JPS6112902B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel 3,4-dihydrocarbostyryl derivatives. The compound of the present invention is a new compound and has the general formula [In the formula, R ₁ represents a hydrogen atom or a lower alkyl group, R ₂ represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group, or an aralkyl group, and -A- represents a vinylene group or a -(CH ₂ ) _o - (n is an integer from 0 to 5). ] 3・4-
It is a dihydrocarbostyryl derivative. The compound has a platelet aggregation inhibitory effect and is useful as a thromboprophylactic agent. In the general formula (), examples of the lower alkyl group include straight chain or branched alkyl groups having 1 to 4 carbon atoms, specifically methyl group, ethyl group, n-propyl group, and isopropyl group. , n-butyl group, tert-butyl group, etc. Carbon number 1
-7 alkyl groups include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, n-amyl group, isoamyl group, sec-amyl group, n- Examples include hexyl group and n-heptyl group. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. Examples of the aralkyl group include aralkyl groups in which the alkyl moiety has 1 to 3 carbon atoms, specifically benzyl group, phenethyl group, 3-phenylpropyl group, 1-methyl-2
Examples include -phenylethyl group. Representative compounds of the present invention are listed below. 6-(4-ethoxycarbonyl-1-hydroxy)butyl-3,4-dihydrocarbostyryl,
6-(4-methoxycarbonyl-1-hydroxy)butyl-3,4-dihydrocarbostyryl,
6-(4-propoxycarbonyl-1-hydroxy)butyl-3,4-dihydrocarbostyryl,
6-(4-isopropoxycarbonyl-1-hydroxy)butyl-3,4-dihydrocarbostyryl, 6-(4-n-amyloxycarbonyl-1
-hydroxy)butyl-3,4-dihydrocarbostyryl, 6-(4-benzyloxycarbonyl-1-hydroxy)butyl-3,4-dihydrocarbostyryl, 6-(4-β-phenethyloxycarbonyl-1 -Hydroxy)butyl-3,4-
Dihydrocarbostyryl, 1-methyl-6-(4
-benzyloxycarbonyl-1-hydroxy)
Butyl-3,4-dihydrocarbostyryl, 1-
Ethyl-6-(4-ethoxycarbonyl-1-hydroxy)butyl-3,4-dihydrocarbostyryl, 1-isopropyl-(4-isobutoxycarbonyl-1-hydroxy)butyl-3,4-dihydrocarbostyryl, 6 -(4-cyclohexyloxycarbonyl-1-hydroxy)butyl-
3,4-dihydrocarbostyl, 6-(4-cyclopentyloxycarbonyl-1-hydroxy)
Butyl-3,4-dihydrocarbostyryl, 6-
(3-methoxycarbonyl-1-hydroxy)propyl-3,4-dihydrocarbostyryl, 6-
(3-ethoxycarbonyl-1-hydroxy)propyl-3,4-dihydrocarbostyryl, 6-
(3-propoxycarbonyl-1-hydroxy)
Propyl-3,4-dihydrocarbostyryl, 6
-(1-carboxy-1-hydroxy)methyl-
3,4-dihydrocarbostyryl, 1-ethyl-
6-(1-carboxy-1-hydroxy)methyl-3,4-dihydrocarbostyryl, 6-(2-
Carboxy-1-hydroxy)ethyl-3,4-
Dihydrocarbostyryl, 6-(3-carboxy-1-hydroxy)propyl-3,4-dihydrocarbostyryl, 1-ethyl-6-(3-carboxy-1-hydroxy)propyl-3,4-dihydrocarbostyryl, 6-(4-carboxy-1
-hydroxy)butyl-3,4-dihydrocarbostyryl, 1-butyl-6-(4-carboxy-
1-hydroxy)butyl-3,4-dihydrocarbostyryl, 1-isopropyl-6-(5-carboxy-1-hydroxy)pentyl-3,4-dihydrocarbostyryl, 6-(5-carboxy-
1-Hydroxy)pentyl-3,4-dihydrocarbostyryl, 6-(6-carboxy-1-hydroxy)hexyl-3,4-dihydrocarbostyryl, 1-isopropyl-6-(6-carboxy-1-hydroxy) Hexyl-3,4-dihydrocarbostyryl, 6-(3-carboxy-1-hydroxy-2-ene)propyl-3,4-dihydrocarbostyryl, 1-ethyl-6-(3-carboxy-1-hydroxy- 2-ene)propyl-
3,4-dihydrocarbostyryl, 6-(1-ethoxycarbonyl-1-hydroxy)methyl-
3,4-dihydrocarbostyryl, 1-propyl-6-(1-hydroxy-2-propoxycarbonyl)ethyl-3,4-dihydrocarbostyryl, 1-isopropyl-6-(1-cyclohexyloxycarbonyl-1-hydroxy ) methyl-
3,4-dihydrocarbostyryl, 6-(1-hydroxy-2-cyclopentyloxycarbonyl)ethyl-3,4-dihydrocarbostyryl,
6-(1-benzyloxycarbonyl-1-hydroxy)methyl-3,4-dihydrocarbostyryl, 6-(5-ethoxycarbonyl-1-hydroxy)pentyl-3,4-dihydrocarbostyryl, 1-tert-butyl -6-(5-isopropoxycarbonyl-1-hydroxy)pentyl-3.
4-dihydrocarbostyryl, 6-(6-butoxycarbonyl-1-hydroxy)hexyl-3.
4-dihydrocarbostyryl, 1-ethyl-6-
(6-cyclohexyloxycarbonyl-1-hydroxy)hexyl-3,4-dihydrocarbostyryl, 6-(3-ethoxycarbonyl-1-hydroxy-2-ene)propyl-3,4-dihydrocarbostyryl, 1-ethyl -6-(6-propoxycarbonyl-1-hydroxy-2-ene)
Propyl-3,4-dihydrocarbostyryl, 6
-(3-n-butoxycarbonyl-1-hydroxy)propyl-3,4-dihydrocarbostyryl, 6-(3-isobutoxycarbonyl-1-hydroxy)propyl-3,4-dihydrocarbostyryl, 6-(3 -amyloxycarbonyl-1
-hydroxy)propyl-3,4-dihydrocarbostyryl, 6-(3-isoamyloxycarbonyl-1-hydroxy)propyl-3,4-dihydrocarbostyryl, 6-(3-benzyloxycarbonyl-1-hydroxy)propyl -3・4
-dihydrocarbostyryl, 6-(3-β-phenethyloxycarbonyl-1-hydroxy)propyl-3,4-dihydrocarbostyryl, 6-
(3-Cyclopentyloxycarbonyl-1-hydroxy)propyl-3,4-dihydrocarbostyryl, 6-(3-cyclohexyloxycarbonyl-1-hydroxy)propyl-3,4-dihydrocarbostyryl, 1-ethyl-6- (3-ethoxycarbonyl-1-hydroxy)propyl-
3,4-dihydrocarbostyryl, 1-propyl-6-(3-isopropoxycarbonyl-1-hydroxy)propyl-3,4-dihydrocarbostyryl The compound of the present invention can be synthesized by various methods, but the preferred method is One example is as shown in the formula below. (In the above reaction formula, R ₁ and A have the same meanings as above, X represents a halogen atom, and R ₃ represents an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group, or an aralkyl group, respectively) Known general The reaction between the compound represented by the formula () and the known compound represented by the general formula () is carried out in the presence of a Lewis acid. A wide variety of known Lewis acids can be used, such as anhydrous aluminum chloride, anhydrous ferric chloride, boron trifluoride, anhydrous zinc chloride,
Examples include titanium tetrachloride and anhydrous aluminum bromide. The amount of Lewis acid to be used can be determined appropriately, but usually starting materials 3 and 4 of formula () are used.
- About 2 to 6 times the mole, preferably about 3 to 4 times the mole of the dihydrocarbostyryl derivative is used. The ratio of the compound of general formula () and the compound of general formula () to be used may be selected as appropriate, but the compound of general formula () is usually used in an equimolar to large excess amount per mole of the compound of general formula (). , preferably 1.5 to 4 times the molar amount. The above reaction is carried out without a solvent or in a solvent used in general Friedel-Crafts reactions, such as carbon disulfide, nitrobenzene, or halogenated hydrocarbons. The reaction temperature is selected appropriately, but is usually room temperature ~
It is desirable to carry out the reaction at 250°C, preferably at room temperature to 80°C. The reaction time is appropriately selected depending on the raw materials, catalyst, reaction time, etc., but is usually about 0.5 to 6.0 hours. The reaction between the compound of general formula () and R ₃ OH is carried out under normal esterification reaction conditions. 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, and p-tosylic acid. ,
Examples include organic acids such as benzenesulfonic acid and ethanesulfonic acid, acid anhydrides such as trifluoromethanesulfonic anhydride, thionyl chloride, and acetone dimethyl acetal. Furthermore, acidic ion exchange resins can also be used as catalysts in the present invention. The amount of the catalyst to be used is not particularly limited and may be used in a normal amount. This reaction proceeds either without a solvent or in a solvent. As the solvent used at this time, solvents used in ordinary esterification reactions can be effectively used, and specifically, aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, dichloroethane, chloroform, and tetrachloride. Examples include halogenated hydrocarbons such as carbon, ethers such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol monomethyl ether.
In this reaction, the ratio of the ketocarboxylic acid represented by the general formula () to the alcohol may be appropriately selected over a wide range, but in order to improve the production rate of the target compound (), it is usually used without a solvent. In this case, it is preferable to use a large excess of the latter relative to the former, and when a solvent is used, the latter is preferably used in an amount of equimolar to 5 times the mole of the former (particularly preferably equimolar to 2 times). In this 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. . The reaction temperature in this reaction may be selected appropriately and is not particularly limited, but is usually -20 to 200°C.
It is preferable to carry out the reaction at a temperature within a certain range (preferably from 0 to 150°C). Although the reaction time depends on the type of raw materials and reaction conditions, the reaction is generally completed in 10 minutes to 20 hours. For the reduction reaction of the compound of general formula () or the compound of general formula () produced as described above, a wide variety of conventionally known reduction methods can be used. Preferred examples include water, methanol, ethanol, isopropanol, ether, dioxane, and other solvents commonly used for catalytic reduction reactions. At this time, catalysts commonly used for catalytic reduction, such as palladium black, palladium carbon, platinum black, Raney nickel, etc., are used for catalytic reduction in an atmosphere of hydrogen at normal pressure to about 10 atm, or sodium borohydride, etc. Reduce using a hydrogenated reducing agent.
When this reduction reaction is carried out using a hydrogenation catalyst, the reduction is carried out in the hydrogen atmosphere at a reaction temperature of 0 to 100°C, more preferably at room temperature to 50°C. The reduction takes about 1 to 10 hours, and the mixture is stirred well to allow sufficient hydrogen to react. Further, when using the above-mentioned hydrogenation reducing agent, the reaction temperature is preferably -10 to 50°C, and more preferably, the reaction is carried out at 0°C to room temperature for 1 to 5 hours. After completion of the reaction, the compound of the present invention obtained by the above reaction is isolated from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent from the reaction mixture. The obtained compound can be further purified, if necessary, by conventional methods such as fractional recrystallization, column chromatography, and thin layer chromatography. In this way, the 3,4-dihydrocarbostyryl derivative of the present invention can be obtained. The present invention also includes optically active forms of 3,4-dihydrocarbostyryl derivatives represented by the general formula (). Further, a carbostyril derivative (true carbostyryl derivative) in which the 3 and 4 positions of the carbostyryl group of the 3,4-dihydrocarbostyryl derivative represented by the general formula () is dehydrogenated, A in the general formula ()
3,4- in which 1 to 2 lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, etc. are substituted at any position of the alkylene group represented by
Dihydrocarbostyryl derivatives and carbostyril derivatives in which the 3rd and 4th positions of the carbostyryl group of the derivatives are dehydrogenated have platelet aggregation inhibiting activity and are compounds that can be used as thrombophilic agents. Typical compounds are listed below. 6-(3-carboxy-2,3-dimethyl-1
-hydroxy)propyl-3,4-dihydrocarbostyryl, 1-ethyl-6-(3-carboxy-2,3-dimethyl-1-hydroxy)propyl-carbostyryl, 6-(3-ethoxycarbonyl-2,3 -dimethyl-1-hydroxy)propyl-3,4-dihydrocarbostyryl, 6-(4
-carboxy-3-methyl-1-hydroxy)butyl-3,4-dihydrocarbostyryl, 6-
(4-Carboxy-3-ethyl-1-hydroxy)butyl-carbostyryl, 1-isopropyl-6-(4-propoxycarbonyl-3-methyl-1-hydroxy)butyl-3,4-dihydrocarbostyryl, 1- Benzyl-6-(4-isopropoxycarbonyl-3-propyl-1-hydroxy)butyl-carbostyryl, 6-(3-carboxy-2,3-dimethyl-2-en-1-hydroxy)propyl-3,4 -dihydrocarbostyryl, 6-(3-cyclohexyloxycarbonyl-2,3-dimethyl-2-ene-1-hydroxy)propyl-carbostyryl, 6-(3-carboxy-2-ene-1-hydroxy)propyl-
