JPS5859980A - Carbostyril derivative - Google Patents

Abstract

NEW MATERIAL:A carbostyril derivative expressed by formulaI(R is OH, alkoxyl, alkanoyloxy, phenylalkoxyl or benzolyoxy; A is alkylene; the carbon bond between the 3- and 4-positions of the carbostyril skeleton is single or double bond). EXAMPLE:6-[4-[1-(2-trans-Benzyloxycyclohexyl)tetrazol-5-yl]butoxy]-3,4- dihydrocarbostyril. USE:A preventing and treating agent for thrombosis, anti-inflammatory, antiulcer, antiasthmatic agents and preventing and treating agent for ischemic heart diseases, e.g. hypertension, angina pectoris or cardiac infraction, and cerebrophthy, e.g. cerebral apoplexy, transient ischemic fit or migraine. PROCESS:A hydroxycarbostyril of formula II and a tetrazole derivative of formula III are dehydrohalogenated to give the compound of formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel carbostyryl derivative, and more particularly to a carbostyril derivative represented by the following general formula (I) and a salt thereof.

(2) [In the formula, k represents a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, a phenyl lower alkoxy group, or a benzoyloxy group, and A represents a lower alkylene group. In addition, the carbon bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond] The carbostyryl derivative represented by the above general formula (I) and its salt have an excellent platelet aggregation inhibiting effect, It has sterase inhibitory effect, thromboxane synthetase inhibitory effect, antiulcer effect, cardiotonic effect, antiinflammatory effect, antihypertensive effect, antihistamine effect, antiallergic effect, etc., and is a prophylactic/therapeutic agent for thrombosis, an antiinflammatory agent, and an antiulcer agent. , anti-asthmatic agents, preventive and therapeutic agents for ischemic heart diseases such as hypertension, angina pectoris, and myocardial infarction, brain diseases such as stroke, transient ischemic attacks, and migraines, as well as antihistamines, anti-allergy agents, etc. Useful.

In this specification, each group represented by k and A is more specifically exemplified by the following groups.

Examples of lower alkoxy groups include those having 1 to 1 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
Examples of the 6 alkoxy groups and lower alkanoyloxy groups include alkanoyloxy having 1 to 6 carbon atoms such as formyloxy, acetyloxy, propionyloxy, iso-propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, and hexanoyloxy. The phenyl lower alkoxy group includes benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 1-
Phenylpropoxy, 2-phenylpropoxy, 3-phenylpropoxy, 1-phenylbutoxy, 2-phenylbutoxy, 3-phenylbutoxy, 4-phenylbutoxy, 1.1-dimethyl-2-phenylethoxy, 5-
Examples include phenylalkoxy groups in which the alkoxy moiety has 1 to 6 carbon atoms, such as phenylpentyloxy, 6-phenylhexyloxy, and 2-methyl-3-phenylpropoxy.

In addition, lower alkylene groups include methylene, ethylene,
Trimethylene, 1-methyltrimethylene, 2-methylmethylene, 2,2-dimethyltrimethylene, tetramethylene, pentamethylene, hexamethylene, etc. with 1 carbon number
~6 alkylene groups are exemplified. Furthermore, the formula (,I)
~ represents cis, trans, or a mixture thereof.

The compound of the present invention can be produced by various methods, for example,
It can be produced by the method shown in the following Reaction Formula-1.

[Reaction formula-1] [■] [In the formula, X represents a halogen atom, and K and A are the same as above].

