WO1991019496A1

WO1991019496A1 - Hypolipidemic agent

Info

Publication number: WO1991019496A1
Application number: PCT/JP1990/000791
Authority: WO
Inventors: Ikuo Iijima; Masakatsu Ozeki; Kunihito Okumura; Tetsuji Mori; Masanori Inamasu
Original assignee: Tanabe Seiyaku Co., Ltd.
Priority date: 1988-09-13
Filing date: 1990-06-18
Publication date: 1991-12-26
Also published as: JPH02167224A

Abstract

A hypolipidemic agent useful for preventing or treating hyperlipidemia, arteriosclerosis and so forth, which contains as the active ingredient a benzoxazole derivative represented by general formula (I), or pharmacologically acceptable salts thereof, wherein R represents an optionally substituted phenyl, naphthyl, cycloalkyl or heterocyclic group; Alk represents a single bond, a lower alkenylene or alkynylene group, or an optionally substituted lower alkylene group; and a broken line means that bond in that position may be a double bond.

Description

Specification

Antilipidemic

Technical field

The present invention relates to an antilipidemic agent.

Background art

Hyperlipidemia is a condition in which the amount of blood lipids such as serum total cholesterol and serum triglyceride is increased, and is considered to be one of the main causes of various adult diseases such as arteriosclerosis. Conventionally, anti-lipidemic agents such as kuguchi fibrate and blobcol have been used as therapeutic and prophylactic agents for hyperlipidemia.

By the way, cholesterol is present in the blood in the form of very low specific lipoprotein (V and DL) cholesterol, low density lipoprotein (LDL) cholesterol, and high density lipoprotein (HDL) cholesterol. Of these, VLDL and LDL promote cholesterol deposition on the arterial wall and cause arteriosclerosis, while HDL prevents cholesterol from sinking into the arterial wall and inhibits arteriosclerosis. Treatment and prevention [Anals of Internal Medicine], Vol. 90, pp. 85-91 (1997)].

Therefore, in recent years, there has been a demand for the development of an antilipidemic agent capable of reducing the amount of blood lipids such as serum total cholesterol and serum triglyceride and simultaneously increasing the amount of HD monocholesterol.

Disclosure of the invention

The present invention has the general formula

(〖)

(However, R is a fur group, naphthyl group, cycloalkyl group or heterocyclic group which may have a substituent, and Alk is a single bond, a lower alkylene group, a lower alkyne group or a substituent. A lower alkylene group which may have a dashed line indicates that the bond at the site may be a double bond.)

Benzoxazole derivative represented by the formula or its physiologically acceptable The present invention relates to an antilipidemic agent comprising a salt as an evening active ingredient.

The benzoxazole conductor (ί) and the salt thereof, which are the active ingredients of the antilipidemic agent of the present invention, are both novel compounds and have an effect of decreasing serum cholesterol level, increasing HDL-cholesterol level and Ζ. Or it has an excellent antilipidemic effect based on its serum triglyceride lowering effect. Furthermore, this compound (I) has low toxicity, for example, 5-[(2,4-dioxothiazolidin-15-yl) methyl] -12-[(2-naphthyl) methyl] benzoxazole Although the CMC virtual cloudy solution was observed orally administered to mice (throw Azukaryou 300 Omg / kg) after Ma 2 hours, deaths observed forces, seven ": ₀

Therefore, compound (I) or a pharmaceutically acceptable salt thereof is a compound useful as an antilipidemic agent, for example, hypolipidemia (eg, hypercholesterolemia), arteriosclerosis (eg, Treatment of atherosclerosis, Menkelberg's arteriosclerosis, etc. * Can be used for prevention. In addition, it has a special feature that raises HDL-cholesterol level while lowering serum total cholesterol level. Can be used for prevention.

