BE887504A - NEW QUINAZOLINE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION - Google Patents

Description

       

  The present invention relates to a series of

  
new piperazinylquinazoline and homopiperazinylquinazoline derivatives with valuable antihyper-

  
tensive, a process for their preparation as well as

  
their applications.

  
We know various quinazoline derivatives,

  
  <EMI ID = 1.1>

  
quinazoline, and we know that many of these have a

  
hypotensive (or antihypertensive) activity. For example, the

  
U.S. patent n [deg.] 3,511,836 described as having precious hypotensive properties a very considerable number

  
  <EMI ID = 2.1>

  
represented by the formula:

  

  <EMI ID = 3.1>


  
in which:

  
  <EMI ID = 4.1>

  
hydrogen atoms or C1 to C3 alkoxy groups,

  
at least one of them representing an alkoxy group;

  
  <EMI ID = 5.1>

  
nyle, a hydroxyalkyl group, a phenyl group, a

  
benzyl group, phenethyl group, furfuryl group

  
or a cycloalkyl group; and

  
Z represents, among many other possibilities,

  
an alkanoyl group, a benzoyl group or a group

  
  <EMI ID = 6.1>

  
The U.S. Patent n [deg.] 4,060,615 also describes

  
various piperazinylquinazoline derivatives which may be

  
represented by the general formula:

  

  <EMI ID = 7.1>
 

  
in which:

  
Re represents an amino or hydrazino group; and

  
  <EMI ID = 8.1>

  
alkyl or cycloalkenyl.

  
The U.S. Patent n [deg.] 3,920,636 describes a series of

  
  <EMI ID = 9.1>

  
dimethoxyquinazoline and suggests that they can be used as blood pressure lowering agents.

  
In practice, however, only one of these known quinazoline derivatives has actually been used. This compound, which is!: One of the compounds described in the US patent. n [deg.] 3,511,836 is called "prazosin" and has the formula:

  

  <EMI ID = 10.1>


  
Although prazosin has very interesting antihypertensive activity, this antihypertensive activity manifests itself very quickly after administration. This very rapid onset of the antihypertensive activity of prazosin can cause unwanted effects, such as static hypotension and dizziness.

  
It follows that it is necessary to have compounds whose antihypertensive activity appears more slowly and whose antihypertensive effect is prolonged. It goes without saying, moreover, that it is necessary to have compounds having better antihypertensive activity than prazosin.

  
The Applicant has now discovered a series of new quinazoline derivatives which have antihypertensive activity and many of which, in one or other of the ways suggested above, are better than the known drug which is prazosin.

  
The compounds according to the invention are compounds corresponding to formula (I):

  

  <EMI ID = 11.1>


  
in which:

  
m is 2 or 3; and

  
R represents a C2 to C9 alkenyl group, a C2 to C9 alkynyl group, a C4 to C9 alkadienyl group, a group corresponding to the formula:

  

  <EMI ID = 12.1>


  
in which:

  
R represents a hydrogen atom or an alkyl group and the two R groups can be identical or different,

  
R2 represents a phenyl group optionally carrying one or more alkyl, alkoxy or halogen substituents.

  
  <EMI ID = 13.1>

  
a hydroxy group, a halogen atom or a group of

  
  <EMI ID = 14.1>

  
  <EMI ID = 15.1>

  
group R3, they can be the same or different,

  
n = 0 or an integer from 1 to 3; and

  
p = 0, 1 or 2;

  
a group corresponding to the formula:

  

  <EMI ID = 16.1>


  
in which:

  
A represents a divalent saturated aliphatic hydrocarbon group, Y represents an oxygen atom or a sulfur atom, q = 0 or 1,

  
R4 represents an alkyl group, a hydroxy group, an alkoxy group, a halogen atom or an amino group optionally carrying one or two alkyl and / or acyl substituents, and

  
n has the above meaning;

  
a group corresponding to the formula:

  

  <EMI ID = 17.1>


  
wherein r represents an integer from 1 to 5;

  
or a group corresponding to the formula:

  

  <EMI ID = 18.1>


  
in which:

  
R5 represents a hydrogen atom, an alkyl group, an alkoxy group or a halogen atom,

  
one of the radicals R represents a hydrogen atom, a phenyl group or a substituted phenyl group carrying as substituents one or more alkyl groups or

  
  <EMI ID = 19.1>

  
all represent hydrogen atoms,

  
  <EMI ID = 20.1>

  
or a halogen atom, and

  
q and r have the above meanings,

  
with the proviso that, when q = 0, one of the radicals R represents a substituted or unsubstituted phenyl group.

  
These compounds can provide addition salts with acids and, therefore, the invention also relates to the addition salts with pharmaceutically acceptable acids of the compounds of formula (I).

  
The compounds of formula (I) can be prepared by a process consisting of:
(a) condensing a 2-haloquinazoline derivative corresponding to formula (II):

  

  <EMI ID = 21.1>


  
in which X represents a halogen atom, with a piperazine or homopiperazine derivative of formula (III):

  

  <EMI ID = 22.1>


  
in which m and R have the abovementioned meanings, by dehalohydration; or
(b) condensing a quinazoline derivative corresponding to formula (IV):

  

  <EMI ID = 23.1>


  
in which m has the abovementioned meaning, with a carboxylic acid of formula (V):

HOOC-R (V)

  
wherein R has the above meaning, or with a reactive derivative of said carboxylic acid.

  
The subject of the invention is also a pharmaceutical composition containing, as active principle, a compound of formula (I) or one of its addition salts with an acid, in mixture with a pharmaceutically acceptable vehicle or diluent.

  
Among the compounds according to the invention, a preferred class is that of the compounds corresponding to the formula
(the) :

  

  <EMI ID = 24.1>


  
wherein m has the above meaning, and R represents a C2 to C9 alkynyl group or a C4 to C9 alkadienyl group.

  
  <EMI ID = 25.1>

  
this group can be straight chain or branched. Examples of such groups include the following groups:

  
  <EMI ID = 26.1>

  
nonenyl, 3-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonënyl and 8-nonenyl.

  
  <EMI ID = 27.1>

  
this group can be straight chain or branched. As examples of such groups, mention will be made of ethyl groups,

  
  <EMI ID = 28.1>

  
  <EMI ID = 29.1>

  
C9, it is preferably a 1,3-butadienyl group,

  
  <EMI ID = 30.1>

  
dienyl or 1,3-nonadienyl.

  
  <EMI ID = 31.1>

  
fere are those in which R represents a C3 or C4 alkenyl group and, better still, a 1-propenyl, 1-butenyl or 3-butenyl group.

  
Another class of preferred compounds is that of the compounds corresponding to formula (Ib):

  

  <EMI ID = 32.1>


  
where m, n and R <2> have the above meanings and x represents an integer from 1 to 3.

  
In the compounds of formula (Ib), R may represent an unsubstituted phenyl group, or may represent a phenyl group carrying one or more substituents chosen from lower alkyl groups, lower alkoxy groups and halogen atoms. Preferred alkyl substituents, which may be straight or branched chain, are C1 to C3, these alkyl groups being methyl, ethyl, propyl and isopropyl. Preferred alkoxy substituents, which may be straight or branched chain, are C1 to C3, these groups being methoxy, ethoxy, propoxy and isopropoxy. Preferable halogen atoms are fluorine, chlorine or bromine atoms.

   When the phenyl group represented by R <2> is substituted, there are preferably 1 or 2 substituents, although there may possibly be more, these substituents being preferably in the ortho and para positions.

