JPS6112624A - Hypotensor - Google Patents

Abstract

PURPOSE:A hypotensor containing a specific 3,7-dioxabicyclo[3,3,0]-octane derivative, exhibiting remarkably long-acting hypotensive effect compared with known homologues, and having low toxicity. CONSTITUTION:A hypotensor is obtained by using the compound of formula (R is H or glucose residue) as an active component. A concrete example of the compound is 4-[4-(3,4-dimethoxyphenyl)tetrahydro-1H,3H-furo[3,4-C]furan-1-yl]- 2-methoxyphenol (R=H). The compound of formula has long-acting and strong hypotensive activity compared with known homologues. It can be used singly as a hypotensor, and is expected to have excellent effects, such e.g. to keep stable activity with decreased frequency of administration.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides a compound having an antihypertensive effect and represented by the following general formula (I) (wherein R means a hydrogen atom or glucose). The present invention relates to an antihypertensive agent containing the present invention.

[Conventional technology]

3,7-thioxabicyclo(3,
3,0)-Octane derivative (bisepoxy lignan) Pharmacological Journal S97 No. 10 p. 1134 (published in 1977), Pharmaceutical Journal Vol. 31 No. 2 p. 131 (published in I977), Vol. 32 No. It is a known compound described in Vol. 33, No. 3, page 150 (published in 1979), No. 3, page 194 (published in 1978).

Some bisepoxy lignans are known to have antihypertensive effects. For example, pirsinol-dijlucosi (P+noresinol-dijlucosi)
de) Journal of the American Chemical Society (J, ^m, Chen.

Soc Vol. 98, p. 5412 (published in 1976)],],] is known to have a strong antihypertensive effect as described in JP-A-53-7698.

However, the antihypertensive effects of these bisepoxylignans are all temporary, and some compounds, such as the compound represented by the general formula (]), have long-lasting and strong antihypertensive effects. is not known.

Generally, antihypertensive drugs are classified into various types based on their site of action and mechanism. Usually, it is impossible to adequately control symptoms with one type of drug, so several types of drugs are administered in combination.

Advantages of combination use include: (I) The dose of each drug can be reduced to prevent the development of tolerance or side effects.

(2) Blood pressure can be lowered smoothly by combining drugs with different points of action.

(3) Side effects can cancel each other out.

etc.

However, from the standpoint of patient compliance (jlit tolerance), it is preferable to use a drug that has fewer side effects, requires fewer doses, and is administered less frequently per day.

Currently, there is a desire to develop a drug that can maintain stable antihypertensive effects throughout the day by administering one tablet once a day.

[Problem that the invention seeks to solve]

The present invention solves the conventional problems of using multiple drugs in combination and increasing the number of doses per day, which burdens patients, as there are few drugs that maintain antihypertensive effects for a long time. The aim is to maintain a stable antihypertensive effect throughout the day by administering the drug only once a day.

Means for Solving Problem C> That is, the present invention relates to an antihypertensive agent characterized by containing a compound represented by the general formula (wherein R means a hydrogen atom or glucose). It is something.

As a compound represented by the general formula 0), when R is a hydrogen atom, 4-[4,-(3,4-dimethoxyf),
enyl)tetrahydro-IH,3H-furo(3,4-
c) Furan-1-yl]-2-methoxyphenol (Phil lygenin), and R
is that of glucose, 4-(4-(3,4-dimethoxyphenyl)tetrahydro-IH,3fl-furo[3
, 4-c) furan-1-yl]-2-methoxyphenyl-β-D-glucopyranoside (phyllin: Phi
For example, the crude drug Forsythia can be obtained by the 8 method.
tbia Fruit, 10th edition Japanese Pharmacopoeia P976
~978 pages], Pharmaceutical Journal, Vol. 97, No. 10, No. 11
34 pages (published in 1977), Pharmaceutical Journal Vol. 31, No. 2, page 131 (published in 1977), Vol. 32, No. 3, 194
Page (published in 1978), Volume 33, No. 3, page 150 (I
It can be obtained by the extraction method described in 1979).

