JPS6130645B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to antihyperlipidemic agents containing sulfonate derivatives. Hyperlipidemia is recognized to be a risk factor for various adult diseases such as arteriosclerosis, cardiorenal vascular disease, and diabetes. As a drug for reducing or preventing hyperlipidemia, there is a possibility that the drug may be used for a long period of time due to the nature of the disease, and a drug with a high degree of safety is required. However, various side effects have been reported for nicotinic acid and its derivatives, dextran sulfate, or clofibrate and its derivatives, which have been widely used as antihyperlipidemic agents.
For example, nicotinic acid and its derivatives are known to have side effects such as skin itching, facial flushing, gastrointestinal disorders, liver dysfunction, and worsening of glucose tolerance due to their vasodilatory effects.
Furthermore, it is a drug with many side effects because it requires large doses of 3 g or more per day. Clofibrate is a representative antilipidemia drug that is widely used worldwide, but recently, carcinogenic effects of clofibrate have been reported as a serious side effect, and various research institutes have conducted animal tests or Although epidemiological studies are being conducted, no final conclusions have been reached, and each country currently imposes restrictions on the clinical use of clofibrate. Furthermore, in addition to this carcinogenicity, there have been reports of an increase in the incidence of gallstones in the gastrointestinal tract due to clofibrate's effect of increasing sterol excretion, and this is being viewed as a new side effect. As a result of repeated research by the present inventors on these antilipemic agents that have various safety issues, we discovered that a new sulfonate derivative has an antilipidemic effect, and that the effect is similar to that of nicotinic acid. It is significantly stronger than its derivatives, dextran sulfate, clofibrate, and its derivatives, and its toxicity is very low, so its safety margin is extremely wide and it is safer than conventional antilipidemic agents. We discovered that this compound is highly useful as a new antilipemic agent.
The present invention has now been completed. The compound which is an active ingredient of the present invention has the general formula R ₁ SO ₃ CH ₂ COR ₂ () [wherein R ₁ is an alkyl group having 1 to 4 carbon atoms, an alkoxyalkyl group having 2 to 6 carbon atoms, an aralkyl group,
A cyclic alkyl group, or an aryl group with or without a substituent (substituents include an alkyl group having 1 to 12 carbon atoms, a lower alkoxy group, a halogen, a hydroxyl group, a carboxyl group, an acetamino group,
nitro group or ethylenedioxymethyl group), _R2 is an alkyl group having 1 to 15 carbon atoms or an alkenyl group having 2 to 15 carbon atoms]. Examples of the alkyl group having 1 to 4 carbon atoms in R ₁ in the above general formula are methyl, ethyl, propyl,
Examples of alkoxyalkyl groups having 2 to 6 carbon atoms include butyl, ethoxymethyl, methoxyethyl,
Ethoxypropyl, methoxybutyl, etc., examples of aralkyl groups include aralkyl groups having 7 to 10 carbon atoms, such as benzyl, phenethyl, phenylpropyl, benzyl, phenethyl, etc. having methyl, ethyl, etc. as a substituent on the benzene nucleus, Examples of the cyclic alkyl group include cyclic alkyl groups having 5 to 8 carbon atoms, such as cyclopentyl, cyclohexyl, and cyclooctyl; examples of the aryl group include phenyl,
Examples of alkyl groups having 1 to 12 carbon atoms as substituents of the aryl group include methyl, propyl, hexyl, decyl, dodecyl, etc., and examples of lower alkoxy groups include 1 to 6 carbon atoms.
alkoxy groups such as methoxy, ethoxy, hexyloxy, etc., and halogens such as fluorine,
Chlorine, bromine, and iodine can be mentioned. Further, examples of the alkyl group having 1 to 15 carbon atoms in _R2 include methyl, ethyl, propyl, hexyl, decyl, dodecyl, pentadecyl, etc., and examples of the alkenyl group having 2 to 15 carbon atoms include vinyl,
Examples include allyl, propenyl, butenyl, decenyl, and tetradecenyl. The compound represented by the general formula () of the present invention can be produced by the following method. <Method A> A compound represented by the general formula N ₂ CHCOR ₂ () (in the formula, R ₂ has the same meaning as above) and the general formula R ₁ SO ₃ H・mH ₂ O () (in the formula, R ₁ has the same meaning as above, m represents 0 or an integer of 1 to 2) <Method B> General formula XCH ₂ COR ₂ () (wherein X is Fluorine, chlorine, bromine, iodine, R ₂ has the same meaning as above) and compounds represented by the general formula R ₁ SO ₃ H () (wherein R ₁ has the same meaning as above) It can be produced by a method of reacting with a metal salt of sulfonic acid. Metals in metal salts include sodium, potassium, magnesium,
Examples include iron, lead, copper, and silver. Method A is usually carried out in a solvent, and the solvent is not particularly limited as long as it does not participate in the reaction, but ethers, aprotic solvents, petroleum fractions, etc. are preferably used. Regarding the ratio of the compounds () and (), it is advantageous to use at least equimolar amounts of () to (). The reaction temperature ranges from -10 to 60°C.
Method B is usually carried out without a solvent or in a solvent, and lower alcohols, ethers, acetonitrile, dimethylformamide, acetone, etc. are used as the solvent. It is advantageous to use equimolar proportions of compounds () and (). The reaction temperature is advantageously in the range from 0° C. to the boiling point of the solvent. The compound used in the present invention is a new compound and has a remarkable antihyperlipidemic effect, and can be formulated into various formulations depending on its administration route. For example, oral preparations include tablets, capsules, granules, powders, and liquid preparations, and parenteral preparations include suppositories. Excipients used in the production of tablets, capsules, granules, and powders include, for example, lactose, sucrose, starch, talc, magnesium stearate, crystalline cellulose, methylcellulose, carboxymethylcellulose, glycerin, sodium alginate, and gum arabic. As binders, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, gum arabic, silica, sucrose, etc. are used, as lubricants, magnesium stearate, talc, etc., and as coloring agents and disintegrants, commonly known ones are used. Can be used. The tablets may be coated by a known method. Liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, etc., and are prepared by commonly used methods. As the base material for producing suppositories, for example, oil-based base materials such as cacao butter, polyethylene glycol, lanolin, fatty acid triglyceride, Witepsol (registered trademark: Dynamite Nobel Co., Ltd.), and the like can be used. The dosage of the antihyperlipidemic agent of the present invention depends on the patient's symptoms,
It varies depending on body weight, age, etc., and cannot be absolutely limited, but it is usually about 50 to 1500 mg per day for adults.
This is preferably administered in 1 to 4 divided doses. Preferably, the content per unit dosage is about 10-1500 mg. Next, production examples, formulation examples, antilipidemic efficacy tests, and acute toxicity tests of the active ingredient compound of the present invention will be shown. Production example 1 84 g of 4-methyl-1-pentene in 350 ml of water, N
Add 177 g of -bromo-succinimide and 4 drops of acetic acid, and stir at room temperature for 12 hours. After the reaction, the precipitated crystals are separated and the liquid is extracted twice with 500 ml of ether. After drying the ether layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
Hydroxy-4-methyl-n-pentane 93.6g
I got it. Yield 52%, MS (M ⁺ ) 180 1-bromo-2-hydroxy-4-methyl-
90g of n-pentane, 85g of sodium dichromate,
45 ml of water was added, and a mixed solution of 98 g of concentrated sulfuric acid and 30 g of water was added dropwise under ice cooling while adjusting the internal temperature to 20 to 30°C.
After dropping, stir at room temperature for 6 hours. Water after reaction 100
ml and extract three times with 200 ml of ether. After drying the ether layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residual liquid was distilled under reduced pressure.
65 g of 4-methyl-1-bromo-2-pentanone with a boiling point of 82-83°C/25 mmHg was obtained. Yield 73.0% MS (M ⁺ ) 178 NMR ( _CDCl3 ) δ (ppm) 3.85s (2H), 2.51d (2H), 2.35~1.90m
(1H), 1.02s (3H), 0.93s (3H) 4-Methyl-1-bromo-2-pentanone 44.5
Dissolve g in 500ml of acetonitrile, add 2, 4, 6
Add 85 g of -trimethyl-benzenesulfonic acid silver salt and heat and stir at 50 to 60°C for 24 hours. After the reaction, insoluble matter was separated and the liquid was distilled off under reduced pressure. Add 100 ml of water to the obtained residue, extract with 500 ml of ether, and wash with water. After drying the ether layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized with petroleum ether to give a 2-
52 g of oxo-4-methyl-pentyl-2,4,6-trimethylbenzenesulfonate was obtained. Yield 69.8% MS (M ⁺ ) 298 NMR (CDCl ₃ ) δ (ppm) 6.98s (2H), 4.38s (2H), 2.61s (6H), 2.35d
(2H), 2.29s (3H), 2.30~1.80m (1H), 0.95s
(3H), 0.88s (3H) Production Example 2 Synthesis was carried out according to Production Example 1 from 98 g of 4-methyl-1-hexene to produce 1-bromo-2-hydroxy-4-methyl-n with a boiling point of 83°C/5 mmHg. -97g of hexane was obtained. Yield 50% MS (M ⁺ ) 194 1-bromo-2-hydroxy-4-methyl-
Synthesis was carried out according to Production Example 1 from 97 g of n-hexane to obtain 68.6 g of 4-methyl-1-bromo-2-hexanone having a boiling point of 102-105°C/24-25 mmHg. Yield 70% MS (M ⁺ ) 192 NMR ( _CDCl3 ) δ (ppm) 3.38s (2H), 2.53t (2H), 2.15~1.70m
(1H), 1.50~1.00m (2H), 1.10~0.85m
(6H) 4-methyl-1-bromo-2-hexanone 48g
Synthesis was carried out according to Production Example 1 from 86 g of p-ethoxybenzenesulfonic acid silver salt and a pale yellow oil was obtained. This oil was purified by column chromatography (silica gel, developing solvent, chloroform) to obtain 58.1 g of 2-oxo-4-methyl-n-hexyl-p-ethoxybenzenesulfonate as a colorless oil. Yield 74.0% MS (M ⁺ ) 314 NMR (CDCl ₃ ) δ (ppm) 7.85d (2H), 6.99d (2H), 4.42s (2H), 4.06q
(2H), 2.33t (2H), 2.15~1.70m (1H), 1.42t
(3H), 1.40~1.05m (2H), 1.00~0.70m
(6H) Representative compounds 1 to 162 of the active ingredient compounds of the antihyperlipidemic agent of the present invention represented by the general formula () are shown in Table 1 below. Next, representative examples of formulations of the present invention will be shown. Formulation example 1 1 capsule containing compound 136 content weight 500
mg of soft capsule Compound 136 250mg Olive oil 250mg The above composition is filled into one capsule according to a conventional method. Formulation Example 2 Tablets each containing Compound 149 weighing 406 mg Compound 149 100 mg Light anhydrous silicic acid 80 mg Crystalline cellulose 140 mg Lactose 80 mg Talc 2 mg Magnesium stearate 4 mg The above composition is molded into one tablet according to a conventional method. Formulation Example 3 One package of 1000 mg granules containing Compound 135 Compound 135 200 mg Light anhydrous silicic acid 170 mg Crystalline cellulose 350 mg Lactose 270 mg Magnesium stearate 10 mg The above composition is prepared into one package of granules according to a conventional method. Formulation Example 4 Suppositories each weighing 2000 mg containing Compound 73 Compound 73 1000 mg Witepsol W-35 1000 mg The above composition is molded into one suppository according to a conventional method. Formulation Example 5 One vial of 20 ml of elixir containing Compound 50 Compound 50 300 mg Ethanol 0.5 ml Granulated sugar 2000 mg Nitskol HCO-60 150 mg Fragrance 0.01 ml Make up to 20 ml with purified water. The above composition is prepared into one vial of elixir according to a conventional method. (1) Antilipidemic effect test Groups of 5 male Wistar rats, 7 weeks old and weighing 200 to 220 g, were used in the test. 100 mg and 200 mg of the compounds of the present invention were dissolved in 10 ml of an olive oil/cholesterol mixture (containing 15% cholesterol) and used in the test. Olive oil/cholesterol mixture containing the compound of the present invention
A dose equivalent to 10 ml/kg is orally administered to rats using a sonde, and after 2 or 8 hours, 6 ml of whole blood is collected from the descending vena cava under ether anesthesia using a syringe containing heparin. 5 of the obtained blood
Centrifuge at 3000 r.pm at ℃ to obtain plasma. 2
After time, the triglyceride content of plasma is
After 8 hours, the total cholesterol content of the plasma was measured using Wako Pure Pharmaceutical's triglyceride measurement kit (Triglyceride-B Test Wako).
and total cholesterol measurement kit (Cholesterol Test Wako). The control group received only the olive oil/cholesterol mixture in the same way, and the normal group received no treatment.
In both groups, triglyceride and total cholesterol contents in plasma were measured in the same manner as in the group treated with the compound of the present invention. The hyperlipidemia suppression rate of the compound of the present invention was calculated using the following formula. Inhibition rate (%) = A-C/A-B×100 A: Control group triglyceride content (cholesterol content) B: Normal group triglyceride content (cholesterol content) C: Triglyceride content (cholesterol content) of the compound-treated group of the present invention It is shown in Table 1. The compounds of the present invention showed excellent antilipidemic effects. (2) Acute toxicity test The compound of the present invention was tested in Table 2 in a group of 5 male Wistar rats, 6 weeks old and weighing 180 to 200 g.
Each dose was suspended in a 30% aqueous solution of polyethylene glycol 6000 and administered orally at the ratio shown in . General poisoning symptoms, body weight, and presence or absence of death were observed daily for one week from the start of the test, and LD ₅₀ was determined.
I found the value. The results are shown in Table 1. In the table, in the antilipidemia effect section, those marked with an asterisk (*) indicate the effect of oral administration at 200 mg/Kg, and those without a mark indicate the effects of oral administration of 100 mg/Kg. In addition, in the same paragraph, TG
"" indicates the triglyceride suppression rate, and "CS" indicates the cholesterol suppression rate.

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Claims (1)

[Claims] 1 General formula R ₁ SO ₃ CH ₂ COR ₂ () [In the formula, R ₁ is an alkyl group having 1 to 4 carbon atoms, 2 carbon atoms
~6 alkoxyalkyl groups, aralkyl groups, cyclic alkyl groups, or aryl groups with or without substituents (substituents include alkyl groups with 1 to 12 carbon atoms, lower alkoxy groups, halogens, hydroxyl groups, carboxyl groups) , acetamino group, nitro group or ethylenedioxymethyl group), _R2 is an alkyl group having 1 to 15 carbon atoms or an alkenyl group having 2 to 15 carbon atoms]. 2 In the general formula (), R ₁ is a substituted phenyl group (substituents include an alkyl group having 1 to 12 carbon atoms, a lower alkoxy group, a halogen, a hydroxyl group, a carboxyl group, an acetamino group, a nitro group, or an ethylenedioxymethyl group). An antihyperlipidemic agent according to claim 1.