  
In the compounds of formula (Ib), n can be equal

  
to 0 or represent an integer from 1 to 3, preferably 1. The integer represented by x can be

  
1 to 3, and is preferably also equal to 1. The

  
  <EMI ID = 33.1>

  
positions 2, 3, 4, 5 or 6 of the benzene ring which carries it as a substituent, but it is preferably in position
4.

  
Another class of preferred compounds according to the invention is that of the compounds corresponding to the formula
(Ic):

  

  <EMI ID = 34.1>


  
  <EMI ID = 35.1>

  
mentioned above.

  
When R4 represents an alkyl group, it is preferably a lower alkyl group which can be linear.

  
  <EMI ID = 36.1>

  
to C3, and are methyl, ethyl, propyl and isopropyl. When R represents an alkoxy group, it is preferably a lower alkoxy group which can be linear or branched. Preferred alkoxy groups are C1 to C3, and are methoxy, ethoxy, propoxy and

  
  <EMI ID = 37.1>

  
it preferably represents a fluorine, chlorine or bromine atom. When R4 represents an amino group, this can carry one or two substituents chosen from alkyl and acyl groups. The alkyl substituents, which may be straight or branched chain, are preferably C1 to C3 and thus are preferably methyl, ethyl, propyl or isopropyl groups. The acyl substituents are also preferably from C1 to C3 and are,

  
  <EMI ID = 38.1>

  
A represents a divalent saturated aliphatic hydrocarbon group, which may be straight or branched chain and is preferably C1 to C6. As examples of such groups represented by A, mention will be made of methylene groups,

  
  <EMI ID = 39.1>

  
methylene. Particularly preferable are the compounds in which A represents a methylene group or an ethylene group.

  
When the compound of formula (Ic) contains an oxygen or sulfur atom represented by Y, it is preferable that it is an oxygen atom. It is preferable

  
that the phenyl group represented in formula (Ic) is unsubstituted, that is to say that n = 0.

  
Another preferred class of compounds according to the invention is that of the compounds corresponding to formula (Id):

  

  <EMI ID = 40.1>


  
in which m has the abovementioned meaning.

  
In the compounds of formula (Id), r represents an integer from 1 to 5, preferably from 2 to 4 and, better still, equal to 2 or 3.

  
Another profused class of compounds is represented by the formula (Ie):

  

  <EMI ID = 41.1>


  
  <EMI ID = 42.1>

  
a linear or branched alkyl group and it preferably contains from 1 to 3 carbon atoms, that is to say is a methyl, ethyl, propyl or isopropyl group. When R5 represents an alkoxy group, this can be straight or branched chain and is preferably C1 to C3, that is to say a methoxy, ethoxy, propoxy or isopropoxy group.

  
  <EMI ID = 43.1>

  
preferably a fluorine, chlorine or bromine atom.

  
When R represents a phenyl group, the latter can be unsubstituted or carry one or more substituents chosen from alkyl groups, alkoxy groups and halogen atoms, preferably linear or branched C1 to C3 alkyl groups (methyl, ethyl , propyl or isopropyl), linear or branched C1 to C3 alkoxy groups (methoxy, ethoxy, propoxy or isopropoxy) or halogen atoms (fluorine, chlorine or bromine).

  
The two R groups in the compound of formula (Ic) are normally and preferably identical. When they represent alkyl groups, they are preferably lower alkyl groups, in particular methyl or ethyl, and, when they represent halogen atoms, they are preferably fluorine, chlorine or bromine atoms.

  
Particularly preferable are the compounds in which r = 1, R6 represents an unsubstituted phenyl group.

  
  <EMI ID = 44.1>

  
hydrogen.

  
Another preferred class of compounds according to the invention is defined by the compounds of formula (If):

  

  <EMI ID = 45.1>


  
  <EMI ID = 46.1>

  
and R represents an alkyl group, an alkoxy group, a hydroxy group or a halogen atom, the preferable compounds of this class being those in which the group

  
  <EMI ID = 47.1>

  
say the compounds corresponding to the formula (Ig):

  

  <EMI ID = 48.1>


  
In the compounds corresponding to formulas (If) and (Ig) the two R groups can be identical or different. When R represents an alkyl group, it may be a linear or branched alkyl group preferably from C1 to C3, that is to say methyl, ethyl, propyl or isopropyl.

  
  <EMI ID = 49.1>

  
a straight or branched chain alkyl group, preferably

  
  <EMI ID = 50.1>

  
or isopropyl. When R9 represents an alkoxy group, it may be a straight or branched chain alkoxy group,

  
  <EMI ID = 51.1>

  
propoxy or isopropoxy. When R9 represents a halogen atom, it is preferably a fluorine, chlorine or bromine atom.

  
The Applicant particularly prefers the compounds

  
  <EMI ID = 52.1>

  
of hydrogen and the other represents a hydrogen atom or an alkyl group (preferably methyl) as well as the compounds in which p = 0 or 1.

  
In all the compounds of formula CI), including the compounds corresponding to formulas (la) to (Ig), the Applicant particularly prefers the compounds in which m = 2, that is to say the piperazinylquinazoline derivatives.

  
Many of the compounds of formula (I) can exist in the form of stereoisomers (including optical isomers and geometric isomers) due to the presence of asymmetric carbon atoms, carbon-carbon double bonds or non-planar ring systems.

  
Although all of these isomers are represented above by a single formula, the present invention encompasses both distinct isomers and mixtures of two or more isomers.

  
Examples of compounds falling within the scope of the present invention are given below. The case

  
  <EMI ID = 53.1>

  
ros which have been assigned to them in the following list:

  
1. 4-amino-2- (4-crotonoyl-1-piperazinyl) -6,7-di-

  
methoxyquinazoline.

  
  <EMI ID = 54.1>

  
  <EMI ID = 55.1>

  
azinyl) quinazoline.

  
12. 4-amino-2- / 4- (2-benzyloxybenzoyl) -1-pipër-

  
  <EMI ID = 56.1>

  
  <EMI ID = 57.1>

  
  <EMI ID = 58.1>

  
  <EMI ID = 59.1>

  
75. 4-aminc-2- / 4- (2-cyclobutyl-2-o-tolylacêtyl) -

  
  <EMI ID = 60.1>

  
l-pipéraziny_l7-6 "7-dimethoxyquinazoline.

  
88. 4-amino-2- / 4- (2-cycloheptyl-2-p-tolylacetyl) -

  
  <EMI ID = 61.1>

  
  <EMI ID = 62.1>

  
  <EMI ID = 63.1>

  
Among these compounds, the preferable compounds are compounds n [deg.] 1, 5, 6, 14, 25, 27, 28, 29, 30, 31, 32,
33, 34, 94, 98, 103, 104, 106 and 114, of which compounds n [deg.] 14, 25, 27, 29, 34 and 103 are particularly preferable.

  
The compounds after addition are bases and thus can form addition salts with acids. The nature of the acid used to prepare these salts is not particularly limited as long as, as is well known in the art, the acid does not significantly increase the toxicity of the free base. Examples of suitable acids include mineral acids (such as hydrochloric acid, phosphoric acid, sulfuric acid or nitric acid) as well as organic acids (such as

  
  <EMI ID = 64.1>

  
lactic acid, ascorbic acid, fumaric acid and maleic acid). Among the various salts, the hydrochlorides are particularly advantageous, in particular the hydrochlorides of the compounds n [deg.] 1, 5, 6, 14, 25, 27, 28, 29,
30, 31, 32, 33, 34, 94, 98, 103, 104, 106 and 114.

  
The compounds according to the invention can be prepared

  
by reacting a 2-haloquinazoline derivative corresponding to formula (II):

  

  <EMI ID = 65.1>


  
(in which X represents a halogen atom) with a piperazine or homopiperazine derivative of formula (III):

  

  <EMI ID = 66.1>


  
in which m and R have the abovementioned meanings.

