JPS5940828B2 - β-Aminopropiophenone derivative, its non-toxic salt and its production method - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula (1) (wherein R is a lower alkyl group, benzyl group, or phenyl group, R1 and R2 are each a lower alkyl group, or both are combined and adjacent nitrogen atoms and represents a saturated nitrogen heterocycle which may be substituted with a lower alkyl group, and n represents an integer of 1 or 2.

), a non-toxic salt thereof, and a method for producing the same. The compounds of the invention are new and exhibit very specific bronchodilator effects. Many of the bronchodilators currently used to treat diseases such as asthma that involve tracheal abnormalities include isoproterenol,
It is an adrenergic beta receptor stimulant, typified by terbutaline, salbutamol, trimetoquinol, and the like. Its pharmacological action is based on dilating the tracheal muscles by stimulating the adrenergic beta receptors in the tracheal muscles. However, since all of these drugs act on the body's adrenergic β receptors, which exist in areas other than the tracheal muscles, clinically, serious side effects such as heart palpitations, vasodilation, and chest tremors may occur. Are 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 conducted various studies to develop a new drug that eliminates the above drawbacks, and found that the compound represented by the above general formula (1) differs from conventional adrenergic β receptor stimulants in that it is selectively effective. It was discovered that it acts on the tracheal muscles, causing relaxation, and has extremely weak effects on the heart and blood vessels, making it useful as a new type of bronchodilator that is unprecedented in terms of its mechanism of action and chemical structure.

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 isomers, so the present invention includes racemates and optical isomers. It is.

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, separating the two formed diastereomeric monosalts, and isolating the optical isomer from each diastereomeric salt. This can be obtained by Representative compounds represented by general formula (1) of the present invention are as follows.

Next, the pharmacological action of the compound of the present invention will be explained.

In order to experimentally evaluate the bronchodilatory effect and side effects in clinical practice, we used guinea pig isolated trachea specimens at InvitrO and dog tracheal vascular bed blood perfusion specimens at InSitU for the former study, and dog femoral specimens for the latter study. Using arterial blood vessel specimens, canine tracheal vascular bed blood perfusion specimens, and canine isolated right atrial blood perfusion specimens, the selectivity for the trachea was expressed as the ratio of the former to the latter. It was praised as teleno nore. Furthermore, we conducted experiments using mice as an indicator of systemic toxicity.

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 A), the blood flow increasing effect was expressed as the μ dose of drug during proximal arterial injection required to increase blood flow by 30 ml/min (B). In addition, B/A was used as an index representing the selectivity of each compound to tracheal muscles, and the B/A value of each compound was calculated when the value of isoproterenol was set to 1. In other words, 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 compound under conditions closer to living organisms, we used a blood perfusion specimen of the canine tracheal vascular bed. The reduction in intratracheal pressure (tracheal dilation effect) and increase in perfusion blood volume (vasodilator effect) during close intra-arterial injection were compared with existing bronchodilator drugs.

The effect of reducing intratracheal pressure is expressed by the μy dose (Q) required to reduce the internal pressure by 200rrLH20, and the effect of increasing tracheal perfusion blood flow is expressed by the μ?dose required to increase the blood flow by 5 m1/min, and the selectivity is expressed by D/ Calculations were made using C and isoproterenol as 1. The results are shown in Table 1. 3) The effect of the above compound on the heart was investigated using blood cross 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.

Table 1 shows the results! C shown. 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 stimulation of adrenergic β receptors, we used the specimen of pharmacological evaluation method (1) to demonstrate that the bronchodilator effect of the compound of the present invention is not due to stimulation of adrenergic β receptors. /ml) was investigated.

The results are shown in Figures 1 and 2, and Figure 1 will be explained below.

Figure 1 shows the action of the present compound 06). First, 10-4 M of histamine was administered to a guinea pig isolated trachea specimen to cause it to contract. The degree of inhibition at each concentration of the drug was plotted on the vertical axis. are shown with a solid line, and then the dose-effect curve of the same drug when 2.5 x 10-5M of 1-propranolol is added to this drug is similarly shown with a dotted line*. be. Comparing the solid line and the dotted line in this figure, there is not much difference. This indicates that this drug does not have a β-stimulating effect. On the other hand, if you look at Figure 2 for isoproterenol, which is said to exhibit a typical β-stimulating effect, there is a noticeable difference between isoproterenol alone (solid line) and propranolol in the coexistence (dotted line). It is.

This indicates that isoproterenol has a large β-stimulating effect. The above experimental results revealed that the compound of the present invention, unlike isoproterenol, does not have a β-stimulating action, but exerts its tracheal muscle dilation action 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.

etc. Examples of the compound represented by the general formula () include formaldehyde and paraformaldehyde.

Compounds represented by the general formula () include dimethylamine, diethylamine, -di-1-propylamine, di-1-propylamine, di-1-butylamine, pyrrolidine, piperidine, piperazine, morpholine, and 4-methylpiperazine. etc., and their salts, preferably hydrochlorides, are usually used.

To produce the compound represented by the general formula (1) of the present invention according to the above formula, 1 equivalent of the propiophenone represented by the general formula () and 1 equivalent or more of formaldehyde or paraformaldehyde, preferably 1.5 to 2. 0 equivalent and general formula (
The reaction may be carried out by the so-called Mannitz reaction in which 1.0 to 1.1 equivalents of a salt of a secondary amine represented by (), preferably a hydrochloride, are reacted in a lower alcohol such as ethanol or butanol.

In this case, the reaction is preferably carried out for 3 to 12 hours near the boiling point of the solvent. To isolate the target product from the reaction mixture, first distill the solvent off, 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, and then the solvent may be distilled off. If the compound obtained above is a thio compound, it can be oxidized with an oxidizing agent such as hydrogen peroxide, or if it is a sulfinyl compound, it can be oxidized with an oxidizing agent as necessary to form the desired general formula (1). It can be a compound represented by:

That is, the inorganic acid or organic acid salt of the compound to be oxidized is dissolved or partially dissolved in water, methanol, ethanol, or a mixed solvent of water-methanol or water-ethanol, and then dissolved in 1 or 2 equivalents of hydrogen peroxide or peroxide. Add sodium iodate, etc. at a temperature of 0°C to room temperature and react for several hours to overnight. After the reaction,
The purpose is to remove the alcohol, neutralize with an alkali such as caustic soda, caustic potash, soda carbonate or bicarbonate, or ammonia, extract the precipitated substance with a solvent, dry the extract with a normal desiccant, and then distill off the solvent. You can get things.

The compound represented by the general formula (1) thus obtained may be recrystallized in a suitable solvent such as dighexane to obtain a pure product, or optionally may be mixed with various physiologically harmless inorganic and organic acids, such as Formation of acid addition salts with hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, fumaric acid, maleic acid, succinic acid, etc., and precipitation as crystals. It can be extracted as a pure product.

Incidentally, the compound of general formula (), which is a starting material used in the present invention, can be synthesized as follows.

That is, general formula (V) (wherein R and n1 have the same meanings as above).

) can be synthesized by condensing the compound represented by propionic acid with lard using the Friedeno-Crafts reaction. Also, in the general formula (), n1
A compound in which n1 is 1 or 2 can also be obtained by oxidizing a thio compound in which n1 is O with an oxidizing agent such as hydrogen peroxide or sodium metaperioate.

*Also, the compound represented by the general formula (I) of the present invention can also be produced by the following method.

[In the formula, R, RhR2, nl and n have the same meanings as above, and Y is -C=CH2 or -CH-CH2X
(Here, X is a halogen atom).

] That is, propiophenones 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, benzene, etc. at o ℃ to room temperature or as the case may be. The reaction was then carried out for 1 hour to overnight near the boiling point of the solvent, and hereafter Y was -CHCH2X
In the case of , by the same treatment as in the case of the reaction formula (^), and in the case of Y is 1 C-CH2, by distilling off the solvent, and when nl is O, nl is 1 In this case, if desired, it can be further oxidized with an oxidizing agent.

The compound represented by the general formula (I) thus obtained is:
It can be made into a pure product by recrystallizing it in an appropriate solvent, or by converting it into an appropriate salt (salt of an inorganic or organic acid) and extracting it as a crystal. Starting material ()
is - general formula (v) (wherein R and nl have the same meanings as above.

) and methacrylic acid halide or α-
Halogenomethylpropionic acid halide and Friedel
It can be produced by condensation using a Crafts reaction. Next, compounds when nl represents o in general formula (), compounds of general formula (), and general formula ()
The following general formula () (in the formula, R, R, and R2 have the same meanings as above) is obtained by the reaction of the compound.

) will be specifically described using reference examples. By oxidizing this thio compound, it can be converted into a sulfinyl compound or a sulfonyl compound represented by the general formula (I) of the present invention. Reference Example 1 Synthesis of 1-(4'-methylthiophenyl)-3-piperidino-2-methylpropanone-1 1-(4'-methylthiophenyl)propanone-1264.6y (1.47
mole), paraformaldehyde 110.49, piperidine hydrochloride 196.6? and 300ml of secondary butanol
5.9 ml of concentrated hydrochloric acid was added to the mixture, and the mixture was heated under reflux for 4 hours.

After the reaction is completed, butanol is distilled off under reduced pressure, and water is added to the residue for washing with ether. Thereafter, the aqueous layer is neutralized with sodium carbonate, and the separated oil is extracted with ether. The ether layer is washed with water and dried over anhydrous magnesium sulfate. After removing the desiccant, the ether is distilled off to give an oily 1-(4'-methylthiophenyl)-3-piperidino-2-methylpropanone-1369.3? (Yield 90.5
%) is obtained. Rl67OCTfL-1C-0 NMR (CDCl3)Ppm; 1.15 (3H..d..J-7.3Hz,.CH3-
C) 1.40 (6H..m, -CH2-) 2.47 (3
H1S,. S-CH3) 2.1-3.0 (6H,.m..N-CH2) 3.60
(1H..m,.CH) When the above compound is dissolved in ether and a salt arsenic gas is introduced into this solution, 1-(4'-
Methylthioenyl)-3-piperidino-2-methylpropanone mono-11 hydrochloride is obtained.

1p146-149 L elementary analysis value (Cl6H24ClNOS) Calculated value; C: 61.22% 7,71% N: 4.4
6% actual value; C: 61.35% 7.90% N: 4
,70%? Examples 2 to 11 The following compounds were synthesized in the same manner as in Reference Example 1.

Next, a method for producing a compound in which nl is 1 or 2 in the general formula (■) will be specifically explained using reference examples. Reference example 121
-(4'-n-propylsulfinyl phenyl)
Synthesis of propanone-1 1-(4'-n-propylthiophenyl)propanone-1 20.83 ml of methanol 6
0 ml, add 2 ml of sodium metaperioate to this solution.
2.4 Drop an aqueous solution containing 69.

After completion of the dropwise addition, the mixture was stirred at room temperature overnight, then methanol was distilled off, the residue was extracted with chloroform, the chloroform layer was washed with water, and then dried over anhydrous magnesium sulfate. Crystals are obtained by filtering and concentrating the magnesium sulfate. This was recrystallized from benzene-hexane and 2 0.8
y (yield 94.5%) of 1-(4'-n-propylsulfinylphenyl)propanone-1 is obtained. m
p 53-56℃ elemental analysis value (C1.

H1602S) Calculated value; C: 6 4.25% H: 7
．． 19% actual value; C: 6 4.38% H: °7.3
9%IR (KBr): 1 674CTfL-1 C=0
1020 -1 SO Reference Examples 13-14 The following compounds were synthesized in the same manner as in Reference Example 12.

Reference Example 15 Synthesis of 1-(4'-methylsulfonylphenyl)propanone-1 1-(4'-methylmercaptophenyl)
Propanone-1 108.2k and 30% hydrogen peroxide 12
Heat 2.5 ml of the mixture to reflux for 15 hours.

After the reaction is complete, the mixture is poured into ice water, and the precipitated crystals are collected by filtration and washed with water.

The crystals are dried and then recrystallized from ethanol. Yield 7 1. ly yield (5 6.3%) mp106-10
8°C elemental analysis value (C,o H12 03 S) Calculated value; C: 5 6.5 8%, H: 5.7 0% Actual value; C: 5 6.71%, H: 5.7 3% Reference Examples 16-20 The following compounds were synthesized in the same manner as in Reference Example 15.

The manufacturing method of the present invention will be specifically explained below with reference to Examples.
1 example
Synthesis of 11-(4'-n-propylsulfinyl phenyl)-13-diethylamino-2-methylpropanone and fumarate 1-(4'-n-propylsulfinyl phenyl) oligopropanone -16.73'7, diethylamine hydrochloride 6.57? and paraformaldehyde2.
Add 0y to 20ml of ethanol, and add 0.2ml of concentrated hydrochloric acid to this.
Add m1 and react under reflux for 24 hours.

After the reaction, ethanol was distilled off under reduced pressure, water and chloroform were added to the residue, and the chloroform-soluble portion was removed.
Cool the aqueous layer with ice and neutralize it by adding carbonate of soda. The precipitated oil is extracted with ether, and the ether layer is washed with water and dried over anhydrous magnesium sulfate. Drying* (Remove the agent and distill off the ether to obtain 1.437 (yield 15.3%) of 1-(4-propylsulfinyl phenyl)-3-diethylamino-2-methylpropanone-1. When this oily 1-(4'-n-propylsulfinyl phenyl)-3-diethylamino-2-methylpropanone is added to an acetone solution containing an equivalent amount of fumaric acid and left to stir, crystals precipitate. This is collected by suction filtration and dried. Melting point: 118-119℃ Elemental analysis value (C2l
H3lNO6S) Calculated values; C: 59.27%, H: 7.34%, N: 3.
29% actual value; C: 59.53%, H: 7.30%, N
:3.50% Examples 2 to 7 The following compounds were synthesized in the same manner as in Example 1.

Example 81-(4'-methylsulfonylphenyl)-
Synthesis of 3-piperidino-2-methylpropanone-1 and hydrochloride 1-(4'-methylsulfonylphenyl)propanone-110.61y1 Piperidine hydrochloride 6.07 and paraformaldehyde 2.25? 15m of ethanol
In addition to 1, 0.2 ml of concentrated hydrochloric acid was added for 15 hours.
Reflux.

After that, extraction is performed by adding water and chloroform, and the aqueous layer is made alkali-based with sodium carbonate, and extracted with chloroform. The chloroform layer is washed with water, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated to obtain crystals. Recrystallizing this crystal with ether gives 10.23
? (yield 66.2%) of 1-(4'-methylsulfonylphenyl)-3-piperidino-2-methylpropanone-1 was obtained. Mp8l. 5-82 pu C0IR (KBr
)(?-1);1674:C=0,131011290
, 1150: SO2NMR (CDCl3) (Ppm):
1.17 (3H.d1J-7, 25Hz,.CH3-C
) 1.38 (6H,.m,.CH2)
*1ass (M+/e) 279 elementary analysis value (Cl
6H23NO3S) Calculated values; C: 6211%, H: 7.49%, N: 4.5
3% actual value; C: 61.95%, H: 7.39%, N:
4.45% The above crystals are dissolved in ether and hydrogen chloride gas is introduced to obtain the hydrochloride.

1P144-147℃ ] Elementary analysis value (Cl6H24ClNO3S) Calculated value; C
: 55.56%, H: 6.99%, N: 4.05% Actual value; C: 55.38%, H: 7.21%, N: 4.23
% Examples 9 to 29 The following compounds were synthesized in the same manner as in Example 8.

Example 30 Synthesis of 1-(4'-methylsulfinylphenyl)-piperidino-2-methylpropanone-1 and fumale 1-(4'-methylthiophenyl)-
3-piperidino-2-methylpropanone-1 hydrochloride 1
Dissolve 3.0y in 120ml of water and add 30% to this at 5℃.
Drop 7.15 m of hydrogen peroxide.

After that, the mixture was stirred at room temperature overnight, and the by-products were removed by extraction with chloroform. The remaining aqueous layer was neutralized with sodium bicarbonate, extracted again with chloroform, and the chloroform layer was washed with water and dried over magnesium sulfate. After removing the drying agent, recrystallization with chloroform-hexane yields 1-(4'=methylsulfinylphenyl)-3-piperidino-2=methylpropanone-1 in 9.74y (yield 8 2.3
%)can get. mp 79-8 1℃IR (KBr
)(cwL-1): 1 6 8 0, C=0, 105
0, SONMR (CDC13) (ppm): 1.18 (
3 H,. d) J=6.81Hz,. CH3-C)1.
4 o(6H,.m,.CH2-C)-2.78(3
H,. s,. CH3=S)2.2~3.0(6
H,. m,. CH2-N)゛3.7 0(IH)m)
CH) Mass (M+/e): 2 9 3 This base 5.8 9 y is fumaric acid 3.4 8 ? When added to 5 oOml of acetone containing acetone and stirred, crystals begin to precipitate.

When this is filtered and dried, fumarate is 7.2 7
y (yield 77.6%) is obtained. mp127-128
°C elemental analysis value (C2o H27 N06 S) calculated value; C: 58.6 6%, H: 6.6 5%, N: 3
．． 4 2% actual value; C: 5 8.8 7%, H: 6
．． 7 2%, N: 3.5 3% Examples 31-42 The following compounds were synthesized in the same manner as in Example 30.

[Brief explanation of the drawing]

Figure 1 shows the relationship between the dose-effect curve of the compound of the present invention and the mixture of the compound of the present invention and propranolol, and Figure 2 shows the relationship between the dose-effect curve of isoproterenol and the isoproterenol-propranolol mixture. be.

Claims (1)

[Claims] 1 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Denotes a saturated nitrogen heterocycle which may be substituted with a lower alkyl group together with the adjacent nitrogen atom, where n is 1
or an integer of 2. ) A β-aminopropiophenone derivative and its non-toxic salt. 2 Propiophenone derivatives represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R represents a lower alkyl group, benzyl group, or phenyl group, and n_1 represents an integer of 0, 1, or 2.) , formaldehyde or paraformaldehyde, and the general formula ▲ Numerical formula, chemical formula, table, etc. When n_1 is 0, if n_1 is 1, it is optionally further oxidized with an oxidizing agent. General formulas characterized by non-toxic salts ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formulas, R, R_1 and R_2 have the same meanings as above,
n represents an integer of 1 or 2. ) A method for producing a β-aminopropiophenone derivative and its nontoxic salt.