JPH01301652A - Naphthalene derivative, its production and synthetic intermediate thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1>-R<7> are lower alkyl) or its pharmacologically allowable salt. EXAMPLE:1-(3, 4-Dimethoxyphenyl)-2, 3-bis(methoxycarbonyl)-4-hydro-xy-6, 7, 8-trimethoxynaphthalene. USE:A drug. A remedy for hyperlipemia. It suppresses the total cholesterol level in blood but increases HDL-cholesterol level. Preferable as a remedy and preventive for arteriosclerosis. It has high safety and can be administered without causing side effect such as hepatic function disorder (e.g. jecur adiposum) at the active dose. Dose: 5-35mg/kg-weight per day. PREPARATION:The objective compound of formula I can be produced by reacting an acetylene compound of formula II with a novel benzaldehyde compound of formula III, its di-lower alkyl acetal or its salt preferably in the presence of a solvent such as benzene and an acid catalyst such as p-toluenesulfonic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a novel naphthalene derivative having excellent antilipidemic activity, a method for producing the same, and intermediates for its synthesis.

(Prior art) Hyperlipidemia, especially hypercholesterolemia, is thought to be one of the main causes of arteriosclerosis, an adult disease. phenoxy)-2-methylpropanoic acid ethyl ester], propukol (chemical name: '4.

Antilipemic agents such as 4''-[(1-methylethylidene)bis(thio)]bis[2,6-bis(1,1-dimethylethyl)phenolcoco] are used as therapeutic and preventive agents.

Cholesterol is a very low density riboprotein (LD) in the blood.
L) Cholesterol, low-density riboprotein (LDL) cholesterol, high-density riboprotein (HDL) cholesterol, etc.; among these, V L D L and L
DL promotes the deposition of cholesterol on the arterial wall and causes arteriosclerosis, but it is known that DL actually prevents the deposition of cholesterol on the artery wall and has the effect of treating and preventing arteriosclerosis. [Δnnals of Int]
ernal Medicine), Volume 90, No. 85~
91 pages (1979)].

Therefore, in the field of treatment and prevention of arteriosclerosis, efforts have been made in recent years to reduce the total amount of cholesterol in the blood and at the same time reduce HDL.
-There is a desire for the development of antilipidemic agents that can conversely increase cholesterol levels.

Also, Journal of the Chemical Society Chemical Communications (J.

Chem, Soc, CI+em, Comm,) 3rd
54 (1980), l(3,4-dimethoxyphenyl)-2,3-bis(m-1-oxycarbonyl)-4
-Hydroxy-6,7-methylenedioxynafucrene is also used as a chemical af'tract (Chem, 8b).
s,) Volume 53 20025i (1959) 1-
Although (3,4-dimethoxyphenyl)-2-ethoxycarbonyl-4-hydroxy-6,7-simethoxynaphthalene has been described, the pharmacological effects of these compounds are so far unknown.

(Structure and Effects of the Invention) The present inventor has discovered a novel naphthalene derivative represented by the following general formula, which has a chemical structure completely different from that of known antilipemic agents and has excellent properties as an antilipemic agent. We have discovered a pharmacologically acceptable salt thereof.

(However, RI and R7 represent a lower alkyl group.) The naphthalene derivative (1) of the present invention or a pharmacologically acceptable salt thereof has an excellent antilipidemic effect, and particularly lowers the total cholesterol level in the blood. It has a desirable feature as a therapeutic/preventive agent for arteriosclerosis in that it increases HD L-cholesterol levels while decreasing HD L-cholesterol levels.

Moreover, the naphthalene derivative (1) of the present invention is highly safe, and there is no fear of side effects such as liver dysfunction (for example, fatty liver) when used in an effective amount. For example, 1000 for mouse
After oral administration of mg/kg and observation for 5 days, there were no deaths and no suppression of weight gain was observed.

As a specific example of the naphthalene derivative of the present invention, general formula (
In 1), compounds in which R1-R7 are linear or branched alkyl groups having 1 to 4 carbon atoms can be mentioned, and pharmaceutically more preferred compounds are compounds in which R1 to R7 are linear or branched alkyl groups having 1 to 3 carbon atoms.
This is a compound that is an alkyl group. Also, R1 and R2
Compounds in which is a methyl group or an ethyl group, R3 and R4 are a methyl group, an ethyl group or a propyl group, and R5 to R7 are a methyl group have particularly excellent antilipidemia effects.

