JPS638948B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () {In the formula, Ar' means a pyridyl group, a pyrimidinyl group, a lower alkyl group, or a phenyl group which may be substituted with a lower alkoxy group, and Y is a single bond or a lower alkylene group (the alkylene group includes a lower alkyl group, phenyl group or lower alkoxy phenyl group may be substituted), Ar is a 2-naphthyl group which may be substituted with lower alkoxy group or [In the formula, X ₁ , X ₂ and X ₃ are each independently a hydrogen atom,
It means a halogen atom, a lower alkyl group, a dialkylamino group, a piperidino group, a morpholino group, a hydroxyl group, or an alkoxy group whose alkyl moiety may be substituted with _a lower alkoxycarbonyl group or a carbamoyl _group ; When both are hydrogen atoms, X ₃ may mean a phenyl group, a benzoyl group, a benzyloxy group, or a phenoxy group (in which a halogen atom or a lower alkoxy group may be substituted on the benzene ring). . ] refers to a substituted or unsubstituted phenyl group. }
Novel 2,5-trans-disubstituted-
The present invention relates to a 1,3-dioxane derivative or an acid addition salt thereof. The compound of the present invention exhibits an excellent hypolipidemic effect and is a useful compound as a medicine. In particular, in the compound of the present invention represented by formula (), Ar' is a 3-pyridyl group or a 5-pyrimidinyl group, and Ar is substituted with a lower alkoxy group, or a phenoxy group which may be substituted with a lower alkoxy group. is a phenyl group, and Y is a methylene group, or Ar is a phenyl group substituted with a lower alkoxy group, and Y is a group represented by the formula _-CH2 -CH( _CH3 )- In some cases, it shows excellent effects. The compound of the present invention represented by the formula () can be produced, for example, by appropriately selecting the method shown below. (In the formula, Ar, Y and Ar' are the same as above. R means a lower alkyl group.) That is, the 1,3-propanediol derivative represented by the formula () and the aldehyde represented by the formula () or the formula ( ) may be reacted by heating it to a desired temperature in an appropriate solvent in the presence of an appropriate amount of an acid catalyst. As the reaction solvent, for example, halogenated hydrocarbons such as chloroform, ethers such as dioxane, aromatic hydrocarbons such as benzene, etc. are often used. Sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid are often used as acid catalysts, but in some cases weak base mineral salts such as pyridine hydrochloride may be used as acid catalysts. It is still possible to obtain compounds of formula (). Note that the required amount of the acid catalyst is sufficient if it is much smaller than the equivalent amount, but if Ar' is a pyridyl group or a pyrimidinyl group in the raw material compound represented by formula () or formula (), the amount of acid catalyst can be increased as desired. Compounds of formula () can be advantageously prepared by using a slight excess of the equivalent amount. formula()
When reacting a compound of formula () or a compound of formula (), an operation to remove water or lower alcohol produced during the reaction from the reaction system, such as azeotroping with water or lower alcohol such as benzene as a reaction solvent. The reaction can be advantageously progressed by a method such as heating the reaction using a solvent and removing the generated water or lower alcohol by azeotropy. The compound thus prepared is a 2,5-trans-disubstituted-1,
3-dioxane derivatives and their 2,5-cis-
It is a mixture of isomers and can be separated and purified by recrystallization. In the target compound of formula (), when Ar' is a basic group such as a pyridyl group or a pyrimidinyl group, a mixture of both 2,5-trans- and 2,5-cis-isomers is added, for example, to a sulfonate, etc. It is possible to easily separate and purify the acid addition salt of the 2,5-trans isomer by recrystallizing it as an acid addition salt of , 5-trans-isomer. The 2,5-trans-isomer of formula () can also be produced by isomerizing the by-product 2,5-cis-isomer. As a method for isomerization, for example, a method of heating a compound of formula () and a compound of formula () or formula () together with an acid catalyst in an appropriate solvent in accordance with the method of the present invention, that is, a method of heating a compound of formula () and a compound of formula (), is frequently used. used. The excellent hypolipidemic effect of the compound of the present invention was confirmed, for example, by the following animal experiments. That is, STD-Wistar male rats (6.5 to 7 weeks old, weight 160 to 180 g) were used as experimental animals.
Hyperlipidemic rats fed a high cholesterol diet (feed supplemented with 1% cholesterol, 0.5% cholic acid, 10% lard, and 5% sugar) were used.
The compound of the present invention was administered at 0.5% to these hyperlipidemic rats.
Sodium Suspended in aqueous carboxymethyl cellulose solution, once daily, 2 times at a dose of 50 mg/Kg/day.
Orally administered for 1 day, while 50 mg/Kg/day of clofibrate, a prominent commercially available lipid-lowering agent, was administered in the same manner.
The two compounds were orally administered for 2 days to compare the serum lipid-lowering effects of both compounds. Blood was collected 17 hours after the final drug administration, and total serum cholesterol was measured using a modified Zatsk-Henry method (Haruhisa Yoshikawa, Motoshi Kitamura et al.: History of Medicine, 33).
Vol., p. 375, 1960), and serum triglyceride levels were measured by a conventional method (using a commercially available measurement kit). The results are illustrated in the table.

