CS226196B2 - Method of preparing monoamide derivative of terephtalic acid - Google Patents

Abstract

PURPOSE:To obtain the title derivative having an excellent pharmaceutical activity, extremely easily in an industrial scale, by the reaction of a derivative of benzoxazine with an alcohol. CONSTITUTION:The title derivative of formula III is obtained by heating a derivative of benzoxazine of formula I (R is lower alkyl) and an alcohol of formula II (R' is lower alkyl) at 50-100 deg.C for 1-50hr, using this alcohol in a large excess amount as a starting material as well as a solvent, or using an inert solvent. The presence of 1-4 times mol of a tertiary amine, e.g. triethylamine, as a reaction assistant gives better result. For example, a lower aliphatic alcohol such as methanol, can be used as the alcohol of formula III.

Description

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

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

(I) coor ₂ wherein R represents a straight or branched (C 1 -C 6) alkyl group which may be the same or different substituents and represents a hydrogen atom or a straight or branched (C 1 -C 6) alkyl group, and pharmaceutically acceptable salts thereof 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 above 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 successfully isolated certain anti-allergic agents that are useful as medicaments, and there are several patents for them. 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-diaminobenzoic acid formula is acylated with terephthalic acid or a monoalkyl ester of the terephthalic acid, and an amino group in the the fourth position is converted to a lower aliphatic amide, wherein the compounds exhibit substantially higher anti-allergic activity than the compounds isolated by the inventors before, and therefore the compounds of the invention are able to inhibit various allergic reactions caused by different animal species; and types of antibodies.

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

Process for the preparation of monoamide terephthalic acid derivatives of the general formula - I:

NHCOR

(I) in which:. R is a straight or branched alkyl group having 1 to 6 carbon atoms,

R 1 and R 8 are the same or different substituents and represent 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 invention, in reacting a compound of formula IV:

(IV) wherein mj is R and Rj are as defined above, with a compound of formula V:

Rg-OH (V) wherein Rg is the same as the above substituent.

In a preferred embodiment of the invention the reaction is performed at a temperature pllurtb ^l jjící of from 50 to 100 ° C for a time ranging from 1-50 hours. Even more preferably, the reaction of the present invention is carried out at a temperature of from 80 to 100 ° C for a period of from 2 to 10 hours.

It is also preferred to carry out the reaction of the present invention in the presence of a solvent selected from the group consisting of alcohol, tetrahydrofuran, dioxane, pyridine and dimethylfomamide.

Preferably, the reaction of the invention is also carried out in the presence of a tertiary amine selected from the group consisting of triethylamine, tributylamine and N-imtylmoofoline.

22Ы9Ъ

Advantages of the process according to the invention are that it is simple to carry out, with the compounds of formula (I) being effective as an anti-allergic agent, since only small doses can be used by intravenous or oral administration to animals to inhibit passive cutaneous enaphylaxis. which is used as a traditional indicator of the anti-allergic effect of a substance.

The compounds of formula (I) of the present invention can be administered in any desired dosage form. By way of example, 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 the compound of formula (I). pharmaceutical compositions such as lectose, starch, crystalline cellulose, talc, calcium carbonate, magnesium stearate, mannt, sorbitol, benzyl alcohol and water.

The particular dosage employed and the route of administration of the compound of formula (I) of the present invention will depend upon the condition of the patient, the severity of the disease, and other factors, the dosage administered being usually in the range of 10 to 2,000 δ / day. treatment ranging from 100 to 1,000 m m / day.

In the case of oral administration of the compounds of the present 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 one to several times daily. In a similar manner, other dosage forms can be prepared according to commonly used and known methods, and also such formulations can be made in an appropriate manner.

Obviously, it is preferred to administer the inhalation agent as it allows for more administration, with an effective amount in the range of 1 to 200 milligrams / day to exhibit a non-allergic effect.

The compound of formula (IV), which is used as a starting material in the process of the present invention, is readily prepared by reducing the nitro-nitro compound to give a compound of formula (VI):

(VI) (VII) ‘COOH in which R | same meaning as above, which then reacts with a compound of formula VII:

RCOCI ¹ wherein R stejný.su ≤ t ≤ learning process as described above, in pyridine.

Examples of suitable alcohols of formula V include lower aliphatic alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutance, secondary butanol and pentanol. These materials are the second starting component of the present invention.

As already mentioned, the process of the invention is carried out under the conditions commonly used for the preparation of amides, i. heating the reaction system at a temperature that is variable

226196 4 ranges from 50 to 100 ° C, and preferably from 80 to 100 ° C, for a time ranging from one to -50 hours, and preferably from 2 to 10 hours using a large excess of alcohol or water such that the reagent also serves as a solvent or an independently inert solvent such as tetrahdrofurene, dioxane, pyridine or dimethylbforaamide may be used.

Better results can be obtained by carrying out the reaction in the presence of an equimolar amount of up to four times the molar amount of the reaction accelerator, such as triebylamine, tributylamine, N-mmethymooroline or other other tertiary amine.

Biological activity assays of the compounds prepared according to the present invention are given below.

Antibodies in rats for egg albumin were prepared by deep sensitization according to the method described in ImmunnOogy, Vol. 7, 681 (1964).

One milligram of egg ^No No ^h oa Tmim yne ¹ - 10 and ^{b 10} UNEKO Haem ^ ^ pertussis illust rearward after ^D Yes rats by injection intramuscularly intraperitcneálně and even after 14 days of injection, serum was isolated. One-tenth of a milliliter of 16-fold diluted serum was injected into rat skin in the dorsal area.

After 48 hours, each rat was intravenously administered as an injection of 0.5 ml / 100 grams body weight of the composition ^1b, quenching equivalent volumes of a 1% Evans Blue solution in physiological saline. After thirty minutes the tulle of each rat was cut off the head and phlebotimized, and then the tulle was skinned, and the coloration produced at the sera injection site was quantitatively evaluated; with a pair of scissors, the blue-colored area was cut into pieces, which were dipped overnight in 5 ml of a 1: 8 mixture of 3 parts 0.5% aqueous sodium sulfate and 7 parts acetone, then centrifuged at 3000 rpm for 10 minutes. minutes, and the tulle supernatant was subjected to absorption examination at - 610 µm.

The compound of formula (I) is dissolved in a saline solution in the presence of potassium carbonate, thereby providing a solution having a pH in the range of 7.5 to 8.5 and administered intravenously to the tail of rats just prior to Evans administration. Blue and egg albumin as an injection or orally as a suspension in an aqueous gum arabic solution 30 minutes before administration of Evans Blue and egg albumin as an injection.

Percent tulle intuition was evaluated by comparing the absorption of Evans Blue solution soaked from the injection site in a group of rats injected with a compound of Formula I with the absorption of berva soaked from the injection site in control animals. Groups of five rats were set up to compare the average intuition efficacy. Results obtained These are given in Tables 1 and 2. In these Tables 1 and 2 means:

++++ Incinerate 90% or more, +++ Incinerate 70 to 00%, ++ Incinerate 50 to 00%, + Incinerate 30 to 50% Inhibitory, 0 to 30 Inhibitory Efficiency

Table 1

Inhibitory efficacy by intravenous administration

Compound Dose (mg / kg) Inhibition efficiency Example 1 compound 1 ++++ Example 1 compound OJ ++ Example 2 compound 2 ++++ Example 3 compound 2 ++++ Table 2 Inhibitory activity when administered orally Compounds Dose (mg / kg) Inhibitory efficacy Example 1 compound 100 ALIGN! ++++ Example 1 compound 25 ++ Example 2 compound 100 ALIGN! ++++ Example 3 compound 100 ALIGN! +++

Example 1

A mixture consisting of 12 grams of 7- (propionamido) -2- [4-carbonylphenyl] -4H-3,1-benzoxazin-4-one, 120 ml of absolute ethanol and 9 ml of triethylamine is prepared. the mixture was then heated at reflux for 8 hours. The mixture is cooled and 9 ml of acetic acid and 500 ml of water are added to precipitate crystals which are separated by filtration and then recrystallized from a solvent mixture of ethanol and water to give 10 g of 2- (4-carboxybenzamido) - Ethyl 4-propionamidobenzoate, the melting point of which is from 246 to 248 ° C.

Elemental analysis for ^C 20 H 20 ^N 2 ^O 6 calculated: 62.5% C, 5.2% H, 7.3% N found: 62.2% C, 5.5% H, 7.2% N

Example 2

In this embodiment, the same procedure as in Example 1 is followed, reacting 7- (propionamido) -2- [4-carboxyphenyl] -4H-3,1-benzoxazin-4-one with N-propanol and treating the resulting reaction product with In the same manner as in Example 1, except that a mixture of dioxane and water was used as the solvent for recrystallization. The resulting product of this example is propyl 2- (4-carbonylbenzamido) -4-propionamldobenzoate, which is obtained with a yield of 80%, the melting point of the product thus obtained being in the range of 233-235 ° C.

Elemeeneal analysis for ^C 21 ^H 22 ^M 2 ° 6 calculated: 63.3% C, 5.6% H, 7.0% N found: 63 /%> C. 5.9% H. 7.0% N

Example 3

IN-. In this embodiment, the same procedure is carried out as in Example 2, in which case 7- (propionamido) -2- [4-carbonylphosphino] -4H-3,1-benzoxazi-4-ol is reacted with n-butanol. , and the reaction product was worked up in the same manner as in Example 2. The resulting product of this example was 2- (4-carbobenzamino) -4-polyopentamido-benzoic acid n-butyl ester, which was collected by filtration. The product is obtained in a yield of 75%, the melting point of this product being 243 to 245 ° C.

Elemental analysis for ^C 22 ^H 24 ^N 2 ° 6 calculated: 64 /% C, 5.9% H, 6.8% N found: 64.0% C, 6.2% H, 6.7% N

Example 4

A mixture of 5 grams of 7-β-propionamido-4-carboxyphenyl-1H-benzoxazin-4-one, 50 ml of dimethylforaamide, 10 ml of water and 8 ml of trielyaamine is heated to a temperature of less than 10 DEG C. The mixture is cooled and treated with a dilute hydrochloric acid solution to adjust the pH in the range of 2 to 3.

In this way, crystals are precipitated, which are separated off, transformed with water and recrystallized from isopropyl alcohol. The final product is 2- (4-carboxybenzamido) -4-propionamidobenzoic acid, which is obtained at 4.1 grams with a melting point of 284-286 ° C (dec.). ).

P. 1 and 5

According to this example, the mixture consisting of 4 grams of 7- (propionamido) -2- [4-ethoxycarbonylphenyl] -4H-3,1-benzoxazin-4-one, 300 ml of absolute alcohol and 10 ml of triethylamine, 2heat under reflux for 24 hours. After the reaction was completed, the mixture was concentrated under vacuum, and the residue was recrystallized from ethanol-water solvent.

The final product of this example is ethyl 2- (4-cyclohexylcarbonylbenzemido) -4-propionamido-benzoate, which is obtained in an amount of 3.8 grams, the melting point of this product being in the range of 172 to 173 °. C.

Example 6

In this example, a mixture of 3.7 grams of 7- (propionamido) -2- [4-ethoxycarbonylphenyl] -54H-3,1-benzoxazin-4-one, 50 ml of dimethylformsmide, 3 ml of triethylamine and 0.2 ml of water The mixture is stirred at 70-90 ° C for 24 hours. After the reaction, 300 ml of water was added to the mixture, followed by dilute hydrochloric acid to adjust the pH of the mixture from 1 to 2. The crystals precipitated, which were filtered off, washed with water and recrystallized from acetonitrile. The final product of this embodiment is 2 '(4-cyclohexylbenzamido) -4-propionsmidobenzoate, which is obtained in a quantity of 3.0 grams, the melting point of the product thus obtained being in the range of 240 to 243 ° C.

Example 7

(a) Preparation of 100 mg tablets:

According to this embodiment, 100 grams of ethyl 2- (4-carbo-benzamido) -4-propionamidobenzoate is intensively mixed with 47 grams of lactose, 100 grams of crystalline cellulose and 3 grams of magnesium stearate, and the mixture is compressed into tablets, each the tablet has a diameter of 9 millimeters and a gravity of 300 milligrams.

(b) Preparation of inhalation agent:

In this example, 10 grams of ethyl 2- (4-carbo-benzamido) -4-amidobenzoate 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 a 1-ml brown ampoule (empty volume is purged with nitrogen) and sterilized at 121 ° C for 20 minutes.

c) Preparation of the injection:

According to this embodiment, 20 grams of the sodium salt of 2- (4-kerboxybenzamido) -4-propionamidobenzoate is dissolved in distilled water for injection. Acetic acid and sodium chloride are used to adjust the pH of the solution to 8.0 and the osmooic pressure is 280 mosm / kg, then the total volume of the solution is adjusted to one liter. Then, the so treated solution is filtered through a 0.45 µm membrane film, the solution is filled into 2 'milliro brown β / ρ Ι (the unfilled space is purged with nitrogen), and then sterilized at 121 ° C for 20 minutes.

Claims (4)

SUBJECT OF THE INVENTION 1. The preparation of a mono-amide terephthalic acid derivative of the formula I NHCOR wherein R is a straight or branched alkyl group containing 1 to 6 carbon atoms, R 1 -R 2 may be the same or different and are hydrogen or a straight or branched (C 1 -C 6) alkyl group, or a pharmaceutically acceptable salt of a compound of formula (IV), characterized in that: reacts with NHCOR Wherein R < 1 > and R < 1 > are compounds of formula V The above meaning, R ₂ - OH (V) wherein R2 has Ji-Z being as previously defined, in přítomnooti tertiary. of an amine, in an organic solvent at a temperature ranging from 50 to 100 ° C for a time ranging from 1 to 50 hours to give a compound of formula pharmaceutically acceptable I, which is optionally converted from to a salt 2. The method of item t 1 in the range of from 80 to 100 The process is carried out in that the temperature for 2 hours is carried out at 10 ° C. a solvent selected from the group consisting of alcohol, tetrahydrofuran, dioxane, pyridine and dimethylformamide. 3. Method according to points 1 and 2, characterized in that said reaction is carried out 4. A process according to any one of claims 1 to 3, wherein said reaction is carried out in the presence of a tertiary amine selected from the group consisting of triethylamine, tributyl amine and N-rneeylmoofooin. Severography, n. P., MOST Price 2,40 Kčs