JP2678652B2 - Novel propranolol derivative and its hydrochloride - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel derivative of propranolol hydrochloride used as a β-blocker for the treatment of hypertension and arrhythmia, and a hydrochloride thereof.

Technical background Propranolol hydrochloride is 1-[(1-methylethyl) amino] -3- (1-naphthalenyloxy) -2-
It is a compound represented by propanol and has the following general formula.

This compound is useful as a β-blocker for treating hypertension and arrhythmia, and is orally administered as a therapeutic agent for these. However, in this case, more than half of the absorbed compound is metabolized and loses its pharmacological activity before entering the systemic circulation because it is susceptible to the first-pass effect.

As a cause of this, one of its main metabolites was found to be a compound in which the hydroxyl group of the side chain of propranolol was conjugated with glucuronic acid, and thus this decreases the bioavailability (biological effectiveness) of propranolol. it is conceivable that.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The present invention, when administered orally as described above, is converted to propranolol only after reaching the systemic circulation (in the blood) without undergoing the first-pass effect, and the bioavailability of propranolol is enhanced. To provide a compound.

More specifically, it is intended to provide a novel ester form which increases the bioavailability of propranolol by esterifying the hydroxyl group of the alkyl side chain of propranolol with a specific group to make it less susceptible to the first-pass effect.

The present invention relates to a propranolol derivative represented by the following general formula or a hydrochloride thereof.

[Wherein R is _{-CH (CH 3) 2, -CH} 2 -CH (CH 3)
_{2, -CH 2 COOCH 3, -CH} 2 COOC 2 H 5, - (CH 2) 2 COOCH 3,
Or a group of-(CH ₂ ) ₃ COOCH ₃ ] The compound in the present invention includes isobutanoylpropranolol (Isobutanoy
lpropranolol), isovaleroyl propranolol (Is
ovaleroylpropranolol), methylmalonylpropranolol (Methylmaronylpropranolol), ethylmalonylpropranolol (Ethylmaronylpropranolol), methylsuccinylpropranolol (Methylsuccinylproprano)
lol), Methylglutaryl propranolol (Methylglu
tarylpropranolol) and the like or their hydrochlorides.

Further, since the compound of the present invention has an asymmetric carbon,
The present invention also includes optical isomers such as racemates, d-isomers and l-isomers of these compounds.

To obtain the compound of the present invention, propranolol hydrochloride may be reacted with an acid chloride corresponding to the target compound.

A preferred production method is to disperse propranolol hydrochloride in anhydrous chloroform, add acid chloride, and reflux for several hours. Chloroform is distilled off from the reaction product, and unreacted acid chloride having a low boiling point is distilled off by adding benzene or toluene. Further, the unreacted acid chloride having a high boiling point is removed by washing with ether. Then, it is recrystallized in an isopropanol-ether system to obtain crystals.

Example 1 Preparation of isobutanoyl propranolol hydrochloride Disperse 1 g of propranolol hydrochloride in 15 ml of anhydrous chloroform, and add isobutyryl chloride.
e) A solution of 0.7 ml dissolved in 20 ml of anhydrous chloroform was added dropwise, and the mixture was refluxed for 3 hours while bubbling nitrogen gas. After evaporation of chloroform, 30 ml of toluene was added to the residue to evaporate it to remove isobutyryl chloride. This operation was repeated 3 times to obtain 1.16 g of a white solid.
White crystals recrystallized from isopropanol-ether system 1.
I got 04g. Yield 84%.

Example 2 Preparation of isovaleroyl propranolol hydrochloride Disperse 1 g of propranolol hydrochloride in 15 ml of anhydrous chloroform and add isovaleryl chloride.
e) A solution of 0.85 ml dissolved in 20 ml of anhydrous chloroform was added dropwise, and the mixture was refluxed for 3 hours while bubbling nitrogen gas.
After evaporation of chloroform, 30 ml of toluene was added to the residue to evaporate it to remove isovaleryl chloride. This operation was repeated 3 times to obtain 1.36 g of a white solid. Recrystallization from an isopropanol-ether system gave 1.1 g of white crystals. 85% yield.

Example 3 Preparation of methylmalonylpropranolol hydrochloride Disperse 1 g of propranolol hydrochloride in 15 ml of anhydrous chloroform, and add methyl malonyl chloride.
A solution of 0.75 ml of hloride) dissolved in 20 ml of anhydrous chloroform was added dropwise, and the mixture was refluxed for 3 hours while bubbling nitrogen gas. After evaporation of chloroform, ether 30
Methyl malonyl chloride was removed by adding ml and washing three times to obtain 1.0 g of a white solid. Recrystallization from an isopropanol-ether system gave 0.9 g of white crystals. Yield 67%.

Example 4 Preparation of ethylmalonylpropranolol hydrochloride Disperse 1 g of propranolol hydrochloride in 15 ml of anhydrous chloroform, and mix with ethyl malonyl chloride.
A solution of 0.85 ml of loride) dissolved in 20 ml of anhydrous chloroform was added dropwise, and the mixture was refluxed for 3 hours while bubbling nitrogen gas. After evaporation of chloroform, 30 ml of ether
Was added and the mixture was washed three times to remove ethylmalonyl chloride to obtain 0.7 g of a white solid. This was recrystallized from an isopropanol-ether system to obtain 0.5 g of white crystals.

Yield 37%.

Example 5 Preparation of methylsuccinyl propranolol hydrochloride Disperse 1 g of propranolol hydrochloride in 15 ml of anhydrous chloroform and add methyl succiny chloride.
A solution of 0.85 ml of chloride) dissolved in 20 ml of anhydrous chloroform was added dropwise, and the mixture was refluxed for 3 hours while bubbling nitrogen gas. After evaporation of chloroform, ether
30 ml was added and the mixture was washed 3 times to remove methylsuccinyl chloride to obtain 1.3 g of a white solid. The crystals were recrystallized from an isopropanol-ether system to obtain 1.24 g of white crystals. 88% yield.

Example 6 Preparation of methylglutaryl propranolol hydrochloride Disperse 1 g of propranolol hydrochloride in 15 ml of anhydrous chloroform, and add methyl glutaryl chloride (Methyl
A solution of 1.0 ml of glutaryl chloride) dissolved in 20 ml of anhydrous chloroform was added dropwise, and the mixture was refluxed for 3 hours while bubbling nitrogen gas. After evaporating chloroform,
30 ml of ether was added and the mixture was washed 3 times to remove methylglutaryl chloride to obtain 1.4 g of a white solid. Recrystallization from an isopropanol-ether system gave 1.25 g of white crystals. 88% yield.

Table 1 shows measured values of elemental analysis of the compounds produced according to Examples 1 to 6 of the present invention. The difference between the measured value and the theoretical value was within 0.5%, which was in good agreement.

Further, FIG. 1 shows IR of isobutanoylpropranolol hydrochloride of Example 1, and FIG. 2 shows its NMR.

3 and 4 show IR and NMR of isovaleroylpropranolol hydrochloride of Example 2, and FIGS. 5 and 6 show methylmalonylpropranolol hydrochloride of Example 3.
IR and NMR, FIGS. 7 and 8 show IR and NMR of ethylmalonylpropranolol hydrochloride of Example 4, and FIGS. 9 and 10 show IR and NMR of methylsuccinylpropranolol hydrochloride of Example 5. 11 and 12 show IR and NMR of methylglutaryl propranolol hydrochloride of Example 6, respectively.

In IR, the appearance of a peak at 1700 to 1750 cm ^-1 based on the stretching vibration of the ester-derived carbonyl was observed. In addition, the peak of the ester portion was confirmed from the NMR chart.

From these elemental analysis, IR and NMR data, it was confirmed that the structures of the compounds synthesized in Examples 1 to 6 of the present invention had the structural formulas shown in the Examples.

Table 2 shows physical properties such as melting points of these compounds.

EFFECTS OF THE INVENTION Each compound of the present invention is added to a buffer solution (pH 1.2 to 7.4, μ = 0.15).
4) Alternatively, dissolve in human plasma to 1 × 10 ^-4 M
Incubated at 37 ° C. The concentration of each compound and propranolol at each time was quantified by HPLC, and the hydrolysis rate constant was calculated from the decrease pattern of each compound.

 The quantification conditions by HPLC are as follows.

Equipment: Hitachi model 655 Column: LiChrosorb RP-18 Select B Flow rate: 1.0 ml / min Mobile phase: pH 4.3 Phosphate buffer-acetonitrile (1: 1) Detection wavelength: 290 nm pH7.4 at 37 ° C The residual rate of the compound is shown in FIG.

All of each compound was converted to propranolol according to the first-order rate, and no other degradation products were observed.

In addition, 1 of hydrolysis at each pH and plasma
Order rate constant [K (min ^-1 )] and half-life [t _1/2 (mi
n)] is shown in Table 3.

At pH 7.4, the hydrolysis rate slowed down when the alkyl side chain had a branch as seen in the ester form of Example Compound 1. Further, in the case of the double ester form of Example Compounds 3 to 6, the hydrolysis rate is high, and particularly from the viewpoint that Example Compounds 3 and 4 have a significantly higher hydrolysis rate than Example Compounds 5 to 6, It was revealed that the hydrolysis rate was significantly affected by the length of the group. These results indicate that the hydrolysis by the hydroxyl group largely contributes to the steric factor as well as the hydrophobicity of the ester portion.

In addition, the half-life in plasma of the double ester is pH 7.4 because the hydrolysis by the enzyme is added to the hydrolysis in plasma.
It is several times shorter than in. On the other hand, in the case of the branched ester, hydrolysis in plasma did not change much from the half-life observed at pH 7.4. Therefore, the enzymatic degradation is largely dependent on the steric effect of the ester group, and the branched ester undergoes almost no enzymatic degradation.

All compounds of the present invention were not decomposed at pH 1 to 4 and slightly decomposed at pH 6. Therefore, when these compounds are orally administered, they are hardly decomposed in the stomach and upper part of the small intestine, and are not decomposed into propranolol only after being absorbed by pH and enzymatic action. As a result, it is possible not only to avoid the first-pass effect, but also to develop compounds having excellent characteristics as prodrugs of propranolol, such as those having fast-acting effect and those having sustained-release property by selection of ester. it can.

[Brief description of the drawings]

FIG. 1 shows the IR of isobutanoylpropranolol hydrochloride of Example 1, and FIG. 2 shows its NMR. Third
FIGS. 4 and 5 show IR and NMR of isovaleroylpropranolol hydrochloride of Example 2, FIGS. 5 and 6 show IR and NMR of methylmalonylpropranolol hydrochloride of Example 3, and FIG. And FIG. 8 are IR and NMR of ethylmalonylpropranolol hydrochloride of Example 4, FIGS. 9 and 10 are IR and NMR of methylsuccinylpropranolol hydrochloride of Example 5, FIG. 11 and FIG. FIG. 12 shows IR and NMR of methylglutaryl propranolol hydrochloride of Example 6, respectively. In addition, FIG. 13 shows the pH of the compound of the present invention of 7.4 (μ = 0.154),
The residual rate of hydrolysis at 37 ° C for each time is shown. △ is the compound of Example 1, ▼ is the compound of Example 3, □ is the compound of Example 4, and ■ is the compound of Example 5, Shows the compound of Example 6, respectively.

 ─────────────────────────────────────────────────── --Continued Front Page (56) References US Pat. No. 4201866 (US, A) International Journal of Pharmaceuticals, 1988, 42 (1-3), 51-60 Drug Development and Industrial Pharma, 131987, 13 (1987). 9-11), 2017-2031

Claims (1)

(57) [Claims] 1. A propranolol derivative represented by the following general formula or a hydrochloride thereof. (Wherein R is _{-CH (CH 3) 2, -CH} 2 -CH (CH 3)
_{2, -CH 2 COOCH 3, -CH} 2 COOC 2 H 5, - (CH 2) 2 COOCH 3 or - (CH ₂₎ shows a ₃ COOCH ₃ groups)