【table】

[Table] shows the results.
As shown in the table above, the compound of the present invention significantly lowered the total amount of cholesterol in the blood and the amount of serum triglyceride, and exhibited an excellent serum lipid-lowering effect, compared to clofibrate, which is a prominent commercially available lipid-lowering agent. Furthermore, it was confirmed that the compound of the present invention has an inhibitory effect in a collagen-induced platelet aggregation inhibition test (in vitro). Further, the compound of the present invention was subjected to an acute toxicity test (oral) in rats, and as a result, the LD ₅₀ was 500 mg/Kg or more, indicating that the compound of the present invention has low toxicity. When administering this drug, it can be processed into various dosage forms such as capsules, tablets, powders, injections, and suppositories using known formulation techniques. Although the dosage of this drug varies depending on the administration method, a dosage of 0.3 to 15.0 g/Kg/day is sufficiently effective. In addition, the method for producing the compound represented by the formula () among the raw material compounds used in the method of the present invention will be specifically described below with reference to Reference Examples 1 to 3. The compound of formula () can be produced by appropriately selecting and implementing the methods of these study examples. Reference example 1-1 2-(4-phenoxybenzyl)propane-1,
Synthesis of 3-diol A mixture of 10 g of 4-phenoxybenzoic acid, 5 ml of concentrated hydrochloric acid, and 120 ml of methanol was stirred and refluxed for 8 hours, concentrated, water was added, and extracted with benzene. The extract is washed with a 5% caustic Soda aqueous solution, washed with water, dried, and the solvent is distilled off to obtain 10.3 g of methyl 4-phenoxybenzoate. Melting point: 57-58°C (recrystallized from petroleum ether). Dissolve 6.5 g of methyl 4-phenoxybenzoate in 100 ml of tetrahydrofuran, add 2 g of lithium aluminum hydride under stirring under ice cooling,
Stir and reflux for 8 hours. After cooling, ethyl acetate, water, 5
% hydrochloric acid and extract with benzene. 5% extract
Wash with hydrochloric acid, water, dry and remove the solvent.
5.8 g of the residue was purified by silica gel chromatography (developing solvent: chloroform) and recrystallized from petroleum ether to obtain 4-phenoxybenzyl alcohol with a melting point of 53-54°C. Add 13 g of 4-phenoxybenzyl alcohol and 10 ml of thionyl chloride to 100 ml of benzene, stir at room temperature for 30 minutes, and then stir and reflux for 1.5 hours. concentrate,
After adding benzene and washing with 5% aqueous sodium bicarbonate solution, washing with water and drying, the solvent was distilled off to obtain 13.1 g of 4-phenoxybenzyl chloride as an oil. 26.4g of dimethyl malonate and metallic sodium
After adding 2.3 g and heating to dissolve, a solution of 11 g of 4-phenoxybenzyl chloride and 40 ml of benzene was added dropwise to 110-120°C with stirring.
The mixture is then stirred and refluxed for 7 hours. After cooling, add water and extract with benzene. If the extract is washed with a 5% aqueous sodium hydroxide solution, washed with water, and dried, the solvent is distilled off to obtain dimethyl 2-(4-phenoxybenzyl)malonate.
13.5 g are obtained as an oil. Use it as is for the next process. Add 100ml of tetrahydrofuran to 11g of dimethyl 2-(4-phenoxybenzyl)malonate,
3.0 g of lithium aluminum hydride under ice-cooling and stirring
was added, and the mixture was stirred and refluxed for 5 hours. After cooling, ethyl acetate, water, and 5% hydrochloric acid were added while stirring under ice cooling, and the mixture was extracted with benzene. The extract is washed with 5% hydrochloric acid and 5% aqueous sodium hydroxide solution, washed with water, dried, and then the solvent is distilled off. The residue was treated with column chromatography using 60 g of silica gel (developing solution: benzene, chloroform, then ethyl acetate), and the solvent of 500 ml of the ethyl acetate effluent was distilled off to give 2-(4-phenoxybenzyl).
6.3 g of propane-1,3-diol are obtained. Colorless scaly crystals, melting point 70-71°C (recrystallized from benzene-petroleum ether). Elemental analysis value C ₁₆ H ₁₈ O ₃ Calculated value (%) C 74.39, H 7.02 Experimental value (%) C 74.80, H 7.14 Reference example 1-2 2-[2-(4-methoxyphenyl)-1- Synthesis of methyl ethyl]propane-1,3-diol A mixture of 10.0 g of 4-methoxybenzyl methyl ketone, 40 ml of methanol, and 1.0 g of sodium borohydride was stirred on ice for 20 minutes, then stirred at room temperature for 40 minutes, and then poured into ice water. Pour into 150ml and extract with ethyl acetate. The extract is washed with water, dried, and the solvent is distilled off to obtain 10.1 g of 1-(4-methoxyphenyl)-2-propanol as an oil. A mixture of 10.1 g of 1-(4-methoxyphenyl)-2-propanol and 100 ml of pyridine was stirred under ice cooling.
After adding 15.0 g of p-toluenesulfonic acid chloride and stirring for 2 hours, the mixture was further stirred at room temperature for 3 hours.
Add water and extract with benzene, wash the extract with 5% hydrochloric acid and 5% aqueous sodium bicarbonate solution, wash with water, dry, and then distill off the solvent to obtain 4-methoxyphenyl-2-propyl p-toluenesulfonate. 17.7 g of pale yellow crystals were obtained. Melting point 78.5-79.5℃
(Recrystallized from methanol). 1.8 sodium metal in 100g of dimethyl malonate
Add 4 g and heat to dissolve at 90-100℃, then 4
Add 12.0 g of -methoxyphenyl-2-propyl p-toluenesulfonate and heat and stir at 110-120°C for 2 hours. After removing excess dimethyl malonate from the reaction solution under reduced pressure, it was poured into 200 ml of ice water and extracted with benzene. The extract is washed with a 5% aqueous solution of caustic soda, washed with water, dried, and then the solvent is distilled off to obtain dimethyl 2-[2-(4-methoxyphenyl)-1-
9.7 g of methylethyl]malonate are obtained as a pale yellow oil. Dimethyl 2-[2-(4-methoxyphenyl)
2.6 g of lithium aluminum hydride is added to a mixture of 9.5 g of -1-methylethyl]malonate and 50 ml of tetrahydrofuran, and the mixture is stirred and refluxed for 3 hours. Next, 5% hydrochloric acid was added while stirring under ice cooling, followed by extraction with ethyl acetate. The extract is washed with a 5% aqueous sodium bicarbonate solution, washed with water, dried, and then the solvent is distilled off. The residue was treated with column chromatography on 150 g of silica gel (developing solution: chloroform, chloroform-methanol (50:1), then ethyl acetate),
From the chloroform-methanol (50:1) mixture and the ethyl acetate effluent, 2-[2-(4-methoxyphenyl)-1-methylethyl]propane-1,3-
2.95 g of diol are obtained as an oil. Mass spectrum; m/e=225 (M+1) ⁺ . Reference example 2 Synthesis of 2-(6-methoxy-2-naphthyl)propane-1,3-diol Ethyl 2-(6-methoxy-2-naphthyl)
1.19 g of acetate was dissolved in 10 ml of dimethyl sulfoxide, and 0.22 g of paraformaldehyde and 0.41 g of 40% trimethylbenzylammonium hydroxide methanol solution were added thereto for 1.5 hours.
Heat to 100℃. After cooling, neutralize with acetic acid and add 100ml of water.
was added, extracted with ethyl acetate, the extract was washed with a 5% aqueous sodium bicarbonate solution and then with water, dried, and the solvent was distilled off. The residue was subjected to column chromatography on 100 g of silica gel [developing solution: benzene, then benzene-ethyl acetate (9:1 and 4:1)].
Ethyl 3-hydroxy-2-
(6-methoxy-2-naphthyl)propionate
0.53 g is obtained as an oil. Lithium aluminum hydride 98 mg in nitrogen stream
Suspended in 2 ml of tetrahydrofuran and heated to -5 to 0°C.