As a specific example of the benzoxazole derivative which is an active ingredient of the antilipidemic agent of the present invention, in the general formula (I), R represents a phenyl group, a naphthyl group, a cyclohexyl group, a 1,3-thiazole- 4-yl, 1,3-oxazolyl 4-yl, pyridine, benzoyl, benzoyl, chelyl, quinolyl, or benzofururyl, or these groups are (lower alkyne) Carbyl group, lower alkoxy group, lower alkyl group, trihalogeno lower alkyl group, lower alkylthio group, lower alkylsulfur group, lower alkylsulfonyl group, furyl group, fusoxy group, lower-substituted lower alcohol group Di-, hydroxyl, halogen, nitro, amino, lower alkylamino, di (lower alkyl) amino, cyclo Kill group, Biro Li Jinomoto, Piperi Jinomoto, compounds Kage換 by a group selected from a morpholino group, and pyromellitic Lil group. As other specific examples of the benzoxazole derivative (I), Alk is a single bond, a linear or branched lower alkylene group, a lower alkylene group or a lower alkylene group. And a lower alkylene group substituted with an oxo group, a fuunyl group or a cycloalkyl group. Compounds which exhibit particularly excellent therapeutic effects include those represented by the formula (I) wherein R is a lower alkoxy group, a lower alkyl group, a trihalogeno lower alkyl group, a fuunyl group, a halogen atom, a nitro group or a di (lower alkyl) group. Kill) a phenyl group, a naphthyl group, a pyridyl group, a 1,3-thiazole-4-yl group or a 1,3-oxazole-4 group which may be substituted with one or two groups selected from an amino group Examples of the compound include a compound having a -yl group, and in particular, a compound in which R is a di (lower alkyl) aminofurinyl group or a naphthyl group.

Other compounds that exhibit particularly excellent therapeutic effects are those in which Al k is a single bond or a lower alkylene group, and the 2,4-dioxothiazolidin, 5-yl (or ylidene) methyl group is a benzoxazole. It is a compound bonded to the 5-position of the ring.

Benzoxazole derivatives (I), which are the active ingredients of the present invention, include lower alkoxy groups, lower alkyl groups, lower alkanoyl groups, The alkylene group includes a alkylene group, a lower alkylene group and a lower alkulene group having 6 or less carbon atoms, particularly preferably having 4 or less carbon atoms, and a cycloalkyl group having 3 to 9 carbon atoms. And especially those having 4 to 7 are preferred.

These benzoxazole derivatives (I) can be used for the purpose of the present invention either in a free form or in the form of a pharmaceutically acceptable salt thereof. Examples of the salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and acid addition salts such as hydrochloride and sulfate.

The antilipidemic agent of the present invention can be administered orally or parenterally, and is used in a usual manner as a suitable pharmaceutical preparation such as a tablet, granule, capsule, powder, or injection. .

The dose of the active ingredient compound of the present invention varies depending on the administration method, the age, body weight and condition of the patient, but is usually about 5 to 20 OmgZkg per day, especially about 10 to 2 OmgZkg per day. Is preferred.

Benzoxazole derivatives (I) can be used as geometric isomers, optically active isomers, And mixtures thereof can be used as the active ingredient of the present invention.

The benzoxazole derivative (I), which is an active ingredient of the present invention, has the following general formula (1):

(However, R ¹ represents a hydroxyl group, a lower alkoxy group or a reactive residue, Y represents an oxygen atom or an imino group, and R and Alk have the same meaning as described above.)

And a compound represented by the general formula

(However, the symbols have the same meaning as described above.)

A condensation reaction with a dioxothiazolidine compound represented by the formula (1) in the presence or absence of a condensing agent (for example, trimethylsilyl diester polyphosphate); (2) — General formula

(However, the symbols have the same meaning as described above.)

Subjecting it to an intramolecular condensation reaction in the presence or absence of a condensing agent (for example, trimethylsilyl polyphosphate), or

(3) General formula

(However, the symbols have the same meaning as described above.)

Can be produced by subjecting an azomethine compound represented by the following to a dehydrogenation reaction in the presence of a dehydrogenating agent (for example, lead tetraacetate).

Further, among the benzoxazole derivatives (I) which are the active ingredients of the present invention,

R- A

(However, the symbols have the same meaning as described above.)

The compound represented by the general formula

(However, the symbols have the same meaning as described above.)

