JPS5919541B2 - New 3,4-dihydrocarbostyryl derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 3,4-dihydrocarbostyryl derivatives.

The compound of the present invention is a new substance, and has the general formula [wherein R_ represents a hydrogen atom, a lower alkyl group, or an aralkyl group whose carbon number in the alkyl moiety is 6 to 6],
R_2 is a hydrogen atom or alkyl moiety with 1 to 6 carbon atoms
, and R_3 is a hydrogen atom, a lower alkyl group, or a phenylalkyl group that may have a lower alkoxy group as a substituent at the 3- and 4-positions of the phenyl ring, and the alkyl moiety has 1 to 6 carbon atoms. Indicates the group.

However, when R_1 is a lower alkyl group, R_1 must not be a hydrogen atom. ] 314-dihydrocarbostyryl derivatives and acid addition salts thereof. In the above general formula, the lower alkyl group is a straight chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group. tert-butyl group, pentyl group, hexyl group, etc. Also, 3 of the phenyl ring
A phenylalkyl group which may have a lower alkoxy group as a substituent at the position and the 4-position and whose alkyl moiety has 1 to 6 carbon atoms refers to a straight chain or branched alkylene group having 1 to 6 carbon atoms and a phenyl group. or a 3,4-dilower alkoxy-substituted phenyl group, and examples of the lower alkoxy group as the substituent include methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. The compound of the present invention has a β-adrenergic action inhibiting action and is useful as a drug for heart diseases such as arrhythmia angina pectoris, and as an antihypertensive drug. It is useful as a drug. The details of the above-mentioned pharmacological action of the compound of the present invention will be explained in the pharmacological test examples described later. Representative examples of the compounds of the present invention include, for example, 1-benzyl-8
-benzyloxy-5-(3-amino-2-hydroxypropoxy)-3,4-dihydrocarbostyryl, 1-
Benzyl-8-benzyloxy-5-(3-ethylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyryl, 1-ethyl-8-hydroxy-5-(3
-isopropylamino-2-hydroxypropoxy)-
3,4-dihydrocarbostyryl, 1-phenethyl-8
-Hydroxy-5-[3-(Sec-butylamino)-
2-hydroxypropoxy]-3,4-dihydrocarbostyryl, 1-benzyl-8-benzyloxy-5-[
3-(Tert-butylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl, 1-isopropyl-8-hydroxy-5-[3-(Tert-butylamino)-2-hydroxypropoxy]- 3,4-dihydrocarbostyryl, ]-ethyl-8-hydroxy-5-(3-hexylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyryl, ]-butyl-
8-hydroxy-5-(3-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyryl,
8-hydroxy-5-(3-phenethylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyryl, 8-hydroxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy ]-3
, 4-dihydrocarbostyryl, 8-hydroxy-5-
{2-hydroxy-3-[1,1-dimethyl-3-(
3,4-dimethoxyphenyl]propylamino]propoxy}-3,4-dihydrocarbostyryl, ]-methyl-8-hydroxy-5-[2-hydroxy-3-(4-
phenylbutylamino)propoxy]-3,4-dihydrocarbostyryl, 8-hydroxy-5-{2-hydroxy-3-[]-methyl-2-(3,4-dimethoxyphenyno(ha)ethylamino) propoxy}-3,4-dihydrocarbostyryl, and the like.

Taking the case where R2 is a benzyl group as an example, the compound of the present invention can be produced as shown in the following formula.

That is, in the case of Rd G-grade alkyl group in the above formula or an aralkyl group whose alkyl moiety has 1 to 6 carbon atoms, the formula (1
) A new tetrahydropyranyl derivative represented by formula () is obtained by reacting a 3,4-dihydrocarbostyryl derivative represented by formula () with dihydropyran as a starting material. A 3,4-dihydrocarbostyryl derivative represented by formula (1) is obtained by reacting the halogenated compound.

Next, the compound of formula (l) is treated with an acid to remove the tetrahydropyranyl group to form a novel 5-hydroxycarbostyryl derivative represented by formula (), and then the compound of formula (l) is treated with epihalogenohydrin. 3,4 represented by formula (V) by reacting the resulting reaction product with an amine represented by R3NH2 without isolating and purifying it.
- Obtaining a dihydrocarbostyryl derivative. Also, in the above formula, R
When 1 is a hydrogen atom, 5-hydroxy-3 of formula ()
, 4-dihydrocarbostyryl derivative as a starting material, reacted with epihalogenohydrin in the same manner as above, without isolating and purifying the reaction product, and then reacted with an amine represented by R3NH2 to obtain the formula (V). A novel 3,4-dihydrocarbostyryl derivative is obtained. The 8-position of the compound of formula (V) thus obtained is deal-alkylated to form an 8-hydroxy-
A 3,4-dihydrocarbostyryl derivative is obtained. Furthermore, if necessary, formula (V) and formula () 3 obtained in the above process
, 4-dihydrocarbostyryl derivatives are reacted with a pharmacologically acceptable acid to obtain each acid addition salt. After completion of the reaction, the compound of this step is isolated from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent from the reaction mixture. The obtained target compound can be further purified by conventional means such as fractional recrystallization, column chromatography, thin layer chromatography, etc. Next, each of the above reactions will be described in more detail.〇The reaction between the compound of general formula (1) and dihydropyran can be carried out using a suitable solvent such as aromatic solvent (benzene, toluene, xylene), n-hexane, microhexane, ether type solvent. Solvent (diethyl ether, 1,2-dimethoxyethane, dioxane, etc.), chloroform, dimethylformamide,
Acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, inorganic acids such as phosphoric acid, organic acids such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid, aluminum chloride, etc. in solvents such as hexamethylphosphoric triamide and dimethylsulfoxide; , subsalt chloride,
The amount of catalyst used in the presence of a Lewis acid such as boron trifluoride and a catalyst such as thionyl chloride is from 0.1% to 5%, preferably from 0.5% to the compound of general formula (1). 3%
The reaction temperature is 0.00 - the boiling point of the solvent, preferably room temperature to 50.0%.

Tetrahydropyranyl derivative of general formula () and general formula Rl
The reaction with leads to an alkali metal salt at the 1st nitrogen atom position. The reaction leading to the alkali metal salt is carried out by using the alkali metal or its compound in a suitable solvent, such as aromatic solvents (benzene, toluene, xylene, etc.), n-hexane, cyclohexane, ether solvents (diethyl ether, 2-dimethoxyethane, dioxane, etc.)
, preferably in an aprotic polar solvent such as dimethylformamide, hexamethylphosphoric triamide, dimethyl sulfoxide, etc.
The reaction is carried out at ~200°C, preferably at room temperature ~50°C. Obtained tetrahydropyranyl derivative (n)
An alkali metal salt of the general formula RlX'7' is prepared by a conventional method.
React with the indicated halogenated compound.

This reaction is preferably carried out at room temperature using a suitable solvent such as dimethylformamide. The proportion of each reactant used is as follows for the compound of general formula (n):
The alkali metal or its compound is 1 to 5 times the mole, preferably 1 to 3 times the mole, and the halogenated compound is 1 to 5 times the mole,
Preferably it is 1 to 3 times the mole. 3 and 4 of general formula (1)
- The tetrahydropyranyl group of the dihydrocarbostyryl derivative can be removed using a suitable solvent such as aromatic solvents (benzene, toluene, xylene), n-hexane, cyclohexane, ether solvents (diethyl ether, 1,2-dimethoxy This is carried out using an acid in a water-containing solvent such as ethane, dioxane, etc.), alcoholic solvent (methanol, ethanol, propanol), chloroform, dimethylformamide, hexamethylphosphoric trigammaide, dimethyl sulfoxide, etc.

As acids, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and organic acids such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid, etc. are widely used, but inorganic and organic weak acids are preferably used. The amount of acid used is not particularly limited and is used in large excess relative to the compound of general formula (l). The reaction temperature is usually room temperature to the boiling point of the solvent, preferably room temperature to 50°C. 5-hydroxy-3 represented by general formula ()
, 4-carbostyryl derivatives and epihalogenohydrin using a suitable basic compound such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
Inorganic basic compounds such as metallic sodium and metallic potassium,
Alternatively, in the presence of organic basic compounds such as pyridine, piperidine, piperazine, etc., without solvent or lower alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, ethers, ethers such as dioxane, benzene, toluene, etc. The reaction is carried out using aromatic hydrocarbons such as xylene, water, etc. as a solvent, among which methanol, ethanol, etc. are advantageously used.

Any compound in which the halogen atom is a chlorine atom, a bromine atom or an iodine atom can be used as the epihalogenohydrin, and these epihalogenohydrins have the general formula (5-5-
The reaction is carried out in an equimolar to excess amount, preferably 5 to 10 times the molar amount, relative to the hydroxy-3,4-dihydrocarbostyryl derivative.

The reaction proceeds at 0 to 150°C, but generally at 50 to 10°C.
It is best to do this at 0°C. Since these hydroxyl groups become (2,3-epoxy)propoxy groups or 3-halogeno-12-hydroxypropoxy groups in the above reaction, the reaction product is ultimately obtained as a mixture. These reaction products can be separated and purified by commonly used purification methods such as fractional recrystallization and column chromatography, but these separations and purifications are particularly necessary for producing the target compound of the present invention. Alternatively, the reaction with the alkylamine may be carried out as a mixture. Examples of the alkylamine used in the present invention include methylamine, ethylamine,
Propylamine, IsO-propylamine, Tert-
Examples include amines having an alkyl group having 1 to 6 carbon atoms such as butylamine. The reaction between these alkylamines and the above-mentioned reaction products can be carried out without a solvent, but in addition to ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, and xylene, water,
Dimethylformamide etc., more preferably methanol,
It is preferable to carry out the reaction in a polar solvent such as ethanol. Alkylamine is used in excess amount with respect to the above reaction product,
Generally, it is preferable to use about 6 to 8 times the molar amount. This reaction proceeds without particular heating, but preferably about 50 to
It is best to do this at 80°C. The dealalkylation reaction at the 8-position of the 3,4-dihydrocarbostyryl derivative of general formula (V) is carried out in the presence of a conventional catalytic reduction catalyst,
As the catalyst, for example, Raney nickel, palladium on carbon, etc. are generally advantageously used.

Further, this reaction proceeds in a solvent, and examples of the solvent used include lower alcohols such as methanol, ethanol, and isopropanol, acetic acid, and water. Although reaction conditions are not particularly limited, the reaction usually proceeds advantageously at room temperature under hydrogen pressure and normal pressure. The 3,4-dihydrocarbostyryl derivatives represented by the general formula () and general formula () obtained in the above steps are treated with a pharmaceutically acceptable acid such as an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid. Acid addition salts can also be formed with organic acids such as , oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid.

Furthermore, the optical properties of the general formula () and the 3,4-dihydrocarbostyryl derivatives of the general formula ()? Naturally, it also includes sexual bodies.

3 of the carbostyryl group of general formula (V) and general formula (),
A true carbostyril derivative in which the hydrogen at the 41-position is dehydrogenated can be easily obtained by dehydrogenating the compounds of general formula (V) and general formula (), and phenoxy as a substituent of R3. 3,4-dihydrocarbostyryl substituted with an alkyl group, substituted phenoxyalkyl group, or alkoxyalkoxy group and its true carbostyryl derivatives are also expected to have pharmacological activity.

Reference examples will be described below to explain the present invention in more detail, but the present invention is not limited thereto.

Reference Example 1 10y of 5-hydroxy-8-benzyloxy-3,4-dihydrocarbostyryl was dissolved in 10y of anhydrous tetrahydrofuran.
00Tf11, para-toluenesulfonic acid 100
1!9, and dihydropyran 109 was gradually added dropwise while stirring at room temperature.

After the dropwise addition, the mixture was stirred at room temperature for 12 hours, poured into a large amount of saturated brine, and extracted with chloroform. After washing with a 5% caustic soda aqueous solution and then water, the taloloform layer was dried over anhydrous potassium carbonate, the chloroform was distilled off under reduced pressure, the residue was crystallized from petroleum ether, and then recrystallized from ethanol and water to give 8-benzyl as colorless needle-like crystals. Oxy-3,4-dihydrocarbostyryl-5-ol-tetrahydropyranyl ether ()9.
Get 57.

Mp: 113.5-114 Te Reference Example 2 8-benzyloxy-3,4-dihydrocarbostyryl-5-ol-tetrahydropyranyl ether () 5r
was dissolved in 100 ml of anhydrous dimethylformamide, and 810 η of sodium hydride was gradually added while stirring.

After further stirring for 1 hour at room temperature, 1.05 TI of methyl iodide was added.
After adding No. 11 dropwise, the mixture was stirred at the same temperature for 2 hours. The reaction product was poured into a large amount of saturated brine, extracted with chloroform, washed with water, dried over anhydrous potassium carbonate, chloroform was distilled off under reduced pressure, and the residue was recrystallized from ligroin to give colorless needle-like crystals of 1-methyl-8.
-benzyloxy-3,4-dihydrocarbostyryl-
5-ol-tetrahydropyranyl ether 1.42y
get. Mp: 110.5-111.5 1-benzyl-8-benzyloxy-3,4-dihydrocarbostyryl-5-ol-tetrahydropyranyl ether is obtained by the same operation. NMR:60MHzinDMS0-D
63.3-4.1 (M.2H), 4.87 (S.2H)
, 5.37(S.2H)PFl Reference Example 31-Methyl-
8-benzyloxy-3,4-dihydrocarbostyryl-5-ol-tetrahydropyranyl ether 14.0
7 was added to a solution of 280 ml of methanol containing 80 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature for 10 minutes.

After making NaOH alkaline and removing methanol under reduced pressure, the crystals precipitated as hydrochloric acid were extracted with chloroform. After washing with water, drying over anhydrous magnesium sulfate, chloroform was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain colorless needle-like crystals of 1-methyl-5-hydroxy-8-benzyloxy-3,4
-dihydrocarbostyril 8.1y is obtained. MP: 19
6-197 Reference Example 4 1-Methyl-5-hydroxy-8'-benzyloxy-3,4-dihydrocarboxylic acid T. Add 5f7 to epichlorohydrin 15y, add 12 drops of piperidine, and stir at 90-100°C for 3 hours.

Excess epichlorohydrin and piperidine were distilled off under reduced pressure.
The residue was dissolved in chloroform, washed with 5% caustic soda, washed with water, dried over anhydrous potassium carbonate, chloroform was distilled off under reduced pressure, and the residue was purified by silica gel chromatography and recrystallized from ethanol to obtain 1-methyl as yellow needles. -5-(2,
3-epoxypropoxy)-8-benzyloxy-3,
3.5y of 4-dihydrocarbostyryl is obtained. Mp:1
11-112.5-C Example] 1-Methyl-5-(2,3-epoxypropoxy)-8
-benzyloxy-3,4-dihydrocarbostyryl 1
．． 7f7 was dissolved in 20 ml of methanol, 1.6 ml of benzylamine was added, and the mixture was stirred at 40 to 50°C for 4 hours.

Methanol and excess benzylamine were distilled off under reduced pressure, and the residue was purified by silica gel chromatography, converted to hydrochloride with ethanol saturated with hydrochloric acid gas, ethanol was distilled off under reduced pressure, and the residue was recrystallized from ethanol-ligroin to give colorless needle-shaped crystals. 1-
Methyl-5-(3-benzylamino-2-hydroxypropoxy)-8-benzyloxy-3,4-dihydrocarbostyryl hydrochloride is obtained. Mp: 155-157 Example 2 -Methyl-5-(2,3-epoxypropoxy)-8
-benzyloxy-3,4-dihydrocarbostyryl 1
．． 4y1 methanol 20ml 11t-butylamine 4.5
1-methyl-5-(3
-t-butylamino-2-hydroxypropoxy)-8
1.5y of -benzyloxy-3,4-dihydrocarbostyryl hydrochloride is obtained.

NMR: 60MHz1nDMS0-D6l. 37 (S.
9H), 5.95 (Br.s.lH.D2O→disappearance),
9.65 (Br.s.lH.D2O → Disappearance) Example 3 1-Benzyl-5-(2,3-epoxypropoxy)-
8-benzyloxy-3,4-dihydrocarbostyryl 1.237, methanol 20ml,. Recrystallization from ethanol-ligroin using 4 ml of t-butylamine was performed in the same manner as in Example 1 to obtain 1-benzyl-5-(3-t-butylamino-2-hydroxyboxy)-8-benzyloxy-3,4. -1.4y of dihydrocarbostyril hydrochloride are obtained.

Mp: 200-201°C Example 4 Add 20 drops of piperidine to 4.5f7 of 8-bendinoleoxy-15-hydroxy-3,4-dihydrocarbostyryl and 5.07% of epichlorohydrin, and stir at 95-100°C for 4 hours. .

After removing the excess Epic rehydrin under reduced pressure, the residue was dissolved in 100 ml of chloroform. D the chloroform layer
Wash with ilNaOH and water and dry with 8Na2S04. After chloroform was distilled off and the residue was dissolved in 30 ml of methanol, 1.5 ml of 3,4-dimethoxyphenethylamine was added.
Add f and stir at 50-55°C for 4 hours. Methanol was distilled off, ether was added to the residue for crystallization, and then recrystallized from acetone to obtain white powder crystals of 5-{3-(3,4
-dimethoxyphenethylamino)-2-hydroxypropoxy}-8benzyloxy-3,4-dihydrocarbostyryl 1.1y is obtained. Mp: 108-109.5 Example 5 5-{(3,4-dimethoxyphenethylamino)-2-
Hydroxypropoxy}-8-benzyloxy-3,4
-dihydrocarbostyril 2.0V in methanol 50m
1, and add ethanol containing hydrochloric acid gas until the solution becomes acidic.

After it becomes a homogeneous solution, 0.77 g of 10% palladium on carbon is added and stirred at room temperature and normal pressure to absorb hydrogen. The reaction ends when hydrogen absorption stops, the catalyst is removed, and the methanol is distilled off. The residue was crystallized by adding a small amount of ethanol, and then recrystallized from ethanol to obtain colorless powder crystals of 5-{(3,4-dimethoxyphenethylamino).
-2-hydroxypropoxy}-8-hydroxy-3,
1.5f7 of 4-dihydrocarbostyryl hydrochloride is obtained.
Mp: ]71-173 Examples 6-8 The following compounds were obtained in the same manner as in Example 5.

Pharmacological Test Example> An adult male dog (body weight 10-16k9) is anesthetized by intravenously administering 30 w/g of pentobarbital sodium salt, and a cannula is inserted into the trachea.

Heparin is administered intravenously at a level of 1000 units to avoid blood clotting. A cannula is then inserted into the right femoral artery. During the experiment, 20m1/snake, 18r. p. m.
Artificial respiration was performed at a rate of Blood pressure was measured using a pressure transducer (MD).
U-0.5 type, made by NippOnKOdenCO), and the heart rate was measured using an instantaneous heart rate tachometer (2
130 dozen SaneiSOkkiCO. Blood pressure was determined from the pulse wave using a commercially available product. Air resistance (AR) is KOnjett-ROssler.
Law [KOnjettH. -&ROsslerR. ,”V
ersuchsanOrdnugzuUnterkuc
hungenanderBrOnchialmOskO
latarlAach. Exp. Path. ,Phar
Mak, Shio'', 71-74, 27-40 (1940)
] According to
LPU-0.1, NippOnKOdenCO. (manufactured by).

The blood pressure and heart rate mentioned above were recorded on a polygraph. (
8S28 type, manufactured by SaneiSOkki) During the experiment, garamin was applied at VC3~ every hour to avoid air resistance fluctuations.
/ Snake administered intravenously. The β-adrenergic blockade effect of the test compound was antagonistic (inhibition %) against the suppression of diastolic blood pressure and increase in heart rate induced by intravenous administration of isoprenaline (1μy/phantom) and histamine (5μy/phantom).
Kf) It was expressed in terms of antagonism (inhibition %) to isoprenaline, which suppresses the increase in air resistance induced by intravenous administration. In this case, histamine was administered 45 seconds after isoprenaline administration. The test compound was administered intravenously at a dose of 300 μf/snake, and the β-adrenergic blocking effect was measured 10 minutes later. The results are shown in Table-1. The following compounds of the present invention and comparative compounds were used as test compounds. Test Compound Black 11-Methyl-5-(3-benzylamino-2-hydroxypropoxy)-8-benzyloxy-3,4-dihydrocarbostyryl hydrochloride 21-Benzyl-5-(3-
t-butylamino-2-hydroxypropoxy)-8-
Benzyloxy-3,4-dihydrocarbostyryl hydrochloride 35-{3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy}-8-hydroxy-3
,4-dihydrocarbostyryl hydrochloride 41-methyl-5
-(3-amino-2-hydroxypropoxy)-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride 51
-benzyl-5-(3-t-butylamino-2-hydroxypropoxy)-8-hydroxy-3,4-dihydrocarbostyryl hydrochloride 65-(3-isopropylamino-2-hydroxy)propoxy-3,4-dihydrocarboxylate Styryl hydrochloride (compound of Example 2 of JP-A-48-103589) As is clear from the results shown in Table 1 above,
The compound of the present invention has a higher effect on the heart as expressed by the heart rate inhibition rate (%), that is, the effect on the β1 receptor, than the comparative compound (test compound F26).
), the effect on the bronchi, etc., that is, the effect on β2 receptors, is stronger than that, and it is found that this drug shows a favorable pattern as a heart disease drug.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 represents a hydrogen atom, a lower alkyl group, or an aralkyl group whose alkyl moiety has 1 to 6 carbon atoms,
R_2 is a hydrogen atom or alkyl moiety with 1 to 6 carbon atoms
R_3 represents a hydrogen atom, a lower alkyl group, or phenyl which may have a lower alkoxy group as a substituent at the 3- and 4-positions of the phenyl ring, and the alkyl moiety has 1 to 6 carbon atoms. Indicates an alkyl group. However, when R_3 is a lower alkyl group, R_1 must not be a hydrogen atom. ] 3,4-dihydrocarbostyryl derivatives and acid addition salts thereof.