  
It is preferable to carry out the reaction in the presence of a solvent; the nature of the solvent used is not particularly limited as long as it does not adversely affect the reaction. Preferable solvents are: aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, tetrahydrofuran or dioxane; alcohols such as methanol, ethanol, propanol or isopentanol; esters, in particular ethyl acetate; fatty acid dimethylamides such as dimethylformamide or dimethylacetamide; or dimethyl sulfoxide.

  
The temperature used for the reaction can vary within wide limits, but is preferably 40 to
200 [deg.] C and, better, from 60 to 150 [deg.] C. The time required for the reaction varies depending on the reagents and the reaction temperature, but generally the reaction is essentially completed in 1 to 24 hours.

  
The Applicant prefers to use equimolar proportions of the compounds of formula (II) and (III), or a molar excess of the compound of formula (III). It is preferable that the molar ratio of compound (I) to compound (III) is from 1/1 to 1/2.

  
As the reaction is a condensation reaction carried out by dehalohydration, it can be facilitated by the presence of an acid-fixing agent, which can be an organic base such as triethylamine or

  
  <EMI ID = 67.1>

  
such as an alkali metal hydrogen carbonate or an alkali metal carbonate.

  
The compounds according to the invention can also be prepared by reacting a piperazinylquinazoline or homopiperazinylquinazoline derivative corresponding to the formula
(IV):

  

  <EMI ID = 68.1>


  
(in which m has the abovementioned meaning) with a carboxylic acid corresponding to formula (V):

HOOC-R (V)

  
(in which R has the abovementioned meaning) or with a reactive derivative of the carboxylic acid (V).

  
Examples of suitable reactive derivatives include acid halides, acid anhydrides or anhydrides of acids mixed with a monoalkylcarbonate, these reactive derivatives being well known for the acylation of amines.

  
It is preferable to carry out the reaction in the presence of a solvent; the nature of the solvent is not particularly limited, as long as it does not adversely affect the reaction. Preferable solvents are: aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, tetrahydrofuran or dioxane; alcohols such as methanol, ethanol, propanol or isopentanol; esters,

  
  <EMI ID = 69.1>

  
fatty like dimethylformamide or dimethylacetamide;

  
and dimethyl sulfoxide.

  
The reaction can be carried out in a wide range

  
  <EMI ID = 70.1>

  
better, between -10 and +50 [deg.] C. The time required for the reaction varies according to the nature of the reactants and the reaction temperature, but the reaction is generally essentially completed in a period of 30 minutes to 24 hours.

  
The Applicant prefers to use the compounds of formula (IV) and (V) in approximately equimolar proportions, or to use a molar excess of the compound of formula (V) or of its reactive derivative. It is very preferable that the molar ratio of compound of formula (IV) to carboxylic acid of formula (V) or its reactive derivative is from 1/1 to 1/2.

  
Although the reaction between the compound of formula (IV) and the acid (V) or its reactive derivative takes place without any aid, it can, in general, be made to continue more regularly, in particular when a reactive acid derivative is used, carrying out the reaction in the presence of an acid scavenger, which may be an organic base such as triethylamine

  
  <EMI ID = 71.1>

  
such as an alkali metal hydrogen carbonate or an alkali metal carbonate.

  
Once the reaction is complete, whatever the procedure used, the desired compound can be collected, for example by filtration of the crystals which have precipitated from the reaction mixture. The desired compound can also be obtained by concentrating the reaction mixture
(for example by evaporation under reduced pressure), extracting the residue using an organic solvent (such as chloroform or ethyl acetate) and distilling the solvent in order to separate it from the extract. If necessary, the product thus obtained can be purified in a conventional manner, for example by recrystallization.

  
According to the procedure used for its preparation, the compound according to the invention can be obtained in the form of a free base or in the form of an addition salt with an acid; for example, if the reaction used releases free acid and if the separation and purification method adopted does not eliminate this acid, an addition salt with an acid is normally obtained. The conversion of the free base to any desired salt or the conversion of the salt to the corresponding free base can be carried out conventionally, before or after the separation and purification sequence suggested above.

  
Biological activity

  
The compounds of the present invention have excellent antihypertensive activity and thus are effective for the prevention and treatment of various forms of hypertension, including essential hypertension, renal hypertension and related hypertension

  
with adrenaline.

  
The antihypertensive activity of the compounds according to the invention is demonstrated by the following test.

  
The animals used in this test are spontaneously hypertensive 15-week-old male rats. 3 to 5 rats are used to test each concentration of each compound. Each animal is treated as follows. The animal is anesthetized by intraperitoneal administration of 50 mg / kg of sodium pentobarbital. We then insert a polyethylene cannula into the abdominal aorta,

  
  <EMI ID = 72.1>

  
both from the body, is attached to the neck. One week after the operation, once the animal has recovered from the post-operative irradiation, this end of the cannula is connected to a device to measure blood pressure and heartbeats without requiring any other anesthesia or restraint. The device used is of a

  
  <EMI ID = 73.1>

  
The compound to be tested is suspended, in the desired concentration, in an aqueous solution of carboxymethylcellulose at 0.3% w / v and is administered orally in a volume of 2 ml / kg of body weight. The tension and the pulsations of each animal are observed for one hour before administration in order to obtain reference values, then the product to be tested is administered when these values are stable. After administration of the test sample, it is measured each animal's blood pressure and heartbeat for 24 hours, every 15 minutes.

  
For comparison, n performs the same test

  
  <EMI ID = 74.1>

  
known seur used in the form of hydrochloride.

  
The results obtained are reported in the following table in which the compounds according to the invention are identified by the numbers which have been assigned to them, and an expression such as "9, hydrochloride hydrate" means that it is the hydrochloride hydrate of the compound n [deg.] 9.

  
In the following table, the abbreviations used are as follows:

  
A max = Maximum voltage variation

  
(mm / Hg) after administration of the test compound;

  
T = Time (in hours) after administration

  
  <EMI ID = 75.1>

  
that the voltage reaches a maximum variation.

  
  <EMI ID = 76.1>

  
sion returns to half of its maximum value.

BOARD

  

  <EMI ID = 77.1>
 

  
TABLE (continued)
  <EMI ID = 78.1>
  <EMI ID = 79.1>

  
It follows from the above table that the compounds according to the invention have an antihypertensive activity comparable to that of prazosin and, in many cases, significantly better; with many of the compounds according to the invention, the time required to obtain the maximum effect is longer than that required for prazosin and / or the antihypertensive effect has a significantly longer duration.

  
It follows that the compounds according to the invention can be used for the treatment of hypertension. The compounds can be administered orally, for example in the form of tablets, capsules, powders, microgranules, granules, solutions or suspensions. They can also be administered parenterally, preferably in the form of injections or suppositories.

  
The preferred dosage for the compounds according to the invention varies according to the type and severity of the hypertension, as well as according to the activity and the duration of the activity of the compound particularly used. Generally, when the compound is administered orally, the daily dosage is from 0.01 to 200 mg, but the preferred dosage varies according to the class of the compound, as follows:

  
for the compounds of formula (Ia), the daily dosage is from 0.1 to 200 mg, and preferably from 1

  
at 50 mg;

  
for the compounds of formula (Ib), the daily dosage is from 0.1 to 200 mg, and preferably from 1

  
at 100 mg;

  
for the compounds of formula (Ic) and the compounds of formula (Id), the daily dosage is preferably

  
  <EMI ID = 80.1>

  
for the compounds of formula (Ic) and the compounds of formula (If), the daily dosage is preferably from 0.05 to 200 mg and, better still, from 0.1 to 50 mg.

