JP2507764B2 - Lower alkylsulfamoylamines, salts thereof and uses thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial application] The present invention relates to amines represented by the general formula (1) or pharmaceutically acceptable salts thereof, and uses thereof. More specifically, the amines represented by the general formula (1) or a pharmaceutically acceptable acid addition salt thereof, for example, a pharmaceutically acceptable acid addition salt thereof, and a heart disease of an animal containing the amine as an active ingredient, particularly arrhythmia, myocardial infarction , A drug useful for the treatment and prevention of angina, heart failure and the like.

[Problems to be Solved by Conventional Techniques and Inventions] The irregular disorder of the contraction motion of the heart is called arrhythmia. The arrhythmias to be treated include those having a markedly decreased cardiac output and causing systemic ischemia, those having a risk of worsening to more serious arrhythmias, and those having strong subjective symptoms. The main treatment for arrhythmia is drug therapy, and many antiarrhythmic agents have been clinically applied so far.

Conventionally, the following proposals have been made regarding antiarrhythmic agents.

U.S. Pat.No. 4,289,787 has the following formula Here, R ¹ is a hydrogen atom or C _{1 to} C ₂ alkyl, R ² is a hydrogen atom or C _{1 to} C ₃ alkyl, and R ³ is C _{1 to} C ₄ alkyl or phenyl C _{1 to} C ₄ alkyl. R ⁴ is C ₁ -C ₈ alkyl, R ⁵ is C ₆ -C ₁₀ alkyl, R ⁶ is hydrogen atom, hydroxy, halogen, nitro, C _1-
It is disclosed that C ₃ alkoxy or C ₁ -C ₃ alkyl, and X is a therapeutically acceptable anion, and that the compound is used as an antiarrhythmic agent.

JP-A-59-98040 discloses the following formula Where R ¹ is hydrogen or C ₁ -C ₂ alkyl, R ² is hydrogen or C ₁ -C ₃ alkyl, R ³ is C ₁ -C ₂ alkyl or phenyl C ₁ -C ₄ alkyl. , R ⁴ is C ₁ -C ₈ alkyl, R ⁵ is C ₆ -C ₁₀ alkyl, R ⁶ is a radioactive iodine atom, and X ⁻ is an anion, including radioactive iodine. It is disclosed that the quaternary ammonium salt and the ammonium salt are useful as an imaging agent, particularly as an imaging agent for heart diagnosis.

JP-A-60-38366 discloses the following formula Here, R is a C ₁ -C ₁₂ linear or branched alkyl, cycloalkyl (lower) alkyl, R ¹ , R ² , R ³ are H or C ₁ -C ₄ straight chain alkyl; R ⁴ , R ⁵ are H, halogen, OH, lower alkyl, lower alkoxy, CN, NO ₂ , carbamoyl, ... or R ⁴ and R ^{5 taken} together on adjacent carbon atoms of Ring A represent methylenedioxy; R ⁶ is H, halogen, OH, C ₁ -C ₆ straight chain alkyl ...
A represents phenyl, furanyl, pyridinyl, pyrrolyl, thiazolyl, oxazolyl, a benzo derivative or thiadiazolyl of the above; n is 0 to 2, p is 0 to 5, t is an integer of 1 to 5; Y represents methylene, hydroxymethylene, aryl methylene, a · · · · ·; Z ^- is a halide, tosylate, Surufueto, phosphates, represent methanesulfonate, in quaternary salts and the quaternary salt with an aromatic dicarboxylic acid represented And molecular compounds thereof and antiarrhythmic agents containing these compounds are disclosed.

JP-A-60-209559 discloses the following formula Where R is lower alkyl, ...; X and X ₁ are H or halogen; R ₁ represents H, lower alkyl, ...; R ₂ is H, lower alkyl ,. R ₃ and R _{4 each} represent H, lower alkyl, ... R ₅ and R ₆ represent H, lower alkyl, ... or a saturated heterocyclic ring having 4 to 6 ring members is represented together. Formed, the ring is substituted by one or more methyl groups or is optionally -O-
Or Optionally contains a bond, p is an integer 0, 1 or 2; R ₆ may be lower alkyl substituted by ... Phenyl, n is 0, 1, 2; Substituted sulfonamide benzamides represented by or pharmaceutically acceptable salts thereof, and the use of these compounds as antiarrhythmic agents are disclosed.

JP-A-60-239458 discloses the following formula Where n is an integer from 0 to 4; Z is N or R ₃ —N ⁺ X ⁻ (X ⁻ is a pharmaceutically acceptable anion, R ₃ is C _{1 to} C ₃ alkyl); R ₁ Is H, C ₁ -C ₄ alkyl, halogen, OH, C ₁ -C ₃ alkoxy, NR ₇ R ₈ (R ₇ , R ₈ are H or C ₁ -C ₃ alkyl), N
O ₂ , CF ₃ or C ₁ -C ₃ thioalkyl; R is C ₁ -C ₄ alkyl or C ₅ -C ₇ cycloalkyl; R ₂ is H or OH (where n is 0) R ₄ and R ₅ are C ₁ -C ₁₀ alkyl, C ₅ -C ₁₂ cycloalkyl or C ₄ -C ₁₂ together with N having one N atom.
R ₆ is H or methyl; and R ₉ is H or C ₁ -C ₄ alkyl, provided that 0 or 1 R ₉ is alkyl. Z is N and / or R ₁ is
A pharmaceutically acceptable acid addition salt thereof in the case of NR ₇ R ₈ is disclosed, as well as the use of these compounds as antiarrhythmic agents.

Antiarrhythmic agents are classified according to their effects on the transmembrane potential difference (membrane potential) by binding to various ion channels of myocardial cell membranes and changing their membrane permeability. Based on the electrophysiological characteristics of the antiarrhythmic agents, various antiarrhythmic agents are classified into Classes I, II, III and IV by Vaughan Williams and commonly used.

A series of changes in membrane potential from the resting state of a cardiomyocyte to stimulation, excitement, and return to the resting state is called the action potential, and the time from the occurrence of the action potential to the restoration of the resting state is active. Action potential duratio
n, hereinafter abbreviated as APD). The myocardium cannot be reexcited immediately after or during the action potential. This is called refractory. The effective refractory period is the period during which excitement cannot be induced by a large stimulus.
d, hereinafter abbreviated as ERP). There is a close relationship between this refractory period and the persistence of action potentials.

Antiarrhythmic drugs belonging to class I are sodium channel suppressors, and their mechanism of action on APD and ERP causes
It is subdivided into a, Ib, and Ic. Ia is a drug that prolongs APD and ERP, and includes quinidine, procainamide, and disopyramide. Ib is a drug that shortens APD and ERP, and includes lidocaine and mexiletine. Ic is a drug that does not change APD and ERP and includes flecainide.

Antiarrhythmic drugs belonging to class II are sympathetic tone suppressors, and many β-blockers fall under this category. class
The antiarrhythmic drugs belonging to III are drugs that prolong APD and ERP, such as amiodarone, bretylium, and sotalol, but they have not been marketed in Japan. Class IV antiarrhythmic agents are calcium channel suppressors, such as verapamil, diltiazem, and nicardipine.

Excitation of the heart is transmitted through the stimulus conduction system from the sinus node to the Purkinje fibers one after another, causing the atria and ventricles to contract.
This excitatory conduction system causes an abnormality and the excitatory conduction turns, which is called re-entry. Excited turn 1
If it ends in times, it will be extra systolic, if it continues, it will become tachycardia, and if reentry occurs here and there at the same time, it will also become coarse and fibrillation.

It has been suggested that agents that significantly prolong APD and ERP can suppress or prevent such ventricular premature contractions, tachycardia and ventricular fibrillation [Animal Reports in Medicinal Chemistry]. (Annual Reports in
Medicinal Chemistry, HJHess; Ed., Academic Pres
S., New York, NY), see review by J. Thomis et al in Volume 18, Chapter 11 (1983)]. Class III antiarrhythmic drugs are drugs that meet this requirement and are useful for the treatment and prevention of ineffective or serious ventricular arrhythmias, but class I, II and IV antiarrhythmic drugs, especially class I antiarrhythmic drugs. The research lags behind the research and development of agents.

As a conventionally known class III antiarrhythmic agent, clofilium (Japanese Patent Laid-Open No. 54-95520)
No. 62-14538, USP Appl.861789 (1977), Eur.Pat.App
l.2604 (1979), melperone, meobentine, pirmenol and the aforementioned amiodarone, bretylium, sotalol, and some of these drugs have a strong class I action. Also, only the latter three are actually clinically applied. The reason for this is that many of these drugs are highly toxic and poorly transferred to tissues, suppression of cardiac function appears on the other side at an effective concentration, and adverse side effects such as unfavorable central effects are exhibited. See. In addition, the inability to be orally administered due to problems with the physical properties of these compounds hinders their clinical application. The above-mentioned clinically applied drugs also have the above-mentioned various problems more or less.

