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The present invention relates to diaryl 1,2,4-triazole derivatives as a highly selective cyclooxygenase-2 inhibitor.
BACKGROUND
Most of non-steroid anti-inflammatory drugs represent
actions such as anti-inflammation, analgesic, and
antipyretic activity by inhibiting the enzymatic activity
of cyclooxygenase or prostaglandin G/H synthase. In
addition, they can suppress the uterine contraction induced
by hormones and the cell proliferation in several kinds of
cancers. First, only cyclooxygenase-1 was known to be
found in cow as a constitutional enzyme. But recently,
cyclooxygenase-2 is identified to be discriminated clearly
from cyclooxygenase-1 and can be provoked easily by mitogen,
endotoxin, hormones, growth factors, cytokines and the like.
Prostagladins have various pathological and
physiological functions. Precisely, cyciooxygenase-1 as a constitutional enzyme participates in the secretion of basic endogenous prostaglandin and plays an important role in physiological aspects such as stomach homeostasis, renal
blood circulation and so on. On the other hand, cyclooxygenase-2 is induced by inflammatory factors, hormones, growth factors, cytokines and the like, and thus plays an important role in pathological effects of prostaglandins. Therefore, selective inhibitors against cyclooxygenase-2 are expected to have no side effect on account of the functional mechanism compared with the anti¬inflammatory drugs such as conventional non-steroid agents and to represent actions such as anti-inflammation, analgesic, and antipyretic activity. Furthermore, it is estimated to suppress the uterine contraction induced by hormones and the cell proliferation in several kinds of cancers. Especially, it probably has a few side effects such as gastrointestinal toxicity, renal toxicity and the like. Also, it is assumed to prevent the synthesis of contractive prostanoids, and thus inhibit the contraction of smooth muscle induced by the prostanoid. Hence, it can be applied usefully to treat a premature birth, dysmenorrhea, asthma and several diseases associated with eosinophilic leukocytes. Besides, it can be widely exploited to cure osteoporosis, glaucoma and athymia, which has been disclosed in many references, especially the usefulness of selective inhibitors against cyclooxygenase-2 [References: John Vane, "Towards a better aspirin" in Nature, Vol.367, p215-216, 1994; Bruno Battistini, Regina Betting and Y. S. Bakhle, "COX-1 and COX-2: Toward the Development of More Selective NSAIDs" in Drug News and
Perspectives, Vol. 7, p501-512, 1994; David B. Reitz and Karen Seibert, "Selective Cyclooxygenase Inhibitors" in Annual Reports in Medicinal Chemistry, James A. Bristol, Editor, Vol. 30, pl79-188, 1995).
The selective inhibitors against cyclooxygenase-2 have been reported to have various structure forms. Among these, the diaryl heterocycle structure, namely a tricyclic system, has been studied most frequently and exploited to construct a lot of candidate substances, In this structure, it is essential that sulfonamide or methanesuIfone group exist onto one phenyl group. The initial substance having the above structure is identified to be Dup697 (Bioorganic s Medicinal Chemistry Letters, Vol 5, No. 18, p2123, 1995). Then, as a derivative, SC-58635 (Journal of Medicinal Chemistry, Vol 40, pl347, 1997} having a pyrrazole structure, MK-966 (WO 95/00501) having a furanone structure and the like are disclosed.
DISCLOSURE OF INVEMTIOM
Based upon the above technical backgrounds, the inventors of the present invention have tried in order to develop novel compounds as a highly selective cyclooxygenase-2 inhibitor. As a result, it is found that diaryl 1,2,4-triazole derivatives of formula 1 containing sulfonamidophenyl or raethylsulfonylphenyl group as a specific structure of conventional chemicals satisfies such
a purpose.
Therefore, an object of the present invention is to provide diaryl 1,2,4-triazole derivatives of formula 1 and pharraaceutically acceptable salt thereof.
Hereinafter, the present invention will be described more clearly.
The present invention relates to diaryl 1,2,4-triazole derivatives of the following formula 1 and pharmaceutically acceptable salt thereof.
substituted by halogens; NO2, NHz, OH, OMe, CO2H or CN and A is CHj or NH2, and W is CH or N.
The compound of the present invention can also exist as a pharmaceutically acceptable salt form, wherein the pharmaceutically acceptable salt means a nontoxic salt containing organic salt and inorganic salt, being accepted pharmaceutically. The inorganic salt includes aluminum, ammonium, calcium, copper, iron, lithium, magnesium.
manganese, potassium, sodium, zinc and the like, and preferably, ammonium, calcium, magnesium, potassium and sodium. The organic salt includes primary-, secondary- or tertiary- amines, naturally substituted amines, cyclic amines, modified salts prepared through basic ion exchange resin and the like. More preferably, the organic salt can be selected from the group consisting of arginine, betain, caffeine, colin, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoehanol, ethanolamine, ethylenediamine, N-ethylmorpholin, N-ethylpiperidine, N-methylglucamine, glucamine, glucosamine, histidine, hydrapamine, N-(2'hydroxyethyl)piperidine, N-(2-hydroxyethyl)pyrrolidine, isopropylamine, lysine, methylglucamine, morpholin, piperazine, plperidine, polyamine resin, procain, purine, teobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Besides, the compound of the present invention can be a salt form of nontoxic acids containing the organic acid and the inorganic acid, being accepted pharmaceutically, in case that it be basic. Preferably, the acid can be selected from the group consisting of acetic acid, adipic acid, aspartic acid, 1,5-naphthalenedisulfonic acid, benzenesulfonic acid, benzoic acid, camposulfonic acid, citric acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, ethylenediaminetetraacetic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, hydriodic acid, hydrobromic acid, hydrochloric acid, icethionic acid,
lactic acid, maleic acid, malic acid, manderic acid, methanesulfonic acid, music acid, 2-naphthalenedisulfonic acid, nitric acid, oxalic acid, parnoic acid, pantothenic acid, phosphoric acid, pivalic acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, 10-undecenoic acid and the like. And more preferably, among succinic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, phosphoric acid, sulfuric acid, tartaric acid and the like.
Preferably, the compound of the present invention of formula 1 as a selective inhibitor against cyclooxygenase-2 is that Ri, R2, R3, R4, and R5 are each independently hydrogen, halogen, CH3 or OCH3, A is CH3 or NH2, and W is CH or N.
For preferred embodiments of the present invention, the compound of formula 1 will be described more clearly as follows:
4-(3-methyl-5~phenyl-[l,2,4,]triazole-1-yl}-benzenesulfonamide;
4-[5-(4-fluoro-phenyl)-3-mehtyl-[1,2,4]triazole-l-yl]-benzenesulfonamide;
4-[5-(4-chloro-phenyl]-3-raehtyl-[1,2,4] triazole-l-yl]-benzenesulfonamide;
4-[5-(4-bromo-phenyl)-3-mehtyl-[1,2,4] triazole-1-yl]-benzenesulfonamide;
4-(3-methyl-5-p-toly-[l,2,4]trizole'-l-yl)-
benzenesulfonamlde;
4-[5-(4-methoxy-phenyl)-3-methyl-[1,2,4]triazole-1-yl]- benzenesulfonamide;
4-[5-(3-fluoro-phenyl)-3-mehtyl-[l,2,4]triazole-l-yl]- benzenesulfonamide;
4-[5-{3-chloro-phenyl)-3-mehtyl-[l,2,4]triazole-1-yl]- benzenesulfonamide;
4-[5-(3-bromo-phenyl)-3-mehtyl-[l,2,4]triazole-l-yll-benzenesulf onamide;
4-[5-(3-methoxy-phenyl)-3-methyl-[1,2,4]triazole-l-yl]- benzenesulfonamide;
4-[5-(2-raethoxy-phenyl)-3-methyl-[l,2,4]triaaole-l-yl]- benzenesulfonamide;
4-[5-(3,4-dimethoxy-phenyl)-3-raethyl-[1,2,4]triazole-1-yl]- benzenesulfonamide;
4-[5-(3, 5-dimethoxy-phenyl)-3-methyl-[l,2,4]triazole-1-yl]- benzenesulfonamide;
6-(3-methyl-5-phenyl~[1,2,4]triazole-1-yl)-pyridine-3-sulfonic acid amide;
6-[5-[4-fluoro-phenyl)-3-mehtyl-[1,2,4]triazolG-l-yl-pyridine-3-sulfonic acid amide;
6-[5-(4-chloro-phenyl)-3-mehtyl-[l,2,4]triazole-1-yl]-pyridine-3-sulfonic acid amide;
6-[5-(4-bromo-phenyl)-3-mehtyl-[1, 2,4]triazole-1-yl]-pyridine-3-sulfonic acid amide;
6-(3-methyl-5-p-toly--[;i,2,4]triazoIe-l-yl)- pyridine¬s-sulfonic acid amide;
6-[5-(4~methoxy-phenyl)-3-methyl-[1,2,4]triazole-1-yl]- pyridine-3-sulfonic acid amide;
6-[5-{3-fluoro-phenyl)-3-niethyl-[l,2,4] triazole-1-yl]- pyridine-3-sulfonic acid amide;
6-[5-(3-chloro-phenyl)-3-methyl-[l,2,4]triazole-1-yl]- pyridine~3- sulfonic acid amide;
6-[5-(3, 5-dimethoxy-phenyl)-S-mehtyl-[1,2,4]triazole-1-yl]- pyridine-3- sulfonic acid amide;
1-(4-methanesulfonyl-phenyl]-3-methyl-5-phenyl-lH-[1,2,4]triazole;
5-(4-fluoro-phenyl)-1-(4-methanesulfonyl-phenyl]-3-inethyl-lH-[l,2, 4] triazole;
5-(4-chloro-phenyl)-1-(4-methanesulfonyl-phenyl)-3-methyl-lH-[l,2, 4]triazole;
5-(4~bromo-phenyl)-1-{4-methanesulfonyl-phGnyl)-3-methyl-lH-[1,2,4]triazole; and
2-[5-[4-broino-phenyl) -3-rnehtyl-[1, 2, 4] triazole-l-yl]-5-methanesulfonyl-pyridine.
On the other hand, the compounds of formula 1 according to the present invention can be prepared by performing the procedures as illustrated below.
However, the process for preparing the compounds of the present invention will not be restricted to following descriptions, especially in reaction solvents, bases, amounts of used reactants and the like.
Moreover, the compound of the present invention can be prepared by exploiting and combining various synthetic
methods described in the present specification or disclosed in other references of those skilled in this arts with a coordinate and arbitrary mode.
Those skilled in the art will appreciate that the conceptions and specific embodiments disclosed in the foregoing description may be readily utilized as a basis for modifying or designing other embodiments.
The compound of formula 1 according to the present invention can be prepared as illustrated schematically in the following reaction formula 1.
and n is 0 or 2.
As demonstrated in the above reaction formula 1, the compound of the present invention can be prepared through two steps from benzoyl halide or benzoyl halide derivatives as initial material.
A detailed description on preparing the compound of the present invention by the above method of Reaction formula 1 is as follows.
In the first step, the reaction of ethylacetimidate or its salt and benzoyl halide or benzoyl halide derivatives should be specifically accomplished in the presence of a base. Concretely, the reaction is performed by using dichloromethane at room temperature. The organic base can be selected from the group consisting of triethylamine, trimethylamine, tripropylamine, pyridine, imidazole and the like, while the inorganic base can be selected from the group consisting of sodium acetate, sodium hydroxide, sodium hydride, potassium hydroxide, sodium carbonate, potassium carbonate and the like. More preferably, triethylamine can be used.
In the second step, the reaction forming triazole is carried out by reacting hydrazine compound and the material obtained in the first step in a mixed solvent with dichloromethane and methanol at room temperature. If the hydrazine compound is a salt form, the reaction is carried out in the presence of the base such as triethylamine, trimethylamine, tripropylamine, pyridine, imidazole and the
like.
Especially, if the hydrazine compound is n=2, an oxidation reaction process should not be needed, but if the hydrazine compound is n=0, an oxidation reaction process should be carried out at the last step.
The above hydrazine can be selected from the group
consisting of 4-niethylsulfanylphenyl hydrazine
hydrochloride, 4-hydrazinobenzenesulfonamide hydrochloride,
5-hydra2inopyridine-3-sulfonic acid amide and 5-
methanesulfonylpyridine-2-yl hydrazine. Among these, 4-
methylsulfanylphenyl hydrazine hydrochloride (Tetrahedron
Letters, vol 28, No 42, p4933, 1987) and 6-
hydrazinopyridine-3-sulfonic acid amide (USP 4,204,870) are
synthesized by the disclosed method. 5-
methanesulfonylpyridine~2-yl hydrazine (The Journal of Organic Chemistry, vol 55, No 16, p4974, 1991) is synthesized by applying the disclosed method.
Oxidation reaction for forming sulfonamide or methylsulfone is carried out by using an oxidizer in dichloromethane. The oxidizer can be selected from the group consisting of MMPP (Magnesium monoperoxyphthalate hexahydrate) , MCPBA (m-Chloro peroxybenzoic acid), Oxone (Potassium peroxymonosulf ate) and the like. More preferably, MMPP can be used.
After completing the reaction, the resulting products can be processed through a common treatment such as chromatography, recrystallization and the like so a.s to be
separated and purified.
The compound of formula 1 according to the present invention has a selective inhibition activity against cyclooxygenase-2 and thus can be employed as an enzymatic inhibitor. The coitipound of formula 1 as a selective inhibitor against cyclooxygenase-2 can be a substitute for conventional non-steroid anti-inf lanunatory drugs. Concretely, it improves side effects of anti-inflammatory drugs in conventional non-steroids and is useful in patients suffering from peptic ulcer gastritis,, partial enteritis, ulcerative colitis, diverticulitis, gastrointestinal haemorrhagia, hypoprothrombinemia and the like. Besides, it is expected to be useful for treating inf lannnatory diseases such as osteoarthritis, rheumatoid arthritis and the like effectively.
The compound of the present invention can be administrated in a single dose or in separated doses, depending upon clinical purposes. The specific dosage for patients will vary, depending upon factors such as a sort of drug compound, body weight, sex, physical condition, diet, administration period, administration method, discharge ratio, drug composition and severity of diseases and the like.
The compound of the present invention can be administered as an oral, a local, a parenteral(subcutaneous, venous and muscular silinge or injection), an inhalational or a rectal drug. In case that these are prepared to a
pharmaceutical drug, one or more cortimonly used vehicles, methods for the preparation and the like can be selected properly from prior arts widely known to those skilled.
In order to attain the desired purpose of clinical administration, the active compound of formula 1 of the present invention can be administered simultaneously with more than one component of other conventional drugs.
However, the pharmaceutical drugs containing the compound of the present invention is not limited to forms described in the above, if it has a purpose for inhibiting cyclooxygenase-2 selectively. All kinds of drugs useful for the enzymatic inhibition can be within the scope of the present invention.
MODES FOR CARRYING OUT THE INVEHTION
Practical and presently preferred embodiments of the present invention are illustrated as shown in the following Examples.
However, it will be appreciated that those skilled in the art, on consideration of this disclosure, may make modifications and improvements within the spirit and scope of the present invention.
Preparation of H-(l-ethQxy -ethylidene)-benzamide
Ethylacetamidate hydrochloride l.Og (a.OSmmol} was dissolved in dichloromethane 40ml at room temperature, added dropwise triethylamine 1,08ml (16.99mmol) and stirred for 30 minutes at room temperature. Then, the reacting solution was cooled to 0°C, benzoylchloride 1.03g [7,35mniol) was slowly added dropwise in the reacting solution for 10 minutes and stirred for 4 hours at room temperature, After completing the reaction, the reacting solution was washed with water and saturated brine, and then dried with anhydrous magnesium sulfate. Then, the resulting product was filtered under reduced pressure and purified through a flash column chromatography {ethyl acetate:normal hexane=2:8). As a result, N-(l-ethoxy~ ethylidene)-benzamide (1.20g, yield: 86%) was obtained as a liquid phase.
H-NMR( 400MHz, CDCI3) 5 1.25 (t, 3H, J-=7.1Hz) , 1.96(s, 3H;, 4.20(q, 2H, J=7.1Hz), 7.32-7.38 (m, 2H) , 7.4 3-7.4 6(m, 1H>, 7.90-7.95(m, 2H)
Preparation of M-(1-ethoxy -ethylidene) -4-niethyl-benzamide
The reaction was carried out through the same method with Reference Example 1, except exploiting p-tolychloride 1.14g (7.35mmol} instead of benzoylchloride. As a result, N- (1-ethoxy-ethylidene)-4-methyl-benzamide (1.23g, yield: 81%) was obtained as a liquid phase.
H-NMR[400MHz, CDCla) 5 1.25[t, 3H, J=7.1Hz}, 1.96(s, 3H), 2.40{s, 3H) , 4.20(q, 2H, J=7.1Hz), 7.28-7.33(m, 2H) , 7.90-7.95(ra, 2H)
Preparation of M-(l-etfaoxy -ethylidene) -4-methoxy-benzamide
The reaction was carried out through the same method with Reference Example 1, except employing p-chloroanisol§ 1.25g (7.35mmol) instead of benzoylchloride. As a result, N-(1-ethoxy-ethylidene)-4-methoxy-benzamide (1.28g, yield: 19%) was obtained as a liquid phase.
-H-NMR( 4 00MHz, CDCla) 8 1.25 (t, 3H, J=7.1H2) , 1.96(s, 3H) , 3.79{s, 3H), 4.20(q, 2H, J=7.1Hz) , 7.28-7.33 (m, 2H), 7.90-7.95 (m, 2H)
Preparation of H-{l-ethoxy-ethylidene) -4-fluoro-benzainide
The reaction was carried out through the same method with Reference Example 1, except employing 4-fluorobenzoylchloride 1.17g (7.35mmol) instead of benzoylchloride. As a result, N-(1-ethoxy-ethylidene)-4-fluoro-benzamide {1.17g, yield: .76%) was obtained as a liquid phase.
H-NMR {400MHz, CDCI3) 5 1.25 (t, 3H, J=7.1H2) , 1.96(s, 3H) , 4.20(q, 2H, J=7.1Hz), 7.28-7.33 (m, 2H) , 7.90-7.95 (m.
Preparation of H-(l-ethoxy -ethylidene) -4-chloro-benzamide
The reaction was carried out through the same method with Reference Example 1, except employing 4-chlorobenzoylchloride 1.29g (7.35mmol) instead of benzoylchloride, As a result, N-(1-ethoxy-ethylidene)-4-chioro-benzamide (1.43g, yield: 8 5%) was obtained as a liquid phase.
H-NMR(4 00MHz, CDCI3) 5 1.25(t, 3H, J=7.1Hz), 1.96(s, 3H) , 4.20 [q, 2H, J=7.1Hz) , 7.2 9{dd, 2H, Ji=4.4Hz, J2=2.4Hz) , 7.91(dd, 2H, Jj-4.0Hz, J2=2.4Hz)
Preparation Q£ H-{l-ethoxy -ethylidene) -4-bronLO-b6nzamide
The reaction was carried out through the same method with Reference Example 1, except employing 4-bromobenzoylchloride l,61g [7.35mmol) instead of benzoylchloride. As a result, N-(1-ethoxy-ethylidene)-4-bromo-benzamide (1.62g, yield: 82%) was obtained as a liquid phase.
H-NMR(400MHz, CDCI3} 5 1.25(t, 3H, J=7.1Hz}, 1.96(s, 3H) , 4.20(q, 2H, J=7.1Hz), 7.29(dd, 2H, Jj=4.4Hz, J2=2.4Hz), 7.91(dd, 2H, Ji=4.0Hz, J2=2.4Hz)
Proparation of lT-(l-ethoxv -ethylidene) -3-£luoro-benzamide
The reaction was carried out through the same method with Reference Example 1, except employing 3-fluorobenzoylchloride 1.17g {7.35mmol) instead of benzoylchloride. As a result, N-(1-ethoxy-ethylidene)-3~ fluoro-benzamide (1.28g, yield: 83%) was obtained as a liquid phase.
H-NMR{400MHz, CDCI3} 5 1.25(t, 3H, J=7.1H2), 1.96(s, 3H), 4.20(q, 2H, J=7.1Kz) , 7.22-7.27 (m, IH) , 7.38-7.4 4(m, IH), 7.66-7.72(111, IH) , 7 . 79-7 . 83 (m, IH)
Preparation of H- (l-e-bhoxy -ethylidene) -S-chloro-benzamide
The reaction was carried out through the same method with Reference Example 1, except employing 3-chlorobenzoylchloride 1.29g (7,35mmol) instead of benzoylchloride. As a result, N-(1-ethoxy-ethylidene)-3-chloro-benzamide (1.41g, yield: 85%) was obtained as a liquid phase.
H-NMR(400MHz, CDCI3) 5 1.25{t, 3H, J-=7.1Hz), 1.96{s, 3H), 4.20(q, 2H, J=7.1H2) , 7.15-7.31 (m, 2H) , 7.7 5-7.85{m, 2H)
[ Prepaxation of H- (1-ethoxy -ethylidene) -3-bronio-benzaiBide]
The reaction was carried out through the same method
with Reference Example 1, except employing 3-
bromobenzoylchloride 1.61g {7.35mmol) instead of
benzoylchloride. As a result, N-(1-ethoxy-ethylidene)-3-bromo-benzaraide (1.57g, yield: 79%) was obtained as a liquid phase.
-H-NMR[4 00MHz, CDCI3) S 1.25 (c, 3H, J=7.1Hz) , 1.96(s, 3H), 4.20 (q, 2H, J="7 . IHz) , 7.13-7.17 (m, IH) , 7.30-7.32 [m, iH) , 7.74-7.76(m, IH) , 7.83-7.87(m, IH}
Preparation of N-(1-ehoxy -ethylidene) -3~inethoxy—benzainide
The reaction was carried out through the same method with Reference Example 1, except employing m-chloroanisole 1.25g (7.35mmol) instead of benzoylchloride. As a result, N-(1-ehoxy-ethylidene)-3-methoxy-benzamide (1.31g, yield: 81%) was obtained.
H-NMR(400MHz, CDCI3) 5 1.25{t, 3H, J7.1H2), 1.96(s, 3H}, 3.75(s, 3H) , 4.20[q, 2H,J=7.1Hz}, 6.55-6.60(ra, IH) , 6.99-7.02(m, IH), 7.03-7.05(m, IH) , 7.33-7.36{m, IH)
Preparation of S-(l-etfaoxy -ethylidene) -2-me'fchoxY-benzainide
The reaction was carried out through the same method with Reference Example 1, except employing o-chloiroanisole 1.25g (7.35r[imol) instead of benzoylchloride. As a result, N-(1-ethoxy-ethylidene)-2-methoxy-benzamide [1.22g, yield: 75%) was obtained.
H-NMR {400MHz, CDCla) 5 1.25(t, 3H, J=7.1Hz), 1.96(s, 3H), 3.30(s, 3H), 4.20 [q, 2H, J=7.1Hz), 7.00(d, IH, J=2.1Hz), 7.10-7.14(m, 3H)
Preparation of N~(l-ethoxy -ethylidene) -3, S-dimethoxy-benzamide
The reaction was carried out through the same method with Reference Example 1, except employing 3,5-dimethoxy ben2oylchloride 1. A7g (7 . 35jnmol) instead of benzoylchloride. As a result, N-(1-ethoxy-ethylidene)-3,5-diraethoxy-benzamide (1.51g, yield: 82%) was obtained as a liquid phase.
H-NMR(400MHz, CDCI3) 5 1.25 {t, 3H, J=7.1Hz), 1.96 (s, 3Hj , 3.80(3, 6H) , 4.20(q, 2H, uJ7,lHz) , 6.63(t, IH, J=2.3Hz), 7.15(d, 2H, J=2.3H2)
Preparation of H-(l-6thoxy -ethylidene) -3 , 4-dimethoxy-benzamide
The reaction was carried out through the same method with Reference Example 1, except employing 3,4-dimethoxy
benzoylchloride 1.25g {7.35mmol) instead of benzoylchloride.
As a result, N- (l-ethoxy-ethylidene) ~3,4-diinethoxy-
benzainide (1.44g, yield: 78%) was obtained as a liquid phase.
H"NMR[400MHz, CDCI3) 6 1.25(t, 3H, J=7.1Hz), 1.96(s, 3H), 3.60(s, 3H) , 3.80(s, 3H), 4.20{q, 2H, J=7.1Hz), 6.91(d, IH, J=2.lHz), 6,98(3, IH), 7.01(d, IH, J=2.1Hz)
Preparation of 4~ (3-methyl-5-phenyl-[1,2 , 4]
triazole-l-yl) -bgnzenesulfonamide
N- (1-ethoxy-ethylidene) -benzamide 4 00ing (2 . 09nimol) was dissolved in a mixed solvent of dichloromethane 20ml and methanol lOrtil and 4-hydrazinobenzenesulf onamide hydrochloride 515mg (2.23mmol) was added to the solution. Then, triethylamine 0.35ml {2.51mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-(3-methyl-5-phenyl- [1,2,4]triazole-l-yl)-benzenesulfonamide (368mg, yield: 56%) was obtained as a solid phase.
H-NMR{400MHz, DMSO-de) 5 2 . 35 {s, 3H) , 7 . 44-7 . 49 (m, 5H), 7.52(s, 2H), 7.56(dt, 2H, Ji-8.7Hz, J-2=2.5Hz), 7.89(dt, 2H, Ji=8.7Hz, J2=2.5Hz]
Melting point : 192~194°C
Preparation of 4-[5-(4-fluoro-phenyl)-3-inethyl-
[1,2,4] triazole-l-yll-benzenesulfonamide
N-(1-ethoKy-ethylidene)-4-fluoro-benzanide 438mg (2.09mmol) was dissolved in a mixed solvent of dichloromethane 20ml and methanol 10ml, and 4-hydrazinobenzenesulfonamide hydrochloride 515mg (2.23mmol) was added to the solution. Then, triethylamine 0.35ml (2.51mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for S hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-{4-fluoro-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-benzenesulfonamide (424mg, yield: 61%) was obtained as a solid phase.
H-NMR(400MHz, DMSO-ds) 5 2.35(s, 3H), 7.27-7.31(m, 2H) , 7.47-7.51(m, 2H) , 7.52[s, 2H) , 7.56Cdt, 2H, Ji=8.7Hz,
J2=2.5Hz) , 7.89 (dt, 2H, Ji=8.7Kz, J2=2.5Hz} Melting point : 220~221°C
Preparation of 4-[5-(4-ehloro--phenyl)-3-methyl-
[1,2,4] triazole-1-yl] -benzenesulfonamide
N-(1-ethoxy-ethylidens)-4-chloro-benzamide 472mg (2.09rriinol) was dissolved in a mixed solvent of dichloromethane 20ml and methanol 10ml, and 4-hydrasinobenzenesulfonamide hydrochloride 515mg (2.23mmol) was added to the solution. Then, triethylamine 0.35ml (2,Slmmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(4-chloro-phenyl)-3-methyl-[l,2,4]tria2ole-l-yl]-benzenesulfonamide (423mg, yield: 58%) was obtained as a solid phase.
H-NNR(400MHz, DMSO-de) 5 2.35(s, 3H) , 7.4 6(dt, 2H, Ji=8.7Hz, J2=2.1Hz), 7.50-7.54(m, 4H) , 7.58(dt, 2H, Ji=8.7Hz, J:=2.5Hz), 7.89(dt, 2H, Ji=8.7Hz, J2=2.5H2)
Melting point: 247~249°C
Preparation o£ 4-[5-(4-bromo-phenyl)-3-nt6thyl-[l ,2 ,4]
triazole-1-yl] -benzeneaulfonamide
N-(1-ethoxy-ethylidene]-4-brorao-benzamlde
565ing (2.09iTmol) was dissolved in a mixed solvent of
dichloromethane 20rnl and methanol 10ml, and 4-
hydrazinobenzenesulfonamide hydrochloride 515mg {2.23nimol) was added to the solution. Then, triethylamine 0.35ml (2.51mmol) was slowly added dropwise at room temperature for: IQ minutes and Stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(4-bromo-phenyll-3-methyl-[l,2, 4] triazde-l-yl]-benzenesulf onamide (600mg, yield: 73%) was obtained as a solid phase.
H-NMR(4 00MHz, DMSO-de) 5 2.35 (s, 3H) , 7.39(dt, 2H, Ji=9.0Hz, J2=2.2Hz), 7.51(s, 2H) , 7.58(dt, 2H, Ji=9.1Hz, J2=2.4Hz), 7.67(dt, 2H, Ji=9.1H2, J2-2.4Hz), 7.91(dt, 2H, Ji=9.2Hz, J-2=2.4Hz)
Melting point: 240-241°C
Preparation of 4-(S-methyl-S-p-toly-[1,2,4]
triazole-l-yl) -benzenesul£onamide
N-[1-ethoxy-ethylidene)-4~methyl-benzamide 429mg
(2.09rnmol} was dissolved in a mixed solvent of
dichloromethane 20ml and methanol lOml, and 4-
hydrazinobenzenesulfonamide hydrochloride 5l5mg (2.23mmol)
was added to the solution. Then, triethylamine 0.35ml
(2.51mmol) was slowly added dropwise at room temperature
for 10 minutes and stirred for 8 hours. After completing
the reaction, water 20ml was added to the reacting solution
and extracted two times with dichloromethane, and then, the
collected organic layer was washed with saturated brine.
The organic layer was dried with anhycirous magnesium
sulfate, filtered and concentrated under reduced pressure,
and the resulting product was re-crystallized in acetone
and hexane phase. As a result, 4-{S-roethyl-S-p-toly-
[1,2,4]triazole-l-yl)-benzenesulfonamide (467mg, yield: 68%) was obtained as a solid phase.
H-NMR {400MHz, DMSO-de) 5 2.30 (s, 3H) , 2.35(s, 3H) , 7.18[d, 2H, J-=8.1Hz), 7.31(d, 2H, J=8.1Hz), 7.52(s, 2H) , 7.53(dd, 2H, Ji=6.8Kz, J2=1.9Hz), 7 . 91 (dd, 2H, Ji=5.8Hz, J2=1.9Hz)
Melting point: 248~249°C
Preparation of 4-[5-{4-methoxv—phenyl)-3-meh1:yl
-11,2,4] triazole-l-ylj-benzenesulfonamide
N- (l-ethoxy-ethylidene) -4-methoxy-benzaniide 462mg
(2.09mmol) was dissolved in a mixed solvent of
dichloromethane 20ml and methan.ol 10ml, and 4-
hydrazinobenzenesulfonamide hydrochloride 515mg (2 . 23itiinol)
was added to the solution. Then, triethylamine 0.35ml
(2.Slmmol) was slowly added dropwise at room temperature
for 10 minutes and stirred for 8 hours. After completing
the reaction, water 20mi was added to the reacting solution
and extracted two times with dichloromethane, and then, the
collected organic layer was washed with saturated brine.
The organic layer was dried with anhydrous magnesium
sulfate, filtered and concentrated under reduced pressure,
and the resulting product was re-crystallized in acetone
and hexane phase. As a result, 4-[5-(4-methoxy-phenyl)-3--
mehtyl-[1,2,4]triazole-1-yl]-benzenesulfonamide (381mg,
yield: 53%) was obtained as a solid phase.
H-NMR (400MHz, DMSO-ds) 6 2.35 (s, 3H) , 3.79(5, 3H1 , 6.98(d, 2H, J=8.9Hz), 7.37 (d, 2H, J=8.9Hz) , 7.52 (s, 2H) , 7.56{d,2H, J-=8.7Hz) , 7.91(d, 2H, J-=8.7Hz}
Melting: 230~231°C
Preparation of 4-[5-(3-fluoro-phenyl)-3-methvl-
[1,2,4] triazole-l-yl]-benzeneaulfonamide
N-(l-ethoxy-ethylidene)-3-fluroro-benzamide 438mg (2.OSmmol) was dissolved in a mixed solvent of dichloroiTLethane 2 0ml and methanol 10ml, and 4-hydrazinobenzenesulf onamide hydrochloride 515mg (2.23niinol) was added to the solution. Then, triethylamine 0.35ml {2.51mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 2 0ml was added to the reacting solution and extracted two times with dich 1 oromethane, and then the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(3-fluoro-phenyl]-3-methyl-[l,2,4]triazole-l"yl]-benzenesulfonamide [382mg, yield: 55%) was obtained as a solid phase.
H-NMR(400MKz, DMSO-de) 8 2.35(s, 3H) , 7.22-7.38(in, 3H), 7.45-7.50(m, IH) , 7.53[s, 2H), 7.58 {dt, 2H, Ji-8.6Hz, J;=2.4Hz), 7.91(dt, 2H, Ji=8.6Hz, J2=2.4Hz)
Melting point: 197~199°C
Preparation of 4-[5-(3-chloro-phenyl)--3-methyl-
[1,2,4] triazole-1-yl]-benzenesulfonamide
N- (1-ethoxy-ethylidene) -3-chloro-benzamide 472ing (2.09mraol) was dissolved ir. a mixed solvent of dichloromethane 20ral and methanol 10ml, and 4-hydrazinobenzenesulfonamide hydrochloride 515rag (2.23ramol) was added to the solution. Then, triethylamine Q.35ml (2.51inraol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(3-chloro-phenyl)-3-methyl" [1,2, 4] triazole-1-yl] -bensenesulf onamide (517irig, yield: 71%) was obtained as a solid phase.
H-NMR{4 00MHz, DMSO-dg) 5 2.35 {s, 3H) , 7.30(d, IH, J=6.8H2), 7.45(t, IH, J=7.7Hz), 7.51-7.62(m, 6H) , 7.91(d, 2H, J=8.3Hz)
Melting point: 146~147°C
Preparation of 4-[5-Q-broMo-pfaenyl)-3-niethyl-[1,2 ,4]_
triazole-l~yl] -benzenesulfonamide
N-(l-ethQxy-ethylidene) -3-bromo-benzamide 5 65mg (2.09mmol) was dissolved in a mixed solvent of dichloromethane 20ml and methanol 10ml, and 4-hydrazinobenzenesulfonaraide hydrochloride 515mg (2,23inmol) was added to the solution. Then, triethylamine 0.35ml (2.51minol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then, the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-{3-bromo-phenyl)-3-methyl-[l,2,4jtria2ole-l-yl]-benzenesulfonamide (54 3mg, yield: 66%) was obtained as a solid phase.
H-NMR[4 00MHz, DMSO-de) 5 2.35 (s, 3H) , 7.33-7.41[m, 2H) , 7.53(s, 2H) , 7.58(dt, 2K, J'i=9.2Hz, c7z=2.5Hz) , 7.66-7.73[m, 2H), 7.91(dt, 2H, >Ji=8.8Hz, J2-2.5Hz)
Melting point : 152~153°C
Preparation of 4-[S-(3-methoxy-phenyl)-3-Biethyl
-[1,2,4] triazole-l-yl] -benzene sulfonamide
N- (1-ethoxy-ethylidene) -3-methoxy-benzamide 462iiig
(2.09mmol) was dissolved in a mixed solvent of
dichlororaethane 20ml and methanol lOml, and 4-hydrazinobenzenesulf onamide hydrochloride 515mg (2 . 23inmol) was added to the solution. Then, triethylaniine 0.35ml (2.51minol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(3-methoxy-phenyi)-3~ methyl-[l,2,4]triazole-l-yl]-benzenesulfonamide {503mg, yield: 70%) was obtained as a solid phase.
H-MMR {4 00MHz, DMSO-ds) 5 2.35 (s, 3H) , 3.70 (s, 3H) , 5.85-7.07(m, 3H), 7.31(t, IH, J=8.0Hz), 7.51 (s, 2H), 7.58 (dd, 2H, Ji=6.6H2, J2-1.9Hz) , 7.91 (dd, 2H, Ji=6.6Hz, 02=1. 9Hz)
Melting point: 211--212°C
Preparation of 4-[5-(2-methoxy-phenyl)-3-methyl
-[1,2,4] triazole-1-yl] -benzenesulfonamide
N--{l-ethoxy-ethylidene) -2-methoxy-benzamide 462mg (2.09mmol) was dissolved in a mixed solvent of dichloromethane 20ml and methanol 10ml, and 4-
hydrazinobenzenesulfonamide hydrochloride 515mg (2.23mitiol)
was added to the solution. Then, triethylamine 0.35ml
[2.51mmol) was slowly added dropwise at room temperature
for 10 minutes and stirred for 8 hours. After completing
the reaction, water 20ml was added to the reacting solution
and extracted two times with dichloromethane, and then, the
collected organic layer was washed with saturated brine.
The organic layer was dried with anhydrous magnesium
sulfate, filtered and concentrated under reduced pressure,
and the resulting product was purified through a flash
column chromatography (ethyl acetate:normal hexane=7:3),
As a result, 4- [5-(2-methoKy-phenyl)-3-methyl-
[1,2,4]triazole-l-yl]-benzenesulfonamide (86mg, yield: 12%) was obtained as a liquid phase.
H-NMR(400MHz, DMSO-ds) 5 2.35(s, 3H) , 3.25(s, 3H) , 7.04 Id, IH, J=8.2Hzl , 7.12{dt, IH, Ji=7.4Hz, J2=1.0Hz), 7.38-7.45 (m, 4H} , 7. 49-7.55{m, 2H] , 7.81 (dt, 2H, Ji=8.7H2,
J2 = l. 9H2)
Preparation of 4- [5- (3 , 4-diniethoxy-ph6nyl) -3-ntehtyl
-[1,2,4] tri.azole-1-ylI-benzenesulfonainide
N-(l-ethoxy-ethylidene)-3,4-dimethoxy-benzamide 536mg (2.09mmol} was dissolved in a mixed solvent of dichloromethane 20ml and methanol 10ml, and 4-hydrazinobenzenesulfonamide hydrochloride 515mg (2.23mn:iol)
was added to the solution. Then, triethylamine 0.35ml (2.51mmol) was slowly added dropwise at room tsrtiperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(3,4-dimethoxy-phenyl)-3-mehtyl-[1,2,4jtria2ole-l-yl]-benzenesulfonamide (575mg, yield: 72%) was obtained as a solid phase.
H~NMR(4 00MH2, DMSO-de) 5 2.35 (s, 3H) , 3.57 [s, 3H) , 3.80(5, 3H), 7.92-7.03(m, 3H) , 7.51(s, IH) , 7.58 (dt, IH, J1-9.1H2, J2-2.6H2), 7.91(dt, 2H, J;=9.1Hz, J3=2.6Hz)
Melting point: 176-"178°C
Prsparabion of 4-[5-{3,5-diiaethoxy-phenyl) -3-met:h.yl
-[1,2,4]triazole-1-yl]-benzenesulfonamide
N-(l-ethoxy~ethylidene)-3,5-dimethoxy~benzamide 536mg (2.09miuol) was dissolved in a mixed solvent of dichloromethane 20ml and methanol 10ml, and 4-hydrazinobenzenesulfonamide hydrochloride 515mg (2.23mmol) was added to the solution. Then, triethylamine 0.35ml (2.51mii:!ol) was slowly added dropwise at room temperature
for 10 minutes and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichlororaethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(3,5-dimethoxy-phenyl)-3-methyl- [1,2,4]triazole-1-yl]-benzenesulfonamide (551mg, yield; 69%) was obtained as a solid phase,
H~NMR(400MHz, DMSO-dg) 5 2.35 (s, 3H) , 3.65 (s, 6H) , 6.54(d, 2H, J=2,2Hz), 6.60(t, IH, J=2,3Hz), 7.51(s, IH) , 7.58(dt, IH, Ji=9.1Hz, J2=2.4Hz), 7.91{dt, 2H, Ji=9.1Hz, J2=2.4Hz)
Melting point: 207~20S'C
Preparation of 6-(3-methyl-5-phenyl-[1,2,4]
triazole-1-yl)-pyridin6-3-3ulfonio acid amide
N~(1-ethoxy-ethylidene)-benzaraide 4 00mg (2.09mmol) was dissolved in a mixed solvent of dichloromethane 20ml and methanol 10ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433rng {2.23mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic
layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystailized in acetone and hexane phase. As a result, 6-(3-methyl-5-phenyl-[1,2,4]triazole-1-yl)-pyridine-3-sulfonic acid amide (336mg, yield: 51%) was obtained as a solid phase.
M-NMR [4 00MHz, DMSO-de) 6 2.35 (s, 3H) , 7.40-7.51{in, 5H), 7.73{s, 2H) , 7.9e(d, IH, 08.5Hz}, 8.4 3(dd, IH, Ji=8.4H2, J2=2.4H2) , 8.68 (dd, IH, Ji=2.5Hz, J2=0.5Hz)
Melting point: 203-204'C
Pi-eparation of 6-C5-f4-fluoro-pheny],)-3-methyl-
[1,2,4]triazole-1-yl]-pyridine-3- sulfonic acid amide
N-(1-ethoxy-ethylidene)-4-fluoro-benzamide 4 38mg 12.09ramol) was dissolved in a mixed solvent of dichloromethans 20ml and methanol 10ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433mg (2,23mmol) was added to the solution and stirred for 8 hours, After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then, the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-
crystallized in acetone and hexane phase. As a result, 6-[5-[4-fluoro-phenyl)-3-iRethyl-[l,2,4]triazDle-l-yl]-pyridine-3- sulfonic acid amide (391mg, yield: 56%) was obtained as a solid phase,
H-NMR(400MHz, DMSO-ds) 5 2.35(s, 3H) , 7.25-7.31(m, 2H) , 7.55-7.69(m, 2H) , 7.73{s, 2H), 7.98(dd, IH, Ji-B.5Hz, J2=0.5Hz), 8.4 3 (dd, IH, Ji=8.5Hz, J'2=2.4Hz), 8.68 (dd, IH, Ji=2.4Hz, J2=0-5H2)
Melting point; 22l-222°C
Preparation o£ 6-[5-(4-chloro-phenyl)-S-methyl-
[1,2 , 4] triazole--l-yl]-pyridlne-3- sulfonic acid amide
N- (l-ethoxy-ethylidene) ~4-chloro-benzarnide 472ing
(2.09inrrLol) was dissolved in a mixed solvent of dichloromethane 20ml and methanol 10ml, and 6-hydrazinopyridine~3-sulfonic acid amide 433mg {2.23ramol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then, the organic layer was washed with saturated brine. The organic laysr was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re--crystallized in acetone and hexane phase. As a result, 5-[5-(4-chloro-phenyll-3-methvl-[1,2,4]triazole-1-yl]-
pyricline-3- sulfonic acid amide (446mg, yield: 61%) was obtained as a solid phase.
H-NMR(400MHz, DMSO-de) 5 2.35(s, 3H) , 7.45-7.51(m, 4H), 7.73(s, 2H) , 7.98[dd, IH, Ji=8.5Hz, Jj-O.SHz), 8.43(dd, IH, Ji=8.5Hz, J3=2.4Hz), 8.68 (d, IH, J-1.6Hz)
Melting point: 215~217°C
Preparation of 6-[5-
trlazole-1-yl]-pyridine-3- sulfonic acid amide
N- (1-ethoxy-ethylidene) -4-brcir.o-benzamide 565mg (2. C9rnraoi) was dissolved in a mixed solvent of di chicromethane 20ml and methanol 10ml, and 6-hydra2inopyridine-3-sulfonic acid amide 4 33mg (2.23mmol} was added to the solution and stirred for 8 hours. After completing the reaction, water 2Oral was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnGsium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(4-bromo-phenyl}-3-methyl-[l,2,4]triazole-l-yl]-pyridine-3- sultonic acid amide i431mg, yield: 53%) was obtained as a solid phase.
H-NMR[400MHz, DMSO-dg) 5 2.35{s, 3H) , 7.45-7.48(m,
2H) , 7.63-7.66(m, 2H) , 7.72(s, 2H) , 7.98(dd, IH, Ji=B.4H2, J2=0.6Hz), 8.41(dd, IH, Ji=8.5Hz, J2=2.5Hz), 8.68 (dd, IH, Ji=2.3Hz, J2=0.6Hz)
Melting point: 221--222'C
Preparation of 6-(3-methyl-5-p-toly" [1,2 , 4]
triazole-1-yl)"pyridine-3- sulfonic acid amide
N-(1-ethoxy-ethylidene)-4-methyl-benzamide 429mg (2.09iranol) was dissolved in a mixed solvent of dichloromethane 20ml and methanol 10ml, and 5-hydrazinQpyridine-3-salfoRic acid araide 433mg (2.23rnmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-{3-methyl-5-p-toly- [1,2,4]triazole-1-yl) -pyridine-3-sulfonic acid amide (372mg, yield: 54%) was obtained as a solid phase.
H-NMR {400MHz, DMSO-de) 5 2.35(s, 3H) , 2.40{s, 3H) , 7.20(d, 2H, J-8.0HZ), 7.35{d, 2H, J=8.2Hz), 7.69(s, 2H) , 7.90(d, IH, J=8.4Hz), a.33ldd, IH, Ji=8.5Hz,
8.68[t, IH, .>0.7H2)
Melting point: 198-199°C
Preparation of 6- [5- (4-mefchoxy-phenyl) -3-meht:yl - [1,2 ,4] triazole-l-vll-pyrid,ine-3- sulfonic acid amide
N-[1-ethoxy-ethylidene)-4-methoxy-benzamide 452mg
(2.09mmol) was dissolved in a mixed solvent of
dichlororae thane 2 0inl and methanol 10ml, and 6-
hydra2inopyridine~3-sulfonic acid amide 433mg (2.23mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(4-methoxy-phenyl)-3-mehtyl~[1,2,4]triazole-1-yl]-pyridine-3-sulfanic acid amide (397mg, yield; 55%) was obtained as a solid phase.
H-HMR(400MHz, DMSO-de) 6 2.35 (s, 3H) , 3.78(s, 3H} , 6.98 (dt, 2H, uJi=9.7Hz, i72=6.0Hz) , 7.42 (dt, 2H, Ji=7. 6Hz, J:-2.9Hz), 7.73(s, 2H) , 7.98(dd, IH, i=8,7Hz, J2=0.6Hz], 8.43 (dd, IH, iJi=8.4Hz, J2=3.4Hz) , 8.68Cdd, IH, iJi=2.4Hz,
J;= 0.6Hz)
Melting point: 191~192°C
Preparation of 6-[5-(3-fluoro-phenyl)-3-mehtyl-
tl,2,41triazole-l-yl]-pyridine-3-sul£oniG acid amide
N- (1-ethoxy-ethylidene) -3-f luoro-benzamide 438mg (2.09minol) was dissolved in a mixed solvent of dichlororaethane 20nil and methanol 10ml, and 6-hydr=zir.opyridine-3-sulfonic acid amide 433mg [2.23miP.ol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 5-[ 5-{3-fluoro-phenyl)-3-mehtyl~[1,2,4 ]triazole-l-yl]-pyridine-3-sulfonic acid amide (370mg, yield: 53%) was obtained as a solid phase.
H-NMR(400MHz, DMSO-de) 6 2.35(s, 3H) , 7 . 30-7 . 38 (ra, 3H), 7.43-7.51(m, IH) , 7.73(s, 2H) , 7.98{d, IH, J-S.lHz), 8.43(dd, IH, Ji=8.5Hz, J2=2.AHz), 8.68(d, IH, J=1.9Hz)
Melting point: 195~196°C
Preparation of 6-[5-
[1,2,4] triazole-l-yll-pyridina-S- sulfonic acid amide
N- [1-ethoxy-ethylidene) -3-chloro-benzainide 472rag
(2.09mmol) was dissolved in a mixed solvent of dichloromethane 20inl and methanol lOml, and 6-hydrazinopyridine-3-sulfonic acid amide 433mg (2.23mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times ' with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crys-aliized in acetone and hexane phase. As a result, 6-[5-[3-chloro-phenyl)-3-methyl'[1, 2, 4] triazole-1-yl]-pyridine-3- sulfonic acid amide {358mg, yield: 49%) was obtained as a solid phase.
H-NMR (400MHz, DMSO-de) 5 2 . 40 (s, 3H) , 7 . 33-7 . 36 (m, 2H), 7.50-7.58(m, IH) , 7.61-7.63(m, IH), 7.75(s, 2H) , 8.00 (d, IH, J=8.5Hz) , 8.37 (dd, IH, Ji=8.5Hz, J2=2.4Hz) , 8.56(dd, IH, uJi=2.3Hz, L72=0.5HZ]
Melting point: 169~168°C
Preparation of 6-[5-(3,5-dimethoxy-phenyl)-3-iiiethyl
-[1F2,4] tg;azole-I-yi]-pyridine-3- sulfonic aoid amide
"ii-ethoxy-ethylidene) -3, 5-dimethoxy-benzamide 536mg (2.09mino],} was dissolved in a mixed solvent of dichloroinethane 20ml and methanol 10ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433mg (2.23mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(3,5-dimethoxy-phenyl)-3-methyl-[1,2,4] triazole-1-yl]-pyridine-3- sulfonic acid amide {4 96mg, yield: 62%) was obtained as a solid phase.
H~NMR(400MHz, DMSO-de) 5 2,35(s, 3H) , 3.70{s, 6H) , 6.57-6.62{m. 2H) , 7.73[s, 2H) , 7.98(dd, IH Ji=8.5H2, J2=0.5Hz) , 8.43 (dd, IH, Ji=8.5Hz, J2=2.3Hz) , 8.7 8 (dd, IH, Ji=2.5Hz, LJ2=0.5HZ)
Melting point: 195~196°C
Preparation of S-methyl-l-(4-methylsul£anyl-phenyl)-5
-Phenyl-IH- [1,2,41triazole
N- (l-ethoxy-ethylidene)-benzamide 400ing (2.09mnol) was dissolved in a mixed solvent of dichloromethane 20ml and methanol lOml, and C-methylsulfanyl-phenyl}-hydrazine hydrochloride 439mg (2.23rranol) was added to the solution. Then, triethylamine O.SSml (2,51mmQl) was slowly added dropwise at room temperature for 10 minutes and stirred for 6 hours. After completing the reaction, water 20nl was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer wa.s dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was purified through a flash coluir.n chromatography (ethyl acetate:normal hexane=l: 1} . As a result, 3-methy1-1- (4-methylsulfanyl-phenyl)-5-phenyl-IH-[1, 2 , 4] triazole (359mg, yield: 61%) was obtained as a liquid phase.
H-NMR(4D0MHz, DMSO-ds) 6 2.35 (s, 3H) , 2.47 (s, 3H) , 7.l8-22(in, 4H), 7.23-7.25(m, 3K] , 7 . 51-7 . 55 (m, 2HJ
Preparation of 1-(4-methanesulfony-phenyl)-3~methyl-5
-phenyl-lH-[1,2,4]triazole
3-methyl-l-{4-methylsulfanyl-phenyl)-5-phenyl-lH-[1,2,4]triazole 281mg (l.Ommol) was dissolved in a mixed solvent of dichloromethane 25ml and methanol 5ml, and MMPP
SOOrag [l.SOrnmol) was slowly added to the solution and stirred for 8 hours. After completing the reaction, the reacting solution was filtered, and the mother liquor was washed with sodium hydrogen carbonate and saturated brine, respectively, and then, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was purified through a flash column chromatography (ethyl acetate:normal hexane=7:3). As a result, 1-(4-methane3ulfony-phenyl)-3-methyl-5-phenyl-1H-[1,2,4]triazole (291mg, yield; 93%) was obtained as a solid phase.
*H-NMR{4 00MH2, DM30-ds> 5 2.35 (s, 3H) , 3.25 (s, 3H) , 7.3e-7.50{m, 5H) , 7.62(dd, 2H, L7I-6.8HZ, J2=2.0HZ), 8.02(dd, 2H, J: = 6.8Hz, J"2=2.0Hz)
Melting point: llB-ligC
Preparation of 5-(4--fluoro-phenyl)-S-meh-byl-l
-(4-methylsuJ.fanyl-phenyl) -IH- [1,2,4] triazole
N- (1-ethoxy-ethylidene) -4-f luoro benzamide 4 38rog (2.09mmol) was dissolved in a mixed solvent of dichloromethane 20ml and methanol 10ml, and (4-methylsulfanyl-phenyl)-hydrazine hydrochloride 439mg (2.23mmol) was added to the solution. Then, triethylamine 0.35ml (2.51inmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After
completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was purified through a flash column chromatography (ethyl acetate:normal hexane=l:l). As a result, 5-(4-fluoro-phenyl)-3-mehtyl-l
-(4-methylsulfanyl-phenyl) -1H--[1, 2, 4] triazole (389mg, yield: 62%) was obtained as a liquid phase.
H-MMRC400MHz, DMSO-de) 5 2.35(s, 3H} , 2.52(s, 3H) , 7.25-7.35{m, 6H), 7.45-7.51(ra, 2H)
Preparation o£ 5-
-methanesulfonyl-phenyl) -S-roethyl-lH- [1,2,4] triazole
5-(4-fluoro-phenyl)-3-methyl-l-(4-methylsulfanyl-phenyl)-IH-[1, 2, 4]triazole 300ing (l.Ornmoi) was dissolved in a mixed solvent of dichloromethane 25ml and methanol 5ml, and MMPP SOOmg (1.30mmol) was slowly added to the solution and stirred for 9 hours. After completing the reaction, the reacting solution was filtered, and the mother liquor was washed with sodium hydrogen carbonate and saturated brine, respectively, and was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure,
and the resulting product was purified through a flash column chromatography {ethyl acetate:normal hexane=7:3). As a result, 5-(4-fluoro-phenyl) -1-(4-methanesulfonyl-phenyl)-3-methyl-lH-[1, 2, 4] triazole (302mg, yield: 91%) was obtained as a solid phase,
H-NMR{400MHz, DMSO-de) 6 2.35(s, 3H} , 3.25(s, 3H) , 7.29(dd, 2H, J=8.9Hz, J2=5.4Hz) , 7.50(dd, 2H, Ji=8.9H2, L72=5.4HZ), 7.62(d, 2H, J-8.8Hz), 8.02{d, 2H/ J-8.8Hz)
Melting point: 143~144°C
Preparation o£ 5-(4--chloro-phenyl)-B-methyl-l
- (4-methylsTil£anyl-phenyl) -IH- [1,2 , 4J triazole
N- (l-ethoxy-ethylidene) -4-chloro benzamide 472ing
[2.09irjnol) was dissolved in a mixed solvent of
dichloromethane 2 0ml and methanol iOml, and {4-
methylsulfanyl-phenyl}-hydrazine hydrochloride 439mg
{2,23mmol) was added to the solution. Then, triethylamine 0.35ml (2.51minol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was
purified through a flash column chromatography (ethyl acetate:normal hexane=l:l). As a result, 5-(4-chloro-phenyl}-3-methyl-l-(4-raethylsulfanyl-phenyl)-IH-[1,2,4]triazole (390g, yield: 59%) was obtained as a liquid phase.
H-NMR(400MHz, DMSO-de) 5 2.35(s, 3H) , 2.47(s, 3H) , 7.19-7.23(m, 4H) , 7.33(d, 2H, J=8.6Hz), 7.42 (d, 2H, J"=8. 6Hz)
Preparation of 5-(4-Ghloro-phenyl)-1-
-methanesulfonyl-phenyl) -3-inethyl-lH- [1,2,4] triazole
5- (4-chloro-phenyl) -3-methyl-l- ( 4-inethylsulf anyl-phenylj-IH-[1, 2, . ] triazole 315mg (l.OmmoI) was dissolved in a mixed solvent of dichloromethane 25Tnl and methanol 5ml, and MMPP 800mg (1.BOramol) was slowly added to the solution and stirred for 8 hours. After completing the reaction, the reacting solution was filtered, and the mother liquor was washed with sodium hydrogen carbonate and saturated brine, and then dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was purified through a flash column chromatography (ethyl acetate:normal hexane=7:3). As a result, 5-(4-chloro-phenyl)-1-(4-methanesulfonyl-phenyl)-3-methyl-lH-[l,2,41triazole {305mg, yield: 88%) was obtained as a solid phase.
H-NMR(400MHz, DMSO-dg) 5 2.35(s, 3H) , 3.25(s, 3H) , 7.49{d, 2H, J=8.8Hz), 7.52[d, 2H, J=8.8Hz), 7.65{d, 2H, J=6.7H2), 8.02(d, 2H, J=6.7Hz)
Melting point: 184~185°C
Preparation of 5-(4-bromo-phanyl)-3-methyl-1- (4-niethylsulfanyl-phenyl) -1H-[1,2 ,4] triazole
N-(1-ethoxy-ethylidene)-4-brQmo benzamide 565mg (2.09mmol) was dissolved in a mixed solvent of dichloromethane 20ml and methanol 10ml, and [4-methy1sulfany1-phenyl)-hydrazine hydrochloride 439mg [2.23mmol) was added to the solution. Then, triethylamine 0.35inl [2, Slimnol) was slowly added drop wise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was purified through a flash column chromatography (ethyl acetate .'normal hexane=l: 1) . As a result, 5- ("i-brorno-phenyl)-3-methyl-l-(4-methylsulfanyl-phenyl)-IH-[1,2,4]triazole (497g, yield: 66%) was obtained as a liquid phase.
H-NMR(400MHz, DMSO-dg) 6 2.35(s, 3H) , 2.47(s, 3H) ,
7.18-7.22(m, -H) , 7.37(ci, 2H, J=S.lHz), 7.49(d, 2H, J=8.7Hz)
Preparation of 5-(4-bromo-ph6nyl)-1-(4-
methanesTJlfony I-phenyl) -3-methyl-lH- [1,2,4] triazole
5- (4-bromo-phenyl3 ~3-inethyl-l- ( 4-methylsulfanyl-phenyl)-IH-[1, 2, 4] triazole 360mg (l.Ommol) was dissolved in a mixed solvent of dichloromethane 25inl and methanol 5ml, and MMPP SOOmg (1.30mmol) was slowly added to the solution and stirred for 8 hours. After completing the reaction, the reacting solution was filtered, and the mother liquor was washed with sodium hydrogen carbonate and saturated brine, and then dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was purified through a flash column chromatography [ethyl acetate:normal hexane=7;3) . As a result, 5-(4-bromo-phenyl)-1-(4-methanesulfonyl-phenyl)-3-methyl-lH-[1,2,4]triazole (357mg, yield: 91%) was obtained as s solid phase.
H-NMR[4 00MHz, DMSO-de) 5 2.35[s, 3H), 3.25(s, 3H), 7.41[d, 2H, Ji=6.72Hz, u72=2.0Hz), 7.65-7.68[m, 4H) , 8.02(d, 2H, J=8.6Hz)
Melting point: 208~209°C
Preparation of 2-[5-(4-bromo-phenyl)-S-nathyl-[1,2,4]
triazole-1-yl] -5-methanesulfonyl-pyridine
N~ (1-ethoxy-ethyIidene) -4-bromD-ben2amide 565ing (2.09mmol) was dissolved in a mixed solvent of dichloromethane 20ml and methanol ICml, (5-methansulfonyl~ pyridine-2-yl)-hydrazine 431mg (2.23mmol) was added to the solution and the solution was stirred for 8 hours. After completing the reaction, water 20ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 2-[5- (4-bromo-phenyl)-3-methyl-[1,2, 4]triazole-1-yl]-5-methanesulfonyl-pyridine (502mg, yield: 61%) was obtained as a solid phase.
H-NMR (400MHz, DMSO-ds) 8 2.35 (s, 3H) , 3.35(s, 3H> , 7.45(d, 2H, Ja.SHz), 7.75(d, 2H, J=8.6Hz}, 8.02(dd, IH, Ji=8.7Hz, J2=0.7Hz) , 8.55 (dd, IH, Ji=8.6Hz, J2=2.5Hz) , 8.80(d, IH, J=1.7H2)
Melting point: 211~212'C
The selective inhibition activity against cyelooxygenase-2
(1) Experimental procedure
In order to investigate pharmacologically the selective inhibition activity against cyclooxygenase-2 enzyme, the inhibitive effects against cyclooxygenase-1 and cyclooxygenase-2 were measured by two methods as follows.
First, the cyclooxygenase-1 was examined by using U-937 through the following procedure.
The cultured U-937 (humane lymphoma cell, obtained from Korean cell line bank) was centrifuged to collect the pellet. Then, the pellet was diluted with IxHBSS (Hanky's balanced salt solutin) at the concentration of 1x10 cells/ml, and 1ml of them was transferred into each well of 12-well plates, and then dissolved with DMSO. 5yfi of the diluted sample solution, and bid of DMSO vehicle were added therein and mixed, and the mixture was cultured at 37°C in CO2 incubator for 15 minutes. Arachidonic acid as a substrate was dissolved in ethanol to prepare a stock solution with a concentration of lOmM, followed by diluting with 1XHBSS to prepare the solution of ImM. lOM of litiM Arachidonic acid solution was added to each of the treated wells, and the mixture was cultured at 37 in CO2 incubator for 30 minutes. The cell solution of each well was collected in the centrifuge tube and was centrifuged at 4 X for 5 minutes at 10, OOOrpm. As PGE2 existed in the supernatant separated from collected cell, the concentration of PGE2 was quantitated by using monoclonal kit from Cayman Chemicals, and the concentration of samples
and vehicle were compared to estimate the inhibition ratio (%) of each compound against cyclooxygenase-1. Ultimately, the inhibition effect against the cyclooxygenase-1 enzyme was obtained from the result.
Second, the cyclooxygenase-2 was examined by using Raw 264.7 through the following procedure.
After seeding 2x10 cells of Raw 264.7 cell(obtained from Korean cell line bank) into each of 12-well plates, the wells was treated with aspirin 250 y M and cultured at 37°C in CO2 incubator for 2 hours. And then, each samples were replaced with new media and cultured for 30 minutes. In addition, the samples was treated with 100 units/ml of interferon y and lOOng/ml of lipopolysaccharide(LPS), and cultured for 18 hours. Then, the media was transferred to other tubes and the PGE 2 was quantitated by using EIA kit from Cayman Chemicals.
(2) Experimental results
The experimental results were described in Table 1 as
follows.
In vitro experiments were observed to measure the
inhibitional ratios against cyclooxygenase-1 and
cyclooxygenase-2. Consequently, in case of the compound of Example 4, 6, 9 and 31, the inhibition effect against
cyclooxygenase-2 and cyclooxygenase-1 was identified to be similar level in low concentration when comparing with a comparative substance, Celecoxib, which was examined under the same condition. So to speak, the selectivity of the cyclooxygenase-2 is hardly different between the Example and the comparative substance-
Meanwhile, In case of the compound of Example 14, 6-( 3-methyi-5-phenyl- [1,2,4]triazole-1-yl)-prydine-3-sulfonic acid amide, the inhibition effect against cyclooxygenase-2 was identified to be more excellent in low concentration than a comparative substance, whereas the inhibition effect against cyclooxygenase-1 was much lower level than a comparative substance. That is to say, the selectivity of cyclooxygenase-2 is confirmed to be better than any other substances, which proves the structural efficacy of diaryl 1,2,4-triazole derivatives in the present invention.
INDUSTRIAL RPPLICRBILITY
As demonstrated and confirmed above, the novel
compound of bipyridinyl derivative is a drug substitute
improving side effects of anti-inflammatory drug in
conventional non-steroids, and is useful for patients
suffering from peptic ulcer, gastritis, partial enteritis,
ulcerative colitis, diverticulitis, gastrointestinal
haemorrhagia, hypoprothrombinemia and the like. Besides, it is expected to be useful for treating inflammatory
diseases such as osteoarthritis, rheumatoid arthritis and the like effectively.
Those skilled in the art will appreciate that the conceptions and specific embodiments disclosed in the foregoing description may be readily utilized as a basis for modifying or designing other embodiments for carrying out the same purposes of the present invention.
Those skilled in the art will also appreciate that such equivalent embodiments do not depart from the spirit and scope of the invention as set forth in the appended claims.
WE CLAIM :
1. A compound of formula 1 and a pharmaceuticaliy
acceptable salt thereof:
substituted by halogens; NO2, NH2, OH, Ome, CO2H or CN, A is CH3 or NH2 and W is CH or N.
2. The compound of formula 1 as claimed inclaim 1, wherein
said compound of formula 1 is selected from a group
consisting of:
4-{3-raethyl-5-phenyl-[l,2,4,]triazole-l-yl)-benzenesulfonamide;
4-[5-(4-fluoro-phenyl)-3-mehtyl-[l,2, 4]triazole-1-yl]-benzenesulfonamide;
4-[5-{4-Ghloro-phenyl)-3-mehtyl-[l,2,4] triazole-1-yl ] -benzenesulfonamide;
4- [5- (4-bromo-phenyl) -3-mehtyl- [1,2,4] triazole-1-
yl ]-benzenesulf onamide ; 4-(3-methyl-5-p-toly-[l,2,4]trlzole-l-yl)-benzenesulf onamide ;
4- [5- (4-methoxy-phenyl) -3-methyl- [1, 2,4] triazole-1-yl]- benzenesulfonamide;
4-{5-(3-fluoro-phenyl)-3-mehtyl-[l,2,4]triazole-l-yl]- benzenesulfonamide;
4- [5- {3-chloro-phenyl) -3-mehtyl- tl, 2 , 41 triazole-l-yl]- benzenesulfonamide;
4-[5-(3-bromo-phenyl)-3-mehtyl-[1, 2, 4]triazole-1-yl]-benzenesulfonamide;
4-[5-(3-methoxy-phenyl)-3-raethyl-[l,2,4]triazole-l-yl]- benzenesulfonamide;
4-[5-{2-methoxy-phenya)-3-niethyl-[l,2,4] triazcle-l-yl]- benzenesulfonamide;
4-[5- {3, 4-dimethoxy-phenyl) -3-methyl-[1, 2, 4] triazole-1-yl]- benzenesulfonamide;
4- [5- (3, S-dimethoxy-phenyl) -3-msthyl- [1,2,4] triazole-1-yl]- benzenesulfonamide;
6- (3-methyl-5-phenyl- [1,2, 4 ] triazole-1-yl) -pyridine-3-3ulfonic acid amide;
6-[5-(4-fluoro-phenyl)-3-mehtyl-[1,2,4]triazole-l-yk]-pyridine-3-sulfonic acid amide;
6- [5- (4~chloro-phenyl) -3-raehtyl-[1, 2, 4] triazole-1-yl]-pyridine~3-sulfonic acid amide;
6-[5~(4-bromo-phenyl)-3-raehtyl-[l,2, 4] triazole-1-yl]-pyridine-3-sulfonic acid amide;
6- (3-methyl-5-p-toly- [1,2,4] triazole-1-yl) - pyridine¬s-sulfonic acid amide;
6-[5- (4-methoxy-phenyl) -3-methyl-[l, 2, 4] triazole-1-yl]- pyridine-3-sulfonic acid amide;
6- [5- (3-f luoro-phenyl) -3-methyl- [1, 2, 4] triazole-1-yl]- pyridine-3-sulfonic acid amide;
6-[5- (3-chloro-phenyl)-3-methyl-[l,2,4] triazole-1-yl]- pyridine-3-9ulfonic acid amide;
6-[5- (3, 5-dimethoxy-phenyl) -3-mehtyl- [1,2, 4] triazole-1-yl]- pyridine-3-sulfonic acid amide;
1- (4-methanesulfonyl-phenyl) -3-methyl-5-phenyl-lH-
[1,2,4]triazole;
5- (4-fluoro-phenyl} -1- (4-methanesulfonyl-phenyl} -3-methyl-lH-[1,2,4]triazole;
5- (4-chloro-phenyl) -1- (4-raethanesulfonyl-phenyl) -3-methyl-lH-[1,2, 4]triazole;
5- (4-bromo-phenyl) -1- {4-methanesulfonyl-phenyl) -3-raethyl-lH- [1,2,4] triazole; and
2- [5- (4-bromo-phenyl) -3-mehtyl- [1,2,4] triazole-1-yl] -
5-methanesulfonyl-pyridine.
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