Carbostyryl, 6-(3-benzyloxycarbonyl-2-ene-1-hydroxy)propyl-
Carbostyryl, 6-(3-ethoxycarbonyl-2-ene-1-hydroxy)propyl-carbostyryl, 6-(1-carboxy-1-hydroxy)methyl-carbostyryl, 1-propyl-6
-(1-carboxy-1-hydroxy)methyl-
Carbostyryl, 1-ethyl-6-(2-carboxy-1-hydroxy)ethyl-carbostyryl, 6-(3-carboxy-1-hydroxy)propyl-carbostyryl, 1-isopropyl-6
-(4-carboxy-1-hydroxy)butyl-
Carbostyryl, 6-(5-carboxy-1-hydroxy)pentyl-carbostyryl, 6-(6
-carboxy-1-hydroxy)hexyl-carbostyryl, 6-(1-propoxycarbonyl-
1-Hydroxy)methyl-carbostyryl, 6-
(2-ethoxycarbonyl-1-hydroxy)ethyl-carbostyryl, 1-ethyl-(3-cyclohexyloxycarbonyl-1-hydroxy)
Propyl-carbostyryl, 6-(4-ethoxycarbonyl-1-hydroxy)butyl-carbostyryl, 1-isopropyl-6-(5-benzyloxycarbonyl-1-hydroxy)pentyl-
Carbostyryl, 6-(6-propoxycarbonyl-1-hydroxy)hexyl-carbostyryl Among these compounds, 3,4-dihydrocarbostyryl derivatives can be prepared by the reaction described above using the corresponding compound of formula (). Manufactured.
Carbostyryl derivatives in which the 3 and 4 positions of the carbostyryl group are dehydrogenated can be easily produced by dehydrogenating the corresponding 3,4-dihydrocarbostyryl derivative using a common dehydrogenating agent. be done. Specifically, the dehydrogenating agent used here is, for example, 2,3-dichloro-5,6
- Dicyanobenzoquinone (DDQ), 2, 3, 5,
Examples include benzoquinones such as 6-tetrachlorobenzoquinone (chloranil), hydrogenation catalysts such as selenium dioxide, palladium on carbon, palladium black, platinum oxide, and Raney nickel, and brominating agents such as N-bromosuccinylimide (NBS) and bromine. . The amount of the above dehydrogenating agent to be used is not particularly limited as long as it is used in a normal amount, but in particular when using the above benzoquinones or brominating agent, it is generally from equimolar to 5 times the amount of the 3,4-dihydrocarbostyryl derivative. It is preferable to use molar amounts, particularly preferably equimolar to 2 times the molar amount. The reaction advantageously proceeds in a solvent. As the solvent used here, solvents normally used in dehydrogenation reactions can be effectively used. Typical solvents include ethers such as dioxane, tetrahydrofuran, methoxyethanol, and dimethoxyethane, benzene, toluene, xylene,
Aromatic hydrocarbons such as cumene, dichloromethane,
Halogenated hydrocarbons such as dichloroethane, chloroform, carbon tetrachloride, alcohols such as butanol, amyl alcohol, hexanol, N.
Examples include aprotic polar solvents such as N'-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoramide. The reaction temperature in this reaction may be selected appropriately, but the reaction generally proceeds in a wide range from room temperature to about 300°C, especially at 50°C.
The reaction proceeds advantageously in the range of ~200°C. As described above, a carbostyril derivative dehydrogenated at the 3rd and 4th positions is obtained. Examples of pharmacological tests conducted on the compounds of the present invention are listed below. <Pharmacological test> The platelet aggregation inhibiting effect was investigated according to the method described in Nature, pp. 927-929 (1962). That is, the platelet aggregation inhibiting effect was measured using an AG-type aggregometer (Bryston Manufacturing Company).
Manufacturing Co.). The blood sample collected from the rabbit is a mixture of sodium citrate and whole blood, with a mixing ratio of 1:9 (volume ratio).
It is. The sample was centrifuged at 1000 rpm for 10 minutes to extract platelet rich plasma.
plasma] (hereinafter referred to as "PRP-1"). The obtained PRP-1 was separated and the remaining blood sample was
Further centrifugation is performed at 3000 rpm for 15 minutes to obtain platelet poor plasma (hereinafter referred to as "PPP"). The number of platelets contained in the PRP-1 was determined by the Bretcher-Cronkhite method.
Adenosine diphosphate (ADP) was measured by diluting PRP-1 with PPP.
A sample containing 300,000/ ^mm3 platelets (hereinafter referred to as "PRP-2") was prepared for the induced aggregation test, and for the collagen induced aggregation test.
A sample containing 450,000/ ^mm3 platelets (hereinafter referred to as “PRP-
3) was prepared. (1) ADP-induced aggregation inhibition test Add 0.6 ml of PRP-2 prepared above to 0.01 ml of a solution containing the compound to be tested at a predetermined concentration.
ml was added, and the mixture was placed in a constant temperature bath at a temperature of 37°C for 1 minute. Then 0.07 ml of ADP solution was added to the mixture. The permeability of this mixture was measured, and the change in permeability was measured using an agglomerometer at a stirrer rotation speed of 1100 rpm. used in this test
The ADP solution was prepared using Oren-Veronal buffer to a concentration of 7.5×10 ⁻⁵ M. The aggregation rate at the time when platelet aggregation reached the maximum (the time when the light transmittance reached the maximum) was calculated using the following formula. Aggregation rate = c ₁ - _{a 1} / b ₁ - _{a 1} × 100 where a ₁ : Permeability of PRP-2 b ₁ : Permeability of PPP c ₁ : Permeability of PRP-2 mixed with test compound and ADP Let the aggregation rate calculated by the above formula be _B1 . In addition, platelets are aggregated in the same manner as above except that no test compound is used, and the aggregation rate is determined, and this aggregation rate is taken as the control aggregation rate _A1 . The platelet aggregation inhibiting effect of the test compound was determined as the inhibition rate (%) relative to the aggregation rate of the control. Inhibition rate (%) = A ₁ - B ₁ / A ₁ × 100 (2) Collagen-induced aggregation inhibition test Add 0.6 ml of PRP-3 prepared above to 0.01 ml of a solution containing the compound to be tested at a predetermined concentration.
ml was added, and the mixture was placed in a constant temperature bath at a temperature of 37°C for 1 minute. Next, add 0.07ml of collagen solution to the mixture.
added. The permeability of this mixture was measured, and the change in permeability was measured using an agglomerometer at a stirrer rotation speed of 1100 rpm. In this test, collagen was ground by adding 5 ml of Oren-Veronal buffer (PH7.35) to 100 mg of collagen, and the resulting supernatant was used. The aggregation rate at the time when platelet aggregation reached the maximum (the time when the light transmittance reached the maximum) was calculated using the following formula. Aggregation rate c ₂ −a ₂ /b ₂ −a ₂ ×100 where a ₂ : Permeability of PRP-3 b ₂ : Permeability of PPP c ₂ : PRP mixed with test compound and collagen
Transmittance of -3 Let the aggregation rate calculated by the above formula be _B2 . In addition, platelets are aggregated in the same manner as above except that no test compound is used, and the aggregation rate is determined, and this aggregation rate is defined as the control aggregation rate _A2 . The platelet aggregation inhibiting effect of the test compound was determined as the inhibition rate (%) relative to the aggregation rate of the control. Rejection rate (%) = A ₂ − B ₂ /A ₂ ×100 For the compounds of the present invention obtained in each example described later,
The results of determining the concentration used (IC ₅₀ ) of each test compound at which the inhibition rate (%) determined above is 50% are shown in
Shown in the table.

【table】

[Table] In order to further clarify the present invention, reference examples and examples are listed below. Reference example 1 Add 27.0 g of anhydrous aluminum chloride and 5.1 g of glutaric anhydride to 50 ml of 1,2-dichloroethane,
While stirring and heating (internal temperature 30 to 40℃), cook for 3-4 minutes.
-1.2 containing 4.4 g of dihydrocarbostyril
- Add dropwise a suspension of 50 ml of dichloroethane. After stirring at the same temperature for 3 hours, the mixture is cooled. The reaction mixture is poured into ice water to remove precipitated crystals, which are dissolved in a 1N aqueous solution of caustic soda to remove insoluble matter. After adding 1N hydrochloric acid aqueous solution to the liquid to adjust the pH to 3, the precipitated crystals were collected and recrystallized from water to give 5.0 g of 6-(γ-carboxy)butyryl-3,4-dihydrocarbostyryl as colorless needle-like crystals. get. Melting point: 244-245℃ Reference example 2: 27.0% anhydrous aluminum chloride in 100ml of carbon disulfide
g and 6.1 g of succinyl dichloride, and while maintaining a temperature of gentle reflux with stirring, 3.4-
Carbon disulfide containing 4.4 g of dihydrocarbostyryl
Add 50 ml of suspension dropwise. After stirring at the same temperature for 30 minutes and cooling, the reaction mixture was poured into ice water and left overnight. The precipitate was collected and washed with water from Step 1, and then dissolved in 100 ml of 1N caustic soda aqueous solution to remove insoluble matter. Add dilute hydrochloric acid to the solution to adjust the pH.
= 3, the precipitated crystals were collected and recrystallized from water-ethanol (ν/ν 1:1) to give colorless needle-like crystals of 6-(β-carboxy)propionyl-3.
4.5 g of 4-dihydrocarbostyryl are obtained. melting point
243-244℃ Reference Example 3 400ml of thionyl chloride was added to 10ml of ethanol under external ice-cooling and stirring, and after stirring at the same temperature for 10 minutes, 6
Add 500 mg of -(β-carboxy)propionyl-3,4-dihydrocarbostyril. After addition
Stir at room temperature for 4.5 hours. Add the reaction solution to saturated saline
Pour into 100ml and extract with chloroform. The chloroform layer is washed with saturated deuterated water and then water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from chloroform-petroleum ether to give colorless needle-like crystals of 6-(β-ethoxycarbonyl)propionyl-3,4-dihydrocarbostyryl.
Get 450mg. Melting point: 158-159°C Reference Examples 4-12 Compounds of Reference Examples 4-6 below are obtained in the same manner as in Reference Example 1. Compounds of Reference Examples 7 to 12 below are obtained in the same manner as Reference Example 3.

【table】

[Table] Example 1 Dissolve 0.4 g of caustic soda in 25 ml of water, and add 6-(3-carboxy)propionyl-3,4-
Added 1.3 g of dihydrocarbostyril, added 0.9 g of sodium borohydride over 5 minutes while stirring under cooling (ice-water), and stirred at the same temperature for 1 hour.
After setting the pH to 2 with a 1N aqueous hydrochloric acid solution, the precipitated crystals were collected and recrystallized from a 50% aqueous ethanol solution to give colorless needle-like crystals of 6-(3-carboxy-1-hydroxy)propyl-3,4-dihydrocarboxylate. styril
Obtain 0.7g. Melting point 147-148℃. Examples 2 to 7 The following compounds were obtained in the same manner as in Example 1.

【table】

[Table] Example 8 6-(γ-ethoxycarbonyl)butyryl-3,4-dihydrocarbostyryl in 100ml of ethanol
1.0 g and 0.1 g of palladium black were added, and catalytic reduction was carried out at 40 to 50° C. for 8 hours under 2 atmospheres of hydrogen pressure. After cooling, remove the catalyst and concentrate the mother liquor. The concentrated residue was recrystallized from chloroform-petroleum ether to give colorless needle-like crystals of 6-(4-ethoxycarbonyl-1-hydroxy)butyl-3,4-dihydrocarbostyryl.
Obtain 0.75g. Melting point 83-84℃. Example 9 Add and dissolve 1.0 g of 6-(γ-benzyloxycarbonyl)butyryl-3,4-dihydrocarbostyryl in 60 ml of ethanol, and stir at room temperature.
Add 0.3 g of NaBH ₄ little by little. After the addition, stir at room temperature for 2 hours. After the reaction, the reaction solution was made acidic with 5% hydrochloric acid under external ice-cooling and stirring, and about 100 ml of water was added, followed by extraction with chloroform. Add the chloroform layer to water, 5
Wash with % NaHCO ₃ water and then water, dry with NaSO ₄ and concentrate. The concentrated residue was recrystallized from acetone-petroleum ether to give colorless edge-shaped crystals of 6-(4-benzyloxycarbonyl-1-hydroxy)butyl-3.
0.65 g of 4-dihydrocarbostyryl is obtained. melting point
96.8~99.0℃. Examples 10 to 19 The compounds of Examples 10 to 18 below were obtained by processing in the same manner as in Example 8, and the compounds of Example 19 below were obtained by processing in the same manner as in Example 9.

【table】

【table】

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ represents a hydrogen atom or a lower alkyl group, R ₂ represents a hydrogen atom, a lower alkyl group, a cyclohexyl group, or a phenyl lower alkyl group,
-A- is a vinylene group or -(CH ₂ ) _o - (n is 0 to
4 integer). ] A 3,4-dihydrocarbostyryl derivative represented by: