JPS6226282A - Hydantoin derivative, production thereof and pharmaceutical containing same - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [X<1> and X<2> are H, halogen, alkyl, akloxy, CF3, etc.; R<1> and R<2> are H, alkyl or together with bonded C form a 5-6C cycloalkyl; Z is group of formula NR<3>R<4> (R<3> and R<4> are H, alkyl, aralkyl, etc.), formula XI (R<5> and R<6> are H, phenyl, etc.) or formula XII; n is 2-7] and its acid addition salt. EXAMPLE:2, 2-Dimethyl-6-fluoro-1'-[3-(4-hydroxypiperidino)propyl]-spiro[chro man-4,4'-imidazolidine]-2',5'-dione. USE:An antiarrhythmic agent free from cardio-suppressive action. It has durable activity, low toxicity and wide safety range. PREPARATION:The compound of formula I can be produced either by reacting the compound of formula II with the compound of formula IV (X and Y are halogen) and reacting the resultant compound of formula III with the compound of formula V-formula VII, or by reacting the compound of formula II with the compound of formula VIII-formula X.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel hydantoin derivatives that have excellent effects as pharmaceuticals. To be more specific, the general formula 〇CN-(CHz) ,,-
Zll
or forms an alkylenedioxy group with adjacent carbon atoms.

R+, Rz mean the same or different hydrogen atoms or lower alkyl groups, or R1 and R2 together with the carbon atoms to which they are bonded represent cs-b (in the formula R3,
R4 means the same or different hydrogen atoms, lower alkyl groups, hydroxyalkyl groups, or substituted or unsubstituted aralkyl groups, or R3 and R4 together with the nitrogen atoms to which they are bonded represent cS -b forms a saturated heterocyclic group, which may further contain an oxygen atom or a nitrogen atom, and further has an alkyl group having 1 to 6 carbon atoms on the nitrogen atom or the ring. A group represented by a different hydrogen atom, a phenyl group, a group represented by 2-0R7 (wherein R7 is a hydrogen atom, an acyl group, a lower alkyl group, a substituted or unsubstituted aralkyl group), or R5 and R
Together with the carbon atom to which 6 is bonded, the oxygen atom becomes 2
4 or 5 cyclic groups containing 4 or 5 cyclic groups, or R5 and R
A hydantoin derivative and a pharmaceutically acceptable acid addition salt thereof: and a pharmaceutically acceptable acid addition salt thereof: method; and an antiarrhythmic agent containing these compounds as active ingredients.

As used in this specification. Suitable examples and explanations of various definitions falling within the scope of this invention are detailed below.

Unless otherwise specified, the term "lower" refers to carbon atoms ranging from 1 to
It means a group having 6 members.

X' of the chemical structural formula (I) of the present invention, X2. R1,R
The "lower alkyl group" seen in the definition of R'l R'IR1 is, for example, methyl, ethyl, propyl, isopropyl.

Butyl, isobutyl, propyl, isopropyl.

Butyl, isobutyl, pentyl, isopentyl.

Examples include linear or branched alkyl groups such as hexyl, more preferably C0-C6 alkyl groups, and still more preferably C0-C, alkyl groups.

The "halogen atom" in Xl and XF includes, for example, fluorine, chlorine, and bromine.

Examples of the "lower alkoxy group" for x', Examples include alkoxy groups.

Further, Xl and x2 form an alkylenedioxy group with adjacent carbon atoms of the benzene ring, and examples of the alkylenedioxy group include a methylenedioxy group and an ethylenedioxy group.

Examples of the "aralkyl group" in R3 and R4 are:
Hensyl, phenethyl, 3,4-dimethoxyphenethyl and the like can be mentioned.

The term "rCs-b saturated heterocyclic group" includes, for example, morpholino, piperazyl, etc., and piperazyl may have a substituent such as an aryl group or a C1-6 alkyl group on the aryl group.

Furthermore, the pharmaceutically acceptable acid addition salts of the hydantoin derivatives of the present invention include, for example, phosphoric acid, hydrochloric acid, sulfuric acid, hydrogen bromide,
Mention may be made of inorganic acids such as hydrogen iodide, and organic acids such as fumaric acid, oxalic acid, acetic acid, methanesulfonic acid, lactic acid, citric acid, tartaric acid, and succinic acid.

Next, typical methods for producing the object compound (1) of the present invention will be listed.

The process is shown as a chemical reaction formula as follows.

In the above process diagram 1, X and Y are chlorine.

means a halogen atom such as bromine, and other XI.

X2. R', R''l R'J R'l and n have the meanings given above.

That is, a compound represented by the general formula (III) is reacted with a compound represented by the general formula (2) (step A).

A compound represented by the general formula is obtained.9 Then, to the compound,
A compound represented by the general formula (2), (II7Il or (2)) is reacted to obtain the desired product (Step B).

Furthermore, the target substance can also be obtained by a first alternative method (Step C). That is, in the compound represented by the general formula (III), the general formula ("1.1i1), ([X) or ■
The target substance (Il) can be obtained by reacting the compound represented by (step c).

Next, each reaction step will be explained in detail.

Reaction Step A Method 1 A compound of general formula (III) is reacted with a solvent such as dimethylpolamide, dimethylacetamide, dimethylsulfoxide, dioxane, ether, tetrahydrofuran, acetonitrile, etc. in the presence of a solvent.

By reacting sodium hydride, potassium hydride, calcium hydride, and sodium amide at ice-cooling to room temperature, and then reacting with a compound represented by the general formula (2).

Compounds shown in the general formula can be obtained.

Method 2 A compound represented by the general formula ([1] is added to 9 in the presence of a solvent such as methanol, ethanol, isopropanol, butanol, dimethylformamide, dimethylacetamide, ether, dioxane, tetrahydrofuran, acetonitrile, etc.).

Sodium alcoholades such as sodium methylate, sodium ethylate, potassium methylate, and potassium ethylate on ice to room temperature.

The compound represented by the general formula can be obtained by reacting with potassium alcoholade or the like and then reacting with compound (2).

Method 3 - Compound of general formula (ml) in the presence of a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, ether, dioxane, tetrahydrofuran, acetonitrile, acetone, methyl ethyl ketone, methanol, ethanol, isopropanol, butanol.

Potassium carbonate, sodium carbonate, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine,
The second compound can be obtained by adding dimethylaminopyridine, pyridine, etc., and then reacting the compound represented by the general formula - at room temperature to reflux.

Reaction step B Method 1 Add compound (V), (VII, or Add sodium hydride, potassium hydride, calcium hydride, sodium amide, etc.

By carrying out the reaction under ice-cooling to reflux.

The target substance +I+ can be obtained.

Method 2 Methanol is a compound represented by the general formula (to).

Ethanol, Improper Tools, Butanol.

Dimethylformamide, dimethylacetamide.

Ether, dioxane, dimethyl sulfoxide.

In the presence of a solvent such as tetrahydrofuran or acetonitrile, a compound represented by the general formula M, ('Q or ■) was added and then sodium methylate was added.

Sodium ethylate, potassium ethylate.

The target substance (I) can be obtained by adding sodium alcoholade such as potassium ethylate, potassium alcoholade, etc. and carrying out the reaction under ice-cooling to reflux.

Method 3 Solvents such as chloroform, dichloromethane, dichloroethane, acetone, methyl ethyl ketone, methanol, ethanol, isopropanol, butanol, dimethylformamide, dimethylacetamide, ether, dioxane, tetrahydrofuran, dimethyl sulfoxide are added to the compound represented by the general formula In the presence of the general formula M,
[Add the compound represented by VII or 1, and then add potassium carbonate, sodium carbonate, and potassium carbonate.

Addition of sodium hydroxide, triethylamine, diisopropylethylamine, dimethylaminopyridine, pyridine, etc., and reaction at room temperature to reflux can yield the target substance +I+.

Reaction Step C Method 1 Add dimethylformamide, dimethylacetamide, and dimethyl sulfoxide to the compound No. 2011.

Dioxane, ether, tetrahydrofuran.

In the presence of a solvent such as acetonitrile, under ice cooling to room temperature,
After the action of sodium hydride, potassium hydride, calcium hydride, sodium amide, etc., a compound represented by the general formula (■), ([Xl or can be obtained.

Method 2 methanol, ethanol to the compound of formula (Ill).

Isopropanol, butanol, dimethylformamide, dimethylacetamide, ether.

After reacting with sodium alcoholade, potassium alcoholade, etc. such as sodium methylate, sodium ethylate, potassium methylate, and potassium ethylate in the presence of a solvent such as dioxane, tetrahydrofuran, or acetonitrile at ice-cooling to room temperature, general To the formula 1. A compound represented by (1) or (2) is added and the reaction is carried out at room temperature to reflux to obtain the desired substance ().

Method 3 Dimethylformamide, dimethylacetamide, dimethylsulfoxide to the compound of formula (II).

Ether, dioxane, tetrahydrofuran.

In the presence of solvents such as acetonitrile, acetone, methyl ethyl ketone, methanol, ethanol, isopropanol, butanol, potassium carbonate, sodium carbonate, aqueous potash, aqueous soda.

Bases such as triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine and the general formula (■
), QXI or ■ is added and the reaction is carried out at room temperature to reflux to obtain the target substance ().

Next, two compounds provided by the present invention are listed.9
The listed compounds are not intended to limit the scope of the invention, but are merely listed to facilitate understanding of the invention. Note that the compounds are described in free form. In addition, the compound of the present invention (9) has one or more asymmetric carbon atoms depending on the type of substituent, so there is a possibility that various stereoisomers and optical isomers exist, but in the present invention, these It includes both.

02.2-dimethyl-6-fluoro-1'-(3-(4
-hydroxybiveridino)propyl] spiro[chroman-4,4'-imidazolidine) -2',5'-dione 06-chloro-2-methyl-1'-(3-(4-7enylbiveridino)propyl] Spiro [Chroman-4,4'
-imidazolidine) -2', 5'-dione o6-chloro2-methyl-1'-[3-(4-hydroxy-4
-Phenylpiperidino)propyl]spiro[chroman-
4,4'-imidazolidine) -2'.

5'-dione 06-fluoro-2-methyl-1'-(3-(4-phenylhyhericino)furovir]spiro[chroman-4,4
'-imidazolidine) -2', 5'-dione 06-
Fluoro-1'-(3-(4-7enylpiveridino)'
Propyllaspiro [chroman-4,4'-imidazolidine) -2', 5'-dione o6-chloro2,2
-dimethyl-1'-(4-(4-phenylpiperidino)
butyl]spiro[chroman-4,4'-imidazolidine)-2',5'-dione o2,2-dipropyl-6
-Fluoro-1-(3-(4-hydroxypiperidino)
propyl]spiro[chroman-4,4'-imidazolidine)-2',5'-dione06-chloro-2,2-dimethyl-1'-[3-(4-
7enylbiperidino)propyl]spiro[chroman-4
,4'-imidazolidine] -2', 5'-dione o
6-chloro2,2-dimethyl-1'-C3-(4-hydroxy-4-phenylpiperidino)propyl]spiro[chroman-4,4'-imidazolidine]-2,5'-
Dione o2,6-cymethyl-1'-(3-(4-phenylpiperidino)propyl]spiro[chroman-4,4-imidazolidine]-2', 5'-dione o6-medoxy2-methyl-1' -(3-(4-2 unyl biveridino)
Pucovircospiro [chroman-4,4-imidazolidine:) -2', 5'-dione 02.2-dimethyl-6
-Medoxy1'-(3-(4-7enyl biveridino)
propyl]spiro[chroman-4,4'-imidazolidine)-2', 5'-dione 02.2-dibutyl-1
'-(3-(4-phenylpiperidino)propyl]spiro[chroman-4,4'-imidazolidine)-2',
5'-dione o2,2-diptyl-1'-C3-(4
-Hydroxy-4-phenylpiperidino)propyl]spiro[chroman-4,4'-imidazolidine) -2'
, 5-dione 06.8-dichloro-2,2-dimethyl-1'-C3-
(4-hydroxypiperidino)propyl]spiro[chroman-4,4'-imidazolidine) -2', 5'
-dione o6,8-dichloro-1'-C3-(4-hydroxypiperidino)propyl]spiro[chroman-4,4'-imidazolidine] -2,5'-dione06,8-dichloro-1' -(4-(4-hydroxypiperidino)butyl]spiro[chroman-4,4-imidazolidine] -2
', 5'-dione 06.8-dichloro-1'-(3-
(4-Phenylpiperidino)propyl]spiro[chroman-4,4'-imidazolidine)-2',5'-dione08-chloro-2,2-dimethyl-1'-[3-(
4-phenylpiperidino)propyl]spiro[chroman-4,4'-imidazolidine)-2', 5'-dione02.2-diethyl-6-fluoro-1'-[3-(
4-hydroxypiperidino)propyl]spiro[chroman-4,4'-imidazolidine)-2',5'-dione02.2-diethyl-6-fluoro-1'-(4-(4
-Hydroxypiperidino)butyl]spiro[chroman-
4,4'-imidazolidine) -2,5'-dione o6
-Fluoro-1'-[3-(4-hydroxypiperidino)propyl]spiro[chroman-4,4'-imidazolidine]-2', 5-dione o6-fluoro-1'-C
4-(4-hydroxypiperidino)butyl]spiro[chroman-4,4'-imidazolidine) -2', 5'
-dione o-5-fluoro-1'-C5-(4-hydroxypiperidino)pentyl]spiro[chroman-4,4
'-imidazolidine) -2', 5'-dione o6-
Chloro-1'-(3-(4-phenylpiperidino)propyl]spiro[chroman-4,4'-imidazolidine]
-2', 5'-dione 06-Medoxie 1'-[3-(4-hydroxypiperidino)propyl]spiro[chroman-4,4'-imidazolidine) -2', 5'-dione 02.2 -dimethyl-6-medoxy1'-(3-(4-hydroxypiperidino)propyl]spiro[chroman-4,4'-imidazolidine] -2', 5'-dione Q2,2-dimethyl-6- Methyl-1'-[3-(4-
hydroxypiperidino)propyl]spiro[chroman-
4,4'-imidazolidine] -2', 5'-dione 02.2-dimethyl-6-methyl-1'-[3-(4-
phenylpiperidino)furovir]spiro[chroman-4
,4'-imidazolidine] -2', 5'-dione o
2,2-dimethyl-6-methyl-1'-[3-(2-methoxypiperidino)propyl]spiro[chroman-4,
4'-imidazolidine) -2', 5'-dione o2
,2-dimethyl-6-medoxy1'-[3-(4-acetoxypiperidino)propyl]spiro[chroman-4
,4'-imidazolidine) -2',5'-dione02.2-dimethyl-6-fluoro-1'-(3-(4
-Floboxybiveridino)propyl]spiro[chroman-4,4'-imidazolidine) -2', 5'-dione 02.2-dipropyl-6-fluoro-1'-(3-(
4-1=)'roxypiperidino)propyl]spiro[chroman-4,4'-imidazolidine)-2',5'-dione02.2-dipesotyl-6-fluoro1'-C4-(
4-hydroxypiperidino)butyl]spiro[chroman-4,4'-imidazolidine)-2',5'-dione o2,2-dimethyl-6-fluoro-1'-C3-(4
-methoxypiperidino)propyl]spiro[chroman-
4,4'-imidazolidine) -2', 5'-dione Q6-fluoro-1'-(3-(4-methoxypiperidino)propylcisspiro[chroman-4,4'-imidazolidine) -2 ', 5'-dione 06-chloro-2
,2-dimethyl-1'-(3-(4-hydroxypiperidino)propylcisspiro[chroman-4,4'-imidazolidine)-2', 5'-dione o6-chloro2
,2-dimethyl-1'-(3-(4-ethoxypiperidino)propylcisspiro[chroman-4,4'-imidazolidine)-2', 5'-dione 06-chloro-2,
2-dimethyl-1'-(4-(4-hydroxypiperidino)butyl)spiro[chroman-4,4'-imidazolidine)-2', 5'-dione o6-bromo2.2
-dimethyl-1'-(3-(4-hydroxypiperidino)propylcisspiro[chroman-4,4'-imidazolidine) -2', 5'-dione 06-bromo-1'-
(3-(4-hydroxypiperidino)propylcisspiro[chroman-4,4'-4 midazolidine)-2',
5'-dione 06-bromo-2,2-dimethyl-1'
-(2-(4-hydroxypiperidino)ethylcisspiro[chroman-4,4'-imidazolidine) -2',
5'-dione 06-bromo-2,2-diethyl-1'-
(4-(4-hydroxypiperidino)butyl]spiro[
chroman-4,4'-imidazolidine)-2',5'-
Dione 02.2-dimethyl-7-medoxy8-methyl-1'-[3-(4-hydroxypiperidino)propylcisspiro[chroman-4,4'-imidazolidine]-2
', 5'-Dione 07-Medicine 8-Methyl-1'-(3-(4-hydroxy-4-phenylpiperidino)lpropyl]spiro[chroman-4,4'-imidazolidine]-2' ,
