KR101484977B1 - Triazole Derivatives, Process for Preparing the Same and Pharmaceutical Composition Comprising the Same - Google Patents

Abstract

TECHNICAL FIELD The present invention relates to triazole derivatives having excellent inhibitory activity on microsomal prostaglandin E ₂ synthetase-1 (mPGES-1), a process for producing the same, and a pharmaceutical composition containing the same as an active ingredient. The triazole derivatives of the present invention can be effectively used for the treatment or prevention of inflammation, arthritis, hyperthermia, pain, cancer, stroke or bone diseases.

Description

TRIAZOLE DERIVATIVES, PROCESS FOR PRODUCING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME Technical Field [0001] The present invention relates to triazole derivatives,

TECHNICAL FIELD The present invention relates to a triazole derivative, a process for producing the same, and a pharmaceutical composition containing the same, and more particularly, to a triazole derivative having excellent inhibitory activity on microsomal prostaglandin E ₂ synthetase-1 (mPGES-1) And a pharmaceutical composition containing the same as an active ingredient.

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

COX-2 inhibitors that selectively inhibit only COX-2 enzyme have been developed as therapeutic agents against such inflammation. Representative COX-2 inhibitors include Pfizer's celecoxib (Celebrex ^TM ) 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However, COX-2 inhibitors have been withdrawn from the pharmaceutical market, except for celecoxib, due to cardiovascular side effects, despite a reduction in the gastrointestinal disorder, the most serious side effect of nonsteroidal anti-inflammatory drugs (NSAIDs). These cardiovascular side effects are reported to be caused by the inhibition of the production of PGH ₂ (prostaglandin H ₂ ), thereby inhibiting the production of PGI ₂ (prostacyclin) and TXA ₂ (thromboxane) as well as PGE ₂ .

Therefore, inhibitors that selectively inhibit the microsomal prostaglandin E ₂ synthetase-1 (mPGES-1) that acts at the terminal stage of PGH ₂ and is involved in the production of PGE ₂ complement the disadvantages of the COX-2 inhibitor Research is underway to identify mPGES-1 as a new drug candidate.

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 expected to be effective in the treatment of inflammation, arthritis, fever, pain, cancer, stroke and bone disease . However, no drug has yet been developed into clinical trials.

The inventors of the present invention have conducted intensive studies to develop a selective inhibitor of microcrystalline prostaglandin E ₂ synthetase-1 (mPGES-1), which is a promising drug development target for the development of anti-inflammatory drugs. As a result, -1 < / RTI > inhibitory activity, thus completing the present invention.

Accordingly, an object of the present invention is to provide a triazole derivative or a pharmaceutically acceptable salt thereof, which is excellent in the mPGES-1 inhibitory effect.

Another object of the present invention is to provide a process for preparing a triazole derivative of the formula (I) or a pharmaceutically acceptable salt thereof.

Still another object of the present invention is to provide a pharmaceutical composition for inhibiting mPGES-1 containing a triazole derivative of the formula (I) or a pharmaceutically acceptable salt thereof.

The present invention relates to triazole derivatives of the general formula (I) or a pharmaceutically acceptable salt thereof.

(I)

In this formula,

R ₁ is hydrogen, a C ₁ -C ₆ alkyl group, a C ₃ -C ₁₀ cycloalkyl group or an aryl group,

R ₂ is a C ₁ -C ₆ alkyl or aryl group,

R ₃ is hydroxy, a C ₁ -C ₆ alkoxy group or amino,

n is an integer of 1 to 3;

In the present specification, the C ₁ -C ₆ alkyl group means a linear or branched hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, i-propyl, n-butyl, , t-butyl, and the like.

In the present specification, the C ₃ -C ₁₀ cycloalkyl group means a cyclic hydrocarbon having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, but is not limited thereto.

As used herein, an aryl group includes both an aromatic group and a heteroaromatic group and a partially reduced derivative thereof. The arometric group is a simple or fused ring group of 5 to 15-ary, and the heteroaromatic group means an arometric 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, imidazolinyl, But are not limited to, oxazolyl, thiazolyl, tetrahydronaphthyl, 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.

The C ₁ -C ₆ alkyl group, the C ₃ -C ₁₀ cycloalkyl group, the aryl group, and the C ₁ -C ₆ alkoxy group may be substituted by one or more of the hydrogen atoms of the C ₁ -C ₆ alkyl group, the C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group of, C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₆ haloalkyl group of, C ₁ -C ₆ alkoxy group, a thioalkoxy group of C ₁ -C _6, aryl An amino group, an alkoxycarbonyl group, a carboxy group, a carbamoyl group, a cyano group, a nitro group, and the like.

In the triazole derivatives of the present invention, R ₁ is preferably hydrogen; A C ₁ -C ₆ alkyl group which is unsubstituted or substituted with an aryl group which is unsubstituted or substituted with a C ₁ -C ₆ alkyl group; A C ₃ -C ₁₀ cycloalkyl group; Or an aryl group which is unsubstituted or substituted by a C ₁ -C ₆ alkyl group, more preferably hydrogen, methyl, butyl, benzyl, 4-methylbenzyl, cyclohexyl, phenyl or 4-methylphenyl.

R ₂ is preferably a C ₁ -C ₆ alkyl group; Or C ₁ -C aryl group is not substituted with a substituent selected from the group consisting of ₆ or more alkyl groups, halogen or a haloalkyl group of C ₁ -C ₆ or optionally substituted, more preferably methyl, ethyl, phenyl, 2-methylphenyl, 4-methylphenyl, 4-fluorophenyl, 2-trifluoromethanephenyl or 2-trifluoromethanphenyl.

R < ₃ > is preferably hydroxy, methoxy or amino.

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.

1- [2- (phenyl sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-1);

1- [2- (phenyl sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid amide (I-2);

1- [2- (N - phenyl sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-3);

Dimethyl-1- [2- (phenyl sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylate (I-4);

1- [2- (N - phenyl phenyl sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-5);

1- [2- (p - toluene sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-6);

1- [2- (N - butyl - p - toluene sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-7);

1- [3- (p - toluene sulfonamido) propyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-8);

1- [2- (methane sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-9);

1- [2- (ethane sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-10);

1- {2- [3- (trifluoromethane) phenylsulfonamido] ethyl} -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-11);

1- {2- [2- (trifluoromethanesulfonate) sulfonamido phenyl] ethyl} -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-12);

1 - [(p - toluene sulfonamido) methyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-13);

1- [2- (N - benzyl phenyl sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-14);

1- {2- [ N - (4-methylbenzyl) phenylsulfonamido] ethyl} -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-15);

1- {2- [ N - ( p -tolyl) phenylsulfonamido] ethyl} -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-16);

1- [2- (N - cyclohexyl phenyl sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-17);

1 - {2- [ N -benzyl-2- (trifluoromethane) phenylsulfonamido] ethyl} -1 H -1,2,3-triazole-4,5-dicarboxylic acid );

1- [2- (N - benzyl - o - toluene sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-19);

1- [2- (N - benzyl-4-fluoro-phenyl sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-20);

1- [2- (N - phenyl - o - toluene sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-21);

1- [2- (N - cyclohexyl - o - toluene sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-22); And

1- [2- (N - phenyl-4-fluoro-phenyl sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-23).

The present invention relates to a process for preparing a triazole derivative represented by the above general formula (I)

(i) coupling reaction of a compound of formula (II): < EMI ID = 15.1 >

(ii) reacting a compound of formula (IV) with an azide to obtain a compound of formula (V); And

(iii) reacting a compound of formula (V)

[Reaction Scheme 1]

Wherein R ₁ , R ₂ and R ₃ are as defined in the above formula (I).

In step (i) above, the compound of formula (II) and the compound of formula (III) are subjected to a coupling reaction, preferably in the presence of a base, to obtain a compound of formula (IV).

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

The compound of formula (III) is preferably used in an amount of 2 to 3 equivalents relative to the compound of formula (II).

As the reaction solvent, dichloromethane, chloroform and the like can be used, and the reaction temperature is preferably room temperature.

The compound of formula (II) is commercially available or can be easily prepared by known methods.

The resulting compound of formula (IV) can be used in the next step without purification after removal of the resulting salt.

In step (ii), the compound of formula (IV) is reacted with the azide compound, preferably under anhydrous conditions, to obtain the compound of formula (V).

As the azide compound, sodium azide, potassium azide, and the like can be used, and sodium azide is preferably used.

As the reaction solvent, dimethylformamide, dimethylsulfoxide and the like can be used, and the reaction temperature is preferably reflux condition.

The obtained compound of formula (V) is preferably used in the next step without removing the resulting salt after purification.

In step (iii), the compound of formula (V) and the compound of formula (VI) are subjected to a click reaction, preferably under anhydrous conditions, to obtain a triazole derivative of formula (I).

The click reaction may be carried out in the presence or absence of a reaction catalyst such as CuI.

As the reaction solvent, tetrahydrofuran, 1,4-dioxane, diethyl ether and the like can be used, and the reaction temperature is preferably reflux condition.

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

Accordingly, the present invention relates to a pharmaceutical composition for inhibiting microcrystalline prostaglandin E ₂ synthetase-1 (mPGES-1) comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, Relates to a pharmaceutical composition for the treatment or prevention of inflammation, arthritis, high fever, pain, cancer, stroke or bone 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 compound of the present invention exhibits excellent microsomal prostaglandin E ₂ synthetase-1 (mPGES-1) inhibitory activity. Thus, the compounds of the present invention can be effectively used in pharmaceutical compositions for the treatment or prevention of inflammation, arthritis, hyperthermia, pain, cancer, stroke or bone diseases.

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.

Preparation Example 1: N - (4-methylbenzyl) ethanolamine (II-15)

p -Toluene aldehyde (1 g, 8.32 mmol) was dissolved in anhydrous methanol, and ethanolamine (0.53 g, 8.74 mmol) was added thereto, followed by reflux stirring at 80 ° C for 4 hours. After confirming the reaction using thin film chromatography, the temperature was lowered to 0 ° C and the pH was adjusted to 3-4 by adding hydrochloric acid. Sodium cyanoborohydride (1.1 g, 16.65 mmol) was added slowly and stirred at room temperature for 2 hours. The reaction was confirmed by thin membrane chromatography and then fractionated using diethyl ether and water. Then, the aqueous layer was adjusted to pH 10 with an aqueous solution of sodium hydroxide, and the dichloromethane solution was extracted with dichloromethane and water. The water was removed using magnesium sulfate, and the solvent was removed using a rotary evaporator Respectively. The residue was purified using silica gel column chromatography with ethyl acetate: n-hexane (1: 1) to give the title compound (II-15) as a yellow liquid (0.68 g, 50%).

^{1 H-NMR (400 MHz,} CDCl 3 -d 1) δ: 2.332 (3H, s), 2.508 (1H, s), 2.763 (2H, t), 3.628 (2H, t), 3.741 (2H, s) , 7.122-7.141 (2H, d), 7.179-7.199 (2H, d)

¹³ C-NMR (100 MHz, CDCl ₃ -d ₁ ) ?: 21.146, 60.516, 53.222, 60.827, 128.153, 129.176, 136.741, 136.867

Preparation Example 2: N - ( p -Tolyl) ethanolamine (II-16)

Copper iodide (2.2 g, 11.37 mmol), dimethanolamine (3.3 ml, 32.997 mmol) and potassium tertiary phosphate (5.3 g, 23.08 mmol) were added to a solution of 4-iodotoluene (2.48 g, 11.37 mmol) And ethanolamine (1 g, 16.37 mmol) were refluxed and stirred at 80 DEG C for 2 days. After confirming the reaction using thin film chromatography and lowering the temperature to room temperature, the ethyl acetate solution was extracted with ethyl acetate and water, the water was removed using magnesium sulfate, and the solvent was removed using a rotary evaporator All were removed. The residue was purified using silica gel column chromatography with ethyl acetate: n-hexane (1: 1) to give the title compound (II-16) as a yellow liquid (1 g, 60%).

^{1 H-NMR (400 MHz,} CDCl 3 -d 1) δ: 2.234 (3H, s), 3.085 (1H, s), 3.223 (2H, t), 3.755 (2H, t), 6.548-6.574 (2H, d), 6.973 - 6.993 (2H, d)

¹³ C-NMR (100 MHz, CDCl ₃ -d ₁ ) ?: 20.421, 46.583, 61.242, 113.588, 127.295, 129.826, 145.839

Example 1: 1- [2- (Phenylsulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-1)

Ethanolamine (0.5 g, 8.2 mmol) was stirred in dichloromethane with triethylamine (3.4 ml, 24.6 mmol). Phenylsulfonyl chloride (4.34 g, 24.6 mmol) was slowly added thereto at 0 ° C using ice water, and the mixture was stirred at room temperature for 4 hours. After confirming the reaction using thin film chromatography, dichloromethane was removed by using a reduced pressure rotary evaporator, and the residue was dissolved in ethyl acetate. The salt was filtered using filter paper, and the filtrate was purified by using a rotary evaporator under reduced pressure . The residue was subjected to silica gel column chromatography using ethyl acetate: n-hexane (1: 3) to obtain a colorless liquid compound (IV-1) (2 g, 70%).

Compound (IV-1) (1 g, 2.9 mmol) was made anhydrous, followed by anhydrous dimethylformamide. Then, sodium azide (0.28 g, 4.4 mmol) was slowly added and the mixture was refluxed at 80 ° C for 6 hours. After confirming the reaction using thin film chromatography, the solvent was completely removed using a rotary evaporator, and the residue was dissolved in tetrahydrofuran. The salt was filtered using a filter paper, and the filtrate was purified by using a rotary evaporator The solvent was removed to obtain the compound (V-1).

Compound (V-1) (0.7 g, 2.9 mmol) was dissolved in anhydrous tetrahydrofuran, acetylenedicarboxylic acid (0.5 g, 4.4 mmol) was added slowly and the mixture was refluxed at 70 ° C for 1 hour. After confirming the reaction using thin film chromatography, the temperature was lowered to room temperature, and activated carbon (2 g) was added thereto. The mixture was stirred at room temperature for 1 hour and then filtered using silica gel. The filtrate was distilled under reduced pressure using a rotary evaporator Respectively. The residue was subjected to silica gel column chromatography using ethyl acetate and then recrystallized from ethyl acetate and diethyl ether to give the title compound (I-1) as a white solid (0.6 g, 60%).

^{MS (ES -) m / z} : 339.00 [MH] -

¹ H-NMR (400 MHz, DMSO-d ₆ )?: 3.251-3.297 (2H, q), 4.767-4.797 (2H, t), 7.546-7.747 (5H, m), 7.866

¹³ C-NMR (100 MHz, DMSO-d ₆ )? 42.130, 49.795, 126.291, 129.166, 132.395, 132.543, 140.185, 140.720, 159.123, 161.253

Example 2: 1- [2- (Phenylsulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylamide (I-2)

The title compound (I-2) was obtained as a white solid (68%) in the same manner as in Example 1, except that acetylenedicarboxylic acid was replaced by acetylenedicarboxylic acid.

^{MS (ES -) m / z} : 337.10 [MH] -

^{1 H-NMR (400 MHz,} DMSO-d 6) δ: 3.288-3.332 (2H, t), 4.813-4.842 (2H, t), 7.555-7.592 (2H, t), 7.614-7.650 (1H, t) , 7.728-7.746 (2H, d), 7.907-7.938 (1H, t), 8.129-8.165

^{13 C-NMR (100 MHz,} DMSO-d 6) δ: 42.006, 50.744, 126.252, 129.165, 131.044, 132.393, 138.824, 140.224, 158.055, 163.315

Example 3: 1- [2- ( N - methylphenylsulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-3)

(I-3) was obtained (81%) as a white solid in the same manner as in Example 1, except that N -methylethanolamine was used in place of ethanolamine.

^{MS (ES -) m / z} : 353.10 [MH] -

¹ H-NMR (400 MHz, DMSO-d ₆ )?: 2.729 (3H, s), 3.479-3.508 (2H, t), 4.833-5.862 (2H, t), 7.595-7.719 (2H, s)

^{13 C-NMR (100 MHz,} DMSO-d 6) δ: 34.889, 47.674, 49.208, 126.872, 129.427, 131.695, 132.994, 136.906, 140.109, 159.166, 161.967

Example 4: Dimethyl 1- [2- (phenylsulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylate (I-4)

(I-4) was obtained (51%) as a white solid in the same manner as in Example 1, except that dimethylacetylene dicarboxylate was used in place of acetylenedicarboxylic acid.

^{MS (ES -) m / z} : 367.10 [MH] -

^{1 H-NMR (400 MHz,} DMSO-d 6) δ: 3.236-3.265 (2H, t), 3.892 (3H, s), 3.940 (3H, s), 4.639-4.668 (2H, t), 7.566-7.6667 (3H, m), 7.745-7.763 (2H, t), 7.954 (1H, s)

¹³ C-NMR (100 MHz, DMSO-d ₆ ) ?: 42.005, 50.096, 52.505, 53.478, 126.334, 129.241, 130.697, 132.530, 132.530, 138.905, 140.042, 158.446, 160.240

Example 5: 1- [2- ( N - phenylphenylsulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-5)

(I-5) was obtained (79%) as a white solid in the same manner as in Example 1, except that N -phenylethanolamine was used in place of ethanolamine.

^{MS (ES -) m / z} : 415.10 [MH] -

¹ H-NMR (400 MHz, acetone-d ₆ )?: 4.257-4.284 (2H, t), 4.926-4.954 (2H, t), 7.146-7.170 (2H, m), 7.341-7.396 , 7.537-7.589 (4 H, m), 7.665-7.709 (1 H, m)

¹³ C-NMR (100 MHz, acetone-d ₆ ) ?: 50.905, 51.105, 128.272, 129.113, 129.951, 130.042, 130.155, 132.770, 133.925, 139.218, 139.379, 139.837, 157.680, 167.470

Example 6: 1- [2- ( p -Toluenesulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-6)

(I-6) was obtained (90%) as a white solid in the same manner as in Example 1, except that p -toluenesulfonyl chloride was used in place of phenylsulfonyl chloride.

^{MS (ES -) m / z} : 353.10 [MH] -

^{1 H-NMR (400 MHz,} DMSO-d 6) δ: 2.376 (3H, s), 3.551-3.597 (2H, q), 4.867-4.897 (2H, t), 7.243-7.263 (2H, d), 7.469 -7.490 (2H, d)

¹³ C-NMR (100 MHz, DMSO-d ₆ ) ?: 39.572, 42.130, 49.795, 126.291, 129.166, 132.395, 132.543, 140.185, 140.720, 159.123, 161.253

Example 7: 1- [2- ( N -Butyl- p -Toluenesulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-7)

The title compound (I-7) was obtained as a white solid (88%) in the same manner as in Example 1, except that N -butyl ethanolamine and p -toluenesulfonyl chloride were used instead of ethanolamine and phenylsulfonyl chloride. ).

^{MS (ES -) m / z} : 409.10 [MH] -

¹ H-NMR (400 MHz, DMSO-d ₆ )?: 0.843 (3H, t), 1.143-1.234 (2H, m), 1.331-1.406 t), 3.548-3.579 (2H, t), 4.855-4.885 (2H, t), 7.343-7.363 (2H, d), 7.569-7.590

¹³ C-NMR (100 MHz, DMSO-d ₆ ) ?: 13.475, 19.138, 20.915, 29.516, 46.966, 47.886, 48.828, 126.713, 129.766, 132.554, 135.930, 140.644, 143.107, 159.080, 161.136

Example 8: 1- [3- ( p - toluenesulfonamido) propyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-8)

The title compound (I-8) was obtained as a white solid (81%) in the same manner as in Example 1, except that propanolamine and p -toluenesulfonyl chloride were used instead of ethanolamine and phenylsulfonyl chloride.

^{MS (ES -) m / z} : 367.10 [MH] -

^{1 H-NMR (400 MHz,} DMSO-d 6) δ: 1.929-2.001 (2H, m), 2.388 (3H, s), 2.783 (2H, s), 4.611-4.646 (2H, t), 7.379-7.399 (2H, d), 7.647-7.667 (2H, d), 8.610 (2H, s)

^{13 C-NMR (100 MHz,} DMSO-d 6) δ: 20.893, 29.568, 47.374, 74.960, 126.444, 129.601, 131.605, 137.186, 139.887, 142.679, 159.254, 161.746

Example 9: 1- [2- (Methanesulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-9)

The title compound (I-9) was obtained as a white solid (72%) in the same manner as in Example 1, except that methanesulfonyl chloride was used instead of phenylsulfonyl chloride.

^{MS (ES -) m / z} : 277.00 [MH] -

^{1 H-NMR (400 MHz,} DMSO-d 6) δ: 2.891 (3H, s), 3.455-3.484 (2H, t), 4.720-4.750 (2H, t), 7.251 (1H, s), 8.982 (2H , s)

¹³ C-NMR (100 MHz, DMSO-d ₆ ) ?: 39.572, 41.958, 50.042, 131.775, 140.057, 159.257, 161.880

Example 10: 1- [2- (Ethanesulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-10)

The title compound (I-10) was obtained as a white solid (70%) in the same manner as in Example 1, except that ethanesulfonyl chloride was used instead of phenylsulfonyl chloride.

^{MS (ES -) m / z} : 291.00 [MH] -

^{1 H-NMR (400 MHz,} DMSO-d 6) δ: 1.123-1.160 (3H, t), 2.518-2.527 (2H, t), 2.938-2.993 (2H, q), 3.455 (2H, s), 6.699 (2H, t), 7.301 (1H, s), 9.116 (2H, s)

^{13 C-NMR (100 MHz,} DMSO-d 6) δ: 7.934, 41.798, 45.590, 50.227, 131.694, 140.072, 159.246, 161.918

Example 11: 1- {2- [3- (Trifluoromethane) phenylsulfonamido] ethyl} -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-11)

The title compound (I-11) was obtained as a white solid (71%) in the same manner as in Example 1, except that 3- (trifluoromethane) phenylsulfonyl chloride was used in place of phenylsulfonyl chloride.

^{MS (ES -) m / z} : 407.00 [MH] -

^{1 H-NMR (400 MHz,} DMSO-d 6) δ: 3.346-3.374 (2H, t), 4.701-4.730 (2H, t), 7.837-7.876 (1H, m), 8.034-8.078 (3H, m) , 8.192-8.221 (1H, m), 10.621 (2H, s)

¹³ C-NMR (100 MHz, DMSO-d ₆ ) ?: 41.919, 48.535, 49.795, 122.002, 122.889, 122.932, 124.714, 129.200, 129.713, 130.039, 130.400, 130.833, 131.751, 140.073, 141.429, 159.183, 161.842

Example 12: 1- {2- [2- (Trifluoromethane) phenylsulfonamido] ethyl} -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-12)

The title compound (I-12) was obtained as a white solid (67%) in the same manner as in Example 1, except that 2- (trifluoromethane) phenylsulfonyl chloride was used in place of phenylsulfonyl chloride.

^{MS (ES -) m / z} : 407.00 [MH] -

^{1 H-NMR (400 MHz,} DMSO-d 6) δ: 3.456-3.499 (2H, q), 4.811-4.840 (2H, t), 7.796-7.872 (2H, m), 7.935-7.953 (1H, d) , 7.989-8.008 (1H, d), 8.158-8.188 (1H, t)

^{13 C-NMR (100 MHz,} DMSO-d 6) δ: 42.049, 48.557, 49.955, 121.434, 124.156, 125.742, 126.063, 128.303, 128.366, 129.697, 132.525, 132.771, 133.165, 139.191, 140.711, 159.182, 161.339

Example 13: 1 - [( p - toluenesulfonamido) methyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-13)

The title compound (I-13) was obtained as a white solid (65%) in the same manner as in Example 1, except that methanolamine and p -toluenesulfonyl chloride were used instead of ethanolamine and phenylsulfonyl chloride.

^{MS (ES -) m / z} : 339.00 [MH] -

^{1 H-NMR (400 MHz,} DMSO-d 6) δ: 2.38 (3H, s), 4.53 (1H, d), 7.4 (2H, d), 7.7 (2H, d), 8.39 (1H, t)

Example 14: 1- [2- ( N - benzyl phenyl sulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-14)

The title compound (I-14) was obtained as a white solid (0.5 g, 50%) in the same manner as in Example 1, except that N -benzylethanolamine was used instead of ethanolamine.

^{MS (ES -) m / z} : 429.10 [MH] -

^{1 H-NMR (400 MHz,} acetone-d 6) δ: 3.722 (2H, t), 4.347 (2H, s), 4.914 (2H, t), 7.277-7.181 (5H, m), 7.628-7.646 (2H , t), 7.665-7.882 (1H, m), 7.903 (2H, d)

¹³ C-NMR (100 MHz, acetone-d ₆ ) ?: 47.568, 51.334, 53.605, 128.266, 128.595, 129.471, 129.673, 130.300, 132.207, 133.881, 136.754, 138.771, 139.788, 157.175, 167.439

Example 15: 1- {2- [ N - (4-methylbenzyl) phenylsulfonamido] ethyl} -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-15)

(I-15) was obtained as a white solid in the same manner as in Example 1, except that N - (4-methylbenzyl) ethanolamine (II-15) obtained in Preparation Example 1 was used instead of N- (60%).

^{MS (ES -) m / z} : 443.10 [MH] -

_{^{1 (acetone-d 6 400 MHz}} ,) δ H-NMR: 2.290 (3H, s), 3.679 (2H, t), 4.292 (2H, s), 4.886 (2H, t), 7.057 (4H, m), 7.605-7.643 (2H, t), 7.680-7.716 (1H, t), 7.883 (2H, d)

Example 16: Preparation of 1- {2- [ N - ( p - tolyl) phenylsulfonamido] ethyl} -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-16)

(I-16) was obtained as a white solid in the same manner as in Example 1, except that N - ( p -tolyl) ethanolamine (II-16) obtained in Preparation Example 2 was used instead of ethanolamine (65%).

^{MS (ES -) m / z} : 429.10 [MH] -

^{1 H-NMR (400 MHz,} DMSO-d 6) δ: 2.291 (3H, s), 4.0442 (2H, s), 4.547 (1H, s), 4.710 (2H, s), 6.908-6.928 (2H, d ), 7.134-7.154 (2H, d), 7.468-7.487 (2H, d), 7.523-7.561 (2H, t), 7.644-7.680

¹³ C-NMR (100 MHz, DMSO-d ₆ ) ?: 20.583, 48.764, 50.228, 127.011, 128.593, 129.202, 129.486, 132.640, 133.047, 135.775, 137.555, 137.881, 140.650, 159.095, 161.111

Example 17: 1- [2- ( N - cyclohexylphenylsulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-17)

The title compound (I-17) was obtained as a white solid (60%) in the same manner as in Example 1, except that N -cyclohexylethanolamine was used instead of ethanolamine.

^{MS (ES -) m / z} : 421.10 [MH] -

¹ H-NMR (400 MHz, MeOD-d ₅ )?: 1.071-1.103 (1H, d), 1.235-1.262 (2H, d), 1.378-1.429 , 1.703-1.731 (2H, d), 3.581 (1H, s), 3.721 (2H, s), 5.061 (2H, s), 7.567-7585 (2H, d), 7.619-7.654 -7.872 (2 H, d)

¹³ C-NMR (100 MHz, MeOD-d ₅ ) ?: 24.674, 25.431, 30.299, 42.731, 50.821, 57.706, 126.677, 129.413, 132.840, 140.203, 140.361, 140.819, 159.170, 161.090

Example 18: 1- {2- [ N -Benzyl-2- (trifluoromethane) phenylsulfonamido] ethyl} -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-18)

(I-18) was obtained as a white solid in the same manner as in Example 1, except that N -benzyl ethanolamine and 2- (trifluoromethane) phenylsulfonyl chloride were used instead of ethanolamine and phenylsulfonyl chloride. (66%).

^{MS (ES -) m / z} : 497.10 [MH] -

¹ H-NMR (400 MHz, MeOD-d ₅ )?: 3.063-3.095 (2H, t), 3.268-3.299 (2H, t), 4.453 (2H, s), 7.154-7.197 -7.686 (2H, m), 7.826-7.845 (1H, t), 7.851-7.859 (1H, d)

¹³ C-NMR (100 MHz, MeOD-d ₅ ) ?: 47.696, 50.559, 53.354, 120.192, 122.907, 125.623, 128.305, 128.342, 128.634, 128.962, 129.237, 129.289, 129.631, 129.784, 129.867, 129.911, 129.976, , 134.070, 134, 219, 137.443, 140.502

Example 19: 1- [2- ( N -benzyl- o -Toluenesulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-19)

The title compound (I-19) was obtained as a white solid (71%) in the same manner as in Example 1, except that N -benzyl ethanolamine and o -toluenesulfonyl chloride were used instead of ethanolamine and phenylsulfonyl chloride. ).

^{MS (ES -) m / z} : 443.10 [MH] -

^{1 H-NMR (400 MHz,} MeOD-d 5) δ: 2.408 (3H, s), 3.692 (2H, s), 4.78 (2H, s), 4.823 (2H, s), 7.189-7.779 (9H, m )

Example 20: 1- [2- ( N -Benzyl-4-fluorophenylsulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-20)

The title compound (I-20) was obtained as a white solid in the same manner as in Example 1 except that N -benzyl ethanolamine and 4-fluorophenylsulfonyl chloride were used instead of ethanolamine and phenylsulfonyl chloride (51 %).

^{MS (ES -) m / z} : 447.10 [MH] -

^{1 H-NMR (400 MHz,} acetone-d 6) δ: 3.721-3.750 (2H, t), 4.376 (2H, s), 4.892-4.920 (2H, t), 6.195-7.268 (5H, m), 7.355 -7.399 (2H, t), 7.923-7.954 (2H, dd)

¹³ C-NMR (100 MHz, acetone-d ₆ ) ?: 47.661, 51.098, 53.488, 117.179, 117.406, 128.639, 129.478, 129.634, 131.220, 131.315, 136.345, 136.664, 157.524, 167.757, 167.267

Example 21: 1- [2- ( N -Phenyl- o -Toluenesulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-21)

The title compound (I-21) was obtained as a white solid (46% yield) in the same manner as in Example 1, except that N -phenylethanolamine and o -toluenesulfonyl chloride were used instead of ethanolamine and phenylsulfonyl chloride. ).

^{MS (ES -) m / z} : 429.10 [MH] -

^{1 H-NMR (400 MHz,} DMSO-d 6) δ: 2.154 (3H, s), 4.146 (2H, s), 4.671 (2H, s), 7.252-7.655 (9H, m)

Example 22: 1- [2- ( N -Cyclohexyl- o -Toluenesulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-22)

The title compound (I-22) was obtained as a white solid in the same manner as in Example 1 except that N -cyclohexylethanolamine and o -toluenesulfonyl chloride were used instead of ethanolamine and phenylsulfonyl chloride (55 %).

^{MS (ES -) m / z} : 435.10 [MH] -

^{1 H-NMR (400 MHz,} DMSO-d 6) δ: 1.013-1.045 (2H, d), 1.161-1.179 (3H, d), 1.560 (6H, s), 1.687-1.718 (2H, d), 3.425 (2H, m), 7.498-7.535 (1H, m), 7.810-7.830 (IH, m), 3.642-3.675 (2H, t), 4.799-4.831 d)

^{13 C-NMR (100 MHz,} DMSO-d 6) δ: 19.910, 24.722, 25.622, 30.700, 42.953, 50.158, 57.553, 126.437, 129.024, 132.497, 132.551, 312.782, 132.851, 136.683, 137.979, 159.048, 161.049

Example 23: 1- [2- ( N Phenyl-4-fluorophenylsulfonamido) ethyl] -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-23)

The title compound (I-23) was obtained as a white solid in the same manner as in Example 1 except that N -phenylethanolamine and 4-fluorophenylsulfonyl chloride were used instead of ethanolamine and phenylsulfonyl chloride (44 %).

^{MS (ES -) m / z} : 433.10 [MH] -

^{1 H-NMR (400 MHz,} DMSO-d 6) δ: 3.603 (3.5H, s), 4.141 (2H, s), 4.731 (2H, s), 7.067-7.549 (9H, m)

^{13 C-NMR (100 MHz,} DMSO-d 6) δ: 48.871, 50.185, 116.347, 116.574, 128.155, 128.834, 129.025, 130.043, 130.139, 132.507, 134.124, 138.276, 159.084, 161.390

Test Example 1: Microcrystalline prostaglandin E ₂  Synthesis enzyme-1 (mPGES-1) inhibitory activity

The inhibitory activity of the compounds on the microsomal prostaglandin E ₂ synthetase-1 (mPGES-1) was determined by a known double enzyme activity assay [ Bull. Korean Chem. Soc. 2010 , Vol. 31, No. 2, 384 to 388).

Specifically, 110 nM of mPGES-1 and 220 nM of 15-PGDH were added to 200 μL of reaction buffer (50 mM Tris-HCl, pH 7.5, 50 μM PMA (phosphomolybdic acid), 2 mM reduced form of glutathione, 1 mM NAD ⁺ , 0.1 mM DTT) with 1 μl of dimethylsulfoxide (DMSO) dissolved in test compound and incubated for 30 min. The reaction was initiated by adding cold PGH ₂ to a final concentration of 14 μM. The amount of NADH in the reaction products was measured with a fluorescence plate reader (DYNEX, USA) using emission and excitation wavelengths of 468 nm and 340 nm. The IC ₅₀ values of the test compounds are shown in Table 1 below.

As shown in Table 1, the triazole compound according to the present invention showed excellent mPGES-1 inhibitory activity. In particular, the triazole compound prepared in Example 5 showed about 3.5 times stronger inhibitory activity than MK886 (purchased from Cayman chemical), which is a positive control substance.

Claims (10)

Claims 1. A triazole derivative represented by the formula (I): < EMI ID =
(I)

In this formula,
R ₁ is hydrogen, a C ₁ -C ₆ alkyl group or phenyl,
R ₂ is phenyl optionally substituted with one or more substituents selected from the group consisting of a haloalkyl group of C ₁ -C ₆ alkyl group and C ₁ -C ₆ of,
R < ₃ > is hydroxy,
n is an integer of 1 to 3; delete The method according to claim 1,
R < ₁ > is hydrogen, methyl, butyl or phenyl,
R ₂ is phenyl, 4-methylphenyl, 2-trifluoromethanephenyl or 3-trifluoromethanephenyl,
Wherein R < ₃ > is hydroxy, or a pharmaceutically acceptable salt thereof. A triazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the following compounds:
1- [2- (phenyl sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-1);
1- [2- (N - phenyl sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-3);
1- [2- (N - phenyl phenyl sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-5);
1- [2- (p - toluene sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-6);
1- [2- (N - butyl - p - toluene sulfonamido) ethyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-7);
1- [3- (p - toluene sulfonamido) propyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-8);
1- {2- [3- (trifluoromethane) phenylsulfonamido] ethyl} -1 H -1,2,3-triazole-4,5-dicarboxylic acid (I-11);
1- {2- [2- (trifluoromethanesulfonate) sulfonamido phenyl] ethyl} -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-12); And
1 - [(p - toluene sulfonamido) methyl] -1 H -1,2,3- triazole-4,5-dicarboxylic acid Rick (I-13). (i) coupling reaction of a compound of formula (II): < EMI ID = 15.1 >
(ii) reacting a compound of formula (IV) with an azide to obtain a compound of formula (V); And
(iii) reacting a compound of formula (V): < RTI ID = 0.0 >

In this formula,
R ₁ is hydrogen, a C ₁ -C ₆ alkyl group or phenyl,
R ₂ is phenyl optionally substituted with one or more substituents selected from the group consisting of a haloalkyl group of C ₁ -C ₆ alkyl group and C ₁ -C ₆ of,
R < ₃ > is hydroxy,
n is an integer of 1 to 3; 6. The process according to claim 5, wherein in step (i), the compound of formula (II) and the compound of formula (III) are subjected to coupling reaction in the presence of a base. 7. The process according to claim 6, wherein the base is triethylamine. The process according to claim 5, wherein the azide is sodium azide. Inflammatory, arthritic, hyperthermia, pain, cancer, stroke or inflammatory pain comprising a triazole derivative according to any one of claims 1 or 3 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition for the treatment or prevention of bone diseases. delete