CS198226B2 - Method of producing quinazolone derivatives - Google Patents

Description

The invention relates to a process for the preparation of quinazolone derivatives of the general formula I

in which

A is -CH = CH-, -S-, or -CH = N-,

R 1 represents a hydrogen atom, a non-fused benzene ring, an amino group, a carboxyl group, a carbamoyl group or a 5-tetrazolyl group, and

R2 represents a carboxyl group, a carbamoyl group or a 5-tetrazolyl group, and salts thereof.

The compounds of formula I may be in the form of free compounds or in the form of salts with basic or acidic components.

The symbol A preferably represents a group -S-, in particular a group -CH = CH-.

According to the invention, the compounds of formula (I) above are prepared by preparing compounds of formula (II)

And has the above meaning,

Q ‘represents a radical R 1 as defined above or a cyano group a

R 'is as defined above, R' or cyano, wherein at least one of Q 'and R' is cyano, reacted with sodium azide or water in the presence of a strong acid or base, at a temperature between room temperature and the boiling point of the reaction mixture; the compound of formula (I) is optionally converted to its salt.

Reaction with water leads to the hydrolysis of the cyano group to the carboxyl or carbamoyl group, and the reaction with sodium azide adds the sodium azide to the cyano group to form a 5-tetrazolyl residue.

The products obtained by the process according to the invention can optionally be converted into addition products

198 salts with acids or, if they contain carboxyl groups, also with salts with organic or inorganic bases. Optionally, compounds of formula I may be liberated from the salts resulting as primary products.

The starting compounds of formula (II) may be prepared from the corresponding acid amides by reaction with thionyl chloride in dimethylformamide, or from the corresponding halide derivatives by reaction with cuprous cyanide in dimethylformamide.

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 may be a compound

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

11-oxo-11-H-pyrido [2,1-b] -2- (1H-tetrazol-5-yl) quinazoline 12-oxo-12-H-quino [2,1-bquinazoline-10- carboxylic acids

For administration, the compounds of the invention are conventionally formulated with carriers and excipients into useful dosage forms, for example, 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. In general, about 20 to 500 μξ, about 0.2 to 10 mg intravenously, and about 1 to 50 mg oral, are administered per kg body weight. For 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.

UV spectra were measured for some products. The measurement was performed by accurately weighing a sample of about 10 to 20 mg, dissolving the sample in 10 mL of dimethylsulfoxide, and diluting the solution with 0.01 N hydrochloric acid to the appropriate volume. In the examples, the absorption maxima in the long wavelength region A _max [nm] and their associated logarithmic extinction coefficients log e are given.

Example 1

11-oxo-11-H-pyrido [2,1-b] -2- (1H-tetrazol-5-yl) quinazoline for the prophylaxis and treatment of allergic diseases such as asthma or hay fever, conjunctivitis, urticaria , eczema and atopic dermatitis. In addition, the disclosed compounds exhibit muscle relaxant (bronchodilator) and vasodilatory effect. 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 in oral administration.

For example, the following compounds of the invention exhibit the following values in the Passive Skin Anaphylaxis Suppression Assay (PCA test):

PCA suppression dose

100 mg mg / kg 76% 100 mg / kg 48% 100 mg / kg 88% 0.6 mg / kg 50% c6 .N-— N O5-! H 5.2 g of 2-cyano-11-oxo-11-H-pyrido [2,1-b] quinazoline, 1.8 g of sodium azide and 1.5 g of ammonium chloride are heated to 90-110 in 60 ml of dimethylformamide for 10 hours. The mixture is then acidified with dilute acetic acid and the resulting tetrazolylquinazoline is filtered off with suction. Pro CisHeNeO calculated: 59.09 «/ o C, found: 58.88% C, H, 3.03; N, 31.82. 3.26 O / O H, 31.96% N.

UV: λ _max [nm], loge 365 4.03

330 4.22.

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

A mixture of 5 g of 2-bromo-11-oxo-11-H-pyrido [2,1-bquinazoline, 2 g of copper (I) cyanide and 40 ml of dimethylformamide is refluxed for 6 hours. hydrochloric acid, 11 ml of water and 7.5 g of ferric chloride, the resulting mixture is stirred at 60-70 ° C for 1 hour, then poured into ice-water.

3.8 g of the 2-cyano-11-oxo-11-H-pyridoph 2,1-bquinazoline thus obtained were refluxed for 8 hours with a mixture of 60 ml of concentrated hydrochloric acid and 50 ml of water. After cooling, 11-oxo-11-H-pyrido [2,1-b] quinazoline-2-carboxylic acid hydrochloride crystallizes.

UV (free acid):

[nm] log

360 3.74

330 3.89.

In analogy to the previous examples, the products of the following examples can also be prepared:

Example 3 11-oxo-11-H-pyrido [2,1-b] quinazoline-3Analysis (hydrochloride): for C12H7N3O3. HCl calculated:

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

About 51.89 / ₀ C, 3.03% H, 15.87% N.

UV (sodium salt):

Λ _max [nm] log

320 3.49.

Example 5

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

For C 13 H 9 N 3 O 2

-carboxylic acid 0 1 il 1 For C 13 H 8 N 2 O 3

calculated:

65.27% C, found:

65.00% C,

UV: λ _max [nm] log

359 4.24

328 4,16.

N, 17.57. H, 3.65; N, 17.38.

Example 6 calculated:

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

H, 3.21; N, 11.79.

UV: λ max [nm] log

365 3.91

334 4,10.

Example 4

12-oxo-12-H-quino [2,1-b] quinazoline-10-carboxylic acid

6-oxo-6-H-pyrimido [2,1-b] quinazoline-8-carboxylic acid

O

COOH

For C17H10N2O3 calculated:

% C, 70.34;% H, 3.45;% N, 9.66; found:

% C, 70.23;% H, 3.50;% N, 9.53;

UV: λ _max [nm] log

358 4.03

282 4,00.

Claims (1)

OBJECT OF INVENTION A process for the preparation of quinazolone derivatives of the formula I A is -CH = CH-, -S- or -CH = N-, R 1 represents a hydrogen atom, a fused benzene ring, an amino group, a carboxyl group, a carbamoyl group or a 5-tetrazolyl group, and R2 represents a carboxyl group, a carbamoyl group or a 5-tetrazolyl group, and salts thereof, characterized in that the compound of the formula II in which: And has the above meaning, Q * is a radical R 1 or cyano as defined above and R ‘is a radical as defined above R @ 2 or cyano, wherein at least one of Q * a R‘ is cyano, reacted with sodium azide or water in the presence of a strong acid or base, at a temperature between room temperature and the boiling point of the reaction mixture, and the compound of formula I obtained is optionally converted into its salt.