KR101251282B1 - Sulfonamide derivatives to inhibit Prostaglandin E2 production and the pharmaceutical composition comprising the derivatives - Google Patents

Abstract

(1)
상기 식에서,
R은 O, N 또는 S를 포함하는 5원 또는 6원의 헤테로고리 중에서 선택된다.The present invention relates to a sulfonamide derivative of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising the same, and more particularly, to a sulfonamide derivative effectively inhibiting prostaglandin E ₂ synthesis and to an active ingredient It relates to a pharmaceutical composition for preventing or treating allergic diseases, inflammatory diseases, Alzheimer's disease or brain diseases.

(One)
In this formula,
R is selected from 5- or 6-membered heterocycles including O, N or S.

Description

Sulfonamide derivatives to inhibit Prostaglandin E2 production and the pharmaceutical composition comprising the derivatives}

The present invention relates to a sulfonamide derivative and a pharmaceutical composition comprising the same, and more particularly, to a sulfonamide derivative or a pharmaceutically acceptable salt thereof of a heterocyclic compound that inhibits prostaglandin synthesis, and a prostaglandin E ₂ comprising the same as an active ingredient. It is to provide a pharmaceutical composition for the prevention and treatment of diseases involved in the synthesis or metabolism of enzyme inhibitors and prostaglandin E ₂ .

Prostaglandin is a bioactive substance synthesized in vivo. It is widely distributed in organs or body fluids and has a very small amount of physiological activity, abbreviated as PG. In 1930, American gynecologist Klutzlock reported that the human semen has the effect of contracting and relaxing the uterus, and later named it prostaglandin, thinking that the active ingredient came from the prostate gland.

In the 1950s, S. Beristen of Sweden succeeded in extracting and crystallizing PG from sheep's seminal vesicles. In vivo, fatty acids are made from enzymes. Kinds are classified into 8 groups from A to H and have various functions. Groups E and F have a function of contracting the uterus and have been put to practical use in induction of labor and abortion. In addition, there are various physiological effects such as capillary expansion, gastric secretion suppression, bronchial muscle contraction, and relaxation.

The PG compound has 20 carbon atoms and a prosthenic acid having a 5-membered ring in the center of the polymer as a basic skeleton. According to the difference of the five-membered ring, it is classified into A ~ J group and 1 ~ 3 types according to the number of double bonds in two side chains. In living organisms, arachidonic acid liberated from membrane phospholipids is activated by phospholipase A2, which is activated in response to stimulation via receptors such as hormones or neurotransmitters or ischemia or convulsions.

Arachidonic acid is not only PG but also a number of bioactive substances collectively referred to as eicosanoids such as thromboxane (TX), leukotriene (LT) and lipoxin (LX) by a series of enzymatic reactions starting from an oxygenation reaction called arachidonic acid cascade. Is converted to. Synthesis of PG biosynthesizes PGH2 from arachidonic acid via PGG2 via PGH synthase (cyclooxygenase) in all tissues and cells, and also isomerase (PGD, PGE, PGI synthase) and reduction specific to organs or tissues The enzyme (PGF synthase) converts two classes of prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), PGF2α and prostaglandin I2 (prostacyclin).

The synthetic pathway of PG and TX is called cyclooxygenase from the primers, and the synthetic pathway of LT and LX is called lipoxygenase. PGD2, PGE2, PGF2α and PGI2 have cell membrane receptors specific for each, and the PGE receptor has four subtypes of EP1, EP2, EP3, and EP4. These PG receptors are all involved in various physiology and conditions as local hormones that regulate the action of the organs through the adenylate cyclase system, the inositol phospholipid metabolism system, or the Ca2 + mobilization system in the G protein conjugate receptor. After working, PG enters venous blood and is rapidly activated by 15-hydroxy PG dehydrogenase.

PG A, B, C group is a PGE group, PGJ group is a natural degradation product of the PGD group as Δ12-PGJ2, PGA series or PGD2 metabolite, enters the cell, reaches the nucleus and has antitumor effect. PGH synthase is derived from constitutive enzymes and inflammatory substances. There are two kinds of inducible enzymes that inhibit glucocorticoids. This enzymatic activity induction and the free phase of arachidonic acid are considered to be the PG biosynthesis step.

