JPS645036B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides ω-piperazinyl-
This invention relates to α-hydroxyalkylalkylenedioxybenzenes and acid addition salts thereof. The compound of the present invention is represented by the following general formula (). In the above general formula, m represents an integer of 1 to 3, and n represents 1
Indicates an integer of ~6. R represents a pyridyl group or a phenyl group, and the phenyl group is a halogen group, a _C1 to C5 alkyl group, or a _C1 to _C5 alkyl group.
It may have one or more groups selected from _-C5 alkoxyl groups and trifluoromethyl groups. The method for producing the compound of the present invention will be explained. The compound of the present invention has the following general formula () (In the above general formula (), m and n are general formula ()
It has the same meaning as m and n in , and X represents a halogen group. ) and the following general formula (): (R in the above general formula () has the same meaning as R in the general formula ()) obtained by reduction of the carbonyl group of In addition, the following general formula () obtained by reduction of ω-halogenoalkanoylalkylene dioxybenes () (In the above general formula, m and n have the same meanings as m and n in the general formula ()). It can also be obtained by reacting with piperazine (). ω-Halogenoalkanoylalkylenedioxybenzenes () and piperazines () are 1:
1, but the reaction usually proceeds more smoothly when an excess of piperazine is used. Therefore, 1 to 10 moles of piperazine are used per mole of ω-halogenoalkanoylalkylenedioxybenzene. Although the reaction proceeds satisfactorily without a solvent, an inert solvent may be used to smoothly collect the reaction. As the solvent, water, dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, lower alcohol, or a mixture of two or more of these solvents is used. The reaction temperature is not particularly limited, but is usually from room temperature.
The temperature is 150℃. The reaction time varies depending on the reaction temperature, reactivity of the raw materials, and type of solvent, but is usually in the range of 10 minutes to 20 hours. Furthermore, bases may be added in order to collect hydrogen halide generated by the reaction and accelerate the reaction. Examples of the bases include inorganic salts such as potassium hydroxide, potassium carbonate, sodium hydroxide, sodium bicarbonate, and sodium carbonate, and tertiary organic amines such as pyridine and triethylamine. The amount used is usually 1 to 5 mol per mol of piperazine. In order to obtain a desired acid addition salt, after the reaction is complete, excess amines and solvent are removed by distillation or washing with water, and if necessary, a strong aqueous base solution such as sodium hydroxide or potassium hydroxide is added to obtain free ω- Piperazinylalkanoylalkylenedioxybenzenes are prepared, and then the present compound is extracted with a solvent such as acetic acid ethyl ether, chloroform, benzene, or toluene. Further, by neutralizing by adding a desired acid, the desired acid addition salt can be obtained. The obtained ω-piperazinylalkanoylalkylenedioxybenzene or its acid addition salt is dissolved in a lower alcohol or an ether solvent such as ether or tetrahydrofuran. It is obtained by reacting an alkanoylalkylene dioxybenzene with a borohydride salt. After the reaction is complete, the reaction solution can be left as is or concentrated, and treated with ethyl acetate, ether, chloroform,
Extract with benzene etc. The amine can be obtained directly as a free amine or can be further neutralized with a desired acid to give an acid addition salt. 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. ,
Examples include organic acids such as citric acid, benzoic acid, toluenesulfonic acid, and methanesulfonic acid. Also, among ω-halogenoalkanoylalkylenedioxybenzenes (), compounds where n is 2 or more are ω-halogenoalkanoyl chloride () and the following formula () (In the above formula, m has the same meaning as m in the general formula ().) It is obtained by a Friedel-Crafts reaction with an alkylene dioxybenzene. Organic Synthesis Collective Volume (Org. Syn. Coll. Vol I 109 pages)
When m = 1 in the alkylene dioxybenzenes of general formula (), that is, in the reaction of 1,3-benzoxole and ω-halogenoalkanoyl chloride, 1,3-benzodioxole undergoes Friedel-Crafts reaction. It is preferable to conduct the reaction at a low temperature because it is easily decomposed by the action of anhydrous aluminum chloride used as a catalyst. The reaction temperature is generally -30℃ to 40℃, but in this case -20℃
The reaction proceeds satisfactorily at 0°C to 0°C. When n is 1 in the general formula (), that is, halogenoacetylalkylene dioxybenzenes are produced by reacting the alkylene dioxybenzenes of the general formula () with acetyl chloride, and using the resulting acetylalkylene dioxybenzenes with halogen molecules. It is produced by reacting with
(Org.Syn.Coll.Vol., page 480) Specific examples of the compounds of the present invention are shown below. 5-[2-(4-phenyl-1-piperazinyl)-1-hydroxyethyl]-1,3-benzodioxole 5-[2-[4-(4-fluorophenyl)-
1-piperazinyl]-1-hydroxyethyl]
-1,3-benzodioxole 5-[2-[4-(3-fluorophenyl)-
1-piperazinyl]-1-hydroxyethyl]
-1,3-benzodioxole 5-[2-[4-(2-fluorophenyl)-
1-piperazinyl]-1-hydroxyethyl]
-1,3-benzodioxole 5-[2-[4-(4-chlorophenyl)-1
-Piperazinyl]-1-hydroxyethyl]-
1,3-benzodioxole 5-[2-[4-(3-chlorophenyl)-1
-Piperazinyl]-1-hydroxyethyl]-
1,3-benzodioxole 5-[2-[4-(2-chlorophenyl)-1
-Piperazinyl]-1-hydroxyethyl]-
1,3-Benzodioxole 5-[2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-1-hydroxyethyl]-1,3-benzodioxole 5-[2- [4-(4-methoxyphenyl)-
1-piperazinyl]-1-hydroxyethyl]
-1,3-benzodioxole 5-[2-[4-(3-methoxyphenyl)-
1-piperazinyl]-1-hydroxyethyl]
-1,3-benzodioxole 5-[2-[4-(2-methoxyphenyl)-
1-piperazinyl]-1-hydroxyethyl]
-1,3-benzodioxole 5-[2-[4-(4-tolyl)-1-piperazinyl]-1-hydroxyethyl]-1,3-
Benzodioxole 5-[2-[4-(3-tolyl)-1-piperazinyl]-1-hydroxyethyl]-1,3-
Benzodioxole 5-[2-[4-(2-tolyl)-1-piperazinyl]-1-hydroxyethyl]-1,3-
Benzodioxole 5-[2-[4-(2-pyridyl)-1-piperazinyl]-1-hydroxyethyl]-1,3
-Benzodioxole In the above examples, in the general formula (), m is 1,
In this case, n is 1, but all compounds in which n is 2 to 6, which correspond to each of the exemplified compounds, are also exemplified as compounds of the present invention. 6-[2-(4-phenyl-1-piperazinyl)-1-hydroxyethyl]-1,4-benzodioxane 6-[2-[4-(4-fluorophenyl)-
1-piperazinyl]-1-hydroxyethyl]
-1,4-benzodioxane 6-[2-[4-(3-fluorophenyl)-
1-piperazinyl]-1-hydroxyethyl]
-1,4-benzodioxane 6-[2-[4-(2-fluorophenyl)-
1-piperazinyl]-1-hydroxyethyl]
-1,4-benzodioxane 6-[2-[4-(4-chlorophenyl)-1
-Piperazinyl]-1-hydroxyethyl]-
1,4-benzodioxane 6-[2-[4-(3-chlorophenyl)-1
-Piperazinyl]-1-hydroxyethyl]-
1,4-benzodioxane 6-[2-[4-(2-chlorophenyl)-1
-Piperazinyl]-1-hydroxyethyl]-
1,4-Benzodioxane 6-[2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-1-hydroxyethyl]-1,4-benzodioxane 6-[2-[4-( 4-methoxyphenyl)-
1-piperazinyl]-1-hydroxyethyl]
-1,4-benzodioxane 6-[2-[4-(3-methoxyphenyl)-
1-piperazinyl]-1-hydroxyethyl]
-1,4-benzodioxane 6-[2-[4-(2-methoxyphenyl)-
1-piperazinyl]-1-hydroxyethyl]
-1,4-benzodioxane 6-[2-[4-(4-tolyl)-1-piperazinyl]-1-hydroxyethyl]-1,4-
Benzodioxane 6-[2-[4-(3-tolyl)-1-piperazinyl]-1-hydroxyethyl]-1,4-
Benzodioxane 6-[2-[4-(2-tolyl)-1-piperazinyl]-1-hydroxyethyl]-1,4-
Benzodioxane 6-[2-[4-2-pyridyl)-1-piperazinyl]-1-hydroxyethyl]-1,4-
Benzodioxane In the above examples, in the general formula (), m is 2,
In this case, n is 1, but all compounds in which n is 2 to 6, which correspond to each of the exemplified compounds, are also exemplified as compounds of the present invention. 1-[2-(4-phenyl-1-piperazinyl)-1-hydroxyethyl]-3,4-trimethylenedioxybenzene 1-[2-[4-(4-fluorophenyl)-
1-piperazinyl]-1-hydroxyethyl]
-3,4-trimethylenedioxybenzene 1-[2-[4-(3-fluorophenyl)-
1-piperazinyl]-1-hydroxyethyl]
-3,4-trimethylenedioxybenzene 1-[2-[4-(2-fluorophenyl)-
1-piperazinyl]-1-hydroxyethyl]
-3,4-trimethylenedioxybenzene 1-[2-[4-(4-chlorophenyl)-1
-Piperazinyl]-1-hydroxyethyl]-
3,4-trimethylenedioxybenzene 1-[2-[4-(3-chlorophphenyl)-
1-piperazinyl]-1-hydroxyethyl]
-3,4-trimethylenedioxybenzene 1-[2-[4-(2-chlorophenyl)-1
-Piperazinyl]-1-hydroxyethyl]-
3,4-trimethylenedioxybenzene 1-[2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-1-hydroxyethyl]-3,4-trimethylenedioxybenzene 1-[ 2-[4-(4-methoxyphenyl)-
1-piperazinyl]-1-hydroxyethyl]
-3,4-trimethylenedioxybenzene 1-[2-[4-(3-methoxyphenyl)-
1-piperazinyl]-1-hydroxyethyl]
-3,4-trimethylenedioxybenzene 1-[2-[4-(2-methoxyphenyl)-
1-piperazinyl]-1-hydroxyethyl]
-3,4-trimethylenedioxybenzene 1-[2-[4-(4-tolyl)-1-piperazinyl]-1-hydroxyethyl]-3,4-
Trimethylenedioxybenzene 1-[2-[4-(3-tolyl)-1-piperazinyl]-1-hydroxyethyl]-3,4-
Trimethylenedioxybenzene 1-[2-[4-(2-tolyl)-1-piperazinyl]-1-hydroxyethyl]-3,4-
Trimethylenedioxybenzene 1-[2-[4-(2-pyridyl)-1-piperazinyl]-1-hydroxyethyl]-3,4
-trimethylenedioxybenzene In the above examples, in the general formula [), m is 3,
In this case, n is 1, but all compounds in which n is 2 to 6, which correspond to each of the exemplified compounds, are also exemplified as compounds of the present invention. The blood pressure lowering effect of the compound of the present invention will be explained below. The antihypertensive effect of the compounds of the present invention was examined using the following method. Specifically, the animals used were spontaneously hypertensive rats (SHR) (300-370 g, 5-7 months old), and blood pressure and heart rate were measured invasively under ether anesthesia with a catheter inserted through the tail artery. After measuring and determining the average blood pressure and heart rate before drug administration, administer the drug at 1, 3, 10, 30 mg/Kg every hour.
was administered orally, and the antihypertensive effect was determined and expressed as a percentage decrease from the pre-administration value. The results are shown in Table-1. In addition, acute toxicity values (LD ₅₀ ) were determined using mice.
Litchfield-Wilcoxon
Wilcoxon) method, and the results are shown in Table 2.
Shown below. The compounds of the present invention are equal to 1 as shown in Table 1.
It exhibits a sufficient blood pressure lowering effect when administered mg/Kg orally, has a rapid onset of efficacy, and has a long-lasting effect. 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】

[Table] Although the compound of the present invention can be administered by any method, the following method is preferably carried out. That is, parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, and intraperitoneal injection, as well as oral administration are possible. 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. When the compound of the present invention is administered orally, it is in the form of tablets, capsules, powders, liquids, elixirs, etc.
In the case of parenteral administration, it is used in a sterilized liquid form such as a liquid or suspension. 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%. Thus, these dosage forms should contain between 5 and 500 mg of active ingredient, preferably between 25 and 250 mg. 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. In general, physiological saline, dextrose or similar sucrose solutions, and glycols such as ethylene glycol, propylene glycol, and polyethylene glycol are preferred as liquid carriers, and in particular, in the case of injections using physiological saline, usually 0.5
~20%, preferably 1-10% by weight of active ingredient. 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. As explained above, the compounds of the present invention can be effectively used as antihypertensive agents. Example 1 5-[3-(4-phenyl-1-piperazinyl)-1-hydroxypropionyl]-1,3
-Benzodioxole 5-(3-chloropropionyl)-1,3-benzodioxole (3 g) and N-phenylpiperazine (2.4 g) were dissolved in DMF (20 ml),
Add triethylamine (1.7 g) and stir at room temperature for 10 hours. After the reaction is complete, pour into water and extract with ethyl acetate. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off and the residue was crystallized from methanol to give 5-[3-(4-phenyl-1
-Piperazinyl)propionyl]-1,3-benzodioxane was obtained, suspended in methanol (50 ml), added with sodium borohydride (0.5 g),
React at room temperature for 10 hours. After the reaction is complete, the reaction solution is evaporated under reduced pressure and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off, and crystallized from methanol to give 5-[3-(4-phenyl-1-piperazinyl)-1-hydroxy. Propyl]1,3-benzodioxole is obtained (3.6 g, 75% yield). The physical properties of this compound are as shown in column No. 9 of Table 3. In the general formula (), m=
Compounds 1 to 3, n=1,2 were also produced, and Table 3
As stated in Example 2 5-[4-(4-phenyl-1-piperazinyl)-1-hydroxybutyl]-1,3-benzodioxole dihydrochloride group 5-(4-chlorobutyryl)-1,3-benzodioxole Sol (3.0 g) and N-phenylpiperazine (2.2 g) are dissolved in DMF (20 ml), triethylamine (1.6 g) is added, and the mixture is heated and stirred at 80°C for 40 hours. After the reaction is complete, pour into water and extract with ethyl acetate. After drying the extract over anhydrous sodium sulfate, the solvent is distilled off. Dissolve the residue in ethyl acetate, add 20% hydrochloric acid/ethanol (6.5 ml), collect the resulting crystals, and recrystallize from ethanol.
5-[4-(4-phenyl-1-piperazinyl)
Butyryl]-1,3-benzodioxole hydrochloride (3.8 g) was obtained, which was suspended in methanol (50 ml), 2N-NaOH (4.5 ml) was added, and sodium borohydride (0.5 g) was added. Stir at room temperature for 10 hours.
After the reaction, the solvent was distilled off, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, added with 20% hydrochloric acid/ethanol (4.9 ml), collected the precipitated crystals, and extracted with ethanol. By recrystallizing, 5-[4-(4-phenyl-1-piperazinyl)-1-hydroxybutyl]-1,3-
Obtain benzodioxole dihydrochloride (3.5 g, 62
%yield). The physical properties of this compound are as shown in column No. 19 of Table 3. By a similar method, in the general formula (), m
Compounds with = 1 to 3, n = 3, 4 were also produced, and the table -
3.

【table】

【table】

【table】

Claims (1)

[Claims] 1. The following general formula (In the above formula, m represents an integer of 1 to 3, and n represents 1 to 3.
6, and R has one or more groups selected from a pyridyl group or a halogen group, a _C1 to _C5 alkyl group, a _C1 to _C5 alkoxy group, and a trifluoromethyl group. Shows good phenyl group. )
ω-piperazinyl-α-hydroxyalkylenedioxybenzenes and acid addition salts thereof.