CS198225B2 - 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 or a carboxyl group;

R2 is carboxy, cyano or 5-tetrazolyl, or when R1 is carboxy, R2 may also be C1-C4alkyl, C1-C4alkoxy or an unfused benzene ring, with at least one R1 and R2 are carboxyl, 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.

A is preferably -S-, in particular - CH-CH-.

According to the invention, the compounds of the above general formula (I) are prepared by the preparation of a compound of the general formula (II)

And has the above meaning,

R 1 'is as defined above, R 1, an ester group of the formula -COOR 5 or an amide group of the formula -CONR 4 R 5, wherein R 3 is C 1 -C 18 alkyl, benzyl or phenyl, and each of R 4 and R 5 is hydrogen, alkyl (C 1 -C 6) -benzyl or phenyl; and

R 2 'represents the radical R 2 as defined above, an ester group of the formula -COOR 3 or an amide group of the formula -CONR 4 R 5, wherein R 5, R 4 and R 5 are as defined above, wherein at least one of the symbols

R 1 'and R 2' represent the above ester or amide group, hydrolyze with an acid or base at a temperature between 0 ° C and the boiling point of the reaction mixture, and optionally convert the obtained compound of formula I to its salt.

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

The starting materials of formula (II) are either described in the literature or can be prepared in a conventional manner.

The novel compounds produced by the process of the invention are useful as non-compound medicaments ...................

13-oxo-13-H-benzo [g] pyrido [2,1-b] quinazoline-10-carboxylic acid 11-oxo-11-H-2-methoxypyrido [2,1b] quinazoline-8-carboxylic acid 11-oxo 11-H-pyrido [2,1-b] quinazoline-3-carboxylic acid 11-oxo-11-H-pyrido [2,1-b] -2- (1H-tetrazol-5-yl) quinazoline sodium 12-oxo -12-H-quino [2,1b] quinazoline-10-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. 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 pulmonary administration. For nasal or ocular administration, about 0.5 to 25 mg of the 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, absorption maxima in the long wavelength region A _max [nm] are reported and serve as intermediates for the preparation of drugs. 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 atopic dermatitis. In addition, the disclosed compounds exhibit muscle relaxation (bronchodilator) 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 the Passive Skin Anaphylaxis Suppression Assay (PCA test):

PCA suppression dose

30 mg / kg 100% 100 mg / kg 50% 100 mg / kg 76% 100 mg / kg 88% 0.6 mg / kg 50%

their respective molar logarithmic extinction coefficients loge.

He did

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

2.8 g of 12-oxo-12-H-chloro [2,1-bquinazoline-10-carboxylic acid ethyl ester was refluxed in 20 ml of 10% sodium hydroxide solution for 30 minutes. The resulting solution was heated on a boiling water bath for 5 hours with 5-fold dilute hydrochloric acid. After dilution of the mixture with water, the precipitated yellow crystalline product is filtered off with suction and washed with water and acetonitrile.

For C17H10N2O3 calculated:

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

β found:

70.23% 17.02% C, O. 3.50% H, N, 9.53 UV: A _max [nm] loge 358 4.03 282 4.00

The same product is obtained when the corresponding methyl, hexyl, isopropyl, octadecyl, benzyl or phenyl ester is used as the starting material instead of the above ester.

Example 2

11-oxo-11-H-pyrido [2,1-b] quinazoline-2-carboxylic acid g of 11-oxo-11-H-pyrido [2,1-bquinazoline-2-carboxamide in 80 ml of dilute hydrochloric acid Boil under reflux for 5 hours. After filtering off the precipitated crystals and washing them with water, the product is dissolved in dilute ammonia, the solution is freed from impurities by shaking with chloroform, filtered over activated carbon and the filtrate is acidified with acetic acid, precipitating 11-oxo-11-H-pyrido [2, 1-b] quinazoline-2-carboxylic acid v. in the form of yellow crystals.

Example 4

13-oxo-13-H-benzo [g] pyridine [2,1-b] quinazoline-10-carboxylic acid

O

HOOC

Analysis (hydrochloride): for C17H10N2O3. HCl calculated:

62,4β% 10,87% C, Cl; 3.37% H, N, 8.58 found: 62,62% C, 3.50% H, 8.33% N, 10.02% Cl. UV: A _max [nm] loge 365 3.91 283 4.40

Example 5 11-oxo-11-H-2-methoxy-pyrido [2,1-b] quinazoline-8-carboxylic acid

UV: λ _max [nm] log

360 3.74

330 3.89

HOOC

OCHa

The same product is obtained when, instead of the above unsubstituted amide, the corresponding N-methyl-, Ν, Ν-diethyl-, N-hexyl-, N-benzyl- or N-phenylcarboxamide is used as the starting material.

In an analogous manner to the previous examples, 1 compounds can be prepared in the following examples:

Example 3 11-oxo-11-H-2-methyl-pyrido [2,1-bquinazoline-8-carboxylic acid

O

Analysis (hydrochloride): for C14H10N2O4. HČ1 calculated:

C, 54.81; H, 3.59; N, 9.14; Cl, 11.58;

found:

% C, 54.78;% H, 3.66;% N, 8.94;

The hydrochloride melts above 300 ° C.

Example 6

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

O

COOH

For C 13 H 8 N 2 O 3 calculated:

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

For C 14 H 10 N 2 O 3 calculated: 66.14% C, 3.94% H, ' 11.02% N; found: 66.19% C, 4.09% H, 11,11% N. UV: Amax loge 335 3.82

found:

H, 3.21; N, 11.79.

UV: λ _max [nm] log

365 3.91

334 4,10

Example 7

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

Analysis (hydrochloride): for C12H7N3O3. HCl calculated:

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

15.87% N. loge 3.49

51.89% C, 3.03% H, UV: (sodium salt): λ _max [nm]

320

COOH

VYNALEZU

Claims (1)

Subject A process for the preparation of quinazolone derivatives of the general formula I, A is —CH = CH—, —S—, or —CH = —N—, R 1 represents a hydrogen atom, an unfused benzene ring, an amino group or a carboxyl group; R2 is carboxy, cyano or 5-tetrazolyl, or when R1 is carboxyl, R2 can also be C1-C4alkyl, C1-C4alkoxy or an unfused benzene ring, with at least one R1 and R2 are carboxyl, and salts thereof. characterized in that the compound of formula (II) in which: And has the above meaning, R 1 'is a radical R 1 as defined above, an ester group of the formula -COOR 3 or an amide group of the formula - CONR 4 R 5, wherein R 5 is C 1 -C 18 alkyl, benzyl or phenyl and each of R 4 and R 5 is hydrogen, alkyl (C 1 -C 6) -benzyl or phenyl; and R 2 'represents the radical R 2 as defined above, an ester group of formula -COOR 3 or an amide group of formula -CONR 4 R 5, wherein R 3, R 4 and R 5 are as defined above, wherein at least one of R 1' and R 2 'is the above ester or amide group; is hydrolyzed with an aqueous acid or base at a temperature between 0 ° C and the boiling point of the reaction mixture, and the compound of formula I obtained is optionally converted to its salt.