (2,3-di Less idrobenzo Furan-5-yl) Sulfonamide ( II -18: MPO -0137)

(74%) of the title compound (II-18) was obtained in the same manner as in Example 1, using the compound (III-6) obtained in Production Example 1-6 and the compound (IV- .

^{1 H-NMR (400 MHz,} CDCl 3) δ: 7.59 (1H, d, J = 8.8 Hz), 7.52 (1H, s), 7.24 (3H, s), 7.13 (2H, d, J = 7.6 Hz) , 6.79 (1H, s), 6.74 (1H, d, J = 7.6 Hz), 6.64 (1H, d, J = 7.6 Hz), 4.68 (2H, t, J = 9.2 Hz), 3.16 (2H, t, J = 8.8 Hz), 2.87-2.82 (4H, m), 2.34 (3H, s), 2.06 (2H, q, J = 7.6 Hz).

Example  19: N - (4-methoxybenzyl) - N -(4- Phenoxyphenoxycarbonyl ) -4-chlorophenylsulfonamide ( II -19: MPO -0138)

(48%) of the title compound (II-19) was obtained in the same manner as in Example 1, using the compound (III-10) obtained in Preparation Example 1-10 and the compound (IV- .

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 7.90 (2H, d, J = 8.8 Hz), 7.72 (2H, d, J = 8.8 Hz), 7.39 (4H, m), 7.15 (1H, t, J = 7.2 Hz), 6.99 (8H, m), 5.10 (2H, s), 3.77 (3H, s).

Example  20: N - (4-methoxybenzyl) - N - (2,3- Dihydro -One H - Inden -5- Oxycarbo Yl) -4- Chlorophenylsulfonamide ( II -20: MPO -0139)

(63%) of the title compound (II-20) was obtained in the same manner as in Example 1, using the compound (III-10) obtained in Production Example 1-10 and the compound (IV- .

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 7.87 (2H, d, J = 8.8 Hz), 7.71 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.4 Hz) , 7.19 (1H, d, J = 8.0 Hz), 6.98 (2H, d, J = 8.4 Hz), 6.80 (1H, s), 6.66 (1H, dd, J = 6.0 and 2.0 Hz), 5.09 (1H, s), 3.77 (1H, s), 2.80 (4H, t, J = 7.2 Hz), 2.00 (2H, q, J = 7.2 Hz).

Example  21: N -benzyl- N -(4- Benzyloxyphenoxycarbonyl ) -4-chlorophenylsulfonamide ( II -21: MPO -0112)

(73%) of the title compound (II-21) was obtained in the same manner as in Example 1, using the compound (III-4) obtained in Production Example 1-4 and the compound (IV- .

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 7.92 (2H, d, J = 8.8 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.45-7.30 (10H, m), 6.99 ( 2H, d, J = 9.2 Hz), 6.88 (2H, d, J = 9.2 Hz), 5.17 (2H, s), 5.08 (2H, s).

Example  22: N -(4- Nitrobenzyl ) - N -(4- Phenoxyphenoxycarbonyl ) -4-chlorophenylsulfonamide ( II -22: MPO -0140)

(II-22) (70%) was obtained in the same manner as in Example 1, using the compound (III-11) obtained in Production Example 1-11 and the compound (IV- .

^{1 H-NMR (400 MHz,} CDCl 3) δ: 8.26 (2H, d, J = 8.8 Hz), 7.83 (2H, d, J = 8.4 Hz), 7.66 (2H, d, J = 8.8 Hz), 7.50 (2H, d, J = 8.8 Hz), 7.34 (2H, t, J = 8.0 Hz), 7.12 (1H, t, J = 7.4 Hz), 6.99-6.93 (4H, m) J = 5.6 Hz), 5.24 (2H, s).

Example  23: N -(4- Nitrobenzyl ) -N- (4- Benzyloxyphenoxycarbonyl ) -4-chlorophenylsulfonamide ( II -23: MPO -0141)

(II-23) (39%) was obtained in the same manner as in Example 1, using the compound (III-11) obtained in Production Example 1-11 and the compound (IV- .

