CS198224B2 - Method of producing derivatives of quinazolone - Google Patents

Description

(54) A method for producing quinazolone derivatives

The present invention relates to a process for the preparation of a quinazolone derivative of the general formula I, which is prepared by the preparation of a compound of the general formula II

O

O

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;

R 2 is a carboxyl group or a radical of formula COR 1, wherein R 1 is C 1 -C 4 alkoxy, amino, hydroxylamino or 5-tetrazolylamino, 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 the group -S-, in particular the group -CH = CH-.

According to the invention, the compounds are as described above

And has the above meaning,

Q represents a radical R 1 as defined above or a group -COC1 and R represents a radical R 2 as defined above or a group -COC1,

Provided that at least one of Q and R is —COC1, it is reacted with a compound of formula III

H-Z (ΠΙ) in which, when Q in the compound of formula (II) is R1, Z represents a hydroxyl group, a C1-C4 alkoxy group, an amino group, a hydroxylamino group or a radical of formula

N — N

II

N - NH and when Q in the compound of formula II is --COC1, Z represents a hydroxyl group 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.

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 salts with organic or inorganic bases. If desired, compounds of the general formula I may be liberated from the salts resulting as primary products.

........... cel. . . ....... ...... ..............

The starting materials can be prepared in a manner known per se, the compound 12-oxo-12-H-quino [2,1-b] quinazoline-10-carboxylic acid ethyl ester, 11-axo-11-H-pyrido [2,1b] chlorazoline-3-carboxylic acid

11-oxo-11-H-pyrido [2,1-b] quinazoline-2-carboxamide 12-oxo-12-H-quino [2,1-b] quinazoline-10-carboxylic acid sodium salt

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. It is generally administered per kg body weight by pulmonary administration of about 20 to 500 mg (Ug, for intravenous administration about 0.2 to 10 mg, and for oral administration about 1 to 50 mg of active ingredient. about 0.5 to 25 mg of active ingredient.

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

UV spectra were measured for some products. The measurement was carried out by accurately weighing a sample of about 10-20 mg, dissolving the sample in 10 mL of dimethylsulfoxide, and diluting the solution with 0.01 N hydrochloric acid to the appropriate volume. Absorption is reported in the examples

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 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

100 mg / kg 70% 100 mg / kg 76% 100 mg / kg 48% 0.6 mg / kg 50%

peaks in the long-wave range Λι, _3Χ [n] and their logarithmic molar coefficients log ε.

Example 1

11-Oxo-11-H-pyrido [2,1-b] quinazoline-2-carboxylic acid methyl ester

O

6.2 g of 11-oxo-11-H-pyrides [2,1-b] quinazoline-2-carboxylic acid hydrochloride are refluxed in a 10-fold amount of thionyl chloride for 1 hour. The insoluble acid chloride is suctioned off and refluxed in a 10 to 20-fold amount of methanol until complete dissolution. After cooling, 11-oxo-11-H-pyrido [2,1-b] quinazoline-2-carboxylic acid methyl ester hydrochloride crystallizes containing 1 mol of methanol and decomposes at 254 ° C.

WITH

For C 14 H 10 N 2 O 3. HCl. CH3OH calculated:

% C, 55.81;% H, 4.65;% N, 8.68;

found:

% C, 55.53;% H, 4.35;% N, 8.82.

11.29% Cl.

UV: [nm] log

360 3.63

330 3.83

Example 2

11-oxo-11-H-pyrido [2,1-b] -N- (1-H-tetrazol-5-yl) quinazoline-2-carboxamide ϊ 9 ✓ N-N

For C 13 H 9 N 3 O 2 calculated: 65.27% C, 3.77% H, N, 17.57; found: 65.00% C, 3.65% H, 17.38% N. UV: 4, xtnm] < loge 359 328 4.24 4.16

Example 4 11-oxo-11-H-pyrido [2,1-b] quinazoline-2-hydroxamic acid

5.53 g of 11-oxo-11-H-pyrido [2,1-b] quinazoline-2-carboxylic acid chloride hydrochloride, prepared as described in Example 1, are added to a solution of 2.1 g at 0 to 10 ° C. aminotetrazole hydrate, 6.1 g triethylamine and 200 ml dimethylformamide. The reaction mixture was stirred for 3 hours, then acetic acid was added until acidic reaction and the precipitated product was filtered off with suction. The product decomposes at 330 ° C.

For C14H9N7O2 calculated:

% C, 54.72;% H, 2.93;% N, 31.92;

found:

% C, 54.93;% H, 3.17;% N, 31.63.

Example 3

11-oxo-11-H-pyrido (2,1-b) chlorosoline-2-carboxamide

From 10 g of 11-oxo-11-H-pyrido [2,1-b] quinazoline-2-carboxylic acid hydrochloride, the acid chloride was prepared as described in Example 1 and stirred at room temperature for 5 hours in a mixture of 200 ml dioxane and 50 ml concentrated ammonia. Dilute acetic acid is then added to the reaction mixture until the acid reaction and the precipitated crystals are filtered off with suction.

5.9 g of 11-oxo-11-H-pyrido [2,1-b] quinazoline-2-carboxylic acid chloride hydrochloride, prepared as described in Example 1, was added to a solution of 2.08 g of hydroxylamine at 20 ° C. hydrochloride and 9.8 ml of diisopropylamine in 100 ml of dimethylformamide, the reaction mixture is stirred for 5 hours, acidified with dilute acetic acid and the product is filtered off with suction.

For C 13 H 9 N 3 O. 1/2 H2O calculated:

% C, 59.09%; N, 15.91; found: % C, 59.20;% H, 3.70; 15.49% N. UV. Imax [nmj loge 362 3.99 330 4.15

The compounds of the following examples were prepared in an analogous manner.

Example 5 /

5-Oxo-5-H-thiazolo [2,3-b] quinazoline-7-carboxylic acid ethyl ester

O V-COOCH, CH. For C 13 H 10 N 2 SO 3 calculated: % C, 56.93;% S, 11.68; H, 3.65; N, 10.22.

found: For C 13 H 8 N 2 O 3 % C, 56.87;% H, 3.82;% N, 10.21%. 11.82% S. calculated: 3.33% H, 65.00% C, 11.67% N; M.p. 148-155 ° C (methanol). found: Example 6 64.95% C, 3.46% H, 11,58% N.

8-Oxo-8-H-isoquino [1,2-b] quinazoline-10-carboxylic acid ethyl ester

For C19H14N2O5

UV: λ _max [nm] log

360 3.74

330 3.89

(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.

calculated:

H, 4.40; N, 8.81;

found:

% C, 71.58;% H, 4.40;

Mp 205-210 ° C.

Example 7

12-Oxo-12-H-quino [2,1-b] quinazoline-10-carboxylic acid ethyl ester

For C19H14N2O3 calculated:

% C, 71.70;% H, 4.40;% N, 8.81;

found:

% C, 71.70;% H, 4.17;% N, 8.67.

Mp 157-163 ° C.

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

CCCr "

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 C15H1SN3O4. HzO calculated:

C 56.43, H 5.33, 13,17% N; found: 57.25% C, 4.96% H, 13,46% N. UV: _{n niax} [nm] loge 360 3.74 330 3.88

c) Triethanolammonium salt

2.4 g of the pyridoquinazolone carboxylic acid are 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: 58,61% C, 5.91% H, N, 10.80; found: 58,89% C, 5.72% H, 11.00% N. UV: Amax [nm] loge 359 3.76 329 3.90

Claims (1)

SUBJECT A process for the preparation of quinazolone derivatives of the formula I O 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 a carboxyl group or a radical of formula COR4, wherein R4 is C1-C4 alkoxy, amino, hydroxylamino or 5-tetrazolylamino, and salts thereof, characterized in that the compound of formula II I INVENT in which And has the above meaning, Q is R1 or —COC1 and R is as defined above R2 or —COC1, provided that at least one of Q and R is —COC1, is reacted with a compound of formula III H — Z (III), wherein when Q in the compound of formula (II) is - R1, Z represents a hydroxyl group, a C1 -C4 alkoxy group, an amino group, a hydroxylamino group or a radical of formula H and when Q in the compound of formula (II) is -COCl, Z is a hydroxyl group 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.