Can be produced by hydrolyzing the imine compound represented by

In the benzoxazole derivative (I) which is an active ingredient of the present invention, the compound (I) in which R is a lower alkylthiophenyl group is oxidized and R is a lower alkylsulfinyl fuunyl group or a lower alkyl thiophenyl group. The compound may be an alkylsulfonylphenyl group, or the compound (I) in which R is a benzyloxy group may be debenzylated to give a compound in which R is a hydroxyphenyl group. . BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described more specifically with reference to Experimental Examples, Production Examples, and Reference Examples.

Experimental example (Serum cholesterol lowering effect, HDL-cholesterol increasing effect and serum triglyceride lowering effect)

SD male rats (weight: 120-140 g, 5 animals per group) were fed a diet containing 2 W / W% cholesterol and 0.5 W / W% sodium cholate for 4 days. They were allowed free intake. Thereafter, the control group the fodder, the specimen-administered group libitum by TsugiMitsuru feed plus sample to the feed at 1 0 O _m g% 0 ratio. 3 After that, the rat was anesthetized with ether, and body weight was measured and blood was collected from the abdominal aorta. The blood was released for 1 hour at room temperature and then arrested and separated to obtain serum, from which serum cholesterol and serum triglyceride contents were measured by an enzyme method. A lipoprotein sedimentation method using dextran sulfate from a part of the serum [Canadian's Journal, Biochemistry (Can. J. Biochem.); , Pp. 1043 (1969)], and HDL-cholesterol was separated, from which the amount of HDL-cholesterol was measured by the enzyme method described above. From these results, the serum cholesterol lowering rate HD-cholesterol level increasing rate and serum triglyceride level were calculated according to the following formulas. Average blood of the sample administration group for which the decrease rate was determined

Serum cholesterol Clear cholesterol level

100% reduction in average serum value of control group

Resteros volume

Average HD of sample administration group

HDL—Cholesterol L—Cholesterol level Increase rate of control average HD L—

Cholesterol amount **

Average blood of sample administration group

Serum triglyceride Clear triglyceride amount

1 X 100 lid reduction rate Average serum serum of control group

Liglyceride amount! M: *

*: Average serum cholesterol level in the control group: 13 7 to 18 2 mg / dl

: Average HDL-cholesterol level in the control group: 16.2 to 20.4 mg / dl *: Average serum triglyceride level in the control group: 74.0 to 97.4 mg / dl The results are as shown in the following table ABC test compound (%) (%) (%) Production example 3 57 37 Production example 5 30 82 46 Production example 6 54 26 Production example 1 0 38 Production example 13 26 Production example 3 1 26 77 Production example 38 46 46 25 Production example S 9 80

-Production example 40 4 1 1 49 Production example 4 1 34 73 Production example 43 44 26 Production example 4 4 3 1 8 3

Production example 4 9 2 6

Production example Ί 0 2 9

Production example Ί 3 3 2 7 0

Note 1) In the experiment, the product obtained in each of the following Production Examples was used as a test compound.

Note 2) A: Serum cholesterol lowering effect

B: HD cholesterol level increasing effect

C: Serum triglyceride lowering effect

Production Example 1

(1) 5-Amino-2-furbenzobenzoxazole 4.8 g, a mixture of 6 ml of oak hydrochloride and 5 O ml of acetone were added to a mixture of sodium nitrite 1 under ice-cooling. 76 g of aqueous solution 5 η are added dropwise. Stir at the same temperature for 10 minutes, further add 12.1 g of methacrylic acid methyl ester, and gradually add 150 ° C. of cuprous oxide while heating to 40 ° C. After the end of the nitrogen gas generation, 35. Heat to C for 20 minutes, dilute the reaction mixture with water, and extract with ethyl acetate _c The extract is washed with water and dried, and then the solvent is distilled off. The residue is purified by silica gel gel chromatography (solvent: cross-ported form) to obtain 3- (2-phenylbenzoyloxazole). —Yl) 1-2-chloro mouth Probionic acid methyl ester 5.13 g is obtained as a pale brown oil. Neat

IRy rnaxCcm " ¹ ): 1 740

(2) Heat a mixture of 5.13 g of this product, 2.30 g of thioprea, 1.50 g of sodium acetate and 35 ml of ethylene glycol monomethyl ether at 100 for 8 hours. The solvent was distilled off from the reaction solution, water and n-hexane were added to the residue, and the precipitated crystals were collected by filtration, washed and dried to give 5-[(2-Imino-4-oxothiazolyl). 5-35-yl) methyl] —2-phenylbenzoxazole, 4,35 g, is obtained as a colorless powder.

M. p. 2 81-283. C (decomposition)

(3) Dissolve 3.18 g of this product in 50 mi of ethylene glycol monomethyl ether, add 2.05 g of toluenesulfonic acid monohydrate and 6 ml of water, and reflux for 1 hour 45 minutes . The solvent is distilled off from the reaction solution, and the residue After adding water, the mixture is extracted with ethyl acetate, washed and dried, and then the solvent is distilled off. The residue was purified by silica gel chromatography [solvent: chloroform-form (1: 1)] to give 5-((2,4-dioxothiazolidin). 1-5-yl) methyl] 1-2-phenylbenzoxazole 1.83 g

M. p. 192-: I94. C

Mass (m / e): 3 24 (M +)

Nujol

I R v max (c¾ "): 3180, 1745, 1680 Production Examples 2 to 4 By treating the corresponding starting compounds in the same manner as in Production Example 1,

Table 1 Obtain compounds listed in Table 1

(I ')

(However, the group represented by the formula ^^ forms a methylene group)

Nujol

IR *: Represents IR v max (cm " ¹ )

Production Example 5

(1) 5- (3-amino-4-hydroxybenzyl) 1,2,4-dioxothiazolidin 3.10 g N, N-dimethylaniline 3.63 g, tetrahydrofura To a mixture of 25 ml of toluene and 5 ml of dimethylformamide, 2-phenyl-4-thiazoleacetate chloride 2.38 g of tetrahydrochloride Add 10 ml of Drofuran solution to 0. Add dropwise with C and stir at room temperature for 20 minutes. After the reaction, the reaction solution is poured into water, extracted with ethyl acetate, washed, dried, and the solvent is distilled off. The residue was crystallized from ether acetate to give N- [5- (2,4-dioxothiazolidin-1-yl) methyl-2-hydroxyhydroxy] 1-2-phenylthiazole-14-acetami 3.35 g are obtained.

M.p. 227-229. C (decomposition)

(2) A mixture of 1.5 g of this product, 3.2 g of phosphorus pentoxide, 6.6 ml of hexamethyldisiloxane and 12.5 ml of 1,2-dichloroethane, and a solution of trimethylsilyl polyphosphate. 100. Heat at C for 30 minutes. After the reaction, the mixture is poured into ice water, extracted with ethyl acetate, dried, and the solvent is distilled off. The residue was recrystallized from methanol to give 5-[(2,4-dioxothiazolidin-1-5-yl) methyl] -12-[(2-phenyl-1,3-thiazole-4-yl ) Methyl] to obtain 80 mg of benzoxazole.

Yield 6 1%

M. p. 86-89. C Nujol

I R v max (cm '): 1 7 5 0, 1 690

Mass (m / e): 4 2 1 (M ⁺ ), 30 5

Production Example 6

(1) 2.03 g of 2-phenyl-4-isodazole acetic acid, 5- (3-amino-4-hydroxybenzyl) 1,2,4-dioxothiazolidine 2.38 g, dicyclohexylcarpoimide A mixture of 2.06 g, 2 ml of dimethylformamide and 20 ml of tetrahydrofuran is stirred at room temperature for 18 hours. After the reaction, remove insolubles and pour into ice water, extract with ethyl acetate, wash with water, dry, and evaporate the solvent. The residue was purified by silica gel chromatography (solvent; chloroform: methanol = 10: 1) and crystallized from ethyl acetate to obtain N— [5— (2,4— 5-year-old oxothiazolidin-5-yl> methyl-2-hydroxyl-yl) 1-2-year-old oxazoluol 4-acetamide 2.83 g

Ό

M.p. 197, 5-199.5. C

(2) This product 63 5 mg 230. Heat at C for 40 minutes. After cooling Purification by gel chromatography (solvent; mouth form: methanol = 10: 1) and recrystallization from acetonitrile yielded 5 — [(2

4-Dioxothiazolidine-1-yl) methyl] 2 [(2-phenyl-1,3-, 3-oxazole-41-methyl) -benzo] -xoxazole 3 83 mg Yield 63% p. 174-: I 77.5. C

Nujol

I R u max (cm '): 1 730, 1 7 1 0

Mass (m / e): 405 (M *), 289 Production example? The corresponding starting compounds were treated in the same manner as in Production Example 5 or 6, and

得る Obtain the self-listed compound Table 2

(Where Y is an oxygen atom, R ¹ is a hydroxyl group, and the group represented by the formula ^ forms a methylene group)

li 06drAcd 96

Production example 3 1

Lin pentoxide 4. Og and hexamethyldisilium beef sun 10 ml, 1

Prepare a solution of trimethylsilyl polyphosphate by heating and refluxing a mixture of 20 ml of 2-dichlorobenzene for 5 minutes. Then 2-fuyu-ru 5-methyl 4-1.5-year-old quinazolic acid 1.52 g and 5- (3-amino 4-hydroxybenzyl) 1-2,4-year-old xothiazolidin

2. Add 17g and 150. Heat at C for 2 hours. After the reaction, the mixture is poured into ice water, extracted with ethyl acetate, washed with water, dried, and the solvent is distilled off. The residue was purified by silica gel chromatographic chromatography (solvent; chloroform: methanol = 100: 1), and recrystallized from a mixture of ethyl acetate and η-hexane to give 5-C (2,4 —Dioxothiazolidine-1-yl> methyl

— 2— [(2-Fuel-5-methyl-1,3-oxazole-14-yl) methyl] benzoxazole 1.99 g Yield 68%

M. p. 175-; C

Nujoi

IR v max (cm- ¹ ): 1 7 4 5, 1 7 0 0, 1 6 4 0

Mass (m / e): 4 19 (NT), 3 4 8, 3 0 3 Production Example 3 2 to 7 2 Corresponding starting compounds were treated in the same manner as in Production Example 31 to give the compounds shown in Table 3 Get

Table 3

(Part 1, Y is an oxygen atom, R ¹ is a hydroxyl group, and the group shown in the formula forms a methylene group.)

ε / ιοeodf / Iodi 09l 6AV

Bird

Colorless powder

Mass (m / e): 4 1 4 (M ⁺ ) IR *: 1 750, 1 6 90

M. p. 175-178. C Mass (m / e): 4 2 8 (M *) I R *: 1 74 0, 1 6 90 Colorless powder

Mass (m / e): 4 1 6, 4 1 4 (M ⁺ )

IR *: 1 750, 1 6 95

Mp 1 37-140 ° C MassCm / e): 368 (M ⁺ )

CH ₃₀

I R *: 1 74 5, 1 70 5

Mp 165-168. C Mass (m / e): 382 (M ⁺ ) IR *: 1 745, 1 7 0 5

M.p. 1 55-1 57. C

C ₄ H, 0-^-CH ₂ -Mass (m / e): 10 (M ⁺ )

I R *: 1 7 50, 1 6 9 0

M. p. 1 22-1 23 ° C ass (m / e): 43 0 (M +) IR *: 1 745, 1 6 9 0

*): Sodium salt

(Part 2, Y is oxygen atom, R ¹ is hydroxyl group, group represented by formula / ^ forms methine group)

mi compound _ (Γ)

.

Example R-Alk- physical properties, etc.

No.

7 0 Mp 2 6 1.5-26 3. C Mass (m / e): 4 17 (M ⁺ )

J CHa 1 R: 1 7 4 0, 1 7 2 0, 1 7 0 0

7 1 M.p. 2 2 1-2 22.5. C Mass, m / e4 on y M) I R *: 1 7 4 0, 1 7 0 5

7 2 Mp 2 18-2 19.5 ^e C

Cl-^-CH »-Mass (m / e): 3 72,3 70 (M *) I R *: 1 7 3 5,1 7 0 5

Production example Ί 3

(1) N- (5-amino-2-hydroxyfurnil) 1-2--clo-fuunil) Acetamide 9.47 g was treated in the same manner as in Production Example 1 to give N- [5 — (2,4-dioxothiazolidine-15-yl) methyl-2-hydroxyphenyl) 1-2- (4-chlorophenyl) acetamide 5.64 g is obtained as a pale yellow powder. p. 207-209. C

(2) 220 5.64 g of the product of (1) above. C for 50 minutes, and after cooling, purify by silica gel column chromatography [solvent: chloroform-methanol (50: 1)] and recrystallize from ether to give 5 — [(2,4 pages) Oxothiazolidin-1-5-yl) methyl] 1-2- (4-cyclobenzyl) benzoxazole 4.0 is obtained.

M.P. 1 69.5 ~: at I 70.5

MassWe): 374, 372 (M *)

Nuiol

IR v max, (cm ' ¹ ): 1 750, 1 690 Production example Ί 4

Ν— (5-amino-1.2-hydroxyphene) 1-4-hydroxy-3,5-di (tert-butyl) benzamide is treated in the same manner as in Production Example 73 to give 5 — [(2,4-Dioxothiazolidine-5-yl) methyl] -1-2- [4-hydroxy-3,5-di (tert-butyl) fuunyl] benzoxazole is obtained. M. p. 2 13-2 16. C

Mass (m / e): 452 (M ⁺ ) Nujol

IR v max (cm ^-1 ): 1 750, 1 700 Production example Ί 5

N- (4-Amino-2-hydroxyfurnil) 1-2- (4-Cross-open-fur) Acetamide was treated in the same manner as in Production Example 73 to give

6-[(2, -4 dioxothiazolidin-1-5-yl) methyl] 1 2-1 [4-cyclopentyl] benzoxazole.

M.p. 2 19.5-220.5. C

Mass (m / e): 374, 372 (M *)

Nujol

IRV max (cm " ¹ ): 1 745, 1695 Production example Ί 6

5 — [(2,4-Dioxothiazolidin-1-5-yl) methyl] 1-2- (412-Tropendyl) Penzoxazole 3.48 g of tetrahydrofuran 7 Ond and methanol 70 Dissolve the mixture in a 1 ml mixture, add 2.5 g of 10% palladium-carbon, and subject it to a reduction reaction in hydrogen at normal pressure. Anti The insoluble material was removed by filtration from the reaction solution, and the filtrate was concentrated and purified by silica gel column chromatography [(solvent: chloroform-form-methanol (20: 1))], and recrystallized from ethyl acetate. This gives 1.86 g of 5-[(2,4-dioxothiazolidin-1-5-yl) methyl] -12- (4-amino benzyl) benzoxazole Mp 180- 1 83 C

Mass (m / e): 3 53 (M ⁺ ) Nujol

IR v max (.era " ¹ ): 1 73 5, 1 7 00 Production example 7 7

5-[(2,4-dioxothiazolidine-1-5-yl) methyl] 1-2- (4-amino benzyl) 0.99 g of benzodioxazole, 2 ml of acetic anhydride and 10 ml of pyridine After stirring the mixture at room temperature overnight, 10% hydrochloric acid was added, extracted with butyl acetate, washed with water, dried and the solvent was distilled off.The residue was recrystallized from ethyl acetate to give 5-((2 0.56 g of, 4-dioxothiazolidine-15-yl) methyl] -12- (4-acetamidobenzyl) benzoxazole is obtained. Mp. 233〜23 6 ^e C

Mass (m / e): 395 (M ⁺ ) Nujol

IR u max (cm " ¹ ): 1 74 5, 1 690 Production example 7 8

5-[(2,4 dioxothiazolidin-1-5-yl) methyl] 1-2- (4-methylthiobenzyl) benzoxazole 1.0 g, 80% m-chloroperbenzoic acid 0.58 g And 25 ml of methylene chloride are stirred at room temperature for 10 minutes. The solvent is distilled off, ethyl acetate is added, and the mixture is washed and dried. After distilling off the solvent, the residue is purified by silica gel column chromatography (solvent; chloroform: methanol == 20: 1). (2,4-Dioxothiazolidin-15-methyl) methyl] -12- (4-Methylsulfinylbenzyl) benzoxazole 0.67 g is obtained as a colorless foam. 64% yield

Mass (m / e): 400 (M *) Nujol

IR max (cm " ¹ ): 1 750, 1 690 Production example Ί 9

5-[(2,4-dioxothiazolidine-1-5-yl) methyl] 1-2- (4-methylthiobenzyl) benzo-oxazole 1.2 g, 80% _m- cro-perbenzoic acid 2.1 g and chloride Stir the mixture of 30 ml of methylene for 20 minutes at room temperature. After the same treatment as in Example 78, the mixture was recrystallized from a mixture of tetrahydrofuran-n-hexane to give 5-((2,4-dioxothiazolidin-1-yl) methyl). 1.2- (4 Methylsulfurbenzyl) 1.2 g of penzoxazole is obtained as a colorless powder.

Yield 69%

M. ρ. 168-: I 69. C

Production 80

5-C (2,4-dioxothiazolidine-1-5-yl) methyl] ― 2--(4-benzyloxybenzyl) benzoxodazole 0.95 g, 25% hydrogen bromide monoacetic acid Stir a mixture of solution 1 Old and 10 ml of acetic acid at room temperature overnight. Ethyl acetate and water are added to the reaction solution, After the layer is washed with water and dried, the solvent is distilled off. The residue was crystallized from n-hexane and recrystallized from a mixture of ethyl acetate and n-hexane to give 5-((2

, 4-Dioxothiazolidin-15-yl) methyl] -12- (4-hydroxypentyl) benzoxazole 0.42 g as colorless needles.

55% yield

M.p. 201 1-204. C

(Preparation of raw material compound)

Reference example 1

(1) 2-amino 4-nitrofunol 6.16 g and 4.77 g of benzyl aldehyde are condensed under ripening to form 2-benzylideneamino-4-nitrofuronol, and then The product is heat-closed in the presence of lead tetraacetate to give 5.08 g of 5-2-tro-2-furenzoxazole.

M. p. 169-17 17 1.5. C

(2) Contact reduction of 8,85 g of the above product in the presence of a palladium-carbon catalyst to give 5-amino-1-phenylbenzoxazole 7.02 g Get.

M.p. 150.5-15-153. C

Reference example 2

(1) Condensation of 14.7 g of 2-amino 412 trophenol and 16.0 g of (1-methylcyclohexyl) carbonyl chloride in the presence of N, N-dimethylaniline, Then, ring closure is carried out by heating in the presence of thioyuryl chloride to obtain 2,7-g of 2- (1-methylcyclohexyl) -1-5-2 pentopenoxazole.

M.p. 57-59 C

(2) The above product is treated in the same manner as in Reference Example 1-1 (2) to give 5-amino-1- (1-methylcyclohexyl) benzoxazole as a colorless oil.

Mass (m / e): 230 (M ⁺ )

Reference Examples 3 and 4

The corresponding starting compound is treated in the same manner as in Reference Example 1 or 2, to obtain the following compound.

Reference example 5

(1) Chlorination of 8.55 g of 4-chlorophenylacetic acid followed by condensation with 7.70 g of 2-amino412-trifluorophenol in the presence of N, N-dimethylaniline to form N- (5 — Nitro 2—hydroxyphenyl) 1 2— (4_black mouth) acetamide 14.2 g is obtained.

Mp 250-252 C (decomposed) (2) Reduce 1.93 g of this product with stannous chloride to reduce N- (5-amino-2-hydroxyphenyl) 1-2- (4-chlorophenyl) acetamide 9.8 Get 6g.