^{1 H-NMR (400 MHz,} CDCl 3) δ: 8.26 (2H, d, J = 6.8 Hz), 7.82 (2H, dd, J = 7.0 and 1.8 Hz), 7.65 (2H, d, J = 8.8 Hz) , 7.49 (2H, dd, J = 6.8 and 2.0 Hz), 7.39-7.26 (5H, m), 6.90 (2H, d, J = 9.2 Hz), 6.80 (2H, d, J = 8.8 Hz), 5.23 ( 2H, s), 5.02 (2H, s).

Example  24: N -(4- Nitrobenzyl ) -N- (4- Benzyloxyphenoxycarbonyl ) -Phenylsulfonamide ( II -24: MPO -0149)

(13%) of the title compound (II-24) was obtained in the same manner as in Example 1, using the compound (III-12) obtained in Production Example 1-12 and the compound (IV- .

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 8.31 (2 H, d, J = 8.4 Hz), 7.99 (2 H, d, J = 7.6 Hz), 7.81 (1 H, t, J = 7.6 Hz), 7.71-7.66 (4 H , m), 7.48-7.30 (5 H, m), 6.98 (2 H, d, J = 9.2 Hz), 6.86 (2 H, J = 8.8 Hz), 5.32 ( 2 H, s), 5.07 (2 H, s).

Example  25: N - (4-methoxybenzyl) - N -(4- Benzyloxyphenoxycarbonyl ) -4-nitrophenylsulfonamide ( II -25: MPO -0159)

(85%) of the title compound (II-25) was obtained in the same manner as in Example 1, using the compound (III-13) obtained in Production Example 1-13 and the compound (IV- .

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 8.48 (1H, t, J = 6.4 Hz), 8.35 (2H, d, J = 8.8 Hz), 7.97 (2 H, d, J = 8.8 Hz ), 7.10 (2H, d, J = 8.8 Hz), 6.79 (2H, d, J = 8.8 Hz), 3.99 (2H, d, J = 6.4 Hz), 3.69 (3H, s).

Example  26: N -(4- Nitrobenzyl ) - N -(4- Benzyloxyphenoxycarbonyl ) -4-nitrophenylsulfonamide ( II -26: MPO -0162)

(73%) of the title compound (II-26) was obtained in the same manner as in Example 1, using the compound (III-14) obtained in Production Example 1-14 and the compound (IV- .

^{1 H-NMR (400 MHz,} DMSO- d 6) δ: 8.47 (2H, d, J = 8.8 Hz), 8.32 (2H, d, J = 8.8 Hz), 8.26 (2H, d, J = 8.8 Hz) , 7.71 (2H, d, J = 8.4Hz), 7.42-7.30 (5H, m), 7.00-6.93 (4H, m), 5.35 (2H, s), 5.07 (2H, s).

Test Example  1: Measurement of cell viability

Raw264.7 (mouse macrophage line) was purchased from Korean Cell Line Bank (KCLB) and was used in a culture medium containing 10% FBS (Fetal Bovine Serum), penicillin (100 unit / ml) and streptomycin sulfate (100 μg / DMEM medium (Dulbecco ' s modified Eagle ' s medium) at 37 [deg.] C in a humidified environment of 5% CO2. Cells were added to 1 × 10 ⁵ / well in a 96-well plate containing 100 ㎕ RPMI 1640 medium containing, 10% FBS and collected by centrifugation and the scraper. 3 beta, 4 beta-epoxy-8a-isobutyryloxyguania-l (10), 11,13-diene-12,6a- The concentration of DMSO in the test did not exceed 0.1%. After overnight, samples and LPS (1 [mu] g / mL) were added and the plates were incubated for 24 hours. Cells were washed once and then 50 μl of FBS-free medium containing 5 mg / ml of MTT was added. After incubation at 37 ° C. for 4 hours, the medium was removed, and the formazan blue formed in the cells was removed. Was dissolved in 100 μl of DMSO, and the absorbance at 540 nm was measured to determine the cytotoxic effect as an IC ₅₀ value. IC ₅₀ means a concentration at which the number of cells shows a 50% reduction effect compared to when the compound is not treated.

