JPS6010008B2 - Platelet aggregation inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a platelet aggregation inhibitor, and more specifically, the present invention relates to a platelet aggregation inhibitor, and more particularly, the present invention relates to a platelet aggregation inhibitor, and more particularly, it is a compound of the general formula [wherein R is a cycloalkyl group or an alkyl group having 1 to 4 carbon atoms as a substituent, alkoxy group,
R2 is a phenyl group with or without one or two halogen atoms, hydroxyl groups, or alkanoylamine/groups having 2 to 4 carbon atoms; R2 is a hydrogen atom, lower alkyl group, lower alkenyl group, phenyl group, or cycloalkyl group; n is 1 to 6
Indicates each integer. Further, the bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond. The present invention relates to a blood clot/plate aggregation inhibitor characterized by containing a carpostyril derivative represented by the following as an active ingredient. The blood 4/plate aggregation inhibitor of the present invention has a strong platelet aggregation inhibitory effect and has a very long duration of action, making it useful as a thrombophilic agent. In the compound represented by general formula [1], R, and R
Examples of the cycloalkyl group represented by 2 include cycloalkyl groups having 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclobentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Examples of the phenyl group having a substituent represented by R include straight mirror or branched alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, and t-butyl groups, methoxy, and ethoxy. 1 carbon number such as propoxy, isopropoxy, butoxy, tert-butoxy groups, etc.
~4 straight chain or branched alkoxy groups, halogen atoms such as chlorine, bromine, iodine, fluorine, etc., hydroxyl groups, acetamino, propionyl amino groups, etc. The same as alkanoylamino groups having 2 to 4 carbon atoms in alkanoyl moieties such as propionyl amino groups Alternatively, a phenyl group having one or two different substituents can be mentioned. The lower alkyl group represented by R2 has 1 to 8 carbon atoms.
A direct mirror or a branched alkyl group can be mentioned,
Specifically, methyl, ethyl, propyl, isopropyl,
n-butyltoisobutyl, sec-butyl, ten-butyl, n-bentyl, isobentyl, neobentyl, 2
-Methylbutyl, n-hexyl, isohexyl, 2-ethylbutyl, n-heptyl, 3-methylhexyl, 2-
Examples include ethylbutyl and n-octyl groups. Examples of the lower alkenyl group represented by R2 include linear or branched alkenyl groups having 2 to 4 carbon atoms, and specific examples thereof include vinyl, allyl, isofrobenyl, and 2-butenyl groups. Typical compounds of the present invention are listed below.
N-aryl-N-cyclobentylaminocarbonylmethoxy) rubostyril o6-(N-n-butyl-N-cyclohexylaminocarbonylmethoxy) rubostyril o6-(N-methyl-N-cycloheptylaminocarbonylmethoxy) rubostyryl o6- (N-methylanilinocarponylmethoxy)rubostyryl o6-(p
-Chloranilinocarbonylmethoxy) Rubostyril o6-(N-Cyclobutylaminocarbonylmethoxy)
-3,4-dihydro. -(N-ethyl-N-cyclohexylaminocarbonylmethoxy)-3,4-dihydrocarpostyryl o6-(N-benty-N-cyclobentylaminocarbonylmethoxy) (N,N-dicyclohexylaminocarbonylmethoxy)-3,4-dihydrocarbosti I
J, 6-(p-methoxyanilinocarbonylmethoxy)-3,4-dihydrocarbostyryl(N-methyl-N-cyclohebutylaminocarbonylmethoxy)
-3,4-dihydrocarbostyryl o6-(N,N-diphenylaminocarbonylmethoxy)-3,4-dihydrocarbostyryl o6-(N-cyclohexylanilinocarbonylmethoxy)-3,4-dihydrocarbostyryl o6- [2-(N-Cycloptylaminocarbonyl)
ethoxy] rubostyryl o6-[2-(N-cyclobentylanilinocarbonyl)ethoxy] rubostyryl o6-[2-(N-methyl-N-cyclohexylaminocarbonyl)ethoxy] rubostyryl o6-[2-(
N-ethyl-N-cyclooctylaminocarbonyl)ethoxy]carbostyryl o6-[2-(o-chloroanilinocarbonyl)ethoxy]rubostyryl o6-[2
-(N-arylN-cycloheptylaminocarbonyl)ethoxy]carbostyryl o6-[2-(N,N-dicyclohexylaminocarbonyl)ethoxy]carbostyryl o6-[2-(N-phenyl-N-cyclopropylaminocarbonyl)ethoxy] -3,4-dihydrocarbostyryl o6-[2-(N-ethyl-cycloptylamino/tricarbonyl)ethoxy]-13,4-dihydrocarbostyryl o6-[21(N-propyl-N-cyclo Bentylaminocarbonyl)ethoxy]-13,4-dihydrocarbostyryl o6-[21(p-hydroxyanilinocarbonyl)ethoxy]13,4-dihydrocarbostyryl o6-[21(N-cyclobutylanilino) carbonyl)ethoxy]-3,4-dihydrocarbosti I
J le o6-[2-(N-aryl-N-cyclohexylaminocarbonyl)ethoxy]-3,4-dihydrocarbostyryl o6-[2-(o,o-dimethylanilinocarbonyl)ethoxy]-3,4-dihydrocarpo styryl o6-[2-(o-chloroanilinocarbonyl)ethoxy]-3,4-dihydrocarbostyryl o6-[3-(
N-cyclopropylaminocarbonyl)propoxy]carbostyryl o6-[3-(N-cyclobentylaminocarbonyl)propoxy]carbostyryl o6-[3-(N-cyclohexylaminocarbonyl)propoxy]
Carpostyryl o6-[3-(N-cycloheptylaminocarbonyl)propoxy]Carpostyryl o6-[3
-(N-arylN-cyclobentylaminocarbonyl)propoxy]carpostylinoleo6-[3-(N-arylN-cyclohexylaminocarbonyl)broboxy]carbostyl'leo6-[31(N-methyl-N-
cyclobutylaminocarbonyl)propoxy]carbostyryl o6-[3-(N-methyl-N-cyclobentylaminocarbonyl)propoxy]carpostyril/shio6
-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carpostylinoleo6-[31(
N-methyl-N-cycloheptylaminocarbonyl)bropoxy]carbostyrinole o6-[3-(N-ethyl-N-cyclobutylaminocarbonyl)propoxy]carbostyryl o6-[3-(N-ethyl-N-cyclobentylaminocarbonyl) Propoxy] carbostyrinoole o6-[3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy] carbostyrinoole o6-[
3-(N-ethyl-N-cycloheptylaminocarponyl)propoxy]carbostyrinoleo6-[3-(N-propyl-N-cyclobutylaminocarponyl)propoxy]carbostyryl. 6-[3-(o-methyl-p-methoxyanilinocarbonyl)propoxy]carbostyryl o6-[3-(o-
Chlor-p-ethoxyanilinocarbonyl)propoxy)-13,4-dihydrocarbostyryl o6-[3-(N
-n-propyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl o6-[3-(N-isopropyl-N-cyclobentylaminocarbonyl)propoxy]carbostyryl o6-[3-(N-isopropyl-N-cyclohexylaminocarbonyl)bropoxy] Carbostyryl o6-[3-(N-n-butyl-N-
cyclohexylaminocarbonyl)propoxy]carbostyryl o6-[3-(o-chloroanilinocarbonyl)propoxy]carbostyryl o6-[3-(p-methoxyanili/carbonyl)propoxy]carbostyryl o6-[3-(o,o -dimethylanilinocarbonyl)
propoxy]carbostyryl o6-[3-(o-methylanilinocarbonyl)propoxy]carpostyryl o6
-[3-(m-hydroxyanilinocarbonyl)propoxy]carpostyryl o6-[3-(N-methylanilinocarbonyl)propoxy]carpostyryl o6-[3
-(N-ethylanili/propyl)propoxy]carpostyryl o6-[3-(N-n-propylanilinocarbonyl)propoxy]carbostyryl o6-[3-(
N-n-butylanilinocarbonyl)propoxy]carbostyryl o6-[3-(N-isobutylanilinocarbonyl)propoxy]carbostyryl o6-[3-(N
-n-bentylanilinocarbonyl)propoxy]carbostyryl o6-[3-(N,N-diphenylaminocarbonyl)propoxy]carbostyryl o6-[3-(
N-methyl-o-methylanili/carbonyl)propoxy]carbostyryl o6-[3-(N,N-dicyclohexylaminocarbonyl)propoxy]carbostyryl o6-[3-(N-cyclobentyl-N-cyclohexylaminocarbonyl)propoxy] Power Rubos Chiril o6
-[3-(N,N-dicyclobentylaminocarbonyl)propoxy]carbostyryl o6-[3-(N-cyclohexyl-N-cycloheptylaminocarbonyl)propoxy]carbostyryl o6-[3-(N- cyclohexylanilinocarbonyl)propoxy]carbostyryl o6-[3-(N-cyclobentylanilinocarponyl)propoxy]carpostyryl o6-[3-(N-cyclobutyrami/bentylanilinocarbonyl)propoxy]-3,4- dihydrocarbostyryl o6
-[3-(N-cyclobentylaminocarponyl)propoxy]-3,4-dihydrocarpostyryl o6-[3
-(N-cyclohexylami/triponyl)propoxy]-3,4-dihydrocarbostyryl o6-[3-(N
-Sik. heptylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl o6-[3-(N-allyl-N-cyclobentylaminocarbonyl)propoxy]-3,
4-dihydrocarbostyryl o6-[3-(N-aryl-N-cyclohexylaminocarbonyl)propoxy]
-3,4-dihydrocarpostyryl o6-[3-(N-methyl-N-cyclobentylaminocarponyl)propoxy]-3,4-dihydrocarpostyryl
o6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl o6-[3-(N-methyl-N-cycloheptylami/carbonyl)propoxy]-3,4 −
dihydrocarbostyryl o6-[3-(N-ethyl-N
-cyclobutylaminocarbonyl)propoxy]-3,
4-dihydro. Rubostyryl o6-[3-(N-ethyl-N-cyclobentylaminocarbonyl)]. . poxy]-3,4-dihydrocarbostyryl o6-[
3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl o
6-[3-(N-ethyl-N-cycloheptylaminocarbonyl)propoxy]-3,4-dihydrocarpostyryl o6-[3-(N-propyl-N-cyclobentylaminocarbonyl)propoxy] -3,4-dihydrocarbostyryl o6-[3-(N-propyl-N
-cyclohexylaminocarbonyl)propoxy]-3
, 4-dihydrocarbostyryl o6-[3-(N-isopropyl-N-cyclobutylaminocarbonyl)]. . poxy]-3,4-dihydrocarbostyryl o6-[
3-(N-isopropyl-N-cyclobentylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl o6-[3-(N-isopropyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarpo styryl o6-[31(N-isopropyl-N
-cycloheptylaminocarbonyl)propoxy)-3
,4-dihydrocarbostyryl o6-[3-(N-n-butyl-N-cyclopropylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl o6-[3-(N-n-butyl-N-cyclobentylaminocarbonyl) carbonyl)propoxy]-3,4-dihydrocarbostyryl o
6-[3-(N-n-butyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihyde. Rubostyril o6-[3-(N-isobutyl-N-cyclobentylaminocarbonyl)propoxy]-3,4
-dihydrocarbostyryl o6-[3-(N-isobutyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl o6-[3-(N
-rt-butyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarpostyryl o
6-[3-(N-benthyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl o6-[3-(N-cyclohexylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyryl o6 -[3-(N,N-diphenylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl o6-[3-(N,N-dicyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl o6- [3-(N-methylanilinocarbonyl)propoxy]m3,4-dihydrocarbostyl/Sio6-[3
-(N-ethylanilinocarbonyl)propoxy]-3
, 4-dihydrocarbostyl'reo6-[3-(N1n
-propylanilinocarponyl)propoxy]-3,4
-dihydrocarbostyryl o6-[3-(N-n-butylanili/triponyl)propoxy]-3,4-dihydrocarbostyryl o6-[3-(N-bentylanilinocarbonyl)propoxy]-3, 4-dihydrocarpostyryl o6-[3-(p-acetaminoanili/triponyl)propoxy]-3,4-dihydrocarpostyryl o6-[3-(m-hydroxyanilinocarponyl)propoxy]-3,4- dihydrocarbostyryl o6
1[31(o-methylanilinocarbonyl)propoxy]13,4-dihydrocarpostyl'leo61(41N
-cyclohexylamine/carpostyril o6-[4-(N-methyl-N-cyclobentylaminocarponyl)butoxy]carpostyril o6-[
4-(N-Methyl-N-cyclohexylaminocarbonyl)butoxy] rubostyril o6-[4-(N-ethyl-N-cyclohexylaminocarbonyl)butoxy]
Rubostyril o6-[4-(N-n-propyl-N-cyclohexylaminocarbonyl)butoxy] Rubostyril o6-[4-(N-isobutyl-N-cyclobentylaminocarbonyl)butoxy] Rubostyril IJruo
6-[4-(N-amy-N-cyclohexylaminocarbonyl)ptoxy]lupostyril o6-(4-anilinocarbonylbutoxy)lubostyryl o6-[
4-(N-methylanilinocarbonyl)butoxy]rubostyryl o6-[4-(N-ethylanilinocarbonyl)butoxy]lupostyryl o6-[4-(N-isobutylanilinocarbonyl)butoxy]rubostyryl o6 1 [41 (o, o-dimethylanilinocarbonyl)
Butoxy] lpostyryl o6-[4-(N-methyl-N-cyclobentylaminocarbonyl)butoxy]-3
,4-dihydrocarbostyryl o6-[4-(N-ethyl-N-cyclohexylaminocarbonyl)butoxy]
-3,4-dihydrocarbostyryl o6-[4-(N-
n-butyl-N-cyclohexylaminocarbonyl)butoxy]-3,4-dihydrocarbostyryl o6-[4
-(N-methylanilinocarbonyl)butoxy] -3,
4-dihydrocarbostyryl o6-[4-(N-ethylanilinocarponyl)butoxy]-13,4-dihydrocarbostyryl o6-[4-(o,o-dimethylanilinocarponyl)butoxy]-3,4- Dihydrocarbostyryl o6-[5-(N-methyl-N-cyclohexylaminocarbonyl)bentyloxy]rubostyryl. 6-[5-(N-cyclohexylanilinocarbonyl)
Bentyloxy]carbostyryl o6-[5-(N-ethylanilinocarbonyl)bentyloxy]carbostyryl o6-[5-(N-ethyl-N-cycloheptylaminocarbonyl)bentyloxy]-3,4-dihydrocarbostyryl o6-[ 5-(N-methylanilinocarbonyl)bentyloxy]-3,4-dihydrocarpostyryl o6-[6-(N-methyl-N-cyclohexylaminocarbonyl)hexyloxy]-rubostyryl o
6-[6-(N-ethylanilinocarponyl)hexyloxy]rubostyryl o6-[6-(N-ethyl-N
-cyclobentylaminocarbonyl)hexyloxy]
-3,4-dihydrocarbostyryl o6-[6-(N-methylanilinocarponyl)hexyloxy]-3,4
-dihydrocarbostyryl o5-(N-methyl-N-cycloheptylaminocarbonylmethoxy)-rubostyryl o5-(N-methylanilinocarbonylmethoxy)-rubostyryl o5-(N-ethyl-N-cyclohexylaminocarbonylmethoxy)-3,4 -dihydrocarbostyryl o5-(N,N-dicyclohexylaminocarbonylmethoxy)-3,4-dihydrocarbostyryl o
5-(p-methoxyaniiJ/p-methoxyaniiJ)-
3,4-dihydrocarbostyryl o5-(N-methyl-
N-cycloheptylaminocarbonylmethoxy)-3,
4-dihydrocarbostyryl o5-[2-(N-methyl-N-cyclohexylaminocarbonyl)ethoxy]rubostyryl o5-[2-(N-n-propyl-N-cycloheptylaminocarbonyl)ethoxy]-3,4-
Dihydrocarbostyryl o5-[2-(p-hydroxyanilinocarbonyl)ethoxy]-3,4-dihydrocarbostyryl o5-[2-(o,o-dimethylanilinocarbonyl)ethoxy]-3,4-dihydrocarbo styryl o5-[3-(N-cyclohexylaminocarbonyl)propoxy] carbostyryl o5-[3-(N-allyl-N-cyclobentylaminocarbonyl)propoxy] carbostyryl o5-[3-(N-ethyl-N-cyclobenzi) [(N-methyl-N-cyclohexylaminocarbonyl) propoxy] carbostirinole o5-[3-(N-methyl-N-cycloheptylaminocarbonyl) propoxy] carbostiri/shio5- [3
-(N-ethyl-N-cyclobutylaminocarbonyl)
Propoxy] carbostyryl o5-[3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]
Calbostili'reo5-[3-(N-propyl-N
-cyclohexylaminocarbonyl)propoxy]carbostyryl o5-[3-(N-isobropy-N-cyclohexylaminocarbonyl)propoxy]carbostyryl o5-[3-(p-methoxyanilinocarponyl)
Propoxy]carpostyryl o5-[3-(N-methylanilinocarbonyl)propoxy]carpostyril o5
-[3-(N-n-propylanilinocarbonyl)propoxy]carbostyryl o5-[3-(N,N-diphenylaminocarbonyl)propoxy]carbostyryl o
5-[3-(N,N-dicyclohexylaminocarbonyl)propoxy]carbostyryl o5-[3-(N-cyclohexylanilinocarbonyl)propoxy]carbostyryl o5-[3-(N-cyclohexylaminocarbonyl)propoxy]- 3,4-dihydrocarbostyryl o5-[3-(o,o-dimethylanilinocarbonyl)propoxy]carbostyryl o5-[3-(N-aryl-N-cyclobentylaminocarbonyl)propoxy]-3,4- dihydrocarpostyril o5-[31(N
-Methyl-N-cyclobentylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl o5-[3
-(N-methyl-N-cyclohexylaminocarponyl)propoxy]-3,4-dihydrocarpostyryl o5
-[3-(N-ethyl-N-cyclobentylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl o5-[3-(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl styryl o5-[3-(N-ethyl-N-cycloheptylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl o5-[3-(N-n-propyl-N-
cyclohexylaminocarbonyl)propoxy]-3,
4-dihydrocarbostyryl o5-[3-(N-isopropyl-N-cyclohexylaminocarbonyl)propoxy]-13,4-dihydrocarbostyryl o5-[3-(N-isobutyl-N-cyclobentylaminocarbonyl)propoxy]-3 ,4-dihydrocarbostyryl o
5-[3-(N rt-butyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl o5-[3-(N-cyclohexylanilinocarbonyl)propoxy]-3,4-dihydrocarbo styryl o5-[3-(N,N-diphenylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl o5-[3-(N-methylanilinocarbonyl)propoxy]-3,4-dihydrocarbostyryl 'Leo51〔
3-(N-n-butylanilinocarponyl)bropoxy]-3,4-dihydrocarbostyryl o5-[4-(N
-Methyl-N-cyclohexylaminocarbonyl)butoxy]carbostyryl o5-[4-(N-ethyl-N-cyclohexylaminocarbonyl)butoxy)carbostyryl o5-[4-(N-methylanilinocarbonyl)
butoxy]carbostyryl o5-[4-(N-ethylanilinocarbonyl)butoxy]carbostyryl o5-[
4-(N-methyl-N-cyclobentylaminocarbonyl)butoxy]-3,4-dihydrocarbostyryl o5
-[4-(N-methylanilinocarbonyl)butoxy]
-3,4-dihydrocarbostyryl o5-[5-(N-methyl-N-cyclohexylaminocarbonyl)bentyloxy]rubostyryl o7-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl o7-[3- (N-ethyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril o7-[3-(N-methylanilinocarbonyl)propoxy]carbostyryl o7-[3-(N-ethylanilinocarbonyl)propoxy]carbo Styryl o7-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-13,4-dihydrocarbostyryl o7-[3-(N-methylanilinocarbonyl)propoxy]-13,4-dihydrocarbostyryl' leo81 [3
1(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostylinoleo8-[31(N-ethyl-N-cyclohexylaminocarbonyl)propoxy]rubostyrinooleo8-[31(N-methylanilinocarbonyl)propoxy] Carbostyril o8-[3
-(N-ethylanilinocarbonyl)propoxy]carbostyryl o8-[3-(N-methyl-N-cyclohexylaminocarbonyl)bropoxy]-3,41dihydrocarpostyryl o8-[3-(N-methylanilinocarbonyl) ) Propoxy]-3,4-dihydrocarpostylic compound of the present invention can be produced by various methods,
For example, methods shown in the following reaction schemes -1 and -2 can be mentioned. Reaction Scheme 1 Reaction Scheme 2 (In the above, x represents a halogen atom. R., R2, n and the bonds at the 3rd and 4th positions are the same as above.) General formula used as a starting material in the present invention The compounds [b] and [m] are known compounds, and are produced, for example, by the following reaction scheme-3. Reaction Scheme-3 (In the above, X represents a halogen atom. The bonds at the n and 3rd and 4th positions are the same as above.) Reaction Scheme-1
The method shown in is a well-known general formula

This is a method of carrying out a conventional dehydrohalogenation reaction between hydroxycarbostyryl or hydroxy-3,4-dihydrocarpostyryl represented by [0] and a known haloamide represented by general formula [W]. Examples of the halogen atoms in the haloamide include bromine, chlorine, and iodine. This dehydrohalogenation reaction is carried out using a basic compound as a dehydrohalogenation agent. A wide variety 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. Examples include metals, alcoholates such as sodium methylate and sodium ethylate, and organic bases such as triethylamine, pyridine, and N,N-dimethylaniline. The reaction is carried out without a solvent or in the presence of a solvent, and any inert solvent that does not adversely affect the reaction can be used, such as methanol, ethanol, etc.
Alcohols such as alcohol, propanol, butanol, and ethylene glycol; ethers such as dimethyl ether, tetrahydrofuran, and dioxa/, monoglyme, and diglyme; ketones such as acetone and methyl ethyl ketone; and aromatic carbons such as benzene, toluene, and xylene. Hydrogens, esters such as methyl acetate and ethyl acetate, N
, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, and other aprotic polar solvents. Further, the reaction is advantageously carried out in the presence of a metal iodide such as sodium iodide or potassium iodide. Hydroxycarbostyryl derivative in the above method

The ratio of [0] and haloamide [N] to be used is not particularly limited and is appropriately selected from a wide range, but usually the latter is used in an equimolar to 5-fold molar ratio to the former, preferably an equimolar to 2-fold molar ratio. It is desirable to use double the molar amount. Although the reaction temperature is not limited, it is usually carried out at room temperature to 200 pm, preferably 50 to 15 pm. The reaction time is usually 1 to 30 hours, preferably 1 to 1 hour. The method shown in Reaction Scheme-2 is based on the general formula [
In this method, a carboxyalkoxycarbostyryl derivative represented by [m] and a known amine represented by general formula [V] are reacted in a conventional amide bond forming reaction. Various methods can be used as the amide bond forming reaction. For example, a) A method of reacting a mixed acid anhydride, that is, a carboxylic acid [m] with an alkylhalocarboxylic acid to form a mixed acid anhydride, and reacting this with an amine [V], b) A method of reacting an activated ester method with a carboxylic acid A method in which [m] is an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and the amine [V] is reacted with the active ester, c) Carbodiimide rule: Carboxylic acid [ A method of dehydrating and condensing amine [V] with m] in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldimidazole; d) Another method is converting carboxylic acid [m] to carboxylic acid anhydride in the presence of a dehydrating agent such as acetic anhydride. A method of reacting a compound with an amine [V], a method of reacting an ester of a carboxylic acid [m] and a lower alcohol with an amine [V] at high temperature, a method of reacting a carboxylic acid halide with an amine [V], etc. can be mentioned. Among these, 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 of the present invention is produced by reacting it with the amine [V] without isolation. The Schotten-Baumann reaction is carried out in the presence of a basic compound. As the basic compound used, compounds commonly used in the Schotten-Baumann reaction are used, such as organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, and N-methylmorpholine, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and hydrogen carbonate. Examples include inorganic bases such as sodium. The reaction is carried out at -20 to 100 pm, preferably 0 to 5 pm, and the reaction time is 5 minutes to 1 hour, preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and amine [V] is -20 to 150 qo, preferably 10
The reaction time is 5 minutes to 1 feeding time, preferably 5 minutes to 5 hours. Mixed anhydride methods are generally carried out in a solvent. As the solvent used, any solvent commonly used in the mixed acid anhydride method can be used.
