LU80470A1 - "NEWS DERIVED FROM 4-ANIMO-2- (PIPERAZIN-1-YL OR HOMOPIPE-RAZIN-1-YL) -QUINAZOLINE, THEIR PRODUCTION PROCESS AND PHARMACEUTICAL COMPOSITION CONTAINING THEM. - Google Patents

Description

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The present invention relates to therapeutic agents which are novel derivatives of 4-amino-2- (piperazin-1-yl or homopiperazin-1-yl) -quinazoline. These compounds have the advantage of being regulators of the cardiovascular system and of being able to be used in particular in the treatment of hypertension.

The new compounds in accordance with the invention correspond to the general formula: ✓R2 .. 4 / - (f X N / N N-C-Jv Jv v / J --- {1) (R) - 2 m K R.

11 vV 1 KH2 in which: 10 (R) n represents a 6,7-di- (lower alkoxy) or 6,7,8-tri- (lower alkoxy) group; m is 1 or 2; X represents a group -CHR - or -CH2CH2-; each of the symbols R1, which may be the same or different, represents a hydrogen atom or a lower alkyl group; and R and R, which may be the same or different, each represents hydrogen or a lower alkyl, lower alkoxy, halo, lower alkanoyl, lower alkoxycarbonyl or a group of formula -CONR ^ R ^ or - SO-NR ^ R ^ wherein R ^ 5 A ^ and R, which may be the same or different, each represents hydrogen or a lower alkyl group; These compounds also exist in the form of their pharmaceutically acceptable acid addition soils.

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In this specification, the term "halogen" refers to fluorine, chlorine, bromine or iodine. The term "lower" applied to an alkyl or alkoxy group means that this group, straight or branched chain, contains 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. The term "lower" applied to an alkanoyl group means that this group, chain. straight or branched, contains 2 to 6 carbon atoms and pre-. ference 2 to 4 carbon atoms.

Pharmaceutically acceptable acid addition salts of the compounds of the invention are the salts formed from acids which give non-toxic acid addition salts containing pharmaceutically acceptable anions pharmaceutical view, for example hydrochlorides, hydrobromides, sulphates or bisulphates, acid phosphates or phosphates, acetates, maleates, fumarates, succinates, lactates, tartrates, citrates, gluconates, saccharates and p-toluenesulfonates.

A preferred group of compounds includes the compounds of formula: / - \ r ° 'τΓ ^ ί yvV \ / Ί> ο ^ 3.

mr—- I - oh1 r3. 5 NHj 'wherein: 20 (R) n is a 6,7-di- (lower alkoxy) or 6,7,8-tri- (lower alkoxy) 9; Λ - R represents a hydrogen atom or a lower alkyl group and R and R, which may be identical or different, each represent hydrogen or a lower alkyl, lower alkoxy, halo, alkanoyl / * radical I. 3.

"4 5 lower or a group of formula -CONR R or -S02NR4R5 in which R4 and R5, which may be the same or different, each represent I Ί hydrogen or a lower alkyl group! , 5 and the pharmaceutically acceptable acid addition salts of these compounds.

; * Another preferred group comprises the compounds of formula (I) in which (R) is a 6,7-dimethoxy, 6,7-diethoxy or 6,7,8-trimethoxy group 5 m is equal to 1 or 2; each i 10 of the symbols R independently represents hydrogen or 2 3 a group CH ^ 5 and R and R each independently represents hydrogen or a lower alkyl, lower alkoxy, halo, lower alkanoyl, alkoxycarbonyl radical lower, -CONH2 or S02N (CH3) 2.

The most preferred compounds have the formula: RV0v ^ <2 / \ 1 "-11.0 CH Osv ^ V / V /? / ÎÎ 0 3

3 Y I I \ _ / 0 R

zi. NOT

; nh2 ^ in which R is a hydrogen atom or a CH ~ group and R and R represent hydrogen or a lower alkyl, lower alkoxy, halo or lower alkanoyl radical.

20 'The individual compound to which most preference is given is 4-amino-2- [4- (1,4-benzodioxane-2-car-bonyl) -piperazin-1-yl] -6,7- dimethoxyquinazoline.

The compounds of the invention containing one or more centers of asymmetry exist in the form of one or more pairs of enantiomorphs, and these pairs or the individual isomers can be separated by physical methods. '·,, I ~ \ 4.

for example by fractional crystallization of suitable salts · The invention includes separate pairs of mime as their mixtures in the form of racemic mixtures or in the form of the individual optically active isomers d- and 1-.

> 5 When X represents a group -CHR -, in which Λ R esc is a lower alkyl radical, a cis- and trans-r isomerism is liable and the two isomers (and their mixtures) fall within the scope of the invention.

The compounds of the invention can be prepared in various ways, for example by the following methods: (1) "The compounds of the invention can be prepared by reaction of a suitably substituted quinazoline of formula: w" - ' 1 1 - (I „- nh2 in which Q represents an easily eliminated group such as a chloro, bromo, iodo, lower alkoxy or (lower alkyl-thio) radical, with a piperazine or a homopiperazine of formula: / r2 '. · ΓΛ 11 hn4 n— c -. JL! - (111) \ / Il I> 0 3

(CH -) - '-OR1 "R

2 m and there is the elimination of an HQ molecule. Q is preferably a chloro or bromo radical.

The reaction is usually carried out by heating the reactants to a temperature which can range from 80 to 150 ° C., for example at reflux, in an organic solvent / Μ 9 5.

Inert, such as n-butanol. When the reaction is substantially complete, the product can be isolated and purified by conventional procedures. For example, in a usual process, the reaction mixture is cooled and the resulting crude solid product is collected, washed for example with cold n-butanol and dried. The crude product can be purified by a conventional operation, by hot dissolving in aqueous dimethylformamide, filtration and concentration of the filtered solution, for example under vacuum. The solution is then cooled and ether is added thereto to precipitate the pure product, which can be filtered and washed with ether.

The intermediate compounds of formulas (II) and (III) are known compounds, or they can be prepared by methods analogous to those of the prior art. For example, the intermediate compounds of formula (III) can be prepared according to the following reaction scheme: / ~ Λ Y ^ I + HC1: m nh: _ + Cl - ç_ vJ H \ / u ^ ° 3 I (IV) (V) (III)

The intermediate compounds of formulas (IV) and (V) are known compounds or can be prepared by pro-

* 11 classic ceded. When X is a group -CHR - in which R

20 is a lower alkyl radical, cis- and trans- isomers of compound (V) may exist. We can use a mixture of! these isomers, but if a predominantly cis- or predominantly trans- end product is desired, the cis- or trans- corresponding starting compound can generally be prepared by a suitable chromatographic technique, to which the es corresponding methyl or ethyl ter, then proceeding to the transformation into acid chloride.

(2) The compounds of the invention can also be / 1 // 6.

prepared by reaction of a quinazoline of formula:

’/ ~ <R

/ N NH ^ --- (VI)

(E) n — l · Jf | J

"> 2 with a carboxylic acid of formula:? Y - (VII)

3} * c ^ o -rc “H

H H1 or with its functional equivalent as an acylating agent, for example an acid chloride or bromide, "activated" ur ester or a mixed anhydride of the compound of formula (VII).

The acid chlorides or bromides can be prepared by conventional operations, for example by reaction of the free acid with the chloride or thionyl bromide respectively.

The preferred "activated" ester is the succinimid-ester of the formula: i °

> J

Ί '- •' 7.

.

Which can again be prepared by conventional methods, for example by reaction of the free acid with N-hydroxy-succinimide in the presence of a dehydrating agent such as: dicyclohexylcarbodiimide. Another popular "activated ester" 5 is the phthalimido-ester.

Suitable mixed anhydrides have the formula! · ^ Y ° Yiî S -, bo.

î ', ΧΛ yçc - o -c - * -

R3 R

in which Y is a lower alkyl or lower alkoxy group, in particular a tert-butyl or isobutoxy group. They can be prepared by conventional operations, for example by reaction of the free acid with lower alkanoyl chloride or respectively the corresponding lower alkyl chloroformate, for example pivaloyl chloride or isobutyl chloroformate, in the presence a base such as triethylamine.

When the compound (VII) is used in the form of the free acid, the reaction must generally be carried out in the presence of a dehydrating agent such as dicyclohexylcarbodiimide.

Preferably, the compounds of formula (VII) are reacted in the form of their chlorides or bromides of acids.

In a common procedure in which an acid chloride of compound (VII) is used, the acid chloride in a suitable solvent such as methylene chloride is added dropwise to a suspension with stirring of quinazoline ( VI) in a suitable solvent such as methylene chloride. The mixture can then be stirred for a few hours at room temperature and the resulting solid is then filtered off and purified by df- / 18.

classic techniques.

1 1

When X is a group -CHR -, in which R is a lower alkyl radical, cis-trans isomerism is possible as mentioned for the procedure (1).

The intermediate compounds of formulas (VI) and (VII) can be prepared by conventional methods.

(3) Pharmaceutically acceptable acid addition salts of the compounds of the invention can be prepared by conventional methods, for example by reaction of the free base with the appropriate acid in an organic solvent. inert, and the resulting salt precipitate is collected - by filtration. If necessary, the product can then be recrystallized for purification. However, the product obtained by methods (1) and (2) is often in the form of the acid addition salt.

The invention also relates to the pharmaceutically acceptable bioprecursors of the compounds of formula (I) as well as their salts.

The term "pharmaceutically acceptable bioprecursor" requires some explanation. A common practice in pharmaceutical chemistry is to remedy any unwanted physical or chemical property of a drug by transforming that drug into a chemical derivative which does not 'do not have these undesirable properties' but which, when administered to an animal or a human being, resumes the form of the initial active substance. For example, if the drug is not well absorbed when When administered to the animal or to the patient orally, it is possible to transform it into a chemical derivative which is well absorbed and which is re-transformed in serum or tissues into the initial drug. if a drug is unstable in solution, it is possible to prepare a chemical derivative of this drug which is stable and which can be administered in solution, but which re-transforms in the body by giving the initial drug . The specialist in the field of pharmaceutical chemistry is fully aware of the possibilities of overcoming the disadvantages which a medicament presents by chemical modifications of this medicament which are only temporary and which are /] 9.

î reversible when administered to animals or patients.

For the purposes of this specification, the expression "pharmaceutically acceptable bioprecursor" of a compound of formula (I) designates a compound whose structure differs from that of the compounds of formula (I), but which, nevertheless , when administered to an animal or a human being, is transformed in the organism of the animal or of man into a compound of formula (I).

The antihypertensive activity of the compounds of the invention is demonstrated by their ability to lower the blood pressure. '' guineaf unaesthetized rats, in spontaneous hypertension, and; * of non-anesthetized dogs with renal hypertension when administered orally at doses up to 5 mg / | kg.

The compounds of the invention can be administered alone, but they are generally administered in admixture with a pharmaceutical carrier or vehicle which is chosen taking into account the desired route of administration and normal pharmaceutical practice. For example, they can be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules, alone or in admixture with excipients, or in the form of elixirs or suspensions containing perfumes or dyes.

They can be injected parenterally, for example intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other dissolved bodies, for example a sufficient amount of sodium chloride or glucose to make the solution soluble. 30 isotonic.

Consequently, the invention also relates to a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt of dracid of this compound, associated with an acceptable diluent or excipient of the Pharmaceutically, the compounds of the invention can be administered to humans for the treatment of hypertension, orally or parenterally, and they can be administered.

orally in doses ranging from 1 to 20 mg per day for an average adult patient (70 kg), in a single dose or in several individual doses (up to three). Intravenous doses should be in the range of about 1/5 to 1/10 5 of the daily oral dose. Thus, for an average weight adult patient, individual oral doses in the form of tablets or capsules are approximately in the range of 1 to 50 mg of active compound. Variations are inevitable depending on the weight and condition of the subject being treated and the particular route of administration which is chosen, as is well known to those skilled in the art.

The compounds of the invention allow the treatment of an animal or a human being suffering from hypertension by administration to the animal or to human beings of an antihypertensive amount of a compound of formula (I) or an addition salt, of a pharmaceutically acceptable acid of this compound or of a pharmaceutical composition as defined above.

The invention is illustrated by the following examples.

EXAMPLE 1 - 4-amino-2-r4- (1,4-benzodioxane-2-carbonyl) -pjperazin-l-yl ~ l-6,7-dimethoxyquinazoline CB3 <(/ \ fc "3Vwcl, · 3 NH2 ° CH30 NH2

140 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 150 g of N- (1,4-benzodioxane-2-carbonyl) -pipe-razine are stirred at reflux in 2 liters of n-butanol for 3:25 a.m. The mixture is then cooled to 80 ° C, the solid product is collected, washed with twice 250 ml of cold n-butanol and dried. The crude product is dissolved hot (80 ° C)

H

!) \ ί! . Ii.

in 530 ml of dimethylformamide and 130 ml of water, the mixture is filtered, concentrated in vacuo to approximately 300 ml and then cooled and 1.8 l of ether are added. The solid substance thus obtained is collected and washed with ether; 215 g of 4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) -piperazin-1-yl] -6,7-dimethoxyquihazoline melting at 289-290 ° are thus obtained. vs.

Analysis: C,% H,% N,% calculated for ^ 23 ^ 5 ^ 0 ^. 1101 56.6 5.4 14.4 R found 56.9 5.4 14.4.

U

• EXAMPLE 2 - 4-amino-2-r4- (1,4-benzodioxane-2-carbonyl) —piper- * zin-l-yll-6,7,8-trimethoxyauinazoline

Heated to reflux in 67 ml of n-butanol 1 g of 4-amino ~ 2-chloro-6,7,8-trimethoxyquinazoline and 1,168 g of N- (1,4-benzodioxane-2-carbonyl) -piperazine with 1 , 87 g of tri-ethylamine for 24 hours. Then, another 0.026 g ί of N- (1,4-benzodioxane-2-carbonyl) -piperazine is added and the mixture is heated at reflux for another 30 hours. Butanol is then removed in vacuo and the residue is partitioned between an aqueous solution of sodium carbonate and chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and evaporated in vacuo leaving 3.4 g of a solid which is taken up in the minimum amount of dimethylformamide. The solution is then left to stand at 0 ° C for about 18 hours. Ether is then added 25 '25 and the cloudy solution is cooled to an even lower temperature I, which gives 0.58 g of 4-amino-2- [4- (1,4 ~ benzodioxane-2- carbonyl) -piperazin-1-yl] ~ 6,7,8-trimethoxyqui- 'nazoline melting at 269-271 ° C.

Analysis: C,% H,% N,% (30 calculated for ^ 24H27N5 ° 6 59.9 5.7 14.6 d 4 found 59.3 5.6 14.1.

ti EXAMPLE 3 - 4-amino-2-f4- (1,4-benzodioxane-2-carbonyl) -piperera- I zin-l-yll-6,7-diethoxyquinazoline J The mixture is heated at reflux for about 18 hours in 1 d 35 30 ml of n-butanol 0.33 g of 4-amino-2-chloro-6,7-diethoxyqui- nazoline and 0.32 g of N- (1,4-benzodioxane-2-carbonyl) - piperazinc ί fi 12.

The mixture is then evaporated in vacuo and the residue is partitioned between a solution of sodium carbonate and chloroform.

The combined chloroform extracts are washed with ether, dried over sodium sulfate, evaporated in vacuo and the residue is chromatographed on 70 g of silica gel, using a mixture of chloroform and methanol (0-5%) as eluent. The similar fractions are combined, evaporated in vacuo, then redissolved in a mixture of chloroform and methanol and the solutioft is treated with a solution of hydrochloric gas in ether. The solution is then evaporated in vacuo and the residue is recrystallized from isopropanol. 0.19 g of 4-amino — 2- [4- (1,4-benzo-dioxane-2-carbonyl) -piperazin-1-yl] -6,7-diethoxyquinazoline hydrate 2.5 molecules is obtained. of water, melting at 180-184 ° C while decomposing.

Analysis: C,% H,% N,% calculated for .HCl.

zo zy 0 0 2 1 / 2h20 53.5 6.3 12.5 found 53.3 5.6 12.2.

2o EXAMPLE 4 - 4-amino — 2-Γ4— (1,4-benzodioxane-2-carbonyl) —homopi— pérazin-l-yl ~ l-6,7-dimethoxyquinazoline The mixture is heated to reflux in 114 ml of n- butanol for 60 hours 1.58 g of 4-amino-2-chloro-6,7-dimethoxyquinazo-line and 2.0 g of N- (1,4-benzodioxane-2-carbonyl) -homopiperazine.

The mixture is then cooled, the butanol is removed in vacuo and the solid residue is triturated with ether, it is taken up in hot methanol, the solution is filtered and cooled. The crude product is collected and then the residual solution is evaporated under vacuum and the residue is taken up in hot isopro-30 panol, it is cooled, it is filtered and then it is evaporated under vacuum. The residue and the initial solid product are combined, the mixture is treated with cold methanol and it is recrystallized from ethanol, which gives 0.57 g of 4-amino-2- hydrochloride [4- ( 1,4-benzodioxane-2-carbony1) -homopiperazin-1-y1] -35 6,7-dimethoxyquinazoline melting at 250-251 ° C.

Analysis: · C,% H,% N,% calculated for C24H27N5 ° 557.4 5.6 14.0 / found 5 7.2 13.8.

7 13.

EXAMPLE 5 - 4-amino-2-r4- (6-methoxy-1,4-benzodioxane-2-car-bonyl) -piperazin-l-yl1-6,7-dimethoxyquinazoline ^ ΓΪΎCH3

Jk il 0 III O 1 3 -HC1

CH N

MH CH3 ° T

2 KH2 * *

A solution of 2.17 g of 6-methoxy-1,4-benzodioxane-2 ~ carbonyl chloride (prepared from acid and thionyl chloride) in 25 ml of dichloromethane is added dropwise. suspension with stirring of 2.48 g of 4-amino-2-piperazin-1-yl-6,7-dimethoxyquinazoline in 50 ml of methylene chloride at room temperature. When the addition is complete, the mixture is stirred at room temperature for 4 hours then filtered and the solid is suspended in an aqueous solution of potassium carbonate, then extracted with chloroform. The combined extracts are washed with water, dried over sodium sulphate and evaporated in vacuo, leaving a solid residue (4.15 g) which is chromatographed on 160 g of silica and eluted with chloroform then a mixture of chloroform and methanol (2.5%). The similar fractions (thin layer chromatography) are combined, evaporated in vacuo, then the residue is taken up in a mixture of ethyl acetate and methanol and treated with a solution of hydrochloric gas in ether. By adding more ether and then cooling, a solid material is obtained which is collected and which is recrystallized from methanol. This gives 0.95 g of 4-amino-2- [4- (6-methoxy-1,4-benzodioxane-2-! Carbonyl) -piperazin-1-yl] -6,7-dimethoxyquinazoline hydrochloride , melting at 220-222 ° C.

ή [! (_ —— J! 14.

Analysis: C <,% H,% N,% calculated for C ^^ H ^ yN ^ Og.HCl53.8 5.6 13.1 found 53.3 5.5 13.4.

EXAMPLES 6-24. The following compounds were prepared by the procedure 4 of Example 5 starting from 4-amino-2-piperazin-1-yl (or 2- [3-methylpiperazin-1-yl]) - 5.7 -dimethoxyquinazoline and corresponding carbonyl chloride.

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ω / k - · - 22 EXAMPLE 25 "- 4-amino hydrochloride - 6,7-dimethoxy-2-r4- (mixture of 6- and 7-carbamoyl-1,4-benzodioxane-2-carbonyl) - piperazinol-quinazoline 2.06 g of dicyclohexylcarbodiimide and 1.15 g of N-hydroxysuccinimide are added to a stirred solution of 2.23 g of 6- and 7-carbamoyl-1,4-benzodioxane-2- acids carboxylic in 70 ml of dimethylformamide at 0 ° C. The mixture is stirred at 0 ° C for 1 hour, then 2.8 g of 4-amino-6,7-dimethoxy-2-piperazinoquinazoline are added and the resulting mixture is stirred at room temperature for 18 hours. The reaction mixture is then filtered, the filtrate is diluted with 500 ml of ether and the resulting oily precipitate is collected.

The product is partitioned between chloroform, isopropanol and a solution of sodium bicarbonate, the chlo-roformic phase is separated, washed with water and evaporated in vacuo. The residue is chromatographed on silica and a crude product is obtained by elution with a mixture of chloroform and methanol at 3%, which gives, by treatment with a solution of hydrochloric gas in ether and recrystallization from a methanol / mixture water / ether / dimethylformamide then a methanol / water / dimethylformamide mixture, hydrated hydrochloride of 4-amino-6,7-dimethoxy-2- [4- (6- and 7- (mixture) -carbamoyl-1,4-benzodioxane -2-carbonyl) -piperazin] -quinazoline melting at 228-235 ° C as it decomposes.

Another recrystallization gives an analytical sample melting at 245-248 ° C.

Analysis: C,% H,% N,%. calculated for C24H26Ng0gHCl.H20 52.5 5.3 15.3 found1 52.6 5.5 14.6.

30 The chromatography analysis in liquid phase under high pressure indicates that the product is a mixture of the isomers 6- and 7- in the ratio of 7: 3.

The preparation of some of the starting compounds is described below: PREPARATION 1. - (A) N- (1,4-benzodioxane-2-carbonyl) -piperazine '25 · ir \ Γ ° Ίθ- »/ ά X ° X5 + hc1

HN NB + Cl — X / ^ O

\ / ο o

A suspension of 11.88 g of piperazine and 20.30 g of sodium acetate in a mixture of 70 ml of water and 95 ml of acetone is stirred at 10-15 ° C., then approximately 35 ml is added. concentrated hydrochloric acid until the pH of the solution reaches 1.5. Then added in portions 31.0 g of 1,4-benzodioxane-2-carbonyl chloride and about 45 ml I of 5N sodium hydroxide, while maintaining the temperature at J 10-15 ° C, the hydroxide sodium now the pH at a value

‘1.7 to 2.2. When the addition is complete, the pH is adjusted

10 to 2.0 by the addition of sodium hydroxide and the above is stirred | board for another 30 minutes. Water * is then added until a homogeneous solution is obtained, the aceto is removed in vacuo and the aqueous residue is extracted with three times 200 ml of chloroform. The aqueous phase is made alkaline at a pH of 8-9 by adding 5N sodium hydroxide, re-extracted with three times 200 ml of chloroform and the extracts are washed with water and dried over sulphate. magnesium and they are evaporated under vacuum. The oily residue is dissolved in ethyl acetate, the solution is treated with a solution of I! > 20 hydrochloric gas in ether, evaporated in vacuo and the solid residue is sorted with ether, then recrystallization is carried out in methanol, to obtain 4.85 g of N- hydrochloride (1.4 -benzodioxane-2-carbonyl) -piperazine melting at -265-267 ° C. - -, I * 25 Analysis: C,% H,% N,% calculated for c ^ 3HigN2 ° 3 * HC'1 '54.8 6.0 9.8 found 54.6 5.5 9.7.

.U --- i / 24 PREPARATION 2. - 6-Methoxy-1,4-benzodioxane-2-carboxylic acid JXI% ocr "

5.02 g of finely ground potassium permanganate in four portions are added to a stirred suspension of 4.52 g of 2-hydroxymethyl-6-methoxy-1,4-benzodioxane in a solution of potassium hydroxide (1 , 47 g in 42 ml of water) at 5 ° C. During the reaction, the temperature is maintained at 5-15 ° C and then, when the addition is complete, it is continued to stir at room temperature for 4 hours, then the reaction mixture is left to stand for approximately 18 hours.

ÎO

The manganese dioxide is removed by filtration, the solid is washed with water and the combined aqueous phases are acidified (pH 1) with concentrated hydrochloric acid, cooled and then extracted with chloroform.

The combined chloroform extracts are washed with twice 40 ml of sodium hydroxide solution (5N), then the basic phase is again washed with chloroform, cooled, acidified (pH 1) with concentrated hydrochloric acid and reextracted with chloroform. This last chloro-'20 formic solution is washed with water, dried over sodium sulfate and evaporated, leaving a crude residue formed of 2.33 g of 6-methoxy-1,4-benzodioxane-2-carboxylic acid. . A sample recrystallized from water melts at 120-121 ° C.

'Analysis: - "C,% H,% 25 calculated for ci0H10 ° 5 57.1 4.8 found 57.1 4.8.

PREPARATION 3. - Acids 8- and 5- (melanae) -isopropyl-1,4-benzo-dioxane-2-carboxylic l_ - I 25! (A) A solution with stirring of 23 g of 3-isopropylcatechol in 250 ml of acetone is heated to reflux, then 28 g of potassium carbonate are added. The heterogeneous mixture is refluxed for a further 15 minutes and then added dropwise; 5 and 10 g of methyl 2,3-dibromopropionate. Three more batches of 28 g of potassium carbonate and 10 g of methyl 2,3- dibromopropionate are added in a similar manner, followed by stirring.

The mixture is refluxed for 12 hours. It is then evaporated, the residue is diluted with 700 ml of water, it is extracted with chloroform and the combined extracts are washed with water, they are dried over magnesium sulphate and they are evaporates. The residual oil gives, by distillation, 29.3 g of methyl e 8 (5) -isopropyl- 1,4-benzodioxane-2-carboxylate boiling at 115-120 ° C / 0.5 mm. 1 13 nuclear magnetic resonance spectroscopy; 15 C confirms the fact that the product is a mixture of isomers! 8 ’(71%) and 5 (29%).

(B) The above product (29.0 g) in 160 ml of 2.5 N sodium hydroxide solution is heated at 100 ° C for; half an hour, then the resulting solution is cooled and! 20 acidified with concentrated hydrochloric acid. The mixture is extracted with three times 200 ml of chloroform, the combined extracts are dried over magnesium sulphate and evaporated in vacuo, and an oil (18 g) remains which solidifies on standing. By recrystallization from methanol, a mixture of 8- and 5-isopropyl-1,4-benzodioxane-2-carboxy-melic acids melting at 86-88 ° C is obtained.

Analysis: C,% H,%. calculated for C ^ 2H14 ° 4 64.9 6.3 found 64.7 6.3 30 High pressure liquid chromatography indicates that the product is a mixture of isomers 8 (86%) and 5 (13%) . [Spectra Physics 3,500 CS apparatus; column, '25, 4 mm x 6.35 mm outside diameter, ”μ Böndapak C-18”; eluent = acetonitrile (1) / 0.15 M potassium acid phosphate buffer, pH 3.5 (2); flow rate = 14 ml / min; pressure 42 bars].

_ L __ i 26 PREPARATION 4. - Mixture of acids 8- and 5-methyl-1,4-benzodio-xane-2-carboxylic

23.15 g of potassium permanganate are added in three portions to a suspension, with stirring, of a mixture of 20 g of 8- and 5-methyl-2-hydroxymethyl-1,4-benzodioxane in a hydroxide solution. potassium (6.5 g in 187 ml of water) at 5 ° C. The reaction temperature is kept below 15 ° C and when the addition is complete, the reaction mixture is stirred at room temperature for 4 hours. The manganese dioxide is removed by filtration, the filtrate is cooled, it is acidified with concentrated hydrochloric acid and the oily product which separates ‘is extracted with chloroform during subsequent cooling. The chloroform extracts are washed with 5N sodium hydroxide solution, the basic phase is washed with chloroform, then it is acidified to pH 1 by addition of concentrated hydrochloric acid. The acid solution is extracted with chlproform, the combined extracts are washed with brine, dried over magnesium sulfate and evaporated in vacuo leaving a mixture (7.3 g) of 8- and 5-methyl-1 acids, 4-benzodioxane-2-carboxyliques in the form of a thick syrupy residue whose spectroscopic properties are consistent. We. esterify a small sample with diazomethane and it is found, by gas chromatography, that it is a mixture of isomers (5: 2).

25 PREPARATION 5. - Acid 6.7-dimethvl-1,4-benzodioxane-2-carboxv- league * CH, CH3

“WtoYy ° -ÆVy ° Y ° 2H

• · ch / ^ ch ^ <bc <^^ 0 J

vs . _ 27 (A) A solution is stirred at reflux of 7 "0g 4t5-dimethylcatecholdans 45 ml of acetone anhydr.ei then 5 g of potassium carbonate are added and the addition of 3 is carried out dropwise. 5 g of ethyl dibromopropionate.

The addition is repeated three more times in an hour and a quarter, then the reaction mixture is stirred at reflux for another 3 hours 45 minutes. After cooling, the mixture is filtered, the solid materials are washed properly with acetone, then the combined filtrates are concentrated under vacuum. • ^ 0 35 ml of water are added, the resulting solid substance is collected, washed with petroleum ether and then taken up in ether. The ether solution is washed with water, dried over sodium sulfate and evaporated in vacuo to give 10.17 g of ethyl 6,7-dimethyl-1,4-benzodioxane-2-carboxylate melting at 70-71 ° C.

Analysis: C,% H,% calculated for Ci3H16 ° 4 66.1 6.8 found 65.7 6.8 (B) By hydrolysis of the above ester (5.0 g) with 2o 13 ml of 10% sodium hydroxide in 125 ml of ethanol as described for the related compounds ("JACS", J77, 5374 (1956) 4.04 g of 6,7-dimethyl-1,4-benzodioxane acid are obtained. Raw 2-carboxylic A sample recrystallized from water melts at 150-151 ° C.

25 Analysis: C,% H,% calculated for C21H12 ° 4 63.5 · 5.8 found 63.9 6.0 PREPARATION 6. - 6,7-Dichloro-1,4-benzodioxane-2-carboxylic acid Hydrolysis of 5.0 g of ethyl 6,7-dichloro-1,4-benzodioxa- he-2-carboxylate with 10.9 ml of 10% sodium hydroxide in 50 ml of ethanol gives 3.4 g of 6,7-dichloro-1,4-benzodioxane-2-carboxylic acid melting at 155-158 ° C, the nuclear magnetic resonance spectrum of which conforms to structure 35 and whose Rf (chromatography on thin layer) is identical to that of an authentic sample.

1_ - 28 PREPARATION 7. - 3-methoxy-1,4-benzodioxane-2-carboxylic acid Stirred at 100 ° C for 1 hour 2.41 g of 8-metho-xy-1,4-benzodioxane-2-carboxamide in 35 ml of 50% hydrochloric acid. The resulting solution is cooled, diluted 5 with 200 ml of water, extracted with three times 100 ml of chloroform, then the extracts are dried over magnesium sulfate and evaporated in vacuo. The solid residue (1.8 g) is recrystallized from water (melting point 75-78 ° C) then from a mixture of ethyl acetate and hexane to obtain the acid 8 -methoxy-1,4-benzodioxane-2 ~ carboxylic melting at 131-132 ° C.

Analysis: C,% H% calculated for c- ^ oH10 ° 5 5 7.1 4.8 found 56.9 4.8 15 PREPARATION 8. - 5-Methoxy-1,4-benzodioxane-2-carboxylic acid

This compound is prepared by the process of Preparation 7 starting from 5-methoxy-1,4-benzodioxane-2-carboxamide.

The product is crystallized from water (melting point 85-87 ° C) and then from a mixture of ethyl acetate and hexane, and thus 5-methoxy-1,4-acid is obtained benzodioxane-2-carboxy-lique, melting at 139-141 ° C.

Analysis: C,% H,% calculated for c ^ qH10 ° 5 57.1 4.8 found 56.9 4.8 25 PREPARATION 9. - 6-acetyl-1,4-benzodioxane-2-carboxylic acid

11.6 ml of Jones' reagent is added dropwise to a stirred solution of 4.0 g of 6-acetyl-2-hydroxymethyl-1,4-benzodioxane in 70 ml of acetone at 10-15 ° C.

The reaction mixture is stirred at room temperature for 30 hours for 18 hours, then diluted with a mixture of isopropanol, water and chloroform, the organic phase is separated and evaporated in vacuo. The residue is redissolved in chloroform, extracted with twice 30 ml of saturated sodium carbonate solution, then the basic phase is washed with chlorofor-35 me, cooled and acidified to an equal pH to 1 by addition of concentrated hydrochloric acid.

29

The acid solution is extracted with chloroform, the combined extracts are washed with a saturated salt solution, they are dried over sodium sulfate and they are evaporated under vacuum to obtain 1.56 g of 6-acetyl-1,4 acid -benzodioxane-2-carbo-5 xylic melting at 159-162 °. A sample recrystallized from a mixture of ethanol and ethyl acetate melts at 174-175 ° C. Analysis: C5% H,% calculated for ^ 3 ^^ 0 ^ 5 59.5 4.5 found 59.0 4.8.

10 PREPARATION 10. - 7-Acetyl-1,4-benzodioxane-2-carboxylic acid (A) A solution of 13 ml of methyl 2,3-dibromopropionate in 50 ml of is added dropwise over half an hour. acetone to a stirred suspension of 15.1 g of 3,4-di-hydroxyacetophenone and 28 g of anhydrous potassium carbonate in 100 ml of acetone heated to reflux. The mixture is stirred under reflux for 4 hours, then evaporated in vacuo and the residue is partitioned between chloroform and water. The chloroform extracts are washed with water, dried over magnesium sulphate and evaporated, leaving a mixture of 18 g of methyl esters of 6- and 7-acetyl-1,4-benzodioxane-2-carbo acids. ~ xylics in the 2: 1 ratio determined by spectroscopy? , 13 of magnetic resonance of the nuclei of C. A sample of this crude product recrystallized from isopropanol melts at 68-80 ° C.

Analysis:. C,% H,% ^ calculated for C ^ 2H12 ° 5 61.0 5.1 found 60.7 4.9 (B) An aqueous solution of sodium hydroxide (1.2 g) is added in 5 ml d water to a stirred solution of 7 g of the product from (A) in 25 ml of ethanol at 15 °. The reaction temperature is kept below 25 ° for half an hour, then the mixture is evaporated in vacuo, the residue is triturated with water, acidified with concentrated hydrochloric acid and extracted with chloroform. The combined chloroform extracts are dried over magnesium sulfate, evaporated in vacuo and the residue (1.46 g) is recrystallized from a mixture of ethyl acetate and methanol to give 7-acetyl acid. 1,4-benzodioxane-2-carboxylic melting at 167- (1368 ° C.

Analysis: C,% H,% calculated for c ^ h ^ q ° 5 59.5 4.5 found 59.0 4.5 5 Chromatography in liquid phase under high pressure indicates an isomeric purity of approximately 96% [ Spectra Physics "3500 CS” device; column 25.4 mm x 6.35 mm outside diameter, "μ-Bondapak C-18”; eluent = acetonitrile (1) / 0.05 M potassium acid phosphate buffer, pH 4.5 (2); vi-10 flow rate 0.6 ml / min; pressure 55 bars].

The acidic aqueous phase is evaporated under vacuum, the residue is extracted with methanol, the extracts, combined - are evaporated under vacuum and the product (5.5 g) is recrystallized from a mixture of ethyl acetate and methanol giving 6-acetyl-1,4-benzodioxane-2-carboxylic acid. High pressure liquid phase chromatography reveals the presence of a single component which corresponds to an authentic sample prepared as indicated under the title "Preparation 9".

PREPARATION 11. - 20 (A) Acid (+) - 1,4-benzodioxane-2-carboxylic acid

21.6 g of 1.4 benzodioxane-2-carbo-xylic acid and 34.26 g of (+) -dehydroabietvlamine are mixed in 1000 ml of hot industrial methylated alcohol, then the mixture is left to stand at room temperature for 24 hours. The precipitate which forms is collected (20 g), the filtrate is concentrated to a volume of 600 ml, then it is left to stand for 48 hours, during which period an additional quantity of solid product (4 g) is formed. The combined product (24 g), melting point 204-210 ° C is subjected to re-crystallized crystallizations in a mixture of industrial methylated alcohol and metha-hol until constant melting point of 229-230 ° C (3.0 g), then • the mother liquors of the two last recrystallizations are combined, their volume is reduced and the solid product (5.6 g) is collected. This salt is converted into the carboxylic acid li ~ 35 bre (5.5 g) [a ^ + 60.1 ° (1% in chloroform)] in the conventional manner then it is recrystallized twice from toluene giving 0.23 g (+) - 1,4-benzodioxane-2-carboxylic acid A, melting at 98-99 ° C, [an = + 62.1 ° (1% solution in chloroform)] 31

Analysis: C,% H,% calculated for C ^ HgO ^ 60.0 4.5 found 60.3 4.4.

'(B) Acid (-) - 1,4-benzodioxane-2-carboxylic 5 The initial mother liquors (600 ml) coming from the experiment above are evaporated under vacuum and the oily residue is taken up in 250 ml 'acetone, then the solution is' allowed to stand until crystallization is complete. The solid product (10.0 g) is collected, crystallized from acetone 10 then the salt (6.0 g) is converted to free acid in the conventional manner using dilute sulfuric acid. The crude product is taken up in chloroform, the solution is chromatographed on silica gel (column 10 × 50 mm) ”the elution is carried out with chloroform, the eluate is evaporated in vacuo then the residue is crystallized from toluene to give 0.90 g of (-) - 1,4-benzodioxane-2-carboxylic acid, melting at 98-99 ° C; aD = -66.1 ° (1% solution in chloroform).

Analysis: C,% H,% calculated for cgHg04 60.0 4.5 20 found 59.9 4.5 PREPARATION 12. - N- (1,4-benzodioxane-2-carbonyl) -homooiperazine This compound is prepared as indicated for preparation 1 using homopiperazine instead of piperazine A sample of the hydrochloride is recrystallized from methanol; it melts at 189 ° C.

Analysis: C,% H,% N,% calculated for 56.3 6.4 9.4 found 56.2 6.2 9.3 PREPARATION 13. - Mixture of acids 6- and 7-chloro-1,4 -benzodio-'30 xane-2-carboxyligues • (A) Chlorine gas is passed through an ice-stirred solution of 10 g of methyl 1,4-benzodio-xane-2-carboxylate in 100 ml of chloroform in the presence of 0.06 g of aluminum chloride. The reaction is stopped after 20 minutes, then the solution is purged with nitrogen, washed with water, with a solution of bicarbonate fl "· = * 52.

of sodium and again in water, it is dried over magnesium tallow and evaporated in vacuo to obtain a residue which consists of a mixture (1: 1 according to spectroscopy 13 of Magnetic resonance nuclei of C) of 6- and 7-chloro-5 l, 4-benzodioxane-2-methyl cafboxylates (12.0 g).

(B) A sample (1-4 g) of the above product in 20 ml of ethanol is made up with a solution of 0.25 g of sodium hydroxide in 1 ml of water at room temperature, and a black color develops. After 48 hours at room temperature, the mixture is concentrated in vacuo, diluted with water, extracted with chloroform and the chloroform phase is discarded. The aqueous phase is acidified with concentrated hydrochloric acid, extracted with chloroform, then the combined extracts are dried over magnesium sulphate and evaporated in vacuo giving a mixed (1.0 g) of acids 6 - and 7— chloro-1,4-benzodioxane-2-carboxylates melting at 145-146 ° C., the spectroscopic properties of which are consistent.

PREPARATION 14. - bridle 2-methyl-1,4-benzodioxane-2-carboxyliaut 33.3 ml of reagent of 20 are added dropwise. Jones to a stirred solution of 5 g of 2-hydroxymethyl-2-methÿl-1,4-benzodio> ane in 300 ml of acetone at 5 ° C, then the reaction mixture is allowed to equilibrate with temperature ambient. 10 ml of isopropanol are then added, followed by 200 ml of water, the solution is extracted with chloroform and the extracts are evaporated in vacuo. The residual oil is taken up in 200 ml of chloroform, puii = the solution is extracted with a dilute solution of sodium bicarbonate and the aqueous phase is further washed with chloroform- EHe is then acidified with hydrochloric acid, extracted with chloroform, collected extracts are washed with water, dried over magnesium sulphate and evaporated in vacuo giving 1.7 g of 2-methyl-1,4-benzodioxane-2-carbox'yt lque acid * A sample recrystallized from toluene melts at 133- * 24ο0.

Analysis:% H,%. 35 calculated for c ^ qH1004 61.9 5.2 found 61.8 5.2.

/ L · '- 33 PREPARATION 15. - Mixture of acids 6- and 7-N, N-dimethylsulfa- moyl-l, 4-benzodioxane-2-carboxyligues (A) 180 g of catechol are added in portions to 138, 5 ml of sulfuric acid with stirring, so that the reaction temperature remains below 25 ° C. When the addition is complete, the semi-solid mixture is heated at 45 ° C. for 60 minutes, then cooled to room temperature and poured into 700 ml of ice water. The solution is neutralized with solid barium carbonate, barium sulfate is collected, the filtrate is acidified to a pH equal to 1 by adding concentrated sulfuric acid, then it is filtered again. The filtrate is evaporated, leaving 182.40 g of crude 3,4-dihydroxybenzenesulfonic acid which is used without purification.

(B) The above product (182.40 g) is conventionally acetylated with 300 ml of acetic anhydride in 500 ml of pyridine and the crude diacetoxy product (302.49 g) is used directly.

(C) 378 g of phosphorus pentachloride are added in portions to a stirred solution of the pyridinium salt of 3,4-diacetoxybenzenesulfonic acid (302.49 g) in 1000 ml of chloroform at 0 ° C so that the reaction temperature does not rise above 15 ° C. When the addition is complete, the reaction mixture is stirred at room temperature for about 18 hours, then it is filtered, the chloroform solution is evaporated in vacuo and the residual oil is poured into ice water. The aqueous phase is extracted with chloroform, the combined extracts are dried over sodium sulfate and evaporated in vacuo, leaving a semi-solid residue which is recrystallized from carbon tetrachloride. This product (26.74 g) is treated with 265 ml of 15% aqueous methylamine solution at 20 ° C, the reaction mixture is kept at room temperature for about 16 hours and then the solution is evaporated in vacuo. The dark colored residue is diluted with 250 ml of acetone, then separated by mechanization, the solution is evaporated in vacuo and the residual oil is stirred with an equal volume of sodium hydroxide solution at room temperature during 2 hours. The sclution / is then acidified with hydrochloric acid ccr.oer.tré

K

34 • and the resulting product is crystallized from water, giving N, N-dimethyl-3,4-dihydroxybenzenesulfamide, melting at 142 ° C.

(D) A solution of 0.61 g of sodium hydroxide in 5 ml of water is added dropwise to a stirred suspension of the above product (3.0 g) and 1.43 ml. of epichlorohydrin in 15 ml of water, then the reaction mixture is heated. at 80 ° C for 1.5 hours. After cooling, the reaction mixture is extracted with methylene chloride, the combined extracts are washed with water, dried over sodium sulphate and evaporated to obtain a mixture (2.84 g) of 6- and 7-N, N-dimethylsulfamoyl-2-hydroxymethyl-1,4-benzo-dioxanes in the form of a sticky oil whose spectroscopic properties are consistent.

(E) 2.15 g of potassium permanganate is added in three portions to a stirred suspension of 2.8 g of the above alcohol in a solution of potassium hydroxide (0.59 g in 20 ml of water) and 10 ml of acetone at 5 ° C, so that the reaction temperature does not rise above 10 ° C. The reaction mixture is kept at room temperature for 3 hours, then the acetone is evaporated and a further 1.5 g of potassium permanganate are added, followed by stirring for approximately 16 hours. Finally, another 3.0 g of potassium permanganate is added and the reaction mixture is stirred at 35-40 ° C under a nitrogen atmosphere for about 16 hours. The manganese dioxide formed is then collected, washed with water, the combined filtrates are acidified with concentrated hydrochloric acid, then they are extracted with chloroform. The combined extracts are washed with twice 40 ml of 5N sodium hydroxide solution, the alkaline phase is acidified with concentrated hydrochloric acid, it is extracted with chloroform and the combined extracts are washed with water, dehydrated over sodium sulfate and evaporated in vacuo. The crude product (0.46 g) is added to the similar substance (0.21 g) obtained by re-extraction of the manganese dioxide initially formed, and a mixture of 6- and 7-N, N-dimethylsulfamoyl acids is obtained. -1.4-benzodioxa-ne-2-carboxylic (0.67 g), melting at 156-162 ° C.

Analysis: C,% H,% N,% calculated for C ^ H. ^ N0gs 46.0 4.6 4.9. found 45.5 4.6 4.90.

155 PREPARATION 16. - Ethyl 3-methyl1-1 "4-benzodioxane-2-carboxylates (cis and trans isomers)

These compounds were separated from each other by preparative liquid chromatography under high pressure and were identified by nuclear magnetic resonance spectroscopy in accordance with the information that has been published (see, for example, "J. Med. Chem. ", 10, 880, 1967). Each isomer is hydrolyzed to the corresponding acid which is transformed into acid chloride without further characterization.

10 PREPARATION 17. - 4-amino-6,7-dimethoxy-2- (3-methyIpiperazin-1-yl) -auinazoline

8.05 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 10 g of 2-methylpiperazine in butanol are heated to reflux for 15 hours. The reaction mixture is then evaporated in vacuo and the residual oil is taken up in 200 ml of chloroform, washed with 4 times 50 ml of water, dried over sodium sulfate and evaporated in vacuo. The residual oil (13 g) is recrystallized from isopropanol, giving 3.0 g of 4-amino-6,7-dimethoxy hemihydrate ~ 2- (3-methylpiperazin-1-20 yl) -quinazoline fondant at 185-187 ° C.

Analysis: _ C,% H,% N,% calculated for 1/21 ^ 0 57.7 7.1 22.4 found '58.1 6.8 22.8.

PREPARATION 18. - Mixture of 6- and 7-carbethoxy-1,4-ben-25 zodioxane-2-carboxylic acids (A) A solution of sodium hydroxide (1, 94 g in 16 ml of water) to a suspension with stirring of 4.6 ml of epichlorohydrin and 8 g of ethyl-3,4-dihydroxybenzoic acid and a solution is obtained. The reaction solution is then heated to 80 ° C. for one and a half hours, cooled and the extract is carried out with dichloromethane, the extracts are washed with water, dried in sodium sulfate and evaporated. under vacuum to obtain a mixture (10.87 g) of 6- and 7-carbethoxy-2-hydroxymethyl-35 1,4-benzodioxanes in the form of a sticky oil whose spectroscopic properties are consistent.

36 * (B) The above alcohol (5.0 g) is oxidized with 12.3 ml of Jones reagent in 70 ml of acetone as described above (preparation 9), giving a mixture (d2: l d 'after high pressure liquid phase chromatography) of 5 6- and 7-carbethoxy-1,4-benzodioxane-2-carboxylic acids (1.78 g) whose spectroscopic properties are compatible.

PREPARATION 19. - Mixture of 6- and 7-carbamoyl-i, 4-benzo-dioxane-2-carboxylic acids 10 (A) A suspension with stirring of 5.6 g of carbonate is heated at reflux for 15 minutes. potassium and 2.7 g of 4-cyanocatechol in 50 ml of acetone, pyis 4.9 g of methyl 2,3-dibromopropionate are added dropwise. The resulting mixture is heated at reflux for 48 hours then evaporated in vacuo, the residue is diluted with water and extracted with chloroform. The combined extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo to give a mixture (1.0 g) of methyl 6- and 7-cyano-1,4-benzodioxane-2-carboxylates. A sample recrystallized from isopropanol melts at 95-96 ° C.

Analysis: C,% H,% calculated for C- ^ H ^ NO ^ 60.25 4.2 found 60.2 4.2 Analysis by high pressure liquid chromatography of the mixture of crude products shows that this • 25 ge is made up of two components in the ratio of 5: 2.

(B) 0.7 ml of 6N sodium hydroxide solution and 1 ml of 30% hydrogen peroxide is added dropwise to a suspension - with stirring of 0.5 g of the above cyanoester in 4 ml ethanol at 15 ° C. The mixture is then heated at 40-50 ° C for 2 hours, cooled, acidified with concentrated hydrochloric acid, the product is collected and then it is recrystallized from a solvent formed from methanol, - ethanol and water. -giving a mixture of 6- and 7-carbamoyl-1,4-benzodioxane-2-carboxylic acids. melting at 258-260 ° C.

35 Analysis: C,% H,% N,% calculated for * - * 10 ^ 9 ^ 5 53.8 4.1 6.3 found 53.2 4.1 6.4 / 1 '

Claims (5)

0 D, 50.100 1. Analog process for the preparation of a compound corresponding to the formula: R1 / R2 / (f aV "(I> I <“ 2> / ° * R3 ΎΝ NH2 in which (R) n represents a group 6, J -dl (lower alkoxy) or a 6,7? 8-tri group (lower alkoxy); m is 1 or 2; X represents a group -CHR * - or a group -CI ^ Cï ^ -; each of the symbols R *, which may be the same or different, represents a hydrogen atom or a lower alkyl group j 2 Ί and- R and R, which may be the same or different, each represent a hydrogen atom, a group lower alkyl, a lower alkoxy group, a halogen aton, a lower alkanoyl group, a lower alkoxy-carbonyl group or a group of formula; -CONR ^ R ^ or -SC ^ NR ^ R '’in which R ^ and R ~ *, which may be the same or different, represent; - each a hydrogen atom or a lower alkyl group 5 as well as pharmaceutically acceptable acid addition salts of this compound, characterized in that it consists in reacting a quinazoline of formula: nh2 / U ! - | (XX) a lower alkyl, a lower alkoxy group, a 4 halogen atom, a lower alkanoyl group, a lower alkoxy-carbonyl group or a group of formula -CONR ^ R ^ or -SC ^ NR ^ R '"' in which R ^ and R “*, which may be the same or different, each represents a hydrogen atom or a lower alkyl group, - as well as pharmaceutically acceptable acid addition salts of this compound, characterized in that it consists in reacting a quinazoline of formula: A _ ™ (VI) (R) n ^ -kjl. N <CH2> / ™ 2 in which (R), R ^ and m have the meanings defined ci - above, with a compound of formula: 2 fY ° N (VII) R1 or with its functional equivalent as an acylating agent, this reaction being optionally followed by the transformation of the product of formula (i) into an addition salt d pharmaceutical acid which is acceptable by reaction with a non-toxic acid. 3. Method according to claim 2, characterized in that the functional equivalent is an acid chloride or bromide or a succinimido-ester of the compound of formula (Vil). 3 · A method according to claim 2, characterized in that the functional equivalent is an acid chloride or bromide or a succinimido-ester of the compound of formula (VII). 4 · A method according to any one of claims 1 to 3a characterized in that (R) is a 6,7-dimethoxy group, a 6,7-diethoxy group or a 6.7 * 8-trimethoxy group, m is equal in 1 or 2, each of the symbols R ^ independently represents a lower alkyl atom, a lower alkoxy group, a halogen atom, a lower alkanoyl group, a lower alkoxy-carbonyl group or a group of formula -CONR ^ R ^ or -SC ^ NR ^ R ^ in which R ^ and R **, which may be the same or different, each represents a hydrogen atom or a lower alkyl group, as well as acid addition salts pharmaceutically acceptable of this compound, characterized in that it consists in reacting a quinazoline of formula: _ / R1 αΜΐγ- "™ ttO / i Kh / NH2 î in which (R) n, R * and m have the defined meanings above, with a compound of formula: r2> <v0 ^ | T (VII) E R1 or with its functional equivalent as acylating agent, this reaction being fac subsequently followed by the transformation of the E product of formula (i) into a pharmaceutically acceptable acid addition salt by reaction with a non-toxic acid. 4. Method according to any one of claims 1 to 3, characterized in that (R) n is a 6,7-dimethoxy group a 6,7-diethoxy group or a 6,7,8-trimethoxy group, m is equal to 1 or 2, each of the symbols R1 independently represents an atom hj ',' · Il,; 2 o ιΒ5ς ·. 'j - .. · of enone or a group CH ^, while R and R represent' “'ί *; ,, uu independently of each other a hydrogen atom, a ί ï „.” o lower alkyl, a lower alkoxy group, an atom .3 -r-MT W * y 4 * ^ „^ Uqiene, 1111 lower alkanoyl group, an alkoxy-carbonyl group, a group -CONH2 or a group -SC ^ NÎCH ^^ * \ i ’5 · A method according to claim 4 * characterized j | ; I ^ that (r) represents a 6,7-dimethoxy group, m is equal to 1.5¾> ΐ ^ of the symbols R represents a hydrogen atom, while 1, 1 p: ..- 1 »1 λ represent each a hydrogen atom. It ~ i ^ umi I '1> ·. , ' have; $ s