JPS6127370B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to new phosphodieslase inhibitors. In the course of a series of studies on carbostyril derivatives, the present inventors found that among carbostyril derivatives useful as anti-inflammatory agents and platelet aggregation inhibitors, cyclic adenosine, which has a pharmacological action completely unrelated to these pharmacological actions, The inventors have discovered that there is a compound that has a phosphodiesterase (PDE) inhibitory effect specific to monophosphate (hereinafter referred to as C-AMP), and have now completed the present invention. That is, the present invention is based on the general formula [In the formula, R ¹ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, or a phenylalkyl group, R ² is a hydrogen atom, a halogen atom, a hydroxyl group, or a phenylalkoxy group, R ³ is a hydrogen atom,
Hydroxyl group or alkyl group having 1 to 4 carbon atoms and R ⁴
and R ⁵ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group with or without a substituent, a phenyl group with or without a substituent, or a phenyl group with or without a substituent on the phenyl ring. (However, the substituent represents a lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, or a halogen atom.), a cycloalkylalkyl group, and an alkenyl group having 2 to 4 carbon atoms. Further, R ⁴ and R ⁵ may form a piperidine ring, a piperazine ring or a morpholine ring together with the nitrogen atom to which they are bonded. l and m each represent 0 or an integer whose sum is 7 or less, and m represents an integer from 1 to 3. In addition, a C-AMP-specific phosphodiesterase inhibitor containing a carbostyryl derivative or a salt thereof as an active ingredient (the carbon bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond) Related. Examples of the alkyl group having 1 to 4 carbon atoms in the above general formula [1] include methyl, ethyl, propyl, ipropyl, butyl, and tert-butyl groups;
Examples of alkenyl groups in 4 include vinyl, allyl, isopropenyl, and 2-butenyl groups, and examples of phenylalkyl groups include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, and 1.1. -dimethyl-2-phenylethyl group, phenylalkoxy groups such as benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 1,1-
Examples of the dimethyl-2-phenylethoxy group include fluorine, chlorine, bromine, and iodine atoms as the halogen atom. In addition to the above alkyl groups, the alkyl groups having 1 to 8 carbon atoms represented by R ⁴ and R ⁵ include pentyl, isopentyl, neopentyl, 2-
Includes methylbutyl, hexyl, isohexyl, 2-ethylbutyl, heptyl, 3-methylhexyl, octyl, and the like. In addition, cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl groups, etc., and cycloalkylalkyl groups include:
4-Cyclohexylbutyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclopentylpropyl, 3-cyclohexylpropyl, cyclopentylmethyl, 2-cyclohexylethyl, 2-cyclohexylpropyl, 2-cycloheptylethyl, 3-cyclobutylpropyl, 1.
1-dimethyl-2-cyclohexylethyl, 1-
Methyl-2-cyclopentylethyl, 2-cyclooctylethyl groups, etc., and groups with or without substituents on the phenyl ring include 4-ethoxybenzyl, 2-(3,4-dimethoxyphenyl)ethyl, 1-(3,5-dimethoxyphenyl)ethyl, 3-(2-butoxyphenyl)propyl, 4
-(3,4-dimethoxyphenyl)butyl, 1.
1-dimethyl-2-(3,4-diethoxyphenyl)ethyl group and the like are included. The above cycloalkyl group may have one or two substituents together with the phenyl group represented by R ⁴ and R ⁵ ,
Examples of the substituent include the following. Straight chain or branched alkyl group or alkoxy group having 1 to 4 carbon atoms; halogen atom; 2 carbon atoms
An alkanoyloxy group in which ~4 linear or branched alkanoyl groups and an oxygen atom are bonded; hydroxyl group. Further, the heterocycle formed by R ⁴ and R ⁵ together with the nitrogen atom to which they are bonded includes piperazine, morpholine, and piperidine rings, and these rings may have the above-mentioned alkyl group as a substituent. Representative examples of the compound represented by the above general formula [1] are listed below. Γ6-(N-allyl-N-cyclopentylaminocarbonylmethoxy) carbostyryl Γ6-(N-methyl-N-cycloheptylaminocarbonylmethoxy) carbostyryl Γ6-(N-methylanilinocarbonylmethoxy)-3,4-dihydro Carbostyryl Γ6-[2-(N-ethyl-N-cyclooctylaminocarbonyl)ethoxy]carbostyryl Γ6-[2-(N-allyl-N-cycloheptylaminocarbonyl)ethoxy]-3,4-dihydrocarbostyryl Γ6-[3-(N-cycloheptylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl Γ6-[3-(N-allyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl Γ6-[3-(N -Methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl Γ6-[3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl Γ6-[3-(N-butyl-N -cyclohexylaminocarbonyl)propoxy]carbostyryl Γ6-[3-(o-chloroanilinocarbonyl)propoxy]carbostyryl Γ6-[3-(p-methoxyanilinocarbonyl)
propoxy]-3,4-dihydrocarbostyryl Γ6-[3-(m-hydroxyanilinocarbonyl)propoxy]carbostyryl Γ6-[3-(N-ethylanilinocarbonyl)propoxy]carbostyryl Γ6-[3-( N・N-diphenylaminocarbonyl)propoxy]carbostyryl Γ6-[3-(N-methyl-o-methylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyryl Γ6-[3-(N・N- dicyclohexylaminocarbonyl)propoxy]carbostyryl Γ6-[3-(N-cyclopentyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl Γ6-[3-(N-cyclohexylanilinocarbonyl)propoxy]-3,4-dihydrocarbo Styryl Γ6-[4-(N-ethyl-N-cyclohexylaminocarbonyl)butoxy]carbostyryl Γ6-[4-(N-methylanilinocarbonyl)butoxy]-3,4-dihydrocarbostyryl Γ6-[4-( o・o-dimethylanilinocarbonyl)butoxy]carbostyryl Γ6-[5-(N-methyl-N-cyclohexylaminocarbonyl)pentyloxy]carbostyryl Γ6-[5-(N-cyclohexylanilinocarbonyl)pentyloxy]carbostyryl Γ6-[6-(N-methyl-N-cyclohexylaminocarbonyl)hexyloxy]-3,4-dihydrocarbostyryl Γ6-[6-(N-ethylanilinocarbonyl)hexyloxy]carbostyryl Γ5-(N-methyl- N-cycloheptylaminocarbonylmethoxy)-3,4-dihydrocarbostyryl Γ5-[2-(N-methyl-N-cyclohexylaminocarbonyl)ethoxy]carbostyryl Γ6-[8-(N-ethyl-N-cyclohexylamino carbonyl)octyloxy]carbostyryl Γ5-[3-(N-allyl-N-cyclopentylaminocarbonyl)propoxy]carbostyryl Γ5-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl Γ5-[3 -(N-propylanilinocarbonyl)
Propoxy] Carbostyryl Γ5-[3-(N-N-dicyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl Γ5-[4-(N-methyl-N-cyclohexylaminocarbonyl)butoxy]-3・4-dihydrocarbostyryl Γ5-[5-(N-methyl-N-cyclohexylaminocarbonyl)pentyloxy]carbostyryl Γ7-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl Γ7-[3 -(N-ethylanilinocarbonyl)propoxy]carbostyryl Γ8-[3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl Γ6-[3-(N-octyl-N-cyclohexylaminocarbonyl)propoxy [Carbostyryl Γ5-[3-(N-heptyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarstyryl Γ6-{3-[N-cyclohexyl-N-(2-phenylethyl)-aminocarbonyl] propoxy}carbostyryl Γ6-{3-[N-methyl-N-(2-cyclohexylethyl)aminocarbonyl]propoxy}
Carbostyryl Γ6-{3-[N-phenyl-N-(2-cyclohexylethyl)aminocarbonyl]propoxy} Carbostyryl Γ1-allyl-5-[1-(p-methoxyanilinocarbonyl)ethoxy]-3,4 -dihydrocarbostyryl Γ1-ethyl-6-[3-(N-methylanilinocarbonyl)propoxy]carbostyryl Γ5,6,7-trichloro-8-[5-(N-ethyl-N-cyclohexylamino)pentyloxy] Carbostyryl Γ1-benzyl-6-[3-(N・N-diphenylaminocarbonyl)propoxy]carbostyryl Γ6-[2-methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl Γ6 -[2-Butyl-3-(N-allyl-N-cyclohexylaminocarbonyl)propoxy]-
3,4-dihydrocarbostyryl Γ6-[4-methyl-5-(N-propyl-N-cyclohexylaminocarbonyl)heptyloxy]carbostyryl Γ5-[2-methyl-3-(N-methyl-N-cyclohexylamino carbonyl)propoxy]carbostyryl Γ8-[2-methyl-3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]-
3,4-dihydrocarbostyryl Γ5-chloro-6-[3-(N-ethyl-o-methylanilinocarbonyl)propoxy]carbostyryl Γ5-fluoro-6-[3-(N-ethyl-N-cyclohexylamino) carbonyl) propoxy]
Carbostyryl Γ5-chloro-6-[2-methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl Γ5,6,7-tribromo-8-[3-( N-methylanilinocarbonyl)propoxy]-3,4
-dihydrocarbostyryl Γ8-bromo-5-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl Γ8-bromo-6-[2-methyl-3-(N-methyl-N-cyclohexylamino carbonyl)propoxy]carbostyryl Γ6,8-dichloro-5-[3-(N-ethylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyrylΓ5,7-dichloro-6-[3-(N-methyl -N
-cyclohexylaminocarbonyl)propoxy]carbostyryl Γ5,7,8-trichloro-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl Γ8-hydroxy-5-[3-(N-methyl -N-
cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl Γ5-benzyloxy-6-[3-(N-ethyl-N
-cyclohexylaminocarbonyl)propoxy]carbostyryl Γ7-hydroxy-6-[3-(N-methyl-N-
cyclohexylaminocarbonyl)propoxy]carbostyryl Γ5,8-dihydroxy-6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl Γ1-(4-phenylbutyl)-5- [3-(N-ethyl-N-cyclopropylaminocarbonyl)
propoxy]-3,4-dihydrocarbostyryl Γ1-(2-butenyl)-6-[3-(N-methyl-
N-cyclohexylaminocarbonyl)propoxy]carbostyryl Γ6,8-dichloro-1-methyl-5-[4-(N
-ethyl-N-cyclohexylaminocarbonyl)butoxy]carbostyryl Γ8-hydroxy-1-ethyl-5-[3-(N-
Methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl Γ1-methyl-7-[2-methyl-3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl Γ5-{1-[N-ethyl- N-(3-methylcyclohexyl)aminocarbonyl]propoxy}
Carbostyryl Γ5-{3-[N-methyl-N-(4-hydroxycyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyryl Γ6-{3-[N-methyl-N-(2-methylcyclohexyl) Aminocarbonyl [propoxy]
Carbostyryl Γ6-{3-[N-methyl-N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy} Carbostyryl Γ6-[3-(N-4-methoxycyclohexylaminocarbonyl)propoxy]-3,4-dihydro Carbostyryl Γ6-{3-[N-methyl-N-(4-acetyloxycyclohexyl)aminocarbonyl]propoxy} Carbostyryl Γ6-{2-methyl-3-[N-methyl-N-(2
-methylcyclohexyl)aminocarbonyl]
propoxy}-3,4-dihydrocarbostyryl Γ1-benzyl-6-[3-(N-4-ethoxycycloheptylaminocarbonyl)propoxy]
Carbostyryl Γ8-hydroxy-5-{1-[N-methyl-N-
(3-Methylcyclohexyl)aminocarbonyl]propoxy}carbostyryl Γ5,6,8-trichloro-6-{3-[N-methyl-N-(4-acetyloxycyclohexyl)aminocarbonyl]propoxy}-3,4
-dihydrocarbostyryl Γ6-{3-[N-methyl-N-(2-hydroxy-5-methylcyclohexyl)aminocarbonyl]propoxy}carbostyryl Γ6-{3-[N-methyl-N-(4-chlorocyclohexyl) ) aminocarbonyl [propoxy]
Carbostyryl Γ6-{3-[N-methyl-N-(3,4-dimethoxycyclohexyl)aminocarbonyl]propoxy} Carbostyryl Γ6-{3-[N-methyl-N-(2,6-dimethylcyclohexyl)amino carbonyl]propoxy}carbostyryl Γ6-{3-[N-ethyl-N-(2,5-dimethoxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl Γ6-{3-[N-methyl-N -(2,5-dichlorocyclohexyl)aminocarbonyl]propoxy}carbostyryl Γ6-{3-[N-cyclohexylmethyl-(2-
chlorocyclohexyl)aminocarbonyl]propoxy}carbostyrylΓ6-[2-hydroxy-3-(N-methyl-N-
cyclohexylaminocarbonyl)propoxy]carbostyryl Γ5-[2-hydroxy-3-(N-ethyl-p-
methylanilinocarbonyl)propoxy]-
3,4-dihydrocarbostyryl Γ6-[2-hydroxy-3-(N-methylanilinocarbonyl)propoxy]carbostyryl Γ1-ethyl-6-[2-hydroxy-3-(N-
Methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl Γ6-{3-[N-methyl-N-(2-3′・4′-dimethoxyphenylethyl)aminocarbonyl]
propoxy}carbostyryl Γ6-{3-[N-allyl-N-(2-3'・4'-dimethoxyphenylethyl)aminocarbonyl]
propoxy}-3,4-dihydrocarbostyryl Γ6-{3-[N-benzyl-N-(2-3′・4′-
dimethoxyphenylethyl)aminocarbonyl]propoxy}carbostyryl Γ6-{3-[N-phenyl-N-(2-3'・4'-
dimethoxyphenylethyl)aminocarbonyl]propoxy}carbostyryl Γ6-{3-[N-cyclohexyl-N-(2-
3′,4′-dimethoxyphenylethyl)aminocarbonyl]propoxy}carbostyrylΓ6-{2-methyl-3-[N-ethyl-N-(2
-3',4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}carbostyrylΓ5-chloro-6-{3-[N-methyl-N-(2
-3',4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}carbostyrylΓ1-methyl-6-{3-[N-methyl-N-(2
-3', 4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl Γ8-hydroxy-5-{3-[N-methyl-N-