5'-dione o6-chloro-1'-C3-(4-hydroxypiperidino)furobylcisspiro[chroman-4,4'-imidazolidine) -2', 5'-dione 02.2-dihexyl-6-fluoro -1'-C3-(4-acetoxypiperidino)propylcisspiro[chroman-4,4'-imidazolidine] -2',5'-dione o2,2-dimethyl-6-fluoro-1'-( 3-(4
-Hydroxy-4-7enylbiperidino)propylcisspiro[chroman-4,4'-imidazolidine:l-2
', 5'-dione o2,2-dimethyl-6-fluoro-1'-[3-(4
-acetoxy-4-phenylpiperidino)propyl]
Spiro [chroman-4,4'-imidazolidine) −
2', 5'-dione o8-chloro-1'-[3-(4-hydroxypiperidino)propylcisspiro[chroman-4,4'-4 midazolidine) -2', 5'-dione o8-chloro -1'
-(3-(4-7atoteciviveridino)furobylcisspiro[chroman-4,4'-imidazolidine) -2'
, 5'-dione o2,2-dimethyl-6-fluoro-
1'-(3-C4-(2-chlorobenzyloxy)piperidinocopropyl)spiro[chroman-4,4'-imidazolidine)-2', 5'-dione 02.2-dimethyl-6-fluoro- 1'-(3-(4
'-(4-chlorobenzyloxy)piperidinocopropyl)spiro[chroman-4,4'-imidazolidine]
-2', 5'-dione 02.2-dimethyl-6-fluoro-1'-[2-(4
-hydroxypiperidino)ethylcisspiro[chroman-
4,4'-imidazolidine) -2',5'-dione o2,2-dimethyl-6-fluoro-1'-C2-(4
-acetoxypiperidino)ethylcisspiro[chroman-
4,4'-imidazolidine) -2', 5'-dione o6-chloro-1'-C4-(4-acetoxypiperidino)butyl]spiro[chroman-4,4'-imidazolidine) -2' , 5'-dione 06-chloro-2,2-diethyl-1'-C3-[4-
hydroxypiperidino)propylcisspiro[chroman-
4,4'-imidazolidine)-2',5'-dione 06
-chloro-2,2-diethyl-1'-C3-(4-phenylpiperidino)propylcisspiro[chroman-4,4
'-imidazolidine) -2', 5'-dione o6-
Chloro-2,2-diethyl-1'-(2-(4-hydroxypiperidino)ethylcisspiro[chroman-4,4'
-imidazolidine) -2', 5'-dione 02.2
-dimethyl-6-fluoro-1'-C4-(4-hydroxypiperidino)butyl]spiro[chroman-4,4'
-imidazolidine) -2', 5'-dione 02.2
-dimethyl-6-fluoro-1'-(4-(4-acetoxypiperidino)butyl]spiro[chroman-4,4'
-imidazolidine] -2', 5' -dione Q2,2-dimethyl-6-fluoro-1'-C4-(4
-7enylpiperidino)butyl]spiro[chroman-4
,4'-imidazolidine) -2',5'-dione02.2-dimethyl-6-fluoro-1'-[3-(4
-oxopiperidino)propylcisspiro[chroman-4
,4'-imidazolidine) -2',5'-dione o2,2-dibutyl-6-fluoro-1'-(3-(4
-oxopiperidino)propylcisspiro[chroman-4
,4'-imidazolidine) -2',5'-dione02.2-dimethyl-6-fluoro-1'-[3-(4
-acetoxypiperidino)propylcisspiro[chroman-4,4'-imidazolidineio2',5'-dione01'-[3-(4-hydroxypiperidino)propylcisspiro[chroman-4,4 '-Imidazolidine]-2
', 5'-dione 01'-[3-(4-hydroxy-4-phenylpiperidino)furovir]spiro[chroman-4,4'-imidazolidine) -2', 5'-dione o2,2- Dimethyl-6-fluoro-1'-(3-biperisinobrovir)
Spiro [chroman-4,4'-imidazolidine)-2
', 5'-dione 0 cyclohexane spiro-2>-
6-chloro-1'-(3-(4-hydroxypiperidino)propylcisspiro[chroman-4,4'-imidazolidine]-2', 5'-dione Ocyclopentane spiro-2>-6 -Fluoro-1'
-(3-(4-hydroxypiperidino)propylcisspiro[chroman-4,4'-imidazolidine) -2',
5'-dione 02.2-dimethyl-6-fluoro-1'-[3-(4
-phenylpiperidino)propylcisspiro[chroman-
4,4'-imidazolidine, 1-2', 5'-dione 02.2-dimethyl-6-fluoro-1'-[3-(4
-ethylenedioxypiperidino)propylcisspiro[chroman-4,4'-imidazolidine]-2', 5'-
Dione 02.2-dimethyl-6-fluoro-1'-C3-(3
-hydroxypiperidino)propylcisspiro[chroman-4,4'-imidazolidine)-2',5'-dione02.2-dimethyl-6-fluoro-1'-(6-(4
-hydroxypiperidino)hexyl]spiro[chroman-4,4'-imidazolidine)-2',5'-dione06-chloro-2,2-dimethyl-1'-[4-(4-
acetoxypiperidino)butyl]spiro[chroman-4
, 4'-imidazolidine) -2', 5'-dione 0
6-chloro-2,2-dimethyl-1'-[5-(4-hydroxypiperidino)pentylcisspiro[chroman-4
,4'-imidazolidine]-2',5'-dione o6
-chloro2,2-dimethyl-1'-(6-(4-hydroxypiperidino)hexyl)spiro[chroman-4,
4'-imidazolidine) -2', 5'-dione o6
-chloro2,2-dimethyl-1'-C7-(4-hydroxypiperidino)pentylcisspiro[chroman-4,
4'-imidazolidine)-2',5'-dione o6-chloro-2,2-dibutyl-1'-C3-C'
4-Hydroxypiperidino)propylcisspiro[chroman-4,4'-imidazolidine)-2',5'-dione0cyclohexanespiro-2)-6-medoxy1'-C3-(4-hydroxypiperidino)peridino)propylcisspiro[chroman-4,4'-imidazolidine)-2
',5'-dioneo6-chloro-2-methyl-1'-(2-dimethylaminoethyl) spiro [chroman-4,4'-4 midazolidine) -2', 5'-dione o6-chloro-2-methyl -1'-(3-dimethylaminopropyl)spiro[chroman-4,4'-imidazolidine) -2', 5'-dione 06-fluoro-2-
Methyl-1'-(2-dimethylaminoethyl)spiro [
chroman-4,4'-imidazolidine) -2', 5
'-dione 06-chloro-2-methyl-1'-(2-diethylaminoethyl)spiro[chroman-4,4'-imidazolidine)-2', 5'-dione 02.2-dimethyl-6-chloro- (3-dimethylaminopropyl)spiro[chroman-4,4'-4 midazolidine) -2', 5'-dione 02-ethyl-6-chloro-(3-dimethylaminopropyl)spiro[chroman-4,4' imidazolidine l) -2', 5'-dione 0 cyclohexane spiro-2) -6-90 rho 1'-
(3-dimethylaminopropyl)spiro[chroman-4
, 4'-imidazolidine) -2', 5'-dione 02.2-dimethyl-6-bromo-1'-(3-dimethylaminopropyl)spiro[chroman-4,4'-imidazolidine)-2' , 5'-dione O cyclopentane spiro-2)-6-chloro-1'-(3-dimethylaminopropyl)spiro[chroman-4,4'-imidazolidine) -2', 5'-dione 02. 2-dimethyl-6-fluoro-8-nitro 1'
