JPH0449536B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 1,4,5,8-tetraalkoxynaphthalene derivatives and salts thereof. The above-mentioned derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1). [In the formula, R ₁ represents a lower alkoxy group. R ₂ and
One of R ₃ represents a hydroxyl group or a lower alkanoyloxy group, and the other represents a group [Formula]. In this group, R ₄ and R ₅ are the same or different and are hydrogen atoms,
A lower alkyl group, a cycloalkyl group, a phenyl group that may have a lower alkoxy group as a substituent on the phenyl ring, or a phenyl lower alkyl group that may have a lower alkoxy group as a substituent on the phenyl ring. Furthermore, R ₄ and R ₅ may be bonded to each other with or without an oxygen atom or a nitrogen atom to form a heterocyclic group together with the adjacent nitrogen atom, and the heterocyclic group may further include a phenyl lower alkyl group. It may be included as a substituent. ] In the above general formula (1), examples of the lower alkoxy group defined by R ₁ include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy groups. Examples of lower alkanoyloxy groups defined for R ₂ and R ₃ include acetoxy, propionyloxy, butyryloxy, isobutyryloxy,
Examples include valeryloxy and isovaleryloxy groups. Examples of lower alkyl groups represented by R ₄ and R ₅ forming the group [formula] include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl groups, etc. represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups, and phenyl groups which may have a lower alkoxy group as a substituent on the phenyl ring include, for example, phenyl, 1
-methoxyphenyl, 2-methoxyphenyl, 3
-butoxyphenyl, 2-methoxy-3-ethoxyphenyl, 3,4-dimethoxyphenyl, 2,
4-dipropoxyphenyl, 3,4,5-trimethoxyphenyl, 2,4,6-triethoxyphenyl groups, etc., and phenyl lower which may further have a lower alkoxy group as a substituent on the phenyl ring. Examples of the alkyl group include benzyl, α-phenethyl, β-phenethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-phenylbutyl, 2-phenylbutyl,
3-phenylbutyl, 4-phenylbutyl, 1-
Phenylpentyl, 3-phenylpentyl, 5-
Phenylpentyl, 1-phenylhexyl, 3-
Phenylhexyl, 5-phenylhexyl, 1,
Unsubstituted phenylalkyl groups such as 1-dimethyl-2-phenylethyl and e.g. 2-methoxybenzyl, 3-ethoxy-β-phenethyl, 4-propoxy-β-phenethyl, 1-(2,3-dimethoxyphenyl) ) propyl, 1-(3,4-diethoxyphenyl)butyl, 3,4,5-trimethoxybenzyl, 3,4-dimethoxy-β-phenethyl, 4-(2,3-dimethoxyphenyl)hexyl group Examples of substituted phenylalkyl groups include the following. Furthermore, examples of the heterocyclic group that can be formed by the above group [formula] include 1-pyrrolidinyl, piperidino,
Examples include piperazinyl and morpholino groups, and the above-mentioned heterocyclic groups substituted with phenyl lower alkyl include:
A piperazinyl group substituted with the above unsubstituted phenylalkyl group, for example, N-benzylpiperazinyl,
Examples include N-α-phenethylpiperazinyl and N-β-phenethylpiperazinyl groups. The derivatives of the present invention represented by the above general formula (1) and their salts, that is, addition salts of inorganic or organic acids, all have therapeutic and preventive effects on heart diseases and hypertension such as instinctive hypertension, etc. It is useful as a drug that utilizes the pharmacological action of, for example, as a therapeutic or preventive agent for congestive heart failure, angina pectoris, myocardial infarction, hypertension, cardiac arrhythmia, hyperkinetic heart syndrome, etc. The derivatives of the present invention can be produced by various methods. Preferred specific examples thereof are shown in the following reaction scheme and will be described in detail. [In the formula, R ₁ , R ₄ and R ₅ are the same as above. R ₂ ′ and
One of R ₃ ' is a hydroxyl group and the other is a group (R ₄ and R ₅ are the same as above). Further, R ₂ ″ and R ₃ ″ represent a lower alkanoyloxy group on one side and a group on the other hand (R ₄ and R ₅ are the same as above). ] According to Reaction Scheme-1, the amine of the general formula (4) is reacted with the epoxide of the general formula (3) obtained by converting a known aldehyde represented by the general formula (2) into an epoxy form. According to general formula (1), R ₂ and R ₃
The compound of the present invention (1a) in which one of R ₂ and R ₃ in the general formula (1) is a lower alkanoyloxy group can be obtained by subjecting the compound (1a) to an acylation reaction. Compound (1b)
can be obtained. The epoxidation reaction of the aldehyde of general formula (2) in the above can be carried out by a known method, such as Merkl (G.
[Angew.Chem., 85 , 867]
(1973)]. That is, about 1 to 5 mole % of a phase transfer catalyst, such as benzyltriethylammonium chloride, tetra-n-
In the presence of a quaternary ammonium salt such as butylammonium iodide, in a two-phase system of 50% alkali hydroxide and dichloromethane, aldehyde of general formula (2),
This is carried out by reacting with trimethylsulfonium iodide in an amount of about 1 to 1.3 times the molar amount. The reaction is carried out at a temperature of about 50°C.
The process is usually completed within 24 to 48 hours, thereby obtaining the epoxide of general formula (3). The epoxide (3) is a new compound that has not been described in any literature, and is important as a synthetic intermediate for the 1,4,5,8-tetraalkoxynaphthalene derivative of the present invention. The reaction between the epoxide (3) and the known amine represented by the general formula (4) is usually carried out in a suitable solvent. Various solvents can be used that do not adversely affect the reaction, and alcoholic solvents such as methanol, ethanol, isopropanol, tert-butanol, and isoamyl alcohol are particularly suitable. The ratio of amine (4) to epoxide (3) is not particularly limited, but is usually at least an equivalent, generally about 1 to 20 times the equivalent. The reaction is approx.
Under temperature conditions ranging from 25°C to the boiling point of the solvent, usually about 5
It will be done in hours to 10 days. This reaction yields the compound of the present invention represented by general formula (1a). This is usually a mixture of a compound in which R ₂ ′ is a hydroxyl group in general formula (1a) and a compound in which R ₃ ′ is a hydroxyl group, and generally, the epoxide of general formula (3) used as a raw material is formed into a naphthalene ring. Since it has an alkoxy group (R ₁ ) which is an electron-donating group, compounds in which R ₃ ' is a hydroxyl group are often obtained as the main product. Such mixtures can be separated according to conventional methods. The acylation reaction of the compound of general formula (1a) subsequent to the above reaction is performed using an acylating agent such as a lower alkyl carboxylic acid anhydride or acid halide in the presence of a base such as pyridine, triethylamine, etc., in accordance with a conventional method. It is done. The ratio of the base and acylating agent to the compound of general formula (1a) can be selected as appropriate, but usually the base is
-100 times equivalent and the acylating agent is preferably used in a range of about 1 to 10 times equivalent. The reaction is carried out at a temperature of about 0 to 30° C. for about 1 to 20 hours, whereby the compound of the present invention represented by general formula (1b) can be obtained. The target products obtained in each of the above steps can be easily isolated and purified by conventional separation means such as solvent extraction, recrystallization, column chromatography, etc. [In the formula, R ₁ , R ₄ and R ₅ are the same as above. ] According to the reaction scheme-2 above, the aldehyde of general formula (2) is reacted with an alkali metal cyanide,
The compound of the present invention in which R ₂ in the general formula (1) is a hydroxyl group can be obtained by converting the cyanohydrin compound of the general formula (5) into a cyanohydrin compound and then subjecting it to a reduction and alkylation reaction. The reaction between the aldehyde of general formula (2) and the alkali metal cyanide can be carried out according to a conventional method, for example, a method involving sodium bisulfite [W.
Revue et al., J.Am.Chem.Soc., 79 , 1932
(1957)]. That is, the aldehyde of general formula (2) is suspended or dissolved in ether, tetrahydrofuran, dioxane, etc., and 2
Add about 3 times the mole of sodium bisulfite aqueous solution and continue stirring for 30 minutes to 2 hours. Then, collect the precipitated crystals. Further, the obtained crystals are suspended in water, and an aqueous solution of alkali metal cyanide in an amount of about 2 to 3 times the mole is added. After stirring for 1 to 2 hours, the precipitated crystals are collected and dried. In this way, a cyanohydrin compound of general formula (5) is obtained. This is a new compound that has not been described in any literature, and 1, 4, and 1 of the present invention.
It is important as a synthetic intermediate for 5,8-tetraalkoxynaphthalene derivatives. The reduction reaction of the above cyanohydrin compound (5) is carried out using a suitable reducing agent such as LiAlH ₄ according to a conventional method.
By catalytic hydrogenation using a palladium-carbon catalyst or by adding an organic acid such as acetic acid or trifluoroacetic acid,
This can be carried out by a method using NaBH ₄ or the like. In particular, considering the ease of use of reagents and the possibility of mass synthesis, there is a method using trifluoroacetic acid-NaBH ₄ system [N. Umino et al., Tetrahedron Lett.,
33, 2875 (1977)] is preferred. More specifically, the method involves suspending NaBH ₄ in a molar amount of about 4 to 8 times, preferably about 5 times, relative to the cyanohydrin compound (5) in a solvent such as ether, tetrahydrofuran, dioxane, etc., preferably tetrahydrofuran. To this, add about 5 times the molar amount of trifluoroacetic acid to the cyanohydrin compound (5) under ice-cooling.
Next, a solution of the cyanohydrin compound (5) in tetrahydrofuran is added to the above mixed liquid, and the reaction is carried out at a temperature of about 0 to 50°C, preferably about 0 to 20°C, usually taking about 2 to 10 hours. Thus, a compound of general formula (1c) is obtained. The alkylation reaction of the compound of general formula (1c) obtained by the above reduction reaction is carried out by a conventional method, for example, using a deoxidizing agent and an alkylating agent in a suitable solvent. Various commonly used deoxidizing agents can be used, such as organic amines such as triethylamine and pyridine, potassium carbonate, and sodium carbonate. As the alkylating agent, common alkyl halides such as methyl iodide, ethyl bromide, benzyl chloride, phenethyl bromide, cyclohexyl chloride, etc. can be used. As the solvent, polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, hexamethyltriamide phosphate, tetrahydrofuran, and acetone can be suitably used. The amount of the deoxidizing agent and alkylating agent to be used is not particularly limited, but the amount of the deoxidizing agent is usually about 1 to 5 times the mole of the compound of general formula (1c), and the amount of the alkyl halide is about 1 to 6 times the mole of the compound of general formula (1c). It is preferable to set it in a range of about twice the molar amount.
The reaction generally proceeds around room temperature and is complete in about 5 to 48 hours. Further, the above alkylation reaction can also be carried out by a conventional method called reductive alkylation. This method is carried out by reducing the Schiff base of the compound of general formula (1c) (amine) and any ketone or aldehyde. Ketones and aldehydes include, for example, acetone,
Examples include cyclohexanone, acetophenone, benzaldehyde, 2-butanone, and anisaldehyde. These are usually used in an amount of equimolar to 10 times the amine of general formula (1c), preferably about 5 times the molar amount. The reaction is carried out by adding the amine of general formula (1c) and a ketone or aldehyde to a suitable solvent such as methanol, ethanol, dimethylformamide-ethanol, dimethylformamide-methanol mixed solvent, etc., and adding a reducing agent such as NaBH to this mixture under ice cooling. ₄ , NaBH ₃ CN, etc. in an equimolar to 5-fold molar amount, preferably in an equimolar to 2-fold molar amount (relative to the compound of general formula (1c)).
It takes about 30 minutes to 20 hours to complete. In addition, the above method
Alternatively, catalytic hydrogenation using a palladium-carbon catalyst may also be used. In this case, a mixture of the compound of general formula (1c) and a ketone or aldehyde dissolved in the above-mentioned solvent is added at room temperature to
It is preferable to perform hydrogenation at a temperature of about 50°C. In this way, the compound of the present invention of general formula (1d) is obtained. Further, the compound of the present invention in which R ₂ in the general formula (1) is a lower alkanoyloxy group can be added to the compound of the general formula (1d) obtained by the method shown in the above reaction scheme-2, as shown in the above reaction scheme-1. It can also be produced by applying a reaction similar to the acylation reaction of the compound of general formula (1a). The compounds obtained by each of the above reaction steps can be easily isolated and purified by conventional separation means such as solvent extraction, recrystallization, column chromatography, etc. The compound represented by the general formula (1) of the present invention is:
By reacting this with a suitable inorganic or organic acid, a pharmacologically acceptable acid addition salt can be obtained, and the present invention also includes such a salt. The above-mentioned salt formation reaction can be carried out in accordance with a conventional method, and the acid used at that time may also be a conventional one. Specific examples include inorganic acids such as sulfuric acid, hydrochloric acid, and nitric acid, and organic acids such as oxalic acid, maleic acid, fumaric acid, and citric acid. Further, the compounds of the present invention may have optical isomers, and the present invention naturally includes such isomers. Below, general formula (3) used for the production of the compound of the present invention
Examples of the production of the epoxide and the cyanohydrin compound of general formula (5) will be listed as reference examples, and then production examples of the compounds of the present invention will be listed. Reference example 1 2-(1,2-epoxyethyl)-1,4,5,
8-tetramethoxynaphthalene [general formula (3),
_1,4,5,8 -tetramethoxy-2-naphthalenecarbaldehyde 5.6g ( _20mM ), trimethylsulfonium iodide 4.3g (21mM) and tetra-n-butylammonium iodide 140
mg is dissolved in 100 ml of methylene chloride and 80 ml of 50% sodium hydroxide solution and heated under stirring at 50° C. for 24 hours to react. After the reaction is completed, the organic layer is separated, dried and concentrated to obtain 5.6 g of pale yellow crystals. This product can be recrystallized from a mixed solvent of ether/n-hexane. Melting point 84-85℃ (after recrystallization) ¹ H-NMR (CDCl ₃ , TMS, ppm) δ = 6.83 (s, 2H), 6.62 (s, 2H), 3.94 (s,
3H), 3.91 (s, 3H), 3.88 (s, 3H), 3.82 (s,
3H), 4.43 (dd, 4.4, 2.6, 1H), 3.22 (dd, 5.7,
4.4, 1H), 2.78 (dd, 5.7, 2.6, 1H) Reference example 2 α-hydroxy-1,4,5,8-tetramethoxynaphthalene-2-acetonitrile [general formula
(5), R ₁ = OCH ₃ ] To a solution of 2.4 g of 1,4,5,8-tetramethoxy-2-naphthalenecarbaldehyde in 10 ml of tetrahydrofuran, a solution of 2.1 g of sodium bisulfite in 6 ml of water was added at room temperature. Stir for 30 minutes. Add 60 ml of ethyl ether to the reaction solution under ice cooling, collect the precipitated crystals, and wash with isopropanol. The resulting crystals are suspended in 30 ml of water, a solution of 1 g of sodium cyanide in 4 ml of water is added, and after stirring for 30 minutes, the resulting crystals are collected to obtain 2 g of the desired product. Melting point 110-116℃ ¹ H-NMR (CDCl ₃ , TMS, ppm) δ = 6.87 (s, 3H), 5.87 (d, 7.3, 1H), 4.12
(d, 7.3, 1H), 3.94 (s, 3H), 3.89 (s,
6H), 3.85 (s, 3H) Example 1 A solution of 3.1 g of trifluoroacetic acid in 2 ml of tetrahydrofuran is added to a solution of 1 g of sodium borohydride in 20 ml of tetrahydrofuran at a temperature below 20°C. To this mixture was added a solution of 1.65 g (5.4 mM) of α-hydroxy-1,4,5,8-tetramethoxynaphthalene-2-acetonitrile obtained in Reference Example 2 in 10 ml of tetrahydrofuran at a temperature below 20°C, and then at room temperature. Continue stirring for 4 hours. The reaction mixture was transferred to water, extracted with methylene chloride, and the organic layer was dried, concentrated, and purified by silica gel column chromatography (methanol/chloroform) to obtain α-aminomethyl-1,4,5,8-tetra 500 mg of methoxynaphthalene-2-methanol are obtained as an oil. The structure and physical properties of the obtained compound are shown in Table 1. Example 2 α-aminomethyl-1,4,5,8-tetramethoxynaphthalene-2-methanol 310 mg
(1mM) and 300mg of acetone in 5ml of methanol, slowly add 65mg of NaBH ₃ CN under ice cooling.
Thereafter, the temperature was gradually returned to room temperature and stirring was continued for 16 hours. The reaction solution was transferred to water, extracted with chloroform,
After drying and concentrating the organic layer, the resulting crude product was purified by silica gel chromatography (chloroform:methanol = 20:1 V/V) to obtain α-(1-methylethyl)aminomethyl-1,4,5 , 8-tetramethoxynaphthalene-2-methanol 272mg
(yield 78%). The structure and physical properties of the compound are shown in Table 1. Examples 3 to 9 Compounds of Examples 3 to 9 shown in Table 1 were obtained in the same manner as in Examples 1 and 2 above. Each of these compounds can also be produced according to the method described in Example 13 below. Example 10 750 mg of α-piperidinomethyl-1,4,5,8-tetramethoxynaphthalene-2-methanol was dissolved in 4 ml of pyridine, and 4 ml of acetic anhydride was added.
Stir at ℃ for 3 hours. Transfer to water, extract with ethyl acetate, and wash the organic layer with water. After concentrating the organic layer, the resulting crude product was purified by silica gel chromatography (methanol/chloroform 1/30V/V).
740 mg (88%) of 2-(1-acetoxy-2-piperidinoethyl)-1,4,5,8-tetramethoxynaphthalene are obtained as an oil. Its structure and physical properties are shown in Table 1. Examples 11 and 12 Compounds of Examples 11 and 12 shown in Table 1 below were obtained in the same manner as in Example 10 above. [Table] [Table] [Table] Example 13 2-(1,2-epoxyethyl) obtained in Reference Example 1
-1,4,5,8-tetramethoxynaphthalene 1
g and 4 g of isopropylamine in methanol 60
ml and stirred at room temperature for 6 days. Thereafter, methanol was distilled off, and the obtained oily substance was purified by silica gel column chromatography (chloroform/methanol = 30/1 V/V) to 360 mg (yield: 3
%) of β-(1-methylethyl)amino-1,4,
5,8-tetramethoxynaphthalene-2-ethanol is obtained as an oil. This product could be obtained as a crystal by dissolving it in ethanol, drying it, acidifying it with hydrochloric acid, and adding ether, and its physical properties were consistent with those of the compound obtained in Example 2 above. In addition, in the above silica gel column chromatography, chloroform/methanol = 2
By continuing to develop at 0/1 (V/V ratio), 400
mg (yield 33%) of α-(1-methylethyl)aminomethyl-1,4,5,8-tetramethoxynaphthalene-2-methanol is obtained as an oil.
This oil is dissolved in ethanol, dried and
After making it acidic with hydrochloric acid, it can be collected as crystals by adding ether. The structure and physical properties of this compound are shown in Table 2 as Example No. 13. Examples 14 to 21 In the same manner as in Example 13, Examples 14 to 2 shown in Table 2 below were prepared along with each compound shown in Examples 3 to 9.
21 compounds were obtained. Examples 22-24 The same operations as in Example 10 were performed to obtain the compounds of Examples 22-24 shown in Table 2 below. [Table] [Table]

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ represents a lower alkoxy group. R ₂ and
One of R ₃ represents a hydroxyl group or a lower alkanoyloxy group, and the other represents a group [Formula]. In this group, R ₄ and R ₅ are the same or different and are hydrogen atoms,
A lower alkyl group, a cycloalkyl group, a phenyl group that may have a lower alkoxy group as a substituent on the phenyl ring, or a phenyl lower alkyl group that may have a lower alkoxy group as a substituent on the phenyl ring. Furthermore, R ₄ and R ₅ may be bonded to each other with or without an oxygen atom or a nitrogen atom to form a heterocyclic group together with the adjacent nitrogen atom, and the heterocyclic group may further include a phenyl lower alkyl group. It may be included as a substituent. ] A 1,4,5,8-tetraalkoxynaphthalene derivative and a salt thereof.