Overproduction of prostaglandins can cause a variety of physiological changes, including inflammation, Alzheimer's disease, high blood pressure, heart attacks, and cancer. Therefore, a substance capable of inhibiting the synthesis of prostaglandins can be developed as a treatment for various diseases associated with prostaglandins.

1 and 2 show the biosynthetic pathway of prostaglandins. The rate limiting step of the prostaglandin biosynthesis pathway is the conversion of arachidonic acid to prostaglandin H ₂ (PGH ₂ ), the first precursor of prostaglandins, which is a cyclooxygenase (COX). Is mediated by an enzyme called. PGH ₂ then biosynthesizes various prostaglandins via PGG ₂ . COX has two types of isoforms, COX-1 and COX-2. COX-1 is present in all cells, while COX-2 is a growth factor, tumorigenic factor, and many other physiological changes. B. It is an enzyme expressed in an inflammatory state.

Since several metabolites, including PGE2 mediated by COX-2, are associated with inflammation, pain, and cancer, COX-2 inhibitors can be used as therapeutic agents for anti-inflammatory, anti-cancer, and selective COX-2 inhibitors. It can also be used for prevention of neurological diseases.

The most well-known compounds of COX-2 inhibitors known to date are celecoxib and refecoxib, which are collectively referred to as Coxibs. However, as their side effects are known recently, the development of new compounds is required.

Also, among the compounds having COX-2 inhibitor activity, compounds having an acyclic central system are known, and stilbene derivatives are also known to have COX inhibitory activity.

The first problem to be solved by the present invention is to provide a sulfonamide derivative having a prostaglandin E ₂ synthesis inhibitory activity and a pharmaceutically acceptable salt thereof.

The second object of the present invention is to provide a prostaglandin E ₂ synthetase inhibitor comprising the sulfonamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

The third problem to be solved by the present invention includes the sulfonamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient, immune diseases such as allergic diseases, viruses, asthma, chronic periodontal disease, chronic obstructive pulmonary disease, chronic Inflammatory diseases such as kidney disease, chronic liver disease, endometriosis, chronic pelvic inflammatory disease, chronic enteritis, tumors caused by inflammation such as Hodgkin's disease, ulcerative colitis, ulcerative duodenitis, and brain diseases such as Alzheimer's disease and Parkinson's disease, and atherosclerosis To provide a pharmaceutical composition for the prevention and treatment of diseases involved in the synthesis or metabolism of prostaglandin E ₂ , such as vascular diseases such as hypertension heart disease.

The present invention provides a sulfonamide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof in order to solve the first technical problem.

(1)

(One)

Where

R is a 5 or 6 membered heterocyclic substituent containing O, N or S.

In the sulfonamide derivative of the formula (1) according to the present invention, R is preferably selected from the following formula (2).

(2)

(2)

In this case, X may be each independently one of the hetero atoms of O, N or S, when X is 2 or more may be the same or different from each other.

In particular, the present invention is more preferably a sulfonamide derivative represented by the following general formula (2).

(1c)

(1c)

The present invention provides a prostaglandin E ₂ synthetase inhibitor, characterized in that the sulfonamide derivative of formula (1) as an active ingredient and a pharmaceutically acceptable carrier.

In another aspect, the present invention, in order to solve the third technical problem, the synthesis or metabolism of prostaglandin E ₂ comprising a sulfonamide derivative of formula (1) as an active ingredient, and comprises a pharmaceutically acceptable carrier Provided is a pharmaceutical composition for preventing or treating a disease associated with the disease, wherein the disease involved in the synthesis or metabolism of prostaglandin E ₂ , for example, allergic diseases, immune diseases such as asthma due to viruses and chronic periodontal disease Inflammatory diseases such as chronic obstructive pulmonary disease, chronic kidney disease, chronic liver disease, endometriosis, chronic pelvic inflammatory disease, chronic enteritis, tumors caused by inflammation such as Hodgkin's disease, ulcerative colitis, ulcerative duodenitis, and Alzheimer's disease, Parkinson's disease It may be one of the same brain diseases as well as vascular diseases such as atherosclerosis and hypertensive heart disease.

