JPS60202820A - Antilipemic agent - Google Patents

Abstract

PURPOSE:An antilipemic agent, containing a specific furyloxazolylacetic acid derivative or a salt thereof as an active constituent, and having improved serum chlolesterol and serum triglyceride lowering action with little side effects such as hepatic dysfunction. CONSTITUTION:An antilipemic agent containing a compound of formula I (R<1> is lower alkyl; R<2> and R<3> are H or lower alkyl; ring A is phenyl or halogenophenyl as an active constituent. The compound of formula I has improved serum cholesterol and serum triglyceride lowering action and further inhibitory action on platelet agglutination and is a compound useful as the antilipemic agent. The compound of formula I has low toxicity and high safety. The preferred oral dose thereof is 5-20mg/kg/day. The compound of formula I is obtained by alkylating a compound of formula II (R<4> is lower alkyl).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an antilipemic agent, and more specifically, the present invention relates to an antilipemic agent, and more specifically, an atom of the general formula or a lower alkyl group, R3 represents a hydrogen atom or a lower alkyl group, and ring A is a phenyl group or a Gt halogenophenyl group. represents. ) Furyl oxacylyl vinegar p
! ! The present invention relates to an anti-81 drug containing a l#f7J conductor or a pharmacologically acceptable salt thereof as an active ingredient.

Hyperlipidemia is considered to be a major cause of arteriosclerosis, and for the treatment and prevention of hyperlipidemia, drugs such as dextran sulfate and synfiplate [chemical name: 2] have been used in the past.
-(4-chlorophenoxy)-2-methylpropionic acid 1,3-propanediyl ester], nicomol [chemical name: 2,2,6,6-texi]-2-methylpropionic acid ethyl ester] and vitamin E. Antilipemic agents such as nicotinates are used.

As a result of various studies aimed at developing better antilipemic agents, the present inventors found that a furyloxacylylacetic acid derivative represented by the general formula CI) has an excellent serum cholesterol lowering effect and serum triglyceride lowering effect. In addition, they discovered that Compound (I) has few side effects such as liver dysfunction, and also has platelet aggregation inhibiting effects, making it an extremely useful compound as an antilipemic agent. It was completed. That is, one aspect of the present invention is an antilipemic agent comprising a furyloxacylylacetic acid derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient.

For example, after allowing rats to ingest feed containing the specimen for one week,
When the serum triglyceride level was measured, it was found that 2-(2-(
4-chlorophenyl)-5-(2-furyl)-4-oxacylyl-2-methylpropion e and cF2-C2-
(4-chlorophenyl)-5-13-7jl]-4-
Oxacylyl]propionate ethyl ester showed serum triglyceride reduction rates of 54% and 45%, respectively.

on the other hand.

The serum triglyceride reduction rate of Grophiplate was 16%.

In addition, the above furyloxasilylacetic acid derivative (1) according to the present invention (
I) has low toxicity and high safety. For example, ゛, 2-(2
-(4-chlorophenyl)-5-(2-7lyl]-4-
When oxacyl]propionate n-kasumi ruthyl ester was orally administered to mice, the maximum tolerated dose of the compound was 2000.
m? It was over yKg.

As the furyloxacylylacetic acid derivative according to the present invention, 1
For example, in the general formula [E], R1 is a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, ethyl group, propyl group, or butyl group, and R1 is a hydrogen atom or a methyl group, ethyl group, propyl group, or butyl group. is a lower alkyl group having 1 to 4 carbon atoms such as Hm is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, ethyl group, propyl group, or butyl group, and ring A is a phenyl group or Compounds which are halogenophenyl groups such as -gulo-7-denyl group and 4-fluorophenyl group can be mentioned. Among these, preferred compounds include compounds having a general nyl group, for example.

In addition, in the compound in which R1 is a lower alkyl group and 11 is a hydrogen atom in the general formula CI), and the compound in which R is a different lower alkyl group, two types of optical isomers may exist. However, the compound CI according to the present invention
) includes such optical isomers, and 1 includes racemates, which are mixtures thereof.

When the group represented by B and R3 in the compound (I) according to the present invention is a hydrogen atom, when the compound CI) is used as a medicine, it can be used in the form of a free carboxylic acid, but
It can also be used in the form of its pharmacologically acceptable salts. As this kind of salt.

For example, alkali-11 metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with basic amino acids such as lysine, ornithine, arginine, and histidine, or ammonium salts are suitable.

When using the compound CI) of the present invention as a medicament.

It can be administered either orally or parenterally.

When the compound CI) of the present invention is administered orally.

It can be made into tablets, powders, capsules, granules, etc., which can be prepared using conventional excipients such as calcium carbonate, calcium phosphate, corn starch, potato starch, sandbox, lactose, targ, magnesium stearate, etc. may contain. It may also be used as a liquid preparation such as an aqueous or oily suspension, solution, syrup, or elixir. Furthermore, if it is administered parenterally, 0, for example, for injection! Ii preparation, suppository, etc., and when making it into an injection preparation, it is prepared in the form of a solution or suspension,
They include distilled water for injection, essential oils (e.g. peanut oil,
It may be free of corn oil) or non-aqueous solvents (eg, bo95 ethylene glycol, polypropylene glycol, lanolin, coconut oil, etc.).

The formulation is also a fungicide and/or an anti-1x agent.

It may also contain auxiliary agents such as stabilizers. Compound C
The pharmaceutical dosage of I) depends on the administration method, age, weight, and condition of the patient! ! Although it varies depending on the disease to be treated, it is usually 1
The preferred daily dose is about 0.1 to
about 50 ηyKg, especially about 5 to about 20 #/9.

Fluoxalyl acetic acid derivative CI) according to the present invention is +a+
A compound represented by the general formula (where R4 represents a lower alkyl group and 4A has the same meaning as above) is subjected to an alkylation reaction to form the compound represented by the general formula (wherein R1, R*, R4 and ring A are the above, The compound [I-a] obtained by the above fal method is hydrolyzed to obtain a 711-ruoxazinoleacetic acid derivative represented by the general formula (where Hl, Hl and bottle A are the same as above). The alkylation reaction of the compound (IF) to form the furyloxasilylacetic acid derivative shown in Usable alkylating agents include common alkylating agents such as alkyl halides such as methyl iodide, ethyl iodide, and butyl bromide, and dialkyl M acid esters such as dimethyl sulfate.As a base catalyst, for example, Alkali-11 metal alcoholades such as 1r sodium ethylate, potassium t-butylade, alkali metal hydrides such as sodium hydride, alkali metal hydroxides such as sodium II hydroxide, potassium hydroxide, alkyl alkali metals such as butyl lithium, etc. can be suitably used.As the solvent, for example, tetrahydro7rane, dibutylformamide, dimethyl sulfoxide, acetonitrile, ethanol, methanol, or a mixture thereof can be suitably used.The reaction temperature is:
Although it varies depending on the solvent, base catalyst, etc. used, it can generally be carried out at a temperature of 14°C to 4°C or -2°C. In this reaction, by appropriately selecting the amount of alkylating agent used, 4 general formula C
In I), a compound in which R1 is a lower alkyl group and R2 is a hydrogen atom, or a compound in which R1 and R1 are both lower alkyl groups can be produced. For example,
By reacting approximately equimolar alkyl halide with the starting compound (n), in the general formula CI-a), R1 is a lower alkyl group and r+-1 is a lower alkyl group. I can do marrow susurkM. On the other hand, R mochi compound (n)
It is also possible to produce a compound in which R1 and R2 are both lower alkyl groups in the general formula [ni a] by reacting alkyl halide in an amount of twice or more in mole.

In addition, a compound in which R1 and R8 are both lower alkylating agent groups in the general formula [Ni-a] can be prepared by reacting the raw material compound (n) with about equimolar alkyl halide to form the general formula (I-Hata). In, R1 is a lower alkyl group, and R3
It can also be produced by preparing a compound in which is a hydrogen atom, and then reacting the compound with an alkyl halide in an amount equal to or more than the same mole. In this case, by appropriately selecting the type of alkylating agent.

A compound in which R1 and R3 are different lower alkyl groups in general formula (I-4) can also be cleaved.

fbl method The hydrolysis reaction of compound CI-a) obtained by the tal method is as follows.

This can be carried out by using an acid or an alkali in a suitable solvent, but it is particularly preferable to use an alkali. As the acid, a mineral acid such as hydrochloric acid or sulfuric acid can be used, and as an example of the alkali, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide can be suitably used. Examples of solvents include water, alkanols (eg, methanol).

industrial tar, propyl, etc.], tetrahydrofuran,
Dioxane or a mixture/solvent thereof can be used. The reaction is carried out at 0°C to 100°C, especially 1'6'/
Preferably, the reaction is carried out at -so°C.

The starting material compound (It) for compound (I) according to the present invention can be produced, for example, by the method shown in the following reaction formula.

A has the same meaning as above] Experimental Example 1 (III quality deterioration effect) A sample was mixed with a powdered rat feed, the sample content was 50 kg, and the mixture was fed to SD male rats (body haze: 120 to 1 kg).
40f, 5 animals per group] were given free access for one week, and then blood was collected from the tail under ether anesthesia. The serum cholesterol level was measured using the Zack method using the collected blood (American Journal of Clinical Laboratories, 24: pp13).
07 (1954)), and serum triglyceride levels were determined by the Pan, Hample-Chylbergemit method, Journal of Laboratory and Clinical Medicine, 50: PP152 (1957) J. From these results, serum cholesterol and triglyceride reduction rates were calculated using the following formula. The results of the serum f11ff lowering effect are encouraging as shown in Table 111 below.

Cholesterol level or triglyceride level of sample pitcher group Table 1 Experimental example 2 (Platelet aggregation inhibitory effect) BD male rats anesthetized with ether (body weight = 250-3
005') was collected from the abdominal aorta, 9 volumes of the blood was immediately mixed with 1 volume of a 3.8 ml/17 um aqueous solution, centrifuged, and the top layer was collected to prepare platelet-rich plasma. (E'RP) was prepared. The remaining blood was centrifuged and the upper layer was collected to prepare platelet poor plasma (PPP). PRP platelet count is diluted with ppp g ~ I Q
After preincubation for 2 minutes at rpm for X I Q' asll/-, the method of Holmsen et al.
DeI! 25 g of the prepared collagen suspension was added to cause platelet aggregation. The aggregation ability was measured by Born's method [Nature, [See 4. PP927 (1962)), and the platelet aggregation inhibition rate was determined by the following formula, and the inhibition rate was 10.
A value less than 10% was determined as (-), and a value of 10% or more was determined as (+).The results are shown in Table 2 below.

Reference example in Table 2 1 Sodium hydride (6011 amounts in paraffin) 4.8
Add 2-(2
-(4-chlorophenyl)-5-(2-furylno-4-
[oxazinol] ethyl acetate varnish 7□7,8 dropwise f6° mixture, -0 Tanitomi. Stir for 1730 minutes. Vinegar in the reaction solution! ! ! +5- was added and then the solvent was distilled off. Add 600% of ethyl acetate and 500% of water to the remaining residue, stir, and separate the layers. Saturate the organic layer! i Wash with backwater and saturated brine, dry over anhydrous magnesium sulfate, and concentrate. 2-
(2-(4-chlorophenyl)-5-(2-furyl)-
4-oxazolyl dipropionic acid ethyl ester 30.
4M' is obtained as colorless needles.

Yield: 88%, P, 97°C to 97.5°C I Ri “air”: 174 ON M
R(CDC1m Jδ: 1.20(3f1.t, J
-7,5Hz).

1, 63 (3H, d, J=7.5Hz), 3
．． 8-44 (3 days, ml.

6.43 (I H, d, d, J-3, 5 and 1
．． 5H1).

6.65 (1fi, d, J-3, 5H237, 32 and 7.92 (2B, eaah.

A/B1. J, , 8H illusion, 7.45 (IH, dd,
J-1,5H! > us mls: 345 (M+3 Reference Examples 2 to 6 The following compounds were prepared according to the procedure of Reference Example 1.

1 Reference Example 7 Dissolve 2-(2-(4-chlorophenyl)-5-(2-furyl)-4-oxacylyl)acetic acid ethyl ester 4.97F in a dimethylformamide (50d)-tetrahydro7ran+30nj) mixture. The mixture was cooled to -15°C and diluted with sodium hydride (50ffi1 in paraffin).
< ) 2.16 Add F. The mixture was heated at the same temperature for 5 minutes.
After stirring for 2'+)<1.86 methyl iodide was added dropwise. The mixture is gradually warmed up and stirred at room temperature for 5 hours. After adding vinegar #11-, tetrahydro7ran is distilled off. After adding 300 ml of ethyl acetate and 200 ml of water and shaking, the organic layer was separated. The organic layer was washed successively with saturated sodium bicarbonate water and Japanese brine, dried, and concentrated. Ethanol 20- was added to the residue and the precipitate was collected by filtration to obtain 2-(2-(4-chlorophenyl)-5-(2-furyl)-4-oxasilyl di-2-methylpionic acid ethyl ester)4. 5 (l) is obtained as nodding needles. Yield 84% M, p, 8.9°C to 90°C NMR (CDcIs) δ: 1.07 (3 Jt,
J=711z).

1.68+6H,a), 4.02(2H,q, J=
7tlz36.44 (IH+dd.

J = 2 and 4H2), 6.59 (IFl, d,, T = 4
Hri7.34 w7.93 (2Heach, As'
B*', J=9HE)7.44CxH,a,J
= 2 blood] M S rn/e: 359 (M+3 Reference Example 8 Based on Reference Example 7, the following compound was produced.

2-(2-(4-chlorophenyl)-5-(3-7lyl)-4-oxazocluto-2-methylpropionic acid ethyl ester (acicular crystals) 14, p, 71°C to 72°C I Rνnuj01((2” ) : 1720) J.S.
a+/e: 359 (M+) Reference Example 9 2-(
2-(4-riphenyl)-5-(2-7IFl]-
4-Oxasilyl upropionic acid ethyl ester 1.7
09 and added 1.12y' of potassium hydroxide to the mixture.
Add. The mixture is stirred at 60°C for 1 hour. After the reaction was completed, methanol was distilled off.

Add 30ml of water to the remaining amount. After washing the resulting aqueous solution with ether, the aqueous solution was adjusted to pH 3 with 10% hydrochloric acid. The aqueous solution is extracted with ethyl acetate, and the 0m extract is dried and concentrated.

2-C2-(4-chlorophenyl)-5- was obtained by adding diisopropyl ether to the residue and collecting the precipitate by filtration.
(2-7lyl]-4-oxasilyl]propionic acid 1.
Get Ov.

Yield 64%", P, 186°C-187°C I Runujol(cii"): 171 ON
M R (CDCIs-CDCl5-D) δ: 1
．． 6 (311, d, J=7.5Hz), 4.12 (1f
f, q, J-7,5Hz), 6.47 (ILmJ.

6.87 (1■llJ, 7.1~8.116H, n+3
゜M S rn/*: 317 (M+) Reference example 1
0 The following compound was produced according to Example 9.

I '): 172 ON M
R(DIJSO-ds)δ: 1.61(6H,s
), 6.6-7.0 (2H, m17.52 and 7.98
(2Haaoh, &B(,J=8Hz).

7.83 (l I'1. broad s ) M S
m/e: 331 (M+) (+fr chemical gold compound 1
] Example 1 To a 160 mj solution of illN-+4-chlorobenzoyl)-(2-7lylcarbonyl J/Nalamine 409 in dimethylformamide, add 7.2 g of 61% sodium hydride at 0°C to -40°C. Add the mixture and stir for an additional 5 minutes. Then, mix the reaction and stir for 1 hour. The reaction temperature was gradually raised to around 0°C, and the mixture was stirred for an additional hour.

After the reaction was completed, the mixture was neutralized with acetic acid and water was added.

Extract with ethyl acetate. The extracted layer was treated with sodium bicarbonate,
After washing with water and drying, the solvent is distilled off under reduced pressure.

By crystallizing the residue from a mixture of diisopropyl ether and hexane, 37.01 of 3-(4-chlorobenzoylamino)-3-(2-furylcarbonyl)propionate ethyl ester is obtained. Yield: 70 M, p, 100℃~102℃ I RW "M core" (cml): 3300.3100
．． 1738°1680.1630.1595 +213-(4-chlorobenzoylamino)-3-(2
-Furylcarbonyl] propionic acid ethyl ester 37
y was dissolved in chloroform (ρ), 64.99% of phosphorus oxychloride was added dropwise to the solution at room temperature, and 8%
Stir and reflux for an hour. After the reaction is complete, the mixture is poured into ice water, made neutral with sodium bicarbonate, and then extracted with ethyl acetate. The extracted layer was washed with water, dried, and then treated with activated carbon.

The solvent is distilled off under reduced pressure. After crystallizing the residue from diisopropyl ether, the crystals were recrystallized from ethanol to obtain 2-C2-(4-chlorophenyl)-s.
-t2-furyl)-4-oxasilyl]acetic acid ethyl ester 307 is obtained. Yield 85.5% Moe, p, 105°C-106°C IRv Xi,: 1 (01”): 1723.1600 Examples 2 +1+ 2- (2-(4-chlorophenyl)-5-(
To 1.07 g of ethyl 2-furyl)-4-oxasilyl acetate was added a solution of 0.47 g of potassium hydroxide in 30 aZ of methanol at 5° C. to 10° C., and the mixture was stirred at room temperature for 10 hours. The precipitated crystals are collected by filtration, washed with ether, and dried to obtain 0.851 of potassium 2-(2-(4-chlorophenyl)-5-(2-furyl)-4-oxacylyl)acetate. Rate 80.2 Curse lJ, p, 250℃ or higher I Ry" Miya 1 ((Ill"): 1610 (212
-(2-<4-chlorophenylJ-5-(2-furyl)-4-oxacylyl) Potassium acetate 0.859 is dissolved in water, hydrochloric acid is added to make the liquid acidic, and the precipitated crystals are collected by filtration. By recrystallizing the crystals from ethanol, 2-(2-(4-chlorophenyl)-5-(2-
0.69 F of furyl]-4-oxasilyl]acetic acid is obtained. Yield: 4190, 9 M, p, 191°C to 194°C (decomposition) I Ryn: Distance (ci”): 1720+31 2-
(2-(4-chlorophenyl)-5-(2-furyl)
After adding 2.0 g of thionyl chloride to a solution of 2.0 g of -4-oxacylyl acetic acid in 20 g of chloroform at room temperature, the mixture was stirred and refluxed for 3 hours. After cooling, 0°67 of n-butanol was added to the reaction solution and stirred at the same temperature for 6 hours. After the reaction is complete, the solvent is distilled off under reduced pressure, and the residue is extracted with ethyl acetate. The extracted layer was washed with an aqueous sodium bicarbonate solution and dried.

The solvent was removed under reduced pressure. By recrystallizing the residue from ethanol, 2-(2-(4-chlorophenyl)-5-(
2-7lyl)-4-oxasilyl]acetic acid n-butyl ester 1.5f! 81. Yield 62.3 Width M, p, 96°C-97°C I Rynujol (ai”): 3050, 17
30ax

Claims (1)

[Claims] 1. Represents an atom of the general formula or a lower alkyl group, - represents a hydrogen atom or a lower alkyl group, and Ring A is a phenyl group or a lower alkyl group.
Express the phenyl group. ] An antilipemic agent comprising a furyloxacylylacetic acid derivative represented by the following or its 1IHJ14 acceptable salt as an active ingredient.