The results are shown in Table 1 below, and the values shown are the average of three times.

Test Example  2: PGE ₂ Production inhibitory activity

Raw264.7 (mouse macrophage line) was purchased from Korean Cell Line Bank (KCLB) and used in DMEM medium containing 10% FBS, penicillin (100 unit / ml) and streptomycin sulfate (100 ㎍ / , 5% CO 2 in a humid environment. RAW264.7 was seeded in 24 wells at a density of 5 × 10 ⁵ cells / mL in DMEM medium by 1 mL, allowed to stand overnight, and then the medium was changed and the drug was treated at a proper concentration. After incubation for 1 hour, LPS was treated with 1 [mu] g / mL and incubated for 24 hours (or the appropriate time). The supernatant was taken and diluted 5-fold. 150 [mu] L of assay buffer was added to NSB (Non Specific Binding) wells, and 100 [mu] L of assay buffer was added to zero standard (BO) wells. To the remaining wells, 100 μL of the standard sample was added and 50 μL of PGE ₂ conjugate was added (excluding NSB). 50 μL of PGE ₂ antibody solution was added and shaken for 2 hours. Each well was aspirated and washed five times with wash buffer. 200 μL of pNPP (para-nitrophenyl phosphate) substrate was added to all wells and incubated for 1 hour at room temperature. Then 50 μL of stop solution was added and absorbance was measured at 405 nm. The amount of PGE ₂ produced was quantified using the measured absorbance value and the standard curve, and the concentration (IC ₅₀ ) that inhibited 50% was obtained as compared with the group treated with only LPS alone.

The results are shown in Table 1, and the values shown are average values of three times.

compound Substituent cell
Survival rate
(μM) PGE ₂ Generation inhibition R ^One R ² R ³ R ⁴ R ⁵ R ⁶ R ⁷ R ⁸ %control
(@ 1 [mu] M) IC ₅₀
( nM ) Example  One
( MPO -0120) H Cl Cl H H H H BnO > 1 84.1 253.92 Example  2
( MPO -0121) H t -Bu H H H H H Pho > 1 83.2 296.46 Example  3
( MPO -0122) H i- Pr H H H H H Pho > 1 77.7 396.67 Example  4
( MPO -0123) H Cl H H H H CH ₂ CH ₂ CH ₂ > 1 66.6 591.38 Example  5
( MPO -0124) CH ₂ CH ₂ O H H H H H BnO > 1 74.7 446.34 Example  6
( MPO -0125) CH ₂ CH ₂ O H Me H H H Pho > 1 82.7 381.24 Example  7
( MPO -0126) CH ₂ CH ₂ O Cl H H H H BnO > 1 83.4 361.42 Example  8
( MPO -0127) CH ₂ CH ₂ O H H H H H Pho > 1 76.5 434.63 Example  9
( MPO -0128) CH ₂ CH ₂ O H Me H H H BnO > 1 92.7 214.51 Example  10
( MPO -0129) CH ₂ CH ₂ O H H H H CH ₂ CH ₂ CH ₂ > 1 66.8 496.74 Example  11
( MPO -0130) CH ₂ CH ₂ O Cl H H H CH ₂ CH ₂ CH ₂ > 1 68.6 522.84 Example  12
( MPO -0131) H MeO H H H H CH ₂ CH ₂ CH ₂ > 1 71.3 530.56 Example  13
( MPO -0132) H Cl H H H MeO H H > 1 63.2 634.88 Example  14
( MPO -0133) H MeO H H NO ₂ H H BnO > 1 93.2 181.46 Example  15
( MPO -0134) H MeO H H NO ₂ H H Pho > 1 88.0 324.54 Example  16
( MPO -0135) H MeO H H NO ₂ H CH ₂ CH ₂ CH ₂ > 1 55.8 852.73 Example  17
( MPO -0136) CH ₂ CH ₂ O Cl H H H H Pho > 1 74.8 499.89 Example  18
( MPO -0137) CH ₂ CH ₂ O H Me H H CH ₂ CH ₂ CH ₂ > 1 64.2 709.68 Example  19
( MPO -0138) H Cl H H MeO H H Pho > 1 80.5 416.50 Example  20
( MPO -0139) H Cl H H MeO H CH ₂ CH ₂ CH ₂ > 1 65.1 634.07 Example  21
( MPO -0112) H Cl H H H H H BnO > 1 74.6 340.69 Example  22
( MPO -0140) H Cl H H NO ₂ H H Pho > 0.1 50.4 (0.1) - Example  23
( MPO -0141) H Cl H H NO ₂ H H BnO > 0.1 78.1 (0.1) - Example  24
( MPO -0149) H H H H NO ₂ H H BnO > 0.1 50.7 (0.1) - Example  25
( MPO -0159) H NO ₂ H H MeO H H BnO > 0.1 54.1 (0.1) - Example  26
( MPO -0162) H NO ₂ H H NO ₂ H H BnO > 0.1 70.8 (0.1) -

As shown in Table 1, the N -benzyl- N -phenoxycarbonyl-phenylsulfonamide derivative according to the present invention showed little cytotoxicity against Raw264.7 (mouse macrophage line) at a concentration of 1 or 0.1 μM. In addition, the compounds according to the invention showed an excellent inhibitory effect of PGE ₂ produced 55.8 to 93.2% of at 1 μM concentration, showed excellent inhibitory effect of PGE ₂ produced 50.4 to 78.1% at 0.1 μM concentration range. In addition, the compounds according to the present invention exhibited potent PGE ₂ production inhibitory activity with IC ₅₀ values ranging from 181.46 to 852.73 nM.

Test Example  3: Foot-edema and ear-edema in animal models edema ) Inhibition experiment

Male SD rats were fed from Orient Bio (Seoul, Korea) at 5 weeks of age (body weight: 160 to 200g) and used in a laboratory for about 7 days. Water and feed were freely taken and the temperature was 23 ± 2 ℃), humidity (50 ± 10%), and light period (12 hours, 07:30 ~ 19:30) were adjusted automatically.

In the case of the foot-edema animal model, the volume of the right hind paw of the rats before the experiment was measured in 7 rats per group, and the compound (MPO-0112) of Example 21 of the present invention was dissolved in DMSO. . In the positive control group, ibuprofen 100 mg / kg was orally administered. One hour after the administration of the drug, 1% carrageenan was prepared as physiological saline and administered to the right hind paw of the rat in a volume of 100 μL, and foot edema was measured after 1, 3 and 5 hours, respectively. The extent of edema was confirmed using a plethysmometer.

The ear-swollen animal model was treated with the compound of Example 21 (MPO-0112) of the present invention in seven mice per group as in the foot-edema model. After 1 hour, 5% croton oil was dissolved in acetone The dissolved solution was applied locally at a volume of 200 μL, and the thickness of both ears was measured after 3 hours. Values of all experimental results are expressed as mean ± standard error. Statistical significance was accepted when * P value <0.05, *** P value <0.001.

The results are shown in Figs. 1A and 1B.

As shown in FIGS. 1A and 1B, MPO-0112-treated group showed a significant decrease compared with the carrageenan or croton oil alone group. In particular, the MPO-0112-treated group showed a foot-edema and ear-edema inhibitory effect almost equivalent to the high dose of ibuprofen (100 mg / kg), which is the control substance, at a low dose of 1 mg / kg.