Specifically, halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, and esters such as methyl acetate and ethyl acetate. Examples include aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide, and hexamethyl phosphate toluamide. The ratio of carboxylic acid [m], alkylhalocarboxylic acid, and amine [V] used in this method is usually equimolar amounts, but the ratio of alkylhalocarboxylic acid and amine to carboxylic acid is 1 to 1. A sealed mole may also be used. The compound of the present invention produced in this manner is isolated and purified by appropriately applying known purification methods such as heating, extraction, and recrystallization. The compounds of the present invention can be administered to animals and humans as is or with conventional pharmaceutical carriers. The dosage unit form is not particularly limited and can be appropriately selected and used as required. Such dosage unit forms include tablets,
Examples include oral preparations such as powders, jaw granules, oral solutions, and parenteral preparations such as injections. 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 necessary to
．． It is preferable to set it to o of 06 to 10. It is also preferable that the dosage unit form contains 1 to 500 9 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 compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, and the like. 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, European capsules, and the like. Syrups or elixirs are prepared by mixing the compound of the present invention with sweeteners such as sugar syrup, preservatives such as methyl- and bropylbarabens, coloring agents, seasonings, and the like. Moreover, parenteral preparations are manufactured according to conventional methods. That is, a drug for parenteral administration is prepared by dissolving the compound of the present invention in a sterile liquid carrier. The preferred spoiler is water or salt water. A solution having the desired clarity, stability, and suitability for parenteral use may contain from about 1 to
It is prepared by dissolving 500 active ingredients in water and an organic solvent and 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-mentioned solution may contain bactericides and fungicides such as pendyl alcohol, phenol, and thimerosal, as well as isotonic agents such as wisteria bran and sodium chloride, local anesthetics, stabilizers, buffers, etc. You may be 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. Preparation of Tablets 1000 sen for oral use containing respectively 5/9/61 [31 (N-methyl-N-cyclohexylaminocarponyl)propoxy) carbostyril] are prepared according to the following formulation. Blend amount (evening) 6-[3-(N-Methyl-N-cyclohexylamine/hydrolbonyl) propoxy]carbostyryl 5 Lactose (Japanese Pharmacopoeia product) 50 Cornstarch (Japanese Pharmacopoeia product) 25 Crystalline cellulose (Japanese Pharmacopoeia product) 25 methyl cellulose (Japanese Pharmacopoeia product)
1.5 Magnesium stearate (Japanese Pharmacopoeia product)
1 6-[3-(N-Methyl-N-cyclohexylaminocarponyl)propoxy]carpostyril, lactose, cornstarch and crystalline cellulose were thoroughly mixed, granulated with a 5% aqueous solution of methylcellulose, and carefully passed through a 200 mesh strip. dry. The dried jaw grains are passed through a 200 mesh section and mixed with magnesium stearate and pressed into tablets. Preparation of Capsules 1000 two-piece hard gelatin capsules containing 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril for intravenous use on 10 days each were prepared according to the following formulation: prepared. Blend amount (6-[3-(N-methyl-N-cyclohexylaminocarbonyl) propoxy] carbostyril 10 Lactose (Japanese Pharmacopoeia product) 80 Starch (Japanese Pharmacopoeia product)
30 Talcum (Japanese Pharmacopoeia product)
5 Magnesium Stearate (Japanese Pharmacopoeia) 1 The above ingredients are finely powdered, mixed thoroughly to form a homogeneous mixture, and then filled into gelatin capsules for oral administration having desired dimensions. Preparation of Injection A sterile aqueous solution suitable for parenteral administration is prepared according to the following recipe. Compounding amount (61 [31 (N-methyl-N-cyclohexylaminocarbonyl) propoxy] carbostyril 1 Polyethylene glycol (Japanese Pharmacopoeia product) Molecular weight: 4000 0.3 Sodium chloride (Japanese Pharmacopoeia product) 0.9 Boroxyethylene bitane monooleate (Japanese Pharmacopoeia product)
0.4 Sodium metabisulfite 0
．． 1 Methyl-paraben (Japanese Pharmacopoeia) 0.18
Propyluparaben (Japanese Pharmacopoeia) 0.
02 Distilled water for injection 100 (skin) The above parabens, sodium metabisulfite and sodium chloride were dissolved in about half the amount of distilled water above at 80 oo while shaking. The resulting solution was cooled to 40oo, and 6-[3-(N-
Methyl-N-cyclohexylaminocarbonyl)bropoxy]carbostyryl, then polyethylene glycol and polyoxyethylene sorbitan monooleate were dissolved into the solution. The solution was then adjusted to the final volume by adding distilled water for injection and sterilized by sterilizing the solution using a suitable filter paper. The results of measuring the excellent platelet aggregation inhibiting effect, in-vivo stability, and acute toxicity of the compound of the present invention are shown below. The compounds used in each test are as follows. The platelet aggregation inhibitory effect was investigated according to the method described in Pharmacological Tests Nature, pages 927-929 (196 Sanno). In other words, the effect of inhibiting blood and plate aggregation was measured using an AG-0 type aggregometer [Priceman Manufacturing Company (Br.
tmingCo. ) manufactured by ). The blood sample collected from the rabbit was a mixture of sodium citrate and whole blood at a mixing ratio of 1:9 (volume ratio). The sample was centrifuged for 10 minutes at 100 pm to remove plasma with a high concentration of blood 4 and plasma.