As shown in reaction formula-1 above, the carbostyril derivative [I] of the present invention is hydroxycarpostyril (I
It is produced by subjecting D and the tetrazole derivative [N) to a dehydrohalogenation reaction in a conventional manner. Examples of the halogen atom in the formula [1[E] include fluorine, bromine, chlorine, and iodine. This dehydrohalogenation reaction is carried out using a basic compound as a dehydrohalogenating agent. A wide range of known basic compounds can be used, including inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, silver carbonate, and alkalis such as sodium and potassium. Metals, alcoholades such as sodium methylate and sodium ethylate, triethylamine, pyridine, N,
N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo(4,
3,0] nonene-5 (DBN), 1,5-diazabicyclo (5,4,03 undecene-5 (DBU), 1,4-
Diazabicyclo[2,2,2]octane (DABCO)
Examples include organic bases such as . The reaction can be carried out without a solvent or in the presence of a solvent, and all inert solvents that do not adversely affect the reaction can be used, such as alcohols such as methanol, ethanol, propatool, butanol, and ethylene glycol. ethers such as dimethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, acetone, methyl ethyl ketone natonoketones, aromatic hydrocarbons such as benzene, toluene, xylene, esters such as methyl acetate, ethyl acetate, N, N- dimethylformamide,
Examples include aprotic polar solvents such as dimethyl sulfoxide and hexamethyl phosphoric triamide. It is also advantageous to carry out the reaction in the presence of a metal iodide such as sodium iodide or potassium iodide.

What is the usage ratio of hydroxycarbostyryl [■] and tetrazole derivative CI [] in the above method?

It is not particularly limited and can be appropriately selected from a wide range, but it is usually desirable to use the latter in an equimolar to 5-fold molar amount, preferably in an equimolar-2 molar amount to the former. Although the reaction temperature is not particularly limited, it is usually between room temperature and
200'C1 Preferably carried out at 50-150°C.

The reaction time is usually 1 to 30 hours, preferably 1 to 15 hours.

Hydroxycarbostyryl-(II), one of the starting materials used in the above method, is a known compound, but the other starting material, the tetrazole derivative [1[[], is a known compound, for example, the reaction formula shown below. It is manufactured by the method shown in -2.

Reaction formula-2= [■] [In the formula, X represents a halogen atom such as fluorine, chlorine, bromine and iodine, and R and A are the same as above].

That is, a haloamide represented by the general formula CIV), which is known or produced by a method similar to the known method, is reacted with PCl5 to form a haloimine derivative CVI, and hydrazoic acid ()'lN5) is produced without isolating this. A tetrazole derivative [■] is obtained by reaction.

The reaction between haloamide (IVI and PCl5 is generally carried out in a solvent. All inert solvents that do not adversely affect the reaction are used, such as aromatic hydrocarbons such as habenzene, xylene, and toluene. Examples include 10-genated aromatic hydrocarbons such as m, chlorobenzene and fromobenzene, ethers such as diethyl ether and dioxane, and hydrocarbons such as n-hexane and n-heptane.Haloamide [■] and PCl5 The ratio of the latter to the former is usually equivalent to 2 times the mole, preferably 1.2 times the same mole.The reaction temperature is usually -20 to 50°C, preferably 0. ~
The temperature is 25°C, and the reaction time is 30 minutes to 5 hours, preferably 1 to 3 hours.

The haloimine derivative [V] obtained as described above is not isolated, but is reacted with HN3 (usually used as a solution in benzene, xylene, diethyl ether, n-hexane, etc.). Haloimine derivative [v] and HN
3 and the latter is usually used in equal molar proportions to the former.
It is selected from the range of 5 times 1 mole, preferably equimolar to 3 times mole. Further, the reaction temperature is 0 to 150°C, and the reaction time is Qi to 2 days.

Furthermore, among the carbostyril derivatives of the general formula [''I],
For compounds where R is a hydroxyl group, the corresponding K is? A compound that is an enyl lower alkoxy group or a lower alkoxy group,
A suitable solvent, such as water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane and tetrahydrofuran, and acetic acid;
or in a mixed solvent thereof, in the presence of a catalytic reduction catalyst such as palladium-carbon or palladium-black, from 0 to 10
Defhenylalkyl (e.g., debenzylation) or dealkylation can be achieved by treatment at around 0°C under hydrogen pressure of 1 to 10 atm for about 0.5 to 3 hours, or by heat treatment in an aqueous solution of hydrobromic acid. It can also be manufactured by

Furthermore, those in which k is a lower alkanoyloxy group or benzoyloxy group can also be produced by acylating, that is, lower alkanoylating or benzoylating, a compound in which the corresponding k is a hydroxyl group.