  
For parenteral administration, an appropriate dose is between one third and one tenth of the dose suggested for oral administration.

  
Although the compounds according to the invention are very effective by themselves for the treatment of various types of hypertension, they can also be used in combination with diuretics and other hypotensive agents, such as blockers of [pound] -adrenergic receptors .

  
The following nonlimiting examples are given by way of illustration of the preparation of compounds according to the invention. If necessary, some of the starting piperazines can be prepared as described in "Organic Preparation and Procedures Int." 8 (2) 85-86 (1976).

  
EXAMPLE 1

  
  <EMI ID = 81.1>

  
hydrated drate).

  
4.55 g of 4-amino-2- are added to 80 ml of isopentanol

  
  <EMI ID = 82.1>

  
piperazine, and the resulting mixture is heated at reflux for 1.5 hours, after which the hot reaction mixture is filtered. The filtrate is cooled, the resulting crystals are collected by filtration and recrystallized from ethanol, thus obtaining 3.52 g of the hydrochloride.

  
  <EMI ID = 83.1>

  
colorless rates melting at 255-256 [deg.] C (with decomposition).

  
Elementary analysis

  

  <EMI ID = 84.1>


  
EXAMPLE 2

  
  <EMI ID = 85.1>

  
quinazoline and 2.6 g of triethylamine, then the mixture is stirred for 30 minutes. 0.6 g of

  
  <EMI ID = 86.1>

  
room temperature for 8 hours. The resulting crystals are collected, by filtration, washed with water and recrystallized from ethanol, thus obtaining 0.8 g of the desired compound n [deg.] 2, in the form of colorless needles melting at 262-263 [deg.] C (with decomposition).

  
Elementary analysis

  

  <EMI ID = 87.1>


  
EXAMPLE 3

  
  <EMI ID = 88.1>

  
dimethoxyquinazoline (Compound n [deg.] 3) To 20 ml of tetrahydrofuran is added 2.4 g of 4-amino-6,7-dimethoxy-2- (1-piperazinyl) quinazoline hydrochloride and 2.6 g of triethylamine, after which the mixture is stirred for 20 minutes. Then 0.7 g of 2,3-dimethylacryloyl chloride is added and the mixture is stirred at room temperature for 12 hours. The resulting crystals are collected, by filtration, washed with water and recrystallized from ethanol, thus obtaining the compound n [deg.] 3 sought, in the form of pale yellow prisms melting at 219.5-221, 5 [deg.] C.

  
Elementary analysis

  

  <EMI ID = 89.1>


  
EXAMPLE 4

  
  <EMI ID = 90.1>

  
line and 2.6 g of triethylamine, after which the mixture is stirred for 20 minutes. Then 0.7 g of 3,3-dimethylacryloyl chloride is added, then the mixture is stirred at room temperature for 15 hours. The resulting crystals are collected by filtration, washed with water and recrystallized from dimethylformamide, thus obtaining 1.24 g of the sought product, in the form of colorless powdery crystals melting at 278-280 [deg.] C ( with decomp.) Elementary analysis

  

  <EMI ID = 91.1>


  
EXAMPLE 5

  
  <EMI ID = 92.1>

  
quinazoline (Nom pos n [deg.] 5)

  
To 20 ml of tetrahydrofuran is added 2.4 g of chlor-

  
  <EMI ID = 93.1>

  
line and 2.6 g of triethylamine, after which the mixture is stirred for 20 minutes. 0.78 g of

  
  <EMI ID = 94.1>

  
and recrystallized from ethanol, thus obtaining 1.23 g of the compound n [deg.] 5 sought, in the form of pale brown needles melting at 246-247 [deg.] C.

  

  <EMI ID = 95.1>


  
EXAMPLE 6

  
  <EMI ID = 96.1>

  
To 20 ml of tetrahydrofuran are added 2.4 g of 4-amino-6,7-dimethoxy-2- (1-piperazinyl) quinazoline hydrochloride and 2.6 g of triethylamine, after which the mixture is stirred for 20 minutes. 0.78 g of 4-pentenoyl chloride is then added, then the mixture is stirred at room temperature for 15 hours. The resulting crystals are collected by filtration, washed and recrystallized from ethanol, thereby obtaining 1.02 g of

  
  <EMI ID = 97.1>

  
melting at 21-19-220 [deg.] C.

  

  <EMI ID = 98.1>


  
EXAMPLE 7

  
  <EMI ID = 99.1>

  
quinazoline (Compound n [deg.] 7)

  
To 20 ml of tetrahydrofuran is added 2.4 g of chlor-

  
  <EMI ID = 100.1>

  
line and 2.6 g of triethylamine, after which the mixture is stirred for 20 minutes. 0.8 g of 3-hexenoyl chloride is then added, then the mixture is stirred at room temperature for 15 hours. The resulting crystals are collected by filtration, washed with water and recrystallized from ethanol, thereby obtaining 1.10 g of the compound n [deg.] 7 sought, in the form of powdery pale yellow crystals melting â 197.5-198.5 [deg.] C.

  

  <EMI ID = 101.1>


  
EXAMPLE 8

  
  <EMI ID = 102.1>

  
30 minutes. 0.53 g of 2hexenoyl chloride is then added, then the mixture is stirred at room temperature for 18 hours. The reaction mixture is then concentrated by evaporation under reduced pressure, the resulting residue is washed with water and recrystallized from ethanol, thus obtaining 1.2 g of the desired semi-hydrated compound n [deg.] 8, under the colorless needle form melting at
220-222 [deg.] C.

  

  <EMI ID = 103.1>


  
EXAMPLE 9

  
  <EMI ID = 104.1>

  
quinazoline and its hydrated hydrochloride (Compound n [deg.] 9 and its hydrated hydrochloride).

  
To 15 ml of tetrahydrofuran is added 1.25 g of 4-

  
  <EMI ID = 105.1>

  
2; 6 g of triethylamine, after which the mixture is stirred for 30 minutes. 0.31 g of crotonoyl chloride is then added, then the mixture is stirred at room temperature for 15 hours. The reaction mixture is concentrated by evaporation under reduced pressure, the resulting residue is extracted with chloroform and the extract is washed with water. The solvent is removed from the extract by distillation under reduced pressure and the residue is recrystallized from ethanol, thus obtaining 0.7 g of the desired compound n [deg.] 9, in the form of colorless crystals melting at 200-202 [deg.] C.

  

  <EMI ID = 106.1>


  
The product is dissolved in ethanol and added to a 10% w / w solution of hydrogen chloride in ethanol. The resulting crystals are collected

  
  <EMI ID = 107.1>

  
sought, melting at 261-263 [deg.] C (with decomposition).

  
Elementary analysis:

  

  <EMI ID = 108.1>


  
  <EMI ID = 109.1>

  
dimethoxyquinazoline (Compound n [deg.] 10)

  
To 20 ml of tetrahydrofuran is added 1.16 g of 4-

  
  <EMI ID = 110.1>

  
triethylamine. 0.52 g of 2,4-hexadienoyl chloride is then added, after which the mixture is stirred at room temperature for 3 hours. The reaction mixture is concentrated by evaporation under reduced pressure, the resulting residue is washed with water and recrystallized from

  
  <EMI ID = 111.1>

  
in the form of pale yellow powdery crystals melting at 231-233 [deg.] C.

