JPH10152481A - Benzo(1,4)thiazine derivative and medicine composed of the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound showing an excellent function of inhibiting an Na<+> /H<+> exchange mechanism, and potentially useful as a remedy for diseases, e.g. those induced by intracellular acidosis during myocardial ischemia, those resulting from hyperplasia, or the like. SOLUTION: This compound is derived from benzo[1,4]thiazine, and shown by formula I (R<1> is H or a lower alkyl; R<2> and R<3> are each H or a 1-2C alkyl; (n) is 0 or 2; and the guanidinocarbonyl group substituting at the 6- or 7-site), e.g. N-(4-isopropyl-3-oxo-3,4-dihydro-2H-benzo[4,4]thiazine-6-carbonyl)guan idine. This medicine may be composed of a pharmacologically permissible salt of the derivative. The objective compound shown by formula I is obtained by reacting a compound shown by formula II (Et is ethyl; and the ethoxycarbonyl and guadinocarbonyl groups substititing at the 6- or 7-site) with 1 to 20 equivalents of guanidine based on the above compound in an inert solvent, e.g. dioxane, at room temperature to melting point of the solvent for 1 to 24h.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel benzo [1,4] thiazine derivative or a pharmacologically acceptable salt and a medicament comprising the same. More specifically, Na
Formula (I) having an inhibitory action on the ⁺ / H ⁺ exchange mechanism

[0002]

Embedded image (Wherein, R ¹ represents a hydrogen atom or a lower alkyl group;
R ² and R ³ are the same or different and each represent a hydrogen atom or a C ₁ -C ₂ alkyl group, and n represents 0 or 2. The substitution position of the guanidinocarbonyl group is 6-position or 7-position
Rank. A) a benzo [1,4] thiazine derivative or a pharmacologically acceptable salt thereof and a medicament comprising the same.

[0003]

2. Description of the Related Art The Na ⁺ / H ⁺ exchange mechanism is responsible for regulating intracellular pH, sodium ion concentration and cell volume. When intracellular acidosis occurs due to ischemia or the like, that is, when the intracellular hydrogen ion concentration increases, the action of this exchange mechanism is enhanced, and excessive incorporation of sodium ions into cells occurs. At this time, water inflow occurs due to a difference in osmotic pressure between the inside and outside of the cell, and the cell volume increases and edema occurs [Biochimica et Biophysica Acta, 988, 73-97 (198
9)]. Also, in cells having a Na ⁺ / Ca ²⁺ exchange mechanism such as myocardium, sodium ions excessively accumulated due to the enhancement of the Na ⁺ / H ⁺ exchange mechanism are pumped out through the Na ⁺ / Ca 2 ⁺ exchange mechanism, and Calcium ions flow into the cell. Excessive accumulation of calcium ions has been reported to cause cardiac dysfunction, myocardial necrosis and arrhythmias [Journal of Ca
rdiovascular Pharmacology, 23, 72-78 (1994)]. Therefore, compounds that inhibit the Na ⁺ / H ⁺ exchange mechanism are disorders induced by intracellular acidosis during myocardial ischemia, for example,
It can be used as a preventive and therapeutic agent for cardiac dysfunction, myocardial necrosis and arrhythmia, which are seen in ischemic heart diseases such as myocardial infarction and angina. Compounds that inhibit the Na ⁺ / H ⁺ exchange mechanism include ischemia / reperfusion injury, such as organ transplantation, coronary artery bypass surgery (CABG), percutaneous transluminal coronary angioplasty (PTCA), and thrombolytic therapy Can be used as a medicament for disorders caused by.

[0004] Furthermore, it is known that the Na ⁺ / H ⁺ exchange mechanism is deeply involved in cell growth induced by growth factors or hormone stimulation [Biochimica et Biophysica Acta, 9
88, 73-97 (1989)]. Therefore, compounds that inhibit the Na ⁺ / H ⁺ exchange mechanism are diseases caused by abnormal cell proliferation,
For example, it may be a therapeutic agent for restenosis after PTCA, arteriosclerosis, fibrosis, prostatic hypertrophy, diabetic complications, and the like. In addition, the enhancement of the Na ⁺ / H ⁺ exchange mechanism not only causes the proliferation of vascular smooth muscle cells but also increases the volume of fluid and is considered to be involved in the development of essential hypertension [Diagnosis and treatment, 8
1, 2209-2213 (1993)], it is considered that a compound that inhibits the Na ⁺ / H ⁺ exchange mechanism may be a therapeutic agent for essential hypertension.

[0005] Conventionally, compounds having an inhibitory effect on the Na ⁺ / H ⁺ exchange mechanism include amiloride represented by the following formula (II) and its derivatives, benzoylguanidine derivatives, indoloylguanidine derivatives, benzo [1,4] oxazine derivatives and the like. It has been known.

[0006]

Embedded image That is, Japanese Patent Publication No. 42-6249, The Journal of Biolo
gical Chemistry, 259, 4313-4319 (1984) discloses amiloride and derivatives thereof disclosed in JP-A-3-106858, JP-A-6-41049, JP-A-6-116230, JP-A-6-228082, and JP-A-6-28082. -234730,
JP-A-7-206823, JP-A-7-267926
And JP-A-8-41028 and JP-A-8-73427 disclose benzoylguanidine derivatives.
No. 0839 discloses an indoloylguanidine derivative, and EP 719766 discloses a benzo [1,4] oxazine derivative.

However, there is no known benzo [1,4] thiazine derivative of the present invention having an Na ⁺ / H ⁺ exchange mechanism inhibitory action.

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to provide Na ⁺
An object of the present invention is to provide a novel compound having a / H ⁺ exchange mechanism inhibitory action and a medicine comprising the same.

[0009]

As a result of various studies, the present inventors have found that the novel benzo [1,4] thiazine derivatives represented by the above formula (I) and their pharmacologically acceptable salts Have excellent Na ⁺ / H ⁺ exchange mechanism inhibitory action, and completed the present invention.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the above formula (I), examples of the lower alkyl group for R ¹ include a methyl group, an ethyl group, a propyl group and an isopropyl group, and an ethyl group and an isopropyl group are preferred. Examples of the C ₁ -C ₂ alkyl group for R ² and R ³ include a methyl group and an ethyl group.
In the above formula (I), when R ² and R ³ are different substituents, the 2-position of the benzo [1,4] thiazine skeleton becomes an asymmetric carbon, and a stereoisomer (optically active substance) derived therefrom. However, these stereoisomers, their mixtures and hydrates are also included in the compounds of the present invention.

Specific examples of the compound (I) of the present invention include N
-(4-methyl-3-oxo-3,4-dihydro-2H
-Benzo [1,4] thiazine-6-carbonyl) guanidine, N- (4-ethyl-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6-carbonyl) guanidine, N- (4-isopropyl-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6-carbonyl) guanidine, N- (4-isopropyl-1,1,3-trioxo-1,2,2 3,4-tetrahydro-1λ ⁶ -benzo [1,4] thiazine-6-carbonyl) guanidine, N- (3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6-carbonyl) Guanidine, N- (4-isopropyl-2-methyl-3-oxo-3,4-dihydro-2H-benzo [1,
4] thiazine-6-carbonyl) guanidine, N-
(2,2-dimethyl-4-isopropyl-3-oxo-
3,4-dihydro-2H-benzo [1,4] thiazine-
7-carbonyl) guanidine and the like.

The pharmacologically acceptable salts of the compound (I) of the present invention include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid and the like, or acetic acid, lactic acid and citric acid. Examples thereof include salts with organic acids such as acid, tartaric acid, methanesulfonic acid, and p-toluenesulfonic acid.

Among the compounds of the present invention, N- (4-ethyl-
3-oxo-3,4-dihydro-2H-benzo [1,
4] thiazine-6-carbonyl) guanidine, N- (4
-Isopropyl-3-oxo-3,4-dihydro-2H
-Benzo [1,4] thiazine-6-carbonyl) guanidine, N- (4-isopropyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1λ ⁶ -benzo [1,4] thiazine -6-carbonyl) guanidine, N
-(4-isopropyl-2-methyl-3-oxo-3,
4-dihydro-2H-benzo [1,4] thiazine-6
Carbonyl) guanidine, N- (2,2-dimethyl-4)
-Isopropyl-3-oxo-3,4-dihydro-2H
-Benzo [1,4] thiazine-7-carbonyl) guanidine and their pharmacologically acceptable salts, such as methanesulfonate, are preferred compounds. Among them, N- (4-isopropyl-3-oxo-
3,4-dihydro-2H-benzo [1,4] thiazine-
6-carbonyl) guanidine is mentioned as a particularly preferred compound.

The compound (I) of the present invention and a pharmacologically acceptable salt thereof can be produced, for example, by the following method A. [Method A]

[0015]

Embedded image (In the formula, R ¹ , R ² , R ³ , and n are the same as above. Et represents an ethyl group, and the substitution position of the ethoxycarbonyl group and the guanidinocarbonyl group is the 6-position or the 7-position.)
Compound (I) of the present invention is prepared by reacting compound (II) in an inert solvent.
The compound (III) can be produced by reacting 1 to 20 equivalents of guanidine with respect to the compound (III) at room temperature to the boiling point of the solvent for 1 to 24 hours.

In order to react guanidine, an acid addition salt of guanidine and a base in an equimolar amount thereto are usually added and reacted.

Examples of the inert solvent include dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethylformamide, dimethylsulfoxide, and the like, or a solvent obtained by appropriately mixing them.

As the base, metal carbonates such as potassium carbonate, metal hydrides such as sodium hydride, and metal alkoxides such as sodium methoxide can be used.

The pharmacologically acceptable salt of the compound (I) of the present invention can be prepared from the compound (I) obtained by the above production method.
Can be produced by allowing the above-mentioned inorganic or organic acid to act according to a conventional method.

The compound (I) of the present invention or a pharmacologically acceptable salt thereof can be converted into a hydrate of the compound by recrystallization from a water-containing solvent such as a water-containing alcohol, if necessary. .

Compound (III) used as a raw material in the above-mentioned Method A [Compounds (IIIa, III wherein n is 0)
b) and Compound (IIIc) wherein n is 2] can be produced, for example, by the following method.

[0022]

Embedded image (In the formula, R ¹ , R ² , R ³ , and Et are the same as above. R ^{1 ′} represents a lower alkyl group, X represents a halogen atom, and the substitution position of the carboxyl group or ethoxycarbonyl group is represented by the formula (I
In (V), (V) and (VI), the substitution position of the ethoxycarbonyl group at the 4- or 5-position of the nitrobenzene derivative is determined by the formulas (IIIa), (IIIb) and (III).
In c), it is the 6th or 7th position. That is, the 2-halonitrobenzene derivative (IV) is reacted with an ethyl thioglycolate derivative such as ethyl thioglycolate in the presence of a base such as pyridine or potassium carbonate to form a thioether compound (V), and then the acid catalyst in ethanol. To give compound (VI). When the compound (VI) is reduced in the presence of a catalyst such as Pd / C in a hydrogen atmosphere in an alcohol, a ring-closure reaction also proceeds, and a compound (IIIa) is obtained. If the ring-closing reaction is incomplete after the reduction reaction, the ring-closing reaction is completed by heating in toluene to obtain (IIIa).

Compound (IIIb) is compound (IIIb)
dimethylformamide a), tetrahydrofuran, in an inert solvent such as dimethoxyethane, t-butoxy potassium, 40% potassium fluoride - presence of a base such as alumina, prepared by reacting an alkyl halide (R ¹ X) be able to.

Compound (IIIc) can be obtained by adding compounds (IIIa) and (IIIb) obtained by the above method to peroxo acid salts such as potassium peroxomonosulfate and potassium peroxodisulfate, and organic peroxides such as m-chloroperbenzoic acid. It can be produced by oxidizing with an oxide.

Compound (I) of the present invention can also be produced by the following Method B. [Method B]

[0026]

Embedded image (In the formula, R ¹ , R ² , R ³ , and n are the same as above. The substitution position of the chlorocarbonyl group and the guanidinocarbonyl group is the 6-position or the 7-position.) That is, the compound (I) of the present invention In an inert solvent, compound (VII) and 1 to 20 equivalents of guanidine based on compound (VII) are added at room temperature to the boiling point of the solvent under the conditions of 1 to 1 equivalent.
It can be produced by reacting for 24 hours.

In the above production method, guanidine can be used in the reaction after converting an acid addition salt of guanidine such as guanidine hydrochloride into guanidine with a base such as sodium methoxide or sodium hydride.

Examples of the inert solvent include dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethylformamide, dimethylsulfoxide and the like, or a solvent obtained by appropriately mixing them.

The pharmacologically acceptable salt of the compound (I) of the present invention can be prepared from the compound (I) obtained by the above production method.
Can be produced by allowing the above-mentioned inorganic or organic acid to act according to a conventional method.

The compound (I) of the present invention or a pharmacologically acceptable salt thereof can be converted into a hydrate of the compound by recrystallization from a water-containing solvent such as a water-containing alcohol, if necessary. .

Compound (VII) used as a starting material in the above-mentioned Method B can be produced by the following method.

[0032]

Embedded image (In the formula, R ¹ , R ² , R ³ and n are the same as described above. The substitution position of the carboxyl group or chlorocarbonyl group is 6-position or 7-position.
Rank. That is, the compound (VII) can be prepared according to a conventional method.
It can be produced by reacting II) with a chlorinating agent such as thionyl chloride.

The compound (V) used in the above production method
III) is to produce a compound (III) in the same manner as in the method for producing the starting compound in the above-mentioned Method A, and then to produce the compound by hydrolyzing it with concentrated hydrochloric acid or the like according to a conventional method. Can be.

The compound (I) of the present invention and a pharmacologically acceptable salt thereof show an excellent inhibitory effect on the Na ⁺ / H ⁺ exchange mechanism, and disorders induced by intracellular acidosis during myocardial ischemia, for example, It can be used as a preventive and therapeutic agent for cardiac dysfunction, myocardial necrosis and arrhythmia, which are seen in ischemic heart diseases such as myocardial infarction and angina. Further, it can be used as a medicament for ischemia / reperfusion injury, for example, an injury caused by an operation such as organ transplantation, CABG, PTCA or thrombolytic therapy.

The compound (I) of the present invention or a pharmaceutically acceptable salt thereof is orally or parenterally administered to a human.

The dosage forms for oral administration include tablets, granules,
Powders, fine granules, hard capsules and the like are included.

Such a preparation can be produced by a conventional method. Tablets, granules, powders or fine granules can be prepared by mixing the compound (I) of the present invention or a pharmaceutically acceptable salt thereof with, for example, lactose, corn and the like. Starch, crystalline cellulose, magnesium stearate, hydroxypropylcellulose, manufactured by mixing with commonly used pharmaceutical additives such as talc, hard capsules are manufactured by filling the above fine granules or powders into appropriate capsules. You.

[0038] Parenteral dosage forms include injections and the like.

These preparations can be manufactured by a conventional method. For example, an injection can be prepared by adding compound (I) of the present invention or a pharmaceutically acceptable salt thereof to purified water for injection, physiological saline or a lipid vehicle. , For example, vegetable oils, oily emulsions,
It is manufactured by dissolving or emulsifying in glycol or the like and aseptically enclosing in ampules or vials. In addition, it can be obtained as a freeze-dried preparation to be dissolved at the time of use by appropriately dissolving in a stabilizer and purified water and freeze-drying by a conventional method.

The dose of the compound of the present invention depends on the condition of the patient,
Depending on the administration route, age, body weight, etc., the compound (I) of the present invention is usually 0.1 to 1 per day per adult.
000 mg, which is administered at one time or in two or three divided doses. Further, the amount can be increased as necessary.

[0041]

The compound (I) of the present invention and a pharmacologically acceptable salt thereof are excellent as shown in the following test examples.
It shows an inhibitory effect on Na ⁺ / H ⁺ exchange mechanism and an inhibitory effect on reperfusion arrhythmia after myocardial ischemia, which is considered to be based on the effect. In addition, the compound has low toxicity without showing any toxicity at the dose of the pharmacological effect.

Accordingly, a medicament comprising the compound (I) of the present invention and a pharmacologically acceptable salt thereof is useful for a disorder induced by intracellular acidosis during myocardial ischemia, such as myocardial infarction and angina pectoris. It is useful for prevention and treatment of cardiac dysfunction, myocardial necrosis and arrhythmia seen in ischemic heart disease. Also, ischemia / reperfusion injury such as organ transplantation, CAB
It is useful for prevention and treatment of disorders caused by surgery such as G and PTCA and thrombolytic therapy.

Test Example 1 Na ⁺ / H ⁺ Exchange Mechanism Inhibitory Activity: The Na ⁺ / H ⁺ exchange mechanism inhibitory activity was determined by the method of Rosskoph et al. [Journal of Hyperten
sion, 9, 231-238 (1991)], using the inhibitory effect of the test compound on sodium propionate-induced platelet swelling as an index. 1) Test compounds Compounds of Examples 1, 2, 3, 4, 5, 7 and 8 (compounds of the present invention) Amiloride (control compound) 2) Test method First, the method of Mammen et al. [Diabetes Research a
nd Clinical Practice, 9 (3), 265-272 (1990)] to prepare platelet-rich plasma. That is, male Wistar rats (body weight: 230 to 300 g) were laparotomized under ether anesthesia, and blood was collected from the abdominal aorta. AC to control clotting
Solution D (65 mM citric acid, 85 mM sodium citrate, 1
After adding 1 mM dextrose mixed solution) and centrifuging (90 × g, 10 minutes), the supernatant was collected to prepare platelet-rich plasma.

Next, a test compound solution (dissolved in dimethyl sulfoxide) was added to a 140 mM sodium propionate buffer, and then the platelet-rich plasma prepared above was added to the platelet aggregometer (turbidimeter) and XY. The decrease in optical density at 37 ° C. was recorded over time by a recorder, and the decrease in optical density after mixing with platelet-rich plasma was determined [the decrease in optical density in the presence of the test compound (D)]. On the other hand, dimethyl sulfoxide was added instead of the test compound solution, and similarly, the decrease in optical density was recorded, and the degree of decrease in optical density was determined [Control (C)]. Next, the expansion suppression rate (%) was calculated by the following equation.

[0045]

[Number 1] swelling inhibition rate (%) = (1-D / C) × 100 Next, the suppressive rate by the test compound was calculated by the least squares method the concentration to be _50% (IC 50). 3) Test results The results are shown in Table 1.

[0046]

[Table 1] Test Example 2 Inhibitory effect on reperfusion arrhythmia : The inhibitory effect on reperfusion arrhythmia was measured by the method of Tagliavini et al. [Eur
opean Journal of Pharmacology, 194, 7-10 (1991)]. 1) Test compound Compound of Example 2 (compound of the present invention) 2) Test method Male Sprague-Dawley rat (body weight: 310 to 510)
g) with sodium pentobarbital (50 mg / k
Anesthetized by intraperitoneal administration of g). Under anesthesia, the rat was cannulated into the trachea and connected to a ventilator. An electrocardiogram (lead II) was guided from an electrode attached to the limb and measured via a bioelectric amplifier.
Maintained. The rat was opened at the left intercostal space and the pericardium was incised to expose the heart. Next, the test compound was dissolved in a mixed solvent of polyethylene glycol 400, ethanol and physiological saline (mixing ratio v / v, 3: 3: 14) and administered into the femoral vein. Ten minutes after drug administration, the origin of the left coronary artery was occluded. After occlusion for 5 minutes, reperfusion was performed for 10 minutes, and the duration (seconds) of ventricular fibrillation occurring after reperfusion (mean ± standard error, n = 5-7) was measured from the electrocardiogram.
Arrhythmia is judged by The Lambeth Convention (The Lamb
eth Convention) [Cardiovascular Rese
arch, 22, 447-455 (1988)].

As a control, the duration (seconds) of ventricular fibrillation when only a mixed solvent of polyethylene glycol 400, ethanol and physiological saline (mixing ratio v / v, 3: 3: 14) was administered was described above. It measured similarly to. 3) Test results The results are shown in Table 2.

[0048]

[Table 2] **: p <0.01 (Mann-Whitney U test)

[0049]

EXAMPLES The present invention will be described more specifically with reference to examples and reference examples.

Example 1 N- (4-isopropyl-3-oxo-3,4-dihydrido
B-2H-benzo [1,4] thiazine-6-carboni
G) guanidine [in the formula (I), R ¹ is isopropyl
Group, R ² and R ³ are hydrogen atoms, n is 0, guanidinocar
Compound wherein the position of substitution of the bonyl group is 6-position] : ethyl 4-isopropyl-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6-carboxylate (Reference Example 4)
(0.70 g), guanidine hydrochloride (2.63)
g), sodium methoxide (1.35 g) and dimethyl sulfoxide (10 ml) at 120 ° C. for 1 hour.
Stirred for hours. After cooling, water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water and dried. Recrystallization from diisopropyl ether-tetrahydrofuran gave the title compound (0.35 g). Melting point: 206-207 ° C NMR (DMSO-d ₆ ) δ; 1.54 (6H, d, J = 7 Hz), 3.28 (2H, s), 4.61-
4.72 (1H, m), 6.99 (4H, br), 7.36 (1H, d, J = 8Hz), 7.83 (1H, d
d, J = 8, 1 Hz), 8.07 (1 H, d, J = 1 Hz). Elemental analysis value (as C ₁₃ H ₁₆ N ₄ O ₂ S): Calculated value (%) C, 53.41; H, 5 N, 19.16 Analytical value (%) C, 53.46; H, 5.54; N, 19.38

Example 2 N- (4-isopropyl-3-oxo-3,4-dihydride
B-2H-benzo [1,4] thiazine-6-carboni
Guanidine methanesulfonate [of formula (I)
R ¹ is an isopropyl group, R ² and R ³ are hydrogen atoms, n
Is 0, and the substitution position of the guanidinocarbonyl group is 6-position
Methanesulfonic acid salt of compound (Example 1)] : N- (4
-Isopropyl-3-oxo-3,4-dihydro-2H
Methanesulfonic acid (66 mg) was added to a solution of -benzo [1,4] thiazine-6-carbonyl) guanidine (see Example 1) (0.20 g) in tetrahydrofuran (5 ml), and the mixture was concentrated. The residue was recrystallized from ethanol to give the title compound (0.20 g). Melting point: 188-190 ° C NMR (DMSO-d ₆ ) δ; 1.51 (6H, d, J = 7 Hz), 2.45 (3H, s), 3.44 (2
H, s), 4.58-4.64 (1H, m), 7.64-7.76 (3H, m), 8.42 (4H, br), 1
1.37 (1H, br) Elemental analysis (as _{C 13 H 16 N 4 O 2} S · CH 3 SO 3 H):. Calculated (%) C, 43.29; H , 5.19; N, 14. 42 Anal. (%) C, 43.07; H, 5.28; N, 14.36.

Example 3 N- (4-isopropyl-1,1,3-trioxo-
1,2,3,4-tetrahydro-1λ ⁶ -benzo [1,
4] Thiazine-6-carbonyl) guanidine methanes
Sulfonate [wherein R ¹ is isopropyl
A group, R ² and R ³ are hydrogen atoms, n is 2, guanidinocarbo
Methanesulfone of a compound in which the substitution position of the nyl group is 6-position
Acid salt] : 4-isopropyl-1,1,3-trioxo-
1,2,3,4-tetrahydro-1λ ⁶ -benzo [1,
4] Ethyl thiazine-6-carboxylate (see Reference Example 5)
(1.00 g), a mixture of guanidine hydrochloride (3.05 g), sodium methoxide (1.77 g) and dimethyl sulfoxide (15 ml) was stirred at 120 ° C. for 3 hours. After cooling, water was added to the reaction mixture, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was dissolved in isopropyl alcohol, methanesulfonic acid (0.11 g) was added, and the precipitated solid was collected by filtration. Recrystallization from isopropyl alcohol-methanol gave the title compound (0.14 g)
I got Mp: 261~263 ℃ NMR (DMSO-d 6) δ; 1.51 (6H, d, J = 7Hz), 2.34 (3H, s), 4.68-
4.80 (1H, m), 4.79 (2H, s), 7.87 (1H, d, J = 8Hz), 7.92 (1H, s),
8.09 (1H, d, J = 8Hz), 8.31 (4H, br), ( as _{C 13 H 16 N 4 O 4} S · CH 3 SO 3 H) 11.52 (1H, br) Elemental analysis:. Calculated ( %) C, 39.99; H, 4.79; N, 13.32 Analytical value (%) C, 39.86; H, 4.93; N, 12.92

Example 4 N- (4-methyl-3-oxo-3,4-dihydro-2
H-benzo [1,4] thiazine-6-carbonyl) gua
Niidine methanesulfonate [In the formula (I), R ¹
Is a methyl group, R ² and R ³ are hydrogen atoms, n is 0, guanidinium
Methane of a compound in which the substitution position of the noncarbonyl group is 6-position
Sulfonate] : ethyl 4-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6-carboxylate (see Reference Example 6) (1.40 g), guanidine hydrochloride (5 .94 g), sodium methoxide (3.0
A mixture of 5 g) and dimethyl sulfoxide (15 ml) was stirred at 120 ° C. for 2 hours. After cooling, water was added to the reaction mixture, the precipitated solid was collected by filtration, dried, the residue was dissolved in methanol, methanesulfonic acid (0.36 g) was added, and the mixture was concentrated and recrystallized from methanol-water to give the title. The compound (0.27 g) was obtained. Mp: 231~233 ℃ NMR (DMSO-d 6) δ; 2.43 (3H, s), 3.43 (3H, s), 3.61 (2H, s),
7.60-7.71 (3H, m), 8.43 (4H, br), 11.35 (1H, br) Elemental analysis (as _{C 11 H 12 N 4 O 2} S · CH 3 SO 3 H):. Calculated (%) C, 39.99; H, 4.47; N, 15.50 Analytical value (%) C, 39.93; H, 4.57; N, 15.59

Example 5 N- (4-ethyl-3-oxo-3,4-dihydro-2
H-benzo [1,4] thiazine-6-carbonyl) gua
Niidine methanesulfonate [In the formula (I), R ¹
Is an ethyl group, R ² and R ³ are hydrogen atoms, n is 0, guanidinium
Methane of a compound in which the substitution position of the noncarbonyl group is 6-position
Sulfonate] : ethyl 4-ethyl-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6-carboxylate (see Reference Example 7) (1.50 g), guanidine hydrochloride (5 .94 g), sodium methoxide (3.0
A mixture of 5 g) and dimethyl sulfoxide (15 ml) was stirred at 120 ° C. for 2 hours. After cooling, water was added to the reaction mixture, the precipitated solid was collected by filtration, dried, the residue was dissolved in methanol, methanesulfonic acid (0.14 g) was added, and the mixture was concentrated and recrystallized from methanol-water. The compound (0.14 g) was obtained. Melting point: 232 to 234 ° C. NMR (DMSO-d ₆ ) δ; 1.18 (3H, t, J = 7 Hz), 2.42 (3H, s), 3.58 (2
H, s), 4.06 (2H, q, J = 7Hz), 7.59-7.68 (2H, m), 7.73 (1H, d, J =
1 Hz), 8.43 (4H, br), 11.35 (1 H, br). Elemental analysis value (as C ₁₂ H ₁₄ N ₄ O ₂ S.CH ₃ SO ₃ H): Calculated value (%) C, 41.70; H, 4.85; N, 14.96 Analytical value (%) C, 41.68; H, 4.88; N, 15.09

Example 6 N- (3-oxo-3,4-dihydro-2H-benzo
[1,4] thiazine-6-carbonyl) guanidine
Tansulfonate [In the formula (I), R ¹ , R ² , R
³ is a hydrogen atom, n is 0, substitution of a guanidinocarbonyl group
Methanesulfonate of a compound at position 6] : 3-
Ethyl oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6-carboxylate (see Reference Example 3) (2.
37 g), a mixture of guanidine hydrochloride (10.51 g), sodium methoxide (5.40 g) and dimethyl sulfoxide (20 ml) was stirred at 120 ° C. for 2 hours.
After cooling, dilute hydrochloric acid was added to the reaction mixture to adjust the pH to 11,
The precipitated solid was collected by filtration, washed with water and dried. After dissolving in methanol, methanesulfonic acid (0.96 g) was added, and the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol-water to give the title compound (0.16 g). Mp: 263~264 ℃ NMR (DMSO-d 6) δ; 2.40 (3H, s), 3.57 (2H, s), 7.52-7.60 (3
. H, m), 8.35 ( 4H, br), 10.77 (1H, br), as 11.20 (1H, br) Elemental analysis _{(C 10 H 10 N 4 O} 2 S · CH 3 SO 3 H): Calculated (%) C, 38.14; H, 4.07; N, 16.18 Analytical value (%) C, 38.14; H, 4.23; N, 16.28

Example 7 N- (4-isopropyl-2-methyl-3-oxo-
3,4-dihydro-2H-benzo [1,4] thiazine-
6-carbonyl) guanidine methanesulfonate [formula
In (I), R ¹ is an isopropyl group, and R ² and R ³ are
One is a hydrogen atom, the other is a methyl group, n is 0, guanidino
The carbonyl group is substituted at the 6-position.
Rufonate] : ethyl 4-isopropyl-2-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6-carboxylate (see Reference Example 11) (2.
00g), guanidine hydrochloride (6.52 g), potassium carbonate (9.43 g) and dimethyl sulfoxide (20 m
The mixture of 1) was stirred at 120 ° C. for 3 hours. After cooling, water was added to the reaction mixture, the precipitated solid was collected by filtration, dried,
Dissolve in ethyl acetate and add methanesulfonic acid (0.50 g)
Was added, and the precipitated solid was collected by filtration. Recrystallization from ethanol gave the title compound (1.12 g). Mp: 183~185 ℃ NMR (DMSO-d 6) δ; 1.29 (3H, d, J = 7Hz), 1.45 (3H, d, J = 7Hz),
1.46 (3H, d, J = 7Hz), 2.42 (3H, s), 3.57 (1H, q, J = 7Hz), 4.53-
4.69 (1H, m), 7.59-7.67 (2H, m), 7.75 (1H, s), 8.43 (4H, br),
11.38 (1H, br) Elemental analysis (as _{C 14 H 18 N 4 O 2} S · CH 3 SO 3 H):. Calculated (%) C, 44.76; H , 5.51; N, 13. 92 Analytical value (%) C, 44.68; H, 5.48; N, 13.93

Example 8 N- (2,2-dimethyl-4-isopropyl-3-oxo
So-3,4-dihydro-2H-benzo [1,4] thiazi
-7-carbonyl) guanidine methanesulfonate
[In the formula (I), R ¹ is an isopropyl group, R ² , R
³ is methyl group, n is 0, guanidinocarbonyl group substitution
Methanesulfonic acid salt of a compound at position 7] : Guanidine hydrochloride (1.91 g) was added to a methanol solution of sodium methoxide prepared from sodium (0.46 g) and methanol (20 ml), and the mixture was stirred at room temperature for 1 hour. rear,
Filtered. The solvent was distilled off under reduced pressure.
To a mixture of 2-dimethoxyethane (15 ml) was added 2,2-
Dimethyl-4-isopropyl-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-7-carbonyl chloride (see Reference Example 17) (0.32 g) in 1,2-dimethoxyethane (15 ml) ) Add solution and add 5
Stirred for minutes. After concentrating the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was dissolved in diisopropyl ether (10 ml). After adding methanesulfonic acid (0.19 g) and stirring at room temperature for 30 minutes, the solvent was distilled off under reduced pressure, and the residue was recrystallized from acetonitrile-isopropanol to give the title compound (210 m
g) was obtained. Melting point: 205-206 ° C NMR (DMSO-d ₆ ) δ; 1.31 (6H, s), 1.45 (6H, d, J = 7 Hz), 2.32 (3
H, s), 4.60-4.75 (1H, m), 7.59 (1H, d, J = 9Hz), 7.87 (1H, dd, J
= 9,2Hz), 7.98 (1H, d, J = 2Hz), 8.26 (4H, br), 11.20 (1H, br). Elemental analysis _{(C 15 H 20 N 4 O} 2 S · CH 3 SO 3 H · a 1 / 10H ₂ O): calculated (%) C, 45.94; H , 5.78; N, 13.39 analytical value (%) C, 45.76; H , 5.71; N, 13.25

Example 9 Preparation Example (Injection) : N- (4-isopropyl-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6-carbonyl) guanidine methanesulfonate (Compound of Example 2) 1 g was dissolved in purified water for injection.
After 0 ml, membrane filter (0.2μm)
The solution is aseptically filtered, dispensed in 1 ml portions into ampules, and sealed. It is then sterilized at 120 ° C. for 20 minutes.

Example 10 Formulation Example (Tablets) : Prescription Components Compounding amount N- (4-isopropyl-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6-carbonyl) guanidine methane Sulfonate (compound of Example 2) 5 Lactose 77.5 Corn starch 28 Crystalline cellulose 25 Hydroxypropylcellulose 3.5 Magnesium stearate 1 Total 140 (Operation) The above components are mixed uniformly to make 140 mg per tablet. To tablet.

Reference Example 1 4-ethoxycarbonylmethylsulfanyl-3-nitto
B benzoic acid [in the formula (V), R ² and R ³ represent a hydrogen atom
Compound] : A mixture of 4-chloro-3-nitrobenzoic acid [Wako Pure Chemical Industries, Ltd.] (100 g), ethyl thioglycolate (72 g) and pyridine (250 ml) was heated to reflux for 8 hours. After cooling, hydrochloric acid was added to the reaction mixture to make it acidic. The precipitated solid was collected by filtration, washed with water, and dried to give the title compound (121 g). A part of this, recrystallized from ethanol, showed the following physical properties. Melting point: 159-161 ° C NMR (DMSO-d ₆ ) δ; 1.18 (3H, t, J = 7 Hz), 4.12 (2H, q, J = 7 Hz),
4.17 (2H, s), 7.70 (1H, d, J = 9Hz), 8.15 (1H, dd, J = 9,2Hz), 8.
63 (as _{C 11 H 11 NO 6 S)} (1H, d, J = 2Hz), 13.46 (1H, br) Elemental analysis:. Calculated (%) C, 46.31; H , 3.89; N , 4.91 Analytical value (%) C, 46.37; H, 3.95; N, 4.51

Reference Example 2 4-ethoxycarbonylmethylsulfanyl-3-nitto
Ethyl benzoate [in the formula (VI), R ² and R ³ are
Compound which is a hydrogen atom] : 4-ethoxycarbonylmethylsulfanyl-3-nitrobenzoic acid (see Reference Example 1)
(30 g), concentrated sulfuric acid (5 ml) and ethanol (30
0 ml) was heated at reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The precipitated solid was collected by filtration, washed with water and dried to give the title compound (33 g). A part of this, recrystallized from diisopropyl ether, showed the following physical properties. _{Mp: 66~67 ℃ NMR (CDCl 3)} δ; 1.27 (3H, t, J = 7Hz), 1.42 (3H, t, J = 7Hz), 3.
78 (2H, s), 4.23 (2H, q, J = 7Hz), 4.42 (2H, q, J = 7Hz), 7.58 (1
H, d, J = 9 Hz), 8.18 (1 H, dd, J = 9, 2 Hz), 8.85 (1 H, d, J = 2 Hz). Elemental analysis value (as C ₁₃ H ₁₅ NO ₆ S): Calculated value ( %, C, 49.83; H, 4.83; N, 4.47 Analytical value (%) C, 49.81; H, 4.83; N, 4.22

Reference Example 3 3-oxo-3,4-dihydro-2H-benzo [1,
4] Ethyl thiazine-6-carboxylate [Formula (IIIa)
Wherein R ² and R ³ are hydrogen atoms.
Ethyl ethoxycarbonylmethylsulfanyl-3-nitrobenzoate (see Reference Example 2) (31 g), 10% Pd
A mixture of / C (3.1 g) and ethanol (300 ml) was stirred under a hydrogen atmosphere at 50 ° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (chloroform) and crystallized from ethyl acetate-hexane to give the title compound (7.8
g) was obtained. A part of this, recrystallized from ethyl acetate-hexane, showed the following physical properties. _{Mp: 159~160 ℃ NMR (CDCl 3)} ; δ1.39 (3H, t, J = 7Hz), 3.46 (2H, s), 4.37 (2H,
q, J = 7Hz), 7.37 (1H, d, J = 8Hz), 7.50 (1H, d, J = 2Hz), 7.69 (1H
. H, dd, J = 8,2Hz ), 7.92 (1H, br) Elemental analysis as _{(C 11 H 11 NO 3 S} ): Calculated (%) C, 55.68; H , 4.67; N , 5.90 Analytical value (%) C, 55.76; H, 4.71; N, 5.75

Reference Example 4 4-isopropyl-3-oxo-3,4-dihydro-2
Ethyl H-benzo [1,4] thiazine-6-carboxylate
[In the formula (IIIb), R ^{1 ′} is an isopropyl group, R
² , a compound in which R ³ is a hydrogen atom] : 3-oxo-3,
4-dihydro-2H-benzo [1,4] thiazine-6
Ethyl carboxylate (see Reference Example 3) (5.70 g), 2
-Iodopropane (6.12 g), potassium t-butoxide (3.14 g) and tetrahydrofuran (57 m
After stirring the mixture of 1) at 60 ° C for 16 hours, 2-iodopropane (3.06 g) and potassium t-butoxide (1.57 g) were added, and the mixture was further stirred at 60 ° C for 24 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue.
The mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (hexane: ethyl acetate =
5: 1) to give the title compound as an oil (3.38 g).
I got _{NMR (CDCl 3); δ1.39 (} 3H, t, J = 7Hz), 1.53 (6H, d, J = 7Hz), 3.
31 (2H, s), 4.42 (2H, q, J = 7Hz), 4.63-4.74 (1H, m), 7.43 (1H,
d, J = 8 Hz), 7.67 (1H, dd, J = 8, 1 Hz), 7.89 (1 H, d, J = 1 Hz). Elemental analysis value (as C ₁₄ H ₁₇ NO ₃ S): Calculated value (%) C, 60.19; H, 6.13; N, 5.01 Analytical value (%) C, 60.17; H, 6.24; N, 5.04

Reference Example 5 4-isopropyl-1,1,3-trioxo-1,2,2
3,4-tetrahydro-1λ ⁶ -benzo [1,4] thia
Ethyl gin-6-carboxylate [of formula (IIIc)
R ¹ is an isopropyl group and R ² and R ³ are hydrogen atoms
Compound] : 4-isopropyl-3-oxo-3,4-
Ethyl dihydro-2H-benzo [1,4] thiazine-6-carboxylate (see Reference Example 4) (1.80 g), potassium peroxomonosulfate (OXONE ^™ , Aldrich)
(7.80 g), ethanol (10 ml) and water (3
After stirring the mixture at room temperature for 16 hours, ethanol (20 ml) and water (30 ml) were added, and the mixture was further stirred at 60 ° C. for 3 hours. The reaction mixture was extracted with ethyl acetate,
The solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (1.00 g) as an oil. _{NMR (CDCl 3); δ1.43 (} 3H, t, J = 7Hz), 1.57 (6H, d, J = 8Hz), 4.
13 (2H, s), 4.46 (2H, q, J = 7Hz), 4.65-4.76 (1H, m), 7.95 (1H,
dd, J = 8, 1 Hz), 8.01 (1 H, d, J = 8 Hz), 8.03 (1 H, d, J = 1 Hz). Elemental analysis value (as C ₁₄ H ₁₇ NO ₅ S): Calculated value (%) N, 4.50 Analytical value (%) C, 54.02; H, 5.49; N, 4.25

Reference Example 6 4-Methyl-3-oxo-3,4-dihydro-2H-be
Ethyl [1,4] thiazine-6-carboxylate [formula
In (IIIb), R ^{1 ′} is a methyl group, and R ² and R ³ are
Compound that is a hydrogen atom] : ethyl 3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6-carboxylate (see Reference Example 3) (2.37 g), iodomethane (2.84 g) , Potassium t-butoxide (1.68 g)
After stirring the mixture of and tetrahydrofuran (24 ml) at room temperature for 1 hour, water was added and the precipitated solid was collected by filtration, dried and recrystallized from diisopropyl ether to give the title compound (1.58 g). Melting point: 110-112 ° C NMR (DMSO-d ₆ ) δ; 1.40 (3H, t, J = 7 Hz), 3.43 (2H, s), 3.49 (3
H, s), 4.39 (2H, q, J = 7Hz), 7.41 (1H, d, J = 8Hz), 7.69 (1H, dd,
J = 8,2 Hz), 7.75 (1 H, d, J = 2 Hz). Elemental analysis (as C ₁₂ H ₁₃ NO ₃ S): Calculated (%) C, 57.35; H, 5.21; N , 5.57 Analytical value (%) C, 57.35; H, 5.20; N, 5.64

Reference Example 7 4-ethyl-3-oxo-3,4-dihydro-2H-be
Ethyl [1,4] thiazine-6-carboxylate [formula
In (IIIb), R ^{1 ′} is an ethyl group, and R ² and R ³ are
Hydrogen atom compound] : ethyl 3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6-carboxylate (see Reference Example 3) (2.37 g), iodoethane (3.12 g) , Potassium t-butoxide (1.68 g)
And a mixture of tetrahydrofuran (24 ml) was stirred at room temperature for 1 hour and further at 50 ° C. for 2 hours. Water was added to the reaction mixture, extracted with ethyl acetate, washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane to give the title compound (1.73 g). Mp: 56~57 ℃ NMR (DMSO-d 6) δ; 1.30 (3H, t, J = 7Hz), 1.40 (3H, t, J = 7Hz),
3.40 (2H, s), 4.10 (2H, q, J = 7Hz), 4.39 (2H, q, J = 7Hz), 7.41
. (1H, d, J = 8Hz), 7.67 (1H, dd, J = 8,2Hz), 7.81 (1H, d, J = 2Hz) ( as C ₁₃ H ₁₅ NO ₃ S) Elemental analysis: Calculated (%) C, 58.85; H, 5.70; N, 5.28 Analytical value (%) C, 58.80; H, 5.60; N, 5.25

Reference Example 8 4- (1-ethoxycarbonylethylsulfanyl)-
3-nitrobenzoic acid [in the formula (V), R ² and R ³
Compound in which one is a hydrogen atom and the other is a methyl group] : 4-
Chloro-3-nitrobenzoic acid [Wako Pure Chemical Industries, Ltd.]
(62.6 g), ethyl 2-methylthioglycolate (50 g) and pyridine (150 ml) were mixed with 2
The mixture was refluxed for 0 hours. After cooling, hydrochloric acid was added to the reaction mixture to make it acidic, and the precipitated solid was collected by filtration, washed with water and dried, and washed with diisopropyl ether to give the title compound (78 g). A part of this, recrystallized from diisopropyl ether, showed the following physical properties. Melting point: 89-91 ° C. NMR (CDCl ₃ ) δ; 1.25 (3H, t, J = 7 Hz), 1.67 (3H, d, J = 7 Hz), 4.
07-4.28 (3H, m), 7.73 (1H, d, J = 9Hz), 8.24 (1H, dd, J = 2,9H
. z), 8.88 (1H, d, as J = 2 Hz) Elemental analysis _{(C 12 H 13 NO 6 S} ): Calculated (%) C, 48.16; H , 4.38; N, 4.68 Analytical value (%) C, 48.22; H, 4.40; N, 4.60

Reference Example 9 4- (1-ethoxycarbonylethylsulfanyl)-
Ethyl 3-nitrobenzoate [In the formula (VI), R
A compound in which one of R ² and R ³ is a hydrogen atom and the other is a methyl group
] : 4- (1-ethoxycarbonylethylsulfanyl) -3-nitrobenzoic acid (see Reference Example 8) (73
g), concentrated sulfuric acid (7.3 ml) and ethanol (730
ml) of the mixture was heated at reflux for 22 hours. The reaction mixture was concentrated under reduced pressure to a third volume, and neutralized by adding an aqueous sodium carbonate solution. After extraction with ethyl acetate, the solvent was distilled off under reduced pressure to obtain the title compound as an oil (74 g). A portion of this was purified by column chromatography (chloroform: methanol = 10: 1) and showed the following physical properties. NMR (CDCl ₃ ) δ; 1.23 (3H, t, J = 7 Hz), 1.41 (3H, t, J = 7 Hz), 1.
66 (3H, d, J = 7Hz), 4.09 (1H, q, J = 7Hz), 4.12-4.26 (2H, m), 4.
42 (2H, q, J = 7Hz), 7.68 (1H, d, J = 9Hz), 8.16 (1H, dd, J = 9,2H
. z), 8.79 (1H, d, as J = 2 Hz) Elemental analysis _{(C 14 H 17 NO 6 S} ): Calculated (%) C, 51.37; H , 5.23; N, 4.28 Analytical value (%) C, 51.16; H, 5.17; N, 4.31

Reference Example 10 2-methyl-3-oxo-3,4-dihydro-2H-be
Ethyl [1,4] thiazine-6-carboxylate [formula
In (IIIa), one of R ² and R ³ is a hydrogen atom,
Compound in which the other is a methyl group] : ethyl 4- (1-ethoxycarbonylethylsulfanyl) -3-nitrobenzoate (see Reference Example 9) (40 g), 10% Pd / C
(4.0 g) and ethanol (400 ml) were stirred at 40 ° C. for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was washed with diisopropyl ether and recrystallized from ethyl acetate-diisopropyl ether to give the title compound (18.85 g). _{Mp: 155~157 ℃ NMR (CDCl 3)} δ; 1.39 (3H, t, J = 7Hz), 1.51 (3H, d, J = 7Hz), 3.5
9 (1H, q, J = 7Hz), 4.39 (2H, q, J = 7Hz), 7.37 (1H, d, J = 8Hz), 7.
56 (1H, d, J = 2Hz), 7.68 (1H, dd, J = 8,2Hz), 8.38 (1H, br) Elemental analysis (as _{C 12 H 13 NO 3 S)} :. Calculated (%) C, 57.35; H, 5.21; N, 5.57 Analytical value (%) C, 57.46; H, 5.23; N, 5.38

Reference Example 11 4-isopropyl-2-methyl-3-oxo-3,4-
Dihydro-2H-benzo [1,4] thiazine-6-cal
Ethyl borate [in the formula (IIIb), R ^{1 ′} is
A ropyl group, one of R ² and R ³ is a hydrogen atom and the other is methyl
Compound as Group] : 2-Methyl-3-oxo-3,4-
Ethyl dihydro-2H-benzo [1,4] thiazine-6-carboxylate (see Reference Example 10) (3.00 g), 2-
After stirring a mixture of iodopropane (6.09 g), 40% potassium fluoride-alumina (5.20 g) and 1,2-dimethoxyethane (60 ml) for 2 days at 60 ° C., the reaction mixture was filtered. A 14% (w / v) solution of hydrogen chloride in dioxane (1.0 ml) was added to the filtrate, and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, diisopropyl ether (20 ml) was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (2.
92 g) were obtained. NMR (CDCl ₃ ) δ; 1.41 (3H, t, J = 7 Hz), 1.43 (3H, d, J = 7 Hz), 1.
51 (3H, d, J = 7Hz), 1.54 (3H, d, J = 7Hz), 3.36 (1H, q, J = 7Hz),
4.39 (2H, q, J = 7Hz), 4.78-4.62 (1H, m), 7.43 (1H, d, J = 8Hz),
7.68 (1H, dd, J = 8, 2 Hz), 7.88 (1 H, d, J = 2 Hz). Elemental analysis value (as C ₁₅ H ₁₉ NO ₃ S): Calculated value (%) C, 61.41; H , 6.53; N, 4.77 Analytical value (%) C, 61.36; H, 6.61; N, 4.50

Reference Example 12 3- (1-ethoxycarbonyl-1-methylethylsulfur
Fanyl) -4-nitrobenzoic acid [in the formula (V),
Compound in which R ² and R ³ are methyl groups] : 3-bromo-4
-Nitrobenzoic acid (3.70 g) [Journal of the Amer
ican Chemical Society, 72, 28-32 (1950)], ethyl 2-mercapto-2-methylpropionate (3.12 g)
A mixture of [US2755278], potassium carbonate (4.1 g) and dimethylformamide (30 ml) was added at 60 ° C. for 24 hours.
Stirred for hours. Ice water was added to the reaction mixture, neutralized with hydrochloric acid, extracted with ether, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform: methanol = 4: 1), and then the title compound (5.14 g) was obtained.
I got Take a part of this, diisopropyl ether-
The product recrystallized from hexane exhibited the following physical properties. Melting point: 86-87 ° C. NMR (CDCl ₃ ) δ; 1.26 (3H, t, J = 7 Hz), 1.57 (6H, s), 4.21 (2H,
q, J = 7Hz), 7.87 (1H, d, J = 7Hz), 8.11 (1H, d, J = 7Hz), 8.31 (1
H, s). Elemental analysis (as C ₁₃ H ₁₅ NO ₆ S): Calculated (%) C, 49.83; H, 4.83; N, 4.47 Analytical (%) C, 49. 81; H, 4.81; N, 4.36

Reference Example 13 3- (1-ethoxycarbonyl-1-methylethylsulfur
Ethyl fannyl) -4-nitrobenzoate [Formula (VI)
Wherein R ² and R ³ are methyl groups] : 3-
(1-ethoxycarbonyl-1-methylethylsulfanyl) -4-nitrobenzoic acid (see Reference Example 12) (3.
85 g), sulfuric acid (0.5 ml) and ethanol (30
ml) of the mixture was heated at reflux for 18 hours. The reaction mixture was concentrated under reduced pressure to about 1/4 volume, and water was added. After extraction with ether and washing with aqueous sodium hydrogen carbonate solution,
The solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 6: 1),
The title compound was obtained as an oil (3.1 g). NMR (CDCl ₃ ) δ; 1.25 (3H, t, J = 7 Hz), 1.42 (3H, t, J = 7 Hz), 1.
56 (6H, s), 4.20 (2H, q, J = 7Hz), 4.42 (2H, q, J = 7Hz), 7.83 (1
H, d, J = 8 Hz), 8.05 (1H, dd, J = 8,2 Hz), 8.23 (1H, d, J = 2 Hz). Elemental analysis value (as C ₁₅ H ₁₉ NO ₆ S): Calculated value ( %, C, 52.78; H, 5.61; N, 4.10 Analytical value (%) C, 52.60; H, 5.58; N, 3.99

Reference Example 14 2,2-Dimethyl-3-oxo-3,4-dihydro-2
Ethyl H-benzo [1,4] thiazine-7-carboxylate
[In the formula (IIIa), R ² and R ³ are methyl groups.
Compound] : ethyl 3- (1-ethoxycarbonyl-1-methylethylsulfanyl) -4-nitrobenzoate (see Reference Example 13) (2.93 g), 10% Pd / C
(0.30 g) and ethanol (60 ml) was stirred at 40 ° C. for 24 hours under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Toluene (30 ml) was added to the residue, and the mixture was heated under reflux for 48 hours. After that, the reaction mixture was concentrated under reduced pressure, and the residue was washed with diisopropyl ether to obtain the title compound (1.25 g). _{Mp: 182~183 ℃ NMR (CDCl 3)} δ; 1.39 (3H, t, J = 7Hz), 1.49 (6H, s), 4.36 (2H,
q, J = 7Hz), 6.84 (1H, d, J = 8Hz), 7.86 (1H, dd, J = 8,2Hz), 7.90
. (1H, br), 8.00 (1H, d, J = 2Hz) ( as C ₁₃ H ₁₅ NO ₃ S) Elemental analysis: Calculated (%) C, 58.85; H , 5.70; N, 5.28 Analytical value (%) C, 58.84; H, 5.73; N, 5.20

Reference Example 15 2,2-Dimethyl-4-isopropyl-3-oxo-
3,4-dihydro-2H-benzo [1,4] thiazine-
Ethyl 7-carboxylate [in the formula (IIIb), R ^{1 ′}
Is an isopropyl group, and R ² and R ³ are methyl groups
] : Ethyl 2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-7-carboxylate (see Reference Example 14) (1.15 g), 2-iodopropane (2.2 g), 40% potassium fluoride-alumina (3.10 g) and 1,2-dimethoxyethane (3
0 ml) was stirred at 60 ° C. for 22 hours. The reaction mixture was filtered, a 14% (w / v) solution of hydrogen chloride in dioxane (0.5 ml) was added to the filtrate, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture under reduced pressure, 2-iodopropane (2.2 g), 40% potassium fluoride-alumina (3.
10 g) and 1,2-dimethoxyethane (30 ml)
Was added and stirred at 60 ° C. for 15 hours. The reaction mixture was filtered and the filtrate was treated with 14% (w / v) hydrogen dioxane (0.1%).
5 ml), and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane:
Purification with ethyl acetate (10: 1 and chloroform) gave the title compound (0.80 g) as an oil. NMR (CDCl ₃ ) δ; 1.37 (6H, s), 1.40 (3H, t, J = 7 Hz), 1.52 (6H,
d, J = 7Hz), 4.37 (2H, q, J = 7Hz), 4.66-4.72 (1H, m), 7.23 (1H,
d, J = 9 Hz), 7.90 (1H, dd, J = 9.2 Hz), 8.04 (1H, d, J = 2 Hz). Elemental analysis value (as C ₁₆ H ₂₁ NO ₃ S.1 / 3H ₂ O) : Calculated value (%) C, 61.32; H, 6.75; N, 4.47 Analysis value (%) C, 61.62; H, 6.72; N, 4.40

Reference Example 16 2,2-Dimethyl-4-isopropyl-3-oxo-
3,4-dihydro-2H-benzo [1,4] thiazine-
7-carboxylic acid [in the formula (VIII), R ¹ is
A compound in which a propyl group, R ² and R ³ are methyl groups and n is 0
] : Ethyl 2,2-dimethyl-4-isopropyl-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-7-carboxylate (see Reference Example 15) (0.8
0 g) was heated to reflux in concentrated hydrochloric acid (20 ml) for 21 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue.
After extraction with ethyl acetate and washing with an aqueous sodium hydrogen carbonate solution, the solvent was distilled off under reduced pressure. The residue was washed with diisopropyl ether to obtain the title compound (0.34 g). Melting point: 134-135 ° C. NMR (CDCl ₃ ) δ; 1.38 (6H, s), 1.52 (3H, d, J = 7 Hz), 1.55 (3H,
d, J = 7Hz), 4.60-4.80 (1H, m), 7.26 (1H, d, J = 9Hz), 7.95 (1H, m
dd, J = 9.2 Hz, 8.10 (1H, d, J = 2 Hz). Elemental analysis value (as C ₁₄ H ₁₇ NO ₃ S.1 / 3H ₂ O): Calculated value (%) C, 58.94 H, 6.01; N, 4.90 Analytical value (%) C, 59.08; H, 5.93; N, 4.79

Reference Example 17 2,2-Dimethyl-4-isopropyl-3-oxo-
3,4-dihydro-2H-benzo [1,4] thiazine-
7-carbonyl chloride [in the formula (VII), R
¹ is an isopropyl group, R ² and R ³ are methyl groups, n is 0
Certain compound] : 2,2-dimethyl-4-isopropyl-
3-oxo-3,4-dihydro-2H-benzo [1,
4] Thiazine-7-carboxylic acid (see Reference Example 16)
(0.30 g) and thionyl chloride (15 g).
The mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure,
The title compound (0.32 g) was obtained. _{NMR (CDCl 3) δ; 1.38} (6H, s), 1.53 (6H, d, J = 7Hz), 4.66-4.7
5 (1H, m), 7.28 (1H, d, J = 9Hz), 7.97 (1H, dd, J = 9,2Hz), 8.12
(1H, d, J = 2Hz).

Claims (10)

[Claims] 1. A compound represented by the following formula (I): (Wherein, R ¹ represents a hydrogen atom or a lower alkyl group;
R ² and R ³ are the same or different and each represent a hydrogen atom or a C ₁ -C ₂ alkyl group, and n represents 0 or 2. The substitution position of the guanidinocarbonyl group is 6-position or 7-position
Rank. Or a pharmacologically acceptable salt thereof. 2. The benzo [1,4] thiazine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is an ethyl group or an isopropyl group. 3. N- (4-isopropyl-3-oxo-
3,4-dihydro-2H-benzo [1,4] thiazine-
6-carbonyl) guanidine or a pharmacologically acceptable salt thereof. 4. A medicament comprising the benzo [1,4] thiazine derivative according to claim 1 or a pharmacologically acceptable salt thereof. 5. The medicament according to claim 4, which is used as a Na ⁺ / H ⁺ exchange mechanism inhibitor. 6. The medicament according to claim 4, for preventing and treating ischemia / reperfusion injury. 7. The medicament according to claim 4, for preventing and treating ischemic heart disease. 8. The medicament according to claim 7, for preventing and treating cardiac dysfunction. 9. The medicament according to claim 7, for preventing and treating myocardial necrosis. 10. The medicament according to claim 7, for preventing and treating arrhythmia.