CH624118A5 - Processes for the preparation of new imidazobenzoxazines - Google Patents

Abstract

Compounds of formula: <IMAGE> in which R3 represents a C1-C5 alkyl are prepared by decarboxylation of a corresponding alkyl ester carrying a carboxyl in position 1. The ester IA can be nitrated in position 8, or hydrolysed to give the carboxylic acid. The esters IA, their nitrated derivatives and the acids, as well as their salts, have antiallergic and bronchodilatory properties; they can be used, especially, in the treatment of allergic asthma.

Description

*

624,118

1. Process for the preparation of new imidazobenzoxazines corresponding to the formula:

'COOÏU

/

(IA)

Certain heterocyclic compounds with a structure close to that of the compounds of formula I described below were already known (US Patent No. 3,929,783).

The present invention relates to processes for the preparation of new imidazobenzoxazines and their salts, said imidazobenzoxazines corresponding to the formula:

in which R3 represents an alkyl radical containing from 1 to 5 carbon atoms, as well as their salts, characterized in that a compound of formula:

(I)

OOR.

(He)

in which R3 has the meaning already indicated.

2. Method according to claim 1, characterized in that products of formula I are prepared, in which R3 represents a methyl or ethyl radical, as well as their salts.

3. Process for the preparation of new imidazobenzoxazines and their salts, said imidazobenzoxazines corresponding to the formula:

✓COOR3

in which R3 represents an alkyl radical containing from 1 to 5 carbon atoms, characterized in that compounds of formula IA are prepared by the process according to claim 1 and nitrate said compounds.

4. Method according to claim 3, characterized in that products of formula I are prepared, in which R3 represents a methyl or ethyl radical, as well as their salts.

5. Process for the preparation of new imidazobenzoxazines corresponding to the formula:

COOH

wherein X represents a hydrogen atom or a nitro radical and R represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms.

In formula I and in what follows, the term alkyl radical containing from 1 to 5 carbon atoms denotes, for example, a methyl, ethyl, propyl, isopropyl, butyl or pentyl radical. The products of formula I, with the exception of those which carry a free carboxyl group, have a basic character;

in this case, the salts formed can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxa acids -30 lique, glyoxylic, aspartic, alkanesulfonic such as methanesulfonic acid, and arylsulfonic such as benzenesulfonic acid.

The products of formula I which carry a carboxyl group have an acidic character; in this case, the salts may be metal salts or addition salts with nitrogenous bases.

(IB) The metal salts may be, for example, the salts of alkali metals, such as sodium, potassium or lithium, of alkaline earth metals, such as calcium or magnesium, or of metals, such as 'aluminum.

The nitrogen base salts can be, for example, ammonium salts or amine salts, such as tromethamine, lysine, arginine, triethanolamine.

Among the products obtained by the process which is the subject of the invention, there may be mentioned in particular the derivatives corresponding to formula I above, as well as their salts, characterized in that in said formula I, X represents an atom of hydrogen or a nitro radical and R represents a hydrogen atom, a methyl or ethyl radical.

Among the products obtained by the process which is the subject of the invention, mention may be made more particularly of 4H-imidazo- [2, 1-c] - [1, 4] -benzoxazine-2-carboxylic acid and its salts.

The process according to the invention is characterized in that a product of formula:

r a-)

and their salts, characterized in that, by the process according to claim 1, compounds of formula IA are prepared and said compounds are hydrolyzed.

jCOOR3

(he)

in which R3 represents an alkyl radical containing from 1 to 5 carbon atoms, to obtain a product of formula:

at

3

624,118

OOR,

in which R3 has the meaning already indicated, hydrogen the latter to obtain a product of formula:

(IA)

in which R3 has the meaning already indicated. Then nitrate said product of formula IA to obtain a product of formula IB:

(VIII)

COOR.

OOR-

in which R3 has the meaning already indicated, then reacts the latter with the halogenated derivative of a haloacetyl of formula: (IB) 15 Hai - CO — CH2 - Hai, in which Hai represents a chlorine, bromine atom or iodine, to obtain a product of formula:

NH-CO ~ CH2-Hal

(VII)

in which R3 has the meaning already indicated, or it is subjected to hydrolysis, to obtain the product of formula:

COOH

25

COOR,

(I ")

and salifies, if desired, the products of formulas IA, IB and I ".

Under preferred conditions for implementing the invention, the preparation process described above is carried out as follows:

a) the decarboxylation of the product of formula II is carried out by heating the product;

b) the nitration of the product of formula IA is carried out by means of a mixture of concentrated nitric and sulfuric acids, the hydrolysis of the product of formula IA is carried out by means of an aqueous solution of an alkaline base such as l 'sodium hydroxide.

The salts of the products of formula I can be prepared by reacting said products with the corresponding acids or bases in substantially equimolecular proportions.

The product of formula II can be prepared by reaction of a product of formula:

vs)

COOR.

in which R3 has the meaning already indicated, with an organic nitrite to obtain a product of formula:

HO.

NOT

in which R3 and Hai have the definition already indicated and that said product of formula VII thus obtained is treated with a base, then with an acid, to give the compound of formula II.

In implementing the method as defined above:

a) the organic nitrite can advantageously consist of amyl nitrite;

b) the halogenated derivative of a haloacetyl of formula: Hal-— CO — CH2 - Hai is advantageously chloro chloride

Roacetyl;

c) the reaction of the product of formula VII with a base is advantageously carried out by means of a weak base such as sodium carbonate and followed by the treatment of a strong acid such as concentrated hydrochloric acid.

The products obtained by the process which is the subject of the present invention have very advantageous pharmacological properties; they are endowed in particular with remarkable antiallergic and bronchodilator properties.

These properties justify the use of the derivatives of formula I and 45 of their pharmaceutically acceptable salts as medicaments.

Among these derivatives of formula I and their pharmaceutically acceptable salts, in particular those described in the examples are retained. As medicaments, the derivatives of formula I and their 50 pharmaceutically acceptable salts find, for example, their use in the treatment of allergic asthma and asthmatic bronchitis of allergic origins.

The usual dose, which varies depending on the product used, the subject treated and the condition in question, may for example be 0.5 mg to 100 mg / day 55 orally in humans.

The products of formula I, as well as their pharmaceutically acceptable salts, can be used to prepare pharmaceutical compositions containing, as active principle, at least one of said products or at least one of said salts. As medicaments, the derivatives corresponding to formula I and their pharmaceutically acceptable salts can be incorporated into (IX) res in pharmaceutical compositions intended for the digestive or parenteral or local route.

These pharmaceutical compositions can be, for example, 65 solid or liquid and are presented in the pharmaceutical forms commonly used in human medicine, such as for example tablets, simple or coated, capsules, granules, syrups, aerosols, suppositories , the preparations

(X)

624118

4

injectables, ointments, creams; they are prepared according to the usual methods. The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

The compounds of formula II above are also new industrial products.

The following examples illustrate the invention.

Example 1:

4H-Imidazo- [2, 1-c] - [1,4J-methyl benzoxazine-2-carboxylate.

Stage A:

a-Oximino-2-oxo-2H-1,4-benzoxazine-3-methyl acetate.

82 g of 2-oxo-2H-1,4-benzoxazine-A3 (4H) x-methyl acetate are suspended (described in "Bull. Chem. Soc. Japan", 1971, 44 (5), pp. 1311 to 1313) in 11 glacial acetic acid, 15 g of trichloroacetic acid are added, then 48 g of amyl nitrite.

The temperature rises to around 60 ° C and the starting material goes completely into solution. After 2 h, thin layer chromatography indicates that only a small amount of starting material remains. 3 g of amyl nitrite are added and the mixture is cooled for 2 h in an ice bath.

The crystals obtained are filtered and washed with ether. After drying in the presence of P2O5, 74.4 g of expected product are obtained.

The mother liquors are concentrated at 70 ° C to a volume of about 200 cm3 and a second jet of 2.3 g of product is obtained, ie in total 76.7 g of the expected product. Mp 169-170 ° C.

Spectrum I.R. (KBr).

Absorption at 771, 979.1022, 1250, 1288, 1754, 3310 cm-i. Stage B:

a-Amino -2-oxo-2H-1,4-benzoxazine A3 (4H) a-methyl acetate.

42.5 g of a-oximino-2-oxo-2H-1,4-ben-zoxazine-3-methyl acetate obtained in Stage A are suspended in 500 cm3 of dry tetrahydrofuran and 0.7 g are added. platinum oxide. The mixture obtained is hydrogenated under a pressure of 4 atm. The hydrogenation is rapid and regular and is completed after 1 h.

The dark red solution obtained is filtered on celite and the filter is washed with chloroform. The filtrate is evaporated to dryness at 45 ° C.

The residue is triturated in 100 cm 3 of cold ethanol. The red crystallized product thus obtained is filtered, washed with ethanol and ether and then dried. 35.5 g of expected product are obtained. M = 122-125 ° C.

Spectrum I.R. (KBr).

Absorption at 750,1218, 1241, 1280, 1302, 1510, 1556,1695, 1728, 3300, 3360 and 3470 cm-i.

Stage C:

2-Chloroacetamido 2- (2-oxo 2H-1,4-benzoxazin-3-yl) methyl acetate.

50.2 g of product obtained in Stage B are suspended in 400 cm3 of glacial acetic acid and 30 g of monochloroacetyl chloride are added. A yellow precipitate forms which dissolves when hot. After 3 h at 50 ° C, thin layer chromatography indicates that the starting material has disappeared. The acetic acid is evaporated, 150 cm 3 of ethanol are added to the residue, the mixture is triturated and cooled. The crystals are filtered and washed with ether and, after drying, 52.6 g of yellow crystals are obtained. M = 129-131 ° C.

Spectrum I.R. (KBr).

Absorption at 765,1226,1533,1670,1745,1767, 3295 cm1. Stage D:

4H-2-methoxycarbonylimidazo- [2, l-c] - [1,4] -benzoxa-zine-l-carboxylic acid.

72 g of the product obtained in Stage C are suspended in a mixture of 400 cm3 of water and 50 cm3 of acetone. 40 g of anhydrous sodium carbonate are added to the solution thus obtained, the mixture obtained is warmed in a water bath for 15 min until a clear yellow solution is obtained. Concentrated hydrochloric acid is added slowly with stirring to the hot solution until pH 2-3. A solid product immediately crystallizes and, after cooling in an ice bath, is filtered. Washed with water, dried in the presence of P2O5 and obtained 43.5 g of the expected product. M = 160-162 ° C.

Spectrum I.R. (KBr).

Absorption at 750, 1243,1276,1508, 1554,1722 cm-i.

Stage E:

4H-Imidazo- [2, 1-cJ- [1,4J-benzoxazine 2-methyl carboxylate.

Heated with stirring at 175-180 ° C, for about 20 min, 20 g of product obtained in stage D. The decarboxylated product thus obtained is dissolved in chloroform, the solution obtained is passed over silica in order to remove the impurities. The solution of methyl 4H-imidazo- [2, l-c] - [1,4] -benzoxazine-2-carboxylate is brought to dryness, triturated in ether, filtered, washed with ether and dried. 14 g of expected product are obtained. Mp 133-134 ° C.

Spectrum I.R. (KBr).

Absorption at 745,1259,1562,1715, 3135 cm-i.

Example 2:

4H-imidazo [2, 1-c] - [1, 4] -benzoxazine-2-carboxylic acid.

10 g of product obtained in Example 1 are suspended in a mixture of 100 cm3 of methanol and 50 cm3 of water. A 2N sodium hydroxide solution is added up to pH 11, the mixture is heated until the starting material is completely dissolved. Thin layer chromatography indicates that the starting material has disappeared. The solution obtained is acidified to pH 2-3 by addition of concentrated hydrochloric acid, the expected product precipitates and, after cooling, filtered and washed with water. The white product obtained is dried in the presence of P2O5 and finally 8.5 g of expected product is obtained. Mp 256-258 ° C.

Spectrum I.R. (KBr).

Absorption at 755, 1191, 1218, 1512, 1559, 1695, 2300, 3500, 3135 cm-i.

Example 3:

Tris (hydroxymethyl) aminomethane salt of 4H-imidazo [2,1-c] - [1,4] -benzoxazine-2-carboxylic acid.

6 g of product obtained in Example 2 are suspended in methanol and 3.5 g of tris (hydroxymethyl) aminome-thane are added. By heating, a clear solution is obtained. Cool, initiate crystallization and finally obtained after filtration and drying 8.1 g of the expected product in the form of white crystals. Mp 203-205 ° C.

Spectrum I.R. (KBr).

Absorption at 750, 1040, 1222, 1277, 1349, 1369, 1403, 1510 to 1600, 2300 to 3500 cm-1.

Example 4:

Methyl 8-Nitro 4H-imidazo [2, 1-c] - [1,4] -benzoxazine-2-carboxylate.

8 g of product obtained in Example 1 are introduced into a mixture of 25 cm3 of concentrated sulfuric acid and 25 cm3 of acid

5

10

15

20

25

30

35

40

45

50

55

60

65

624,118

concentrated nitric with stirring at 10 ° C. The starting ester gradually goes into solution, the solution turning yellow, and after 3 h at room temperature, thin layer chromatography indicates that the starting product has disappeared. 500 cm3 of water are added, the yellow crystallized product obtained is filtered, washed with

water, dries in the presence of P2O5 and finally obtains 7.5 g of the expected product. M = 270-272 ° C.

Spectrum I.R. (KBr).

Absorption at 1276, 1348, 1541, 1728, 3150 cm-i.

R