JPS60233053A - Aminoacetic acid derivative and application to medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to N-(3-phenylmethylthio-1-oxopropyl)aminoacetic acid derivatives, processes for their production, and pharmaceutical compositions containing them.

The present invention relates to the following general formula: [wherein R1 is 1 or 2 halogen atoms, 1 or 2 methyl groups, trifluoromethyl, methoxy,
When R2 is a cyano, nitro, carbamoyl or benzoyl group, a fused benzene nucleus, or (3-indolyl)methyl or 2-methylthioethyl, R1 may represent a hydrogen atom, and R7 is a hydrogen atom or a linear Alternatively, a branched C1-4 alkyl group, a carbamoylmethyl or 2-carbamoylethyl group, a 2-methylthioethyl group, a benzyl group optionally substituted with a hydroxyl group, or (
The present invention provides aminoacetic acid derivatives in the form of enantiomers or mixtures thereof, or pharmacologically acceptable salts thereof.

The compound represented by formula (1) is a free acid and can form a salt with a pharmacologically acceptable base.

When R7 is not a hydrogen atom, the molecule of the aminoacetic acid derivative according to the present invention contains an asymmetric carbon atom.

This derivative may therefore exist in the form of two enantiomers, which together with mixtures thereof are included within the scope of the invention.

The method for producing the compound of formula (I) is illustrated by the following reaction formula.

This reaction step consists of three reaction steps of a known type in which a halogen derivative (U) bearing nine selected substituents R1 is first reacted with mercaptopropionic acid in a basic aqueous medium such as aqueous NaOH.

The acid (1) thus obtained is converted to acid chloride (IV) by reacting with thionyl chloride, and this acid chloride (■) is reacted with an amino acid of the formula Ht N CHOOH and the first step. React under similar reaction conditions.

The obtained compound of formula (1) can also be converted to the 2-su compound (() by converting the substituent RI.

For example, a cyano group can be hydrolyzed to a carbamoyl group. Furthermore, the compound of formula (1) can also be converted into a salt by reacting with a base.

Examples are given below to illustrate the method for producing the compound according to the present invention. The structure of the obtained compound was confirmed by IR and NMR spectra and elemental analysis.

Example I N-[(2-chlorophenyl)-3-methylthio-1-oxopropyl]aminoacetic acid 3-mercaptopropionic acid 2+, 2 g (0.2 mol), water 1601,
A mixture of 16 g (0.4 mol) of sodium hydroxide and 32.2 g (0.2 mol) of -chloro-2-chloromethylbenzene is vigorously stirred at 70 DEG C. in a round-bottomed flask.

- After 15 minutes, add about 150 g of ground water, then 12N
Add 20jII2 of hydrochloric acid. Collect the precipitate, wash with water and dry. This was taken in a mixture of benzene+00112 and thionyl chloride 21.9j+ff (0.3 mol) and heated under reflux for 2 hours.

The solvent was distilled off under reduced pressure, and the residue was mixed with 100 ml of water, 30 g (0.4 mol) of glycine and 1 mol of sodium hydroxide.
69 (0.4 mol) at 0° C. with vigorous stirring. One crystal forms at a temperature of about 10°C and dries. M, P,: l 01-102°C.

After stirring for 5 minutes, the mixture was diluted with 1 volume of water and
Add 40 liters of 12N hydrochloric acid. The obtained precipitate was collected, washed, and reconstituted from an ethanol/water mixture. Example 2 N-[(4-carbamoylphenyl)' -
3-Methyldiotoxopropylcoaminoacetic acid a) Under the same conditions as in Example 1, first N-[(4-cyanophenyl)-3-methylthio-1-oxopropyl]aminoacetic acid is prepared. M, P: 116-118°C.

b) Next, 12 g (0,043 mol) of the above compound was dissolved in 100 x C of formic acid, and 0 to 1 liters of hydrogen chloride gas was added to this solution.
Bubble for 30 minutes at 0°C. Leave for 1 day at ambient temperature and protected from moisture. The mixture is distilled under reduced pressure and the residue is taken up in water, filtered, washed, recrystallized twice from methanol and once from a mixture of dimethylpolamide and water and dried. M, P, +206-208°C.

Guhuangsen 3 a-[3-(2-chlorophenylmethylthio)-l-oxopropylamino]-α-(l-methylpropyl)acetic acid 3-mercaptopropionic acid 21.21 J (0.2 mol), water 160 village, sodium hydroxide 16g (0.4 mo)
and l-chloro-2-chloromethylbenzene 32.2
9 (0.2 mol) is vigorously stirred at 70° C. in a round bottom flask. After 15 minutes, approximately 150 g of crushed ice is added and 20 d of 12N hydrochloric acid are added. Collect the precipitate, wash with water, and dry. This is benzene 100i1! and 219ml of thionyl chloride! (0.3 mol) and heated under reflux for 2 hours.

The solvent was distilled off under reduced pressure and the residue 14.99 was poured with 50 J11 of water cooled in a water bath at a rate that the temperature did not exceed 10° C. with constant vigorous stirring! , 1. -isoleucine 26
．． 2 g (0,2 mol) and 8 g (0
, 2 mol).

This mixture was stirred for 10 minutes without exceeding 10°C,
Then dilute with 50 ONIQ water and add 20 mQ concentrated hydrochloric acid. The formed crystals were left to stand, separated, washed with water, and passed through again. Dry after recrystallization from an ethanol/water mixture. M, P:, 108-109°C.

The physical properties and structures of other compounds according to the present invention produced in the same manner as in the above examples are shown in Table 1 below.

When the compounds according to the present invention were subjected to pharmacological experiments, it was found that these compounds are useful as mucus-destroying agents, anti-inflammatory agents, anti-ulcer agents, secretion suppressants and analgesics.

In order to examine mucus-disrupting activity, 1. , Re1d ("Experimental considerations on mucus hypersecretion during the bronchial phase 1," British Journal of Experimental Pathology, BriL, J.

Exp, PaLhol, )+ 96.3.44,437
), A, Q.

The method improved by Uevauviller et al.
on and Le Coeur, 1970, 26. No,
1.71-80) on an experimental model of sulfur dioxide bronchitis in rats. Sprague Dawley SPI? Male rats (Garles River, France) (average body weight 300 g) were used as experimental animals and randomly divided into groups using a dispersion table. 3 sulfur dioxide at a concentration of 500 or 600 100 m
Inhalation was given at 1 dose for 5 or 6 hours per day for 2 days. From day 4 to day 133, the animals were treated with a compound according to the invention at a rate of 61 kg I'OO per day. A control group of animals received only a 1% solution of Tween 80.

On days 8, 9 and 1, all animals were again inhaled with sulfur dioxide (300 ppm) for 1 or 2 hours and administered the compound of the invention or its vehicle.

Twenty-four hours after the last procedure, the animals are anesthetized with Pen I barbiturate and sacrificed by cutting the abdominal aorta. After cutting, the tracheobronchial system is buffered to pH 7 and fixed in Noko 10% formalin solution.

To assess tracheobronchial depression, the main bronchi and trachea are cut longitudinally, the tissue is fixed with alcohol, and the mucus is stained with 0.7% Alcian blue solution.

Endobronchial depressions are assessed in the major bronchial and tracheal regions of the left lung and right basal lobe. The main bronchi and trachea are conveniently divided into three parts (i.e., for the bronchi, the hilar 173, the middle 173 and the distal 1/3; for the trachea the upper 1/3 and the middle 173
and 173 at the bottom). The depressive zone was evaluated using binocular loupes in each 17'8 area.

Since mucus retention in the airways can have a variety of different macroscopic appearances, we have selected four basic forms of obstruction: deposits, nodular adhesions, secretions, and dense mucus plugs.

Each of these forms, excluding dense mucus plugs, can be differentiated into several types depending on the volume of the occlusion in question.

Estimate the retention volume for each animal by assigning to each observed shape a value corresponding to the volume occupied by this obstruction in the lumen of the bronchus or trachea of the l/3 segment tested. . That is, the number 1
5 corresponds to complete occlusion with a dense mucus plug occupying 100% of the bronchial or tracheal lumen, and the number 1 corresponds to minimal occlusion with a small amount of deposits occupying about 1/15 of the bronchial or tracheal lumen. Equivalent to.

The mucus-disrupting activity of a compound on the diseased tracheobronchial mucus depressive zone is determined by the overall reduction in the depressive zone, i.e. the volume of secreted mucus (average volume per animal and average volume per animal and per section). Expressed as a function of

In the bronchial region, the maximum score for the total amount of depressive zone is 90 (when 1/3 of the 6 bronchi are occluded with 6 dense mucus plugs: 6XI5 = 90), and the two main bronchial regions are Evaluate.

In the tracheal region, the total depressive zone volume is calculated as 3 1/3, with a maximum score of 45 (when 3 1/3 of the trachea is occluded by 3 dense mucus plugs: 3 x 15 = 45). Since we are only evaluating the area, we double the numbers to be able to relatively represent the endobronchial and endotracheal zones for each animal.

The total tracheobronchial depression value obtained by adding the endotracheal depression value and the endobronchial depression value equally accounts for both areas of pathological mucus depression.

Statistical analysis of the results obtained is performed using the non-parametric Man-Whit test.

It was found that animals treated with the compounds according to the invention reduced the overall volume of the tracheobronchial depression by up to 50% compared to control animals.

To examine the anti-inflammatory activity, we used the method of Winter et al.
Proc, Soc, Exp, Biol, Med
) 1962. Ill, 544-547) using carrageenan-induced edema in rats.

Sprague from Charles River (France)
Dawley S P F bull (average weight 1509
) were used as experimental animals and randomly grouped using a dispersion table.

Carrageenin 1% suspension in sterile physiological serum 0,
Test compounds 20 and 200 wti/kFI were administered orally 1 h before injection into the plantar membrane of the hind paw. Control animals received Tween 80 as a placebo.
Administer a 1% solution of The volume increase in the hind paw is measured 3 hours after carrageenin injection using a Yugo Paysail plethysmometer.

Results Compared to the control animal group, the edema volume of animals treated with the compounds according to the invention showed a 40% reduction at doses between 40 and 200 m9/kfl.

To investigate anti-ulcer activity, tests were performed on rat ulcers induced by phenylbutacin or ethanol. In these two models, female Wistar rats (I rfa Credo) were used, fasted for 18 hours, and randomly divided into groups using a dispersion table. 1 molar solution of phenylbutacin in sodium hydroxide (dose 20019/&9) or 50%
Ulcers are induced by oral administration of ethanol (dose @ 5 yzg/ky).

Test compounds are administered orally 30 minutes prior to administration of the ulcerogenic agent. Control animals received 1% of Towin 80 as a placebo.
Give only the solution.

Animals are killed by inhalation of chloroform 2 hours after administration of phenylbutacin or 1 hour after administration of ethanol. The stomach was removed and the degree of ulcer was evaluated in a blinded manner from 0 to 0.
It is evaluated on a 3-grade scale and the ulcer index (severity of ulcer x 100 percent of animals showing ulcer) is calculated.

■ The compound group of the present invention is 4 for phenylbutacin.
g9/kg to 151g/kg for ethanol9
5 compared to the control animal group for the ulcer incidence index.
Reduced by 0%.

In order to investigate the antisecretory activity of the stomach, Shay et al.
975', 5.43-61) by Passcard and Lauby (``Pharmacological studies on gastric antisecretory and ulcer protective thiocarboxamides'', Arzneim, forsc.
Tests were carried out on rats whose pylorus was ligated according to the method described by J. H., 1971.10.1547-1553).

The animals used were Wistar female rats (I fra Credo) with an average weight of 200 to 250 g.
After fasting for 8 hours, the animals were randomly divided into groups using a dispersion table. After gastric lavage with 4x (l) of physiological serum of Lukewara+, the pylorus is ligated under light ether anesthesia.

Test compounds are administered intraperitoneally immediately after pylorus ligation.

Control animals received 1% of Tween 80 as a placebo.
Administer the solution. Animals are killed after 4 hours by inhalation of chloroform. Remove the stomach contents and centrifuge. Gastric secretion, free acidity and total acidity are determined by titration.

The compounds of the present invention showed a 50-80% reduction in gastric acid secretion from a dose of 9/1019 compared to the control animal group.

To examine the analgesic activity, the method of Koster et al.
), the test was conducted using the "rising test" in mice using acetic acid. The animals used were Charles River CDs (France) with an average weight of 20 g.
I male mice are used after being fasted for 18 hours. 0
0.6% acetic acid solution in a solution of 2% Tween 80 and 0.25% carboxymethylcellulose 10rxQ/
Intraperitoneal injection of 9 induces stretching and writhing symptoms in mice after 2.3 minutes, which are considered manifestations of diffuse abdominal pain. Stretching is counted during the first 15 minutes after this injection.

One test compound is administered orally 30 minutes before the acetic acid injection. Control animals received 1% of Tween 80 as Brasavo.
Administer the solution.

Animals treated with the compounds of the present invention have between 20 and 200 mt.
i/kg dose reduced the number of acetic acid-induced stretches compared to the control animal group.

As a result of the above, the compounds of the present invention are useful in various disorders of the bronchial-respiratory system involving mucus hypersecretion, such as bronchitis, tracheobronchitis, bronchorrhea, asthma, and in general associated with mucus secretion or transport disorders. It can be used as an active ingredient in medicaments and pharmaceutical compositions intended for the treatment of various disorders caused by inflammation, for the treatment of pain of various causes, and for the treatment of ulcers and hypersecretion of gastric juices.

For this purpose, the compounds of the invention may be administered in suitable dosage forms for enteral or parenteral administration, such as tablets, gelatin capsules, dragees, syrups, and solutions or suspensions for drinking or injection. can do.

The daily dosage of the active ingredient of the invention is 0.5-100 u/
9, which is about 25-7000JIg
corresponds to

Patent applicant: Synthelabo

Claims (1)

[Claims] Formula 16 (■): [In the formula, R, is! or two halogen atoms, ■ or two methyl groups, trifluoromethyl, methoxy,
When R9 is a cyano, nitro, carbamoyl or benzoyl group, a fused benzene nucleus, or (3-indolyl)methyl or 2-methylthioethyl, R1 may represent a hydrogen atom, and R3 is a hydrogen atom or a linear or a branched C1-4 alkyl group, a carbamoylmethyl or 2-carbamoylethyl group, a 2-methylthioethyl group, a benzyl group optionally substituted with a hydroxyl group, or
Aminoacetic acid derivatives in the form of enantiomers or mixtures thereof representing (3-indolyl)methyl group. 2, Formula (I) [wherein R1 is 1 or 2 halogen atoms, 1 or 2 methyl groups, trifluoromethyl, methoxy,
When R1 is a cyano, nitro, carbamoyl or benzoyl group, a fused benzene nucleus, or (3-indolyl)methyl or 2-methylthioethyl, R1 may represent a hydrogen atom, and R9 is a hydrogen atom or a linear Or branched C3-. Alkyl group, carbamoylmethyl or 2-carbamoylethyl group, 2-methylthioethyl group, benzyl group optionally substituted with hydroxyl group or (
3-indolyl) methyl group] A method for producing an aminoacetic acid derivative represented by the formula (■): (wherein R1 has the same meaning as above) is reacted with mercaptopropionic acid. The acid represented by formula (III) (in which R has the same meaning as above) was reacted with thionyl chloride to form formula (I
V) (wherein RI has the same meaning as above) was obtained, and the obtained acid chloride (IV
) is reacted with an amino acid represented by the formula ・H7NCHCOOH R9 (in the formula, R7 has the same meaning as above), and optionally, by converting the substituent R1 of the obtained compound of formula (1), another formula ( A method characterized in that the compound of formula (1) is obtained and, if necessary, the obtained compound of formula (1) is reacted with a base to convert it into a salt thereof. 3. Formula (1) [wherein R1 is I or two halogen atoms, ■ or two methyl groups, trifluoromethyl, methoxy,
When R2 is a cyano, nitro, carbamoyl or benzoyl group, a fused benzene nucleus, or (3-indolyl)methyl or 2-methylthioethyl, R1 may represent a hydrogen atom, and R7 is a hydrogen atom or a linear Alternatively, a branched Cl-4 alkyl group, a carbamoylmethyl or 2-carbamoylethyl group, a 2-methylthioethyl group, a benzyl group optionally substituted with a hydroxyl group, or (
A pharmaceutical composition comprising an aminoacetic acid derivative represented by the formula 3-indolyl)methyl group as an active ingredient.