(2-3',4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}carbostyryl Γ6-{3-[N-octyl-N-(2-methylcyclohexyl)aminocarbonyl]propoxy}carbostyryl Γ6-{3 -[N-heptyl-N-(3-hydroxycyclohexyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl Γ6-{3-[N-octyl-N-(2-chlorocyclohexyl)aminocarbonyl]propoxy} Carbostyryl Γ6-[3-(N-cyclohexyl-N-cyclohexylmethylaminocarbonyl)propoxy]
Carbostyryl Γ6-{3-[N-(2-cyclopentyl-1-methylethyl)aminocarbonyl]propoxy}
Carbostyryl Γ6-{2-[N-(2-cyclopentylethylaminocarbonyl]ethoxy}-3,4-dihydrocarbostyryl Γ6-[3-(N-butyl-N-cyclooctylaminocarbonyl)propoxy]carbostyryl Γ6 -[3-(N-benzylaminocarbonyl)propoxy]carbostyryl Γ6-[3-(N-ethyl-N-cyclooctylaminocarbonyl)propoxy]carbostyryl Γ6-[3-(N-methylaminocarbonyl)propoxy] Carbostyryl Γ6-[3-(N-methyl-N-isopropylaminocarbonyl)propoxy] Carbostyryl Γ6-(3-piperidinocarbonylpropoxy)
Carbostyryl Γ6-(3-morpholinocarbonylpropoxy)
Carbostyryl Γ6-[3-(4-methylpiperazinocarbonyl)
[propoxy]carbostyril The compound represented by the above general formula [1] used as the active ingredient of the inhibitor of the present invention is mostly a new compound, and can be produced, for example, by the method shown in the following reaction scheme -1 and -2. Ru. Reaction formula-1 Reaction formula-2 (In the above formula, X represents a halogen atom. R ¹ ,
R ² , R ³ , R ⁴ , R ⁵ , m, l, n and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ) The general formula [2] used as the starting material in the above,
Each compound represented by [3], [4] and [5] is a known compound or a new compound,
It is produced by the method shown in Reaction Scheme-3 to Reaction Scheme-9 below. In the method shown by Reaction Scheme-1, a hydroxycarbostyryl derivative represented by the general formula [2] and a haloamide represented by the general formula [3] are subjected to a dehydrohalogenation reaction. This reaction is usually carried out using a basic compound as a dehydrohalogenating agent. Examples of basic compounds include inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, silver carbonate, alkali metals such as sodium and potassium, sodium methylate, sodium Alcoholates such as ethylate, organic bases such as triethylamine, pyridine, N.N-dimethylaniline and the like can be used. The reaction can be carried out without a solvent or with alcohols such as methanol, ethanol, propanol, butanol, and ethylene glycol, ethers such as dimethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme,
Ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as methyl acetate and ethyl acetate,
The process proceeds in the presence of a solvent such as an aprotic polar solvent such as N.N-dimethylformamide, dimethyl sulfoxide, and hexamethyl phosphoric triamide. Further, the reaction is advantageously carried out in the presence of a metal iodide such as sodium iodide or potassium iodide. The ratio of the hydroxycarbostyryl derivative [2] and haloamide [3] to be used in the above method is not particularly limited, but the latter is usually used in an equimolar to 5-fold molar amount, preferably in an equimolar to 2-fold molar amount to the former. is desirable. Further, the reaction temperature is not particularly limited, but it is usually carried out at room temperature to 200°C, preferably 50 to 150°C. The reaction time is usually 1 to 30 hours, preferably 1 to 15 hours. In the method shown in Reaction Scheme-2, a carboxyalkoxycarbostyryl derivative represented by the general formula [4] and an amine represented by the general formula [5] are reacted to form an amide bond. In this method, a compound whose carboxy group is activated may be used instead of the compound of general formula [4]. For the above-mentioned amide bond-forming reaction, the conditions of known amide bond-forming reactions as shown in (a) to (d) below can be easily applied. (a) Mixed acid anhydride method A method in which carboxylic acid [4] is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, and this is reacted with amine [5], (b) Active ester method Carboxylic acid [4] A method of reacting p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc. with amine [5], (c) Carbodiimide method to carboxylic acid [4] A method in which amine [5] is dehydrated and condensed in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole, (iv) Other methods Carboxylic acid [4] is converted into a carboxylic acid anhydride using a dehydrating agent such as acetic anhydride. A method of reacting an amine [5] with an ester of a carboxylic acid [4] and a lower alcohol under high pressure and high temperature, a method of reacting an acid halide of a carboxylic acid [4], that is, a carboxylic acid halide with an amine [ 5] Method for reacting. Among the above methods, the mixed acid anhydride method is preferred.
Examples of the alkylhalocarboxylic acids used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. The mixed acid anhydride is obtained by the usual Schotten-Baumann reaction, and the compound represented by the general formula [1] is produced by reacting it with the amine [5] without isolation. The Schotten-Baumann reaction can be carried out using basic compounds commonly used in the reaction, such as
The reaction is carried out in the presence of an organic base such as triethylamine, trimethylamine, pyridine, dimethylaniline or N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate. The reaction is carried out at -20 to 100℃
It is preferably carried out at a temperature of 0 to 50°C for 5 minutes to 10 hours, preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and amine [5] is carried out at a temperature of -20 to 150°C, preferably 10 to 50°C, for 5 minutes to 10 hours, preferably 5 minutes to 5 hours. The mixed acid anhydride method uses solvents commonly used in the method, specifically halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, diethyl ether, tetrahydrofuran, and dimethoxyethane. Ethers such as methyl acetate, esters such as ethyl acetate,
This is carried out using an aprotic polar solvent such as N.N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, or the like. The ratio of carboxylic acid [4], alkyl halocarboxylic acid, and amine [5] used in this method is usually equal moles, but the ratio of alkyl halocarboxylic acid and amine [5] to carboxylic acid [4] is 1.5. It may be used up to twice the mole. Of the compounds represented by general formula [2] used as starting materials in reaction scheme-1, R ²
Compound [2b] in which R is a halogen atom is a compound [2a] (known compound) in which R ² is a hydrogen atom among the compounds represented by the general formula [2], as shown in the following reaction scheme-3. It is easily manufactured by Reaction formula-3 (In the above formula, X represents a halogen atom. R ¹ , m and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above.) The above halogenation reaction is carried out using a known halogenating agent. It can be carried out advantageously. Examples of halogenating agents include fluorine, chlorine, bromine, iodine, xenon difluoride, sulfuryl chloride, sodium hypochlorite, hypochlorous acid,
Examples include hypobromous acid and bleaching powder. The amount of the halogenating agent to be used may be appropriately selected from a wide range depending on the number of halogen atoms to be introduced into the compound [2a], and when one halogen atom is introduced, it is usually equimolar to the compound [2a]. ~2 times the molar amount, preferably an equimolar ~1.5 times the molar amount of the halogen atom.
When introducing 1.5 times the molar amount to a large excess amount,
It is preferable to use 2 to 3 times the molar amount, and when three halogen atoms are introduced, usually 2.5 times to a large excess amount, preferably 3 to 5 times the molar amount. Such halogenation reactions usually involve water, methanol, ethanol, chloroform, carbon tetrachloride,
It is preferable to carry out the reaction in a suitable solvent such as acetic acid or a mixed solvent thereof. The reaction temperature may be appropriately selected from a wide range, but is usually about -20 to 100°C, preferably 0°C to room temperature, and the reaction is completed within about 30 minutes to 10 hours. Among the compounds of general formula [2b] obtained by the above reaction scheme-3, m is 1 [2c]
can also be easily produced by the method shown in Reaction Scheme-4 below. Reaction formula-4 (In the above formula, R ⁶ represents an alkyl group. R ¹ , The hydroxy-halogenocarbostyryl derivative represented by the general formula [2c] can be produced by halogenating the carbostyril derivative and then hydrolyzing the obtained acyloxy-halogenocarbostyryl derivative represented by the general formula [7]. The reaction conditions for the halogenation reaction may be the same as those described above, and the conditions for the hydrolysis reaction may be the same as those shown below. In the reaction scheme-2 mentioned above, general formula [4]
In the compound represented by R ² is a halogen atom,
The compound exhibiting a hydroxyl group or phenyl alkoxy group is a new compound, and is produced, for example, by the method shown in Reaction Scheme-5 below. Reaction formula-5 (In the above formula, R ² represents a halogen atom, hydroxyl group or phenyl alkoxy group, R ⁷ represents an organic residue, X, R ¹ , R ³ , m, l, n and the 3rd position of the carbostyril skeleton) and the carbon-carbon bond at the 4-position are the same as above.] That is, by reacting the hydroxycarbostyryl derivative represented by the general formula [2d] with the ester derivative represented by the general formula [8], the ester derivative represented by the general formula [4a] is obtained. The desired compound is obtained.The compound of the general formula [4a] can be hydrolyzed to obtain the desired compound of the general formula [4b].The reaction between the compound [2d] and the compound [8] can be carried out by conventional dehalogenation. The hydrolysis reaction of compound [4a] is carried out under hydrogen reaction conditions, and the specific conditions are as shown in the above-mentioned reaction scheme-1. sodium,
It is carried out in the presence of basic compounds such as potassium hydroxide and barium hydroxide, mineral acids such as sulfuric acid, hydrochloric acid, and nitric acid, and organic acids such as acetic acid and aromatic sulfonic acids. The reaction generally proceeds advantageously in a conventional manner in a solvent such as water, lower alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, or a mixed solvent thereof. The reaction temperature is usually room temperature to 200°C, preferably 50 to 150°C, and the reaction is generally completed in about 5 minutes to 10 hours. Further, the amine represented by the general formula [5] in Reaction Scheme-2 can be easily produced, for example, by the methods shown in Reaction Scheme-6, Reaction Scheme-7 and Reaction Scheme-8 below. Reaction formula-6 Reaction formula-7 Reaction scheme-8 (In the above formula, R ₄ ' represents a phenyl group or a phenyl alkyl group with or without a substituent,
R ⁴ ″ represents a cyclohexyl group or a cyclohexyl alkyl group with or without a substituent, and
indicates a halogen atom. R ⁴ and R ⁵ are the same as above. ) According to Reaction Scheme-6, the amine represented by the general formula [5] is the same as the known amine represented by the general formula [8] and the general formula

It is easily produced by dehydrohalogenating a known halogen compound represented by [9] in the presence of a basic compound. According to Reaction Scheme-7, the amine represented by the general formula [5] is prepared by combining the known amine represented by the general formula [10] and the known halogen compound represented by the general formula [11] into a basic compound. It is easily produced by dehydrohalogenation reaction in the presence of These reactions may be carried out in the same manner as the dehalogenation reaction between the compound of general formula [2] and the compound of general formula [3]. According to Reaction Scheme-8, the cyclohexylamine derivative or cyclohexylalkylamine derivative represented by the general formula [5b] can be easily produced by reducing the benzene nucleus of the known compound represented by the general formula [5a]. . Although general nuclear hydrogenation reactions are widely used to reduce benzene nuclei, a method using catalytic reduction is particularly advantageous. Catalytic reduction is carried out by hydrogenation using a catalyst in a suitable solvent according to a conventional method. Catalysts that can be used include platinum catalysts such as platinum black, platinum oxide, and colloidal platinum, palladium catalysts such as palladium black, palladium carbon, and colloidal palladium, rhodium catalysts such as asbestos-attached rhodium, and rhodium alumina, ruthenium catalysts, Raney nickel, and nickel oxide. Conventional catalysts are used for nuclear hydrogenation reactions, such as nickel catalysts and cobalt catalysts. Examples of the solvent used include lower alcohols (methanol, ethanol, isopropanol, etc.), water, acetic acid, acetic ester, ethylene glycol, ethers (tetrahydrofuran, dioxane, etc.), and cycloalkanes (cyclohexane, cyclopentane, etc.). The reaction is preferably carried out under hydrogen pressure (preferably 1 to 100 atmospheres), the reaction temperature is room temperature to 100°C, and the reaction time is preferably 1 hour to 2 days. The haloamide represented by the general formula [3] used in the reaction scheme-1 is, for example, an amine represented by the general formula [5] and a known halocarboxylic acid represented by the general formula [12], as shown in the following reaction scheme-9. It is easily produced by reacting with. Reaction formula-9 (In the above formula, R ³ , R ⁴ , R ⁵ , l, n and X are the same as above) The reaction between compound [5] and compound [12] may be carried out in the same manner as the amide bond forming reaction described above. . Moreover, in the above, a compound whose carboxy group is activated may be used instead of compound [12]. Furthermore, among the compounds represented by the general formula [1], R ¹
is a hydrogen atom and 3 of the carbostyril skeleton
A compound in which the carbon-carbon bond at the position and the 4-position is a double bond can form lactam-lactim type tautomers ([1e] and [1f]) as shown in the following reaction scheme-10. Reaction equation-10 (In the above formula, R ² , R ³ , R ⁴ , R ⁵ , m, l and n are the same as above.) Among the compounds represented by the general formula [1], compounds having an acidic group are pharmacologically acceptable. It can easily form salts with basic compounds that can be used. Specific examples of such basic compounds include metal oxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, and aluminum hydroxide, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, and carbonic acid. Metal carbonates such as sodium hydrogen,
Examples include alkali metal alcoholates such as sodium methylate and potassium ethylate, inorganic basic compounds such as alkali metals such as sodium and potassium, and organic basic compounds such as morpholine, piperazine, piperidine, diethylamine, and aniline. Further, among the compounds represented by the general formula [1], those having a basic group can easily form a salt with a common pharmacologically acceptable acid. Examples of such acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, and hydrobromic acid, and organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, succinic acid, and benzoic acid. can be exemplified. The target compound represented by the general formula [1] thus obtained can be easily isolated and purified by commonly used separation means. Examples of such means include precipitation methods, extraction methods, recrystallization methods, column chromatography, preparative thin layer chromatography, and the like. The phosphodiesterase inhibitor of the present invention is a compound represented by the general formula [1] or a salt thereof obtained by the various methods described above, and is prepared as it is or by mixing it with a conventional pharmaceutical carrier to form a suitable dosage unit form. Examples of the form include tablets, granules, oral preparations such as oral solutions, and parenteral preparations such as injections.
The amount of the active ingredient to be administered is not particularly limited and can be appropriately selected from a wide range, but in order to achieve the desired effect, it should be 0.01 to 1 kg body weight per day.
It is recommended to take 10mg. Further, it is preferable that the dosage unit form contains 1 to 500 mg of the active ingredient. In the present invention, oral preparations such as tablets, capsules, and oral solutions are manufactured according to conventional methods. That is, tablets are prepared by mixing the active ingredient compound with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, and the like. Capsules are prepared by mixing the active ingredient compound with an inert pharmaceutical filler or diluent, and filling the mixture into hard gelatin capsules, soft capsules, and the like. Syrups or elixirs are produced by mixing the active ingredient with sweeteners such as sucrose, preservatives such as methyl- and propylparabens, colorants, seasonings, and the like. In addition, parenteral preparations are manufactured by dissolving the active ingredient compound in a sterilized liquid carrier. The preferred carrier is water or saline. Solutions having the desired clarity, stability and suitability for parenteral use contain about 1 to 500 mg of active ingredient dissolved in water and organic solvents and have a molecular weight of 200 to 500 mg.
It is manufactured by dissolving it in polyethylene glycol. Preferably, such liquid formulations contain lubricants such as sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and the like. Furthermore, the above liquid preparation may contain bactericides and fungicides such as benzyl alcohol, phenol, and thimerosal, isotonic agents such as sucrose and sodium chloride, local anesthetics, stabilizers, buffers, and the like. To further increase stability, parenterally administered drugs may be frozen after filling and water removed by freeze drying techniques known in the art. The lyophilized powder can then be reconstituted immediately before use. Thus, the C-AMP-specific phosphodiesterase inhibitor of the present invention is obtained. Substances that exhibit PDE inhibitory activity, such as the C-AMP-specific phosphodiesterase (PDE) inhibitor of the present invention, are described in, for example, the Annual Review of Pharmacology and Toxicology.
Toxicology, Vol. 17, pp. 441-477 (1977), it is useful for the prevention or treatment of various diseases in which a decrease in C-AMP is observed due to metabolic abnormalities. That is, in general, intracellular C-
AMP is produced from adenosine triphosphate (ATP) via adenylate cyclase by the sympathetic nervous system transmitters catecholamines and various peptide hormones, and is degraded by phosphodieslase (PDE). It is known that it is a biological component that is And the C-
AMP not only transmits the effects of biogenic amines and peptide hormones into cells, but also plays a role in cell division, fertilization, embryonic growth and differentiation, smooth muscle tone, cardiac contraction and metabolism, central and autonomic nervous system function, It affects immune reactions, reproductive reactions, the release of substances contained in intracellular storage granules such as insulin, histamine, and serotonin, and the lysosomal enzyme system. It is closely related to various diseases such as the development of cancer, bronchial asthma, diabetes, arteriosclerosis, circulatory failure, hypertension, psychosis, and psoriasis, and the use of PDE inhibitors specific to C-AMP can be used to prevent these various diseases. Effective for treatment or prevention. In particular, among the PDE-inhibiting powder substances, the above C
- It is a fact that substances that have a specific effect on AMP are effective, for example, Molecular Pharmacology 13 , 400-406.
(1976). The usefulness of PDE inhibitors as therapeutic and preventive agents for various diseases will be clarified below. <Cancer drugs> Proceedings of the National Academy of
As described in Science of United States of America, Vol. 68, p. 425 (1971), theophylline, a known PDE inhibitor, has the effect of normalizing cancerous and tumorous cells. This shows that PDE inhibitors are effective as cancer therapeutics. <Bronchial asthma treatment drug> Journal of Clinical Investigation Volume 52
48 (1973) states that relaxation of tracheal smooth muscle is caused by an increase in C-AMP content due to the β-action of catecholamines, which are sympathetic neurotransmitters, and that C-AMP in tracheal smooth muscle of bronchial asthma patients is It is noted that the content generally shows a decreasing tendency.
PDE inhibitors inhibit the decomposition of C-AMP, thereby making it possible to increase the content of C-AMP and thereby relax tracheal smooth muscle. Facts publicly known PDE
Theophylline, an inhibitor, is known as a therapeutic agent for bronchial asthma due to this mechanism of action. <Treatment of allergic asthma> As reported in Journal of Immunology Vol. 108, p. 695 (1972), allergic asthma patients generally receive treatment based on the release of histamine, a chemical mediator, from mast cells, etc. Contraction of tracheal smooth muscle is observed. The above-mentioned release of histamine from mast cells occurs due to a decrease in C-AMP. Therefore, by increasing the C-AMP content, the above-mentioned histamine release can be suppressed, resulting in treatment of allergic asthma or Effective for prevention. <Diabetes treatment drug> Cyclic Nucleotides in Disease, Baltimore,
As shown in Univ., Parkpress, p. 211 (1975), the most important hormone that lowers blood sugar is insulin. The secretion of insulin is enhanced by glucose, catecholamines, glucagon, etc., and prior to its secretion, C-
An increase occurs in AMP. Elevation of C-AMP in the pancreas may have the effect of enhancing isulin secretion, and therefore
The use of PDE inhibitors is effective for increasing C-AMP, promoting insulin secretion, and thereby treating diabetes. <Arteriosclerosis treatment> Japanes Heart Journal Vol. 16, p. 76 (1975)
In 2010), a decrease in C-AMP content was observed in vascular endothelial cells undergoing arteriosclerosis;
Increased AMP content enhances lipolysis.
PDE inhibitors increase C-AMP content and promote lipolysis in vascular endothelial cells, making them useful for treating arteriosclerosis. <Circulation improving drugs> Advances in Cyclic Nucleotide Research
Volume 1, page 175 (1972) and Molecular
Pharmacology Vol. 6, p. 597 (1970),
It has been reported that when a PDE inhibitor acts on vascular smooth muscle, its C-AMP content increases, resulting in expansion of the smooth muscle and improvement of blood flow conditions. This shows that PDE inhibitors are useful as circulation improving drugs. <Hypertension drugs and diuretics> In spontaneously hypertensive rats (SHR), the C-AMP content decreases in diseased arteries;
A report that this is due to an increase in PDE activity and attenuation of adenylate cyclase activity in response to vasodilatory stimulation (Science Vol. 179, p. 807, 1973)
). This is thought to worsen the relaxation response of vascular smooth muscle. Therefore, inhibiting PDE and increasing C-AMP can reduce vascular resistance and treat hypertension. Furthermore, in cases of renal hypertension, the use of diuretics reduces the total blood volume and exerts a hypotensive effect. Known diuretic benzothiazine derivatives include:
It has an inhibitory effect on PDE (Annals of New York
Academy of Science Vol. 150 No. 256 1968
), and the increase in C-AMP enhances the diuretic effect (Journal of Clinical Investigation, Vol. 41, p. 702 (1968). <Psychiatric drugs> As stated in Federation Proceedings, Vol. 30, p. 330 (1971). As described above, pharmacological psychotic drugs have a primary site of action on C-C of the central nervous system.
Varying AMP content. For example, phenothiazine antipsychotics inhibit activation of PDE by calcium-dependent activator proteins in the brain, increasing intracellular C-AMP concentration, and tricyclic antidepressants dibenzazepines inhibit activation of PDE by calcium-dependent activator proteins in the brain. It has a PDE inhibitory effect, making it effective as a psychosis treatment drug. Therefore, PDE inhibitors, like these psychotic drugs, can be used to treat psychosis caused by a decrease in C-AMP concentration. <Psoriasis treatment> Journal of Investigative Dermatology No. 64
psoriasis spreads rapidly on the skin, and in this psoriatic lesion C-
AMP content is decreased, PDE activity is increased about three times the normal value, and C-GMP content is increased. Furthermore, glycogen retention is also observed. C-
AMP suppresses cell proliferation and differentiation and promotes glycogenolysis. Papaverine, a clinically known PDE inhibitor, is actually used for the treatment of psoriasis, and it has been found that PDE inhibitors are effective as this therapeutic agent. Examples of the production of starting material compounds for producing compounds to be used as active ingredients of the inhibitors of the present invention are listed below as reference examples. Reference Example 1 24 g of 5-hydroxy-3,4-dihydrocarbostyryl is suspended in 200 ml of acetic acid and 300 ml of chloroform. The suspension was heated to 40 to 50°C, and 36 ml of sulfuryl chloride was added dropwise to the suspension while stirring, and the mixture was stirred at the same temperature for 1 hour. Pour the reaction solution into ice water to remove the precipitate. Recrystallization from methanol yields 20 g of colorless scaly crystals of 5-hydroxy-6,8-dichloro-3,4-dihydrocarbostyryl. Melting point: 246-248°C The following compound was obtained in the same manner as in Reference Example 1 above.

[Table] Reference Example 6 Dissolve 4.5 g of 5-hydroxy-8-bromo-3,4-dihydrocarbostyryl in 100 ml of ethanol. To this solution were added 3.8 g of ethyl bromoacetate and 3.8 g of potassium carbonate, and the mixture was stirred under reflux for 4 hours. The reaction solution was poured into ice water, and the precipitate was collected and recrystallized from methanol to obtain 3.8 g of 5-ethoxycarbonylmethoxy-8-bromo-3,4-dihydrocarbostyryl in the form of colorless needles. Melting point: 215-216°C The following compound was obtained in the same manner as in Reference Example 6 above.

[Table] Carbostyril reference example 14 Dissolve 3.6 g of 5-ethoxycarbonylmethoxy-8-bromo-3,4-dihydrocarbostyril in 150 ml of ethanol, and dissolve 5 g of potassium hydroxide in water.
Add 50 ml of solution and reflux for 5 hours. The solvent is distilled off and the residue is dissolved in water. The precipitate was acidified with hydrochloric acid and recrystallized from aqueous ethanol to give colorless needle-like crystals of 5-carboxymethoxy-8-bromo-3.
2.5 g of 4-dihydrocarbostyryl are obtained. Melting point: 255-256°C (decomposition) The following compound is obtained in the same manner as in Reference Example 14 above.

