JP2000072759A - 8-substituted benzo[1,4]oxazine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new 8-substituted benzo[1,4]oxazine derivative having an excellent Na+/H+ exchange mechanism-inhibiting action, and useful as a medicine for treating arterial sclerosis, restenosis after percutaneous transluminal coronary arteries angioplasty, etc. SOLUTION: A compound of formula I (R1 is a lower alkyl; R2, R3 are each H or a lower alkyl; X is a halogen or a lower alkoxy) or its pharmacologically acceptable salt, for example, N-(8-chloro-4methyl-3-oxo-3,4-dehydro-2H- benzo[1,4]oxazine-6-carbonyl)guanidine, etc. The above compound is obtained by reacting (A) a compound of formula II with (B) guanidine in an amount of 1-20 equivalents based on the component A in an inert solvent such as methanol under a temperature condition ranging from ice cooling to the boiling point of the solvent for about 1-24 hr.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel 8-substituted benzo [1,4] oxazine derivative or a pharmaceutically acceptable salt thereof. More specifically, the following formula (I) having an Na ⁺ / H ⁺ exchange mechanism inhibitory action

[0002]

Embedded image (Wherein, R ¹ represents a lower alkyl group, and R ² and R
³ represents the same or different and represents a hydrogen atom or a lower alkyl group, and X represents a halogen atom or a lower alkoxy group. 8) -substituted benzo [1,4] oxazine derivatives or pharmacologically acceptable salts thereof.

[0003]

2. Description of the Related Art The Na ⁺ / H ⁺ exchange mechanism is based on intracellular p
It is responsible for regulating H, 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 activity of this exchange mechanism is increased, 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, and the cell volume increases and edema occurs [Biochimica et Biophysica Acta, 988, 73-97 (1
989)]. 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. Calcium ions flow in. Excessive accumulation of calcium ions has been reported to cause cardiac dysfunction, myocardial necrosis and arrhythmias [Jou
rnal of Cardiovascular Pharmacology, 23, 72-78 (199
Four)]. Thus, compounds that inhibit the Na ⁺ / H ⁺ exchange mechanism are useful for disorders induced by 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 graft surgery (CABG), percutaneous transluminal coronary angioplasty (PTCA), and thrombolytic therapy. Can be used as a medicament for disorders caused by.

Further, 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 Ac].
ta, 988, 73-97 (1989)]. Thus, compounds that inhibit the Na ⁺ / H ⁺ exchange mechanism are useful for diseases caused by abnormal cell proliferation, such as percutaneous transluminal coronary angioplasty (PTCA)
It may be a treatment for later restenosis, arteriosclerosis, fibrosis, prostatic hypertrophy, diabetic complications, etc.

[0005] 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, 81, 2209-2213 (1993)], it is considered that a compound that inhibits the Na ⁺ / H ⁺ exchange mechanism may be a therapeutic agent for essential hypertension.

[0006] Various compounds are known as compounds having an Na ⁺ / H ⁺ exchange mechanism inhibitory action.

For example, Japanese Patent Publication No. 42-6249, The Jo
urnal of Biological Chemistry, 259, 4313-4319 (1984)
Discloses amiloride and its derivatives in JP-A-3-10
6858, JP-A-6-41049, JP-A-6-11
No. 6230, JP-A-6-228082, JP-A-6-2
No. 34730, WO94 / 26709, WO96 / 0
No. 4241, etc., a benzoylguanidine derivative, JP-A-7-10839, JP-A-8-208602, an indoloylguanidine derivative, and JP-A-8-2255.
No. 13 and the like, a naphthoylguanidine derivative, JP-A-8-277269, a quinolinecarbonylguanidine derivative, WO97 / 11055, an acryloylguanidine derivative, and JP-A-9-59245, a propenoylguanidine derivative. , WO 97/23476
JP-A-10-152481 discloses a benzothiazine derivative.

The benzo [1,4] oxazine derivative is also disclosed in JP-A-9-77753, but there is no description about the 8-substituted benzo [1,4] oxazine derivative of the present invention.

[0009]

SUMMARY OF THE INVENTION The object of the present invention is
An object of the present invention is to provide a novel compound having an inhibitory action on the ⁺ / H ⁺ exchange mechanism.

[0010]

As a result of various studies, the present inventors have found that novel 8-substituted benzo [1,4] oxazine derivatives represented by the above formula (I) and pharmacologically acceptable derivatives thereof. It has been found that the resulting salt has an excellent Na ⁺ / H ⁺ exchange mechanism inhibitory action, and the present invention has been completed.

[0011]

In the above formula (I), examples of the lower alkyl group for R ¹ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a cyclopentyl group and a cyclohexyl group. .
Especially, an ethyl group and an isopropyl group are preferable. R
Examples of the lower alkyl group for ² , R ³ include a methyl group,
Examples include an ethyl group, a propyl group, and a butyl group. X
Examples of the lower alkoxy group include a methoxy group and an ethoxy group.Examples of the halogen atom include chlorine,
Bromine and the like.

