JPS58219114A - Hypotensive agent - Google Patents

Abstract

PURPOSE:A hypotensive agent, containing an alkylenedioxybenzene derivative or an acid addition salt thereof as an active constituent, having the hypotensive action, rapidly developing the efficacy, and having prolonged action with a weak acute toxicity and high safety. CONSTITUTION:A hypotensive agent containing an alkylenedioxybenzene derivative of formula I [m is an integer 1-3; X is Z-(CH2)n, (CH2)4 or formula II, IIIor IV: Z is OCH2, NHCO, S(O)lCH2 (l is 0, 1 or 2), etc.; n is 2 or 3] or an acid addition salt thereof as an active constituent. The drug can be orally or parenterally administered. The active constituent is obtained by reacting a halogenoalkylenedioxybenzene derivative of formula V (Y is halogen) with an amine of formula VI in the presence of a solvent preferably at 0 deg.C-room temperature. 5- [3-{1,4- Benzodioxan-2-ylmethyl)amino}-2-hydroxypropoxy]-1,3-benzodioxole, etc. may be cited as a specific example of the compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an antihypertensive agent containing an alkylene dioxybenzene derivative or an acid addition salt thereof as an active ingredient.

The above compound in the present invention has the following general formula (1)% formula% [wherein m represents an integer of 1 to 3, and X represents Z (CHt
) n- 15(o)jcu, -(1 is 0, l or λ) or 〒 -NCR. Here, the wings are hydrogen atoms, carbon number -7
~3 alkyl group or COR'(R' is a hydrogen atom or a COR' group having 1 to 3 carbon atoms).

Also, n indicates ko or 3); (CHl)4; -Go CH! −: H −CHCH,−? 8 or -0CH2CHCH,-] In the above general formula (1), the substitution position of the aminoalkoxy group on the dioxybenzene ring is not particularly limited.

Next, a method for producing the compound represented by general formula (I) will be explained below.

(A) General formula (1) K, X is -Z (CH
t) n--8(0), FCH,-(j) is 0. / or co) or an alkyl group of several 1 to 3 or -〇〇R'(R' is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms), and n indicates co or J), the following general A halogenoalkylenedioxybenzene derivative represented by the formula (II) (in the above general formula, m has the same meaning as m in K in the general formula (1), and Y represents a halogen atom) and a halogenoalkylenedioxybenzene derivative represented by the following formula (1) Obtained from reaction pressure with amine.

The halogenoalkylene 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 /-70 mol per t mol of the halogenoalkylene dioxybenzene II conductor.

Although the reaction proceeds satisfactorily even without a solvent, an inert solvent may be used to facilitate the reaction. Water as a solvent,
Dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, lower alcohols, or a mixture of two or more of these solvents are used.

The reaction temperature is not particularly limited, but is usually -750 from IOC.
It is ℃. Preferably the temperature is from OC to room temperature.

The reaction time varies depending on the reaction temperature, the reactivity of the raw materials, and the type of solvent, but is usually in the range of io minutes to 20 hours. In addition, bases are added to collect hydrogen halide produced by the reaction and accelerate the reaction. You may. Examples of bases include inorganic salts such as potassium hydroxide, potassium carbonate, sodium hydroxide, sodium hydrocarbon, and sodium carbonate, and tertiary organic amines such as pyridine and triethylamine. The amount used is usually 1 mole per 1 mole of the amine of general formula (1).

In order to obtain a desired acid addition salt, after the reaction is complete, excess amine and solvent are removed by distillation or washing with water, and a strong base aqueous solution such as sodium hydroxide or potassium hydroxide is added to form an alkylenedioxybenzene conductor with 1 m of alkylene dioxybenzene. , and then extract the compound with a solvent such as ether, chloroform, benzene, or toluene. Further, by neutralizing by adding a desired acid, the desired acid addition salt can be obtained.

CB) In the general formula (I), X is -OCH,C
In the case of HCH, -H; In the method (A) above, in place of the compound represented by general formula (Il), the following general formula (IV) (where m has the same meaning as m in general formula (1)) It can be obtained by the same method except that the epoxides shown in ) are used.

The above epoxides are made by combining a compound represented by the following general formula (V) (in the above formula, m has the same meaning as m in general formula (1) and represents an alkali metal) and epichlorohydrin, such as dimethylformamide. K can be obtained by reaction in an aprotic solvent.

[CD In general formula (I), X is -(j''HCH
, - is obtained from a compound represented by the general formula () (where m has the same meaning as in the general formula (I) vc) obtained by the method (A) above.