) (hereinafter referred to as "PRP-IJ").The obtained PR
P-1 was separated and the remaining blood sample was incubated at 300 pm for 18 min.
If the blood platelet concentration is low after 0 minutes, the blood platelet concentration is low.
(hereinafter referred to as “PPP”)
). The number of platelets contained in the PRP-1 was determined by the Bretcher-Cronkite method.
r-CIonkiteMethod), PRP
-1 was diluted with PPP and adenosine diphosphate (
ADP) - 300,000/- for subjected to induced agglutination test
A sample containing 450,000/skin 3 platelets (hereinafter referred to as "PRP-2") was prepared, and a sample containing 450,000/skin 3 platelets (hereinafter referred to as "PRP-2") was prepared for the collagen-induced aggregation test.
PRP-3) was prepared. [11 ADP-induced aggregation inhibition test] A solution containing a predetermined concentration of the compound to be tested.
0.01 of PRP-2 prepared above was added to 0.6' of PRP-2, and the mixture was placed in a constant temperature bath at a temperature of 370 for 1 minute. Then 0.07' of ADP solution was added to the mixture. The permeability of this mixture was measured, and the change in permeability was measured using an agglutinometer at a rotation speed of 110 pm. The ADP solution used in this test was prepared using Oren-Veronal buffer to a concentration of 7.5 x 10-5M. The aggregation rate at the time when platelet aggregation reached the maximum (the time when the light transmittance reached the maximum) was calculated using the following formula. Aggregation rate = X・oo Here, a,: Permeability of PRP-2 q: Permeability of PPP c,: Permeability of PRP-2 mixed with test compound and ADP The aggregation rate calculated by the above formula is Let it be B. In addition, platelets are aggregated in the same manner as above except that no test compound is used, and the aggregation rate is determined, and this aggregation rate is defined as the control aggregation rate A. The platelet aggregation inhibiting effect of the test compound was determined as the inhibition rate (%) relative to the aggregation rate of the control. Inhibition rate (%) = 233XIoo '2 - Collagen-induced aggregation inhibition test A solution containing the compound to be tested at a predetermined concentration.
0.6' of PRP-3 prepared above was added to 01' of PRP-3, and the mixture was placed in a constant temperature bath at a temperature of 37q0 for 1 minute. Next, 0.07 μm of the collagen solution of the mixture was added. The permeability of this mixture was measured, and the change in permeability was measured using an agglutinometer at a rotational speed of 110 pm on a rope scale. In this test, the collagen was prepared by adding 5 parts of Oren-Veronal buffer (7.35 centigrade) to 100/9 collagen and grinding the mixture, and then using the above solution. The aggregation rate at the time when platelet aggregation reached the maximum (the time when the light transmittance reached the maximum) was calculated using the following formula. Aggregation rate = perforation x 100 where a2: Permeability of PRP-3 etc.: Permeability of PPP c2: PRP-3 mixed with test compound and collagen
Let B2 be the aggregation rate calculated using the above formula. In addition, platelets are aggregated in the same manner as above except that no test compound is used, and the aggregation rate is determined, and this aggregation rate is taken as the control aggregation rate. The platelet aggregation inhibiting effect of the test compound was determined as the inhibition rate (%) relative to the aggregation rate of the control. Winning rate=Raw B2×loo Table 1 shows the inhibitory effect on rabbit platelet aggregation induced by collagen, and Table 2 shows the inhibitory effect on rabbit platelet aggregation induced by ADP. The numerical values in Tables 1 and 2 are inhibition rates (%). Table 1 Table 2 Test compound D suspended in water was orally administered at 30 doses to male Wistar rats and male beagle dogs that had been fasted overnight, and after a certain period of time, blood was collected to obtain a blood count. Add 0.1 normal NaOH2-3 to the obtained blood count 1.
The mixture was shaken and extracted using a shaker for 2 hours, and after centrifugation, the organic layer was washed with 0.1 N of HC12. After freezing and thawing the organic layer and removing chloroform under a nitrogen stream, the residue was redissolved in 100% chloroform and dissolved in Silica GI6 Misaki 254 manufactured by Merck & Co.
Spotted on the thin plate. This was developed with a mixed solvent of chloroform:butanol=5:1, and a spot having the same Rf value as the test compound was measured by absorbance method using a Shimadzu CS-91 model thin layer chromatography scanner for quantitative determination. The blood concentration of test compound D was determined. The results are shown in Table 3.
Table 3 Similar tests were conducted on test compounds A to C and E to L, and the same results as in Table 3 were obtained. Acute toxicity test Test compounds C and D were orally administered to mice and LD5. (9/k9) was measured. The results are shown in Table 4.
Reference examples and examples in Table 4 are listed below. Reference Example 1 Add 98 g of 6-hydroxy-3,4-dihydrocarbostyryl to 400 g of pyridine and dissolve at room temperature. Add 80 g of acetic anhydride and incubate for 3 hours. After the reaction, dissolve the reaction solution in 2 g of water. The poured crystals are removed from the furnace and washed with water. The obtained crystals were recrystallized from ethanol to give colorless plate-like crystals of 6-acetoxy-3,4-dihydrocarbostyryl 10.
Get 3 evenings. Melting point: 170-170 Reference example: To 250 ml of carbon tetrachloride, 10 ml of finely ground 6-acetoxy-3,4-dihydrocarbostyryl was added, and under reflux, 3 bromine was added.
．． 50 m' of a carbon tetrachloride solution containing 0.5 ml of penzoyl peroxide and 0.5 ml of penzoyl peroxide are added dropwise. After passing through the water for two hours, the Touzusa water was refluxed for another three hours. After cooling, the insoluble matter is removed in an oven, the crystals are washed with carbon tetrachloride, and recrystallized from methanol. 7.5 hours of 6-acetoxycarbostyryl are obtained in the form of pale yellow needles. Melting point 222-223 pm Reference example 3 380 mg of concentrated hydrochloric acid was added to 6-acetoxycarbostyryl 382, refluxed for 4 hours, allowed to cool, and the precipitated crystals were collected in a furnace.
Wash with water. The obtained crystals are recrystallized from methanol to obtain colorless needle-like crystals of 6-hydroxycarbostyryl 27. Melting point 31
3 to 316.500 Reference Example Add 26% of N-methylcyclohexylamine to 400% of 4-ethyl acetate, cool on ice externally, and add 25% of 4-chlorobutyryl chloride and 33.5% of triethylamine. Drop simultaneously while keeping the temperature at 10-20 oo. The mixture is added dropwise over 20 minutes, and then heated at room temperature for 1 hour. After the reaction, water is added to the reaction solution to separate the layers, and the organic layer is washed with water, saturated aqueous potassium carbonate solution, 10% hydrochloric acid, and water, and dried over anhydrous sodium sulfate. The sodium sulfate was removed in the oven, the mother liquor was concentrated, and then distilled under reduced pressure to obtain colorless liquid N-(4-chlorobutyryl)N-methylcyclohexylamine 41.
Get 5 evenings. Boiling point 133-13 is 0 (2 legs Hg) Reference example 5 6-hydroxycarbostyryl 16 days and potassium carbonate 14 days were added to DMF 200 skin, and at 60-7000, ethyl-y-furomobutyrate was added 25 days and 30 days. It takes several minutes to get through. After cooling at the same temperature for 5 hours, pour into 1.5 hours of saturated NaCI water, take out the precipitated crystals, and wash with water. The obtained crystals are recrystallized from aqueous ethanol to obtain colorless needle-like crystals of 6-(3-ethoxycarbonylpropoxy)carbostyryl. Melting point: 130-13 ○Reference example 6 Add 6 ml of NaOH to 500 ml of water and dissolve it.
Add 3-ethoxycarbonylbu 1 copoxy) Carbos Z Tyril 28 evenings and cross the ocean at 50-60 qo for 2 hours. After cooling, the reaction solution is made acidic by adding concentrated hydrochloric acid, and the precipitated crystals are removed from the furnace and washed with water. The obtained crystals are recrystallized from methanol to obtain 6-(3-carboxypropoxy)carbostyryl 21 in the form of colorless needles. Z melting point: 257-258°C Compound Production Example 1 To 200% of methylene chloride was added 2.5% of 5-(3-carboxy)propoxy-3,4-dihydrocarbostyryl and 2.0% of N-methylmorpholine. Under the external ice-cold lamp, the internal temperature of methyl chloroformate was 1.0 to 10-2.
Drop while keeping the temperature at 0oo. After dropping at room temperature for 30 minutes, N-ethylaniline 1.
Add 3 mints and boil for 4 hours at the same temperature. After the reaction is completed, water is added to the reaction solution to separate the layers, and the organic layer is diluted with a dilute NaOH aqueous solution,
Wash with dilute dihydrochloric acid and water in that order, and dry with Nabu 04. After removing the inorganic substances in an oven and concentrating the mother liquor, the residue was recrystallized from ethanol to give colorless needle crystals of 5-[3-(N-ethylanilinocarbonyl)propoxy]-3,4-dihyde. Obtain 2.6 doses of carbostyril. Melting point 3179.5-180.5
00 Compound Production Example 2 Tetrahydrofuran 50' to 6-1 (3-ruboxy)
Propoxycarbostyryl 2.5 yen and pyridine 1.8 yen
External ice loss by adding 3 chloride of bromoformate 1.
0 while keeping the internal temperature at 5 to 15 oo. After the dropwise addition, the mixture was heated at room temperature for 1 hour, and then 1.2 hours of N-methylcyclohexylamine was added, and the mixture was incubated for an additional 3 hours. The reaction solution was poured into 200 volumes of saturated saline, and the precipitated crystals were taken out of the oven and washed with water. The obtained crude crystals are recrystallized from chloroform-ethanol to obtain colorless needle-like crystals of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl. Melting point 184.5~1
86°C Compound Production Example 3 50% dimethylformamide,
Add 2.5 mols of 6-(3-carboxy)proboxy-3,4-dihydrocarbostyryl and 1.4 ml of potassium carbonate, cool on ice and heat on top of 1.1 ml of isobutyl chloroformate to an internal temperature of 10 to 20 ml. Drip while keeping the temperature at 0:00. 1. At 30-40°C after dropping. After heating for a while, 1.4 hours of N-allylcyclohexylamine was added, and the mixture was heated for another 2 hours at the same temperature. The reaction solution was poured into a 200% saturated saline solution, and the precipitated crystals were removed from the furnace and washed with water. The obtained crude crystals were recrystallized from ethyl acetate and petroleum ether to give colorless needle crystals of 6-[3-(N-allyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyryl 2.7 Get the evening. Melting point 105-107q0
Compound Preparation Example 4 To 200 g of ethyl acetate, 2.5 g of 6-(3-carboxy)propoxy-3,4-dihydrocarbostyryl and 1.6 g of triethylamine were added, and the mixture was cooled with ice outside.
Add 1.0 μl of ethyl chloroformate dropwise while maintaining the internal temperature at 10-20 oo. After the dropwise addition, it was heated at room temperature for 1 hour, and then N-methylaniline 1.
Add step 1 above and do rope azusa for 2 hours. Water is added to the reaction solution to separate the layers, and the organic layer is washed successively with a dilute aqueous NaOH solution, dilute hydrochloric acid, and water, and dried over Na2S04. After removing the inorganic substances in the furnace, the mother liquor was concentrated, and the residue was recrystallized from chloroform and petroleum ether to give colorless needle-like crystals of 6-[3-(N-methylani IJ).
2.2% of 1-3,4-dihydrocarbostyryl (propoxy(propoxy)) is obtained. Melting point 129.5-131.5
Compounds shown in Table 5 below were obtained in the same manner as in Compound 00 Production Example 4. Compound Production Example 45 6-(3-carboxy)bropoxycarpostyryl 2.