In the above formula (I), R ² , R ³
Are different substituents, the 2-position of the benzo [1,4] oxazine skeleton becomes an asymmetric carbon. Alternatively, R ^{1 to} R ³
It may itself contain an asymmetric carbon. In each case, stereoisomers (optically active forms) derived therefrom exist, and these stereoisomers and mixtures thereof are also included in the compounds of the present invention.

Specific examples of the compound (I) of the present invention include N
-(8-chloro-4-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carbonyl) guanidine, N- (8-chloro-4-ethyl-
3-oxo-3,4-dihydro-2H-benzo [1,
4] Oxazine-6-carbonyl) guanidine, N-
(8-chloro-4-isopropyl-3-oxo-3,4
-Dihydro-2H-benzo [1,4] oxazine-6-
Carbonyl) guanidine, N- (8-methoxy-4-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carbonyl) guanidine,
N- (4-ethyl-8-methoxy-3-oxo-3,4
-Dihydro-2H-benzo [1,4] oxazine-6-
Carbonyl) guanidine, N- (4-isopropyl-8)
-Methoxy-2,2-dimethyl-3-oxo-3,4-
Dihydro-2H-benzo [1,4] oxazine-6-carbonyl) guanidine, N- (8-chloro-4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [1 , 4] oxazine-6-carbonyl) guanidine, N- (8-bromo-4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6 Carbonyl) guanidine and the like.

Among the compounds of the present invention, N- (8-chloro-
4-ethyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carbonyl) guanidine, N- (8-chloro-4-isopropyl-3-oxo-3,4-dihydro -2H-benzo [1,4] oxazine-6-carbonyl) guanidine, N- (4-ethyl-
8-methoxy-3-oxo-3,4-dihydro-2H-
Benzo [1,4] oxazine-6-carbonyl) guanidine, N- (4-isopropyl-8-methoxy-2,2
-Dimethyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carbonyl) guanidine, N- (8-chloro-4-isopropyl-2,2-dimethyl-3-oxo- 3,4-dihydro-2H-benzo [1,4] oxazine-6-carbonyl) guanidine,
N- (8-bromo-4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carbonyl) guanidine and their pharmacologically acceptable The preferred salts are listed as preferred compounds.

The pharmacologically acceptable salts of 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, and acetic acid, lactic acid, citric acid and the like. Examples thereof include salts with organic acids such as acid, tartaric acid, methanesulfonic acid, and p-toluenesulfonic acid.

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

[0017]

Embedded image (In the formula, R ¹ , R ² , R ³ and X are the same as described above.) That is, the compound (I) of the present invention can be produced by reacting the compound (II) with guanidine.
This reaction is carried out by reacting compound (II) and 1 to 20 equivalents of guanidine with respect to compound (II) in an inert solvent under ice-cooling to the boiling point of the solvent for 1 to 24 hours. can do.

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

In the above production method, guanidine may be used in the reaction after converting a salt of guanidine such as guanidine hydrochloride into guanidine with a base such as sodium methoxide or sodium hydride. In addition, compound (II) can be reacted with a guanidine salt in the presence of a base such as potassium carbonate.

The optically active compound (I) of the present invention can be obtained, for example, by separating and purifying from a stereoisomer mixture of the compound (I) obtained by the above-mentioned production method according to a conventional method.

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

The compound (II) used as a starting material for the above production method can be produced by the following method.

[0023]

Embedded image (Wherein R ¹ , R ² , R ³ and X are the same as above.) That is, the compound (III) is obtained by reacting an α-halocarboxylic acid halide with an o-aminophenol derivative (IV) in the presence of a base. And then cyclizing the amide in the presence of a base.

The above o-aminophenol derivative (IV)
The reaction for obtaining the compound (III) from the compound and the α-halocarboxylic acid halide can also be carried out without isolating the amide.

The o-aminophenol derivative (IV) used in the above production method can be produced by reacting the corresponding o-nitrophenol derivative with a reducing agent such as hydrorazine-iron trichloride-activated carbon.

In addition, α-
The halocarboxylic acid halide is prepared according to a conventional method using the corresponding α
-By reacting a halocarboxylic acid with a halogenating agent such as thionyl chloride.

Compound (II) is obtained by reacting compound (III) obtained by the above method with an alkyl halide in an inert organic solvent such as dimethylformamide in the presence of a base such as sodium hydride or potassium carbonate. Can be manufactured. The compound (I) of the present invention and a pharmacologically acceptable salt thereof exhibit an excellent Na ⁺ / H ⁺ exchange mechanism-inhibiting action, so that disorders induced by acidosis during myocardial ischemia, such as myocardial infarction and narrowing 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 heart disease. Also, ischemia / reperfusion injury such as organ transplantation, coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTC)
It can be used as a medicine for disorders caused by surgery or thrombolytic therapy such as A).

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

The dosage form for oral administration includes 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.

Examples of dosage forms for parenteral administration include injections.

These preparations can be produced 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 excipient, For example, it is produced by dissolving or emulsifying in vegetable oil, oily emulsion, glycol or the like, and aseptically encapsulating in ampules or vials.

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 in the range of 0.3 to 600 mg, preferably 1 to 200 mg per day for an adult,
This is administered once or in two or three divided doses. Also,
The amount can be increased if necessary.

[0034]

The compound (I) of the present invention and a pharmacologically acceptable salt thereof can be prepared according to the method of Rosskoph et al. [Jou
rnal of Hypertension, 9, 231-238 (1991)], the results of investigations using as an index the inhibitory effect of the test compound on sodium propionate-induced platelet swelling showed excellent Na ⁺ /
H ⁺ exchange mechanism inhibitory effect was exhibited.

Therefore, the compound (I) of the present invention and a pharmacologically acceptable salt thereof show an excellent inhibitory effect on Na ⁺ / H ⁺ exchange mechanism, and the disorder induced by 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.

It is also useful for the prevention and treatment of ischemia / reperfusion injury, for example, organ transplantation, coronary artery bypass graft surgery (CABG), percutaneous transluminal coronary angioplasty (PTCA), and other disorders caused by thrombolytic therapy. It is.

[0037]

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

The NMR spectrum was measured by Hitachi-R24B (60 MHz).
Alternatively, measurement was performed using a Bruker DPX-250 (250 MHz).

Example 1 N- (8-chloro-4-methyl-3-oxo-3,4-
Dihydro-2H-benzo [1,4] oxazine-6-ca
Rubonyl) guanidine [in the formula (I), R ¹ is methyl
A group in which R ² and R ³ are a hydrogen atom and X is a chlorine atom
Compound] : Guanidine hydrochloride (5.00 g) was added to a sodium methoxide solution prepared from sodium (1.05 g) and methanol (10 ml), and the mixture was stirred at room temperature for 10 minutes and then filtered. 8-chloro-4-methyl-3-oxo- was added to the filtrate.
3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester (see Reference Example 6)
(0.70 g) was added and the mixture was heated under reflux for 10 minutes. Water was added to the reaction mixture, and extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethanol to give the title compound (0.60 g). Melting point: 267-269 ° C NMR (60 MHz, DMSO-d ₆ ) δ 3.37 (3H, s), 4.82 (2H, s), 8.78 (1H,
d, J = 2 Hz), 8.93 (1 H, d, J = 2 Hz), 8.20 (4 H, br). Elemental analysis value (as C ₁₁ H ₁₁ ClN ₄ O ₃ ): Calculated value (%) C, 46.74 H, 3.92; N, 19.82 Analytical value (%) C, 46.86; H, 3.99; N, 20.01

Example 2 N- (8-chloro-4-ethyl-3-oxo-3,4-
Dihydro-2H-benzo [1,4] oxazine-6-ca
Rubonyl) guanidine [in the formula (I), R ¹ is ethyl
A group in which R ² and R ³ are a hydrogen atom and X is a chlorine atom
Compound] : Guanidine hydrochloride (0.81 g) was added to a sodium methoxide solution prepared from sodium (0.18 g) and methanol (6 ml), and the mixture was stirred at room temperature for 10 minutes and filtered. The filtrate is concentrated and methyl 8-chloro-4-ethyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylate (see Reference Example 7).
(0.23 g) of 1,2-dimethoxyethane (10 m
l) The solution was added and stirred at 90 ° C. for 30 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 obtained crystals were recrystallized from ethyl acetate to give the title compound (0.19 g). Melting point: 211-213 ° C. NMR (60 MHz, DMSO-d ₆ ) δ 1.20 (3H, t, J = 7 Hz), 3.96 (2H, q, J = 7)
Hz), 4.76 (2H, s), 7.34 (4H, br), 7.77 (1H, d, J = 2Hz), 7.90 (1
H, d, J = 2 Hz). Elemental analysis (as C ₁₂ H ₁₃ ClN ₄ O ₃ ): Calculated (%) C, 48.58; H, 4.42; N, 18.88 Analysis (%) ) C, 48.53; H, 4.48; N, 18.65.

Example 3 N- (8-chloro-4-isopropyl-3-oxo-
3,4-dihydro-2H-benzo [1,4] oxazine
-6-carbonyl) guanidine hydrochloride [in formula (I)
R ¹ is an isopropyl group, R ² and R ³ are hydrogen atoms
And guanidine hydrochloride (1.48 g) was added to a sodium methoxide solution prepared from sodium (0.32 g) and methanol (12 ml), and the mixture was stirred at room temperature for 10 minutes. Filtered. The filtrate was concentrated and 1,2-dimethoxyethane (15 m
1) and 8-chloro-4-isopropyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester (see Reference Example 8).
(0.23 g) of 1,2-dimethoxyethane (10 m
l) The solution was added and stirred at 80 ° C. for 30 minutes. After concentrating the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. After evaporating the solvent under reduced pressure and adding 4 N hydrogen chloride-ethyl acetate to make a hydrochloride, the obtained crystals were recrystallized from ethanol to give the title compound (0.15 g). Mp: 269~271 ℃ NMR (60MHz, DMSO -d 6) δ1.51 (6H, d, J = 7Hz), 4.71 (2H, s), 4.
54-5.04 (1H, m), 7.09 (2H, s), 8.63 (4H, br). Elemental analysis (as C ₁₃ H ₁₅ ClN ₄ O ₃ .HCl): Calculated (%) C, 44.97 H, 4.65; N, 16.14 Analytical value (%) C, 44.83; H, 4.66; N, 16.17;

Example 4 N- (8-methoxy-4-methyl-3-oxo-3,4
-Dihydro-2H-benzo [1,4] oxazine-6-
Carbonyl) guanidine [in the formula (I), R ¹ is methyl
R ² and R ³ are hydrogen atoms and X is a methoxy group
Compound] : Guanidine hydrochloride (6.70 g) was added to a sodium methoxide solution prepared from sodium (1.50 g) and methanol (15 ml), and the mixture was stirred at room temperature for 30 minutes and filtered. 8-methoxy-4-methyl-3-oxo- was added to the filtrate.
3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester (see Reference Example 10)
(1.50 g) was added and the mixture was heated under reflux for 20 minutes. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration and recrystallized from acetonitrile to obtain the title compound (1.20 g). Melting point: 246-248 ° C. NMR (60 MHz, DMSO-d ₆ ) δ 3.32 (3H, s), 3.88 (3H, s), 4.64 (2H,
s), 7.38 (4H, br), 7.59 (2H, s). Elemental analysis (as C ₁₂ H ₁₄ N ₄ O ₄ ): Calculated (%) C, 51.80; H, 5.07; N , 20.13 Analytical value (%) C, 51.82; H, 5.03; N, 20.00

Example 5 N- (4-ethyl-8-methoxy-3-oxo-3,4
-Dihydro-2H-benzo [1,4] oxazine-6-
Carbonyl) guanidine [in the formula (I), R ¹ is
R ² and R ³ are hydrogen atoms and X is a methoxy group
Compound] : Guanidine hydrochloride (2.50 g) was added to a sodium methoxide solution prepared from sodium (0.84 g) and methanol (5 ml), and the mixture was stirred at 50 ° C. for 15 minutes and filtered. 4-ethyl-8-methoxy-3-oxo- was added to the filtrate.
3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester (see Reference Example 11)
(1.10 g) was added and the mixture was refluxed for 15 minutes. Water was added to the reaction mixture, and extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from acetonitrile to obtain the title compound (0.22 g). Melting point: 204-207 ° C NMR (60 MHz, DMSO-d ₆ ) δ 1.25 (3H, t, J = 7 Hz), 3.88 (3H, s), 4.
00 (2H, q, J = 7Hz), 4.60 (2H, s), 7.38 (4H, br), ( as _{C 13 H 16 N 4 O 4} ) 7.65 (2H, s) Elemental analysis:. Calculated ( %, C, 53.42; H, 5.52; N, 19.17 Analytical value (%) C, 53.41; H, 5.50; N, 19.35

Example 6 N- (4-isopropyl-8-methoxy-2,2-dimethyl
Tyl-3-oxo-3,4-dihydro-2H-benzo
[1,4] oxazine-6-carbonyl) guanidine
[In the formula (I), R ¹ is an isopropyl group, R ² and
Compound in which R ³ is a methyl group and X is a methoxy group] : Guanidine hydrochloride (2.50 g) is added to a sodium methoxide solution prepared from sodium (0.84 g) and methanol (5 ml), and the mixture is stirred at 50 ° C. for 15 minutes. After that, it was filtered. 4-isopropyl-8-methoxy-2,2- was added to the filtrate.
Dimethyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester (see Reference Example 12) (0.60 g) was added, and the mixture was heated under reflux for 15 minutes. Water was added to the reaction mixture, and extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from acetonitrile to obtain the title compound (0.40 g). Mp: 222~224 ℃ NMR (60MHz, DMSO -d 6) δ1.39 (6H, s), 1.52 (6H, d, J = 7Hz), 3.
85 (3H, s), 4.43-4.93 (1H, m), 7.25 (4H, br), 7.55 (1H, d, J = 2
Hz), 7.70 (1H, d, J = 2 Hz). Elemental analysis (as C ₁₆ H ₂₂ N ₄ O ₄ ): Calculated (%) C, 57.47; H, 6.63; N, 16. 76 Anal. (%) C, 57.52; H, 6.60; N, 16.99.

Example 7 N- (8-chloro-4-isopropyl-2,2-dimethyl)
Ru-3-oxo-3,4-dihydro-2H-benzo
[1,4] oxazine-6-carbonyl) guanidine
Hydrochloride [In the formula (I), R ¹ is an isopropyl group, R ²
And a salt of a compound wherein R ³ is a methyl group and X is a chlorine atom.
Acid salt] : 8-chloro-4-isopropyl-2,2-dimethyl-3
-Oxo-3,4-dihydro-2H-benzo [1,4]
Oxazine-6-carboxylic acid methyl ester (Reference Example 9
) (0.30 g), guanidine hydrochloride (1.01 g)
g), a mixture of potassium carbonate (1.33 g) and dimethylsulfoxide (5 ml) was stirred at 120 ° C. for 1 hour.
Water was added to the reaction mixture, and extracted with ethyl acetate. After evaporating the solvent under reduced pressure and adding 4 N hydrogen chloride-ethyl acetate to make a hydrochloride, the obtained crystals were recrystallized from ethanol to give the title compound (0.12 g). Melting point: 259-261 ° C. NMR (250 MHz, DMSO-d ₆ ) δ1.42 (6H, s), 1.46 (6H, d, J = 7 Hz),
4.67-4.83 (1H, m), 7.88 (2H, s), 8.49 (4H, br), 11.89 (1H, b
r) Elemental analysis (as C ₁₅ H ₁₉ ClN ₄ O ₃ .HCl): Calculated (%) C, 48.01; H, 5.37; N, 14.93 Analytical value (%) C, 47 .90; H, 5.34; N, 14.98

Example 8 N- (8-bromo-4-isopropyl-2,2-dimethyl)
Ru-3-oxo-3,4-dihydro-2H-benzo
[1,4] oxazine-6-carbonyl) guanidine
Hydrochloride [In the formula (I), R ¹ is an isopropyl group, R ²
And a salt of a compound wherein R ³ is a methyl group and X is a bromine atom.
Acid salt] : 8-bromo-4-isopropyl-2,2-dimethyl-3
-Oxo-3,4-dihydro-2H-benzo [1,4]
Oxazine-6-carboxylic acid methyl ester (Reference Example 1)
3) (0.13 g), guanidine hydrochloride (0.38
g), a mixture of potassium carbonate (0.50 g) and dimethylsulfoxide (5 ml) was stirred at 120 ° C. for 1 hour.
Water was added to the reaction mixture, and extracted with ethyl acetate. After evaporating the solvent under reduced pressure and adding 4 N hydrogen chloride-ethyl acetate to make a hydrochloride, the obtained crystals were recrystallized from ethanol to give the title compound (0.08 g). Melting point: 260-262 ° C NMR (250 MHz, DMSO-d ₆ ) δ1.41 (6H, s), 1.46 (6H, d, J = 7 Hz),
4.67-4.85 (1H, m), 7.98 (1H, d, J = 2Hz), 8.05 (1H, d, J = 2Hz),
8.50 (2H, br), 8.70 (2H, br), 12.19 (1 H, br). Elemental analysis (as C ₁₅ H ₁₉ BrN ₄ O ₃ .HCl): Calculated (%) C, 42.93; H , 4.80; N, 13.35 Analytical value (%) C, 42.81; H, 4.85; N, 13.38.

Reference Example 1 8-chloro-3-oxo-3,4-dihydro-2H-be
Nzo [1,4] oxazine-6-carboxylate methyles
Ter [In the formula (III), R ² and R ³ are hydrogen atoms;
A compound wherein X is a chlorine atom] : dimethylformamide (8.00 g) of 3-amino-5-chloro-4-hydroxybenzoic acid methyl ester (8.
0 ml) to the solution, potassium carbonate (11.0 g) was added.
After chloroacetyl chloride (4.90 g) was added dropwise at 70 ° C, the mixture was stirred at 70 ° C for 2 hours. Add water to the reaction solution,
The precipitated crystals were collected by filtration to give the title compound (4.50 g). A product obtained by partially recrystallizing this from methanol showed the following physical properties. Mp: 238~240 ℃ NMR (60MHz, DMSO -d 6) δ3.85 (3H, s), 4.79 (2H, s), 7.48 (1H,
d, J = 2 Hz), 7.59 (1 H, d, J = 2 Hz), 11.10 (1 H, br). Elemental analysis (as C ₁₀ H ₈ ClNO ₄ ): Calculated (%) C, 49.71; H N, 5.80 Analytical value (%) C, 49.63; H, 3.34; N, 5.59

Reference Example 2 8-chloro-2,2-dimethyl-3-oxo-3,4-
Dihydro-2H-benzo [1,4] oxazine-6-ca
Rubonic acid methyl ester [in formula (III), R ² and
And R ³ is a methyl group and X is a chlorine atom] : 3-amino-5-chloro-4-hydroxybenzoic acid methyl ester (4.00 g) in ethyl acetate (40 ml);
Sodium bicarbonate (2.50 g) was added to a mixed solution of water (40 ml), and 2-bromo-2-methylpropionyl bromide (5.01 g) was added dropwise at 0 ° C.
After stirring the reaction mixture at 0 ° C. for 30 minutes, the organic layer was separated and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in dimethylformamide (60 ml), potassium carbonate (3.01 g) was added, and the mixture was stirred at room temperature overnight and at 60 ° C for 2 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain the title compound (4.25 g). A product obtained by partially recrystallizing this from methanol showed the following physical properties. Melting point: 209-211 ° C. NMR (250 MHz, CDCl ₃ ) δ 1.61 (6H, s), 3.92 (3H, s), 7.46 (1H,
d, J = 2 Hz), 7.76 (1 H, d, J = 2 Hz), 8.74 (1 H, br). Elemental analysis (as C ₁₂ H ₁₂ ClNO ₄ ): Calculated (%) C, 53.44; H N, 5.19 Anal. (%) C, 53.34; H, 4.51; N, 5.19.

Reference Example 3 8-methoxy-3-oxo-3,4-dihydro-2H-
Benzo [1,4] oxazine-6-carboxylate
Stele [In the formula (III), R ² and R ³ are hydrogen atoms
And a compound in which X is a methoxy group] : To a solution of 3-amino-4-hydroxy-5-methoxybenzoic acid methyl ester (5.00 g) in dimethylformamide (40 ml), potassium carbonate (8.30 g) was added. ℃, chloroacetyl chloride (3.40g)
Then, the mixture was stirred at room temperature for 30 minutes and at 50 ° C. for 1 hour. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain the title compound (5.50 g). A product obtained by partially recrystallizing this from methanol showed the following physical properties. Melting point: 229-231 ° C. NMR (60 MHz, DMSO-d ₆ ) δ 3.95 (6H, s), 4.61 (2H, s), 7.23 (2H,
s), 10.71 (1H, br). Elemental analysis (as C ₁₁ H ₁₁ NO ₅ ): Calculated (%) C, 55.70; H, 4.67; N, 5.90 Analytical (%) C, 55.70; H, 4.66; N, 5.74.

Reference Example 4 8-methoxy-2,2-dimethyl-3-oxo-3,4
-Dihydro-2H-benzo [1,4] oxazine-6-
Carboxylic acid methyl ester [in the formula (III), R ²
And R ³ is a methyl group and X is a methoxy group
] : 3-Amino-4-hydroxy-5-methoxybenzoic acid methyl ester (3.90 g) in ethyl acetate (40 m)
l) To a mixed solution of water (40 ml) was added sodium hydrogen carbonate (2.00 g), and at 0 ° C, 2-bromo-2-methylpropionyl bromide (5.00 g) was added dropwise. After stirring the reaction mixture at 0 ° C. for 15 minutes, the organic layer was separated and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in dimethylformamide (50 ml), potassium carbonate (3.00 g) was added, and the mixture was stirred at 50 ° C for 4 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain the title compound (4.20 g). A product obtained by partially recrystallizing this from methanol showed the following physical properties. Melting point: 205-207 ° C NMR (60 MHz, DMSO-d ₆ ) δ 1.49 (6H, s), 3.88 (6H, s), 7.29 (2H,
s), 10.25 (1H, br). Elemental analysis (as C ₁₃ H ₁₅ NO ₅ ): Calculated (%) C, 58.86; H, 5.70; N, 5.28 Analytical (%) C, 58.86; H, 5.67; N, 4.99.

Reference Example 5 8-bromo-2,2-dimethyl-3-oxo-3,4-
Dihydro-2H-benzo [1,4] oxazine-6-ca
Rubonic acid methyl ester [in formula (III), R ² and
And R ³ is a methyl group and X is a bromine atom] : 3-amino-5-bromo-4-hydroxybenzoic acid methyl ester (3.00 g) in ethyl acetate (30 ml);
Sodium bicarbonate (1.54 g) was added to a mixed solution of water (30 ml), and 2-bromo-2-methylpropionyl bromide (3.09 g) was added dropwise at 0 ° C.
After stirring the reaction mixture at 0 ° C. for 30 minutes, the organic layer was separated and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in dimethylformamide (50 ml), potassium carbonate (1.85 g) was added, and the mixture was stirred at room temperature overnight and at 60 ° C for 2 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain the title compound (2.97 g). A product obtained by partially recrystallizing this from methanol showed the following physical properties. Melting point: 216-218 ° C. NMR (250 MHz, CDCl ₃ ) δ 1.60 (6H, s), 3.91 (3H, s), 7.51 (1H,
d, J = 2 Hz), 7.92 (1 H, d, J = 2 Hz), 8.97 (1 H, br). Elemental analysis value (as C ₁₂ H ₁₂ BrNO ₄ ): Calculated value (%) C, 45.88; H , 3.85; N, 4.46 Analytical value (%) C, 45.81; H, 3.88; N, 4.45.

Reference Example 6 8-chloro-4-methyl-3-oxo-3,4-dihydride
B-2H-benzo [1,4] oxazine-6-carboxyl
Acid methyl ester [in the formula (II), R ¹ is methyl
A group in which R ² and R ³ are a hydrogen atom and X is a chlorine atom
Compound] : 8-chloro-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester (see Reference Example 1) (1.20 g) in dimethylformamide (30 ml) )) 60% sodium hydride (oily) (0.25 g) and methyl iodide (0.90 g) were added to the solution, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane-ethyl acetate to give the title compound (0.80 g). Melting point: 165-168 ° C NMR (60 MHz, CDCl ₃ ) δ 3.43 (3H, s), 3.94 (3H, s), 4.77 (2H,
s), 7.67 (1H, d, J = 2 Hz), 7.75 (1 H, d, J = 2 Hz). Elemental analysis (as C ₁₁ H ₁₀ ClNO ₄ ): Calculated (%) C, 51.68; H N, 5.48 Analytical value (%) C, 51.68; H, 3.97; N, 5.35.

Reference Example 7 8-Chloro-4-ethyl-3-oxo-3,4-dihydride
B-2H-benzo [1,4] oxazine-6-carboxyl
Acid methyl ester [in the formula (II), R ¹ is ethyl
A group in which R ² and R ³ are a hydrogen atom and X is a chlorine atom
Compound] : 8-chloro-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester (see Reference Example 1) (1.50 g) in dimethylformamide (20 ml) )) 60% sodium hydride (oily) (0.30 g) and ethyl iodide (1.10 g) were added to the solution.
C. and stirred at 50.degree. C. for 5 minutes. Add water to the reaction solution,
The precipitated crystals were collected by filtration and recrystallized from hexane-ethyl acetate to give the title compound (0.24 g). Melting point: 122-125 ° C NMR (60 MHz, CDCl ₃ ) δ 1.25 (3H, t, J = 7 Hz), 3.86 (3H, s), 4.00
. (2H, q, J = 7Hz), 4.70 (2H, s), ( as _{C 12 H 12 ClNO 4) 7.52} (1H, s), 7.72 (1H, s) Elemental analysis: Calculated (%) C H, 4.49; N, 5.19 Analytical value (%) C, 53.62; H, 4.55; N, 5.08.

Reference Example 8 8-chloro-4-isopropyl-3-oxo-3,4-
Dihydro-2H-benzo [1,4] oxazine-6-ca
Rubonic acid methyl ester [In the formula (II), R ^{1 is}
A propyl group, R ² and R ³ are hydrogen atoms and X is a chlorine atom
Compounds that are children: 8-chloro-3-oxo-3,4-dihydro -2H- benzo [1,4] oxazine-6-carboxylic acid methyl ester (see Example 1) in dimethylformamide (3.00 g) (30 ml) 60% sodium hydride (oil-based) (0.60 g) and isopropyl iodide (2.30 g) in a solution.
g) was added at 0 ° C, and the mixture was stirred at 50 ° C for 2 hours. After adding water to the reaction solution and extracting with ethyl acetate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography [hexane: ethyl acetate = 4: 1 (v / v)]. Recrystallization from hexane-ethyl acetate gave the title compound (0.50
g) was obtained. Mp: 127~128 ℃ NMR (60MHz, CDCl 3) δ1.58 (6H, d, J = 7Hz), 3.94 (3H, s), 4.55
-4.95 (1H, m), 4.64 (2H, s), 7.80 (2H, s) Elemental analysis (as _{C 13 H 14 ClNO 4):} . Calculated (%) C, 55.04; H , 4. 97; N, 4.94 Analytical value (%) C, 55.01; H, 4.96; N, 4.89

Reference Example 9 8-chloro-4-isopropyl-2,2-dimethyl-3
-Oxo-3,4-dihydro-2H-benzo [1,4]
Oxazine-6-carboxylic acid methyl ester [formula (I)
In I), R ¹ is an isopropyl group, and R ² and R ³ are
Compound in which methyl group and X are chlorine atoms] : 8-chloro-2,2-dimethyl-3-oxo-3,4-
Dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester (see Reference Example 2) (3.75)
g), a mixture of isopropyl iodide (7.09 g), 40% potassium fluoride (alumina) (6.08 g), and 1,2-dimethoxyethane (70 ml) was stirred at 60 ° C. for 2 days. The reaction mixture was adjusted to pH 3 by adding 4N hydrogen chloride-1,4-dioxane and then stirred at 60 ° C. for 1 hour.
After filtration, the solvent of the filtrate was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography [hexane: ethyl acetate =
5: 1 (v / v)] to give the title compound (0.32 g)
I got A part thereof recrystallized from acetonitrile showed the following physical properties. Melting point: 83-84 ° C NMR (250 MHz, CDCl ₃ ) δ 1.51 (6H, s), 1.54 (6H, d, J = 7 Hz), 3.
93 (3H, s), 4.67-4.83 (1H, m), 7.72 (1H, d, J = 2Hz), 7.79 (1H,
d, J = 2 Hz). Elemental analysis (as C ₁₅ H ₁₈ ClNO ₄ ): Calculated (%) C, 57.79; H, 5.82; N, 4.49 Analytical value (%) C, 57 H. 5.87; N, 4.50

Reference Example 10 8-Methoxy-4-methyl-3-oxo-3,4-dihi
Dro-2H-benzo [1,4] oxazine-6-carbo
Acid methyl ester [in the formula (II), R ¹ is methyl
The groups R ² and R ³ are hydrogen atoms and X is a methoxy group
Compound] : 8-methoxy-3-oxo-3,4-dihydro-2H-
A solution of benzo [1,4] oxazine-6-carboxylic acid methyl ester (see Reference Example 3) (2.40 g) in dimethyl sulfoxide (30 ml) in 60% sodium hydride (oil-based) (0.50 g), methyl iodide (1.70 g)
Was added and stirred at room temperature for 1 hour and at 60 ° C. for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from acetonitrile to give the title compound (1.
70 g) were obtained. Mp: 156~158 ℃ NMR (60MHz, CDCl 3) δ3.40 (3H, s), 3.90 (6H, s), 4.70 (2H,
s), 7.39 (2H, s). Elemental analysis (as C ₁₂ H ₁₃ NO ₅ ): Calculated (%) C, 57.37; H, 5.22; N, 5.58 Analytical (%) C, 57.40; H, 5.20; N, 5.52.

Reference Example 11 4-ethyl-8-methoxy-3-oxo-3,4-dihi
Dro-2H-benzo [1,4] oxazine-6-carbo
Acid methyl ester [in the formula (II), R ¹ is ethyl
The groups R ² and R ³ are hydrogen atoms and X is a methoxy group
Compound] : 8-methoxy-3-oxo-3,4-dihydro-2H-
60% sodium hydride (oil-based) (0.50 g) in a solution of benzo [1,4] oxazine-6-carboxylic acid methyl ester (see Reference Example 3) (2.40 g) in dimethyl sulfoxide (40 ml), ethyl iodide (1.70 g)
Was added and stirred at room temperature for 3 hours. After adding water to the reaction solution and extracting with ethyl acetate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography [hexane: ethyl acetate = 2: 1 (v / v)]. Recrystallization from acetonitrile gave the title compound (1.20 g). Melting point: 132-134 ° C. NMR (60 MHz, CDCl ₃ ) δ1.32 (3H, t, J = 7 Hz), 3.96 (6H, s), 4.07
. (2H, q, J = 7Hz), 4.72 (2H, s), ( as _{C 13 H 15 NO 5) 7.42} (2H, s) Elemental analysis: Calculated (%) C, 58.86; H , 5.70; N, 5.28 Analytical value (%) C, 58.82; H, 5.69; N, 5.27

Reference Example 12 4-Isopropyl-8-methoxy-2,2-dimethyl-
3-oxo-3,4-dihydro-2H-benzo [1,
4] Oxazine-6-carboxylic acid methyl ester [formula
In (II), R ¹ is an isopropyl group, R ² and R
Compound wherein ³ is a methyl group and X is a methoxy group] : 8-methoxy-2,2-dimethyl-3-oxo-3,4
-Dihydro-2H-benzo [1,4] oxazine-6-
Carboxylic acid methyl ester (see Reference Example 4) (2.00
g) in dimethylformamide (30 ml) solution
Sodium hydride (oil-based) (0.40 g) and isopropyl iodide (2.00 g) were added, and the mixture was stirred at 60 ° C for 1.5 hours. After adding water to the reaction solution and extracting with ethyl acetate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography [hexane: ethyl acetate = 4: 1 (v / v)]. Recrystallization from acetonitrile gave the title compound (0.70 g). Melting point: 125-127 ° C NMR (60 MHz, CDCl ₃ ) δ 1.53 (6H, s), 1.58 (6H, d, J = 7 Hz), 3.97
(6H, s), 4.64-5.00 (1H, m), 7.50 (1H, d, J = 2Hz), 7.64 (1H, d,
J = 2 Hz). Elemental analysis (as C ₁₆ H ₂₁ NO ₅ ): Calculated (%) C, 62.53; H, 6.84; N, 4.56 Analytical (%) C, 62.67. H, 6.93; N, 4.56

Reference Example 13 8-bromo-4-isopropyl-2,2-dimethyl-3
-Oxo-3,4-dihydro-2H-benzo [1,4]
Oxazine-6-carboxylic acid methyl ester [formula (I)
In I), R ¹ is an isopropyl group, and R ² and R ³ are
Compound wherein methyl group and X are bromine atom] : 8-bromo-2,2-dimethyl-3-oxo-3,4-
Dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester (see Reference Example 5) (2.50
g), a mixture of isopropyl iodide (4.06 g), 40% potassium fluoride (alumina) (3.48 g), and 1,2-dimethoxyethane (60 ml) was stirred at 60 ° C. for 2 days. The reaction mixture was adjusted to pH 3 by adding 4N hydrogen chloride-1,4-dioxane and then stirred at 60 ° C. for 1 hour.
After filtration, the solvent of the filtrate was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography [hexane: ethyl acetate =
5: 1 (v / v)] to give the title compound (0.20 g)
I got A part thereof recrystallized from acetonitrile showed the following physical properties. Mp: 103~105 ℃ NMR (250MHz, CDCl 3) δ1.51 (6H, s), 1.54 (6H, d, J = 7Hz), 3.
93 (3H, s), 4.67-4.83 (1H, m), 7.72 (1H, d, J = 2Hz), 7.79 (1H,
d, J = 2 Hz). Elemental analysis (as C ₁₅ H ₁₈ BrNO ₄ ): Calculated (%) C, 50.58; H, 5.09; N, 3.93 Analytical (%) C, 50 .62; H, 5.13; N, 3.96

Claims (2)

[Claims] 1. A compound represented by the following formula (I): (Wherein, R ¹ represents a lower alkyl group, and R ² and R
³ represents the same or different and represents a hydrogen atom or a lower alkyl group, and X represents a halogen atom or a lower alkoxy group. Or a pharmacologically acceptable salt thereof. 2. The 8-substituted benzo [1,4] oxazine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is an ethyl group or an isopropyl group.