JPS63179868A - 1,4-benzodioxane derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (p is 0, 1 or 2; X and Y are H, OR, CN or COOH; R is H, lower alkyl, lower alkoxycarbonyl, acyl or group of formula II; m is 1 or 2; n is 1, 2 or 3; excluding the case that p=0 and X and Y are H) or its salt. EXAMPLE:8-Hydroxy-2-nitratomethyl-7-nitro-1,4-benzodioxane. USE:A drug effective to ischemic cardiopathy, cardiac insufficiency and blood pressure control in surgical operation. PREPARATION:The compound of formula I or its pharmacologically permissible salt can be produced either by nitrating a compound of formula III or reacting a compound of formula IV (q is 1 or 2; Z is H, CN or COOH when q is 1 or Z is H when q is 2) with a compound of formula R-Hal (R is the R defined above excluding H; Hal is halogen) and optionally converting the reaction product to a salt.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 1,4-benzodioxane derivatives having excellent medicinal effects. More specifically, general formula (1) is represented by the formula -OR (wherein R is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, an acyl group, or the formula (in the formula, m means an integer of 1 or 2)) cyano group or carboxy group.・ means an integer from 1 to 3. However, p=o and X=Y=
Except when it is H. The present invention relates to a 1,4-benzodioxane derivative represented by: or a pharmaceutically acceptable salt thereof; a method for producing the same; and a medicament containing the same.

In the above general formula (1), the "lower alkyl group" seen in the definition of R refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl,
It means an alkyl group such as n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl, and the like. Further, "lower alkoxy" in "lower alkoxycarbonyl group" means one derived from the above-mentioned lower alkyl group.

Examples of acyl groups include formyl, acetyl,
An acyl group derived from an aliphatic monocarboxylic acid having 1 to 6 carbon atoms such as propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, or a heterocyclic carboxylic acid such as a nicotinoyl group. Examples include acyl groups.

In the definition of R, when R is a hydrogen atom, the compound (1) of the present invention can be used as a salt thereof such as Na, C,
Alkali metal salts, alkaline earth metal salts, such as winter a.
There are salts of organic bases such as ethanolamine, and the present invention naturally includes these salts.

Furthermore, some compounds may contain, for example, their salts of inorganic acids such as their hydrochlorides, hydrobromides, hydroiodides, maleates, fumarates, succinates, malonates, acetates, citrates, etc. It can be a pharmaceutically acceptable salt such as a salt of an organic acid such as an acid salt or a methanesulfonate.

Nitrite drugs represented by nitroglycerin (hereinafter simply referred to as rNGJ) have been used for over 100 years and are still effective drugs for angina pectoris. Furthermore,
After that, isosorbide dinitrate (hereinafter simply rlsD)
(abbreviated as NJ), etc., emerged and continues to this day.

The mechanism of action of nitrites is not always clear, but nitrites dilate venous vessels and create venous retention, which reduces venous perfusion, reduces left ventricular end-diastolic pressure, and lowers left ventricular tension. It is believed that the theory that intramyocardial oxygen consumption decreases because

Under the above-mentioned circumstances, the present inventors have solved the conventional NG,
We have been conducting intensive research for many years on a compound that is a nitro agent different from l5DN and has stronger activity than these drugs, and we have discovered that a compound with the following structural formula can achieve the desired purpose.

That is, the compound of the present invention has the general formula (in the formula, p means an integer of θ to 2.
In the formula, R is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, an acyl group, or a formula (in the formula, m is 1 or 2
means an integer of )), a cyano group, or a calphox group. n means an integer from 1 to 3. However, the case where p=0 and X=Y=H is excluded. ) or a pharmaceutically acceptable salt thereof.

The compounds of the invention described above have the following advantageous characteristics.

(11) These compounds have a strong vasodilatory effect on the coronary arteries, blood vessels of the peripheral arterial system, and blood vessels of the peripheral venous system.

Therefore, in addition to increasing coronary blood flow, these compounds have the beneficial effect of reducing both preload and afterload on the heart. In this context, its activity is more potent than NG and 15DN.

(2) These compounds cause vasodilatory effects both when administered intravenously and when administered into the intestine, and exhibit good absorption effects from the gastrointestinal system.

(3) These compounds inhibit N in mice.
LD higher than G. Since it has a value, there is a wide margin of safety.

These compounds form significantly less methemoglobin than NG.

When R in the compound (1) of the present invention is a hydrogen atom, the solubility can be improved by, for example, forming it into a sodium salt. In addition, nitro agents tend to be adsorbed to infusion sets when injected intravenously, which often poses a problem. However, the compounds of the present invention are advantageous in that they have less adsorption compared to conventional nitro agents.

The indications for using the compound of the present invention as a medicine include heart failure, ischemic heart disease represented by various types of angina (effort angina, angina at rest, modified angina). variant angina), etc.].

These compounds can also be advantageously used for blood pressure control during surgery.

Therefore, the purpose of the present invention is to provide a new 1,4-benzodioxane derivative that is effective for ischemic heart disease, heart failure, blood pressure control during surgery, etc., a method for producing the same, and an anti-inflammatory drug containing these compounds as active ingredients. The goal is to provide effective drugs for blood pressure management during blood heart disease, heart failure, and surgery.

There are various possible methods for producing the compound of the present invention, but
Representative methods among these will be specifically described in detail below.

Seisan Yuta clay (In the formula, n, X and Y have the same meanings as above 6) (In the formula, p, n, X and Y have the same meanings as above.

) That is, a compound represented by formula (II) is selected as a starting material, and this is nitrated by a conventional method to produce the target substance (1). In the case of nitration, the reaction is carried out in the presence or absence of a solvent using a nitrating agent such as acetic anhydride-fuming nitric acid, fuming nitric acid, or fuming nitric acid-concentrated sulfuric acid. This reaction is usually carried out at about 0 to -40°C, and preferred solvents include acetonitrile, chloroform, dichloromethane, and acetic acid.

Through this reaction, various target substances are produced as a mixture depending on the degree of nitration (p=θ~2). These target substances can be separated and purified by, for example, silica gel chromatography to obtain a single target substance.

When Y is a hydroxyl group at the 8-position, -((:H,)OH is bonded to the 2-position, and X=H and n=l, the starting material is the following structural formula (I[+ 8-hydroxy-2-hydroxymethyl-1,4-benzodioxane represented by ) is, for example, a compound described in US Pat. No. 3,101,345, and In other words, it can be produced by reacting pyrogallol with epichlorohydrin.

Particularly, 8-hydroxy-2-nitratomethyl-7-nitro-1,4-benzodioxane, which is a representative compound of the present invention, is shown by the following reaction formula.

(III) '(IV) The method of 1.4-
Suitable for producing benzodioxane derivatives.

In this case, it can be manufactured by manufacturing method 1, but it can also be easily obtained by the following method.

This reaction is a condensation reaction, and is carried out by a conventional method. Usually, the reaction is carried out in the presence of a base such as pyridine, potassium carbonate, or triethylamine, and the solvent is acetone, DMF, etc.
etc. gives preferable results.

Next, pharmacological experimental examples will be shown to explain the effects of the present invention in more detail.

1. Method: After anesthetizing a male SHR on a gold plate for 20 weeks with bentoparbital sodium 40 mg/kg ip, a cannula was inserted into the carotid artery and jugular vein, and polygraph using an electric sphygmomanometer was performed. Blood pressure was measured from the carotid artery. The test compound was administered intraduodenally in 0.9% NaCl-1%.

Compound A (8-hydroxy-2-nitratomethyl-7-nitro-1,4-benzodioxane) was selected as a representative example of the compounds of the present invention.

2. Results The results are shown in FIGS. 1 and 2.

Figure 1 shows the blood pressure lowering effect during intravenous injection in spontaneously hypertensive rats (SIR) under anesthesia.

FIG. 2 shows the blood pressure lowering effect upon intraduodenal administration in anesthetized spontaneously hypertensive rats (SnI2).

In Figures 1 and 2, the vertical axis means the maximum reduction rate (%) of mean aortic pressure, and the horizontal axis represents the dose of test compound (μ
g/kg). ■mark is compound A1・mark is N
G, ○ mark is l5DN, Δ mark is nicorandil (N-(2
- to troxy)ethylg(3-pyridinecarboxamide) respectively. Each point and vertical bar in Figures 1 and 2 indicate the mean value and standard error. n indicates the number of examples.

Compound A caused significant hypotension when administered intravenously at doses as small as 0.3 μg/kg.

The ability of Compound A to cause a 30% reduction in mean aortic pressure was 5-fold, 250-fold, and 300-fold greater than N'G, 15DN, and nicorandil, respectively. Compound A also caused dose-related hypotension upon intraduodenal administration. The ability of compound A is nicorandil, N
It was approximately 5 times or more, 10 times or more, and 30 times or more than G and 15DN, respectively.

+11 Method A mongrel dog (12 to 16 kg) was given inhalation anesthesia with enflurane, positive pressure breathing was performed, and the chest was opened at the fourth intercostal space on the right side.

Aortic pressure and pulmonary artery pressure were measured using catheter tip pressure transducers inserted and fixed into the thoracic aorta and right pulmonary artery, respectively.

The test compound was cumulatively administered at 30-minute intervals through catheter X placed in the left femoral vein and duodenum, and the maximum hypotensive effect on the pre-drug administration value (diastolic blood pressure) was measured in the arterial system (aortic pressure) and venous system ( We compared the vasodilatory effect on pulmonary artery pressure).

(2) Results The results are shown in Table 1.

Table 1 After intravenous administration, the compounds reduced aortic and pulmonary artery pressure in a dose-dependent manner. Compound A in the arterial and venous systems as assessed by the reduction in aortic pressure and pulmonary artery pressure, respectively.
The vasodilatory effect of was approximately three times more potent than that of nicorandil. The effect of 15DN on aortic pressure was minimal over a dose range of 30 times greater than that of Compound A.

Compound A also produced a dose-dependent reduction in aortic and pulmonary artery pressure upon intraduodenal administration. Compound A
The ability of NG was about three times higher than that of NG.

(11 Method) Using a 9i1ffi dog (9 to 14 kg), under inhalation anesthesia with halothane, positive pressure breathing was performed, and a thoracotomy was performed at the fourth intercostal space on the left side. A blood flow measurement probe was attached to the left coronary artery rotation technique, and coronary The flow rate was measured.The test compound was administered cumulatively at z'/10 minute intervals through a catheter inserted and fixed into the left femoral vein.

(2) Results The results are shown in Table 2.

Table 2 Intravenous administration of Compound A caused a significant dose-dependent increase in coronary blood flow at small dose ranges such as 1-10 μg/kg.

The effect of Compound A on coronary flow was approximately three times more potent than that of NG.

From the above line flux, it is clear that the compound of the present invention has a strong vasodilatory effect on coronary arteries, peripheral arteries, and peripheral blood vessels.
This means that it is useful as a therapeutic agent for ischemic heart diseases such as angina pectoris and myocardial infarction, and cardiac dysfunction.

The toxicity of the compounds of the present invention will be explained below.

That is, 8-hydroxy-2-nitratomethyl-7-
As a result of examining the acute toxicity of nitro-1,4-benzodioxane using mice, the LDso after intravenous injection was 2.
00 to 250 mg/kg, and oral doses of 500 to 1
,000 mg/kg. As a result of conducting a similar experiment with NG using intravenous injection, it was found that LD5. is 10-15m
g/kg.

From this, it is clear that the compound of the present invention is an extremely safe compound compared to NG, and from this aspect as well, the present invention is extremely valuable.

As is clear from the results of the above-mentioned pharmacological experiments, the compounds of the present invention can be used to treat ischemic heart diseases such as myocardial infarction and various types of angina pectoris.
It is effective for the treatment and prevention of heart failure and blood pressure control during surgery, and has superior characteristics compared to existing nitro agents, and is also safer than conventional nitro agents. is of extremely high value.

When the compound of the present invention is used for the above-mentioned indications, it is administered orally or parenterally (injection, external preparation, etc.). The dosage varies depending on the disease, severity of symptoms, age, whether it is an emergency or not, and is not particularly limited, but is usually about 0.1 to 100 mg per day for adults, preferably 0.5 to 40 mg. , more preferably 1 to 20 m
It is about g.

In the case of injection preparations, for example, about 0.1 to 5 mg/hou
It is also possible to administer the drug by intravenous drip infusion, preferably about 0.5 to 3 mg/hour.

In order to formulate a compound of the present invention, it is formed into a dosage form such as a tablet, granule, powder capsule, injection, external preparation, crude drug, etc. by a conventional method in the technical field of formulation.

In other words, when preparing a solid preparation for oral use, excipients are added to the crude drug, and if necessary, binders, disintegrants, lubricants, colorants, flavoring agents, etc. are added, and then tablets are prepared by conventional methods. Form into coated tablets, granules, powders, capsules, etc.

Examples of excipients include lactose, cornstarch, white sugar,
Glucose, sorbitol, crystalline cellulose, etc., and binders include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxyprobilserpene, agar, gelatin powder, crystalline cellulose, carbonic acid. Calcium, sodium bicarbonate, calcium citrate, dextrin, pectin, etc. are allowed to be added to pharmaceuticals, lubricants such as magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc. are allowed to be added to pharmaceuticals as colorants. The flavoring agents used are cocoa powder, honeydew, aromatic acids,
Peppermint oil, Dennou, cinnamon powder, etc. are used. It goes without saying that these tablets and granules may be coated with sugar coating, gelatin coating, or other coatings as appropriate.

When preparing injections, add pH adjusters, buffers, stabilizers, solubilizers, preservatives, etc. to the herbal medicine as necessary, and prepare subcutaneous, intramuscular, or intravenous injections using conventional methods. .

When making an intravenous infusion, use the injection solution as it is or dilute it with physiological saline or glucose solution and use it as an intravenous infusion.

Examples of the present invention will be listed next, but it goes without saying that the present invention is not limited to these only.

Draw 1.757 g (6.0 mol) of 4-benzodioxane pyrogallol, 3 g of sodium sulfite, 2.21 g of water and 317 g of anhydrous sodium borate
g (1.58 mol) was added to a 5J12jII neck flask and dissolved with stirring. This was replaced with argon and stirred at room temperature.
30 g of sodium iodide, 120 g (3.0 mol) of caustic soda dissolved in 300 mA of water and 610 g (6.6 mol) of epichlorohydrin are processed and stirred for - days. Furthermore, 12 g (0.3 mol) of caustic soda and 167 g (1.8 mol) of epichlorohydrin were added,
Stir at room temperature for 3 days. The reaction solution was then washed with dichloromethane for 21iil. To the aqueous layer was added 800 g of caustic soda/1.51 g of water under water-cooling and stirring, and then the temperature was returned to room temperature.
Stir for an hour.

Then, 1.41 g of concentrated hydrochloric acid is added to adjust the pH to about 8.0, and the mixture is extracted three times with ethyl acetate. The ethyl acetate layer was saturated Na2
After washing twice with BaO9 aqueous solution and then with saturated brine, ethyl acetate was distilled off under reduced pressure. The obtained light yellowish brown oil was subjected to silica gel chromatography (approximately 2 kg of silica gel,
Then, 540 g of chloroform-n-hex (yield: about 50%) is obtained.

Melting point ("c): 98-102 8-hydroxy-2-hydroxymethyl-1,4-benzodioxane obtained by the method of (1) 127.4
g (0.7 mol), urea 1.5 g and acetonitrile 17! was placed in a 21-necked flask, and while cooling and stirring (inner bath approximately -35°C), acetyl nitrate (99% in acetonitrile) was added.
% fuming nitric acid 134mj! , prepared from 375 g of acetic anhydride and several drops of concentrated acid). Approximately 15 minutes later, water 240m
120 g of caustic soda dissolved in A' is carefully added dropwise at -30°C or lower.

Then, the mixture was poured into about 30 liters of water, and after stirring overnight, the precipitate was collected by filtration and washed with water and methanol in that order. 500m7 of hot methanol to the precipitate! was added, stirred, and after cooling, the precipitate was collected by filtration. Further, 1.5 liters of hot chloroform was added to the precipitate, and the mixture was filtered while hot to remove insoluble matter. Insoluble matter is extracted in the same manner with hot chloroform III, the chloroform solutions are combined, about 200 g of silica gel is added, stirred, and then filtered. Next, after distilling off the chloroform in the filtrate, it was dissolved in hot acetone, methanol was added thereto, and the precipitated crystals were collected by filtration to give the title compound 8-hydroxy-2-nitratomethyl-7-nitro-1,4- as yellow crystals. 58 g (yield 30%) of benzodioxane are obtained.

・Melting point ('C): 160-162 ・Elemental analysis value: HN as CJsNzOe Theoretical value (χ) 39.71 2.96 10.2
9 Actual value (χ) 39.73 2.88 10.
31 大挌冓 8-Methoxy-2-nitratomethyl-7-nito 0-1.
4-Benzodioxane 8-hydroxy-2-nitratomethyl-7-nitro-1,4-benzodioxane obtained according to Example 1 20
Add 0 mg to 30 mβ of methanol and add an excess of ether solution of diazomecan at room temperature. The mixture was extracted and concentrated to dryness for 30 minutes to obtain 220 mg of the title compound as an oil. When left in the refrigerator, it solidified and had a melting point of 73-74°C.

・Elemental analysis value: CH as C+oH+oNzOs
N Theoretical value (χ) 41.96 3.52 9.
79 actual measurement value (χ> 42.13 3.eo
9.65 Trouble 1,4-Benzodioxane 8-Hydroxy-2-nitratomethyl-7-nitro-1,4-benzodioxane obtained according to Example 1 20
0 mg was dissolved in 5 ml of pyridine, 5 ml of acetic anhydride was added thereto, and the mixture was heated to 80 to 85°C to carry out a reaction. The residue was then concentrated to dryness under reduced pressure and recrystallized from methanol to obtain 200 mg of the title compound as colorless needle crystals.

・Melting point ("C): 115-116 -IR (Nujol) cm-': 1773
(>C=O) - HN Theoretical value (χ) 42.05 3.21 8.9
2 Actual value (χ) 42.22 3.26 8.
According to the methods of Examples 1 to 3, the compounds listed in Tables 3 and 4 below were obtained.

1N Kaisho 63-179868 (15) JP-A-63-1798GB (18)

[Brief explanation of the drawing]

FIG. 1 shows the blood pressure lowering effect of hydration in anesthetized spontaneously hypertensive rats (SHR). FIG. 2 shows the blood pressure lowering effect of anesthesia spontaneous hypertension rough (St(R)) upon intraduodenal administration.

Claims (18)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ {In the formula, p means an integer from 0 to 2. and In the formula, m means an integer of 1 or 2)], a cyano group or a carboxyl group. n means an integer from 1 to 3. However, the case where p=0 and X=Y=H is excluded. } A 1,4-benzodioxane derivative or a pharmaceutically acceptable salt thereof. (2) 1 and 4 according to claim 1, where n=1
- A benzodioxane derivative or a pharmaceutically acceptable salt thereof. (3) 1 according to claim 1, where n=p=1
, 4-benzodioxane derivative or a pharmaceutically acceptable salt thereof. (4) 1 and 4 according to claim 1, where p=2
- A benzodioxane derivative or a pharmaceutically acceptable salt thereof. (5) A 1,4-benzodioxane derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein Y is bonded to the 5-position. (6) The 1,4-benzodioxane derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein Y is bonded to the 8-position. (7) 1 according to claim 1, wherein Y is a hydroxyl group
, 4-benzodioxane derivative or a pharmaceutically acceptable salt thereof. (8) The 1,4-benzodioxane derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein Y is bonded to the 8-position and is a hydroxyl group. (9) 1 according to claim 1, in which n=p=1, Y means a hydroxyl group at the 8-position, and a nitro group is bonded to the 7-position.
, 4-benzodioxane derivative or a pharmaceutically acceptable salt thereof. (10) X and/or Y are cyano group and/or
1 according to claim 1, which is a carboxyl group;
4-benzodioxane derivative or a pharmaceutically acceptable salt thereof. (11) 8-hydroxy-2-nitramethyl-7-nitro-1,4-benzodioxane or a pharmaceutically acceptable salt thereof. (12) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ {In the formula, n means an integer from 1 to 3, and
is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, an acyl group, or a group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, m means an integer of 1 or 2)] group, cyano group or carboxyl group. } There are general formulas, mathematical formulas, chemical formulas, tables, etc. that are characterized by nitration of the compound represented by The above-mentioned 1,4-benzodioxane is obtained by obtaining a 1,4-benzodioxane derivative represented by A method for producing a derivative or a pharmaceutically acceptable salt thereof. (13) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, n means an integer of 1 to 3, p means an integer of 0 to 2, and q means an integer of 1 or 2. When q=1, Z represents a hydrogen atom, a cyano group, or a carboxyl group, and when q=2, Z represents a hydrogen atom). group, lower alkoxycarbonyl group, acyl group, or a group represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (in the formula, m means an integer of 1 or 2). Hal means a halogen atom] General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, n, p, q, R and Z have the above meanings. ) The above-mentioned 1,4-benzodioxane derivative is obtained, and if necessary, the obtained 1,4-benzodioxane derivative is subjected to a salt-forming reaction, or A method for producing a pharmaceutically acceptable salt thereof. (14) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ {In the formula, p means an integer from 0 to 2. and In the formula, m means an integer of 1 or 2)], a cyano group or a carboxyl group. n means an integer from 1 to 3. However, the case where P=0 and X=Y=H is excluded. } A therapeutic/preventive agent for ischemic heart disease comprising a 1,4-benzodioxane derivative represented by the following or a pharmaceutically acceptable salt thereof as an active ingredient. (15) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, p means an integer from 0 to 2. is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, an acyl group, or a group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, m means an integer of 1 or 2)] group, cyano group, or carboxyl group. n means an integer of 1 to 3. However, cases where p = 0 and Y = H are excluded.) 1,4-benzodioxane derivatives represented by or a pharmaceutically acceptable salt thereof as an active ingredient for the treatment or prevention of heart failure. (16) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ {In the formula, p means an integer from 0 to 2. and m means an integer of 1 or 2), a cyano group or a carboxyl group. n means an integer of 1 to 3. However, when p=0, and X=Y=H.) A drug effective for controlling blood pressure during surgery, which contains a 1,4-benzodioxane derivative or a pharmaceutically acceptable salt thereof as an active ingredient. (17) p=1, m=1, X=H, Y=OH(8-
Claims 15 to 1, comprising a compound represented by (position) or a pharmaceutically acceptable salt thereof as an active ingredient
Pharmaceutical composition according to item 7. (18) Claim 1 comprising 8-hydroxy-2-nitratomethyl-7-nitro-1,4-benzodioxane or a pharmaceutically acceptable salt thereof as an active ingredient.
Pharmaceutical compositions according to items 5 to 17.