That is, forsythia is extracted with methanol under heating, and the methanol extract is concentrated to about 1,710 g. Approximately 1
After adding 0 times the amount of water and removing the precipitate, the solution I is extracted with knee, chill, and chloroform in this order.

The ether extracted layer is subjected to silica gel column chromatography and developed with chloroform-ethyl vinegar (C2:1) to obtain the compound (phylligenin) of the general formula (1).

Further, when the chloroform extracted layer is subjected to silica gel column chromatography and developed with chloroform-ethanol (4:1), a compound of the general formula (1) (filirin) is obtained in the same manner.

In this case, the forsythia is called Phorstia suspensa.
Pearl (Forsythia 5uspensa Va
hl) is preferred because the yield of the compound represented by formula (2) is high.

As described below, the compound represented by General 2〇 shows a sustained antihypertensive effect and has low toxicity in the essential hypertensive rat (SIR) test, and it can be administered orally or parenterally alone or together with a diluent. It is administered in the form of

When manufacturing tablets, capsules, pills, etc., starch,
Fillers and extenders such as sugar, mannitol, and silica, binders such as carboxymethylcellulose and polyvinylpyrrolidone, wetting agents such as glycerin, agar, sodium carbonate,
Deterioration inhibitors such as calcium carbide, dissolution retardants such as paraffin, absorption enhancers such as quaternary ammonium compounds,
Diluents such as surface bulking agents such as cetyl alcohol and glycerin monostearate, adsorption carriers such as kaolin and bentonite, and lubricants such as talc and stearin-magnesium are used. Furthermore, these preparations may be made into sustained-release preparations by coating with a protective matrix or the like, microencapsulation, or the like.

When producing solutions, emulsions, etc., commonly used solvents such as water, ethanol, ethylene glycol, glycerin, sorbitan fatty acid esters, oils and fats, and diluents such as solubilizers and emulsifiers are used.

For parenteral administration of parenteral preparations, they are sealed in ampoules, vials, etc. using commonly used diluents such as water and sodium chloride. Alternatively, it may be dissolved before use. In this case, the formulation must be sterile and adjusted to be blood isotonic upon administration.

In the case of oral administration, the dose of the compound administered in General 2〇 is 50 to 1.500 mg/day, preferably 300 to 1.500 mg/day.
5QOmg/day, 10-200rn for parenteral administration
s/day, preferably 40 to 150 mJ/day.

At this time, the dose is adjusted as appropriate depending on symptoms, age, dosage form, etc.

[For production]

Next, the antihypertensive effect and acute toxicity of the antihypertensive agent of the present invention will be explained.

The antihypertensive effect was determined using essential hypertensive rats (SIR) by the method of Rya Tabej, (C
Iin, Pharm, & Tbcrap, Volume 11 26
9-274 (published in 1970)].

That is, using 5HR (#t 11 weeks old, approximately 300 fi), intravenous injection of bendoparbital 5 Gmg/kg body weight,
The animals were anesthetized with a subcutaneous injection of urethane at 1.751 kg/kg body weight, and a cannula was inserted into the common carotid artery under natural breathing, and blood pressure was measured in multiple ways. The sample was 1010 m in 5%-ethanol.
The suspension was suspended at a concentration of 1l7 and injected into the hind limb vein at a rate of 1 mQ/kg body weight (I0/kg body weight).

In addition, the blood pressure before sample administration showed 175-190+mHs. The results are shown in Table 1 below.

It has been found that the compound represented by the general formula (I) in Table 1 (filirin, filigenin) has a sustained antihypertensive effect.

Acute toxicity is determined by the Litchfield-Wilcochran method CJ
-Pharm-E'xp, Ther, Volume 96, page 99 (
The measurement was performed by intraperitoneal administration using 5-week-old ddY Itoo mice (body weight 19-24 seconds).

The results are shown in Table 2 below.

As is clear from the results in Table 2 and above, it is clear that the antihypertensive agent of the present invention containing the compound represented by the general formula (3) exhibits a sustained antihypertensive effect and has low acute toxicity.

〔Example〕

The present invention will be explained in more detail below with reference to 1g production examples and formulation examples, but the present invention is not limited thereto.

Production example Forsytbia 5uspensa
Vahl) Using 11 for 50, Pharmaceutical Journal Vol. 97, No. 1
0, pages 1134 to 1137 (published in 1977), 4-(4-(3,4-dimethoxyphenyl)
Tetrahydro-IH,3H-furo(3,4-e)furan-1-yl]-2-methoxyphenyl-〇-D-glucopyranoside (phyllin) 16.751! , 4-(4-
(3,4-dimethoxyphenyl)tetrahydro-1)1
．． 3) 1-furo[3,4-c)furan-1-yl]-2
- 450 mJ of methoxyphenol (phylligenin) was obtained. The physical properties are as follows.

Filirin Melting point: 146-148℃ Specific rotation: (α)D”46.9 (C=0.25,
methanol) Ultraviolet absorption spectrum λMeOH (nm): ax 229.278 Infrared absorption spectrum νKBr (an-') ・ax 1590, 1518 Nuclear magnetic resonance spectrum (CDCQ, ), ? =6.76
．． 3.83.3.73 Mass spectrometry spectrum m/e: 37 so, 219, 205.166, 165.15
2.151 Elemental analysis・C1Jfi4011・Calculated value as 1/2H,0; C: 59.59 H: 6.43 Actual value, C:
59-59 H: 6.61 phylligenin Melting point: 133-134 °C Specific rotation: (a);” 120 (C=O-04
, methanol) Ultraviolet absorption spectrum λm'a': (nm);23
1.5. 280 Infrared absorption spectrum νe (C+”-’): 34
30.1600.1585, 1510 nuclear magnetic resonance spectrum (cocQ,)a:6.87.5.43-5.
80.4.87.4.43.3.70-4.30, 3
．． 88.3.33 Elemental analysis: Calculated value as C,, H,, O, C: 67.73 H: 6.50 Actual value,
C:67-86) 1:6.54 Reference example Eucomnia ulmoides 0l
(Tetrahydro-IB, 3M
-furo[3.4-c)flazi-1,4-diyl)bis-
(2-methoxy-4゜1-phenylene)bis〇-D-
Glucopyranoside (bisolesinol diglucoside:
Pin'oresin.

1-diElucoside) 2.544 was obtained. Physical properties were as disclosed in the literature.

Formulation Example 1 100J of phylloline, 60g of lactose, 30g of corn starch, 2s of forged magnesium stearin, and Ss of talc were mixed in a V-type mixer for 5 minutes, and the resulting mixed powder was directly compressed into a flat, rounded corner shape with a diameter of 8.0m+n. Compress the tablets using a punch to a diameter of 8-0 mm and a thickness of 3. Qmm, weight 2
1,000 tablets of 00 m5 were obtained.

Formulation example 2 120 g of phylligenin, 50 g of calcium hydrogen phosphate,
After mixing 76 g of 2s1 crystalline cellulose of interstitial aluminum and 2 Jl of magnesium stearate in a V-type mixer for 5 minutes, the mixture was passed through a sieve and mixed well, followed by a conventional method to obtain LOOO capsules each weighing 300 mg.

Formulation Example 3 Filirin 5018 was sterilized and filled into vials. When this is used, it is dissolved in sterilized water to form a repellent solution.

〔Effect of the invention〕

As described above, according to the antihypertensive agent of the present invention, filigenin and filirin represented by the general formula ω are known compounds, but the antihypertensive effect is significantly higher than that of conventionally known homologous compounds. In addition, since the acute toxicity is low, it can be used alone as an antihypertensive agent, and various excellent clinical effects can be expected, such as maintaining a stable antihypertensive effect throughout the day and reducing the number of times the drug is taken.

Claims (1)

[Claims] 1) Contains a compound represented by the general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(I) (In the formula, R means a hydrogen atom or glucose) An antihypertensive agent characterized by: