JPS6388176A - Novel biphenyl derivative, production thereof and improver containing said derivative as active ingredient for hepatopathy - Google Patents

Abstract

NEW MATERIAL:A biphenyl derivative expressed by formula I (R1 is H or lower alkyl; R2 is lower alkyl). EXAMPLE:Dimethyl-2', 3'-diethoxy-4, 4'-dimethoxy-2, 3-methylenedioxy-1,1'-biphe nyl-6,6'dicarboxylate. USE:Useful as an improver for hepatopathy, having improving action thereon and effective in treating acute, chronic hepatitis, etc. PREPARATION:For example, a compound compound formula II or formula III is reacted with an alkylating agent in alcohols as a solvent to afford the aimed compound expressed by formula I. Furthermore, the compound expressed by formula II is synthesized by using methyl gallate as a raw material and passing through methylenedioxy derivative, compounds expressed by formula IV and formula V.

Description

[Detailed Description of the Invention] [Industrial Field of Application] The present invention provides a novel biphenyl derivative that has an effect of improving liver damage and is effective in treating acute and chronic hepatitis, a method for producing the same, and a method for producing the same, and a method using the derivative as an active ingredient. This invention relates to a liver disorder improving agent.

[Conventional technology and problems] Currently, there are 200 patients with liver diseases such as acute and chronic hepatitis nationwide.
It is said that this disease affects up to 10,000 people, and the development of therapeutic drugs to treat these diseases is actively underway. For the treatment of such liver diseases, 5chisandr.
aceae)
It is known that dibenzocyclooctadiene-type lignans contained in Schisandra, which is the fruit of A. chinensis BAILL, are useful (Japanese Patent Application No. 122560/1986), and are also more useful for liver damage. There is a need for drugs that have ameliorating effects.

Means for Solving Problem E] The present inventors have conducted extensive research in order to discover substances that have a more effective effect on improving liver damage, and have already discovered several compounds (Patent Application No. 1983). -136261).

As a result of further research, a compound represented by formula I was discovered and the present invention was completed.

That is, the compound of the present invention has the following formula I (wherein R1 represents a hydrogen atom or a lower alkyl group, and R
, indicates a lower alkyl group. ) is a novel biphenyl derivative (hereinafter referred to as compound I) represented by:

Compound (1) is, for example, a compound represented by the following formula (1) OCH3 [methyl 6°-carboxy-4,4
'-dimethoxy-2,3-methylenedioxy-2°.

3″~oxomethylenedioxy, biphenyl-6
- carpoquinlate (hereinafter referred to as compound ①) or a compound represented by the following formula ① CH3 [dimethyl 4.4゛-dimethoxy-
Alkylation of 2,3-methylenezoxy-2゛,3°-oxomethylenedioxy-t,t'-biphenyl-6,6°-dicarboxylate (hereinafter referred to as compound ■) using an alcohol as a solvent. It can be obtained by alkali hydrolysis of a compound represented by the following formula (wherein R represents a lower alkyl group) (hereinafter referred to as compound (2)).

Compound (1), which is a raw material, can be obtained, for example, as follows.

One of the hydroxyl groups at the meta position of commercially available gallic acid methyl ester is selectively methylated, then the remaining two hydroxyl groups are treated with short methane in the presence of a base to form methylenedioxy, and the 2nd position is further brominated. After that, it is coupled by Ullmann reaction to [Xie;-N'ttA, V+nl
17 NA I-n)2~')1 (l
Qll! 2) The compound represented by the following formula A obtained in 1 [dimethyl 4.4°-dimethoxy7-
2. Add lead tetraacetate to biphenyl-6,6-dicarboxylate (hereinafter referred to as compound A) for 2', 3°-dimethylenedioquino, and add benzene, toluene,
A compound represented by the following 2B [dimethyl 2°, 3'-acetoxymethyleneoxy-4.4' -dimethoxy-2,3-methylenedioxy-1,biphenyl-6,6°-dicarboxylate (hereinafter referred to as compound B)] is obtained, acetic acid is added thereto, and the mixture is heated under reflux for 3 to 8 hours to react. This can be obtained by

A specific example of the production of compound H is as follows.

Specific example 1 Methyl 3.4.5-trihydroxybenzoate 36
．． Dissolve 8g in 5% borax aqueous solution 2.95C and add 1
child. After stirring at room temperature for 5 hours, 110.57 g of dimethyl sulfate and a sodium hydroxide solution were added dropwise, and the mixture was further stirred for 5 hours. After cooling 1. The mixture was acidified with s4 sulfuric acid, extracted with ethyl acetate, and the solvent was removed to obtain 25.5 g of methyl 5-methoxy-3,4-dihydrobenzoate (yield: 6445%).

Infrared absorption spectrum ν"n2'xc7n-': 344
4, +690.1620. +600°1524.14
40,1338,1268°1240.1108,10
88,1002° Proton nuclear magnetic resonance spectrum (δppm in CDCl2): 3.82 (s, 3 H), 3.87 (s, 3
H).

7.1 6 (d, J=2.0, 1).

7.22 (d, J=2.0.IH) mass spectra m/z (%) +98 (70, M”).

183(5), 168(10).

+67(100), 139(20) Specific Example 2 19°8 g of methyl 5-methoxy-3,4-dihydroxyhenzoate obtained in Specific Example 1 was added to 600 g of anhydrous acetone.
87 g of anhydrous potassium carbonate and 80.4 g of short methane were added, and the mixture was refluxed for 37 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, ethyl acetate was added to the concentrated solution, washed with water, and the solvent was removed to obtain 15.2 g of a pale yellow solid. This was recrystallized from anhydrous ethanol to obtain 13.6 g of methyl 5-methoxy-3,4-methylenenoquine benzoate (yield: 65%).

Melting point: 91°C Infrared absorption spectrum: C71-”2956.
2932, 2900, 1706°+638.1604,
1506,1454゜1432.1368,1330,
1240°+188.1176.1108,1038° Proton nuclear magnetic resonance spectrum (δppm in CDC13): 3.88 (s, 3 H), 3.93 (s, 3
H).

6.04 (s, 2H).

7.20 (d, J=1.5.IH).

7.33 (d, J = 1.5.I H) mass spectrum: m/z (%) 210 (72, M').

179(100), 151(23) Specific Example 3 Methyl 5-methoxy-3,4-methylenedioxybenzoate IO, 5g, was dissolved in acetic acid 35. Bromine solution (8 g of bromine diluted with 25 ml of acetic acid)
was added dropwise over 1 hour, and after stirring at room temperature for 10 hours, the reaction solution was poured into ice water, the precipitate was collected by filtration, recrystallized using ethanol, and methyl 2-bromo-5-methoxy-
7.4 g of 3,4-methylenedioquinobenzoate was obtained.
This (yield 51%).

Melting point = 103-105 °C Infrared absorption spectrum m2ICan-”2944.1726
．． 1626,1488°1462.1434,1404
,1326°1248.1194,1176.1108
゜1040.936 Proton nuclear magnetic resonance spectrum (δppm in CDCl: 3.90 (s, 3 H), 3.92 (s, 3
H).

6.11 (s, 2H), 7.27 (s, IH) mass spectrum: m/z (%) 290 (89, M'').

288 (91, M”).

259(100), 257(100) Specific Example 4 Methyl 2-bromo-5-methoxy-3 obtained in Specific Example 3
, 14.5 g of crystals of 4-methylenedioxybenzoate were thoroughly ground, and the mixture was mixed with 70 g of activated steel.
It was dried for 3 hours under reduced pressure while heating at ~90°C. Then, the pressure was returned to normal, and the reaction temperature was maintained at 146 to 150°C while heating for 15 hours.

After cooling, the reaction mixture was extracted with chloroform, and the residue after removing the solvent was recrystallized with ethanol to obtain 7.5 g of compound A (yield: 72%).

Infrared absorption spectrum νm2f-': 1718, +638.1594, 1492°1466,
l 436,1320,1264゜1242.1186
．． 1+72.1136°1108.1042.928 Proton nuclear magnetic resonance spectrum (δppm in CDC13): 3.66 (s, 6 H), 3.96 (s, 6
H).

5.96 (s, 4 H), 7.37 (s, 2
H) Mass spectrum: m/z (%) 418 (100, M").

3 5 9 (22), 3 2 8 (13) Specific Example 5 4.18 g of the compound A obtained in Specific Example 4 was dissolved in 50% of benzene, and 13.3 g of lead tetraphrate was added under a nitrogen stream for 5 hours. It refluxed. After refluxing, the mixture was allowed to cool to room temperature, extracted with ethyl acetate, and the solvent was removed from the extract to obtain 85.12 g of the crude compound.
I got it.

Infrared absorption spectrum νm2'x c7/1-':
1760.1722.1640 Proton nuclear magnetic resonance spectrum (δppm in CDC13): 2.09 (s, 3H), 3.65 (s, 6H).

3.92 (s, 3 H), 3.98 (s, 3
H).

5.97 (s, 2 H), 7.38 (s, l
H).

7.44 (s, IH),' 7.70 (s, IH) mass spectrum: m/z (%) 476 (13,4), 432 (8,
4).

