JPH0121143B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel derivative and an antilipidemic agent containing the same. The derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula ().
It is a sulfonate derivative. [In the formula, R ₁ represents an alkyl group or an alkoxy group, l represents 0 or an integer of 1 to 3, and R ₂ represents an alkyl group. ] The alkyl group represented by R ₁ and R ₂ in the above general formula () is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl group. Examples of the alkoxy group represented by R ₁ include lower alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy, propyloxy, isopropyloxy, and butyloxy groups.
Each of the substituents represented by R ₁ above may be present at any position on the benzene ring, and there is no need for one substituent, and two to three substituents may be present. Furthermore, the substituent represented by R ₂ can be present at any position on the cyclohexyl ring, and its configuration is trans. Therefore, the derivative of the present invention is trans-1-(benzenesulfonyloxy)
It is called a -2-cyclohexyl-2-ethanone derivative. The compound represented by the above general formula () of the present invention can be produced, for example, by the following <Method A> and <Method B>. <Method A> General formula [In the formula, R ₂ is the same as above. ] and the trans-diazo compound represented by the general formula [In the formula, R ₁ and l are the same as above. m represents 0, 1 or 2. ] is reacted with the compound represented by The reaction in Method A above is usually carried out in a solvent. The solvent is not particularly limited as long as it does not participate in the reaction, but generally dimethyl ether, diethyl ether, tetrahydrofuran,
Ethers such as dioxane, aprotic solvents such as acetonitrile, chloroform, dichloromethane, petroleum ether, ligroin, etc. are preferably used. The ratio of the trans-diazo compound () and the compound () to be used may be selected as appropriate, but it is generally advantageous to use the compound () in an equimolar or more amount to the compound (). The reaction generally proceeds advantageously at a temperature of about -10 to 60°C, preferably about 0°C to room temperature. The trans-diazo compound () used as a raw material in the above is usually obtained by reacting thionyl chloride () with a known compound (), which is a cis-trans mixture, as described below to obtain the compound (), which is a cis-trans mixture. , is reacted with diazomethane () to obtain compound (-a) which is a cis-trans mixture, which is then subjected to conventional methods such as chromatography to separate the trans form (). [In the formula, R ₂ is the same as above. ] The reaction between the above compound () and thionyl chloride (), the reaction between the compound () and diazomethane (), and the separation of the trans isomer () from the resulting compound (-a) by column chromatography are as follows:
Each can be carried out according to a conventional method. For example, the reaction between compound () and diazomethane () is generally carried out using at least twice the mole of diazomethane () relative to compound () in the same solvent as exemplified in method A above, at a temperature of about -10°C to room temperature. It is carried out under favorable conditions. Details of each of the above reactions are as shown in Reference Examples below. <Method B> General formula [In the formula, R ₂ is the same as above. ] to the trans-1-(hydroxyacetyl)-cyclohexane derivative () represented by the general formula [In the formula, R ₁ and l are the same as above. ] benzenesulfonyl chloride is reacted. The reaction in Method B above is carried out in a suitable solvent in the presence of a base as a dehydrochlorination agent. As the solvent, those that do not participate in the reaction, such as halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, can be suitably used. In addition, the bases used as dehydrochlorination agents include common ones such as pyridine, triethylamine, N,
N-diisopropylethylamine, 1,8-diazabicyclo(5.4.0)-7-undecene (DBU)
etc. may be used advantageously. trans-1-(hydroxyacetyl)-cyclohexane derivative (),
The proportion of benzenesulfonyl chloride () to be used can be determined as appropriate and is not particularly limited, but it is usually preferable to use equimolar amounts of both. The reaction is usually carried out at about -10 to 50°C, preferably about -5°C.
Progresses well under temperatures in the range ~5°C. The trans-cyclohexane derivative (), which is one of the raw material compounds used in the above method B, is a cis-trans mixture (
-a) is reacted with sodium alkoxide (XI) in alcohol to convert the cis isomer to the trans isomer, the resulting trans isomer () is brominated according to a conventional method, and then the resulting bromide (XII) is It can be produced by hydrolysis using, for example, ethyl formate, potassium hydroxide, and methanol according to a conventional method. The details of each reaction are as shown in the reference examples described later. The compounds of the present invention obtained by the above methods A and B can be isolated by conventional separation means such as column chromatography, recrystallization, vacuum distillation, etc. The compounds of the present invention have esterase inhibitory activity, chymotrypsin inhibitory activity, and antilipidemic activity, and are useful as antilipemic agents, anti-inflammatory agents, and immunomodulatory agents. - Antilipidemic agents containing sulfonate derivatives are also included. Hyperlipidemia is recognized as a risk factor for various adult diseases such as arteriosclerosis, cardiorenal vasculopathy, and diabetes. may last for a long time,
There is a need for highly safe drugs. However, various side effects have been reported for nicotinic acid and its derivatives, dextran sulfate, clofibrate and its derivatives, etc., which have been conventionally known as antilipemic agents. That is, 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 vasodilatory effects, and furthermore, large doses of 3 g or more per day are required. For this reason, it is a drug with many side effects. In addition, clofibrate is a representative antilipemic drug that is widely used worldwide, but recently, carcinogenic effects of clofibrate have been reported as a serious side effect, and animal studies have been carried out in various research institutions. Alternatively, epidemiological studies are being conducted, but no final conclusions have been reached, and each country currently imposes restrictions on the clinical use of clofibrate. In addition to this carcinogenicity, clofibrate has also been reported to increase the incidence of gallstones in the gastrointestinal tract due to its action of increasing sterol excretion, and is considered a new side effect. The antilipidemic agent of the present invention exceeds known nicotinic acid and its derivatives, dextran sulfate, clofibrate and derivatives in its antilipidemic effect, and its toxicity is very low and within the safety range. It is extremely widely used and is characterized by higher safety than conventional antilipidemic agents. The antilipemic agent of the present invention can be formulated into various formulations depending on its administration route. For example, oral preparations may take various forms such as tablets, capsules, granules, powders, and liquids, and parenteral preparations may take the form of suppositories. Preparation into these various forms is carried out in accordance with conventional methods using conventional carriers and other additives. 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. etc., binders such as polyvinyl alcohol, polyvinyl ether, ethyl cellulose, gum arabic, silica, sucrose, etc., lubricating agents such as magnesium stearate, talc, etc., and other commonly known coloring agents, disintegrants, etc. Agents can optionally 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 according to conventional methods using conventional diluents and other additives. As bases for producing suppositories, oily bases such as cacao butter, polyethylene glycol, lanolin, fatty acid triglycerides, and Witepsol (registered trademark: Dynamite Nobel) can be used. The dosage of the antilipemic agent of the present invention depends on the patient's symptoms,
Although it varies depending on body weight, age, etc., and cannot be absolutely limited, the amount of the active ingredient compound per day for adults may be approximately 50 to 1,500 mg, and this is preferably administered in 1 to 4 divided doses. Ru. In addition, the active ingredient compound content per unit preparation is, for example, about 10 to 1500.
It is preferable to set it as mg. Typical compounds of the trans-diazoketone derivatives represented by the general formula () used to produce the compounds of the present invention are shown in Table 1 below. Representative compounds are shown in Table 2. Table 3 also lists representative compounds of the trans-sulfonate derivatives represented by the general formula () of the present invention.
-(1) and -(2). In each table, MS indicates the mass spectrum analysis results (M ⁺ ), and H-NMR indicates
The results of nuclear magnetic resonance spectrum analysis (δppm value) measured in CDCl ₃ are shown.

【table】

【table】

【table】

[Table] Hereinafter, production examples of each compound listed in Tables 1 and 2 above are listed as reference examples. Reference Example 1 25.0 g of 4-isopropylbenzoic acid was hydrogenated in acetic acid using 1.0 g of Adams type platinum oxide at room temperature and 100 atmospheres to obtain 23.0 g of 4-isopropylcyclohexane-1-carboxylic acid with a boiling point of 131-134°C/1 mmHg.
g (yield 88.8%) was obtained. (The ratio of cis isomer and trans isomer was confirmed to be approximately 3:1 from the results of H-NMR analysis.) 23.0 g of 4-isopropyl-cyclohexane-1-carboxylic acid was treated with thionyl chloride to obtain a mixture with a boiling point of 140.
23.0 g of 4-isopropyl-cyclohexane-1-carbonyl chloride at ~142°C/45 mmHg (yield
90.1%). From 6.0 g of 4-isopropyl-cyclohexane-1-carbonyl chloride and excess diazomethane, pale yellow oily 1-diazo-2-(4-isopropylcyclohexyl)-2-ethanone was quantitatively obtained. The mixture of cis and trans forms of 1-diazo-2-(4-isopropyl-cyclohexyl)-2-ethanone (3:1) obtained above was separated and purified by silica gel column chromatography (developing solvent: chloroform). From the previous fraction, a pale yellow oily cis-1-diazo-2-(4-isopropyl-
3.5 g of cyclohexyl)-2-ethanone was obtained, and trans-1-diazo-2-(4-isopropyl-cyclohexyl)- having a melting point of 34-34.5°C was obtained from the subsequent fractions.
