JPS6054955B2 - β-Aminopropiophenone derivative, its non-toxic salt and its manufacturing method - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula (I) (wherein R is a methyl group or an ethyl group, Rl and R2 are each a lower alkyl group or both are combined, and 1N<P1, a pyrrolidino group, It represents a piperazino group, a morpholino group, or a 4-methylpiperazino group.

) β-aminopropionphenone derivative represented by
This invention relates to its non-toxic salt and its production method. The compounds of the invention exhibit novel and highly specific bronchodilator effects.

Many of the bronchodilators currently used to treat diseases associated with tracheal abnormalities such as asthma are beta-adrenergic receptor stimulants, such as isoproterenol, terbutaline, salbutamol, and trimetoquinol. Its pharmacological action is based on dilating the tracheal muscles by stimulating adrenergic beta receptors in the tracheal muscles.
However, since all of these drugs act on the body's adrenergic beta receptors that exist in areas other than the tracheal muscles, clinically they cause serious side effects such as heart palpitations, vasodilation, and tremors. It is known. Therefore, when administering these drugs, there is a serious drawback in that the above-mentioned side effects must be carefully considered depending on the patient's condition. Therefore, it is essential that the currently desirable bronchodilators act selectively only on the tracheal muscles. Therefore, the present inventors have developed a new product that eliminates the above drawbacks. As a result of various studies to develop a drug, we found that the compound represented by the above general formula (1), unlike conventional adrenergic β receptor stimulants, selectively acts on the tracheal muscles and causes relaxation. Its action on the heart and blood vessels is extremely weak, and its mechanism of action and chemistry are limited. It was discovered that it is structurally useful as a new type of bronchodilator.

The present invention was completed based on the above findings. Since the novel compound of the present invention has at least one asymmetric carbon in the molecule, there are theoretically two optical/optical isomers, so the present invention includes racemates and optical isomers. It is something to do.

The optically active form is obtained by a known method from the racemic form, for example, by forming a salt with an optically active acid, then separating the two formed diastereomeric salts, and isolating the optical isomer from each diastereomeric salt. This can be obtained by On the other hand, as a compound similar to the compound of the present invention, the general formula (
Compounds in which R is substituted with an n-propyl or n-butyl group in 1) are known, but they are known as local anesthetics (see Patent No. 426718) and have bronchodilatory effects like the compounds of the present invention. is not known.

Representative compounds represented by general formula (1) of the present invention are as follows.

Compound No. Compound name (1) 1-(4″-methylthiophenyl)-3-dimethylamino-2-methylpropanone-1(2) 1-(4″)
-methylthiophenyl)-3-diethylamino-2-methylpropanone-1(3)1-(4″-methylthiophenyl)-3-pyrrolidino-2-methylpropanone-1(
4) 1-(4″-Methylthiophenyl)-3-piperidino-2-methylpropanone-1(5) 1-(4″-methylthiophenyl)-3-morpholino-2-methylpropanone-1(6)1- (4″-methylthiophenyl)-3
1(4″5-methylpiperazino)-2-methylpropanone-1(7)1-(4″1-ethylthiophenyl)-3-
Dimethylamino-2-methylpropanone-1(8)1-
(4″-ethylthiophenyl)-3-diethylamino-2-methylpropanone-1(9) 1-(4″-ethylthiophenyl)-3-pyrrolidino-2-methylpropanone-1(111-(4″) 1-ethylthiophenyl)-3-piperidino-2-methylpropanone-1(11)1-(4
``1-ethylthiophenyl)-3-morpholino-2-methylpropanone-1U2) 1-(4''-1-ethylthiophenyl)-3-(4''-methylpiperazino)-2-methylpropanone-1 Clinical bronchodilator effect In order to experimentally evaluate the effects and side effects, InvitrO
A guinea pig tracheal specimen and an in situ dog tracheal bed blood perfusion specimen were used.For the latter study, a canine femoral artery blood vessel specimen, a dog tracheal vascular bed blood perfusion specimen, and a dog right atrial blood perfusion specimen were used. The selectivity for the trachea was expressed as the ratio of the former to the latter, and compared with isoproterenol, an existing general bronchodilator.

Furthermore, we conducted experiments using mice as an indicator of systemic toxicity.

The approximate 50% lethal dose is shown in Table 1. Pharmacological evaluation method (1) To compare the pharmacological effects of each compound, the effect of relaxing isolated tracheal muscles in guinea pigs and the effect of increasing blood flow in the femoral artery of anesthetized dogs were used.

The tracheal muscle relaxing effect is determined by the molar concentration of the drug required to relax 50% of the isolated tracheal muscle contracted with 10-4 M histamine (
In 4), the blood flow increasing effect was expressed as the Pg dose (B) of the drug during proximal arterial injection required to increase the blood flow by 330 m1/min. In addition, BIA was used as an index representing the selectivity of each compound to tracheal muscles, and the BIA value of each compound was calculated when the value of isoproterenol was set to 1. That is,
The larger this value is, the higher the selectivity for the trachea is. Table 1 shows the results for the main compounds of the present invention. )) In order to confirm the medicinal efficacy of the above compounds under conditions more similar to those of living organisms, we used blood perfusion specimens from the tracheal vascular bed of dogs. The effectiveness of this drug was compared with that of existing bronchodilators.

The effect of reducing intratracheal pressure is the dose (C) required to reduce the internal pressure by 2 micrograms, and the effect of increasing tracheal perfusion blood flow is the dose (C) required to reduce the intratracheal pressure by 5 micrograms.
expressed in μg dose (2) required to increase m1/min;
DIC was used as an index representing selectivity, and calculations were made with isoproterenol as 1. The results are shown in Table 1.
3) The effect of the above compound on the heart was investigated using blood perfusion in the isolated right atrium of a dog.

The drug is administered intraarterially, and the change in sinus rhythm E (beat rate/min) is measured.
It was expressed as The results are shown in Table 1. 4) Using acutely toxic mice, the approximate 50% lethal dose upon intraperitoneal administration was determined.

The results are shown in Table 1. The above results revealed that the compound of the present invention acts more selectively on tracheal muscles than existing bronchodilators. (5) Next, in order to prove that the bronchodilator effect of the compound of the present invention is not due to the stimulation of adrenergic β receptors, we used the specimens from pharmacological evaluation method (1) to demonstrate that propranolol, an adrenergic β blocker,
The relaxing effect in the presence of 10-7g Im1) was investigated.

The results are shown in FIGS. 1, 2, and 3, and these figures will be explained below. Figure 1 shows compound No. (4), Figure 2 shows compound No. (11 effects are shown. First, 10-4 M of histamine is administered to a guinea pig isolated trachea specimen to cause it to contract. The degree of inhibition at each concentration of the drug is plotted on the vertical axis, and the results are connected and shown with a solid line.) , Next, the dose-effect curve of the same drug when 2.5 x 10-5 M of propranolol is added to this drug is similarly shown with a dotted line.Comparing the solid line and the dotted line in the figure, it is found that There was no difference.This indicates that the beta-stimulatory effect of this drug is extremely small.

On the other hand, looking at Figure 3 for isoproterenol, which is said to exhibit a typical β-stimulating effect, there is a difference between isoproterenol alone (solid line) and in the coexistence of propranol (dotted line). The difference is significant.

This indicates that isoproterenol has a large β-stimulating effect. From the above experimental results, it has become clear that the compound of the present invention, unlike isoproterenol, does not have a β-stimulating effect, but exhibits a tracheal muscle dilating effect through another mechanism of action.

The compound represented by the general formula (1) of the present invention can be produced by the method shown by the following formula.

(In the formula, R.Rl and R2 have the same meanings as above, and m is an integer of 1 or more.

The compound represented by the above general formula (■) is 1-(4
'-Methylthiophenyl)propanone-1 and 1-(4
``1-ethylthiophenyl)propanone-1 has the general formula 0
Compounds represented by D include formaldehyde and paraformaldehyde.

Examples of the compound represented by the general formula (■) include dimethylamine, diethylamine, di-n-propylamine, di-1-propylamine, di-n-butylamine, pyrrolidine, piperidine, piperazine, morpholine, and 4-methylpiperazine. The salts thereof, preferably the hydrochloride, are usually used.

To produce compound 0) of the present invention according to the above formula, the general formula (■
) and the general formula (■
) or more than 1 equivalent, preferably 1.5 to 2.0 equivalents of formaldehyde or paraformaldehyde represented by formula (■) and 1.0 to 1.1 equivalent of a secondary amine salt represented by general formula (■), preferably a hydrochloride. The so-called Mannitz reaction, in which equivalent amounts are reacted in a lower alcohol such as ethanol or butanol, may be used.

In this case, the reaction is preferably carried out around the boiling point of the solvent for a period of 3 to 151 hours. To isolate the target product from the reaction mixture, first distill off the solvent, add water to the resulting residue to dissolve the contents, and then neutralize with an alkali such as caustic soda, caustic potash, soda carbonate, sodium bicarbonate, or ammonia. The precipitated crystals or oil may be extracted with a non-hydrophilic organic solvent such as ether, benzene, or chloroform, and the extract may be washed with water and dried in a conventional manner, followed by distilling off the solvent. The compounds of the present invention thus obtained can be used, if desired, with various physiologically harmless inorganic and organic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, fumaric acid, It can be made into a pure product by forming acid addition salts with maleic acid, succinic acid, etc.

．． , [In the formula, R, Rl, and R2 have the same meanings as above, and νvio^J! (or)

] That is, probiophenones represented by the general formula (■) and secondary amines represented by the general formula (■) are mixed in a solvent that does not participate in the reaction, such as ethanol, chloroform, or benzene, at 0°C to room temperature or at room temperature as the case may be. In some cases, the reaction is allowed to occur for one hour to overnight near the boiling point of the solvent. 、． ．．
．． .

The compound (1) of the present invention thus obtained can be made into a pure product by purification in the same manner as described above.

The starting material (■) has the general formula (■) (In the formula, R has the same meaning as above.

) and methacrylic acid halide or α-
Halogenomethylpropionic acid halide and Friedel
It can be produced by condensation using a Crafts reaction. The present invention will be specifically explained below using Examples.

Example 1 Synthesis of 1-(4''-methylthiophenyl)-3-piperidino-2-methylpropanone-1 and hydrochloride Compound (1) of the present invention can also be produced by the following method.

1-(4'-methylthiophenyl)propanone-12
64.6g 1 rose formaldehyde 110. 196.6 g of Tsukuda and piperidine hydrochloride were added to 350 m of secondary butanol.
1, add 5.9 ml of concentrated hydrochloric acid, and heat under reflux for 4 hours.

After the reaction, butanol was distilled off under reduced pressure, and water was added to the residue.
eAdditionally perform ether washing. After that, the aqueous layer is neutralized with soda carbonate and the oily substance that separates is extracted with ether.
The ether layer is washed with water and then dried over anhydrous magnesium sulfate. After removing the desiccant, the ether is distilled off, resulting in 369.
3 g (yield 95.0%) of 1-(4″-methylthiophenine)-3-piperidino-2-methylpropanone-1 is obtained.IRl67OCm-1C=O NMR(CDCl3)Ppm: 1.15( 3H, d, J = 7.3 [1z, CH3-C)
1.40 (6H, m, -CH2-) 2.47 (311,
s, S-CH3) 2.1-3.0α old, M, N-CH2) 3.60 (1H, m, CH) 7.27 (2H, d, J=9.0Hz, 7.90 (2H , d, J=9.0Hz, -yo 5F)
When the above oil is dissolved in ether and hydrogen chloride gas is introduced into this solution, 1-(4″-methylthiophenyl) is produced.
-3-Piperidino 2-methylpropanone-1 hydrochloride is obtained.

Mpl46-149 obtained elemental analysis value (Cl6H24ClNOS) Calculated value C: 61.22%, H: 7.71%, N: 4.4
6% actual value C: 61.24%, H: 7.76%, N: 4
．． 36% Example 21-(4″monoethylthiophenyl)-
1-(4″-Methylthiophenyl) of Synthesis Example 1 of 3-piperidino-2-methylpropanone-1 and hydrochloride
When propanone-1 was replaced with 1-(4-ethylthiophenyl)propanone-1 and treated in the same manner, 1-(4″
1-ethylthiophenyl)-3-piperidi-1-2-methylpropanone-1 is obtained.

Yield 85.8% Hydrochloride Mpl58-1600C Elemental analysis (Cl7H26ClNOS) Examples 3 to 10 The reaction was carried out in the same manner as in Example 1, except that the reaction solvent was changed from butanol to ethanol, and the extraction solvent for the product was changed from ether to benzene. The following compound was synthesized.

Example 11 1-(4-ethylthiophenyl)-3-morpholino 2
-Synthesis of methyl-propanone-1 hydrochloride 1-(4'-monoethylthiophenyl)propanone-140.7g1 Morpholine hydrochloride 25.94g and paraformaldehyde9.
Add 46g to 80ml of ethanol and add 1T of concentrated hydrochloric acid.
Add ILI and reflux for 1 full hour.

Crystals are obtained by distilling off the ethanol. When this was recrystallized from acetone, 58.93g (95.6%) of 1
-(4゛monoethylthiophenyl)-3-morpholino 2
-Methylpropanone-1 hydrochloride is obtained. Mpl6
O-161C elemental analysis value (Cl6H24ClNO2S
) Calculated value C: 58.25%H: 7.35%N: 4.25
% Actual value C: 58.27% H: 7.31% N: 4.17
% Example 121-(4″-monoethylthiophenyl)-3-
Synthesis of dimethylamino-2-methylpropanone-1 hydrochloride 1-(4″-1ethylthiophenyl)-3-dimethylamino-2-methylpropanone hydrochloride was synthesized in the same manner as in Example 11.

(Yield 75.7%) Mpl25-128℃

[Brief explanation of drawings]

Figure 1 shows the relationship between the dose-effect curves of Compound 4 of the present invention and a mixture of Compound 4 and propranolol, and Figure 2 shows the relationship between the dose-effect curves of Compound 10 of the present invention and a mixture of Compound 10 and propranolol of the present invention. FIG. 3 shows the relationship between isoproterenol and a dose-effect curve for a mixture of isoproterenol and propranolol.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R is a methyl group or an ethyl group, R_1 and R_2 are each a lower alkyl group or both together, ▲ Numerical formula, chemical formula, There are tables etc. ▼ for pyrrolidino group, piperidino group,
Indicates a morpholino group or a 4-methylpiperazino group. ) and a non-toxic salt thereof. 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R represents a methyl group or ethyl group.) A propiophenone derivative represented by formaldehyde or paraformaldehyde and the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 and R_2 are each a lower alkyl group or a combination of both, and ▲ has a mathematical formula, chemical formula, table, etc. ▼ indicates a pyrrolidino group, piperidino group, morpholino group, or 4-methylpiperazino group.) It is characterized by reacting the following secondary amines. A method for producing a β-aminopropiophenone derivative and its non-toxic salt represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R, R_1 and R_2 have the same meanings as above.)