JPS597169A - Carbostyryl derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is H, alkyl, alkenyl, alkynyl or phenylalkyl; R<2> is H, OH or alkoxy; R<3> is H, halogen, alkanoyloxy or group of formula II (R<4> and R<6> are alkyl; R<5> is alkanoyl); the bond between the 3- and 4-positions of carbostyryl skeleton is single or double; the position of CH2R<3> is 3-8 position of carbostyryl skeleton] and its salt. EXAMPLE:3-Hydroxymethylcarbostyryl. USE:The compound has antiulcer activity in itself, and is also useful as a synthetic intermediate of a compound having excellent antiulcer activity and remarkably effective to prevent and remedy chronic ulcer. PROCESS:A compound of formula I wherein R<3> is OH can be prepared by reducing the carboxylic acid compound of formula II directly or after esterification. The product can be converted to another compound of formula I wherein R<3> is halogen or group of formula III by successively reacting with a halogenation agent and the compound of formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel carbostyril derivatives, more specifically,
General formula [wherein R1 is a hydrogen atom, lower alkyl, lower alkenyl, lower arginine/L/or phenyl lower alkyl 7L]
/ ; R2 represents a hydrogen atom, a hydroxyl group or a lower alkoxy; R3 represents a hydroxyl group, a rogen atom, a lower alkanoyl (lower alkyl); R5 represents a lower alkanoyl (lv);

The bond between the 3rd and 4th positions of the carbostyril bone nucleus shows a single bond or a double bond. The position of the substituent is either 8.4.5, 6.7 or 8 of the carbostyril bone core. ] The present invention relates to a carbostyril derivative represented by the following and a salt thereof.

The compound of the present invention has an anti-ulcer effect per se, and also has anti-ulcer activity.
It has excellent anti-ulcer properties, especially.

It is useful as a synthetic intermediate for the compound represented by the following general formula (2), which has remarkable preventive and therapeutic effects on chronic ulcer pathologies such as experimental acetic acid ulcers and burnt ulcers.

[In the formula, R1 is a hydrogen atom, lower alkyl, lower alkenyl, lower alkynyl or phenyl lower argyl, R
2 is a hydrogen atom, hydroxyl group or lower alkoxy; R' is a hydrogen atom or lower alkyl; R'' is a hydrogen atom or group -
COR (R is a group selected from halogen atom, lower alkyl, lower alkoxy, nitro, and amino as a substituent on the lower alkyl, cycloargyl, or phenyl ring that may have an amino group or a phenyl lower alkoxycarbonylamino group as a substituent) (a phenyl group which may have 1 to 3 of the following), the formula of the substituent means a double bond, and the substitution position of this substituent is 3.4.5 of the carbostyril bone core. 6.7th or 8th place Izusu L. In addition, the bond between the 3rd and 4th positions of the carbostyril bone core represents a single bond or a double bond] In this specification, lower alkyl has 1 to 6 carbon atoms.
straight-chain or branched-chain alkyls, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, lower alkenyls include straight-chain or branched alkenyls having 2 to 6 carbon atoms. , such as vinyl, allyl, 2-butenyl, 3-butenyl, ]-
Methylallyl, 2-pentenyl, 2-hexenylnato.

Further examples of lower alkynyl include straight-chain or branched alkynyl having 2 to 6 carbon atoms, such as ethynyl.

Examples include 2-propynyl, 2-butynyl, 3-butynyl, 1-methy)v-2-flobinyl, 2-pentynyl, 2-hexynyl, and the like.

Examples of phenyl lower alkyl include phenylalkyl whose alkyl moiety is a straight or branched alkyl having 1 to 6 carbon atoms, such as evabenzyl, 2-phenylethyl,
-Phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5
-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, etc.; cycloalkyl includes cycloalkyl having 3 to 8 carbon atoms, such as cyclopropyl, cyclobuty/L/+ cyclopentyl, cyclohexyl, cycloheptyl; /1. /+ cyclooctyl and the like.

Lower alkoxy is straight-chain or branched-chain alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, impropoxy, butoxy.

Examples include tert-butoxy, pentyloxy, hexyloxy, etc., and the halogen atom is fluorine.

Mention may be made of chlorine, bromine and iodine.

For phenyl lower alkoxycarbonylamino group,
Phenyl alkoxycarbonylamino in which the alkoxy moiety is a straight chain or branched chain alkoxy having 1 to 6 carbon atoms, such as benzyloxycarbonylamino, 2-
Phenylethoxycarbonylamino, 1-phenylethoxycarbonylamino, 3-phenylpropoxycarbonylamino, 4-phenylethoxycarbonylamino.

■, 1-dimethy/I/-2-phenylethoxycarbonylamino, 5-phenylpentyloxycarbonylamino, 6-phenylhexyloxycarbonylamino, 2
-methy)v-3-phenylpropoxycarbonylamino and the like. However.

Examples of the lower alkyl which may have an amine group or a phenyl lower alkoxycarbonylamino group include the above-mentioned lower alkyl when there is no substituent, and when it has one substituent, for example, aminomethyl, 2-aminoethyl, 2- or 3-aminopropyl, 1-methy) L/-2-aminoethyl, 2-13- or 4-aminobutyl, 1゜1-dimethyl-2-aminobutyl, 2-
4ri1riB-aminopentyl, 4-aminohexyl,
Penzyloxycarbonylaminomethyl, 2-penzyloxycarbonylaminoethyl, 2-pencyloxycarbonylaminopropyl, 3-pencyloxycarbonylaminopropyl, 4-penzyloxycarbonylaminobutyl, 3-penzyloxycarbonylaminobutyl, 5 -benzyloxycarbonylaminopentyl, 6-
Benzyloxycarbonylaminohexyl 22-phenylethoxycarbonylaminomethyl, l-phenylethoxycarbonylaminomethyl, 2-(2-phe= )V
Ethoxycarbonylamino)ethyl, 3-(1-phenylethoxycarbonylamino)propyl.

2-(3-phenylpropoxycarbonylamino)ethyl, 4-(4-phenylbutoxycarbonylamino)butyl, 2-(5-phenylpentyloxycarbonylamino)ethyl, 2-(6-phenylhexyloxycarbonylamino) Ethyl, 1,1-dimethy/l/-2-(
benzyloxycarbonylamino)ethyl, (1,1-
Examples include dimethyl-2-phenylethoxycarbonylamino)methyl.

On the phenyl ring, which may have 1 to 3 groups selected from a -rogen atom, lower alkyl, lower alkoxy, nitro, and amino as a substituent, for example, phenyl, 2-. 3- or 4-chlorophenyl,
2-13- or 4-fluorophenyl, 2-. 3-Also 1d4-bromophenyl, 2-13- or 4-iodophenyl/1/.

3.5-dichlorophenyl + 2.6-cyclophenyl, 3.4-dichlorophenyl/l/, 3.4-
Difluorophenyl-3,5-dibromophenyl, 2-
．． 3-or 4-methylphenyl, 2-. 3-Sword or 4
-ethylphenyl, 4-propylphenyl, 3-isopropylphenyl, 2-butylphenyl, 4-hexylphenyl, 3-pentylphenyl, 4-tert-butylphenyl/l/, 3.4-dimethylphenyl, 2,
5-dimethylphenyl, 2-. 34 or 4-methoxyphenyl, 2-1s-'! ! : or 4-ethoxyphenyl, 3-propoxyphenyl, 4-impropoxyphenyl, 3-butoxyphenyl, 2-pentyloxyphenyl, 4-LerL-butoxyphenyl, 4-hexyloxyphenyl, 3.4-cymethoxy Phenyl, 3.4
-jethoxyphenyl, 2,5-dimethoxyphenyl,
2-18-4+”t is 4-nitrophenyl, 2,4-dinitrophenyl, 2-13- or 4-aminophenyl, 2,4-diaminophenyl+3-methyl-4-chlorophenyl, 2-chloro-6 -methylphenyl, 2-methoxy-3-chlorophenyl, 8,4.5-)rimethoxyphenyl, 8,4.5-)limethylpheny)v,
Examples include 3.4°5-trichlorophenyl.

Examples of lower alkanoyloxy include straight chain or branched alkanoyloxy having 1 to 6 carbon atoms, such as formyloxy, acetyloxy, propynyloxy, butyryloxy, imbutyryloxy, pentanoyloxy,
Examples include tert-butylcarbonyloxy and hexanoyloxy.

The compound of the present invention has optical isomers, and these are also included in the present invention.

The compounds of the present invention can be produced by various methods. For example, if the substituted JE R3 is a group other than lower alkanoyloxy (-R1
When (i.e., R3'-hydroxyl group, . . . 3'), it can be produced by the method shown in the following reaction formula (2).

[Reaction formula-■]

(1b) (1c) [wherein, R1, R2, R4, R5, R6 and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above. R indicates] For the reaction of the carboxylic acid compound (3) and alcohol-/L/(4) in the above reaction formula -■, the reaction conditions of a normal esterification reaction are adopted.For example, (1) dehydration in a solvent. (11) in the presence of an acidic or basic catalyst in a suitable solvent. Examples of the solvent used in method (1) include methylene chloride,
Halogenated carbons such as chloroform and dichloroethane, benzene, and toluene.

Aromatic hydrocarbons such as xylene, diethyl ether,
Examples include ethers such as tetrahydrofuran and dimethoxyethane, and aprotic polar solvents such as dimethylformamide, dimethylnulphoxide, and hexamethylphosphoric triamide.

Examples of dehydrating agents include dicyclohexylcarbodiimide and carbonyldiimidazole.

The ratio of alcohol/L/(4) to compound (3) is at least equimolar, preferably equimolar -1.5 times 7l. The proportion of the dehydrating agent used is at least equimolar, preferably equimolar) to 1.5 times the mole of compound (3). The reaction temperature is usually room temperature to 150°C, preferably 50°C.
At ~100°C, the reaction is generally complete in 1 to 10 hours.

Examples of acidic catalysts used in method (11) include hydrochloric acid gas, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, inorganic acids such as perchloric acid, trifluoro-a acid, lifluoromethanesulfonic acid, and naphthalene. Sulfonic acid, P-tosylic acid, benzenesulfonic acid.

Examples include organic acids such as ethanesulfonic acid, acid anhydrides such as trichloromethanesulfonic anhydride and trifluoromethanesulfonic anhydride, thionyl chloride, and acetone dimethyl acetal. Furthermore, acidic ion exchange resins can also be used as catalysts in the present invention. A wide range of known basic catalysts can be used. For example, inorganic bases such as monolithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, silver carbonate, sodium methylate, etc. , alcoholades such as sodium ethylate.

This reaction proceeds either without a solvent or in a solvent.

As the solvent to be used, solvents commonly used in etherification reactions can be effectively used, specifically aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, and dichloroethane.

Examples include halogenated hydrocarbons such as chloroform and carbon tetrachloride, and ethers such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol monomethyl ether. Furthermore, the above reaction is advantageously carried out using a drying agent such as anhydrous calcium chloride, anhydrous copper sulfate, anhydrous calcium sulfate, or phosphorus pentoxide. The ratio of compound (3) and alcohol)v(4) used in this reaction is not particularly limited and can be appropriately selected from a wide range, but in the case of no solvent, the latter is used in large excess relative to the former, and the solvent is When used, the latter is used in a molar ratio of equimolar/I/ to 5 times, preferably equimolar/V to 2 times molar, relative to the former. The reaction temperature is not particularly limited, but is usually about -20 to 200°C.

The temperature is preferably about 0 to 150°C, and one reaction time is usually about 1 to 20 hours.

Compound (5) obtained by the esterification can be reduced to lead to compound (1a), which is one of the compounds of the present invention. Note that this compound (1a) can also be obtained by directly reducing compound (3). These reduction reactions are usually carried out using hydrogenated reducing agents.

Examples of the water turbine reducing agent include sodium borohydride, lithium aluminum hydride, diborane, etc., and the amount used is usually determined by the amount of compound (3) or (5).
at least equimolar to

The preferable range is equimolar/L/ to 3 times mole. When lithium aluminum hydride is used as the hydrogenation reducing agent, it is convenient to use the same weight of compound (3) or (5). This reduction reaction is usually carried out in a suitable solvent such as water, methanol, ethanol.

Lower alcohols such as isopropanol, ethers such as tetrahydrofuran, ethyl ether, diglyme, etc. are used, and the temperature is about -60 to 50°C, preferably -30°C.
~ It is carried out at room temperature for about 10 minutes to about 5 hours. In addition, when lithium aluminum hydride or diborane is used as a reducing agent, it is preferable to use an anhydrous solvent such as ethyl ether lv, tetrahydrofuran, or diglyme.

Compound (la) is halogenated to produce another compound of the present invention
For the reaction leading to the seed compound (1b), the reaction conditions for the usual halogenation reaction of a hydroxyl group are adopted.
For example, a compound (
This is carried out by reacting la) with a genifying agent. Examples of the halogenating agent used include 1, hydrohalic acid such as hydrochloric acid and hydrobromic acid, N,N-jeti/L'-1,2
, 2-) lychlorvinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, and the like. Examples of the inert solvent include ethers such as dioxane and tetrahydrofuran, and chloroform hydrocarbons such as methylene chloride and carbon tetrachloride. The ratio of the compound (la) and the halogenating agent is such that the latter is at least equimolar to the halogenating agent, usually in an excess amount. The reaction is 1 normal.

The mixture is kept at room temperature to about 150°C, preferably room temperature to 80°C, for 1 to 6 hours.

When compound (1b) is reacted with compound (6), compound (IC), which is another one of the compounds of the present invention, can be obtained. This reaction is carried out in the presence of a dibasic compound in a suitable inert solvent.
1 at room temperature to 200°C, preferably 60 to 120°C
This is carried out for about 24 hours. Examples of inert solvents that can be used include ethers such as dioxane, tetrahydrofuran, etching glycol/L/+ dimethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, methanol, ethanol, and isopropanol.

Lower alcohols such as dimethylformamide.

Examples include polar solvents such as dimethyl sulfoxide. Examples of basic compounds include calcium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, and potassium hydroxide.

A wide variety of bases can be used, including inorganic bases such as sodium amide, sodium hydride, potassium hydride, sodium methylate, sodium ethylate, and tertiary amines such as triethylamine, tripropylamine, pyridine, and quinoline. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide as a reaction promoter, if necessary.

The ratio of compound (1b) and compound (6) to be used is not particularly limited, but the latter is usually used in an amount of 1 to 7 moles to an excess of the former, preferably 2 to 5 moles, preferably 2 to 5 moles, and preferably 1 mole to 1 mole of the latter.
~1.2 times the mole.

The compound of formula (1) can also be led to other compounds of formula (1) by the methods shown in reaction formulas -1 and m below.

[Reaction formula-■]

(ld) (le) [in the formula a
2, R3, X and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above. R1' represents lower alkyl, lower alkenyl, lower alkynyl or phenyl lower alkyl] The reaction between the above compound (1d) and compound (7) is 1, for example, sodium hydride, potassium hydride, metallic potassium, metallic sodium, sodium amide. , in a suitable solvent in the presence of a basic compound such as potassium amide. Examples of solvents used include dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, benzene, and toluene.

Examples include aromatic hydrocarbons such as xylene, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. Compound (ld) and compound (7)
There are no particular restrictions on the usage ratio.

Usually, the former is mixed with 6t L in an amount of at least equimolar, preferably equimolar to 2 times the latter. The reaction is usually 0-70°
The process is carried out at a temperature of about 30° C., preferably from 0° C. to room temperature, and is generally completed in about 30 minutes to 12 hours.

"Reaction formula-m" (lf) (1g) [where R
', R2 and R3 are the same as above] the above compound (1
The reaction of dehydrogenating f) to lead to compound (1g) is carried out by treating with a dehydrogenating agent in a suitable solvent. Examples of dehydrogenating agents include benzoquinones such as 2,3-cyclo-5,6-dicyazbenzoquinone, 2,8,5゜6-titrachloropenzoquinone (common name: chloranil), N-
Bromosuccinimide, N-chlorosuccinimide, halogenating agents such as bromine, selenium dioxide, palladium on carbon.

Examples include dehydrogenation catalysts such as palladium black, bawasium oxide, and Raney nickel. The amount of the dehydrogenating agent to be used is not particularly limited, but in the case of a halogenating agent, it is usually used in an amount of 1 to 5 times the mole, preferably 1 to 2 times the mole of compound (1f). In the case of catalysts, it is generally best to use an excess amount. In the case of other dehydrogenating agents as well, equimolar to excess amounts are usually used. As a solvent, dioxane, tetrahydrofuran, methoxyethanol, dimethoxycheta:
/-1 etc. (D ethers, benzene, toluene-xylene, aromatic hydrocarbons of cumenato, dichloromethane,
Dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, butanol.

Alcohols such as amyl alcohol and hexanol,
Polar protic solvents such as acetic acid, dimethylformamide,
Examples include aprotic polar solvents such as dimethyl sulfoxide and hexamethyl phosphoric triamide. The reaction is usually carried out at room temperature to 300°C2, preferably room temperature to 200°C.
Generally, it takes about 1 to 40 hours.

Further, compound (1g) can be reduced to lead to compound (1f), and this reduction reaction is carried out under the usual conditions for catalytic reduction, for example, in the presence of a metal catalyst in a suitable solvent. Examples of the catalyst include metal catalysts such as palladium, palladium on carbon, platinum, and Raney nickel, which are used in normal catalytic amounts. Examples of the solvent used include water, methanol, ethanol, inpropatol, dioxane, tetrahydrofuran, hexane, cyclohexane, ethyl acetate, or a mixed solvent thereof. Although the reaction can be carried out either under normal pressure or under elevated pressure, it is usually carried out under normal pressure to 20 kz/1yn2.
Preferably at normal pressure to 10 kg/cm", 0 to 150
C1 Preferably carried out at room temperature to 100°C.

Among the compounds of the present invention, compounds in which R3 is a hydroxyl group, a halogen atom, or lower alkanoyloxy can also be produced by the methods shown in Reaction Formulas-IV to Vll below.

[Reaction formula-IV] (8) (9), N, a)
[In the formula, R1, R2 and the 3rd position of carbonutyryl bone nucleus, compound (8) is reduced in the above reaction formula to form compound (9)
The reaction leading to is the compound (
It is carried out under the same reducing conditions as in the case of reducing 3) to compound (1a). This reduction reaction is also carried out by catalytic reduction in the presence of a suitable reduction catalyst, and examples of the reduction catalyst used include conventional catalytic reduction such as platinum, platinum oxide, palladium black, palladium carbon, and Raney nickel. A reduction catalyst is included, and the amount used is usually in the range of about 0.2 to 0.5 times the weight of the compound (71 times the weight of the compound). - In a solvent such as hydrofuran or ethyl ether, in a hydrogen atmosphere of 1 to 10 atm, preferably 1 to 3 atm, at -30°C to the boiling point altitude of the solvent, preferably 0°C to room temperature, This is done by shaking well.

There are various methods for further reducing compound (9) to lead to compound (la'), and for example, a reduction method using a hydrogen reducing agent is preferably used. The hydrogenation reducing agent used is 1, for example, sodium aluminum hydride, lithium aluminum hydride, diisobutylaluminum hydride, 1,1-dimethyl hydride/1. /-1-diisopropylmethylboron [i-C3H7)(CH3)20BH2
] etc., and the amount used is usually the same as that of compound (9).
The weight is equal to that of the This reduction reaction is carried out in a suitable solvent such as diethyl ether, tetrahydrofuran, cedarime, etc., usually at about -60 to 50°C, preferably from -30°C to room temperature, for 10 minutes to 5 hours. It ends with.

[Reaction formula-V]

(10)(11)(1b') [In the formula, R2 and X are the same as above] In the above reaction formula, compound (10) is ring-closed to form compound (1
The reaction leading to 1'l is carried out in the presence of N,N-substituted formamide and an acid catalyst (commonly referred to as Willsmeier's reagent) in a suitable solvent or in the absence of a solvent.

The N,N-substituted formamide used here is:
NUN-dimethylformamide.

Examples include N,N-diethylformamide, N-ethyl-N-methylformamide, and N-methyl-N-phenylformamide. Examples of acid catalysts include phosphorus oxychloride, thionyl chloride, and phosgene. The solvent used is chloroform + 1.2-
Dichloroethane, 1,2-dichloroethylene, etc.
Examples include logenated hydrocarbons and aromatic hydrocarbons such as chlorobenzene and 1,2-dichlorobenzene.

The amount of N,N-substituted formamide and acid catalyst to be used is xt L relative to the compound of general formula (10), usually in large excess, preferably 2 to 5 times the molar amount of the former, and 5 to 10 times the molar amount of the latter. Good to use. The reaction temperature is usually 0 to 150°C, preferably 50 to 100°C (nearly f).

Anti-LE. V13 to end in about 24 hours.

Also, the reaction to obtain compound (1 b') from compound ¥//J(ll) is as follows.

Compound (11), for example, in hydrochloric acid. Inorganic acids such as hydrobromic acid, hydrobromic acid, sulfuric acid, and phosphoric acid.

In the presence of alkali metal hydroxides such as potassium hydroxide, sulfur and lithium hydroxide, inorganic alkali compounds such as sodium carbonate, potassium carbonate, and potassium hydrogen carbonate, or organic acids such as acetic acid, This is achieved by heating at 150°C, preferably 70 to 120°C, for about 0.5 to 24 hours.

[Reaction formula-■]

(la') [in formula. R2i-yohiX is the same as above] In the above reaction formula, the halogenation reaction of compound (12) is carried out by treating compound (12) with a halogenating agent in an appropriate solvent. Examples of the halogenating agent used include halogen molecules such as chlorine and bromine.

Examples include N-halogenosuccinimides such as N-fomosuccinimide and N-chlorosuccinimide, copper halides such as sulfuryl chloride, copper chloride, and copper bromide. The solvent is dichloromethane.

Examples include halogenated hydrocarbons such as dichloroethane, chloroform, and carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran, and dioxane, and acetic acid. The amount of this chlorogenating agent used is as follows: Compound (12)
in equimolar excess, preferably equimolar/I/~1.
It is twice the mole. The reaction is usually carried out at 0"C - around the boiling point of the solvent, preferably at room temperature to 40°C, and usually at 1 to 1
It took about 0 hours. Note that a radical reaction initiator such as peroxide such as hydrogen peroxide may be used in this reaction.

The reaction of ring-closing compound (13) to lead to compound (la'l) is carried out in a suitable solvent in the presence of a condensing agent.

The condensing agent used is, for example, phosphorus pentoxide.

Examples include hydrogen fluoride, sulfuric acid, polyphosphoric acid, aluminum chloride, zinc chloride, and other acid acids.

Chloroform, dichloromethane, ■ as a solvent.

Examples include 2-dichloroethane, etc.), rogenated hydrocarbons, ethers such as diethyl ether and dioxane, and aromatic hydrocarbons such as nitrobenzene and chlorobenzene. The ratio of compound (11) and condensing agent to be used is not particularly limited, but the latter should be used in an amount of 1 molar to 10 times, preferably 3 to 6 times, per mI. This reaction is usually carried out at 50 to 250°C, preferably 70 to 200°C, for about 20 minutes to 6 hours.

[Reaction formula-■]

The bond between the 3rd and 4th positions is the same as above. R9 represents lower alkanoyl] The reaction between compound (lb) and compound (14) in the above reaction formula is preferably carried out using a basic compound as a dehydrohalogenating agent in an appropriate solvent at room temperature to 200゛C1. The mixture is heated at room temperature to 150°C for several hours to 15 hours. As for the solvent used.

Examples include lower alcohols such as evaporated methanol, ethanol, and isopropanol, and aromatic hydrocarbons such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, toluene, and xylene. Examples include ketones such as acetone and methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, hexamethyl, phosphoric acid triamide, and acetic anhydride. Examples of basic compounds include sodium hydroxide, potassium hydroxide,
sodium carbonate.

Inorganic bases such as potassium carbonate, sodium hydrogen carbonate, potassium carbonate, silver carbonate, alkali metals such as sodium and potassium, and sodium amide.

Alcoholades such as sodium hydride, sodium methylate, sodium ethylate, potassium ethylate,
Examples include tertiary amino acids such as triethylamine, tripropylamine, pyridine, quinoline, N,N-dimethylaniline, and N-methylmorpholine. Although an alkali metal iodide such as potassium iodide or sodium iodide may be used as a reaction accelerator in the above reaction, the ratio of compound (lb') and compound (14) to be used is not particularly limited.

Usually, the amount of the latter is at least equal to the former, preferably about 1 to 5 moles.

When the obtained compound (1h), which is one type of the compounds of the present invention, is hydrolyzed, the compound (l a
'). This hydrolysis reaction can be carried out using 2 hydrohalic acids such as hydrochloric acid and hydrobromic acid, 2 mineral acids such as sulfuric acid, phosphoric acid, and alkali metal hydroxides such as potassium hydroxide and IJium hydroxide. Usually in the presence of an alkali metal carbonate or bicarbonate such as sodium carbonate, potassium carbonate, or sodium bicarbonate. 50 ~ 150°c2
Preferably, the reaction is carried out by thermal reaction at 70 to 100'C for about 3 to 24 hours.

Note that among the compounds (1) of the present invention, compounds in which R1 is a hydrogen atom and the bond between the 3rd and 4th positions of the carbostyril bone nucleus is a double bond are lactam lactams as shown by the following formula. It can have tautomerism of the form type.

[In the formula, R2 and R3 are the same as above] Among the compounds represented by the general formula (1), a compound having an acidic group can form a salt with a pharmacologically acceptable basic compound. Examples of such basic compounds include sodium hydroxide and potassium hydroxide.

Metal oxides such as calcium hydroxide, sodium carbonate,
Examples include alkali metal carbonates or bicarbonates such as sodium hydrogen carbonate, alkali metal alcoholades such as sodium methylate, potassium ethylate, and the like.

The compound of the present invention produced by the above method can be easily isolated and purified from the reaction system by ordinary separation methods such as distillation, recrystallization, column chromatography, prevaritape thin layer chromatography, solvent extraction, etc. .

The starting materials and intermediate compounds (3) and (5) in the above reaction formula -1 can be produced by the methods shown in 1: Reaction formula -1 to Kari.

[Reaction formula-■]

(5a) [wherein R2 is the same as above. R10 represents a hydrogen atom or lower alkyl] In the above reaction formula, the reduction reaction of the nitro group of compound (15) employs any of the usual reduction reaction conditions for the nitro group. For example, (1) catalytic reduction in an appropriate solvent. (11) using a mixture of a metal or a metal salt and an acid, or a metal or a metal salt and an alkali metal hydroxide, sulfide, or ammonium salt as a reducing agent in a suitable inert solvent; This is done by reducing using

In the case of catalytic reduction (1), examples of solvents used include water, acetic acid, methanol, and ethanol.

Alcohols such as isopropanol, butanol, ethylene glycol, diethyl ether, dimethyl ether, tetrahydrofuran, dioxane, monoglyme,
Ethers such as diglyme.

Examples include hydrocarbons such as hexane and cyclohexane, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as N,N-dimethylformamide. Examples of catalytic reduction catalysts include palladium, palladium black, and palladium carbon.

Examples include platinum, platinum oxide, copper chromite, and Raney nickel. The amount of these catalysts to be used is preferably 0.2 to 1.00 times (by weight) the amount of compound (15).

The reaction is usually carried out at a temperature of -20 to 150° C., preferably 0° C. to around room temperature, and a hydrogen pressure of 1 to 10 intensities for about 30 minutes to 10 hours.

When method (11) is used, d, a combination of iron, zinc, tin or stannous chloride as a reducing agent and a mineral acid such as hydrochloric acid or sulfuric acid, iron, ferrous sulfate, zinc or tin and sodium hydroxide; Alkali metal hydroxides such as.

Sulfides such as ammonium sulfide, ammonia water.

Combinations with ammonium salts such as ammonium chloride are used. Inert solvents used are, for example, water, acetic acid, methanol, ethanol.

Examples include dioxane. The reaction temperature for 1 hour is appropriately selected depending on the type of catalyst used. For example, in the case of a combination of ferrous sulfate and aqueous ammonia, the reaction temperature is 50 to 150°.
It is advantageously carried out in the vicinity of C for about 30.1 minutes to about 10 hours. The amount of the reducing agent used is usually at least an equimolar amount, preferably an equimolar amount to V to 5 times the molar amount of compound (15).

The reaction between compound (16) and compound (17) can be carried out in a suitable solvent in the presence of a basic compound. Examples of basic compounds include inorganic bases such as thorium hydroxide, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, sodium methylate, and sodium methylate.

1-ethylamine, pyridine, α-picoline, NN-
Dimethylaniline, N-methylmorboline.

A wide range of amines such as piperidine and pyrrolidine can be used. Examples of solvents include ethers such as dioxane, tetrahydrofuran, glyme, and diglyme, aromatic hydrocarbons R such as toluene and xylene, lower alcohols such as methanol, ethanol, and isopropanol, and polar solvents such as dimethylpolamide and dimethyl sulfoxide. can be mentioned. The reaction is carried out at room temperature to 150°C, preferably 60 to 120°C, for about 1 to 24 hours.The ratio of compound (16) and compound (17) to be used is not particularly limited, but the latter is usually 1 to 150°C. An equimolar excess of , preferably equimolar/I/~5 times molar, is used.

[Reaction formula-■]

] In the above reaction, compound (]8) is converted into RCOX or (RC
O) 20 [wherein R is the same as ['Ii]. X represents a halogen atom] to form compound (18a).

Compound (3a) can be obtained by sequential hydrolysis. General formula (18) and RCOX or (RC
O) The reaction with 20 is carried out in the presence or absence of a basic compound. Examples of the basic compounds used include alkali metals such as sodium metal and potassium metal, hydroxides and carbonates of these alkali metals, monobicarbonates, and aromatic amine compounds such as pyridine and piperidine. The reaction proceeds either without a solvent or in a solvent. Examples of solvents include acetone, ketones such as methyl ethyl ketone, and ether.

Ethers such as dioxane, benzene, 1-toluene,
Examples include aromatic hydrocarbons such as xylene, water, and pyridine. The amount of the RCOX or (Rco)2° compound to be used is at least equimolar to the compound of general formula (18), but it is generally preferred to use 1 equimolar to an excess amount. Although the reaction proceeds at a temperature of 0 to 200°C, it is generally preferable to carry out the reaction at a temperature of 20 to 15°C. The reaction time is approximately 0.5 to 10 hours.

The hydrolysis reaction of general formula (18a) can be carried out using a hydrolysis catalyst 1 in an aqueous solution, for example, an alkali metal hydroxide such as potassium hydroxide, IJium hydroxide, an inorganic alkali such as thorium carbonate, potassium carbonate, or sodium hydrogen carbonate. In the presence of the compound, the temperature is usually 50 to 150°C, preferably 70 to 10°C.
This is done by heating at 0'C for about 0.5 to 10 hours.

[Reaction formula-X]

(3) (5) [In the formula, R1, R2, R7, X and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as in njI. R11 represents an aromatic amine residue] In the above reaction formula, compound (19) and aromatic amine (
The reaction with 20) is carried out in a suitable solvent or without solvent. All inert solvents that do not adversely affect the reaction are used, such as chloroform, methylene chloride, dichloromethane, halogenated hydrocarbons such as carbon tetrachloride, diethyl ethyl, tetrahydrofuran, dioxane, and dimethoxyethane. Aprotic polar ethers, alcohols such as methanol, nigenol, isopropanol, butanol, esters such as methyl acetate and ethyl acetate, N,N-dimethylformamide, dimethyl nulfoxide, hexamethyl phosphate triamide, etc. Examples include solvents and acetonitrile. Examples of aromatic amines include pyridine and gynoline. The amount of the aromatic amine to be used is at least equimolar to compound (19), preferably in large excess.

Reaction temperature is 50-200°C, preferably 70-150°
C, and the reaction is completed in about 3 to 10 hours.

The obtained compound (21) is hydrolyzed in water in the presence of an inorganic base such as sodium hydroxide or potassium hydroxide at a room width of 150° C. for about 1 to 10 hours.

Further, the enetherization of compound (21) with compound (4) is carried out by reacting in the presence of a basic compound in a solvent or in the absence of a solvent. The solvent used is
For example, chlorogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic 1M hydrocarbons such as benzene, toluene, and dichloromethane, diethyl ether,
Examples include ethers such as tetrahydrofuran, dioxane, and cymethoxyethane, and aprotic solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. Examples of the basic catalyst used include triethylamine, l-limethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4,8,0]nonene-5 (DBNI, 1.
5-diazabicyclo[5,4,0'l undecene-5(
DBU), 1,4-diazabicyclo E2.2.2
Examples include organic bases such as 3-octane (DABCO) and inorganic bases such as potassium carbonate, thorium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. The ratio of the basic compound used here is the general formula (2
For the compound of 1), at least the
It is preferable to use up to 1.5 times the molar amount. The proportion of the compound of general formula (4) to be used is as follows:
It is preferable to use at least equimolar amounts, usually in large excess.

The reaction temperature is usually room temperature to 150°C, preferably 50°C to
The temperature is close to 100°C, and the reaction is generally completed in 30 minutes to 10 hours.

[Reaction formula-M]

In the above reaction formula, Compound (22) and compound (23)
The reaction with (24) is generally referred to as the Friedel-Crauff reaction (1), usually in a suitable solvent.

1. Performed in the presence of Lewis acid. Ru. As the solvent used, those commonly used in this type of reaction are advantageously used, such as carbon disulfide, nitrobenzene, chlorobenzene, Schiff 110 methane, dichloroethane, trichloroethane, carbon tetrachloride and the like. All commonly used Lewis acids can be used, including aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, a-sulfuric acid, and the like. The amount of Lewis acid to be used is determined as appropriate. Usually, compound (22)
The amount of compound (23) or (24) used is usually at least equimolar, preferably equimolar, relative to compound (22). -3 times the mole. The reaction temperature is usually -50 to 1
The temperature is about 20°C, preferably 0 to 70°C, and the reaction time varies depending on the raw materials used, the catalyst, the reaction temperature, etc., but is usually about 30 minutes to 24 hours.

The nitration of the obtained compound (25) is carried out under the same conditions as those for ordinary nitration reactions of aromatic compounds.1 For example, it is carried out by the action of a nitrating agent in a suitable inert solvent or in the absence of a solvent. . Examples of inert solvents include acetic acid, acetic anhydride, a-sulfuric acid, etc., and examples of nitrating agents include fuming nitric acid.

Concentrated nitric acid, nitric acid and other acids (sulfuric acid, oleum, phosphoric acid.

Examples include mixed acids with acetic anhydride), mixtures of alkali metal nitrates such as potassium nitrate and sodium nitrate, and mineral acids such as sulfuric acid. The amount of the nitrating agent used is the compound (25
), the reaction temperature is preferably about -10° C. to room temperature, and the reaction is carried out for 5 minutes to 4 hours.

The obtained compound (26) was reduced and ring-closing compound (3
b). This reaction is carried out under the same conditions as those for the reduction reaction of compound (15) in the above-mentioned reaction formula (1), except when the catalytic reduction method (i) is used.

The reaction temperature is preferably 0 to 50°C, and the reaction proceeds advantageously when a basic compound such as sodium hydroxide or potassium hydroxide is present in the reaction system.

Furthermore, when using the method (II), usually -50 ~
The reaction proceeds at 100°C and is completed in about 0.5 to 10 hours. for example.

When using stannous chloride and hydrochloric acid as reducing agents.

The reaction is advantageously carried out at temperatures between -20 and 50°C. The amount of the reducing agent to be used is preferably at least equimolar, usually equimolar to 3 times the molar amount of the raw material compound. By the above method, the dinitro group is reduced and the ring is closed simultaneously to obtain compound (3b).

However, when using the catalytic reduction catalyst (1), carbonyl groups may also be reduced and converted to methylene, but such conversion can be avoided by appropriately selecting reaction conditions.

[Reaction formula-■]

(27) (29) (B, -) [wherein R2 and X are m [same as in the formula]. R12 represents a hydrogen atom or lower alkyl; R represents lower alkyl] In the above reaction formula, the reaction between compound (27) and compound (28) is usually carried out using an appropriate reaction in the presence or absence of a dehydrohalogenating agent. It is done in a solvent. Basic compounds are usually used as the dehydrohalogenating agent2, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4,3,0]nonene. -5(DBN), 1,5-diazabicyclo[5,4,
0] undecene-5 (DBU), organic bases such as 1,4-diazabicyclo[2,2,2]octane (DABCO), potassium carbonate, sodium carbonate, potassium bicarbonate.

Sodium bicarbonate, sodium hydroxide-water (potassium mide, sodium hydride, potassium hydride.

Examples include alkali metal alcoholades such as silver carbonate, sodium methylate, and sodium ethylate. Incidentally, the reaction compound compound (30) can also be used as a dehydrohalogenation agent by using an excess amount. Solvents include halogenated carbons such as methylene chloride, chloroform, and dichloroethane.

Aromatic hydrocarbons such as benzene, toluene, xylenato, diethyl ether, and tetrahydrofuran.

Ethers such as dimethoxyethane, methyl acetate.

Nethers such as ethyl acetate, dimethylformamide 2
Aprotic polar solvents such as dimethylnulphoxide, hexamethylphosphoric triamide, pyridine, acetone, acetonitrile, as well as methanol, ethanol, propatool, butano-lv+3-methoxy-1-butanol, ethylcerone/lev, methyl cellosolve, etc. Examples include alcohols, pyridine, acetone, acetonitrile, and mixed solvents of two or more thereof. The ratio of compound (27) to compound (28) is not particularly limited and may be selected from a wide range, but the latter should be at least equimolar, preferably equimolar to 5 times mole to 1-1]. Mole used. The reaction temperature is usually about -30 to 180'C, preferably about 0 to 150'C, and the reaction is generally completed in 5 minutes to 30 hours.

The ring-closing reaction of compound (29) is carried out in a suitable solvent or in the absence of a solvent in the presence of an acid. The acid is not particularly limited, and ordinary organic or inorganic acids can be used, such as inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, aluminum chloride,
Lewis acids such as boron trifluoride and titanium tetrachloride, formic acid,
Examples include organic acids such as acetic acid, ethanesulfonic acid, and p-)luenesulfonic acid. Among these, inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid are preferred. The amount of acid used is not particularly limited, and is usually at least the same weight, preferably 10 to 50 times the weight of compound (29).

Further, as the solvent, a normal inert solvent is used.

Hosomi Id Water, lower alcohols such as methanol, ethanol, and propatool, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, and xylene, and 7, such as methylene chloride, chloroform, and carbon tetrachloride. Examples include aprotic polar solvents such as hydrogenated hydrocarbons, acetone, dimethyl nulphoxide, dimethyl formamide, and hexamethyl phosphoric triamide. Among these, water-soluble solvents such as lower alcohols, ethers, acetone, dimethyl sulfoxide, dimethyl formamide, and hexamethyl phosphoric triamide are preferred. The reaction is usually carried out at O to 100'C.
, preferably at room temperature ~60"C, usually for 5 minutes to 6 minutes.
It will finish in about an hour.

In addition, the compound (3) has N as shown in the above reaction formula -■
Other compounds of formula (3) can be similarly derived by the alkylation method and the dehydrogenation or reduction reaction shown in reaction formula (1).

Furthermore, compound (19), which is the starting material in the reaction formula-X, can also be produced by the method shown in the following reaction formula.

[For reaction formula-X]

In formula C, R1,
The reaction with is carried out under the same conditions as the reaction between compound (22) and compound (23) or (24) in the reaction formula -1. However, the degree of 1 reaction group is usually 20 to 120°
C1 is preferably about 40 to 70°C, and the reaction time varies depending on the raw materials and the degree of reaction of the catalyst, but is usually 30 minutes to 24°C.
It takes about an hour.

Also, the intermediate compound (9
) can be produced, for example, by the method shown in Reaction Formula -XIv below.

[Reaction formula-XIV] (81) (82) (9a) [in the formula a
2 is the same as above] In the above reaction formula, compound (31) is ring-closed to form compound (8
The reaction leading to 2) is carried out under the same conditions as in the ring-closing reaction of compound (lO) in Reaction Formula - (1).

Moreover, the reaction to obtain compound (9a) from compound (32) is
Compound (32) is, for example, hydrohalic acids such as hydrochloric acid and hydrobromic acid, and inorganic acids such as sulfuric acid and phosphoric acid.

In the presence of an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide, an inorganic alkali compound such as thorium carbonate, potassium carbonate, or potassium hydrogen carbonate, or an organic acid such as acetic acid, the temperature is 50 to 150°C, preferably 70°C.
This is achieved by heating at ~120°C for 0.5 to 24 hours.

For producing a compound useful as an anti-ulcer agent from the compound (1) of the present invention, there is, for example, a method shown in the following reaction formula-XV.

[Reaction Formula-XV] (2d) [In the formula, R, R, R, R, R, f and the bond between the 3rd and 4th positions of the carbonutyryl bone core are the same as above.

Alk represents lower alkyl] That is, the compound of formula 1 (IC) is hydrolyzed and, if desired, the product is led to the carbostyryl derivative (2) by acylation, esterification, or a combination thereof.

The reaction of hydrolyzing this compound (IC) to lead to the compound of formula (2a), which is one of the compounds (2), is carried out using a suitable hydrolysis catalyst 1, such as a hydrohalic acid such as hydrochloric acid or hydrobromic acid, Inorganic acids such as sulfuric acid and phosphoric acid, sulfur and lithium hydroxide,
In the presence of inorganic alkaline compounds such as alkali metal hydroxides such as potassium hydroxide, alkali metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate.

Solvent-free or in a suitable solvent (e.g., water or a mixed solvent with a lower atom such as aqueous tomethanol or ethanol), 50 to 150°C, preferably 70 to 1
The treatment may be carried out at 00°C for about 3 to 24 hours.

Acylation of compound (2a)i or compound (2C) with a carboxylic acid of formula (33) can lead to other corresponding compounds (21)) or (,2d), respectively. Acylation is achieved by a conventional amide bond forming reaction. In this case, the carboxylic acid (33) may be an activated compound.

The conditions for the amide bond forming reaction can be applied to the amide bond forming reaction. For example, (a) mixed acid anhydride method,
That is, carboxylic acid (33) is reacted with an alkyl leno-rocarboxylic acid to form a mixed acid anhydride, and compound (2) is reacted with this to form a mixed acid anhydride.
a) Method of reacting i or (2C), (b) Active ester method or activated amide method, that is, carbonic acid (33
) Examples: Eva p-nitrophenyl ester, N-hydroxyconolylic acid imide ester, 1-hydroxybenzo 1
- A method in which an active ester such as lyazole-en-tel or penzoxazoline is prepared into an active amide with 2,000 ions and reacted with the compound (2a) or (2C); (iii) a carbodiimide method.

That is, compound (2a) or (
2C) is dehydrated in the presence of a dehydrating agent such as evadicyclohydropodiimide or carbonyldiimidazole; and 2C) is a carboxylic acid halide method, that is, the carboxylic acid (33) is induced into a wide form, and then A method of reacting compound (2a) or (2C), 0→Another method is to convert carboxylic acid (33) into a carboxylic acid anhydride using a dehydrating agent such as acetic anhydride, and then reacting compound (2a) or (2C) with the carboxylic acid anhydride. How to react.

Examples include a method in which compound IIJ (2a) or (2C) is reacted with ester /I/ of carboxylic acid (33) and, for example, a lower alcohol under high pressure and high temperature. Additionally, carboxylic acid (33) was activated with a phosphorus compound such as triphenylhonuphine or diethyl chlorophosphate.

A method of reacting this with compound (2a) or (2C) may also be adopted. Examples of the alkylhalocarboxylic acids used in the mixed acid anhydride method include methyl chloroformate, methyl bromate, ethyl chloroformate, ethyl bromate, and isobutyl chloroformate. The mixed acid anhydride is obtained by the usual Schotten-Baumann reaction, and is reacted with compound (2a) or (2c) without isolation to form compound (2b)-4.
or (2d) is produced.

The Schotten-Baumann reaction usually involves rI of basic compounds:
As the basic compound to be pressurized, compounds commonly used in the Schotten-Baumann reaction are used, such as triethylamine, trimethylamine, pyridine,
Dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4,8,
0] nonene-5 (DBN), 1,5-diazabicyclo[
5,4,0] undecene-5 (DBU'), 1,4-diazabicyclo[2°2.2]octane (DABC, 0)
organic bases such as

Potassium carbonate, 1-lium carbonate, potassium hydrogen carbonate,
Examples include inorganic bases such as 1-lium hydrogen carbonate. The reaction is carried out at about -20 to 100°C, preferably from 0 to 50°C.
The reaction time is about 5 minutes to 10 hours, preferably 5 minutes to 2 hours.

The obtained mixed acid anhydride and compound (2a) or (2C)
The reaction with
5 minutes to 10 hours at 50°CVC, preferably 5 minutes to
It will last about 5 hours. Although the mixed acid anhydride method does not require the use of a solvent, it is generally carried out in a solvent. Any solvent commonly used in the mixed acid anhydride method can be used, and specifically, methylene chloride, chloroform,
Tonohalogenated carbons such as dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, esters such as methyl acetate and ethyl acetate, dimethylformamide, dimethyl sulfoxide, and hexamethyl Non-polymer polar solvents such as phosphoric acid triamide and the like can be mentioned. Carboxylic acids in nuclear law (33
), alkylhalocarboxylic acid and compound (2a')t
The ratio of the alkylhalocarboxylic acid and the compound (2a) or (2C) to the carboxylic acid (33) is usually at least one equimole.
It is preferable to use twice the molar amount.

In the above (b) active ester measurement or active amide method, for example, when using benzoxazoline-2-thionamide, 1) an appropriate solvent that does not affect the reaction, 1) mixed acid anhydride, etc. Using the same solvent as used in the physical method or 1-methyl-2-picolidone, etc.,
The reaction is carried out at 0°C for 5 to 75 hours. In this case, the ratio of compound (2a) or id' (2c) to benzoxazoline-2-thionamide is usually at least equimolar, preferably equimolar to twice the molar ratio of the latter to the compound.

The carboxylic acid halide method of (c) above, carboxylic acid (33
) A VC halokenizing agent is reacted to form a carboxylic acid halide, this carboxylic acid halide is isolated and purified, and -! or compound (2a) or (2a) without isolation and purification.
2c) is carried out by reacting.

This carboxylic acid halide and compound (2a) or (2C
') is carried out in a suitable solvent in the presence of a dehydrohalogenating agent. As the dehydrohalogenating agent, a basic compound is usually used.1 In addition to the basic compounds used in the Schotten-Baumann reaction mentioned above, alkalis such as 1-lium hydroxide, potassium hydroxide, and lithium hydride ethylate are also used. Examples include metal alcoholade. It is also possible to use an excess amount of compound (2a) or (2C) as a reactive compound to serve as a dehydrohalogenating agent. Examples of solvents include the solvent used in the Schotten-Baumann reaction described in n1J, alcohols such as water, methanol, ethanol, propatool, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, and acetone. , acetonitrile, or a mixed solvent of two or more thereof. The ratio of compound (2a)-4 or (2c) and carboxylic acid halide to be used is not particularly limited and can be selected from a wide range, but usually [1]
] i[The latter is used in an amount of at least equimolar, preferably equimolar to twice the molar amount. The reaction temperature is usually -30~
The reaction is completed at about 180°C, preferably about 0 to 150°C, and generally in 5 minutes to 30 hours.

The carboxylic acid halide used is carboxylic acid (33)
It is produced by reacting a halogenating agent with a halogenating agent in a hot solvent or a solvent. As a solvent, any solvent can be used as long as it does not adversely affect the reaction.For example, aromatic hydrocarbons such as benzene, toluene, and xylene, chloroform, methylene chloride, carbon tetrachloride, natonohalogenated hydrocarbons, dioxane, tetrahydrofuran, Examples include ethers such as diethyl ether, dimethylformamide, and dimethyl sulfoxide. As the halogenating agent, a common halogenating agent that converts the hydroxyl group of a carboxy group into a halogen can be used, such as thionyl chloride.

Phosphorus chloride, phosphorus oxybromide, phosphorus pentachloride.

Examples include phosphorus pentabromide.

The ratio of the carboxylic acid (33) and the halogenating agent to be used is not particularly limited and is selected appropriately, but when the reaction is carried out without a solvent, the latter is usually used in a large excess amount relative to the former, or in the solvent. When the reaction is carried out, the latter is usually used in an amount of at least about the same molar amount per liter of the former, preferably 2 to 4 times the molar amount of the former. The reaction temperature and reaction time are also not particularly limited, but are usually about room temperature to 100°C, preferably 50°C.
It is carried out at ~80'C for about 30 minutes to 6 hours.

Further, the method of activating carboxylic acid (88) with a phosphorus compound such as I-riphenylphosphine or diethylchlorophonufate and reacting it with compound (2a) or (2c) is carried out in a suitable solvent. Any solvent can be used as long as it does not affect the reaction, and specifically, halogenated carbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, Ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane.

Examples include esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. In this reaction, since compound (2a) or (2C) itself acts as a basic compound, the reaction proceeds well by using it in excess of the theoretical amount, but if necessary, other bases 11: compound , such as triethylamine, trimethylamine, pyridine, dimethylaniline, N
-Methylmorpholine, 4-dimethylaminopyridine, 1
．． 5-Diazabicyclo[4,8,0]nonene-5 (DB
N), 1,5-diazabicyclo[5,4,0]undecene-5 (DBU), 1,4-diazabicyclo[:2.2
．． 2] Organic bases such as octane (DABCo), potassium carbonate, thorium carbonate, potassium bicarbonate.

Inorganic bases such as 1-lium hydrogen carbonate can also be used. The reaction is about 0-150'c, preferably about 0-1
This is achieved by carrying out the reaction at 00°C for about 1 to 30 hours. The ratio of the phosphorus compound and carboxylic acid (33) to compound (2a) or (2C) is:

Each usually contains at least an equimolar amount, preferably 1
~3 times the molar amount.

In the reaction formula -Xv, compound (2a) or (2
b) The corresponding compound (2C) or (2
The reaction leading to d) is the compound (3) in the above reaction formula -■
can be carried out under the same conditions as the esterification with compound (4).

The compounds of the present invention are also useful as anti-ulcer agents.

It is usually used in the form of a common pharmaceutical preparation. The formulation contains commonly used fillers, thickeners, binders, (1) wetting agents,
Disintegrant 1 Using a diluent or excipient such as a surfactant or a lubricant, 1. ', l is made. Various forms of this pharmaceutical preparation can be selected depending on the treatment, and representative examples include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, full-fill forms, and injections ( liquid agents, suspension agents, etc.). When forming tablets into four forms, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, and danfun. Calcium carbonate, kaolin, crystalline cellulose,
Excipients such as silicic acid, water, ethanol, propatool,
Monosyrup, glucose solution, densate solution, gelatin solution, and levoximetifle cellulose.

Binders such as shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate.

Disintegrants such as polyoxyethylene rubber fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter dihydrogenated oil, quaternary ammonium bases, lauryl sulfate, etc. Absorption enhancers such as 1-lium, moisturizers such as chrycerin and starch, starch,
Lactose, kaolin.

Bentokai 1-. Adsorbents such as colloidal silicic acid.

Examples include purified talc, stearate, boric acid powder, and lubricants such as polyethylene glycol.

Furthermore, if necessary, the tablet can be made into a tablet with a conventional shell, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a pill form, a wide variety of carriers known in the art can be used, such as glucose,
Examples include excipients such as lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and binders such as ethanolate, and disintegrants such as laminaran and agar. When molding into a fully opened form, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao IIL higher alcohol, esters of higher alcohols, gelatin,
Examples include semi-synthetic glycerides. Prepared as an injection.

When formulated into solutions, emulsions, and suspensions, the solutions and suspensions are preferably sterile and isotonic with blood.

Also commonly used in this field as a diluent -
For example, water, ethyl alcohol/L/, propylene glycol, nidoxylated isostearyl alcohol, polyoxylated instearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be used. In addition.

In this case, the anti-ulcer agent may contain a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution, and the usual solubilizers, buffers, soothing agents, etc. may be added as necessary. Colorant according to.

Preservatives, fragrances, flavors, sweeteners, and other pharmaceutical agents may also be included in the therapeutic agent.

The amount of the compound of the present invention to be contained in the anti-ulcer agent of the present invention is not particularly limited and can be selected within a wide range, but is generally 1 to 70% by weight, preferably 5 to 50% by weight based on the total composition. It is.

There are no particular restrictions on the method of administering the anti-ulcer agent of the present invention, and it can be administered in a manner depending on various formulation forms, age, sex and other conditions of the patient, degree of disease, etc.

For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. In the case of injections, it is administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, it can also be administered intramuscularly alone.

Administered subcutaneously or intraperitoneally. If fully dilated, it is administered rectally.

The dosage of the anti-ulcer agent of the present invention depends on the usage and age of the patient.

The amount of the compound of the invention is preferably 0.6 to 50 m7 per kg of body weight per day, although it is appropriately selected depending on gender, other conditions, degree of disease, etc. It's Kade.

The dosage unit form preferably contains 10 to 1000"V of active ingredient.

Next, the present invention will be explained in more detail with reference to reference examples and actual sister examples, but the present invention is not limited thereto.

Reference Example 1 100 g of m-aminobenzoic acid was suspended in ether 11,
At room temperature, press PJt, and add 44.6 f of β-ethoxyacrylic acid chloride. After reacting this mixture at 40°C for 5 hours, the precipitate is added. The crystals were washed three times with water, dried, and recrystallized from methanol to give m-carboxy-N-(β-ethogycyacryloyl/I/)aniline 6 as a colorless flocculent.
Get 0f. Melting point 200.5-202.0°C0 Reference example 2 Methyl 3-phenylpropionate 50y, chloroacetyl chloride 51.6y and dichloromethane 250m
Cool the mixture of 1 to 0°C. Add aluminum chloride 1221 slowly under stirring at 0-10°C. Then stir at room temperature for 2 hours. After standing overnight at room temperature, the reaction mixture was poured into ice-a-hydrochloric acid and extracted with chloroform. The chloroform layer is dried and the chloroform is distilled off. The remaining /FF K isopropyl ether is added to crystallize, the crystals are added, and the crystals are recrystallized from ethanol to form colorless needle-shaped 3-( Obtain 534 g of methyl 4-chloroacetylphenyl/L/) propionate. Melting point: 90.0-92.0
°C0 Reference Example 3 3-(4-chloroacetylphenyl) 10 m
t-)va 6.26 y'/)jA hMMg20
Dissolved in 0 mt.

20.9 g of fuming nitric acid cd=], 52) was stirred under cooling with ice water and 11 g of the remaining 3-F was added. After stirring at room temperature for 3 hours.

The reaction mixture was poured into ice water and extracted with chloroform.
Le. After washing the chloroform layer with water and drying it, chloroform)v
Mura Wi leaves. The residue was subjected to silica gel column chroma 1-
Purify with Kujihui and add ether to crystallize. ρ-1 crystals were taken and recrystallized from methanol to give pale yellow 3-(4-carboxy-2-nitrophenyl) of Briz J.
Methyl propionate 26.7 g? 8ru. Melting point 120
0-1220℃.

Reference example 4 467 g of chloroacetyl chloride dichloromethane 4
Add 735 g of aluminum chloride in 1/3 portions to the 00mlf8 solution while stirring at 30°C or below. Next, add Lupostiril 200 Q with stirring at the same temperature.

After heating and refluxing the mixture for 6 hours, the reaction mixture was poured into ice-concentrated hydrochloric acid and the precipitated crystals were collected. This was washed with methanol and hot methanol to produce 6-chloroacetylcarbostyryl. E4ru. The mother liquor was concentrated to dryness, and the residue was purified by silica gel chromatography and recrystallized with methanol to obtain 35.41 g of 8-IJ loacetyl carbostyryl in the form of light yellow needles. Melting point 1775. ~179.0°C0 Reference Example 5 8-chloroacetylcarbostyryl 3o and pyridine 3
00rnl and stirred under heat for 2.5 hours at 1 J at 80~90'.The reaction solution was cooled with ice water, the precipitated crystals were added, washed with ether, and then recrystallized from methanol to form colorless needles. Obtain crystalline 8-(α-pyridinium acetyl)carbostyryl chloride 40.8'5 f/. Melting point 26.
1°5-264°C (decomposition).

Reference Example 6 To a diethyl ether 300i bath containing 295 g of methyl m-aminobenzoate, 11.53 g of β-engineered toxyacrylic acid chloride was added dropwise at 17 to 27°C with stirring. After dropping, the mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected. After washing with ether, the crude crystals were dissolved in chloroform, z, and VC.
Wash with N hydrochloric acid, saturated sodium bicarbonate, and saturated A11jE brine. After drying, the chloroform was distilled off, and the residue was purified using a silica gel column chromatograph, and then recrystallized from methanol to obtain a colorless prism-like product.
3.63 g of m-methoxycarbonyl-N-(β-ethoxyacryloyl/I/)aniline are obtained. Melting point 108~
110°C0 reference, old f row 7 (a) t', --(α-chloroacetyl) carbostyril 60 g was suspended in 0.5 pyridine paste, 80-9
Stir for 2 hours at 0°C, then stir for 1 hour under water cooling.

The precipitated product was taken as III and recrystallized from methanol to obtain 70 g of colorless 6-(α-pyricinium toacetyl/I/)carbos-1-lirucuronoid 1/2 hydrate.

Melting point 3()0℃1so,j-.

(1) +6-(α-pyridinium acetyl)carbostyryl chloride 69.75 g of thorium hydroxide is dissolved in water at 0.6 tVC and stirred at 60 to 70'C for 3 hours. Add concentrated hydrochloric acid to the ice-cooled reaction mixture to bring the pH to -2. yr-r IIv L
, I) Ms: Recrystallized from light brown powdered crystal 6
- Carboxycarbostyril 4], 4g? j). Melting point over 300°C.

Reference Example 8 The following compound was obtained in the same manner as in Reference Example 7 using appropriate starting materials.

6-Carboxy-3,4-dihydrocarbostyryl, pale yellow needle crystals (dimethylformamide), melting point above 300°C.

8-Carboxycarbostyryl, colorless needle crystals (methanol-chloroform), melting point 320'C or higher'h-NM
R(DMSO)δ6.57 (d, J = 9,5
11z.

11(), 7.25 (L, J=8.0f(z,
1JJL, 7.94, (d, d, J=
=8.0Hz, ], 5Hz, III), 7.9
8 (rJ, J=9.5Hz, 10 L 8.14 (
rJ, rI.

J = 8. OH7,1,5H2, ], H).

Reference Example 9 6-carboxy-3,4-dihydrocarbostyryl 10
g and 60 g of N-hydroxysuccinimide are suspended in 200 ml VC of cyoxane. Next, water-cooled FR, J゛t' F, dicyclohexylcarbodiimide 124
Dispense 50 ml of dioxane solution. The mixture was heated and stirred at 90°C for 4 hours. After the reaction was completed, it was left to cool at room temperature, the precipitated crystals were removed, the /1'8i solution was concentrated to dryness, and the residue was recrystallized from dimethylformamide-ethanol to obtain colorless phosphorus gavage crystal succinimide. 3,4-
cyhydrocarponutyryl-6-galbogysile-1-1
Obtain 0.8 g. Melting point: 234.5-236°C.

Reference Example In In-Carphogoxy N-(β-ethoxyacryloyl)aniline (8 g) was dissolved in concentrated sulfuric acid (80 g). nt, plus 2 in the chamber order
time, followed by stirring at 50°C for 1 hour. Pour the reaction solution into water and add 1) H3 to 4 with ION sodium hydroxide aqueous solution.
Adjust to. The precipitated product was added, washed with water, and recrystallized from DMF to obtain 5-carboxycarbostyryl/1.26i7 as a pale yellow powder. Melting point 320°C or higher.

NMR (DMSO) 66.58 (d, J = 9
．． 5Hz.

l11), 7.40-7.8 (1(m, 3H)
, 8.69 (d, J=9.5Hz, LH).

Reference Example 11 Methyl 3-(4-carboxy-2-21-lophenyl)propionate 51i', 2.226N 1-lium hydroxide in methanol 1418.8? , nt-methanol 10
0, I/and 5% pa-cr (50% water content) are mixed and fused and reduced at room temperature and pressure. Add force to the catalyst.

Add concentrated hydrochloric acid to the mother liquor to adjust the pH to f-1, collect 173 precipitated crystals, and recrystallize the colorless Shibushi crystal from methanol to obtain 3.62 g of -7-carpoquine-3.4-dihydrocarbostyryl. . Melting point: 320℃ or higher.''

NMR (DMSO) δ2.33-2.60 (m,
2H), 2.77-3.05 (m, 2H), 7.2
1 (d.

J = 8.5 Hz, I H'1.7.38~7.
53 (n, 21-1),]0. ]5(s, IH)
.

Reference Example 12 A log of m-methoxycarbonyl-N-(β-ethoxyacroyl)aniline was gradually poured into 100 ml of rH hydrochloric acid and stirred at room temperature for 2 hours and at 45°C for 4 hours. The reaction solution was poured into water, and the precipitated crystals were acidified and washed with water. The obtained crude crystals were IQ crystallized with methanol-chloroform to obtain -6
, 97 g of 5-methoxycarbonylcarbostyryl are obtained. Melting point: 277.5-279.0° (J 6 Reference Example 13 5-)) Rebogishiki Lupostyril 2gWater 30m
The crystals are suspended in water and an aqueous solution of ION hydroxide is added thereto to dissolve the crystals. 10% PL-C500r in solution
yt, hydrogen pressure 3-4 kq/crn, 70
Place contacts at °C. After the reaction, remove the catalyst and add 6 to the p liquid.
Add 13 hydrochloric acid to 1) 14 to 1 and add the precipitated product.

820 m'i of colorless 5-carboxy-3,4-cyhydrocarbostyryl crystallized from methanol
(Illu). Melting point 309-311'C.

Reference example 14 5-carboxycarbostyryl 2y as methanol/lz1
The suspension was suspended at 0.00 m/ml, saturated by bubbling hydrochloric acid gas, and then refluxed for 3 hours. The reaction aν is concentrated λ until it reaches the livelihood Vc.
The precipitated crystals were purified by silica gel column chromatography, and then purified with methanol-
Crystallize from chloroform to obtain 5-methoxycarbonylcarbostyryl 23omy as a colorless powder. Melting point: 277.5-279°C6 Reference Example 15 2 g of 8-(α-pyridinium-11-acetyl)carbostyryl chloride is dissolved in methanol at 20 mi VC, 1.01 P of DBU is added thereto, and the mixture is refluxed for 1 hour.

The reaction solution was evaporated to dryness, and the residue was mixed with water and chloroform.

Add IN hydrochloric acid. The 110 form layer was washed with water, saturated aqueous 1-lium bicarbonate solution, and saturated saline in that order, and then dried. The product was purified by muchromatoclaphite, and then recrystallized from methanol to obtain 130 m2 of 8-methoxycarbonyl carbostyryl in colorless separate pieces. Melting point 140~
142°C0 Reference Example 16 (a) Weighed 175- of water, 10.51 of ferrous sulfate heptahydrate, 0.5-1 of concentrated hydrochloric acid, and 6 g of O-nitrobenzaldehyde in a four-loaf flask, and heated to 90°C on a water bath. Heat.

Add 25 grams of concentrated ammonia water all at once while stirring. Furthermore, 30 mt of ammonia water was added in 3 portions every 2 minutes. Immediately after the addition is complete, steam and vapor distillation are carried out. Stay!
Collect 250- twice. The first distillate is cooled and the precipitate is added. The strawberry liquid and the second distillate were combined, saturated with 1 common salt, and extracted with ether. The ether solution is dried over sodium sulfate and the ether is distilled off. The residue and the previous crystals are combined and dried to obtain 2.9 g of 0-aminobenzaldehyde in the form of yellow scales. Melting point 88-39°C.

(bl Core for dissolving 2 g of malonic acid in 15-pyridine.

To this were added 1.2F of 0-aminobenzaldehyde and 2- and 7-piperidines, and the mixture was stirred at 90°C for 5 hours.

Pour the reaction solution into an aqueous hydrochloric acid solution to increase the amount of precipitated crystals.

Recrystallized from methanol-chloroform to give colorless needle-like 3
- Carboxycarbostyril 1.2y is obtained.

Melting point over 300°C.

Reference Example 1 140rnt of acetic anhydride was added to 60f of fisatin and refluxed for 4 hours. Thereafter, more precipitated crystals were added and washed with ether to obtain 58 g of N-acetylisatin.

Dissolve 30 g of IJ hydroxide in 1.5 t of water.

The above N-acetylizatin 58FI was added to this and refluxed for 1 hour. Cool slightly, add activated carbon, and reflux for 30 minutes. Apply force to activated carbon when hot. The mother liquor is cooled and adjusted to pH 3-4 with 6N hydrochloric acid. Try the crystals that precipitate
Take it out, wash it with water, and then dry it.

4-Carboxycarbost IJ/45y is obtained. Melting point 300℃ or higher.

Reference Example 18, (al N, N-dimethylformamide 96., l
Phosphorus oxychloride (322-) was added dropwise to the solution under ice-cooling and stirring.

At the same temperature, add 67.5 g of acetanilide and heat to 75°C.
Stirring was carried out for 18.5 hours. Pour the reaction solution into ice, scrape off the precipitated crystals, and dry. Recrystallized from ethyl acetate to give yellow needles of 2-chloro-3-formylcarbostyryl (b) 2-chloro/v-3-formylquinoline 87f to 4
Add 600 ffI of normal hydrochloric acid and reflux for 1 hour. In the future, we will increase the precipitated product and recrystallize it from ethanol-chloroform to form pale yellow needle-like crystals of 3-formylcarbostyryl 84.
get f. Melting point 308-309°C0 Reference Example 19 64.44 g of phosphorus oxychloride is added dropwise to N,N-dimethylformamide 11,6- while stirring at O'C.

At the same temperature, N-phenyl-3-chloropropionamide 1
Add 8.4f. Stir at 75-80°C for 10 hours. Pour the reaction solution into ice water to increase the amount of precipitated crystals. Recrystallization from ethanol gives colorless prismatic 2-chloro-3-chloromethylquinoline 6,71. Melting point 116-11
8°C0 Example 3 - 34g of formylcarbostyryl was added to 80g of methanol.
Suspend at 0 mt. While cooling with water and stirring, add 7.4 g of sodium borohydride little by little. Under water cooling.

Stir for 3 hours. Take /7j of the precipitated product. Recrystallized from methanol to give colorless prismatic 3-hydroxymethylcarbonutyryl 8B. Get 2f. Melting point 238-289
．． 5°C0 Example 2 16 g of lithium aluminum hydride is suspended in dry Te1-rahydrofuran 2αCjml Ic. 3-Methoxycarbonylcarbostyryl 16i without stirring at room temperature
Add f. Stir at room temperature for 5 hours. Add ethyl acetate dropwise to decompose excess lithium aluminum hydride.

After adding more water, the mixture is concentrated under reduced pressure. Dilute sulfuric acid was added to the residue to increase the precipitate, and recrystallization from Melol'/-ol gave colorless prismatic 3-hydroxymethylcarbomethyl9,
3.71.

Melting point: 238-2B 9.5°C0 Examples Using appropriate starting materials, the compounds shown in the following table were obtained in the same manner as in Examples 1 and 2.

Example 8 47% hydrobromic acid 50- was added to 3-hydroxymethylcarpostil/shi5y and stirred at 70 to 80"C for 3 hours. In the future, the precipitated product was added and recrystallized from methanol. to obtain colorless acicular 3-bromomethylcarbostyryl 6f, melting point 21s, 5-219°C (decomposition).

Example 9 3-Hydroxymethylcarpostyryl 3y is suspended in chloroform 100-. While stirring at room temperature, a solution of 2 g of thionyl chloride in chloroform is added dropwise. 1 at room temperature
Stir for an hour. Concentrate under reduced pressure.

The residue was recrystallized from methanol to give 2.91 as colorless needles of 3-chloromethyl carpostyl. Melting point 204~
205°C0 Example 10 2.8 g of 2-chloro)v-3-chloromethylquinoline is dissolved in 30-acetic acid and refluxed for 2 hours. Pour the reaction solution into water and take off the precipitate. Recrystallization from methanol gives colorless sword-like 3-chloromethylcarpostyryl 2.1f. Melting point 204-205°G.

Examples 11 to 15 The compounds shown in the following table were obtained in the same manner as in Example 10 using appropriate starting materials.

Example 16 Sodium ethylate is made from 1.5 g of sodium and 150.7 g of dry ethanol. Add 12g of diethyl acetamidomalonate to this and add 4Jfl at room temperature at 11am.
do. Add 12 g of 4-chromium methylcarbostyryl and reflux for 2 hours. Ethanol is distilled off and water is added to the residue to increase the amount of precipitated crystals. Recrystallization from ethanol gives colorless prismatic ethyl 2-acetamido-2-carboethoxy-3-(2-quinolon-4-yl)propionate 1317. Melting point 224-226°C (decomposition)
.

Examples 17-26 The compounds shown in the following table are obtained in the same manner as in Example 16 using appropriate starting materials.

Example 27 Ethyl 2-acedeamide-2-carboethoxy-8-(
5.6 g of 2-quinolon-3-yl)propione are dissolved in 150 g of tetrahydrofuran. To this is added 50% oily sodium hydrogen o, sy while stirring at room temperature. Add 4.5 g of methyl iodide dropwise and stir at room temperature for 3 hours. Concentrate under reduced pressure, pour the residue into water, and evaporate the precipitate. Ethyl 2-acetamido-2-carboethoxy-3-(1-
Methyl-2-quinolon-3-yl)propione)3.
Obtain 5g. Melting point: 190.5-192°C In the same manner as in Example 27 above, using appropriate starting materials, the compounds of mJ Reported Cases 21-24 are obtained.

Example 28 1.9 g of lithium aluminum hydride was dried in 100 g of tetrahydrofuran. Suspend in I/. To this was added 3-carboxycarbostyryl 1°9y while stirring at room temperature. Stirring is carried out overnight at room temperature. Excess lithium aluminum hydride is decomposed by dropping ethyl acetate. Add dilute sulfuric acid to make acidic. After distilling off tetrahydrofuran under reduced pressure,
Count the number of crystals that precipitate. Recrystallization from methanol yields 0.5 g of colorless prismatic 3-hydroxymethylcarbostyryl. Melting point 238-239.5°C0 Using appropriate starting materials in the same manner as in Example 28 above, i
Compounds of iJ Report Cases 3 to 7 are obtained.

Example Acetoacetanilide 301i' is dissolved in chloroform 30-. To this was added 27 g of bromine and 30 ml of chloroform while stirring at room temperature. Drop the solution. After dropping, reflux is performed for 30 minutes. Concentrate under reduced pressure and add the residue to 70.7 g of concentrated sulfuric acid with stirring. Add while maintaining the internal temperature at 70-75°C, and stir at 95°C for 30 minutes. Pour the reaction solution into ice water and count the precipitated crystals.

Recrystallized from methanol-chloroform to give colorless needle-like 4
- Obtain 20 g of bromomethylcarbostyryl. Melting point 26
The compounds of Examples 8 to 9, 11 to 13 and 15 are obtained in the same manner as in Example 29 using appropriate starting materials.

Example 30 3-chloromethyl-6-m1-xycarbostyryl 2.
2 g is dissolved in 20-acetic anhydride. Add 12 g of potassium acetate to this mixture and stir at 60-7°C for 3 hours. Pour the reaction solution into ice water to increase the amount of precipitated crystals. Recrystallization from acetone gives colorless prismatic 3-acel-oxymethyl-6-methoxycarbostyryl 2fI. Melting point: 166-168 DEG C0 Example 3 - 2 g of acetomethylcarbostyl is dissolved in methanol/I/30 containing 0.6 g of sodium hydroxide and refluxed for 3 hours. After distilling off the methanol, water is added to the residue and the precipitated crystals are collected. Recrystallization from acetone yields 1.3 g of 3-hydroxymethyl-6-medoxycarbostyryl in the form of pale yellow needles.

Melting point 196-197°C0 Using appropriate starting materials in the same manner as in Case 31 above,
Compounds of sister examples 1 and 4 to 7 are obtained.

Reference Example 20 Ethyl 2-acetamido-2-carboxy-3-(2-
150% of 20% hydrochloric acid was added to 5 g of quinolon-4-yl) propionate and refluxed for 9 hours. Concentrate under reduced pressure and recrystallize the residue from ethanol-water to obtain colorless prismatic 2
3.2 g of -amino-3-(2-quinolon-4-yl)propionic acid hydrochloride hydrate are obtained. Melting point 220-225
°C (decomposition).

Reference Example 21 1.6 g of 2-amino-3-(2-quinolon-3-yl)propionate hydrochloride and 2.4 g of potassium carbonate are dissolved in 60 - of acetone and 3 - of water. Add 1.2 f of P-chlorobenzoyl chloride to 1 o of acetone while cooling with water and stirring.
, ll solution dropwise. Stir for 2 hours under water cooling. After distilling off the acetone, water is added to the residue to remove insoluble materials. '/P
Make H acidic with hydrochloric acid.

Offshore the precipitated crystals. Recrystallized from ethanol-water,
2-(4-chlorobenzoylamino)-3 in white powder form
1.5 g of 42-quinolon-3-yl)pro1pionic acid are obtained. Melting point 270-271.5°C (decomposition).

Reference example 22 2-amino-3-(6-methoxy-2-quinolone-3-
1.57 g of sodium hydroxide is dissolved in a solution of 0.8 g of sodium hydroxide in water.

1 g of P-chlorobenzoyl chloride was added dropwise over water cooling.

Stir. Raw materials are eliminated by thin layer chromatography.

Aqueous solution of 1-lium N-hydroxide and acid chloride are added at appropriate times until they are completely lost. After the reaction is completed, the mixture is acidified with hydrochloric acid to increase the amount of precipitated crystals. After washing with ether, recrystallization from methanol-water yields a yellow powder of 2-(4-chlorobenzoylamino)-3,(6-medoxy-2-quinolone-3).
0.7 g of -yl)propionic acid are obtained. Melting point 284.5
~236°C (decomposition).

Reference example 23 2-amino-3-(6-hydroxy-2-quinolone-3
2 g of 1-methyl-2-pyrrolidone is suspended in 50 g of 1-methyl-2-pyrrolidone, 2.2 g of 3-(4-chlorobenzoyl)benzoxazoline-2-thione is added, and the mixture is stirred at room temperature for 3 days.

Pour the reaction solution into ice water and count the precipitated crystals. N crystal
- After dissolving in an aqueous sodium hydroxide solution, acidify with 10% hydrochloric acid and collect the precipitated crystals. After drying the crystals, wash them with chloroform. Recrystallization from methanol-water gives pale yellow powder of 2-(4-chlorobenzoylamino)-8-(6-
Hydroxy-2-quinolon-3-yl)propionic acid 1
．． Get 5y.

Melting point 223-227°C (decomposition).

Reference Example 24 2-Amino-3-(2-quinolon-3-yl)propionic acid 1.217, DCCIJg and p-chlorobenzoic acid 1. Og is suspended in dioxane 10-60-70
Stir at °C for 5 hours. After the reaction is complete.

The solvent was distilled off, and ether was added to remove the precipitated crystals. f
After concentrating the three liquids, the residue is dissolved in chloroform and washed with water and saturated brine. After drying with sodium sulfate, the solvent is distilled off. Recrystallized from ethanol-water to give white powder 2-(4-chlorhensoylamino)-3,
-(2-quinolon-3-yl)propionic acid 850'
Gain IQ. Melting point: 270-271.5°C (decomposition).

Reference Example 25 1.2 g of 2-amino-3-(2-quinolon-3-yl)propionic acid and 0.8 g of l-ethylamine were suspended in 10-tetrahydrofuran, and diethylchlorophosphate was added to the solution under stirring at room temperature. )1. , Cl in tetrahydrofuran 10. nl solution dropwise and stirred at room temperature for 3 hours. To this mixture was added 7 m of a solution of 1°Og of p-chlorobenzoic acid in 10 rnl of tetrahydrofuran, and the mixture was further stirred at room temperature for 10 hours. After the reaction is complete, the precipitated crystals are removed from the oven, the molasses liquid is concentrated, saturated soybean powder is poured into the residue, and the mixture is extracted with chloroform.

The organic layer is washed with water and saturated brine, dried over sodium sulfate, and then the solvent is distilled off. Recrystallization from ethanol-water yields 0.9 g of 2-(4-chlorobenzoylamino)-3-(2-quinolone-3-y/l/)propionic acid in the form of a white powder. Melting point 270-271.5°C (decomposition).

Reference Example 26 To a solution of 4.84 g of P-chlorobenzoic acid and 4-triethylamine in 50-dimethylformamide, a solution of 8.87 f of isobutyl chloroformate in 2-dimethylformamide is added dropwise. After stirring for 30 minutes at room temperature, 2-amino-3-(2-quinolon-3-yl)propionic acid6.
A 3-solution of osy in dimethylformamide is added dropwise and stirred for 30 minutes at room temperature and then for 1 hour at 50-60°C. The reaction mixture is poured into a large amount of saturated brine, extracted with chloroform, washed with water, and then dried. The crude crystals obtained by distilling off the solvent were recrystallized from ethanol-water to obtain 2-
8.79 of (4-chlorobenzoylamino)-3-(2-quinolon-3-yl)propionic acid are obtained. Melting point 270
~271.5°C (decomposed).

Reference Example 27 Ethyl P-chlorobenshade 1.66 g, sodium ethylate 0.5 g and 2
-Amino-3-(2-quinolon-3-yl)propionic acid 2.099% was added and placed in an autoclave at 110 atm.
React at 140-150°C for 6 hours. From now on, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform at 200. After washing sequentially with 1% potassium carbonate aqueous solution, dilute hydrochloric acid and water, drying with sodium sulfate, distilling off the # medium and recrystallizing from ethanol-)V water, a white powder of 2-( 4-
Chlorbenzoylamino)-8-(2-quinolone-3-
il) propionic acid 300 m? get. Melting point 270~
271.5°C (decomposition).

Patent applicant Otsuka Pharmaceutical Co., Ltd. Representative Patent Attorney Aoyama Aoyama and 1 other person

Claims (1)

[Claims] (1) General formula [wherein R1 is a hydrogen atom, lower alkyl, lower alkenyl, lower alkynyl or phenyl lower alkyl; R2
is a hydrogen atom, a hydroxyl group or a lower alkoxy, R3 is a hydroxyl group, a rogen atom, a lower alkanoyl, a lower alkyl,
, R5 represents lower alkanoyl). The bond between the 3rd and 4th positions of the carbostyril bone nucleus shows a single bond or a double bond. The position of the substituent is either 8.4.5.6.7 or 8 of the carbostyl skeleton.] Carbonutyl derivatives and salts thereof.