JP3093419B2 - 1,4-benzothiazepine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[Background of the Invention]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a 1,4-benzothiazepine derivative effective for ischemia-reperfusion arrhythmia.

[0002]

BACKGROUND OF THE INVENTION Ischemia-reperfusion arrhythmias are defined as ischemic conditions in which the coronary vessels of the heart contract or occlude for any reason, which is resolved after a period of time and when blood flow is resumed, leukocytes are lost. This is an arrhythmia caused by excessive flow of Ca and Ca ²⁺ . Clinically, how this ischemia-reperfusion arrhythmia occurs and how much arrhythmia it is has to wait for further research, but in the heart after angina or myocardial infarction, It is thought to occur on a daily basis, and a drug that can prevent and treat this has been desired. Born Williams (Voug
han-Williams) class I antiarrhythmic agents,
For example, lidocaine, procainamide, and the like are also known to be effective in rat models, but their effects are weak, and side effects such as cardiac depressant effects have also been observed.
There has been a demand for a compound having a strong antiarrhythmic action and a weak cardiosuppressive action.

[Summary of the Invention]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel compound which is effective for the above-mentioned ischemia-reperfusion arrhythmia and has a weak cardiac-suppressing action.

[0004]

The object of the present invention has been attained by a 1,4-benzothiazepine derivative having a specific structure and a pharmaceutically acceptable salt thereof. That is, the compound according to the present invention is a racemic, optically active (+) or (−) form of a 1,4-benzothiazepine derivative represented by the following formula [I], or a pharmaceutically acceptable salt thereof. .

Embedded image [In the formula, R represents a phenyl group or a benzyl group, or a phenyl group or a benzyl group having OH or OR ³ (where R ³ represents an alkyl group having 1 to ³ carbon atoms) as a substituent. X represents a hydrogen atom, OH or OR ⁴ (where R ⁴ represents an alkyl group having 1 to 3 carbon atoms). Y represents O or _{H 2.} R
₁ and R ₂ represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and may be the same or different. Also,
R ₁ and R ₂ may combine with a carbon atom or a nitrogen atom to form a piperidine or piperazine ring. n
Represents 1 or 2. The present invention also relates to the use of the above compound as an antiarrhythmic drug. That is, the antiarrhythmic drug according to the present invention contains one or more of the above 1,4-benzothiazepine compounds as an active ingredient.

[Specific description of the invention] 1,4-benzothiazepine derivatives and salts thereof The 1,4-benzothiazepine derivatives according to the present invention are represented by the following formula [I], Is as described above, which can take a racemic form, an optically active (+) form, or a (-) form (each substituent is as described above).

Embedded image Since the compound represented by the formula [I] has a basic nitrogen atom, an acid addition salt may be present at this position.
The acid to form the acid addition salt should be pharmaceutically acceptable. Accordingly, pharmaceutically acceptable salts of the compounds of formula [I] are also within the scope of the compounds according to the present invention. Examples of such salts include inorganic acid salts such as hydrochloride and sulfate, and organic acid salts such as citrate, maleate, fumarate, benzoate, succinate, acetate, tartrate and the like. Can be given. Representative examples of the compound of the present invention are shown in Experimental Examples described later, and examples of particularly preferable compounds include the following. 4-diethylaminoacetyl-3- (4-methoxy) benzyl-
2,3,4,5-tetrahydro-1,4-benzothiazepine, 4-diethylaminoacetyl-7-methoxy-3
-(4-methoxy) benzyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, 4-diethylaminoacetyl-3- (4-methoxy) phenyl-2,3
4,5-tetrahydro-1,4-benzothiazepine, 3
-Benzyl-4-diethylaminoacetyl-2,3
4,5-tetrahydro-1,4-benzothiazepine, 4
-(2-Diethylamino) ethyl-3- (4-methoxy) benzyl-2,3,4,5-tetrahydro-1,4
-Benzothiazepine, 4- (4-methylpiperazinylacetyl) -3- (4-methoxy) benzyl-2,3,
4,5-tetrahydro-1,4-benzothiazepine, 4
-(3-Diethylamino) propionyl-3- (4-methoxy) benzyl-2,3,4,5-tetrahydro-
1,4-benzothiazepine.

Production of 1,4-Benzothiazepine Compounds The compounds of the present invention represented by the formula [I] can be produced by a number of routes, for example, by the reactions of the following routes A) to C) Can be manufactured. Path A): This path is generally shown as follows.

Embedded image Compound (3) derived from an amino acid (optically active or racemic) in the presence of a base such as sodium hydride, sodium methoxide or potassium t-butoxide in an aprotic solvent such as dimethylformamide And at 0 ° to room temperature to obtain a sulfide form (2). The compound (4) is obtained by heating this in a high boiling point solvent such as diphenyl ether or o-dichlorobenzene in the presence of an organic acid such as toluenesulfonic acid or camphorsulfonic acid. This is reacted in a solvent such as tetrahydrofuran or diethyl ether in the presence of a suitable reducing agent, for example, lithium aluminum hydride, diborane or the like at 0 ° to room temperature or refluxed to obtain a compound (5).
Next, the compound (5) is reacted with bromoacetyl chloride in an aprotic solvent such as methylene chloride, chloroform, tetrahydrofuran or the like, preferably at 0 ° to room temperature, in the presence of a base such as triethylamine or diisopropylethylamine. (6) is obtained. This is reacted with amines in a solvent such as acetonitrile or the like in the presence of a base such as potassium carbonate, potassium hydroxide, sodium hydroxide or sodium carbonate to obtain the compound (7) of the present invention. The product is isolated and purified by a conventional method. Path B): This path is generally shown as follows.

Embedded image Compound (5) is acetonitrile, tetrahydrofuran,
Compound (8) is obtained by reacting with acryloyl chloride at 0 ° to room temperature in a solvent such as chloroform or methylene chloride in the presence of a base such as triethylamine or diisopropylethylamine. This is reacted with amines in a solvent such as methylene chloride, chloroform, methanol, ethanol or tetrahydrofuran at room temperature to obtain the present compound (9). The product is isolated and purified by a conventional method. Path C): This path is generally shown as follows.

Embedded image The compound (10) is reacted with a suitable reducing agent such as lithium aluminum hydride, sodium methoxyethoxyaluminum hydride, diborane at 0 ° to room temperature in an aprotic solvent, preferably tetrahydrofuran, or heated. By refluxing, the present compound (11) is obtained. The compound of the present invention which can be produced in this manner can be converted into an acid addition salt as described above by a conventional method.

Usefulness of the compound of the present invention The 1,4-benzothiazepine derivative represented by the formula [I] and the pharmaceutically acceptable salt thereof according to the present invention are as shown in the results of the pharmacological tests described below. Has an antiarrhythmic effect and can be a preventive and therapeutic agent for various arrhythmias.
When the compound of the present invention is used as a prophylactic or therapeutic agent for arrhythmia, the dose varies depending on the degree of the disease, the weight of the patient or the route of administration, and is not particularly limited. 10mg-1000
About mg can be administered orally or parenterally (eg, intravenously) about 1 to 3 times a day. Examples of the dosage form include powders, fine granules, granules, tablets, capsules, injections and the like. In the case of formulation, a usual formulation carrier (for example, magnesium stearate,
The required dosage form can be prepared by a conventional method using corn starch, crystalline cellulose, gum arabic).

[Experimental example]

The following experimental examples illustrate the present invention more specifically, but the present invention is not limited to these experimental examples unless it exceeds the gist of the present invention. <Synthesis of Compound> Synthesis examples of the compound according to the present invention and physicochemical properties thereof are as follows. In addition, the measurement of the nuclear magnetic resonance spectrum (NMR) was performed using tetramethylsilane as an internal standard, and is indicated in ppm. The unit indicates a capacitance unit. Experimental Example 1: 2-tert-butoxycarbonylamino
-3- (2-Methoxycarbonyl) phenylthio-1-
Preparation of (4-methoxy) phenylpropane 2-methoxythiophenol (8.4 g) was dissolved in dimethylformamide (200 ml), and sodium hydrogen (60%) (1.84 g) was added thereto at 0 ° to form a foam. After the temperature had subsided, (±) -2-tert-butoxycarbonylamino-3-methanesulfonyloxy-1- (4-methoxy) benzylpropane (15.0 g) was added, and the mixture was stirred at room temperature for 12 hours. After adding excess ammonium chloride, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel C
-200, 300 g) and n-hexane (80
Part) + ethyl acetate (20 parts)
(±) -2-tert-butoxycarbonylamino-3
-(2-methoxycarbonyl) phenylthio-1- (4
(-Methoxy) phenylpropane (7.5 g) was obtained. ¹ H-NMR (CDCl ₃ , 100 MHz) δ: 1.4
0 (9H, s), 2.87-3.09 (4H, m),
3.78 (3H, s), 3.93 (3H, s), 4.0
0 to 4.22 (1H, m), 4.79 (1H, br)
s), 6.83 (2H, d, J = 8.5 Hz), 7.0
6-7.99 (6H, m). FD-MS (m / z): 431 (M ^<+> ). (S) or (R) -2-tert-butoxy using (S) or (R) -2-tert-butoxycarbonylamino-3-methanesulfonyloxy-1- (4-methoxy) benzylpropane as a reactant Carbonylamino-3- (2-methoxycarbonyl) phenylthio-1- (4-methoxy) phenylpropane was obtained.

Experimental Example 2: 3- (4-methoxy-2-me
Toxicarbonyl) phenylthio-2-tert-but
Xycarbonylamino-1- (4-methoxy) phenyl
Preparation of propane 4-methoxy-2-methoxycarbonylthiophenol (4.0 g), 60% sodium hydride (0.88 g)
And (±) -2-tert-butoxycarbonylamino-1-methanesulfonyloxy-3- (4-methoxy) benzylpropane (7.9 g) were reacted in the same manner as in Experimental Example 1 to give (±)- 3- (4-methoxy-2-
Methoxycarbonyl) phenylthio-2-tert-butoxycarbonylamino-1- (4-methoxy) phenylpropane (5.9 g) was obtained. ¹ H-NMR (CDCl ₃ , 100 MHz) δ: 1.4
1 (9H, s), 2.88 to 3.07 (4H, m),
3.78 (3H, s), 3.80 (3H, s), 3.9
3 (3H, s), 4.00 to 4.21 (1H, m),
4.79 (1H, brs), 6.83 to 7.93 (7
H, m). FD-MS (m / z): 461 (M ^<+> ).

Experimental Example 3: 2-tert-butoxycal
Bonylamino-1- (2-methoxycarbonyl) phenyl
Preparation of luthio-2-phenylethane 2-methoxycarbonylthiophenol (9.7 g),
(±) -2-tert-butoxycarbonylamino-1
-Methanesulfonyloxy-2-phenylethane (2
0.0g) and 60% sodium hydride (2.7 g) were reacted in the same manner as in Experimental Example 1 to make (±) -2-ter
t-butoxycarbonylamino-1- (2-methoxycarbonyl) phenylthio-2-phenylethane (16.
0 g). ¹ H-NMR (CDCl ₃ , 100 MHz) δ: 1.4
0 (9H, s), 3.25 to 3.34 (2H, m),
3.87 (3H, s), 5.09 to 5.27 (2H,
m), 7.02-7.95 (9H, m). FD-MS (m / z): 387 (M ⁺ ).

Experimental Example 4: 2-tert-butoxycal
Bonylamino-1- (2-methoxycarbonyl) phenyl
Preparation of luthio-2- (4-methoxy) phenylethane 2-methoxycarbonylthiophenol (6.6 g),
(±) -2-tert-butoxycarbonylamino-1
-Methanesulfonyloxy-2- (4-methoxy) phenylethane (13.5 g) and 60% sodium hydride (1.7 g) were reacted in the same manner as in Experimental Example 1 to react (±) -2-tert. -Butoxycarbonylamino-1
-(2-methoxycarbonyl) phenylthio-2- (4
-Methoxy) phenylethane (17.5 g) was obtained. ¹ H-NMR (CDCl ₃ , 90 MHz) δ: 1.41
(9H, s), 3.27 to 3.37 (2H, m);
78 (3H, s), 3.89 (3H, s), 4.71-
5.20 (1H, m), 6.84 (2H, d, J = 9.
0 Hz), 7.11 to 7.95 (6H, m). FD-MS (m / z): 417 (M ^<+> ).

Experimental Example 5: 2-tert-butoxycal
Bonylamino-3- (2-methoxycarbonyl) phenyl
Preparation of luthio-1-phenylpropane 2-methoxycarbonylthiophenol (7.7 g),
(±) -2-tert-Butoxycarbonyl-1-methanesulfonyloxy-3-phenylpropane (15.0
g), 60% sodium hydride (2.0 g) in Experimental Example 1
(±) -2-tert-butoxycarbonylamino-3- (2-methoxycarbonyl) phenylthio-1-phenylpropane (11.5
g) was obtained. ¹ H-NMR (CDCl ₃ , 100 MHz) δ: 1.3
9 (9H, s), 2.90 to 3.12 (4H, m),
3.92 (3H, s), 3.99-4.26 (1H,
m), 4.73-4.94 (1H, m), 7.09-
7.87 (9H, m). FD-MS (m / z): 401 (M ^<+> ). (S) or (R) -2-tert-butoxycarbonyl-1-methanesulfonyloxy-1-
(S) or (R) -2-t using phenylpropane
ert-butoxycarbonylamino-3- (2-methoxycarbonyl) phenylthio-1-phenylpropane was obtained. (S) Form [α] _D ²⁵ + 13.5 ° (c = 1.
0, CHCl ₃ ) (R) form [α] _D ²⁶ −6.8 ° (c = 1.0,
CHCl ₃ )

Experimental Example 6: 3- (4-methoxy) benzyl
Ru-5-oxo-2,3,4,5-tetrahydro-1,
Production of 4-benzothiazepine (±) -3- (2-methoxycarbonyl) phenylthio-2-tert-butoxycarbonylamino-1-
(4-Methoxyphenyl) propane (7.7 g) was dissolved in diphenyl ether (80 ml), and p-ruenesulfonic acid monohydrate (1.0 g) was added thereto.
Heat at 0 ° for 40 minutes. After standing to cool, silica gel column chromatography (Wakogel C-200, 200g)
And n-hexane (55 parts) + ethyl acetate (4
5)) and eluted with (±) -3- (4-methoxy) benzyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzothiazepine (3.6 g). I got ¹ H-NMR (CDCl ₃ , 100 MHz) δ: 2.7
0 to 3.63 (5H, m), 3.77 (3H, s),
6.80 (2H, d, J = 8.8 Hz), 7.05 (2
H, d, J = 8.8 Hz), 7.23 to 7.72 (6
H, m). FD-MS (m / z): 299 (M ⁺ ). (S) or (R) -3 using (S) or (R) -2-tert-butoxycarbonylamino-3- (2-methoxycarbonyl) phenylthio-1- (4-methoxy) phenylpropane as a reactant -(4-Methoxy) benzyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzothiazepine was obtained. (S) Form [α] _D ²⁵ 275.1 ° (c = 1.
0, CHCl ₃ ) (R) form [α] _D ²⁵ 256.3 ° (c = 1.
0, CHCl ₃ )

Experimental Example 7: 7-methoxy-3- (4-me
Toxy) benzyl-5-oxo-2,3,4,5-tetra
Preparation of lahydro-1,4-benzothiazepine (±) -3- (4-Methoxy-2-methoxycarbonyl) phenylthio-2-tert-butoxycarbonylamino-1- (4-methoxy) phenylpropane (2. 9g), p-toluenesulfonic acid-hydrate (50
0 mg) was reacted in the same manner as in Experimental Example 6 (±)-
7-methoxy-3- (4-methoxy) benzyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.8 g) was obtained. ¹ H-NMR (CDCl ₃ , 100 MHz) δ: 2.6
6 to 3.62 (5H, m), 3.77 (3H, s),
3.82 (3H, s), 6.79 (2H, d, J = 8.
8 Hz), 7.05 (2H, d, J = 8.8 Hz),
6.90 (1H, dd, J = 8.5, 2.9 Hz),
7.18 (1H, d, J = 2.9 Hz), 7.38 (1
H, d, J = 8.5 Hz), 7.48 (1H, br)
s). FD-MS (m / z): 329 (M ⁺ ).

Experimental Example 8: 5-oxo-3-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiaze
Preparation of Pin (±) -2-tert-Butoxycarbonylamino-1- (2-methoxycarbonyl) phenylthio-2-
Phenylethane (1.9 g) and p-toluenesulfonic acid-hydrate (100 mg) were reacted by the same production method as in Experimental Example 6 to give (±) -5-oxo-3-phenyl-2,3.
4,5-tetrahydro-1,4-benzothiazepine (7
00 mg). ¹ H-NMR (CDCl ₃ , 100 MHz) δ: 3.1
1 to 3.52 (2H, m), 4.21 to 4.49 (1
H, m), 6.58 (1H, brs), 7.15-
7.73 (9H, m). FD-MS (m / z): 255 (M ⁺ ).

Experimental Example 9: 3- (4-methoxy) phenyl
Ru-5-oxo-2,3,4,5-tetrahydro-1,
Preparation of 4-benzothiazepine (±) -2-tert-butoxycarbonylamino-1- (2-methoxycarbonyl) phenylthio-2-
(4-Methoxy) phenylethane (4.0 g) and p-toluenesulfonic acid-hydrate (700 mg) were reacted by the same production method as in Experimental Example 6 to give (±) -3- (4-methoxy).
Phenyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzothiazepine (840 mg) was obtained. ¹ H-NMR (CDCl ₃ , 90 MHz) δ: 3.37
-3.43 (2H, m), 3.81 (3H, s), 4.
20-4.41 (1H, m), 6.31 (1H, br)
s), 6.86 (2H, d, J = 9.0 Hz), 7.1
5-7.81 (6H, m). FD-MS (m / z): 285 (M ⁺ ).

Experimental Example 10: 3-benzyl-5-oxo
-2,3,4,5-tetrahydro-1,4-benzothia
Production of Zepin The above (±) -2-tert-butoxycarbonylamino-3- (2-methoxycarbonyl) phenylthio-1-
Phenylpropane (6.7 g) and p-toluenesulfonic acid (800 mg) were reacted by the same production method as in Experimental Example 5 to make (±) -3-benzyl-5-oxo-2,3,4,5-
Tetrahydro-1,4-benzothiazepine (2.8 g)
I got ¹ H-NMR (CDCl ₃ , 100 MHz) δ: 2.7
3-3.32 (4H, m), 3.39-3.69 (1
H, m), 7.00 to 7.69 (9H, m). FD-MS (m / z): 255 (M ⁺ ). Using (S) or (R) -2-tert-butoxycarbonylamino-3- (2-methoxycarbonyl) phenylthio-1-phenylpropane as a reactant,
(S) or (R) -3-benzyl-5-oxo-
2,3,4,5-Tetrahydro-1,4-benzothiazepine was obtained. (S) body [α] _D ²⁶ + 296.1 ° (c = 1.
0, CHCl ₃ ) (R) form [α] _D ²⁵ -282.2 ° (c = 1.
0, CHCl ₃ )

Experimental Example 11: 3- (4-methoxy) ben
Jill-2,3,4,5-tetrahydro-1,4-benzo
Preparation of thiazepine (±) -3- (4-methoxy) benzyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzothiazepine (3.6 g) was added to tetrahydrofuran (80 ml).
And lithium aluminum hydride (1.9
g) was added and the mixture was heated under reflux for 4 hours. After adding excess sodium sulfate decahydrate, the mixture was filtered through celite. The filtrate was concentrated and (±) -3- (4-methoxy) benzyl-2,3,
4,5-Tetrahydro-1,4-benzothiazepine (3.1 g) was obtained. ¹ H-NMR (CDCl ₃ , 100 MHz) δ: 2.4
0 to 2.97 (4H, m), 3.22 to 3.45 (1
H, m), 3.78 (3H, s), 3.97 (1H,
d, J = 14.1 Hz), 4.16 (1H, d, J = 1)
4.1 Hz), 6.86 (1H, d, J = 8.5H)
z), 7.07-7.59 (6H, m). FD-MS (m / z): 285 (M ⁺ ). (S) or (R) using (S) or (R) -3- (4-methoxy) benzyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzothiazepine as a reactant ) -3- (4-Methoxy) benzyl-2,3
4,5-Tetrahydro-1,4-benzothiazepine was obtained. (S) Form [α] _D ²⁵ -92.4 ° (c = 1.
0, CHCl ₃ ) (R) form [α] _D ²⁶ + 108.0 ° (c = 1.
0, CHCl ₃ )

Experimental Example 12: 7-methoxy-3- (4-
Methoxy) benzyl-2,3,4,5-tetrahydro-
Preparation of 1,4-benzothiazepine (±) -7-methoxy-3- (4-methoxy) benzyl-5-oxo-2,3,4,5-tetrahydro-
1,4-benzothiazepine (7.5 g) and lithium aluminum hydride (3.6 g) were reacted in the same manner as in Experimental Example 11 to react (±) -7-methoxy-3- (4-methoxy). ) Benzyl-2,3,4,5-tetrahydro-
1,4-benzothiazepine (7.1 g) was obtained. ¹ H-NMR (CDCl ₃ , 500 MHz) δ: 2.3
8 to 2.98 (4H, m), 3.23 to 3.48 (1
H, m), 3.78 (3H, s), 3.81 (3H,
s), 3.96 (1H, d, J = 14.2 Hz);
15 (1H, d, J = 14.2 Hz), 6.85-7.
59 (7H, m). FD-MS (m / z): 315 (M
⁺ ).

[0020]Experimental Example 13: 3-phenyl-2,3
Preparation of 4,5-tetrahydro-1,4-benzothiazepine
Construction The above (±) -5-oxo-3-phenyl-2,3,4
5-tetrahydro-1,4-benzothiazepine (510
mg) and lithium aluminum hydride (310mg)
The reaction was conducted in the same manner as in Example 11 to give (±) -3-phenyl
Ru-2,3,4,5-tetrahydro-1,4-benzothi
Azepine (330 mg) was obtained.¹ H-NMR (CDCl₃, 100 MHz) δ: 2.7
7 to 3.00 (2H, m), 3.97 to 4.38 (3
H, m), 6.83-7.59 (9H, m). FD-MS (m / z): 241 (M⁺).

Experimental Example 14: 3- (4-methoxy) fe
Nyl-2,3,4,5-tetrahydro-1,4-benzo
Preparation of thiazepine (±) -3- (4-methoxy) phenyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.8 g), lithium aluminum hydride (980 mg) ) Was reacted in the same manner as in Experimental Example 11 to give (±) -3- (4-methoxy) phenyl-2,3,4,
5-tetrahydro-1,4-benzothiazepine (1.1
g) was obtained. ¹ H-NMR (CDCl ₃ , 90 MHz) δ: 2.80
２2.89 (2H, d, J = 2.2 Hz), 3.77
(3H, s), 4.00 to 4.41 (3H, m), 6.
83 (2H, d, J = 9.0 Hz), 7.11 to 7.6
2 (6H, m). FD-MS (m / z): 271 (M ⁺ ).

[0022]Experimental Example 15: 3-benzyl-2,3
Preparation of 4,5-tetrahydro-1,4-benzothiazepine
Construction The above (±) -3-benzyl-5-oxo-2,3,4
5-tetrahydro-1,4-benzothiazepine (7.0
g), experiment with lithium aluminum hydride (3.6 g)
The reaction was carried out in the same manner as in Example 11 to give (±) -3-benzyl.
Ru-2,3,4,5-tetrahydro-1,4-benzothi
Azepine (6.2 g) was obtained.¹ H-NMR (CDCl₃, 500 MHz) δ: 2.5
2 to 2.57 (1H, m), 2.75 to 2.88 (3
H, m), 3.36 to 3.42 (1H, m), 7.12
-7.53 (9H, m). FD-MS (m / z): 255 (M⁺). (S) or (R) -3-benzyl-5 as a reactant
-Oxo-2,3,4,5-tetrahydro-1,4-b
(S) or (R) -3-B using nzothiazepine
Benzyl-2,3,4,5-tetrahydro-1,4-ben
Zothiazepine was obtained. (S) body [α]_D ²⁶ −110.0 ° (c = 1.
0, CHCl₃) (R) -form [α]_D ^{twenty five} + 105.7 ° (c = 1.
0, CHCl₃)

Experimental Example 16: 4-bromoacetyl-3-
(4-methoxy) benzyl-2,3,4,5-tetrahi
Preparation of dro-1,4-benzothiazepine (±) -3- (4-methoxy) benzyl-2,3
4,5-Tetrahydro-1,4-benzothiazepine (1.7 g) and triethylamine (1.2 g) were dissolved in tetrahydrofuran, bromoacetyl chloride (1.8 g) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. did. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 80 g), and n-hexane (80 parts) + ethyl acetate (20 parts)
Part) and elute with 4-bromoacetyl-3-
(4-Methoxy) benzyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.2 g) was obtained. ¹ H-NMR (CDCl ₃ , 500 MHz) δ: 2.8
7-5.30 (9H, m), 3.79 + 3.80 (3
H, each s), 6.84 to 7.53 (8H,
m). (S) or (R) -3- (4-methoxy) benzyl-2,3,4,5-tetrahydro-1,4
(S) or (R) -4 using benzothiazepine
-Bromoacetyl-3- (4-methoxy) benzyl-
2,3,4,5-Tetrahydro-1,4-benzothiazepine was obtained. (S) Form [α] _D ²⁵ + 38.2 ° (c = 1.
0, CHCl ₃ ) (R) form [α] _D ²⁶ -34.1 ° (c = 1.
0, CHCl ₃ )

[0024]Experimental Example 17: 4-bromoacetyl-7-
Methoxy-3- (4-methoxy) benzyl-2,3
Preparation of 4,5-tetrahydro-1,4-benzothiazepine
Construction (±) -7-methoxy-3- (4-methoxy) benne
Jill-2,3,4,5-tetrahydro-1,4-benzo
Thiazepine (2.3 g), bromoacetyl chloride
(1.7 g) and triethylamine (1.4 g) as experimental examples
(±) -4-bromoa
Cetyl-7-methoxy-3- (4-methoxy) benzyl
-2,3,4,5-tetrahydro-1,4-benzothia
Zepin (1.8 g) was obtained. ¹H-NMR (CDCl₃, 500 MHz) δ: 2.8
5 to 3.85 (7H, m), 4.21 to 5.32 (2
H, m), 6.69-7.39 (7H, m).

Experimental Example 18: 3-benzyl-4-bromo
Acetyl-2,3,4,5-tetrahydro-1,4-b
Preparation of nzothiazepine (±) -3-benzyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.4 g), bromoacetyl chloride (1.1 g), triethylamine (1.2 g) Was reacted in the same manner as in Experimental Example 16 to give (±) -3-benzyl-4-bromoacetyl-2,3,
4,5-Tetrahydro-1,4-benzothiazepine (1.8 g) was obtained. ¹ H-NMR (CDCl ₃ , 500 MHz) δ: 2.8
7 to 5.37 (9H, m), 7.13 to 7.54 (9
H, m). (S) or (R) -3-benzyl- as a reactant
(S) or (R) -3-benzyl-4 using 2,3,4,5-tetrahydro-1,4-benzothiazepine
-Bromoacetyl-2,3,4,5-tetrahydro-
1,4-benzothiazepine was obtained. (S) Form [α] _D ²⁵ + 36.8 ° (c = 1.
0, CHCl ₃ ) (R) form [α] _D ²⁵ -33.6 ° (c = 1.
0, CHCl ₃ )

[0026]Experimental Example 19: 4-Acryloyl-3-
(4-methoxy) benzyl-2,3,4,5-tetrahi
Production of Dro-1,4-benzothiazepine The above (±) -3- (4-methoxy) benzyl-2,3
4,5-tetrahydro-1,4-benzothiazepine
(3.0 g), triethylamine (2.4 g), acrylic
Preparation of loyl chloride (1.6 g) as in Example 16
(±) -4-acryloyl-3- (4-
Methoxy) benzyl-2,3,4,5-tetrahydro-
1,4-benzothiazepine (1.5 g) was obtained. ¹H-NMR (CDCl₃, 500 MHz) δ: 2.8
7 to 3.23 (5H, m), 3.79 (3H, s),
4.42 to 6.59 (5H, m), 6.84 (2H,
d, J = 8.5 Hz), 7.12 to 7.53 (6H,
m). FD-MS (m / z): 339 (M⁺).

Experimental Example 20: 4-Diethylaminoacetyl
Ru-3- (4-methoxy) benzyl-2,3,4,5-
Tetrahydro-1,4-benzothiazepine (compound ~
The above (±) -4-bromoacetyl-3- (4-methoxy) benzyl-2,3,4,5-tetrahydro-1,4
-Benzothiazepine (530 mg) was added to acetonitrile (3
0 ml), potassium carbonate (360 mg) and diethylamine (290 mg) were added, and the mixture was heated under reflux for 2 hours. After extraction with chloroform, the extract was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel C-2).
00, 30 g) and eluted with a mixed solvent of methanol (2 parts) + chloroform (98 parts) to give (±) -4-
Diethylaminoacetyl-3- (4-methoxy) benzyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (compound) (460 mg) was obtained. ¹ H-NMR (CDCl ₃ , 100 MHz) δ: 0.9
2 (6H, t, J = 7.1 Hz), 2.30 to 2.58
(4H, m), 2.85 to 3.35 (5H, m), 3.
80 (3H, s), 4.41 to 5.51 (4H, m),
6.77-7.61 (8H, m). FD-MS (m / z): 398 (M ⁺ ). (S) or (R) -4-bromoacetyl-3- (4-methoxy) benzyl-2,3,4,5-
(S) or (R) -4-diethylaminoacetyl- using tetrahydro-1,4-benzothiazepine
3- (4-Methoxy) benzyl-2,3,4,5-tetrahydro-1,4-benzothiazepine was obtained. (S) Form (compound) [α] _D ²⁵ + 20.2 °
(C = 1.0, CHCl ₃ ) (R) form (compound) [α] _D ²⁵ -22.5 °
(C = 1.0, CHCl ₃ ) This compound (0.5 g) was dissolved in methanol (5 ml), and hydrogen chloride-methanol solution (10% (w / w),
ml) and acidified. After evaporating the solvent, the residue was washed with ether to obtain a hydrochloride (0.45 g) as a powder.

[0028]Experimental Example 21: 4-Diethylaminoacetyl
Ru-7-methoxy-3- (4-methoxy) benzyl-
2,3,4,5-tetrahydro-1,4-benzothiaze
Manufacture of pins (compounds) The above (±) -4-bromoacetyl-7-methoxy-3-
(4-methoxy) benzyl-2,3,4,5-tetrahi
Dro-1,4-benzothiazepine (1.50 g), carbonic acid
Potassium (1.42 g), diethylamine (0.75 g)
g) was reacted in the same manner as in Experimental Example 20 to give (±)-
4-diethylaminoacetyl-7-methoxy-3- (4
-Methoxy) benzyl-2,3,4,5-tetrahydro
-1,4-benzothiazepine (compound) (1.38
g) was obtained. ¹H-NMR (CDCl₃, 500 MHz) δ: 0.9
1 to 0.93 (6H, m), 2.38 to 3.24 (11
H, m), 3.77-3.79 (6H, m), 4.51
５5.43 (2H, m), 6.60 to 7.38 (7H,
m). FD-MS (m / z): 428 (M⁺).

[0029]Experimental Example 22: 4-Diethylaminoacetyl
Ru-3-phenyl-2,3,4,5-tetrahydro-
Production of 1,4-benzothiazepine (±) -3-phenyl-2,3,4,5-tetrahi
Dro-1,4-benzothiazepine (1.50 g), bro
Moacetyl chloride (1.46 g), triethylamine
(1.25 g) was reacted in the same production method as in Experimental Example 16.
(±) -4-bromoacetyl-3-phenyl-2,
3,4,5-tetrahydro-1,4-benzothiazepine
(1.95 g) was obtained.This compound (0.96 g), potassium carbonate (0.70 g)
g) and diethylamine (0.29 g) as in Experimental Example 20.
(±) -4-diethylaminoa
Cetyl-3-phenyl-2,3,4,5-tetrahydro
-1,4-benzothiazepine (0.95 g) was obtained. ¹H-NMR (CDCl₃, 500 MHz) δ: 0.8
9 (3H, t, J = 7.3 Hz), 0.99 (3H, t, J = 7.3 Hz)
t, J = 7.3 Hz), 2.43 to 3.64 (8H,
m), 4.23 to 5.13 (2H, m), 5.95 to
6.29 (1H, m), 7.09 to 7.44 (9H,
m). FD-MS (m / z): 354.

Experimental Example 23: 4-Diethylaminoacetyl
Le-3- (4-methoxy) phenyl-2,3,4,5-
Tetrahydro-1,4-benzothiazepine (compound)
Production of (±) -3- (4-methoxy) phenyl-2,3
4,5-tetrahydro-1,4-benzothiazepine (1.10 g), triethylamine (0.77 g), and bromoacetyl chloride (1.10 g) were reacted by the same production method as in Experimental Example 16 (±). -4-bromoacetyl-
3- (4-Methoxy) phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.10 g) was obtained. This compound (450 mg), potassium carbonate (320 mg),
Diethylamine (170 mg) was reacted by the same production method as in Experimental Example 20 to give (±) -4-diethylaminoacetyl-
3- (4-methoxy) phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (compound) (4
10 mg). ¹ H-NMR (CDCl ₃ , 500 MHz) δ: 0.9
0 (3H, t, J = 7.4 Hz), 0.99 (3H,
t, J = 7.4 Hz), 2.43 to 3.60 (8H,
m), 3.80 (3H, brs), 4.20-5.10.
(2H, m), 5.98-6.30 (1H, m), 7.
10-7.45 (8H, m). FD-MS (m / z): 354 (M ⁺ ).

[0031]Experimental Example 24: 3-Benzyl-4-diethyl
Ruaminoacetyl-2,3,4,5-tetrahydro-
Production of 1,4-benzothiazepine (compound) (±) -3-benzyl-2,3,4,5-tetrahi
Dro-1,4-benzothiazepine (1.4 g), trie
Tylamine (1.2 g), bromoacetyl chloride
(1.1 g) was reacted in the same manner as in Experimental Example 16.
(±) -3-benzyl-4-bromoacetyl-2,3,
4,5-tetrahydro-1,4-benzothiazepine
(1.8 g) was obtained. ¹H-NMR (CDCl₃, 500 MHz) δ: 2.8
7 to 5.37 (9H, m), 7.13 to 7.54 (9
H, m). This compound (1.82 g), potassium carbonate (1.34)
g) and diethylamine (0.46 g) as in Experimental Example 20.
(±) -4-diethylaminoa
Cetyl-3-benzyl-2,3,4,5-tetrahydro
-1,4-benzothiazepine (compound) (1.78
g) was obtained. ¹H-NMR (CDCl₃, 500 MHz) δ: 0.8
8 to 0.94 (6H, m), 2.36 to 2.55 (5
H, m), 2.87-3.40 (5H, m), 4.50
５5.46 (4H, m), 7.10 to 7.52 (9H,
m). FD-MS (m / z): 368 (M⁺). The reactant was treated with (S) or (R) -3-benzyl-2,
3,4,5-tetrahydro-1,4-benzothiazepine
The above reaction is carried out using (S) or (R) -3.
-Benzyl-4-diethylaminoacetyl-2,3
4,5-tetrahydro-1,4-benzothiazepine
Was. (S) body [α]_D ^{twenty five} + 21.7 ° (c = 1.
0, CHCl₃) (R) -form [α]_D ^{twenty four} −22.5 ° (c = 1.
0, CHCl₃)

[0032]Experimental Example 25: 4- (3-diethylamido
No) propionyl-3- (4-methoxy) benzyl-
2,3,4,5-tetrahydro-1,4-benzothiaze
Manufacture of pins (compounds) The above (±) -4-acryloyl-3- (4-methoxy)
Benzyl-2,3,4,5-tetrahydro-1,4-b
Nzothiazepine (1.62 g) in chloroform (6 ml)
And diethylamine (1.73 g) was added thereto.
Left for 4 days. Column chromatography (Wakoge)
And purified with chloroform (9 g).
Eluted with a mixed solvent of 7 parts) + methanol (3 parts)
(±) -4- (3-Diethylamino) propionyl-3
-(4-methoxy) benzyl-2,3,4,5-tetra
Hydro-1,4-benzothiazepine (compound) (2.
0 g). ¹H-NMR (CDCl₃, 500 MHz) δ: 0.9
3 (3H, t, J = 7.3 Hz), 0.98 (3H,
t, J = 7.3 Hz), 2.25 to 3.18 (13H,
m), 3.80 (3H, s), 4.28-5.40 (2
H, m), 6.83 to 6.86 (2H, m), 7.11
７7.47 (6H, m). FD-MS (m / z): 412 (M⁺).

Experimental Example 26: 4- (4-Methylpiperazi)
Nyl) acetyl-3- (4-methoxy) benzyl-2,
3,4,5-tetrahydro-1,4-benzothiazepine
(Compound)) Preparation of (±) -4-bromoacetyl-3- (4-methoxy) benzyl-2,3,4,5-tetrahydro-1,4
-Benzothiazepine (630 mg), potassium carbonate (43
0 mg) and methylpiperazine (310 mg) were reacted in the same manner as in Experimental Example 20 to give (±) -4- (4-methylpiperazinyl) acetyl-3- (4-methoxy) benzyl-2,3. 4,5-Tetrahydro-1,4-benzothiazepine (compound) (600 mg) was obtained. ¹ H-NMR (CDCl ₃ , 100 MHz) δ: 2.0
5 to 2.50 (8H, m), 2.38 (3H, s),
2.73 to 3.36 (5H, m), 3.77 (3H,
s) 4.32-5.48 (4H, m), 6.69-
7.50 (8H, m). FD-MS (m / z): 425 (M ^<+> ).

[0034]Experimental Example 27: 4- (4-benzylpiperi
Dinyl) acetyl-3- (4-methoxy) benzyl-
2,3,4,5-tetrahydro-1,4-benzothiaze
Manufacture of pins The above (±) -4-bromoacetyl-3- (4-methoxy)
B) benzyl-2,3,4,5-tetrahydro-1,4
-Benzothiazepine (380 mg), 4-benzylpiperi
Example of gin (250mg) and potassium carbonate (260mg)
The reaction was carried out in the same manner as in (20) (±) -4- (4-
Benzylpiperidinyl) acetyl-3- (4-methoxy)
Benzyl-2,3,4,5-tetrahydro-1,4-b
Nzothiazepine (360 mg) was obtained. ¹H-NMR (CDCl₃, 100 MHz) δ: 1.0
5-3.23 (16H, m), 3.71 + 3.80 (3
H, each s), 4.39-5.49 (4H,
m), 6.74-7.56 (8H, m). FD-MS (m / z): 500 (M⁺).

[0035]Experimental Example 28: 4- (2-diethylamido)
No) Ethyl-3- (4-methoxy) benzyl-2,3
4,5-tetrahydro-1,4-benzothiazepine
Production) The above (±) -4-diethylaminoacetyl-3- (4-
Methoxy) benzyl-2,3,4,5-tetrahydro-
1,4-benzothiazepine (1.52 g), hydrogenated alcohol
Minium lithium (610 mg) was prepared in the same manner as in Experimental Example 11.
(±) -4- (2-diethylamino)
Ethyl-3- (4-methoxy) benzyl-2,3,4
5-tetrahydro-1,4-benzothiazepine (compound
) (1.23 g).¹ H-NMR (CDCl₃, 100 MHz) δ: 0.9
8 (6H, t, J = 7.3 Hz), 2.32 to 3.39
(13H, m), 3.79 (3H, s), 3.89 (1
H, d, J = 15.3 Hz), 4.51 (1H, d, J)
= 15.3 Hz), 6.85 (2H, d, J = 8.5H)
z), 7.07-7.63 (6H, m). FD-MS (m / z): 384 (M⁺).

<Pharmacological test> Rat cardiac coronary artery ligation-Examination of the inhibitory effect of ventricular arrhythmia induced by recanalization Test method Male Wistar rats (300 to 350 g) were anesthetized with urethane, and thoracotomy was performed under artificial respiration. The anterior descending branch was ligated for 5 minutes and reopened. The arrhythmia was observed for 5 minutes immediately after reopening with left ventricular pressure, heart rate, and electrocardiogram (lead II). As the arrhythmia duration, VT (ventricular tachycardia) and VF (ventricular fibrillation) immediately after recanalization were tabulated, and those that lasted 180 seconds or longer were set to 180 seconds. The number of VF occurrence animals / the number of experimental animals x 100 (%) was defined as the VF occurrence frequency. The test substance was administered into the femoral vein 5 minutes before ligation. Compound dose / kg (number of cases) Arrhythmia duration (sec) VF incidence Lidocaine 1 mg (5) 96 ± 30 60% disopyramide 1 mg (3) 145 ± 35 67% procainamide 3 mg (2) 180 100% Compound 0.3 mg (7) 26 ± 100 1 mg (9) 6 ± 30 Compound 1mg (2) 10 Compound 1mg (2) 00 Compound 1mg (4) 8 ± 70 Compound 1mg (3) 1 ± 10 Compound 1mg ( 4) 1 ± 10 Compound 1mg (2) 130 Compound 1mg (5) 17 ± 40 Compound 1mg (3) 1 ± 10 Physiological saline (13) 155 ± 11 85 As is clear from the above test results. The compounds 化合物 clearly had a stronger effect of suppressing arrhythmia duration than the control drugs such as Lidocaine. The occurrence of VF was also suppressed. As described above, the compounds are a group of substances effective as a drug component for suppressing arrhythmia.

[0037]

The compound according to the present invention has a strong reperfusion arrhythmia inhibitory action, and can provide an excellent agent for preventing and treating arrhythmias.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-4-230681 (JP, A) JP-B-43-15820 (JP, B1) JP-A-7-503724 (JP, A) (58) Field (Int. Cl. ⁷ , DB name) C07D 281/10 A61K 31/00-31/80 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A racemic, optically active (+) or (-) form of a 1,4-benzothiazepine derivative represented by the following formula [I], or a pharmaceutically acceptable salt thereof. Embedded image [In the formula, R represents a phenyl group or a benzyl group, or a phenyl group or a benzyl group having OH or OR ³ (where R ³ represents an alkyl group having 1 to ³ carbon atoms) as a substituent. X represents a hydrogen atom, OH or OR ⁴ (where R ⁴ represents an alkyl group having 1 to 3 carbon atoms). Y represents O or _{H 2.} R
₁ and R ₂ represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and may be the same or different. Also,
R ₁ and R ₂ may combine with a carbon atom or a nitrogen atom to form a piperidine or piperazine ring. n
Represents 1 or 2. ] 2. An antiarrhythmic drug comprising one or more of the 1,4-benzothiazepine derivatives or the pharmaceutically acceptable salts thereof according to claim 1 as an active ingredient.