The sulfonamide derivatives according to the present invention have an IC ₅₀ value of 0.013 μM, showing an inhibitory effect of at least 30-40 times that of compounds used in the prior art for inhibiting prostaglandin synthesis. Thus Accordingly prostaglandin E it is possible to effectively suppress the _second synthesis, the condition relating to the synthesis or metabolism of prostaglandin E _2, for example, allergic diseases, asthma, etc. caused by virus immune diseases as chronic periodontal disease, chronic obstructive pulmonary Diseases, chronic kidney disease, chronic liver disease, endometriosis, chronic pelvic inflammatory disease, inflammatory diseases such as chronic enteritis, tumors caused by inflammation such as Hodgkin's disease, ulcerative colitis, ulcerative duodenitis, and brain diseases such as Alzheimer's disease and Parkinson's disease. It can be used as a pharmaceutical composition for vascular diseases such as atherosclerosis, hypertensive heart disease.

1 and 2 are schematic diagrams showing the biosynthetic pathway of prostaglandins.
3 is a view showing a docking model of formula (1c) in an active site of Protein Data Bank code 1CX2 (COX-2). Specifically, a model of the state in which the formula (1c) (red) and SC-558 (gray) are overlapped, hydrogen bonds and possible parts are indicated by dotted red lines and solid orange lines, respectively. Key amino acid residues are shown in green. Clarify by showing only active site residues.
FIG. 4 shows compounds (COX-2 mRNA expression in lipopolysaccharide (LPS) induced mouse macrophage RAW264.7 cells examined using reverse transcriptase-polymerase chain reaction (PT-PCR) analysis. It is a figure which shows the inhibitory effect of 1c). RAW264.7 cells (5ｘ105 cells / ml) were incubated for 24 hours and then treated with 1 mg / ml LPS for 5 hours without addition of compound of formula (1c) or with various concentrations of compound of formula (1c) It was. Total RNA was isolated and 1 mg of RNA was used for reverse transcription. CDNA was obtained using polymerase chain reaction using Taq DNA polymerase and specific primers. PCR products were separated by 2% agarose gel electrophoresis, stained with SYBR Gold and observed by UV transilluminator.
5 is an NMR graph of formula (1c) according to the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples and drawings.

The sulfonamide derivatives or pharmaceutically acceptable salts thereof according to the present invention are characterized by the following formula (1).

(1)

(One)

Where

R is selected from 5- or 6-membered heterocyclic substituents including O, N or S.

In the sulfonamide derivative of the formula (1) according to the present invention, R is preferably selected from the following formula (2).

(2)

(2)

In this case, X may be each independently one of the hetero atoms of O, N or S, when X is 2 or more may be the same or different from each other.

According to one embodiment of the present invention, sulfonamide derivatives represented by the following general formula (1c) or pharmaceutically acceptable salts thereof are more preferable for the inhibition of prostaglandin E2.

(1c)

(1c)

The prostaglandin E ₂ synthetase inhibitor according to the present invention is characterized by including the sulfonamide derivative of the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

In addition, the pharmaceutical composition for preventing or treating a disease involved in the synthesis or metabolism of prostaglandin E ₂ according to the present invention comprises a sulfonamide derivative of formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, It is characterized in that it includes a carrier that is acceptable.

According to one embodiment of the invention, the sulfonamide derivatives may be used in pharmaceutical compositions as such or in the form of pharmaceutically acceptable salts. Such salts are not particularly limited as long as they are pharmaceutically acceptable, and for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid , Salts of benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid.

In addition, the pharmaceutical composition according to an embodiment of the present invention may further include a suitable carrier, excipient or diluent commonly used in the preparation of the pharmaceutical composition.

Carriers, excipients or diluents that may be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium Silicates, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The pharmaceutical composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method .

When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants that are commonly used are prepared. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations are prepared by mixing at least one or more excipients, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like. do.

In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Meanwhile, diseases in which the pharmaceutical composition comprising the sulfonamide derivative or the pharmaceutically acceptable salt thereof according to the present invention may be used, that is, diseases related to the synthesis or metabolism of prostaglandin E ₂ may be used, for example, allergic diseases and viruses. Inflammatory diseases such as asthma, chronic periodontal disease, chronic obstructive pulmonary disease, chronic kidney disease, chronic liver disease, endometriosis, chronic pelvic inflammatory disease, chronic enteritis, Hodgkin's disease, ulcerative colitis, ulcers It may be one of the tumors due to inflammation including sexual duodenitis, and may be one of Alzheimer's disease, brain diseases including Parkinson's disease or vascular diseases including atherosclerosis, hypertensive heart disease, but is not limited thereto. no.

Hereinafter, the present invention will be described in more detail through Synthesis Examples and Experimental Examples, which are intended to illustrate the present invention and should not be construed as being limited thereto.

