JPH0582388B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to benzothiadiazine derivatives having antihypertensive activity and acid addition salts thereof. (Structure of the Invention) The gist of the present invention is the following general formula (I):

[In the following general formula (I), R ¹ , R ² and R ³ represent a hydrogen atom or a C ₁ to C ₃ alkoxy group,
Also, if R ¹ and R ² or R ² and R ³ are combined -
It may also represent O-(CH ₂ ) _n -O- (m represents an integer of 1 to 3). However, R ¹ , R ² and R ³ do not represent hydrogen atoms at the same time. ^R4 represents a hydrogen atom or a _C1 - _C3 alkyl group. n represents an integer of 2 to 4. ] These include benzothiadiazine derivatives and acid addition salts thereof. In the above general formula (I), examples of the alkoxy group for R ¹ to ^{R 3} include C ₁ to _{C 3} alkoxy groups such as methoxy group, ethoxy group, propoxy group and isopropoxy group, and as the alkyl group for R ⁴ Examples include C ₁ -C ₃ alkyl groups such as methyl group, ethyl group, propyl group and isopropyl group. Specific examples of the compounds of the present invention include the following compounds. 2-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-dimethoxy-
3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-methylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[2-[4-(2-methoxy phenyl)-1-
Piperazinyl]ethyl]-6,7-dimethylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[2-[4-(2-methoxy phenyl)-1-
Piperazinyl]ethyl]-6,7-trimethylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[2-[4-(2- methoxyphenyl)-1-
Piperazinyl]ethyl]-5,6-dimethylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[2-[4-(2-methoxy phenyl)-1-
Piperazinyl]ethyl]-5,6-trimethylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[3-[4-(2- methoxyphenyl)-1-
Piperazinyl]propyl]-6,7-dimethoxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[3-[4-(2-methoxyphenyl) )-1-
Piperazinyl]propyl]-6,7-methylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[3-[4-(2-methoxy phenyl)-1-
Piperazinyl]propyl]-6,7-dimethylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[3-[4-(2-methoxy phenyl)-1-
Piperazinyl]propyl]-6,7-trimethylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[3-[4-(2- methoxyphenyl)-1-
Piperazinyl]propyl]-5,6-dimethylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[3-[4-(2-methoxy phenyl)-1-
Piperazinyl]propyl]-5,6-trimethylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[4-[4-(2- methoxyphenyl)-1-
Piperazinyl]butyl]-6,7-dimethoxy-
3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[4-[4-(2-methoxyphenyl)-1-
Piperazinyl]butyl]-6,7-methylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[4-[4-(2-methoxy phenyl)-1-
Piperazinyl]butyl]-6,7-dimethylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[4-[4-(2-methoxy phenyl)-1-
Piperazinyl]butyl]-6,7-trimethylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[4-[4-(2- methoxyphenyl)-1-
Piperazinyl]butyl]-5,6-dimethylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[4-[4-(2-methoxy phenyl)-1-
Piperazinyl]butyl]-5,6-trimethylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide The above examples show that in general formula (I) In cases where R ⁴ is a methyl group, compounds in which R ⁴ is ethyl, propyl and isopropyl are also encompassed by the invention. Particularly preferred compounds are as follows. 2-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-trimethylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 2-[2-[4-(2- methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-dimethylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide In addition, acid addition salts of the various compounds mentioned above are also available. It is included as an active ingredient of the drug according to the present invention. Acids used as addition salts include inorganic acids such as hydrochloric acid, hydrooxalic acid, sulfuric acid, phosphoric acid, and nitric acid, acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, and oxalic acid. , citric acid, benzoic acid, toluenesulfonic acid, methanesulfonic acid, and other organic acids. Next, a method for producing the compound of the present invention will be explained. The compound of the present invention () has the following general formula ():

[Chemical formula] (In the above general formula (), R ¹ , R ² , R ³ , R ⁴ and n are as defined in the above general formula (I).) It can be obtained by heating with urea or by ring-closing condensation using trichloromethyl chloroformate. In addition, the compound of the present invention () has the following general formula ():

[In the general formula () above, R ¹ , R ² and R ³ are
As defined in the above general formula (I). ) and the following general formula ():

[Chemical formula] (In the above general formula (), X represents a halogen atom, and R ⁴ and n are as defined in the above general formula (I).) It can also be obtained by
In this case, the benzothiadiazine derivative () is converted into a sodium salt by using caustic soda or caustic potassium; a metal alkoxide such as sodium methoxide; or a metal hydride such as sodium hydride;
Various inert solvents (e.g. dimethylformamide, dimethyl sulfoxide, water, alcohol, etc.)
It can be obtained by reacting with a piperazine derivative () at a temperature from room temperature to about 100°C. The compound of the present invention () obtained by the above method can be obtained, for example, by recrystallizing the crystals generated by adding water to the reaction mixture with alcohol or the like, or by concentrating the reaction solution and then applying silica gel chromatography. It can be purified by graphie. Further, the compound () of the present invention forms an acid addition salt with the above-mentioned organic acid or inorganic acid. (Effects of the Invention) The compounds of the present invention are useful as antihypertensive agents, as shown in the test examples described below. The administration method may be any known method, including parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, and intraperitoneal injection, as well as oral administration. The dosage is determined depending on the patient's age, health condition, weight, type of concurrent treatment, if any, frequency of treatment, nature of desired effect, etc. Generally, the daily dose of active ingredient is 0.1-100mg/
Kg body weight, usually 1-30 mg/Kg body weight, administered in one or more doses. For oral administration, tablets, capsules, powders,
It is used in the form of solutions, elixirs, etc., and in the case of parenteral administration, it is used in the form of sterile liquids such as liquids or suspensions. When used in such forms, solid or liquid non-toxic pharmaceutical carriers can be included in the composition. As an example of a solid carrier, conventional gelatin-type capsules are used. The active ingredient may also be packaged as a tablet or powder, with or without adjuvants. These capsules, tablets, and powders generally contain 5 to
Contains 95% by weight of active ingredient, preferably 25-90%. i.e., 5 to 500 mg for these modes of administration;
Preferably, it contains 25 to 250 mg of active ingredient. As the liquid carrier, water or oils of animal or plant origin or synthetic oils such as petroleum, peanut oil, soybean oil, mineral oil, sesame oil, etc. are used. Also commonly used are physiological saline, dextrose or similar sucrose solutions, propylene glycol,
Glycols such as polyethylene glycol are preferred as liquid carriers, and especially in the case of injection solutions using physiological saline, the amount is usually 0.5 to 20%, preferably 1%.
Contain ~10% active ingredient by weight. In the case of liquid preparations for oral administration, suspensions or syrups containing 0.5 to 10% by weight of the active ingredient are preferred. In this case, aqueous excipients such as fragrances, syrups, and pharmaceutical micelles are used as carriers. (Examples) Hereinafter, the present invention will be further explained in detail using Examples and Test Examples, but the present invention is not limited to the following Examples unless it exceeds the gist thereof. Example 1 2-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-dimethoxy-
3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide 6,7-dimethoxy-3,4-dihydro-1,
2,4-Benzothiadiazin-3-one 1,1
-Dissolve the dioxide (1.5 g) in dimethylformamide (10 ml), add sodium hydride (50% oil) (280 mg) and heat to 80°C. A solution of 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl chloride (1.5 g) dissolved in dimethylformamide (5 ml) was added dropwise to the reaction solution. After completion of the dropwise addition, the mixture was heated and stirred at 80°C for 5 hours.
After the reaction is complete, pour into water, collect the resulting crystals, and recrystallize from methanol to obtain 1.0 g (36% yield) of the desired benzothiadiazine derivative.
The physical properties of this compound are shown in the No. 2 column of Table 1. Example 2 2-[2-[4-(2-methoxyphenyl)-1-
Piperazinyl]ethyl]-6,7-trimethylenedioxy-3,4-dihydro-1,2,4-benzothiadiazin-3-one 1,1-dioxide N-[2-[4-(2- methoxyphenyl)-1-
Piperazinyl]ethyl]-2-amino-4,5-
Trimethylenedioxybenzenesulfonamide (32g) and triethylamine (15.4ml) were dissolved in methylene chloride (350ml), and the solution was added dropwise to a solution of trichloromethyl chloroformate (4.2ml) in methylene chloride (140ml) at 5°C or below. do. After completion of the dropwise addition, the mixture was gradually returned to room temperature and stirred for 1 hour. After that, saturated sodium chloride solution was added and the mixture was stirred for 30 minutes. The methylene chloride was dried with sulfur salt and concentrated. The residue was purified by silica gel chromatography and crystallized from ethanol, resulting in the desired benzothinyl chloride. 24.7 g (73.1% yield) of Asiazine derivative are obtained. The physical properties of this compound are shown in column No. 4 of Table 1. Other benzothiadiazine derivatives were also synthesized according to the above examples. In addition, as a comparative example, compound No. 1
(when R ¹ , R ² and R ³ simultaneously represent hydrogen atoms) was synthesized in the same manner. The results are shown in Table-1.

[Table] Test Example The antihypertensive effect of the compound of the present invention was investigated using the following method. Specifically, using spontaneously hypertensive rats (SHR) (300-370 g, 5-7 months old), blood pressure and heart rate were measured invasively under ether anesthesia with a catheter inserted through the tail artery. After determining the average blood pressure and heart rate before administering the drug, administer the drug orally, measure the blood pressure and heart rate until 6 hours after administration, and calculate the maximum hypotensive response from the pre-administration value and express it as a rate of change. . In addition, acute toxicity values (LD ₅₀ ) were determined using mice.
Calculated using the Litchfield-Wilcoxon method. The results are shown in Table-2. In addition, as a comparative example, Compound No. 1
(when R ¹ , R ² and R ³ simultaneously represent hydrogen atoms) was used. As is clear from Table 2, the compound of the present invention has 1
Oral administration of mg/Kg or 3 mg/Kg exhibits a sufficient blood pressure lowering effect, and the onset of drug efficacy is far from occurring, and the action is long-lasting. In addition, it has low acute toxicity, and considering the amount of medicinal efficacy expressed, it is presumed to be a very safe drug.

[Table] * Corresponds to compound No. in Table-1.

Claims (1)

[Claims] 1 The following general formula (I) [In the following general formula (I), R ¹ , R ² and R ³ represent a hydrogen atom or a C ₁ to C ₃ alkoxy group,
Also, if R ¹ and R ² or R ² and R ³ are combined -
It may also represent O-(CH ₂ ) _n -O- (m represents an integer of 1 to 3). However, R ¹ , R ² and R ³ do not represent hydrogen atoms at the same time. ^R4 represents a hydrogen atom or a _C1 - _C3 alkyl group. n represents an integer of 2 to 4. ] A benzothiadiazine derivative and its oxidized salt.