JPH07116170B2 - 1,5-Benzothiazepine derivative and process for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a 1,5-benzothiazepine derivative and a novel method for producing the same.

[0002]

2. Description of the Related Art 2- (4-Methoxyphenyl) -3-alkanoyloxy (or hydroxy) -5- [2-
(Dialkylamino) ethyl] -8-chloro-2,3-
Dihydro-1,5-benzothiazepin-4 (5H) -one has an excellent antihypertensive action and / or cerebral / coronary vasodilatory action, and the benzothiazepine derivative is the corresponding thiazepine ring 5-position. It is known that the compound can be prepared by reacting the N-unsubstituted compound of the above with a dialkylaminoethyl halide (JP-A-59-22517).
4 publication).

[0003]

The present invention provides a 1,5-benzothiazepine derivative useful as a synthetic intermediate for pharmaceutical compounds and a process for producing the same.

[0004]

The present invention has the general formula [II]

[0005]

[Chemical 4]

(Wherein R ¹ , R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a lower alkyl group;
¹ and X ² each represent a hydrogen atom and the other represents a chlorine atom), and a 1,5-benzothiazepine derivative or a salt thereof.

Examples of the compound [II] include R ¹ and R ³
And R ⁴ are the same or different and are a hydrogen atom or a lower alkyl group such as a methyl group, an ethyl group, a propyl group or a butyl group, ^one of X ¹ and X ² is a hydrogen atom, and the other is a chlorine atom. There is a certain compound. Of these, preferred compounds include R ¹ as a lower alkyl group, R ³ as a hydrogen atom or a lower alkyl group, and R ⁴
Is a lower alkyl, ^one of X ¹ and X ² is a hydrogen atom, and the other is a chlorine atom. Even more preferred compounds are those in which R ¹ is a methyl group, R ³ is a hydrogen atom, or a methyl group, an ethyl group, a propyl group or a butyl group, and R ⁴ is a methyl group, an ethyl group, or a butyl group, X ¹ and X ² One of them is a compound in which one is a hydrogen atom and the other is a chlorine atom. The most preferred compound is, in the general formula [II], R ¹ is a methyl group, R ³ is a hydrogen atom or a methyl group, R ⁴ is a methyl group, X ¹ is a chlorine atom, and X ² is a hydrogen atom. Another example is a compound in which X ¹ is a hydrogen atom and X ² is a chlorine atom.

The compound [II] of the present invention can form a salt, and examples of such a salt include salts with inorganic salts such as hydrochloric acid and perchlorate, and organic acids such as oxalic acid, fumaric acid and maleic acid. I can give you some salt.

The compound [II] of the present invention has one asymmetric carbon atom and has two optical isomers, but the present invention includes any of these optical isomers or racemates. It is a thing.

The compound [II] of the present invention has the general formula [IV]

[0011]

[Chemical 5]

(However, R ⁶ represents a lower alkyl group, and R ^6
1 , R ³ , R ⁴ , X ¹ and X ² have the same meanings as described above) or a salt thereof can be intramolecularly ring-closed.

The intramolecular ring-closing reaction of compound [IV] can be carried out in the presence of a base in a suitable solvent.

Examples of the base include lithium diisopropylamide, lithium isopropylcyclohexylamide, lithium hexamethyldisilazide and butyllithium, and examples of the solvent include ether, tetrahydrofuran, hexamethylphosphoric triamide, dioxane or a mixture thereof. And the like can be preferably used. The reaction is -70 ° C to -25 ° C, especially -60 ° C to
Suitably proceeds at -20 ° C.

The compound [II] thus obtained is reduced to give a compound of the general formula [IA]

[0016]

[Chemical 6]

(However, R ¹ , R ³ , R ⁴ , X ¹ and X
² represents the same meaning as described above) or a salt thereof, and, if necessary, a compound [IA] or a salt thereof is represented by the general formula [III]

[0018]

[Chemical 7]

(Wherein R ⁵ represents a lower alkyl group) or by condensation with a reactive derivative thereof, a compound of the general formula [IB]

[0020]

[Chemical 8]

(Wherein R ¹ , R ³ , R ⁴ , R ⁵ , X ¹ and X ² have the same meanings as described above), and if necessary, the compound [IA] or [I -B] is used as a salt thereof to give a compound of the general formula [I]

[0022]

[Chemical 9]

(Wherein R ² represents a hydrogen atom or a lower alkanoyl group, and R ¹ , R ³ , R ⁴ , X ¹ and X ² have the same meanings as described above). .

In the above compound [I], R ³ and R ⁴
Compounds in which are both lower alkyl groups are useful as hypotensive agents and / or cerebral / coronary vasodilators, and R ³ and R ⁴ are both hydrogen atoms or one of them is a lower alkyl group, and the other is A compound that is a hydrogen atom is a useful pharmaceutical compound that exhibits a strong and persistent inhibitory effect on platelet aggregation even when orally administered. For example, (-)-cis-
2- (4-methoxyphenyl) -3-hydroxy-5-
[2- (N-methylamino) ethyl] -8-chloro-
2,3-Dihydro-1,5-benzothiazepine-4 (5
H) -one hydrochloride and (+)-cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N-methylamino) ethyl] -9-chloro-2,3-dihydro Oral administration of -1,5-benzothiazepine-4 (5H) -one hydrochloride to SD rats (dose: 10 mg / k
g), both compounds inhibit collagen-induced rat platelet aggregation by 50% or more.

The reduction reaction of the compound [II] is
It can be carried out by treating I] with a reducing agent or by catalytic reduction.

The reaction of treating the compound [II] with a reducing agent can be carried out in a suitable solvent, and examples of the reducing agent include alkali metal borohydrides such as sodium borohydride, potassium borohydride and lithium borohydride. It can be preferably used. Examples of the solvent include lower alkanols such as methanol, ethanol and propanol, a mixed solution of lower alkanol and water, tetrahydrofuran or dioxane.

The catalytic reduction of compound [II] can be carried out in the presence of a catalyst in a suitable solvent.

As the catalyst, for example, palladium carbon, palladium black or the like can be used, and as the solvent, those used in the reaction between the compound [II] and the reducing agent can be preferably used.

The reaction suitably proceeds at about 0 to 40 ° C. in both cases of using a reducing agent and catalytic reduction.

The hydroxy compound [I-
A] is obtained as a racemate, and the racemate can be optically resolved by a conventional method to produce an optically active form of the hydroxy compound [IA]. For example, a racemate of a hydroxy compound [IA] is reacted with an optical resolving agent such as P-hydroxyphenylglycine ester, cinchonidine, camphorsulfonic acid, etc. in a suitable solvent (acetone, methyl ethyl ketone, ethyl acetate, methanol, etc.),
Two diastereomeric salts are formed, and then the diastereomeric salts are fractionally crystallized, and the diastereomeric salt obtained is taken as an acid ( For example, the optically active hydroxy compound [IA] can be produced by treatment with hydrochloric acid. Further, the optically active compound of the hydroxy compound [IA] is the racemic compound of the hydroxy compound [IA] and the optically active compound 1-
Also produced by reacting (2-naphthylsulfonyl) pyrrolidine-2-carbonyl chloride to form two diastereomers, separating the diastereomers by fractional crystallization or column chromatography, and hydrolyzing. can do.

The hydroxy compound [IA] can be converted to its salt by subjecting it to a salt forming reaction according to a conventional method.

The condensation reaction between the hydroxy compound [IA] and the reactive derivative of the carboxylic acid compound [III] can be carried out in a solvent in the presence or absence of a deoxidizing agent.

Examples of the reactive derivative of the carboxylic acid compound [III] include acid anhydrides (eg acetic anhydride, propionic anhydride, butyric anhydride) or acid halides (eg acetyl chloride, propionyl chloride, butyryl chloride). . As the solvent, for example, pyridine,
Tetrahydrofuran, dioxane, benzene, toluene, methylene chloride or acetic acid may be mentioned. Examples of the deoxidizing agent include pyridine, triethylamine, N-methylpiperidine, N-methylmorpholine, N-methylpyrrolidine, N-ethyl-N, N-diisopropylamine and the like.

When an excess amount of acetic anhydride is used as a reactive derivative of the carboxylic acid compound [III] in the reaction, it also serves as a solvent, so that it is not always necessary to use a solvent. The reaction is preferably carried out at about 20 to 130 ° C when an acid anhydride is used as the reactive derivative of the carboxylic acid compound [III], and at about -10 to 60 ° C when an acid halide is used.

In this method, carboxylic acid compound [III] (free carboxylic acid) and hydroxy compound [I
The condensation reaction with -A] or a salt thereof can be carried out in a solvent in the presence of a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide, N, N′-carbonyldiimidazole, 1-methyl-2-halopyridinium iodide (eg 1-methyl-2-bromopyridinium iodide), methoxyacetylene or triphenylphosphine-tetrachloride. Examples thereof include carbon, and examples of the solvent include methylene chloride, chloroform, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran,
Dioxane or the like can be used.

The reaction is about 0 to 50 ° C., especially about 0 to 25.
It is preferably carried out at ° C.

Since this reaction proceeds without racemization, the optically active alkanoyloxy compound [IB] can be prepared by using the optically active hydroxy compound [IA]. The alkanoyloxy compound [IB] can be converted into its salt by subjecting it to a salt-forming reaction according to a conventional method.

The starting compounds [IV] of the present invention are all novel compounds and can be produced, for example, according to the following reaction formula.

[0039]

[Chemical 10]

(Provided that X ³ to X ⁵ are each a halogen atom, and R ¹ , R ³ , R ⁴ , R ⁶ , X ¹ and X ² have the same meanings as described above), that is, the compounds [VI] and [VI]. VI
I] is reacted with a deoxidizing agent (alkali metal carbonate, alkali metal hydrogen carbonate, water) in a suitable solvent (lower alkanol, tetrahydrofuran, dioxane, acetonitrile, benzene, toluene, dimethylformamide or a mixture thereof). In the presence of an alkali metal oxide, an alkali metal hydride, pyridine, an organic base such as triethylamine, an alkali metal alkoxide), the reaction can be carried out at 0 to 80 ° C., particularly 20 to 60 ° C., and the compound [VIII] can be produced. The reduction reaction of compound [VIII] can be carried out by catalytic reduction in the presence of a catalyst (palladium carbon, palladium black, etc.) in a solvent (lower alkanol, tetrahydrofuran, dioxane, etc.) to give compound [IX]. it can. The reaction between the compound [IX] and the compound [X] is carried out in the presence of a deoxidizing agent (alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal hydroxide, organic base, etc.) in a solvent (methylene chloride, chloroform, acetic acid). 0-40 in ethyl, tetrahydrofuran, dioxane, acetone or mixtures of these with water)
C., especially 0 to 25.degree. C., and compound [XI] can be produced. The reaction between the compounds [XI] and [XII] is carried out in the presence of a deoxidizing agent (alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal hydroxide, sodium hydride, etc.) in a solvent (acetone, ethyl acetate, acetonitrile). , Dimethylformamide, dioxane, dimethylsulfoxide, etc.), 20 to 100 ° C., especially 20
It can be carried out at ˜70 ° C. to produce the compound [IV].

[0041]

EXAMPLES Example 1 (1) 3-Chloro-6-nitrothiophenol 3.3
g, ethanol 50 ml and tetrahydrofuran 20
5.3 ml of sodium ethylate was added to the mixed solution of ml under ice cooling and stirred for 10 minutes. Then, 3 g of paramethoxybenzyl chloride is added, and the mixture is stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were collected by filtration,
By recrystallizing from ethanol, 4.5 g of 1- (4-methoxybenzylthio) -3-chloro-6-nitrobenzene is obtained as yellow needle crystals.

M. P. : 122 to 123.5 ° C. (2-1) Ethanol 4 was prepared by using 1 g of the compound obtained in (1) above.
Suspend in 0 ml, add 3.8 g of stannous chloride dihydrate, and stir at 70 ° C. for 1.5 hours. After the reaction, the mixture is cooled, the reaction solution is poured into ice water, and sodium bicarbonate is added to adjust the pH to 7-8. Extract with chloroform and dry the extract. The solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; benzene: hexane = 2: 1) to give 1-
0.78 g of (4-methoxybenzylthio) -3-chloro-6-aminobenzene is obtained.

M. P. : 84 to 85.5 ° C. (2-2) 1 g of the compound obtained in the above (1), methanol 1
A mixture of 5 ml, tetrahydrofuran 15 ml, concentrated hydrochloric acid 1 ml and 10% palladium-carbon 0.2 g is catalytically reduced at room temperature under atmospheric pressure. After the reaction, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure.

The residue was recrystallized from a mixed solution of ethyl acetate-ethanol to give 1- (4-methoxybenzylthio).
-3-Chloro-6-aminobenzene / hydrochloride 0.84 g
To get

M. P. : 191 to 193 ° C. (3) Compound (free) 1.53 obtained in the above (2-1)
g, baking soda 0.92 g, water 20 ml and methylene chloride 30
While vigorously stirring the mixture of ml, chloroglyoxalic acid ethyl ester (ClCOCOOC ₂ H ₅ ) 1.3.
6 g are added dropwise. After stirring for 30 minutes, methylene chloride is collected. The aqueous layer is extracted with methylene chloride.

The methylene chloride layers are combined, washed with water and dried, and then the solvent is distilled off. By recrystallizing the residue from isopropanol, 1.81 g of N- {4-chloro-2-[(4-methoxybenzyl) thio] phenyl} oxamic acid ethyl ester is obtained as colorless needle crystals.

M. P. : 99.5-100 ° C. (4) 1.5 g of the compound obtained in (3) above, 1.27 g of dimethylaminoethyl chloride, 1.64 g of potassium carbonate.
And a mixture of 30 ml of acetonitrile are stirred at 50 ° C. for 3 hours. After the reaction is complete, it is cooled, the reaction solution is poured into 50 ml of water and extracted with ethyl acetate. The extract is washed with water and dried, and the solvent is distilled off. The residue is silica gel column chromatography (solvent;
N- {4-chloro-2-[(4-methoxybenzyl) thio] phenyl} -N- [2- (dimethylamino) ethyl] oxamic acid ethyl ester by purification with chloroform: ethanol = 10: 1) 1.7 g are obtained as a yellow oil.

IR (CHCl ₃ ) cm ⁻¹ : 1740,1
670 NMR (ppm, CDCl ₃ ) δ: 1.04 (3H,
t, J = 7 Hz), 2.17 (6H, S), 3.79.
(3H, S), 3.97 (2H, q, J = 8Hz),
4.11 (2H, S) (5) A mixture of 0.2 g of the compound obtained in (4) above, 65 ml of tetrahydrofuran, and 0.075 g of hexamethylphosphoric triamide is cooled to -60 ° C. Lithium diisopropylamide (diisopropylamine 0.103 g, n-butyllithium 0.64 ml (1.
6 mol-hexane solution) and tetrahydrofuran 3 ml
Is prepared by a conventional method using a. After stirring at the same temperature for 10 minutes, the reaction solution is poured into a saturated ammonium chloride aqueous solution. This is extracted with ethyl acetate, washed with water and dried to remove the solvent. The residue was purified by silica gel chromatography (solvent; chloroform: ethanol = 20: 1) to give 8-chloro-5- [2- (dimethylamino) ethyl].
0.102 g of 2- (4-methoxyphenyl) -1,5-benzothiazepine-3,4 (2H, 5H) dione is obtained as a pale yellow oil. Yield: 56.7% IR (CHCl ₃ ) cm ⁻¹ : 1720,1660 NMR (CDCl ₃ ) δ: 2.20 (6H, SN (C
_{H 3) 2), 3.75 (} 3H, S, OCH 3), 5.3
8 (broad peak 1H, CH) oxalate M.I. P. 110 to 113 ° C. (decomposition) (recrystallization from ethanol) Reference Example 1 (1) 8-Chloro-5- [2- (dimethylamino) ethyl] -2- (4-methoxyphenyl) -1,5-benzo A solution of thiazepine-3,4 (2H, 5H) dione (compound obtained in Example 1, free) 0.1 g, ethanol 5 ml and water 1 ml was added with sodium borohydride 0.
Add 01 g and stir at room temperature for 1 hour. Then, the reaction solution is diluted with water and extracted with ethyl acetate. The extract is washed with saturated saline and dried, and then the solvent is distilled off. By recrystallizing the residue with ethanol, cis-8-chloro-5- [2- (dimethylamino) ethyl] -3-hydroxy-2- (4-
0.081 g of methoxyphenyl) 2,3-dihydro-1,5-benzothiazepin-4 (5H) -one is obtained as needle crystals.

Yield: 80.6% M. P. : 169.5-170 ° C Hydrochloride / 1/2 ethanol M.I. P. 136-139 ° C. (recrystallized from a mixed solution of chloroform-ethanol-ether) (2) A mixture of 1 g of the compound (hydrochloride) obtained in (1) above, 2 ml of acetic anhydride and 2 ml of acetic acid is stirred at 110 ° C. for 4 hours. The reaction mixture is concentrated under reduced pressure and the solvent is distilled off. Ether was added to the residue, and the precipitated crystals were collected by filtration to give cis-8-chloro-5- [2- (dimethylamino).
Ethyl] -3-acetoxy-2- (4-methoxyphenyl) -2,3-dihydro-1,5-benzothiazepine-
1.08 g of 4 (5H) -one hydrochloride is obtained. This product becomes needle crystals (ethanol adduct) when recrystallized from a mixed solution of chloroform, ethanol and ether.

M. P. 159-161 ° C. Reference Example 2 (1) 9-Chloro-5- [2- (dimethylamino) ethyl] -2- (4) produced from 2-chloro-6-nitrothiophenol in the same manner as in Example 1. -Methoxyphenyl)
By treating 1,5-benzothiazepine-3,4 (2H, 5H) -dione in the same manner as in Reference Example 1- (1), cis-9-chloro-5- [2- (dimethylamino) ethyl] was obtained. -3-hydroxy-2- (4-methoxyphenyl)
-2,3-Dihydro-1,5-benzothiazepine-4
(5H) -one is obtained.

M. P. : 143-144 ° C Hydrochloride monohydrate M.I. P. : 228 to 230 ° C. (decomposition) (wet from 143 ° C.) (recrystallized from methanol) (2) The compound (free) obtained in (1) above is converted into an optically active compound 1
(+)-Cis-9-chloro-5- [2- (dimethylamino) ethyl] -3-hydroxy-2- obtained by optical resolution using-(2-naphthylsulfonyl) pyrrolidine-2-carbonyl chloride. (4-methoxyphenyl)
-2,3-Dihydro-1,5-benzothiazepine-4
(5H) -one was treated in the same manner as in Reference Example 1- (2), and then converted into the hydrochloride salt, (+)-cis-9-chloro-5- [2- (dimethylamino) ethyl] -3. -Acetoxy-2- (4-methoxyphenyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one-hydrochloride-hydrate is obtained.

M. P. : 140 to 143 ° C. [α] _D ²⁰ : + 13.0 ° (C = 0.347, methanol) Reference Examples 3 to 39 By treating in the same manner as in Examples 1 and 2 and Reference Examples 1 and 2, the following 1 The compounds listed in Table 1 are obtained.

Table 1

[0054]

[Chemical 11]

[0055]

[Table 1]

[0056]

[Table 2]

[0057]

[Table 3]

[0058]

[Table 4]

[0059]

[Table 5]

[0060]

[Table 6]

[0061]

INDUSTRIAL APPLICABILITY According to the present invention, when a pharmaceutical compound [I] useful as a blood pressure lowering agent and / or a brain / vasodilator is used, the compound [II] is used as a synthetic intermediate to improve the efficiency. The compound [I] can be obtained well.

[0062]

Claims (2)

[Claims] 1. A compound represented by the general formula [II]: (However, R ¹ , R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a lower alkyl group, and X ^1, X ²
Represents that one of them is a hydrogen atom and the other is a chlorine atom), a 1,5-benzothiazepine derivative or a salt thereof. 2. A compound represented by the general formula [IV]: (However, R ¹ , R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a lower alkyl group, R ⁶ represents a lower alkyl group, and ^one of X ¹ and X ² is a hydrogen atom, and the other is Represents a chlorine atom) or a salt thereof is intramolecularly ring-closed, and if necessary, the product is a salt thereof. [II] embedded image (Wherein R ¹ , R ³ , R ⁴ , X ¹ and X ² have the same meanings as described above), and a method for producing a 1,5-benzothiazepine derivative or a salt thereof.