JPS58146579A - Dibenzo-p-dioxine derivative - Google Patents

Abstract

NEW MATERIAL:A dibenzo-p-dioxine derivative of formulaI(R is H, lower alkyl, lower alkenyl, phenyl-lower-alkyl, lower alkanoyl) and its salt. EXAMPLE:1-(3,5-Diacetyloxyphenoxy)-2,4,7,9-tetraacetyloxy-dibenzo-p-di oxine. USE:It has a strong activity of antiplasmin inhibitor and is used as a preventive or curing agent for thrombosis caused by fibrinolytic exasperation. It is also used as an assistant for conventional thrombosis curing agent. PREPARATION:For example, a sea weed, KUROME (Ecknonia Kurome Okamura) is extracted with a usual polar solvent such as methanol or ethanol and the extract is concentrated under reduced pressure to prepare the primary extract. The resultant extract is subjected to the intersolvent-distribution extraction and the extract is concentrated under reduced pressure. Further, the concentrate is subjected to celite-column chromatography, eluted with a solvent to give the compound of formulaIwhere R is H.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel dibenzydo-dio+syn derivatives.

The dibenzy I-dio+syn derivative of the present invention is a novel compound that has not been described in any literature, and is represented by general formula (1).

R [In the formula, R is the same or different and is a hydrogen atom, lower! Le cow le group, low grade! rukenyl group, phenyl lower alkyl group or lower! Indicates a lucanoyl group. ] The inventors have discovered that seaweed is 0me (
Ee41tpnia Kuron*t04amatr
We have been conducting intensive research on extracts of .tx). And plasmin in the extract.

The present inventors recognized the existence of a compound that has an inhibitory effect on jasmin 5nkottar and succeeded in extracting and isolating the compound, thereby completing the present invention.

In this specification, lower alkyl groups include, for example, methyl, ethyl, diyl, isodyl, butyl, ta
Examples of lower acykenyl groups include rt-butyl, pentyl, he+cyl groups, etc., such as vinyl,! Lil, l
-butenyl, 2-dznyl, l-methyl-Plyl 2"
Examples include pentenyl and 2-pentenyl groups.

Examples of phenyl lower alkyl groups include besidyl, 2
-Phenylethyl, l-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, ■, 1-dimethyl-2
Examples include -phenylethyl-phenylpentyl, 6-phenylsil, 2-methyl-3-phenylproyl, and the like.

Low class! Examples of the lucanoyl group include lumyl, acetyl, butydioyl, butyryl, isobutyryl, beni/tsunoyl, ttrl-butylcarbonyl, and hesanoyl groups.

The compound of the present invention represented by the above general formula (1) has alpha 2 and plasmin bitter (α2-to1assstan*5kt), which is the main plasmin bitter in blood.
bJtar) and PLyP-2-mayag0purine (α2-matrtpgltybmliss)
It has physiological activity that strongly inhibits the activity of

Various biological reactions such as blood coagulation and fibrinolytic phenomena (fibrinolysis) are mediated by various proteolytic enzymes, but the functions of these proteolytic enzymes are dependent on inhibitory protein present in the body. It is controlled. It is known that the above-mentioned plasmin inhibitor has a strong inhibitory effect on plasmin, which is involved in the fibrinolytic system, and acts as an inhibitor of the fibrinolytic system. In addition, in the case of 0 therapy due to the activation (generation) of plasmin by administering Uroshinase or Streptonas, which are currently used as blood powder dissolvers, the above-mentioned plus-di inhibitors strongly suppress the generated plasmin. It is known to inhibit Therefore, there is a strong desire in the industry to develop drugs that can induce sho@ichikushin by inhibiting the action of plasmin and bitter in the blood [Nobuo Aoki et al.: Proteolytic enzyme inhibitors in vivo; Metabolism, Vol. 14, No. 6, No. 1099-
1111j [(1977), Tamotsu Matsuda: Blood coagulation photoprogress, low molecular weight de↑Strauss 0+Nase Literature Collection No. 1-15
(Reference: igi collection, published by Otsuka Pharmaceutical Co., Ltd., January 10, 1978).

The compound/substance of the present invention represented by the following general formula (1) has a strong anti-positive inhibitor activity, which is clear from the pharmacological test results described below, and therefore, it is effective in preventing thrombosis caused by fibrinolytic 7C progression. It is useful as a prophylactic and therapeutic agent, and is also useful as an adjuvant to conventional thrombosis therapeutic agents.

The compound of the present invention is produced, for example, according to the method shown below.

Among the compounds of the present invention, the compound represented by the following formula (1a) is extracted and isolated from seaweed, for example, in the following manner. That is, first, seaweed is mixed with methanol, ethanol,
Extraction is carried out using a common polar solvent such as isopropanol, a water-containing alcohol thereof, or ethyl acetate, and the extract is concentrated under reduced pressure F to obtain a primary extract. The method for collecting the compound of general formula (1a) from the secondary extract is not particularly limited, and any of the various known methods utilizing ring chemical properties can be employed. For example, the difference between dissolved carbon and impurities, the adsorption #II for ordinary adsorbents such as activated carbon, XAD-), silica gel, ion exchange resin, Sephadax, etc.
This can be carried out by a method that utilizes the difference in I power, the difference in the distribution ratio between two liquid phases, etc., or by a combination of these methods.

Specifically, the extract is extracted from the above-mentioned primary extract using a solvent such as vinegar-ethyl, phosphoric acid, ether, etc., and then this extract is concentrated under reduced pressure. , celite column, tfix LM-2Q column, etc., and a suitable solvent such as ethyl ether,
? It should be eluted with a solvent such as methanol, etc.
) Take (1 g) can be obtained.

Among the compounds of the present invention, compounds other than the compound of formula V(tn) above are produced, for example, by the method shown below.

Reaction formula-1 [In the formula, R1 and R2 are 4- or different, a hydrogen atom,
Lower alyal group, lower! Rukenyl group, phenyl lower alkyl group or lower! Indicates a lucanoyl group. However, at least 411 of each R shall represent a hydrogen atom, and R
All of these shall not represent hydrogen atoms. ] For the acylation of the compound of formula (1b), a wide range of reaction conditions for ordinary acylation reactions can be employed. As the acylating agent, a wide variety of conventionally known acylating agents can be used, such as acetic acid, lower alkanoic acids such as pionic acid, lower phosphoric acid anhydrides such as acetic anhydride, acetyl chloride, pionic acid, etc. Examples include lower alkasiic acid IXO fluoride. The amount of such acylating agent to be used is not particularly limited and can be selected as appropriate within a wide range, but usually at least the amount of the acylating agent used in the raw material is It is best to use an amount of about 10 times the same temperature, preferably 7 times the amount of the same temperature. - When an acid anhydride or an acid anhydride is used as the acylating agent, the acylation reaction is preferably carried out in the presence of a basic compound.

Examples of basic compounds include alkali metals such as sodium metal and potassium metal, hydroxides, carbonates, or bicarbonates of these alkali metals, lithium,
Examples include tertiary amine compounds such as lysine, -methylpiperidine, and triethylamine. Further, when a lower alkashic acid is used as the acylating agent, the acylation reaction is preferably carried out in the presence of a dehydrating agent. Specific examples of dehydrating agents include mineral acids such as sulfuric acid and hydrochloric acid, paratoluene sulfone, and Beshit! Examples include sulfonic acids such as thissulfonic acid and ethanesulfonic acid. The acylation reaction is carried out either without a solvent or in a solvent. Examples of solvents include a ketone such as det)p, methyl ethyl ketone, ether, dioxin, or an ether in tetrahydrochloride. Aromatic hydrocarbons such as benzene, toluene, and silane, water, dilysine, dimethyl chloride, methyl phosphate triazide, 1
．． Examples include 2-dimethothethane. The reaction proceeds either under cooling, at room temperature, or under heating, but it is usually preferable to carry out the reaction at 0-150°C.

In particular, it is preferable to carry out the reaction at 0 to 80°C when using an acid anhydride or a ryogenide as the acylating agent, and at R50 to 120°C when using a lower alkashic acid as the acylating agent. It is preferable to do this. The reaction is generally completed in 0.5-24 hours at degrees S.

For the alkylization of the compound of formula (1b), the usual! A wide variety of reaction conditions can be adopted for the ru+rulation reaction. For example, for alkylization of the compound of formula (1h), the reaction conditions for the P-sylation reaction described above are used, except that a suitable alkali-forming agent is used instead of the acylating agent and the reaction temperature is -80 to 150°C. It can be applied as is.

As the alkylating agent, a wide range of conventionally known alkylating agents can be used, such as the general formula % (2) [wherein R2' is a lower FJI/naru group, a lower alkenyl group, or a phenyl lower alkyl group]. group, and X represents a hetene atom. ] A compound represented by, di! dir%) P oaks such as rimethane, sialic sulfur tubes such as dimethyl sulfur, meerwine (Mttr) such as trimethyl fluoride borate, etc.
mttn) reagents, etc. General formula (
Specifically, the compounds of 2) include methyl chloride, methyl bromide, ethyl iodide, l-bromide, l-bentyl iodide, 1-allyl iodide, l-butenyl bromide, and bromide. benzil,
Examples include 1-bromide-2-phenylethyl, 1-iodide-2-methyl-3-phenyldivir, and the like. Real-alkanes and medicinal agents are used as arunalizing agents! When using a wine reagent, it is preferred to carry out the reaction at a-so-so°C. In addition, when using diaryPIt/guns as an arunalizing agent, tetrafluoroboron hydride,
・/, -) Luenesulfonic acid, BF3・o (c2#,
)2 etc. may be present, thus formula (1
Compound e) is produced.

In the above al+rulation, the al+lulation agent is of the general formula (
If the compound of 2) is used, an alkali metal hydride is present in the reaction system, and the reaction is carried out at -78 to -15°C,
Compounds in which R2 is introduced at the 9th position of the dipenzi-dio+cy skeleton (9-substituted product), compounds introduced at the 4th and 9th positions (4,9-disubstituted product), and the 2nd and 4th positions It is also possible to advantageously produce a compound introduced at the 9-position (2,4,9-trisubstituted product). Of the compounds of general formula (2), 1-
If about 3 times the amount of ton is used, alkali lithium is present in the reaction system, and the reaction is carried out at about -78 to -25°C, 2
, 4-disubstituted products can be advantageously prepared. As a phosphorylating agent, sialylkane was used in a molar amount varying from 3 to 6 times that of the compound of formula (1k), tetrafluoroboron hydride was present in the reaction system, and the temperature was adjusted from -78°C to room temperature. If the reaction is carried out, 9-substituted products, 4t9-tl-substituted products and 2,4.9-tri-substituted products can be advantageously produced. In addition, as an alkylation agent, realkanes were used with the formula (1#
) is used in an amount about 3 times the molar amount of the compound, and at room temperature -50
The 9-substituted product, the 4°9-disubstituted product, and the 2,4.9-)-disubstituted product can also be advantageously produced by reacting at about .degree. In this case, if the sialylkane is used in large excess (at least 3 times the mole or more) relative to the compound of formula (1k), a 2,4.9-trisubstituted product can be obtained as a product. Furthermore, an excess amount (usually 1.5-
9-substituted, 4,9-disubstituted and 2-substituted
, 4.9-) can be advantageously prepared.

The formula (
Compound 1b) can be produced, for example, in seconds by the method shown below.

Reaction formula-2 (11) [In the formula, each R is the same or different and is a hydrogen atom or lower! Indicates a lucanoyl group. However, at least one of each R is low grade. shall indicate a lucanoyl group. ] Acylation of formula (1tx) can be carried out under the same reaction conditions as for acylation of formula (1k).

N [In the formula, each R is the same or different and represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a phenyl lower alkyl group. However, at least one of each R represents a lower P group, a lower alkenyl group, or a phenyl lower group. ) of formula (1a)! The formula (1k)
can be carried out under the same reaction conditions as for the acylation of

When converting the lower alkanoyl group of the compound of formula (1d) above into a hydrogen atom, a wide range of conventional hydrolysis reaction conditions can be adopted, for example, it is carried out in an appropriate solvent in the presence of an acid or a smoking compound. . Examples of solvents include water, methanol, lower alcohols such as isodolhenol, ethers such as dioxin, tetrahydrofuran, etc.
Mixed solvents of these can be mentioned. Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and examples of basic compounds include metal compounds such as sodium hydroxide, potassium hydroxide, and calcium hydroxide. The hydrolysis reaction company usually 0-150℃
The reaction proceeds at a suitable rate and is generally completed in about 1 to 15 hours.

In addition, when converting the lower alkyl group, lower alkenyl group, or phenylene group of the compound of formula (II) above into a hydrogen atom, for example, hydrobromic acid, boron trichloride,
Lewis acids such as boron tribromide, aluminum chloride/minium chloride, tin chloride, alkaline ruthiol/BF3.0 (C2#,)
2, BCl3.5 (CH3)2, BBr3.5 (CH3
)2, Li5R3 (R3 is a lower alkyl group), (CHs
) ss *I, (CH3)3s s B r etc. The compound of formula (1#) may be treated in a suitable solvent. The above reagent is preferably present in the reaction system in at least a catalytic amount, usually 7 to 10 times the amount of the compound of formula (IC). As the solvent, a wide variety of solvents used in the above-mentioned hydrolysis reactions can be used. This treatment is usually carried out at about -78 to 50°C for about 0.5 to 24 hours. In the case of a compound in which R represents a benzyl group among the compounds of formula (1#), an ordinary catalytic reduction or the like can be applied.

This catalytic reduction is carried out in a solvent similar to that used in the above hydrolysis reaction, such as palladium-carbon, palladium-carbon
The reaction is carried out in the presence of a catalytic reduction catalyst such as black or platinum black at 0° C. to room temperature for about 0.5 to 5 hours. The catalytic reduction catalyst is usually used in an amount of about 10-501% based on the compound of formula (II).

In these elimination reactions, selective elimination can be carried out by appropriately selecting the type of reagent used, the amount used, the reaction temperature, etc. For example, in the compound of formula (11), R is lower! In the case of a compound exhibiting oxidation, boron trichloride is present in the reaction system at an amount of K1-6 times ℃, and -2
If the treatment is carried out at about 0°C to room temperature, or if 1 to 3 times the amount of boron tribromide is present in the reaction system and the treatment is carried out at about -78 to -50°C, the 9-position of the dibenzydo-dio+syn skeleton is or 2
, 9-position can be selectively de-allated, and 3-6 times more boron tribromide is present in the reaction system at -30-0°C.
If processed with a degree of
．． If the 9-position or the 2-4-9 position can be selectively de-lower altylated, and if further 3-6 times the amount of boron tribromide is present in the reaction system and treated at about O'C-room temperature. , 2.4 of the skeleton
．． A compound of the formula (1-) which can selectively de-altylate the 7.9-position or the 4.9-3.5-position and further has different substituents on the dipendyl-dio+syn skeleton, It can be easily produced from the compound of frit (see d) by appropriately combining the above-mentioned P-sylation, alkylization, hydrolysis, dealkylation, etc.

The compound of the present invention obtained in this way can be subjected to various isolation and purification operations, such as solvent distillation, solvent extraction, precipitation, recrystallization, force 5 muk 0 mudgraphy, prebalatic filtration, high-speed liquid lysis, etc. Of the compounds of general formula (1) thus obtained, those having a steep group include, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc. It can easily form a salt by reacting with a strong basic compound such as, etc., and the present invention also includes salts of such dibenzied-diosic acid 5 derivatives.

When the compound of general formula (1)° and its salt form are used as a prophylactic or therapeutic agent for hematuria, they are usually used in the form of a general pharmaceutical preparation. The formulation usually uses fillers,
It is prepared using diluents or excipients such as fillers, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, tablets, powders, liquids,
Suspensions, emulsions, tablets, suppositories, injections (solutions, suspensions, etc.) and the like can be mentioned. When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride,
Excipients such as glucose, urea, tanzune, calcium carbonate, kaolin, crystalline trose, silicic acid, water, ethanol/propanol, monofilament, glucose solution, dempsie solution, gelatin solution , carboxydimethylcellulose, shellac, methylcellulose, potassium phosphate, binder such as polyvinyl dihydrone, dry starch, sodium aruin stirrup, agar powder, laminaran powder, sodium carboxylate, carbon-calcium <Disintegrants such as polio bovine sieteresisol ditan fatty acid esters, sodium lauryl sulfate, stearic acid t-noglypeptide, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, quaternary ammonium Bases, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene diglycol. Examples include lubricants such as. In addition, the tablets must be tablets with a conventional coating according to IEK, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets or double-coated tablets.
It can be a multi-layered tablet. When molding the tip side, a wide range of carriers known in the art are used, such as excipients such as glucose, lactose, cacao butter, hydrogenated vegetable oil, kaolin, talc, etc. ! Examples include binders such as maggot powder, tracanth powder, Zelatis, and ethanol, and disintegrants such as ramie, oak, and agar. When forming into a suppository, a wide range of conventionally known carriers can be used, such as polyethylene glycol, chikuo fat, higher alcohols, esters of higher alcohols, wax ten, and semi-synthetic lystrilides. etc. can be mentioned. When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood;
14, all the agents commonly used in this field can be used as the buffering agent, such as water, ethyl alcohol, pyrene glycol, isostearyl alcohol cocoate, isostearyl alcohol polyoxylate, and polyolefin. Examples include shinsiechirensolpitan fatty acid ester. In this case, the drug may contain enough salt, glucose, or chrycerin to prepare an isodominant solution.
Further, usual solubilizing agents, buffering agents, soothing agents, etc. may be added. Coloring agents, preservatives, fragrances, flavoring agents, sweeteners, and other pharmaceutical agents may be added to the gloss as needed.

The amount of the compound of general formula (1) to be contained in the drug of the present invention is not particularly limited and can be selected within a wide range, but is usually 0.1-70% by weight based on the total composition, preferably 0.5-70% by weight. 30
Weight%.

There are no particular restrictions on the administration method of the drug of the present invention, and it can be used in various ways.
The method of administration depends on the patient's morphology, patient's age, gender and other conditions, and the severity of the disease. For example, tablets, emulsions, liquids,
Suspensions, emulsions, granules and capsules are administered orally. In the case of injections, it can be used alone or with glucose,! It is administered intravenously in a mixture with conventional replacement fluids such as trinoic acids, and Sarak is administered alone as needed intramuscularly, subcutaneously, subcutaneously, or intraperitoneally. Suppositories are administered rectally.

The dosage of the drug of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but the dosage of the compound of general formula (1), which is usually the active ingredient, is 90% per day. It is preferable to set it at about 0.05-1001F per liter of body weight.

The results of pharmacological tests on the compounds of the present invention are shown below.

Test Compound Genus 1.1-(3,5-Dihydro+Dipheno+Si)-me 4.
7,9-Tetra Shimo 0+Shijibenrijijigiojushin-・2,,l-(3,5-Jishido0 Spicy Shi, Phenoyashi)
-2゜4.7-Torishido 0 medium sea 9-Metho spicy Shijibeshiri door-Gio beef Shin 3.1-(3,5-dimeth + Dipheno beef Shi) -2,4
゜7.9-Tetrahuman 0 Spicy Sijibenli-do-Gio Spicy Shin 4.1-(3,5-Diishido 0 Spicy Diphenospic Shin-2.4
．． 9-) Lihydro 0 Spicy Sea 7-Metho + Seage Helly I
-Gio Gyushin 5.1-(3,5-dimetoshidipheno+shi)-2-Metoyashi-4,7,9-)Rishichido0+shijibenjito-Gio+shin6.1-(3t5-gI Met↑Difenoshi 6) -2
,79-Trid 0+Shi4-Metho+Shijibenryt
- Geogyoshin [Pharmacological test-1] The method of Biocktwa6.Mtd, 1±, 162 (Biocktwa6.
1975) Talc F-2 and Macrok O made from paper net according to 1.
I used Pleats.

Alpha, 2 Mac0ri 0purin 17μf 0.1M
Sodium chloride containing 0.05&) Lis-Salyo buffer (p
lj = 7.4) Mixed with 0.1 m of 10% methanol aqueous solution of various concentrations of the test compound in 0.3 d and heated at 37°C.
It was held at the bottom for 20 minutes.゛Then, LOpf/stomach j beef torizushi:/(manufactured by Sigma Chemical Co., Ltd., rftl seal) 0.1 d
was added to the above mixture and kept at 37°C for 2 minutes. 2% sulfuric acid o9. : N (manufactured by Sigma Chemical Co., Ltd., Cra
Add 0.5 Il/dt x) of the above buffer solution and
Leave it for a minute. The reaction was stopped by adding 3 ml of 18% trichloroacetic acid aqueous solution, left for 1 hour, centrifuged, 50 μg of supernatant was taken into a test tube, and 0.01% 8-trichloric acid + Nori was added. y 1.5N-Hydroxylic acid specific gravity thorium aqueous solution 4
d. A 0.1% aqueous solution of octally imide is added and stirred to develop a color, and the absorbance at 500 nm was measured. Plasmin inhibitor activity inhibition rate (%) was calculated using the F formula.

-8 A: Talf F-2 Makol! Absorbance B when the purine and the test compound are not included: Absorbance when the test compound is not included and Alpha 2/Macroglobulin is included C: Absorbance when the P-2 macroglobulin and the test compound are included Table 1 shows the results of determining the concentration of the test compound at which the inhibition rate determined above is 50% (50% inhibition concentration).

Table 1 [Pharmacological test-2] Alpha 2 pusmin inhibitor was used as a plasmin-inhibitor.

P-2 plasmin inhibitor was produced using the method of B, Wimtxn et al.
r.

J, BIOtktWl, 178119 (1977)
), and torasmin was prepared from human plasma by the method of 1JIJ Chi (D, G, Dtymtzck) et al. (5tizptez).

170.1095 (1970)), the method of AfoMorai et al. (-J, Biol, Cktm, 251.595
6 (1976)) was activated with the O + nana bond t-phase and subjected to the test.

Contains PL Far 2 and Plasmin In Shijiter 3 μf.
), 09# containing sodium chloride 0.06 M)
Salt-adjacent buffer (H = 7.4) 0.7 d, 10
A test compound of each lII concentration dissolved in %1 tanoyl was added to the mixture and maintained at 37°C for 20 minutes. then 2
Add a solution of 0.5 mL/d of human plus 30% S (O, tS) dissolved in sodium phosphate buffer (H = 7.4) containing 5% critin, 37' C13
After heating for 0 seconds, concentrate as a medium! S- of t 3 MH
2251 aqueous solution (//-D-Val-L-Ltw
-L-Lyg-door-nitrognslidt;
Daiichi Kagaku) 0.1 m was added to the nail and reacted at 37°C for 3 minutes. The reaction is 0. It was stopped by adding 1d of 50% aqueous acetic acid. The absorbance of the reaction solution at 4Q5n* was measured, and the inhibition rate of 5-sumin inhibitor activity was calculated based on F hypertrophy.

A: Absorbance when alpha 2 plasmin injector and test compound are not included B: Absorbance when alpha 2 plasmin injector alone is included without test compound P-2・
Absorbance of plasmin containing bitter and test compound? The concentration at which the inhibition rate is 50% (50% inhibitory concentration) against Schifday 2 and Plus 3 inhibitors is shown in Table 2.

Table 2 Examples and formulation examples are listed below.

Real pigeon example 1 (1) Fresh 0 pigeons (collected in Irino, Kochi Prefecture) 600
The extract was extracted with methanol at room temperature. The extract was concentrated under reduced pressure to obtain a gummy secondary extract.5 This was extracted repeatedly with acetic acid solution and water (1:lF/l') until the upper layer became colorless. Condensation was carried out under reduced pressure to obtain 5.7 kQ of a second extract.

(2) The second extract i', 7h obtained above was t-lighted (manufactured by Jyks Mantpillx) 3.4
# and dried under reduced pressure. The returned solids are finely ground and packed into a glass column to produce penzene (IEI).
), methylene chloride <361 ), ethyl ether (54
g) and then methanol. 552g eluted with ethyl ether was added to Cephadex LH-20.
(3,5t9) attached to kalamku 0 mad, a7ton (1
51), and fractions of 1' and 2000 me were obtained. Decompression of Fraction &4'FKII! The crude crystals obtained by condensation are recrystallized from hot water to give 1-(3,5-dihydro+diphenoloxy)-2,4,7,9-tetrahydro+hydro+syn [formula Compound (1a)] 40f was obtained. The physical properties of the obtained compound are shown below.

Melting point 243-244'C Colorless plate crystal λ,,,ax:236'((=30,000 >290
t'g43. t6o >sm'KHr,'
・IR(νmay)・3250', 16os, 1475.

1370.1260.1200.

1160.1140,1110° 1083.1040.1010.

805 ff1-' High-resolution mass spectrum measured value 372.0460 Theoretical value 372.0481 (as C,8H□209) PMR (lQQMHz, DMSO-et6, pp
m>”.

5.73 C2H, d, /=2.1), 5.
81 (lf, d, J=2.6), 5.
82 (1#, t?/=2.1)
, 5.97 (1/f, d, /=2.6
), 6.16 (1#, 1), 9.
15 (28.

I), 9.18 (1#, j), 9.19 CIM, 1)
, 9.46 (LH, 1), 9.51 (1#, j) CMR (lQQMHz % DMSO-d6, Pltl
l) :94.0.96.3.98.4.98.
7.122.6, 122.9, 123.5, 137.3
．． 141.9, 142.7.145.9, 146.1.
153.0.158.7, 160.4 Example 2 l -(3,5-dide 0+dipheno+
C) -2,4,7,9-tetrahydride 0+Sijibenzido-dio+Syn 20011F was mixed with 2 ml of pyridine and 1 wtl of acetic anhydride, and reacted at room temperature for 20 hours.

The reaction mixture was added to ice water, and the resulting precipitate was separated in a furnace and recrystallized from benzene-methanol to give l-(3,5-
-2,4゜799-tetraacetylated ↑Shijibenjito-Giochushin 280
I got q.

Melting point 211-212.5°C Colorless lithium crystal ErMs<m7g): 624 CM), 582.
540.498.456. 414.372.69.43 By IR(ν):2900.2850.1750.1
595. 1490.1435. 1360.1175. 1120.1100, lO wood・0.8751g-1/' M R (4Q Q M Piz, CDC1
3, I'l1M): 1.96 (3/f, f),
2.13 (3H.

C6H, f ), 2.34 (3H, I), 6.50
(1#, d, I=2.6), 6.58
<2H, d, /=2.0 ), 6.63 (1
#, d, /=2.6), 6.66CLH,
1), 6.73 (1//.

1, J=2.0) Example 3 1- (3,5-jishido0spicyshi7technical/+shi)-24-7
, 9-Tetra Shido 0↑Shiji Benji Door-Gio Shishin 5
A mixture of 00q, 1.3F anhydrous potassium carbonate, 3d methyl iodide, and 110w1 anhydrous was stirred at room temperature for a day and night.After acidifying the reaction solution by adding 2M aqueous hydrochloric acid,
Extracted with ethyl acetate. The extracted layer was thoroughly washed with water and saturated brine, dried (over magnesium sulfate), and the solvent was distilled off under reduced pressure to obtain a red oil. Add this oil to silica gel (10
F: Wakopur C-200) Column purified to 5
The obtained crystals were recrystallized from ether-methoxychloride to give 1-(3,5-dimethoxy)-2,4,7
, 9-Tetramet+Shijibenjido-Gio+Shin51
Obtained Oq.

Melting point 171-172°C Colorless prismatic crystal Br IR (ν): 2925.2830, Iw+gx ■590.1500. 1450.1370. 1'200.1tio, 1050.970.910°810.7sscM-1 EIMS CgN/M): 456 (M')P
MR (4QQMHz, CDC et al., Ifim): 3
．． 66 C3N, 1), 3.71 (9#.

, 3.77 (3H, 19), 3.92 (3H, t
), 6.09 (171/ , d , /=2.9),
6-13 (LH9ts/=2.1), 6. L7C2H
, d, j -2, 1), 6.26 (1/f,
1') Example 4 1- (3,5-spicy diphenolic beef)-2・4・
7. Pldl (5Q% oil) 216JIF was added to 200 q of DMF5d@ solution of 9-Tet 5 Shidoro + Sijibenjito-Jioshinshin at 0°C in a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 20 minutes. Benzylpromite 0.5
After adding s/ dropwise and stirring at room temperature for 5 hours, ice water was added, acidified with 2Iv-hydrochloric acid aqueous solution, and extracted with ether. The ether layer was washed with water and saturated brine, dried (magnesium sulfate), and then dried under reduced pressure to obtain an oil.The oil was applied to a silica LC5f) column and eluted with benzene to obtain crystals. was recrystallized from ether to obtain l-(3,5-dibenzyl-diphenol) -
400q of 2,4゜7.9-tetrabenzyl alcohol was obtained.

Melting point 141-142°C Colorless prismatic crystals EIMSC1PI/l)', 912CM) Examples
5 1- (3,5-dihydro + dipheno + di) -2,4゜7.9-tetrahydro + dibenzidoor - Add 216q of NaH (59% oil) to a 0M 15yd solution of Geogyushin 20011F with O "C was added under a nitrogen stream and stirred at room temperature for 20 minutes. Allyl bromide 484q was added dropwise, and after further stirring at room temperature for 5 hours, ice water was added, and the reaction solution was acidified with a 2N aqueous hydrochloric acid solution and extracted with ether. After washing the ether layer with water and saturated saline and drying (magnesium sulfate),
The ether was removed under reduced pressure to obtain the amorphous 1-(3,5-
300 q of 2,4,7,9-tetraaryloxyphenol, 2,4,7,9-tetralyloxyphenol, and cycloalkylbenzene were obtained.

film.

IR(ν), 3100, 3025,
Tsubayo ag 2950.2900. 1605, 1510. 1460, l 425. 1360, 1245. 1210% 1130. 1050.990. 930.820.7303-1 zihts <mix>: 612 (/>Example 6 l-(3s5-WI7doo+Schiffx]+shi)-214+
7.9-Tetra Shiji Benji Door-Gio Shinshi:
15 drops of tJF remethane-ether solution produced from Nido Otsu Methylurea 2001F were added dropwise to the methanol 5d solution of /100"F in an o"cv, and the vessel was allowed to stand overnight at room temperature. The solvent was distilled off under reduced pressure to obtain a viscous liquid, which was applied to a silica gel (10F) column.
The above compounds were successively isolated by elution with a 0.00% methanol solution.

(a) l -(3,5-dishidoroshifu X/
＋! / ) -2*4.9-) Rimetoshishi 7-shido0hirashijipenjido-jioshishin colorless needle crystals (ri00 form-methanol) Yield 30q Melting point 267-268°C EIMS (m/z) : 414 (M″), 3
82.315.260.217. 123.69.53 PMR (4QpMix, CDCl/DMSO-
46 units m): 3.65 (3#, j), 3.75 (3
M.

S), 3.89 (3H, j), 6.00 (2H, d, /
=2.0), 6.05 (LH, t', J=2.0), 6.07<lH, d, J
=2.6), 6.15 (1#,d,/=2.6), 6.24 (1#,'), 8.25 C2H,j), 8.60(
LH, y) (#) l - (3,5-dihydro + diphenolic)
-2゜7-Dishidoro Nakashi 4,9-Dimethospicy Shijibenry voice-Giogyushin colorless prismatic crystals (ri00 form-methanol) yield
43MI Melting point 287-288℃ EIMS (ms/g): 4 Q Q (#”)
, 367.276.246.203, i i l, 69 PMR (4QQMHz, DMSO-46-m):
3.62 (3/f, g), 3.76 (3M.

, ), 5.74C2H,d, J=2.2), 5.83
(1N, t, J=2.2), 5.96 (1
/f, d, / = 2.4), 6.29 (1#
, j), 6.08 (L H.

d, J=2.4), 9.18 (2N, 1), 9.45C
2H, 1) (ζ)1-(3,5-Dishido0+Dipheno+Si)-2゜4.7-)Lihydo0+Si9-Metho+Sidioben,)-
Colorless crystals (methanol-water) Yield: 30 Melting point: 196-197°C EIMSCwt/l): 386 CM), 35
3.232.193.69 PMR (4QQA#/j, DMSO-d6 Toto m
): 3.62 (3H, s), 5.73 (2#
.

d, J=2.0>, 5.81 (1#, /.

/-40), 5.96 (1#, d, /=2.1
), 6.07 (1//, d, / = 2.7)
, 6.16 (1#, j), 9.15 (2H.

I), 9.24 (1//, j), 9.43 (1#, j)
, 9.50 (1#, f) l! Example 7 1- (3,5-jishido 0+sipueno+shi) -2,4
゜7.9-Tetrashido D+Shijibeshijido-Giogyushin 300wI anhydrous THF I O*l and (j anhydrous HM
0.7 s of the +san solution was added dropwise to the PA at -78°C in a nitrogen stream F. After the dropwise addition, the mixture was stirred at -78°C for 10 minutes, and then 164q of benzyl bromide in THF/solvent was added dropwise, followed by further stirring at -78°C for 30 minutes and then at 0°C for 1 hour. Take a part of this reaction solution, 1- (3,5-
The production of 2,4-dibenzyloxyphenol)-2,4-dibenzyloxypropylene 7.9-dicyclopropylene + dibenzyloxypropylene was confirmed. (EIMS (m/i): 552
CM''), 461.370.444.262.91] WaH (59% oil) 200% was added to the reaction solution obtained above.
After stirring for 10 minutes, 0.8 g of methyl iodide was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 5 hours, ice water was added, and the mixture was extracted with ether. After washing the ether layer with saturated saline and drying the heel (magnesium sulfate),
The residue was distilled off under reduced pressure to obtain 1 oil 57711I. A portion of this oil was taken and the formation of 1-(3,5-dimeth↑dipheno+ci)-2,4-dibenzyl-7,9-dimeth+dipheno-diot-syn was confirmed. [zix
scppt/1: 608 CM'), 594.5
80.566.517.426.91) This oil was dissolved in 10 s of ethanol, 5 ml of ethyl acetate, and 3 drops of vinegar, and hydrogenated to 10% Pd-C (2011I) catalyst F. After the catalyst is separated from the furnace, the solvent is distilled off and [
The resulting oil was applied to Bits-Bead SX-12 and eluted with bempine to obtain 1-(3,
5-Dimethot dipheno + C) -2,4-dihydro D + C 7.9-Dimeth + C dibenzyto - Geojushi:, 1
601g was obtained.

Colorless amorphous EIMS (m/g): 428 CM''>, 39
7.291.260.214. 170.125.95.53 P M J? (4Q Q MHs, CD Cg s
, p-solution ) ; 3.65 C3H, j ), 3.
73 (3H.

l), 3.75 (6#, j), 6. lO(lH, d,
I=2.7), 6.11 <LH, d, J=2.7), 6.17 (1#, t, /=2.1), 6.21C2
H, d, /=2.1), 6.32 (1//, ri, 5.15 (1#, f), 5.21 (1/f, j) Example 8 l-(3,5 -dimeth+dipheno+shi) -2,4,7
゜9-Tetrameth Cow Seajibenji Door-°Geo + Shitsu 6
1.55&-BCI in 0q of methane 2d solution,
After dropping 0.26 d of a methane solution of 0.2 g at -78°C, the mixture was stirred at the same temperature for 3 hours, and then stirred at room temperature for 3 hours. Water was added, and 2 was acidified with a monohydrochloric acid solution, extracted with dichloromethane, and the solvent was distilled off under reduced pressure to obtain oil 501F. This oil was transferred to a medium pressure column 9D (Rebar).
Liekraprtp Si-6Q, Type
A) Add 00 bottles of ethyl vinegar (9:lV/V)
) to sequentially isolate the following compounds.

(−) l −(3,5-dimeth+Schiff x)+Sh)
-2+47-Dorimeto+C9-Sido O+Shijibeshijito-Gioshin colorless prismatic crystals (ether-dichloromethane) yield
30 da melting point 196-197°C EIMS Ce1l/1): 442 CM'),
380.353.288.207. 151.69 PMR (4QQMHs, CD C1s, 2 units-
w): 3.69C3H, 1), 3.75 (6H.

S), 3.80 (3#, j), 3.93C3H9x),
4.93CLH, 1), 6.12 (1/f, d
, J=2.8), 6.13 (2H, d, /=2
．． 2), 6.16 (1#, t, /=2.2
), 6.17 (1#, d, J=2.8) (
”) 1- (3,5-”ii toshinashi”)
) -2,9-dimethoxychloride 4,7-dimethoxychloride chloride amorphous yield 15q EIMS (ell/j): 428 CM"),
385.274.214.151, 9 F MR (4Q Q MHx, CD Cj s
, fi, 15911): 3.69 (37/t
J), 3.75 (6H.

j), 3.89 (3#, j), 6.16<LH, d, J
=2.8), 6.11 (LHt i , /=2.8), 6.18 (2H, d
, J=2.2 n , 6.20 (1#, j, /=
2.2), 6.35 (1#, j), 4.78 (1'/, j), 5.22 (I
M, 1) Example 9 1- (3,5-dimeth+dipheno+shi) -2,4,
7゜9-tetramethane+C'-lhenjido-geo-thin 10011g of 0.83g in methane 4d solution
57 ml of a solution of 8 MgBr2 in dichloromethane was added dropwise at 0°C, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 20 hours. Water was added, acidified with 2N hydrochloric acid, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain oil 701F. Apply this oil to silica gel (5F) and methanol solution (L: 9V/V).
The following compounds were successively isolated by elution.

(a) l -(3,5-dimethodosif 1/?
C) -2,4e7.9-tetrahydride t-dioscine amorphous yield 27q EIMSCm/I): 400 CM"), 352.
325.287.260. 245.193.154. 122.69 PMR (4oQMHx, DMSO-d6, IIkf
iler): 3.68 C6H, j), 5.
80 (1//.

d, J=2. 'l), 5.96 (1#, d.

1=2.7), 6.00 (2// , xi , /=2.
2), 6.14 (L H,l, / = 2.2)
, 6.16 (1//, j), 9.19 (1#.

1), 9.27 (1#, j), 9.50 (1//, z
>, 9.51 (LH, I) (b) 1- (3,5-
Amorphous yield 25 Misaki EIMS (m/z): 386 (M″), 325.2
87.246.123, 95.69 PMR (4QQMHz, CDCl3+ l Q%DMS
O-dts Todo #1): 3.71 (3H?1),
5.99<IH*d*1=2.7>, 6.03(2'
t't'=2-2), 6.03(1ff
*dt/=2.7), 6. lOCIN,t,J=2
．． 2) sJ! Example 10 1- (3,5-Dishidoro Medium Diphenospicy) -2,4
゜7-Dori Shichido O Nakashi 9-Meto Spicy Shiji Benji Door-
Geo + Shin lO kohji lysine 0.5sj and anhydrous vinegar #
0. It was mixed with I Wt and reacted for 5 hours. The reaction solution was added to ice water, and the resulting precipitate was separated and recrystallized from methanol to give 1-(3,5-Schiff and diphenol+Si)-Z4.7-)! Sechiluo Middle Sea 9-Methospicy Siji Benli-Gio Beef Shin fiml was obtained.

Colorless lithium crystal EIMS Ce1l/l): 596 CM"),
554.512.470.428. 409.386.357. 315.278.232. 191% 137.109. 69.43 P M R (4Q Q Mll z, cnc13.pl
m) i, o9<3x, z), 2.25 (9H.

I), 2.32C3N, 1), 3.66 (3#, z)
, 6.28CLH, d.

/=2.5), 6.32 (1#, d, J=2.5), 6
．． 62CLH, 1), 6.64 (2#*d tJzz,
ot, 6.67CIN, t*J=2.0> Example ii 1- (3,5,-di-seven-doro!/7e/ya-shi)-2,
7-dimethod, cijibenziioyashin 151F, dilysine 0.8 Wt and acetic anhydride 0.2- were reacted for 5 hours. Add the reaction solution to ice water,
After the generated precipitate was separated in a furnace, it was recrystallized from methanol.
-(3,5-thiatyloxydiphenol↑shi) -2,
7-Diacetyl 4,7-dimethoxybenry
Toji Saiya got 15 drops.

Colorless prismatic crystals Melting point 201-202°C EIMSCIPI/l): 568 CM), 526
．． 484.442.400. 371.315.292. 246.203.177. 123.69.43 PMR (4QQMHx, CDCl,,/)g):
2.12 (3#, j), 2.25 (6H.

I), 2.29C3N, 1), 3.66C3N, 1),
3.86 (3ff, j), 6.28 (1#, d
, J=2.5), 6.40 (1#, d, /=
2.5), 6.42 (1#, j), 6.61 (2H
.

I), 6.66 (1//*z, J=2.0
>Example 12 1- (3s5-'I Metoyashiphenospicashi) -2,4
,7゜9-Tetrametoshijibenjidoor-Gio↑shi5
0.838 in 10011F methylene chloride 4s/#I solution
#BBr3noji 90 Fj 9:, IO, 79dfl
Solution J was added dropwise at -25°C. After stirring at -25°C for 2 hours,
The mixture was added to a water kettle and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then distilled off under reduced pressure to obtain oil 60 Misaki.

This is methanol-L O,1s? Dissolves in high speed liquid 0
Matokurahui = (Hyptrxil -OD S, 1
°X300fi, solvent 5 Q V/V% water-methanol, flow rate 3d! The following compound was obtained by purification using 1mlN).

(-) 1- (3,5-dimeth+!/)I/
+ ”,t) -2,7゜9-TrichtD+C4
-Methospicy Seajibenrito - Geo+Sin Colorless powder Above HPI, C retention time 23 minutes Yield 30 MI' EIMS (m Otsu 1:414 (#), 366.339.3
01.274. 207.165.122. 69, 53, 28 (SPM
R(4Q Q MHz, CDCl5, Ifill
l): 3.75 (, -6M, 1), 3.8
8 (3H.

S), 6.04 (LH, tt t J=2.7 >,
6.08 (1#, d, J=2.7), 6.
17 (2#, d, /=2.1), 6.20 (1
#, t, /=2.1), 6.34(if, j
) (b) l-(3,5-dimethoxydiphenol) −
2,4゜9-triside 0-7-methoxybenry-dioxysine Colorless powder The above HPLC retention time 25 minutes Yield 5q EIMS (1/l): 414 (M), 371
．． 316.260.207. 177.123.95. 69.53.28 1- (3,5-dimethodipheno↑shi)-2-metogyushi4,7,9-) Sushi Doro + Shiji Benjijiio + Syn Colorless powder on f3HPLc retention time 28 minutes Yield 4511F EIMS Ce1l/#): 414 CM'),
383.339.274.193. 151%122.69, 9 FMR (4QQMHz, C7) C43, I'fi
fn): 3.75C9N, 1), 6.02(1
//.

d, J=2.7), 6.08 (if, d.

J=2.7), 6.15 (1#, #, /=2.1), 6
．． 32 (1//, d I J =2.1), 6.
32 (1#, j) Reference Example 1 Compound of the present invention (compound of Example 1) 500# Glucose After dissolving the sodium salt of the compound of the present invention and glucose in 250q distilled water for injection 5
Inject into ml ampoules. After purging with nitrogen, pressure fractionation is performed at 121°C for 15 minutes to obtain an injection.

Reference example 2 - Lactose 33.5 f Dicalcium phosphate 70. Of sodium lauryl sulfate 15. Of polydinyl 0-ridone 15. Ofcosis starch
30. Of Dry Sodium Lauryl Sulfate
3. Of Dry Stearinf Magnesium
3. Of ethanol An appropriate amount of the compound of the present invention, citric acid, lactose, calcium phosphate, Zion F-68, and sodium trisulfate are mixed.

The above heated mixture was sieved with a 460 screen, and poly 6000
wet granulation in an alcoholic solution consisting of Add alcohol if necessary to make the powder into a pasty mass.

Add cornstarch and continue mixing until uniform particles are formed. Pass through a 410 screen, place in a tray and dry in an oven at 100°C for 12-14 hours. The dry particles are sieved through a 416 screen, dried sodium chloride sulfate and dried magnesium stearate are added and mixed, and compressed into the desired shape using a tablet machine.The above core is treated with varnish, sprinkled with talc and made into a9C. Prevent absorption. A subbing layer is applied around the core. Apply a sufficient number of coats of varnish for internal use. Further subbing layers and smooth coatings are applied to make the tablet perfectly round and smooth. Apply i-color coatings until the desired shade is obtained. After drying, the agent 11a is polished to give a uniformly glossy tablet.

[Brief explanation of drawings]

Figure 1 shows 5j! 2 is a PMR spectrum diagram of the compound obtained in Example 1. FIG. . FIG. 2 is a CMR spectrum diagram of the compound obtained in Example 1. Figure 3 shows 5j! 3 is a PMR spectrum diagram of the compound obtained in Example 3. FIG. Fourth
The figure is a PMR spectrum diagram of the compound obtained in Example 6(a). FIG. 5 is a PMR spectrum diagram of the compound obtained in Example 6(b). Figure 6 shows Example 6
Figure 7 is a PMR spectrum diagram of the compound obtained in Example 7. Figure 8 is a PMR spectrum diagram of the compound obtained in Example 8 (-). It is a spectrum diagram. @9 figure is Example 8 (
It is a PMR spectrum diagram of the compound obtained in b). FIG. 10 is a PMR spectrum diagram of the compound obtained in Example 9(a). FIG. 11 is a PMR spectrum diagram of the compound obtained in Example 9(a). It is a PMR spectrum diagram of the compound obtained in Example 9(b). FIG. 12 is a PMR spectrum diagram of the compound obtained in Example 12(a). Figure 13 line, sJ! It is a PMR spectrum diagram of the compound obtained in Example 12(c). (Above) Procedural amendment (Own ship June 1, 1981 1, IN'l indication 1982 Patent Application No. 50282 2 *Mei Oam Tabeshiji - Geo-Chinese Shishi derivative 3, Person making the amendment 4 Agents, Heiwa Building, 2-10, Hirano-cho, Higashi-ku, Osaka, Japan 06-20
3-0941 (Government) Voluntary Act 6, Number of Inventions Increased by Amendment Contents of Amendment 1 ``Kwrawst J'' in the third line from the bottom of page 2 of the specification is corrected to [-Tanrang J. 2 Specification No. 2 The bottom three lines of the page r6.32 (If, d. /==2.1) J is r6.I 3 (if,
d. J = 2.1) Correct as J. (that's all)

Claims (1)

[Scope of Claims] ■ General Formula [In the formula, R is the same or different and represents a hydrogen atom, a lower P-rukenyl group, a lower P-rukenyl group, a phenyl lower Ili alkyl group, or a lower alkanoyl group. ] A dibenzyo-jioshishishi derivative represented by: and its salt.