[Table] Chiril reference example 22 Add 17 g of p-methylaminophenol, 20 ml of triethylamine, and 9 g of 5% rhodium alumina to 200 ml of methanol, and adjust the hydrogen pressure to 3 to 4 atm and temperature.
Shake and hydrogenate at 60-70°C for 16 hours. After the reaction, the catalyst is removed, the mother liquor is concentrated to dryness, the residue is separated by adding 500 ml of chloroform and 200 ml of 5% NaOH water, and the chloroform layer is washed with water and concentrated. The residue is distilled under reduced pressure. Colorless solid with boiling point 123-129℃ (22mmHg) 4-
11 g of methylaminocyclohexanol are obtained. Reference example 23 19 g of 2-aminocyclohexanol and isopropyl iodide in 50 ml of dimethylformamide (DMF)
Add 20g and 15g of potassium carbonate and heat at 80-90℃
Stir for 20 hours. After the reaction, it is concentrated, the residue is dissolved in chloroform, washed with water, and dried over anhydrous sodium sulfate (Na ₂ SO ₄ ). The desiccant was removed, the mother liquor was concentrated, the residue was crystallized with petroleum ether, and the obtained crystals were recrystallized from ethanol to give two colorless crystals.
- 8 g of isopropylaminocyclohexanol are obtained. Melting point: 54-55°C Reference example 24 Add 26 ml of N-methylcyclohexylamine to 400 ml of ethyl acetate, and add 25 ml of 4-chlorobutyl chloride and 33.5 ml of triethylamine simultaneously dropwise while stirring while keeping the internal temperature at 10-20°C. do. The mixture was added dropwise over 20 minutes, and then stirred at room temperature for 1 hour. After the reaction, water was added to the reaction solution to separate the layers, and the organic layer was mixed with water, saturated potassium carbonate aqueous solution (K ₂ CO ₃ water), 10
% hydrochloric acid and then water, and dried with Na ₂ SO ₄ .
After removing the sodium sulfate and concentrating the mother liquor, it was distilled under reduced pressure to obtain colorless liquid N-(4-chlorobutyryl)-N.
-41.5 g of methylcyclohexylamine are obtained. Melting point: 133-136°C (2 mmHg) Examples of the production of the active ingredient compound of the inhibitor of the present invention will be given below. Production example 1 2.5 5-(3-carboxy)propoxy-3,4-dihydrocarbostyryl in 200 ml of methylene chloride
Add 2.0 ml of N-methylmorpholine, and add 1.0 ml of methyl chloroformate to the internal temperature under external ice-cooling and stirring.
Drop while keeping the temperature at 10-20℃. 30 minutes at room temperature after dropping
After stirring for several minutes, 1.3 ml of N-ethylaniline was added and stirred at the same temperature for 4 hours. After the reaction is completed, water is added to the reaction solution to separate the layers, and the organic layer is washed in this order with dilute NaOH aqueous solution, dilute hydrochloric acid, and water, and dried over Na ₂ SO ₄ . After removing the inorganic substances and concentrating the mother liquor, the residue was recrystallized from ethanol to obtain 2.6 g of 5-[3-(N-ethylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyryl in the form of colorless needles. . Melting point 179.5-180.5℃ Production example 2 6-(3-
Add 2.5 g of carboxypropoxycarbostyryl and 1.8 ml of pyridine, and add 1.0 ml of methyl bromoformate dropwise while stirring while externally cooling with ice while maintaining the internal temperature at 5 to 15°C. After the dropwise addition, the mixture was stirred at room temperature for 1 hour, then 1.2 g of N-methylcyclohexylamine was added, and the mixture was further stirred for 3 hours. Pour the reaction solution into 200 ml of saturated saline, remove the precipitated crystals, and wash with water. The obtained crude crystals are recrystallized from chloroform-ethanol to obtain 2.3 g of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl in the form of colorless needles. Melting point: 184.5-186℃ Production example 3 To 50 ml of DMF, add 2.5 g of 6-(3-carboxy)propoxy-3,4-dihydrocarbostyryl and 1.4 g of potassium carbonate, and add 1.1 ml of isobutyl chloroformate to the mixture under external ice-cooling and stirring. Harvest while keeping the temperature at 10-20℃. After stirring at 30 to 40°C for 1.5 hours, 1.4 g of N-allylcyclohexylamine was added, and the mixture was further stirred at the same temperature for 2 hours. reaction solution
Pour into 200ml of saturated saline solution and remove crystals that precipitate and wash with water. The obtained crude crystals were recrystallized from ethyl acetate-petroleum ether to give colorless needle-like crystals of 6-[3-(N
2.7 g of -allyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl are obtained. Melting point 105-107℃ Production example 4 6-(3-carboxy)propoxy-3,4-dihydrocarbostyryl 2.5 in 200ml of ethyl acetate
Add 1.6 ml of triethylamine and 1.0 ml of ethyl chloroformate under external ice cooling and stirring to bring the internal temperature to 10~10 ml.
Harvest while keeping at 20℃. After stirring at room temperature for 1 hour, 1.1 ml of N-methylaniline was added and stirring was continued for 2 hours. After the reaction, water was added to separate the layers, and the organic layer was washed in the order of dilute NaOH aqueous solution, dilute hydrochloric acid, and water.
Dry _{with Na2SO4} . After removing the inorganic substances, the mother liquor was concentrated, and the residue was recrystallized from chloroform-petroleum ether to give colorless needle-like crystals of 6-[3-(N-methylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyryl. Obtain 2.2g. Melting point: 129.5-131.5°C Compounds shown in Table 1 below are obtained in the same manner as in Production Example 4.

【table】

【table】

【table】

【table】

【table】

【table】

[Table] Production Example 60 Add 2.5 g of 6-(3-carboxy)propoxy-3,4-dihydrocarbostyryl and 1.6 ml of triethylamine to 150 ml of DMF, and add 1.3 ml of isobutyl chloroformate while stirring under external ice cooling to bring the internal temperature to 10-20 Harvest while keeping at ℃. After stirring at room temperature for 30 minutes, 1.3 ml of cyclohexylmethylamine was added and stirred for 1 hour. After the reaction, pour the reaction solution into about 1 part of water to remove the precipitated crystals and wash with water. The obtained crystals are dried and then recrystallized from chloroform-petroleum ether to obtain 3.0 g of 6-{3-[N-(cyclohexylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyryl in the form of colorless needles. . Melting point: 170-172°C Compounds listed in Table 2 below are obtained in the same manner as in Production Example 60.

[Table] Production Example 64 Add 1.3 g of 5-(3-carboxy-2-methylpropoxy)-3,4-dihydrocarbostyryl and 0.8 ml of triethylamine to 50 ml of DMF at an internal temperature of 0 to 10°C under external ice cooling and stirring. Remove 0.65 ml of isobutyl chloroformate. After removal, stir at the same temperature for 30 minutes and add 0.7 N-ethylcyclohexylamine.
Stir at room temperature for 2 hours. The solvent was distilled off, and the residue was dissolved in 200 ml of chloroform, washed successively with dilute hydrochloric acid, K ₂ CO ₃ water, and water, and dried over Na ₂ SO ₄ . The drying agent was removed, the mother liquor was concentrated, and the residue was recrystallized from ligroin-benzene to give colorless needle crystals.
-[3-(N-cyclohexyl-N-ethylaminocarbonyl)-2-methylpropoxy]-3,4-
0.8 g of dihydrocarbostyril is obtained. Melting point 114-115.5℃ Production example 65 6-(3-carboxy-2-methylpropoxy)carbostyryl 1.3g and N-methyl-2-
Production example using 0.8ml of methylcyclohexylamine
64 to obtain 0.4 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy}carbostyryl in the form of colorless needles. Melting point: 146-149℃ Production example 66 Add 2.6 g of 1-methyl-6-(3-carboxypropoxy)-3,4-dihydrocarbostyryl and 1.8 ml of pyridine to 50 ml of THF, and while stirring under external ice cooling, 1.0 methyl bromoformate is obtained. Remove the ml while keeping the internal temperature at 5-15°C. After stirring at room temperature for 2 hours, 1.2 g of N-methylcyclohexylamine was added and the mixture was further stirred for 3 hours. Pour the reaction solution into 200 ml of saturated saline, remove the precipitated crystals, and wash with water.
The obtained crude crystals were recrystallized from ligroin to obtain 2.1 g of 1-methyl-6-[3-(N-cyclohexyl)-N-methylaminocarbonylpropoxy]-3,4-dihydrocarbostyryl as colorless needle crystals. obtain. Melting point: 104.5-106.5°C Reactions were carried out in the same manner as in Production Examples 64-66 above to obtain the compounds shown in Table 3 below.

【table】

【table】

[Table] Compounds shown in Table 4 below were also obtained by carrying out the reaction in the same manner as in Production Examples 64 to 66 above.

【table】

【table】

【table】

【table】

[Table] Production Example 112 6-13-[N-benzyl-N-(2-3'·4'-dimethoxyphenylether)aminocarbonyl]propoxy} was prepared in the same manner as in Production Example 65 using appropriate starting materials. -3,4-dihydrocarbostyryl is obtained. The compound is identified by the following physicochemical properties. Γ Properties Colorless oily Γ Silica gel thin layer chromatography (Silica gel: Merck & Co., Ltd. "Silica gel 60F-
254” Developing solvent: Chloroform-methanol (V/
V)=8:1) Rf=0.65 Γ elemental analysis value (as C ₃₀ H ₃₄ N ₂ O ₅ ) Calculated value (%) C71.69 H6.82 N5.57 Actual value (%) C71.84 H6.75 N5.29 Γ nuclear magnetic resonance spectroscopy (NMR) δ ^CDCl3 = 1.9-3.1ppm (10H, m), 3.4ppm
(2H, t), 3.7-4.0ppm (8H, m),
4.4ppm (d, 2H), 6.4~6.7ppm (6H,
m), 6.9-7.3ppm (7H, m), 9.3ppm
(1H, br.) However, the above signal at 6.9 to 7.3 ppm overlaps with the proton signal of _CHCl3 . Γ Infrared absorption spectrum analysis (IR) ν ^film _nax (cm ^-1 ) = 3320, 3002, 2940, 2840
,
1670, 1638, 1595, 1500, 1450, 1360,
1240, 1157, 1013, 960, 850, 800, 740 Production example 113 5-chloro-6-(3-carboxypropoxy) carbostyril 5.0 g, triethylamine
Add 2.97ml to 100ml DMF and stir under external ice cooling.
Isobutyl chloroformate 2.33 while keeping the internal temperature at 10℃
Drop ml. After the addition, the mixture was stirred at room temperature for 1 hour, and 2.8 g of N-butylcyclohexylamine was added dropwise thereto, followed by stirring at room temperature for 3 hours. After the reaction, the solvent was distilled off and the residue was dissolved in 600 ml of chloroform, washed with dilute hydrochloric acid, K ₂ CO ₃ water and water, and dried over NaSO ₄ .
Remove the drying agent and concentrate the mother liquor. The residue was recrystallized from ethanol to give colorless needle-like crystals of 5-chloro-6.
-[3-(N-cyclohexyl-N-butylaminocarbonyl)propoxy]carbostyryl 2.5
get g. Melting point: 178.5-179.5°C The reaction was carried out in the same manner as in Production Example 113 above to obtain the compounds shown in Table 5 below.

【table】

【table】

[Table] Examples of formulations are listed below. Formulation Example 1 1000 tablets for oral use, each containing 5 mg of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril, are prepared according to the following formulation. Blending amount (g) 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl
5 Lactose (Japanese Pharmacopoeia) 50 Cornstarch (Japanese Pharmacopoeia) 25 Crystalline cellulose (Japanese Pharmacopoeia) 25 Methylcellulose (Japanese Pharmacopoeia) 1.5 Magnesium stearate (Japanese Pharmacopoeia) 1 According to the above formulation 6- [3-(N-Methyl-N-cyclohexylaminocarbonyl)propoxy] Carbostyryl, lactose, cornstarch and crystalline cellulose were thoroughly mixed, and 5% of methylcellulose was added.
Granulate with aqueous solution, pass through a 200 mesh sieve and carefully dry. Formulation Example 2 In the same manner as Formulation Example 1, 5 mg of 6-{3
1000 tablets for oral use containing [N-methyl-N-(4-acetoxycyclohexyl)aminocarbonyl]propoxy}carbostyril are prepared according to the following formulation. Amount (g) 6-{3-[N-methyl-N-(4-acetoxycyclohexyl)aminocarbonyl]propoxy}carbostyryl 5 Lactose (Japanese Pharmacopoeia product) 50 Cornstarch (Japanese Pharmacopoeia product) 25 Crystalline cellulose (Japanese Pharmacopoeia) 25 Methylcellulose (Japanese Pharmacopoeia) 1.5 Magnesium stearate (Japanese Pharmacopoeia) 1 Formulation example 3 10 mg each of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy] 1000 two-piece hard gelatin capsules for oral use containing carbostyril are prepared according to the following formulation. Blending amount (g) 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl
10 Lactose (Japanese Pharmacopoeia) 80 Starch (Japanese Pharmacopoeia) 30 Talc (Japanese Pharmacopoeia) 5 Magnesium stearate (Japanese Pharmacopoeia) 1 Finely powder the above ingredients and stir thoroughly to form a uniform mixture. It is then filled into gelatin capsules for oral administration having the desired dimensions. Formulation example 4 10 mg each of 6-{3-[N-methyl-N-
One thousand two-piece hardened gelatin capsules for oral use containing (4-acetoxycyclohexyl)aminocarbonyl]propoxy}carbostyril are prepared according to the following formulation. Amount (g) 6-{3-[N-methyl-N-(4-acetoxycyclohexyl)aminocarbonyl]propoxy}carbostyryl 10 Lactose (Japanese Pharmacopoeia product) 80 Starch (Japanese Pharmacopoeia product) 30 Talc ( 5 Magnesium stearate (Japanese Pharmacopoeia) 1 Formulation example 5 A sterile aqueous solution suitable for parenteral administration is prepared according to the following recipe. Blending amount (g) 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl
1 Polyethylene glycol (Japanese Pharmacopoeia) Molecular weight: 4000 0.3 Sodium chloride (Japanese Pharmacopoeia) 0.9 Polyoxyethylene sorbitan monooleate (Japanese Pharmacopoeia) 0.4 Sodium metabisulfite 0.1 Methyl-paraben (Japanese Pharmacopoeia) 0.18 Propyl-paraben (Japanese Pharmacopoeia product) 0.02 Distilled water for injection 100 (ml) The above parabens, sodium metabisulfite and sodium chloride were 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-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril, followed by polyethylene glycol and polyoxyethylene sorbitan monooleate were dissolved in the solution. did. The solution was then adjusted to the final volume by adding distilled water for injection and sterilized by passing through a suitable filter paper. Formulation Example 6 In the same manner as Formulation Example 5, a sterile aqueous solution suitable for parenteral administration is prepared according to the following formulation. Blend amount (g) 6-{3-[N-methyl-N-(4-acetoxycyclohexyl)aminocarbonyl]propoxy}carbostyryl 1 Polyethylene glycol (Japanese Pharmacopoeia product) Molecular weight: 4000 0.3 Sodium chloride (Japanese Pharmacopoeia product) 0.9 Polyoxyethylene sorbitan monooleate (Japanese Pharmacopoeia) 0.4 Sodium metabisulfite 0.1 Methyl-paraben (Japanese Pharmacopoeia) 0.18 Propyl-paraben (Japanese Pharmacopoeia) 0.02 Distilled water for injection 100ml Below, the present invention Pharmacological tests were conducted on the compound represented by the general formula [], which is the active ingredient of the inhibitor. The results are shown below. <Pharmacological test I> Inhibitory effect on cyclic adenosine monophosphate phosphodiesterase (C-AMP-PDE) This test was conducted in Biochimica et Biophysica Acta No.
Volume 429, pages 485-497 (1976) and Biochemistry
It is carried out according to the activity assay method described in Medicine, Vol. 10, pp. 301-311 (1974). That is, first of all,
To the precipitated platelets obtained by centrifuging rabbit PRP at 3000 rpm for 10 minutes, 10 ml of a solution of 1 mmol MgCl ₂ added to 50 mmol Tris-HCl buffer at pH 7.4 was added to suspend the platelets. Grind the platelets using a Teflon potter type homogenizer, repeat freeze-thaw twice, apply ultrasonic waves at 200 watts for 300 seconds to disrupt the platelets, and then ultracentrifuge at 100,000 G for 60 minutes to extract the supernatant as a crude enzyme solution. shall be. Preliminary 50 mmol-Tris acetate buffer (PH6.0)
Pass 10 ml of the crude enzyme solution prepared above through a 1.5 x 20 cm DEAE-cellulose column buffered with
Wash and elute with 30 ml of 50 mmol Tris acetate buffer, and elute by applying a linear gradient to this buffer with 0 to 1 M sodium acetate-Tris acetate buffer (total eluate volume: about 300 ml). The flow rate is
The flow rate was 0.5 ml/min, and 5 ml of each fraction was collected. By the above operation, 100 μmol of high C-
It has weak activity at AMP substrate concentrations below 2 nmol/ml/min and at C-AMP substrate concentrations as low as 0.4 μmol.
Collect fractions with strong activity greater than 100 pmol/ml/min. This is called C-AMP-PDE. 0.1 ml of test compound aqueous solution of each concentration was determined in advance.
A total of 0.2 ml of a mixture containing 0.4 μmol of C-AMP (tritium C-AMP) at pH 8.0 and 40 mmol Tris-HCl buffer (containing 50 μg of bovine serum albumin and 4 mmol of _MgCl2 ) was added to the substrate solution. and add the C-AMP-PDE solution of a certain concentration prepared above to this.
Add 0.2 ml and react at 30°C for 20 minutes to generate tritium 5'-AMP from tritium C-AMP. Next, after immersing in boiling water for 2 minutes to stop the reaction, the reaction solution was cooled in ice water, 0.05 ml of snake venom (1 mg/ml) was added as 5'-nucleotidase, and the reaction was allowed to proceed for 10 minutes at 30°C. Converts 5′-AMP to tritium adenosine. The entire amount of the reaction solution obtained was transferred to a cation exchange resin [AG・50W×
4. Bind only the tritiated adenosine produced by adding 200 to 400 mesh (Bio-Rad product), column size 0.5 x 1.5 cm, wash with 6 ml of distilled water, and elute with 1.5 ml of 3N ammonia water. let
PDE activity is measured by adding 10 ml of a triton-toluene type scintillator to the entire volume of the eluate and measuring the tritiated adenosine produced using a liquid scintillation counter. PDE of each test compound measured according to the above method
From the activity value (V _s ) and control value (V _c ) (water not containing the test compound), the PDE gross damage rate (%)
is calculated using the following formula. PDE inhibition rate (%)=V _c -V _s /V _c ×100 The obtained inhibition rate (%) is shown in Table 6. Table 6 shows the known papaverine and 1-
The results of a similar test using methyl-3-isobutylxanthene and the like are also shown. <Pharmacological test> Acute toxicity test Each test compound is orally administered to male mice to determine its acute toxicity (LD ₅₀ mg/Kg). The results are shown in Table 6. The test compounds used in each of the above tests are as follows. Test compound No. 1 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl No.2 6-[3-(N-methylaminocarbonyl)propoxy]carbostyryl No.3 6- (3-anilinocarbonylpropoxy)carbostyryl No.4 6-[3-(N-methyl-N-isopropylaminocarbonyl)propoxy]carbostyryl No.5 6-[3-(N-methylanilinocarbonyl)propoxy ] Carbostyryl No. 6 6-[3-(N-isopropyl-N-cyclohexylaminocarbonyl)propoxy] Carbostyryl No. 7 1-Methyl-6-[3-(N-butyl-N
-cyclohexylaminocarbonyl)propoxy]carbostyryl No.8 5-chloro-6-[3-(N-butyl-N
-cyclohexylaminocarbonyl)propoxy]carbostyryl No.9 6-[3-(N-octyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl No.10 6-[3-(N-methyl-N-cyclohexylaminocarbonyl) ) propoxy]-3・4
-Dihydrocarbostyryl No.11 6-[3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]Carbostyryl No.12 8-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3・4
-Dihydrocarbostyril No. 13 6-[3-(N-Ethyl-N-cyclopentylaminocarbonyl)propoxy] Carbostyril No. 14 6-[3-(N・N-dicyclohexylaminocarbonyl)propoxy] Carbostyril No. 15 6-[3-(N-cyclohexyl-N-benzylaminocarbonyl)propoxy]carbostyryl No.16 6-[3-(N-ethyl-N-cyclohexylmethylaminocarbonyl)propoxy]carbostyryl No.17 6- {3-[N-methyl-N-(4-hydroxycyclohexyl)aminocarbonyl]propoxy}carbostyryl No.18 1-allyl-6-[6-(N-cyclohexylaminocarbonyl)hexyloxy]carbostyryl No.19 8-Hydroxy-5-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl No. 20 6-(N-ethyl-N-cyclohexylaminocarbonylmethoxy)carbostyryl No. .21 6-[3-(N-butyl-N-cyclooctylaminocarbonyl)propoxy]carbostyryl No.22 6-{3-[N-cyclohexyl-N-
(2-phenylethyl)aminocarbonyl]propoxy}carbostyryl No.23 6-[3-(N-propyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl No.24 7-[3-(N-methyl-N- cyclohexylaminocarbonyl)propoxy]-3,4
-dihydrocarbostyryl No.25 1-methyl-6-[3-(N-methyl-N
-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl No.26 6-[3-(N-ethyl-N-cyclopropylaminocarbonyl)propoxy]carbostyryl No.27 6-[3-(N- cyclohexylaminocarbonyl)propoxy]carbostyryl No.28 6-{3-[N-cyclohexyl-N-
(2-3', 4'-dimethoxyphenylethyl)aminocarbonyl]propoxy}carbostyryl No.29 6-[3-(N-butyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl No.30 6-[ 3-(N-ethyl-N-cycloheptylaminocarbonyl)propoxy]carbostyryl No. 31 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)-2-methylpropoxy]carbostyryl No. 32 6- {3-[N-methyl-N-(4-acetyloxycyclohexyl)aminocarbonyl]propoxy}carbostyryl No.33 6-(3-morpholinocarbonylpropoxy)-3,4-dihydrocarbostyryl No.34 6-[ 3-[3-(4-methyl-1-piperazinylcarbonyl)propoxy]-3,4-
Dihydrocarbostyryl No.35 6-[3-(N-ethyl-N-cyclooctylaminocarbonyl)propoxy] Carbostyryl No.36 5-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3・4
-dihydrocarbostyryl No.37 6-{3-[N-(2-chlorocyclohexyl)-N-cyclohexylmethylaminocarbonyl]propoxy}carbostyryl No.38 6-[4-(N-methyl-N-cyclohexylamino carbonyl)butoxy]-3,4-
Dihydrocarbostyryl No.39 6-{3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]propoxy}Carbostyryl No.40 6-(3-piperidinocarbonylpropoxy)-3,4- Dihydrocarbostyryl No.41 6-[3-(N-hexyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl No.42 1-benzyl-6-[3-(N-methyl-
N-cyclohexylaminocarbonyl)propoxy]carbostyryl No.43 6-{3-[N-methyl-N-(2-3′・
4'-dimethoxyphenylethyl)aminocarbonyl)propoxy}carbostyryl No.44 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl No. 45 8-Benzyloxy-5-[3-(N-methyl-N-cyclohexylaminocarbonyl)
propoxy]-3,4-dihydrocarbostyryl No.46 6-{3-[N-(3-methylbutyl)-N
-cyclohexylaminocarbonyl]propoxy}carbostyryl No. 47 6-[3-(N-butyl-N-cyclohexylmethylaminocarbonyl)propoxy]carbostyryl No. 48 6-[5-(N-ethyl-N-cyclohexylamino carbonyl)pentyloxy]carbostyryl No.49 6-[3-(N-pentyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl No.50 6,8-dichloro-5-[3-(N-ethyl-N -cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl No. 51 6-[3-(N-allyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl No. 52 6-[2-(N-ethyl -N-cyclohexylaminocarbonyl)ethoxy]carbostyryl No.53 6-[3-(2,6-dichloroanilinocarbonyl)propoxy]-3,4-dihydrocarbostyryl No.54 6-(3-aminocarbonyl propoxy)-3,4-dihydrocarbostyryl No.55 6-[3-(N・N-diphenylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl No.56 6-[3-(2・4 -dimethoxyanilinocarbonyl)propoxy]carbostyryl No.57 6-[4-(N-ethyl-N-cyclohexylaminocarbonyl)butoxy]carbostyryl No.58 1-Methyl-3-isobutylxanthine (control) No.59 Papaverine (control) No.60 Theophylline (control) No.61 Dipyridamole (control)

【table】

【table】

[Table] <Pharmacological test> A crude enzyme solution obtained from human platelets was similarly measured according to the method for measuring PDE inhibition described in the above pharmacological test.
DEAE-cellulose column fractionation yields 100 μmol of high C-
It has weak activity below 6 nmol/ml/min at GMP (cyclic guanosine monophosphate) substrate concentration and at low C-GMP substrate concentration of 0.4 μmol.
A fraction having a high activity of 100 pmol/ml/min or more is designated as C-GMP-PDE (F).
In addition, a fraction having a weak activity of 1 nmol/ml/min or less at a high C-AMP substrate concentration of 100 μmol and a strong activity of 100 pmol/ml/min or more at a low C-AMP substrate concentration of 0.4 μmol. C-AMP
−PDE(F). The test method for each test compound against C-AMP-PDE in human platelets follows the measurement method for the pharmacological test described above. The test method for each test compound against C-GMP-PDE was also the same as above except that C-GMP was used as the substrate. of the test compound for F obtained above.
The Ki values (affinity of the compound for the enzyme/PDE) and the similar Ki values for F and the ratio of these Ki values (F/F ratio) are shown in Table 7 below. In addition, each
The Ki value was determined by the Dickson plot described in "Introductory Enzyme Kinetics", pages 1 to 19 (published by Kyoritsu Publishing Co., Ltd.), and indicates the affinity of the test compound for the enzyme (PDE). It is a constant, and the smaller this value is, the greater the PDE inhibitory activity is. In addition, the F/F ratio is
It is possible to evaluate the selectivity of PDE inhibitory activity to C-AMP, and the larger the F/F ratio, the more the C-AMP
Indicates high selectivity to AMP.

[Table] The pharmacological effects of the C-AMP-specific PDE inhibitor of the present invention are shown below for each item. <Cancer control effect> Proceedings of the National Academy mentioned above
According to the method described in Science of USA, 3-
0.1 to 1 mmol of dibutyryl C- to mouse embryonic fibroblast cells that had become cancerous with methylcholanthrene and rat sarcoma cells that had become tumorigenic with Sarcomarius of Rous.
AMP, a combination of 3 mmol C-AMP and 1 mmol theophylline, plus 3 mmol C-AMP and 10
When ~100 mmol of test compound No. 35 was added,
Each of the above cells underwent contact inhibition and changed into a shape that was indistinguishable from normal cells with monolayer orientation. <Effect on bronchial asthma> Catillo and Beer's method [The Journal of
Pharmacology and Experimental Therapeutics
90, p. 104 (1947)], the trachea removed from guinea pigs was cut into rings, and changes in tracheal smooth muscle tone (changes in tracheal diameter) due to administration of a PDE inhibitor were examined. Test compound No. 29 was used as a PDE inhibitor and theophylline was used as a control compound in this test. The following table shows the effects of these inhibitors on normal tracheal smooth muscle and the relaxing effect on contraction induced by acetylcholine 10 ^-6 g/ml and histamine 2 x 10 ^-6 g/ml, respectively. In addition, the effect on normal muscle is at an inhibitor concentration (g/ml) that lowers the curve on the medium by about 1 cm, and the relaxing effect on contracting muscle is at an inhibitor concentration (g/ml) that relaxes 75 to 100% of the contraction. expressed.

[Table] <Effect on allergic asthma> Mast cells were collected from rats according to the method described in Journal of Immunology Vol. to induce histamine release, and the suppressive effect of PDE inhibitors was investigated. In this test, test compound No. 1 showed an inhibitory effect of 95% or more at a concentration of 0.5 to 5 mmol. Furthermore, theophylline showed a 90% inhibitory effect at 20 mmol. <Effects on diabetes> “Cyclic AMP Conference Conference Abstracts” No. 2
Rat pancreata were collected according to the description in Vol. 32, 1977, and refluxed with a reflux solution containing 60 mg/100 ml of glucose, where insulin secretion of approximately 20 μU/ml was observed. To this, 0.5 to 2 m of test compound No. 32 was added.
When mol was added, the above insulin secretion was 500μ
It was increased to U/ml. Furthermore, addition of 15 mmol of theophylline increased the above secretion to 400 μU/ml. <Effect on arteriosclerosis> Feed 0.5% cholesterol feed to domestic rabbits according to the method described in "Applied Pharmacology" Vol. 14, p. 599 (1977).
Continued use for 14 weeks to induce atherosclerosis in the aorta.
The 12 hardening-induced animals were divided into two groups, and 6 animals in the first group received 50 mg/Kg/day of test compound No. 28, and 6 animals in the second group (control group) received the same amount of potato starch placebo. Administer each. Four weeks after the start of administration, all the animals were sacrificed, the aortas were excised and incised, and after Sudan staining, the degree of lipid deposition was evaluated on a five-point scale and expressed using an atheroma index, and the results are as follows.

[Table] <Circulatory improvement effect> (a) 3 to 10 μg/ml of test compound No. 11 was added to the excised rabbit ear flap blood vessel specimen according to the method described in “Applied Pharmacology” Vol. 10, p. 695 (1975). When applied, an increase in the amount of perfusion fluid was observed. Its efficacy was approximately 1000 times that of theophylline under the same test. (b) According to the method shown in the literature mentioned in (a) above, predetermined amounts of 30 to 1000 μg/Kg of test compound No. 11 and 300 to 3000 μg/Kg of theophylline were intravenously administered to cats, and the cerebral blood flow was The amount of change was measured. The results are shown below, and test compound No.11
showed a stronger increasing effect on cerebral circulation than theophylline. Change in cerebral blood flow (ml/min)
indicates the difference from the normal value in the blank test using the normal value as a reference.

[Table] <Effect on hypertension> American Journal of Medical Science No. 259
According to the method described in Vol. 257 (1970), 10 mg/Kg of test compound No. 15 was intraperitoneally administered to hypertensive rats (SHR) aged 4 to 5 months.
After hours, the systolic blood pressure of the test animal ranged from 190 mmHg to
It decreased to 140mmHg. In addition, for experimental renal hypertensive rats (RHR) (created by ligating the left renal artery together with a statorlet with a diameter of 0.36 mm and removing the contralateral kidney, the rats 2 months after surgery were used for the experiment). No.15-20
When mg/Kg was administered intraperitoneally, 4 hours after administration,
The animal's systolic blood pressure decreased from 185 mmHg to 130 mmHg.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, or a phenyl alkyl group, R ² is a hydrogen atom, a halogen atom, a hydroxyl group, or a phenyl alkoxy group, R ³ is a hydrogen atom,
Hydroxyl group or alkyl group having 1 to 4 carbon atoms and R ⁴
and R ⁵ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group with or without a substituent, a phenyl group with or without a substituent, or a phenyl group with or without a substituent on the phenyl ring. (However, the substituent represents a lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, or a halogen atom.), a cycloalkylalkyl group, and an alkenyl group having 2 to 4 carbon atoms, respectively. . Further, R ⁴ and R ⁵ may form a piperidine ring, a piperazine ring or a morpholine ring together with the nitrogen atom to which they are bonded. l and n are each 0 or an integer whose sum is 7 or less, and m is 1 to 3
indicates an integer. In addition, the carbon bonds at the 3rd and 4th positions of the carbostyril skeleton are single or double bonds). inhibitor.