JPH0341458B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel benzene derivatives and salts thereof. The benzene derivative of the present invention is a new compound that has not been described in any literature, and is represented by the following general formula (1). [In the formula, R ¹ represents a cycloalkyl group having 3 to 8 carbon atoms which may have a lower alkyl group having 1 to 6 carbon atoms as a substituent. R ² represents a lower alkyl group having 1 to 6 carbon atoms. A represents a lower alkylene group having 1 to 6 carbon atoms. Many of the conventional β-blockers undergo oxidative metabolism in vivo, and many of their metabolites have strong β-blocking activity and other pharmacozoological activities. Therefore, when used clinically, it has been difficult to determine the appropriate amount because of the long duration of efficacy and the fact that metabolites have side effects. In particular, when used to treat arrhythmia, angina, hypertension, etc. that suddenly occur during surgery, it is extremely difficult to determine the appropriate amount of conventional β-blockers because they have the above-mentioned drawbacks. It was hot. The present inventors have conducted intensive research to develop a β-blocker that does not have the above drawbacks, and have found that the compound represented by the above general formula (1) is hydrolyzed faster than it undergoes oxidative metabolism in vivo. It was discovered that the β-blocking activity of the metabolites produced as a result of this metabolization is extremely weak, making it possible to control the drug concentration in the body and making it possible to become a clinically extremely useful drug. . The present invention has been completed based on this knowledge. The compound of the present invention represented by the above general formula (1) is:
It has an excellent β-adrenergic nerve blocking effect and is useful as a therapeutic agent for, for example, angina pectoris, arrhythmia, and hypertension. In particular, the compounds of the present invention undergo hydrolytic metabolism in vivo faster than they undergo oxidative metabolism, and are metabolized to carboxylic acid derivatives having no β-blocking activity. Therefore, the β-blocking activity of the compounds of the present invention is different from that of the conventional β-blocking activity.
Compared to blockers, it has an extremely short duration and has extremely weak side effects.
Therefore, the compound of the present invention is extremely useful as a therapeutic agent for arrhythmia, angina pectoris, hypertension, etc. that occur suddenly during surgery or the like. More specifically, the groups represented by R ¹ , R ² and A in this specification include the following. Lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,
Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms such as pentyl and hexyl groups. Cycloalkyl groups that may have lower alkyl groups include cyclopropyl, 2-methylcyclopropyl, 3-ethylcyclopropyl, 2-ethylcyclopropyl,
Butylcyclopropyl, 3-pentylcyclopropyl, 2-hexylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 2,3-dimethylcyclobutyl, 3-butylcyclobutyl, 4-hexylcyclobutyl, 2,3,3- Trimethylcyclobutyl, 3,3,4,4-tetramethylcyclobutyl, cyclopentyl, 2-methylcyclopentyl, 3-ethylcyclopentyl, 4-butylcyclopentyl, 5-methylcyclopentyl, 3
-pentylcyclopentyl, 4-hexylcyclopentyl, 2,3-dimethylcyclopentyl,
2,2,5,5-tetramethylcyclopentyl,
2,3,4-trimethylcyclopentyl, 2,4
-dimethyl-3-ethylcyclopentyl, 2,
2,3,4,4-pentamethylcyclopentyl,
2,2,3,3,4,4,5,5-octamethylcyclopentyl, 2,3-dimethyl-3-propylcyclopentyl, cyclohexyl, 2-methylcyclohexyl, 3-ethylcyclohexyl, 4
-propylcyclohexyl, 5-butylcyclohexyl, 2,6-dimethylcyclohexyl, 2,
3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,3,4-trimethylcyclohexyl,
2,3-dimethyl-5-ethylcyclohexyl,
2,5-dimethyl-6-propylcyclohexyl, 2,4-dimethyl-3-butylcyclohexyl, 3,3,5,5-tetramethylcyclohexyl, 2,2,4,4-tetramethylcyclohexyl, 3,3, 6,6-tetramethylcyclohexyl, 3,3,4,5,5-pentamethylcyclohexyl, 3,3,4,5,5,6-hexamethylcyclohexyl, 2,3,3,4,5,5, 6-
heptamethylcyclohexyl, 2,2,3,3,
4,5,5,6-octamethylcyclohexyl,
2,3,3,4,4,5,5,6-octamethylcyclohexyl, 2,2,3,3,4,4,5,
5,6,6-decamethylcyclohexyl, 3,
3,5-trimethyl-4-ethylcyclohexyl, 3,4,4-trimethyl-5-propylcyclohexyl, cycloheptyl, 3-methylcycloheptyl, 4-hexylcycloheptyl, 5-propylcycloheptyl, 6-butylcycloheptyl , 7-methylcycloheptyl, cyclooctyl, 2-methylcyclooctyl, 3-ethylcyclooctyl, 5-pentylcyclooctyl, 6-
Hexylcyclooctyl, 3,3,4-trimethylcyclooctyl, 3,3,5,5-tetramethylcyclooctyl, 3,3,5-trimethyl-
4,6-diethylcyclooctyl, 3,4,5,
Examples include cycloalkyl groups having 3 to 8 carbon atoms that may have linear or branched alkyl groups having 1 to 6 carbon atoms, such as 5,6,8-hexamethyl-7-ethylcyclooctyl group. Lower alkylene groups include methylene, ethylene, trimethylene, 2-methyltrimethylene,
Examples include alkylene groups having 1 to 6 carbon atoms such as 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, and hexamethylene. The compound of the present invention can be produced, for example, by the method shown in the following reaction scheme. [In the formula, R ¹ , R ² and A are the same as above. Z is

[Formula] or

[Formula] is shown. X represents a halogen atom. ] General esterification reactions can be widely applied to the esterification reaction of general formula (2), which is a known compound.
It can be produced by reacting an alcohol represented by R ¹ OH (wherein R ¹ is the same as above). The reaction between the compound of general formula (2) and R ¹ OH can be carried out under a wide range of esterification reaction conditions, but is usually carried out in the presence of a catalyst. As the catalyst used in this case, a wide variety of catalysts that are used in ordinary esterification reactions can be used. Typical examples include hydrochloric acid gas, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, inorganic acids such as perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, p-tosyl acids, organic acids such as benzenesulfonic acid and ethanesulfonic acid, trifluoromethanesulfonic anhydride,
Examples include thionyl chloride and acetone dimethyl acetal. Furthermore, acidic ion exchange resins can also be used as the catalyst. The amount of these catalysts to be used is not particularly limited, and is used within the range used in ordinary esterification reactions. The above reaction proceeds either without a solvent or in a solvent. As the solvent used at this time, for example, solvents used in ordinary esterification reactions can be effectively used, and specifically, benzene, toluene,
Aromatic hydrocarbons such as xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, diethyl ether,
Examples include ethers such as tetrahydrofuran, dioxane, and ethylene glycol monomethyl ether. In the above reaction, the ratio of the compound of general formula (2) and R ¹ OH to be used may be appropriately selected over a wide range, but in order to improve the production rate of the target product of the present invention, solvent-free is usually used. In this case, the latter is used in a large excess amount relative to the former, and when a solvent is used, the latter is usually used in an equimolar to 5 times the molar amount, particularly preferably in an equimolar to 2 times the molar amount of the former. good. In addition, when carrying out the above reaction, it is also possible to further increase the production rate by removing the produced water from the reaction system using a drying agent such as anhydrous calcium chloride, anhydrous copper sulfate, anhydrous calcium sulfate, or phosphorus pentoxide. be. The reaction temperature in this reaction may be selected as appropriate and is not particularly limited, but is usually about -20 to 200°C.
It is best to carry out the temperature within a range of about 0 to 150 degrees Celsius.
It is preferable to do this in moderation. Although the reaction time depends on the type of raw materials and reaction conditions, the reaction is generally completed in about 10 minutes to 20 hours. The reaction between the compound of general formula (3) and the epihalogenohydrin of general formula (4) can be carried out using, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
Inorganic basic compounds such as sodium methoxide, sodium ethoxide, sodium hydride, metallic sodium, metallic potassium, sodium amide, piperidine, pyridine, triethylamine,
1,5-diazabicyclo[4,3,0]nonene-
5(DBN), 1,5-diazabicyclo[5,4,
0] In the presence of ordinary basic compounds such as organic bases such as undecene (DBU), 1,4-diazabicyclo[2,2,2]octane (DABCO), or in the absence of a solvent, such as methanol, ethanol, isopropanol, etc. lower alcohols, ketones such as acetone, dioxane, tetrahydrofuran (THF),
The reaction is carried out in an inert solvent such as ethers such as ethylene glycol monomethyl ether, and aromatic hydrocarbons such as benzene, toluene, and xylene.
In this reaction, the amount of epihalogenhydrin represented by general formula (4) to be used is usually about equimolar to excess amount relative to the compound represented by general formula (3),
Preferably, the amount is 5 to 15 times the molar amount. The reaction proceeds at about 0°C to 150°C, but preferably
It is carried out at 50-100°C. In the above reaction, the epihalogenohydrin represented by the general formula (4) reacts with the hydroxyl group of the compound represented by the general formula (2), usually converting the compound into (2,3
-epoxy)propoxy group or 3-halogeno-2
-Gives a hydroxypropoxy group. Generally, the reaction product is obtained as a mixture of these. The reaction between the compound represented by general formula (5) and the amine represented by general formula (6) is carried out without a solvent or in a commonly used inert solvent at room temperature to about 200°C, preferably 60 to 120°C. It is usually completed within 30 minutes to 24 hours. In the above reaction, the inert solvent is not particularly limited and can be used as long as it does not adversely affect the reaction, such as the above-mentioned ethers,
Examples include aromatic hydrocarbons, lower alcohols, esters such as ethyl acetate, DMF, and DMSO. Further, in the above reaction, a common basic compound can be added as necessary. Examples of the basic compound include sodium carbonate, sodium hydroxide, sodium hydrogen carbonate,
Inorganic basic compounds such as sodium amide and sodium hydride, triethylamine, tripropylamine, pyridine, quinoline, DBN, DBU,
Examples include organic bases such as DABCO. The proportion of the amines represented by the general formula (6) to be used is generally from an equimolar amount to an excess amount, preferably from an equimolar amount to about 7 times the molar amount of the compound represented by the general formula (2). Further, the compound of the present invention has R ¹ in general formula (1)
It can also be obtained by esterifying a compound in which is a hydrogen atom. The esterification reaction is
It can be carried out under the same conditions as for the esterification of the compound of general formula (2). The target products obtained in each step can be easily isolated and purified by conventional separation means. As the separation means, for example, solvent extraction method,
Dilution method, recrystallization method, column chromatography,
Examples include preparative thin layer chromatography. Note that the present invention naturally also includes optical isomers. The benzene derivative represented by the general formula (1) of the present invention can be easily converted into an acid addition salt by the action of a pharmaceutically acceptable acid, and the present invention also includes this acid addition salt. Examples of acids in the above include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid,
Organic acids such as malonic acid, methanesulfonic acid, benzoic acid, etc. can be used. The compound of general formula (1) and its salts can be used to treat angina pectoris,
When used as a therapeutic agent for arrhythmia, etc., it is usually formulated into a pharmaceutical composition together with a pharmaceutical carrier. As carriers, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc., which are commonly used to prepare drugs according to the usage form, can be used. I can give an example. Various dosage unit forms can be selected depending on the therapeutic purpose; typical examples include tablets,
Examples include pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), and injections are preferred. When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar Disintegrants such as powder, laminaria powder, sodium bicarbonate, calcium carbonate, Twin, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, quaternary ammonium Bases, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin,
Examples include adsorbents such as bentonite and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, macrogol, and solid polyethylene glycol. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, Tragacanth powder, gelatin,
Examples include binders such as ethanol, and disintegrants such as laminaria and agar. Furthermore, the tablets can be made into conventionally coated tablets, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets, if necessary. When forming into a suppository, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood, and when formed into the form of solutions, emulsions and suspensions, diluents known in the art are used. All those commonly used in the art can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, and the like. In this case, the therapeutic agent may contain a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution, and may also contain conventional solubilizing agents, buffers, soothing agents, preservatives, etc. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, and other pharmaceutical agents may be included in the therapeutic agent, if necessary. The amount of the compound of general formula (1) or its salt to be included in a therapeutic drug for angina pectoris, arrhythmia, etc. is not particularly limited and can be appropriately selected within a wide range, but usually 1% of the total composition.
The content is preferably 7.0% by weight. Furthermore, there are no particular restrictions on the use of the therapeutic agents for angina pectoris, arrhythmia, etc., and they can be administered in a manner appropriate for various forms. For example, tablets, pills, solutions, suspensions,
Emulsions, granules, and capsules are administered orally; injections are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, intramuscularly alone. , administered intradermally, subcutaneously, or intraperitoneally. The dosage of the therapeutic agent containing the compound of the present invention as an active ingredient can be appropriately selected depending on the purpose of use, symptoms, etc.
For example, when treating arrhythmia that suddenly occurs during surgery, angina pectoris, high blood pressure, etc., the amount of active ingredient per dose is
A drug containing 0.5 to 6 mg/Kg may be administered. Furthermore, if necessary, continuous administration can be carried out at appropriate intervals, for example, 30 to 60 minutes after administration. Reference examples and examples will be described below. Reference example 1 6 g of cyclohexyl alcohol, 7.6 g of 4-hydroxyphenylacetic acid and p-toluenesulfonic acid
A solution of 1 g of benzene in 300 ml is refluxed for 8 hours with continuous separation of water. Cool the reaction mixture and add 10%
Wash with an aqueous sodium carbonate solution and water in that order, and dry with magnesium sulfate. Distill the solvent under reduced pressure
12.24 g of cyclohexyl 4-hydroxyphenylacetate are obtained. Reference example 2 2,6-dimethylcyclohexyl alcohol
11.4g, 4-hydroxyphenylacetic acid 9.12g and p
- A solution of 1 g of toluenesulfonic acid in 300 ml of benzene is heated under reflux for 20 hours while continuously separating water. The reaction mixture is filtered, washed successively with 10% aqueous sodium carbonate solution and water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 8.02g of 2,
6-dimethylcyclohexyl 4-hydroxyphenyl acetate is obtained. Reference example 3 3,3,5,5-tetramethylcyclohexyl alcohol 6.24g, 4-hydroxyphenylacetic acid
6.08 g of benzene and 1 g of p-toluenesulfonic acid
The 300 ml solution is heated to reflux for 8 hours with continuous water separation. The reaction mixture is cooled, washed sequentially with 10% aqueous sodium carbonate solution, water, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure,
12.3 g of 3,3,5,5-tetramethylcyclohexyl 4-hydroxyphenylacetate are obtained. NMR (CDCl ₃ , TMS, ppm): 7.00 (d, J=8Hz, 2H) 6.60 (d, J=8Hz, 2H) 5.00 (broad, 1H) 3.40 (s, 2H) 1.8−0.80 (m, 18H) Reference example 4 Ethyl-4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate
Add 29.5 g to 200 ml of 1N aqueous sodium hydroxide solution and 200 ml of ethanol, boil for 1 hour, and then dry under reduced pressure. Dissolve the residue in 200 ml of water to remove insoluble matter, then carefully neutralize with dilute hydrochloric acid while cooling, collect the precipitated crystals, wash with water, and dry. 4-(2-hydroxy-3-
Isopropylamino)propoxyphenylacetic acid
Get 20g. mp212-213℃ Example 1 9.18 g of cyclohexyl 4-hydroxyphenylacetate and 1 ml of DBU of epichlorohydrin
Heat the 50 ml solution to reflux for 2 hours. The reaction mixture is evaporated under reduced pressure. A solution of 20 ml of isopropylamine in 100 ml of acetonitrile is added to the resulting residue, and the mixture is heated under reflux for 4 hours. The reaction mixture is distilled off under reduced pressure, the resulting residue is dissolved in acetone, and an acetone solution of oxalic acid is added dropwise to the resulting solution. The precipitated crystals were collected and recrystallized with acetone to obtain 6.05 g of cyclohexyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate monooxalate 3/4 hydrate. mp131-132°C Example 2 A solution of 8.00 g of 2,6-dimethylcyclohexyl 4-hydroxyphenylacetate and 1 ml of DBU in 50 ml of epichlorohydrin is heated under reflux for 2 hours. The reaction mixture is evaporated under reduced pressure. To the resulting residue add 20 ml of isopropylamine and 100 ml of acetonitrile.
ml solution and heated under reflux for 4 hours. The reaction mixture is dried under reduced pressure, the residue is dissolved in acetone, and an acetone solution of oxalic acid is added to the solution. The precipitated crystals were collected, washed with acetone, and recrystallized from acetone to give 6.4 g of 2,6-dimethylcyclohexyl 4
-(2-hydroxy-3-isopropylamino)
Propoxyphenylacetate monooxalate monohydrate is obtained. mp89-91℃ Example 3 10.86g of 3,3,5,5-tetramethylcyclohexyl 4-hydroxyphenylacetate was added to 8
% potassium hydroxide dissolved in 20ml of methanol solution,
Dry under reduced pressure. Add 50 ml of epichlorohydrin to the residue and heat under reflux for 2 hours. The reaction mixture was distilled off under reduced pressure, and the resulting residue was extracted with 200 ml of benzene. After washing with water and drying, evaporate under reduced pressure. A solution of 20 ml of isopropylamine in 100 ml of acetonitrile is added to the residue and heated under reflux for 8 hours. The reaction mixture was distilled off under reduced pressure, and acetone was added to the residue. Add an acetone solution of oxalic acid to the solution and collect the precipitated crystals. Recrystallize from acetone to obtain 8.06g of 3,3,
5,5-tetramethylcyclohexyl 4-(2
-Hydroxy-3-isopropylamino)propoxyphenyl acetate monooxalate 3/4 hydrate is obtained. mp96-97℃ Example 4 13.4g of 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetic acid was dissolved in 50ml of cyclohexyl alcohol, saturated with hydrochloric acid gas under cooling, and then heated at 70℃ for 4 hours. Stir. Excess cyclohexyl alcohol is distilled off under reduced pressure, and the residue is dissolved in 200 ml of water and brought to pH 9 with 10% aqueous sodium carbonate solution. The precipitated oil is extracted with 200 ml of chloroform, washed with water, dried, and the solvent is distilled off under reduced pressure. Dissolve the residue in 100ml of acetone,
Add 10% oxalic acid acetone solution and adjust the pH to 5.
Take the precipitated crystals, wash with acetone, and dry.
Recrystallized from acetone to give cyclohexyl 4-
11.8 g of (2-hydroxy-3-isopropylamino)propoxyphenyl acetate monooxalate 3/4 hydrate is obtained. mp131−132℃ Reference example 5 (1) Reaction rate coefficient analysis method High performance liquid chromatography (HPLC) method,
The reaction rate coefficient was determined. Chromatographic analysis was performed using Model 600-A Solvent Delivery.
Measurements were made at 254 nm and 280 nm using a model U-6K injector and a model 440 dual channel absorption detector (both manufactured by Waters Associates). Also, as a separation column, 30cm x 3.9mm
(inner diameter) reverse phase micro bonder pack (μ
A Bondapak) C18 column (manufactured by Waters Associates) was used at room temperature. When analyzing plasma samples, use a guard column (2.3 cm x 3.9
mm (inner diameter)) (manufactured by Waters Associates)
protected by. Test compound 3 and its decomposition products 4-
The mobile phases used to separate (2-hydroxy-3-isopropylamino)propoxyphenylacetic acid were water, 1-hexane sulfuric acid acetic acid solution (B-6
Reagent, Waters Associates), 0.1M triethanolamine and methanol (100:
1:100:799). Flow rate 2.0ml/
min, retention time of test compound 3 is 3.95 minutes, 4-
(2-Hydroxy-3-isopropylamino)propoxyphenylacetic acid is 1.34 minutes. Test compounds 1 and 2 and decomposition product 4-(2-hydroxy-3-
The mobile phases used for the separation of isopropylamino)propoxyphenylacetic acid were water, 1-hexane sulfonic acid acetic acid solution (B-6 reagent,
Waters), 0.1 molar triethanolamine and methanol (390:1:10:599). (2) How to determine the hydrolysis rate coefficient in an aqueous solution A 0.01M phosphate buffer and a 0.01N sodium hydroxide solution were prepared with distilled deionized water. Ionic strength was treated with 0.1 molar sodium chloride. Phosphate buffer was determined at 37.0°C with a standardized PH meter. To determine the hydrolysis rate constant, a methanolic solution of the test compound is added to the previously equilibrated hydrolysis medium at the required temperature until the initial concentration is approximately 5 x 10 ^-4 mol/l. Mix thoroughly. All reactions proceed as pseudo-first-order reactions. 25 μl of the test compound was injected onto the column at various time intervals and pseudo-first-order kinetic coefficients were determined from the disappearance of the compound by linear regression of the natural logarithm of the peak height against time. Half-life and standard error were calculated for each system. Table 1 shows the results using a 0.01N aqueous sodium hydroxide solution, pH 12.0, and 27.3±0.2°C.

【table】

[Table] Hydrolysis in 0.01 molar phosphate buffer (PH7.4, 37°C) is very slow. (3) How to determine the enzymatic hydrolysis rate in human plasma Plasma was obtained from Civitan Regional Blood [Gainesville,
Florida] and anticoagulant citrate dextrose solution.
80 diluted with phosphate dextrose solution)
% plasma. Store the plasma in the refrigerator.
The plasma was used within one week from the day it was collected. During the experiment, the plasma hydrolysis activity was determined by the effect of the hydrolysis rate of Test Compound 3 and was kept constant. Add 50 μl of a methanol solution of the test compound to 10 ml of plasma and place it in a water bath at 37.0 ± 0.1 °C to pre-equilibrate. The initial concentration is 1×
Mix thoroughly until the concentration is 10 ^-3 mol/l. Remove a 1 ml sample of plasma from the test medium,
Immediately add 4.0 ml of ice-cold 95% (V/V) ethanol, mix, centrifuge, and analyze the supernatant by HPLC. Similar to the hydrolysis rate constant in aqueous solution,
The first-order reaction rate coefficient was determined. The results are shown in Table 2.

【table】

[Table] The results of pharmacological tests on the compounds of the present invention are listed below. <Test compound> 1 Cyclohexyl 4-(2-hydroxy-3
-isopropylamino)propoxyphenylacetate 2 2,6-dimethylcyclohexyl 4-(2
-Hydroxy-3-isopropylamino)propoxyphenylacetate 3 3,3,5,5-tetramethylcyclohexyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate Pharmacological test 1 Splashes weighing 268-290g - Thirty-eight Sprague-Dawley rats were anesthetized with sodium pentobarbital (45 mg/Kg, ip).
A PE-50 tube is cannulated into the Kay artery. Insert this canule under the skin around the neck and bring it out between the bones of the back. This canueure was soaked with heparin solution (300μ/ml),
Seal with 22 gauge bar. Each treated rat was placed in a stainless steel cage and allowed to recover from surgery for 2 days. On the day of the experiment, wait 1 hour for the animal to calm down and then measure its basal heart rate before the experiment. Test compound 3 is administered intraperitoneally at 6 mg/Kg.
Test compounds are dissolved in ethanol:water (3:1). Also, only ethanol:water (3:1) was administered to control rats. Isoproterenol at 25 μg/Kg, 15 minutes after administration of test compound (13 animals);
Administer in the order of 60 minutes (12 animals) and 90 minutes (13 animals). After isoproterenol administration 3, 5, 10, 15, 20,
Measure the heart rate three times at 30, 45, and 60 minutes. During the experiment, both the control and experimental rats were allowed to run freely in the cage without being restrained. Heart rate was statistically calculated from the data and determined at each time interval. The results are shown in Figure 1. All data in Figure 1 are mean ± standard error. Also, * in the figure is P
<0.005, ** means P<0.025. Pharmacological Test 2 Healthy mongrel dogs are anesthetized by administering morph insulfate (2.0 mg/Kg subcutaneously) followed by sodium pentobarbital (15 mg/Kg intraperitoneally) 20 minutes later. Give additional pentobarbital if necessary. Catheterize a polyethylene tube through the femoral vein to the level of the heart to administer the drug solution. A polyethylene tube containing heparin-containing saline is inserted through the femoral artery to measure arterial pressure, and advanced into the thoracic aorta. Insert a Miller transducer tip catheter into the left carotid artery for left ventricular pressure (LVP) measurements. From the signal of rising LVP,
Measures dp/dt, an estimate of myocardial contraction.
Heart rate was determined using a Grass heart rate monitor using the R wave of the electrocardiogram as the triggering factor. All changes were recorded on Glass' polygraph. Dose-response curves represent the decrease in blood pressure and increase in heart rate for intravenous doses of the β-adrenergic antagonist isoproterenol. Leave for 3-5 minutes after administration until values return to baseline. Subsequently, the test compound is administered intravenously over 1 minute. 15, 30, 45, after administration of test compound
The amount of decrease in blood pressure and the amount of increase in heart rate at 60, 75, and 90 minutes are determined, and a dose-response curve is drawn for isoproterenol. As a criterion, 50 1
Using the heart rate increase per minute (50 bpm), the amount of isoproterenol required to increase the heart rate by 50 bpm when the test compound was administered versus the amount of isoproterenol required to increase the heart rate by 50 bpm in the control at each time. The blocking effect was determined. The amount of the test compound used in the experiment was determined from the amount that exhibited a blocking effect of about 2 to 4 times the increase in heart rate compared to isoproterenol from previous experiments. From the above data, 1 mg/Kg of each test compound
The time required to reach the maximum blocking effect (A) was determined from the pre-administration and post-administration dose-response curves. Furthermore, after administering 1 mg/Kg of each test compound, the time (B) required for the effect of isoproterenol to return to the control level was determined. These results are shown in Table 3 below.

[Table] Formulation example 1 Cyclohexyl 4-(2-hydroxy-3-
Isopropylamino) propoxyphenylacetate monooxalate 3/4 hydrate 500mg Polyethylene glycol (molecular weight: 4000) 0.3g Sodium chloride 0.9g Polyoxyethylene sorbitan monooleate
0.4g Sodium metabisulfite 0.1g Methyl-paraben 0.18g Propyl-paraben 0.02g Distilled water for injection 100ml The above parabens, sodium metabisulfite and sodium chloride are dissolved in distilled water at 80°C with stirring. The obtained solution was cooled to 40°C, the compound of the present invention, polyethylene glycol, and polyoxyethylene sorbitan monooleate were sequentially dissolved therein, and then distilled water for injection was added to the solution to adjust the final volume. , sterilize using appropriate filter paper, and dispense 1 ml into ampoules to prepare an injection.

[Brief explanation of the drawing]

FIG. 1 is a graph showing the relationship between heart rate per minute and time.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a cycloalkyl group having 3 to 8 carbon atoms which may have a lower alkyl group having 1 to 6 carbon atoms as a substituent. R ² represents a lower alkyl group having 1 to 6 carbon atoms. A represents a lower alkylene group having 1 to 6 carbon atoms. ] A benzene derivative and its salt represented by these.