JPH0637479B2 - Novel pyrimidine derivative, production method thereof and antiarrhythmic agent containing the same - Google Patents

Description

TECHNICAL FIELD OF THE INVENTION The present invention provides a compound of the general formula (I): (In the formula, R is a hydrogen atom or a lower alkyl group, R is a hydrogen atom or a lower alkyl group, A is an NH or a sulfur atom, B is an NH or a sulfur atom, R is a phenyl group, a naphthyl group, an indolyl group. , A tetrahydronaphthyl group, 2 or more lower alkyl-substituted phenyl groups, a phenyl lower alkanoyl-substituted phenyl group, 2 or more lower alkoxy-substituted phenyl groups, a cyano-substituted indolyl group or halogen and 2 or more lower alkyl-substituted phenyl groups .N
Is an integer of 2 or 3. However, both A and B are NH, and R is a phenyl group, 2 or more lower alkyl-substituted phenyl groups, phenyl lower alkanoyl-substituted phenyl groups, 2 or more lower alkoxy-substituted phenyl groups, or halogen and 2 or more The present invention relates to a pyrimidine derivative represented by a lower alkyl-substituted phenyl group) or an acid addition salt thereof, a process for producing the same, and an antiarrhythmic agent containing the same.

2. Description of the Related Art Arrhythmia has a complicated mechanism of generation and is said to be composed of abnormality in stimulus generation and disorder of conduction system, or a combination thereof.
The reentry theory is typical for excitatory conduction disorders.
As a condition of occurrence, there is non-uniformity of the refractory period in each part of the heart,
One-way block, shortening of refractory period, conduction delay, existence of turning path, etc.

Antiarrhythmic drugs are classified into 4 groups according to their mechanism of action. That is, EMVaughan Williams classified the antiarrhythmic drugs into the following four groups by their action on the action potential of the myocardium or the ionic current that causes it.

Class I; Sodium Channel Inhibitors Antiarrhythmic drugs that suppress sodium currents, which usually have little or no effect on action potential duration and decrease the maximum rate of rise of sodium current (Vmax). Antiarrhythmic drugs belonging to this class have a strong antiarrhythmic action, but on the other hand, they also strongly suppress cardiac function, and caution should be exercised when administered to patients with heart failure and hypotension.

Class II; β-blockers β-blockers represented by propranolol are useful for arrhythmias involving the sympathetic nerve. As a side effect, cardiac function is suppressed by β-blocking action, bronchial asthma attack is induced, and hypoglycemic attack is induced.

Class III: Drugs that prolong action potential duration Prolongs action potential duration of myocardium and prolongs effective refractory time. Therefore, reentry arrhythmia is considered to be suppressed. Amiodarone and bretylium are known as typical drugs, but both have serious side effects and should be used with caution.

Class IV; Calcium antagonists Suppresses calcium channels and suppresses arrhythmias due to autonomic hyperactivity of sinus node and ventricular tachycardia including AV node in reentry circuit.

Although there is a continuing search for an ideal antiarrhythmic drug for arrhythmia therapy that has a complex mechanism of development and requires long-term administration of an antiarrhythmic drug, no such compound is known yet.

Problem to be Solved by the Invention An object of the present invention is to provide a therapeutic agent for arrhythmia having a drug effect far superior to that of currently known antiarrhythmic drugs.

Means for Solving the Problems The inventors of the present invention have been earnestly studying to solve the above problems.
As a result of discovering the compounds of general formula (I) and their acid adducts and investigating the pharmacological properties of these compounds, the action potential duration of cardiomyocytes was markedly prolonged, and further, animal experiments using adult dogs. In the above, the inventors have found a pharmacological property that prolongs the ventricular refractory period, and completed the present invention.

That is, the compound of the present invention is a compound represented by the above general formula (I), and specific examples thereof include the compounds of Examples 1 to 6.

In the compound of the general formula (I), the lower alkyl group is C ₁
~ C ₅ straight or branched alkyl group, for example, methyl, ethyl, propyl, butyl, isopropyl, isobutyl,
It means tertiary butyl, secondary butyl and the like. Halogen is a fluorine atom, iodine atom, bromine atom, or chlorine atom, and lower alkoxy is a C _{1 to} C ₅ linear or branched alkyl group. More specifically, it means methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy and the like.

The compound of general formula (I) has at least one asymmetric carbon and optical isomers.

The 1-body is dominant in the β-adrenergic receptor inhibitory action. The class III antiarrhythmic activity of the present invention shows almost the same activity for the l-form, d-form and racemic form. It is preferable that the class III antiarrhythmic agent does not have a β-adrenergic receptor inhibitory action that acts to suppress cardiac function.

The method for producing the compound of the general formula (I) of the present invention is as follows.

That is, first, one method is represented by the general formula (II) R-OCH ₂ -X (II) (wherein R is a phenyl group, a naphthyl group, an indolyl group,
A tetrahydronaphthyl group, two or more lower alkyl-substituted phenyl groups, a phenyl lower alkanoyl-substituted phenyl group, two or more lower alkoxy-substituted phenyl groups, a cyano-substituted indolyl group or a halogen and two or more lower alkyl-substituted phenyl groups are shown.

X is Indicates. Hal represents halogen. ) And a compound represented by the general formula (III) (Wherein A, B, R ₁ and n are the same as described above), the compound represented by the formula is used in the absence of solvent or in a suitable solvent such as alcohols such as methanol and ethanol, dioxane and dimethylformamide at −10 ° C. To the boiling point of the reaction mixture, the compound of the general formula (I) can be obtained by reacting for 1 to 20 hours.

The compound of the general formula (II) used in this method can be obtained by a known method. For example, it can be obtained by reacting a compound having a phenolic hydroxyl group with epichlorohydrin, epibromhydrin or a suitably protected reactive derivative of glycerin in the presence of a suitable base.

The compound of general formula (III) can also be obtained by applying a known method. For example, when both A and B mean NH, the compound of the general formula (V) and an excess amount of H ₂ N- (C
It can be obtained by heating H ₂ ) _n —NH ₂ in a suitable solvent, for example, a solvent such as chloroform, benzene, toluene or dioxane.

Further, the compound of general formula (I) can also be obtained by the following method. Nanachi, general formula (IV), (Wherein R, A and B are the same as above) and the compound represented by the general formula (V) (Wherein R ₁ represents hydrogen or a lower alkyl group, Hal represents halogen) in a solvent-free or suitable non-reactive solvent such as alcohols, tetrahydrofuran, dioxane, dimethylformamide, etc. Then, the compound of the general formula (I) can be obtained by reacting at room temperature to the boiling point of the reaction mixture for 1 to 10 hours.
In this case, a suitable basic substance such as triethylamine or pyridine may be allowed to coexist as a deoxidizing agent.

The compound of the general formula (IV) used in this method can also be obtained by applying a known method. For example, when A and B both represent NH, the compound of general formula (II) and an excess amount of NH ₂ — (CH ₂ ) _n —NH ₂ are added in a suitable solvent, for example, chloroform, benzene, toluene, dioxane. It is obtained by heat treatment in a solvent such as.

When either A or B in the general formula (III) is a sulfur atom, it can be obtained by almost the same method. In this case, by utilizing the fact that the thiol group is more reactive than the amino group, it is determined whether the sulfur atom is introduced into A or B in the general formula (I) depending on the general formula (II ) And a compound of general formula (III), or a compound of general formula (IV)
Can be achieved by reacting with a compound of the general formula (V).

The compound of the present invention obtained by the above method has optical isomers, and the separation of optical isomers can be achieved by a general optical method. For example, a method in which an optically active acid such as tartaric acid or camphorsulfonic acid, a compound of the general formula (I) and a diastereomeric salt are produced and fractionally recrystallized to obtain one optically active substance. A method using an optically active intermediate in the production process of the general formula (1). Furthermore, use of column chromatography for separation of optical isomers. A desired optically active substance can be produced by using these methods.

Further, when the compound of general formula (I) is converted into a pharmaceutically acceptable salt thereof, the compound of general formula (I) is treated with an inorganic acid or an organic acid such as hydrochloric acid in water or an organic solvent or a mixed solvent thereof. , Hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, etc. can be reacted for conversion.

The antiarrhythmic agent of the present invention comprising the compound of the general formula (I) of the present invention or an acid addition salt thereof as an active ingredient is orally administered, for example, as tablets, granules, powders, suspensions or capsules, and It can be prepared parenterally, for example, as a suppository, injection or isotonic solution for infusion.

For example, as a non-aqueous injection, the compound of the present invention is 50 to 100 m
g to be dissolved in about 10 ml of an oil selected from cottonseed oil, corn oil, peanut oil, olive oil, etc., and as an aqueous injection, the above-mentioned non-aqueous injection is further water-soluble.
About 20 ml can be added to prepare an emulsion in the presence of a surfactant (eg HCO-60 etc.).

As an example of a tablet, crystalline cellulose (150 to 120 mg) and light anhydrous silicic acid (3 to 30 mg) are added as excipients to about 50 mg of the compound of the present invention, and corn starch (94 mg) as an excipient. ˜97 mg) and finally magnesium stearate (3 mg) to prepare 300 mg.

When the compound of the present invention is used as an antiarrhythmic agent, the dose, the dosage form vary depending on the physical properties of the compound and the symptoms of the subject to be administered, but a dose of 1 to 1000 mg per day for an adult is effective.

Action and effect The compound of the general formula (I) of the present invention showed pharmacological properties as a class III antiarrhythmic agent in a pharmacological test. For example, the compound of Example 5 prolongs myocardial action potential duration by 10% at 3 μg / ml. In a study on ventricular muscle refractory period in adult dogs, intravenous administration 0.1 mg / kg, 0.3 mg
/ kg, 1.0mg / kg, 3.0mg / kg, refractory period 4.3,
It was extended by 6.7, 11.3 and 15.3%.

Examples Hereinafter, the present invention will be described in detail with reference to Examples.

Example 1 4- {3- [2- (1,3-dimethyl-2,4-dioxo1,2,3,4-tetrahydropyrimidin-6-yl) aminoethylamino] -2-hydroxypropoxy} -1H -Indole carbonitrile
Method for producing hydrochloride 4- (2,3-epoxypropoxy) -1H-indole-2-carbonitrile 1.1 g and N- (1,3-dimethyl-2,4-dioxo-1,2,3,4
-Tetrahydropyrimidin-6-yl) ethylenediamine 70
0 mg was dissolved in 70 ml of methanol, the solvent was distilled off under reduced pressure, and the residue was heated at 70 ° C. for 2 hours. This was recrystallized from ethanol to obtain 870 mg of the free form of the title compound. This was treated with hydrogen chloride gas-methanol solution to obtain the title compound. As mp two hundred and thirty-six to two hundred thirty-seven ° C. Elemental analysis _{C 20 H 24 N 6 O 4} · Hcl · H 2 O Example 2 3- [2- (1,3-Dimethyl-2,4-dioxo1,2,3,4-tetrahydropyrimidin-6-yl) aminoethylthio] -1-phenoxy-2-propanol hydrochloride A solution of 3.9 g of phenylglycidyl ether in 10 ml of methanol was added to a solution of 2.0 g of aminoethanethiol in 30 ml of methanol under ice cooling, and the mixture was stirred at the same temperature for 5 minutes and then at room temperature for 4 hours. The solvent was distilled off under reduced pressure to obtain 6.1 g of 1- (2-aminoethylthio) -3-phenoxy-2-propanol as a pale yellow oily substance. 1- (2-aminoethylthio) -3-phenoxy-2-propanol 3.0 g, 6-chloro-1,3-dimethyluracil 1.5 g, triethylamine 3 ml, ethanol 3 m
The mixture of 1 was heated and stirred at 70 ° C. for 3 hours. The solvent was distilled off, and the residue was purified by silica gel column (chloroform / methanol = 30: 1 to 15: 1) to give the free form of the title compound 2.
57 g are obtained. The title compound was obtained as a hydrochloride with hydrogen chloride gas-methanol.

As mp from 138.5 to 141 ° C. Elemental analysis _{C 17 H 23 N 3 D 4} S · HCl Example 3 1- [2- (1,3-Dimethyl-2,4-dioxo1,2,3,4-tetrahydropyrimidin-6-yl) mercaptoethylamino] -3-phenoxy-2-propanol hydrochloride Preparation of 2-aminoethanethiol 6 g in a solution of 1.4 g in 20 ml of methanol
-Chloro-1,3-dimethyluracil 3.15 g methanol 15 ml
-A 5 ml solution of benzene was added at room temperature. After stirring at the same temperature for 5 hours, the solvent was distilled off to obtain 6- (2-aminoethylmercapto) -1,3-dimethyluracil hydrochloride (4.55 g). mp 119
~ 202 ℃.

To the solution of 6- (2-aminoethylmercapto) -1,3-dimethyluracil hydrochloride 2.52 g obtained above in methanol 15 ml-5 ml of water was added 0.4 g of sodium hydroxide, and then 1.2 g of phenylglycidyl ether was added. The mixture was heated and stirred at 4 ° C for 4 hours. The solvent was distilled off under reduced pressure, and the residue was chloroform (150 ml).
Was dissolved in water, washed with water, and dried. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform / methanol = 100: 1 to 100: 10) to give 0.81 g of the free form of the title compound.
(Oil) was obtained. The title compound was obtained as the hydrochloride salt using HCl-methanol.

mp 175-177 ℃ Elemental analysis C ₁₇ H ₂₃ N ₃ O ₄ S ・ HCl Examples 4 to 12 The compounds shown in Table 1 were synthesized in the same manner as in Example 1.

Example 13 4- [3- {2- (1,3-dimethyl-2,4-dioxo1,2,3,4-tetrahydropyrimidin-6-yl) aminoethylamino} -2-hydroxypropoxy] -1H -Indole carbonitrile
Method for producing tablets containing hydrochloride as an active ingredient 1 g of the title compound, 123 g of lactose and 20 g of corn starch were mixed well, and this was mixed and granulated with a solution in which 5 g of hydroxypropyl cellulose was dissolved in 100 ml of water, and the mixture was granulated at 50 ° C.
To dry for 4 hours. Magnesium stearate 1
150g per tablet using a tablet machine
Tablets are obtained with the weight of.

Example 14 4- [3- {2- (1,3-dimethyl-2,4-dioki 1,2,3,4-tetrahydrosopyrimidin-6-yl) aminoethylamino} -2-hydroxypropoxy]- 1H-indolecarbonitrile
Method for producing capsule containing hydrochloride as active ingredient 5 g of title compound, 120 g of lactose and 25 g of corn starch
Mix well. A hard capsule is filled with 150 mg of this using a capsule filling machine to obtain a capsule.

Example 15 4- [3- {2- (1,3-dimethyl-2,4-dioxo1,2,3,4-tetrahydropyrimidin-6-yl) aminoethylamino} -2-hydroxypropoxy] -1H -Indole carbonitrile
Method for producing injection containing hydrochloride as active ingredient Take 20 mg of the title compound and 0.85 g of sodium chloride,
This is dissolved in an appropriate amount of distilled water for injection to a total volume of 100 ml to prepare an injection.

Example 16 Using the compound obtained in Example 5, the effects on the myocardial action potential maintenance time and the effects on the ventricular muscle refractory period were tested as therapeutic agents. The test methods are as follows.

Effects on myocardial action potential duration Adult dogs were anesthetized with 30 mg / kg intravenous pentobarbital, and the right ventricle free wall was excised in Tyrode's solution from which the heart was removed. The cut out right ventricle free wall was fixed in a constant temperature bath at 37 ° C. and subjected to 1 Hz field stimulation. As for the action potential, a glass microelectrode (10 to 20 MΩ) was inserted into the Purkinje fiber, and it was drawn on the oscilloscope tube via an amplifier.
Waveform analysis was performed using a computer. The duration of myocardial action potential from the time of action potential generation to the time of 75% repolarization was defined as (APD75). The compound of the present invention was added to a nutrient solution (20 ml) for perfusion of a sample, and the change in the duration of myocardial action potential after incubation for 20 minutes was 100% compared with the value before drug administration.
It was expressed as a percentage and defined as the effect of the drug.

Effect on ventricular muscle refractory period After anesthetizing adult dogs with pentobarbital (30 mg / kg) intravenously, sew a silver-silver chloride electrode with a gap of 3 mm to the right ventricle of the right thorax, 400 msec stimulation interval, 4 msec duration Electrical stimulation is performed with a current twice as long as the threshold value. After that, a small amount of alcohol is intravenously injected from the sinus artery to eliminate the pacemaker activity, and the ventricular muscle refractory period (ERP) is measured under ventricular pacing. That is, 10 trains are set as one train, and the train-to-train interval is usually set to 400 msec. However, when measuring the refractory period, the train interval is shortened by 10 msec. The interval was the refractory period. A cardiac stimulator (DHM-226-3, manufactured by Diametical Co., Ltd.) was used for these electrical stimuli, and program stimulation was performed. The refractory period before drug administration was defined as 100%, and the prolongation effect of the drug on the refractory period was expressed in percentage. The drug was administered intravenously or intraduodenally. As a result, the compound of Example 5 prolonged the myocardial action potential duration by 10% at 3 μg / ml. In a study on ventricular muscle refractory period in adult dogs, intravenous administration 0.1 mg / kg, 0.3 mg / kg, 1.0 mg / kg, 3.0 mg / kg
, The refractory period was extended by 4.3, 6.7, 11.3 and 15.3%, respectively.

Continued Front Page (72) Inventor Masaaki Ishii 2142 Togo, Mobara-shi, Chiba Examiner Shinichi Naito

Claims (4)

[Claims] 1. A general formula (I) (In the formula, R ¹ is a hydrogen atom or a lower alkyl group, A is an NH or a sulfur atom, B is an NH or a sulfur atom, and R is a phenyl group, a naphthyl group, an indolyl group, a tetrahydronaphthyl group, or 2 groups. The above lower alkyl-substituted phenyl groups, phenyl lower alkanoyl-substituted phenyl groups, 2
One or more lower alkoxy-substituted phenyl groups, a cyano-substituted indolyl group or halogen and two or more lower-alkyl substituted phenyl groups. n is an integer of 2 or 3. However, both A and B are NH, and R is a phenyl group, 2 or more lower alkyl-substituted phenyl groups, phenyl lower alkanoyl-substituted phenyl groups, 2 or more lower alkoxy-substituted phenyl groups, or halogen and 2 or more Except when it is a lower alkyl-substituted phenyl group. ) The pyrimidine derivative represented by these or its acid addition salt. 2. General formula (II) R—OCH ₂ —X (II) (wherein R is a phenyl group, a naphthyl group, an indolyl group,
A tetrahydronaphthyl group, two or more lower alkyl-substituted phenyl groups, a phenyl lower alkanoyl-substituted phenyl group, two or more lower alkoxy-substituted phenyl groups, a cyano-substituted indolyl group or a halogen and two or more lower alkyl-substituted phenyl groups are represented by X, Is Indicates. Hal represents halogen. ) And a compound represented by the general formula (III) (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, A represents an NH or a sulfur atom, B represents an NH or a sulfur atom, and n is an integer of 2 or 3). General formula (I) characterized by reacting (In the formula, R ¹ is a hydrogen atom or a lower alkyl group, A is an NH or a sulfur atom, B is an NH or a sulfur atom, and R is a phenyl group, a naphthyl group, an indolyl group, a tetrahydronaphthyl group, or 2 groups. The above lower alkyl-substituted phenyl groups, phenyl lower alkanoyl-substituted phenyl groups, 2
One or more lower alkoxy-substituted phenyl groups, a cyano-substituted indolyl group or halogen and two or more lower-alkyl substituted phenyl groups. n is an integer of 2 or 3. However, both A and B are NH, and R is a phenyl group, 2 or more lower alkyl-substituted phenyl groups, phenyl lower alkanoyl-substituted phenyl groups, 2 or more lower alkoxy-substituted phenyl groups, or halogen and 2 or more Except when it is a lower alkyl-substituted phenyl group. ) A method for producing a pyrimidine derivative represented by
In the general formula (II), R is a phenyl group, two or more lower alkyl-substituted phenyl groups, a phenyl lower alkanoyl-substituted phenyl group, two or more lower alkoxy-substituted phenyl groups, or a halogen and two or more lower alkyl-substituted phenyl groups. And in the general formula (III), A and B are both NH). 3. General formula (IV) (In the formula, A is NH or sulfur atom, B is NH or sulfur atom, R is phenyl group, naphthyl group, indolyl group, tetrahydronaphthyl group, 2 or more lower alkyl-substituted phenyl group, phenyl lower alkanoyl-substituted phenyl A group, two or more lower alkoxy-substituted phenyl groups, a cyano-substituted indolyl group or halogen and two or more lower-alkyl substituted phenyl groups, n is an integer of 2 or 3, provided that A and B are both NH. , And R
Is a phenyl group, two or more lower alkyl-substituted phenyl groups, a phenyl lower alkanoyl-substituted phenyl group, two or more lower alkoxy-substituted phenyl groups, or a halogen and two or more lower alkyl-substituted phenyl groups. ) And a compound represented by the general formula (V) (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group;
1 represents halogen. ) A compound represented by the general formula (I) (In the formula, R ¹ is a hydrogen atom or a lower alkyl group, A is an NH or a sulfur atom, B is an NH or a sulfur atom, and R is a phenyl group, a naphthyl group, an indolyl group, a tetrahydronaphthyl group, or 2 groups. The above lower alkyl-substituted phenyl groups, phenyl lower alkanoyl-substituted phenyl groups, 2
One or more lower alkoxy-substituted phenyl groups, a cyano-substituted indolyl group or halogen and two or more lower-alkyl substituted phenyl groups. n is an integer of 2 or 3. However, both A and B are NH, and R is a phenyl group, 2 or more lower alkyl-substituted phenyl groups, phenyl lower alkanoyl-substituted phenyl groups, 2 or more lower alkoxy-substituted phenyl groups, or halogen and 2 or more Except when it is a lower alkyl-substituted phenyl group. The manufacturing method of the pyrimidine derivative represented by these. 4. The general formula (I) (In the formula, R ¹ is a hydrogen atom or a lower alkyl group, A is an NH or a sulfur atom, B is an NH or a sulfur atom, R is
Is a phenyl group, naphthyl group, indolyl group, tetrahydronaphthyl group, 2 or more lower alkyl-substituted phenyl groups, phenyl lower alkanoyl-substituted phenyl group, 2 or more lower alkoxy-substituted phenyl groups, cyano-substituted indolyl group or halogen and 2 groups The above lower alkyl-substituted phenyl groups are shown. n is an integer of 2 or 3. However, both A and B are NH, and R is a phenyl group, 2 or more lower alkyl-substituted phenyl groups, phenyl lower alkanoyl-substituted phenyl groups, 2 or more lower alkoxy-substituted phenyl groups, or halogen and 2 or more Except when it is a lower alkyl-substituted phenyl group. ) An antiarrhythmic agent comprising a pyrimidine derivative represented by the formula (4) or an acid addition salt thereof as an active ingredient.