That is, the compound represented by the above general formula (Vl),
It can be obtained by treatment with a metal hydride salt such as boron hydride (CD) as it is or by neutralizing the acid addition salt in water or a lower alcohol such as methanol or ethanol, or a mixed solvent thereof. ) In the general formula (I), X is -NHCHt
When (CH,)rr-; General formula () () obtained by the method [A] above (where m and n have the same meanings as in general formula (1))
Obtained from the compound represented by

That is, the compound represented by the general formula (Vll) can be obtained by using an organic solvent such as tetrahydrofuran. Specific examples of the compounds used in the present invention are shown below.

3-[3-(xDarbenzodioxan-1-ylmethyl)amino)-11-hydroxygloboxy]-13-benzodioxole b-(,7-(tDarpenzodioxane-λ=Nylmethylamine) -cohydroxyproboxy)-1,1,
1-Benzodioxane/-[3-(1hiro-penzodioxane, san-coylmethyl)amino)-cohydroxyproboxy]-,l+-trimethylenedioxybenzender(,?-(l-penzodioxane- t-[a-((Xderbenzodioxane-coylmethel)amino)-11-hydroxypropoxy]-t4I
-Benzodioxane/-[,? -((141-benzodioxane-choylmethyl)amino)-11hydroxypropo#'/]-2
，? -)rimethylenedioxybenzene s-[:J-((t4I-penzodioxane-coylmethel)amine]propoxy)-ta-benzodioxole s-[J-((x-benzodioxane-coyl methyl)amino)butoxy)-ta-benzodioxolter[,7-((/darbenzodioxane-coylmethyl)amine)propoxy]-1,y-' benzodioxole 1-[:J-(ni) ##quibutoxy]-13-benzodioquinol A-[,7-((ldarbezodioxane-coylmethyl)amine)propoxy)-ta-benzodioxane A-(3-1(/darpenzodioxane-choylmethyl)amine)butoxy]-t41-benzodioxane s-[3-((ldarpenzodioxane-choylmethyl)amino)propoxy]7x41-benzo Dioxane s-(,7-(i-benzodioxane-coylmethyl)amino)butoxy 1-,i, ,a-benzodioxane/-[,? -((/tei-penzodioxane-co-ylmethyl)amino)probogyi]-aa-trimethylenedioxybenzene-t-(,?-(l-benzodioxane-co-ylmethyl)amine)butoxy]-J, 41 -trimethylenedioxybenzene/-(J-4(ill-benzodiogysan-coylmethyl)amino)globoxy]-23-trimethylenedioxybenzene/-(,?-((X4+-benzodioxane-1 -ylmethyl), amino)butoxy]-2J-)rimetelenedioxybenzene s-(co'(14t-benzodioxan-2-ylmethyl)aminecoacetyl)-<3-benzodioxole s- to z-( (7-derbenzodioxane-ylmethyl)amine]'-7-hydroxyethyl]-13-benzodioxole 6-[co[(t,Q-benzodioxane-ylmenal)amine]acetyl]- 10-benzodioxane 6-[co[(l-benzodioxane-coylmethyl)amino 1-i-hydroxyethyl]- to terbenzodioxane i-[-1((zu-benzodioxan-2-ylmethyl) [amino]acetyl] -, y, q -) rimetelenedioxybenzene i-[co((llI-bennedioxane-coylmethyl)amino]-1-hydroxyethyl:) -3,!
-t') methylenedioxybenzene j-[#-[(/
darpenzodioxane-ylmethyl)amine]butyl]-tJ-benzodioxole 6-[hiro-((ta-benzodioxane-coylmethyl)amino]butyl]-t4t-benzodioxane l-[ter C(l-benzodioxane-co-ylmethyl)aminecobutyl)-xlI-trimethylenedioxybenzene N -(,y-((x4I-benzodioxane-ylmethyl)amino)propionyl)-ay-methylenedioxy Aniline N -(,?-((llI-benzodioxane-choylmethyl)amine)propyl] -,,?,e-methylenedioxyaniline N-(3-((x4I-benzodioxane-choylmethyl) )amino)propionyl)-ay-dimethylene°dioxyaniline N-(,y-((ldarpenzodioxane-coylmethyl)amino)propyl]-a+-dimethylenedioxyaniline N-(:,y- ((xDarpenzodioxan-1-ylmethyl)amino)gropionyl)-341-trimethylenedioxyaniline N-[3-((zDarpenzodioxan-1-ylmethyl)amino)propyl)-3u-trimethylene Dioxyaniline b-,(,y-((xdarpenzodioxane-coylmethyl)amino)propylthio)-111-benzodioxane t-'(,?-((/darbenzodioxane-choylmethyl)amino) ) glopyrutheo]-4hiro-trimethylene, dioxybenzene, and acid addition rings of the various compounds mentioned above are also included as active ingredients of the drug according to the present invention. Examples of acids used as addition salts include hydrochloric acid, Inorganic acids such as hydrooxalic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, adipic acid,
Examples include organic acids such as propionic acid, tartaric acid, fumaric acid, machiic acid, oxalic acid, citric acid, benzoic acid, toluenesulfonic acid, and methanesulfonic acid.

Although the drug according to the present invention can be administered by any method,
Preferably, the following method is 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 according to the patient's age, health condition, weight, type of concurrent treatment, if any, frequency of treatment, nature of desired effect, etc.

In general, the daily dose of the active ingredient is Q/-100 to /# body weight, usually 1 to 30 kg/kt body weight, administered once or more.

For oral administration, it is in the form of tablets, capsules, powders, liquids, elixirs, etc., and for parenteral administration, it is in the form of sterile liquids such as liquids or suspensions, as described above. If used, a non-toxic pharmaceutical carrier, such as a liquid or a liquid, 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 are commonly available in KS~9S,
Preferably it contains from 90 to 90 kg of active ingredient.

That is, with these modes of administration, j-! t00■, preferably 2g-21089 of active ingredient.

As the liquid ring, water, petroleum, animal, vegetable, or synthetic oils such as peanut oil, soybean oil, mineral oil, and sesame oil are used.

In general, physiological saline, dextrose or similar sucrose solutions, and glycols such as ethylene glycol, glopylene glycol, and polyethylene glycol are preferred as liquid carriers, particularly in the case of saline-based injections. -10% by weight of active ingredient.

In the case of solutions for oral administration, they may be suspensions or syrups containing as-io@weight of the active ingredient.

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

Hereinafter, the present invention will be further explained in detail with reference to Examples and Test Examples.

Example 1 s-(:,y-((,cdarpenzodiocan-1-ylmethyl)amine)-cohydroxyproboxy]-4
3-Benzodioxole hydrochloride N,N-dimethylformamide sowt and SO related sodium hydride SO da? N,N-dimethylformamide 5 was added to a suspension of
ae-methylenedioxyphenol dissolved in 00-/
Add 3g/f solution dropwise.

Part 61, epichlorohydrin 4' at a time 42. !
? , remove the water bath, and stir at room temperature for an hour. The reaction solvent was distilled off under reduced pressure, and the residue contained 50% of benzene and 20% of water.
The aqueous layer was separated and washed with water. The benzene layer was dried over anhydrous sodium sulfate, and the benzene was distilled off under reduced pressure.

The residue was distilled under reduced pressure to give hp/3θ~/,? ,t C/
/ 1
and co-aminomethyl-t-benzodioxane 4<?
, P was added, and the mixture was heated to reflux while stirring for a certain period of time.

The reaction solvent was distilled off under reduced pressure, ethyl acetate 100- and water SQ- were added to the residue, the aqueous layer was separated, and the ethyl acetate layer was dried with anhydrous sulfuric acid. Add cola.

Separate the precipitated crystals, recrystallize from ethanol,
-(J-((l-penzodioxane-ylmethyl)amine)-cohydroxyproboxy]-43-benzodioxole hydrochloride was obtained in 2.2 cm (yield: 71 cm).

The physical properties of this compound are shown in the A/ column of Table 1.

Compounds 'Mukoda' in Table 7 were produced in the same manner, and the physical properties of the obtained compounds are shown in Table 1 together with the above compounds.

Example 5-(3-((<Hiro-benzodioxane-choylmethyl)amino)propoxy]-t,3-benzodioxole hydrochloride Potassium hydroxide ('ZjP) is dissolved in water (Ku), t
- Butanol (120ml) was added to a solution containing 1. ! Add coumethylene dioxyphenol (15y> and 13-dizolomopropane (#fP) and stir under heating under reflux for 3 hours. After the reaction is complete, the solvent is distilled off, and benzene is added.
Wash with water. After drying the benzene layer with anhydrous sodium sulfate and distilling off the solvent, vacuum distillation L, jt-(3-glomoproboxy)-13-benzodioxole (yield 23?, boiling point/
Obtain J O//5ilH%:'l.

5-(3-promogloboxy)-43-benzodioxole (Of) was dissolved in DMF (30 ml), and coaminomethane-tlI-benzodioxane (,1
/5l-) and triethylamine C, 201F> were added, and the mixture was stirred at 70°C for 71 hours.

After the reaction is complete, water is added and extracted with ether.

The extract was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was dissolved in alcohol.
16 Add HCI/BtOH. By counting the generated crystals and recrystallizing them with alcohol, j-1:
? -((lp-penzodioxane-choylmethyl)amine)propoxy]-/! 3-benzodioxole hydrochloride (yield: 70%) is obtained.

The physical properties of this compound are shown in the JI6S column of Table 1.

Compounds A6 to // in Table 1 were produced in the same manner, and the physical properties of the obtained compounds are shown in Table 1 together with the above compounds.

Example 3 5-[Co[(141-penzodioxane-coylmethel)aminecoacetyl)-lJ-benzodioxole hydrochloride S-(α-bromoacetyl)-lJ-benzodioxole(-〇 F> was dissolved in tetrahydrofuran (30-) VC, and coaminomethyl-44I-benzodioxane (/
! 41) and triethylamine (/:jd),
React for S hours at room temperature. After the reaction is complete, ethyl acetate is added, the mixture is washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off. Dissolve the residue in ethanol, add hydrochloric acid/ethanol, and add ethyl ether to crystallize. After the crystals are separated, they are recrystallized with ethanol and s-
(co((te-benzodioxane-coylmethyl)
aminocoacetyl)' -i J-benzodioxole (Yuko t.

73% yield).

The physical properties of this compound are as described in A/JK in Table 1. In the same manner, compound No. 13, A/41+ in Table 7 was obtained and had the physical properties as listed in Table 1.

Example-tei! -[Co((X*-benzodioxane-ylmethyl")amino)-1-hydroxyethyl]=43-benzodioxole 3-[Co((441-Benzodioxane-ylmethyl")amino)-1-hydroxyethyl] dioxan-1-ylmethyl)ino]acetyl]-
Dissolve 3-benzodioxole hydrochloride (10f) in methanol (tzmt), neutralize with -N-NaOH aqueous solution, add sodium borohydride (10O1n9), and stir at room temperature for 4 hours. After the reaction is completed, the solvent is distilled off, dissolved in ethyl acetate, and washed twice with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off and crystallized using water-alcohol. to θ■, 't9 yield) is obtained.

The physical properties of this compound are as described in /IfL20 in Table-7. Similarly, Table-1OJf62/,
A compound of 16 λ was also obtained and has the physical properties as described in Table 1.

Example 5 t-[q-((ta-benzodioxan-ylmethyl)amino]butyl]-1 d-trimethylenedioxybenzene hydrochloride 1-(4I-chlorobutyl)-2hiro-)1j methylenedioxybenzene Coconut benzene (!Ire), (41-benzodioxane-λ-ylmethyl)amine (9!/)) and triethylamine (j?) in dimethylformamide (ri.-)
Dissolve and heat and stir at 50°C for 4 hours. After the reaction is completed, the solvent is distilled off under reduced pressure, JNNaOH is added, and the mixture is extracted with ether. The ether layer was washed with saturated brine, dried over anhydrous Nat 804, and then the solvent was distilled off. The resulting residue was dissolved in ether and cooled on ice. HCI/ethyl acetate was added, the resulting crystals were separated, and recrystallized from ethanol to give /-[4'-C(/darpenzodioxane-coylmethyl)aminecobutyl)-a41-
Trimethylenedioxybenzene hydrochloride (taqy, 4t
tA yield).

The physical properties of this compound are as described in Table 4/1 of Table 1.

In addition, the same pressure was applied to obtain the compound A/, 1%414 in Table 1, whose physical properties are as described in Table 1.

Example 6 N-[,? -((,<Cubenzodioxan-1-ylmethyl)amino)propionyl)-ay-methylenedioxyaniline hydrochloride N-(3-chloropropionyl)-a4I-methylenedioxyaniline Cl0f) in dimethylformamide SO
-, and add l-benzodioxan-2-ylmethylamine (19?) and trimethylamine (19?) to this.
) is added and the mixture is stirred for 10 hours at SO 0 C. After the reaction is complete, water is added and the mixture is extracted with ethyl acetate.

The ethyl acetate layer is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off. Dissolve the residual liquid in ethyl acetate,
Add 2 ofb hydrochloric acid/ethyl acetate. The crystalline F produced
It was collected, recrystallized with ethanol, and N-[,? -((/darbenzodioxane-coylmethel)amino)propioni n, ]3. q-methylenedioxyaniline (t
aqy, yield of over 7) is obtained.

The physical properties of this compound are listed in Table 10116/l.

Examples N-(3-((xderbenzodioxane-coylmethyl)amino)propyl)-,7,a-methylenedioxyanilinetetrahydrofuran(,tarid)KLithium aluminum hydride(/,1tP) suspend.

N-(J-((10-pensoshioxan-ylmethyl)amine)propionyl)-,y,q-methylenedioxyaniline (mu θ) obtained by the method of Example 6
? ) is dissolved in tetrahydrofuran (iomt) K and added dropwise to the above suspension.

After the addition is complete, the mixture is stirred at SO 0 C for an hour. After the reaction is completed, the reaction mixture is post-treated with lithium aluminum hydride using a conventional method, and the formed precipitate containing aluminum hydroxide is removed by filtration.The F solution is concentrated and then dissolved in ethyl acetate to obtain the The solution is washed with saturated brine and dried over anhydrous sodium sulfate.

Next, add hydrochloric acid/ethyl acetate, separate the resulting crystals, recrystallize with ethanol, N-(:, y-((
llI-penzodioxane-choylmethyl)amino)
Propyl]-ethermethylenedioxyaniline (j:A
7. The physical properties of this compound are listed as /1f119 compound in Table 1.

Similarly, AJ in Table-1! Obtain a compound and list its physical properties.
/ Shown in /.

The following compounds can also be obtained in the same manner as in the above examples.

N-(,y-((14I-benzodioxane-choylmethyl)amino)propyl]-N-methyl-, Z $
-Methylenedioxyaniline N-[dar((111-benzodioxan-2-ylmethyl)amino)butyl]-
N-globil=uta=trimethylenedioxyaniline N
(J-((<*-benzodioxane-coylmethyl)
amino)propyl]-N-aceteru J l-methylenedioxyaniline N-[der(1derpenzodioxane-coylmethyl)amino)butyl]-N-formyl-,11-dimethylenedioxyaniline N-[Hiroshi −((
lHiro-benzodioxane-choylmethyl)amine)butyl] -J, lI-methylenedioxyaniline N-[, dar((/darpenzodioxane-ylmethyl)amino)butyryl)-a4I-trimethylene Dioxyanidine t-(,y-((tdarpenzodioxan-λ-ylmethyl)amino)propyl]sulfinyl-,i 4'-
) IJ methylenedioxybenzene t-[, y-((x
Darpenzodioxane-coylmethyl)amino)propyl]sulfonyl-,241-trimethylenedioxybenzene N-(,?-((xDa-penzodioxane-λ
-ylmethyl)amino)propyl]-N-mef44
I-dimethylenedioxyaniline N-[3-((zhiro-
Benzodioxane-coylmethyl)amino)propyl)-N-15-ru a dat trimena dioxyaniline N-[,y-((,<gubenzodioxan-1-ylmethyl°)amino)propyl)-? J-acetelium 2
a-dimethylenedioxyaniline N-(,?-((z-derbenzodioxan-1-ylmethyl)amine)propyl)=N-acetyl-1da-trimethylenedioxyaniline-[,7-(1-derbenzodioxane) -coylmethyl)amino)propyl]sulfinyl-derpenzodioxane Test Example Hypotensive effect and acute toxicity The hypotensive effect of the drug according to the present invention was examined by the following method. That is, the animals were spontaneously hypertensive rats (8HR).
Blood pressure and heart rate were measured invasively under ether anesthesia using a catheter inserted from the caudal artery under ether anesthesia. It was determined and expressed as the rate of decline from the pre-administration level.

The results are shown in Table-2.

Table -- *1 The structure of the compound is listed in the corresponding column of Table-7.

*Comparative example In addition, the acute toxicity value (LDso) was determined using mice and shown in Table-
Shown in 3.

Table 3 The structures of the compounds are listed in the corresponding column in Table 1.

As shown in Table 2, the drug according to the present invention has 11n9/
Oral administration of kt shows a sufficient blood pressure lowering effect, the onset of drug efficacy is rapid, and the action is long-lasting. or.

Acute toxicity is also relatively weak, and considering the amount of medicinal efficacy expressed, it is presumed to be a very safe drug.

Claims (1)

[Claims] (1) General formula (1) [In the formula, m represents an integer of 7 to 3, and X represents Z (CH,
) n- 1 (2 is -OCH, -1-CCH, -1-NHCO-1-
8 (0) JICH, - (t is θ, l or co) or ■ -NCR. Here, R is a hydrogen atom, number of carbon atoms/-
J represents alk, a kyl group or -can'(R' is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms). In addition, n represents co or 3; A blood pressure lowering agent with active ingredients.