DD261786A5 - PROCESS FOR THE PREPARATION OF NAPHTHALIN DERIVATIVES - Google Patents

Abstract

The invention relates to the preparation of naphthalene derivatives of general formula (I) and pharmaceutically acceptable salts thereof. The naphthalene derivatives (I) and their salts have excellent hypolipidemic activity and are suitable for the treatment or prophylaxis of hyperlipidaemia and / or arteriosclerosis. Formula (I)

Description

The invention relates to a process for the preparation of naphthalene derivatives which are valuable hypolipidemic agents.

CHARACTERISTICS OF THE KNOWN TECHNICAL SOLUTION :

Hyperlipemia / as hypercholesterolemia, they are known to be the major risk factors for arteriosclerosis, including atherosclerosis, and as hyperlipemic agents are already drugs, such as clofibrate (chemical name: 2- (4-chlorophenoxy) -2-methylpropansäureethylester), probucol (chemical name: 4, 4 '- / T1 -methylethylidene) bis (thio) _7bis / 2, 6-bis (1, 1-dimethylethyl) phenol) and cholestyramine resin.

It is known that cholesterol in the blood serum in

13 3.87-461472

various forms such as very low density lipoprotein (VLDL) cholesterol, low density lipoprotein (LDL) cholesterol and high density lipoprotein (HDL) cholesterol. In this context, it is also known that HDL has a therapeutic or prophylactic effect on atherosclerosis because it deposits the effect of cholesterol on the arterial wall, while VLDL and LDL induce the deposition of cholesterol and thereby cause arteriosclerosis (Annals of Internal Medicine, Vol. 90, pages 85 to 91 (1979)).

Therefore, there is a need in the art of therapy or prophylaxis of arteriosclerosis to provide hypolipidemic agents which lower the total serum cholesterol level while increasing the serum HDL-cholesterol level.

OBJECT OF THE INVENTION:

The object of the invention is therefore, "new hypolipa. To provide mixing means which have the aforementioned property.

30 PRESENTATION OF THE INVENTION OF THE INVENTION:

On the basis of investigations it was found that

the following new naphthalide derivatives of the general formula (I) 9 ^H

R "

and their pharmaceutically acceptable salts are valuable hypolipidemic agents. In this mean:

R is a hydrogen atom or lower alkoxycarbonyl and R is lower alkoxycarbonyl,

Each of the radicals R and R is lower alkoxy or one of the radicals R and R is a hydrogen atom or the other radical is lower alkoxy; and

Ring A is a substituted or unsubstituted benzene ring with the restriction that

(A)

1 2

if both radicals R and R are methoxycarbo-

nyl or the ring A is a benzene ring of the formula or

(B)

when R is a hydrogen atom, R is ethoxy

carbonyl and the ring A is a benzene ring of the formula

is

each of the radicals R ³ . and R is lower alkoxy having at least 2 carbon atoms, or one of R and R represents a hydrogen atom and the other is lower alkoxy.

The naphthalene derivatives (I) or pharmaceutically acceptable salts thereof have a strong hypolipemic activity and have a special property of increasing the serum HDL-cholesterol level while decreasing the total cholesterol level. For example, the effect of a test compound (20 mg-% dietary dose) on total cholesterol level and serum HDL-cholesterol level was studied by feeding rats with a diet enriched with cholesterol and sodium cholate. Incidentally, 1- (3,4-dimethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6,7,8-trimethoxynaphthalene of the present invention showed a 52% reduction in the total cholesterol level and an 86% increase In addition, the naphthalene derivatives of formula (I) and their pharmaceutically acceptable salts are of very low toxicity and have substantially no undesirable side effects, such as hepatic dysfunction Mice at a dose of 1,000 mg / kg of 1- (3,4-dimethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6,7,8-trimethoxynaphthalene did not die within 5 days of the mice oral administration.

Typical examples of naphthalene derivatives of the present invention are those of the formula (I), in

wherein R represents a hydrogen atom or lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl) and wherein R represents a lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl);

3 4 each of the radicals R and R means low

alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,

3 4

Butoxy) or one of R and R is a hydrogen atom and the other is lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy); and the ring A is an unsubstituted benzene ring, a benzene ring substituted with a lower alkylenedioxy group (eg, methylenedioxy, ethylenedioxy), or a benzene ring having 1 to 3 substituents selected from the group consisting of NLedrigalkyl (eg, methyl, ethyl, Propyl, isopropyl, butyl), lower alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy), phenylloweralcoxy (e.g., benzyloxy, phenethyloxy), hydroxy, and halogens (eg, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom).

Of these derivatives, preferable examples are those

1 of the formula (I) wherein R is a hydrogen atom or

a lower alkoxycarbonyl and R represents a lower alkoxycarbonyl, and each of R and

4 3

R is lower alkoxy or one of the radicals R

4 and R represents a hydrogen atom and the other lower alkoxy ^ ', and the ring A is a B.enzolring the formulas

wherein R is a hydrogen atom, a lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl) or lower alkoxy (e.g., methoxy, ethoxy, propoxy, iso);

propoxy, butoxy); R is lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl); R ^{C is} a hydrogen atom, lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl) or a phenyl lower alkyl (eg, benzyl, phenethyl); and each of R, R and R represents lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl), and each of X ^a and X is a halogen atom (eg, fluorine atom, chlorine atom, bromine atom or iodine atom).

Further preferred examples of the compound (I) are ( "" ^N , those of the formula (I) in which:

1 2 (A) each of R and R is lower alkoxycarbonyl and

3 4 (a) each of R and R is lower alkoxy,

3 4

or one of R and R is a hydrogen atom and the other is lower alkoxy, and Ring A is an unsubstituted benzene ring, a benzene ring of the formula

or a benzene ring of 1 to 3 (J.

Substituents selected from the group consisting of lower alkyl, lower alkoxy, phenyl-lower alkoxy, hydroxy and a halogen atom; or

3 4 (b) each of R and R is lower alkoxy

with at least 2 carbon atoms or

3 4

one of R and R is a hydrogen atom and the other is lower alkoxy, and Ring A is a benzene ring of the formula

χ.

or

1 2

(B) R is a hydrogen atom, R is lower alkoxycarbonyl and

3 4 (a) each of R and R is lower alkoxy

3 4

or one of the radicals R and R is a hydrogen atom and the other is low

alkoxy, and the ring A is an unsubstituted

substituted benzene ring, a benzene ring substituted with lower alkylenedioxy, a benzene ring substituted with one or three lower alkoxy groups, a benzene ring having one to three substituents

selected from the group consisting of lower alkyl and halogen atoms, or a benzene ring of the formula RO '> * z ^ wherein R ^g

R ^g O-

Hydrogen atom or phenyl-lower alkyl

and R has the meaning given above; or

3 4 (b) each of the radicals R and R is a low

alkoxy having at least 2 carbon atoms

3 4

or one of R and R is a hydrogen atom and the other is lower alkoxy, and Ring A is a benzene ring substituted with two lower alkoxy groups;

Still further preferred examples of compound (I)

are those of formula (I), wherein

1 2 each of the radicals R and R is lower alkoxy

carbonyl and

3 4

each of R and R is lower alkoxy or one of R and R is a hydrogen atom and the other is lower alkoxy, and Ring A is a benzene ring of the formulas

or

wherein R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , X ^a and X ^{b have} the meanings given above; or

^: B

 3 4

each of R ^J and R lower alkoxy having at least 2 carbon atoms

3 4

or one of R and R is a hydrogen atom and the other is lower alkoxy, and * Ring A is a benzene ring of the formula

Further preferred compounds are those of formula (I) wherein each of R and R is lower alkoxycarbonyl and each of R and R is lower alkoxy, and Ring A is a benzene ring of formula

d e f wherein R, R and R are as defined above

have is.

Further preferred examples of the compound (I) are those of the formula (I) wherein each of R and R; R ^{2 is} lower alkoxycarbonyl, and

3 4 (A) each of the radicals R and R is lower alkoxy and the ring A is a benzene ring of the formulas

'C

or Cl

means; or

each of R and R is lower alkoxy

having at least 2 carbon atoms or one

3 4

R and R represents a hydrogen atom and the other methoxy, and the ring A is a benzene ring of the formulas / O ^ _r ^> ^ ^/ ' or

Still other preferred examples of compound (I) are those of formula (I) wherein each R and R represents lower alkoxycarbonyl and each

TO

3 4 R and R are lower alkoxy and ring A is

a benzene ring of the formulas

or ΟΙ

Other preferred examples are also those of

1 2

Compound (I) wherein each of R and R represents lower alkoxycarbonyl and each R and R

4 R is lower alkoxy, and the ring A is a benzene

ring of the formula

Most preferred are compounds of formula (I),

1 2

wherein each of the radicals R and R is methoxycarbonyl or -

3 4 is ethoxycarbonyl, and R and R are both methanyl

and ring A is a benzene ring of the formula

nyl HCO

OCH.

is.

Still other preferred examples are those of the

1 2

Compound (I) wherein each of R and R is lower alkoxycarbonyl and both R and R are methoxy, and Ring A is a benzene ring of the formulas (^ C 'f *** ^ or C1'Y ^N CH.

Cl is.

to> sc

The novel compounds of the formula (I) can be prepared by reacting a compound of the formula

R ¹ -C 1 C - CR ² (II)

1 2 wherein R and R have the meanings given above

have, with an aldehyde compound of the formula

(III)

wherein R ³ , R ⁴ and ring A have the meanings given above, or a Diniedrigalkylacetal or a salt thereof condensed.

The condensation reaction of the compound (II) with an aldehyde compound (III) or its di-lower alkyl acetal or a salt thereof may be carried out in the presence of an acid in or without a solvent. Examples of the di-lower alkyl acetal of the compound (III) are dimethyl acetal, diethyl acetal, dipropyl acetal, dibutyl acetal and the like.

The salt of the aldehyde compound (III) or its lower alkyl acetal includes alkali salts (e.g., potassium salts or sodium salts) and alkaline earth salts (e.g., the calcium salt). The acid used in this reaction includes, for example, inorganic acids such as hydrochloric acid or sulfuric acid, or organic acids such as formic acid, acetic acid, p-toluenesulfonic acid or methanesulfonic acid. Benzene, toluene, xylene or dimethylformamide are solvents

suitable. The reaction is preferably carried out at a temperature between 0 and 150 ^° C., in particular at 50 to 100 ^° C.

The aldehyde compound (III) usable in the above reaction is in equilibrium with the compound (III ¹ ) as shown in the following scheme:

Here R, R and the ring A have the meanings given above. Therefore, the compound (III) includes the compound (III ¹ ) and mixtures of the compounds (III) and (III ¹ ).

In the product (I) thus obtained, if the lower alkoxycarbonyl group represented by R is identical to R, the product may be incorporated into the

Compound (I), -V in which the lower alkoxycarbonyl groups are different from each other,

convict by using the former connection with

1a 1a

a lower alkanol of the formula R -OH (where R

a lower alkyl other than R ^). Examples of lower alkanols are methanol, ethanol, propanol and butanol. Preferably, the reaction is carried out in the presence of an alkali metal, such as sodium or potassium. Furthermore, it is preferred to carry out the reaction at a temperature between 0 ^° C. and reflux temperature.

ZLi 7

If the product (I) thus obtained has at least one phenyl-lower alkoxy group in the ring A, it is possible, if desired, to convert the phenyl-lower alkoxy group into a hydroxy group by catalytic hydrogenation. The catalytic hydrogenation may, for example, in the presence of a catalyst (such as palladium-on-charcoal) at 10 to 5O ⁰ C in a hydrogen atmosphere.

The naphthalene derivative (I) of the present invention can be used as a drug either in free form or in the form of a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts are alkali salts (e.g., sodium salt, potassium salt), alkaline earth salts (e.g., calcium salt), quaternary ammonium salts (e.g., tetramethylammonium salt, tetraethylammonium salt), and the like. Such salts are readily obtained by conventional means, e.g. by reacting the naphthalene derivative (I) with an alkaline agent such as an alkali hydroxide (e.g., sodium hydroxide, potassium hydroxide) or alkaline earth hydroxide (e.g., calcium hydroxide) or a quaternary ammonium hydroxide (e.g., tetramethylammonium hydroxide or tetraethylammonium hydroxide) and the like in a solvent.

As starting compounds, the pi-lower alkyl acetal of the compound (III) can be prepared, for example, by reacting an aldehyde compound of the formula

CHO

(V)

3 4

wherein R and R have the meanings given above, with an Aceta! compound of the formula

CHOIR )

[VI)

wherein R is lower alkyl and the ring A has the meaning given above, is reacted. If desired, the di-lower alkyl acetal of the compound (III) thus obtained may be converted to the aldehyde compound (III) by treating the former compound with an acid.

Alternatively, the aldehyde compound (III) in which the ring A is a benzene ring of the formulas or R

R ^e 0

wherein R ^d , R ^e and R ^f

have the meanings given above, for example, by preparing the compound (V) with a compound of the formula

CH = NR

wherein the ring B "is a benzene ring of the formulas

or

is and R

R ^e and R ^f the

previously given meanings, implemented.

The reaction of the compound (V) with the compound VI or VII can be carried out in the presence of an alkyl lithium in a solvent at a temperature between -100 ⁰ C and reflux temperature. The conversion of the di-lower alkyl acetal of the compound (III) to the free aldehyde compound (III) can be carried out by reacting the di-lower alkyl acetal with an acid (eg, hydrochloric acid or trifluoroacetic acid) in a solvent (eg, aqueous methanol or aqueous ethanol) at 0 to 3 0 ⁰ C treated.

As already mentioned, the naphthalene derivatives (I) and their pharmaceutically acceptable salts have potent hypolipidemic activity. In particular, the naphthalene derivatives (I) or their salts are characterized by lowering the total serum cholesterol level while increasing blood serum HDL cholesterol level. Therefore, the naphthalene derivatives (I) and their salts are effective agents for the treatment or prophylaxis of hyperlipidemia (e.g., hypercholesterolemia) or arteriosclerosis (including atherosclerosis, Mönkeberg's sclerosis, and arteriolosclerosis) in warm-blooded animals, including humans.

The daily dose of the naphthalene derivative (I) or a pharmaceutically acceptable salt thereof may vary widely and depends on the severity of the disease, the age, weight and condition of the patient, etc., with preferred daily doses generally being Range of 1.5 to 35 mg, especially 5 to 25 mg per kg of body weight.

The naphthalene derivative (I) or a pharmaceutically acceptable salt thereof may be administered orally or parenterally to warm-blooded animals, including humans, preferably selecting the oral route. One may use a naphthalene derivative (I) or a salt thereof in a pharmaceutical composition in admixture with a pharmaceutically acceptable adjuvant or carrier. For example, a pharmaceutical composition for oral administration may be in solid dosage form in the form of tablets, pills, powders, capsules or granules and may contain as pharmaceutically acceptable adjuvant or carrier calcium carbonate, calcium phosphate, corn starch, potato starch, sugar, lactose, talc, magnesium stearate and the like. In addition, the pharmaceutical composition of the solid form may also contain binders, diluents, disintegrants, humectants and the like. Alternatively, a pharmaceutical composition for oral administration may also be in a liquid dosage form such as an aqueous or oily suspension, solution, syrup, elixir or the like. Suitable adjuvants for a liquid dosage form include liquid carriers, suspending agents, surfactants, as well as non-liquid carriers and the like. Furthermore, one may formulate the pharmaceutical compositions for parenteral administration as injections or suppositories. The injections may be in the form of a solution or suspension and may contain a pharmaceutically acceptable carrier such as an essential oil (e.g., peanut oil, corn oil) or an aprotic solvent (e.g., polyethylene glycol, polypropylene glycol, lanolin or coconut oil).

/ \ Ci loh vu η ? > ce '-> | ^{? e} - ^e

Practical and presently preferred embodiments of the invention are shown in the following experiments and examples.

In the specification and in the claims, "lower alkyl", "lower alkoxy", "lower alkoxycarbonyl" and "lower alkylenedioxy" respectively denote alkyl groups of 1 to 4 carbon atoms, alkoxy groups of 1 to 4 carbon atoms, alkoxycarbonyl groups of 2 to 5 carbon atoms and alkylenedioxy groups of 1 or 2 carbon atoms.

ATTEMPT

Effect on total cholesterol level and serum HDL-cholesterol level

Male SD rats (body weight 110 to 170 g, one group each consisting of 5 rats) were fed ad libitum for 4 days with a diet of 2 W / W% cholesterol and 0.5 W / W% sodium cholate. Then the. Ad libitum rats were fed the same diet containing 100 mg% and 20 mg% of the test compound, respectively. Further, a control group of the rats was fed with a diet which did not contain the test compound. Three days later, the rats were anesthetized with ether. After the body weight of the rats was measured, blood was collected from the abdominal aorta. The blood was allowed to stand at room temperature for 1 hour and then centrifuged. Then, the total cholesterol level in the serum thus obtained was measured enzymatically by the method described in Clinical Chemistry, Vol. 20, page 470 (1974). Serum HDL cholesterol was from the other species

of cholesterol according to the lipoprotein sedimentation method using dextran sulfate (Canadian Journal of Biochemistry, Vol. 47, page 1043 (1969)) and measured enzymatically by the aforementioned method. Based on the results obtained, the effects of the test compounds on the serum total cholesterol level and on the serum HDL-cholesterol level were then calculated according to the following formula:

(percentage decrease in serum total cholesterol level)

1 -

average value of serum total cholesterol level in the treated group average value of serum total cholesterol level in the control group * _

χ 100

(percentage increase in serum HDL cholesterol level)

- Average value of serum HDL-cholesterol level in the treated

group

average value of the serum HDL cholesterol level at the control

"group**

- 1

χ

Annotation: *

Mean serum total cholesterol level in the control group was 152-230 mg / dl;

** Mean serum HDL cholesterol level in the control group was 13.6 to 27.6 mg / dl.

The results are shown in Table 1 and Table 2.

TABLE 1

Test compound (amount in the diet: 20 mg%) Decrease (%) in serum total cholesterol level Increase (%) in serum HDL cholesterol level 1- (3,4-Dimethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6,7,8-trimethoxynaphthalene 1- (3,4-Dimethoxyphenyl) -2,3-bis (methoxycarbonyl) 4-hydroxy-7,8-methylenedioxynaphthalene 52 52 86 23

TABLE 2

Test compound (amount in diet: 100 mg%) Decrease (%) in serum total cholesterol level Increase (%) in serum HDL cholesterol level 1- (3,4-Dimethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-7-methylnaphthalene 1- (3,4-Dimethoxyphenyl) -2,3-bis (ethoxycarbonyl) -4-hydroxy -6,7,8-trimethoxynaphthalene 1- (3,4-dimethoxyphenyl) -2-methoxycarbonyl-3-ethoxycarbonyl-4-hydroxy-6,7,8-trimethoxynaphthalene 1- (3,4-dimethoxyphenyl) -2 ethoxycarbonyl-3-methoxycarbonyl-4-hydroxy-6,7,8-trimethoxynaphthalene 48 57 71 68 76 93 178 144

PORTFOLIO TABLE 2

1- (3,4-Diethoxyphenyl) -2-methoxycarbonyl-4-hydroxy-6,7-methylenedioxynaphthalene 1- (3,4-Dimethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6-methoxy 7-benzyloxynaphthalene 1- (3,4-diethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6,7-methylenedioxynaphthalene 4 9 45 60 44 57 67

I7U

Further, immediately after the blood collection in the above-mentioned experiments, the liver of each rat was taken out and its weight measured. The relative liver weight was examined according to the following formula and the average relative liver weight was compared with that of the control group. The test compounds used in the above-mentioned experiments caused no substantial increase in the relative liver weight. 10

relative liver weight * 100 15

EXAMPLE 1

(1) A solution of 1, 55 M n-butyl lithium in 430 ml of hexane was added dropwise to a solution of 204.0 g of 2-bromo-3,4,5-trimethoxybenzaldehyde dimethyl acetal in 800 ml of tetrahydrofuran. The addition was carried out at -70 to -5O ⁰ C with stirring while about

25 15 minutes. The mixture was at -70 for 15 minutes

stirred until -60 ⁰ C. Then a solution of 105.5 g of 3,4-dimethoxybenzaldehyde in 00 3 ml of tetrahydrofuran was added to the mixture at -70 to -50 ⁰ C during 15 minutes. The mixture was stirred at the same temperature for 15 minutes and then poured into 2 liters of water. To the aqueous mixture was added 4 liters of ethyl acetate. After shaking, the organic

Layer separated from the mixture, washed with water, dried and filtered to remove inorganic materials. The organic layer was evaporated under reduced pressure and the solvent was removed to give 266 g of 2- (3,4-dimethoxy-oxyhydroxybenzyl) -3,4,5-trimethoxybenzaldehyde dimethylacetal as a yellow syrup.

NMR _(CDCl3) ό: _t 3.25 (S, 6H), 10 3.80 (S, 6H), 3.89 (S, 3H), 4.05 (D, 1H), 5.35 (S, 1H), 6.20 (D, 1H), 15 6.6 to 7 2 (m, 4H) _TTJ a Nujol, -1. XR τ learning) max : 3450, 16 00 Mass (m / s): 376 (M ⁺ -CH ^ OH) 20

(2) 266 g of 2- (3,4-dimethoxy-o-C-hydroxybenzyl) -3,4,5-trimethoxybenzaldehyde dimethyl acetal were dissolved in 95 ml of benzene. 95 ml of dimethyl acetylenedicarboxylate and 3 00 mg of p-toluenesulfonic acid monohydrate were added to the solution. After 2 hours of reflux, the mixture was cooled and evaporated under reduced pressure to remove the solvent. To the residue were added 600 ml of methanol and the mixture was allowed to stand overnight at -30 ⁰ C.

The crystalline precipitate was filtered off and off

Recrystallized ethyl acetate to give 202 g of 1- (3,4-dimethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6,7,8-trimethoxynaphthalin as colorless prisms.

F:

178 to 179 ° C

NMR (DMSO-d ..) ο

^iR v; £ r- < ^c * - ¹ > 3.21 (s, 3H), 3.45 (s, 3H),

3.73 (s, 3H),

3.74 (s, 3H), 3.82 (s, 3H), 3.92 (s, 3H), 4.0 (s, 3H), 6.5-7.1 (m, 3H), 7.6 (s, 1H),

11 12.5 (br, 1H),

1730, 1660, 1595, 1510

EXAMPLES 2 to

, CHO

+ H ₃ COOCc = CCOOCH ₃ H (OCH.)

OH

OCH,

COOCH.

3 · COOCH ₃

OCH.

CH.

C A]

The compounds shown in Table 3 below were obtained by treating the corresponding starting materials in the same manner as described in Example 1 (1) and 1 (2).

cn υ O τ- ε 5 ¹ U O O O ε H t U O _ τ- ε rh S U O O τ- ε i C ο (N Ι O τ- O τ- ο O S _- O r- r ~ + Ι υ 0 0 τ- I O  Η ^ * in - · vo O σι in ο Χ σι in T- -π Χ VO tn OO τ- H cn O r- ^ · 3 ro VD O t 3 (TJ ιη τ- r-l O ro (N ·· t ~ (N CN ·· s ε ^ * τ- O I • η X I ^^ I ·. "^ I ". ο- Ι • η Χ CN O 3 rö ·· σ> Φ OD O ^ ' OO O di  · CN O 3 rö 00 σι s ε ^^ σι Γ ^ co pi ·· O σι H * -> p ^ σι s ε τ- in Φ τ- G r- in τ- H , ^, CN in Φ r- in ^ - * Φ ". O it pm in = <   · O Q ·· O di (N H * - ^ Φ σι G CN Cm CN H VO cn in J / QJ VD ) ( Φ VD k / Φ T- φ O) cn Φ t r-l t Φ H T- Ö e-l cn iH co > -1 Φ rh ro cn H » W cn S rh ·. cn (Tj ·. 32 cn ta V rö O ta rö O cn 4y O rö  μ O ro VD + J 4J vo (TS tn vo S cn VO O tn VO cn tn VD S vo • Η VO C • Η τ- -Ή •H τ- τ- φ M \ M in ! ^ -μ iii Ο / J in Ο Ο M-I * ro (N Φ ro Φ ro rö Φ Φ 32 φ Come on O Come on r »- O cn cn U cn r- Λ ro τ- VO cn O O O S-I 32 C H i-l H ·· rö U (TJ ·· φ X! ^ _ 4-1 tn U U γ- • Η rö rö ro Ι ι " ... W HI 4-t "+ -Ι O ¹ P (JP Φ ⁴ \ = ro ro C] VD in I- ϋ \\ 2J cn r t * • t · "- • Η I O φ Φ (N  Η r ^ + J ro (O 3 3 in <*> U Φ Φ • Η Λ • t U) cn cn 3 3 Φ CN ro α, _ε Ki < Cn C 3 φ τ5 cn C r- + O cn  Η τ- rö M S Φ ··  Η Φ • Η O CU CN cn -CH φ

Note: * The NMR spectra of the compounds shown in Table 3 were as follows:

Compound of Example 2 (GDCl ₃ ) 6 ·

3.58 (s, 3H), 3.76 (s, 3H), 3.90 (s, 3H), 3.99 (s, 3H), 6.7-7.2 (m, 3H), 7 , 4-7.9 (m, 3H), 8.3-8.6 (m, 1H), 11-13 (br, 1H)

Compound of Example 3 (DMSO-d, + CF-COOD) ά:

2.40 (s, 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, 1H, J = 9Hz)

Compound of Example 4 (DMSO-d,) 6 :

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 (DMSO-d, -) 0:

3.55 (s, 3Ht, 3.68 (s, 3H), 3.78 (s, 3H), 3.88 (s, 3H), 3.93 (s, 3H), 3.97 (s , 3H), 6.7-7.0 (m, 3H), 7.10 (d, 1H, J = 8Hz), 7.66 (s, 1H), 10-12 (br, 1H)

ZU7U

Compound of Example 6 (CDCl) ά =

3.55 (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, 1H), 6.75 (s, 1H),

6.72 (d, 1H, J = 8Hz), 6.90 (d, 1H, J = 8Hz), 7.20 (s, 5H),

7.70 (s, 1H)

EXAMPLES 7 to 9

CH (OCH ..),

Sr

C B J

The compounds in Table 4 were obtained by treating the corresponding starting compounds in the same manner as described in Examples 1 (1) and 1 (2).

TABLE 4

Example no. Connection / B / Ri 1 / r5 Physical Properties* 7 R ¹ = COOCH-R ² = COOCH- Yield: 54%; colorless crystals; F: 158-159 "C IRV ^{> NujOl} (cm ^-1 ): 1750, 1660, 1620, 1600, 1595 Ul ei X α. Mass (m / e): 468 (M) 8th R ¹ '= COOC ₂ H ₅ R' ² = COOC ₂ H Yield: 59%; colorless crystals; Q: 150-151 ⁰ C _IR V> ^Nu ^ ^ol (cm ^"1): 1740, 1640, 1620, 1600, 1580, 1520 ^max, 1500 Mass (m / e): 496 (M ⁺⁾ 9 R ¹ = H R ' ² = COOC ₂ H ₅ Yield: 59%; F: 169-171 ⁰ C _IR ^> Nujol _(cm -1j _{3400 /} T670, 1625, 1580, 1540, 1515 fflclX Mass (m / e): 424 (M)

Note: * The NMR spectra of the compounds shown in Table 4 were as follows:

Compound of Example 7 (CDCl_) 6 ·

1.40 (t, 3H), 1.48 (t, 3H), 3.50 (s, 3H), 3.91 (s, 3H),

4.10 (q, 2H), 4.15 (q, 2H), 6.00 (s, 2H), 6.72 (s, 1H),

6.78 (d, 1H, J = 9Hz), 6.80 (s, 1H), 6.95 (d, 1H, J = 9Hz),

7.70 (s, 1H), 12.12 (s, 1H)

Compound of Example 8 _(CDCl3) 6: 15

1.01 (t, 3H), 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, 1H ), 6.82 (d, 1H, J = 9Hz), 6.85 (s, 1H), 6.97 (d, 1H), 7.72 (s, 1H), 12.32 (s, 1H)

Compound of Example 9 (CDCl) ο:

0.93 (t, 3H), 1.41 (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, 1H), 7.6 (s, 1H)

EXAMPLE 10 30

2-bromo-3,4,5-trimethoxybenzaldehyde dimethyl acetal and. 3,4-dimethoxybenzaldehyde and diethyl acetylenedicarboxylate

were treated in the same manner as described in Example 1 (1) and 1 (2) to give 1- (3,4-dimethoxyphenyl) -2,3-bis (ethoxycarbonyl) -4-hydroxy-6,7,8- trimethoxynaphthalene as colorless crystals.

F:

138-140 ⁰ C

10 15 20

NMR (CDCl ₃ )

Mass (m (e)

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) m

6.90 (s, 3H),

7.72 (s, 1H),

12.59 (s, 1H)

1735, 1720, 1655, 1590, 1510,

514 (M ⁺ )

25

EXAMPLE

2-Bromo-3,4,5-trimethoxybenzaldehyde dimethyl acetal, 3,4-diethoxybenzaldehyde and dimethylacetylenedicarboxylate were prepared in the same manner as in Example 1 (1) and

1 (2) to give 1- (3,4-diethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6,7,8-trimethoxynaphthalene as colorless crystals.

F: 138-1 40 ° C 3H), NMR _(CDCl3) 6: 1.05 (T, 3H), 1, 40 (T, 3H), 3.31 (S, 3H), 3.90 (S, 3H), 3.95 (S, 3H), 3.97 (S, 3H), 4.10 (S, 2H), 4.15 (Q, 2H) m 4.20 (Q, (m, 3H), 6.7 to 7 , 0 1H), 7.69 (S, , 1H) * 12.36 (S 1660, 1590 _ττ3 Λ Nujol. -1. ^IRV max ^(cm): 1740, ⁺ ) Mass (m / e): 514 (m

EXAMPLE

2-Bromo-4,5-methylenedioxybenzaldehyde dimethyl acetal, 4-methoxybenzaldehyde and dimethyl acetylenedicarboxylate 30 are treated in the same manner as described in Example 1 (1) and 1 (2) to give 1- (4-methoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6,7-methylenedioxynaphthalene as colorless crystals.

Yield: F:

NMR _(CDCl3) ά

Max

(cm " ¹ )

15 mass (m / e):

63% 169-171 ° C

3.55 (s, 3H), 3.88 (s, 3H), 3.95 (s, 3H), 6.03 (s, 2H), 6.72 (s, 1H), 6.9-7 , 4 (m, 4H), 7.75 (s, 1H), 12.20 (s, 1H)

1740, 1660, 1610, 1520,

410 (M ⁺ )

20

25

30

EXAMPLE 13

(1) A solution of 7 g of 3,4-dihydroxybenzaldehyde in 20 ml of dimethylformamide was added dropwise to a mixture of 4.8 g of 60% sodium hydride in 70 ml of dimethylformamide over a period of 15 minutes under ice cooling. The mixture was stirred at the same temperature for 15 minutes. Then, 50 g of n-propyl iodide was added. After stirring for 12 hours, the mixture was evaporated to remove the solvent. The residue was extracted with ether and the extract was washed with water, dried and inorganic materials were filtered off,

Then, the solvent was evaporated to obtain 8.5 g of 3,4-dipropoxybenzaldehyde as a pale yellow oil.

F:

130-136 ° C (at 0.2 mmHg)

(2) 2-Bromo-3,4,4-trimethoxybenzaldehyde dimethyl acetal, 3,4-dipropoxybenzaldehyde and dimethyl acetylenedicarboxylate were treated in the same manner as described in Example 1 (1) and 1 (2), substituting 1 - (3,4 - Dipropoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6,7,8-trimethoxynaphthalene as colorless needles.

F:

NMR (CDCl ₃ )

30 IR;> ^NU 3 ^O1 (CITT ^{1) v} max

132 ° C

0.99 (t, 3H), 1.05 (t, 3H), 1.6-2.1 (m, 4H), 3.21 (s, 3H), 3.42 (s, 3H),

3.73 (s, 3H), 3.77 (s, 3H), 3.89 (s, 3H), 3.8-4.2 (m, 4H),

6.74 (s, 1H) ,. 6.76 (s, 2H), 7.59 (s, 1H), 12.25 (s, 1H)

1740, 1660, 1570, 1510

li 1-SC

EXAMPLE 14

(1) A solution of 1.55 M n-butyl lithium in 20 ml of hexane was added dropwise to a solution of 9.24 g of N- (3,4-methylenedioxybenzylidene) cyclohexylamine in 100 ml of tetrahydrofuran. The addition took place at -70 to -6O ⁰ C with stirring during 15 minutes. Then, the mixture was stirred at the same temperature for further 15 minutes, and 6.65 g of a solution of 3,4-dimethoxybenzaldehyde in 15 ml of tetrahydrofuran was added dropwise at the same temperature over a period of 15 minutes. The mixture was stirred for a further 15 minutes at the same temperature and then poured into a mixture of 300 ml of water and 300 ml of ethyl ether. The organic layer was separated from the mixture, washed with water, dried and evaporated under reduced pressure to remove the solvent. The resulting yellow syrup was column chromatographed over silica gel (solvent: benzene-ethyl ether (4: 1), saturated with water) and the eluate was evaporated under reduced pressure. The resulting colorless crystals were recrystallized from a mixture of ethyl acetate and hexane to give 8.7 g of 3,4-methylenedioxy-2- (3,4-dimethoxy-c-C-hydroxybenzyl) benzaldehyde as colorless needles in a yield of 69% ,

F: 129-130 ⁰ C

NMR _(CDCl3) ei

Max

Mass (m / e):

3.55 (d, 0.3H, J = 9Hz),

3.70 (d, 0.4H, J = 9Hz),

5.45 (d, 0.3H, J = IOHz),

3.85 (s, 3H),

3.86 (s, 3H),

5.90 (closed m, 2H), 6.0-7.5 (m, 6.7H),

9.70 (s, 0.3H)

3410, 3300, 1610, 1600, 1520

316 (M ⁺ )

(2) 6.5 g of 3,4-methylenedioxy-2- (3,4-dimethoxy-C-hydroxybenzyl) benzaldehyde was dissolved in 10.5 ml of benzene with heating. 6.5 ml of dimethyl acetylenedicarboxylate and 3 mg of p-toluenesulfonic acid monohydrate were added to the solution. The mixture was refluxed for 30 minutes. After cooling to room temperature 3 00 ml of methanol were added to the mixture and the mixture was stirred at -30 ⁰ C allowed to stand overnight. The crystalline precipitate was filtered off and recrystallized from a mixture of tetrahydrofuran and methanol to give 7.5 g of 1- (3,4-dimethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-7,8-methylenedioxynaphthalene obtained pale yellow prisms in a yield of 83%.

^F: 228-229 ° C

NMR (DMSO-cL x) 6 : 3.50 (s, 3H),

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, 1H, J = 9Hz), 8.05 (d, 1H, J = 9Hz)

_m3v (cm " ¹ ): 1730, 1659, 1630, 1590, 1510 (br)

IU α. Χ

Mass (m / e): 440 (M)

EXAMPLE 15

(1) 2-Bromo-3,4-dichlorobenzaldehyde and 3,4-dimethoxybenzaldehyde are treated in the same manner as in Example 1- (1) to give 2- (3, 4-dimethoxy-3-hydroxybenzyl) - 3,4-dichlorobenzaldehyde.

^ Nujol ( _cm - ¹ ). 3350, 1605, 1600, 1520 max iii.

(2) 2- (3,4-Dimethoxy- <X-hydroxybenzyl) -3,4-dichlorobenzaldehyde and dimethylacetylene dicarboxylate are treated in the same manner as in Example 1- (2) using 1 - (3,4- Dimethoxyphenyl) -2,3-bis (methoxycarbonyl) -A- hydroxy-7,6-dichloronaphthalene as colorless prisms.

F:

209-210 ⁰ C

NMR (DMSO-d,) O

3.50 (s, 3H), 3.75 (s, 3H), 3.85 (s, 3H), 3.95 (S, 3H), 6.6-7.1 (m, 3H), 7 , 8 (d, IH, J = 9Hz), 8.4 (d, 1Η, J = 9Hz), 11.98 (S, 1H)

Max

1730, 1660, 1605, 1580, 1510

EXAMPLE 16

2-Bromo-4,5-methylenedioxybenzaldehyde dimethyl acetal, 3,4-diethoxybenzaldehyde and methyl acetylene carboxylate are treated in the same manner as in Example 1- (1) and 1- (2) to give 1- (3,4-diethoxyphenyl ) 2-methoxycarbonyl-4-hydroxy-6,7-methylenedioxiynaphthalene as colorless crystals.

F:

189-19O ⁰ C (recrystallized from methanol

NMR _(CDCl3) 6

1.38 (t, 3H),

1.44 (t, 3H),

3.53 (s, 3H),

4.05 (q, 2H),

4.13 (q, 2H),

5.93 (s, 2H), 6.6-7.0 (m, 4H),

7.21 (s, 1H),

7.50 (s, 1H)

EXAMPLE 1 7

9.72 g of 1- (3,4-dimethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6,7,8-trimethoxynaphthalene, obtained according to Example 1, were added to a sodium ethoxide solution prepared from 500 ml of ethanol and 2.76 g of metallic sodium. The mixture was refluxed for 3 hours. The reaction mixture was cooled and then 7.2 ml of acetic acid was added. The mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 200 ml of chloroform. The chloroform solution was washed with water, dried, filtered off from inorganic materials and evaporated to remove the solvent.

The crystalline precipitate thus obtained was recrystallized from ethyl acetate to give 7.2 g of 1- (3,4-dimethoxyphenyl) -1-methoxycarbonyl-S-ethoxycarbonyl-hydroxy-6,7,8-trimethoxynaphthalene as colorless prisms.

F: 151-152 ° C

NMR _(CDCl3) 6 1.31 ζ (t, 3H);

3.22 (s, 3H),

25 3.41 (s, 3H),

3.80 (s, 3H),

3.87 (s, 3H),

3.90 (s, 3H),

4.00 (s, 3H),

30 4.35 (q, 2H),

6.76 (s, 3H),

7.60 (s, 1H),

12.42 (s, 1H).

EXAMPLE 18

1- (3,4-Dimethoxyphenyl) -2,3-bis (ethoxycarbonyl) -4-hydroxy-6,7 / 8-trimethoxynaphthalene obtained according to Example 10 was treated in sodium methoxide solution in the same manner as described in Example 14, wherein to give 1- (3,4-dimethoxyphenyl) -2-ethoxycarbonyl-3-metftoxycarbonyl-4-hydroxy-6,7,8-trimethoxynaphthalene as colorless prisms

 10

F: 157-159 ° C

NMR _(CDCl3) 6: 1.03 (t, 3H),

3.22 (s, 3H), 15 3.8 (s, 3H),

3.75 (s, 3H),

3.87 (s, 6H),

3.9 (q, 2H),

3.98 (s, 3H), 20.6.77 (s, 3H),

7.59 (s, 1H),

12.29 (s, 1H).

25.

EXAMPLE .19

2-Bromo-4,5-methylenedioxybenzaldehyde dimethyl acetal, 3-methoxybenzaldehyde and dimethyl acetylenedicarboxylate were treated in the same manner as described in Example 1 to give 1- (3-methoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy- 6,7-methylenedioxynaphthalene.

EXAMPLE

.42

F:

152-154 ° C

NMR (DMSO-d,) O: D 3.5 (s, 3H), 660 . 3.80 (s , 3H) 3,90 (s , 3H) 2H), 6.15 (s , 2H) 1H), 6.60 (s , 1H) 6.7-6.9 (M, . 6.9-7.2 (M, H) 7.4 (d, 1H), 1610 7.57 (s , 1H) 11-12 (br, 1 _ λ nu j ol, -1. , ^IRV max ^(cm) · 1730, 1 Mass (m / e): 410 (M ⁺ )

2-Bromo-4,5-methylenedioxybenzaldehyde dimethyl acetate, 3,4-diisopropoxybenzaldehyde and diethyl acetylenedicarboxylate were treated in the same manner as described in Example 25 1 to give 1- (3,4-diisopropoxyphenyl) -2,3-bis (ethoxycarbonyl) - 4-hydroxy-6, 7-methylenedioxynaphthalene in 51% yield.

F:

123-124 ⁰ C

Mass (m / e):

524 (M ⁺ )

U U

NMR (DMSO-dg) 6 : 0.94 (t, 3H),

1.35 (t, 3H), 1.30 (d, 6H), 1.36 (d, 6H), 3.96 (q, 2H), 4.35 (q, 2H), 4.3-4 , 7 (m, 2H), 6.09 (s, 2H), 6.6-7.1 (m, 4H), 7.55 (s, 1H), 12.19 (s, 1H)

EXAMPLE .21

2 g of 1- (3,4-dimethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6-methoxy-7-benzyloxynaphthalene, obtained according to Example 6, were dissolved in a mixture of 200 ml of tetrahydrofuran and 50 ml of methanol solved. The solution was stirred in the presence of 2 g of 10% palladium on carbon in a hydrogen atmosphere at 2.8 bar (40 psi). After the conversion, the kata-. lysator filtered off and the filtrate was evaporated to dryness under reduced pressure. The crude crystals obtained were tritiated with methanol to give 1.5 g of 1- (3,4-dimethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6-methoxy-7-hydroxynaphthalene.

F: 231 ^° C (decomposition)

NMR (DMSO-dg) 6 : 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, 1H), 9,7-10,4 (br, 1H)

^ -j ^ol (cnf ¹ ): 3400, 1730, 1650, 1620, 1600,

1590, 1580, 1510

EXAMPLE 22

2-Bromo-3,4,5-trimethoxybenzaldehyde dimethyl acetal, 3-methoxy-4-ethoxybenzaldehyde and dimethyl acetylenedicarboxylate were treated in the same manner as described in Example 1 to give 1- (3-methoxy-4-ethoxyphenyl) -2, 3-bis (methoxycarbonyl) -4-hydroxy-6,7,8-trimethoxynaphthalene as, colorless needles in 67% yield.

F:

NMR (CDCl ₀ )

159 ° C

1.47 (t, 3H) m

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, 1H), 12.21 (s, 1H)

1730, 1710, 1660, 1590, 1510

EXAMPLE

2-Bromo-3,4,5-trimethoxybenzaldehyde dimethyl acetal, 3-ethoxy-4-methoxybenzaldehyde and dimethyl acetylenedicarboxylate were treated in the same manner as described in Example 1 to give 1- (3-ethoxy-4-methoxyphenyl) -2,3- obtained bis (methoxycarbonyl) -4-hydroxy-6,7,8-trimethoxynaphthalene as colorless needles in a yield of 65%.

F:

NMR (CDCl ₃ )

max 158 ° C

3.42 (t, 3H),

3.22 (s, 3H),

3.45 (s, 3H),

3.85 (s, 3H),

3.89 (s, 3H),

3.89 (s, 3H),

4.08 (q, 2H),

6.76 (s, 3H),

7.56 (s, 1H),

12.21 (s, 1H)

1740, 1655, 1590, 1510

Claims (7)

CLAIM THE INVENTION Process for the preparation of a naphthalene derivative of general formula (I) OH R ' (I) where R is a hydrogen atom or a lower 2 3 4 alkoxycarbonyl, R lower alkyl, each R and R 3 4 Lower alkoxy or one of R and R is a hydrogen atom and the other lower alkoxy and the ring A is a substituted or unsubstituted benzene ring / with the exception that 20 (A) 2
when R and R "methoxycarbonyl and the ring A is a benzene ring of the formula or is (b) when R is a hydrogen atom, I and the ring A is a benzene ring of the formula ethoxycarbonyl U> I 3 4
is, each of R and R low alkoxy with at least 3 represents 2 carbon atoms or one of R and R represents a hydrogen atom and the other denotes lower alkoxy, or a pharmaceutically acceptable salt thereof, g ekennzei ch η e t characterized in that a SI - "-" ι '' "''" '- Compound of the formula R ¹ -C = CR ² 1 ? wherein R and R ^{Ä have} the meanings given above, with an aldehyde compound of the formula , CHO OH wherein R, R and Ring A have the meanings given above, or a Diniedrigalkylacetal or a salt thereof condensed and, if desired, the product is converted into a pharmaceutically acceptable salt. gekennzeich- 2. Method according to point 1,
0 net in that R is lower alkoxycarbonyl and (A) 3 4
each of R and R is lower alkoxy or 3 4
one of R and R is a hydrogen atom and the other is lower alkoxy and the A ring is a benzene ring of the formulas or wherein R is a hydrogen atom, a lower alkyl b c or a lower alkoxy, R is a lower alkyl, R is a hydrogen atom, a lower alkyl or a phenyl ef
R and R a low lower alkyl, each of R alkyl and each X ^a and X is a halogen atom, or (B) 3 4
each of R and R is a lower alkoxy at least 2 carbon atoms or one of R and R is a hydrogen atom and the other is a lower alkoxy, and the ring A is a benzene ring of the formula ο 3. Method according to point 2, net in that gekennzeich- (A) 3 4
each of R and R is lower alkoxy and Ring A is a benzene ring of the formula: - SO- CH ₃ OHO O Y-J or C Ι or (B) 3 4
each of R and R is lower alkoxy with at least 2 carbon atoms or one of 3 4
R and R is a hydrogen atom and the other is methoxy and the ring A is a benzene ring of the formulas or A method according to item 2, geken _ n drawing - in that each of R and R is lower alkoxy and Ring A is a benzene ring of the formulas: CH or lit - SA ' marked t 5. Method according to point 2, in that both R and R are lower alkoxy and the ring A is a benzene ring of the formula wherein each of the radicals R indicates. ef
R and R are lower alkyl 6. Procedure according to point 4, qekennzeich - net in that ring A is a benzene ring of the formula is ^CH 3 ° ^CH 3 ° 7. A process according to item 5, characterized gekennzeich n et by using it for the preparation of 1- (3, 4-dimethoxyphenyl) -2,3-bis (methoxycarbonyl) -4-hydroxy-6,7,8-trimethoxynaphthalene or a pharmaceutically acceptable salt thereof. 8. A process according to item 5, characterized ge by 1 - (3,4-dimethoxyphenyl) -2,3-bis (ethoxycarbonyl) -4-hydroxy-6,7,8-trimethoxynaphthalene or a pharmaceutically acceptable salt of it manufactures.