JPS63146845A - Naphthalene derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> and R<2> are lower alkoxycarbonyl or R<1> and R<2> form group shown by formula II further R<1> is H; R<3> and R<4> are lower alkoxy and one of R<3> and R<4> may be H; ring A is substituted or nonsubstituted benzene ring; with the proviso that when (a) R<1> and R<2> are COOCH3 and ring A is group shown by formula III, (b) R<1> is H R<2> is COOC2H5 and ring A is group shown by formula IV or (c) R<1> and R<2> are group shown by forming II and ring A is group shown by formula III IV, one of R<3> and R<4> is >=2C lower alkoxy or H] or a salt thereof. EXAMPLE:1-( 3,4-Dimethoxyphenyl )-2, 3-bis(methoxycarbonyl)-4-hydroxy-6,7,8-tri methoxynaphthalene. USE:An antilipemic agent which lowers a total cholesterol value in blood but raises HDL-cholesterol value. PREPARATION:A compound shown by formula V (R<11> is R<1> except group shown by formula II; R<5> is lower alkyl) is reacted with a compound shown by formula VI or a lower alkylacetal derivative or a salt thereof to give a compound shown by formula I wherein R<1> and R<2> are not group shown by formula II.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to novel naphthalene derivatives.

(Prior art) Hyperlipidemia is thought to be one of the main causes of arteriosclerosis, an adult disease, and clofibrate [chemical name: 2
-(4-chlorophenoxy)-2-methylpropanoic acid ethyl ester], probucol (chemical name: 4.4'-
((1-methylethylidene)bis(thio)] bis[2
,6-bis(1,1-dimethylethyl)phenol]
Antilipemic agents such as these are used as therapeutic and preventive agents. Of hyperlipidemia.

Hypercholesterolemia has a particularly strong relationship with arteriosclerosis. However, cholesterol exists in the blood in the form of very low density lipoprotein (VLDL) cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, etc. HDL and LDL promote the deposition of cholesterol on the arterial wall and cause arteriosclerosis, whereas HDL prevents the deposition of cholesterol on the artery wall and is useful for the treatment and treatment of arteriosclerosis.
It has been found that it has a preventive effect [Annals・
Of Internal Medicine (AnnalSof)
Internal Medicine), Vol. 90, pp. 85-91 (1979)]. Therefore, in the field of treatment and prevention of arteriosclerosis, there has recently been a desire for the development of antilipidemic agents that can increase the amount of DL-cholesterol while decreasing the total amount of cholesterol in the blood.

On the other hand, Journal of the Chemical Society Chemical Communications (J.

Chem, Soc, Chem, Comm,
), page 354 (1980), 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxycarbonyl)
-4-hydroxy-6゜7-methylenedioxynaphthalene and 1-(3,4-dimethoxyphenyl)-3-hydroxymethyl-4-hydroxy-6,7-methylenedioxy-2-naphthoic acid lactone are also・Abstraf) (Chem, Abs,) Volume 53, 200
25i (1959) contains 1-(3,4-dimethoxyphenyl)-3-hydroxymethyl-4-hydroxy-
6,7-Simethoxy 2-naphthoic acid lactone and 1-
(3,.

4-dimethoxyphenyl)-2-ethoxycarbonyl-
4-Hydroxy-6,7-simethoxynaphthalene is described. However, until now nothing has been known about the pharmacological effects of these compounds.

(Object of the Invention) An object of the present invention is to provide a useful pharmaceutical compound having excellent antilipidemic effect.

(Structure and Effects of the Invention) The present invention relates to a naphthalene derivative or a salt thereof represented by the following general formula.

H (in the formula I R' is a hydrogen atom or a lower alkoxycarbonyl group, R1 is a lower alkoxycarbonyl group, or RL and R2 are bonded to each other to form a group represented by the formula: ? The expression l R'' and R4 are lower alkoxy groups, or one of R1 and R4 is a hydrogen atom and the other is a lower alkoxy group, and ring A represents a substituted or unsubstituted benzene ring.

a) R'' and R2 are both methoxycarbonyl groups, ring A
Is it a substituted benzene ring represented by the formula =<:, cX?

b) R' is a hydrogen atom, and R1 is an ethoxycarbonyl group.

ring or a substituted benzene ring represented by CHsO,C)E
4 In case.

Is one of Rs and R4 a lower alkoxy group and the other a lower alkoxy group having 2 or more carbon atoms?

Alternatively, one of R1 and R4 is a hydrogen atom and the other is a lower alkoxy group. ) The naphthalene derivative (1) or a pharmacologically acceptable salt thereof of the present invention is characterized in that it has an antilipemic effect, and in particular, it lowers the total cholesterol level in the blood, but increases the HDL-cholesterol level. There is. For example, 2W/W
Rats were fed with a diet containing 96 cholesterol and 0.5 W/W 96 sodium cholate for 4 days, and then the sample was mixed with the same feed at a ratio of 20 η%, and the rats were kept for 3 days to determine the serum cholesterol level lowering effect and HDL- When the cholesterol level increasing effect was investigated, the compound of the present invention, 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6,7゜8
- Trimethoxynaphthalene showed a 52% reduction in serum cholesterol levels and an 8696 increase in HDL-cholesterol levels compared to the control group.

Furthermore, the toxicity of the naphthalene derivative (1) is low (and there are no side effects such as liver dysfunction (eg, fatty liver).

For example, when the above compound was orally administered to mice at a dose of 1000"W/? and observed for 5 days, no deaths were observed, and no suppression of weight gain was observed.

Naphthalene derivatives (1) of the present invention include 1, for example, in general formula (1), I R' is a hydrogen atom or a lower alkoxycarbonyl group (for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group); I R" is a lower alkoxycarbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group) (e.g., methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group), or one of R1 and R4 is a hydrogen atom and the other is a lower alkoxy group (eg, methoxy group, nidoxy group).

propoxy group, inpropoxy group, butoxy group), and ring A is a substituted or unsubstituted benzene ring. Examples of substituted benzene rings include 9, for example, lower alkyl groups (eg.

Methyl group, ethyl group, propyl group, isopropyl group, butyl group), lower alkoxy group (e.g. methoxy group,
ethoxy group, propoxy group, isopropoxy group, butoxy group), phenyl-lower alkoxy group (e.g. benzyloxy group, phenethyloxy group), hydroxy group and halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom) ), a benzene ring substituted with 1 to 3 groups selected from

Examples include a benzene ring substituted with a methylenedioxy group, an ethylenedioxy group, and the like.

Among these, a preferred compound is one in which NR' and R2 are lower alkoxycarbonyl groups in general formula (I).

a) R'' and R4 are lower alkoxy groups, or one of R1 and R4 is a hydrogen atom and the other is a lower alkoxy group;

Majin is a general formula: [In the above formula, R11 is a hydrogen atom, a lower alkyl group (e.g., methyl group, ethyl group, propyl group, isopropyl group, butyl group) or a lower alkoxy group (e.g., methoxy group, ethoxy group, propoxy group) Base.

Rb is a lower alkyl group (eg, methyl group, ethyl group, propyl group, isopropyl group, butyl group); Ro is a hydrogen atom.

Lower alkyl groups (e.g. methyl, ethyl).

propyl group, isopropyl group, butyl group) or phenyl-lower alkyl group (e.g. benzyl group).

Rd, R@ and R' are lower alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl); xl and Xb are gen atoms (e.g. fluorine, chlorine) , bromine atom, iodine atom). ] or b) One of R'' and R4 is a lower alkoxy group and the other is a lower alkoxy group having 2 or more carbon atoms.

Or one of R1 and R4 is a hydrogen atom and the other is a lower alkoxy group.

or a) R'' and R4 are lower alkoxy groups, or R
One of `` and R4 is a hydrogen atom, and the other is a lower alkoxy group.

Ring A has the general formula: (In the above formula, Rg represents a hydrogen atom or a phenyl-lower fluorine group, R', Rb, R', R@, R'
, X' and xb have the same meanings as above. ) or b) One of R'' and R4 is a lower alkoxy group and the other is a lower alkoxy group having 2 or more carbon atoms.

Or one of R8 and R4 is a hydrogen atom and the other is a lower alkoxy group.

R1 represents a lower alkyl group, and Rh has the same meaning as above. ) Compounds having a substituted benzene ring represented by the following can be mentioned.

As a more preferable compound, in general formula (1), R
1 and R2 are lower alkoxycarbonyl groups and A) R''
and R4 is a lower alkoxy group.

Majinga formula: Is it a substituted or unsubstituted benzene ring represented by

Or B) One of R'' and R4 is a lower alkoxy group and the other is a lower alkoxy group having 2 or more carbon atoms, or one of RA and R4 is a hydrogen atom and the other is a methoxy group.

Mention may be made of compounds in which ring A is a substituted benzene ring represented by the formula: <:, Ql" or =: RI.

A more preferred compound is one in which I R' and R2 are lower alkoxy groups in general formula (1).

and ring A is a substituted benzene ring represented by the formula:

Another preferred compound is one in which R1 and R1 are lower alkoxycarbonyl groups in general formula (1).

Has taste. ), preferred among these are compounds in which l R' and R2 are lower alkoxycarbo and the naphthalene derivative (I) of the present invention is also in free form.

Its salt can also be used for pharmaceutical purposes.

Salts include alkali metal salts (e.g. sodium salts,
Potassium salts), alkaline earth metal salts (eg, calcium salts), quaternary ammonium salts (eg, tetramethylammonium salts, tetraethylammonium salts), and the like.

The naphthalene derivative (I) of the present invention can be administered either orally or parenterally, but oral administration is particularly preferred, and the dosage is as follows.

Type and severity of disease: Depending on the patient's age, body weight, condition, etc.9 The usual daily dose is 1.5 to 35'9/day.
KP is preferably from 5 to 25/immediate.

As mentioned above, the naphthalene derivative ('I) of the present invention and its pharmacologically acceptable salts have excellent antilipidemic effects, and in particular, while lowering total cholesterol levels in the blood,
Since DL-cholesterol levels are characterized by increased levels, hyperlipidemia (e.g. hypercholesterolemia),
It can be used for the treatment and prevention of arteriosclerosis (eg, atherosclerosis, Mönckeberg's arteriosclerosis), etc.

According to the present invention 1ζ, R1 of the naphthalene derivative (I) is a hydrogen atom or a lower alkoxycarbonyl group I R
Compounds in which " is a lower alkoxycarbonyl group are acetylene compounds represented by the general formula % (in the formula, R11 represents a hydrogen atom or a lower alkoxycarbonyl group, and R' represents a lower alkyl group) and the general formula (In the formula, I R'' l R' and ring A have the same meanings as above.) It can be produced by reacting with an aldehyde compound represented by the formula, a di-lower alkyl acetal thereof, or a salt thereof.

(In the formula, e R' and R7 represent a lower alkyl group, ring B represents a substituted or unsubstituted benzene ring, and I R'' and R4 have the same meanings as above. However,

In the case of a substituted benzene ring, one of m R'' and R4 is a lower alkoxy group and the other is a lower alkoxy group having 2 or more carbon atoms, or one of R1 and R4 is a hydrogen atom and the other is a lower alkoxy group. It can be produced by subjecting a 2,3-di-lower alkoxycarbonylnaphthalene compound or a salt thereof to a reductive lactonization reaction.

The reaction between the acetylene compound (n) and the aldehyde compound (1) or its di-lower alkyl acetal or its salt can be carried out without a solvent or in a suitable solvent in the presence of an acid.

As the acid used in the reaction, both inorganic acids (for example, hydrochloric acid, sulfuric acid) and organic acids (for example, formic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid) can be used, and as the solvent, benzene is used.

Toluene, xylene, dimethylformamide, etc. can be suitably used. The reaction was carried out at 0-150°C.

It is particularly preferable to carry out the reaction at a temperature of 5°C.

In addition, the reductive lactonization reaction of a 2,3-di-lower alkoxycarbonylnaphthalene compound (IT) or a salt thereof can be carried out by treating the compound with a reducing agent according to a conventional method, and then treating the product with an acid in an appropriate solvent. It can be implemented by As a reducing agent.

For example, it is preferable to use poran complex, sodium borohydride-boron trifluoride ether complex, calcium borohydride, lithium borohydride, lithium aluminum hydride, etc., while the acid is an inorganic acid (for example, hydrochloric acid-1 sulfuric acid) and organic acids (e.g. formic acid, acetic acid, methanesulfonic acid, trifluoroacetic acid)
Any of these can be used, preferably in catalytic amounts.

As a solvent for the acid treatment, lower alkanol, tetrahydrofuran, ethyl acetate, dioxane, etc. can be used, and the acid treatment can be carried out at room temperature.

Conversion of naphthalene derivative (1) to its salt.

The compound is dissolved in a suitable solvent such as an alkali metal hydroxide,
Treatment with alkaline earth metal hydroxide, quaternary ammonium hydroxide, etc. can be carried out.

Note that the di-lower compound (III) of the starting material compound (III) used in the above reaction (in the formula, s R'' and R4 have the same meanings as above)
A benzaldehyde compound represented by the following formula and a di-lower alkyl acetal of a 2-bromobenzaldehyde compound represented by the general formula (wherein ring A has the same meaning as above) are placed in a suitable solvent.

It can be produced by reacting in the presence of an alkyllithium, and if necessary, the aldehyde compound (I) can be obtained by further treating the compound with an acid.

In the present specification, "lower alkyl group", "lower alkoxy group", "lower alkylenedioxy group", and "1-lower alkoxycarbonyl group" respectively refer to an alkyl group having 1-4 carbon atoms, an alkoxy group having 1-4 carbon atoms, It represents an alkylene dioxy group having 1 or 2 carbon atoms and an alkoxycarbonyl group having 2 to 5 carbon atoms, and the group represented by the formula: ? is bonded to the adjacent naphthol ring to form 9- represented by the formula: This indicates that a hydroxynaphtho[2,3-C)furan-3(IH)-one structure is formed.

Experimental example (serum cholesterol level lowering effect and HDL-cholesterol level increasing effect) SD male and female rats body weight: 110-1705', 1
(Group of 5 animals) were given free access to feed containing 2 W/W96 cholesterol and 0.5 W/W96 sodium cholate for 4 days. After this, the control group received the above diet.

For the sample administration group, add the sample to the above feed! Oo■Z or 2゜”
The animals continued to have free access to feed added at a ratio of 96%.

Three days later, the rats were anesthetized with ether, their weight was measured, and blood was collected from the abdominal aorta. The blood was left at room temperature for 1 hour and then centrifuged to obtain serum, which was then used to determine the amount of serum cholesterol using an enzymatic method (Clinical Chemistry)! J-(Cl1
n, Chem, ), vol. 20, p. 470 (1974)
]. In addition, a riboprotein precipitation method using dextran sulfate from a portion of the serum [Canadian Journal on Biochemist! J-(Can, J,
Biochem, ), Volume 47, Page 1043 (196
9)] to separate HDL-cholesterol.

From this, the amount of HDL-cholesterol was measured by the enzymatic method described above. From this result, according to the formula below, serum cholesterol level decreased by 2! and the rate of increase in HDL-cholesterol levels.

・: Average serum cholesterol amount of control group: 152-23
0'? /dl: Average HDL-cholesterol amount of control group: 13.
6-27.6DI7dl The results are shown in Tables 1 and 2 below.

Table 1 Table 2 In addition, in the above experiment 1, the liver was removed immediately after blood collection and the weight was measured, and relative weight was calculated using the following formula in conjunction with the results of the previous body weight measurement. The average relative weight of the sample was compared with that of the control group.

The groups administered the compounds of Tables 1 and 2 did not show a substantial increase in relative weight l.

Example 1 (1) 2-bromo-3,4,5-trimethoxybenzaldehyde dimethyl acetal 204. Stir in 800 Inl of tetrahydrofuran solution of OF at -70 to -50°C.
1.55M n-butyllithium in hexane solution 4
Add 30d over a period of approximately 15 minutes. Mixed liquid -70-16
After heating at 0°C for 15 minutes, a solution of 105.5M 3,4-dimethoxybenzaldehyde in 300 rnl of tetrahydrofuran was added to the mixture at -70 to -50°C over a period of about 15 minutes. Pour the Haifu 1 reaction solution into 21 ml of water at the same temperature for 15 minutes, add 41 ml of ethyl acetate, shake, and separate the organic layer. Wash the organic layer with water.

After drying, the inorganic matter was filtered off, and the solvent was distilled off from the filtrate under reduced pressure to obtain 2-(3,4-dimethoxy-α-hydroxybenzyl)-3,4,5-)! J methoxypenzalde dimethyl acetal 2662 is obtained as a yellow oil.

NMR (CDC/,)a: 3.25 (s, 6H
), 3.80 (s, 6H).

3.89 (s, 3H), 4.05 (d, IH)
, 5.35 (s, IH).

6.20 (d, IH), 6.6-7.2 (m,
4H) IRyμKichi 1 (am-'): 3450.1
600Mass (m/e): 376 (M-
CHIOH) (2) Compound 2667 obtained in (1) above was dissolved in benzene 95-, dimethyl acetylene dicarboxylate 95- and PT toluenesulfonic acid l hydrate 300''P were added to the solution, and heated for 2 hours. Reflux. After cooling the reaction solution, the solvent was distilled off under reduced pressure, and the remaining residue was added with methanol 60 (In
/ and leave it at -30°C overnight. Filter the precipitated crystals.

By recrystallizing from ethyl acetate, 1-(3゜4-
Dimethoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6,7,8-)rimethoxynaphthalene 2029 is obtained as a colorless prism product.

m, p, 178-179°C NMR (DMSO-d@) δ: 3.21 (5!,
3H), 3.45 (a.

3H), 3.73 (s, 3H), 3.74 (s, a
) D, 3.82 (s, 3 pieces.

3.92 (s, 3B), 4.0 (s, 31
H), 6.5-7.1 (m, 3H).

7.6 (so IH), 11-12.5 (br
, IH) IRy '=”,!,” (am-') ”
173(L 166(L 1595+ 1510 Examples 2-9 Table 3 OCR.

(1-A) Note: The IR and NMR data of the compounds in Table 3 of the above collection are as follows.

Compound 1 of Example 2: IR)-pl(ax'): 1740.1660.1
620.1590.152ONMR(CDCI!s)
8: 3.58 (s, 3H), 3.76 (
s, 3H).

3.90 (8,3H), '3.99 (S,,3H
), 6.7-7.2 (m, 3H).

7.4-7.9 (m, 3H), 8.3-8.6 (m,
LH), 11-13(br, IH) Compound of Example 3: NMR (DMSO-d@+CF mcOgD)
δ 2 2.40 (3, 3H).

3.55 (S, 3H), 3.76 (s, 3H),
3.88(S, 3H)-3,95(s, 3H),
6.7-7.2 (m, 3H), 7.2-7.6
(m, 3H), 8.35 (d, IH, J=9Hz
) Compound of Example 4: IRy'(tx'): 1725.1660s
1595.1580.151ONMR (DMSO-da
) δ: 3.55 (s, 3H), 3.75 (
s, 3H).

3.85 (s, 3H), 3.95 (s, 6H),
6.7-7.8 (m, 6H) Compound of Example 5: IRy",",4"(tx'): 1730,16
60-1620, 1590+ 151ONMR(DMS
O-ds)! :3.55 (s, 3H), 3.
68 (s, 3H), 3.78 (s, 3H),
3.88 (s, 3H), 3.93 (a, 3H)
.

3,97 (s, 3H), 6.7-7.0 (m,
3H), 7.10 (d, IH.

J=8Hz), 7.66(S, IH)-1O-12
(br, IH) Compound of Example 6: IRν −-2°l (,≦;′): 1730.
1660. 1620. 1590. 151ONM
R (CDCJs) 13.55 (s, 3H), 3
．． 79 (s, 3H)-3,90 (s, 3H),
4.00 (s, 3H), 4.05 (s, 3H)
, 5.01 (s, 2H), 6.65 (s, I
H), 6.75 (s,' IH), 6.72 (
d.

IH, J=8Hz), 6.90 (d, LH, J=8Hz
), 7.20 (s, 5H), 7.70 (s, IH) Table 4 H [1-333 Note: The IR and NMR data of the compounds in Table 4 above are as follows.

Compound of Example 7: IRv4°': 1750.1660.16
20.1600.1595NMR(CDC/,)δ:
1.40 (t, 3H), 1.48 (t, 3H).

3.50 (s, 3H), 3.91 (s, 3H)
), 4.10 (q, 2H).

4.1s(q, 2H), 6. oO(s, 2H),
6.72 (s, IH).

6.78 (d, IH, J=9), 6.80 (s,
IH), 6.95 (d.

IH, J=9Hz), 7.70 (S, LH), 1
2.12(s, LH) Compound of Example 8: IR Shin2114@l(♂”): 1740.1640
．． 1620.1600.1580°1520, 150O NMR (CDC/m) 8: 1.01 (t, 3
H)-1,38(t, 3H)-1,45(t, 3H)
, 1.50(t, 3H), 4.02(q, 2H
).

4.10 (q, 2H), 4.20 (q, 2H),
4.40(q, 2H).

6.04 (s, 2H), 6.79 (s, IH),
6.82 (d, IH, J = 9Hz), 6.85
(S, LH), 6.97 (d, IH), 7.7
2 (S.

IH), 12.32(s, LH) Compound of Example 9: IRj/2H4"r,;"): 3400.167
0.1625.15B0.1540°NMR (CDCJ
! , ) δ: 0.93 (t, 3H), 1. /H(t
, 3H).

1.50 (t, 3H), 3.9-4.4 (m, 6H),
6.00 (s, 2H).

6.7-7.3 (m, 4H), 7.38 (s, IH),
7.6(s,IH) Example 10 By treating the corresponding raw material compound in the same manner as in Example 1, 1-(3,4-dimethoxyphenyl)-2,3-bis(ethoxycarbonyl)-4-hydroxy -6, 7, 8
-Trimethoxynaphthalene is obtained as colorless crystals.

m, p, 138-140°C NMR (CDC/s) a: 1.05 (t, 3
H), 1.40 (t, 3H).

3.31 (s, 3H), 3.90 (S, 3H)
, 3.95(S, 3H), 3.95(q, 2H
), 3.97(s, 3H), 4.10(s, 3
H), 445(q, 2H), 6.90(s, 3
H), 7.72(s, IH), 12.59(s
, IH) IR C2'',4''<,,;'>: 1735.172
0.1655.1590.1510Mass (m/e
): 514 ('M'') Examples 11 to 15 The corresponding raw material compounds were treated in the same manner as in Example 1.
5 Table R [I-C) Example compound [1-C)'') Chemistry property value etc. 1!ゝNew, Ring A cxsW Colorless crystal, m, p, 138-1
40℃an, , Mass (rn/e):
514 (M+) Yield: 6396. Colorless crystal 12 (', Cm-p, 169-171'CMB55
(rn/e): 410 (M+) Two formulas; [yield near 996. Colorless needle crystals 13 m, p,
132℃ pale yellow prism crystal 14) $ m, p, 228-229℃ □
Mass (m/e): 440 (M
') 15 -jC7N Colorless prism crystal Note 1 = Among the examples in Table 5 above, in Example 11, I R'' and R4 are ethoxy groups; in Example 12, a R'' is a hydrogen atom J R' is Methoxy group; Example 1
In Examples 14 and 15, +R'' and R4 are methoxy groups.

Note 2: The IR and NMR data of the compounds in Table 5 above are as follows.

Compound of Example ti: IRv2-4''<,,'>: 1740.1660
．． 1590.151ONMR (CDC/,) a:
1.05 (t, 3H), 1.40 (t, 3
H).

3.31 (S, tsu'H), 3.90 (s,
3H), 3.95(s, 3H).

3.97 (s, 3H), 4.10 (s, 3H),
4.15(q, 2H).

420 (q, 2H), 6.7-7.0 (m, 3H
), 7.69 (s, IH).

12.36 (S, LH) Compound of Example 12: IRv:'! ”(c;'): 1740.1660.
1610.152ONMR (CDCJ,) δ: 3.5
5 (s, 3H), 3.88 (s, 3H).

3.95 (S, 3H), 6.03 (S, 2H),
6.72 (s, IH).

6.9-7.4 (m-4H), 7.75 (s, IH),
12.20(s, IH) Compound of Example 13: IRv Nuj0'(ai'): 1740.166
0.1570.151ONMR(CD(IJ-δ: 0
．． 99 (t, 3H), 1.05 (t, 3H)
.

1.6~2.1 (@4H), 3.21 (s, 3
H), 3.42 (s, 3H) 3.73 (s, 3
H), 3.77 (s, 3H), 3.89 (s
, 3H)=3.8-4.2 (m, 4H), 6.
74 (s, IH), 6.76 (!1.2H).

7.59 (s, IH), 12.25 (s, IH)
Example 14 IRII Knee 4", (cm'): 1730.
1659. 1630. 1590. 1510(
br) NMR (DMSO-d,) δ: 3.50 (s, 3
H), 3.74 (s, 3H).

3.82 (s, 3H), 3.91 (s, 3H),
5.92 (s, 2H).

6.7-7.05 (m, 3H), 7.40 (d,
IH,J = 9Hz), 8.05(d, IH,J
= 9 Hz) Example 15 IRv2-3''(I;'): 1730.1660.
1605.1580.151ONMR (DMSO-d,
) a: 3.50 (s, 3H), 3.75
(s, 3H).

3.85 (S, 3H), 3.95 (S, 3H), 6.
6-7.1 (m, 3H).

7.80 ((1,1H, J=9Hz), 8.4 (
d, IH, J = 9HzLL1.98 (s, IH) Example 16 By treating the corresponding raw material compound in the same manner as in Example 1, 1-(3,4-jethoxyphenyl)-2-methoxycarbonyl-4 -Hydroxy-6,7-methylenedioxynaphthalene is obtained as colorless crystals. Further recrystallization of Honjima from methanol yields colorless needle crystals.

m, p, 189-190°C NMR (CDCjs) δ: 1.38 (t, 3H),
1.44 (t, 3H).

3.53 (s, 3H), 4.05 (C1,2H
), 4-13 (Q, 2H).

5.93 (S, 2H), 6.6-7.0 (m,
4H), 7.21 (S, IH).

7.50 (S, IH) Example 17 1-(3,4-dimethoxyphenyl)-2,3-bis(
0.77 g of (methoxycarbonyl)-4-hydroxy-7-methylnaphthalene is dissolved in 30 g of tetrahydrofuran. Add 0.24771/ml of borane-methyl sulfide complex to the solution and heat under reflux for 4 hours. After cooling the reaction solution, it was concentrated under reduced pressure, and the residue was dissolved in 300 J of methanol to which 1 drop of trifluoroacetic acid had been added, and the mixture was left to stand at room temperature for 12 hours to obtain 1-(3゜4-dimethoxyphenyl).
-3-Hydroxymethyl-4-hydroxy-7-methyl-2-naphthoic acid lactone 450 Mi is obtained as colorless needles.

Yield near 696 m-p, 234-236°C NMR (DMSO-d,)! : 2.4 (s, 3
H), 3.75 (s, 3H).

3.89 (S, 3H), 5.40 (S, 2H),
6.7-8.4 (m, 6H).

10.2-10.7 (br, IH) IRv2:4”
(am'): 3500.1730.1660.16
20.1590゜Mass (mie): 350
(M) Examples 18 to 27 The corresponding raw material compounds were treated in the same manner as in Example 17.
6 Table 1'MJ (ID) Note: IR and NMR data for the compounds in Table 6 above are as follows.

Compound of Example 18: IRνN"ol(011'): 1740.1630
．． 1600.152001m! NMR (DMSO-d,) a: 3.77 (S, 3H
), 3.90 (3,3H).

5.46 (s, 2H), 6.8-7.3 (m,
3H), 7.4-7.9 (m, 3H).

8.3-8.5 (m, IH) Compound of Example 19: IR Cy': 2°1 (Rho'): 3200.174
0.1620.1580.152ONMR(DMSO-
d,) δ: 3.69 (s, 3H), 3.90
(s, 3H).

4.00 (s, 3H) e5.45 (s, 2H),
6.8-7.3 (m, 4H).

7.6-7.9 (Turtle 2H) Compound of Example 20: IRνN month"(an-'): 3200.1740
．． 1720.16201600, 1590.154O NMR (DMSO-city) δ: 3.22 (s, 3H)
, 3.71 (s, 3H) 3.80 (s, 3H), 3
．． 82 (s, 3H), 4.00 (s, 3H), 5.35
(s, 2H), 6°6-7.1 (m, 3H),
7.55 (s, LH).

10.45 (S, IH) Compound of Example 21: IRu9j''(,,;'): 3420.1730
．． 1620.1590.1540゜''51O NMR (DMSO-da) δ: 3.75 (S, 3H
), 3.85 (L 3H).

5.35 (s, 2H), 5.91 (s, 2H),
6.0-7.1 (m, 3H).

7.40 (d, IH, J=8Hz), 8.00 (
d, LH, J=8Hz) ・10-11 (br,
IH) Compound of Example 22: NMR (DMSO-ds) 8: 3.75 (s,
3H), 3.91 (s, 3H).

4.00 (s, 3H), 5.00 (s, 2H
), 5.38 (s, 2H), 6.6-7.1 (
m, 4H), 7.30 (3,5H), 7.65 (
S, IH).

10.0-10.6 (br, IH) 7th
Table H (1-E) Note: IR and NMR data for the compounds in Table 7 above are as follows.

Compound of Example 23: IRνN month''(ts'): 3300.1760.1
630.1580.1540°1520, 150O N MR (DM So -di) δ: 1.31
(t, 3H), 1.40 (t, 3H).

4.05 (q, 2H), 4.10 (q, 2H)
, 5.35 (s, 2H), 6.15 (s, 2H
), 6.89 (s, IH), 6.6-7.2 (m, 3H
).

7.6 (S, IH), 10.31 (S, IH) Compound of Example 24: IRνN"jol(cs'): 3150.1720
．． 1620.1540.152ONMR(DMSO-d
@) 8: 3.89 (s, 3H), 5.3
9 (S, 2H).

6.18 (s, 2H), 6.85 (s, IH
), 7.0-7.4 (m, 4H).

7.65 (s, IH) Table 8 GJ (I-F) Note 2 Among the examples in Table 8 above, in Example 25 R1 and R4 are ethoxy groups; in Example 26 R
'' and R4 are methoxy groups; in Example 27, R1 and R4 are propoxy groups.

Note 2 = IR and NMR data of the compounds in Table 8 above are as follows.

Compound of Example 25: IRν""' (czar): 3300.1760
．． 1605.150ONMR(DMSC)di)δ:
1.32 (t, 3H), 1.40 (t, 3H
).

3.22 (s, 3H), 3.81 (s, 3H
), 4.01 (s, 3H), 4.03 (q,
2H), 4.11 (q, 2H), 5.35
(s, 2H), 6.6-7.0 (m, 3H),
7.56 O, lH), 1.0.40 (brs,
IH) Compound of Example 26: IRν=2"(am")' 3200.1725.1
620.1595.151ONMR (DMSO-d,)
8: 3.64 (s, 3H), 3-79 (s, 3H).

5.30 (s, 2H), 6.5-7.0 (m, 3H),
7.65 (d, LH.

J=9Hz), 8.25(d, IRJ=9Hz),
10.85 (brs, LH) Compound of Example 27: NMR (CDCZ, + DMSO-d,) δ: 0.9
9 (t, 3H).

104 (t, 3H), 1.6-2.1 (m, 4
H), 3.26(s, 3H).

3.85 (s, 3H), 3.95 (s, 3H)
), 3.7-42 (m, 4H).

5.25 (S, 2H), 6.75 (S, 2H
), 6.80 (S, IH).

7.49 (S, IH), 9.50 (broa
dS, IH) Examples 28 and 29 Table 9 r■2 (1-G) Note: The NMR data of the compounds in Table 9 above are as follows.

Compound of Example 28: NMR (CDCI!s) 8: 1.31 (t,
3H), 3.22 (s, 3H).

3.41 (s, 3H), 3.80 (s, 3H),
3.87 (s, 3H).

3.90 (s, 3H), 4.00 (s, 3H),
4.35(q, 2H).

6.76 (8,3H), 7.60 (S, IH),
12.42 (s, IH).

Compound of Example 29: NMR (CDCI!,) δ: 1.03 (t, 3H)
, 3.22(s, 3H).

3.80 (s, 3H), 3.85 (s, 3H)
, 3.87 (s, 6H).

3.90 (q, 2H), 3.98 (s, 3H),
6.77 (s, 3H).

7.59 (S, IH), 12.29 (S, IH)
Example 30 By treating the corresponding raw material compound in the same manner as in Example 1, 1-(3-methoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6°7-methylenedioxynaphthalene was produced. obtain.

m, p, 152-154°C NMR (DMSO-ds) a' 3.5 (S
= 3H) -3,80(-s, 3H).

3.90 (s, 3H), 6.15 (s, 2H),
6.60 (s, IH).

6.7-6.9 (m, 2H), 6.9-7.2
(m, IH), 7.4 (d, IH).

7.57 (s, LH), 11-12 (br, IH
) IRI/N""(am'): 1730.1660
．． 1610.1600Mass (m/e): 41
0 (M+) Example 31 By treating the corresponding raw material compound in the same manner as in Example 1, 1-(3,4-diisopropoxyphenyl)-2,3
-bis(ethoxycarbonyl)-4-hydroxy-6,
7-methylenedioxynaphthalene is obtained.

Yield: 5196 m, I), 123-124°C NMR (DMSO-d,)! : 0.94(t, 3H
), 1°35 (t, 3H).

1.30 (d, 6H), 1.36 (d, 6H), 3.
96(q, 2H).

4.3s (q, 2H), 4.3-4.7 (m, 2H)
, 6.09 (8,2H).

6.6-7.1 (m, 4H), 7.55 (s, IH),
12.19 (s, IH).

Mass (m/e): 524 (M) Example 32 The corresponding raw material compound was treated in the same manner as in Example 17,
1.1-(3-methoxyphenyl)-3-hydroxymethyl-4-hydroxy-6,7-methylenedioxy-2
- Obtain naphthoic acid lactone. Yield: m, I), 275
°C (decomposition) NMR (DMSO-d,) 8: 3.80 (8,
3H), 5.40 (8,2H).

6.15 (s, 2H), 6.80 (s, IH
), 6.8-7.2 (m, 3H).

7.4 (d, IH), 7.65 (s, IH),
11.4(br s, LH)IRν=;x” (d”
) ” 3200.1740-1720s 1620
-1600.

1590, 1540 Mass (m/e): 350 (M+) Example 33 By treating the corresponding raw material compound once in the same manner as in Example 17, 1-(3,4-diisopropoxyphenyl)-3
-Hydroxymethyl-4-hydroxy-6°7-methylenedioxy-2-naphthoic acid lactone is obtained. Yield: 8
296 m, I), 223°C NMR (CDC/,)! : 1.33 (d, 6
H), 1.40 (d, 6H).

43-4.8(m, 2H), 5.33(s, 2H
), 6.02 (s, 2H).

6.7-7.1 (m, 4H), 7.64 (s,
IH), 8-10 (br, IH) Example 34 By treating the corresponding raw material compound in the same manner as in Example 1, 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxycarbonyl) - 4,7-dihydroxy-6
-1.52 of methoxynaphthalene are obtained.

m, p, 231°C (min. NMR (DMSO-d,) a: 3.5 (s,
3H), 3.74 (s, 3H).

3.82 (s, 3H), 3.90 (s, 3H)
), 3.95 (s, 3H).

6.6-7.1 (m, 4H), 7.61 (S, IH
), 9.7~10.4 (br, IH) IR1/::4"(ca+'): 3400.173
0.1650, 1620.1600°1590.158
0.1510 Example 35 By treating the corresponding raw material compound in the same manner as in Example [7], 1-(3,4-dimethoxyphenyl)-3-hydroxymethyl-4,7-sihydroxy-6-methoxy2
- Naphthoic acid lactone is obtained as colorless fine needles.

m-p, > 270°C NMR (DMS O-d@) 8' 3.77 ($
-3H) -3,89(S-3H)-3,99(s,
3H), 5.35(s, 2H), 6.7-7.3
(Kame 4H).

7.6 (S', IH), 9゜O-11,5 (br
, 2H)IRy::4”(am'): 3420.
1750.1620.1600.1580 (sharp
), tsi.

Mass (m/e): 382 (M) Example 36 By treating the corresponding raw material compound in the same manner as in Example 1, 1-(3-methoxy-4-ethoxyphenyl)-2,
3-bis(methoxycarbonyl)-4-hydroxy-6
, 7,8-)rimethoxynaphthalene as colorless needles. Yield: 67% m-p, 159°C NMR (CDC/,) δ: 1.47 (t, 3H),
3.22 (s, 3H).

3.42 (s, 3H), 3.80 (s, 3H),
3.85 (s, 3H).

3.87 (s, 3H), 4.00 (s, 3H),
4.12 (Q, 2H) = 6.75 (s, 3H)
, 7.56(s, LH), 12.21(s, I
H).

IRj2:4@1(cii”): 1730.171
0.1660.1590.1510 Example 37 By treating the corresponding raw material compound in the same manner as in Example 1, 1-(3-ethoxy-4-methoxyphenyl)-2,
3-bis(methoxycarbonyl)-4-hydroxy-6
, 7,8-trimethoxynaphthalene is obtained as colorless needles. Yield: 65% m-p, 158°C NMR (CDCI!,) δ: 3.42 (t, 3H)
, 3.22(s, 3H).

3.45 (s, 3H), 3.85 (s, 3H),
3.89 (r,, 3H).

3.98 (s, 3H), 4.08 (q, 2H), 6.7
6 (s, 3H).

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is hydrogen, an atom, or a lower alkoxycarbonyl group, R^2 is a lower alkoxycarbonyl group, or R^1 and R^2 are combined with each other to form the formula: ▲ Formula,
There are chemical formulas, tables, etc. This indicates that a group shown by ▼ is formed, and R^1^0 and R^4 are lower alkoxy groups, or one of R^2 and R^4 is a hydrogen atom. ,
The other is a lower alkoxy group, and Ring A represents a substituted or unsubstituted benzene ring. However, a) R^1 and R^2 are both methoxycarbonyl groups,
Is ring A a substituted benzene ring represented by the formula: ▲ Numerical formula, chemical formula, table, etc.? b) R^1 is a hydrogen atom, R^2 is an ethoxycarbonyl group, Ring A is a formula: ▲ Numerical formula, There are chemical formulas, tables, etc. ▼ Substituted benzene ring, or c) R^1 and R^2 are bonded to each other to form a group represented by the formula: ▲ Numerical formulas, chemical formulas, tables, etc. ▼ has formed,
When ring A is a substituted benzene ring represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, one of R^2 and R^4 is lower alkoxy group, the other is a lower alkoxy group having 2 or more carbon atoms, or one of R^2 and R^4 is a hydrogen atom and the other is a lower alkoxy group. ) A naphthalene derivative or a salt thereof.