SU1454247A3 - Method of producing derivatives of benzoic acid or monooxalate thereof - Google Patents

Abstract

Benzoic acid derivatives represented by general formula (I) (wherein R<1> represents lower alkyl, R<2> represents optionally protected carboxy, and X represents halogen) or salts thereof, particularly those wherein R<2> represents a carboxy group protected by a group represented by formula (II) (wherein n represents an integer of 2 to 4, R<3> and R<4> may be the same or different and each represents hydrogen or alkyl or, when taken together with the adjacent nitrogen atom, R<3> and R<4> may form a heterocyclic group) or salts thereof, have excellent anti-asthmatic and anti-inflammatory effects, thus being utilized as anti-asthmatic and anti-inflammatory agents for mammals.

Description

where R, -C -C-alkyl; an optionally protected N, N-dimethylamino-C 4 -alkyl carboxyl group, or their monoxalates, which are antagonistic anaphylaxis agents that can be used in medicine. The goal is to create new, more active substances of the specified class. The synthesis is carried out by acylation of the corresponding benzoic acid derivative by introducing the group (0) J with the help of the corresponding anhydride. The selection of the target product is carried out either in free form or in the form of monoxalate. The new substances inhibit bronchial anaphylaxis from a LTD at a dose of 45-47 µmol / kg and are of low toxicity. 1 tab.

Yu vl

 CM

This invention relates to an organic HIM1SH, in 4acTFiocTH, to a process according to (R2).

Jiic; o-o.

20

15

where R, С, -Сз is alkyl, 10

RI is an optionally protected N, N-dimethylamino-C-C-alkyl carboxyl group or their monooxalates.

The aim of the invention is to develop a method for producing benzoic acid derivatives and their monooxalates having an antagonistic effect on the slow-reacting anaphylaxis substance (MPB-A), which is a group of chemical mediators and exhibiting a more pronounced inhibitory effect on spasmophronchus.

Example 1, B a mixture of pyridine (10 4 l) and acetic anhydride (10 ml) is dissolved 4- 3- (4-acetyl 3-hydroxy-2-propylphenoxy) propoxy J-3-bromobenzoic acid (2 g). The solution is heated at 100-120 ° C for 14 hours, the OO is then concentrated. The residue is dissolved in chloroform. The solution is washed with dilute hydrochloric acid and dried over sodium sulfate. The solvent was removed by blending from the resulting product, and the residue was subjected to chromatographic separation on a silica gel column. Elution is carried out with mixtures of hexane and ethyl acetate (3: 1), then (2: 1) and (1: 1) and noTOM jQ with ethyl acetate in this order, and the Ethyl acetate fractions are combined and concentrated. The residue is crystallized from a mixture of chloroform and hexane, semi-

35

EXAMPLE 2 A mixture of (4-acetyl-3-hydroxy-2-propylphenoxy) -propoxy-3-bromobenzoic acid (2.0 g), pyriidine (10 ml) and propionic anhydride (10 ml) is heated at 100-1 for approximately 30 hours, then the solvent is evaporated. The residue is dissolved in chloroform, then the solution is washed with dilute hydrochloric acid, then water. The solution is dried (sodium sulfate) and then subjected to chromatographic separation on a column of silica gel. Elution was carried out with a mixture (5: 1) of chloroform and ethyl acetate. The eluate is evaporated and the residue is recrystallized from hexane to obtain 1.77 g of (4-acetyl-3-pro-pyonyloxy-2-propyl phenoxy) propoxy 3-bromobzoic acid, m.p. 136-137 ° C

Example 3 A mixture of (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy-3-bromobenzoic acid (2 g), chloroform (20 ml) and thionyl chloride (5 ml) was boiled in reverse. fridge for 30 minutes, then chloroform is expanded. The residue is dissolved in 40 ml of acetone. To the solution, 500 mg of 3- (K, H-dimethyl-amino) -1-propanol and 4 mp of triethyl-1 is added. The mixture is stirred at room temperature for 2 hours. The precipitate formed is filtered off and the filtrate is concentrated. The rest of the pump 4 SZ- (3-acetoxy-4-acetyl-2-propyl-5) is transferred to the chromatographic section-phenoxy) -propoxy-J-3-bromobenzoic acid (1.0 g), mp. 155-156 C. Calculated %: C 56.00; H 5.11.

on a silica gel column. Elution is carried out with ethyl acetate and then with a mixture of etrshatsetat and triethylamine (10: 1). The residue is recrystallized from hexane to give crystals of 3- (M, M-dimethylamino) propyl ester (4-acetyl-3-hydroxy-2-propylphenoxy) -propoxy-3-bromobenzoic acid (1.8 g), t pl. 71-.

With jBrO.

Found,%: C 55.94; H 5.10.

IR KB g

ms ("with

cm-: 1760 1710,

1680, 1650, 1595, 1260, 1110.

H-NMR (CDClj) cr: 0.89 (3N, t); 1.2-1.7 (2H, m); 2.35 (ZN, s): 2.50 (ZN, s); 2.25-2.65 (4H, m); 4.30 (4H, t); 6.81 (1H, d, I 9 Hz), 6.91, (1H, d, I 9 Hz); 7.71 (1H, d, I; 9 Hz); 8.03 (1H, dd, I 3 and 8 Hz); 8.29 (1H, d, I 3 Hz).

for obtaining new benzoic acid derivatives of general formula

EXAMPLE 2 A mixture of (4-acetyl-3-hydroxy-2-propylphenoxy) -propoxy-3-bromobenzoic acid (2.0 g), pyriidine (10 ml) and propionic anhydride (10 ml) is heated at 100-1 for approximately 30 hours, then the solvent is evaporated. The residue is dissolved in chloroform, then the solution is washed with dilute hydrochloric acid, then water. The solution is dried (sodium sulfate) and then subjected to chromatographic separation on a column of silica gel. Elution was carried out with a mixture (5: 1) of chloroform and ethyl acetate. The eluate is evaporated and the residue is recrystallized from hexane to obtain 1.77 g of (4-acetyl-3-pro-pyonyloxy-2-propyl phenoxy) propoxy-3-bromobzoic acid, m.p. 136-137 ° C

Example 3 A mixture of (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy-3-bromobenzoic acid (2 g), chloroform (20 ml) and thionyl chloride (5 ml) was boiled in reverse. fridge for 30 minutes, then chloroform is boiled out. The residue is dissolved in 40 ml of acetone. To the solution, 500 mg of 3- (K, H-dimethyl-amino) -1-propanol and 4 mp of triethyl-1 is added. The mixture is stirred at room temperature for 2 hours. The precipitate formed is filtered off and the filtrate is concentrated. The residue is subjected to chromatographic section-

on a silica gel column. Elution is carried out with ethyl acetate and then with a mixture of etrshatsetat and triethylamine (10: 1). The residue is recrystallized from hexane to give crystals of 3- (M, M-dimethylamino) propyl ester (4-acetyl-3-hydroxy-2-propylphenoxy) -propoxy-3-bromobenzoic acid (1.8 g), t pl. 71-.

In a mixture of 5 ml of pyridine and 5 ml of acetic anhydride, 1 g of 3- (H, H-dimethylamino) propyl ether (D-acetyl-3-hydroxy-2-pro.) Is dissolved. 5

ten

15

35

40

3145A247

pylphenoxy) propoxy-3-bromobenzonnon acid. The solution is heated at 110-120 ° C for 18 hours while reshaping, and then concentrated. The residue is subjected to chromatographic separation on a column of silica gel. Elution is carried out with ethyl acetate, and the eluate is quenched. The oily oil formed is dissolved in ether, to which is added an ethereal solution of anhydrous oxalic acid. The crystals formed are collected by filtration, washed with ethanol and then with isopropyl ether, and then dried to obtain 866 mg of 3- (N, N-dimethylamino) propyl ether (4-acetyl-3-acetoxy-2-last-shphenoxy) propoxy7 -3-bromobenzoic acid, monooxalate, t. Pl. 141- 142 C.

Calculated,%: C 53.90, H 5.73, N 2.10.

C28H34RrN07C n, j04.

Found: C, 53.99; H, 5.68; N, 2.17.

IR cm-: 1760, 1710, 1600, 1260, 1110.

 H-NMR (CDCl1) J: 0.90 (3N, t); 1.1-2.75 (UN, m); 2.27 (6H, s); 2.37 (3N, s); 2.50 (3N, s); 4.15- 4.55 (6H, m); 6.80 (1H, d, 1 8 Hz); 6.90 (1H, d, 1 8 Hz); 7.69 (1H, d, Hz); 7.91 (1H, dd, I 2 and 3 Hz); 8.17 (1H, d, I 2 Hz); ) t - free form).

Guinea pigs of the Hartley line (both males and females) with a body weight of about 400 g were divided into groups of 6-10 animals and the compression of the bronchi caused by the LTD was measured according to the Conzsett-Rössler method. Each guinea pig is fixed in the supine position under the urethane anesthesia (1.5 g / kg, intraperitoneally), cut by the trachea and connected to the respirator through a hollow tube. A branch from this tracheal hollow tube is connected to a bronchial spasm transducer. At 4-7 ml of air per stroke (70 strokes per minute), the loading pressure in the lungs is 100 mm of water, the flow of air is recorded

and within 15 minutes, the bronchi are compressed. The substance is used in the form of a suspension in a 5% solution of Arabic gum or in an aqueous solution and orally in a volume of 0.2 ml per 100 body weight 1 hour before the supply of the LTD. The substance of the LTD is used in the form of a solution in physiological saline, which is taken from the reserve, stored at -70 ° C in methanol (1 mg / 1 ml of methanol).

Results for

(SNGNS

o- (d) oh

HV СО-0 СНзСС

are shown in the table.

COOR

45

50

Vdzo (50% inhibition dose

Each value was calculated from the ratio between the dose and the rate of inhibition of the flowing volume (in percent) from the respiratory tract at the moment of maximum response, i.e. 30 seconds after the administration of DTT4.

The acute toxicity of the compound (I in mice is determined as follows.

Five week old male mice (five in each group) of a lelrlCR line weighing about 30 g are used. Each Compound (I) is suspended in a 5% solution of Arabic gum and administered pralo in an amount of 0.2 ml per 10 body weight.

Oral administration of compound (I) at a dose of 500 mg / kg does not cause any symptoms that could be

on the device Rectigraph-85 (through 55 they are attributed to compound (I). Autopsy

maker). After the administration of gallamine triethodide (1 mg / kg, intravenously), the LTD solution in saline (10 µg / mg) is intravenously administered.

after 7 days, you didn’t reveal any problems, i.e. the toxicity of the compound (I) is very low; it can be classified as low toxic.

and within 15 minutes, bronchial compression is recorded. The substance is used as a suspension in a 5% solution of Arabic gum or in an aqueous solution and is administered orally in a volume of 0.2 ml per 100 g of body weight 1 hour before the supply of the LTD. The LTD substance is applied in the form of a solution in a physiological solution, which is withdrawn from the stored stock. at -70 ° C in methanol (1 mg / 1 ml of methanol).

Results for

(SNGNS

o- (d) oh

HV СО-0 СНзСС

are shown in the table.

COOR

Vdzo (50% inhibition dose

Each value was calculated from the ratio between the dose and the rate of inhibition of the flowing volume (in percent) from the respiratory tract at the time of maximum response, i.e. 30 seconds after administration of DTT4.

The acute toxicity of compound (I) in mice is determined as follows.

Five week old male mice (five in each group) of a lelrlCR line weighing about 30 g each are used. Compound (I) is suspended in a 5% solution of Arabic gum and administered orally in an amount of 0.2 ml per 10 g of body weight.

Oral administration of compound (I) at a dose of 500 mg / kg causes no symptoms, which could be

attributed to compound (I). Autopsy

after 7 days, you did not detect any violations, i.e. the toxicity of the compound (I) is very low; it can be classified as low toxic.

The substance of formula (I) and its salt (monooxalate) are suitable for the treatment of diseases caused by MRV-A, such as asthma, senna fever, chronic bronchitis, and; -1 allergic eye diseases, allergic diseases of the stomach and intestines , cardiovascular disorders, allergies145D2476

dosage forms such as tablets, capsules, granules, pellets, liquid, syrup, etc. For parenteral administration, a substance of formula (I) or its salt (monooxalate) can be formulated with pharmaceutically acceptable carriers, medicaments or diluents (eg ecKHe dermatitis and other inflammatory | o measures, white petrolatum, hydrophilic

Diseases. For example, as an anti-asthma or anti-inflammatory drug, a substance of formula (I) or its salt can be prescribed orally or parenteral- 15 tto mpecopitanicim (for example, myish, guinea pig, human) (weft dosage of about 1 ft to 20 mg / kg.

Claims (1)

: For oral administration, a substance 20. formula (I) or its salt (monoox-Yat) may be formulated with a pharmaceutically acceptable carrier, medicament or diluent (for example, lactose, starch, pro-25 Formula: cellulose, stearic acid, magnesium stearate, sucrose, gelatin, gum arabic (ointment perebasis, oily bases, glycerides, polyethylene glycol, etc.). and process them into ointments, suppositories, sprays, inhalants, injections, etc. These dosage forms can be obtained by conventional pharmaceutical techniques. Thus, a method has been developed for the preparation of benzoic acid derivatives of general formula (I) and their monooxapats that exhibit a more severe inhibitory effect on bronchospasm. the invention The method of obtaining benzoic acid derivatives of the general formula Bg (CH) RiCO - O (SNgb- de RI RI SNSSO C -Cj -; - alkyl, optionally protected N, N-dimethylIra-C-C 4 alkyl carboxyl group, (CH) i but SNSSO where R has the indicated meaning, 45 where R has the indicated meaning, is reacted with an acyliru, followed by substitution of the general formula product obtained by the agent, either as a compound of general formula (I) or as its mo- (R, CO) 0, (III a) nooxalate. measures, white petrolatum, hydrophilic Formula ointment bases, oily bases, glycerides, polyethylene glycol, etc.). and process them into ointments, suppositories, sprays, inhalants, injections, etc. These dosage forms can be obtained by conventional pharmaceutical techniques. Thus, a method has been developed for the preparation of benzoic acid derivatives of general formula (I) and their monooxapats that exhibit a more severe inhibitory effect on bronchospasm. the invention Formula H The method of obtaining derivatives of zoic acid of the general formula Bg (I) or their monooxalates, about tl and h and - 35 th and with the fact that the compound of the formula (Ii)