Synthetic example  One

In the above formula, the reaction conditions are as follows.

(a) n -BuLi, THF, rt; aqueous workup ( 5a , E / Z = 2: 1, 68%; 5b , E / Z = 2.1: 1, 65%; 5c , E / Z = 2.2: 1, 75%; 5d , E / Z = 2.3: 1, 70%);

(b) I ₂ , heptane, reflux;

(c) oxone, THF, rt; isolation (2 a , 75%; 2 b , 70%; 2 c , 100%; 2 d , 80%);

(d) LDA, (iodinemethyl) trimethylsilane, THF, -78 ^o C to rt; aqueous workup ( 7a , 42%; 7b , 42%; 7c , 50%; 7d , 51%);

(e) TBAF, THF, reflux;

(f) H ₂ NOSO ₃ H, rt (3 a , 52%; 3 b , 48%; 3 c , 60%; 3 d , 48%)

As shown in the above scheme, the compound according to the present invention was synthesized from commercial 4-methylthiobenzaldehyde. Phosphonium bromide 4a-d and 4-methylthiobenzaldehyde were reacted in the presence of n-butyllithium to obtain a mixture of Chemical Formulas 5a to 5d ( E / Z ratio of about 2: 1). The E / Z mixture of formula 5 is converted to E -isomer when heated with catalytic amount of iodine while refluxing heptane. By oxidizing the SMe substituent of the E -isomer of formula 5 using an aqueous solution of oxone, compounds of formulas 6a to 6d, which are the methylsulfone products according to the present invention, were obtained.

The reaction was then carried out to convert the methylsulfone group to the corresponding sulfonamide group. Treatment of the compounds of formulas 6a-6d with LDA (lithium diisopropylamide) and (iodinemethyl) trimethylsilane results in the formation of compounds of formula 7 which are trimethylsilylethyl sulfone intermediates. The desilylation reaction was carried out with TBAF, and the sulfinate obtained was treated with hydroxylamine-O-sulfonic acid to obtain an appropriate amount of sulfonamide of the formula (1).

Experimental Example  One

(1) biological methods

Cultured Lipopolysaccharide ( LPS Induced mouse macrophage RAW264 Within .7 COX By -2 PGE ₂  Measurement of accumulation:

Prostaglandin E ₂ (PGE ₂ ) production levels were measured by enzyme-immunometric assay, as indicated above. RAW264.7 macrophages were maintained in DMEM filled with penicillin streptomycin and 10% FBS at 37 ^° C. with 5% CO ₂ humidified air. To assess the inhibitory activity of test substances on COX-2, the cells were allowed to attach for 2 hours in the presence of 250 μM aspirin in 96-well culture plates, changed to fresh medium, and further cultured for 22 hours. . The attached cells were washed twice with PBS and then incubated in fresh medium at 1 mg / mL LPS. The test substances were added to each well simultaneously. After an additional 20 hours of incubation, the medium was removed and analyzed by PGE ₂ enzyme immunoassay (EIA). In this assay, 100% activity is defined by the difference in PGE ₂ accumulation in the absence and presence of LPS for 20 hours, from repeated measurements at least three times.

The inhibition (%) is represented by the following formula.

[1- (PGE ₂ levels / handling PGE ₂ levels in the treated control group of the sample;

RAW264 .7 within the cell COX -2 mRNA of Reverse transcription - Polymerase chain reaction RT - PCR ) analysis:

RAW264.7 cells: RAW264.7 cells (5 × 10 ⁶ cells-10 cm dish) were incubated with varying concentrations of test sample with or without LPS (1 μg / ml). After washing twice with PBS, total RNA was isolated from cell pellets using an RNA isolation kit (Missouri, St. Louis, Sigma Chemical, Tri-reagent). The total amount of RNA was measured by absorbance at 260 nm.