Test Example  4: Animal model manual avoidance experiment (Efficacy test for memory improvement)

Male ICR mice were given 5 days of age (body weight 26-28 g) from Orient Bio Inc. (Seoul, Korea) and used in a laboratory for about 7 days. Water and feed were freely consumed. ℃), humidity (50 ± 10%), and light period (12 hours, 07:30 ~ 19:30) were adjusted automatically. Each group used 10 mice. The compound (MPO-0112) of Example 21 of the present invention was suspended in 30% cremophor and then orally administered to the prepared experimental animals. Donepezil 5 mg / kg was given in the positive control group and 30% cremophor was administered in the control group. Scopolamine was administered intraperitoneally at a dose of 1 mg / kg 30 minutes after the drug administration. In the negative control group, only scopolamine was administered intraperitoneally at a dose of 1 mg / kg without drug administration. Thirty minutes after administration of scopolamine, the mice were placed in the illuminated bright compartment, allowing the guillotin door to open into the dark compartment after a 10-second seek time. At this time, the mouse which did not enter the dark side within 60 seconds after the opening of the guillotine door led to go into the dark side. After the Gilotin door was opened, the time until the mouse entered the dark side was measured. Once the mouse enters the dark side, the guillotine door closes and an electric shock of 0.5 mA flows through the bottom of the grid for 3 seconds and the mouse remembers this electrical action. This study was performed 24 hours after the learning test. After the mouse had been navigated for 10 seconds, the gilotin door was opened and the latency time (retention time) for all four feet to the dark side was measured up to 300 seconds. The longer the time taken, the better the learning and memory of passive avoidance. Values of all experimental results are expressed as mean ± standard error. The results of the manual avoidance test were statistically analyzed using one way ANOVA. When the significance was recognized, the Student-Newman-Keuls test was used to conduct a significance test at a 95% confidence level or less. Statistical significance was accepted when P value <0.05.

The results are shown in FIG. 2 and Table 2.

Figure 2 shows the improvement effect of MPO-0112 in a scopolamine-induced memory decay model in a passive avoidance experiment.

As can be seen from FIG. 2 and Table 2, retention time was significantly decreased in all experimental groups compared to the control group, indicating that the memory decay model was produced. Further, in the administration of the MPO-0112 group, only the retention time of the group administered scopolamine 39.44 ± 3.5 cho inde whereas 0.3 and 1 mg / kg, respectively 135.8 ± 8.1 (p <0.05) and 97.5 ± 8.6 (p <0.05 in the group ), Respectively.

Based on the useful concentration of the compound according to the present invention obtained from the above experiment, it was confirmed at a concentration of 0.3 mg / kg in the subsequent experiments.

As shown in Table 2, compounds MPO-0121 (Example 2), MPO-0126 (Example 7) and MPO-0134 (Example 15) of the present invention were administered in a scopolamine-induced memory decay model in a passive avoidance experiment (P <0.05), 95.9 ± 15.6 (p <0.05), and 79.1 ± 12 (p <0.05), respectively, at the dose of 0.3 mg / kg compared with the group receiving only scopolamine .

compound Mean ± SEM (unit: second) P value MPO-0112 (Example 21: 0.3 mg / kg) 135.8 ± 8.1 P < 0.05 MPO-0112 (Example 21: 1 mg / kg) 97.5 ± 8.6 P < 0.05 MPO-0121 (Example 2: 0.3 mg / kg) 92.1 ± 18.4 P < 0.05 MPO-0126 (Example 7: 0.3 mg / kg) 95.9 ± 15.6 P < 0.05 MPO-0134 (Example 15: 0.3 mg / kg) 79.1 ± 12 P < 0.05

Test Example  5: mPGES -1 inhibitory activity

A549 Microcytic fraction of human lung cancer cells

A549 human lung cancer cells were cultured in a 5% CO ₂ incubator at 37 ° C using DMEM medium supplemented with 100 units / mL penicillin-streptomycin and 10% FBS. The cells were cultured in a 100-mm ² dish at 1 × 10 ⁶ cells / mL and cultured in a 5% CO ₂ incubator at 37 ° C. for one day. The medium was replaced with 2% FBS DMEM. After 1 hour, 1 ng / mL). After 48 hours of incubation, the cells were washed with PBS and reacted with 2 mL of Trypsin / EDTA for 5 minutes. Cells were separated by addition of 3 mL of DMEM, and the cells were collected by centrifugation at 1,000 rpm for 5 minutes. Lt; / RTI &gt; Prepared cells were resuspended in 1 mL of homogenization buffer (0.1 M potassium phosphoate buffer, pH 7.4, 2.5 mM glutathione, 0.25 M sucrose), incubated on ice for 10 min, sonicated (3 × 20 sec) Minute and 174,000 × g for 1 hour at 4 ° C. The microsomes were fractionated by centrifugation. The microsomal fraction was redissolved in 50 μL of homogenization buffer and protein quantification was performed by the Bradford assay.

mPGES -1 enzyme activity measurement

The compound of Example 21 (MPO-0112), DMSO or MK886 as a positive control was added to a final concentration of 5 μg / 100 μL protein and reaction buffer (0.1 M potassium phosphate buffer, 2.5 mM GSH) mu L, and the cells were incubated on ice for 15 minutes. After the addition of PGH ₂ (20 μM), the reaction was started. Two minutes later, the reaction was terminated by adding 100 μL of stop solution (40 mM FeCl ₂ , 80 mM citric acid). PGE ₂ production was measured using a PGE ₂ ELISA kit.

The mPGES-1 enzyme inhibition experiment result of the compound (MPO-0112) of Example 21 of the present invention is shown in FIG. 3, and the IC ₅₀ value is 7.37 μM.

As shown in FIG. 3, the compound of Example 21 of the present invention (MPO-0112) showed almost the same mPGES-1 enzyme inhibitory activity as the high concentration (5 μM) of the positive control group MK886 at a low concentration of 100 nM.

Test Example  6: CYP450  Active inhibition

(Phenacetin 50 μM, Diclofenac 10 μM, S-mephenytoin 100 μM, Dextromethorphan 5 μM, and Midazolam®) were mixed with human liver microsomes (0.25 mg / ml) and 0.1 M phosphate buffer 2.5 μM) and the compound of Example 21 of the present invention (MPO-0112) were added at concentrations of 0 and 10 μM, respectively, and preincubated at 37 ° C. for 5 minutes. Then, the NADPH generation system solution was added and incubated at 37 ° C. for 15 minutes Respectively. The reaction was terminated by adding an acetonitrile solution containing an internal standard (Terfenadine), centrifuging for 5 minutes (14,000 rpm, 4 ° C) and injecting the supernatant into the LC-MS / Metabolites were simultaneously analyzed to evaluate the ability of MPO-0112 to inhibit drug metabolizing enzymes. The inhibitory potency of each CYP kinase activity by MPO-0112 was expressed as the% activity against the control without the inhibitor.

The results are shown in Table 3 below.

CYP450 Dong Enzyme (% of control activity ) CYP1A2 99.4 CYP2C9 97.0 CYP2C19 56.9 CYP2D6 > 100 CYP3A4 > 100

As shown in Table 3, the compound (MPO-0112) of the present invention shows low inhibitory activity against the drug metabolizing enzyme.

Claims (10)

N -Benzyl- N -phenoxycarbonyl-phenylsulfonamide derivative of the following formula (II): or a pharmaceutically acceptable salt thereof:
&Lt; RTI ID = 0.0 &

