CS198223B2 - Method of producing derivatives of quinazolone - Google Patents

Description

A is --CH — CH— or —CH — N—,

R 1 represents a carboxyl group, and when R 2 represents a carboxyl group, R 1 can also represent a hydrogen atom or a group - NHCOCH 3 and

R 2 represents a carboxyl group or a methoxy group attached at the a or b position and salts thereof.

In accordance with the invention, the compounds of formula (I) above are obtained by compounds of formula (II)

in which '

A, R 1 and R 2 are as defined above and

R is an acyl residue of a C 2 -C 4 fatty acid or benzoyl group, treated with a strong oxidizing agent and then acidified.

The oxidation can be effected, for example, by treatment with potassium permanganate in an aqueous solution buffered with magnesium sulfate. Mineral acids such as hydrochloric acid, but also organic acids such as acetic acid can be used for acidification.

The reaction temperature, which is directly related to the activity of the oxidizing agent and other reaction conditions, can be varied within a wide range. In general, the reaction is carried out at a temperature between about 30 DEG C. and the boiling point of the reaction mixture, in particular between 40 DEG and 90 DEG C.

The starting materials of formula (II) are prepared by conventional methods. When R1 or R2 is a carboxyl group, these starting materials can also be prepared in situ from the corresponding methyl derivatives or other derivatives containing residues which can be converted into the carboxyl group under the reaction conditions.

The products obtained according to the invention may optionally be converted into acid addition salts or, if they contain carboxyl groups, also into salts with organic bases. Optionally, compounds of formula I may be liberated from the salts resulting as primary products.

The novel compounds produced by the process of the invention are useful as pharmaceuticals or serve as intermediates for the preparation of pharmaceuticals. Preferred is the antiallergic effect of the disclosed compounds, which can be used for the prophylaxis and treatment of allergic diseases such as asthma or hay fever, conjunctivitis, urticaria, eczema and the atopic compound.

11-oxo-11-H-pyrido [2,1-b] quinazoline-3-carboxylic acid sodium salt 11-oxo-11-H-pyrido [2,1-b] quinazoline-2-carboxylic acid sodium salt of 6-oxo 6-H-pyrimidido [2,1-b] quinazoline-8-carboxylic acid

For administration, the compounds of the invention are conventionally formulated with carriers and excipients into useful dosage forms such as capsules, tablets, dragees, solutions and suspensions for oral administration, aerosols for pulmonary administration, sterile isotonic aqueous solutions for parenteral and oral administration. for creams, ointments, lotions, emulsions or sprays for topical application.

The unit dose depends on the indication, for example the nature of the allergic condition. Generally, about 1 to about 50 pg for pulmonary administration, about 0.2 to about 10 mg intravenous administration, and about 1 to about 50 mg oral administration are administered per kg body weight. When nasal. or ocular administration, about 0.5 to 25 mg of active ingredient is used.

The invention is illustrated by the following non-limiting examples.

Example 1

11-oxo-11-H-pyrido [2,1-b] quinazoline-2-carboxylic acid

O

Condensation of molar amounts of 2,4-dimethylaniline and 2-bromopyridine at 1-10 ° C gives 2,4-dimethyl-N-pyridin-2-ylaniline which melts at 65-68 ° C after purification through the fumarate. N-pyridine dermatitis is obtained from this product with heating with acetic anhydride. In addition, the disclosed compounds exhibit muscle relaxation (bronchodilation) and vasodilator activity. In the case of the most important use of these substances, which is the prophylaxis of asthma, their advantage over the commercial preparation, cromoglycic acid, should be a longer duration of action and, in particular, efficacy when administered orally.

For example, the following compounds of the invention exhibit the following values in a test for suppressing passive cutaneous anaphylaxis (PCA).

dose suppression of PCA 100 mg / kg 76% 0.6 mg / kg 50% 50 mg / kg 70%

-2-yl-N-2,4-dimethylphenylacetamide. 60 g of acetamide are oxidized at 40 to 90 ° C with 218 g of potassium permanganate and 75.5 g of magnesium sulfate in 2 liters of water. The resulting manganese dioxide is filtered off with suction, the mother liquors are acidified with acetic acid and the slowly crystallizing compound is filtered off with suction. After stirring for one hour with a 5-fold amount of concentrated hydrochloric acid at 60-70 ° C, the mixture was diluted with a 10-fold amount of water. 11-oxo-11-H-pyrido [2,1-bquinazoline-2-carboxylic acid is slowly precipitated and washed with water and acetonitrile.

For C 13 H 8 H 2 O 3 calculated:

% H, 3.33;% N, 11.67.

found:

H, 3.46; N, 11.58.

The same product is obtained when the corresponding butyramide is used in place of the corresponding acetamide in the above reaction.

Similar results as in the above example are obtained when the oxidation is carried out at a temperature ranging from 30 ° C to the boiling point of the reaction mixture instead of at a temperature of 40 to 90 ° C.

(a) Sodium salt

From the obtained pyridoquinazolone carboxylic acid, a sodium salt is prepared in water by treatment with a calculated amount of sodium bicarbonate followed by ethanol precipitation.

WITH

b) Ethanolammonium salt

1.2 g of the obtained pyridoquinazolone carboxylic acid are suspended in 3 ml of water, 0.31 ml of ethanolamine are added and the ethanolammonium salt is precipitated with acetonitrile.

For C15H15N3O4. H2O calculated:

C 56.43, H 5.33, N 13.17;

found *

% C, 57.25;% H, 4.96;% N, 13.46.

c) Triethanolammonium salt

2,4-pyridoquinazolonecarboxylic acid is suspended in 20 ml of acetonitrile and addition of 3.6 g of about 85% triethanolamine yields the above salt decomposing above 200 ° C.

For C19H23N3O6 calculated:

C 58.61, H 5.91, N 10.80;

found:

% C, 58.80;% H, 5.72;

Example 2

11-oxo-11-H-pyrido [2,1-b] quinazoline-3-carboxylic acid

, 2,5-dimethylaniline and 2-bromopyridine are converted in analogy to Example 1 via N-pyrid-2-yl-N- (2,5-dimethylphenyl) acetamide followed by oxidation with potassium permanganate to 11-oxo-11-H-pyrido [2,1-b] quinazoline-3-carboxylic acid For C 13 H 8 N 2 O 3 calculated:

% C, 65.50;% H, 3.33;% N, 11.67;

found:

H, 3.21; N, 11.79.

The same reaction product is obtained when N-pyrid-2-yl-N- (2,5-dimethylphenyl) benzamide is used instead of N-pyrid-2-yl-N- (2,5-dimethylphenyl) acetamide.

Example 3

O-OXO-OII pyrimido [S, 1 · b] ctiinazoline-8-carboxylactic acid

O

9.5 g of 2-aminopyrimidine together with 18.5 g

Of 4-bromo-m-xylene, 13.8 g of potassium carbonate and 0.5 g of copper powder was heated at 180 ° C for 5 hours, the mixture was diluted with water and extracted with ether. Evaporation of the solvent gave 2,4-dimethyl-N-pyrimid-2-yl-aniline, m.p. 95-99 ° C.

In analogy to Example 1 for a similar pyridyl derivative, this product is acetylated, then oxidized with potassium permanganate, and 6-oxo-6-H-pyrimido- (2,1-b) quinazoline-8- hydrochloride is isolated after cyclization. For C 12 H 7 N 3 O 3 · HCl calculated:

% C, 51.89;% H, 2.88;% N, 15.33;

found:

% C, 51.89;% H, 3.03;% N, 15.87.

Dissolve the hydrochloride in water and add 2 mol of sodium bicarbonate and precipitate with ethanol to give the sodium salt.

11-oxo-11-H-2-methoxypyrido [2,1-b] quinazoline-8-carboxylic acid can also be obtained and converted into salts in an analogous manner to Examples 1-3.

Example 4

8-Acetamido-11-H-11-oxopyrido [2,1-b] quinazoline-2-carboxylic acid

Treatment of 23.8 g of 2-chloro-5-nitropyridine with 19 grams of 2,4-dimethylaniline at 160 ° C affords 2,4-dimethyl-N- (5-nitro-2-pyridyljaniline) from which 76 g is reduced. Stannous chloride and acetylation with 210 ml of acetic anhydride gave N- (5-diacetylamino-2-pyridyl) -N- (2,4-dimethylphenyl) acetamide, 9.5 g of this compound was stirred in water / butanol (2: 1) for 4 hours at room temperature. 80 DEG-85 DEG C. with 26.5 g of potassium permanganate and 3.5 g of magnesium sulfate After aspirating and evaporating the mixture, the residue is heated with dilute acetic acid for 1 hour, and 8-acetamido-11-H-11-oxopyrido is slowly crystallized. [2,1-b] quinazoline-2-carboxylic acid, which is filtered off with suction and washed with acetonitrile and ether.

For C 15 H 11 H 3 O 4. H2O calculated:

% C, 57.14;% H, 4.76;% N, 13.33.

5.7% H 2 O;

found:

% C, 57.68;% H, 4.69;% N, 13.15;

4.1% H2O.

1BÍ223

Claims (2)

SUBJECT A process for the preparation of quinazolone derivatives of the general formula I wherein: A is -CH = CH- or -CH = N, R 1 represents a carboxyl group, and when R 2 represents a carboxyl group, R 1 can also represent a hydrogen atom or -NHCOCH 3 groups and R2 represents a carboxyl or methoxy group attached to the a or b position and salts thereof, characterized in that the compound of formula II and I INVENT in which A, R 1 and R 2 are as defined above and R is an acyl residue of a C 2 -C 4 fatty acid or benzoyl group, treated with a strong oxidizing agent, for example potassium permanganate in a buffered aqueous solution, and then acidified, whereupon the resulting products are optionally converted into their salts or the free bases. 2. The process according to claim 1, wherein the reaction is carried out at a temperature of from 30 DEG C. to the boiling point of the reaction mixture.