JPS5826881A - (omega-aminoalkyl)alkylenedioxybenzene derivative and its acid addition salt - Google Patents

Abstract

NEW MATERIAL:The (omega-aminoalkyl)alkylenedioxybenzene derivative of formulaI(m is 1-3; n is 3-5) and its acid addition salt. EXAMPLE:5-[3-[(1,4-Benzodioxan-2-ylmethyl)amino]propyl]-1,3-benzodioxol. USE:Useful as a hypotensor. It has rapid and long acting activity, low acute toxicity, and extremely high safety. PROCESS:The compound of formulaIis prepared e.g. by reacting the halogeno- alkylalkylenedioxybenzene derivative of formula II (Y is halogen) with the amine of formula III in an inert solvent preferably water, dioxane, etc., at room temperature - 150 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a (6+-aminoalkyl)alkylenedioxybenzene impurant and its acid addition salt having hypotensive action.

The compound of the present invention is represented by the following general formula (1).

In the above general formula, m represents an integer of 1 to 3, and n represents J-7()
Indicates an integer.

The method for producing the compound of the present invention will be explained below.

The compound of the present invention is a halogen alkyl alkyl compound represented by the following general formula (II) (in the above general formula, m and n have the same meanings as m1n in the general formula (1) K, and Y represents a halogen atom). It is obtained by reacting a dioxybenzene derivative with an amine represented by the following formula (1).

The halogenoalkylalkylene dioxybenzene derivative and the amine react in a ratio of 1:1, respectively, but the reaction usually proceeds more smoothly when the amine is used in excess. Therefore, the amine is used in an amount of 7 to 70 moles per 10 genoalkylalkylene dioxybenzene derivatives.

The reaction Fi, which progresses well even with a non-fertile medium, slows down the reaction. An inert solvent may be used to facilitate the process.

As the solvent, water, dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, low alcohol, or a mixture of two or more of these solvents can be used.

The reaction temperature is not particularly limited, and i is usually from room temperature to /! 0°C
It is.

The reaction time varies depending on the reaction temperature and the type of reactive solvent used as the raw material, but is usually in the range of 70 minutes to 20 hours.

Further, carrier groups may be added in order to collect hydrogen halide generated by the reaction and accelerate the reaction. *S's include inorganic salts such as potassium hydroxide, potassium carbonate, sodium hydroxide, sodium bicarbonate, and sodium carbonate, and tertiary organic ammoniums such as pyridine and triethylamine. The amount used is usually t -S mol per 1 mol of the amine of formula (■, 1).

In order to obtain the desired acid addition salt, after the reaction is complete, excess amine and solvent are removed by distillation or washing with water, and a strong aqueous base such as sodium hydroxide or potassium hydroxide is added to remove the free (-monoanoalkyl)alkyl salt. Conductor for dioxybenzene, then ether, chloroform,
Extract this compound with a solvent such as benzene or toluene. Further, by neutralizing by adding a desired acid, the desired acid addition salt can be obtained.

Specific examples of the compounds of the present invention are illustrated below.

r-[3-((/, darbenzodioxane-choylmethyk)aminocopropyl] -/, J-benzodioxole j-[dar[(/, darbenzodioxane-choylmethyl)amino]butyl ]-/, J-benzodioxole s (r-[:('*darpenzodioxane-coylmethyl)amino]pentyl]-/, J-benzodioxole b -L 3- [(' -benzodioxane-coylmethyl)aminocoflovir) -'tdarpenzodioxane 6-[darC(/,benzodioxane-coylmethyl)aminocobutyl] -/, pedenzodioxane b [t[ ('w benzodioxane-choylmethyl)aminocopentyl] -/, #-benzodioxane-/-C3-C</, lI-benzodioxane-choylmedek)amino]propyl]-3. -trimetele/dioxybenzene l-[dar[('tdarbenzodioxane-coylmethel)amino]butyl]-3,dartrimethylenedioxybenzene1-Cs [('*tei-benzodioxane-coyl methyl)aminocopentyl] -3,II-)rimeteredioxybenzene Acid addition salts of the various compounds mentioned above are also included within the scope of the present invention. Acids used as addition salts include hydrochloric acid, hydrooxalic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, oxalic acid. Examples include organic acids such as citric acid, benzoic acid,) luenesulfonic acid, and methanesulfonic acid.

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.

In other words, the dynamism of spontaneously hypertensive rats (S 肚) (30
Using a catheter inserted from the tail artery under ether disintegration, blood pressure and heart rate were measured vaguely under non-anesthesia, and mean blood pressure and heart rate were measured before drug administration. After asking for the drug i, every hour
The antihypertensive effect was determined by orally administering s,, to/yu, and expressed as the rate of decrease from the pre-administration value. The maximum blood pressure reduction rate indicates the maximum decrease in blood pressure from the mean blood pressure of the administration, 5DBP.

The value is the io% hypotensive maintenance dose for 70 days (da/kg P
, O-) The results are shown in Table 1.

1PjJIl is shown in Table 1.

Compound F of the present invention! , as shown in Table-7, 'y~/
It exhibits a sufficient blood pressure lowering effect when administered orally, has a rapid onset of medicinal effects, and has a long-lasting effect. Furthermore, as shown in Table C, negative toxicity is relatively weak, and considering the amount of medicinal efficacy expressed, it is presumed to be a very safe drug.

Table-/ *1 Compound structure #i Same as the compound in the corresponding column of Table-2.

*2 Comparative data The structure of this compound is the same as the compound in the corresponding column of Table 3.

Although the compound of the present invention can be administered by any method, the method described above is preferably used.

That is, parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, and oral administration are also possible.

The dosage is determined depending on the patient's age, health status, body weight, type of concurrent treatment (if any), frequency of treatment, nature of desired effect, etc.

Generally, the 7-day dosage of the active ingredient is 0. / -100a'
lF/k19 body weight, usually t-J o mg/K14
The drug may be administered in one or more doses.

When the compound of the present invention is administered orally, it is used in the form of tablets, capsules, preparations, solutions, elixirs, etc., and when administered parenterally, it is used in the form of sterilized liquids such as liquids or suspensions. When used in a form as described above, a solid or liquid non-toxic pharmaceutical carrier can be included in the composition.

As an example of an internal carrier, a conventional Zewotentig capsule is used. The active ingredient may also be packaged as a tablet or powder, with or without adjuvants.

These capsules, tablets, and powders are generally j~de! %,
Preferably Ko! Contains ~90% active ingredient by weight.

i.e. in these forms of administration! ~j00q.

Preferably Ko! It is preferable to contain an active ingredient of ~kot0~.

As the liquid carrier, water or oils of animal or plant origin, such as petroleum, peanut oil, soybean oil, mineral oil, garbage oil, etc., or synthetic oils, etc. are used.

In general, physiological saline, dextrose or similar citric sugar solutions, and glycols such as ethylene glycol, propylene glycol, and polyethylene glycol are preferred as liquid carriers. In particular, in the case of injections using physiological saline, θ, ! ~0.000, preferably /-10.00, by weight of active ingredient.

For liquid preparations for oral administration, 0. ! Suspensions or syrups containing ~1 o I 11 weight of active ingredient are preferred.

In this case, aqueous excipients such as fragrances, syrups, and pharmaceutical micelles are used as carriers.

As explained above, the compound of the present invention lowers blood pressure by +1 It can be used effectively as Shun.

Example / /-[1-((/,l-penzodioxane-choylmethyl)aminecobutyl]~j,!-)limethylenedioxybenzene hydrochloric acid field l-(darkchloropter) -,7,$ -trimethylene Dioxybenzene(de,zat)% ('?'-henzodioxane-choylmethyl)amine(de, #7
) Lumamide (rOIIl) K111! The mixture was stirred and heated at 10° C. for 41 hours. After the reaction is completed, the solvent is distilled off under reduced pressure, and concentrated NaOH is added, followed by extraction with ether. The ether layer was washed with saturated brine, dried over anhydrous Mat S O4, and then all the solvent was distilled off. The resulting residue was dissolved in ether and washed with 0% HC! under ice cooling. 1-[+-((/, darbenzodioxane-choylmether)aminocobutyl]-3,II-trimethylene Dioxybenzene base salt (lO0977, ti's yield) is obtained.

The physical properties of this compound are as described in Table Jf) AjK.

Other compounds were also obtained in the same manner and are listed in Table 3.

Continuation of page 1 0 shots Akira Osamu Fukami 2-7 Fujigaoka, Midori-ku, Yokohama City No. 5 0 shots by Ken Nakao 4-18 Soshigaya, Setagaya-ku, Tokyo Address number 24 0 shots by Mamoru Kanno 5-3 Komazawa, Setagaya-ku, Tokyo ground 7

Claims (1)

[Claims] (1) The following general formula (in the above formula, IIFi/~J represents an integer, and n is 3~!
Indicates the number of e. ) (ω-aminoakyl)
Alkylenedioxybenzene derivatives and their acid addition salts