Add 5 parts of N-methylhexylhexylamine and 1.2 parts of N-methylhexylhexylamine to a mixed solvent of 20 parts of dioxane and 20 parts of methylene chloride, and add 2.1 parts of N,N'-dicyclohexylcarbodiimide under external ice-cooling. A solution prepared by dissolving water on top of 5 parts of methylene chloride is added dropwise while maintaining the concentration at 10 to 20 qo. After dropping, the mixture was heated at the same temperature for 3.5 hours. The precipitated crystals are removed from the furnace, and the furnace liquid is concentrated and dried under reduced pressure. The resulting residue was dissolved in 100 g of methylene chloride, and the organic layer was washed with a 5% aqueous hydrochloric acid solution, a 5% aqueous sodium bicarbonate solution, and water in this order. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was recrystallized from chloroform-ethanol to obtain colorless needle crystals of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyryl (1.9 g). Production example 466-[3-(p-nitrophenoxycarboel) of o compound with a melting point of 184.5 to 18
3.7 mg of [propoxy]carbostyril was dissolved in 40 mg of dimethylformamide, 2.0 mg of cyclohexylamine was added, and the mixture was left at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, and the resulting Zenizumi was subjected to silica gel column chromatography (silica gel: Wako C-2
00, eluent: chloroform) and recrystallized from ethanol to obtain colorless needle-like crystals of 6-[3-(N-cyclohexylaminocarbonyl)propoxy]carbostyryl 1.
．． Get 5 evenings. Melting point 251-25〆○Compound Production Example 47 Dimethyl sulfoxide 50I, 6-hydroxy-3,
4-dihydrocarpostyril 3.2 liters, potassium hydroxide 0.9 liters, sodium iodide 3.2 liters and N-methyl-N-chlorobutyrylcyclohexylamine 5.0 liters were added at 70 to 80 qo. ．． Insect Time Light Azusa. After the reaction is completed, the reaction solution is poured into 400ml of saturated saline solution, and the precipitated crystals are taken out in a furnace and washed with water. The obtained crude crystals were recrystallized from benzene and petroleum ether to give colorless needle-like crystals of 6-[3-(N
-Methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarpostyryl 2.9 times were obtained. Melting point: 144-14,600 Compound Production Example 48 30% dioxane, 1.6% of 5-hydroxy-3,4-dihydrocarbostyryl, 0.8% of pyridine, 1.8% of potassium iodide, and N-methyl-N- Add 2.8 hours of (4-chlorobutyryl)-cyclohexylamine and reflux for 1 hour. After the reaction is completed, the reaction solution is poured into 200M saturated saline solution, and the precipitated crystals are collected in a furnace. The crude crystals were dissolved in chloroform at 50 °C and the organic layer was washed with IN-sodium hydroxide solution (50 °C).
2) After washing with water and anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was recrystallized from ethyl acetate to obtain colorless crystals of 5-[3-(N-methyl-N-cyclohexyl). 0.8 g of aminocarbonyl)propoxy]-3,4-dihydrocarbostyryl is obtained. Melting point 133~
134qo compound production example 49 6-hydroxycarbostyryl 1 in ethanol 30
．． After 6 nights, 0.7 nights of sodium ethylate, 1.6 hours of sodium iodide, and 2.4 nights of N-methyl-N-(4-chlorobutyryl)-aniline were added, and the mixture was refluxed under Takazusa for 6 hours. After the reaction is completed, the reaction solution is poured into 200 g of saturated saline solution, and the precipitated crystals are taken out of the furnace and washed with water. The obtained crude crystals were recrystallized from chloroform and petroleum ether to give cool-colored needle-like crystals of 6-[3-(
1.3 times of N-methylanilinocarbonyl)propoxy]carbostyryl is obtained. Production example 50 of a compound with a melting point of 187 to 18 0. Add 0.5 liters of metallic sodium to 50 ml of methanol under ice cooling and dissolve, and then add 3.2 liters of 6-hydroxy-3,4-dihydrocarbostyryl to iodide. 3.2 hours of sodium and 4.6 hours of N-(4-chlorobutyryl)-cyclohexylamine were added, and the mixture was refluxed under concentrated water for 5 hours. After the reaction is completed, the reaction solution is poured into 400 g of saturated saline solution, and the precipitated crystals are taken out in a furnace and washed with water. The obtained crude crystals are recrystallized from methanol to obtain colorless needle-like crystals of 6-[3-(N-cyclohexylaminocarbonyl)propoxy-3,4-dihydrocarbostyryl]. Melting point: 220-22ro Compound Preparation Example 51 DMF30 6-hydroxycarbostyryl 1.6 hours, K2C03 1.4 hours, sodium iodide 1.6 hours and N-methyl-N-(4-chlorobutyryl)monocyclohexylamine 2. 70-80 including 5 evenings
We worshiped at the foot of the mountain for 4 hours at qo. After the reaction, the reaction solution was poured into 200 g of saturated NaCI water, and the precipitated crystals were collected in a furnace and washed with water. The obtained crystals were recrystallized from chloroform-ethanol to give colorless needle-like crystals of 6-[3-(N
-Methyl-Ncyclohexylaminocarbonyl)propoxy]carbostyryl 1. Get a fish. Melting point: 184.5~
18 is o Compound Production Example 5 according to the method of Compound Production Example 51
Compounds 30 and 32 to 44 were obtained and confirmed to have the same melting point and properties. The compounds shown in Table 6 below are obtained in the same manner as in Compound Production Example 4 above. Table 6

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 is a cycloalkyl group, or as a substituent, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halogen R_2 is a phenyl group with or without one or two atoms, a hydroxyl group, or an alkanoylamino group having 2 to 4 carbon atoms, R_2 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a phenyl group, or a cycloalkyl group, n represents an integer from 1 to 6, respectively. Furthermore, the bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond. ] A platelet aggregation inhibitor characterized by containing a carbostyril derivative represented by the following as an active ingredient.