While cooling and stirring, add ethyl 3-hydroxy-2
A solution of 470 mg of -(6-methoxy-2-naphthyl)propionate and 20 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 6 hours. Then, 5% hydrochloric acid was added while stirring under ice cooling, and the mixture was extracted with ethyl acetate. The extract is washed with a 5% aqueous sodium bicarbonate solution and then with water, dried, and the solvent is distilled off to obtain 399 mg of 2-(4-methoxy-2-naphthyl)propane-1,3-diol. White plate-like crystals, melting point 132-135℃
(Recrystallized from ethyl acetate-benzene). Elemental analysis value C ₁₄ H ₁₆ O ₃ Calculated value (%) C 72.39, H 6.94 Experimental value (%) C 72.63, H 7.11 Reference example 3 2-(4-phenoxybenzyl)propane-1,
Synthesis of 3-Diol A mixture of 5.3 g of 4-phenoxyacetophenone, 4.5 g of paraformaldehyde and 0.7 g of boron trifluoride etherate is stirred at 100° C. for 24 hours in a sealed tube. After cooling, benzene was added, and the mixture was washed with a 5% aqueous sodium hydroxide solution, washed with water, dried, and the solvent was distilled off to obtain 7.5 g of a crystalline oil. 100 g of silica gel was treated with column chromatography (developing solution: benzene, chloroform, then ethyl acetate) to obtain 4.9 g of 5-(4-phenoxybenzoyl)-1,3-dioxane from the benzene and chloroform effluent. Colorless crystals, melting point 63°C (recrystallized from methanol-petroleum ether). Dissolve 3.0 g of 5-(4-phenoxybenzoyl)-1,3-dioxane in 100 ml of acetic acid, add 0.3 g of 10% palladium charcoal and 1.5 ml of 70% aqueous perchloric acid solution, and heat to 40-50°C. Contact reduction for 1.5 hours.
The catalyst is filtered off, mixed with 500 ml of water, and extracted with ethyl acetate. The extract was mixed with 5% sodium bicarbonate aqueous solution,
Next, it was washed with water, and after drying, the solvent was distilled off, and 5-
(4-phenoxybenzyl)-1,3-dioxane
2.6 g are obtained as a colorless oil. A mixture of 2.04 g of 5-(4-phenoxybenzyl)-1,3-dioxane, 5 ml of concentrated sulfuric acid, 50 ml of water and 50 ml of methanol is refluxed for 22 hours. After cooling, methanol was distilled off, extracted with dichloroethane, the extract was washed with water, 1N aqueous sodium bicarbonate solution, water and saturated brine, and after drying, the solvent was distilled off.
2-(4-phenoxybenzyl)propane-1,
1.83 g of 3-diol are obtained. Melting point: 70-71°C (recrystallized from benzene-petroleum ether). The present invention will be explained below with reference to Examples. Example 1 2-(4-phenoxybenzyl)propane-1,
3-diol 2.6g, pyridine-3-aldehyde
A mixed solution of 1.5 g of p-toluenesulfonic acid, 2.1 g of 1-quartz, and 100 ml of benzene was attached to a Dean-Starck water separator, stirred and refluxed for 1.5 hours, and left overnight at room temperature to yield 5-(4- phenoxybenzyl)-trans-2-(3-pyridyl)-
1,3-dioxane/p-toluenesulfonate precipitates as crystals. Colorless crystals, melting point 144-146
°C (recrystallized from chloroform-ethyl acetate). Elemental analysis value C ₂₉ H ₂₉ O ₆ As NS Calculated value (%) C 67.04, H 5.63, N 2.70 Experimental value (%) C 66.88, H 5.66, N 2.68 This p-toluenesulfonate was dissolved in water and 5
% aqueous sodium bicarbonate solution and then extracted with benzene. If the extract is washed with an aqueous sodium bisulfite solution, washed with water, and dried, the solvent is distilled off.
-(4-phenoxybenzyl)-trans-2-
1.4 g of (3-pyridyl)-1,3-dioxane are obtained. Colorless scaly crystals, melting point 108-109℃ (benzene-
(recrystallized from petroleum ether). Elemental analysis value as C ₂₂ H ₂₁ O ₃ N Calculated value (%) C 76.06, H 6.09, N 4.03 Experimental value (%) C 75.93, H 6.24, N 4.17 The above 5-(4-phenoxybenzyl)- trans-2-(3-pyridyl)-1,3-dioxane.
The benzene filtrate obtained by filtering the crystals of p-toluenesulfonate was cooled with a 5% aqueous sodium hydroxide solution and then with a saturated aqueous solution of sodium bisulfite, washed with water, dried, and the solvent was distilled off to obtain crude 5-(4-phenoxybenzyl). )-cis-2-(3-pyridyl)-1,3-dioxane 2.0g (cis:trans isomer ratio is 3:1)
It is obtained as an oily substance. Add 60ml of benzene and p-
Add 1.4 g of toluenesulfonic acid monocrystal, attach a Dean-Starck water separator, and stir and reflux for 4 hours. 5-(4-phenoxybenzyl)-trans-2-(3-pyridyl)-1, which was precipitated after cooling.
3-dioxane/p-toluenesulfonate was treated in the same manner as above to give 5-(4-phenoxybenzyl)-trans-2-(3-pyridyl)-1,3-
Obtain dioxane 1.0. Melting point 108-109℃. Example 2 2-[2-(4-methoxyphenyl)-1-methylethyl]propane-1,3-diol 2.90 g, pyridine-3-aldehyde 1.66 g, p
- A mixed solution of 3.20 g of toluenesulfonic acid monocrystal and 50 ml of benzene was attached to a Dean-Starck water separator and stirred and refluxed for 1.5 hours. Thereafter, in the same manner as described in the first and middle sections of Example 1, 5-[2-(4-methoxyphenyl)-1-methylethyl]-trans-2-(3-pyridyl)-
2.01 g of 1,3-dioxane is obtained. Melting point 76.5~77
°C (recrystallized from aqueous methanol). Elemental analysis value C ₁₉ H ₂₃ O ₃ Calculated value (%) C 72.82, H 7.40, N 4.47 Experimental value (%) C 72.89, H 7.39, N 4.47 Example 3 2-(6-methoxy-2-naphthyl) Propane-1,3-diol 2.00g, pyridine-3-aldehyde 1.11g, p-toluenesulfonic acid monocrystal
A mixture of 2.07 g and 200 ml of benzene was attached to a Dean-Starck water separator and stirred and refluxed for 1.5 hours. Thereafter, in the same manner as described in the first and middle sections of Example 1, 5-(6-methoxy-2
-naphthyl)-trans-2-(3-pyridyl)-
1.15 g of 1,3-dioxane are obtained. Melting point 171-173
°C (recrystallized from methanol). Elemental analysis value as C ₂₀ H ₁₉ O ₃ N Calculated value (%) C 74.76, H 5.96, N 4.36 Experimental value (%) C 75.07, H 5.96, N 4.45 Example 4 2-(4-Phenoxybenzyl) propane-1,
7.75g of 3-diol, p-toluenesulfonic acid.
A mixed solution of 6.38 g of pyrimidine-5-diethyl acetal obtained by acetalizing 1-quartz crystal and pyrimidine-5-aldehyde by a conventional method and 150 ml of benzene was refluxed for 30 minutes while benzene was distilled off. After that, 5-(4-
5-( 6.13 g of 4-phenoxybenzyl)-trans-2-(5-pyrimidinyl)-1,3-dioxane are obtained. Colorless scaly crystals, melting point 119-121°C (recrystallized from methanol). Elemental analysis value C ₂₁ H ₂₀ N ₂ O ₃ Calculated value (%) C 72.39, H 5.79, N 8.04 Experimental value (%) C 72.14, H 5.83, N 8.18 Examples 5-53 Method of Examples 1-4 The following compound was prepared according to the following procedure.

【table】

【table】

【table】

【table】

【table】

【table】

【table】

【table】

Claims (1)

[Claims] 1. General formula {In the formula, Ar′ means a phenyl group which may be substituted with a pyridyl group, a pyrimidinyl group, a lower alkyl group, or a lower alkoxy group, and Y represents a single bond or a lower alkylene group (a lower alkyl group, a phenyl group, or a lower alkoxy group) (Phenyl group may be substituted.)
, and Ar is a 2-naphthyl group which may be substituted with a lower alkoxy group or the formula [In the formula, X ₁ , X ₂ and X ₃ are each independently a hydrogen atom,
It means a halogen atom, a lower alkyl group, a dialkylamino group, a piperidino group, a morpholino group, a hydroxyl group, or an alkoxy group whose alkyl moiety may be substituted with a lower alkoxycarbonyl group or a carbamoyl group, and both X ₁ and X ₂ are When it is a hydrogen atom
X ₃ may mean a phenyl group, a benzoyl group, a benzyloxy group, or a phenoxy group (in which a halogen atom or a lower alkoxy group may be substituted on the benzene ring). ] means a substituted or unsubstituted phenyl group. } 2,5-trans-disubstituted-1,3-dioxane derivatives and acid addition salts thereof.