419 (10,4), 418 (44,9).

406(7,2), 388(7,4).

375 (20,7), 374 (100).

359 (12,1), 330 (15,2).

3 1 5 (13,2), 269 (7,0) Specific Example 6 5.12 g of the crude compound B obtained in Specific Example 5 was dissolved in 80% acetic acid 50
F! The solution was dissolved in jQ and refluxed for 5 hours. After refluxing, let it cool,
Suction filtration gave 3.1 g of compound I (total yield 74.
3%).

Infrared absorption spectrum ν2-α-1:3392.17
16.1624.1574゜1500.1488,14
62. +434°1412.1400,1338,12
84°1262.1220,1172. +092°10
40.1018.776 Proton nuclear magnetic resonance spectrum (δppm in CDC13): 3.83 (s, 3 H), 4.00 (s, 3
H).

4. 0 1 (s, 3H), 6
．． 1 4 (s, 2 to I).

7.22 (s, I H), 7.65 (s, I H)
Mass spectrum.

m/z (%) 374 (100, M-44).

34 3 (9,4), 3 3 5 (6,0).

3 29 (11,5), 328 (12,9).

3 1 5 (20,1), 3 1 3 (8,5).

2 8 7 (12, 5), 2 8 5 (7, 9).

2 7 5 (8, 2), 2 7 2 (9, 4).

2 7 1 (10,1), 2 6 9 (19,9)
,'257(8,2) Further, compound (1) and compound (2), which serve as raw materials, can be obtained by methylating compound (2) obtained as described above.

Methylation of compound H can be achieved by using a methylating agent such as dimethyl sulfate or methyl iodide.

When dimethyl sulfuric acid is used, the reaction is carried out in a solvent such as methanol, ethanol, propatool, etc. within a temperature range from room temperature to the boiling point of the solvent used for 1 to 12 hours. At this time, in order to increase the reactivity, it is preferable to add a base such as potassium carbonate or sodium carbonate, and DMSO (
A solubilizing agent such as u-methyl sulfoxide) may be added.

When using methyl iodide, in a solvent such as acetone, methanol, ethanol, propatool, etc., at room temperature to 40°C.
Let it stand at about C for about 5 to 25 hours.

At this time, it is preferable to add a base such as potassium carbonate or sodium carbonate to increase reactivity.

After the reaction is completed, the desired product can be easily obtained by extraction with ethyl acetate, ether, etc., and can be recrystallized with benzene, hexane, etc.

Specific examples of the production of Compound (1) and Compound (2) are shown below.

Specific Example 7 After dissolving 1100 mg of the compound l obtained in Specific Example 6 in 1077 acetone, 60 mg of potassium carbonate and 68 mg of methyl iodide were added, and the mixture was stirred at room temperature for 12 hours.

After the reaction was completed, the residue from which acetone was removed was extracted with ethyl acetate, and the solvent was further removed to obtain a compound (1) having the following physical and chemical properties (yield: 94.5%).

Infrared absorption spectrum ν'4a'xc7tt-': 17
26.1634.1600,1568°1484.14
32. + 408.1392°1368.1342,1
278,1246°1226.1!94.1172.1
+40°1108.1034.974,928,774
Proton nuclear magnetic resonance spectrum (δppm in CDC13): 3.84 (s, 3H), 3.96 (s, 3
H).

4.0 1 (s, 3 H), 4.0 3 (
s, 3H).

6.14 (s, 2H), 7.21 (s, IH).

7.64 (s, IH) Mass spectrum: m/z (%) 389 (21,6, M" -4
3).

388 (100, M'-44).

3 7 3 (8, 4), 3 5 7' (6, 2).

34 3 (7,4), 34 2 (8,4).

3 2 9 (7, 1), 3 1 4 (8, 0).

3 0 2 (6,5), 2 7 1 (5,8) Specific Example 8 2.59 g of the compound I obtained in Specific Example 6 was dissolved in methanol and DMSO, and 8.6 g of potassium carbonate and 7.5 g of dimethyl sulfate were dissolved. 8 g was added and refluxed for 8 hours. After cooling, methanol was removed, the residue was extracted with ethyl acetate, and ethyl acetate was removed. Furthermore, recrystallization using benzene yields dimethyl 2゜3-methylene dioxo-2゜, 3゜, which has the following physical and chemical properties where R7 is a methyl group in compound
for 4,4°-tetramethoxy, 1°-biphenyl-6,
6'-dicarboxylate was obtained (yield 79.5%).