  

  <EMI ID = 112.1>


  
EXAMPLE 11

  
  <EMI ID = 113.1>

  
quinazoline (compound n [deg.] ll)

  
To 20 ml of ethyl acetate is added 0.32 g of sodium tetololate (systematic name: sodium but-2-ynoate) and 0.38 g of ethyl chlorocarbonate, after which the mixture is stirred overnight. 2.6 g of triethylamine are then added and the mixture is stirred for 3 hours. To the resulting mixture is added 0.4 g of 4-amino-6,7-dimethoxy-2- (1piperazinyl) quinazoline, after which the mixture is stirred at room temperature for 15 hours. The reaction mixture is concentrated by evaporation under reduced pressure and the resulting residue is washed with water and recrystallized from ethanol, thus obtaining 0.32 g of the desired compound, in the form of pale yellow prisms melting at
250-252 [deg.] C.

  

  <EMI ID = 114.1>


  
EXAMPLE 12

  
  <EMI ID = 115.1>

  
hydrochloride hydrate)

  
0.848 g of 4-amino-2chloro-6,7-dimethoxyquinazoline is added to 15 ml of isopentanol, followed by 1.05 g of 1- (2-

  
  <EMI ID = 116.1>

  
sulting at reflux for 2 hours. After cooling the mixture, the resulting crystals are collected by filtration and recrystallized from methanol, obtaining

  
  <EMI ID = 117.1>

  
the form of a colorless powder melting at 2l5-2l6 [deg.] C (with decomposition).

  

  <EMI ID = 118.1>


  
EXAMPLE 13

  
  <EMI ID = 119.1>

  
dimethoxyquinazoline, hydrochloride hydrate (Compound n [deg.] 13, hydrochloride hydrate)

  
To 70 ml of isopentanol is added 3.48 g of 4-amino-2chloro-6,7-dimethoxyquinazoline and 3.93 g of 1- (3-benzyloxybenzoyl) piperazine, and the resulting mixture is heated under reflux for 4 hours . After having cooled the mixture, the resulting crystals are collected by filtration and recrystallized from ethanol, thus obtaining 6.59 g of the compound n [deg.] 13 (hydrochloride hydrate) sought, in the form of pale yellow prisms melting at 180-182 [deg.] C
(with decomposition).

  
Elementary analysis

  

  <EMI ID = 120.1>


  
EXAMPLE 14

  
  <EMI ID = 121.1>

  
dimethoxyquinazoline, hydrochloride dihydrate

  
(Compound n [deg.] 14, hydrochloride dihydrate)

  
To 15 ml of isopentanol is added 0.77 g of 4-amino-2chloro-6,7-dimethoxyquinazoline and 1.04 g of 1- (4-benzyl-

  
  <EMI ID = 122.1>

  
at reflux for 2.5 hours. After cooling the mixture, the resulting crystals are collected by filtrate-ion, and they are recrystallized from methanol, thus obtaining 1.63 g of compound n [deg.] 14 (hydrochloride dihydrate) sought as yellow powdery crystals pale fondant

  
  <EMI ID = 123.1>

  
Elementary analysis

  

  <EMI ID = 124.1>


  
EXAMPLE 15

  
  <EMI ID = 125.1>

  
6,7-dimethoxyquinazoline, hydrochloride dihydrate
(Compound n [deg.] 15, hydrochloride dihydrate)

  
To 12 ml of isopentanol is added 0.72 g of 4-amino-2chloro-6,7-dimethoxyquinazoline and 1.0 g of 1- (4-benzyloxybenzoyl) homopiperazine, and the resulting mixture is heated under reflux for 2 hours . After cooling the mixture, the resulting crystals are collected by filtration and recrystallized from ethanol, thus obtaining 1.43 g of compound n [deg.] 15 (hydrochloride dihydrate) sought, in the form of pale yellow powdery crystals melting at 167-169 [deg.] C.

  
Elementary analysis:

  

  <EMI ID = 126.1>


  
EXAMPLE 16

  
  <EMI ID = 127.1>

  
(Compound n [deg.] 22, hydrochloride)

  
To 20 ml of isopentanol is added 0.75 g of 4-amino-2chloro-6,7-dimethoxyquinazoline and 1.14 g of 1- / 4- (4-

  
  <EMI ID = 128.1>

  
resulting age at reflux for 2 hours. After cooling the mixture, the resulting crystals are collected by filtration and recrystallized from methanol, thus obtaining 1.35 g of the compound n [deg.] 22 (hydrochloride) sought, in the form of pale yellow needles melting at

  
  <EMI ID = 129.1>

  
Elementary analysis

  

  <EMI ID = 130.1>


  
EXAMPLE 17

  
  <EMI ID = 131.1>

  
(Compound n [deg.] 23, hydrochloride dihydrate)

  
0.56 g of 4-amino-2- is added to 15 ml of isopentanol

  
  <EMI ID = 132.1>

  
resulting age at reflux for 4 hours. After cooling the mixture, the resulting crystals are collected by filtration and recrystallized from ethanol, thus obtaining 0.26 g of the compound n [deg.] 23 (hydrochloride dihydrate) sought, in the form of pale yellow powdery crystals melting at 235-237 [deg.] C (with decomposition).

  
Elementary analysis

  

  <EMI ID = 133.1>


  
EXAMPLE 18

  
  <EMI ID = 134.1>

  
hydrated (Compound n [deg.] 24, semi-hydrated hydrochloride)

  
To 27 ml of isopentanol is added 1.0 g of 4-amino-2-

  
  <EMI ID = 135.1>

  
resulting mixture at reflux for 4 hours. After cooling the mixture, the resulting crystals are collected by filtration and recrystallized from an aqueous ethanol solution at 50% vol / vol, thus obtaining 2.32 g of compound n [deg.] 24 (hydrochloride semi-hydrate ) sought, in the form of pale yellow powdery crystals melting at

  
  <EMI ID = 136.1>

  

  <EMI ID = 137.1>


  
EXAMPLE 19

  
  <EMI ID = 138.1>

  
hydrate)

  
To 50 ml of isopentanol is added 1.2 g of 4-amino-2-

  
  <EMI ID = 139.1>

  
both at reflux for 3 hours. After cooling the mixture, the resulting crystals are collected by filtration and recrystallized from a 10% vol / vol solution of water in ethanol, thus obtaining 2.1 g of compound n [deg.] 21 (hydrochloride hydrated) sought, in the form of colorless powdery crystals melting at 222-224 [deg.] C

  
(with decomposition).

  
Elementary analysis

  

  <EMI ID = 140.1>


  
This hydrochloride is then dissolved in a 10% vol / vol solution of water in ethanol and neutralized by adding a 10% w / w aqueous solution of sodium hydroxide. After concentration of the mixture by evaporation under reduced pressure, the resulting residue is recrystallized from ethanol, thereby obtaining the desired semihydrated compound n [deg.] 21, in the form of colorless powdery crystals melting at 251-253 [deg.] C (with decomposition). Elementary analysis

  

  <EMI ID = 141.1>


  
EXAMPLE 20

  
  <EMI ID = 142.1>

  
(Compound n [deg.] 16, hydrochloride hydrate)

  
1.16 g of 4 amino-6,7- dimethoxy-2- (1-piperazinyl) quinazoline and 1.16 g of triethylamine are added to 20 ml of tetrahydrofuran, and the mixture is then stirred for
30 minutes. To the resulting solution is added 0.9 g of 2-phenoxybenzoyl chloride; and the mixture is stirred at room temperature for 15 hours. The resulting crystals are collected by filtration, washed with water and dissolved in an ethanol-chloroform solution to
50% vol / vol, after which a 10% solution is added

  
  <EMI ID = 143.1>

  
  <EMI ID = 144.1>

  
siré (n [deg.] 16) under melting of colorless powdered crystals melting at 257-258 [deg.] C

  
  <EMI ID = 145.1>

  

  <EMI ID = 146.1>
 

  
EXAMPLE 21

  
  <EMI ID = 147.1>

  
of 2-phenoxypropionyl, after which the mixture is stirred at room temperature for 15 hours. We concentrate

  
the reaction mixture by evaporation under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with chloroform,

  
which provides 1.48 g of the compound n [deg.] sought, in the form of a yellow oil. This product is dissolved in ethanol and the resulting solution is added to a 10% w / w solution of hydrogen chloride in ethanol. The resulting crystals are collected by filtration,

  
  <EMI ID = 148.1>

  
drate semi-hydrated) sought, in the form of pale yellow powdery crystals melting at 211-213 [deg.] C (with decomposition).

  
Elementary analysis:

  

  <EMI ID = 149.1>


  
EXAMPLE 22

  
  <EMI ID = 150.1>

  
phenoxypropionyl) piperazine, and the resulting mixture is heated to reflux for 4 hours. Once the reaction is complete, the reaction mixture is filtered hot and the filtrate is cooled. The resulting crystals are collected by filtration and recrystallized from ethanol, thus obtaining 4.02 g of the compound n [deg.] 26 (hydrochloride semi-hydrate) sought, in the form of pale yellow powdery crystals melting at 189- 191 [deg.] C (with decomposition).

  
Elementary analysis

  

  <EMI ID = 151.1>


  
EXAMPLE 23

  
  <EMI ID = 152.1>

  
quinazoline, hydrochloride hydrate

  
(Compound n [deg.] 27, hydrochloride hydrate)

  
To 20 ml of tetrahydrofuran is added 1.16 g of 4-

  
  <EMI ID = 153.1>

  
triethylamine. The resulting mixture is added with 0.7 g of phenoxyacetyl chloride and the mixture is stirred at room temperature for 4 hours. The reaction mixture is concentrated by evaporation under reduced pressure, and gold. extract the residue with chloroform. The extract is washed with water, then the solvent is removed by distillation under reduced pressure. The resulting residue is dissolved in ethanol, and this solution of a 10% w / w solution of hydrogen chloride in ethanol is added. The resulting crystals are collected by filtration and dried, thus obtaining 1.04 g of the compound n [deg.] 27 (hydrochloride hydrate) sought, in the form of powdery yellow crystals melting at 238-240 [deg.] C (with decomposition).

  
Elementary analysis

  

  <EMI ID = 154.1>


  
EXAMPLE 24

  
  <EMI ID = 155.1>

  
quinazoline, hydrochloride hydrate (Compound # [deg.] 28, hydrochloride hydrate)

  
To 20 ml of tetrahydrofuran is added 1.16 g of 4-

  
  <EMI ID = 156.1>

  
triethylamine. The resulting mixture is then added with 0.58 g of phenylacetyl chloride, after which the mixture is stirred at room temperature for 15 hours. The reaction mixture is concentrated by evaporation under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 4% vol / vol solution of ethanol in chloroform, thus obtaining 0, 5 g of an oil which is then dissolved in ethanol. We add the solution

  
  <EMI ID = 157.1>

  
drogen in ethanol, the resulting crystals are collected by filtration and dried, which gives 0.30 g of the compound n [deg.] 28 (hydrochloride hydrate) sought, in the form of colorless powdery crystals melting at 173- 175 [deg.] C.

  
Elementary analysis

  

  <EMI ID = 158.1>


  
EXAMPLE 25

  
  <EMI ID = 159.1>

  
(Compound n [deg.] 29, hydrochloride hydrate)

  
To 25 ml of tetrahydrofuran is added 1.16 g of 4-

  
  <EMI ID = 160.1>

  
triethylamine. The resulting mixture is then added with 0.6 g of 3-phenylpropionyl chloride, after which the mixture is stirred at room temperature for
12 hours. The reaction mixture is then concentrated by evaporation under reduced pressure and the residue is extracted with chloroform. After washing the extract with water, the solvent is distilled off and the residue is dissolved in ethanol. The resulting solution is added to a 10% w / w solution of hydrogen chloride in ethanol, and the resulting crystals are collected by filtration, thus obtaining 0.75 g of compound n [deg.] 29
(hydrochloride hydrate) sought, in the form of colorless powdery crystals melting at 212-2l5 [deg.] C (with decomp.).

  
Elementary analysis

  

  <EMI ID = 161.1>


  
EXAMPLE 26

  
4-amino-6,7-dimethoxy-2- (4-phenylthio-) hydrochloride

  
  <EMI ID = 162.1>

  
at reflux for 4 hours. After cooling the reaction mixture, the resulting crystals are collected by filtration and recrystallized from ethanol,

  
  <EMI ID = 163.1>

  
in the form of colorless needles melting at 254-255 [deg.] C
(with decomposition).

  
Elementary analysis

  

  <EMI ID = 164.1>


  
EXAMPLE 27

  
  <EMI ID = 165.1>

  
of triethylamine, after which the mixture is stirred for
30 minutes. The mixture of 0.63 g of

  
  <EMI ID = 166.1>

  
nappy at room temperature for 8 hours. The reaction mixture is concentrated by evaporation under reduced pressure and the residue is extracted with chloroform. After washing the extract with water, the solvent is distilled off and the residue is dissolved in ethanol. This solution of a 10% w / w solution of hydrogen chloride in ethanol is added and the resulting crystals are collected by filtration, thus obtaining 1.05 g <EMI ID = 167.1>

  
form of colorless powdery crystals melting at 210-
212 [deg.] C (with decomposition).

  
Elementary analysis

  

  <EMI ID = 168.1>


  
EXAMPLE 28

  
  <EMI ID = 169.1>

  
(Compound n [deg.] 32, hydrochloride hydrate)

  
To 25 ml of tetrahydrofuran is added 1.16 g of 4-

  
  <EMI ID = 170.1>

  
of triethylamine, after which the mixture is stirred for
30 minutes. This mixture of 0.57 g of cyclopentylideneacetyl chloride is added, then the mixture is stirred at room temperature for 15 hours. The reaction mixture is concentrated by evaporation under reduced pressure and the residue is extracted with chloroform. After washing the extract with water, the solvent is distilled off and the residue is dissolved in ethanol. We add this-

  
  <EMI ID = 171.1>

  
drug in ethanol and the resulting crystals are collected by filtration, thus obtaining 0.60 g of the compound

  
  <EMI ID = 172.1>

  
colorless powdery crystals melting at 238-240 [deg.] (with decomposition).

  
Elementary analysis

  

  <EMI ID = 173.1>


  
EXAMPLE 29

  
  <EMI ID = 174.1>

  
(Compound n [deg.] 33, hydrochloride hydrate)

  
To 24 ml of isopentanol is added 1.2 g of 4-amino-2-

  
  <EMI ID = 175.1> cyclopropylcarbonyl) piperazine. The resulting mixture is heated at reflux for 4 hours, then the resulting crystals are collected by filtration and recrystallized from an aqueous solution of 50% vol / vol of ethanol, thus obtaining 1.74 g of compound n [deg.] 33 (hydrochloride hydrate) sought, in the form of colorless prisms fondani at 287-288 [deg.] C (with decomposition).

  
Elementary analysis

  

  <EMI ID = 176.1>


  
EXAMPLE 30

  
  <EMI ID = 177.1>

  
(Compound n [deg.] 63, hydrochloride hydrate)

  
To 25 ml of isopentanol is added 1.0 g of 4-amino-2-

  
  <EMI ID = 178.1>

  
cyclohexylcarbonyl) piperazine, and the resulting mixture is heated to reflux for 4 hours. The crystals obtained are collected by filtration and neutralized by the addition of an aqueous solution of sodium hydroxide to
10% w / w. The resulting mixture is extracted with chloroform and the extract is chromatographed on silica gel, eluting with chloroform. Adding the elution product of an ethanolic solution of hydrogen chloride at 10% w / w and the resulting crystals are collected by filtration, thus obtaining 0.93 g of compound n [deg.] 63 (chlorhy-

  
  <EMI ID = 179.1>

  
slow pale yellow melting 5 278-279 [deg.] C (with decomposition). Elementary analysis

  

  <EMI ID = 180.1>


  
EXAMPLE 31

  
  <EMI ID = 181.1> To 25 ml of isopentanol is added 1.2 g of 4-amino-2-

  
  <EMI ID = 182.1>

  
resulting in reflux for 4 hours. The resulting crystals are collected by filtration and recrystallized from a hydroethanolic solution at 50% vol / vol, thus obtaining 1.90 g of the compound n [deg.] 60 (hydrochloride hydrate) sought, in the form of powdery colorless crystals melting at 277-278 [deg.] C (with decomposition).

  
Elementary analysis

  

  <EMI ID = 183.1>


  
EXAMPLE 32

  
  <EMI ID = 184.1>

  
(Compound n [deg.] 34, hydrochloride dihydrate)

  
To 25 ml of isopentanol are added 1.2 g of 4-amino-2chloro-6,7-dimethoxyquinazoline and 1.4 g of 1- (trans-2phenylcyclopropylcarbonyl) piperazine, and the resulting solution is heated at reflux for 4 hours . The resulting crystals are collected by filtration and neutralized by the addition of an aqueous solution of sodium hydroxide at 20% w / w. The resulting mixture is extracted with chloroform and the extract is introduced into a column of chromatography on silica gel, and elution is carried out with chloroform. Adding the elution product of an ethanolic solution of hydrogen chloride at 10% w / w and collecting the resulting crystals by filtration, thus obtaining 1.22 g of compound n [deg.] 34 (hydrochloride dihydrate) sought, in the form of colorless powdery crystals melting at 195-198 [deg.] C (with decomposition).

  
Elementary analysis
  <EMI ID = 185.1>
 EXAMPLE 33

  
  <EMI ID = 186.1>

  
To 25 ml of isopentanol is added 1.2 g of 4-amino-2chloro-6,7-dimethoxyquinazoline and 1.63 g of 1- (2-cyclopentyl-2-phenylacetyl) piperazine, and the resulting mixture is heated to reflux for 4 hours. The resulting crystals are collected by filtration and neutralized by adding an aqueous solution of sodium hydroxide to
10% w / w. The resulting mixture is extracted with chloroform, the extract is chromatographed on a column of silica gel, eluting with chloroform. The elution product is added to an ethanolic solution of hydrogen chloride at 10% w / w and the resulting crystals are collected by filtration, thus obtaining 1.15 g of compound n [deg.]
79 (hydrochloride) sought, in the form of pale yellow powdery crystals melting at 222-224 [deg.] C (with decomp.) Elemental analysis

  

  <EMI ID = 187.1>


  
  <EMI ID = 188.1>

  
  <EMI ID = 189.1>

  
(Compound n [deg.] 83, hydrochloride hydrate)

  
To 25 ml of isopentanol are added 1.2 g of 4-amino-2chloro-6,7-dimethoxyquinazoline and 1.72 g of 1- (2-cyclohexyl-2-phenylacetyl) piperazine, and the resulting mixture is heated to reflux for 4 hours. The resulting crystals are collected by filtration and neutralized by the addition of an aqueous solution of sodium hydroxide
10% w / w. The resulting mixture is extracted with chloroform, the extract is chromatographed on a silica gel column and eluted with chloroform. Adding the elution product of an ethanolic solution of hydrogen chloride at 10% w / w and collecting the resulting crystals by filtration, thus obtaining 1.33 g of compound n [deg.] 83 (hydrochloride hydrate) sought, in the form of colorless needles melting at 224-226 [deg.] C (with decomposition).

  
Elementary analysis

  

  <EMI ID = 190.1>


  
EXAMPLE 35

  
  <EMI ID = 191.1>

  
(Compound n [deg.] 103, sesquihydrate hydrochloride)

  
To 20 ml of isopentanol is added 0.9 g of 4-amino-2chloro-6,7-dimethoxyquinazoline and 1.4 g of 1- / 4- (1-

  
  <EMI ID = 192.1>

  
resulting in reflux for 4 hours. The resulting crystals are collected by filtration and neutralized by adding an aqueous solution of sodium hydroxide to

  
  <EMI ID = 193.1>

  
silica and eluted using a 1% vol / vol solution of ethanol in chloroform. The eluate is added to an ethanolic solution of hydrogen chloride at 10% w / w and the resulting crystals are collected by filtration, thus obtaining 0.69 g of the compound n [deg.] 103 (hydrochloride sesquihydrate) sought, in the form of colorless powdery crystals melting at 18l-l85 [deg.] C (with decomposition). Elementary analysis

  

  <EMI ID = 194.1>


  
EXAMPLE 36

  
  <EMI ID = 195.1>

  
(Compound n [deg.] 103, sesquihydrate hydrochloride)

  
To 20 ml of anhydrous tetrahydrofuran is added 0.9 g of 4-amino-6,7-dimethoxy-2- (1-piperazinyl) quinazoline and <EMI ID = 196.1>

  
drofuran, and the mixture is stirred at room temperature for one hour, after which it is allowed to stand overnight. Then, the reaction mixture is concentrated by evaporation under reduced pressure and neutralized by addition of an aqueous solution of sodium hydroxide at 10% w / w. The resulting mixture is extracted with chloroform, chromatographed on a column of silica gel and eluted using a solution of 1% vol / vol of ethanol in chloroform. Adding the elution product of an ethanolic solution of hydrogen chloride at 10% w / w, and collecting the resulting crystals by filtration, thus obtaining 0.21 g of compound n [deg.] 103 (hydrochloride sesquihydrate ) sought, in the form of colorless powdery crystals having the same properties as the product of Example 35.

  
EXAMPLE 37

  
  <EMI ID = 197.1>

  
hydrated (Compound n [deg.] 94, hydrochloride semi-hydrated)

  
To 25 ml of isopentanol is added 1.2 g of 4-amino-2-

  
  <EMI ID = 198.1>

  
oxy-3-methoxybenzoyl) piperazine, and the resulting mixture is heated at reflux for 4 hours. The resulting crystals are collected by filtration and neutralized by adding an aqueous solution of sodium hydroxide to
10% w / w. The resulting mixture is extracted with chloroform and the extract is chromatographed on a column, eluting with chloroform. The elution product is added to an ethanolic solution of hydrogen chloride at 10% w / w and the resulting crystals are collected by filtration, thus obtaining 1.64 g of compound n [deg.] 94 (semi hydrochloride

  
  <EMI ID = 199.1> Elementary analysis

  

  <EMI ID = 200.1>


  
EXAMPLE 38

  
  <EMI ID = 201.1>

  
(Compound n [deg.] 98, semi-hydrated hydrochloride)

  
  <EMI ID = 202.1>

  
chloro-6,7-dimethoxyquinazoline and 2.1 g of 1- (4-benzyloxy-3-chlorobenzoyl) piperazine, and the resulting mixture is heated at reflux for 4 hours. The resulting crystals are collected by filtration and neutralized by adding an aqueous solution of sodium hydroxide to
10% w / w. The resulting mixture is extracted with chloroform, the extract is chromatographed on a silica gel column and eluted with chloroform. The elution product is added to an ethanolic solution of hydrogen chloride at 10% w / w and the resulting crystals are collected by filtration, thus obtaining 1.65 g of compound n [deg.] 98 (semi hydrochloride hydrated) sought, in the form of colorless powdery crystals melting at 253-
254 [deg.] C (with decomposition).

  
Elementary analysis

  

  <EMI ID = 203.1>


  
EXAMPLES 39 and 40

  
By operating as described in Example 38, the following compounds are prepared, both in the form of colorless powders:

  
  <EMI ID = 204.1>

  
n [deg.] 104, hydrochloride) melting at 170-174 [deg.] C.


    

Claims (1)

1. Compounds which can be used in particular as antihypertensive agents, corresponding to formula (I):  <EMI ID = 205.1> in which: m is 2 or 3; and R represents a C2 to C9 alkenyl group, a C2 to C9 alkynyl group, a C4 to C9 alkadienyl group, a group corresponding to the formula:  <EMI ID = 206.1> where: <EMI ID = 207.1>  <EMI ID = 208.1> different,  <EMI ID = 209.1> one or more alkyl, alkoxy or halogen substituents.  <EMI ID = 210.1> a hydroxy group, a halogen atom or a group of  <EMI ID = 211.1>  <EMI ID = 212.1> group R3, they can be the same or different, n = 0 or an integer from 1 to 3; and p = 0, 1 or 2; a group corresponding to the formula:  <EMI ID = 213.1> in which: A represents a divalent saturated aliphatic hydrocarbon group, Y represents an oxygen atom or a sulfur atom, q = C or 1, R4 represents an alkyl group, a hydroxy group. an alkoxy group, a halogen atom or an amino group optionally carrying one or two alkyl and / or acyl substituents, and n has the above meaning; a group corresponding to the formula:  <EMI ID = 214.1> wherein r represents an integer from 1 to 5; or a group corresponding to the formula:  <EMI ID = 215.1> in which:  <EMI ID = 216.1> an alkoxy group or a halogen atom, one of the radicals R6 represents a hydrogen atom, a phenyl group or a substituted phenyl group carrying as substituents one or more alkyl or alkoxy groups or halogen atoms, and the other radicals R all represent hydrogen atoms,  <EMI ID = 217.1> or a halogen atom, and q and r have the above meanings, with the proviso that, when q = 0, one of the radicals R6 represents a substituted or unsubstituted phenyl group, as well as their addition salts with pharmaceutically acceptable acids. <EMI ID = 218.1> in that they correspond to the formula (Ia):  <EMI ID = 219.1> wherein: m is as defined in claim 1 and R represents a C2 to C9 alkenyl group, a C2 to C9 alkynyl group or a C4 to C9 alkadienyl group. 3. Compounds according to claim 2, characterized  <EMI ID = 220.1> 4. Compounds according to claim 2, characterized  <EMI ID = 221.1> m = 2. 5. Compounds according to claim 1, characterized in that they correspond to formula (Ib):  <EMI ID = 222.1> wherein m, n and R <2> are as defined in claim 1; and x represents an integer from 1 to 3.  <EMI ID = 223.1> in that R2 represents an unsubstituted phenyl group or a phenyl group carrying 1 or 2 substituents chosen from C1 to C3 alkyl groups, C1 to C3 alkoxy groups and halogen atoms. 7. Compounds according to claim 6, characterized in that the substituents are in the para, ortho or ortho and para positions. 8. Compounds according to claim 5, characterized in . what: m = 2; n = 1; R2 represents a phenyl group or a substituted phenyl group having, in the ortho, para or ortho and para positions, one or two substituents chosen from C1 to C3 alkyl groups, the groups <EMI ID = 224.1> 9. Compounds according to claim 1, characterized in that they correspond to formula (Ie):  <EMI ID = 225.1> in which m, n, q, A, Y and R4 are as defined to claim 1. 10. Compounds according to claim 9, characterized in that R4 represents a C1-C3 alkyl group, a C1-C3 alkoxy group, a hydroxy group or a halogen atom. 11. Compounds according to claim 9, characterized in that A represents an aliphatic hydrocarbon group  <EMI ID = 226.1> 12. Compounds according to claim 9, characterized in that: m = 2; n = 0; q = 0 or 1; A represents a methylene or ethylene group; Y represents an oxy- atom  <EMI ID = 227.1> methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy and isopropoxy groups and the fluorine, chlorine and bromine atoms.  <EMI ID = 228.1> er, what they answer to the formula (Id):  <EMI ID = 229.1> wherein m and r are as defined in claim 1. 14. Compounds according to claim 13, characterized in that! represents an integer from 2 to 4. 15. Compounds according to Claim 13, characterized in that r = 2 or 3 and m = 2. 16. Compounds according to Claim 1, characterized in that they correspond to the formula (Ie):  <EMI ID = 230.1> wherein R, R6, R7, m, q and r are as defined in claim 1. 17. Compounds according to claim 16, characterized in that R represents a hydrogen atom, a group-  <EMI ID = 231.1> halogen atom. 18. Compounds according to claim 17, characterized in that r = 1, R represents a phenyl group inc  <EMI ID = 232.1> mes of hydrogen and m = 2. 19. Compounds according to claim 1, characterized  <EMI ID = 233.1>  <EMI ID = 234.1> in which: m, p and R are as defined in re-  <EMI ID = 235.1> vendication 1; and R represents an alkyl group, an alkoxy group, a hydroxy group or a halogen atom. 20. Compounds according to claim 19, characterized in that they correspond to the formula (Ig):  <EMI ID = 236.1> wherein m, p, R <1> and R9 are as defined in claim 19. 21. Compounds according to claim 19 or 20, characterized in that each group R represents a hydrogen atom or a C1 to C3 alkyl group. 22. Compounds according to claim 19 or 20, characterized in that one of the radicals R represents a hydrogen atom and the other represents a hydrogen atom or a C1 to C3 alkyl group. 23. Compounds according to claim 19 or 20,  <EMI ID = 237.1> caux R represents a hydrogen atom and the other represents a hydrogen atom or a methyl group; and R 9 represents a C1-C3 alkyl group, a C1-C3 alkoxy group, a hydroxy group, a fluorine atom, a chlorine atom or a bromine atom. 24. Compounds according to claim 1, characterized  <EMI ID = 238.1> <EMI ID = 239.1> as well as their hydrochlorides. 25. Process for the preparation of compounds of formula (I) according to any one of the preceding claims, as well as their addition salts with acids, characterized in that a 2-haloquinazoline derivative corresponding to formula (II) is condensed:  <EMI ID = 240.1> in which X represents a halogen atom, with a piperazine or homopiperazine derivative corresponding to formula (III):  <EMI ID = 241.1> in which m and R are as defined in claim 1 and, if necessary, the free base thus obtained is salified and / or, if necessary, the resulting salt is converted into the corresponding free base. 26. The method of claim 25, characterized in that the addition salt with an acid is the hydrochloride.  <EMI ID = 242.1> (I) according to any one of claims 1 to 24, as well as their addition salts with acids, charac-  <EMI ID = 243.1> corresponding to formula (IV):  <EMI ID = 244.1>  in which m is as defined in claim 1, with a carboxylic acid corresponding to formula (V): HOOC - R (V)  <EMI ID = 245.1> or with a reactive derivative of said carboxylic acid and, if necessary, the resulting free base is salified in order to obtain one of its addition salts with a pharmaceutically acceptable acid and / or, if necessary, said salt is converted into the free base corresponding. 28. The method of claim 27, characterized in that the addition salt with an acid is the hydrochloride. 29. Method according to claim 27 or 28, characterized in that the reactive derivative is an acid halide, an acid anhydride or a mixed acid anhydride with a monoalkylcarbonate. 30. Pharmaceutical composition containing, as active principle, a hypotensive compound in association with a pharmaceutically acceptable vehicle or diluent, characterized in that the hypotensive compound is a compound according to any one of claims 1 to 24.