JPH0143746B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides a novel method for producing carbostyril derivatives, more specifically, the general formula [In the formula, A represents a lower alkylene group. B is a group-
Indicates CO−. Z represents a nitrogen atom. ] The present invention relates to a method for producing a carbostyl derivative represented by the following. Specifically, each group in this specification is as follows. Lower alkyl group...methyl, ethyl, propyl,
Isopropyl, butyl, tert-butyl, pentyl, hexyl groups, etc. Halogen atoms: fluorine, chlorine, bromine and iodine atoms. Lower alkoxy groups: methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy groups, etc. Lower alkylene group...methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene,
Methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene groups, etc. A phenyl group that may have 1 to 3 halogen atoms, lower alkoxy groups, or lower alkyl groups as substituents on the phenyl ring... phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2-bromphenyl, 3-bromphenyl, 4-bromphenyl, 2-iodophenyl, 4-iodophenyl,
3,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,5-dibromphenyl,
3,4,5-trichlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl,
4-ethylphenyl, 3-isopropylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 2,5-dimethylphenyl, 3,4,5
-trimethylphenyl, 2-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl,
2-ethoxyphenyl, 3-ethoxyphenyl,
4-ethoxyphenyl, 4-isopropoxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 3,4,5-trimethoxyphenyl, 2, 5
-dimethoxyphenyl group, etc. The carbostyril derivative represented by the above general formula (1) produced by the present invention is a new compound that has not been described in any literature. The compound has central nervous system depressant and antihistamine effects and is useful as a central nervous system depressant and antihistamine. More specifically, the compound obtained by the present invention has the following characteristics as a central nervous system depressant. In other words, the compound has a strong effect on suppressing fighting behavior in mice isolated for long periods of time, and has a more remarkable effect on suppressing fighting behavior in mice than diazepam, which is conventionally thought to have a strong effect. Excellent as a medicine. In addition, the compound has strong anesthetic and sleep-enhancing effects such as various anesthesia and sleeping pills, and has a strong suppressive effect on fighting behavior in mice, making it excellent as a pre-anesthetic and sleep-inducing drug. The compound also has central nervous system depressant effects such as muscle relaxation, blepharoptosis, hypothermia, locomotor activity suppression, hyperemotional suppression in olfactory bulbectomized rats (OB rats), antimethamphetamine effects, and methamphetamine group toxicity reduction. It has anticholinergic effects, analgesic effects, anti-epinephrine effects, etc.
Cardiac depressant and catalepsy-inducing effects are extremely weak. Therefore, a central nervous system depressant containing this compound as an active ingredient has almost no side effects such as thirst, constipation, tachycardia, parkinsonism, and tardive dyskinesia, which conventional central nervous system depressants have. It is useful as, for example, a central muscle relaxant, a sleep-inducing drug, a preoperative drug, an antischizophrenic drug, a sedative and tranquilizer, an anxiolytic, an antimanic-depressant, an antipyretic analgesic, an antihypertensive, and the like. Furthermore, since the compound is easily metabolized in vivo, it is useful as a short-acting central nervous system depressant, especially as a sleep-inducing drug and a preoperative drug, and has extremely few side effects on the liver. Furthermore, the compound obtained according to the present invention has the following characteristics as an antihistamine agent. In other words, antihistamines are described in Gutsman Gilman's Book of Pharmacology [Part 1] Fundamentals and Clinical Practice of Drug Treatment, pp. 781-835.
Published by Hirokawa Shoten (1974), New Applied Pharmacology by Hisashi Hano, pp. 307-319, Nagai Shoten (1970), New Drugs and Clinical Practice, Vol. 20, No. 11, pp. 129-133 (1971) and Basics. As described in ``And Clinical Research,'' Vol. 10, No. 10, pp. 17-27 (1976), rather than suppressing the release of bound histamine due to allergic antigen-antibody reactions, the release of active histamine is and histamine receptor binding (competitive antagonism)
It exerts antihistamine action. Therefore, antihistamines containing the compound obtained in the present invention can be used to treat various diseases caused by the binding of histamine to histamine receptors, such as allergic symptoms of the respiratory tract such as combing, nasal discharge, itching of the eyes, nose and throat, and hay fever. Fever, hay fever, acute acne (itching, edema, redness, etc.), angioedema, pruritus, atopic dermatitis,
Contact dermatitis such as insect stings and sumac rash;
It is effective as a therapeutic or prophylactic drug for allergic diseases such as serum sickness, edematous disorders, allergic rhinitis, allergic conjunctivitis, and keratitis. Furthermore, antihistamines containing the compounds obtained according to the present invention can be used as adjuncts in treating systemic anaphylaxis in which autacoids other than histamine are thought to play an important role. Furthermore, the antihistamine containing the compound obtained according to the present invention can also be used as a diagnostic agent for measuring the acid secretion ability of the stomach. According to the method of the present invention, the carbostyryl derivative represented by the above general formula (1) can be produced in high yield and with high purity. The benzene derivative of general formula (2) used as a starting material in the present invention is produced by the method shown below. Reaction formula-1 [In the formula, X ¹ represents a halogen atom. R, X and A
is the same as above. ] The reaction between compound 6 and compound 7 or 8 is generally called Friedel-Crafts reaction, and this reaction is carried out in a solvent in the presence of a Lewis acid. As the solvent used in this case, those commonly used in this type of reaction are advantageously used, and examples thereof include carbon disulfide, nitrobenzene, chlorobenzene, dichloromethane, dichloroethane, trichloroethane, and tetrachloroethane. Furthermore, conventionally used Lewis acids are preferably used, such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid, and the like. The amount of Lewis acid to be used may be determined appropriately, but it is usually about 2 to 6 times the mole of Compound 6, preferably about 3 to 4 times the mole. The amount of compound 7 or 8 to be used is usually at least an equimolar amount, preferably an equimolar amount to twice the molar amount of compound 6. The reaction temperature is selected appropriately, but is generally about -50 to 120°C, preferably 0°C.
It is best to keep the temperature at ~70°C. Although the reaction time varies depending on the raw materials, catalyst, reaction temperature, etc., it cannot be stated unconditionally, but the reaction usually completes in about 0.5 to 24 hours. The nitration reaction of Compound 9 is carried out under conventional nitration reaction conditions for aromatic compounds, for example, without a solvent or in a suitable inert solvent using a nitration agent. Examples of inert solvents include acetic acid, acetic anhydride,
Examples of nitrating agents include fuming nitric acid, concentrated nitric acid, mixed acids (sulfuric acid, oleum, phosphoric acid, or acetic anhydride and nitric acid), alkali metal nitrates such as potassium nitrate, sodium nitrate, and sulfuric acid. . The amount of the nitrating agent used may be an equimolar or more excess amount relative to the starting material compound, and the reaction is preferably carried out at -30°C to around room temperature for 5 minutes to 4 hours. In the present invention, first, the benzene derivative of the general formula (2) is reduced and ring-closed to obtain the carbostyril derivative of the general formula (3). This reaction is carried out by reduction using a catalytic reduction catalyst in a suitable solvent, or by reducing a metal or a metal salt and an acid or a metal or a metal salt and an alkali metal hydroxide, sulfide, ammonium salt, etc. in a suitable inert solvent. The reduction is carried out by using a mixture of and the like as a reducing agent. When using catalytic reduction, the solvent used is, for example, water,
Alcohols such as acetic acid, methanol, ethanol and isopropanol; hydrocarbons such as hexane and cyclohexane; ethers such as diethylene glycol dimethyl ether, dioxane, THF and diethyl ether; esters such as ethyl acetate and methyl acetate; aprotons such as DMF Examples include polar solvents. Examples of the catalytic reduction catalyst used include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, and Raney-nickel. The amount of catalyst to be used is preferably 0.02 to 1.00 times the weight of Compound 2. The reaction is carried out at -20 to 100°C, preferably at 0
~50℃, hydrogen pressure is generally 0.5~10 at 1~10 atm
It will finish in about an hour. Alternatively, when using iron, zinc, tin or stannous chloride and a mineral acid such as hydrochloric acid or sulfuric acid, or iron, ferrous sulfate, zinc or tin and an alkali metal hydroxide such as sodium hydroxide, sulfide Sulfides such as ammonium, aqueous ammonia, and mixtures with ammonium salts such as ammonium chloride are used as reducing agents. Examples of the inert solvent used include water, acetic acid, methanol, ethanol, and dioxane. The conditions for the above-mentioned reduction reaction may be appropriately selected depending on the reducing agent used, and the reaction usually proceeds at -50 to 100°C and is completed in about 0.5 to 10 hours. For example, when stannous chloride and hydrochloric acid are used as reducing agents, the reaction is advantageously carried out at around -20 to 50°C. The amount of the reducing agent to be used is preferably at least equimolar, usually equimolar to 3 times the molar amount of the raw material compound. In the above reaction, the nitro group of the compound of general formula (2) is first converted to an amino group by a reducing agent, and the compound of the general formula [In the formula, R, X, A and B are the same as above. It is thought that a benzene derivative represented by the formula (3) is produced, and then this compound is ring-closed to produce a carbostyryl derivative of the general formula (3). Further, in reducing Compound 2, the carbonyl group is not changed in the above case, but in the case of , the carbonyl group may be converted to a methyl group. However, it is of course possible to maintain the carbonyl group as it is by appropriately selecting reaction conditions. The reaction between the carbostyril derivative represented by the general formula (3) and the compound of the general formula (4) is carried out without a solvent or in a common inert solvent at a temperature of about room temperature to 200°C, preferably room temperature to 120°C. Under certain conditions, it can be completed within a few hours to 24 hours. Examples of inert solvents include ethers such as dioxane, THF, ethylene glycol dimethyl ether, and diethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, and isopropanol, DMF, DMSO, Polar solvents such as hexamethylphosphoric triamide, acetone, and acetonitrile can be used. The above reaction is more advantageously carried out using a basic compound as a deoxidizing agent. Examples of the basic compound include tertiary amines such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, triethylamine, tripropylamine, pyridine, and quinoline. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide or hexamethylphosphoric acid triamide as a reaction promoter, if necessary. The ratio of Compound 3 and Compound 4 used in the above reaction is not particularly limited and is appropriately selected within a wide range, but usually the latter is used in an equimolar to excess amount of the former, preferably an equimolar to 5 times the molar amount, more preferably an equimolar to 5 times the latter. is preferably 1 to 1.2 times the molar amount. The reaction between the benzene derivative of general formula (2) and the compound of general formula (4) is carried out under the same reaction conditions as the reaction between the carbostyryl derivative of general formula (3) and the compound of general formula (4). be able to. The reduction and ring closure of the benzene derivative of general formula (5) is
This is carried out in the same manner as the reduction and ring closure of the benzene derivative of general formula (2). In this case as well, the compound of general formula (5) is first converted from the nitro group to an amino group by a reducing agent, and the compound has the general formula [In the formula, R, R ² , X, A and B are the same as above. ] It is thought that a benzene derivative represented by the formula (1) is produced, and then this compound is ring-closed to produce a carbostyryl derivative of the general formula (1). The carbostyril derivative represented by the general formula (1) of the present invention can be easily converted into an acid addition salt by reacting with a pharmaceutically acceptable acid. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid. . Further, among the carbostyryl derivatives represented by the general formula (1) of the present invention, a compound having an acidic group can be easily formed into a salt by reacting with a pharmaceutically acceptable basic compound. Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, and the like. The target compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include a solvent extraction method, a dilution method, a recrystallization method, a column chromatography, and a pre-paradave thin layer chromatography. Incidentally, the present invention naturally also includes optical isomers. When using the compound of general formula (1) and its salt as an antihistamine and a central nervous system depressant,
It is usually in the form of a pharmaceutical composition with a pharmaceutical carrier. As carriers, fillers, extenders, binders, etc. commonly used to prepare drugs according to the usage form can be used.
Examples include diluents or excipients such as wetting agents, disintegrants, surfactants, and lubricants. Various dosage unit forms for antihistamines and central nervous system depressants can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, liquids, suspensions, emulsions, granules, and capsules. ,
Examples include suppositories, injections (solutions, suspensions, etc.), ointments, and the like. 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 powder, laminaria powder Disintegrants such as sodium bicarbonate, calcium carbonate, Twin, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa budder, hydrogenated oil, quaternary ammonium base, sodium lauryl sulfate absorption enhancers such as glycerin, humectants such as starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, purified talc, stearate, boric acid powder, macrogol, solid polyethylene glycol, etc. Examples include lubricants and the like. 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, Binders such as tragacanth powder, gelatin, and ethanol,
Examples include disintegrants such as laminaria and agar. Furthermore, the tablets can be made into conventionally coated tablets, such as sugar-coated tablets, gelatin-encapsulated tablets, dissolution-coated tablets, film-coated tablets, double-layered tablets, or multilayered 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,
Examples include gelatin and semi-synthetic glycerides. 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, fragrances, flavors, sweeteners, and other pharmaceuticals may be included in the therapeutic agent, if necessary. When forming into a paste, cream or gel form, a wide variety of diluents conventionally known in this field can be used, such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like. The amount of the compound of general formula (1) or its salt to be contained in antihistamines and central nervous system depressants is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 70% by weight of the total composition. good. Furthermore, the above-mentioned antihistamines and central nervous system depressants are not particularly limited in their use, and can be administered in a manner appropriate for various forms. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules, and capsules, it is administered orally, and in the case of injections, it is administered intravenously alone or mixed with normal replenishing fluids such as glucose and amino acids. If necessary, it can be administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally; in the case of a suppository, it can be administered rectally; and in the case of an ointment, it can be applied. The dosage of the antihistamine and central nervous system depressant of the present invention is appropriately selected depending on the purpose of use, symptoms, etc., and the formulation usually contains about 40 μg to 2 mg/Kg/day of the compound of general formula (1) or its salt. The drug may be administered in 3 to 4 doses. Pharmacological test results, reference examples, examples, and formulation examples are listed below. Pharmacological test Suppressive effect on jumping behavior in mice induced by methamphetamine and L-dopa Male DDY mice weighing 17 to 25 g and fasted overnight are used. A group of 6 animals. The test compound was administered orally, 40 minutes later, 4 mg/Kg of methamphetamine was administered intraperitoneally, and 15 minutes after methamphetamine administration, L.
- Administer Dopa 400 mg/Kg intraperitoneally. The number of jumps of the mouse is measured for 60 minutes after L-dopa administration. Mice were placed one by one in two glass beakers for measurement, and those that jumped 10 times or less within 1 hour after L-dopa administration were considered positive for inhibition, and those that jumped more than 10 times were considered negative. Group 6
Calculate the effective dose (ED ₅₀ value) of the test compound that can cause 3 of the animals to become positive. The number of jumping times per hour for the saline administration group was 150.
~200 times. [H.Lal, FCcolpaert and P.
Laduron, European J.Pharm., 30 , 113–116.
(1975)] Test compound Compound 17-[1-oxo-3-(4-phenyl-
1-piperazinyl)propyl]-3,
4-dihydrocarbostyryl compound 27-{1-oxo-[4-(2,3-dimethylphenyl-1-piperazinyl)butyl)-3,4-dihydrocarbostyryl compound 37-{3-[4-(2 -ethoxyphenyl)
-1-piperazinyl]-1-oxopropyl}-3,4-dihydrocarbostyryl compound 46-[α-(4-phenyl-1-piperazinyl)propionyl]-3,4-dihydrocarbostyryl (JP-A-1973-
Compound 51-Methyl-6-[3-(4-methylpiperazin-1-yl)-2-methylpropionyl]-1,2,3,4-tetrahydro (compound disclosed in Example 11 of Publication No. 16478) Quinoline-2-one (Unexamined Japanese Patent Publication No. 1983
- Compound disclosed in No. 4 of the lower left column on page 375 of Publication No. 83749)

[Table] Reference example 1 Methyl 3-phenylpropionate (100g)
and 84 g of 4-chlorobutyryl chloride were added to 450 ml of dichloromethane, and 250 g of anhydrous aluminum chloride was added little by little while stirring under ice cooling. After the addition is complete, the reaction mixture is stirred at room temperature overnight. Pour the reaction mixture into ice water and extract with dichloromethane.
After drying the dichloromethane extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and recrystallized from ether-petroleum ether to obtain methyl 3-[4-(4-chloro-1-oxobutyl)phenyl]propionate. Yield 164g, mp45-46℃, pale yellow prismatic crystals NMR ( _CDCl3 )δ ^TMS _PPM 2.17 (m, 2H, _CH2 ) 2.62 (m, 2H, _CH2 ), 2.97 (m, 2H,
CH ₂ ) 3.11 (t, 6Hz, 2H, CH ₂ ), 3.61 (t, 6Hz, 2H, CH ₂ ), 3.61 (s, 3H, OMe), 7.24 (d, 8Hz,
2H, Hb) 7.84 (d, 8Hz, 2H, Ha) Reference example 2 Methyl 3-phenylpropionate 30g, 3
-24 g of chloropropionyl chloride, 140 ml of dichloromethane and 75 g of aluminum chloride were treated in the same manner as in Reference Example 1 to obtain oily methyl 3-[4-(3
51.8 g of -chloro-1-oxopropyl)phenyl]propionate are obtained. NMR (CDCl ₃ ) δ ^TMS _PPM 2.67 (m, 2H, CH ₂ ) 2.99 (m, 2H, CH ₂ ), 3.40 (t, 6Hz,
2H, CH ₂ ) 3.66 (s, 3H, OMe), 3.88 (t, 6Hz,
2H, CH ₂ ) 7.29 (d, 8Hz, 2H, Hb), 7.88 (d, 8Hz, 2H, Ha) Reference Example 3 A mixture of 630 ml of nitric acid and concentrated sulfuric acid 5 was cooled to -20°C and mixed with methyl 3-[ Add 164 g of 4-(4-chloro-1-oxobutyl)phenyl]propionate. After stirring the reaction solution at -20 to -10°C for 1 hour, it was poured into ice water and extracted with dichloromethane. After drying the dichloromethane extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain oily methyl 3-[4-(4-chloro-1-oxobutyl)-
2-Nitrophenyl]propionate is obtained. Yield 174g NMR (CDCl ₃ ) δ ^TMS _PPM 2.24 (m, 2H, CH ₂ ) 2.72 (m, 2H, CH ₂ ), 3.22 (m, 2H,
CH ₂ ) 3.39 (t, 6Hz, 2H, CH ₂ ), 3.67 (t, 6Hz, 2H, CH ₂ ) 3.67 (s, 3H, OMe) 7.53 (d, 8Hz, 1H, Hb) 8.08 (d-d, 8Hz, 1.5Hz, 1H, Ha) 8.43 (d, 1.5Hz, 1H, Hc) Reference example 4 10g of methyl 3-[4-(3-chloro-1-oxopropyl)phenyl]propionate was dissolved in concentrated sulfuric acid
A mixed solution of 73 g of concentrated sulfuric acid and 61 g of nitric acid (specific gravity: 1.42) was added dropwise to the solution while stirring and cooling to -30°C. After the dropwise addition was completed, the mixture was stirred at -10 to -15°C for 30 minutes, poured into ice water, extracted with dichloromethane, and the dichloromethane extract was dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to obtain oily methyl 3-[4-
(3-chloro-1-oxopropyl)-2-nitrophenyl]propionate is obtained. Yield 9.0g NMR (CDCl ₃ ) δ ^TMS _PPM 2.72 (m, 2H, CH ₂ ) 3.27 (m, 2H, CH ₂ ), 3.48 (t, 6Hz,
2H, CH ₂ ) 3.65 (s, 3H, OMe) 3.90 (t, 6Hz, 2H, CH ₂ ) 7.56 (d, 8Hz, 1H, Hb) 8.08 (d-d, 8Hz, 1.5Hz, 1H, Ha) 8.47 (d, 1.5Hz, 1H, Hc) Reference Example 5 3 g of methyl 3-[4-(3-chloro-1-oxopropyl)-2-nitrophenyl]propionate and 1.8 g of NaI were suspended in 50 ml of acetone,
Reflux for an hour and then cool. Add 1.7 g of 4-phenylpiperazine and 1.3 g of triethylamine under ice-cooling and mix for 20~
Stirred at 30°C for 30 minutes. After adding concentrated hydrochloric acid, the mixture was dried under reduced pressure, dichloromethane and water were added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried under reduced pressure and the residue was recrystallized from ethanol-water to give methyl 3
-{4-[3-(4-phenyl-1-piperazinyl)
-1-oxopropyl]-2-nitrophenyl}
Obtain 3.3g of propionate hydrochloride. Colorless needle crystals, mp _164-165 °C Example 1 (a) Add methyl 3-[ _4- (3-chloro-
1-oxopropyl)-2-nitrophenyl]
After adding 20 g of propionate, the mixture is allowed to react at room temperature for 2 hours with stirring. The reaction solution was diluted with chloroform.
Extract with methanol mixture. After drying the extracted layer over anhydrous sodium sulfate, the solvent was distilled off, and the residue was recrystallized from ethanol to obtain colorless needle-like crystals of 7-(3
-chloro-1-oxopropyl)-3,4-dihydrocarbostyryl is obtained. Yield 15.6g,
mp153-154℃ (b) 3g of the compound produced in (a) above and 3g of NaI
was added to 20 ml of dimethylformamide and stirred for 1 hour at 40-50°C under an argon stream. Next, 2.1 g of 1-phenylpiperazine and 1.5 g of triethylamine were added to the reaction solution with 5 ml of dimethylformamide.
After adding the solution added to the solution, stir at the same temperature for 1 hour. The solvent was distilled off under reduced pressure, and after adding deuterium water to the residue, the mixture was extracted with chloroform. After distilling off the solvent in the chloroform layer under reduced pressure, the residue was recrystallized from ethanol to obtain colorless needle-like crystals of 7-[3-(4
-phenyl-1-piperazinyl)-1-oxopropyl]-3,4-dihydrocarbostyryl is obtained. Yield 3.8 g, mp 195-196°C (decomposition) The following compound was obtained in the same manner as in Example 1. Note that the yield indicates the total yield of steps (a) and (b). 7-{3-[4-(2-ethoxyphenyl)piperazinyl]-1-oxo-propyl}-3,4-dihydrocarbostyryl hydrochloride Colorless needle crystals (recrystallized from ethanol-water) mp217-218 °C (decomposition) Yield 69% 7-{3-[4-(3-chlorophenyl)-1-piperazinyl]-1-oxopropyl}-3,4-dihydrocarbostyryl Colorless needles (ethanol) mp153-154 °C Yield 73% Example 2 (a) Methyl 3-[4-(4-chloro-1-oxobutyl)-2-nitrophenyl] was added to a mixture of 520 ml of concentrated hydrochloric acid and 174 g of SnCl _{2.2H 2} O with stirring under ice cooling.
Add 174g of propionate. Next, the reaction solution was stirred at room temperature for 2 hours, and then chloroform-
Extract with methanol. After drying the extracted layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give colorless plate-like crystals of 7-
(4-chloro-1-oxobutyl)-3,4-dihydrocarbostyryl is obtained. Yield 45g,
mp156-157℃ (b) 5 g of the compound obtained above and 5 g of NaI were added to 30 ml of dimethylformamide under an argon atmosphere.
Stir at 70°C for 3 hours. Next, 3.3 g of 1-phenylpiperazine and 2.4 g of triethylamine were added, followed by stirring at the same temperature for 1 hour. Then, the solvent was distilled off under reduced pressure, and after adding dehydrated water to the residue, the mixture was extracted with dichloromethane. After drying the dichloromethane layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in concentrated hydrochloric acid and ethanol, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol-water to give light brown needle-like crystals of 7-[4-(4-phenyl-1-piperazinyl)-1-oxobutyl]-3,4-dihydrocarbostyryl hydrochloride. obtain. Yield 5.8g,
mp251-252°C (decomposition) The following compound is obtained in the same manner as in Example 2 (a) and (b). Note that the yield indicates the total yield of steps (a) and (b). 7-{4-[4-(2-ethoxyphenyl)piperazinyl]-1-oxo-butyl}-3,4-dihydrocarbostyryl hydrochloride Colorless needle crystals (recrystallized from ethanol-water) mp219-220 °C (decomposition) Yield 71% 7-{4-[4-(2,3-dimethylphenyl)
piperazinyl]-1-oxo-butyl}-3,4-
Dihydrocarbostyril Light brown powder crystals (recrystallized from ethanol) mp178-179℃ Yield 68% 7-{4-[4-(3-chlorophenyl)-1-piperazinyl]-1-oxobutyl}-3,4- Dihydrocarbostyryl hydrochloride hydrate Colorless needle crystals (ethanol-water) mp252-253℃ (decomposition) Yield 74% Example 3 Methyl 3-{4-[3-(4-phenyl-1-)
30 g of (piperazinyl)-1-oxopropyl]-2-nitrophenyl}propionate hydrochloride is added to a mixture of 60 ml of concentrated hydrochloric acid and 46 g of SnCl ₂ .2H ₂ O while stirring under ice cooling, and then reacted at room temperature for 2 hours with stirring. The reaction solution is extracted with a chloroform-methanol mixture. After drying the extracted layer with anhydrous sodium sulfate,
The solvent is distilled off. Purified by chromatography and recrystallized from ethanol, 7-
{4-[3-(4-phenyl-1-piperazinyl)-
24.9 g of 1-oxopropyl]-3,4-dihydrocarbostyryl are obtained. mp195-196°C (decomposition) The following compound is obtained in the same manner as in Example 3. 7-{4-[4-(2-ethoxyphenyl)piperazinyl]-1-oxo-butyl}-3,4-dihydrocarbostyryl hydrochloride Colorless needle crystals (recrystallized from ethanol-water) mp219-220 °C (decomposition) Yield 85% 7-{4-[4-(2,3-dimethylphenyl)
piperazinyl]-1-oxo-butyl}-3,4-
Dihydrocarbostyryl Light brown powder crystals (recrystallized from ethanol) mp178-179℃ Yield 82% 7-{3-[4-(2-ethoxyphenyl)piperazinyl]-1-oxo-propyl}-3,4 -Dihydrocarbostyril hydrochloride Colorless needle crystals (recrystallized from ethanol-water) mp217-218℃ (decomposition) Yield 86% 7-[4-(4-phenylpiperazinyl)-1-
Oxobutyl]-3,4-dihydrocarbostyryl hydrochloride Light brown needle crystals (recrystallized from ethanol-water) mp251-252℃ (decomposition) Yield 87% 7-{4-[4-(3-chlorophenyl)- 1-Piperazinyl]-1-oxobutyl}-3,4-dihydrocarbostyryl hydrochloride hydrate Colorless needle crystals (ethanol-water) mp252-253℃ (decomposition) Yield 83% 7-{3-[ 4-(3-chlorophenyl)-1-piperazinyl]-1-oxopropyl}-3,4-dihydrocarbostyryl Colorless needle crystals (ethanol) mp153-154℃ Yield 85% Formulation example 1 6-{1-oxo -3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyryl 10mg Cornstarch 127mg Magnesium stearate 18mg Lactose 45mg Total 200mg Tablets of the above composition are prepared in a conventional manner. Formulation example 2 6-{1-oxo-4-[4-(2,3-dimethylphenyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl 5 mg Cornstarch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets containing the above composition are prepared in a conventional manner.

Claims (1)

[Claims] 1. General formula [In the formula, R represents a hydrogen atom or a lower alkyl group.
X represents a halogen atom. A represents a lower alkylene group. B represents a group -CO-. ] By reducing and ring-closing the benzene derivative represented by the general formula [In the formula, X, A and B are the same as above. ] A carbostyril derivative represented by [In the formula, R ² represents a phenyl group that may have 1 to 3 halogen atoms, lower alkoxy groups, or lower alkyl groups as substituents on the phenyl ring. Z
indicates a nitrogen atom. ] A general formula characterized by reacting a compound represented by [In the formula, A, B, R ² and Z are the same as above. ] A method for producing a carbostyryl derivative represented by: 2 General formula [In the formula, R represents a hydrogen atom or a lower alkyl group.
X represents a halogen atom. A represents a lower alkylene group. B represents a group -CO-. ] The benzene derivative represented by the general formula [In the formula, R ² represents a phenyl group that may have 1 to 3 halogen atoms, lower alkoxy groups, or lower alkyl groups as substituents on the phenyl ring. Z
indicates a nitrogen atom. ] By reacting the compound represented by the general formula [In the formula, R, A, B, R ² and Z are the same as above. ] A general formula characterized in that it is a benzene derivative represented by and then reduced and ring-closed. [In the formula, A, B, R ² and Z are the same as above. ] A method for producing a carbostyryl derivative represented by: