WO1998013357A1

WO1998013357A1 - Benzo[1,4]thiazine derivatives and drugs comprising the same

Info

Publication number: WO1998013357A1
Application number: PCT/JP1997/003373
Authority: WO
Inventors: Takeshi Yamamoto; Ikuo Watanabe; Kengo Harada; Shoji Ikeda
Original assignee: Kanebo Limited
Priority date: 1996-09-25
Filing date: 1997-09-22
Publication date: 1998-04-02
Also published as: JPH10152481A

Abstract

Benzo[1,4]thiazine derivatives represented by general formula (I) or pharmacologically acceptable salts thereof, wherein R1 represents hydrogen or lower alkyl; R?2 and R3¿ are the same or different and each represents hydrogen or C¿1-2? alkyl; n is 0 or 2; and the guanidinocarbonyl substituent is attached to the 6- or 7-position. These compounds exhibit an excellent inhibitory effect on the Na?+/H+¿ exchange system. Thus, drugs containing these compounds as the active ingredient are useful as preventives and remedies for disorders induced by intracellular acidosis at myocardial ischemia, for example, heart action disorders, myocardial necrosis and irregular pulse observed in ischemic heart diseases such as myocardial infarct and angina pectoris.

Description

Specification

[1,4] Thiazine derivatives and pharmaceuticals comprising them

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, the following formula (I) having an action of inhibiting the Na ⁺ / H ⁺ exchange mechanism

(I)

(Wherein, R ¹ represents a hydrogen atom or a lower alkyl group, R ² and R are the same or different and represent a hydrogen atom or a C ₂ alkyl group, and n represents 0 or 2. guanidinocarbonyl The substitution position of the group is the 6-position or the 7.-position.) The present invention relates to a benzo [1,4] thiazine derivative represented by the formula or a pharmacologically acceptable salt thereof, and a drug comprising the same.

¾¾¾¾

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 is increased, 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 the osmotic pressure difference between the inside and outside of the cell, causing an increase in cell volume and edema [Biochimica et Biophysica Acta, 988, 73-97 (1989)]. In cells that have a Na + / Ca2 ⁺ exchange mechanism, such as myocardium, sodium ions that are excessively accumulated due to the enhancement of the Na + / H2 + exchange mechanism are pumped out via the Na + / Ca2 ⁺ exchange mechanism, and are instead replaced by intracellular cells. Calcium ions flow into the system. It has been reported that excessive accumulation of calcium ions causes cardiac dysfunction, myocardial necrosis and arrhythmias [Journal of Cardiovascular Pharmacology, 23, 72-78 (1994)]. Thus, compounds that inhibit the Na + / H + exchange mechanism may be useful for disorders induced by intracellular acidosis during myocardial ischemia, such as ischemia such as myocardial infarction and angina. It can be used as a prophylactic and therapeutic agent for cardiac dysfunction, myocardial necrosis and arrhythmias found in sexual heart disease. In addition, compounds that inhibit the Na ⁺ / H + exchange mechanism may be caused by ischemia, reperfusion injury, such as organ transplantation, coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), or thrombolytic therapy. It can be used as a medicine for the resulting disorders.

Furthermore, it is known that the Na + / H ⁺ exchange mechanism is deeply involved in cell proliferation induced by growth factors or hormones [Biochimica et Biophysics Acta, 988, 73-97 (1989)]. Therefore, compounds that inhibit the Na + / H ⁺ exchange mechanism are therapeutic agents for diseases caused by abnormal cell proliferation, such as restenosis after PTCA, arteriosclerosis, fibrosis, prostatic hypertrophy, and diabetic complications. there is a possibility. In addition, the enhancement of the Na + / H ⁺ exchange mechanism not only increases vascular smooth muscle cell proliferation but also increases fluid volume, and is considered to be involved in the development of essential hypertension [Diagnosis and treatment, 81, 2209-2213 ( 1993)] Thus, compounds that inhibit the Na + / H ⁺ exchange mechanism may have therapeutic potential for essential hypertension.

Conventionally, compounds having an inhibitory effect on the Na ⁺ / H + exchange mechanism include amyloid rides represented by the following formula (II) and derivatives thereof, benzoylguanidine derivatives, indoloyluguanidine derivatives, and benzo [1,4〗 Oxazine derivatives and the like are known.

2 _(π)

That is, Japanese Patent Publication No. Sho 42-6249 and The Journal of Biological Chemistry, 259, 4313-4319 (1984) describe amiguchi rides and their derivatives as disclosed in JP-A-3-106858, JP-A-6-41049 and Kaihei 6-1 16230, JP-A-6-228082, JP-A-6-234730, JP-A-7-206823, JP-A-7-267926, JP-A-8-41028, JP-A-8-73427, etc. Is a benzoylguanidine derivative, and JP-A 7-10839 discloses And benzo [1,4] oxazine derivatives are disclosed in US Pat.

However, the benzo [1,4] thiazine derivative of the present invention having an Na + / H ⁺ exchange mechanism inhibitory action is not known.

The present inventors have made various studies for the purpose of providing a novel compound having a Na ⁺ / H + exchange mechanism inhibitory action and a medicament comprising the same.

Disclosure of the invention

As a result of various studies, the present inventors have found that the novel benzo [1,4] thiazine derivative represented by the formula (I) and a pharmacologically acceptable salt thereof have excellent Na ⁺ / H + exchange mechanism. The inventors have found that they have an inhibitory action, and completed the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

In the 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 preferable. The R ^2, an alkyl group of Ci -C ₂ of R ^3, methyl group, and E Ji Le group. Further, 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 the stereoisomer (optical activity ), But these stereoisomers, mixtures and hydrates thereof 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-13,4-dihydro-2H-benzo [1,4] thiazine-16-carbonyl) guanidine and N— (4 —Ethyl-3—oxo-1,3 dihydro— 2 H—Venzo [1,4] thiazine—6—carbonyl) guanidine, N— (4-Isopropyl-3-oxo—3,4 dihydro 2H— benzo [1, 4] thiazine one 6-carbonyl) guanidine, N-(4-isopropyl-one 1, 1, 3-Toriokiso 1, 2, 3, 4 Tetorahi chondroitinase 1 scan ⁶ - base down zone [1, 4] Thiazine-1-6-carbonyl) guanidine, N- (3-oxo-3,4-dihydro 2H-benzo [1,4] thiazin-6-carbonyl) guanidine, N- (4-isopropyl-2--2-) Methyl-3-oxo-1,3,4-dihydro-2H-benzo [1.4] thiazine-16-carbon) guanidine, N— (2, 2-Dimethyl 4-isopropyl-1 3-oxo-1 3,4-dihydro-2H-benzo [1,4] thiazine-7-carbonyl) guanidine.

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, and carbonic acid, or acetic acid, lactic acid, citric acid, and tartaric acid. And salts with organic acids such as methanesulfonic acid and p-toluenesulfonic acid.

Of the compounds of the present invention, N- (4-ethyl-3-oxo-3,4-dihydro2H-benzo [1,4] thiazine-6-carbonyl) guanidine, N- (4-isopropyl-1-oxo) 1,3,4-dihydro-2H-benzo [1.4] thiazine — 6-carbonyl) guanidine, N— (4-isopropyl-1,1,3-trioxo-1,2,3,4-tetrahydro- ⁶ —Venzo [1,4] thiazine-1-6-carbonyl) guanidine, N— (4-isopropyl-1-2-methyl-3-oxo-4,4 dihydro-2H-benzo [1,4] thiazine-1-6-carbonyl) Guanidine, N- (2,2-dimethyl-4-isopropyl-13-oxo-1,3,4-dihydro-2H-benzo [1,4] thiazine-17-carbonyl) Guanidine and their pharmacologically acceptable Salts, for example, methanesulfonate, are preferred conjugates. And the like. Among them, N- (4-monoisopropyl-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6-carbonyl) guanidine is mentioned as a particularly preferred compound.

Compound (I) of the present invention and a pharmacologically acceptable salt thereof can be produced, for example, according to the following Method A.

[Method A]

(ΠΙ) I

(Wherein R ¹ , R ² , R ³ and n are the same as above. Et represents an ethyl group, ethoxy o The carbonyl or guanidinocarbonyl group is substituted at the 6-position or the 7-position. That is, the compound (I) of the present invention is prepared by mixing a compound (III) and 1 to 20 equivalents of guanidine with respect to the compound (III) in an inert solvent from room temperature to the boiling point of the solvent for 1 to 24 times. It can be produced by reacting for 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-dimethoxetane, dimethylformamide, dimethylsulfoxide, and the like, or a solvent obtained by appropriately mixing them.

As the base, a metal carbonate such as potassium carbonate, a metal hydride such as sodium hydride, or a metal alkoxide such as sodium methoxide can be used.

The pharmacologically acceptable salt of the compound (I) of the present invention can be produced by reacting the above-mentioned inorganic acid or organic acid with the compound (I) obtained by the above production method according to a conventional method. it can.

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.

The compound (III) [compound (I lia, II lb) where n is 0 and compound (III c) where n is 2] used as a raw material in the above Method A can be produced, for example, by the following method. it can.

(Wherein, 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 positions of the carboxyl group and the ethoxyquin carbonyl group are represented by the formula

In (IV), (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

In (I I I c), it is the 6th or 7th position. )

That is, a 2-octoronitrobenzene derivative (IV) is reacted with a thioglycolate ethylyl derivative such as thioglycolate ethyl ester in the presence of a base such as pyridine or potassium carbonate to form a thioether (V), which is then acid-catalyzed in ethanol. Esters in the presence of to give compound (VI). When the compound (VI) is reduced in the presence of a catalyst such as PdZC in an alcohol in a hydrogen atmosphere, the ring-closure reaction also proceeds, and the compound (Ilia) is obtained. If the ring closure reaction is incomplete after the reduction reaction, the ring closure reaction is completed by heating in toluene to obtain (Ilia).

Compound (II lb) was added to compound (I lia) in an inert solvent such as dimethylformamide, tetrahydrofuran, or dimethoxetane, and potassium t-butoxide, It can be produced by reacting an alkyl halide (R ¹ X) in the presence of a base such as 40% potassium fluoride-alumina.

The compound (IIIc) is obtained by adding the compound (IIIa) or (II lb) obtained by the above method to a benzoate such as potassium peroxomonosulfate or potassium peroxodisulfate, or m-chloroperbenzoic acid. It can be produced by oxidizing an organic peroxide.

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

[Method B]

(I)

(In the formula, R ¹ , R ² , R ³ , and n are the same as described above. The substitution position of the carbonyl group and the guanidino carbonyl group is the 6-position or the 7-position.)

That is, the compound (I) of the present invention is prepared by mixing the compound (VII) and 1 to 20 equivalents of guanidine with respect to the compound (VII) in an inert solvent at room temperature to the boiling point of the solvent for 1 to 24 times. It can be produced by reacting for hours.

In the above production method, guanidine can be used for 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.

The compound (I) of the present invention or a pharmacologically acceptable salt thereof may be, if necessary, Recrystallization from a water-containing solvent such as a water-containing alcohol can lead to hydrates of these compounds.

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

(VI) (1)

(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 the carbonyl group is the 6-position or the 7-position.)

That is, compound (VII) can be produced by reacting compound (VIII) with a quenching agent such as thionyl chloride according to a conventional method. The compound (VIII) used in the above-mentioned production method is prepared by first producing a compound (III) in the same manner as in the production method of the starting compound in the above-mentioned Method A. It can be produced by hydrolysis with a method such as

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 a disorder induced by intracellular acidosis at the time of myocardial ischemia. It can be used as a preventive and therapeutic agent for cardiac dysfunction, myocardial necrosis and arrhythmia seen in ischemic heart diseases such as infarction and angina. It can also be used as a medicament for ischemia and reperfusion injury, for example, for organ transplantation, CABG, PTCA and other disorders caused by surgery and thrombolytic therapy.

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

Oral dosage forms include tablets, granules, powders, fine granules, hard capsules and the like.

Such preparations can be manufactured in a conventional manner, and may be tablets, granules, powders or fine granules. Is a compound (I) of the present invention or a pharmaceutically acceptable salt thereof, and a commonly used pharmaceutical additive such as lactose, corn starch, crystalline cellulose, magnesium stearate, hydroxypropylcellulose, talc, etc. And hard capsules are prepared by appropriately filling the above-mentioned fine granules or powders into capsules.

Parenteral dosage forms include injections and the like.

These preparations can be manufactured by a conventional method. For example, an injection is a compound of the present invention.

(I) or a pharmacologically acceptable salt thereof is dissolved or emulsified in purified water for injection, physiological saline or a fatty excipient, for example, vegetable oil, oily emulsion, glycol, or the like, and sterilized in a sample or vial. It is manufactured by encapsulating it. In addition, it can be obtained by dissolving in a stabilizer and purified water as appropriate as a freeze-dried preparation to be dissolved at the time of use, and freeze-drying by an ordinary method.

The dose of the compound of the present invention may vary depending on the patient's condition, administration route, age, body weight, etc., but generally ranges from 0.1 to 100 mg as the compound (I) of the present invention per adult. This is administered once or in two or three divided doses. It can also be increased as needed.

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

Therefore, a drug comprising the compound U) of the present invention and a pharmacologically acceptable salt thereof is useful for a disorder induced by intracellular acidosis during myocardial ischemia, for example, ischemic diseases such as myocardial infarction and angina It is useful for preventing and treating cardiac dysfunction, myocardial necrosis and arrhythmias seen in heart disease. It is also useful for the prevention and treatment of ischemia / reperfusion injury, for example, damage caused by surgery or thrombolytic therapy such as organ transplantation, CABG, PTCA and the like.

Hereinafter, the effects of the compound of the present invention will be described with reference to Test Examples.

Test example 1

Na + ZH + exchange mechanism inhibitory action: The inhibitory effect of the Na ⁺ / H ⁺ exchange mechanism is based on the inhibitory effect of the test compound on sodium propionate-induced platelet swelling according to the method of Rosskoph et al. [Journal of Hypertension, 9, 23 238 (1991)]. We considered it as an index.

1) Test compound

Compounds of Examples 1, 2, 3, 4, 5, 7 and 8 (Compounds of the Invention)

Ami-mouth ride (control compound)

2) Test method

First, platelet-rich plasma was prepared according to the method of Mamen et al. [Diabetes Research and Clinical Practice, 9 (3), 265-272 (1990)]. That is, Wistar male rats (body weight: 230 to 300 g) were laparotomized under ether anesthesia, and blood was collected from the abdominal aorta. Add ACD solution (a mixture of 65 mM citric acid, 85 mM sodium citrate, and 11 mM dextrose) to suppress clotting, centrifuge (90 X g, 10 minutes), collect supernatant, and collect platelet-rich plasma Was prepared. Next, a test compound solution (dissolved in dimethyl sulfoxide) is added to a 14 OmM sodium propionate buffer solution, and then the platelet-rich plasma prepared above is added, and a platelet aggregometer (turbidimeter) and XY The decrease in optical density at 37 ° C was recorded over time with a recorder, and the decrease in optical density after mixing with platelet-rich plasma was determined.

[Degree of 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 the decrease in optical density was recorded in the same manner, and the degree of decrease in optical density was determined [Control (C)]. Next, the expansion rate (%) was calculated by the following equation.

Swelling suppression rate (%) = (1 -D / C) X 100

Next, the concentration (IC _5Q ) at which the inhibition rate became 50% by the test compound was calculated by the least square method.

3) Test results

The results are shown in Table 1. Test compound Compound of Example 1 0.012 Compound of Example 2 0.0091 Compound of Example 3 Ό.Ό Δ Compound of Example 4 0.19 Compound of Example 5 0.051 Compound of Example 7 0.018 Compound of Example 8 U 0.053 Mouth Ride 13 ~ '

Test example 2

Inhibitory effects on re-arrhythmia:

The inhibitory effect on reperfusion arrhythmia was examined using a rat acute myocardial infarction model according to the method of Tagliavini et al. [European 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 rats (body weight: 310 to 50 g) were anesthetized by intraperitoneal administration of sodium pentobarbital (50 mgZkg). Under anesthesia, a force neuron was inserted into the trachea of the rat and connected to a ventilator. The electrocardiogram (lead II) was induced from electrodes attached to the limbs and measured via a bioelectric amplifier. Body temperature was maintained at 37 ° C. The rat was opened in the left intercostal space and the pericardium was incised to expose the heart. Next, the test compound is dissolved in a mixed solvent of polyethylene glycol 400, ethanol, and physiological saline (mixing ratio vZv, 3: 3: 14) and injected into the femoral vein. Was administered. 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 SEM, n = 5 to 7) was measured from the electrocardiogram. Arrhythmias were determined according to the guidelines of The Lambeth Convention [Cai "diovascular Research, 22, 447-455 (1988):".

In addition, as a control, the duration (seconds) of ventricular fibrillation when only a mixed solvent of polyethylene glycol 400, ethanol, and saline (mixing ratio vZv, 3: 3: 14) was administered was set as described above. Measured.

3) Test results

The results are shown in Table 2.

**: p <0.01 (Mann-Whitney U test)

Next, the present invention will be described more specifically with reference to examples and reference examples.

Example 1

N- (4-Isopropyl-1-3-oxo-3,4-dihidro 2 H-Venzo

[1, 4] thiazine-1-6-carbonyl) guanidine [In the formula (I), R ¹ is an isopropyl group, R ³ is a hydrogen atom, n is 0, and guanidinocarbonyl is substituted at position 6. Compound Ί:

4-Isopropyl-3-oxo-1,3,4-dihydro-2H-benzo [1,4] thiazine-6-carboxylate (See Reference Example 4) (0.70 g), guanidine hydrochloride (2.63 g) A mixture of sodium methoxide (1.35 g) and dimethyl sulfoxide (10 ml) was stirred at 120 ° C. for 1 hour. 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). 1 Melting point: 206-207 ° C

NR (DMS0-d ₆ ) 5; 1.54 (6H, d, J = 7Hz), 3.28 (2H, s), 4.61-4.72 (1H, m), 6.99 (4H, br),

7.36 (111, d, J = 8Hz), 7.83 (1H, dd, J = 8, 1Hz), 8.07 (1H, d, J = lHz).

Elemental analysis (as _{_{_{_{C 13 H 16 N 4 0 2}}}} S):

Calculated value (%) C, 53.41; H, 5.52; N, 19.16

Analytical value (%) C, 53.46; H, 5.54; N, 19.38

Example 2

N— (4-Isopropyl-1-oxo-3,4-dihydro-2H-benzo “1,4] thiazine-1-6-carbonyl) guanidine methanesulfonate In the formula (I), R ¹ is isopropyl Methanesulfonate of a compound (Example 1) in which the group, R ² and R ° are hydrogen atoms, n is 0, and the substitution position of the guanidinocarbonyl group is 6-position]:

N- (4-Isopropyl-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-1-6-carbonyl) guanidine (see Example 1) (0.20 g) of tetrahydrofuran ( 5 ml) The solution was added with methanesulfonic acid (66 mg) and concentrated. The residue was recrystallized from ethanol to give the title compound (0.20 g).

Melting point: 188-190. C

NMR (DMS0-d ₆ ) 5; 1.51 (6H, d, J = 7 Hz), 2.45 (3H, s), 3.44 (2H, s), 4.58-4.64 (1H, m),

7.64-7.76 (3H, m), 8.42 (4H, br), 11.37 (1H, br).

Elemental analysis (as _{_{_{_{C 13 H 16 N 4 0 2}}}} S · CH 3 S0 3 H):

Calculated value (%) C, 43.29; H, 5.19; N, 14.42

Analytical value (%) C, 43.07; H, 5.28; N, 14.36

Example 3

N-(4 one isopropyl one 1, 1. 3 trioxo - 1.2, 3, 4 Tetora hydro - 1 scan ⁰ - benzo "1, 4, thiazine one 6-carbonyl). Guanidine methane sulfonate" formula In (I), methanesulfonate of a compound in which R ¹ is an isopropyl group, R ² and R ³ are hydrogen atoms, n is 2, and the guanidinocarbonyl group is substituted at the 6-position, 4 one isopropyl one 1, 1, 3-trioxo one 1, 2, 3, 4 Tetorahidoro one 1 lambda ⁶ one base emission zone [1, 4] thiazin-one 6-force carboxylic acid Echiru (see Reference Example 5)

A mixture of (1.00 g), guanidine hydrochloride (3.05 g), sodium methoxide (1.77 g) and dimethyl sulfoxide (15 m 1) was 120. The mixture was stirred at 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. Dissolve the residue in isopropyl alcohol and add 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).

Melting point: 261-263. C

NMR (DMSO-d ₆ ) 5; 1.51 (6H, d, J = 7 Hz) 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), 11.52 (1H, br). elemental analysis _{_{_{(C 13 H 16 N 4 0}}} 4 S · as CH _₃ S0 ₃ H):

Calculated value (%) C, 39.99: H, 4.79;, 1 3.32

Analytical value (%) C, 39.86; H, 4.93; N, 12.92

Example 4

N— (4-methyl-13-oxo-1,3,4-dihydro-2H-benzo 门 .41 thiazine-6-carbonyl) guanidine methanesulfonate “In the formula (I), R ¹ is a methyl group, R ² A methanesulfonate of a compound in which R ³ is a hydrogen atom, n is 0, and the substitution position of the guanidinocarbonyl group is 6:

4-Methyl-3-oxo-1,3,4-dihydro-12H-benzo [1,4] thiazin-6-potassium ethyl ester (see Reference Example 6) (1.40 g), guanidine hydrochloride ( A mixture of 5.94 g), sodium methoxide (3.05 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 filtered off, dried, the residue was dissolved in methanol, methanesulfonic acid (0.36 g) was added, and the mixture was concentrated and recrystallized from methanol-water. The title compound (0.27 g) was obtained.

Melting point: 23-233 ° C

NMR (DMSO-dg) 5; 2.43 (3H, s), 3.43 (3Η, s), 3.61 (2H, s), 7.60-7.71 (3Η, m), 8.43 (4H, br), 11.35 (1H, br) ). Elemental analysis (as _{_{_{_{C U H 12 N 4 0 2}}}} S · CH 3 S0 3 H): Calculated (%) C, 39. 99; H, 4. 47; N, 1 5. 50

Analytical value (%) C. 39.93; H, 4.57; N, 15.59

Example 5

N— (4-Ethyl-3-oxo-1,3,4-dihydro-2H-benzo “1.41 Thiazine-16-carbonyl” guanidine methanesulfonate [In the formula (I), R ¹ is an ethyl group, R , R ⁰ hydrogen atom, n force 0, guanidinocarbonyl group The substitution position of the methanesulfonate of the compound at position 6 ：:

4-Ethyl-3-oxo-1,3,4-dihydro-1H-benzo [1,4] thiazin-6-potassium ethyl ester (see Reference Example 7) (1.50 g), guanidine hydrochloride (5.94 g) A mixture of sodium methoxide (3.05 g) and dimethyl sulfoxide (15 ml) was stirred at 120 for 2 hours. After cooling, water was added to the reaction mixture, and the precipitated solid was taken into consideration. After drying, the residue was dissolved in methanol, methanesulfonic acid (0.14 g) was added, and the mixture was concentrated and recrystallized from methanol-water This gave the title compound (0.14 g).

Melting point: 232 ~ 234 ° C

_{MR (DMS0-d 6) 5} ; 1.18 (3H, t, J = 7Hz), 2.42 (3H, s), 3.58 (2H, s), 4.06 (2H, q, J = 7Hz), 7.59-7.68 (2H , M), 7.73 (1H, d, J = lHz), 8.43 (4H, br), 11.35 (1H, br).

Elemental analysis (as _{_{_{_{C 12 H 14 N 4 0 2}}}} S ♦ CH 3 S0 3 H):

Calculated value (%) C, 4 1.70; H, 4.85; N, 1 4.96

Analytical value (%) C, 4 1.68; H, 4.88: N, 15.09

Example 6

N— (3-oxo—3,4-dihydro-2H—benzo “1,41 thiazine-1-6 carbonyl” guanidine methanesulfonate “In the formula (I), R ¹ , R ² , and R ³ represent a hydrogen atom, Methanesulfonic acid salt of a compound in which n is 0 and the substitution position of the guanidinocarbonyl group is 6-position]:

3-oxo-1,3,4-dihydro-2H-benzo [1,4] thiazine-16-ethyl carbonate (see Reference Example 3) (2.37 g), guanidine hydrochloride (10.5 1 g) ), Sodium methoxide (5.40 g) and dimethyl sulfoxide (20 ml) was stirred at ¹²⁰ eC for 2 hours. After cooling, dilute hydrochloric acid was added to the reaction mixture to set 11 to 11, and 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).

Melting point: 263-264 ° C

NMR (DMS0-d ₆ ) δ; 2.40 (3H, s), 3.57 (2H, s), 7.52-7.60 (3H, m), 8.35 (4H, br), 10.77 (1H, br), 11.20 (lH, br).

Elemental analysis (as _{_{_{_{C 10 H 10 N 4 0 2}}}} S · CH 3 S0 3 H):

Calculated value (%) 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-13-oxo-1,3,4-dihydro-2H-benzo [1,4] thiazine-6-carbonyl) guanidine.Methanesulfonic acid salt In the formula (I), R Methanesulfonic acid salt of a compound in which ¹ is an isopropyl group, one of R ² and R ^J is a hydrogen atom, the other is a methyl group, n is 0, and the substitution position of the guanidinocarbonyl group is 6-position]:

4-Isopropyl-2-methyl-1-oxo-3,4-dihydro 2 H-benzo [1.4] thiazine-6-ether ethyl ester (see Reference Example 11) (2.00 g), A mixture of guanidine hydrochloride (6.52 g), potassium carbonate (9.43 g) and dimethyl sulfoxide (20 ml) 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, dissolved in ethyl acetate, 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).

Melting point: 183-185. C

NMR (D S0-d ₆ ) <5; 1.29 (3H _t d, J = 7 Hz), 1.45 (3H, d, J = 7 Hz), 1.46 (3H, d, J = 7 Hz), 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), lL38 (lH, br) .

Elemental analysis (as _{_{_{_{C 14 H 18 N 4 0 2}}}} S · CH 3 S0 3 H):

Calculated value (%) C, 44.76; H, 5.51; N, 1 3.92 Analytical value (%) C, 44.68; H, 5.48: N, 13.93

Example 8

N- (2,2-Dimethyl-4-isopropyl-1-oxo-3,4-dihydro-2H-benzo [1.4] thiazine-1 7-carbonyl) guanidine.methanesulfonate [Formula (I) Wherein R ¹ is an isopropyl group, R ² and R ³ are methyl groups, n is 0, and the substitution position of the guanidinocarponyl group is 7-position.

To a methanolic solution of sodium methoxide prepared from sodium (0.46 g) and methanol (20 ml) was added guanidine hydrochloride (1.91 g), and the mixture was stirred at room temperature for 1 hour and filtered. The solvent was distilled off under reduced pressure, and a mixture of the obtained residue and 1,2-dimethoxyxetane (15 ml) was added to 2,2-dimethyl-4,1-isopropyl-13-oxo-1,3,4-dihydro-2H-benzo. [1,4] thiazine-7-carbonyl chloride (see Reference Example 17) (0.32 g) of 1,2-dimethoxetane

(15 ml) solution was added and stirred for 5 minutes. After the reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The solvent is distilled off under reduced pressure, and the residue is 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 obtain the title compound (21 Omg).

Melting point: 205-206 ° C

NMR (DMS0-d ₆ ) 5; 1.31 (6H, s), 1.45 (6H, d, J = 7 Hz), 2.32 (3Η, s), 4.60-4.75 (IH, m), 7.59 (IH, d, J = 9Hz), 7.87 (IH, dd, J = 9, 2Hz), 7.98 (IH, d, J = 2Hz), 8.26 (4H, br), 11.20 (IH, br).

Elemental analysis _{_{_{(C 15 H 20 N 4 0}}} 2 S · CH 3 S0 3 H - as 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

Formulation example (injection):

N- (4-Isopropyl-1-3-oxo-3,4-dihydro 2H-benzo [1,4] thiazine-6-carbonyl) guanidine methanesulfonate (implemented Dissolve 1 g in purified water for injection to make 10 Oml, filter aseptically with a membrane filter (0.2 / m), dispense 1 ml into ampoules, and seal. It is then sterilized at 120 ° C for 20 minutes.

Example 10

Formulation example (tablet):

Prescription

Compounding amount

N— (4-Isopropyl-1-3-oxo-1,3,4-dihi draw

2H-benzo [1,4] thiazine-6-carbonyl)

Guanidine methanesulfonate (compound of Example 2) 5 Lactose 77.5 Maize starch 28 Microcrystalline cellulose 25 Hydroquinopropyl cellulose 3.5 Magnesium stearate 1

Total 140

(Operation) The above ingredients are mixed uniformly and compressed into tablets of 14 Omg per tablet.

Reference example 1

4-Itoquincarbonylmethylsulfanyl 3-nitrobenzoic acid [Compound of formula (V) wherein R ² and R ³ are hydrogen atoms]:

(4) A mixture of (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: 1 59-161. C

NR (DMS0-d ₆ ) <5; 1.18 (3H, t, J = 7Hz), 4.12 (2H, q, J = 7Hz), 4.17 (2H, s), 7.70 (1H, d, J = 9Hz), 8, 15 (1H, dd, J = 9, 2Hz), 8.63 (1H, d, J = 2Hz), 13.46 (1H, br).

Elemental analysis value (as C ^ HnNOe S): Calculated value (%) 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-ethyl nitrobenzoate [Compound of formula (VI) wherein R ² and R ³ are hydrogen atoms]:

A mixture of 4-ethoxycarbonylmethylsulfanyl-3-nitrobenzoic acid (see Reference Example 1) (30 g), concentrated sulfuric acid (5 ml) and ethanol (30 Oml) was heated to 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.

Melting point: 66-67 ° C

NMR (CDClo) (5; 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 (IH, d, J = 9Hz), 8.18 (IH, dd, J = 9, 2Hz), 8.85 (IH, d, J = 2Hz).

Elemental analysis (as _{_{_{C 13 H 15 N0 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- Okiso one 3, 4 dihydric chondroitinase 2 H- benzo门, in 41 thiazine one 6-local bon acid Echiru "Formula (III _a), compound R ^2, R ³ is a hydrogen atom L:

4-ethoxycarbonylmethylsulfanyl-3-ethyl-2-ethyl benzoate (See Reference Example 2) (31 g), 10% Pd / C (3.1 g) and ethanol (300 ml) in a hydrogen atmosphere Stirred at 50 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). A part of this, recrystallized from ethyl acetate-hexane, showed the following physical properties.

Melting point: 159-160. C NMR (CDCI3); 51.39 (3H, t, J = 7 Hz), 3.46 (2H, s), 4.37 (2H, q, J = 7 Hz), 7.37 (IH, d, J =

8Hz), 7.50 (1H, d, J = 2Hz), 7.69 (IH, dd, J = 8, 2Hz), 7.92 (IH, br).

Elemental analysis value (as CnHnNOg S):

Calculated value (%) 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-1,3,4-dihydro-2H-benzo [1,41 thiazine-16-potassium ethyl ester "In the formula (II lb), R '' is an isopropyl group, R ² , R Compound 1 in which ³ is a hydrogen atom:

3-oxo-1,3,4-dihydro-2H-benzo [1,4] thiazine-1-6-ethyl carbonate (see Reference Example 3) (5.70 g), 2-iodopropane (6.

A mixture of 12 g), potassium t-butoxide (3.14 g) and tetrahydrofuran (57 ml) was stirred at 60 ° C for 16 hours, and then 2-odopropane (3.06 g) and potassium t-butoxy ( 1.57 g) was added, and the mixture was stirred at 60 with further stirring 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 purified by column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (3.38 g) as an oil.

麵 (CDClo); 51.39 (3H, t, J = 7Hz), 1.53 (6Η, d, J = 7Hz), 3.31 (2H, s), 4.42 (2H, q, J = 7Hz), 4.63-4.74 (1H , Ra), 7.43 (IH, d, J = 8 Hz), 7.67 (IH, dd, J = 8, 1 Hz), 7.89 (1H, d, J = 1 Hz).

Elemental analysis (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 one 1, 1, 3-trioxo one 1.2, 3, in 4 Tetorahidoro one 1 lambda ⁶ one base emission zone "1.41 thiazine one 6-force carboxylic acid Echiru" formula (III c), R ¹ Is an isopropyl group, and compound 1 in which R ² and R ³ are hydrogen atoms:

4-Isopropyl-1-3-oxo-1,3,4-dihydro-2Η-benzo [1,4] Thiazine—6-ethyl propionate (See Reference Example 4) (1.80 g), potassium peroxomonosulfate (OXONE ^™ , Aldrich) (7.80 g), ethanol

After stirring a mixture of (10 m 1) and water (37 m 1) 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, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane: ethyl ester = 4: 1) to give the title compound as an oil.

(1.00 g) was obtained.

(CDClo); 51.43 (3H, t, J = 7Hz), 1.57 (6Η, 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 (1H, d, J = 8 Hz) '8.03 (1H, d, J = 1 Hz).

Elemental analysis (as _{_{_{C 14 H 17 N0 5 S)}}} :

Calculated value (%) C, 54.01; H, 5.50; N, 4.50

Analytical value (%) C, 54.02; H, 5.49; N, 4.25

Reference example 6

4 1-methyl-1,3-oxo-3,4-dihydro-1 2H-benzo "1,4] thiazin-6-ether ethyl ribonate" In the formula (II lb), R ¹ 'is a methyl group, R and R ³ are Compound 1 that is a hydrogen atom:

3-oxo-1,3,4-dihydro-2H-benzo [1,4] thiazine-16-ethyl carbonate (see Reference Example 3) (2.37 g), iodomethane (2.84 g), t A mixture of potassium butoxy (1.68 g) and tetrahydrofuran (24 ml) was stirred at room temperature for 1 hour, water was added, the precipitated solid was collected, dried, and recrystallized from diisopropyl ether to give the title compound (1 58 g) were obtained.

Melting point: 110-112. C

NMR (DMSO-d ₆ ) 5; 1.40 (3H, t, J = 7 Hz), 3.43 (2H, s), 3.49 (3H, s), 4.39 (2H, q, J = 7 Hz),

7.41 (1H, d, J = 8Hz), 7.69 (1H, dd, J = 8, 2Hz), 7.75 (1H, d, J = 2Hz).

Elemental analysis (as _{_{_{C 12 H 13 N0 3 S)}}} :

Calculated value (%) 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-1,3-oxo-1,3,4-dihydro-2H-benzo 1,4-thiazin-6-ethyl rubonate In formula (IIIb), R ¹ ′ is an ethyl group, R ² , R Compound 1 in which ³ is a hydrogen atom:

3-oxo-1,3,4-dihydro-1 2H-benzo [1,4] thiazine-16-ethyl carbonate (see Reference Example 3) (2.37 g), eodoethane (3.12 g), A mixture of potassium t-butoxide (1.68 g) and 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).

Melting point: 56-57 ° C

_{NMR (DMS0-d 6) 5} ; 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 (IH, d, J = 8Hz), 7.67 (IH, dd, J = 8, 2Hz), 7.81 (IH, d, J = 2Hz).

Elemental analysis (as _{_{_{C 13 H 15 N0 3 S)}}} :

Calculated value (%) C, 58.85; H, 5.70; N, 5.28

Analytical value (%) C, 58.80; H, 5.60; N, 5.25

Reference Example 8

4- (11-ethoxycarbonyldiethylsulfanyl) -13-nitrobenzoic acid In the formula (V), one of R ² and R ³ is a hydrogen atom, and the other is a methyl group.

(4) A mixture of monochloro-3-benzo-2-benzoic acid [Wako Pure Chemical Industries, Ltd.] (62.6 g), ethyl 2-methylthioglycolate (50 g) and pyridine (150 ml) for 20 hours Heated to reflux. 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, 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 (CDClo) δ; 1.25 (3Η, t, J = 7 Hz), 1.67 (3H, d, J = 7 Hz), 4.07-4.28 (3H, m), 7.73 (IH, d, J = 9 Hz), 8.24 ( IH, dd, J = 2, 9Hz), 8.88 (IH, d, J = 2Hz). Elemental analysis (as _{_{_{C 12 H 13 N0 6 S)}}} :

Calculated value (%) 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 -ethoxycarbonyldiethylsulfanyl) 1-3-nitrothyl monoethyl acrylate [In the formula (VI), a compound in which one of R ² and R ³ is a hydrogen atom and the other is a methyl group] :

A mixture of 4- (1-ethoxyquinolethylsulfanyl) -3-nitrobenzoic acid (see Reference Example 8) (73 g), concentrated sulfuric acid (7.3 ml) and ethanol (730 ml) was heated under reflux for 22 hours. The reaction mixture was concentrated under reduced pressure to one third volume, and neutralized by adding aqueous sodium carbonate solution. After extraction with ethyl acetate, the solvent was distilled off under reduced pressure to obtain an oily title compound (74 g). A part of this, purified by column chromatography (form: methanol = 10: 1), showed the following physical properties.

Thigh (CDC) 5; 1.23 (3H, t, J = 7Hz), 1.41 (3Η, t, J = 7Hz), 1.66 (3H, d, J = 7Hz), 4.09

(IH, q, J = 7Hz), 4.12-4.26 (2H, ra), 4.42 (2H, q, J = 7Hz), 7.68 (1H, d, J = 9Hz), 8.16 (IH, dd, J = 9 , 2Hz), 8.79 (IH, d, J = 2Hz).

Elemental analysis (as _{_{_{C 14 H 17 N0 6 S)}}} :

Calculated value (%) 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-1,3,4-dihydro-1H-benzo "1,4] thiazin-6-carboxylate" In the formula (IIIa), one of R ² and R ³ is a hydrogen atom, Compound in which the other is a methyl group]:

4- (1-ethoxycarbonylethylsulfanyl) ethyl 3--3-nitrobenzoate (see Reference Example 9) (40 g), 10% Pd / C (4.0 g) and ethanol (400 m 1) The mixture was stirred under a hydrogen atmosphere for 4 hours (TC for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with diisopropyl ether, and recrystallized from ethyl diisopropyl ether acetate to give the title compound. (1 8. 85 g) were obtained.

Melting point: 155-157 ° C

_{NMR (CDC1 3) 5; 1.39} (3H, t, J = 7Hz), 1.51 (3H, d, J = 7Hz), 3.59 (1H, q, J = 7Hz), 4.39 (2H, q, J = 7Hz) , 7.37 (IH, d, J = 8Hz), 7.56 (IH, d, J = 2Hz), 7.68 (IH, dd, J = 8, 2Hz), 8.38 (IH, br).

Elemental analysis (as _{_{_{C 12 H 13 N0 3 S)}}} :

Calculated value (%) C, 57.35; H, 5.21; N, 5.57

Analytical value (%) C, 57.46; H, 5.23; N, 5.38

Reference example 1 1

4-Isopropyl-2-methyl-3-oxo-1,3,4-dihydro-1 2H-benzo "1,41 thiazine-16-ether ethyl ester" In the formula (II lb), R ¹ 'is an isopropyl group, Compound in which one of ³ is a hydrogen atom and the other is a methyl group]:

2-methyl-1,3-oxo-3,4-dihydro-2H-benzo [1,4] thiazin-6-potassium ethyl ester (see Reference Example 10) (3.00 g), 2-hydroxy-1 After stirring a mixture of dopropane (6.09 g), 40% potassium fluoride-alumina (5.20 g) and 1,2-dimethoxetane (60 ml) at 60 ° C for 2 days, the reaction mixture was filtered. . A 14% (w / v) solution of dioxane hydrogen chloride (1.0 ml) was added, 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) as an oil.

_{NMR (CDC1 3) δ; 1.41} (3Η, t, J = 7Hz), 1.43 (3H, d, J = 7Hz), 1.51 (3H, d, J = 7Hz), 1.54

(3H, d, J = 7Hz), 3.36 (IH, q, J = 7Hz), 4.39 (2H, q, J = 7Hz), 4.78-4.62 (IH, m), 7.43 (IH, d, J = 8Hz) ), 7.68 (IH, dd, J = 8, 2Hz), 7.88 (IH, d, J = 2Hz).

Elemental analysis (as _{_{_{C 15 H 19 N0 3 S)}}} :

Calculated value (%) C, 61.41; H, 6.53; N, 4.77

Analytical value (%) C, 6 1.36; H, 6.61; N, 4.50

Reference Example 12 O

3- (1-ethoxycarbonyl-2-1-methylethylsulfanyl) -14-nithobenzoic acid [Compound 1 in which R ² and R ³ are methyl groups in the formula (V)]

3-Bromo-412-benzoic acid (3.70 g) [Journal of the American Chemical Society, 72, 28-32 (1950)], 2-mercapto-2-ethyl propionate (3.12 g) ) A mixture of [US2755278], potassium carbonate (4.1) and dimethylformamide (30ml) was stirred at 60 ° C for 24 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 (form: methanol = 4: 1) to give the title compound (5.14 g). A part of this, recrystallized from diisopropyl ether-hexane, showed the following physical properties.

Melting point: 86-87 ° C

NMR (CDCl) <5; 1.26 (3H, t, J = 7Hz), 1.57 (6H, s), 4.21 (2H, q, J = 7Hz) '7.87 (1H, d, J =

7Hz), 8.11 (1H, d, J = 7Hz), 8.31 (IH, s).

Elemental analysis (as _{_{_{C 13 H 15 N0 6 S)}}} :

Calculated value (%) C, 49.83; H, 4.83; N, 4.47

Analytical value (%) C, 49.81; H, 4.81; N, 4.36

Reference Example 13

3- (1-ethoxyquincarbonyl 1-methylethylsulfanyl) -41-2ethyl ethyl benzoate In the formula (VI), compounds in which R ² and R ³ are methyl groups

3-(1-Ethoxycarbonyl 1-methylethylsulfanyl) A mixture of 1,4,2-benzobenzoic acid (see Reference Example 12) (3.85 g), sulfuric acid (0.5 ml) and ethanol (30 ml) Was heated to reflux for 18 hours. The reaction mixture was concentrated to about 1/4 volume under reduced pressure, and water was added. After extraction with ether and washing with an aqueous solution of sodium hydrogen carbonate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 6: 1) to give the title compound (3.1) as an oil.

NMR (CDC1 ₃ ) δ; \ .25 (3Η, t, J = 7Hz), 1.42 (3H, t, J = 7Hz), l.56 (6H, s), 4.20 (2H, q, J2 7Hz) , 4.42 (2H, q, J = 7Hz), 7.83 (IH, d, J = 8Hz), 8.05 (IH, dd, J = 8, 2Hz), 8.23 (IH, d, J = O

2Hz).

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-13-oxo-1,3,4-dihydro-12 H-benzo [1,41 thiazine-7-ethyl carboxylate "In formula (IIIa), R ² and R ³ are methyl groups Compound 1:

3- (1-ethoxyquinone-l-methylethylsulfanyl) 141-2 ethyl benzoate (see Reference Example 13) (2.93 g), 10% Pd / C (0.30 g) And a mixture of 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). Melting point: 182 ~ 183 ° C

NR (CDC1 ₃ ) (5; 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).

Elemental analysis (as C ₁₃ H ₁₅ NO ₃ S):

Calculated value (%) 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-1-4-isopropyl-3-oxo3.4-dihydro-2H monobenzo [1,4] thiazine-17-ethyl ethyl rubonate [In formula (II lb), R ¹ ' Is an isopropyl group, and R ² and R ³ are methyl groups.

2,2-Dimethyl-3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-17-carboxylate (See Reference Example 14) (1.15 g), 2-hydroxypropane A mixture of (2.2 g), 40% potassium fluoride mono-alumina (3.10 g) and 1,2-dimethoxetane (30 ml) was used. The mixture was stirred at C for 22 hours. The reaction mixture was filtered, and the filtrate was added with 14% (w / v) dioxane hydrogen chloride (0. 5 ml) solution was added and 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-dimethoxetane (30 ml) were added, and the mixture was stirred at 60 ° C for 15 hours. The reaction mixture was filtered and the filtrate was added to 14% (w / v) dioxane hydrogen chloride.

(0.5 ml) solution was added, and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 10: 1 and chloroform) to give the title compound (0.80 g) as an oil.

_{NMR (CDC1 3) 5; 1.37} (6H, s), 1.40 (3H, t, J = 7Hz), 1.52 (6H, d, J = 7Hz), 4.37 (2H, q, J = 7Hz), 4.66-4.72 (IH, m), 7.23 (IH, d, J = 9Hz), 7.90 (1H, dd, J = 9, 2Hz), 8.04 (IH, d, J = 2Hz).

Elemental analysis (as _{_{_{C 16 H 21 N0 3 S ·}}} 1/3 H 2 ◦):

Calculated value (%) C, 6.1.32; H, 6.75; N, 4.47

Analytical value (%) C, 61.62; H, 6.72: N, 4.40

Reference Example 1 6

2,2-dimethyl-4-isopropyl-3-oxo-3,4-dihydro-2H monobenzo [1,4] thiazine-17-carboxylic acid "In the formula (VIII), R ¹ is an isopropyl group, Compound 1 in which R ² and R ³ are methyl groups and n is 0:

2,2-Dimethyl-1-4-isopropyl_3-oxo-1,3,4-dihydro-2H-monobenzo [1,4] thiazine-7-Ethyl rubonate (See Reference Example 15) (0.80 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 give the title compound (0.34 g).

Melting point: 1 3 4 to 1 3 5 ° C

Fiber (1 CDC) δ; 1.38 (6Η, s), 1.52 (3H, d, J = 7Hz), 1.55 (3H, d, J = 7Hz), 4.60-4.80 (IH, m), 7.26 (IH, d , J = 9Hz), 7.95 (IH, dd, J = 9, 2Hz), 8.10 (IH, d, J = 2Hz).

Elemental analysis value (as C ₁₄ H ₁₇ N〇 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-4,1-isopropyl-1,3-oxo-1,3,4-dihydro-2H-benzo "1,4] thiazine-17-carbonyl chloride [in the formula (VII), R ¹ is an isopropyl group, R ² , Compound 1 in which R ³ is a methyl group and n is 0:

2,2-Dimethyl-4-1-isopropyl-1,3-oxo-1,3,4-dihydro-2H-benzo [1,4] thiazine-7-carboxylic acid (See Reference Example 16) (0.30 g) A mixture of thionyl chloride (15 g) was heated at reflux for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.32 g).

NMR (CDClo) <5; 1.38 (6H, s), 1.53 (6H, d, J = 7Hz), 4.66-4.75 (1H, ra), 7.28 (1H, d, J = 9Hz), 7.97 (111, dd) , J = 9, 2Hz), 8.12 (1H, d, J = 2Hz)

Claims

The scope of the claims

1. The following formula (I)

(Wherein, R ¹ represents a hydrogen atom or a lower alkyl group, R ² and R are the same or different and represent a hydrogen atom or a C ₂ alkyl group, and n represents 0 or 2. guanidinocarbonyl The substitution position of the group is the 6-position or the 7-position.) The benzo [1, 4] thiazine derivative represented by) or its pharmacologically acceptable

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-13-oxo-1,3,4-dihydro-1 2H-benzo [1,4] thiazine-16-carbonyl) Guanidine or a pharmaceutically 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 and reperfusion injury.

7. The medicament according to claim 4, for prevention and treatment of 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.