Infrared absorption spectrum νm: xc712-'・+722
．． 1638, 1594, 1492° 1462.1434
．． 1394.1338°+324.1274.1244
,1218°1188.1168. +126.110
0°1042.992 Proton nuclear magnetic resonance spectrum (δppm in CDC13): 3.61 (s, 6 H), 3.65 (s, 3
H).

3.93 (s, 3 H), 3.94 (s, 3
H).

3.97 (s, 3H).

5.96 (d, J = 2.44.2 H).

7.37 (s, IH), 7.39 (s, IH) mass spectrum: m/z (%) 434 (100), 403 (12,
2).

375 (9,0), 373 (6,6).

3 6 0 (7,4), 3 5 9 (5,3).

34 5 (9,1), 34 4 (10,5).

3 = 1 3 (9,0), 3 2 9 (7,2)
.

3 1 5 (6,7), 2 2 3 (4=19) Compound I can be obtained by reacting Compound (1) or Compound (2) obtained as described above with an alkylating agent using an alcohol as a solvent. Specific examples of alcohols include methanol, ethanol, propatool, isopropanol, n-butanol, isobutanol, 5ec-butanol, tert-butanol, n-pentanol, isopentanol, n-hexanol, etc.
Examples of the alkylating agent include dimethyl sulfate, diethyl sulfate, and alkyl halides having 1 to 7 carbon atoms.

If necessary, a base such as potassium carbonate, sodium carbonate, or sodium hydroxide may be added to promote the reaction, and DMSO (dimethylsulfoquine) or the like may be added as a solubilizing agent.

The reaction temperature ranges from room temperature to the fluorocarbon temperature of the alcohol used, and the reaction is completed in about 3 to 100 hours. After the reaction is completed, the desired product can be easily obtained by extraction with ethyl acetate or ethers, and can be recrystallized with a common recrystallization solvent such as benzene or hexane.

Alternatively, it may be purified by commonly used column chromatography.

The alkaline hydrolysis of compound (1) can be carried out by a commonly used method, and specific examples of the base include potassium hydroxide, sodium hydroxide, and the like.

[Effects of invention According to the present invention, the following effects can be obtained.

(2) Compound I of the present invention has a liver disorder-improving effect and is effective in treating liver disorders.

(2) The production method of the present invention has a high yield, can be purified by recrystallization, and is very simple to operate, so it is suitable for industrialization.

■Selective transesterification is possible.

Next, the fact that Compound I has an effect of improving liver damage will be explained using experimental examples.

Experimental Example 7 A group of 10 SD rats of the same age were fasted for 24 hours, and then compound 10 obtained in Examples 1 to 6 described below was prepared.
0 mg/kg each with 1% Tween
After 30 minutes, 4 mg/kg of 25% carbon tetrachloride-Oliveura was orally administered, and 24 hours later, blood was collected and liver was removed. The group was treated in the same manner as above except that the compounds obtained in Examples 1 to 6 were not added, and this group was used as a control group.

The results are shown in Table 1.

Table 1: Compounds of the Invention in Rats with Carbon Tetrachloride Hepatopathy From these results, Compound I was found to have a liver damage-improving effect.

Next, the compounds obtained in Examples 1 to 9 described later were orally administered to ddY mice (10 mice in each group of 311).
No deaths were observed even at doses up to 000 mg/kg.

Furthermore, in consideration of the above results, the effective dose of the liver disorder improving agent of the present invention that is recognized to be appropriate is 5 to 80 mg per day for adults when administered orally, and 0 to 80 mg per day for adults when administered parenterally, based on the weight of compound ■. It seems appropriate to administer 1 to 10 mg in several doses.

Compound I of the present invention can be formulated into solutions, powders, granules, tablets, enteric-coated formulations, capsules, etc. according to conventional methods for manufacturing formulations using appropriate solvents, excipients, adjuvants, etc. used in formulations. can be made.

In the formulation, it can also be combined with other medically active ingredients.

For oral administration, tablets, pills, capsules, powders,
It can be formulated into granules, etc.

In addition to the above-mentioned excipients, this type of preparation may contain, for example, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc, binders such as dextrin, crystalline cellulose, polyvinylpyrrolidone, gum arabic, corn starch, and gelatin. agent, sodium cellulose gelcholate, potassium cellulose gelcholate, potato starch,
A disintegrant such as carboquine methylcellulose and a fluidity promoter such as light silicic anhydride can be used. In addition, the drug of the present invention can be used in suspensions, emulsions, syrups,
It can also be administered as an elixir, and these various dosage forms may contain flavorings and coloring agents.

When producing an injection, diluents that can generally be used include distilled water for injection, physiological saline, aqueous dextrose solution, vegetable oil for injection, propylene glycol, polyethylene glycol, and the like.

