CS226189B2 - Method of preparing monoamide derivative of terephtalic acid - Google Patents

Description

(54) A process for preparing a monoamide terephthalic acid derivative

The present invention relates to a process for the preparation of monoamide terephthalic acid derivatives of the general formula I:

NHCOR

(I) wherein R represents a straight or branched alkyl group having 1 to 6 carbon atoms,

R 1 and R ₂ may be the same or different substituents and represent a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms, and pharmaceutically acceptable salts of these compounds. The compounds of the present invention can be used as anti-allergic agents, the compounds of the present invention being the active ingredients. The compounds of formula I are useful as agents for preventing or treating allergic bronchial asthma, allergic dermatitis and other allergic diseases.

Of the numerous bis-amides derived from 2,4-diaminobenzoic acid, the authors, who are also authors of the present invention, have succeeded in obtaining certain anti-allergic substances which are useful as medicaments, and there are several patents for these substances. Further studies and experiments of the present inventors result in compounds of formula I above wherein the amino group in the second position in the 2,4-dieminobenzoic acid formula is acylated with terephthalic acid or a monoalkyl ester of this terephthalic acid, and the amino group in the fourth position is The compounds of the present invention are capable of inhibiting various allergic reactions caused by different animal species and antibody types.

More interestingly, it is found that analogous derivatives in which the amino group of 2,4-diaminobenzoic acid in the second position is acylated with phthalic or isophthalic acid have only weak anti-allergic activity.

The process for the preparation of monoamide terephthalic acid derivatives of the general formula I:

wherein R represents a straight or branched alkyl group having 1 to 6 carbon atoms,

R _; and R 8 are the same or different substituents, being a hydrogen atom or a branched or straight alkyl group having 1 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof, according to the present invention consists in condensing a compound of formula II:

NH ₂ ky - NHCOcoor ₂

COOR- | (II) wherein R 1 and R 8 are as defined above, with a reactive derivative at the carboxyl group, of a compound of formula III:

RCOOH (III) in which R is as defined above, in the presence of an alkaline agent in an organic solvent at a temperature ranging from -10 to 100 ° C, wherein the molar ratio of the compound of formula II to the compound of formula III is in the range 1: 1 to 8.

Preferably, the compound of formula (III) is an acid halide, acid snhydride or mixed acid anhydride with carbonic acid, sulfuric acid, phosphoric acid or sulfonic acid.

It is also preferred that the above reaction be carried out at a temperature in the range of 0 to 70 ° C. It is further preferred that the compound of formula II is reacted with 1.2 to 3 times the equivalent amount of the reactive derivative of formula III.

The solvent is preferably selected from the group consisting of water, benzene, toluene, tetrahydrofuran, diethyl ether, dioxane. dimethylformamide, chloroform, methylene chloride, pyridine, acetonitrile and mixtures of these solvents.

The above reaction is preferably carried out in the presence of an alkali metal or alkaline earth metal hydroxide, an inorganic basic compound selected from the group consisting of carbonates and acetates, or in the presence of an organic basic compound selected from the group comprising pyridine, triethylamine and picoline.

Advantages of the process according to the invention are that they are easy to carry out and the substances obtained are effective anti-allergic agents, since only small doses can be used when inhibiting passive cutaneous anaphylaxase, which is used as traditional indicator of the antiallergic effect of the substance.

The compound of formula (XX) mentioned above, which is used as a starting material in the process of the present invention, is readily obtainable by condensation of 4-nitroantranilic acid or ester thereof with terephthalic acid derivatives, optionally followed by hydrolysis of said capacitor, and reducing the nitro group by commonly used and known methods.

Examples of suitable reactive derivatives of the compound of formula (III) on a carboxyl group include acid halides, acid anhydrides, mixed anhydrides with carbonic, sulfuric, phosphoric, sulfonic and the like.

The above process of the present invention for the preparation of compounds of formula (I) is carried out under conditions commonly used to prepare amides. In particular, as mentioned above, the compound of formula II is reacted with an equivalent amount of up to eight times the equivalent amount, and preferably 1.2 to 3 times the equivalent amount, of a reactive derivative of the compound of the formula III, at a temperature ranging from -10 to 100 ° C, and preferably from 0 to 70 ° C, in the presence of a suitable solvent.

Examples of suitable solvents include water, benzene, toluene, tetrahydrofuran, ether, dioxane, dimethylformamide, chloroform, methylene chloride, pyridine, acetonitrile, and the like, which may be used alone or in the form of a mixture.

Optionally, condensation agents may be used in the process of the present invention, such as, for example, alkali metal hydroxide or alkaline earth metal hydroxide, an inorganic basic compound such as carbonate or ethyl acetate, as exemplified, or an organic basic compound such as pyridine or triethylamine.

The compounds of formula I may be administered in any desired dosage form. Specifically, tablets, powders, capsules or liquid preparations may be prepared using conventional methods by adding to the compound of formula (I) an adjuvant, binder, solvent or other substances generally used in the preparation of pharmaceutical compositions, such as lactose, starch, crystalline cellulose, talc, calcium carbonate, magnesium stearate, mannitol, sorbitol, benzyl alcohol and water.

The individual doses employed and the route of administration of the compound of formula I according to the invention depend on the condition of the patient, the degree of severity of the disease and not other factors, the amount administered being usually in the range of 10 to 2000 mg / day. treatment in the range of 100 to 1000 mg / day.

In the case of oral administration of the compounds prepared according to the invention, 50 to 200 milligrams of a compound of formula I are mixed with a suitable excipient and then compressed to form a tablet, and the tablets thus prepared are administered once to several times a day. In a similar manner, other dosage forms can be prepared according to commonly used and known methods, and the administration of these preparations can also be carried out in an appropriate manner.

Obviously, it is preferable to administer the inhalation agent, or to allow external administration, with effective amounts ranging from 1 to 200 milligrams / day to exert an antiallergic effect.

In the following, the biological activity assays of the compounds prepared according to the process of the invention will be presented.

Antibodies in rats for ovalbumin were prepared by homologous sensitization according to the method described in Immunology, Vol. 7, 681 (1964).

One milligram of egg albumin and 10% of Heemophilus pertussis cells was administered to rats by injection intramuscularly and intraperitoneally, and serum was isolated 14 days after injection. One-tenth of a milliliter of 16-fold diluted serum was given as an injection to rats in the dorsal skin.

After 48 hours, each rat was injected intravenously with 0.5 ml (100 grams body weight of the composition) containing equivalent volumes of 1% Evans Blue in physiological saline. the skin was retracted, and the coloration formed at the site of sera injection was quantitatively evaluated; with a pair of scissors, the blue-colored area was cut into pieces, which were immersed overnight in 5 ml of a mixture containing 3 parts of 0.5% aqueous sodium sulfate solution and 7 parts of acetone, then centrifuged at 3000 rpm for 10 minutes. minutes and the supernatant was subjected to absorption examination at 610 µm.

The compound of formula (I) was dissolved in physiological saline in the presence of potassium carbonate to give a pH of 7.5-8.5 and was administered intravenously to rat tails just prior to Evans Blue administration. and egg albumin as an injection, or orally as a suspension in an aqueous gum arabic solution 30 minutes prior to administration of Evans Blue and egg albumin as an injection.

Percent inhibition was evaluated by comparing the absorption of the Evans Bleu solution soaked from the injection site in the group of rats given the compound of Formula I with the absorption of the dye soaked from the injection site in control animals. Groups of five rats were set up to determine the average inhibition efficiency. The results obtained are shown in Tables 1 and 2. In these Tables 1 and 2 means:

++++ inhibitory activity of 90% or more, +++ inhibitory activity of 70 to 90%, ++ inhibitory activity of 50 to 70%, ~ + inhibitory activity of 30 to 50%, and + inhibitory activity of 0 to 30%.

Table 1

Inhibitory efficacy by intravenous administration Compound Dose (mg / kg) Inhibition efficiency Compound of of Example 1 1 +++ Compound of of Example 2 1 +++ Compound of of Example 3 1 +++ Compound of of Example 4 1 ++++ Compound of of Example 4 0.5 ++++ Compound of of Example 5 1 +++ Compound of of Example 8 1 +++ Compound of of Example 9 1 ++++

Table 2

Inhibitory activity when administered orally

Compounds Dose (mg / kg) Inhibitory efficacy Example 6 compound 300 +++ Example 8 compound 100 ALIGN! +++ The compound of Example 9 200 ++++ Example 10 compound 200 ++++

Example 1

A solution of 1.5 g of 2- (4-carboxybenzamido) -4-aminobenzoic acid in 50 ml of pyridine is mixed with 3.3 g of isobutyroyl chloride and the mixture is heated at a temperature ranging from 50 to 60 ° C for 2 hours.

The reaction mixture is then further mixed with a solution of 4 g of sodium hydroxide in 20 ml of water and concentrated in vacuo. The residue thus obtained is then diluted with water b with hydrochloric acid, which is used to adjust the pH of the solution to between 1 and 2.

The precipitated crystals are filtered, washed with water and then recrystallized from a solvent mixture of methanol and water to give 1.1 g of 2- (4-carboxybenzamido) -4-isobutyramidobenzoic acid, m.p. Mp 312 - 314 ° C (dec.).

Elemental analysis for C ₍ gH ₁ gNgOg):

H, 4.9; N, 7.6

Found: 61.7% G, 5.1% H, 7.7% N

Example 2

In the same manner as in Example 1, 2- (4-carboxybenzamido) -4-aminobenzoic acid is reacted with acetic anhydride, and the reaction product thus obtained is treated in the same manner as in Example 1 to form an acid. 2- (4-carboxybenzamido) -4-azetamidobenzoic acid is obtained in 63% yield, m.p. 302 DEG-304 DEG C. (dec.).

Elemental eelysis for C ^ HH ^ ^O^

H, 4.1; N, 8.2

Found: C 59.7, H 4.2, N 8.2

Example 3

The process was carried out in the same manner as in Example 1, wherein 2- (4-kerboxybenzamido) -4-aminobenzoic acid was reacted with n-butyl chloride, and the reaction product obtained was treated in the same manner as in Example 1. is 2- (4-kerboxybenzamido) -4- [n-butyramido] benzoic acid, which is obtained in 70% yield, the melting point of the product thus obtained being between 297 and 299 [deg.] C. (with decomposition).

For C analýza proH ^N ^Og

H, 4.9%; N, 7.6%

Found: 61.5% H, 5.0% H, 7.7% N

Example 4

In the same manner as in Example 1, 2- (4-carboxybenzamido) -4-aminobenzoic acid was reacted with propionyl chloride, and the reaction product thus obtained was treated in the same manner as in Example 1, except that isopropanol is used as the solvent for crystallization in this process.

The resulting product is 2- (4-carboxybenzamido) -4-propionamidobenzoic acid, melting at 284-286 ° C (dec.) To yield 62%.

Elemental analysis for C C ^H ^ NNgOg

H, 4.5; N, 7.9

Found: C, 60.7; H, 4.6; N, 7.8

Example 5. *

In the same manner as in Example 1, 2- (4-carboxybenzamido) -4-aminobenzoic acid is reacted with isocaproyl chloride, and the reaction product obtained is treated in the same manner as described in Example 1. 4. The product of this embodiment is 2- (4-carboxybenzamido) -4-isocaponamidobenzoic acid, which is obtained in a yield of 65%, the melting point of the product being from 297 to 300 ° C. (with decomposition).

Elemental analysis for ^ 21 ^ 22 ^ 2 ^

Calculated: C 63.3%, H 5.6%, N 7.0%

Found: C, 63.4; H, 5.6; N, 7.0

Example 6

To a solution of 3 grams of ethyl 2- (4-ethoxycarbonylbenzamido) -4-aminobenzoate in 30 ml of pyridine, 5 grams of propionic anhydrides are added and the mixture is heated at a temperature in the range from 50 to 60 ° C for 2 hours.

After cooling the solution, 200 ml of water are added gradually.

Crystals are precipitated, which are filtered off and then recryatalized from a mixture of ethanol and water to give the final product 2- (4-atoxycarbonylbenzamido) -4-propionamidobenzoate (2.2 g), m.p. in the range of 172 to 173 ° C.

Elemental analysis for ^C 22 ^H 24 ^N 2 ° 6

Calculated: C 64.1%, H 5.9%, N 6.8%

Found: C 64.3%, H 5.8%, N 6.7%

Example 7 i>

To 1.6 g of 2- (4-methoxycarbonylbenzamido) -4-aminobenzoic acid in 30 ml of pyridine, 2 grams of isomeric anhydride are added, and the mixture is heated at a temperature in the range of from 40 to 50 ° C for 2 hours. 10 ml of water were added to the reaction mixture, followed by 10 ml of triethylamine, and the mixture was heated to a temperature in the range of 70 to 80 ° C. 20 ml of water are added and the reaction mixture is maintained at the above reaction temperature for 10 minutes and then allowed to cool.

The pH of the solution is adjusted to a value of 2 to 3 by dilute hydrochloric acid solution to precipitate crystals, which are filtered and then recrystallized immediately from a solvent mixture of methanol and water, 2- (4-methoxycarbonylhenzamido) -4-isobutylaminobenzoic acid, 2 g, melting at 244-247 [deg.] C. (with decomposition) is obtained.

Elemental analysis for ° 20 ^ 20 ^Ν 2θ6 i

H, 5.2; N, 7.3

Found: C, 62.4; H, 5.4; N, 7.2

Example 8

In the same manner as in Example 7, 2- (4-ethoxycarbonylbenzemido) -4-aminobenzoic acid was reacted with isobutyric acid anhydride, and the reaction product thus obtained was treated in the same manner as in Example 7. of Example 7, except that a mixture of ethanol and water is used as the solvent for recrystallization.

The resulting product is 2- (4-ethoxycarbonylbenzamido) -4- (isobutyramidobenzoic acid), which is obtained in 62% yield, m.p. 230-235 ° C (dec.) Elemental analysis for θ21 ^ 22 ^Ν 2 ° 6

Calculated: C 63.3, H 5.6, N 7.0

Found: C, 63.1; H, 5.8; N, 7.1

Example 9

In the same manner as in Example 10, 2- (4-ethoxycarbonylbenzamido) -4-aminobenzoic acid was reacted with propionic acid anhydride, and the reaction product thus obtained was treated in the same manner as in Example 7 above. except that acetonitrile is used as the solvent for recrystallization. The product is 2- (4-ethoxycarbonylbenzenamido) -4-propionamidobenzoic acid, obtained in 60% yield, mp 240-243 ° C.

Elemental analysis for ^C 20 ^H 20 ^N 2 ^O 6

H, 5.2; N, 7.3

Found: C, 62.4; H, 5.4; N, 7.2

He did

The procedure of Example 7 is repeated, wherein 2- (4-propoxycarbonylbenzamido) -4-aminobenzoic acid is reacted with propionic anhydride, and the reaction product obtained is treated in the same manner as described above. of Example 7, except that ethyl acetate is used as the solvent for recrystallization. The final product of this embodiment is 2- (4-propoxycarbonylbenzamido) -4-propionamidobenzoic acid, which is obtained in 64% yield, the melting point of the product thus prepared is from 199 to 200 ° C.

Elemental Analysis for C | | ^H 22 ^N 2 ° 6

Calculated; 63.3% C, 5.6% H, 7.0% N

Found: C 63.3%, H 5.8%, N 7.1%

He did!

In the same manner as in Example 7, 2- (4-butoxycarbonylbenzonitrile) -4-aminobenzoic acid is reacted with propionic anhydride, and the reaction product thus obtained is treated in the same manner as in Example 7, with the difference A mixture of water and dioxane is used as the solvent for recrystallization.

The final product of this embodiment is 2- (4-butoxycarbonylbenzamido) -4-propionamidobenzoic acid, which is obtained in 60% yield, the melting point of the product thus obtained being in the range of 184-187 ° C.

Elemental analysis for ° 22? 24 ^N 2 ° 6

Calculated: C 64.1%, H 5.9%, N 6.8%

Found: C 64.2%, H 6.1%, N 6.7%

Example 12

A solution of 3 grams of ethyl 2- (4-carboxybenzamido) -4-aminobenzoate in 30 ml of pyridine is mixed with 3 grams of propiononyl chloride and the mixture is maintained at a temperature ranging 40 to 50 ° C for 3 hours. 20 ml of water are gradually added to the mixture, which is then kept at the above temperature for one hour. After a further 10 ml of water was added, hydrochloric acid was used to adjust the pH in the range of 1 to 2, whereupon crystals precipitated, which were filtered off, washed with water and recrystallized from a solvent mixture of ethanol and water to obtain the final product, ethyl 2- (4-carboxybenzamido) -4-propionamidobenzoate, is 2.2 g, the melting point of the product being 246-248 ° C.

Elemental analysis for ^C 20 ^H 20 ^N 2 ^O 6

H, 5.2; N, 7.3

Found: C, 62.4; H, 5.5; N, 7.4

Example 13

In this embodiment, the same procedure as in Example 15 is followed, wherein propyl methyl 2- (4-carboxybenzamido) -4-aminobenzoate is reacted with propionic anhydride, and the reaction product thus obtained is treated in the same manner as in Example 12 except The method according to claim 1, characterized in that a mixture of dioxane and water is used as the solvent for recrystallization. The final product of this embodiment is propyl methyl 2- (4-carboxybenzamido) -4-propionemidobenzoate, which is obtained in 67% yield, mp 233-235 ° C.

Elemental analysis for C ₂₁ ^H 22 ^N 2 ° 6

Calculated: 63.3% C, 5.6% H, 7.0% N Found: 63.2% C, 5.8% H, 6.9% N Example 1 a and 14 According to of this example design The procedure was as in Example 12

in which case 2- (4-carboxybenzamido) -4-aminobenzoate butyl is reacted with propionic anhydride and the product thus obtained is treated in the same manner as in Example 12, the final product of this embodiment being 2-4-carboxybenzamido) -4 Butyl propionamide benzoate is obtained in 65% yield, the melting point of the product thus obtained is in the range of 243 to 245 ° C.

Elemental analysis for g2 ^ ^H 24 ^N 2®6

Calculated: C 64.1%, H 5.9%, N 6.8%

Found:% C, 64.0;% H, 5.9;% N, 6.9

Example 15

In the same manner as in Example 7, 2- (4-isopropyloxycarbonylbenzamido) -4-eminobenzoate was reacted with propynoic anhydride, and the reaction product was worked up in the same manner as in Example 7, whereby the resulting the product of this embodiment was 2- (4-isopropyloxycarbonylbenzamido) -4-propionemidobenzoate, which was obtained in 65% yield, the melting point of the product thus obtained was from 219 to 221 ° C. Elemental analysis for ° 2Ι ^Η 22 ^Κ 2θ6

Calculated: C 63.3%, H 5.6%, N 7.0%

Found:% C, 63.1;% H, 5.8;% N, 7.0

Example 16

a) Preparation of 100 mg tablets

In this embodiment, 100 grams of ethyl 2- (4-carboxybenzemido) -4-propionamidobenzoate is intimately mixed with a mixture of 47 grams of lactose, 100 grams of crystalline cellulose and 3 grams of magnesium stearate, and the mixture is compressed into tablets, each tablet having a diameter 9 millimeters and a weight of 300 milligrams.

b) Preparation of an inhalation agent

In this embodiment, 10 grams of ethyl 2- (4-carboxybenzamido) -4-propionamidobenzoate potassium salt is dissolved in distilled water. A buffer solution is used to adjust the pH to 8.5, and then the total volume of the solution is adjusted to one liter. The solution is filtered through a 0.45 µm membrane filter and filled with 1 ml brown ampoules (empty volume is purged with nitrogen) and sterilized at 121 ° C for 20 minutes.

c) Preparation of the injection

In this embodiment, 20 grams of ethyl 2- (4-carboxybenzamido) -4-propionamidobenzoate is dissolved in distilled water for injection. Acetic acid and sodium chloride are used to adjust the pH of the solution at 8.0 .mu.m and the osmotic pressure is 280 mosm / kg, after which the total volume of the solution is adjusted to not more than one liter. The treated solution is then filtered through a 0.45 µm membrane filter, filled into 2 ml brown ampoules (the empty space is purged with nitrogen), and then sterilized at 121 ° C for 20 minutes.

Claims (6)

SUBJECT OF THE INVENTION A process for the preparation of a monoamidoyl terephthalic acid derivative of the general formula I NHCOR wherein R is a straight or branched alkyl chain containing 1 to 6 carbon atoms, R 1 and R g may be the same or different substituents, being a hydrogen atom or a straight or branched (C 1 -C 6) alkyl group, or a pharmaceutically acceptable salt thereof, characterized in that it condenses a compound of formula II in which they have R 2 substituents , and Rg has the same meaning as above, with a reactive derivative at the carboxyl group of the compound of formula III RCOOH (III) wherein R is as defined above, in the presence of an alkaline reagent, in an organic solvent, at temperatures ranging from -10 to 100 ° C, and at a molar ratio of the compound of formula II to the compound of formula of formula III in the range of 1: 1 to 8 to form a compound of formula I, which is optionally converted to a pharmaceutically acceptable salt. 2. A process according to claim 1, wherein the compound of formula (III) is an acid halide, acid anhydride or mixed acid anhydride with carbonic acid, sulfuric acid, phosphoric acid or sulfonic acid. 3. The process of claim 1 wherein the reaction is carried out at a temperature in the range of 0 to 70 ° C. 4. The process of claim 1 wherein the compound of formula (II) is reacted with 1.2 to 3 times the equivalent amount of a reactive derivative of formula (III). 5. The process of claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of water, benzene, toluene, tetrahydrofuran, diethyl ether, dioxane, dimethylformamide, chloroform, methylene chloride, pyridine, acetonitrile, and mixtures thereof. 6. The process of claim 1 wherein the reaction is carried out in the presence of an alkali metal or alkaline earth metal hydroxide, an inorganic basic compound selected from the group consisting of carbonates and acetates, or in the presence of an organic basic compound selected from pyridine, triethylamine. and picoline.