The naphthalene derivative (1) of the present invention can be used for pharmaceutical purposes either in free form or as a salt thereof. Examples of the salts include alkali metal salts (e.g., sodium salts, potassium salts), alkaline earth metal salts (e.g., calcium salts), quaternary ammonium salts (e.g., te-1-ramethylammonium salts, tetraedylammonium salts). ), etc.

The naphthalene derivative (1) of the present invention and its salt can be used to treat hyperlipidemia (e.g., hypercholesterolemia), arteriosclerosis (e.g., atherosclerosis, Menga-Herck's arteriosclerosis)
The administration method may be either oral or parenteral administration. The dosage depends on the type and severity of the disease; the age, weight, and condition of the patient, but it is usually 1.5 mg per day. Preferably it is between 5 and 35 mg/kg, especially between 5 and 25 mg/kg.

According to the present invention, the naphthalene derivative (1) is an acetylene compound represented by the general formula (% formula %) (wherein B+ and R2 have the same meanings as above) and a general formula (wherein R3-R7 are the same as above). It can be produced by reacting an aldehyde compound represented by (having the same meaning as ), its di-lower al-)-acecool, or a salt thereof.

Acetylene compound (II) and aldehyde compound (■),
The reaction with di-lower alkyl acecul or a salt thereof can be suitably carried out in the presence of an acid. As the dialkyl acecule of the aldehyde compound (III), any one acetalized with an alkyl group having 1 to 4 carbon atoms can be suitably used;
As the salt of III) or its di-lower alkyl acecure, alkali metal salts, alkaline earth metal salts, etc. can be used as appropriate. Examples of acids include inorganic acids (e.g., hydrochloric acid,
Sulfuric acid) and organic acids (eg, formic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid) can both be used. The reaction can be carried out without solvent or in a suitable solvent (e.g.
Preferably, the reaction is carried out in a solution of 50 to 100° C., for example 0 to 150° C., preferably 50 to 100.degree.

As shown in the following formula, the aldehyde compound (I[[) is in an equilibrium relationship with the phthalane compound (IA), but the same target product can be obtained from either compound.

(III) (1-A) (However, Il
l to R7 have the same meanings as above. ) Also, according to the present invention, if desired, the generated naphthalene derivative (I)
for example, alkali metals (e.g. sodium metal,
The lower alkyl group at the carboxylic acid ester moiety can also be converted to another lower alkyl group by reacting with a lower alkanol in the presence of metallic potassium).

The raw material compound (III) and its di-lower alkyl acetal used in the above reaction are a henzaldehyde compound represented by the general formula (wherein R3 and R' have the same meanings as above) and a henzaldehyde compound represented by the general formula (however, R5
~R7 has the same meaning as above. It can be produced by reacting the 2-promohenzaldehyde compound shown in ) with a C-grade alkyl acecure in an appropriate solvent in the presence of an alkyl lithium, and optionally treating with an acid.

Experimental example (serum cholesterol level lowering effect and HD L-cholesterol level increasing effect) Male and female SD rats body weight = 110 to 170 g.

(5 animals per group) were allowed to freely consume a diet containing 2 w/w% cholesterol and 0.5% w/w sodium cholate for 4 days. After this, the control group received the above feed, and the sample administration group received 20 m of the test compound listed in Table 1 below.
The animals continued to receive ad libitum feed mixed with g% or 100+ng%. After 3 days, the rats were anesthetized with ether and
Body weight was measured and blood was collected from the abdominal aorta. After leaving the blood at room temperature for 1 hour, it was centrifuged to obtain serum, and the amount of serum cholesterol was measured using the enzyme method C Clinical Chemistry (CI in, Chem), Vol. 20, p. 470 (1).
974)]. On the other hand, the amount of HDL-cholesterol was determined by precipitating and removing LDL- and LDL-cholesterol in the above serum using dextran sulfate [Canadian Journal of Biochemistry (Can, J.

Biochem, ), vol. 47, p. 1000 (1969
)), ](] DL-cholesterol was measured by the above enzymatic method. Based on these experimental results, according to the following formula:
Serum cholesterol lowering rate and HD L- of test compound
The cholesterol increase rate was determined.

*: Average serum cholesterol of control group! ;152-23
0tng/d1 **: Average HDLD cholesterol of control group; 13°6-27.6/a The results of the experiment are shown in Table 1 below.

Table 1 *: Rate of decrease in serum cholesterol *: Rate of increase in HDL-cholesterol In addition, in the above experiment, the liver was removed immediately after blood collection,
The liver weight was measured, and the relative liver weight (liver weight The group administered with the test compounds listed in the table showed no substantial increase in relative liver weight.

Example 1 (1) 2-bromo-3,4,5-trinotoxyhenzaldehyde dimethylacecool 20/1. 800 ml of tetrahydrofuran solution of Og was pressed down, -7(]-
At −50° C., 430 d of a 1.55 M n-butyllithium solution in hexane is added over about 15 minutes. Mixed liquid -
Stir extrusion at 70 to -60°C for 15 minutes, and add 3.
A solution of 105.5 g of 4-dimethoxyhenzaldehyde in 300 ml of tetrahydrofuran is added over a period of about 15 minutes at -70 to -50°C. After extrusion at the same temperature for 15 minutes, the reaction solution was poured into water 22°C, ethyl acetate was added at 4°C, and after shaking, the right layer a was separated. After washing the organic layer with water and drying, inorganic substances were removed by filtration, and the solvent was distilled off from the filtrate under reduced pressure to obtain 2-(3,4-dimethoxy-α-human 1koxyhenzyl)-3,4,5-tri 266 g of methoxyhenzaldehyde dimethylacecool are obtained as a yellow oil.

NMR (CDCI!, 3) δ: 3.26 (
s, 31(), 3.28 ('s, 3H), 3.5
3 (s, 3l-1), 3.82 (s, 3H),
3.85 (s, 6H), 3.89 (s, 3H)
, 4.08 (d, LH), 5.35 (s,
IH), 6. 16 (d, 1) 1), 6.6~
7. 2 (m, 4H) Ma s s (m/
e): 376 (M'-CIl:tol+
) (2) 266 g of the product from (1) above was heated to 95 m
2, and 95d of acetylene dicarboxylic acid dimethyl ester and 300 mg of p-h luenesulfonic acid monohydrate were added to the solution, and the mixture was heated under reflux for 2 hours.

After cooling the reaction solution, the solvent was distilled off under reduced pressure, and methanol 6 was added to the residue.
Add 0.00% and leave it at -30°C overnight.

By filtering the extrudate and recrystallizing it from ethyl acetate, 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6,7,8
- 7202 g of trimethoxynafukure are obtained as colorless prismatic crystals.

M, p, 178-179°C NMR (DMSO-d,) δ: 3. 21
(s, 3 ト■) , 3, 45 (s, 3
H), 3. 73 (s, 3H), 3, 74
(s, 31(), 3.82 (s, 3H)
, 3.92 (s, 3H), 4.0 (s, 3H)
, 6.5-7. 1 (m, 3H), 7.6 (s
, LH) 1 1-12. 5 (br, IH
) (3) A suspension of 0.38'7 g of 62.5% sodium hydride in 10 m2 of te-1-rahydrofuran was thus pressed down, and the above (
4.86 g of the product of 2) 100 g of tetrahydrofuran
ml solution at room temperature and stirred at the same temperature for 1 hour.

After the reaction, the solvent was distilled off under reduced pressure at 30°C or below, and the residue was powdered with petroleum ether to give 1-(3,4-dimethoxyphenyl)-2,3-bis(methquincarbonyl)-4-. 4.8 g of hydroxy-6,7,8-trif 1-kidinaphthalene nat/rum salt is obtained as a powder.

Example 2 (1) After washing 4.8 g of 60% sodium hydride with petroleum ether, 70 g of N,N-dimethylbormamide was added thereto, and further ice-cooled, calyx pressed, and 3.4-dihydroxyhenzaldehyde. 7g of N.

A solution of N-dimethylformamide 20 is added over a period of 15 minutes. Push out at the same temperature for 15 minutes, and then iodide n-
50 g of propyl was added over 15 minutes, extruded at room temperature for 12 hours, and the solution was distilled off under reduced pressure. The residue is extracted with ether, washed with water and dried, the inorganic substances are filtered off, and the solvent is distilled off from the filtrate under reduced pressure to obtain 8.5 g of 3,4-diproboxyhenzaldehyde as a pale yellow residue.

B, p, 130-136 °C (0,2 mml-Ig) (
2) The product of (1) above, 2-bromo-3,4,5-trimethoxyhenzaldehyde dimethyl acecool and acetylene dicarboxylic acid dimethyl ester, was prepared in Example 1-
By processing in the same way as (1) and (2), 1-(
3,4-dipropoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroc1-cy6.7.8-
Trimethoxynaphthalene is obtained as colorless crystals.

M, P, J 32°C Examples 3 to 5 (1) Compounds listed in Table 2 below are obtained by treating the corresponding raw material compounds in the same manner as in Example 1 (1).

Table 2*: The NMR data of the compounds listed in Table 2 above are as follows.

[Compound of Example 3-O)] NMR (DMSC-d6) δ: 1.26 (t, 3H)
, 2.8.9 (s, 3H) , 3. ' 26(s, 3
H), 3.61 (s, 3H), 3°68 (s,
3H), 3.74 (s, 31(), 3.78 (s,
3+-1), 3.93 (q, 2l-1), 5.49
(s, IH), 3.58 (d.

IH, J=5Hz), 6.11 (d, LH), 6.5
~7.0 (m, 4H) [Compound of Example 5-(])] NMR (DMSC)-d6) δ: 1. ．． 27(t, 6H
), 2.86 (s, 3H), 3.27 (,s,
3H), 3. 60 (s, 3H
), 3°74 (s, 3H), 3.76 (s
, 3H), 3.89 ((1,2H), 3.94 (C
1,2H), 5.48 (s, IH), 3.58 (d
.

IH, J=5Hz), 6.10 (d, IH), 6.5
~7.0 (m, 4H) **; Physical property values were not measured (subjected to next step.

(2) The product of (1) above is treated in the same manner as in Example 1-(2) to obtain the compounds listed in Table 3 below.

Table 3 Example 6 2-(3,4-dimethoxy-α-hydroxyhendyl)
-3,4,5-1-rime 1-this)-shenzaldehyde dimethyl acecool and acetylene dicarboxylic acid diethyl ester were treated in the same manner as in Example 1-(2), and 1-
(3,4-dimethoxyphenyl)-2,3-bis(ethoxycarbonyl)-1-L droxy-6,7,8-trimethoxynaphthalene is obtained as colorless crystals.

M, p, 138-140°C NMRCCDC1,3) δ: 1.05 (t, 3H)
, 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, 3H), 4.45 (q, 2H),
6.90 (s, 3H), 7.72. (s, LH), 1
2.59 (s, IH) 1590.1510 Mass (m/e): 514 (M”
) Example 7 l-(3,4-dimethoxyphenyl)-2,3-his(
methoxycarbonyl)-4-hydroquine-6,7,8-
Add 9.72 g of trimethoxynaphthalene to a solution of 2.76 g of trimethoxynaphthalene and 500 ml of ethanol,
Heat to reflux for an hour. After cooling, 7.2 ml of acetic acid was added to the reaction solution, and the solvent was distilled off under reduced pressure.

The residue was dissolved in 200 ml of chloroborum, washed with water, dried, and then the inorganic substances were removed by filtration, and the solvent was distilled off from the filtrate under reduced pressure. By further recrystallizing the residue from ethyl acetate, ], −
(]3.4-dimethoxyphenyl-2-methoxycarbonyl-3-ethoxycarbonyl-4-hydroxy-6,
7.2 g of 7,8-1-rimethoxynafucrene are obtained as colorless prismatic crystals.

M, p, 151-152°C Example 8 l-(3,4-dimethoxyphenyl)-2,3-hys(ethny-1-dicarbonyl-6, 7,8-1-rimethoxynaphculene and methanol) By processing in the same manner as in Example 7, 1-(3.
4-dimethoxyphenyl)-2-ethco-1-dicarbonyl-hydroxy-6,7.8-trimethoxynaphthalene is obtained as colorless prismatic crystals.

M. p. 157-159°C

Claims (1)

[Claims] 1. Naphthalene derivatives represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (wherein R^1 to R^7 represent lower alkyl groups) or their pharmacologically acceptable Urushio. 2. The naphthalene derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein R^1 to R^7 are alkyl groups having 1 to 3 carbon atoms. 3, R^1 and R^2 are methyl group or ethyl group, R^3
and R^4 is a methyl group, ethyl group or propyl group, R^
The naphthalene derivative or a pharmacologically acceptable salt thereof according to claim 2, wherein 5 to R^7 are methyl groups. 4,1-(3,4-dimethoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6,7,
8-Trimethoxynaphthalene or a pharmacologically acceptable salt thereof. 5,1-(3,4-dimethoxyphenyl)-2,3-bis(ethoxycarbonyl)-4-hydroxy-6,7,
8-Trimethoxynaphthalene or a pharmacologically acceptable salt thereof. 6. Benzaldehyde compound or its di-lower alkyl acetal or its salt represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^3 to R^7 represent lower alkyl groups.) 7. General formula R^1_2OC-C≡C-CO_2R^2 (However, R^1 and R^2 represent lower alkyl groups.)
Acetylene compounds represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ that are characterized by reacting with and, if necessary, converting the product into a pharmacologically acceptable salt. (However, R^1 to R^7 are lower grade (represents an alkyl group) or a pharmaceutically acceptable salt thereof.