Furthermore, an isotonizing agent, a stabilizer, a preservative, a soothing agent, etc. may be added as appropriate. It is also desirable for this type of dosage form to be dissolved in a sterile injectable solution.

EXAMPLES The present invention will be specifically described below with reference to Examples, but the present invention is not limited thereto.

Example 1 209 mg of the compound IJ obtained in Example 6 and 15 ml of methanol were suspended in DMS 057, and 346 mg of potassium carbonate and 386 mg of diethyl sulfate were added.

After refluxing the mixture for 5 hours, the solvent was removed, and the residue was extracted with ethyl acetate and dried to obtain an oil. This is recrystallized to form dimethyl 2゛,3゜- which has the following physical and chemical properties.
95 mg (yield: 84%) of fetquin-4,4'-dimethoxy-2'3-methylenedioxy-1,1'-biphenyl-6,6'-dicarboxylate I was obtained.

Melting point = 107~108℃ Infrared absorption spectrum: I? 2'2-"1722.1642
,1598,148°6°1464,! 434.141
4.1384°1350.1322,1268,124
4°1192.1044 Proton nuclear magnetic resonance spectrum (δ Ppm in CDC1,) 1.00 (t, J = 7.08 Hz, 3 H).

1.37 (t, J = 7, '08 Hz, 3 H
).

3. 60 (s, 3H), 3. 6
6 (s, 3H).

3.81 (q, d, J = 7.08.4.88Hz
, 2H).

3.92 (s, 3 H), 3.97 (s, 3
H).

4.15 (q, J=7.08Hz, 2H).

5.97, 5.93 (AB, J = I, 47Hz,
21().

7.36 (s, IH), 7.37 (s, IH) mass spectrum; m/z (%) 462 (62, M”), 434 (1
8).

418(23), 402(23).

374(100), 359(15).

345(28), 343(22).

331(12), 329(17).

328(15), 315(23).

302(16), 287(II).

271 ([3), 237 (67).

205 (+4) Example 2 111.25 g of the compound obtained in Specific Example 6 and 75) d of ethanol were added to DMS O251J, and 2.1 g of potassium carbonate and 2.3 g of diethyl sulfate were added.

After refluxing the mixture for 2 days, the solvent was removed and the residue was extracted with ethyl acetate and dried to obtain an oil. This was subjected to flat column chromatography [Silica gel: Merck 6].
0, Solvent: Ethyl acetate-n-hexane (1:l), Diethyl 2°, 3'-jetoxy-4 purified by pressure crab 0,5 kg/cm'l and having the following physical and chemical properties
,4°-dimethoxy-2,3-methylenezoxy-1j
970
mg (yield 66%).

Infrared absorption spectrum ν=,, em −': 171
2.1642,1596. +484°1464, +44
2,1=114,138f3゜1370.1346,1
334.1318°1298.1242,1178.1
102° proton nuclear magnetic resonance spectrum (δ ppm in CDC13) 0.98 (t, J-7,08Hz, 3H).

1.02 (t, J = 7.08 Hz, 3H).

1. 0 3 (t, J = 7.0
8 Hz, 3 H).

1.38 (t, J = 7.08 Hz, 3H).

3.83 (q, J = 7.08 !lz, 2 H)
.

3.91 (s, 3 H), 3.97 (s, 3
H).

4.03 (q, d, J = 7.08, 3.42) 1z, 2
H)'.

4.08 (q, J = 7', 08 Hz, 2 H)
.

4.13(q, J=7.08)1z,2H).

5.95, 5.98 (AB, J= 1.22Hz, 2H
).

7.37 (s, [H), 7.37 (s, I H) mass spectrum m/z (%) 490 (100, M').

4 7 6 (11), 4 1 6 (14).

388(28), 371(10).

359(11), 343(13).

3 1 5 (13), 2 5 2 (l l).

Example 3 111.3 g of the compound obtained in Specific Example 7 was added to 70 g of methanol.
d and DMSO307d, 2 g of potassium carbonate and 2.2 g of diethyl sulfate were added, and the mixture was flushed with A overnight.

After the reaction was completed, the mixture was extracted with ethyl acetate and dried to obtain an oily substance. This oil was recrystallized from ethyl acetate to give dimethyl 2'-ethoxy-2,3-methylenedioxy-3',4,4°-trimethquine-1, which has the following physical and chemical properties.
°-Biphenyl-6,6゛-dicarboxylate 966
mg (yield 74.5%).

Melting point, 93-94℃ Infrared absorption spectrum νR7α: ! 720.1642,1598. I486°+464.
1432.1414. +384°1350.1322,
1270,1246°+192.1174,1124.
1102° Proton nuclear magnetic resonance spectrum (δ ppm in CDC1,) 3.6 1 (s, 3 F-1), 3.6 6
(s, 3H).

3.8 0 (q, d, J = 7.08.2.6 9
Hz, 2H).

3.93 (s, 61-(), 3.9 8 (s
, 3 H) 5.9 5, 5.9 7 (AB, J =
1.4 6Hz, 2) ().

7.36 (s, IH), 7.38 (s, IH) mass spectrum: m/z (%) 4 4 8 (100, M”
).

434 (10), 418 (+2).

3 89 (+ 8), 3 88 (45).

3 7 3 (13), 3 5 7 (12).

329(10), 237(65).

Example 4 11.72g of the compound obtained in Specific Example 7 was added to 11.72g of ethanol.
00- and dissolved in DMSO357, potassium carbonate 2.7
6 g and 2.52 g of dimethyl sulfate were added and refluxed overnight.

After the reaction was completed, the mixture was extracted with ethyl acetate and dried to obtain an oily substance. This was purified by flash column chromatography [silica gel: Merck 60, solvent: ethyl acetate-n-hexane (3:2), pressure crab 0, 5 kg/cm2] to obtain diethyl 2,3 having the following physical and chemical properties. -Methylenezoxy-2', 3', 4.4'-tetramethoxy1. 1.16 g (yield 63%) of l°-biphenyl-6,6°-dicarboxylate was obtained.

Melting point: 69-69.5°C Infrared absorption spectrum: α-1: 1712.1642, 1596.1486°+462.
1428.1398, 1370°1334.1320.
1300,1244°1+92.1178.1126.
1102° proton nuclear magnetic resonance spectrum (δ ppm in CDC13) 0.99 (t, J = 7.08 Hz, 3 H).

1.05 (t, J = 7.08 Hz, 3H).

3.63 (s, 3 H), 3.94 (s, 6
H).

3.98 (s, 3H).

4.04 (q, J = 7.08Hz, 2H).

4.07 (q, J = 7.05Hz, 21().

5.96, 5.99 (AB, J= 1.46H2, 2H
).

7.38 (s, IH), 7.39 (s, IH
) Mass spectrum: m/z (%) 462 (100, M").

3 4 5 (14), 3 4 4 (I 1).

329 (10), 237 (+6).

Example 5 980 mg of the compound (1) obtained in Example 7 was dissolved in 71 fl of n-propatool 60I and 207 d of DMSO, 1.57 g of potassium carbonate and 1.75 g of diethyl sulfate were added, and the mixture was refluxed for 5 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and dried to obtain an oily substance. This was subjected to flash column chromatography [silica gel, Merck 60, solvent: ethyl acetate].
n-hexane (I・1), pressure crab 0, 5 kg/c
Methyl having the following physical and chemical properties after being purified by
2″-Ethoxy-2,3-methylenedioxy-6″-propoxycarbonyl-3°, 4.4°trimethoxy-1
, 1'-biphenyl-6-carboxylate 645mg
(yield: 60%).

Melting point: 74.5-76°C Infrared absorption spectrum Iα River: 720.1642, 1598.1486°1464.
1428, 1414, 1386° 1350, + 336
．． 1320. +268°1244.1192.1176
．． 1102° proton nuclear magnetic resonance spectrum (δ ppm in CDCl5) 0.75 (t, J = 7.33 Hz, 3 H).

1.01 (t, J = 7.08 Hz, 3H).

1.40 (m, 2 H), 3.65 (s, 3
H).

3.80 (q, d, J=7.08, 1.95Hz, 2H
).

3.92 (s, 6 H), 3.97 (s, 3
H).

3.92-3.97 (2H).

5.95, 5.97 (AB, J= 1.22Hz, 2H
').

7.37 (s, IH), 7.38 (s, IH) mass spectrum: m/z (%) 476 (100, N-do).

462(12), 389(19).

388(43), 373(12).

575 (15), 329 (+7).

265(17), 224(11).

Example 6 748 mg of the compound IJ obtained in Example 7 was mixed with 45.5 mg of n-propatool. d and DMSO15.7, 1.19 g of potassium carbonate and 1.33 g of diethyl sulfate were added, and the mixture was refluxed for 2 days. After the reaction was completed, the mixture was extracted with ethyl acetate and dried to obtain an oily substance. This was subjected to flash column chromatography [silica gel, Merck 60, solvent: ethyl acetate-n-
Hexane (1:1), pressure crab 0,5 kg/cm'
] Dipropyl with the following physical and chemical properties
2゛-Ethoxy-2,3-methylenedioquine-3°,4
, 4°-trimethoxy, 1°-biphenyl-6,6°
-495 mg (yield 57%) of carboxylate was obtained.

Melting point: 4 l ~ 42°C Infrared absorption spectrum +a':x C7n -"17
14.1642.1596.1486°1464.14
28,1414. +390°1350.1320,12
42.1178°1102.1042 Proton nuclear magnetic resonance spectrum (δ ppm in CDC13) 0.74 (t, J = 7.33 Hz, 3 H).

0.79 (t, J = 7.33 Hz, 3 H).

1. 0 1 (t, J = 7.0 8
) Iz, 3 H).

1.33-I, 49 (m, 4H).

3.80 (q, d, J = 7.08.1.71Hz,
2H).

3.96 (t, J = 6.38 Hz, 2 I()
.

3.99 (t, J = 6.83 Hz, 2H).

3.92 (s, 3 H), 3.93 (s, 3
H).

3.97 (s, 3H).

5.94.5.97 (AB, J= 1.46Hz, 2H
).

7.38(s, 1 F(), 7.3
9 (s, L H) mass spectrum: m/z (%) 504 (89, M'').

490(14), 417(13).

416(32), 359(11).

357(15), 331(12).

330(11), 329(18).

3+5(l　I),　U65(22).

224(12), 223(100) Example 7 1.3 g of the compound ■ obtained in Example 8 was added to dioxane 507d.
Add 107d of 5% potassium hydroxide and heat at 70°
C. and stirred overnight. When the pH was adjusted to 1 with 3N hydrochloric acid, crystals were precipitated. The precipitated crystals were collected by filtration and recrystallized with ethanol to obtain 2,3-methylenedioquine-2',3' having the following physical and chemical properties.

4.4°-tetramethokino-1, l'-biphenyl-6
゜6'-Dicarboxylic anrad 1. I2g (yield 92%) was obtained.

Melting point: 257.7~259°C Infrared absorption spectrum WOW Can-': 3000~
2500, 1690.1638°1594.1492.
1454. I422゜1392.1324,1270.
1234°1196.1156.1130.1104°+038,984,928 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5) 3.16 (s, 3H), 3.94 (s, 3H).

3.95 (s, 3 H), 3.98 (s, 3
H).

5.99.6.00 (AB, J=1.47Hz, 2H)
7.43 (s, IH), 7.46 (s, IH) FD
Mass spectrum m/z (%) 434 (M') Example 8 Diethyl obtained in Example 2 2', 3'-jethoxy-4
49
．． 79 was dissolved in dioxane 4-, and after adding one volume of 5% potassium hydroxide aqueous solution, the mixture was heated to 70'C and stirred overnight. After adjusting the pH to 1 to 2 with 3N hydrochloric acid, extraction with chloroform and removal of the solvent yielded 2", 3'-fethoxy-4,4'-dimethoxy-2,3-methylenedioxy, which has the following physical and chemical properties. Biphenyl-6,6-ene carpoquine ricand 38 TI9 (yield 88%) was obtained.

Melting point: 262-263°C Infrared absorption spectrum ('7'! -': 2750-2
500.1696, 1640°1598, +486.1
464.1438°14]4.1384,1328.1
278°1252.1196. +160.1128°1
102.1038 Proton nuclear magnetic resonance spectrum (δ ppm in CDC13) 0.98 (t, J = 7.08 Hz, 3 H).

1.32 (t, J=7.08Hz, :3t().

3.6-3.9 (m, 2H).

3.92 (s, 3 H), 3.97 (s, 3
H).

4.15 (q, J=7.08Hz, 2r-1).

5.94, 5.98 (AB, J=1.22Hz, 2H)
.

7.42 (S, IH), 7.45Cs, IH
)・FD mass spectrum: m/z (%) 434 (M”) Example 9 Methyl obtained in Example 5 2°-Ethoxy-2,3-methylenezoxo-6′-propoxycarbonyl-3°,4
．． For 4'-trimethoxy, dissolve 48 mq of biphenyl-6-carboxylate in dioxane 4-5%
After adding potassium hydroxide aqueous solution 1-, the mixture was heated to 70°C and stirred overnight. After adjusting the pH to 1 with 3N hydrochloric acid, extraction with chloroform and removal of the solvent produced 2° ethoxy-2,3-methylenedioquine-3', which has the following physical and chemical properties.4.
4'-trimethoxy-1,1°-biphenyl-6,6°
-dicarboxylic anrad 36 m9 (yield 86
%) was obtained.

Melting point, 236-237°C Infrared absorption spectrum:':':"an-':2700-
2400.1694, 1642°+600.1486.
+462.1414°1384.1322,1284,
1260°1196.1180.1158.1130° Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5) 0.97 (t,, J=7.08Hz, 3H).

3.7-4.0 (m, 2H).

3.91 (s, 6) (), 3.96 (s, 3H)
.

5.94, 5.98 (AB, J = I, 221 (z,
2H).

7.41 (s, IH), 7.44 (s, IH)F
D mass spectrum: m/z (%) 420 (Ml Example 10 0.5 g of the compound obtained in Example 1 was made into a fine powder, mixed with 98.5 g of lactose and 1 g of magnesium stearate, and this mixture was made into a single powder. A slug tablet with a diameter of 20 mm and a weight of 2.3 g is made by compressing the tablet using a type slug tablet machine, which is then crushed using an oscillator, sized, and sieved to obtain good granules with particles of 20 to 50 Metsutsuyu. Ta.

This granule contains 5 mg of the compound obtained in Example 1 in 1 g, which is taken three times a day.

Example 11 0.5 g of the compound obtained in Example 2 was made into a fine powder, mixed with 98.5 g of lactose and Ig of magnesium stearate, and this mixture was compressed using a single-shot slug key machine to form tablets with a diameter of 20 mm. A heavy ffi 2.3 g slug tablet was made, crushed with an oscillator, sized, and sieved.
Good particle size of 0-50 meshes.

Granules were obtained.

Each gram of this granule contains 5 mg of the compound obtained in Example 2, and the dose is 1 to 5 g three times a day, depending on the symptoms.

Example 12 Microcrystalline cellulose 9 was added to 2.5 g of the compound obtained in Example 3.
3 g of sodium cellulose gelcholate and 1.5 g of magnesium stearate were added and mixed, and the mixture was pressed into tablets using a single-shot key press to form tablets with a diameter of 9 mm and a weight of ffi2.
00mgo) tablets were manufactured.

Each tablet contains 5 mg of the compound obtained in Example 3, and one to five tablets are taken three times a day depending on the symptoms.

Example 13 Microcrystalline cellulose 93 was added to 2.5 g of the compound obtained in Example 4.
g, 3 g of sodium cellulose gelcholate and 1.5 g of magnesium stearate were added and mixed, and this mixture was compressed using a single-shot key press to form tablets with a diameter of 9 mm and a weight of 200 mg.
tablets were manufactured.

Each tablet contains 5 mg of the compound obtained in Example 4, and one to five tablets should be taken three times a day depending on the symptoms.

Example 14 5 g of the compound obtained in Example 5 was made into a fine powder, and this was mixed with 91% of lactose.
5 g of silicic acid anhydride and 3 g of microcrystalline cellulose, and each loOmg of this was filled into hard capsules to obtain capsules.

This capsule contains 5 mg of the compound obtained in Example 5 per capsule, and is taken 1 to 2 capsules at a time, three times a day, depending on the symptoms.

Example 15 5 g of the compound obtained in Example 6 was made into fine powder, and this was mixed with lactose 91
5 g, 0.5 g of light anhydrous silicic acid, and 3 g of microcrystalline cellulose were mixed, and 100 mg of each was filled into hard capsules to obtain capsules.

This capsule contains 5 mg of the compound obtained in Example 6 per capsule.
Take capsules three times a day.

Example 16 10ml of the compound obtained in Example 8 was sealed in a sterile vial, dissolved in a 5% glucose solution or physiological saline before use, and infused for 2 to 4 hours per 500ml of infusion. Administer intravenously.

Example 17 10 m9 of the compound obtained in Example 9 was filled into a sterilized vial, sealed, dissolved in 5% glucose solution or physiological saline before use, and infused for 2 to 4 hours per 500 d of infusion. Note.

Claims (3)

[Claims] (1) The following formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I (In the formula, R_1 represents a hydrogen atom or a lower alkyl group,
R_2 represents a lower alkyl group. ) A novel biphenyl derivative represented by (2) A compound represented by the following formula II ▲There are mathematical formulas, chemical formulas, tables, etc.▼II, or a compound represented by the following formula III ▲There are mathematical formulas, chemical formulas, tables, etc.▼III. The following formula is characterized by the action of a curing agent I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I (In the formula, R_1 represents a hydrogen atom or a lower alkyl group,
R_2 represents a lower alkyl group. ) A method for producing a novel biphenyl derivative represented by (3) The following formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I (In the formula, R_1 represents a hydrogen atom or a lower alkyl group,
R_2 represents a lower alkyl group. ) A liver disorder improving agent containing a novel biphenyl derivative represented by the following as an active ingredient.