Examples of the lower alkanoylating agent used include lower alkanoic acids such as acetic acid and propionic acid, lower alkanoic anhydrides such as acetic anhydride, and lower alkanoic acid halides such as acetyl chloride and propionyl bromide. Examples include benzoyl chloride, benzoyl bromide and other benzoic acid halides;
Examples include benzoic acid anhydride and benzoic acid. When an acid anhydride or an acid halide is used as the acylating agent, the acylation reaction is carried out in the presence of a basic compound.

Examples of the basic compounds used include alkali metals such as sodium metal and potassium metal, hydroxides, carbonates, and bicarbonates of these alkali metals, and aromatic amine compounds such as pyridine and piperidine. Although this process can be carried out either without a solvent or in a solvent, it is usually carried out using a suitable solvent. Examples of the solvent include ketones such as acetone and methyl ethyl ketone, ethers such as ether and dioxane, benzene, toluene, xylene nanoaromatic hydrocarbons, water, and pyridine.

The acylating agent is used in at least an equimolar amount relative to the raw material compound, but it is generally preferable to use an equimolar amount to a large excess.

In addition, the reaction proceeds at a temperature of 0 to 150°C, but generally 0 to 150°C.
It is best to carry out at a temperature of ~80°C.

The reaction time is approximately 0.5 to 10 hours.

In addition, when using acids such as lower alkanoic acids or benzoic acids as acylating agents, mineral acids such as sulfuric acid and hydrochloric acid and sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid, and ethanesulfonic acid are used as dehydrating agents in the reaction system. The diacylation reaction proceeds advantageously by adding acids and maintaining the reaction temperature preferably between 50 and 120°C.

A glue of the compound of the present invention represented by general formula (I).

A compound in which R represents a hydroxyl group can also be produced by hydrolyzing a corresponding compound in which R represents a lower alkanoyloxy group or a benzoyloxy group. This hydrolysis is carried out in a suitable solvent in the presence of an acid or basic compound. Examples of the solvent include water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane and tetrahydrofuran, and mixed solvents thereof. Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and examples of basic compounds include metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide. The reaction is usually carried out at room temperature to 1
The process is suitably carried out at 50° C., preferably 80 to 120° C., and is generally completed for about 1 to 15 hours.

Furthermore, among the carbostyril derivatives of general formula [I],
A compound where k is a phenyl lower alkoxy group has the corresponding k
is a hydroxyl group, phenyl lower alkyl halide (
For example, it can also be produced by lower alkoxylating phenyl with benzyl chloride, benzyl bromide, etc.). This reaction can be carried out under the same reaction conditions as in the reaction of the compounds represented by the general formulas [■] and [■].

Further, a compound in which k is a lower alkoxy group can also be obtained by alkylating a corresponding compound in which R is a hydroxyl group. Alkylating agents used in this method include methyl iodide, ethyl chloride, ter
Examples include lower alkyl halides such as t-butyW bromide, dimethyl sulfate, diethyl sulfate, and other alkylating agents such as diazomethane.

The reaction is carried out using, in addition to the solvent used in the acylation reaction,
Inert solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc. can be used, and in addition to the basic compounds used in the acylation reaction,
Silver oxide etc. can be used as a catalyst. Reaction temperature is 0°C
~ boiling point of the solvent, the proportion of the alkylating agent used is in the range of 1 to 3 times the molar amount of the compound of the general formula CI] in which K is a hydroxyl group. The reaction takes about 1 to 15 hours to complete.

A compound having an acidic group among the carbostyryl derivatives represented by the general formula (I) of the present invention 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, and potassium hydrogen carbonate.

The compound of general formula (Ill) thus produced can be easily isolated and purified by ordinary separation means. Examples of such separation means include solvent extraction, solvent dilution, recrystallization, liquid chromatography, etc. can.

The carbostyryl derivative [1] of the present invention has optical isomers. The present invention also includes these optical isomers.

The compounds of the present invention can be administered to animals and humans as such or together with conventional pharmaceutical carriers.

The dosage unit form is not particularly limited and may be appropriately selected and used as required. Examples of such dosage unit forms include oral preparations such as tablets, capsules, granules, and various oral liquid preparations, and parenteral preparations such as injections and waste preparations. The amount of the active ingredient to be administered is not particularly limited and is appropriately selected from a wide range, but in order to achieve the desired effect, it is preferably 0.06 to 10 per IKg of integrated product per day. .

Further, it is preferable that the dosage unit form contains 1 to 500q of the active ingredient.

In the present invention, oral preparations such as tablets, capsules, and oral liquid preparations are manufactured according to conventional methods. That is, tablets are prepared by mixing the compound of the present invention with seven pharmaceutical excipients: gelatin, starch, lactose, magnesium stearate, talc, and gum arabic. Capsules are prepared by mixing the compound of the present invention with an inert pharmaceutical filler or diluent, and filling the mixture into hard gelatin capsules, soft capsules, and the like. Oral liquid syrups and elixirs are prepared by mixing the compound of the present invention with sweetening agents such as sucrose, preservatives such as methyl- and propylparabens, coloring agents, flavoring agents, and the like. In addition, parenteral preparations are manufactured according to conventional methods, for example, by dissolving the compound of the present invention in a sterilized liquid carrier. The preferred carrier is water or saline. A solution having the desired clarity, stability, and suitability for parenteral use is about 1 to 50
It is produced by dissolving 0 mg of the active ingredient in water and an organic solvent, and then in polyethylene glycol having a molecular weight of 200-5000. Preferably, such a liquid agent contains a lubricant such as sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, or polyvinyl alcohol.

Furthermore, the above liquid preparation may contain bactericides and fungicides such as benzyl alcohol, phenol, and thimerosal, as well as isotonic agents such as sucrose and sodium chloride, local anesthetics, stabilizers, buffers, etc., as necessary. You can leave it there. In addition, from the viewpoint of stability, drugs for parenteral administration may be filled into capsules, etc., frozen, water removed using normal freeze-drying techniques, and liquid preparations prepared from the freeze-dried powder immediately before use. can.

Next, the results of pharmacological tests on the compounds of the present invention are shown.

Platelet aggregation inhibitory effect: The platelet aggregation inhibitory effect of the compound of the present invention was determined by the Born method [
G, V, RoBorn, Nature 927-929
(1962)].

That is, a blood sample taken from a rabbit was ioo.

Centrifuge for 10 minutes at rpm to remove serum with high platelet concentration (
PRP) is obtained and further centrifuged at 3000 rpm for 15 minutes to obtain serum with a low platelet concentration (ppp). The obtained PRP was diluted appropriately with PPP to prepare a PNP sample for adenosine diphosphate (ADP)-induced aggregation test (platelet concentration: 300.00/gaF) and a PRP sample for collagen-induced aggregation test (platelet concentration: 4so
, ooo/5rj).

A solution containing 0.4 to 10-) moles of test compound.
Add 0.6 ml of each sample prepared above to 01-,
The tube is kept in a constant temperature bath at 7.degree. C. for 1 minute, 0.07 Tnl of collagen or ADP solution is added thereto, and the permeability is measured. Based on these results and the separately measured permeability of PPP and PRP, the aggregation rate was calculated according to the following formula: The aggregation inhibitory effect was measured by the inhibition rate (C%) compared to the aggregation rate when no compound was added (control).

The inhibitory effect on collagen-induced aggregation is shown in Table 1.
The inhibitory effect on DP-induced aggregation is shown in Table 2. The test compounds are as follows. Note that acetylsalicylic acid was used as a control substance.

1, 6-(4-[1-(24 lance-benzyloxycyclohexyl)tetrazol-5-yl]butoxy)
-3,4-dihydrocarbostyryl 2,6-(4-(1-(2-trans-hydroxycyclohexyl)tetrazol-5-yl]butoxy)-
3,4-dihydrocarbostyryl 3, 6-(4-1:
1-(4-trans-benzyloxycyclohexyl)
Tetrazol-5-yl]butoxy)-3,4-dihydrocarbostyryl 4,6-(4-(1-(4-1-lance-hydroxycyclohexyl)tetrazol-5-yl]butoxy)
-3,4-dihydrocarbostyril Table 1 Acute toxicity test: The same test compound as above was orally administered to male mice to achieve LD5.
o (11 g/Kg) was measured. The results are shown in Table 3.

Table 3 Next, the present invention will be explained in more detail with reference to Reference Examples, Examples, and Formulation Examples.

Reference Example I N-(2-) lance-benzoylcyclohexyl) -
5-chlorovaleramide is suspended in 9.5-1-benzene (90-), and 6.72% of phosphorus pentachloride is added while stirring and cooling on an ice-water bath, followed by stirring at room temperature for 1 hour.

Next, under water-cooled stirring, a benzene solution of hydroazoic acid (0,
345N) 100WLl is added dropwise. After the dropwise addition, the mixture was stirred at room temperature overnight, and then the solvent was distilled off under reduced pressure. Dissolve the residue in chloroform and wash with water. After drying with magnesium sulfate, the solvent is distilled off. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol-50:1) to give 1-(2-trans-benzyloxycyclohexyl)-5-(4-chlorobutyl)tetrazole 4.
．． Get 87. Melting point 78.5-79.5°C0 Reference example 2 N-(2-) lance-methoxycyclohexyl)-5-
Chlorovaleryl amide 7,29 is suspended in 90i, cooled on an ice-water bath, and 6.72 g of phosphorus pentachloride is added thereto, followed by stirring at room temperature for 1 hour.

Next, under water-cooled stirring, a benzene solution of hydroazoic acid (0,
345N) 100mZ dropwise. After the dropwise addition, the mixture was stirred at room temperature overnight, and then the solvent was distilled off under reduced pressure. Dissolve the residue in chloroform and wash with water. After drying with magnesium sulfate, the solvent is distilled off. The residue was subjected to silica gel column chromatography (eluent: chloroform:methanol = 50:1
) to give 1-(2-)trans-methoxycyclohexyl)-5-(4-chlorobutyl)tetrazole 32
get.

Elemental analysis value: C12H21N40C6 (M, W, 2
72.78) Calculated value UC, 52,,84; H,7,
76HN, 20°54 Actual value (goods) C, 52, 64
, H, 7,95iN.

20.36 Example 1 6-Hydroxy-3,4-dihydrocarbostyryl 1.
63F and 0.7y of potassium hydroxide are added to 40ml of isopropanol and heated to reflux to dissolve. Ko (7)
Solution K, 1-(2-trans-benzyloxycyclohexyl)-5-(4-chlorobutyl)tetrazole 4
．． 57 and heated under reflux for 5 hours. After the reaction, the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol = 50:l), recrystallized from chloroform-petroleum ether,
2.4 g of 6-(4-(1-(2-)lans-benzyloxycyclohexyl)tetrazol-5-yl]butoxy)-3,4-dihydrocarbostyryl are obtained in the form of colorless needles. Melting point 117-118°C0 Examples 2-16 The following compounds are obtained in the same manner as in Example 1 using appropriate starting materials.