[Means for Solving Problems] In view of the problems, the present inventor has developed a new useful class.
III As a result of diligent search to develop an antiarrhythmic drug, a novel compound represented by the following general formula (1), which has not been described in the literature, has an extremely favorable biological activity, that is, APD and ERP are significantly prolonged in dogs, and The present invention has been completed by showing that it exhibits antiarrhythmic activity in various arrhythmia models, and clarified that it is a drug meeting the object of the present invention.

That is, according to the present invention, the following formula (1) Where R ¹ is a lower alkyl group and Z is And R ² is the following formula (1) −a: Here, R ³ , R ⁴ and R ⁵ are independently hydrogen atom or lower alkyl, and are represented by the following formula (1) -b. The following formula (1) -c Here, R ⁶ is a hydrogen atom or lower alkyl, represented by the following formula (1) -d Wherein R ⁷ and R ⁸ are each independently a hydrogen atom or lower alkyl, and are represented by the following formula (1) -e And the following formula (1) -f Here, R ⁹ , R ¹⁰ and R ¹¹ are each independently a hydrogen atom or lower alkyl, which is a group selected from the group consisting of the group represented by: a lower alkylsulfamoylamine represented by: There is provided a pharmaceutically acceptable salt thereof, and an antiarrhythmic agent containing the novel compound of the present invention as an active ingredient.

In the above formula (1), R ¹ is lower alkyl. Lower alkyl preferably has 1 to 4 carbon atoms. The lower alkyl may be linear or branched. Examples of lower alkyl include methyl, ethyl,
Examples thereof include n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl and the like.

In formula (1), Z is Is.

Further, in the formula (1), R ² is the above formula (1) -a, (1).
It is a group selected from the group consisting of groups represented by -b, (1) -c, (1) -d, (1) -e and (1) -f. Equation (1) R ³ in -a, R ^4, R ^5, formula (1) R ⁶ in -c, wherein (1) R ⁷ in -d, R ⁸ and Equation (1) -f in
R ⁹ , R ¹⁰ and R ¹¹ are each independently a hydrogen atom or lower alkyl. As the lower alkyl, the same ones as described above for R ¹ can be mentioned.

Examples of the lower alkylsulfamoylamines represented by the above formula (1) include, for example, Etc. can be mentioned.

The compound of the above formula (1) can be produced by a method known per se. That is, in the above formula (1), Z is Is a compound of the formula Here, the definition of R ¹ is the same as the above, and the 4-chloroacetylated product of the alkylsulfonic acid anilide represented by It can be produced by subjecting a corresponding heterocyclic compound selected from the group consisting of to a nucleophilic addition reaction.

The chloroacetylated product can be produced from the corresponding alkylsulfonic acid anilide and chloroacetyl chloride by the Friedel-Crafts reaction. The nucleophilic substitution reaction is carried out by heating 1 to 10 mol of the heterocyclic compound per mol of the chloroacetylated product in an aprotic inert organic solvent such as acetonitrile to a temperature of, for example, 50 to 100 ° C. At this time, sodium potassium carbonate or the like may be added as an inorganic base.

In the general formula (1), Z is Is a compound in which Z obtained as described above is Can be prepared by selective catalytic reduction by a method known per se or by reducing with a reducing reagent such as LiAlH ₄ .

As described above, the compound of the general formula (1) of the present invention is
It is a valuable compound as a class III type antiarrhythmic agent having prolongation effect of APD and ERP, and exhibits antiarrhythmic effect in various arrhythmia models. Further, some of the compounds of the general formula (1) also have an inhibitory effect on the maximum rise rate (max) of myocardial action potential possessed by class I type antiarrhythmic agents, while other compounds have an inhibitory effect on this max. It is a pure class III antiarrhythmic drug with no. Thus, the compound of general formula (1) has a valuable antiarrhythmic action,
Ischemic heart disease that causes or may cause arrhythmia,
Myocardial infarction, angina, cardiomyopathy, valvular disease, hypertensive heart disease,
It is used for the treatment and prevention of heart failure.

Further, some of the compounds of the present invention have antihypertensive action, β-blocking action, cardiotonic action, bradycardia action and are expected to be applied to hypertension, heart failure and the like.

The compound of the general formula (1) is usually used in the form of a pharmaceutical composition, and various oral, subcutaneous, intramuscular, intravenous, duodenal, intranasal, ocular, sublingual, cutaneous penetration and rectal routes can be used. The animals are dosed by the route

The present invention includes a pharmaceutical formulation containing a pharmaceutically acceptable carrier and a compound of general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. Pharmaceutically acceptable salts include, for example, acid addition salts.

Examples of the pharmaceutically acceptable salt of the general formula (1) include, for example, hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acidic phosphate, acetate, oxalate and malein. Acid salt,
Fumarate, succinate, lactate, tartrate, benzoate, citrate, gluconate, sugar salt, cyclohexylsulfamate, methanesulfonate, p-toluenesulfonate, naphthalene Included are salts or hydrates thereof formed from acids which form non-toxic acid addition salts with pharmaceutically acceptable anions such as sulfonates.

The composition of the present invention includes, for example, tablets, capsules, powders, granules, troches, sublingual tablets, cachets, elixirs, emulsions, solutions, syrups, suspensions, aerosols, ointments, eye drops, sterile syringes, and molding pads. , Tapes, soft and hard gelatin capsules, suppositories and sterile packaging powders and the like. Examples of pharmaceutically acceptable carriers are lactose, glucose, sucrose, sorbitol, mannitol, corn starch, crystalline cellulose, gum arabic, calcium phosphate, alginate, calcium silicate, calcium sulfate, microcrystalline cellulose, polyvinylpyrrolidone, tragacanth gum. , Gelatin, syrup, methylcellulose, carboxymethylcellulose, sodium benzoate, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, inert polymers, water or mineral oil, peanut oil acceptable for injection , And suppository bases such as glyceride.

Either solid or liquid compositions may contain fillers, binders, lubricants, lubricants, disintegrating agents, emulsifying and suspending agents, preservatives, sweetening agents or flavoring agents and the like as described above. The composition can also be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient.

For oral administration, the compound of general formula (1) is mixed with a carrier and a diluent and formed into tablets, capsules and the like. For parenteral administration, the active ingredient is dissolved in 10% dextrose in water, isotonic saline, sterile water or similar liquids and placed in vials or ampoules to be administered intravenously by infusion or injection or by intramuscular injection. It is sealed. Advantageously, solubilizers, local anesthetics, preservatives and buffers can also be included in the medium. To increase stability, the composition can be lyophilized after injection into vials and ampoules. Other examples of parenteral administration include ointments and preparations which are transdermally administered as patches. In this case, a molded pulp or a tape is advantageous.

The composition contains from 1 μg to 1 g, more usually from 10 μg to 500 mg of active ingredient per unit dosage form.

The compounds of general formula (1) are effective over a wide dosage range. For example, the daily dose is usually 0.1
It falls within the range of μg / kg to 100 mg / kg. The actual amount of the compound to be administered depends on the compound to be administered, the age of the individual patient, the body weight, the reaction, the degree of the patient's condition (for example, in the case of arrhythmia, the type and strength of the arrhythmia, etc.), the administration route, etc. It is decided by the doctor and veterinarian. Therefore, the above dosage range is not intended to limit the scope of the present invention. It is appropriate that the daily dosage is 1 to 6 times, usually 1 to 4 times.

The compound of the general formula (1) is an effective antiarrhythmic agent by itself, and is also a therapeutic agent or preventive agent for ischemic diseases, myocardial infarction, angina, heart failure, etc. It can also be administered in combination with other active drugs of the species. Such additional agents include, for example, dipyridamole,
Vasodilators such as isosorbide dinitrate, molsidomine, trapidil, nicorandil, nitroglycerin, pentaerythritol tetranitrate, ethafenone hydrochloride, oxyphedrine hydrochloride, trimetazidine hydrochloride, dilazep hydrochloride, carbochromene; diltiazem hydrochloride, verapamil hydrochloride, niphedipine, etc. Calcium antagonists; cardiotonics such as digitoxin, digoxin, lanatoside, amrinone, milrinone; trichlormethiazide, hydrochlorothiazide, furosemide, bumetanide, mefluside,
Diuretics such as triamterene clofenamide, spironolactone; hydralazine hydrochloride, laurolfia alkaloids, resinamine, reserpine, dihydroergotoxin mesylate, prazosin hydrochloride, clonidine hydrochloride, guanhuacin hydrochloride, indapamide hydrochloride, labetalol, captopril, guanabenz acetate, tripamide. Antihypertensive agents such as methicran, methyldopa, guanethidine sulphate, betanidine sulphate; β-blockers such as propranolol hydrochloride, pindolol, metoprolol tartrate and the like; sympathomimetics such as efuedrine hydrochloride and various antiarrhythmias as described above. Examples include agents.

Formulation examples and biological activities of the compound of the general formula (1) used in the present invention will be explained in detail below with reference to Examples and Experimental Examples, but the present invention is not limited thereto. The examples of the compositions given below use as active ingredient one of the compounds mentioned in the text or one of the other pharmaceutical compounds contained in the general formula (1).

Example 1 3- [2- [4- (Methanesulfonylamino) phenyl] -2-oxoethyl] -thiozolium chloride 2.48 g (10 mmol) of N- [4- (2-chloro-1-oxoethyl) phenyl] methanesulfonamide, 2.5 g (29 mmol) of thiazole and 60 ml of acetonitrile were mixed and refluxed for 11 hours. After cooling, the crystals were collected by filtration and dried under reduced pressure to give the title compound (3.98 g, yield 59%).

Melting point: 183-187 ° C., ¹ H-NMR (DMSO-d ₆ solution, δ ppm): 3.15 (3 H, s),
6.48 (2H, bs), 7.44 (2H, d, J = 8Hz), 8.02 (2
H, d, J = 8Hz), 8.42 (1H, m), 8.56 (1H, m),
10.34 (1H, m), 10.72 (1H, bs).

Examples 2 to 4 In place of thiazole in Example 1, the starting amine in Table 1 was used (Examples 2 and 3), or N- [4
N- [4- (2-chloro-1) instead of-(2-chloro-1-oxoethyl) phenyl] methanesulfonamide
-Hydroxyethyl) phenyl] methanesulfonamide was used (Example 4) to synthesize the compounds in Table 1 in the same manner.

Example 5 2- [2- [4- (Methanesulfonylamino) phenyl] -2-hydroxyethyl] amino-4- (N, N-diethylamino) -6-methylpyrimidine hydrochloride 1.32 g (2.9 mmol) of the compound of Example 2 was dissolved in 80 ml of water-methanol (1: 1), 0.13 g of 10% Pd-carbon was added, and the mixture was heated under a hydrogen atmosphere at a pressure of 4 kg / cm ² at 70 ° C. for 8 hours. I stirred it for a while. After cooling, solids were removed by filtration and the filtrate was concentrated. The obtained oily substance was purified by silica gel column chromatography (developed with MeOH / CHCl ₃ = 1/4) and recrystallized from chloroform to give 0.10 g of the title compound (yield 8%) as colorless crystals. Obtained.

Melting point: 225 to 227 ° C, ¹ H-NMR spectrum (CDCl ₃ -CD ₃ OD solution, δppm): 1.26
(6H, t), 2.36 (3H, s), 3.00 (3H, s), 3.60
(6H, m), 4.90 (1H, dd, J = 4 and 8Hz), 5.90
(1H, s), 7.24 (2H, d, J = 9Hz), 7.40 (2H,
d, J = 9 Hz), 7.46 (1H, s).

Reference Example 1 2- [4- [2- (4-Methanesulfonylamino) phenyl) -2-oxoethyl] -piperazino] -6-methyl-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine 2.76 g (11.1 mmol) of N- [4- (2-chloro-1-oxoethyl) phenyl] methanesulfonamide, 6
-Methyl-2-piperazino-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine 2.59 g (11.1 mmol), potassium carbonate 1.54 g (11.1 mmol) and a mixture of acetonitrile 40 ml 50 Stirring was continued at 8 ° C for 8 hours. Then, it was extracted with water and chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.5 g of the desired product (yield 71%).

Example 6 2- [4- [2- (4-Methanesulfonylamino) phenyl] -2-hydroxyethyl] piperazino] -6-methyl-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine 2.52 g of 2- [4- [2- (4-methanesulfonylamino) phenyl) -2-oxoethyl] -piperazino] -6-methyl-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine 5.7 mmol), in a mixture of methylene chloride 30 ml, was added a _{2M-BH 3 -Me 2 S /} THF solution 5 ml (10 mmol), stirred for 30 minutes at room temperature, refluxing was continued for 4 hours under stirring. The reaction mixture was cooled and 6 ml of methanol was added. EtO
The mixture was adjusted to pH 3 with H / HCl, stirred at room temperature for 2 hours, and then stirred under reflux for 1 hour. After that, the solvent was distilled off under reduced pressure, and the residue was extracted with a saturated sodium hydrogen carbonate solution and methylene chloride. The methylene chloride layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.4 g of the desired product (yield 16%).
Melting point: 214-217 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.56 (4H,
m), 2.76 (2H, m), 3.00 (3H, s), 3.15 (3H,
s), 4.02 (4H, m), 4.23 (2H, s), 4.79 (1H,
t, J = 7Hz), 7.24 (2H, d, J = 8Hz), 7.40 (2H,
d, J = 8Hz), 8.67 (1H, s).

Example 7 4- [6-Methyl-5,6-dihydro (7H) pyrrolo [3,4-
d] Pyrimidin-2-yl] -1- [2- (4- (methanesulfonylamino) phenyl) -2-hydroxyethyl] -1-ethylpiperazinium-bromide 2- [4- [2- (4- (methanesulfonylamino) phenyl) -2-hydroxyethyl] piperazino] -5,6
-Dihydro (7H) pyrrolo [3,4-d] pyrimidine 0.39 g
(0.9 mmol), ethyl bromide 9 g, acetonitrile 50 ml
The mixture was continuously stirred under reflux for 140 hours. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.1 g of the desired product (yield 20%).

Melting point: 175 to 180 ° C. (decomposition), ¹ H-NMR spectrum (DMSO-d ₆ solution, δ ppm): 1.40 (3
H, t, J = 7Hz), 2.80 (3H, s), 3.08 (3H, s),
3.2 ~ 4.0 (8H, m), 4.28 (2H, m), 4.40 (2H,
s), 5.18 (1H, t, J = 7Hz), 7.10 (2H, d, J = 8)
Hz), 7.30 (2H, d, J = 8Hz), 8.20 (1H, brs), 8.
70 (1H, s), 9.80 (1H, brs).

Example 8 A tablet containing 10 mg of active ingredient is prepared as follows.

Per tablet Active ingredient 10 mg Corn starch 55 mg Crystalline cellulose 35 mg Polyvinylpyrrolidone 5 mg (as a 10% aqueous solution) Carboxymethyl cellulose calcium 10 mg Magnesium stearate 4 mg Talc 1 mg Total 120 mg Active ingredient, starch and crystalline cellulose passed through a 80 mesh sieve and completely Mix. The obtained powder is mixed with a polyvinylpyrrolidone solution, granulated, and then passed through an 18-mesh sieve. The granules thus produced are dried at 50-60 ° C and sized again using an 18 mesh sieve. Calcium carboxymethylcellulose calcium and magnesium stearate and talc, which have been previously sieved with 80 mesh, are added to the granules and, after mixing, produced in tablets in a tablet machine, each weighing 120 mg.

Example 9 A tablet containing 100 mg of active ingredient is prepared as follows.

Per tablet Active ingredient 100 mg Corn starch 50 mg Crystalline cellulose 42 mg Soft anhydrous silicic acid 7 mg Magnesium stearate 1 mg Total 200 mg The above ingredients are passed through an 80 mesh sieve and mixed thoroughly. The resulting powder is compression molded to produce tablets weighing 200 mg.

Example 10 Capsules containing 50 mg of active ingredient are prepared as follows.

Per capsule Active ingredient 50 mg Corn starch 40 mg Lactose 5 mg Magnesium stearate 5 mg Total 100 mg The above ingredients are mixed and passed through an 80 mesh sieve and mixed thoroughly. 100 mg of the obtained powder is filled into capsules.

Example 11 A ready-to-use vial-containing injection containing 5 mg of the active ingredient is prepared as follows.

 When using 5 mg of active ingredient per vial and 50 mg of mannitol, dissolve in 1 ml of distilled water for injection and use.

Example 12 An injection in ampule containing 20 mg of an active ingredient is produced as follows.

Active ingredient per ampoule 20 mg Sodium chloride 18 mg Distilled water for injection Appropriate amount 2 ml Example 13 An adhesive patch preparation containing 17.5 mg of active ingredient is produced as follows.

Dissolve and print 10 parts of ammonium polyacrylate in 60 parts of water. Meanwhile, 2 parts of glycerin diglycidyl ether are dissolved in 10 parts of water while heating. On the other hand, 10 parts of polyethylene glycol (grade 400), 10 parts of water and 1 part of the active ingredient are dissolved by stirring. Then, while stirring the aqueous solution of ammonium polyacrylate, an aqueous solution of glycerin diglycidyl ether and an aqueous solution containing active ingredient of polyethylene glycol were added and mixed to prepare a drug-containing hydrogel solution in which the active ingredient was 0.5 per square centimeter in a flexible plastic film. It was applied so as to be mg, and the surface was covered with a release paper and cut into 35 square centimeters to prepare a preparation.

Example 14 An adhesive patch containing 10 mg of active ingredient is produced as follows.

100 parts sodium polyacrylate, 100 parts glycerin,
Water 150 parts, triepoxypropyl isocyanurate 0.2
Parts, ethanol 100 parts, isopropyl myristate 25
Parts, 25 parts of propylene glycol and 15 parts of the active ingredient were mixed to prepare an aqueous sol solution. Next, this sol solution was applied to the non-woven fabric surface of a composite film composed of rayon non-woven fabric and polyethylene film to a thickness of 100 μm to form an adhesive layer containing a drug. The content of release assisting substances (isopropyl myristate and propylene glycol) contained in this layer is about 20.
% By weight. Thereafter, crosslinking was carried out at 25 ° C. for 24 hours, a release film was attached to the interface of the pressure-sensitive adhesive, and this was further cut into 35 square centimeters to give a preparation.

The pharmacological effect of the compound of the general formula (1) of the present invention on the heart was examined. In vitro, in vivo using the heart of a hybrid dog
The effect of the compound of general formula (1) was tested in. The heart of an anesthetized dog was excised, fixed in a constant temperature bath at 37 ° C, a drug was added to the nutrient solution for perfusing the heart sample, and the myocardial action potential duration (AP
D) and the presence or absence of inhibition of the maximum rise rate of myocardial action potential were measured. In addition, anesthetized dogs were thoracotomized, electrodes were sewn into the right ventricle for electrical stimulation, and then pacemaker activity was eliminated, and ventricular muscular refractory period (ERP) was measured before and after drug administration under ventricular pacing.

Further, the anesthetized dog is thoracotomy, a bipolar electrode is sewn on the right atrium, stimulation electrodes are attached to the cervical vagus nerves, and atrial fibrillation is Goldbe
rger et al. (AL Goldberger et al; International J
ournal of Cardiology, 13 , 47 (1986)),
The defibrillation effect of the drug was investigated. An anesthetized dog was thoracotomized and the left anterior descending branch was ligated, and 90 minutes later, the blood flow was reopened to create a myocardial infarct lesion that was likely to induce tachycardia. At the same time, a bipolar electrode was inserted into the ventricular septum near the ligation site and fixed. A few days after the operation, tachycardia was induced by applying early stimulation under ventricular pacing, and the tachycardia elimination effect of the drug was examined.

From these tests, the compound of the general formula (1) has a remarkable AP.
It was shown that it is a valuable compound as a class III type antiarrhythmic agent having a prolonging effect on D and ERP, and that it exhibits an antiarrhythmic effect in an arrhythmia model. Further, some of the compounds of the general formula (1) also have an inhibitory effect on the maximum rise rate (max) of myocardial action potential possessed by class I type antiarrhythmic agents, while other compounds have an inhibitory effect on this max. It was identified as a pure class III antiarrhythmic drug with no drug. Further, it has been found that the compound of the general formula (1) has a prolonging effect on APD and ERP which is equal to or higher than that of the control clofilium or sotalol. Further, when a toxicity test of the compound of the general formula (1) was carried out, it was found that its toxicity was relatively weak and that it was used as a medicine with a wide safety margin.

Experimental Example 1 (Action on APD) A mixed-breed dog was intravenously administered with pentobarbital (30 mg / kg) after anesthesia, the heart was excised, and the right ventricle free wall was excised in Tyrode's solution. The free wall of the right chamber was fixed in a constant temperature bath at 37 ° C, and a 1 Hz field stimulation was performed. The action potential is to insert a glass microelectrode (10 to 20 MΩ) into Purkinje fibers,
The image was drawn on an oscilloscope via an amplifier, and the waveform was analyzed using a computer. For APD, the time from the generation of action potential to the time of 75% repolarization (APD ₇₅ ) was used as an index. The drug was added to the nutrient solution (20 ml) that perfused the specimen, and the effect of the drug was shown in%, with the change in APD after the incubation for 20 minutes as 100% before the drug administration. Table 2 shows the results.

Experimental Example 2 (Effect on ERP) After anesthetizing a mongrel adult dog, right thoracotomy is performed and a silver-silver chloride electrode is sewn on the right ventricle, and a stimulation interval of 400 msec, a duration of 4 msec,
Electrical stimulation was performed at a current twice the threshold. Then, a small amount of alcohol was injected from the sinus artery to eliminate the pacemaker activity, and ERP was measured under ventricular paging. That is, 10 trains were defined as one train, and the train-to-train interval when the reaction of the first train disappeared was defined as ERP. For these electrical stimulations, a cardiac stimulator (DHM-226-3 manufactured by Diamedical) was used to perform program stimulation. Drug administration (intravenous (iv) or intraduodenal (i.
d.)) The prolongation of the refractory period by the drug was expressed in% with the previous ERP as 100%. The results are shown in Table 3.

Experimental Example 3 (Atrial Fibrillation Model) After anesthetizing a mixed-breed dog, the chest was opened on the right side, and bipolar electrodes (silver and silver-silver chloride electrode) for stimulation and recording were sewn on the right atrium. Next, the vagus nerves on both sides of the cervix were peeled off and then cut off, and a stimulation electrode was attached to the distal end. Atrial Fibrillation is Goldberg
By the method of Er et al., bilateral vagus nerves were stimulated to cause cardiac arrest, and then the right atrium was subjected to high-frequency stimulation to generate it. Compound (600) etc. was able to eliminate continuous fibrillation by iv administration of 1 to 15 mg / kg.

Experimental Example 4 (Acute Toxicity) Male ddY 5-week-old mice were used in groups of 3 to 4 and the compound of the general formula (1) was dissolved in physiological saline or suspended in methylcellulose to give an oral (po) or After intraperitoneal (ip) administration, toxicity was determined 24 hours after administration. The results are shown in Table 4.

[Effects of the Invention] As shown in Experimental Examples 1 to 3 and Tables 2 and 3, the compound of the general formula (1) of the present invention has the same or higher cardiac electrophysiological activity as that of the control clofilium, sotalol, and the like. It was shown to have arrhythmic activity. Further, the toxicity of the compound of the general formula (1) of the present invention is generally weak as shown in Experimental Example 4 and Table 4. As described above, the compound of the general formula (1) of the present invention is generally considered to be a useful and highly safe drug having high activity or weak toxicity.

Therefore, the compound of the general formula (1) of the present invention is an antiarrhythmic compound,
It is useful as a therapeutic / prophylactic agent for ischemic heart disease, myocardial infarction, angina, heart failure and the like. Particularly, in the conventional antiarrhythmic therapeutic agents belonging to Class I to Class IV, the compound of the general formula (1) of the present invention can be preferably used for arrhythmia which is difficult to treat. It can be applied to patients with ventricular tachycardia accompanied by sudden death or ventricular arrhythmia including ventricular fibrillation, patients with the risk thereof, and its effectiveness is expected.

Continuation of front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location C07D 239/48 C07D 239/48 277/22 277/22 487/04 140 9271-4C 487/04 140 146 9271- 4C 146 (72) Inventor Joji Kamiya 2141 Togo, Mobara-shi, Chiba (72) Inventor Kanji Yoshihara 1 of 90 Machiho, Mobara-shi, Chiba (72) Inventor Masaaki Ishii 2142, Togo, Mobara-shi, Chiba (72) Invention Akira Awaya 1541 Yabe-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture (72) Inventor Takuo Nakano 20-23-1, Kamigo-cho, Sakae-ku, Yokohama-shi, Kanagawa Prefecture

Claims (2)

(57) [Claims] 1. The following formula (1) Where R ¹ is a lower alkyl group and Z is And R ² is the following formula (1) −a: Here, R ³ , R ⁴ and R ⁵ are independently hydrogen atom or lower alkyl, and are represented by the following formula (1) -b. The following formula (1) -c Here, R ⁶ is a hydrogen atom or lower alkyl, represented by the following formula (1) -d Wherein R ⁷ and R ⁸ are each independently a hydrogen atom or lower alkyl, and are represented by the following formula (1) -e And the following formula (1) -f Here, R ⁹ , R ¹⁰ and R ¹¹ are each independently a hydrogen atom or lower alkyl, which is a group selected from the group consisting of the group represented by: a lower alkylsulfamoylamine represented by: A pharmaceutically acceptable salt thereof. 2. The following formula (1) Where R ¹ is a lower alkyl group and Z is And R ² is the following formula (1) −a: Here, R ³ , R ⁴ and R ⁵ are independently hydrogen atom or lower alkyl, and are represented by the following formula (1) -b. The following formula (1) -c Here, R ⁶ is a hydrogen atom or lower alkyl, represented by the following formula (1) -d Wherein R ⁷ and R ⁸ are each independently a hydrogen atom or lower alkyl, and are represented by the following formula (1) -e And the following formula (1) -f Here, R ⁹ , R ¹⁰ and R ¹¹ are each independently a hydrogen atom or lower alkyl, which is a group selected from the group consisting of the group represented by: a lower alkylsulfamoylamine represented by: An antiarrhythmic agent containing a pharmaceutically acceptable salt thereof as an active ingredient.