-(3-dimethylaminopropyl)spiro[chroman-
4,4'-imidazolidine] -2', 5'-dione o2,2-dimethyl-6-fluoro-1'-(3-dimethylaminopropyl)spiro[chroman-4°4'-imidazolidine) -2 ', 5'-dione 06-fluoro-2-methyl-1'-(3-dimethylaminopropyl)spiro[chroman-4,4'-imidazolidine:]
-2', 5'-dione 02.2-dimethyl-6-fluoro-1'-(2-diethylaminoethyl)spiro[chroman-4,4'-imidazolidine) -2', 5'
-dione Q2,2-dimethyl-6-fluoro-1'-(
2-diisopropylaminoethyl)spiro[chroman-
4,4'-imidazolidine) -2', 5'-dione o2,2-dimethyl-6-fluoro-1'-(3-diethylaminopropyl)spiro[chroman-4゜4'-imidazolidine] -2' , 5'-dione o2.2'-
Dimethyl-6-fluoro-1'-(3-n-flobylaminopropyl)spiro[chroman-4,4'-imidazolidine)-2', 5'-dione02.2-dimethyl-1'-(3 -dimethylaminopropyl) spiro[chroman-4,4'-imidazolidine) -2', 5'-
dione o6-chloro2,2-di-n-propyl-1'-(3
-dimethylaminopropyl)spiro[chroman-4,4
'-imidazolidine) -2', 5'-dione 02.
2-dimethyl-6-chloro-1'-(3-dimethylaminobutyl)spiro[chroman-4,4'-imidazolidine]-2', 5'-dione 02.2-dimethyl-6
-chloro-1'-(3-dimethylaminopentyl)spiro[chroman-4,4'-imidazolidine)-2',
5'-dione 02.2-dimethyl-6-chloro-1-
(3-dimethylaminohexyl)spiro[chroman-4
, 4'-imidazolidine) --2', 5'-dione 02, 2'-dumenal-6-chloro-1'-(3-dimethylaminohebbutyl)spiro[chroman-4,4'-imidazolidine] -2', 5'-dione 06-chloro-2-methyl-1'-(3-dimethylaminohexyl)spiro[chroman-4,4'-imidazolidine] -
2', 5'-dione 02.2-dimethyl-6-fluoro-1'-(3-dimethylaminohexyl)spiro[chroman-4゜4'-imidazolidine) -2', 5'
-dione 02.2-dimethyl-6-fluoro-1'-(
3-dimethylaminobutyl) spiro[chroman-4,4
'-imidazolidine] -2', 5'-dione 02.
2-dimethyl-6-fluoro-1'-(3-morpholinopropyl)spiro[chroman-4,4'-imidazolidine)-2', 5'-dione 02.2-dimethyl-6
-Fluoro-1'-(3-(3-hydroxyamino)propyl]spiro[chroman-4,4'-imidazolidine)-2',5'-dione o2,2-dimethyl-6-fluoro-1'- (3-[bis(2-hydroxyethyl)amine]propyl)spiro[chroman-4,4'-imidazolidine]-2', 5
'-dione 06-chloro-1'-(3-dimethylaminopropyl)
Spiro[chroman-4,4'-imidazolidine]-2'
, 5'-dione 08-chloro-1'-(3-dimethylaminopropyl)
Spiro[chroman-4,4'-imidazolidine]-2'
, 5'-dione o2,2-dimethyl-6-fluoro-1'-(3-dimethylaminoethyl)spiro[chroman-4,4'-imidazolidine) -2', 5'-dione 0l-(3- dimethylaminopropyl) spiro[chroman-4,4'-
imidazolidine) -2', 5'-dione o2,2-dimethyl-6-fluoro I: = -1'-(3-
[2-(3,4-dimethoxyphenyl)ethylmethylaminocoflovir)spiro[chroman-4,4'-imidazolidine)-2', r-dione o2,2-dimethyl-6-fluoro-1'- (3-(4-(2-methoxyphenyl)piperazinocoflovir)spiro[chroman-4
,4'-imidazolidine) -2', 5'-dione02.2-dimethyl-6-bromo-1'-(3-dimethylaminohexyl)spiro[chroman-4,4'-imidazolidine) -2' , 5'-dione o2,2-dimethyl-6-bromo-1'-(3-dimethylaminobutyl)spiro[chroman-4,4'-imidazolidine) -
2', 5'-dione o2,2-dimethyl-6-methyl-1'-(3-dimethylaminopropyl)spiro[chroman-4,4'-imidazolidine) -2', 5'-
Dione o2,2-dimethyl-6-medoxy1'-(3
-dimethylaminopropyl)spiro[chroman-4゜4
'-imidazolidine) -2', 5'-dione 02.
2-dimethyl-6-di)C7-1'-(3-dimethylaminopropyl)spiro[chroman-4,4'-imidazolidine)-2', 5'-dione o2,2-di-n-
Butyl-6-chloro-1'-(3-dimethylaminopropyl)spiro [chroman-4,4'-imidazolidine]
-2'',5'-dione o2,2-di-n-hexyl-6-chloro-1'-(3-dimethylaminopropyl)
Spiro [chroman-4,4°-imidazolidine) -2
',5'-dione o6-chloro-2-n-hexyl-1'-(3-dimethylaminopropyl)spiroC chroman-4,4°-imidazolidine]-2"15'-dione o2,2-dimethyl -6-nitro-1'-[3-(4-hydroxypiperidino)propylcisspiro[chroman-4,4°-imidazolidine] = 2'', 5-dione o2,2-dimethyl-6,8- Dinitro-1”-[3-
(4-Hydroxypiperidino)propylcisspiro[chroman-4,4"-imidazolidine]-2", 5"-
dione o2,2-dimethyl-6-fluoromethyl-1'-(3
-(4-hydroxypiperidino)propylcisspiro[chroman-4,4'~imidazolidine) -2',5"
-dione o 2.2-dimethyl-6-chloro-1'-(3-(4
-octanoyloxypiperidino)propylcisspiro [
Chroman-4,4'-imidapridine]-2°, 5'
-dione o2.2-dimethyl-β,β,β-trifluoroethoxy-1°-(3-(4-hydroxypiperidino)propylcisspiro[chroman-4,4′-imidazolidine]-
2",5'-dione o2,2-dimethyl-6-chloro-1'-(3-benzylaminopropyl)spiro[chroman-4,4'-imidazolidine) -2,5'-dione o2,2- dimethyl-6-chloro-1”(3-(4
-methylpiperidino)propylcisspiro[chroman-4
, 4"-imidazolidine) -2', 5"-dione The compound (I) of the present invention and its salts are new compounds that have not been described in any literature, and have excellent antiarrhythmic activity and low toxicity, so they can be used in various types. It is useful as an antiarrhythmic agent to treat arrhythmia.

The compound of the present invention has the chemical structural formula shown in (1), and is structurally unique and significantly different from conventional antiarrhythmic agents.

The compound of the present invention is characterized by having no cardiac depressant effect, and is therefore extremely preferable as an antiarrhythmic agent.

Furthermore, the antiarrhythmic activity of the compounds of the present invention is sustained;
It also has low toxicity (with a wide safety margin), making it extremely preferable as an antiarrhythmic agent.

Below, the results of pharmacological tests are shown to specifically demonstrate the usefulness of the compounds of the present invention.

Experimental Example +11 Chloroform arrhythmia (mice) Experimental ventricular arrhythmia was induced in mice by the following method.

Mice are placed in a container filled with chloroform gas, and after they stop breathing, they are recorded using an electrocardiogram to count the ventricular beats. Activity was evaluated. The lethal dose, toxic dose, and minimum effective dose were determined for each test compound. The test compound was tested using two administration routes, oral administration and intravenous injection, to estimate the relative oral efficacy, and to evaluate the drug efficacy when the time interval between administration of the test compound and treatment of mice with chloroform was varied. The durability of the effect was estimated from the change in .

Table 1 below shows the experimental results regarding the antiarrhythmic effective dose and lethal dose when the test compound was orally administered one hour before chloroform treatment. Incidentally, quinidine, disopyramide, and phenytoin were selected as standard comparative drugs. This chloroform method is described in J. Lawson (J. W. Lawson).
, Pharmacol.

exp, Ther, 160.22 (1968)
has been disclosed.

As is clear from Table 1, the compounds of the present invention had stronger antiarrhythmic activity than the comparative drugs, and also exhibited a wider safety margin (ratio of lethal dose to effective dose).

The effects of these test compounds lasted for 3 or 6 hours after oral administration.

(2) Aconitine-induced arrhythmia (mice) We focused on premature ventricular contractions that occur when a toxic dose of aconitine is administered to mice. When 0.1 mg/kg of aconitine was injected intraperitoneally, ventricular tachycardia occurred within 20 minutes, but the test compound was orally administered at a dose determined in the same manner as in (1), and after an arbitrary period of time. Afterward, aconitine was injected, and the presence or absence of arrhythmia and the number of premature ventricular contractions were read from the electrocardiogram, and antiarrhythmic activity was measured. Aconitine 0.1
Table 2 shows the results of an experiment in which the test compound and comparative standard drugs (quinidine and disobiramide) were orally administered 1 hour before the intraperitoneal injection of mg/kg. This method is published by Shunji Igarashi I [IPHAR.

9th International Congress
s of Phammacology
ts 454p).

The effective doses shown in Table 2 are doses that reduce aconitine-induced ventricular tachycardia to an approximately 1:1 ratio of normal sinus rhythm to ventricular beats, but many of the series of test compounds It was effective at lower doses than

In addition, aconitine-induced ventricular arrhythmia was normalized to complete sinus rhythm at a dose higher than the effective dose shown in the table, and the effect was sustained even 6 hours after oral administration.

(3) Acute toxicity (rat) 6-chloro-2,2-dimethyl-1'-(3-(4-hydroxypiperidino)propyl)spiro[chroman-4,4'- imidazolidine)
-2', 5'-dione (compound 1) and 2,2-dimethyl-6-fluoro-? '-C3-(4-hydroxypiperidino)propyl] spirochroman-4,4'-
imidazolidine) -2', E knee dione (compound 2
), an acute toxicity test was conducted using rats (oral administration). The results are shown in Table 31ζ.

Table 3 The above-mentioned experimental examples show that the compound of the present invention has excellent sustained antiarrhythmic activity, low toxicity, and a wide safety margin.
It was confirmed that it is extremely preferable as an antiarrhythmic agent.

Regarding the mechanism of antiarrhythmic action of the compounds of the present invention.

The effects on the resting potential and action potential of isolated myocardium from guinea pigs and pigs were tested using the microelectrode method. As a result, the compound of the present invention (9) did not affect the resting potential at all, but attenuated the rising speed of the action potential. The action potential suppression effect was particularly strong under conditions of high electrical stimulation. This property is common to class 2 arrhythmic agents (such as quinidine and disoviramide)9 and the mechanism of action and indications (supraventricular and ventricular arrhythmias) of the compounds of the present invention are common to other class 2 arrhythmic agents. This suggests that

One of the pharmacological characteristics of the compounds of the present invention is that they have little inhibition on myocardial contractility, making them extremely preferable as antiarrhythmic agents. In other words, quinidine and disoviramide attenuate myocardial contractility at a dose several times higher than the dose at which the antiarrhythmia effect occurs,9 but in the case of the compounds of the present invention, even a dose 10 times the effective dose for the antiarrhythmia effect reduces the myocardial contractility. It had no effect.

When the compound of the present invention is used as an antiarrhythmic agent.

For example, it is effective in the treatment and prevention of various types of arrhythmia, such as ventricular arrhythmia and atrial (supraventricular) arrhythmia.

When the compound of the present invention is used as an antiarrhythmic agent, oral administration or parenteral administration (intramuscular, subcutaneous, intravenous, etc.)
administered by. The dosage varies depending on the disease, severity of symptoms, age, etc.

Although not particularly limited, 9 Usually about 1 to 1.0 per day for adults
00B, preferably about 100 to 300 cm, administered 1 to 3 times a day.

In order to formulate the compound of the present invention, 1ζ is formed into a dosage form such as a tablet, granule, powder, capsule, injection, or active drug by a conventional method in the technical field of formulation.

That is, when preparing a solid preparation for oral use, the main drug 1ζ excipient, and if necessary, a binder and a disintegrant.

Lubricants 1. After adding coloring agents, flavoring agents, etc., it is rolled in a conventional manner to form tablets, coated tablets, granules, powders, capsules, etc.

Examples of excipients include lactose and cornstarch.

White sugar, butosugar, sorbitol, crystalline cellulose, etc.
Examples of binders include polyvinyl alcohol, vinyl ether, and ethyl cellulose.

Methylcellulose, gum arabic, tragacanth.

Gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc., and disintegrants include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, etc. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil.2 Colorants that are permitted to be added to pharmaceuticals are used as flavor correctives and odor agents.

Cocoa powder, peppermint, aromatic acid, peppermint oil, cybernetic acid.

Cinnamon powder etc. are used. Of course, one of these tablets or granules may be coated with sugar coating, gelatin coating, or other coating as appropriate.

When preparing injections, adjust the pH of the active ingredient 1 to 5 if necessary.
A preparation, a buffer, a stabilizer, a solubilizer, a preservative, etc. are added, and a subcutaneous, intramuscular, or intravenous injection is prepared by a conventional method.

Next, typical examples of the present invention are listed below.

It goes without saying that the present invention is not limited to these only.

Example 1 Monodione 2.2-dimethyl-6-fluoro-spiro[chroman-
4,4'-imidazolidine)-2',5'-dio76.
6g (25mM) and 1,3-dibromopropane IC)
, sodium hydroxide (609
6 mineral oil suspension) 1.0 g (25 mM) was added.

Stir at room temperature for 5 hours. After pouring the reaction solution into ice water.

Extract with ethyl acetate, and wash the ethyl acetate layer with water.

Dry with magnesium sulfate. The solvent was distilled off under reduced pressure, and 12.7 g of the residue was purified by silica gel f-ram chromatography (developing solvent: dichloromethane:ethanol) to obtain the title compound 6.959 (yield: 72.296).

O melting point: 190-192℃ 0 elemental analysis value: HN as C+6H+sBr'F'NtO3 Theoretical value (3) 49.87 4.71 7.27
Analysis value (96) 49.63 4.59 7.15
0 Nb-1R (CDC13) δ: 1-32 (3H,
s), 1.50 (3H, s).

2.02 (IH, d, J = 16 outputs), 2.2
4 (2H, q, J=8 output), 2.60 (IH
, (1, J = 1 pin), 3-40 (2H.

t, J=B out), 3.74 (2H, t, J=8-)
, 6.36 (IH, s), 6.45-7.10
(3H, m) 6.0 g of professional human body obtained in Example (1) (
15,6rnl■, 4-hydroxypiperidino 3.15
9 (312mM), 4.31 g of carbonate carbonate (312mM),
312mM) and a small amount of potassium iodide in dimethylformamide (70 nL) were reacted at 80°C for 5 hours.

Add the reaction solution to water and extract with ethyl acetate. The ethyl acetate layer was washed with water and then dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-ethyl acetate.

Title compound 5.85. (92,6%) is obtained. Furthermore, it was made into a hydrochloride by a conventional method.

0 melting point: 211-213°C (7-unit) 195-1
97' (:: (Hydrochloride) 0 elemental analysis value: C,, H,, FN, O, HN as theoretical value <56) 62.20 6.96 10.36
Analysis value (9ri) 61.92 7.01 10.
25o NMR (CD0D) δ: 1.32 (3:EI
, s), 1.52 (3H, s).

160~3.00 (14H, m), 3.62 (2
H, t, J=t), 3.45~3.80 (IH
, m), 6.50 to 7-10 (3H, m) Example 2 8-chloro-spiro [chroman-4,4'-4 midazonadine) -2', 5'-dione L 52 g (6 mM)
1 30wLL solution of dimethylformamide, temperature 56
Sodium hydroxide (suspended in 60% mineral oil) at C 240
=g (6mM) and stirred for 10 minutes. Next.

3-dimethylaminopropyl chloride 802■ (6,
6mM) dimethylformamide 3d solution at room temperature for 10
After dropping for minutes, react at 80-90°C for 5 hours. Pour the reaction solution into ice water and extract with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue 2.659 was purified by silica gel column chromatography (developing solvent: dichloromethane-ethanol).

Title compound 1.60. (yield 79-0%).

Furthermore, it was made into a hydrochloride by a conventional method.

0 melting point: 15B -159″c (FreF! Closed) 20
2-204'C (HCl salt) 0 elemental analysis: C,,H,,OIN,0. CIHN Theoretical value (%) 56.89 5.97 12-4
4 analysis value (96) 56,84 5.93 12
．． 39o NMR (CDCl5) δ: 1-60 to 1.
96 (2H, m), 2.14 (6H, s), 2
．． 00~2.44 (4H, m), 3.58 (2H
.

t, J==82h), 4.18~4-44 (
IH, m), 4.6 to 4.9B (IH, m), 6
．． 16 (IH, s), 6.60-7.02 (2H,
tn), 7.16-7.36 (IH, m) Example 3
~82 (1) According to the method (1) of Example 1, intermediates shown in Tables 4 and 5 below were obtained.

(2) Next, the target compounds shown in Tables 6 and 71 below were obtained according to the method described in (2) of Example 1 or Example 21.

Next, specific examples of formulations for carrying out the present invention will be described in Formulation Examples 1 and 2. Furthermore, what are crude drugs?

2.2-dimethyl-6-fluoro-1'-(4-(4-
hydroxypiperidino)butyl]spiro[chroman-4
, 4'-imidazolidine) -2', 5'-dione
means hydrochloride.

Formulation example 1 tablet crude drug 10.0 parts milk
Sugar 53.5 Microcrystalline cellulose 18.0 Cornstarch
18.0 Calcium stearate 0,
5. Mix the above ingredients according to a conventional method.

It is made into granules and compressed into tablets of 100 iag each.

Formulation example 2 Capsule crude drug 10.0 parts milk
@7C), 0 corn starch added, 0 Capsules each having a weight of 100 mp are prepared according to the above-mentioned formulation in a conventional manner.

Aoi Ganto's agent Kaoru Furuya

Claims (9)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ {In the formula, X^1 and X^2 are the same or different hydrogen atoms,
It forms an alkylenedioxy group with a halogen atom, lower alkyl group, lower alkoxy group, trifluoromethyl group, trifluoroethoxy group, nitro group, or an adjacent carbon atom. R^1 and R^2 mean the same or different hydrogen atoms or lower alkyl groups, or R^1 and R^2 together with the carbon atoms to which they are bonded represent C_5_-_6 cyclo Z means an alkyl group, and Z is a formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^3 and R^4 are the same or different hydrogen atoms, lower alkyl group, hydroxyalkyl group,
or a substituted or unsubstituted aralkyl group, or R^3 and R^4 together with their bonded nitrogen atoms form a C_5_-_6 saturated heterocyclic group, and this heterocycle (The formula group may further contain an oxygen atom or a nitrogen atom) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^5 and R^6 are the same or different hydrogen atoms, Phenyl group, formula -
OR^7 (in the formula, R^7 is a hydrogen atom, an acyl group, a lower alkyl group, a substituted or unsubstituted aralkyl group), or together with the carbon atom to which R^5 and R^6 are bonded represents a 4 or 5 cyclic group containing two oxygen atoms, or R^5 and R^6 together form the formula =
0 means a group represented by] or hydantoin derivative represented by the formula ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼, where n means an integer from 2 to 7} and pharmaceutically acceptable acid addition salts thereof. (2) The hydantoin derivative according to claim 1, wherein Z is a group represented by the formula ▲A mathematical formula, a chemical formula, a table, etc.▼ (wherein R^3 and R^4 have the above-mentioned meanings) and pharmaceutically acceptable acid addition salts thereof. (3) Z is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^
The hydantoin derivative and pharmaceutically acceptable acid addition salt according to claim 1, wherein 5 and R^6 have the above-mentioned meanings. (4) The hydantoin derivative and pharmaceutically acceptable acid addition salt according to claim 1, wherein Z is a group represented by the formula ▲ which includes a mathematical formula, a chemical formula, a table, etc. ▼. (5) The compound is 2,2-dimethyl-6-fluoro-1'
-[3-(4-hydroxypiperidino)propyl]spiro[chroman-4,4'-imidazolidine]-2',5
'-dione, 6-chloro-2-methyl-1'-[3-(4-phenylpiperidino)propyl]spiro[chroman-4,4'-
imidazolidine]-2',5'-dione, 6-chloro-
2-Methyl-1'-[3-(4-hydroxy-4-phenylpiperidino)propyl]spiro[chroman-4,4
'-Imidazolidine]-2',5'-dione, 6-fluoro-2-methyl-1'-[3-(4-phenylpiperidino)propyl]spiro[chroman-4,4'
-imidazolidine]-2',5'-dione, 6-fluoro-1'-[3-(4-phenylpiperidino)propyl]spiro[chroman-4,4'-imidazolidine]-2',5 '-dione, 6,8-cyclo-2,
2-dimethyl-1'-[3-(4-hydroxypiperidino)propyl]spiro[chroman-4,4'-imidazolidine]-2',5'-dione, 2,2-diethyl-6-fluoro -1'-[3-(4-
hydroxypiperidino)propyl]spiro[chroman-
4,4'-imidazolidine]-2',5'-dione, 6
-chloro-2,2-dimethyl-1'-[3-(4-hydroxypiperidino]propyl]spiro[chroman-4,
4'-Imidazolidine]-2',5'-dione, 6-chloro-2,2-dimethyl-1'-[4-(4-hydroxypiperidino)butyl]spiro[chroman-4,4'-
imidazolidine]-2',5'-dione, 2,2-dimethyl-6-fluoro-1'-[3-(4-hydroxy-
4-phenylpiperidino)propyl]spiro[chroman-4,4'-imidazolidine]-2',5'-dione, 6-chloro-1'-[4-(4-acetoxypiperidino)butyl] Spiro[chroman-4,4'-imidazolidine]-2',5'-dione, 2,2-dimethyl-6-fluoro-1'-[4-(4-hydroxypiperidino)butyl]spiro[chroman] -4,4'-imidazolidine]
-2',5'-dione, 2,2-dimethyl-6-fluoro-1'-[3-(4-
oxypiperidino)propyl]spiro[chroman-4,
4'-imidazolidine]-2',5'-dione, 2,2-dimethyl-6-fluoro-1'-[3-(4-
acetoxypiperidino)propyl]spiro[chroman-
4,4'-imidazolidine]-2',5'-dione, 2,2-dimethyl-6-fluoro-1'-[3-(4-
phenylpiperidino)propyl]spiro[chroman-4
,4'-imidazolidine]-2',5'-dione, 2,2-dimethyl-6-fluoro-1'-[3-(4-
ethylenedioxypiperidino)-propyl]spiro[chroman-4,4'-imidazolidine]-2',5'-dione, 6-chloro-2-methyl-1'-(3-dimethylaminopropyl)spiro [Chroman-4,4'-imidazolidine]-2',5'-dione, 6-fluoro-2-methyl-1'-(2-dimethylaminoethyl)spiro[chroman-4,4'-imidazolidine] -2',5'-dione, 6-chloro-2-methyl-1'-(2-diethylaminoethyl)spiro[chroman-4,4'-imidazolidine]-2',5'-dione, 2,2 -dimethyl-6-chloro-(3-dimethylaminopropyl)spiro[chroman-4,4'-imidazolidine]-2',5'-dione, cyclohexane<spiro-
2>-6-chloro-1'-(3-dimethylaminopropyl)spiro[chroman-4,4'-imidazolidine]-
2',5'-dione, 2,2-dimethyl-6-fluoro-1'-(3-dimethylaminopropyl)spiro[chroman-4,4'-imidazolidine]-2',5'-dione, 2 ,2-diethyl-6-chloro-1'-(3-dimethylaminopropyl)
Spiro[chroman-4,4'-imidazolidine]-2'
, 5'-dione, 6-fluoro-2-methyl-1'-(
3-dimethylaminopropyl) spiro[chroman-4,
4'-imidazolidine]-2',5'-dione, 2,2
-dimethyl-6-fluoro-1'-(2-diethylaminoethyl)spiro[chroman-4,4'-imidazolidine]-2',5'-dione, 2,2-dimethyl-6-fluoro-1'- (3-n-propylaminopropyl)spiro[chroman-4,4'-imidazolidine]-2',
5'-dione, 2,2-dimethyl-6-fluoro-1'-[3-(3-
hydroxyamino)propyl]spiro[chroman-4,
4-Imidazolidine]-2',5'-dione, 2,2-dimethyl-6-fluoro-1'-{3-[bis(2-hydroxyethyl)amino]propyl}spiro[
Chroman-4,4'-imidazolidine]-2',5'-
dione, 6-chloro-1'-(3-dimethylaminopropyl)spiro[chroman-4,4'-imidazolidine]-2',
5'-dione, or 2,2-dimethyl-6-fluoro-1'-{3-
[2-(3,4-dimethoxyphenyl)ethylmethylamino]propyl}spiro[chroman-4,4'-imidalidine]-2',5'-dione or a pharmaceutically acceptable acid addition salt of these compounds. A compound according to claim 1. (6) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ {In the formula, X^1 and X^2 are the same or different hydrogen atoms,
It forms an alkylenedioxy group with a halogen atom, lower alkyl group, lower alkoxy group, trifluoromethyl group, trifluoroethoxy group, nitro group, or an adjacent carbon atom. R^1 and R^2 mean the same or different hydrogen atoms or lower alkyl groups, or R^1 and R^2 together with the carbon atoms to which they are bonded represent C_5_-_6 cyclo Forms an alkyl group. n means an integer from 2 to 7. In addition, Y means a halogen atom) Compounds represented by the general formula ▲ have mathematical formulas, chemical formulas, tables, etc. ▼ (wherein R^3 and R^4 are the same or different hydrogen atoms, lower alkyl groups, hydroxyalkyl group, or a substituted or unsubstituted aralkyl group, or R^3
and R^4 together with their bonded nitrogen atoms form a C_5_-_6 saturated heterocyclic group, which may further contain an oxygen or nitrogen atom) There are compounds represented by the general formula ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, R^5 and R^6 are the same or different hydrogen atoms,
A phenyl group, a group represented by the formula -OR^7 (in the formula, R^7 is a hydrogen atom, an acyl group, a lower alkyl group, a substituted or unsubstituted aralkyl group), or a group in which R^5 and R^6 are bonded together. or R^5 and R^6 together represent a 4 or 5 cyclic group containing two oxygen atoms, or R^5 and R^6 together form the formula =0
) or structural formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ General formulas characterized by reacting compounds represented by ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, X ^1, X^2, R^1, R^2, and n have the meanings given above. Z is a general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^3 in the formula
and R^4 have the above meanings), - General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (where R^5
and R^6 has the above-mentioned meaning), or a group represented by the formula ▲ where there are mathematical formulas, chemical formulas, tables, etc.] A method for producing a hydantoin derivative represented by the following. (7) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X^1 and X^2 are the same or different hydrogen atoms,
It forms an alkylenedioxy group with a halogen atom, lower alkyl group, lower alkoxy group, trifluoromethyl group, trifluoroethoxy group, nitro group, or an adjacent carbon atom. R^1 and R^2 mean the same or different hydrogen atoms or lower alkyl groups, or R^1 and R^2 together with the carbon atoms to which they are bonded represent C_5_-_6 cyclo forming an alkyl group),
By reacting a compound represented by There are chemical formulas, tables, etc. ▼ (wherein X^1, X^2, R^1, R^2, n and Y have the above meanings). There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^3 and R^4 mean the same or different hydrogen atoms, lower alkyl groups, hydroxyalkyl groups, or substituted or unsubstituted aralkyl groups, or R ^3 and R^4 together with their bonded nitrogen atoms form a C_5_-_6 saturated heterocyclic group, which may further contain an oxygen or nitrogen atom. There are compounds represented by the general formula ▲ mathematical formulas, chemical formulas, tables, etc. 7 is a hydrogen atom,
acyl group, lower alkyl group, substituted or unsubstituted aralkyl group), or R^5 and R^
Together with the carbon atom to which 6 is bonded, the oxygen atom becomes 2
represents a 4 or 5 cyclic group containing R
^5 and R^6 together mean a group represented by the formula = 0], or a compound represented by the structural formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Characterized by reacting. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, X^1, X^2, R^1, R^2 and n have the above meanings. X is a group represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, R^3 and R^4 have the meanings above), General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( In the formula R^5
A method for producing a hydantoin derivative represented by a group represented by the formula ▲ (which has a numerical formula, chemical formula, table, etc.)); (8) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X^1 and X^2 are the same or different hydrogen atoms,
It forms an alkylenedioxy group with a halogen atom, lower alkyl group, lower alkoxy group, trifluoromethyl group, trifluoroethoxy group, nitro group, or an adjacent carbon atom. R^1 and R^2 mean the same or different hydrogen atoms or lower alkyl groups, or R^1 and R^2 together with the carbon atoms to which they are bonded represent C_5_-_6 cyclo Forms an alkyl group. ) Compounds represented by the general formula ▲ have mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X means a halogen atom, and n means an integer from 2 to 7. It means different hydrogen atoms, lower alkyl groups, hydroxyalkyl groups, or substituted or unsubstituted aralkyl groups, or R^3 and R^
4 together with their bonded nitrogen atoms form C_
5_-_6 Forms a saturated heterocyclic group, and this heterocyclic group may further contain an oxygen atom or a nitrogen atom) Compounds represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. 〔 In the formula, X means a halogen atom, n means an integer of 2 to 7,
R^5 and R^6 are the same or different hydrogen atoms, phenyl groups, or the formula -OR^7 (wherein R^7 is a hydrogen atom, an acyl group, a lower alkyl group, or a substituted or unsubstituted aralkyl group); or R^5 and R^6 together with the carbon atom to which they are bonded represent a 4 or 5 cyclic group containing two oxygen atoms, or R^5 and R^6 are Together, it means a group represented by the formula = 0] or a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by reacting with compounds represented by have meaning. Z is a general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R in the formula
^5 and R^4 have the above meanings), general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in the formula R^5
A method for producing a hydantoin derivative represented by a group represented by the formula ▲ (which has a numerical formula, chemical formula, table, etc.)); (9) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ {In the formula, X^1 and X^2 are the same or different hydrogen atoms,
It forms an alkylenedioxy group with a halogen atom, lower alkyl group, lower alkoxy group, trifluoromethyl group, trifluoroethoxy group, nitro group, or an adjacent carbon atom. R^1 and R^2 mean the same or different hydrogen atoms or lower alkyl groups, or R^1 and R^2 together with the carbon atoms to which they are bonded represent C_5_-_6 cyclo Z means an alkyl group, and Z is a formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^3 and R^4 are the same or different hydrogen atoms, lower alkyl group, hydroxyalkyl group,
or a substituted or unsubstituted aralkyl group, or R^3 and R^4 together with their bonded nitrogen atoms form a C_5_-_6 saturated heterocyclic group, and this heterocycle (The formula group may further contain an oxygen atom or a nitrogen atom) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^5 and R^6 are the same or different hydrogen atoms, Phenyl group, formula -
OR^7 (in the formula, R^7 is a hydrogen atom, an acyl group, a lower alkyl group, a substituted or unsubstituted aralkyl group), or together with the carbon atom to which R^5 and R^6 are bonded represents a 4 or 5 cyclic group containing two oxygen atoms, or R^5 and R^6 together form the formula =
0 means a group represented by] or hydantoin derivative represented by the formula ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼, where n means an integer from 2 to 7} or an antiarrhythmic agent containing a pharmaceutically acceptable acid addition salt thereof as an active ingredient.