JPS6281383A - Pentacyclic compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R1 is H or alkyl; R2 is H, (protected) carboxyl, protected carboxyamino, amino, acylamino, carbamoyl, etc.,; R3 is H, alkyl, alkenyl, alkynyl, aralkyl or aryl; X1 and X2 are H, alkyl, alkoxy, OH, halogen, CF3, NO2, NH2, etc.,] and its salt. USE:An antiarrhythmic agent. PREPARATION:For example, a compound shown by the formula II (R<a>2 is H, alkoxycarbonyl, aralkyloxycarbonyl or allyloxycarbonyl) is subjected to intramolecular ring closure reaction and, if necessary, subjected to isomerization reaction or to conversion reaction of the substituted R<a>2, to give a compound shown by the formula I. The compound shown by the formula II is obtained by reacting an alkali metallic salt of a compound shown by the formula III with a compound shown by the formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel bicyclic compounds useful as pharmaceuticals with antiarrhythmic properties.

As a result of repeated research into the composition of the invention, it was discovered that the bicyclic compound represented by the general formula (1) below, produced by a novel synthesis method, is a compound useful as a medicine with anti-arrhythmic action. The invention was completed.

The object compound of the invention is a compound represented by the general formula and a pharmacologically acceptable salt thereof.

In the above formula, R1 represents a hydrogen atom or a concave alkyl group, and R2 represents a water atom, a carboxyl group, a protected carboxyl group, a protected carboxyamino group, an amino group, a mono- or di-substituted amine group, Represents an acylamino group, a carbamoyl group, a monoalkyl-substituted carbamoyl group optionally having an amino substituent, a di-substituted carbamoyl group, a ureido group, a mono- or di-substituted ureido group, a carbazol group, or an I&substituted carbamoyl group, and R3 is hydrogen. atom, lower alkyl group, lower alkenyl group, lower alkynyl group, aralkyl group or aryl group, xl
and x2 represents a haloken atom, a) trifluoromethyl group, a nitro group, an amine group, a carboxyl group, a protected carboxyl group, a mono- or di-substituted carbamoyl group, or a cyano group.

(However, R1 represents a hydrogen atom, and R2 represents a hydrogen atom, a carboxyl group, a protected carboxyl group, or a protected carboxyamino group.

represents a mono- or di-substituted ureido group, R5 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, an [[alkynyl group''!i or an aralkyl group, and xl and
Except when 2 are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, an aralkyloxy group, a hydroxyl group, a halogen atom, a trifluoromethyl group, a nitro group, or yc represents an amino group. ) In the general formula (1), Rj is preferably a hydrogen atom;
Represents a lower alkyl group such as methyl, ethyl, n-propyl, R2 is a water atom; carboxyl group; methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl Lower alkoxycarbonyl groups such as allyloxy groups, 2-methyl-2-flobenyloxy, optionally substituted allyloxy groups such as 2-chloroallyloxy, 2-bromoethoxycarbonyl, 3-dicarbonyl, lolobroboxycarbonyl, etc. Halo lower alkoxycarbonyl group, benzyloxycarbonyl,
Aralkyloxycarbonyl group % such as p-nitrobenzyloxycarbonyl, phenethyloxycarbonyl
2-dimethylaminoethoxycarbonyl, 3-aminoproboxycarbonyl, 3-dimethylaminepropoxycarbonyl, 2-(1-pyrrolidinyl)ethoxycarbonyl, 2-hyhelicinoethoxycarbonyl, 2-morpholinoethoxycarbonyl, 2-(4 -Methyl-1-piperazinylfethoxycarbonyl, 2-(4-(1)-methylphenyl)-1-piperazinylfethoxycarbonyl I 2-[:4-tm-methylphenyl)-1-piperazinylfethoxy Carbonyl, 2-[4-(3,4,
5-trimethoxycinnamoyl]-1-piperazinyl]
Carboxyl groups such as amine lower alkoxycarbonyl groups such as ethoxycarbonyl: methoxycarbonylamino, ethoxycarbonylamino, te
Lower alkoxycarbonylamino groups or aralkyloxycarbonylamino groups such as rt-butoxycarbonylamino, benzyloxycarbonylamino, p-nitrobenzyloxycarbonylamino, cyclopentyloxycarbonylamino, cyclohexyloxycarbonylamino, bornan-2-yloxy Reflected carboxyamino groups such as cycloalkoxycarbonylamino groups such as carbonylamino and inbornan-2-yloxycarbonylamino; amino groups; methylamino, dimethylamino, ethylamino, 2-hydroxyethylamino, diethylamino, n-propylamino,
Di-n-propylamino, infrobylamino, diisopropylamino, N-methyl-N-ethylamino, N-
Methyl-N-benzylamino, N-(2-hydroxyethyl)-N-methylamino% N-(3-hydroxypropyl)-N-methylamino, N-(2-methoxyethyl)-N-methylamino, N -(2-carboxyethyl)-N-methylamino.

Amino group substituted with a substituted or unsubstituted lower alkyl group and/or aralkyl group such as N-(3-carboxy-10-byl)-N-ethylamino; 1-pyrrolidinyl, morpholino, piperidino% 1-piperazinyl, 4 -Mef-1-piperazinyl, 4-phenyl-
Cyclic amino groups such as 1-piperazinyl; acetylamino.

11-substituted or unsubstituted alkanoylamino groups such as propionylamino, diethylaminoacetylamino; carbamoyl group; N-methylcarbamoyl, N,N-dimethylcarbamoyl, N.

N-diisopropylcarbamoyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, 14-)f-1
-piperazinylcarbonyl, 4-phenyl-1-piperazinylcarbonyl, N-(2-(N,N-dimethylamino)ethyl]carbamoyl, N-(2-(N, N-
diethylamino]ethyl]carbamoyl, N-(2-cyclohexylethyl]carbamoyl, N-(2-(1-
pyrrolidinyl)ethyl]carbamoyl, N-(2-piperidinoethyl)carbamoyl, N-(2-morpholinoethyl)carbamoyl.

N-(3-morpholinopropyl)carbamoyl.

N-(2-(4-methyl-1-piperazinyl)ethyl)
Carbamoyl, N-(2-(4-722-1-piperazinyl)ethyl)carbamoyl, N-[2-(4-ethoxycarbonyl-1-piperazinyl)ethyl]carbamoyl% N-7enethylcarbamoyl A thing or thing.

Disubstituted carbamoyl group; ureido h I N-dithylaminocarbonylamino, N,N-dimethylaminocarbonylamino, 4-phenyl-1-piperazinylcarbonylamino, 4-(ffl-methylphenyl)-1-piperazine mono- or di-substituted clade groups such as carbonylamino; carbazole groups; 3-methylcarbazoyl, 3,3-dimethylcarbazoyl, 3,3-diisopropylcarbazoyl, 3-(2-
hydroxyethyl)carbazoyl, 3-(2-ethoxyethyl)carbazoyl, 3-(2-(N,N-dimethylamino)ethyl]carbazoyl% 3-(2-(N,N
-diethylamino]ethyl]carbazoyl, 3-(2-
(1-pyrrolidinyl)ethyl]carbasoyl, 3-(2
-Piperidinoethyl]carbazoyl.

3-(2-morpholinoethyl)carbasoyl.

3-(3-morpholinopropyl)carbazoyl, 3-(
2-(4-methyl-1-piperazinyl)ethyl]carbazoyl, 3-(2-[4-ethoxycarbonyl-1-piperazinyl]ethyl]carbasoyl, 3-benzylcarbasoyl% 3-(4-methoxybenzyl)carbazoyl, 3-(,3,4-dimethoxy7enethyl)carbazoyl, 3-(3-chlorophenethyl)carbazoyl, N
-morpholinocarbamoyl, N-(1-piperazinyl)
-carbamoyl, N-biperidinocarbamoyl, R5 is a hydrogen atom; methyl, ethyl, n-propyl, isopropyl% n-butyl, isobutyl, butyl, tert-7'thyl, n- Straight chain or branched alkyl groups such as pentyl, impentyl; allyl, 1-propenyl, 2-butenyl, 3
- Straight-chain or branched lower alkenyl groups such as methyl-2-butenyl; lower alkynyl groups such as 1-propynyl, 2-propynyl, 2-butynyl; benzyl, p-methylbenzyl% p-methoxybenzyl ,p-/
Loropenzyl, 2-phenethyl, 2-(1)-methoxyphenyl)ethyl, 2-(s,4-dimethoxyphenyl)ethyl, 2-(3,4,5-)dimethoxyphenyl)
represents an aralkyl group such as ethyl, α-methylbenzyl, 3-phenylpropyl, or an aralkyl group such as phenyl, p-methoxyphenyl, p-chlorophenyl, 3,4-dimethoxyphenyl, and Xj and x2 are the same or different hydrogen atoms; methyl, ethyl% n-propyl, inflovir, n-butyl, isobutyl, tert
- Straight chain or branched lower alkyl groups such as butyl; straight chain or branched lower alkoxy groups such as methoxy, ethoxy, n-proboxy, impropoxy, n-butoxy, imbutoxy; benzyl Aralkyloxy groups such as oxy, p-methoxybenzyloxy, p-chlorobenzyloxy, phenethyloxy, and 3-phenylpropoxy; hydroxyl groups; rogone atoms such as fluorine, chlorine, bromine, and iodine; trifluoromethyl groups; Nitro group; amino group, carboxyl group; protected carboxyl group such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl; carbamoyl group; II-methylcarbamoyl, N,N-dimethylcarbamoyl, N, It represents a substituted carbamoyl group such as N-diethylcarbamoyl, N,N-diisopropylcarbamoyl; or a cyano group.

When the compound having the general formula (I) of the present invention is basic, inorganic acids or hydrochloric acid,
Salts of mineral acids such as hydrobromic acid, hydriodic acid, sulfuric acid or phosphoric acid, and organic acid salts include formic acid, acetic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, succinic acid, citric acid,
Examples include salts of organic carboxylic acids such as tartaric acid, aspartic acid, and benzoic acid, and salts of sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Moreover, in the compound (1) of the present invention, the compound having a carboxyl group can also be a pharmacologically acceptable metal salt. Such salts include salts of alkali metals or alkaline earth metals such as sodium, potassium, and calcium.

Moreover, the compound (1) of the present invention has stereoisomers and optical isomers, and these stereoisomers, optically active forms, and racemic forms are all present in the present invention represented by the general formula (I). It is included in the compounds of.

As specific compounds represented by the general formula (I) of the present invention, the compounds listed in the table below can be exemplified.

Preferred compounds in the above table include compounds 1, 2,
6,12,13,14,22,23゜24.27,28
,29,34,35,39°43.44,53.82F
9 and 63 can be given.

The target compound of the present invention having the general formula (1) is as follows.

General formula (wherein, R2 represents a water bulk atom, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, or an allyloxycarbonyl group which may be kl, and R1,'B
3. x1. x2 has the same meaning as described above. ] is subjected to an intramolecular ring-closing reaction to form a compound having the general formula (wherein R+ , R#+ R3'e X+ , X2
C indicates the same meaning as Mtr description L vehicle. ), and then, if necessary, isomerization reaction and substitution Q
- Can be produced by subjecting a compound in which R2 is a carboxylic acid ester to the corresponding carboxylic acid, acid amide, acid hydrazide, substituted alkyl ester, urethane, urea, or amine compound in appropriate combinations. .

(a) The reaction to obtain the cyclization product, the compound having the general formula CI&), from the compound having the general formula (1) is as follows: 1. This is a novel intramolecular ring-closing reaction, and the compound (II
) in the presence or absence of a catalyst, in a solvent or in a solvent-free state.

1wL substituent R in the above formula? Preferred examples include groups corresponding to the substituent R2 in the compound having the general formula (I) described above, and particularly preferred are a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group, an allyloxycarbonyl group, Examples include benzyloxycarbonyl group and p-nitrobenzyloxycarbonyl group.

There are no special restrictions on the solvent used in the reaction as long as it does not participate in this reaction, but benzene is the preferred solvent.

Hydrocarbons such as toluene, xylene, mesitylene, tetrahydronaphthalene, decahydronaphthalene, biphenyl, halogenated hydrocarbons such as methylene chloride, chloroform, chlorobenzene, 〇-dichlorobenzene, ethyl ether, tetrahydrofuran, dioxane, biphenyl. Ethers such as ethers, amides such as dimethylformamide, dimethylacetamide, dialkylanilines such as N,N-dimethylaniline, N,N-diethylaniline, DOWHERM [F]- ('powtherm, DOW chem, qo)
etc. are suitable. The reaction is carried out under normal pressure or in a pressurized container at room temperature or around the boiling point of the solvent used, and the reaction time varies depending on the reaction temperature, but usually
The duration ranges from 5 minutes to 100 hours. Particularly preferably, the above-mentioned high boiling point solvent (for example, boiling point of around 160° C. or higher) can be used and the reaction can be carried out under heating under reflux.

Examples of the catalysts used include metal catalysts such as aluminum chloride, zinc chloride, tin chloride, ferric chloride, methane tetrachloride, ethylaluminum chloride, dimethylaluminum chloride, diethylaluminium chloride, and poron trifluoride. .

After completion of the reaction, the target compound CI&) of this reaction can be isolated from the reaction mixture according to a conventional method, but it can also be used in the next reaction without being isolated.

(b) The reaction of isomerizing the compound having the general formula R3 thus obtained to obtain the compound having the general formula is performed by treating compound (Ia) in a solvent in the presence or absence of a catalyst. Indicates the same meaning as

This reaction is preferably carried out in the presence of a catalyst, and examples of catalysts used include Balajicum carbon, gold! Silver, metallic palladium, tris(triphenylphosphine) rhodium chloride.

Metal catalysts such as rhodium chloride, cuprous chloride, iron pentacarbonyl, ruthenium chloride, or acid catalysts such as hydrogen chloride, sulfuric acid, nitric acid, phosphoric acid, acetic acid, methanesulfonic acid, p-)luenesulfonic acid, aluminum chloride, etc. Among these, hydrogen chloride is particularly preferred.

The solvent used is not particularly limited as long as it does not participate in this reaction, but includes hydrocarbons such as benzene, toluene, xylene, and mesitylene, methanol, ethanol, n-
Preferred are alcohols such as prono(nol), ethers such as tetrahydrofuran and dioxane, and amides such as dimethylformamide and dimethylacetamide.The reaction is carried out at room temperature or near the boiling point of the solvent used under reflux. The reaction time varies depending on the reaction temperature, but is usually 1 minute to 10 hours.

(C) The reaction of removing the carboxyl protecting group from the ester compound having the general formula to obtain the compound having the general formula is the ester compound LIV)
This can be achieved by subjecting K to a hydrolysis or reductive removal reaction in a solvent.

In the above formula, R4 is a lower alkyl group such as methyl or ethyl, or benzyl, and p-nitro is as defined above. It is carried out by contacting the compound (IT) with an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in a solvent according to the method.The reaction solvent is not limited as long as it does not participate in this reaction, methanol, ethanol, etc. Mixed solvents of water and organic solvents such as alcohols such as Tetrahydrofuran and ethers such as dioxane are suitable. Although the reaction temperature is not particularly limited, it is usually carried out at room temperature or heated to around the boiling point of the solvent used.

The reaction time varies depending on the reaction temperature, but is usually 5 minutes to 2 minutes.
It is days.

On the other hand, the reductive removal reaction of the aralkyl ester compound (1v) in which %R4 is an aralkyl group is carried out by catalytic reduction with hydrogen at room temperature in the presence of a catalyst according to a conventional method.

Catalysts used include palladium-carbon, platinum oxide,
Examples include Raney nickel.

The solvents to be used are not particularly limited as long as they do not participate in this reaction, but include alcohols such as methanol and ethanol, ethers such as tetrahydro7rane, dioxane, dimethylformamide, and dimethylacetamide (d) General formula The reaction of removing the (substituted) allyl group R5 of the compound having the general formula to obtain the compound having the general formula is carried out by adding a catalytic amount of the compound (Vl) in a solvent in the presence of a proton supplying compound and a ligand to palladium. This is achieved by treatment with a zero-valent baladicum complex.

In the above formula, R1, R5, R5, Xl and x2 have the same meanings as described above.

Proton-donating compounds used in this reaction include formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, 2-ethylhexanoic acid, cyclohexanecarboxylic acid, benzoic acid,
Carboxylic acids such as anisic acid or alkali metal salts thereof such as sodium salts and potassium salts, phenols such as phenol and cresol.

or its alkali metal salts such as sodium salts and potassium salts, and compounds with active methylene graves such as diethyl malonate, ethyl cyanoacetate, malonitrile, and methyl acetoacetate. These proton-supplying compounds are compounds (■). It is used in an amount of 1 to 3 times the molar amount.

The ligand for palladium is not particularly limited as long as it is used in ordinary organometallic complex chemistry, but trivalent phosphorus compounds are preferred, such as triphenylphosphine, tri-n-butylphosphine, and triethylphosphine. Phosphites, etc., and a particularly preferred aK is triphenylphosphine, and these ligands are used in one of the palladium complexes used.
It is used in 1 to 10 times the molar amount.

Examples of zero-valent palladium complexes include tetrakis(triphenylphosphine)palladium(0)% palladium(○)bis(dibenzylideneacetone). used in percentages.

There are no particular limitations on the solvent that is not involved in this reaction, but hydrocarbons such as hexane and benzene, and halogenated hydrocarbons such as dichloromethane and chloroform are used.

Ethers such as ethyl ether, tetrahydro7rane, dioxane, methanol, ethanol, tart
- Alcohols such as butanol, ketones such as acetone and methyl ethyl ketone, esters such as methyl acetate and ethyl acetate, amides such as dimethyl formamide and dimethyl acetamide, dimethyl sulfoxide, etc. They may be mixed and used as appropriate. This reaction is carried out in a nitrogen stream at a temperature of 0 to 40°C, and the reaction time varies depending on the reaction temperature, but is usually 30 minutes to 24 hours, and is carried out under stirring or by standing.

After completion of the reaction, the target compound (9) of the above reaction can be counted according to a conventional method. For example, it can be obtained by collecting and washing crystals precipitated from a reaction mixture under acidic conditions,
The nine target compounds obtained can be further purified by a recrystallization method or the like.

The reaction of reacting a carboxylic acid having a formula or a reactive derivative thereof with an amine having a general formula to obtain a compound having a general formula is accomplished in a solvent in the presence of a condensing agent or a base.

2Vi% of carbamoyl which may be substituted with n, such as carbamoyl, N,N-dimethylaminocarbonyl, 1-pyrrolidinylcarbonyl, 4-methyl-1-piperazinylcarbonyl group, N-(2-(N, N -dimethylaminone ethyl]carbamoyl, N-(2-(1-
pyrrolidinyl)ethyl]carbamoyl, N-(2-hiheIJ dinoethyl)carbamoyl, N-(2-(4-methyl-1-piperazinyl)ethyl)carbamoyl or an optionally substituted carbazolyl group 1, such as carbazoyl.

3-methylcarbazoyl, 3-[2-(N.

N-diethylami)ethyl]carbazoyl, 3-(2-
(1-pyrrolidinyl)ethyl]carbazoyl, 5-(2
-(4-methyl-1-piperazinyl]ethyl]carbazoyl, 3-(2-piperidinoethyl)carbazoyl, etc., and R5, Xj and x2 have the same meanings as described above.

The condensation reaction between the carbonated compound (1) and the amine (■) is carried out in a solvent in the presence of a condensing agent.

Condensing agents used include dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole, N,N
'-Carbonyl-8-triazine, N-hydroxyphthalimide, diethyl cyanophosphate, etc.
Diethyl cyanate is preferably used.

The reaction is preferably carried out in the presence of a base, and the base used is triethylamine.

Examples include 4-dimethylaminopyridine. The reaction solvent is not particularly limited as long as it does not participate in this reaction, but it may be tetrahydrofuran.

Examples include ethers such as dioxane and ethyl ether, amides such as dimethylformamide and dimethylacetamide, halogenated hydrocarbons such as methylene chloride and chloroform, and aromatic hydrocarbons such as benzene and toluene. I can do it. The reaction temperature is not particularly limited, and the reaction can be carried out at room temperature or by heating around the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, but is usually 1 hour to 2 days. The method for producing acid amide (■) by the condensation reaction is carried out in a solvent, if necessary in the presence of a base.

The solvent to be used is not particularly limited as long as it does not participate in this reaction, and may include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane, and aromatic solvents such as benzene and toluene. There are 8 types of hydrocarbons. The reaction is usually carried out at room temperature or under heating at around the boiling point of the solvent used, and the reaction time varies depending on the reaction temperature, but can range from 5 minutes to 2 days.

The carboxylic acid chloride used in this reaction can be obtained by contacting the carboxylic acid compound with a halogenating agent such as thionyl chloride or oxalic acid chloride according to a conventional method.

(f)　　General formula (a carboxylic acid having the general formula %formula%() by reacting with a haloalkanol.

The reaction of producing a haloalkyl ester having the general formula and then reacting it with an amine having the general formula to obtain a compound having the general formula B5 is carried out in a solvent in the presence of a condensing agent or a base: A be done.

In the above formula, X3 represents a halogen atom such as chlorine, bromine or iodine, and 1m represents an atom of 2 or 3.
5, R6, R7, Xl, X2 and the bonds containing dotted lines have the same meanings as described above.

The initial carboxylic acid compound M and the haloalkanol (11
The condensation reaction with 0 is carried out in a solvent in the presence of a condensing agent.

The condensing agents used in this reaction include hydrogen chloride, m powder,
Examples include dicyclohexylcarbodiimide, N,III'-carbonyldiimidazole, diethyl cyanophosphate, and dicyclohexylcarbodiimide is particularly preferred. The reaction is carried out if necessary in the presence of a base, in which case the base may be an organic base such as triethylamine, 4-dimethylaminopyridine or an alkali metal carbonate such as sodium carbonate or sodium bicarbonate. I can do it. The reaction bath agent is not particularly limited as long as it does not participate in this reaction, but examples include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as tetrahydrofuran and dioxane, and amides such as dimethylformamide. dioxane is preferred for the buttock. The reaction temperature is not particularly limited.

It is carried out at room temperature or under heating near the boiling point of the solvent used.

The reaction time varies depending on the reaction temperature, but is usually 10 minutes to 2 days.

Then, the reaction of the haloalkyl ester (material) thus obtained with the amine (■) is carried out in a solvent, if necessary in the presence of a base.

The base used may be an organic base such as triethylamine or pyridine, or an alkali metal carbonate such as sodium carbonate or sodium bicarbonate. There are no particular restrictions on the reaction medium as long as it does not participate in this reaction, and aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide, and dimethyl Examples include fatty acid esters such as sulfoxide, methyl acetate, and ethyl acetate.

The reaction temperature is not particularly limited, and the reaction is carried out at room temperature or under heating near the boiling point of the solvent used.

The reaction time varies depending on the reaction temperature, but is usually 30 minutes to 24 hours.

(g) Using a carboxylic acid reactive fat conductor having the general formula (9) as a raw material, Fretan LXIY) and urinary cord cast conductor (
The reaction for producing XV) can be achieved by the steps shown below.

kt5 (XV) In the above formula (XIV), NllIC02R8 is a conjugated carboxyamino group in the above-mentioned compound (1), such as methoxycarbonylamino, benzyloxycarbonylamino, p-nitrobenzyloxycarbonylamino or isobornane. -2-yloxycarbonylamino group/R9, etc., and in formula (XV), -NHOON represents a compound\RIO compound (ureido group or mono- or di-substituted ureido group in IJK, e.g. ureido group%NlN-dimethylamino Represents carbonylamino or 4-phenyl-1-piperazinylcarbonylamino group, R1, R5
, Xl and x2 have the same meanings as described above.

The reaction to obtain the carboxylic acid azide compound (M) in the first step is carried out by bringing an acid chloride, which is a reactive derivative of carboxylic acid (2), into contact with sodium azide in a solvent. The reaction solvent is not particularly limited as long as it does not participate in this reaction trap, but includes ketones such as acetone and methyl ethyl ketone, ethers such as tetrahydrofuran and dioxane, fatty acid esters such as methyl acetate and ethyl acetate,
A mixed or two-phase solvent consisting of water and an organic solvent such as a halogenated hydrocarbon a such as methylene chloride or chloroform, or an aromatic hydrocarbon such as benzene, toluene or xylene is suitable. The reaction temperature is usually water-cooled or around room temperature, and the reaction time is usually 5 minutes to 3 hours.

Carboxylic acid azide compounds (■) can also be obtained by contacting a carboxylic acid with ethyl chloroformate in the presence of a base such as triethylamine to form a mixed acid anhydride, which is then reacted with sodium azide. The reaction solvent, reaction temperature and reaction time are as follows:
This method is substantially the same as the method using fP: and 'fR chloride described above.

The reaction product of the first process described above can be used in the next second reaction without being isolated.

The reaction to obtain the incyanate compound (XI[) in the second step is carried out by Curtius rearrangement reaction of carboxylic acid azide LXl[). The reaction solvent is not particularly limited as long as it does not participate in this reaction, but examples include benzene, toluene, xylene,
Aromatic hydrocarbons such as mesitylene, chloroform,
1. Norogenated hydrocarbons such as 2-dichloroethane, ethers such as tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone,
Fatty acid amides such as dimethylformamide and dimethylacetamide are suitable. The reaction is usually carried out by heating near the boiling point of the solvent. The reaction time varies depending on the reaction temperature and is usually 5 minutes to 6 hours.

Incyanate compound LXIII) can also be obtained by heating a carboxylic acid compound (■) with diphenylphosphoryl azide in the presence of an organic base such as triethylamine. The time is approximately the same as that of the Curtius transfer reaction method described above.

The reaction to obtain the urethane conductor (xlV) or urethane conductor (tXV) in the third step is carried out in a solvent by contacting it with an alcohol having the general formula %() or an amine having the general formula %(). In the above formula, R8, R9 and RIO have the same meanings as described above.

The solvent used in the reaction is not particularly limited as long as it does not participate in this reaction, but benzene is used.

Examples include aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran and dioxane, and amides such as dimethylformamide and dimethylacetamide. . The reaction is usually carried out at room temperature or under heating near the boiling point of the bath agent used, and the reaction time is 5 minutes to 5 hours.

The reaction to obtain the compound having the general formula from the urethane derivative having the general formula is achieved by catalytic reduction of the compound CXIVa) with hydrogen in a solvent in the presence of a catalyst.

In the above formula, %R8- is t in the above-mentioned compound (X■)
Of the substituents R8, it represents an aralkyl group such as benzyl or l)-nitropenzyl, and %R1°R5,'':.Xl and x2 have the same meanings as described above.

This reaction is carried out by a catalytic reduction method at room temperature in accordance with a conventional method, and the catalysts used include palladium-carbon, platinum oxide, 2N nickel, platinum black, rhodium-carbon, and rhodium-alumina. The solvent to be used is not particularly limited as long as it does not participate in the reduction reaction, but alcohols such as methanol and ethanol,
Tetrahydrofuran.

Suitable are ethers such as dioxane, amides such as dimethylformamide and dimethylacetamide, acetic acid, and the like. The reaction is usually carried out at room temperature and under normal pressure, and the reaction time is 10 minutes to 5 hours.

In addition, in this reaction, substituent X1. of the starting compound (xB!a) In the case of an aralkyloxy group such as X2capendyloxy or p-nitrobenzyloxy, these groups are converted to a hydroxyl group. Compound (XVI)
is obtained.

The amino compound (X[) can also be obtained by treating a urethane compound (xy) in which the substituent R8 is a benzyl group with a mixture of trifluoroacetic acid and thioanilin or dimethyl sulfide at around room temperature.

The amino compound (1) can also be obtained by reacting a urethane compound (XI) in which the substituent hole 8 is a tart-butoxy group with a catalytic amount of acid. Examples include acetic acid and p-)luenesulfonic acid. The solvent to be used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, dichlorohydrocarbons such as methylene chloride and chloroform,
Aromatic hydrocarbons such as benzene and toluene are suitable. The reaction is usually carried out at room temperature or at the boiling point of the solvent, and the reaction time is 10 minutes to 2 days.

Furthermore, in the amino compound (xvti), the substituent R8 represents a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl, or an aralkyl group such as benzyl or p-nitrobenzyl, R1, R3, Xl and Xl can also be obtained by reacting a urethane compound (xy) having the same meaning as described above with boron tribromide. The solvent to be used is not particularly limited as long as it does not participate in this reaction, but halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride are suitable. The reaction is usually carried out at -70°C to room temperature, and the reaction time is 5 minutes to 24 hours. In addition, in this reaction, the starting compound (xy
) substituent X1. Xl is methoxy, ethoxy, n-polya
In the case of a lower alkoxy group such as boxy or an aralkyloxy group such as benzyloxy or p-nitropenzyloxy, a compound (■) in which these groups are converted to a hydroxyl group is obtained.

(1) The reaction for obtaining a mono- or di-substituted amine compound from the amino compound (xm) is carried out by contacting the compound (XI) with an alkyl halide or an aralkyl halide in a solvent according to a conventional method. The solvent to be used is not particularly limited as long as it does not participate in this reaction, but includes ethers such as tetrahydrofuran and dioxane, alcohols such as methanol, ethanol and propatool, methylene chloride, chloroform, 1.2-
dichromitane halogenated hydrocarbon M, -<
Suitable examples include aromatic hydrocarbons such as toluene, toluene, and xylene, fatty acid amides such as dimethylformamide and dimethylacetamide, and fatty acid esters such as methyl acetate and ethyl acetate. The reaction temperature is not particularly limited, but it is usually carried out under heating near the boiling point of the solvent.
The reaction time varies depending on the reaction temperature, but is from 30 minutes to 3 days.

Note that the dimethylamino compound can also be obtained by heating the amine compound (U) in formalin and formic acid according to a conventional method.

The target compounds of the present invention obtained by each of the above reactions are:
It can be isolated and purified by known separation and purification means, such as extraction, recrystallization, column chromatography, etc.

The compound represented by the general formula (1), which is a raw material compound for the production method of the present invention, is prepared by the general formula (wherein, R2a, X, and Xl have the same meanings as described above) according to a conventional method. alkali metal salts of the compound, such as sodium salt or potassium salt, and reactive derivatives of the compound having the general formula (wherein R has the same meaning as defined above), such as acid chloride, acid bromide, etc. It can be obtained by reacting an acid halide or a mixed acid anhydride obtained by contacting carboxylic acid (XX) with, for example, ethyl chloroformate in the presence of a base such as triethylamine.

The compound represented by the general formula (1) of the present invention shows an excellent antiarrhythmic effect as a result of pharmacological tests, and the pharmacological test methods and test results will be explained below.Test method: 2I desiccator Pour 150ml of chloroform into the
Stir with a magnetic stirrer and heat with an incandescent light. Once the inside was saturated with chloroform gas, the mouse (IOR) was removed.

The animal's body weight (20 to 25 y) was placed in a desiccator for 2 minutes, and then the chest was opened. A silver bipolar electrode is placed in close contact with the ventricle and an electrocardiogram is taken.
Record for minutes. The test drug was intraperitoneally administered 10 to 20 minutes before the test. The ventricular heart rate read from the electrocardiogram is 400 be
If ats/min or less, the test drug is effective (
It was determined that

Test results: As is clear from the above pharmacological test results, the general formula (
The compounds of the present invention having I) and their pharmacologically acceptable salts exhibit antiarrhythmic activity and are therefore useful as antiarrhythmic agents. Examples of the administration form include oral administration using tablets, capsules, granules, powders, and syrups, and parenteral administration using subcutaneous injections, intravenous injections, suppositories, and the like. These various preparations are prepared according to normal pharmaceutical techniques, and are prepared by adding solubilizing agents, suspending agents, excipients, binders, disintegrants, lubricants, and flavoring agents to the main drug depending on the purpose, which are commonly used in the pharmaceutical formulation field. It can be formulated using known adjuvants. The amount used depends on the patient's symptoms,
It varies depending on age, weight, etc., but usually 1 for adults.
20q to 21)01+9 can be administered 1 to 3 times a day.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is not limited to these scopes.

Example 1 Compound 61 Minocarbonyl-1-(1-ethyl-2-cyclohexen-1-yl)acetyl-IH-y/dol-3-yl]acrylic) 15.06N was added to 50 g of mesitylene. Heat to reflux for an hour. Next, 1 ml of 1596HOI-ethanol was added, heated under reflux for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (
After purification using ethyl acetate:hexane=1:2), recrystallization from ethyl acetate gave colorless prismatic crystals of 3.25 F with a melting point of 122-124°C.

Elemental analysis [(a) Calculated value as 029H56N20A: 0.73.08; H,? , 61; N, 5
．． 88° Actual value: 0.73.14; H, 7,67
; N, 5.86°IRyK"'(cN-'):
1730.1702 (c=o)aX NMR (onoj5) δ: 8.38 (IH, d,
J=9H2, 9th position-H) Mass (m/e): 47B (M+) Example 2
, Compound 66 Compound 67.3.1F and 2.37 N potassium 2-ethylhexanoate were mixed with ethyl acetate 2o- and dichloromethane 10
Dissolve in the mixed solvent of d, add triphenylphosphine 0.37F and tetrakis(triphenylphosphine)haladium TOI 0.381 in a nitrogen stream, and stir at room temperature for 7 hours. After that, ether was added to the reaction mixture, the precipitated gum was taken out, an aqueous citric acid solution was added, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized with ethyl acetate and washed to give a melting point of 2.
1B 2.15N of colorless powder crystals at -220°C were collected.

Example Sodium fluoride 14γI was dissolved in 10 ml of water and added to 50 ml of water.
Stir for 1 minute, pressurize the reaction mixture into ice water, extract with dichloromethane, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. The residue was dissolved in 30% xylene and heated under reflux for 1 hour, then 3 ml of benzyl alcohol was added and the mixture was heated under reflux for 8.5 hours. Concentrate the reaction mixture under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give a melting point of 172.
2.3f of colorless powder crystals at -174°C were obtained.

Example 4 Compound 68.12f was dissolved in N,N-dimethylformamide 2
0-, and add 1 g of 10% palladium-carbon catalyst to absorb hydrogen. After the absorption of hydrogen was completed, the reaction mixture was filtered, the P solution was concentrated under reduced pressure, and the residue was washed with ethyl acetate to obtain 1.2f of colorless powder crystals with a melting point of 104-106°C.

Colorless powder crystals with a melting point of 290° C. (decomposed) were obtained as a hydrochloride by a conventional method.

Elemental analysis value (%) Calculated value as 025H33N302-HOj: 0.67.63: H,? , 72;
N, 9.46; 01, 1.9B.

Actual value: 0.67.28; H,? , 43; N
, 9.30; Oj, 7.99°IRl/KBr(a-'): 1712 (c=o
)ax NMR(DMso-d6)δ: 12g (1H,d
, J=9H1゜9th-H) Mass (m/e): 4G? (freeM”)
Example 5 O$C 1-(1-phenyl-2-(cyclohexene-
1-yl)acetyl-IH-indol-3-yl]acrylate] 4.4 f was extracted with mesitilate and the reaction mixture was concentrated under reduced pressure. The residue was crystallized with isopropyl ether, washed, and recrystallized from ethyl acetate-isopropyl ether to give a pale yellow crystalline powder with a melting point of 220-222°C.
1 ik%.

Elemental analysis value (%) Calculated value as 03sHssNOa:
o, 79.07: H, 6, 26; N* 2.
63 actual measurement value: 0.7B, 37; H, 6,32;
N, 2.58IRν (a-'): IT2S,
169B (c=0)ax NMR (opo15) δ: 8.32 (IH, d,
J=9Hz, 9th position-H) Mass (m/e): 531 (M”) Example 6
゜Compound 41,2.21 and ethyl cyanoacetate 0.88 tons
was dissolved in 50s+/ of dichloromethane, 9611g of triphenylphosphine and 96gIiI of tetrakis(triphenylphosphine)palladium(0) were added in a nitrogen stream, and after stirring at room temperature for 7 hours, the apparatus was heated overnight.

The reaction mixture was washed with water, saturated hydrogen carbonate), washed with saturated citric acid, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-isopropyl ether and then recrystallized from dioxane-isopropyl ether. , pale yellow powder crystals, melting point 232-234°C 1.26
I got II.

Elemental analysis ([(%) 052H29NOA, 17
Calculated value as 2H20: 0.76.7JI; H,
6,04; N, 2.80 Actual value: 0.76.89
; H, 153; N, 2.50way (
cll-1): t7o2 (c=o)ix NMR (DM80-d4) δ: 120 (IH, d
, J=9Hz.

9th place-H) Mass (m/e): 491 (M”) Example T
.

Compound 4z 0.331 ml of ethyl carbonate was added dropwise and stirred for 30 minutes, then 0.23 F of sodium azide was dissolved in 10 ml of water and stirred for 30 minutes. The reaction mixture was placed under pressure in ice water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 20 ml of xylene and heated under reflux for 1 hour, then benzyl alcohol 2- was added and heated under reflux for 2 hours.
Concentrate the reaction mixture under reduced pressure. The residue was washed with isopropyl ether and recrystallized from ethyl acetate-hexane to give a melting point of 2.
0g -209°C pale yellow needle crystals were obtained.

Elemental analysis value (%) Calculated value as 059H36N20A: 0.78.50; H, 6,08; N, 4.
69 actual value: 0.78.17; H, 6,21;
N, 4.59IRν (CIll-'): t7
to, t692 (c=o)ax NMB (oDo13) δ: 8.35 (
IH, d, J = 10Hz.

9th place-H) Mass (m/e): 596 (M+)
Example 8 Compound 42.19 was dissolved in N,N-dimethylformamide 50
- and add 0.51% of 10% palladium-carbon catalyst to absorb hydrogen. After hydrogen absorption was completed, the reaction mixture was filtered and Ffi was concentrated under reduced pressure. The residue was recrystallized from dioxane to give 0.261 kg of colorless powder crystals with a melting point of 288-290°C (decomposed).

Elemental analysis value (%) Calculated value as 024M24N202: 0.7? , 39; H, s, so; N, 7
．． 52 actual value: 0.77.39: H, 6,51;
N, 7.33IRyKBr(cs-'): 16
82 (c=o)ax Mass (m/e): 372 (M”) Example 9
゜Melting point 222-2 obtained in the same manner as Examples 1 and 2
6-benzyloxy-12aβ-ethyl-1,2,3,3aβ,4α,S,tt with 24°C.

12,12aβ,12bβ-decahyde a-11-oxobenz[d,e]indo0[&2,1-ij') 1.339 quinoline-4β-carboxylic acid was dissolved in dichloromethane and stirred for 30 minutes, followed by 80% hydrazine hydrate. Add 3-proof powder dropwise and stir for 30 minutes. Water was added to the reaction mixture, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ether to give 0.95 f of colorless powder crystals with a melting point of 187-189°C (decomposed).

NMR (ODOj4) δ: 8.0? (IH, d,
J=9)iz, s position-H) Example 10° Compound? 2,0.95 g was dissolved in 10 slIc of N,N-dimethylformamide, and 0.41 g of 10% palladium-carbon catalyst was added to absorb hydrogen. After hydrogen absorption is completed, the reaction mixture is filtered and the liquid is concentrated under reduced pressure. 80% residue
% ethanol, melting point 28G -281℃
(Decomposition) A colorless crystalline powder 03115f was obtained.

Elemental analysis value (96) 021 Calculated value as H25N503: 0.88.84; H, 6,86; N,
11.44 actual measurement [: 0.6B, 511; H, 6,
93; N, 11.35Xa yKB'(3-')
: 1710 (c=o)ax NMR (DM80-d6) δ: 7.74 (IH, d
, J=8Hz.

9th place-H) Mass (m/e): 3B? (M”) Example 1
1°N,N-dimethylformamide 10Ill in a nitrogen stream
, the melting point 240 obtained in the same manner as in Examples 1 and 2.
7-benzyloxy-12aβ with -242'C
-Ethyl-1,2,3,3aβ, 4α, 5°N, 12
．． 12aβ, 12bβ-decahydro-11-oxobenzCd,e]indoa[3,2,1-ij]]quinoline-4β-carboxylic acid 1.33f, 1-(2-aminoethyl)pyrrolidine 0.38g, diethyl cyanphosphate 0.54f and triethylamine 0.46 g/!
Add and stir at room temperature for 5 hours. Place reaction mixture on ice.

Pressurize into water, add sodium hydrogen carbonate, extract with dichloromethane, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate → ethanol), and the melting point was 165-170'.
A crystal 1f of C was obtained.

NMR (cDa15) δ: 8.17 (IH, J,
d=10Hz.

9-H) Example 12゜Compound 73. When 1 g of N,N-dimethylform had been added, the reaction mixture was filtered and the P solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% triethylamine/ethanol) to obtain 0.396 II colorless amorphous crystals. .

Elemental analysis value (%) 02yHssN30s, 4H20
Calculated value: 0.62.17; H, 8,31;
N, 8.06 Actual side constant: 0,6λGo: H,7,
98; N, 7.85FMR (OD30D) δ: 8
．． 08 (IH, d, J=9Hz, 9-H) MS (m/e): 449 (M”) Example 13゜] Examples 1 and 2 were added to N,N-dimethylformamide IQmt in a nitrogen stream. Melting point 24G obtained in the same manner as
T-benzyloxy-12aβ-ethyl-1,2,3,3aβ,4α,5°11,12.1 with -242°C
2aβ, 12bβ-decahydro-11-oxobenz [
de']indo[3,2,1-ij]]quinoline-4-carboxylic acid 1.3311.1-(2-hydrazinoethyl)pyrrolidine 0.43F, diethyl cyanophosphate 0
．． Add 54g, Mitoriechi, Ruamine Q, 46ml,
Stir at room temperature for 5 hours. The reaction mixture was pressurized into ice water, sodium hydrogen carbonate was added, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate→ethanol→3% triethylamine/ethanol) to obtain crystal 1.1f with a melting point of 174-177°C.

NMR (onoj5) δ: 1211 (IH,
d, J=IQHz.

9-H) Example 14 Compound 74,1.1 ftt After the completion of the N,N-dimethylform collection, the reaction mixture was filtered and the r solution was concentrated under reduced pressure.

The residue was subjected to silica gel column chromatography (5%-
Purification with triethylamine/ethanol) gave 0.4862 colorless amorphous crystals.

Elemental analysis value (96) 02zHs6N40s, 1/2
Calculated value as H20: 0.68.47: H,7,
87; N, 11.83 Actual value: 0.68.39
; H, 7,55; N, 11.6a NMR (OD3
0D) δ: 8. H (IH, d, J = 9Hz.

9-H) MS (m/e): 464 (M”) Reference Example 1゜Allyl (E)-3-C5-(N, N-diethylaminocarbamoyl)-1H-indol-3-yl]acrylic) 4 After soaking .39 with N and N, under water cooling,
Add 2.51 g of (1-ethyl-2-cyclohexen-1-yl)acetyl chloride and stir for 1 hour. The reaction mixture was pressurized into ice water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane:
2:5) to give a pale yellow oil 5.25
I got 1.

Elemental analysis value (%) Calculated value as 029H56N204: 0.73.08; H, 7,51; N, 5.
88 actual value: 0.73.29; H, 8, 0+1
; N, 5.411Rv ""d"m (3'):
1713 (C:O)ax Mass (m/e): 476 (M”) Reference Example 2゜Allyl (B) -3-(5-benzyloxy-1H-
indol-3-yl) acrylate 3,34I N,
Dissolved in 50 liters of N-dimethylformamide, added 0.42B of sodium hydride (55%) and stirred at room temperature for 30 minutes, followed by (1-phenyl-2-cyclohexen-1-yl)acetyl chloride 2. Add 58y and 30
Stir for a minute. The reaction mixture was pressurized into ice water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane = 1:4) to obtain 4.42 of a pale yellow paste.

NMR (cDo13) δ: 8.24 (IH, d,
J=9Hz, 9th place-H)

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R_1 represents a hydrogen atom or a lower alkyl group, and R_2 represents a hydrogen atom, a carboxyl group, or a protected carboxyl group. , a protected carboxyamino group,
Amino group, mono- or di-substituted amino group, acylamino group, carbamoyl group, monoalkyl-substituted carbamoyl group optionally having an amino substituent, di-substituted carbamoyl group, ureido group, mono- or di-substituted ureido group, carbamoyl group, or represents a substituted carbazole group, R_3 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aralkyl group, or an aryl group;
_1 and X_2 are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkoxy group, an aralkyloxy group,
It represents a hydroxyl group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a carboxyl group, a protected carboxyl group, a mono- or di-substituted carbamoyl group, or a cyano group. However, R_1 represents a hydrogen atom, and R_2 represents a hydrogen atom, carboxyl group, protected carboxyl group, protected carboxyamino group, amino group, mono- or di-substituted amino group, acylamino group, carbamoyl group, mono- or represents a di-substituted carbamoyl group, a ureido group, or a mono- or di-substituted ureido group, R_3 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or an aralkyl group, and X_1 and X_2
This excludes cases in which are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, an aralkyloxy group, a hydroxyl group, a halogen atom, a trifluoromethyl group, a nitro group, or an amino group. ) and pharmacologically acceptable salts thereof.