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CN109810073B - 4-arylthiazole derivatives and pharmaceutical compositions thereof - Google Patents

4-arylthiazole derivatives and pharmaceutical compositions thereof Download PDF

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CN109810073B
CN109810073B CN201910158612.6A CN201910158612A CN109810073B CN 109810073 B CN109810073 B CN 109810073B CN 201910158612 A CN201910158612 A CN 201910158612A CN 109810073 B CN109810073 B CN 109810073B
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冯明声
姚晓敏
姚其正
曹于平
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Nanjing Hicin Pharmaceutical Co ltd
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Abstract

The invention designs and synthesizes 4-arylthiazole derivatives with xanthine oxidase inhibitory activity, which have the chemical structure shown as (I), wherein Y represents O, S and NH; r 1 Represents H, C 1 ‑C 4 The alkane of (1); r 2 Represents formyl, - (CH) 2 ) n CO 2 H or- (CH) 2 ) n COR 5 Wherein n =0 to 4,R 5 Is C 1 ～C 4 Alkoxy groups or amino acids of (a); r 3 Represents formyl, cyano, nitro, amino or hydroxyamino; r 4 Represents C 1 ～C 8 Straight or branched alkyl, C 2 ～C 8 Straight-chain or branched alkenyl or conjugated or unconjugated polyalkenyl, C 2 ～C 8 Straight-chain or branched alkynyl or C 2 ～C 8 Straight or branched conjugated or non-conjugated alkinyl. The 4-arylthiazole compound has the activity of inhibiting xanthine oxidase, can be used for preparing medicaments for preventing and treating diseases such as hyperuricemia, gout and the like, and has wide application in pharmacy.

Description

4-arylthiazole derivatives and pharmaceutical compositions thereof
Technical Field
The present invention relates to 4-arylthiazole derivatives and pharmaceutical compositions thereof. More particularly, the present invention relates to 4-arylthiazole derivatives having xanthine oxidase inhibitory action and uricosuric action, and pharmaceutical compositions thereof.
Background
Gout (Gout) is a disease caused by excessive uric acid production due to purine metabolic disorder in vivo and uric acid deposition in vivo, and is the second major metabolic disease after diabetes. Purine metabolic disorder or excessive purine intake in the body leads to excessive purine content in the body, so that uric acid is excessively generated, and the uric acid is deposited in joints and the like, and finally gout is formed. Statistical data show that with the continuous improvement of living standard and the acceleration of life rhythm of people, the incidence rate of gout is in a continuous rising trend in recent years, and the disease is listed as one of 21 century twenty-old persistent ailments by united nations. Therefore, the research and development of a series of medicines with good anti-gout effect have very important practical significance.
The uric acid level rise is the biochemical basis of gout, and asymptomatic hyperuricemia, namely the blood uric acid level exceeds the standard, but the disease without the clinical symptoms of gout is the early stage state of gout, and gout is necessarily accompanied with hyperuricemia. It follows that control of uric acid levels is critical for the prevention and treatment of gout.
The generation of reactive oxygen species has been identified as a cause of many diseases, such as ischemia-reperfusion disorders, inflammatory diseases, diabetes, cancer, atherosclerosis, or neurological diseases. Therefore, inhibition of the production of active oxygen can be effective in the treatment and prevention of these diseases. Since xanthine oxidase has been found to be involved in the production of active oxygen, xanthine oxidase inhibitors are capable of inhibiting the production of active oxygen. At present, uric acid production inhibitors represented by allopurinol and uricosuric agents represented by benzbromarone are used for the treatment of hyperuricemia. However, allopurinol and benzbromarone are often used with side effects such as rash, liver damage, bone marrow suppression, etc. In addition, benzbromarone has been withdrawn from the market in some countries due to its production of severe liver damage.
In recent years, some non-purine xanthine oxidase inhibitors have been reported, such as febuxostat (Teijin/TAP), Y-700 (Welfide) and Topiroxostat (Kotobuki):
Figure BSA0000179820350000011
febuxostat was marketed in 2008 in the european union, usa, japan and china for the treatment of chronic hyperuricemia with already occurring uric acid deposits (including tophus, gouty arthritis). Is a novel non-purine xanthine oxidase inhibitor, which provides a research direction for xanthine oxidase inhibitors. However, it still exhibits some significant side effects such as liver dysfunction, diarrhea, headache, rash, nausea, etc.
Therefore, the inhibitor taking Xanthine Oxidoreductase (XO) as an action target has good anti-gout application prospect.
Disclosure of Invention
The object of the present invention is to provide novel thiazole derivatives having xanthine oxidase inhibitory action and uricosuric action, and pharmaceutical compositions containing the same as an active ingredient.
4-arylthiazole derivatives represented by the following general formula (I) or pharmaceutically acceptable salts thereof,
Figure BSA0000179820350000021
here, the
Y represents O, S, NH; r 1 Represents H, C 1 -C 4 The alkane of (1); r 2 Represents formyl, - (CH) 2 ) n CO 2 H or- (CH) 2 ) n COR 5 Wherein n =0 to 4,R 5 Is C 1 ～C 4 Alkoxy or amino acid of (a); r 3 Represents formyl, cyano, nitro, amino or hydroxylamino; r 4 Represents C 1 ～C 8 Straight or branched alkyl, C 2 ～C 8 Straight-chain or branched alkenyl or conjugated or unconjugated polyalkenyl, C 2 ～C 8 Straight-chain or branched alkynyl or C 2 ～C 8 Straight or branched conjugated or non-conjugated alkinyl.
The 4-arylthiazole derivatives represented by the above general formula (I) or pharmaceutically acceptable salts thereof, among which preferred are:
y is O, S, NH; r is 1 Represents H or methyl; r is 2 represents-COOH or a carboxamido group; r is 3 Represents cyano or nitro; r 4 Represents C 1 ～C 6 Straight or branched alkyl, C 3 ～C 6 Straight-chain or branched alkenyl or conjugated or non-conjugated polyene, C 3 ～C 6 Straight or branched alkynyl.
The 4-arylthiazole derivatives of the above general formula (I) or pharmaceutically acceptable salts thereof, wherein more preferred are:
y is O, S, NH; r 1 Represents a methyl group; r 2 represents-COOH; r is 3 Represents cyano; r is 4 represents-CH 3 、-C 2 H 5 、-C 3 H 7 -n、-C 3 H 7 -i、-C 4 H 9 -n、-C 4 H 9 -i、-C 5 H 11 -n、C 5 H 11 -i、-CH 2 Ph、-CH 2 CH＝CH 2 、-CH 2 CH＝CHCH 3 、-CH 2 C(CH 3 )＝CH 2 、-CH 2 CH＝C(CH 3 ) 2 、-CH(CH 3 )CH＝CH 2 、-CH 2 CH＝CHCH＝CH 2 、-CH 2 CH＝CHCH＝CHCH 3 、-CH 2 C(CH 3 )＝CHCH＝CH 2 、-CH 2 CH＝CHC(CH 3 )＝CH 2 、-CH 2 C≡CH。
The thiazole derivative and the pharmaceutically acceptable salt thereof are xanthine oxidase inhibitors and uricosuric agents.
The compound improves physicochemical properties, enhances cell permeability, is easy to enter cells, and further improves bioavailability.
The thiazole derivative and the pharmaceutically acceptable salt thereof are used for preparing the medicine for treating gout or hyperuricemia.
The thiazole derivative and the pharmaceutically acceptable salt thereof are used for preparing medicaments for treating ischemia-reperfusion diseases, inflammatory diseases, diabetes, cancers, atherosclerosis or nervous system diseases.
Best mode for carrying out the invention
In the 4-arylthiazole derivatives represented by the general formula (I) of the present invention, Y represents O, S, NH; r is 1 Preferably methyl; r is 2 preferably-COOH; and R is 3 Preferably a cyano group; r 4 Preferably C 1 ～C 6 Straight or branched alkyl, C 3 ～C 6 Alkenyl or polyalkenyl, C 3 ～C 6 Alkynyl groups of (a) such as: -CH 3 、-C 2 H 5 、-C 3 H 7 -n、-C 3 H 7 -i、-C 4 H 9 -n、-C 4 H 9 -i、-C 5 H 11 -n、C 5 H 11 -i、-CH 2 Ph、-CH 2 CH＝CH 2 、-CH 2 CH＝CHCH 3 、-CH 2 C(CH 3 )＝CH 2 、-CH 2 CH＝C(CH 3 ) 2 、-CH(CH 3 )CH＝CH 2 、-CH 2 CH＝CHCH＝CH 2 、-CH 2 CH＝CHCH＝CHCH 3 、-CH 2 C(CH 3 )＝CHCH＝CH 2 、-CH 2 CH＝CHC(CH 3 )＝CH 2 、-CH 2 C ≡ CH. The preferred structures of the 4-arylthiazole derivatives are shown in Table 1.
TABLE 1 aryl thiazole derivatives
Figure BSA0000179820350000031
Figure BSA0000179820350000041
* Where the chiral carbon is in the S configuration
In the thiazole derivatives of the present invention, pharmaceutically acceptable salts include, but are not limited to, salts with, for example, the following acids: hydrochloric acid, hydrobromic acid, naphthalenedisulfonic acid (1, 5), phosphoric acid, nitric acid, sulfuric acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, acetic acid, propionic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, succinic acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids, and the like. Such salts may be hydrates, solvates, and the like.
In the thiazole derivatives of the present invention, pharmaceutically acceptable salts include, but are not limited to, salts with, for example, the following metals: lithium, sodium, potassium, magnesium, calcium, zinc, iron, and the like. Such salts may be hydrates, solvates, and the like.
In the pharmaceutical composition of the present invention, there is no limitation on any dosage form that can be optionally used. For example, there can be exemplified oral administration forms such as tablets, capsules, granules, powders or liquid preparations, or parenteral administration forms such as injections, topical products or suppositories, which can be formulated in a conventional manner or unconventional methods such as liposomes and the like.
When the pharmaceutical composition of the present invention is used as a therapeutic agent for gout or hyperuricemia, or for diseases such as ischemia-reperfusion, inflammatory diseases, diabetes, cancer, atherosclerosis, nervous system diseases, the amount thereof to be used is in the range of approximately 1mg to 1g per day for adults, depending on the age, sex, body weight and degree of symptoms of each patient, and the daily dose may be divided into several doses.
The compound represented by the general formula (I) is the newly synthesized 4-arylthiazole derivative. All newly synthesized compounds are structurally characterized by a plurality of physical methods, mainly comprising nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR), mass Spectrometry (MS) and Elemental Analysis (EA), etc., the compounds were synthesized by reference to and modification of published methods.
The compounds of formula (I) can be synthesized as follows. Unless otherwise specified, various symbols used in the following reaction formulae are defined as above.
Figure BSA0000179820350000051
In the formula: y = O, S or NH; r 1 ＝H、-CH 3 ；R 4 ＝-CH 3 、-C 2 H 5 、-C 3 H 7 -n、-C 3 H 7 -i、-C 4 H 9 -n、-C 4 H 9 -i、-C 5 H 11 -n、C 5 H 11 -i、-CH 2 Ph、-CH 2 CH＝CH 2 、-CH 2 CH＝CHCH 3 、-CH 2 C(CH 3 )＝CH 2 、-CH 2 CH＝C(CH 3 ) 2 、-CH(CH 3 )CH＝CH 2 、-CH 2 CH＝CHCH＝CH 2 、-CH 2 CH＝CHCH＝CHCH 3 、-CH 2 C(CH 3 )＝CHCH＝CH 2 、-CH 2 CH＝CHC(CH 3 )＝CH 2 、-CH 2 C ≡ CH, etc., hal = Cl, br, I.
Firstly, the alpha position of ketone of the compound a is halogenated to obtain a compound b. Useful solvents are polar aprotic solvents, such as CH 2 Cl 2 、CHCl 3 Etc., the halogenating agent may be Cl 2 、Br 2 Or N-chlorosuccinimide and N-bromosuccinimide. The compound e is obtained by directly mixing the compound b with 2-amino-2-ethyl thioacetate (d) or reacting the compound b with the compound d in a solvent, wherein the solvent can be any solvent which does not cause side reaction, such as hydrocarbons such as benzene, toluene and cyclohexane, ethers such as dioxane, tetrahydrofuran, ethylene glycol monomethyl ether and ethylene glycol dimethyl ether, alcohols such as methanol, ethanol and isopropanol, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide and acetonitrile. Compound e is formylated by either the Vilsmeier-Haack reaction (ZHARSKII V L, A new modification of the Vilsmeier-Haack reaction, zhumal organic heskoi Khimii,1991, 27 (11): 2460-1) or the Duff reaction to give compound f. Then oximation and dehydration are carried out under the action of hydroxylamine hydrochloride, formic acid and sodium formate to generate a compound h, and the compound h and halogenated alkane (R) are further reacted 4 -Hal) or with p-toluenesulfonate (p-TsOR) 4 ) Reacting to obtain a general formula (i); the compounds e may also be initially substituted with haloalkanes (R) 4 -Hal) or with p-toluenesulfonate (p-TsOR) 4 ) Reaction, oximation and dehydration to obtain the general formula (i). Then alkaline hydrolysis and acidification are carried out to obtain j. Reacting the compound j with amino acid ester hydrochloride by a dehydrating agent such as N, N-dicyclohexyl imine (DCC) to obtain a compound k, and then performing alkaline hydrolysis and acidification to obtain a compound l.
Compound d is usually prepared by adding tetraphosphorus decasulfide or Lawson's reagent (reference: bull. Soc. Chim. Belg.87, 223 (1978)) to a solution of the corresponding formamide in benzene or toluene.
Or by introducing hydrogen sulfide (ref.: organic Syntheses, col. Vol.8, p.597 (1993); vol.66, p.142 (1988)) into a solution of the corresponding nitrile compound in benzene, toluene, cyclohexane, or the like.
Detailed Description
The following examples illustrate specific process steps of the present invention, but are not intended to limit the invention.
Terms used in the present invention generally have meanings commonly understood by those of ordinary skill in the art, unless otherwise specified.
The present invention is described in further detail below with reference to specific examples and with reference to the data. It will be understood that these examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
The melting point of the 4-arylthiazole derivative prepared in the experiment is measured by a Mel-TEMP melting point apparatus, and a thermometer is not corrected; the nuclear magnetic resonance spectrum is measured by a Bruke AV-500 (500 MHz) or Bruke AV-300 (300 MHz) nuclear magnetic resonance instrument, and the internal standard is Tetramethylsilane (TMS); the mass spectrum is measured by an Shimadzu GC-T2010 EI (70 eV) mass spectrometer or an Agllent 1100 LC/MS ESI (70-100 eV) mass spectrometer; elemental analysis was measured using an Elementa variao EL type III elemental analyzer. Thin layer chromatography plate (GF) 254 ) Purchased from silica gel development ltd, jiangyou, tai.
The reagents are all commercially available chemically pure or analytically pure products and are used without treatment unless otherwise specified.
Example 1- (3-cyano-4-methoxyphenyl) thiazole-2-carboxylic acid (j-1)
(1) 4- (4-hydroxyphenyl) thiazole-2-carboxylic acid ethyl ester (e-1)
Figure BSA0000179820350000061
215g (1 mol) of alpha-bromo-p-hydroxyacetophenone (b-1) and 133g (1 mol) of ethyl 2-amino-2-thioacetate (d) were added to 600mL of ethanol, heated to reflux and kept warm for 4h. Then cooling and crystallizing. Filtering and washing with ethanol. Drying to obtain 191.5g of off-white solid (e-1). The yield thereof was found to be 76.8%. mp:162 to 163 ℃.
(2) 4- (3-formyl-4-hydroxyphenyl) thiazole-2-carboxylic acid ethyl ester (f-1)
Figure BSA0000179820350000071
900mL of trifluoroacetic acid (TFA) was added to a 2000mL three-necked flask, the temperature was reduced to 10 ℃ or lower in an ice-water bath, and 101.3g (0.72 mol) of urotropin (HMTA) was added thereto under stirring, and after the addition, the mixture was stirred at room temperature for 0.5 hour. Then 150g (0.602 mol) of the compound e-1 is added, stirring and heating are carried out till reflux, heat preservation is carried out for 10 hours, about 2/3 of solvent is recovered, the residue is poured into about 2000mL of ice water, stirring is carried out for 0.5 hour, filtering and washing are carried out till neutrality, recrystallization is carried out by ethyl acetate, and 111.5g of off-white solid (f-1) is obtained, and the yield is 66.8%. 1 H-NMR(DMSO-D 6 ，ppm)δ：1.47(t，3H，CH 3 ，J＝7.1Hz)，4.52(q，2H，CH 2 ，J＝7.1Hz)，7.06(d，1H，CH，J＝8.7Hz)，7.69(s，1H，CH)，8.04(dd，1H，CH，J＝8.7Hz，J＝2.2Hz)，8.26(d，1H，CH，J＝2.2Hz)，9.99(s，1H，CHO)，11.12(s，1H，OH)；EI(+)/70eV：278.1[M+H] + ，EI(-)/70eV：276.0[M-H] - (ii) a Elemental analysis C 16 H 16 NO 3 S, found (%): c56.18, H3.87, N4.88; theoretical value (%): c56.31, H4.00, N5.05; mp:112 to 114 ℃.
(3) 4- (3-formyl-4-methoxyphenyl) -2-thiazolecarboxylic acid ethyl ester (g-1)
Figure BSA0000179820350000072
Adding 9g (32.5 mmol) of compound f-1,6.9g of methyl iodide and 6.7g of anhydrous potassium carbonate into 45mL of N, N-dimethylformamide, heating to 60 ℃, controlling the temperature to be 60-70 ℃, preserving the temperature for 4-5 hours, recovering the solvent under reduced pressure until the solvent is dry, then cooling to below 10 ℃ in an ice water bath, adding 50mL of ice water, and stirring for 3-5 hours. Filtering, washing with ice water to obtain an off-white solid, recrystallizing with ethyl acetate, and drying to obtain 8.1g of off-white solid (g-1), with the yield of 85.7%.
(4) 4- (3-cyano-4-methoxyphenyl) -2-thiazolecarboxylic acid ethyl ester (i-1)
Figure BSA0000179820350000073
Adding 8g (27.5 mmol) of compound g-1,2.86g (41.2 mmol) of hydroxylamine hydrochloride and 2.8g (41.2 mmol) of sodium formate into 80mL of anhydrous formic acid, stirring and heating to reflux, preserving the heat for 4.5-5 hours (TLC shows that the reaction is finished), recovering about 1/2 of the solvent under reduced pressure, then adding 50mL of ice water, stirring for 2-3 hours below 10 ℃, filtering, washing with water to be neutral, and drying to obtain 6.8g of white-like solid (i-1), wherein the yield is 85.9%.
(5) 4- (3-cyano-4-methoxyphenyl) thiazole-2-carboxylic acid (j-1)
Figure BSA0000179820350000081
6g (20.8 mmol) of compound i-1,1.25g (31.3 mmol) of sodium hydroxide and 5mL of water are added into 60mL of 95% ethanol, stirred and heated to 50 ℃, the temperature is controlled between 50 and 60 ℃, and the temperature is kept for 1 to 1.5 hours. TLC shows that after the reaction is finished, heating is stopped, the reaction solution is poured into 60mL of ice water, the temperature is cooled to be below 10 ℃ in ice water bath, the pH value is adjusted to be 1-2 by 2mol/L hydrochloric acid, stirring is carried out for 0.5 hour, filtering, washing by ice water and drying are carried out, 4.3g of off-white solid (j-1) is obtained, and the yield is 79.4%. R f =0.59 (developing solvent: ethyl acetate: methanol: acetic acid = 10: 1 d). 1 H-NMR(DMSO-D 6 ，ppm)δ：3.99(s，3H，CH 3 )，7.36(d，1H，J＝8.9Hz，CH)，8.28(dd，1H，J＝8.8Hz，J＝2.3Hz，CH)，8.33(d，1H，J＝2.2Hz，CH)，8.50(s，1H，CH)，14.00(br，1H，COOH)；ESI(-)/70eV：259.1[M-H] - (ii) a Elemental analysis C 10 H 8 N 2 O 3 S·0.125H 2 O, found (%): c54.96, H3.21, N10.52; theoretical value (%): c54.90, H3.17, N10.67; mp: 123-125 ℃.
Example 2- (3-cyano-4-ethoxyphenyl) thiazole-2-carboxylic acid (j-2)
(1) 4- (3-formyl-4-methoxyphenyl) -2-thiazolecarboxylic acid ethyl ester (g-2)
Figure BSA0000179820350000082
9g (32.5 mmol) of compound f-1,7.1g (64.9 mmol) of bromoethane, 1.1g (6.6 mmol) of potassium iodide and 9g (64.9 mmol) of anhydrous potassium carbonate are added into 45mL of N, N-dimethylformamide, the temperature is raised to 50 ℃, the temperature is controlled to be 50-60 ℃, the temperature is kept for 4-5 hours, the solvent is recovered under reduced pressure until the solvent is dried, then an ice water bath is cooled to below 10 ℃, 50mL of ice water is added, and the mixture is stirred for 3-5 hours. Filtering, washing with ice water to obtain an off-white solid, recrystallizing with ethyl acetate, and drying to obtain 8.6g of off-white solid (g-2), wherein the yield is 86.8%.
(2) 4- (3-cyano-4-ethoxyphenyl) -2-thiazolecarboxylic acid ethyl ester (i-2)
Figure BSA0000179820350000083
The procedure was identical to that for the synthesis of compound i-1, except that 8g (26.2 mmol) of compound g-2 was charged to give 6.3g of off-white solid (i-2) in 79.5% yield.
(3) 4- (3-cyano-4-ethoxyphenyl) thiazole-2-carboxylic acid (j-2)
Figure BSA0000179820350000091
The procedure was identical to that for the synthesis of compound j-1, and 6g (19.8 mmol) of compound i-2 was charged to give 4.5g of off-white solid (j-2) in 82.7% yield. 1 H-NMR(DMSO-D 6 ，ppm)δ：1.39(t，3H，J＝7.0Hz，CH 3 )，4.24(q，2H，J＝7.0Hz，CH 2 )，7.32(d，1H，J＝8.9Hz，CH)，8.23(dd，1H，J＝8.8Hz，J＝2.2Hz，CH)，8.28(d，1H，J＝2.2Hz，CH)，8.46(s，1H，CH)，13.20(br，1H，COOH)；ESI(-)/70eV：273.1[M-H] - (ii) a Elemental analysis C 13 H 10 N 2 O 3 S·0.875H 2 O, found (%): c53.87, H3.98, N9.68; theoretical value (%): c53.83, H4.08, N9.66; mp:116 to 118 ℃.
Example 3- (3-cyano-4-isobutoxyphenyl) -5-methyl-2-thiazolecarboxylic acid (j-3)
(1) 4- (4-hydroxyphenyl) -5-methylthiazole-2-carboxylic acid ethyl ester (e-3)
Figure BSA0000179820350000092
The procedure was carried out for the synthesis of compound e-1, charging 20g (87.3 mmol) of α -bromo-p-hydroxyphenylacetone (b-2) to give 16.7g of an off-white solid (e-3) with a yield of 72.6%. 1 H-NMR(CDCl 3 ，ppm)δ：1.40(t，3H，CH 3 ，J＝7.1Hz)，2.58(s，1H，CH 3 )，4.54(q，2H，CH 2 ，J＝7.1Hz)，6.70(brs，1H，OH)，6.84(d，2H，CH，J＝8.6Hz)，7.43(d，2H，CH，J＝8.6Hz)。
(2) 4- (3-formyl-4-hydroxyphenyl) -5-methyl-2-thiazolecarboxylic acid ethyl ester (f-3)
Figure BSA0000179820350000093
In the synthesis of compound f-1, 150g (570 mmol) of compound e-3 was charged to yield 103g of off-white solid (f-3) in 62.1% yield. mp:107 to 109 ℃.
(3) 4- (3-formyl-4-isobutoxyphenyl) -2-thiazolecarboxylic acid ethyl ester (g-3)
Figure BSA0000179820350000101
For a specific experiment, the same procedure as used for the synthesis of compound g-1 was followed, and 9g (32.5 mmol) of compound f-3 was charged to give 8.6g of a white-like solid (g-3) in a yield of 79.5%.
(4) 4- (3-cyano-4-isobutoxyphenyl) -5-methyl-2-thiazolecarboxylic acid ethyl ester (i-3)
Figure BSA0000179820350000102
The procedure was carried out for the synthesis of compound i-1, 5g (14.4 mmol) of compound g-3 was charged to give 4.2g of an off-white solid (i-3) in 84.7% yield.
(5) 4- (3-cyano-4-isobutoxyphenyl) -5-methyl-2-thiazolecarboxylic acid (j-3)
Figure BSA0000179820350000103
The procedure was the same as that for the synthesis of compound j-1, except that 6g (17.4 mmol) of compound i-3 was charged to give 4.2g of off-white solid (j-3) in a yield of 76.2%. 1 H-NMR(DMSO-D 6 ，ppm)δ：1.03(d，6H，J＝6.7Hz，2CH 3 )，2.11(m，1H，CH)，2.63(s，3H，CH 3 )，3.98(d，1H，J＝6.5Hz，CH)，7.35(d，1H，J＝8.9Hz，CH)，7.95(dd，1H，J＝8.8Hz，J＝2.3Hz，CH)，7.99(d，1H，J＝2.2Hz，CH)，13.93(brs，1H，COOH)；ESI(+)/70eV：303.1[M+H] + (ii) a Elemental analysis C 16 H 16 N 2 O 3 S·0.5H 2 O, found (%): c57.56 H4.46, N8.78; theoretical value (%): c57.56, H4.86, N9.00; mp:110 to 112 ℃.
Example 4- (3-cyano-4-n-propoxyphenyl) -2-thiazolecarboxylic acid (j-4)
Figure BSA0000179820350000104
The procedure was as in example 2. 4.3g of an off-white solid (j-4) was obtained in a yield of 78.6%. 1 H-NMR(DMSO-D 6 ，ppm)δ：1.00(t，3H，J＝7.4Hz，CH 3 )，1.79(m，2H，CH 2 )，4.12(t，2H，J＝6.5Hz，CH 2 )，7.31(d，1H，J＝9.0Hz，CH)，8.21(dd，1H，J＝8.8Hz，J＝2.3Hz，CH)，8.28(d，1H，J＝2.3Hz，CH)，8.59(s，1H，CH)；ESI(+)/70eV：289.2[M+H] + (ii) a Elemental analysis C 14 H 12 N 2 O 3 S·2H 2 O, found (%): c51.75, H4.80, N8.61; theoretical value (%): c51.85, H4.97, N8.64; mp:112 to 114 ℃.
Example 5- (3-cyano-4-isopropoxyphenyl) -2-thiazolecarboxylic acid (j-5)
Figure BSA0000179820350000111
The procedure is as in example 2. 4.1g of off-white solid (j-5) was obtained with a yield of 75.0%. 1 H-NMR(DMSO-D 6 ，ppm)δ：1.36(d，6H，J＝6.0Hz，CH 3 )，4.87(m，1H，CH)，7.40(d，1H，J＝9.1Hz，CH)，8.25(dd，1H，J＝9.0Hz，J＝2.3Hz，CH)，8.31(d，1H，J＝2.3Hz，CH)，8.50(s，1H，CH)，14.00(br，1H，COOH)；ESI(+)/70eV：289.1[M+H] + (ii) a Elemental analysis C 14 H 12 N 2 O 3 S·H 2 O, found (%): c55.06, H4.61, N9.15; theoretical value (%): c54.90, H4.61, N9.15; mp: 120-121 ℃.
Example 6- (3-cyano-4-n-butoxyphenyl) -2-thiazolecarboxylic acid (j-6)
Figure BSA0000179820350000112
The procedure is as in example 2. 4.4g of off-white solid (j-6) was obtained with a yield of 80.1%. 1 H-NMR(DMSO-D 6 ，ppm)δ：0.94(t，3H，J＝7.4Hz，CH 3 )，1.50(m，2H，CH 2 )，1.75(m，2H，CH 2 )，4.17(t，2H，J＝6.4Hz，CH 2 )，7.34(d，1H，J＝9.0Hz，CH)，8.24(dd，1H，J＝8.8Hz，J＝2.3Hz，CH)，8.29(d，1H，J＝2.2Hz，CH)，8.46(s，1H，CH)；ESI(+)/70eV：303.2[M+H] + (ii) a Elemental analysis C 15 H 14 N 2 O 3 S·1.5H 2 O, found (%): c54.54, H5.42, N8.34; theoretical value (%): c54.71, H5.20, N8.51; mp:108 to 110 ℃.
Example 7- (3-cyano-4-isobutoxyphenyl) -2-thiazolecarboxylic acid (j-7)
Figure BSA0000179820350000113
The procedure is as in example 2. 4.5g of an off-white solid (j-7) was obtained in a yield of 82.0%. 1 H-NMR(DMSO-D 6 ，ppm)δ：1.04(d，6H，J＝6.7Hz，CH 3 )，2.11(m，1H，CH)，3.98(d，1H，J＝5.9Hz，CH)，7.38(d，1H，J＝9.0Hz，CH)，8.26(d，1H，J＝8.9Hz，CH)，8.33(s，1H，CH)，8.51(d，1H，J＝1.1Hz，CH)，14.00(br，1H，COOH)；ESI(+)/70eV：303.1[M+H] + (ii) a Elemental analysis C 15 H 14 N 2 O 3 S·0.5H 2 O, found (%): c57.56, H4.46, N8.78; theoretical value (%): c57.56, H4.86, N9.00; mp: 109-111 ℃.
Example 8- (3-cyano-4-n-pentyloxyphenyl) -2-thiazolecarboxylic acid (j-8)
Figure BSA0000179820350000121
The procedure is as in example 2. 4.0g of an off-white solid (j-8) was obtained, with a yield of 72.6%. 1 H-NMR(DMSO-D 6 ，ppm)δ：0.91(t，3H，J＝7.2Hz，CH 3 )，1.37～1.46(m，4H，CH 2 )，1.78(p，2H，CH 2 )，4.19(t，2H，J＝6.49Hz，CH 2 )，7.36(d，1H，J＝9.0Hz，CH)，8.27(dd，1H，J＝8.9Hz，J＝2.3Hz，CH)，8.32(d，1H，J＝2.2Hz，CH)，8.49(s，1H，CH)，13.40(br，1H，COOH)；ESI(+)/70eV：317.1[M+H] + (ii) a Elemental analysis C 16 H 16 N 2 O 3 S·0.75H 2 O, found (%): c58.56, H5.28, N8.32; theoretical value (%): c58.27, H5.35, N8.49; mp: 97-99 deg.C
Example 9- (3-cyano-4-isopentyloxyphenyl) -2-thiazolecarboxylic acid (j-9)
Figure BSA0000179820350000122
The procedure was as in example 2. 4.2g of an off-white solid (j-9) was obtained with a yield of 76.2%. 1 H-NMR(DMSO-D 6 ，ppm)δ：0.95(d，6H，J＝6.6Hz，2CH 3 )，1.67(q，2H，J＝6.6Hz，CH 2 )，1.81(m，2H，CH 2 )，4.21(t，2H，J＝6.5Hz，CH 2 )，7.36(d，1H，J＝8.9Hz，CH)，8.27(dd，1H，J＝8.8Hz，J＝2.3Hz，CH)，8.30(d，1H，J＝2.2Hz，CH)，8.47(s，1H，CH)；ESI(-)/70eV：314.9[M-H] - (ii) a Elemental analysis C 16 H 16 N 2 O 3 S·0.5H 2 O, found (%): c59.19, H5.13, N8.58; theoretical value (%): c59.06, H5.27, N8.61: mp:106 to 107 ℃.
Example 10- (3-cyano-4-benzyloxyphenyl) -2-thiazolecarboxylic acid (j-10)
Figure BSA0000179820350000131
The procedure was as in example 2. 4.5g of off-white solid (j-10) was obtained, the yield being 81.3%. 1 H-NMR(DMSO-D 6 ，ppm)δ：5.34(s，2H，CH 2 )，7.35～7.51(m，5H，CH)，8.26(dd，1H，J＝8.9Hz，J＝2.3Hz，CH)，8.34(d，1H，J＝2.2Hz，CH)，8.49(s，1H，CH)，14.20(br，1H，COOH)；ESI(-)/70eV：335.0[M-H] - (ii) a Elemental analysis C 18 H 12 N 2 O 3 S·0.5H 2 O, found (%): c63.03, H3.64, N8.11; theoretical value (%): c62.60, H3.79, N8.11; mp:105 to 107 ℃.
Example 11- (3-cyano-4-allyloxyphenyl) -2-thiazolecarboxylic acid (j-11)
Figure BSA0000179820350000132
The procedure was as in example 2. 4.6g of an off-white solid (j-11) was obtained with a yield of 84.2%. 1 H-NMR(DMSO-D 6 ，ppm)δ：4.80(d，2H，J＝4.5Hz，CH 2 )，5.37(d，1H，J＝10.5Hz，CH 2 )，5.51(d，1H，J＝17.2Hz，CH 2 )，6.11(m，1H，CH)，7.34(d，1H，J＝8.9Hz，CH)，8.27(d，1H，J＝8.8Hz，CH)，8.31(s，1H，CH)，8.47(s，1H，CH)；ESI(-)/70eV：284.9[M-H] - (ii) a Elemental analysis C 14 H 10 N 2 O 3 S·H 2 O, found (%): c55.46, H3.91, N9.29; theoretical value (%): c55.25, H3.97, N9.21; mp:106 to 108 ℃.
Example 12- (3-cyano-4-methoxyphenyl) -2-thiazolecarboxylglycine (l-1)
(1) 4- (3-cyano-4-methoxyphenyl) thiazole-2-formylglycine ethyl ester (k-1)
Figure BSA0000179820350000133
A25 mL single-necked flask was charged with 0.8g (3.07 mmol) of 4- (3-cyano-4-methoxyphenyl) -2-thiazolecarboxylic acid (j-1), 1.27g (6.15 mmol) of DCC, 0.86g (6.15 mmol) of glycine ethyl ester hydrochloride, 2mL of pyridine, and 10mL of N, N-Dimethylformamide (DMF), and stirred at room temperature for 24 hours while allowing a solid to precipitate. Filtering, pouring the filtrate into 100mL of ice water under stirring, adding concentrated hydrochloric acid to adjust the pH value to 2, extracting with dichloromethane (25 mL multiplied by 3), drying with anhydrous sodium sulfate, concentrating to dryness, and recrystallizing with a proper amount of anhydrous ethanol to obtain 0.72g of off-white solid (k-1). The yield thereof was found to be 67.8%.
(2) 4- (3-cyano-4-methoxyphenyl) thiazole-2-formylglycine (l-1)
Figure BSA0000179820350000141
To 8mL of ethanol were added 0.7g (2.03 mmol) of Compound k-1,0.16g (4.05 mmol) of sodium hydroxide and 2mL of water, and the mixture was heated to 60 ℃ with stirring and then incubated for 1 hour. TLC shows that after the reaction is finished, 0.1g of activated carbon is added, the temperature is kept for 5min, the mixture is filtered thermally, the filtrate is poured into 80mL of ice water, the pH value is adjusted to 1-2 by 2mol/L hydrochloric acid, the mixture is stirred for 0.5h, the mixture is filtered, the ice water is washed to be neutral, and the white-like solid (L-1) is obtained by drying, wherein the yield is 87.1%. 1 H-NMR(DMSO-D 6 ，ppm)δ：3.98～3.99(5H，CH 2 、CH 3 )，7.39(d，1H，J＝9.0Hz，CH)，8.34(dd，1H，J＝8.9Hz，J＝2.2Hz，CH)，8.47(s，1H，CH)，9.21(t，1H，CONH)，12.77(brs，1H，COOH)；ESI(-)/70eV：316.0[M-H] - (ii) a Elemental analysis C 14 H 11 N 3 O 4 S, found (%): c53.28, H3.33, N12.81; theoretical value (%): c52.99, H3.49, N13.24; mp:227 to 229 ℃.
Example 13- (3-cyano-4-methoxyphenyl) -2-thiazolecarboxyl-. Beta. -alanine (l-2)
Figure BSA0000179820350000142
The specific procedure is the same as in example 12. 0.45g of white solid (l-2) was obtained with a yield of 69.7%. 1 H-NMR(DMSO-D 6 ，ppm)δ：1.40(t，3H，J＝6.9Hz，CH 3 )，3.98(d，2H，J＝6.2Hz，CH 2 )，4.26(q，2H，J＝6.9Hz，CH 2 )，7.36(d，1H，J＝9.0Hz，CH)，8.31(dd，1H，J＝8.9Hz，J＝2.2Hz，CH)，8.45(s，1H，CH)，9.20(t，1H，CONH)，12.76(brs，1H，COOH)；ESI(-)/70eV：330.0[M-H] - (ii) a Elemental analysis C 15 H 13 N 3 O 4 S, found (%): c54.53, H3.70, N12.37; theoretical value (%): c54.37, H3.95, N12.68; mp:242 to 244 ℃.
Example 14- (3-cyano-4-ethoxyphenyl) -2-thiazolecarboxylglycine (l-3)
Figure BSA0000179820350000143
The specific procedure was the same as in example 12. 0.35g of white solid (l-3) was obtained, yield 75.9%. 1 H-NMR(DMSO-D 6 ，ppm)δ：1.40(t，3H，J＝7.0Hz，CH 3 )，3.98(d，2H，J＝6.1Hz，CH 2 )，4.26(q，2H，J＝7.0Hz，CH 2 )，7.35(d，1H，J＝9.0Hz，CH)，8.31(dd，1H，J＝8.9Hz，J＝2.2Hz，CH)，8.44(s，1H，CH)，8.45(s，1H，CH)，9.16(br，1H，CONH)，12.81(brs，1H，COOH)；ESI(-)/70eV：330.1[M-H] - (ii) a Elemental analysis C 15 H 13 N 3 O 4 S, found (%): c54.28, H3.77, N12.41; theoretical value (%): c54.37, H3.95, N12.68: mp:238 to 240 ℃.
Example 15- (3-cyano-4-ethoxyphenyl) -2-thiazolecarboxyl-. Beta. -alanine (l-4)
Figure BSA0000179820350000151
The specific procedure was the same as in example 12. 0.44g of white solid (l-4) was obtained, yield 79.3%. 1 H-NMR(DMSO-D 6 ，ppm)δ：1.40(t，3H，J＝7.0Hz，CH 3 )，2.58(t，2H，J＝7.1Hz，CH 2 )，3.52(q，2H，J＝7.0Hz，CH 2 )，4.26(q，2H，J＝6.9Hz，CH 2 )，7.33(d，1H，J＝9.0Hz，CH)，8.29(dd，1H，J＝8.9Hz，J＝2.2Hz，CH)，8.40(s，1H，CH)，8.43(d，1H，J＝2.2Hz，CH)，8.90(t，1H，CONH)，12.28(brs，1H，COOH)；ESI(-)/70eV：344.0[M-H] - (ii) a Elemental analysis C 16 H 15 N 3 O 4 S, found (%): c56.00, H4.18, N12.00; theoretical value (%): c55.64, H4.38, N12.17; mp: 193-195 ℃.
Example 16- (3-cyano-4-ethoxyphenyl) -2-thiazolecarboxyl-L-phenylalanine (L-5)
Figure BSA0000179820350000152
The specific procedure was the same as in example 12. 0.46g of white solid (l-5) was obtained, the yield was 81.8%. 1 H-NMR(DMSO-D 6 ，ppm)δ：1.40(t，3H，J＝7.0Hz，CH 3 )，3.26(m，2H，CH 2 )，3.52(q，2H，J＝7.0Hz，CH 2 )，4.27(q，2H，J＝7.0Hz，CH 2 )，4.71(m，1H，CH)，7.17～7.31(m，5H，CH)，7.36(d，1H，J＝9.0Hz，CH)，8.31(dd，1H，J＝8.9Hz，J＝2.3Hz，CH)，8.43(s，1H，CH)，8.44(d，1H，J＝2.3Hz，CH)，8.95(d，1H，CONH)，12.99(s，1H，COOH)；ESI(-)/70eV：420.0[M-H] - (ii) a Elemental analysis C 22 H 19 N 3 O 4 S, found (%): c62.76, H4.47, N9.73; theoretical value (%): c62.69, H4.54, N9.97; mp:218 to 220 ℃.
Example 17- (3-cyano-4-n-propoxyphenyl) -2-thiazolecarboxylglycine (l-6)
Figure BSA0000179820350000153
The specific procedure is the same as in example 12. 0.49g of white solid (l-6) was obtained with a yield of 81.5%. 1 H-NMR(DMSO-D 6 ，ppm)δ：1.02(t，3H，J＝7.4Hz，CH 3 )，1.79(m，2H，CH 2 )，3.99(d，2H，J＝6.2Hz，CH 2 )，4.16(t，2H，J＝6.5Hz，CH 2 )，7.34(d，1H，J＝9.0Hz，CH)，8.29(dd，1H，J＝9.0Hz，J＝2.3Hz，CH)，8.43(s，1H，CH)，8.44(d，1H，J＝2.3Hz，CH)，9.18(t，1H，J＝6.2Hz，CONH)，12.75(brs，1H，COOH)；ESI(-)/70eV：344.0[M-H] - (ii) a Elemental analysis C 16 H 15 N 3 O 4 S, found (%): c55.80, H4.22, N12.27; theoretical value (%): c55.64, H4.38, N12.17; mp: 217-219 ℃.
Example 18- (3-cyano-4-allyloxyphenyl) -2-thiazolecarboxylglycine (l-7)
Figure BSA0000179820350000161
The specific procedure was the same as in example 12. 0.54g of white solid (l-7) was obtained, yield 83.4%. 1 H-NMR(DMSO-D 6 ，ppm)δ：4.01(d，2H，J＝6.2Hz，CH 2 )，5.34(m，1H，CH 2 )，5.50(m，1H，CH 2 )，6.11(m，1H，CH)，7.38(d，1H，J＝9.0Hz，CH)，8.32(dd，1H，J＝8.9Hz，J＝2.3Hz，CH)，8.46(s，1H，CH)，8.48(d，1H，J＝2.2Hz，CH)，9.22(t，1H，J＝6.2Hz，CONH)，12.79(brs，1H，COOH)；ESI(-)/70eV：342.0[M-H] - (ii) a Elemental analysis C 16 H 13 N 3 O 4 S, found (%): c55.90, H3.68, N12.32; theoretical value (%): c55.97, H3.82, N12.24; mp:235 to 236 ℃.
According to the methods of examples 1,2, 3 and 12, 36 4-aryl thiazole compounds (I) with the structures shown in Table 1 were designed and synthesized, and all the novel compounds were subjected to Mass Spectrometry (MS) and nuclear magnetic resonance hydrogen spectroscopy (M:) 1 H-NMR) and Elemental Analysis (EA).
Example 19 Effect of 4-arylthiazoles of the present invention on xanthine oxidase Activity
(1) Instruments and reagents
Full wavelength ultraviolet plate reader (Multiskan Spectrum, thermoelectricity company), ultraviolet analysis plate (96-well, kotzmo biotechnology limited), xanthine oxidase (XO, sigma company), protein content 51g/L, enzyme activity 0.2U/mg, xanthine (national drug group chemical agents limited), febuxostat (homemade).
(2) Detailed description of the invention
1) Preparation of reagents
Preparing a buffer solution A: 0.26mol/L NaH 2 PO 4 ·2H 2 O is added to 0.10mol/L Na under stirring 2 HPO 4 ·12H 2 O, until pH7.4;
b xanthine oxidase: mu.L of the xanthine oxidase stock solution was added to 10mL of the buffer solution to give 13.3U/L of the enzyme solution, and the whole process was carried out at 5 ℃ or lower.
C, xanthine: 1.52mg of xanthine dissolved in 1mL of 0.1mol/L NaOH was diluted 40-fold with buffer to obtain 250. Mu. Mol/L solution.
D, enzymatic reaction termination solution: 1mol/L HCl solution
E, febuxostat solution: 6.32mg of Febuxostat dissolved in 1mL of DMSO, diluted 10 with buffer 6 Doubling to obtain a 20nmol/L solution.
F test compound solution: 1mg of compound was dissolved in 1mL DMSO and diluted 10 with buffer 4 Get 10 times of -4 g/L of the solution.
2) Experimental procedure
A96-well ultraviolet analysis plate is used as a screening carrier, 20 mu L of a compound to be detected and 40 mu L of XO preparation solution are added into each well, the mixture is incubated for 15 minutes at 37 ℃,40 mu L of xanthine is added to activate the reaction, the reaction is carried out for 20 minutes at 37 ℃ (the total reaction volume is 100 mu L), and 20 mu L of 1mol/L HCl is added to stop the reaction. Each plate was simultaneously provided with model control, positive control and blank control wells. The model control well and the positive control well were each replaced with 20. Mu.L of a reaction buffer and a febuxostat preparation solution, and the reaction conditions were the same. Blank control wells contained 80. Mu.L of reaction buffer and 20. Mu.L of xanthine. After the reaction, the UV absorbance at 292nm was measured. Selecting high activity sample according to set positive standard, diluting to 7 concentrations, performing gradient re-screening, and calculating IC 50 . Since the compound itself has a certain absorbance at 292nm, another UV plate was prepared for each plate to determine the absorbance of the compound, 20. Mu.L of the compound to be tested, 20. Mu.L of dilute HCl and 80. Mu.L of buffer were added to each well, and the measured absorbance was subtracted from the background UV absorbance.
3) Data processing
The absorbance of the sample was expressed as follows:
Figure BSA0000179820350000171
and (4) calculating the enzyme activity inhibition rate.
The screening results are shown in table 2: after the gradient concentration is sieved again, according toPerforming linear regression on enzyme inhibition rate and sample concentration to calculate IC 50 。
TABLE 2 inhibition and IC of xanthine oxidase by aryl thiazoles (I) 50
Figure BSA0000179820350000172
Figure BSA0000179820350000181
* The inhibition of XO at a test compound concentration of 0.1mg/L (i.e., between 40 and 70nmol/L, respectively);
* At this time, the concentration of febuxostat is 40nmol/L;
as can be seen from Table 2, most of the compounds of the present invention show strong inhibitory activity against xanthine oxidase, and the inhibitory activity of some compounds is superior to that of febuxostat, indicating that these compounds can be used for the treatment of metabolic diseases caused by elevated uric acid levels in vivo, such as gout and hyperuricemia.

Claims (10)

1. A4-arylthiazole derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof,
Figure FSA0000179820340000011
here, the
Y represents O, S, NH;
R 1 represents H, C 1 -C 4 An alkane of (a);
R 2 represents a formyl group, - (CH) 2 ) n CO 2 H or- (CH) 2 ) n COR 5 Wherein n =0 to 4,R 5 Is C 1 ～C 4 Alkoxy or amino acid of (a);
R 3 represents formyl, cyano, nitro, amino or hydroxyamino;
R 4 represents C 1 ～C 8 Straight or branched alkyl, C 2 ～C 8 Straight-chain or branched alkenyl or conjugated or unconjugated polyalkenyl, C 2 ～C 8 Straight-chain or branched alkynyl or C 2 ～C 8 Straight or branched conjugated or non-conjugated alkinyl.
2. The 4-arylthiazole derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein Y represents O, S, NH; r is 1 Represents H, methyl or ethyl; r is 2 Represents formyl or-COOH; r is 3 Represents cyano or nitro; r is 4 Represents C 1 ～C 6 Straight or branched alkyl, C 3 ～C 6 Straight-chain or branched alkenyl or conjugated or non-conjugated polyene, C 3 ～C 6 Straight or branched alkynyl.
3. The 4-arylthiazole derivative or the pharmaceutically acceptable salt thereof of claim 2, wherein R 1 Represents a methyl group.
4. The 4-arylthiazole derivative or the pharmaceutically acceptable salt thereof of claim 3, wherein R 3 Represents cyano.
5. The 4-arylthiazole derivative or the pharmaceutically acceptable salt thereof according to claim 4, wherein R 4 represents-CH 3 、-C 2 H 5 、-C 3 H 7 -n、-C 3 H 7 -i、-C 4 H 9 -n、-C 4 H 9 -i、-C 5 H 11 -n、C 5 H 11 -i、-CH 2 Ph、-CH 2 CH＝CH 2 、-CH 2 CH＝CHCH 3 、-CH 2 C(CH 3 )＝CH 2 、-CH 2 CH＝C(CH 3 ) 2 、-CH(CH 3 )CH＝CH 2 、-CH 2 CH＝CHCH＝CH 2 、-CH 2 CH＝CHCH＝CHCH 3 、-CH 2 C(CH 3 )＝CHCH＝CH 2 、-CH 2 CH＝CHC(CH 3 )＝CH 2 、-CH 2 C≡CH。
6. A pharmaceutical composition comprising the 4-arylthiazole derivative or the pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.
7. The pharmaceutical composition of claim 6, which is a xanthine oxidase inhibitor.
8. The pharmaceutical composition according to claim 6 or 7, which is a uricosuric agent.
9. The pharmaceutical composition according to claim 6, which is a pharmaceutical preparation for treating gout or hyperuricemia.
10. The pharmaceutical composition of claim 6, which is a pharmaceutical formulation for the treatment of an ischemia-reperfusion disorder, an inflammatory disease, diabetes, cancer, atherosclerosis or a neurological disease.
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