1.2 g of 2-ethanone (compound A) was obtained. Reference Example 2 Compounds B to D listed in Table 1 were synthesized by the same operation as in Reference Example 1. Reference Example 3 12 g of a cis-trans mixture of 1-acetyl-4-isopropylcyclohexane was heated and stirred with equimolar sodium methoxide in 150 ml of methanol for 6 hours. After the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 ml of water, and 50 ml of ether was dissolved.
Extracted 3 times with ml. The extract was washed with water and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off under reduced pressure, and the residual liquid is distilled under reduced pressure to obtain a boiling point of 109~113℃/18~
9 g of trans-1-acetyl-4-isopropylcyclohexane of 19 mmHg was obtained. trans-1-acetyl-4-isopropyl-
8 g of cyclohexane was dissolved in 130 ml of methanol. At room temperature, 8 g of bromine was added at once and stirred for 4 hours. After the reaction, sodium hydrogen carbonate was added to neutralize, the solvent was distilled off under reduced pressure, 30 ml of water was added to the residual liquid, and the mixture was extracted twice with 100 ml of ether. The extract was washed with water and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off under reduced pressure, and the remaining liquid is distilled under reduced pressure to determine the boiling point.
8.5 g of trans-1-(bromoacetyl)-4-isopropyl-cyclohexane at 113-115/2 mmHg
I got it. 4.5 g of potassium hydroxide was dissolved in 60 ml of methanol, 6.6 g of ethyl formate was added under ice cooling, and the mixture was heated and stirred for 2 hours. Next, the mixture was cooled again, 10 g of trans-1-(bromoacetyl)-4-isopropyl-cyclohexane obtained in the above reaction was added, and the mixture was heated and stirred for 10 hours. After the reaction, the solvent was distilled off under reduced pressure, water was added to the residual liquid, and the mixture was extracted twice with 100 ml of ether. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The resulting residual liquid was crystallized from petroleum ether to obtain 6 g of trans-1-(hydroxyacetyl)-4-isopropyl-cyclohexane (compound E) having a melting point of 43 to 44°C. Reference Example 4 Compounds F, G, and H listed in Table 2 were obtained in the same manner as in Reference Example 3 above. Reference Example 5 Add 1.6 g of sodium metal to 200 ml of methanol to make an alcoholate, and add 2-(4-isobutyl-cyclohexyl)-, which is a cis and trans mixture, to this.
12 g of 2-ethanone was added, and the mixture was heated and stirred for 16 hours. After cooling the reaction, it was neutralized with a methanol-sulfuric acid mixture.
50 ml of methanol was added, 9.0 g of bromine was added at room temperature, and the mixture was stirred until decolorized. Next, neutralize with sodium bicarbonate and add potassium hydroxide to 40ml of methanol.
A solution containing 4.5 g was added dropwise while keeping the reaction temperature below 5°C. After the dropwise addition, the mixture was stirred for 1 hour. Next, PH with 3N-hydrochloric acid.
= 2 to 3 and stirred for 1 hour. Thereafter, the pH was adjusted to 7 to 8 using 1N sodium hydroxide solution, and the solvent was distilled off under reduced pressure. The residual liquid was extracted three times with 50 ml of ether, washed with water, and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure and the resulting residue was
-Recrystallize from hexane to obtain white crystals (compound F).
6.9g (53%) was obtained. Examples of the production of the compounds of the present invention are listed below as examples. Example 1 Trans-diazo-2 obtained according to Reference Example 1
0.5 g of -(4-isopropyl-cyclohexyl)-2-ethanone (compound A) was dissolved in 30 ml of ether, an excess of benzenesulfonic acid was added, and the mixture was stirred until no nitrogen was generated. After the reaction was completed, it was washed with water and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure, and the remaining liquid was subjected to column chromatography (developing solvent: chloroform) to obtain a melting point of 48.
0.65 g (yield) of trans-1-(benzenesulfonyloxy)-2-(4-isopropyl-cyclohexyl)-2-ethanone (compound 1) at ~49°C
77.8%). Example 2 Compounds 2 to 8 listed in Table 3 were obtained by the same operation as in Example 1. Example 3 trans-1-(hydroxyacetyl)-4-
1.1 g of isopropylcyclohexane and 1.1 g of benzenesulfonyl chloride were dissolved in 1.5 ml of anhydrous dichloroethane. While cooling to below 5℃, add 1 ml of triethylamine dropwise.
After stirring for an hour, the mixture was poured into ice-hydrochloric acid, extracted with 50 ml of chloroform, washed with water, and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure, and the resulting oil was crystallized from petroleum ether, filtered, and the crystals collected were recrystallized from ethanol to give trans-1-( 1.5 g of benzenesulfonyloxy)-2-(4-isopropyl-cyclohexane)-2-ethanone (compound 1) was obtained (yield: 81%). Example 4 Compounds 2 to 8 were synthesized by the same operation as compound 3. Next, pharmacological tests conducted on the trans-sulfonate derivatives of the present invention will be explained. Antilipidemia Effect Test Male Wistar rats, 7 weeks old and weighing 200 to 220 g, are used in the test in groups of 5 rats. 100 mg of the compound of the present invention is dissolved in 5 ml of olive oil and used for the test. Olive oil containing the compound of the present invention is orally administered to rats at the equivalent of 5 ml/kg using a sonde, and 2 hours later, under ether anesthesia, 6 ml of whole blood is collected from the descending vena cava using a syringe containing heparin. The obtained blood is centrifuged at 5° C. and 3000 rpm to obtain plasma. The triglyceride content of the obtained plasma is measured using a triglyceride measurement kit (Triglyceride Test Wako) manufactured by Wako Pure Chemical Industries, Ltd.
Olive oil alone is similarly administered to the control group. No treatment is given to the normal group. In both groups, the triglyceride content in plasma is measured in the same manner as in the group treated with the compound of the present invention. The hyperlipidemia inhibition rate of the compound of the present invention is calculated using the following formula. Inhibition rate (%) = A-C/A-B x 100 A: Control group triglyceride content B: Normal group triglyceride content C; Triglyceride content treated group with the compound of the present invention Acute toxicity test Wistar strain, 6 weeks old, weight 180-200 g The compound of the present invention is suspended in an aqueous solution of 30% polyethylene glycol 6000 and orally administered to a group of 5 male rats. General poisoning symptoms, body weight, and presence or absence of death were observed daily for one week from the start of the test.
Find the LD ₅₀ value. Table 4 shows the results of each of the above tests. In Table 4, the triglyceride inhibition rate is expressed as TG inhibition rate.
In Table 4, using the cis isomer obtained in each of the above-mentioned Reference Examples 1 and 2, and operating in the same manner as in Example 1 or 2,
Cis form corresponding to the obtained compound of the present invention (trans form) (reference compound, same as the present compound No. in the table)
The results of repeating the same test as above using the same test as above are also listed.

[Table] As is clear from No. 4 above, the trans-sulfonate derivatives of the present invention represented by the general formula ( It is found that it has a lipemic effect. Next, examples of formulations of the present invention will be shown. Formulation Example 1 1 capsule containing Compound 2 Contents weight: 500
mg of soft capsule Compound 2 250 mg Olive oil 250 mg The above composition is filled into one capsule according to a conventional method. Formulation Example 2 One tablet containing Compound 8 weighs 406 mg Compound 8 100 mg Soft silicic anhydride 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 Suppositories each containing Compound 4 weighing 2000 mg Compound 4 1000 mg Witepsol W-35 1000 mg The above composition amounts are molded into one suppository according to a conventional method. Formulation Example 4 One package of 1000 mg granules containing Compound 7 Compound 7 200 mg Light silicic anhydride 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. Production Example 5 Compound 1 and 1 vial containing 20 ml of elixir Compound 1 300 mg Ethanol 0.5 ml Granulated sugar 2000 mg Nikkol 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.

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ represents an alkyl group or an alkoxy group, l represents 0 or an integer of 1 to 3, and R ₂ represents an alkyl group. ] A trans-1-(benzenesulfonyloxy)-2-cyclohexyl-2-ethanone derivative represented by: 2 General formula [In the formula, R ₁ represents an alkyl group or an alkoxy group, l represents 0 or an integer of 1 to 3, and R ₂ represents an alkyl group. ] An antilipemic agent containing a trans-1-(benzenesulfonyloxy)-2-cyclohexyl-2-ethanone derivative represented by: