JPH0637480B2 - Naphthothiazepine derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel naphthothiazepine derivative, and more particularly to a naphthothiazepine derivative having excellent antihypertensive action and vasodilatory action, and a pharmacologically acceptable acid addition salt thereof.

(Prior Art) U.S. Pat. No. 4,652,561 discloses (±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-naphtho [ 1,2-
It has been disclosed that a naphthothiazepine derivative such as b] [1,5] thiazepin-4 (5H) -one has a hypotensive action and is useful as a calcium channel blocker.

(Structure and Effect of the Invention) The novel naphthothiazepine derivative of the present invention has the following general formula (I):
Indicated by.

[Wherein R ¹ represents a lower alkoxy group, R ² represents a hydrogen atom or a lower alkanoyl group, and R ³ and R ⁴ are the same or different and represent a hydrogen atom or a lower alkyl group] In the above formula (I), And lower alkyl groups have 1 to 5 carbon atoms
Represents a straight chain or branched chain alkyl group of, and examples thereof include methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl and the like.

The lower alkoxy group represents a linear or branched alkoxy group having 1 to 5 carbon atoms, such as methoxy, ethoxy,
Propoxy, sec-butoxy, pentyloxy and the like can be mentioned.

The lower alkanoyl group represents a straight chain or branched chain alkanoyl group having 2 to 6 carbon atoms, and examples thereof include acetyl, propionyl, butyryl, isobutyryl and hexanoyl.

According to the present invention, compound (I) may have, for example, the general formula: [Wherein R ¹ and R ² are the same as above] and a salt thereof and a general formula: [Wherein R ³ and R ⁴ are the same as above, X ¹ represents a halogen atom] or a salt thereof.

The compound (I) of the present invention in which R ² is a lower alkanoyl group is
Compound (I) wherein R ² is a hydrogen atom or a salt thereof and a compound represented by the general formula: R ² ′ -COOH (IV) [wherein R ² ′ represents a lower alkyl group] or a reactive derivative thereof. It can also be produced by reacting.

Further, the compound (I) of the present invention in which R ³ is a lower alkyl group and R ⁴ is a hydrogen atom is prepared by reacting the compound (I) in which both R ³ and R ⁴ are lower alkyl groups with a reactive derivative of halogenoformic acid. It can also be prepared by treating with water, a lower alkanol, or a mixture thereof, or with zinc in the presence of a lower alkanoic acid.

Examples of the salt of the raw material compound (II) are alkali metal salts, compounds of the raw material compound (III) and compound (I) in which R ² is a hydrogen atom or R ³ and R ⁴ are both lower alkyl groups. An acid addition salt can be given as an example of the salt.

The reaction of compound (II) or a salt thereof with compound (III) or a salt thereof, in the presence or absence of an alkaline reagent,
It can be carried out in a suitable solvent. Compound in free form
When using (II), the condensation reaction is preferably carried out in the presence of an alkaline reagent. As an alkaline reagent,
Alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide), alkali metal carbonates (eg sodium carbonate, potassium carbonate), alkali metal hydrides (eg sodium hydride) and the like can be used.
The condensation reaction is carried out at 20 to 100 ° C., especially 25 to 7 ° C.
It is preferably carried out at 0 ° C.

Compound (I) wherein R ² is a hydrogen atom or a salt thereof and a compound
The condensation reaction with (IV) can be carried out in a suitable solvent in the presence of a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide, N, N'-diisopropylcarbodiimide, N, N'-di-p-tolylcarbodiimide and the like. This reaction is preferably carried out at 0 ° C to 30 ° C.

Compound (I) wherein R ² is a hydrogen atom or a salt thereof and a compound
The condensation reaction of (IV) with the reactive derivative can be carried out in a suitable solvent. Examples of the reactive derivative of the compound (IV) include corresponding acid halides (eg, chloride, bromide), acid anhydrides, mixed acid anhydrides (eg, ethoxycarbonyl ester, isopropoxycarbonyl ester, isobutoxycarbonyl ester), active compounds. Esters (eg p-nitrophenyl ester, 2,4,
5-trichlorophenyl ester, 2,4,6-trichlorophenyl ester, N-hydroxysuccinimide ester, 1-benzotriazole ester) and the like. In carrying out the reaction, when the compound (IV) is used in the form of an acid halide, 0 ° C to 30 ° C, when the compound (IV) is used in the form of an acid anhydride, 15 ° C to 100 ° C.
When (IV) is used in the form of a mixed acid anhydride, 0 ° C to 30 ° C,
When the compound (IV) is used in the form of active ester,
It is preferably carried out at 80 ° C. When the compound (IV) is used in the form of acid halide, the reaction is preferably carried out in the presence of a deoxidizing agent. Examples of the deoxidizing agent include pyridine, triethylamine, alkali metal carbonates (eg sodium carbonate, potassium carbonate), alkali metal hydrogen carbonates (eg sodium hydrogen carbonate, potassium hydrogen carbonate), alkali metal hydroxides (eg sodium hydroxide). , Potassium hydroxide) and the like.

The reaction of the compound (I) in which both R ³ and R ⁴ are lower alkyl groups with the reactive derivative of halogenoformic acid can be carried out in the presence or absence of a base in a suitable solvent. Examples of reactive derivatives of halogenoformic acid include the corresponding acid halides (eg carbonyl fluoride, phosgene, carbonyl bromide, carbonyl iodide) and mono-, di-,
Alternatively, a trihalogeno lower alkyl ester (eg, trichloromethyl chloroformate, α-chloroethyl chloroformate, β, β, β-trichloroethyl chloroformate) can be mentioned. Examples of the base include triethylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, tetramethylurea, hexamethylphosphoric triamide, quinoline and the like. This reaction is preferably carried out at 0 ° C to 140 ° C. The compound (I) in which R ³ is a lower alkyl group and R ⁴ is a hydrogen atom can be obtained by treating the compound thus obtained with water, a lower alkanol or a mixture thereof. This reaction is 20
It is preferable to carry out at a temperature of from 120 to 120 ° C.

α-chloroethyl chloroformate or β, β, β
When trichloroethyl chloroformate is used as the haloalkyl ester of halogenoformic acid, the compound (I) in which R ³ is a lower alkyl group and R ⁴ is a hydrogen atom is obtained by treating the compound thus obtained with zinc in a lower alkanoic acid. Can be obtained.

Examples of suitable solvents used in the above reaction include benzene, dioxane, methylene chloride, chloroform, acetone, acetonitrile, ethyl acetate, dimethylformamide and the like.

The compound (I) of the present invention comprises naphthothiazepine skeletons 2 and 3
Since there are two asymmetric carbon atoms in position, there are four isomers [ie (+)-cis, (-)-cis, (+)-trans and (-)-trans isomers]. , All of the above reactions proceed without racemization, the compound (I
If the optically active substance of I) is used, the optically active substance of compound (I) of the present invention can be easily obtained.

The starting compound (II) of the present invention has, for example, a general formula: And a compound represented by the general formula: [In the formula, R represents an ester residue, and R ¹ is the same as above], and can be produced by reacting with a β-substituted glycidic acid ester. According to another method, a compound in which the amino group of the compound of formula (V) is substituted with a nitro group is used as a starting material, and the nitro compound is reacted with the compound (VI), and then the nitro group is subjected to a conventional method. It can also be produced by reducing with.

When the compound (I) of the present invention is used as a medicine, it can be used as a free compound or as a pharmacologically acceptable acid addition salt thereof. Such pharmacologically acceptable acid addition salts include, for example, inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate and phosphate, and oxalate. Acid salt, maleate,
Examples thereof include organic acid addition salts such as fumarate, tartrate, methanesulfonate and succinate. These salts are
For example, it can be easily obtained by treating the compound (I) with an acid. Compound (I) or a pharmaceutically acceptable acid addition salt thereof can be administered orally or parenterally.

The compound (I) of the present invention and a pharmaceutically acceptable acid addition salt thereof have excellent antihypertensive action and cerebral / coronary vasodilatory action, and can be used as a preventive or therapeutic agent for various vascular diseases.

As a vasodilator, for example, 5-[(3,4-dimethoxyphenethyl) methylamino] -2- (3,4-dimethoxyphenyl) -2-isopropylvaleronitrile (generic name:
Verapamil) and the like have already been put on the market, but it is said that such a vasodilator suppresses atrioventricular conduction time and prolongs atrioventricular conduction time, and such conduction disorder sometimes causes arrhythmia. However, unlike the known vasodilators, the compound (I) of the present invention and salts thereof show almost no side effects (for example, atrioventricular conduction inhibitory action, heart rate reducing action) and low toxicity. Therefore, compound (I) and its salts have a high therapeutic index for cerebral or coronary vasodilatory action against side effects (atrioventricular conduction inhibitory action), and are highly safe when used as a cerebral or coronary vasodilator. It has features. Therefore, the compound
(I) and its salt are useful for the treatment and prevention of cerebral vasospasm, cerebral ischemia, cerebral infarction, and other cerebral diseases; angina, myocardial infarction, and other cardiac diseases.

Furthermore, the compound (I) of the present invention and a salt thereof have an excellent inhibitory effect on platelet aggregation. The inhibitory effect on platelet aggregation is useful for the treatment of cerebral diseases such as cerebral vasospasm, cerebral ischemia and cerebral infarction in combination with the cerebral vasodilatory effect.

When the compound (I) of the present invention or a pharmacologically acceptable acid addition salt thereof is used as a medicine, a medicine obtained by mixing the compound (I) or a salt thereof with a pharmaceutical excipient suitable for oral or parenteral administration It can be used as a formulation. Examples of such excipients include den powder, lactose,
Glucose, potassium phosphate, corn powder, gum arabic, stearic acid, and other usual pharmaceutical excipients can be preferably used. Pharmaceutical formulations are tablets,
Solid preparations such as pills, capsules and suppositories may be used, and liquid preparations such as solutions, suspensions and emulsions may be used. Furthermore, when administered parenterally, this pharmaceutical preparation can be used as an injection solution.

The daily dose of the compound (I) of the present invention or a pharmacologically acceptable salt thereof will vary depending on the administration method, age of the patient, body weight, condition and type of disease, but is usually the daily dose. Is preferably about 0.05 to 10 mg / kg, particularly preferably about 0.5 to 10 mg / kg for oral administration and about 0.05 to 2 mg / kg for parenteral administration (eg, intravenous injection).

Hereinafter, the present invention will be described in more detail with reference to Examples and Production Examples, but the present invention is not limited thereto.

Experimental Example 1 Antihypertensive Action (Method) A sample (dose: 30 mg / kg) dissolved or suspended in water was orally administered to spontaneously hypertensive rats (SHR) that had been fasted overnight. After administration, the systolic blood pressure of the rat was measured by the plethysmograph method (The Journal of Laboratory and Clinical Medicine, Vol. 78, p. 957 (1
971)). The antihypertensive effect of the sample was evaluated by the “hypotensive blood pressure value (ΔmmHg)” calculated by the following formula.

Blood pressure drop value (ΔmmHg) = [blood pressure immediately before sample administration] − [blood pressure after sample administration] (Results) The results are shown in Table 1 below.

(±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3
-Dihydro-naphtho [2,1-b] [1,5] thiazepine-4
(5H) -one fumarate Example 1 (±) -cis-2- (4-methoxyphenyl) -3-hydroxy-2,3-dihydro-naphtho [2,1-b] [1,5] Thiazepine-4 (5H) -one 3.52 g, 2- (dimethylamino) ethyl chloride.HCl 1.17 g, K ₂ CO ₃ 3.24 g,
Reflux in 135 ml of acetone. After completion of the reaction, inorganic substances are removed and the filtrate is concentrated under reduced pressure. The residue is dissolved in chloroform, washed with water, dried, concentrated, and separated by silica gel chromatography.

Elution with chloroform: methanol (30: 1) gave
First, (±) -cis-2- (4-methoxyphenyl) -3
-Hydroxy-5- [2- (dimethylamino) ethyl]
2.01 g of -2,3-dihydro-naphtho [2,1-b] [1,5] thiazepin-4 (5H) -one are obtained.

This is treated with fumaric acid and recrystallized from ethanol to give the corresponding fumarate.

Mp: 216-218 ° C. (decomposition) Mass (m / z): 422 (M ⁺ ) IR (Nujol, cm ⁻¹ ): 3460, 3050, 1730, ¹
660 elemental analysis value (as C ₂₄ H ₂₆ N ₂ O ₃ S ・ C ₄ H ₄ O ₄ ) Then from the eluting portion (±) -cis-2- (4-methoxyphenyl) -3- [2- (dimethylamino) ethyl]
400 mg of oxy-2,3-dihydro-naphtho [2,1-b] [1,5] thiazepin-4 (5H) -one are obtained.

Mp: 136-138 ° C (recrystallization solvent: ethanol) Mass (m / z): 422 (M ⁺ ) IR (Nujol, cm ^-1 ): 3340, 3310, 3270, 3
110, 3060, 1660 Example 2 (±) -cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (dimethylamino) ethyl] -2,3
-Dihydro-naphtho [2,1-b] [1,5] thiazepine-4
2.32 g of (5H) -one was added to 70 ml of acetic acid-acetic anhydride (1: 1).
Reflux in. After completion of the reaction, the mixture was concentrated under reduced pressure, the residue was dissolved in a small amount of ethanol, and fumaric acid was added to this solution to recrystallize the precipitated crystals from (±) -cis-2.
-(4-Methoxyphenyl) -3-acetoxy-5-
[2- (Dimethylamino) ethyl] -2,3-dihydro-
Naphtho [2,1-b] [1,5] thiazepine-4 (5H) -on ・
2.0 g of fumarate is obtained.

Mp: 216-218.5 ° C (decomposition) Mass (m / z): 464 (M ⁺ ) IR (Nujol, cm ^-1 ): 3060, 3040, 2600-2
300, 1740, 1690 Elemental analysis value (as C ₂₆ H ₂₈ N ₂ O ₄ S ・ C ₄ H ₄ O ₄ ) Example 3 (±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3
-Dihydro-naphtho [2,1-b] [1,5] thiazepine-4
An aqueous solution of K ₂ CO ₃ was added to 788 mg of (5H) -one fumarate to make it alkaline, which was extracted with CHCl ₃ , washed with water and dried, and then CHCl ₃ was distilled off. The free base oil obtained was dissolved in 10 ml of toluene and 192 mg of Et ₃ N was added. Then, under ice cooling, trichloromethyl chloroformate (TCF) 4
After adding 03 mg, the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residual oily matter was mixed with Et ₂ O—CHCl ₃ (1: 1).
Dissolved in a mixture of 10% HCl, then washed with H ₂ O,
Unreacted raw material was removed. The organic layer was dried and then concentrated, and the residual oily substance was dissolved in 10 ml of CH ₃ CN and 10 ml of H ₂ O.
Was added and refluxed for 40 minutes. After the reaction is complete, CH ₃ CN
Was distilled off under reduced pressure, the remaining aqueous solution was made alkaline with NaHCO ₃ under ice cooling, and extracted with CHCl ₃ . The CHCl ₃ layer was washed with water, dried and concentrated, the residual oily substance was replaced with a fumarate salt, and recrystallized from EtOH to obtain (±) -cis-2- (4-
Methoxyphenyl) -3-acetoxy-5- [2- (methylamino) ethyl] -2,3-dihydro-naphtho [2,1-
b] [1,5] thiazepine-4 (5H) -one fumarate 6
32 mg (82%) was obtained.

Mp: 199-202 ° C (decomposition) IR (Nujol, cm ^-1 ): 3060, 3040, 1740, ¹
680, 1660 Elemental analysis value (as C ₂₅ H ₂₆ O ₄ N ₂ S ・ C ₄ H ₄ O ₄ ) Production Example i) 1-Aminonaphthalene-2-thiol 7.86 g, 3-
12.16 g of methyl (4-methoxyphenyl) glycidate are heated to 100 ° C. in 80 ml of toluene. After the reaction,
This solution was concentrated under reduced pressure, diisopropyl ether was added to the residual oil, and the precipitated crystals were collected by filtration and recrystallized from methanol to give (±) -3- (1-amino-2-naphthyl).
6.49 g (38%) of threo of methyl thio-3- (4-methoxyphenyl) -2-hydroxypropionate is obtained.

Mp: 131.5-135 ° C Mass (m / z): 383 (M ⁺ ) IR (Nujol, cm ^-1 ): 3500, 3420, 3120, ¹
730 Elemental analysis value (as C ₂₁ H ₂₁ NO ₄ S) ii) 1.00 g of the compound obtained in i) above was added to 10 m of ethanol.
After stirring at room temperature for 2 hours in a mixed solution of 1, 2 ml of THF and 2.6 g of 5% NaOH aqueous solution, the pH is adjusted to 2-3 with diluted HCl, and the mixture is extracted with chloroform. The extract is washed with water, dried and concentrated under reduced pressure. The residue is recrystallized from ethanol to obtain 770 mg of the following compound.

(±) -Threo-3- (1-amino-2-naphthyl) thio-3- (4-methoxyphenyl) -2-hydroxypropionic acid Mp: 164-165 ° C (decomposition) (recrystallization solvent: ethanol) Mass (m / z): 369 (M ⁺ ) IR (Nujol, cm ⁻¹ ): 3450, 3400, 3360, 3
200,1800-1640 Elemental analysis (as C ₂₀ H ₁₉ NO ₄ S) 3.0 g of this compound was added to 18 ml of DMF and 45 ml of CH ₂ Cl ₂
Stir with 1.2 g of 1-hydroxybenzotriazole and 2.0 g of DCC at 2 ° C to 2 ° C for 2 hours and then at room temperature overnight. The precipitated DCU crystals are filtered off and washed with ethanol. The filtrate was washed with 5% NaHCO ₃ , washed with water, concentrated under reduced pressure, and the remaining crystals were recrystallized from chloroform-ethanol to obtain (±) -cis-2- (4-methoxyphenyl) -3.
-Hydroxy-2,3-dihydro-naphtho [2,1-b] [1,
5] Thiazepin-4 (5H) -one 2.8 g (98%) is obtained.

Mp: 263-267 ° C Mass (m / z): 351 (M ⁺ ) IR (Nujol, cm ^-1 ): 3520, 3200, 3100, 3
080, 3060, 1660 Elemental analysis value (as C ₂₀ H ₁₇ NO ₃ S)

Claims (9)

[Claims] 1. A general formula: [Wherein, R ¹ represents a lower alkoxy group, R ² represents a hydrogen atom or a lower alkanoyl group, and R ³ and R ⁴ are the same or different and represent a hydrogen atom or a lower alkyl group], or a naphthothiazepine derivative or A pharmacologically acceptable acid addition salt thereof. 2. The compound according to claim 1, wherein R ³ and R ⁴ are both lower alkyl groups. 3. R ¹ is an alkoxy group having 1 to 5 carbon atoms, R ² is a hydrogen atom or an alkanoyl group having 2 to 6 carbon atoms, and R ³ and R ⁴ are the same or different and are hydrogen atoms or 1 carbon atoms.
5. The compound according to claim 1, which is an alkyl group of 5 to 5. 4. The compound according to claim 1, wherein R ¹ is a methoxy group, R ² is a hydrogen atom or an acetyl group, R ³ is a methyl group, and R ⁴ is a hydrogen atom or a methyl group. 5. The method according to claim 1, wherein R ¹ is a methoxy group, R ² is a hydrogen atom or an acetyl group, R ³ and R ⁴ are methyl groups, and the configurations of the 2- and 3-positions of the naphthothiazepine skeleton are cis. Compound of. 6. (±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino).
Ethyl] -2,3-dihydro-naphtho [2,1-b] [1,5]
Thiazepine-4 (5) H-one or a pharmaceutically acceptable salt thereof. 7. (±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (methylamino) ethyl] -2,3-dihydro-naphtho [2,1-b]. [1,5] Thiazepine-4 (5) H-one or a pharmaceutically acceptable salt thereof. 8. (±) -cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (dimethylamino)
Ethyl] -2,3-dihydro-naphtho [2,1-b] [1,5]
Thiazepine-4 (5) H-one or a pharmaceutically acceptable salt thereof. 9. A general formula: [Wherein, R ¹ represents a lower alkoxy group, R ² represents a hydrogen atom or a lower alkanoyl group], or a salt thereof.