In this formula,
R ¹ is hydrogen, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group,
R ² is hydrogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a nitro, a C ₁ -C ₆ haloalkyl group or an aryl group,
R &lt; ¹ &gt; and R &lt; ² &gt; together with the carbon atoms to which they are attached form a 4- to 7-membered hydrocarbon ring or a heterohydrocarbon ring,
R ³ is hydrogen, a C ₁ -C ₆ alkyl group, a halogen, a nitro or a C ₁ -C ₆ alkoxy group,
R ⁴ is hydrogen, a C ₁ -C ₆ alkyl group, a halogen, a nitro or a C ₁ -C ₆ alkoxy group,
R ⁵ is hydrogen, a C ₁ -C ₆ alkyl group, a halogen, a nitro or a C ₁ -C ₆ alkoxy group,
R ⁶ is hydrogen, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group,
R ⁷ is hydrogen, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group,
R ⁸ is hydrogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or an aryloxy group,
R &lt; ⁷ &gt; and R &lt; ⁸ &gt; together with the carbon atoms to which they are attached form a 4- to 7-membered hydrocarbon ring or a heterohydrocarbon ring. The method according to claim 1,
R &lt; ¹ &gt; is hydrogen,
R ² is hydrogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen or a nitro group,
R ¹ and R ² together with the carbon atom to which they are attached form a 4- to 7-membered heterohydrocarbon ring,
R &lt; ³ &gt; is hydrogen or halogen,
R ⁴ is hydrogen or a C ₁ -C ₆ alkyl group,
R ⁵ is hydrogen, nitro or a C ₁ -C ₆ alkoxy group,
R ⁶ is an alkoxy group of hydrogen or C ₁ -C _6,
R &lt; ⁷ &gt; is hydrogen,
R ⁸ is hydrogen or an aryloxy group,
R ⁷ and R ⁸ are N -benzyl- N -phenoxycarbonyl-phenylsulfonamide derivatives or pharmaceutically acceptable salts thereof, which form a 4- to 7-membered hydrocarbon ring together with the carbon atoms to which they are attached. The method according to claim 1,
R &lt; ¹ &gt; is hydrogen,
R ² is hydrogen, i-propyl, t-butyl, methoxy, chloro or nitro,
R &lt; ¹ &gt; and R &lt; ² &gt; together with the carbon atoms to which they are attached form a pentagonal oxoolefin,
R &lt; ³ &gt; is hydrogen or chloro,
R &lt; ⁴ &gt; is hydrogen or methyl,
R &lt; ⁵ &gt; is hydrogen, nitro or methoxy,
R &lt; ⁶ &gt; is hydrogen or methoxy,
R &lt; ⁷ &gt; is hydrogen,
R &lt; ⁸ &gt; is hydrogen, phenoxy or benzyloxy,
R ⁷ and R ⁸ are N -benzyl- N -phenoxycarbonyl-phenylsulfonamide derivatives or pharmaceutically acceptable salts thereof, which form a pentagonal hydrocarbon ring together with the carbon atoms to which they are attached. The N -benzyl- N -phenoxycarbonyl-phenylsulfonamide derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the following compounds:
N - (2- chlorobenzyl) - N - (4- benzyloxy-phenoxycarbonyl) phenyl-4-chloro-sulfonamide (II-1);
N -benzyl- N- (4-phenoxyphenoxycarbonyl) -4- t -butylphenylsulfonamide (II-2);
N -benzyl- N- (4-phenoxyphenoxycarbonyl) -4- i -propylphenylsulfonamide (II-3);
N -benzyl- N- (2,3-dihydro- 1H -indene-5-oxycarbonyl) -4-chlorophenylsulfonamide (II-4);
N -benzyl- N- (4-benzyloxyphenoxycarbonyl) - (2,3-dihydrobenzofuran-5-yl) sulfonamide (II-5);
N - (3- methylbenzyl) - N - (4- phenoxy phenoxycarbonyl) - (2,3-dihydro-benzofuran-5-yl) sulfonamide (II-6);
N - (2- chlorobenzyl) - N - (4- benzyloxy-phenoxycarbonyl) - (2,3-dihydro-benzofuran-5-yl) sulfonamide (II-7);
N -Benzyl- N- (4-phenoxyphenoxycarbonyl) - (2,3-dihydrobenzofuran-5-yl) sulfonamide (II-8);
N - (3- methylbenzyl) - N - (4- benzyloxy-phenoxycarbonyl) - (2,3-dihydro-benzofuran-5-yl) sulfonamide (II-9);
N -benzyl- N- (2,3-dihydro- 1H -indene-5-oxycarbonyl) - (2,3-dihydrobenzofuran-5-yl) sulfonamide (II-10);
N - (2- chlorobenzyl) - N - (2,3-dihydro -1 H-inden-5-butyloxycarbonyl) - (2,3-dihydro-benzofuran-5-yl) sulfonamide (II- 11);
N - benzyl - N - (2,3- dihydro -1 H - inden-5-oxy-carbonyl) -4-methoxy phenyl sulfonamide (II-12);
N -benzyl- N- (2-methoxyphenoxycarbonyl) -4-chlorophenylsulfonamide (II-13);
N - (benzyl-4-nitro) - N - (4-benzyloxy-phenoxycarbonyl) -4-methoxy phenyl sulfonamide (II-14);
N - (benzyl-4-nitro) - N - (4-phenoxy phenoxycarbonyl) -4-methoxy phenyl sulfonamide (II-15);
N - (benzyl-4-nitro) - N - (2,3- dihydro -1 H - inden-5-oxy-carbonyl) -4-methoxy phenyl sulfonamide (II-16);
N - (2- chlorobenzyl) - N - (4- phenoxy phenoxycarbonyl) - (2,3-dihydro-benzofuran-5-yl) sulfonamide (II-17);
N - (3- methylbenzyl) - N - (2,3-dihydro -1 H-inden-5-butyloxycarbonyl) - (2,3-dihydro-benzofuran-5-yl) sulfonamide (II- 18);
N - (4- methoxybenzyl) - N - (4- phenoxy phenoxycarbonyl) -4-chlorophenyl sulfonamide (II-19);
N - (4- methoxybenzyl) - N - (2,3- dihydro -1 H - inden-5-oxy-carbonyl) -4-chlorophenyl sulfonamide (II-20);
N-benzyl-N- (4-benzyloxyphenoxycarbonyl) -4-chlorophenylsulfonamide (II-21);
N - (4-nitro-benzyl) - N - (4-phenoxy phenoxycarbonyl) -4-chlorophenyl sulfonamide (II-22);
N - (benzyl-4-nitro) - N - (4-benzyloxy-phenoxycarbonyl) phenyl-4-chloro-sulfonamide (II-23);
N - (benzyl-4-nitro) - N - (4-benzyloxy-phenoxycarbonyl) -phenyl-sulfonamide (II-24);
N - (4- methoxybenzyl) - N - (4- benzyloxy-phenoxycarbonyl) phenyl-sulfonamide (II-25) 4-nitro; And
N - (benzyl-4-nitro) - N - (4-benzyloxy-phenoxycarbonyl) phenyl-sulfonamide (II-26) 4-nitro. N -benzyl- N -phenoxycarbonyl-phenylsulfonamide derivative of formula (II), comprising the step of reacting a compound of formula (III)
(III)

(IV)

&Lt; RTI ID = 0.0 &

In this formula,
R ¹ is hydrogen, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group,
R ² is hydrogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen, a nitro, a C ₁ -C ₆ haloalkyl group or an aryl group,
R &lt; ¹ &gt; and R &lt; ² &gt; together with the carbon atoms to which they are attached form a 4- to 7-membered hydrocarbon ring or a heterohydrocarbon ring,
R ³ is hydrogen, a C ₁ -C ₆ alkyl group, a halogen, a nitro or a C ₁ -C ₆ alkoxy group,
R ⁴ is hydrogen, a C ₁ -C ₆ alkyl group, a halogen, a nitro or a C ₁ -C ₆ alkoxy group,
R ⁵ is hydrogen, a C ₁ -C ₆ alkyl group, a halogen, a nitro or a C ₁ -C ₆ alkoxy group,
R ⁶ is hydrogen, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group,
R ⁷ is hydrogen, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group,
R ⁸ is hydrogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or an aryloxy group,
R &lt; ⁷ &gt; and R &lt; ⁸ &gt; together with the carbon atoms to which they are attached form a 4- to 7-membered hydrocarbon ring or a heterohydrocarbon ring. 6. The process according to claim 5, wherein the compound of formula (III) and the compound of formula (IV) are reacted in the presence of a base. 7. The process according to claim 6, wherein the base is triethylamine. 6. The process according to claim 5, wherein the reaction is carried out in the absence of a separate reaction solvent. A microcrystalline prostaglandin comprising an N -benzyl- N -phenoxycarbonyl-phenylsulfonamide derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. E ₂ synthetic enzyme-1 (mPGES-1). 10. A pharmaceutical composition according to claim 9 for the treatment or prophylaxis of inflammation, arthritis, hyperthermia, pain, cancer, stroke or Alzheimer's disease.

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