(2) 6-(4-CI-(4-trans-benzyloxycyclohexyl)tetrazol-5-yl]
(3) 6- (4-1: 1- (2-cis-benzyloxycyclohexyl) ) Tetrazol-5-yl]
(4) 6-(4-(:1-(4-cis-benzyloxycyclohexyl)tetrazole -5-yl]butoxy)-3,4-dihydrocarbostyryl, colorless needles, melting point 149-151°C (chloroform-petroleum ether) (5) 6-(4-CI-(3-trans-benzyloxy) cyclohexyl)tetrazol-5-yl]
(6) 6- (4-CI-(2-trans-benzyloxycyclohexyl)tetrazole-5- il]
butoxy) carbostyril, can-colored powder crystals, melting point 181
．． 5-183.5°C (hydrous ethanol) (7) 5
- (4-(1-(2-trans-benzyloxycyclohexyl)tetrazol-5-yl]butoxy)-3
,4-dihydrocarbostyryl, colorless needle crystals, melting point 16
5.5-166°C (chloroform-petroleum ether) (8) 6-(4-(1-(2-1-lance-hydroxycyclohexyl)tetrazol-5-yl]butoxy)-3,4-dihydrocarbostyryl , colorless needle crystals, melting point 176-177°C (hydrated ethanol) (9) 6-(4-[1-(4-trans-hydroxycyclohexyl)tetrazol-5-yl]butoxy)-3,4-dihydrocarbo styryl, colorless needles,
Melting point 199-201.5°C (hydrous ethanol) (10) 6-(4-(1-(2-cis-hydroxycyclohexyl)tetrazol-5-yl]butoxy)-3,4-dihydrocarbostyryl, colorless needles Crystalline, melting point 158-160°C (hydrous ethanol) (u) 6-
(4-(1-(4-cis-hydroxycyclohexyl)tetrazol-5-yl)butoxy)-3,4-dihydrocarbostyryl, colorless powder crystal, melting point 196-19
7°C (hydrous ethanol) (2) 6-(4-(1-(
2-trans-hydroxycyclohexyl)tetrazol-5-yl]butoxy)carbostyryl, colorless powdery crystals, melting point 203-205°C (hydrous ethanol) 03)
6-(4-CI-(2-1-lance-acetyloxycyclohexyl)tetrazol-5-yl]butoxy)-3,4-dihydrocarbostyryl, colorless powder crystal, melting point 132.5-133.5 °C (Aqueous ethanol) OA) 6-(4-(1-(2-) lance-methoxycyclohexyl]tetrazol-5-yl]butoxy)
-3,4-dihydrocarbostyryl, colorless powdery crystals, melting point 158-159.5°C (Metanol-ether) 6-(4-[:1-(2-trans-benzoyloxycyclohexyl) ) Tetrazol-5-yl]butoxy)-3,4-dihydrocarbostyryl, colorless powder crystals, melting point 174-175.5°C (methanol-
ether) (2) 5-(4-[1-(2-trans-hydroxycyclohexyl)tetrazol-5-yl]butoxy)
-3,4-dihydrocarbostyryl, colorless needle crystals, melting point 195-197°C (hydrated ethanol) Example 17 6-(4-C1-(2-trans-benzyloxy)cyclohexyltetrazol-5-yl) ]Butoxy)-3
, 8 g of 4-dihydrocarbostyril was suspended in a mixed solvent of 50 tnl of methanol and 50 tnl of acetic acid.
Add 0.57 of 0.096 palladium-hydrogen catalyst, and the initial pressure is 2.
Catalytic reduction is carried out at atmospheric pressure and 60-70°C. After the reaction, the catalyst was filtered, the filtrate was concentrated, and recrystallized from aqueous ethanol to obtain colorless needle-like crystals of 6-(4-(1-(2-1-lans-hydroxycyclohexyl)tetrazol-5-yl). ] Butoxy)-3,4-dihydrocarbostyryl 1.21 is obtained.

Melting point 176-177°C0 The following compound is obtained in the same manner as above.

6-(4-(1-(2nodorans-hydroxycyclohexyl)tetrazol-5-yl]butoxy)-3,4
-dihydrocarbostyryl, melting point 176-177°C 6-(4-(1-(4-trans-hydroxycyclohexyl)tetrazol-5-yl]butoxy)-3,4
-dihydrocarbostyril, melting point 199-201.5°
C6-(4-(1-(2-cis-hydroxycyclohexyl)tetrazol-5-yl)butoxy)-3,4-dihydrocarbostyryl, mp 158-160'C6-(4-[1-(4 -cis-hydroxycyclohexyl)tetrazol-5-yl]butoxy)-3,4-dihydrocarbostyryl, melting point 196-197°C 6-(4-(1-(24 lance-hydroxycyclohexyl)tetrazol-5-yl)butoxy ) carbostyril, melting point 203-205°C3-(4-(:1-(2
-trans-hydroxycyclohexyl)tetrazol-5-yl]butoxy)-3,4-dihydrocarbostyryl, melting point 195-197°C Example 18 6-(4-(1-(21 lance-hydroxycyclohexino″L/) Tetrazol-5-yl]butoxy)-3
, 200 WIg of 4-dihydrocarbostyryl were added with 2 d of pyridine and 1 d of acetic anhydride, and the mixture was stirred at room temperature for 3 hours. The reaction solution was dissolved in chloroform, and the organic layer was dissolved in 5z hydrochloric acid,
Wash with water, saturated sodium bicarbonate solution, saturated potassium bisulfate, water.

After drying with magnesium sulfate, the solvent is distilled off. Recrystallization from aqueous ethanol yields colorless powdery crystals of 6-(4-(1
-(2-)Lance-acetoxycyclohexyl)tetrazol-5-yl]butoxy)-3,4-dihydrocarbostyryl 200 capes are obtained. Melting point 132.5-133.
5°C0 In the same manner as above, using appropriate starting materials,
The following compound is obtained.

6-(4-1:1-(2-trans-benzoyloxycyclohexyl)tetrazol-5-yl]butoxy)
-3,4-dihydrocarbostyryl, melting point 174-17
5.5℃.

Example 19 6-[4-[1-(2-1 lance-hydroxycyclohexyl)tetrazol-5-yl]butoxy)-3,4
-Dissolve 200 cape of dihydrocarbostyril in 2 tnl of DMF, add 180 sy of silver oxide, add 0.051 nl of methyl iodide, and stir at room temperature for 9 hours. After removing insoluble materials, chloroform is added to the filtrate and the mixture is washed with water. After drying with magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol = 50:1), recrystallized from methanol-ether, and 6- (4-[1
-(2-trans-methoxycyclohexyl)tetrazol-5-yl]butoxy)-3,4-dihydrocarbostyryl 20 days are obtained. Melting point 158-1159.5℃
.

Formulation Example 1 Preparation of Tablets Each 5q of 6-(4-[1-(2-trans-benzyloxycyclohexyl)tetrazol-5-yl]
1000 tablets for oral use containing phthoxy)-3,4-dihydrocarbostyryl are prepared according to the following formulation.

Mixing amount (7) 6-(4-
(1-(2-trans-benzyloxycyclohexyl 5)tetrazol-5-yl]butoxy)-3,4-dihydrocarbostyryl lactose (Japanese Pharmacopoeia) 50 Cornstarch (Japanese Pharmacopoeia) 25 Crystalline cellulose (Japanese Pharmacopoeia) 25 Methylcellulose (Japanese Pharmacopoeia) 1.5 Magnesium Stearate (Japanese Pharmacopoeia) 16-(4-[
:1-(2-trans-benzyloxycyclohexyl)tetrazol-5-yl]butoxy)-3,4-dihydrocarbostyryl, lactose, cornstarch and crystalline cellulose were thoroughly mixed, granulated with a 5z aqueous solution of methylcellulose, and Pass through a mesh sieve and dry carefully. The dried granules are passed through a 200 mesh sieve, mixed with magnesium stearate and pressed into tablets.

Formulation Example 2 Preparation of Injection A sterile aqueous solution suitable for parenteral administration is prepared according to the following recipe.

6-(4-(1-(2-)lans-hydroxycyclohexyl)tetrazole-
5-yl]butoxy)23,4-dihydrocarbostyryl chloride) IJium (Japanese Pharmacopoeia crystal) 0.9 Sodium metabisulfite 0.1 Methyl-paraben (
Japanese Pharmacopoeia Crystal) 0.18 Propyl-paraben (
Japanese Pharmacopoeia crystal) 0.02 Distilled water for injection
100 Crd) the above parabens,
Sodium metabisulfite and sodium chloride are dissolved in about half the amount of distilled water above at 80° C. with stirring. The resulting solution was cooled to 40°C and 6-(4-1:1-(
2-) lance-hydroxycycloyxyl)tetrazol-5-yl]butoxy)-3.4. - dihydrolupostil, then polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the solution. The solution is adjusted to the final volume by adding distilled water for injection and sterilized by filtration using a suitable filter to obtain 1 injection.

Patent applicant Otsuka Pharmaceutical Co., Ltd. Representative Patent Attorney Aoyama T’M 11 people Continuation of page 1 15100 257100) 0 shots clearer Tatsuyoshi Tanaka 21-3, Yoshinari, Todoroki, Ojin-cho, Tokushima City 0 shots by Takao Nishi 21 Kita 16-jo Nishi 3-chome, Kita-ku, Sapporo earth ■Developer: Medium dose 774-1 Omatsu, Kawauchi-cho, Tokushima City

Claims (1)

[Claims] (1) General formula [In the formula, K represents a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, a phenyl lower alkoxy group or a heptabenzoyloxy group, and A represents a lower alkylene group. Further, carbostyril derivatives and salts thereof represented by the following formula: the carbon bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond.