JPH0227989B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel isohomocarbostyryl derivatives. The isohomocarbostyryl 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 (1). [In the formula, R represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom. A represents a lower alkylene group. n represents an integer of 0, 1 or 2. ] The compound of the present invention has a central nervous system depressant effect and an antihistamine effect, and is useful as a central nervous system depressant and an antihistamine agent. The compound of the present invention has a central nervous system depressing effect, such as suppressing fighting behavior in long-term isolated mice, suppressing fighting behavior in mice, anesthetic and sleep enhancing effects such as various anesthesia and sleeping pills, muscle relaxing effect, blepharoptosis effect, and body temperature lowering effect. , has locomotor activity suppressing effect, hyperemotional suppressing effect in olfactory bulbectomized rats (OB rats), anti-methamphetamine effect, methamphetamine group toxicity reducing effect, analgesic effect, anti-epinephrine effect, etc.
Therefore, central nervous system depressants containing the compound of the present invention as an active ingredient include, for example, central muscle relaxants, sleep-inducing drugs,
It is useful as a preoperative drug, an antischizophrenic drug, an analgesic and sedative, an anxiolytic, an antimanic-depressant, an antipyretic analgesic, an antihypertensive, and the like. Furthermore, the compound of the present invention has the following characteristics as an antihistamine. That is, antihistamines are
Gutsudman, Gilman, Pharmacology Book [Part 1] Fundamentals and Clinical Practice of Drug Treatment, pp. 781-835, published by Hirokawa Shoten (1974), New Applied Pharmacology, written by Hisashi Hano, pp. 307-319.
Page, Nagai Shoten (1970), New Drugs and Clinical Practice, Vol. 20, No.
11, pp. 129-133 (1971) and Basic and Clinical Studies, No.
As described in 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 and histamine receptors It exerts antihistamine action by blocking the binding with (competitive antagonism). Therefore, the antihistamine of 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, hay fever, hay fever, and acute Ginmachine (itch, 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, the antihistamine of the present invention can be used as an adjunct in treating systemic anaphylaxis in which autacoids other than histamine are thought to play an important role. Furthermore, the antihistamine of the present invention can also be used as a diagnostic agent for measuring the acid secretion ability of the stomach. More specifically, each group represented by R and A in the above general formula (1) is as follows. Examples of lower alkyl groups include linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl groups. Examples of lower alkoxy groups include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,
Examples include tert-butoxy, pentyloxy, and hexyloxy groups. Examples of halogen atoms include fluorine, chlorine, bromine, and iodine atoms. Examples of the lower alkylene group include straight chain or branched alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, and methyl. Examples include methylene, ethylmethylene, tetramethylene, pentamethylene, and hexamethylene groups. The compounds of the present invention can be produced by various methods. Specifically, it can be produced, for example, as shown in the following reaction scheme-1. [Reaction formula-1] [In the formula, X represents a halogen atom. R, A and n are the same as above. ] As shown in Reaction Scheme-1, the isohomocarbostyryl derivative represented by general formula (1) is represented by general formula (2).
It is produced by reacting a halogenoalkoxyisohomocarbostyryl derivative represented by the formula (3) with a piperazine derivative represented by the general formula (3).
The piperazine derivative represented by the general formula (3) is easily produced by a known method or according to a known method. In the above, the reaction between the compound represented by the general formula (2) and the compound represented by the general formula (3) is carried out in the absence of a solvent or in an inert solvent at room temperature to 200°C, preferably at 60°C to 200°C.
The process is completed in a few hours to 24 hours at a temperature of 120°C.
Examples of inert solvents include ethers such as dioxane, tetrahydrofuran, ethylene glycol, and dimethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, and isopropanol, dimethylformamide, dimethyl sulfoxide, and the like. Polar solvents can be used. The above reaction is more advantageously carried out using a basic compound as dehydrohalogenating agent. Examples of the basic compound used in the above reaction include calcium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, triethylamine, tripropylamine, pyridine,
It may be selected from a wide range of known basic compounds such as tertiary amines such as quinoline. Further, the above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide as a reaction promoter, if necessary. The ratio of the compound represented by the general formula (2) and the compound represented by the general formula (3) in the above reaction is not particularly limited and can be appropriately selected within a wide range, but usually the latter is equal to the former. The amount may be mol to excess, preferably equimolar to 5 times the mole, more preferably equimolar to 1.2 times the mole. In this way, the compound of the present invention represented by the general formula (1) of the present invention can be produced. The halogenoalkoxyisohomocarbostyryl derivative represented by the general formula (2) is a new compound, and can be produced, for example, by the method shown in Reaction Scheme-2. [Reaction scheme-2] [In the formula, A and X are the same as above. X ¹ represents a halogen atom. ] The reaction between the known isohomocarbostyryl derivative of general formula (4) and the compound represented by known general formula (5) is preferably carried out using a basic compound as a dehydrohalogenating agent in an appropriate solvent at room temperature to It is carried out at 200°C, preferably room temperature to 150°C, for several hours to 15 hours. Suitable solvents include, for example, lower alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methyl ethyl ketone, ethers such as dioxane and diethylene glycol dimethyl ether, aromatic hydrocarbons such as toluene and xylene, dimethyl formamide, and dimethyl. Examples include sulfoxide and hexamethylphosphoric triamide. Basic compounds that can be used as dehydrohalogenating agents include, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium hydride, metallic potassium, sodium Examples include tertiary amines such as amide, pyridine, quinoline, triethylamine, and tripropylamine. In the above, an alkali metal iodide compound such as potassium iodide or sodium iodide can also be used as a reaction accelerator. Isohomocarbostyryl derivatives represented by general formula (4) and general formula
There is no particular restriction on the proportion of the compound represented by (5), but it is preferable to use 1 mol or more of the latter, usually 1 to 5 mol, preferably 1 to 1.5 mol, per 1 mol of the former. In this way, a compound represented by general formula (2) used as a starting material in the present invention is obtained. The compound of the present invention can also be produced by the method shown in Reaction Scheme-3 below. [Reaction scheme-3] [In the formula, R, A and n are the same as above. X ² represents a halogen atom. ] In Reaction Scheme-3, the compound of the present invention represented by general formula (1) is obtained by reacting an isohomocarbostyryl derivative represented by general formula (4) with a piperazine derivative represented by general formula (6). Manufactured by. The piperazine derivative represented by general formula (6) can be easily produced by a known method or a method similar to a known method. The reaction between the isohomocarbostyryl derivative represented by the general formula (4) and the piperazine derivative represented by the general formula (6) is carried out by the reaction scheme -
The reaction conditions for the reaction between the isohomocarbostyryl derivative represented by general formula (4) and the compound represented by general formula (5) in 2 can be applied. 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. . The target compounds obtained in each step can be easily isolated and purified by conventional separation methods such as solvent extraction, dilution, recrystallization, column chromatography, preparative thin layer chromatography, etc. . The present invention naturally also includes optical isomers. When the compound of general formula (1) and its acid addition salt are used as antihistamines and central nervous system depressants, they are usually put into the form of 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 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 and suspensions), and ointments. 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, calcium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaria powder, carbonic acid Disintegrants such as sodium hydrogen, calcium carbonate, Twin, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, quaternary ammonium base, sodium lauryl sulfate, etc. absorption enhancers, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, macrogol, solid polyethylene glycol, etc. Examples include brighteners 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, Examples include binders such as tragacanth powder, gelatin, and 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 a suppository, a wide range 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 injectables, solutions and suspensions are preferably sterile and isotonic with blood. When forming into an injection form, all carriers commonly used in this field can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxygenate isostearyl alcohol. Examples include oxyethylene sorbitol and sorbitan ester. In this case, sufficient amounts of common salt, glucose, or glycerin may be included in the therapeutic agent to provide an isotonic solution. Furthermore, conventional solubilizing agents, buffering agents, soothing agents, Preservatives and the like may be added to the therapeutic agent. When forming into a paste or cream, 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, etc. The amount of the compound of general formula (1) or its acid addition 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 is usually 1 to 70% by weight based on the total composition. is preferable. 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 alone or mixed with normal replacement fluids such as glucose solutions and amino acid solutions. The injection is administered intravenously, and if necessary, the injection is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. In the case of suppositories, it is administered rectally;
It is also applied as an ointment. 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 usually contains about 40 μg to 2 mg/Kg/day of the compound of general formula (1) or its acid addition salt. The pharmaceutical composition may be administered in 3 to 4 doses. Formulation example 1 6-[3-(4-phenyl-1-piperazinyl)propoxy]-3,4-dihydroisohomocarbostyryl 5mg Cornstarch 132mg Magnesium stearate 18mg Lactose 45mg Total 200mg Formulation example 2 6-{3-[4 -(3-Ethoxyphenyl)-1-piperazinyl]propoxy}-3,4-dihydroisohomocarbostyryl 10 mg Corn starch 130 mg Magnesium stearate 18 mg Lactose 42 mg Total 200 mg Tablets with the above composition are manufactured according to a conventional method. Reference examples and examples will be described below. Reference example 0.54g of 6-hydroxy-3,4-dihydroisohomocarbostyryl in 10ml of dimethylformamide
Add 0.7 g of potassium carbonate and stir at room temperature for 1 hour. Thereafter, 0.7 g of 1,3-bromochloropropane was added and reacted for 12 hours at room temperature. After the reaction is complete, pour the reaction mixture into water to remove the precipitated crystals.
Washed with water, 0.41 g of 6-(3-chloropropyl)-
3,4-dihydroisohomocarbostyryl is obtained. Example 1 5.1 g of 6-(3-chloropropoxy)-3,4-dihydroisohomocarbostyryl and 3.5 g of sodium iodide were mixed in 50 ml of isopropanol,
Heat to reflux for an hour. Next, 40 ml of isopropanol was added, followed by 4.4 g of 4-(3-chlorophenyl)piperazine and 3.0 g of triethylamine, and the mixture was reacted with stirring at 70 to 80°C for 7 hours. The reaction solution was poured into 80 ml of 2% aqueous sodium hydrogen carbonate solution, and the organic layer was extracted with chloroform. The chloroform layer is washed with water, dehydrated, and the chloroform is distilled off. Recrystallized from ethanol-water to give colorless prismatic crystals of 6-{3-[4-(3-chlorophenyl)-1-
2.8 g of piperazinyl]propoxy}-3,4-dihydroisohomocarbostyryl are obtained. Example 2 1.7 g of 6-hydroxy-3,4-dihydroisohomocarbostyryl and 0.48 g of 50% oily NaH are mixed with 30 ml of dimethylformamide and stirred. Next, add 4.6 g of 1-chloro-3-[4-(3-chlorophenyl)piperazinyl]propane, and
Incubate at 60°C for 2.5 hours. The reaction solution was distilled off under reduced pressure,
The residue is extracted with chloroform. After distilling off the chloroform, the resulting residue was recrystallized from ethanol-water to give colorless prismatic crystals with a mp of 123 to 125°C.
1.4 g of {3-[4-(3-chlorophenyl)-1-piperazinyl]propoxy}-3,4-dihydroisohomocarbostyryl is obtained. The following compounds are obtained in the same manner as in Examples 1 and 2 using appropriate starting materials. 【table】

Claims (1)

[Claims] 1. General formula [In the formula, R represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom. A represents a lower alkylene group. n represents 0, 1 or 2. ] An isohomocarbostyryl derivative or a salt thereof.