WO1990011278A1

WO1990011278A1 - Thiazole compounds and applications thereof

Info

Publication number: WO1990011278A1
Application number: PCT/JP1990/000385
Authority: WO
Inventors: Tomokazu Goto; Tadashi Okano; Naoki Sugiyama; Fumihiko Akaboshi; Shinichiro Ono; Yoichiro Naito; Yasunari Yamaura; Chikara Fukaya; Kazumasa Yokoyama
Original assignee: The Green Cross Corporation
Priority date: 1989-03-24
Filing date: 1990-03-22
Publication date: 1990-10-04

Abstract

The invention provides thiazole compounds and pharmacologically acceptable salts thereof excellent in analgesic, antiinflammatory and antipyretic activities, represented by general formula (I), wherein R?1 and R2¿ represent each independently hydrogen, halogen, alkyl, alkenyl, nitro, CF¿3?, phenyl, substituted phenyl, pyridyl, substituted pyridyl, carboxyl, alkoxycarbonyl, -CONR?5R6¿ (wherein R?5 and R6¿ represent each hydrogen or alkyl), acyl, hydroxy, alkoxy or thioalkyl, or alternatively R?1 and R2¿ are combined together to form -(CH¿2?)m- (wherein m is 3 to 5); R?3¿ represents hydrogen or alkyl; R4 represents hydroxy, alkoxy or -NR7R8 (wherein R?7 and R8¿ represent each hydrogen or alkyl); X represents carbonyl or -(CH¿2?)n- (wherein n is 0 or 1); and Y represents hydrogen, halogen, alkyl, nitro, CF3, -NR?9R10¿ (wherein R?9 and R10¿ represent each hydrogen or alkyl), hydroxy (only when the position of X is para to the CHR3COR4 group), alkoxy (only when the position of X is para to the CHR3COR4 group), or alkylthio.

Description

Specification

Thiazole compounds and uses thereof

"Technical field"

The present invention relates to a novel compound having an anti-inflammatory effect and its use as a pharmaceutical.

"Background technology"

Currently, various drugs are clinically used as non-steroid anti-inflammatory agents. Research and development are also being actively pursued, and various new compounds have been created with the aim of enhancing or sustaining action, reducing fever, and reducing side effects. No. 5 9 — 2 5 3 8 1, No. 50 — 6 9 0 76, No. 50-9 5 2 61, No. 50 — 14 9 6 68, No. 5 4-6667 publication).

"Disclosure of the invention"

In view of the above circumstances, the present inventors conducted further research and found that the compound represented by the following general formula (I) has an excellent anti-inflammatory effect. Was completed.

The present invention has the general formula

[In the formula, R ¹ and R ² are the same or different, and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a nitro group, a trifluoromethyl group, a phenyl group, a substituted phenyl group, a pyridyl group. , Substituted pyridyl group, carboxyl group, lower alkoxycarbonyl group, — CON (R ⁵ ) (R ⁶ ) (R ⁵ and R ⁶ are the same or different and represent a hydrogen atom or a lower alkyl group), lower α R ¹ and R ² may form one (CH ₂ ) _m — (m is 3 to 5) with a sil group, a hydroxyl group, a lower alkoxy group or a lower alkylthio group, and R ³ is a hydrogen atom or R ⁴ is a hydroxyl group, a lower alkoxy group, or N (R ⁷ ) (R ⁸ ) (R ⁷ and R ⁸ are the same or different and represent a hydrogen atom or a lower alkyl group); A bonyl group or one (CI) _n — (n represents 0 or 1), and Y represents a hydrogen atom, a halogen atom, a lower alkyl group, a nitro group, a trifluoromethyl group, a N (R ⁹ ) ^{(R '.) (R 9} , R 1. is shown the same or different and each represents a hydrogen atom or a lower alkyl group ), Hydroxyl group (however, the substitution position of X is CH (R ³⁾ only if a rose-position of C 0 R ^4), lower alkoxycarbonyl key sheet group (provided that the substitution position of X

CH (R ³ ) C 0 R ⁴ only) or a lower alkylthio group] (hereinafter referred to as thiazole compound (I)) or a thiazole compound (I). It relates to pharmacologically acceptable salts.

Furthermore, the present invention relates to a pharmaceutical composition comprising a thiazole compound, a pharmaceutically acceptable salt thereof, and a carrier.

In this specification, each group means the following. Examples of the halogen atom include chlorine, bromine, fluorine, and iodine.

The lower alkyl group may be straight-chained or branched, and preferably has 1 to 4 carbon atoms, and specifically includes a methyl group, an ethyl group, Examples include an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, and a t-butyl group.

The lower alkenyl group may be linear or branched, and preferably has 2 to 4 carbon atoms, and specifically includes a vinyl group, an isopropenyl group, a 1-propenyl group, Aryl group, 1—methylol 1-butanol group, 2—methylenol 1—propenyl group, 1—methylaryl group, 2—methylaryl group, 1—butyr group, 2-butyr group, 3-butul group and the like.

The lower alkoxy group may be linear or branched, and preferably has 1 to 4 carbon atoms, and specific examples include a methoxy group, an ethoxy group, and a propoxy group.

The lower alkylthio group may be linear or branched and preferably has 1 to 4 carbon atoms, and specific examples include a methylthio group, an ethylthio group, and a propylthio group.

The lower alkoxycarbonyl group may be either straight-chain or branched, and preferably has 1 to 4 carbon atoms, and specifically includes a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxy group. And a carbonyl group.

The lower acyl group may be linear or branched and is preferably an alkanol group having 2 to 5 carbon atoms, specifically, an acetyl group, a propionyl group and a butyl group. And a valeryl group.

A substituted phenyl group is an amino group, a nitro group or a tri-substituted one or two substituents such as a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group and a lower alkyl group. Fluoromethyl group, etc. Is a furyl group substituted by one or two arbitrary positions.

The pyridyl group may be any of a 2-pyridyl group, a 3-pyridyl group and a 4-pyridyl group.

The substituted pyridyl group is a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group, an amino group in which one or two lower alkyl groups are substituted, a nitro group, a trifluoromethyl group. Are viridyl groups having one or two substituents at any positions.

The compounds of the present invention include tautomers. For example, when R ¹ is a hydroxyl group,

Also include the compound represented by the above formula

As the substitution position of each substituent,

Or

(In each formula, each symbol is as defined above.)

Etc. are exemplified.

Also, pharmacologically acceptable salts include alkali metal salts (such as sodium salts and potassium salts), alkaline earth metal salts (such as calcium salts), and organic amine salts (such as calcium salts). Pyridin salt and the like). The compound of the present invention is specifically produced by the following production method.

(1) a compound of the formula (I) wherein X is a carbonyl group

(Wherein, R ¹ , R ² , R ³ , R ⁴ and Y are as defined above)

Reaction (i) is carried out in an organic solvent such as tetrahydrofuran or hexane for about 100 to 195 for about 0.5 to 2 hours.

The reaction (ii) is carried out in an organic solvent such as tetrahydrofuran for 100- 30 to 5 to 12 hours.

The reaction (iii) is carried out in an organic solvent such as acetate for about 10 to 10 hours.

(2) a compound of the formula (I) wherein X is (CH ₂ ) _n — and n is 1

(Π)

(iii) Η ₂

(IV)

(R ¹ , R ² , R ³ , R ⁴ and Y are as defined above)

The reactions (i) and (ii) are carried out in the same manner as the reactions (i) and (ii) in the preceding paragraph (1).

Reaction (iii) is performed under a hydrogen atmosphere, and acetic acid or the like is used as a solvent. The reaction is carried out at 60 to 80'C for about 10 to 20 hours.

(3) Compounds of the formula (I) in which X is (CH _z ) _n — and n is 0

Hz

(V) H ₂

(R ¹ , R ^z , R ³ , R ⁴ and Y are as defined above)

Reaction (i) is carried out by adding concentrated hydrochloric acid to acidify, adding sodium nitrite, reacting at 12 to 2'C for about 10 to 60 minutes, and returning to neutrality. Will be

The reaction (ii) is carried out for about 10 to 60 minutes, and then for about 40 to 50'C for about 1 to 3 hours.

Reaction (iii) is carried out in an organic solvent such as dimethylformamide for about 80 to 100 hours and about 1 to 10 hours.

Reaction (iv) is preferably performed under a nitrogen atmosphere. The reaction is carried out by heating and refluxing for about 1 to 5 hours in an organic solvent such as ethanol.

Compounds (11), (I) and (V) are substantially known compounds.

The thiazole compound (I) of the present invention and a pharmacologically acceptable salt thereof are novel compounds which have not been described in any literature, and are used in mammals such as humans, mice, rats, dogs, mice and rats. It is an industrially useful compound that has excellent pharmacological actions such as analgesic, anti-inflammatory and antipyretic effects, and is a pharmaceutical product such as an analgesic, anti-inflammatory and antipyretic. The thiazole compound (I) and its pharmacologically acceptable salt can be formulated orally or parenterally (injection, rectum, skin) by itself or formulated by a conventional means with a carrier known per se. Administered to

Examples of the preparation include tablets, capsules, powders, syrups, suppositories, injections, and skin patches.

The dosage of the thiazole compound (I) and its pharmacologically acceptable salt varies depending on the condition, body weight, age, sex, administration route, etc., and is usually 1 to 100 nig, 1 to several times a day. It is administered in divided doses.

Examples will be given in order to explain the present invention in more detail, but the present invention is not limited by these.

Example 1

2 — [3 — (4 —phenylthiazole— 2 —ylcarbonyl) phenyl] puccinic acid

(1) 2 — (3 —Promofanil) probionic acid 3.604 g of a solution of 55 ml of dry tetrahydrofuran (THF) was cooled with the cooling medium of 97.8. 20 ml of a butyllithium hexane solution (1.6 N) was added dropwise. After stirring for 55 minutes under the same cooling, a solution of 2.994 g of 2-formyl-4-phenylthiazole in 35 ml of dry THF was added dropwise under the same cooling. After completion of the dropwise addition, the reaction temperature was increased to room temperature, and the mixture was further stirred at room temperature overnight. The reaction solution was poured into 5% hydrochloric acid under ice cooling, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the ethyl acetate layer were combined, and the solvent was distilled off to obtain a reaction mixture. The reaction mixture was subjected to silica gel column chromatography (eluent; Purification was carried out by using (formanol-methanol system), and 3.32 g of 1- (4-phenylthiazole-12-ecle) -13- (1-carboxyl) benzyl alcohol was obtained. Obtained at 63%.

I R V: 3480-2740, 1705

(2) 2.400 g of the benzyl alcohol obtained above was dissolved in Π ml of acetone, and 2.5 ml of dione's reagent (10 N) was added dropwise thereto under cooling with ice and salt, followed by stirring for 4 hours under the same cooling. The reaction solution was extracted with ethyl acetate to obtain a crude product. This was purified by silica gel chromatographic method (eluent closed-mouth form) and recrystallized from ethyl acetate-hexane to give 2— [3— (4—phenylthiazol-2-ylcarbonyl). ) Phenyl) propionic acid

1.7 12 g as BB with a yield of 72%

Melting point: 1 47.5-1 4 8 'C

IR cm " ¹ : 3200-2600, 1688, 1632, 1293, 1255, 1220,

758, 689, 667

¹ HNMR (C Ό C £ ₃ ) δ: 9.10-8.20 (brs, 1H), 8.67-8.58 (m, 1H), 8.52-8.47 (m, 1H), 7.97-7.91 (m, 2H), 7.83 (s , 1H), 7.63-7.34 (m, 5H), 3.87 (q, J = 7.2Hz, 1H), 1.59 (d, J = T.2H _Z) 3H)

Example 2

2- [3— (4-phenylthiazole-2—inomethyl) phenyl] probionic acid

(1) Example 1 In the same manner as in Example (1), 2-(3-bromofuunyl) pulp bionic acid 4.172 g and 2-formyl 4- 4-phenylthiazole 3.48 5 g of the mixture, and then use the silica gel column chromatographic method. (Eluent; black-form-methanol system) to give a crude product of α- (4-1-phenylthiazole-2-yl) 13- (1-carboxyshetyl) benzyl alcohol. 3.306 g of the obtained crude benzyl alcohol 2.980 g was dissolved in ether 30 ^ in a solution of diazomethane in ether under ice-cooling (0.476). ramol /) 30 drops were dropped. After stirring for 40 minutes under ice-cooling, acetic acid 4 was added under ice-cooling, and then saturated aqueous sodium bicarbonate was added and the mixture was stirred. Extraction with ether gave a crude product. This was purified by silica gel column chromatography (eluent; ethyl hexane monoacetate) to give α- (4-phenylthiazole_2-yl) 13- (1-methoxycarbonylethyl) benzyla. The alcohol was obtained in 1.620 g with a yield of 52%.

IRV Sl ^ cw- ¹ : 3660-3130, 1726, 1225, 1198, 1167, 740, 694

(2) To a solution of 1.743 g of the benzyl alcohol obtained above in 16 ^ acetic acid was added 933.4 mg of 10% palladium-carbon and 70.0% of perchloric acid (70.0%). Drops were added, and the mixture was stirred at a viral temperature of 70 under a hydrogen atmosphere for 17 hours. Palladium-carbon was filtered off, and the filtrate was distilled off. The residue was extracted with ethyl acetate to obtain a crude product. This was purified by silica gel column chromatogram method (eluent; hexane-ethyl acetate system), and methyl 2- (3 — (-4—fudylthiazol-2-ylmethyl) phenyl) propionate was converted to 1.0. 61 g was obtained in a yield of 64%.

IRV Sl ^ cm- ¹ : 1727, 1222, 1193, 1164, 732, 704, 688

(3) Ethanol was added to 1.594 g of the methyl ester obtained above. 12 ml and 2.5 N sodium hydroxide 12 ml were added, and the mixture was refluxed for 2 hours. Ethanol was distilled off, water was added, and the mixture was washed with ethyl acetate. Under ice-cooling, 4 NHC 1 was added to the aqueous layer to adjust the pH to 1, followed by extraction with ethyl acetate to obtain a product. This was purified by silica gel chromatography chromatography (eluent; chromatographic form-methanol system) and recrystallized from ethyl acetate-hexane to give 2— [3— (4—Fe [Dithiazol-1- (2-methyl) phenyl] propionic acid was obtained as white crystals in 1.093 g in a yield of 72%.

Melting point 82.0 ~ 83.0

_{^{^{IR ^ l x r cm- 1:}}} 3640-3275, 3275-2750, 1700, 1220, 736, 730, 705, 688

¹ HNMR (CDC £ ₃ ): 9.10-8.04 (brs, 1H), 7.88-7.82 (m, 2H), 7.44-7.23 (m, 8H), 4.35 (s, 2Η), 3.72 (q, J = 7.2Hz , 1H), 1.50 (d, J = 7.2Hz, 3H)

Example 3

2 — [3 — (4 — phenylthiazolu-2-yl) phenyl] probionic acid

(1) Water 7 was added to 7.38 g of ethyl 2-propionate (3-aminopropyl), and then concentrated hydrochloric acid 10 was added dropwise under ice cooling. Next, a solution of 2.852 g of sodium nitrite dissolved in water 21 was added dropwise at a reaction temperature of 0 to 12'C. After completion of the dropwise addition, the mixture was stirred at a reaction temperature of 2 to 2 minutes for 20 minutes. A solution prepared by dissolving 2.586 g of sodium carbonate (monohydrate) in 24 ^ water was added dropwise at a reaction temperature of 2'C or lower to neutralize the reaction solution. On the other hand, dissolve 6.633 g of cuprous cyanide and 9.8 11 g of potassium cyanide in water 70 Neutral diazonium salt was added dropwise with vigorous stirring at a reaction temperature of 1 to 0. After completion of the dropwise addition, the mixture was allowed to stand at a reaction temperature of 0 ° C for 38 minutes, and then allowed to stand still to raise the reaction temperature from 0 ° C to 50 ° C for 1 hour. The sample was allowed to stand for 5 hours. Water was added to the reaction solution and extracted with ether to obtain a crude product. This was purified by silica gel column chromatographic method (eluent: ethyl hexane monoacetate), and 6.527 g of 2- (3-cyanofuunyl) ethyl propionate was collected. Obtained at a rate of 84%.

IRV

: 2980-2880, 2240, 1728, 805, 780, 692

(2) 5.066 g of 2- (3-cyanophenyl) probionate obtained above and dried triethylamine 3.50 ^ are dried in N,

Dry hydrogen sulfide gas was slowly blown into the solution dissolved in N-dimethylformamide (DMF) 44 at a reaction temperature of 85 to 95. After blowing for 4 hours, the reaction solution was poured into water containing a little amount of ice, and extracted with ethyl persulfate to obtain a crude product. This was purified by silica gel column chromatography (eluent; hexane-monoacetate system) to give 3- (1-ethoxycarbonylethyl) phenylcarboamide. 5.773 g, yield 98%.

IRV Si ^ cm- ¹ : 330Q, 3180, 2980 and 2940, 1720, 1620, 805, 700

(3) A solution of 5.568 g of the thioamide obtained above and 5.430 g of bromide and phenyl in dry ethanol 120 was refluxed under a nitrogen atmosphere for 2 hours. Ethanol was distilled off to obtain a crude product. This was purified by silica gel chromatographic method (eluent; hexane-ethyl ester) to give 2— [3— (4 —Ru 2 — (ino) phenyl) ethyl propionate was obtained in 6.85 g in a yield of 87%.

IRV Si ^ cm " ¹ : 3100-2880, 1728, 735, 695

(4) A solution comprising 3.684 g of the ethyl ester obtained above, 30 mL of ethanol and 30 ffiE of a 2.5 N aqueous sodium hydroxide solution was refluxed for 2 hours. After evaporating the solvent, water was added to the residue, and hydrochloric acid was added under ice cooling to adjust the pH of the reaction solution to 4. Extraction with ethyl acetate gave a crude product. This was purified by silica gel column chromatogram method (cloform form-methanol system), and further recrystallized from ethyl acetate-hexane to give 2— [31- 4-phenythiazole-12-phenylene) propionic acid was obtained in 2.114 g in a yield of 63%.

Melting point: 97.5 ~ 99.0

v ll cm " ¹ : 3140-2800, 1702, 738, 695

1 HNMR (CDC £ ₃ ) 10 .: 10.40-8.77 (brs, 1H), 7.99-

7.85 (m, 4Η), 7.47-7.22 (m, 6Η), 3.82 (q, J = 7.2Hz,

1H), 1.56 (d, J = 7.2Hz, 3H)

Example 4

2- [4- (4-phenylthiazole-1-2-inophenol) phenyl] probionic acid

(1) In the same manner as in Example 2 (1), 2- (4-bromophenyl) propionic acid and 2-formyl-4-phenylthiazole were converted to-(4-phenylthiazole-1). 2-yl)-4-1 (1-carboxyl shetyl) benzyl alcohol, a crude product was obtained, which was treated with diazomethane, silica gel gel chromatographic method (solution). Effluent: Hexane monoacetate (purified by hexyl monoacetate) to give-(4-phenethylthiazole-2-inole) -4-1 (1-methoxycarbonylethyl) benzyl The alcohol was obtained in a yield of 41%.

1 RV gf ^ cm " ¹ : 3680-3140, 1722, 860, 738, 695

(2) 4.031 g of methyl ester obtained above, ethanol

A solution consisting of 28.5 and 2.5 N sodium hydroxide 28.5 was refluxed for 2 hours. The solvent was distilled off, water was added to the residue, and hydrochloric acid was added under ice cooling to adjust the pH to 1, followed by extraction with ethyl acetate to obtain a crude product. This was purified by silica gel chromatography chromatography (eluting solution; black form-methanol system), and 1- (4-phenyl-2-thiazole-2-yl) -14- (1-carboxyethyl) was purified. 2.69 g of benzyl alcohol was obtained as a white solid in a yield of 69%.

IRV! JH cm " ¹ : 3650-2730, 1698, 1208, 860, 738, 690

(3) The benzyl alcohol obtained as described above was subjected to an oxidation reaction in the same manner as in Example 1 (2), and was subjected to a silica gel gel ram chromatogram method (eluate; black-mouthed form-methanol). After purification with ethyl acetate, recrystallization from ethyl hexane acetate yielded 2— [4- (4-phenylthiazole-12-ylcarbonyl) phenyl] propionic acid as yellow crystals in a yield of 5 Obtained at 1%. , Melting point: 1 3 5 ~ 1 3 '6

IRV cm " ¹ : 3260-2730, 1695, 1293, 1256, 875, 755, 684, 668

^{_{1 HNMR (CDC £ 3):}} 10.28-8.78 (brs, 1H), 8.62-8.57 (m, 2H), 7.97-7.91 (m, 2H), 7.83 (s, 1H), 7.53-7.32 (m, 5H), 3.86 (q, J = 7.1Hz, 1H), 1.58 (d, J = 7.2 (Hz, 3H) Example 5

2-[4 — (4_phenylthiazol-1 2 -inomethyl) phenyl] probionic acid

(1) Example 4 (1- (4-phenylthiazol-2-yl)-(1-methoxycarbonylethyl) benzylbenzyl alcohol obtained in Example 1 (1) was used in Example 2 (2 ) To give a hydrogenolysis reaction in the same manner as in) to give methyl 2-([4- (4-phenylthiazole-12-ylmethyl) phenyl] probionate in a yield of 73%. Was.

IV Sl ^ cm- ¹ : 1733, 1205, 1162, 852, 732, 690

(2) The methyl ester obtained above was subjected to a hydrolysis reaction in the same manner as in Example 2 (3), followed by silica gel chromatography chromatography.

(Eluate: black-mouthed form-methanol system), followed by recrystallization from ethyl acetate-hexane to give 2 —

[4- (4-Fluorthiazol-1-2-methyl) phenyl] propionic acid was obtained as white needle crystals in a yield of 79%.

Melting point: 1 27.0 to 1 28.0

IRV SI ^ cm " ¹ : 3280-2740, 1698, 1227, 740, 694

^{_{1 HNMR (CDC jg 3) 5}} : 10.87-9.88 (brs, 1H), 7.87-7.81

(m, 2H), 7.43-7.22 (m, 8H), 4.33 (s, 2Η), 3.71 (q,

J = 7.2Hz, 1H), 1.48 (d, J = 7.2Hz, 3H)

Example 6

2 — [4 — (4 — phenylthiazoyl 2 phenyl) phenyl] propion (1) In the same manner as in Example 3 (1), 2- (4-aminophenyl) propionate was converted to 2- (4-cyanophenyl) propionate ethyl ester in a yield of 7- (4-aminophenyl) propionate. 8%.

IRV Si ^ cm ' ¹ : 2220, 1728, 1242, 1202, 1170, 842

(2) The ethyl 2- (4-cyanophenyl) propionate obtained above was reacted with hydrogen sulfide in the same manner as in Example 3 (2) to give 4— (1-Ethyl). (Kishika levonylethyl) phenylcarboamide was obtained in a yield of 91%.

IRV UIS cm " ¹ : 3270, 3120, 1727, 1275, 1255, 1200,

1172, 1160, 846

(3) By reacting the thioamide obtained above with phenacyl bromide in the same manner as in Example 3 (3), 2— [4— (4—phenylthiazol-2-y) was obtained. Phenyl) brobionate was obtained with a yield of 90%.

IRV Sl ^ cm " ¹ : 1728, 1202, 1172, 844, 729, 690, 675

(4) The ethyl ester obtained above was subjected to a hydrolysis reaction in the same manner as in Example 3 (4), followed by silica gel chromatography chromatography (eluate; black form-methanol). After purification with ethyl acetate, recrystallization was performed from ethyl hexane acetate, and the yield of 2— [4— (4-monounylthiazol-2-yl) phenyl] propionic acid was converted to white crystals. %. -Melting point: 15.7.5-15.0'C

IR ^ cm " ¹ : 3640-3250, 3250-2730, 1692, 1224, 736, 690, 675

¹ HNMR (DMSO— d ₆ ) 5: 8.15 (s, 1H), 8.08-7.96 (m, 4H), 7.53-7.34 (m, 5H), 3.76 (q, J = 7.1Hz, 1H), 1.41 (d, J = 7.1Hz, 3H)

Example 7

2- [3- (2-thiazolylcarbonyl) phenyl] provonic acid

(1) In the same manner as in Example 2 (1), 2- (3-bromofuunyl) propionic acid and 2-formylthiazole were used to prepare 2- (1-thiazolyl) -3- (1-ca). A crude product of ruboxyl) benzyl alcohol is obtained, treated with diazomethan, and purified by silica gel chromatography (eluent; hexyl monoethyl acetate). , O — (2 — thiazolyl) — 3 —

(1-methoxycarbonylethyl) benzyl alcohol was obtained in a yield of 9%.

IRVS! ^ Cm- ¹ : 1730, 1430, 1370, 1240, 1200, 1170,

1045, 780, 710

(2) The 1- (2-thiazolyl) 13- (1-methoxycarbonylethyl) benzyl alcohol obtained above was subjected to a hydrolysis reaction in the same manner as in Example 4 (2). By recrystallizing from ethyl acetate-hexane, or- (2-thiazolyl) 13- (1-carboxyl) benzyl alcohol was obtained in a yield of 47%.

IRV ίίΐ ^ cm " ¹ : 3400-2900, 1730, 1500, 1420, 1180, 1045, 743, 705

(3) The or — (2-thiazolyl) — 3 — (1 — carboxy shetyl) benzyl alcohol obtained above was subjected to an oxidation reaction in the same manner as in Example 3 (2) to give ether-hexane. By recrystallizing from 2— [3— (2-Thiazolylcarbonyl) phenyl] propionic acid was obtained in a yield of 57%.

Melting point: 80.5 ~ 81.5

IRV cm— ¹ : 3200-2700, 1690, 1640, 1570, 1380, 1325,

1280, 1235, 850, 740

1 HNR (CDC £ ₃ ) 5: 12.5 (brs, 1H), 8.24-8.38,

4H), 7.52-7.69 (m, 2H), 3.83 (q, J = 7.1Hz _s 1H), 1.43

(d, J = 7.1Hz, 3H)

Example 8

2 — ί4-(2 — thiazolylcanolebonyl) phenyl] propionic acid

(1) The reaction was carried out in the same manner as in Example 1 (1) using 2- (4-bromophenyl) brobionic acid and 2-formylthiazol, and the product was recrystallized from chloroform-methanol. As a result, or- (2_thiazolyl) -14- (1-carboxyl shetyl) benzyl alcohol was obtained in a yield of 13%.

IR cm " ¹ : 3640-3130, 1675, 1258, 1230, 865

(2) The α- (2-thiazolyl) —4— (1-carboxyl shetyl) benzyl alcohol obtained above was subjected to an oxidation reaction in the same manner as in Example 3 (2), and silica gel gel chromatogram method was used. (Eluent; chloroform-methanol system) and recrystallized from ethyl acetate-hexane to give 2- (4- (2-thiazolylcarbonyl) phenyl) probio. Acid was obtained in a yield of 82%. Melting point 1 73.0-1 74.0

IR 1 / il ^ cm- ': 3640-3280, 3200-2800, 1725, 1328, 1293, 1208, 872

¹ HNMR (COC £ ₂ ) δ: 13.37-10.88 (brs, 1H), 8.40-

8.36 (m, 2H), 8.30 (d, J = 3.1Hz, 1H), 8.25 (d, J = 3.1Hz, 1H), 7.56-7.51 (m, 2H), 3.85 (q, J = 7.1Hz, 1H ), 1.44 (d, J = 7.1Hz, 3H)

Example 9

2 — [4-1 (2-thiazolyl) phenyl] probionic acid

(1) In the same manner as in Example 3 (1), 2— (4—aminofurnyl)

2- (4-Cyanophenyl) -l- 2-ethylmethyl methylate was obtained from getyl 2-methylmalonate in a yield of 61%.

IRV iSf ^ cm " ¹ : 2970, 2201, 1725, 1603, 1500, 1460,

1375, 1248, 1102, 1018, 858

(2) By reacting the above-obtained 2-((4-cyanophenyl) -12-methyl getyl malonate with hydrogen sulfide in the same manner as in Example 3 (2), Jethyl 2- (4-thiocarbamoylphenyl) malonate was obtained in a yield of 93%.

IRV! S cm " ¹ : 3090, 2970, 2900, 1725, 1600, 1475,

1395, 1204, 1061, 879, 726, 618

(3) 1.583 g of bromoacetaldehyde dodecyl acetal and 1.933 g of dimethyl 2- (methylthio) -2- (4-thiocarbamoylphenyl) malonate obtained above The resulting product was dissolved in acetic acid (10), and thereto was added 75 μg of P-toluenesulfonate monohydrate, and the mixture was heated and stirred in an oil bath at about 100 in a nitrogen atmosphere for 1.5 hours. The solvent was distilled off, the residue was dissolved in ethyl acetate, and the solution was added to a saturated aqueous sodium hydrogen carbonate solution. Extract with ethyl acetate and extract the crude product Purified by Lukaram chromatogram method (eluent; ethyl hexyl monoacetate) to give 2-methyl-2-[[4- (2-thiazolyl) phenyl] getyl malonate 1.62 8 g, 78% yield. IRV

¹ : 2960, 1721, 1601, 1478, 1243: 1102,

1016, 973, 858, 628

(4) Dissolve 1.485 g of 2-methyl-2-([1- (2-thiazolyl) phenyl] getyl malonate) obtained in the above in ethanol 1 and add potassium hydroxide. The mixture was added with 988 mg, and the mixture was heated and stirred with a 100 ° C. oil bath for 1.5 hours. The solvent was distilled off, water was added to the residue, and the mixture was washed with ethyl acetate. The aqueous layer was poured into ice-cooled concentrated hydrochloric acid, extracted with ethyl acetate, purified by silica gel column chromatographic method (eluent; hexane-ethyl acetate), and re-formed from chloroform-hexane. By crystallization, 2-([4- (2-thiazolyl) phenyl] probionic acid was obtained in 5.55 m with a yield of 53%.

/

Melting point: 1 49.0-: L 51.0

IR cm ' ¹ : 3150-2150, 1690, 1600, 1482, 1243, 1204.

1045, 979, 858, 826, 640

1 HNMR (CDC £ ₃ ) 5: 1.5-4 (d, J = 7.2 Hz, 3H), 3.79 (q,

J = 7.2Hz, 1H), 7.32 (d, J = 3.3Hz, 1H), 7.40 (d, J = 8.3Hz

2H), 7.75-8.20 (m, 4H)

Example 10

In the same manner as in Example 9, 2— [3—black mouth—41- (2-thiazolyl) fuunil] provionic acid was prepared.

Melting point: 8 1 to 8 2 IR cm " ¹ : 3250-2200, 1687, 1590, 1450, 1372, 1312, 1281, 1259, 1218, 1050, 922, 861, 618

¹ HNMR (C Ό C £ ₅ ) δ: 1.54 (d, J = 7.2 Hz, 3H), 3.76 (q, J = 7.2 Hz, 2H), 7.33 (dd, J = 8.2 Hz, 1.8 Hz, 1H), 7.7 (d, J = 1.8Hz, 1H), 7.50 (d, J = 3.4Hz, 1H), 7.97 (d, J = 3.3Hz, 1H), 8.09 (d, J = 8.2Hz, 1H), 7.7-8.6 (brs, 1H)

Example 1 1

In the same manner as in Example 9, 2-[[3-fluoro-4- (2-thiazolyl) phenyl] propionic acid was prepared.

Melting point 1 5 2 to 1 5 4

IR i / iJIi cm " ¹ : 3100-2300, 1700, 1610, 1560, 1500, 1480, 1420, 1215, 1110, 815, 735, 700, 642, 550, 520

^{_{1 HNMR (DMS 0- d 6)}} 5: 1.45 (d, J = 7.1Hz, 3H), 3.77 (q, J = 7.1Hz, 1H), 7.25-7.31 (m, 2H), 7.76-7.80 (m, 1H), 7.94-7.97 (m, 1H), 8.20 (t, J = 8.0Hz, 1H)

Example 1 2

In the same manner as in Example 9, 2- (3,5-dichloro-1- (2-thiazolyl) phenyl] propionic acid was prepared.

Melting point 17 1 〜 1 7 2

IR or ¹ : 3200-2200, 1900, 1705, 1593, 1540, 1398, 1240, 1220, 1141, 1098, 796

¹ HNMR (CDC £ ₃ ) 5: 1.51 (d, J = 7.2 Hz, 3H), 3.71, J = 7.2 Hz, 1H), 7.36 (s, 2H), 7.61 (d, J: 3.3 Hz, 1H), 8.04 (d, J = 3.3Hz _: 1H), 8.0-9.0 (brs, 1H)

Example 13 In the same manner as in Example 9, 2-[[3-methyl-4- (2-thiazolyl) phenyl] propionic acid was prepared.

Melting point 82.5 to 8 4

IR l _x ^r cm " ¹ : 3000-2300, 1700, 1600, 1215, 1205, 800, 775

¹ HNMR (C Ό C & ₃ ) 6: 1.52 (d, J = 7.2Hz, 3H), 2.53 (s, 3H), 3.74 (q, J = 7.2Hz, 1H), 7.20-7.26 (m, 2H) , 7.39 (d, J = 3.3H _Z) 1H), 7.64 (d, J = 7.8Hz, 1H), 7.93 (d, J = 3.3Hz, 1H)

Example 14

In the same manner as in Example 9, 2— [3—curo mouth —41- (4-phenylthiazol-12-yl) phenyl] propionic acid was prepared. Melting point 1 6 8 ~ 1 7 0

IR (M- ¹ 3250-2350, 1690, 1597, 1469, 1440, 1393,

1268, 1231, 1060, 975, 739, 681

1 HNMR (COC £ ₃ ) δ: 1.55 (d, J = 7.2 Hz, 3H), 3.78 (q,

J = 7.2Hz, 1H), 7.30-7.48 (m, 5H), 7.61 (s, 1H), 7.99

(dt, J = 7.8Hz, 1.5Hz, 2H), 8.34 (d, J = 8.2Hz, 1H), 7.0-

9.0 (brs, 1H)

Example 15

2 — ί 3-(2 — thiazolylmethyl) phenyl:] Propion tub

(1) 2.29 g of a- (2-thiazolyl) -13- (1-methoxycarbonylethyl) benzyl alcohol was dissolved in 40% acetic acid. Add 500 g of perchloric acid (70%), 10% Pd-C 2 g, The mixture was stirred at a hydrogen bath temperature of 80'C for 12 hours and 20 minutes under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered, and the filtrate was distilled off. The residue was extracted with ethyl acetate to obtain a crude product.

This crude product was dissolved in ether-methanol and treated with diazomethane.

This was purified by silica gel chromatographic method (eluent; hexane monoethyl acetate) to give methyl 2- (3— (2-thiazolylmethyl) phenyl) propionate in 9 69 nig. Yield 45%.

IRV Rl ^ cm- ': 1730, 1600, 1495, 1430, 1200, 1160.' HNMR (CDC £ ₃ ) 5: 1.48 (d, J = 7.2 Hz, 3H), 3.65 (s, 3H), 3.71 (q , J = 7.2Hz, 1H), 4.34 (s, 2H), 7.17-7.33 (m, 5H), 7.71 (d, J = 3.3Hz, 1H)

(2) 1.40 g of 2-[[3- (2-thiazolylmethyl) phenyl] propionate obtained in (1) was dissolved in ethanol 3 »?. Then, 2.5 N sodium hydroxide solution 4.29 was added, and the mixture was stirred at an oil bath temperature of 90 to 100 for 1.5 hours. After completion of the reaction, the solvent was distilled off, a small amount of ice water was added, and the mixture was made weakly acidic with dilute hydrochloric acid and extracted with methylene chloride to obtain a crude product.

This was purified by silica gel chromatographic method (eluent; hexane-ethyl acetate system) to give 98 mg of 2- (3— (2-thiazolylmethyl) phenyl) propionic acid. Obtained in a yield of 74% (oil-like).

IRV

^-1 : 3500-2300, 1700, 1600, 1500, 1440, 1370, 1180, 1100, 720, 700 ¹ HNR (CDC £ z) δ: 1.49 (d, J = 7.1Hz, 3H), 3.71, J = 7.1Hz, 1H), 4.34 (s, 2H), 7.16-7.28 (m, 5H), 7.71 (d , J = 3.3Hz, 1H), 10.84 (bs, 1H)

Example 16

In the same manner as in Example 9, 2-([4- (2-thiazolyl) -13-trifluoromethyltyl unit] propionic acid was prepared.

Melting point 103 to 105

1 R ^ l _x ^r cm " ¹ : 2850, 1722, 1612, 1488, 1312, 1167, 1124, 1059, 984, 904, 735

¹ HNMR (COC £ ζ) δ: 1.44 (d, J = 7.1Hz, 3H), 3.95 (q = J = 7.1Hz, 1H), 7.71 (s, 2H), 7.82 (s, 1H), 7.93 (d , J = 3.2Hz, 1H), 7.98 (d, J = 3.2Hz, 1H), 12.64 (s, 1H)

In the same manner as in Example 7, 2-[[4-chloro3- (2-thiazolylcarbonyl) phenyl] propionic acid was prepared.

Melting point 1 2 8 to 1 3 0

IR cm " ¹ : 3500-2300, 3080, 2960, 2910, 1708, 1661, 1587, 1460, 1369, 1327, 1232, 1055, 932, 844, 800

'' HNMR (OMSO-άδ: 1.40 (d, J = 7.1Hz, 3H), 3.79 (q, J = 7.1Hz, 1H), 7.53, 7.55 (s, 2H), 7.60 (s, 1H), 8.17 ( d, J = 3.0Hz, 1H), 8.34 (d, J = 3.0Hz, 1H), 12.55 (brs, 1H)

Example 18

In the same manner as in Example 7, 2-[[2-cyclo-3- (2-thiazolylcarbonyl) phenyl] propionic acid was prepared. IR v cm " ¹ : 3000, 1720, 1670, 1580

¹ HNMR (CDC £ ₃ ) 5: 8.07 (d, J = 2.9, 1H), 7.78 (d,

J = 2.9, 1H), 7.56-7.37 (m, 3H), 4.33 (q, J = 7.2, 1H),

1.54 (s, 3H)

Example 19

In the same manner as in Example 9, 2-([4- (4-methylthiazo-1-yl) -2-yl) fuunil] propionic acid was prepared.

Melting point 18 1 〜 18 3 'C

IRV cm " ¹ : 3000-2800, 1720, 1600, 1530,〗 440, 1135, 1215, 1000, 815, 745

¹ HNMR (DMS 0-d ₆ ) ^: 1.37 (d, J = 7.1 Hz, 3H), 2.40 (d, J = 0.7 Hz _s 3H), 3.73 (q, J = 7.1 Hz, 1H), 7.29

(apparent-d, J-0.7Hz, 1H), 7.38 (apparent-d, J-8.3Hz, 2H), 7.85 (apparent-d, J = 8.3Hz, 2H), 12.4 (s, 1H) 0

In the same manner as in Example 9, 2-([4- (5-methylthioazo-1-yl-2-yl) phenyl] propionic acid was prepared.

IR on— ¹ : 3000-2500, 1705, 1450, 1340, 1305, 1225, 1155

¹ HNR (DSO-d6) (?: 1.39 (d, J = 7.1 Hz, 3H), 2.49 (s, 3Η), 3.73 (q, J = 7.1Hz, 1H), 7.38 (d, J = 8.2Hz) 2H), 7.56 s, 1H), 7.81 (d, J = 8.2Hz, 2H), 12.4 (bs, 1H) ppm.

Example 2 1

In the same manner as in Example 9, 2— [4- (4-vinylthiazol) 2- (yl) phenyl] propionic acid was prepared.

Melting point 1 1 4 to 1 1 4.

IR ^ l _x ^r cm " ¹ : 3200-2500, 1700, 1480, 1460, 1410, 1220, 950, 910, 840, 770

¹ HNR (C Ό C £ ₃ ) 6 1.53 (d, J = 7.1 Hz, 3H), 3.78 (q, J = 7.1 Hz, 1H), 5.40 (dd, J = 1.6, 10.8 Hz, 1H), 6.14 ( dd, J = 1.6, 17.3Hz, 1H), 6.76 (dd, J = 10.8, 17.3Hz, 1H), 7.10 (s, 1H), 7.38 (apparent- d, J = 8.4Hz, 2H), 7.92 (apparen t-d, J = 8.Hz, 2H) ppm.

Example 22

In the same manner as in Example 9, 2— [4— (4—trifluoromethyl thiazole-1-2-yl) fuunyl] propionic acid was prepared. Melting point 1 4 2 to 1 4 4

IR u A cm " ¹ : 3500-2600, 1710, 1695, 1460, 1230, 1070, 1040, 980

¹ HNR (CDC £ 3 / TMS) δ: 1.55 (d, J = 7.2 Hz, 3H), 3.80 (q, J = 7.2 Hz, 1H), 7.42 (apparent-d, J = 6.7 Hz, 2H) 7.72 ( d, J = 0.9Hz, 1H) , 7.81 (apparent-d, J = 6.7Hz 1 2H) ppm.

Example 23

In the same manner as in Example 9, 2— [4— (4,5-dimethyldithiazole-2-yl) phenyl] propionic acid was prepared.

Melting point 1 73.5-1 75.5 * C

IRJ Uli cm " ¹ : 3620-3280, 3000-2800, 1700, 1224, 858, 842, 827 ¹ HNMR (DMS 0 — d ₆ ) 5: 13.44-11.28 (brs, 1H), 7.82-7.76 (m, 2H), 7.40-7.36 (m, 2H), 3.74 (q, J = 7.1Hz, 1H), 2.36 (s, 3H), 2.31 (s, 3H), 1.39 (d, J = 7.1Hz, 3H)

Example 2 4

In the same manner as in Example 9, 2- [4- (4-ethylthiazol-2-yl) phenyl] propionic acid was prepared.

Melting point 1 25.0-1 27.0 'C

IR «1 ^ cm— ¹ : 3640-3250, 3000-2800, 1724, 1213, 858: 836

¹ HNMR (also DMS 0-d) δ: 12.79-12.02 (brs, 1H), 7.91 7.86 (m, 2Η), 7.44-7.40 (m, 2Η), 7.29 (t, J = 0.7H _Z! 1H), 3.76 (q, J = 7.1Hz, 1H), 2.79 (dq, J = 7.5, 0.7Hz, 2H), 1.41 (d, J = 7.1H _{Z j} 3H), 1.27 (t, J = 7.5Hz, 3H) Example 2 5

In the same manner as in Example 9, 2— [2—black mouth—4— (2-thiazolyl) phenyl] propionic acid was prepared.

Melting point 1 2 2 to 1 2 4 'C

IR cm— ¹ : 3500-2300, 3080-2960, 2910, 1708, 1661, 1587, 1460, 1369, 1327, 1232, 1055: 932, 844, 800

¹ HNMR (C Ό C £ ₃ ) δ: 1.40 (d, J = 7.1 Hz, 3H), 3.79 (q, J = 7.1 Hz, 1H), 7.53, 7.55 (s, 2H), 7.60 (s, 1H) _: 8.17 (d, J = 3.0Hz, 1H), 8.34 (d, J = 3.0Hz, 1H), 12.55 (brs, 1H)

Example 26 to 39 The following compounds of the present invention were prepared in a similar manner.

Claims

The scope of the claims

Wherein, R ', R ² are the same or different, a hydrogen atom, a halogen atom, a lower alkyl group, lower alkenyl group, two collected by filtration group, Application Benefits off Ruo Lome butyl group, full Weniru group, a substituted off Weniru group, Pyridyl group, substituted pyridyl group, carboxyl group, lower alkoxy group rubidium group, one CON (R ⁵ ) (R ⁶ ) (R ⁵ and R ⁶ are the same or different and are hydrogen atoms or lower alkyl group shows a), lower § sill group, a hydroxyl group, a lower alkoxycarbonyl key sheet group or a lower alkylthio group, or R ¹ and ^{_{R 2 - (CH 2) m}} - a (m is. 3 to 5), R ³ Represents a hydrogen atom or a lower alkyl group; R ⁴ represents a hydroxyl group, a lower alkoxy group, or _N (R ⁷ ) (R ^e ) (R ⁷ and R ⁸ are the same or different and represent a hydrogen atom or a lower alkyl group; ) and, X is or a carbonyl group _{- (CH 2) "- (} n is 0 or 1) , Y is a hydrogen atom, a halo gen atom, a lower alkyl group, two collected by filtration group, Application Benefits Furuo Lome butyl ^{group, -. N (R 9)} (R 10) (R ', R 1 are the same or different and each represents a hydrogen atom or is a lower alkyl group), a hydroxyl group (provided that the substitution position of X is CH (R ³⁾ only if it is the para position of the C 0 R ^4), lower alk co key sheet group (wherein the substituent of X position is CH (R ³⁾ C 0 only if in the para-position of R ⁴⁾ or thiazole compounds are tables in a lower alkylthio represents a group] or a pharmaceutically acceptable salt thereof,

2 formula

(Wherein each symbol is as defined above) or a pharmaceutically acceptable salt thereof according to claim 1.

3 expression

(Wherein each symbol has the same meaning as described above).

4. The compound according to claim 1, wherein R ³ is a lower alkyl group, and R ⁴ is a hydroxyl group, or a pharmaceutically acceptable salt thereof.

5.2— [3— (4—Phenylthiazole-12-inolecarbonyl) phenyl] propionic acid,

2 — [3 — (4 — phenylthiazole 1-2-methyl) phenyl] brovionic acid,

2-[3-(4-phenylthiazole 1-yl) phenyl] propionic acid,

2 — [4-(4 1-phenylthiazole _ 2 —ylcarbonyl) Phenyl) propionic acid,

2 — [4-1 (4-phenylthiazolu-2-dimethyl) phenyl] brobionic acid,

2 — (4-(4 — phenylthiazole-1- 2) phenyl) propionic acid,

2 — [3- (2-thiazolylcarbonyl) phenyl] propionic acid,

2 — [4- (2-thiazolylcanolebonyl) phenyl] propionic acid,

2 — (4-(2 — thiazolyl) phenyl) probionic acid, 2-[3-chloro-4-(2-thiazolyl) phenyl] probionic acid,

2 — [3 — Fluoro 4 — (2 — thiazolyl) phenyl] brobionic acid

2-[3, 5-dichloro mouth 1 4- (2-thiazolyl) phenyl] probionic acid,

2-[3-Methyl-1-41 (2-thiazolyl) phenyl] propionic acid,

2— [3—chloro-4— (4—phenylthiazol-1-2-) phenyl) propionic acid,

2— [3— (2—thiazolylmethyl) phenyl] probionic acid,

2 — [4 — (2 — thiazolyl) -1 3 — trifluormetylfuryl] propionic acid,

2 — [4-chloro-3 — (2-thiazolylcarbonyl) ph Nil) propionic acid,

2— [2—chloro-3— (2_thiazolylcarbonyl) phenyl] propionic acid,

2— [4— (4-Methylthiazole-2-yl) phenyl] propionic acid,

2— [4— (5—methylthiazole—2—yl) phenyl] probionic acid,

2— [4— (4—vinylthiazole—2—yl) phenyl] probionic acid,

2 — [4-1 (4-trifluoromethyl thithiazol-2-yl) phenyl] probionic acid,

2 — (4-(4, 5 — dimethyl thithiazol-2-yl) phenyl) probionic acid,

2 — (4- (4-ethylthiazol-1-yl) phenyl) propionic acid,

2 — [2—Cro- mouth 4 — (2-Thiazolyl) phenyl] propionic acid,

2 — [4-1 (4-carboxitythiazole-2-yl) phenyl] probionic acid,

2-[4- (4-l-rubamoyl thiazole-2 -yl) phenyl] propionic acid,

2 — [4 — (4 — N —methylcarbamoyl norethiazole- 1 -yl) phenyl] probionic acid,

2 — [4- (4-N, N-dimethylcarbamoyl luthiazole 1-2-yl) fuunil] propionic acid, 2-[4- (4-methoxythiazole-2-yl) phenyl] propionic acid,

2- [4- (4-ethoxythiazol-2-yl) phenyl] propionic acid,

2- [4- (4-butylthiazol-2-yl) phenyl] propionic acid,

2-[3-Hydroxy-1 4- (2-thiazolyl) phenyl] propionic acid,

2 — [3 — methoxy 4 — (2 — thiazolyl) phenyl] pi pionic acid,

2-[3 -methylthio 1-4-(2-thiazolyl) phenyl] probionic acid,

2— [3—nitro—4-1- (2-thiazolyl) phenyl] propionic acid,

2 — [3 — amino 4 — (2 — thiazolyl) phenyl] propionic acid,

2— [4— (4-Acetylthiazole-2-yl) phenyl] propionic acid,

2. The compound according to claim 1, wherein the compound is selected from the group consisting of 2-[4-1 (5, 6-dihydro 4H-cyclopenta [d] thiazol-2-yl) phenyl] propionic acid.

6. A pharmaceutical composition comprising the compound according to claim 1 and a carrier.

7. The pharmaceutical composition according to claim 6, which is used for analgesia, anti-inflammatory or antipyretic.