1 μg of RNA was reverse transcribed into cDNA using avian myeloblastosis virus (AMV) reverse transcriptase and oligo (dT) ₁₅ primer (US, Wisconsin, Madison, Promega). The PCR sample (50 μL reaction mixture) was prepared in 50 mM KCl, 5 mM MgCl ₂ , 0.16 mM dNTP, 5.0 units of Taq DNA polymerase (US, CA, Valencia, Qiagen), and 10 mM Tris-HCl (pH 8.3). It consists of 20 pmol of sense and antisense primers. The sensing and antisense primers for COX-2 were 5'-GGAGAGACTATCAAGATAGTGATC-3 'and 5'-ATGGTCAGTAGACTTTTACAGCTA-3', respectively. Sense and antisense primers for actin were 5'-TGTGATGGTGGGAATGGGTCAG-3 'and 5'-TTTGATGTCACGCACGATTTCC-3', respectively. The PCR amplification was performed under the following conditions: 94 using an amplifier (GeneAmp PCR Systems 2400; PE Applied Biosystems, USA) ^o for 27 cycles denaturation for 1 hour at C for 15 seconds, annealing at 55 ^o C, 72 for an hour ^o Extension from C. Amplified PCR production was continued on 2% agarose gels and made visible by SYBR gold staining.

(2) molecules modelling  Way

Coordinates for the three-dimensional structure of COX-2 were obtained from the Protein Data Bank (http://www.rcsb.org/pdb/, entry code 1CX2). The 3D structure of compound (1c) was generated using SYBYL 7.0 (Tripos Associates, Saint Louis, MO, USA). The modeled structure of compound (1c) at several different torsion angles for ^three rotatable bonds was minimized by conjugate gradient method with Guesteiger-Hukel charges, and the minimized structure was put into the database. To dock the inhibitor, the protein structure of 1CX2 was minimized by the powell method. The active site is defined as a pocket having a radius of 10.1 mm 3 from the crystallized reference ligand SC-558, and the core subpocket is defined as a pocket having a radius of 2.9 mm 3. Inhibitors were docked using the FlexX suite module with a plurality of ligands in the database. The resulting COX-2-inhibitor complex was ordered according to a drugscore that reflects the energy of interaction between the inhibitor and the active site residue. Also, Flexidock was performed with the flex X- docked coordinates (FlexX -docked coordinates) to the initial position. Each module was implemented 5 times or more in order to confirm the docking result reliably.

(3) Evaluation result

The inhibitory activity in PGE ₂ production in lipopolysaccharide (LPS) induced mouse macrophages RAW264.7 was evaluated for the compounds synthesized in the above examples. As shown in Table 1 below, among the sulfone derivatives synthesized, the compound of formula 6c containing 2-thienyl group showed the most effective inhibitory activity with IC ₅₀ = 0.38 μM. On the other hand, it was found that the effect of sulfonamide derivatives having p -SO ₂ NH ₂ is closely related to the heterocyclic structure. The sulfonamide derivatives of formula 1d containing 3-thienyl groups showed almost the same results as sulfone compound 6d in this analytical evaluation.

In addition, 2-thienyl sulfonamide derivative 1c showed the most effective inhibitory activity with an IC ₅₀ value of 0.013 μM. This potency is at least 30-fold higher than the inhibitory activity of sulfone derivative 6c with similar ring structure. Table 1 below summarizes the results of measuring inhibitory activity of sulfonamide derivatives in PGE ₂ production in lipopolysaccharide (LPS) -induced mouse macrophages RAW264.7.

compound R IC ₅₀ (μM) * Comparative Example (6a) Me 1.18 Comparative Example (6d) Me 0.52 Example (1c)   NH₂ 0.013 Example (1d)   NH₂ 0.44

* IC ₅₀ values were measured by tripliate test.

We conducted molecular modeling experiments on COX-2 interactions with compounds of formula (1c), the most likely derivatives. As shown in FIG. 4, the docking studies of compound (1c) and COX-2 showed that the space positions of sulfonamide groups overlapped with compounds (1c) and SC-558 (a celecoxib analogue), and their benzenesulfonamides The groups show almost overlap. The Ar—SO ₂ NH ₂ group of Compound (1c) interacts with amino acid residues linked to COX-2 binding sites (Gly519, Phe518, Ala516, Gln192, Arg513 and His90). The two oxygen atoms of the Ar—SO ₂ NH ₂ group form two hydrogen bonds with the main chain NHs of His90 and Arg513 (distance = 2.87 kPa). It was also observed that hydrogen bonding is possible between the nitrogen of the SO ₂ NH ₂ group and the backbone carbonyl group at Gln192 (distance = 3.72 kV / Phe518 (distance = 3.84 kV / Leu352 (distance = 4.12 kPa)). It suggests that the ring sulfonamides preferably interact within the COX-2 binding site.

To understand the molecular mechanism that induces inhibition of PGE2 production, the inhibitory effect of compound (1c) on COX-2 mRNA expression was investigated using reverse transcription-polymerase chain reaction (PT-PCR) analysis. Treatment with LPS for 5 hours resulted in a sharp increase in the expression of COX-2 mRNA and inhibition of induction by treatment of compound (1c) in a concentration dependent manner as shown in FIG. 5. Based on these observations, it may be assumed that the inhibitory effect of sulfonamide derivative (1c) on LPS-induced PGE ₂ may be partially correlated with the inhibition of COX-2 mRNA expression. However, since the inhibitory effect of Formula (1c) on COX-2 mRNA expression did not fully reach the IC ₅₀ value of PGE ₂ production, other mechanisms such as direct COX-2 mRNA inhibitory activity would not be excluded. Therefore, inhibition of PGE ₂ production by sulfonamide derivatives according to the present invention in lipopolysaccharide (LPS) induced mouse macrophages RAW264.7 is due to other inhibition of COX-2 expression or direct inhibition of COX-2 enzyme activity. I think it might have been.

These results suggest that, despite the recent attention to cardiovascular side effects caused by vicinal diaryl sulfonamide derivatives aimed at modulating COX-2 activity, it is necessary to explore new templates that reduce cardiovascular side effects. Shows that there is. To identify potential modulators, this study prepared a series of heterocyclic derivatives and evaluated their effects on the production of COX-2-mediated PEG ₂ .

In particular, (E) -4- (2- (thiophen-3-yl) vinyl) benzenesulfonamide represented by formula (1c) according to the present invention has an effective inhibitory activity against the overproduction of PGE ₂ which causes inflammation. It is expected that it may serve as a novel therapeutic for the treatment of diseases mediated by PGs. In addition, the present invention also confirmed the structure-activity relationship of sulfonamide derivatives that are valuable for the research and development of novel inhibitors of PG synthesis.

Claims (10)

Sulfonamide derivatives represented by the following general formula (1) or pharmaceutically acceptable salts thereof:

(One)
In this formula,
R is

,

,

,

. delete The method of claim 1,
Sulfonamide derivatives represented by the following formula (1c) or pharmaceutically acceptable salts thereof:

(1c) delete Involved in the synthesis or metabolism of prostaglandin E ₂ comprising a sulfonamide derivative of formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier As a pharmaceutical composition for preventing or treating a disease,
Diseases involved in the synthesis or metabolism of the prostaglandin E ₂ are allergic diseases, asthma caused by viruses, chronic periodontal disease, chronic obstructive pulmonary disease, chronic kidney disease, chronic liver disease, endometriosis, chronic pelvic inflammatory disease, chronic enteritis, Hodgkin's A pharmaceutical composition, characterized in that selected from the disease, ulcerative colitis, ulcerative duodenitis, Alzheimer's disease, Parkinson's disease, atherosclerosis, hypertensive heart disease. The method of claim 5,
The disease that is involved in the synthesis or metabolism of the prostaglandin E ₂ is an allergic disease, one of the immune diseases such as asthma due to viruses, pharmaceutical compositions. The method of claim 5,
Diseases involved in the synthesis or metabolism of prostaglandin E ₂ are chronic periodontal disease, chronic obstructive pulmonary disease, chronic kidney disease, chronic liver disease, endometriosis, chronic pelvic inflammatory disease, inflammatory diseases such as chronic enteritis, Hodgkin's disease, ulcerative Pharmaceutical composition, characterized in that one of the tumors due to inflammation, including colitis, ulcerative duodenitis. The method of claim 5,
The disease is involved in the synthesis or metabolism of the prostaglandin E ₂ pharmaceutical composition, characterized in that the brain disease, including Alzheimer's disease, Parkinson's disease. The method of claim 5,
The disease involved in the synthesis or metabolism of the prostaglandin E ₂ is a pharmaceutical composition, characterized in that one of vascular diseases including atherosclerosis, hypertensive heart disease. Involved in the synthesis or metabolism of prostaglandin E ₂ comprising a sulfonamide derivative of formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier As a pharmaceutical composition for preventing or treating a disease,
The disease involved in the synthesis or metabolism of the prostaglandin E ₂ is a pharmaceutical composition, characterized in that selected from immune diseases, inflammatory diseases, tumors caused by inflammation, brain diseases, vascular diseases.

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