Mp 1 64 ~: I 67 ^e C

Reference example 6

4-Hydroxy-1,3,5-di (tert-butyl) benzoic acid and 2-amino-4-trifluorophenol are treated in the same manner as in Reference Example 5- (1) and Reference Example 1- (2). N— (5-amino 2-hydro-shuffle) X 1-4-Hydroxy-3,5-di (tert-butyl) benzamide is obtained.

M. p. 222-225. C (decomposition)

Reference Example 7

(1) 4-Hydroxy-3-N-Trobenzaldehyde 18.0 g and 2,4-di-oxothiazolidine 12.74 g are heated and condensed in the presence of viridine to form 5- (4 -Hydroxy-3-2-trobenzilidene) 1,2,4-Dithioxiazolizidine 14.82 g is obtained. Yield 5 2%

M.p. 2 5 6.5-2 58 * C

(2) This product 1 2.85 g was reduced with sodium hypophosphite in the presence of a palladium-carbon catalyst to give 5- (3-amino-4-hydroxybenzylidene) 1-2,4-dioxane.丰 Obtain 10.86 g of sothiazolidin.

Yield 95%

M.p. 260.5-26 1.5 (decomposition)

Reference Example 8

(1) L-Hydroxy-3-nitrofuranalanine 13.3 g was treated with sodium nitrite in 3N-sulfuric acid in the presence of rhodium bromide to give 2-bromo. 1-3- (4-Hydroxy-1-3-nitrofuunil) Probionic acid 15.2 g is obtained as a brown solid.

(2) This product is heated and condensed with 15.1 g of this product and 6.14 g of urea urea in the presence of sodium phosphate to form 5- (4-hydroxy-3-nitrobenzyl) 1-2-y To obtain 12.2 g of 1-oxothiazolidinone as yellow powder. Mp 221-223. C (decomposition)

(3) 12.1 g of this product is hydrolyzed in the presence of hydrochloric acid to give 10.4 g of 5- (4-hydroxyl-3-nitrobenzyl) -1,2,4-dioxothiazolidin. Obtained as a yellow powder.

M.p. 141-14-13.5. C

(4) 10.3 g of this product is catalytically reduced in the presence of a palladium-carbon catalyst to give 8.77 g of 5- (3-amino-4-hydroxypentyl) -1,2,4-dioxothiazolidine as a pale yellow powder obtain.

M.p.2 15-2 17.5. C

Claims

The scope of the claims

1. General formula

(0

(However, R is a furyl group, a naphthyl group, a cycloalkyl group or a heterocyclic group which may have a substituent, and Alk has a single bond, a lower alkylene group, a lower alkynylene group or a substituent. In some cases, a lower alkylene group and a dotted line indicate that the bond at the site may be a double bond.)

An antilipidemic agent comprising, as an active ingredient, a benzoxazole derivative represented by or a pharmacologically acceptable salt thereof <

2. R is substituted with one or two groups selected from a lower alkoxy group, a lower alkyl group, a trihalogeno lower alkyl group, a furyl group, a halogen atom, a nitro group and a di (lower alkyl) amino group. A phenyl group, a naphthyl group, a pyridyl group, a 1,3-thiazol-4-yl group or a 1,3-thiazol-4-yl group. The antilipidemic agent as described.

3. The antilipidemic agent according to claim 1, wherein R is a di (lower alcohol) aminophenyl group or a naphthyl group.

4. A claim in which Alk is a single bond or a lower alkylene group, and a 2,4-dioxothiazolidin-1-5-yl (or ylidene) methyl group is bonded to the 5-position of the benzoxazole ring. Antilipidemic agent as described in item 1, 2 or 3.

5.5 — [(2,4-Dioxothiazolidin-1-yl) methyl] — 2 -— (41- (dimethylamino) pentyl) Benzoxazole or a pharmaceutically acceptable salt thereof is effective Antilipidemic as an ingredient.

6.5 — [(2,4-dioxothiazolidine-1-yl) methyl] —2 — [(2-naphter) methyl] benzoxazole or its pharmaceutically acceptable salt Antilipidemic agent as an active ingredient.