BE889515A - NOVEL 3-AMINOPROPOXYBENZENE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS - Google Patents

Description

       

   <EMI ID = 1.1>

  
their preparation and their application as medicaments.

  
 <EMI ID = 2.1>

  
their application in -therapeutics, title of active principles of drugs.

  
The invention relates more particularly to the compounds corresponding to the formula

  

 <EMI ID = 3.1>


  
in which '

  
R signifies a phenyl group optionally carrying a,

  
two or three substituents chosen from halogen atoms having an atomic number from 9 to 35 and alkyl and alkoxy groups each containing from 1 to 4 carbon atoms,

  
 <EMI ID = 4.1>

  
atomic number from 9 to 35, an alkyl, alkoxy or alkylthio group each containing from 1 to 4 carbon atoms, a cycloalkyl group containing from 3 to 7 carbon atoms, an alkanoyl group containing from 1 to 5 carbon atoms, a group trifluoromethyl, 1pyrrolyl, cyano or carbamoyl, or an alkenyl group containing from 2 to 5 carbon atoms or alkenyloxy containing from 3 to 5 carbon atoms, the double bond of the 'alkenyloxy group having to be fixed

  
on a carbon atom other than the carbon atom adjacent to the oxygen atom,

  
 <EMI ID = 5.1>

  
 <EMI ID = 6.1>

  
carbon atoms, a cycloalkylalkyl group with <EMI ID = 7.1>

  
carry one., two or three substituents chosen from among the

  
 <EMI ID = 8.1>

  
 <EMI ID = 9.1>

  
carbon atoms,

  
 <EMI ID = 10.1>

  
or sulfur:

  
represents an oxygen or sulfur atom, and

  
Z means an oxygen atom and, in this case, n means

  
2 or 3.

  
 <EMI ID = 11.1>

  
 <EMI ID = 12.1>

  
cation other than the formula remnants
 <EMI ID = 13.1>
 <EMI ID = 14.1> a bond or an oxygen atom, Y means an oxygen atom, and c) when "2 represents an unsubstituted phenyl group <EMI ID = 15.1>

  
 <EMI ID = 16.1>

  

 <EMI ID = 17.1>


  
 <EMI ID = 18.1>

  
of carbon.

  
 <EMI ID = 19.1>

  
they preferably carry alkoxy substituents, which are preferably identical.

  
The preferred compounds of the invention are those in which the hydroxy group located in position 2 of the side chain is in a non-esterified form.

  
 <EMI ID = 20.1>

  
preferred alkenyl groups are those containing 2 or 3:; carbon atoms, in particular the allyl group. The

  
 <EMI ID = 21.1> <EMI ID = 22.1>

  
X preferably signifies a direct bond or an oxygen atom, .- - in particular one. oxygen atom.

  
 <EMI ID = 23.1>

  
preferably mono- or disubstituted ,; . in particular mono.substituted. R is preferably substituted by a group

  
 <EMI ID = 24.1>

  
 <EMI ID = 25.1>

  
substituted, it preferably carries the two substituents

  
 <EMI ID = 26.1>

  
 <EMI ID = 27.1> <EMI ID = 28.1>

  
it is preferably an acetyl group.

  
 <EMI ID = 29.1>

  
 <EMI ID = 30.1>

  
 <EMI ID = 31.1>

  
 <EMI ID = 32.1>

  

 <EMI ID = 33.1>


  
in which

  
 <EMI ID = 34.1>

  
 <EMI ID = 35.1>

  
 <EMI ID = 36.1>

  
is e
- In a particular group of compound: formula la, 1 ^ is different from hydrogen.

  
 <EMI ID = 37.1>

  

 <EMI ID = 38.1>
 

  
in which

  
R and R1 have the meanings already given,

  
 <EMI ID = 39.1>

  
of carbon,

  
 <EMI ID = 40.1>

  
represents a direct bond or an oxygen atom, and nb signifies 2 or 3,

  
and their hydrolyzable derivatives, acceptable from the point of

  
physiological view, in which the hydroxy group located in position 2 of the 3-aminopropoxy side chain is in esterified form.

  
In a particular group of compounds of formula

  
 <EMI ID = 41.1>

  
 <EMI ID = 42.1>

  
Another group of compounds of the invention comprises the compounds corresponding to the formula Ipa

  

 <EMI ID = 43.1>


  
in which

  
 <EMI ID = 44.1>

  
substituted by 1, 2 or 3 alkoxy groups each containing from 1 to 4 carbon atoms,

  
 <EMI ID = 45.1>

  
having an atomic number from 9 to 35,

  
 <EMI ID = 46.1>

  
of carbon,

  
Apa means an alkylene group containing 2 to 5 atoms

  
carbon, and

  
np means 2 or 3, <EMI ID = 47.1>

  
formula

  

 <EMI ID = 48.1>


  
 <EMI ID = 49.1>

  
the compounds corresponding to the formula Ipb

  

 <EMI ID = 50.1>


  
in which

  
 <EMI ID = 51.1>

  
 <EMI ID = 52.1>

  
carbon, and

  
 <EMI ID = 53.1>

  
of carbon,

  
 <EMI ID = 54.1>

  
Another group of compounds of formula I includes compounds of formula Ipc
 <EMI ID = 55.1>
 in which

  
 <EMI ID = 56.1>

  
 <EMI ID = 57.1>

  
 <EMI ID = 58.1>

  
 <EMI ID = 59.1>

  
carbon or a cycloalkyl-alkyl group the

  
 <EMI ID = 60.1>

  
and the alkyl residue contains from 1 to 4 carbon atoms,

  
 <EMI ID = 61.1>

  
carbon, and

  
 <EMI ID = 62.1>

  
 <EMI ID = 63.1>

  
of formula

  

 <EMI ID = 64.1>


  
 <EMI ID = 65.1>

  
 <EMI ID = 66.1>

  
Another group of compounds of formula I includes the compounds of formula Ipd

  

 <EMI ID = 67.1>


  
in which

  
 <EMI ID = 68.1>

  
 <EMI ID = 69.1>

  
 <EMI ID = 70.1> <EMI ID = 71.1>

  
 <EMI ID = 72.1>

  
carbon atoms,

  
 <EMI ID = 73.1>

  
an alkyl group.

  
 <EMI ID = 74.1>

  
the compounds corresponding to the formula Ipe

  

 <EMI ID = 75.1>


  
in which

  
 <EMI ID = 76.1>

  
 <EMI ID = 77.1>

  
having an atomic number from 9 to 35 or a cyano group,

  
 <EMI ID = 78.1>

  
by 1, 2 or 3 alkoxy groups each containing from 1 to 4 carbon atoms, and

  
Ape represents an alkylene group containing from 2 to 5

  
carbon atoms.

  
 <EMI ID = 79.1>

  
symbol Rp advantageously represents a substituted phenyl group.

  
Another group of compounds of formula I includes the compounds of formula Is

  
(formula Is see next page)
 <EMI ID = 80.1>
 in which

  
 <EMI ID = 81.1>

  
by 1 or 2 alkoxy groups each containing from 1 to 4 carbon atoms,

RS

  
1 means a hydrogen atom. or halogen having

  
an atomic number from 9 to 35, a cyano or carbamoyl group or an alkenyl group containing from 2 to 5 carbon atoms or cycloalkyl group containing 5 or 6

  
 <EMI ID = 82.1>

  
phenylalkyl group containing 7 or 8 carbon atoms, the phenyl residue of which is optionally substituted by 1 or 2 alkoxy groups each containing from 1 to 4 carbon atoms,

  
 <EMI ID = 83.1>

  
ns means 2 or 3,

  
 <EMI ID = 84.1>

  
alkyl group, and

  
 <EMI ID = 85.1>

  
has a cyclopropylmethyl group and XS signifies a direct bond,

  
and their hydrolyzable derivatives, acceptable from the point of

  
 <EMI ID = 86.1>

  
tion 2 of the 3-aminopropoxy side chain is in esterified form.

  
In a particular group of compounds of

  
 <EMI ID = 87.1>

  
 <EMI ID = 88.1>

  
alkyl group.

  
The invention also includes a process for preparing these compounds. According to this process, the compounds of the invention are obtained by reacting a corresponding compound of formula II

  

 <EMI ID = 89.1>


  
 <EMI ID = 90.1>

  
 <EMI ID = 91.1>

  
react with a primary amine to form a 2- group

  
 <EMI ID = 92.1>

  
with an appropriate compound of formula III

  

 <EMI ID = 93.1>


  
in which A, X and R have the meanings already given,

  
and, where appropriate, by suitably esterifying the position 2 of the 3-aminopropoxy side chain in the compounds of formula I thus obtained.

  
The amination process can be carried out according to the usual methods for the production of analogous 3-amino-2-hydroxypropoxyaryl compounds. R can

  
 <EMI ID = 94.1> <EMI ID = 95.1>

  
tolyl or lower alkyl. L means in particular chlorine. The reaction is preferably carried out in ethanol or in a suitable ether such as dioxane.

  
It is optionally possible to use an excess of the amine of formula III as solvent. The reaction can also be carried out in the molten mass. The operation is carried out at temperatures between approximately 20 and 200 [deg.], Advantageously at the reflux temperature of the reaction mixture when a solvent is used.

  
The possible esterification of the. hydroxy group located in position 2 of the side chain, can be carried out according to the usual methods for the production of analogous esters of 3-amino-2-hydroxypropoxyaryl compounds; if necessary, selective reactions are recommended when other reactive groups are present.

  
 <EMI ID = 96.1>

  
 <EMI ID = 97.1>

  
usual; from salts, the bases can be released according to known methods. Acids suitable for salt formation include hydrochloric acid, malonic acid and fumaric acid.

  
The compounds of the invention comprise in position 2 of the 3-aminopropoxy side chain an atom of

  
 <EMI ID = 98.1>

  
Therefore in the form of racemates or individual optical isomers. The preferred optical isomers are those

  
having the S configuration on this asymmetric carbon atom of the 3-aminopropoxy side chain. The individual optical isomers can be obtained according to the usual methods, for example by using optically active starting materials or by fractional crystallization of the racemates using optically active acids.

  
The starting materials can be obtained according to known methods, from known products.

  
In particular, the compounds of formula Ir are obtained by introducing a group by 0-alkylation
-OCH2-Rx in a compound of formula IV
 <EMI ID = 99.1>
 <EMI ID = 100.1>

  
already given. The compounds of formula IV are preferably used in anionic form.

  
The compounds of formula IVa

  

 <EMI ID = 101.1>


  
in which

  
Y and 3 * 2 have the meanings already given, neither means 2 or 3, and

  
 <EMI ID = 102.1>

  
 <EMI ID = 103.1>

  
alkoxy or alkylthio each containing from 1 to 4 carbon atoms, a cycloalkyl group containing from 3 to 7 carbon atoms, an alkanoyl group containing from 1 to 5 carbon atoms, 1-pyrrolyl, cyano or carbamoyl, or an alkenyl group containing 2 to 5 carbon atoms or alkenyloxy containing 3 to 5 carbon atoms, the double bond present in the alkenyloxy group having to be fixed on a carbon atone other than the carbon atom adjacent to the oxygen atom ,

  
can be obtained for example by elimination of the protective group in a compound of formula V

  

 <EMI ID = 104.1>


  
in which Ri, R2. n 'and Y have the meanings already given and Bz represents a protective group, for

  
 <EMI ID = 105.1>

  
appropriate conditions, for example in the presence of palladium on carbon or by acid hydrolysis.

  
The compounds of formula IVb can be prepared

  

 <EMI ID = 106.1>


  
in which

  
 <EMI ID = 107.1>

  
R "represents an alkylthio group containing from 1 to 4

  
carbon or trifluoromethyl atoms,

  
for example by selective etherification of the hydroxy group

  
 <EMI ID = 108.1>

  
corresponding 1,4-dihydroxy derivative, for example by reaction with a molar equivalent of a compound of formula

  
 <EMI ID = 109.1>

  
already given, and Hal represents a halogen atom, preferably in an inert solvent such as acetone and in the presence of a base such as potassium carbonate.

  
To prepare the compounds of formula Va

  

 <EMI ID = 110.1>


  
in which Bz, Y, R2 and n have the meanings already given,

  
 <EMI ID = 111.1>

  
 <EMI ID = 112.1>

  
suitable, advantageously according to a reaction comprising more than one step, for example by first forming the remainder <EMI ID = 113.1> the remainder R2.

  
The compounds of formula Vb are prepared

  

 <EMI ID = 114.1>


  
 <EMI ID = 115.1>

  
 <EMI ID = 116.1>

  
 <EMI ID = 117.1>

  
hydrogen atom,

  
for example by introducing a chlorine, bromine or iodine atom, in an ortho position relative to the group

  
 <EMI ID = 118.1>

  
hydrogen atom,

  
and, where appropriate, the hydroxy group is protected from

  
 <EMI ID = 119.1>

  
bromine, which gives the compounds of formula Vc
 <EMI ID = 120.1>
 in which R2, Y, n 'and Bz have the meanings already given. It is then possible, if desired, to transform a compound of formula V c by a reaction of the Grignard type, for example with lithium, into

  
 <EMI ID = 121.1>

  
 <EMI ID = 122.1>

  
alkyl group containing from 1 to 4 carbon atoms, cycloalkyl containing from 3 to 7 carbon atoms or alkenyl containing from 2 to 5 carbon atoms. The compounds of formula Vc can also be transformed into corresponding cyan derivatives, for example by reaction

  
 <EMI ID = 123.1>

  
if necessary, the cyano group is hydrolyzed which mistletoe gives

  
 <EMI ID = 124.1>

  
a carbamoyl group. It is possible, if desired, to transform this carbamoylated compound by a degradation according to Hofman into a corresponding amino derivative and then to transform this amino derivative, for example by reaction with 2,5 dimethoxyfuran, into the corresponding compound of formula Vb

  
 <EMI ID = 125.1>

  
if desired, transform the amino derivative into the corresponding diazonium salt, for example with nitrous acid, then react this diazonium salt with, for example, potassium fluoride in water, which allows

  
 <EMI ID = 126.1>

  
fluorine atom. It is also possible to transform the diazonium salt by reaction with an aqueous acid into the corresponding hydroxy compound and then to etherify the latter, this mistletoe.

  
 <EMI ID = 127.1>

  
represents an alkoxy group containing from 1 to 4 carbon atoms or alkenyloxy containing from 3 to 5 carbon atoms, the double bond of the latter group being fixed on a carbon atom other than the carbon atom adjacent to the atom d 'oxygen.

  
 <EMI ID = 128.1>

  
alkanoyl can be obtained by acylation according to Friedel-Crafts. If necessary, the diazonium group can be transformed into various other residues, for example into an alkyl ththio group by reaction with a thiolate of

  
 <EMI ID = 129.1>

  
can be obtained by fluorination of a corresponding carboxylic group, the latter being obtained by hydrolysis of a cyano group.

  
Instead of using compounds of formula Vb containing protective groups, it is also possible to directly use the corresponding unprotected compounds. So we can introduce

  
 <EMI ID = 130.1>

  
ment of Claisen, which gives the ortho-cyclopent-2-enylphenol which is then hydrogenated.

  
The compounds of formula IVc

  

 <EMI ID = 131.1>


  
in which

  
 <EMI ID = 132.1>

  
 <EMI ID = 133.1>

  
n "means 1, 2 or 3, can for example be obtained in an analogous manner

  
to that described above for the preparation of the compound

  
of formula IVa from the corresponding protected compounds.

  
If appropriate, the protecting group can be a group

  
 <EMI ID = 134.1>

  
The protective group removal reaction can be carried out in the presence of a metal alkyl thiolate.

  
 <EMI ID = 135.1>

  
di f ferent, a hydrogen atom or an alkylthio group or

  
 <EMI ID = 136.1>

  
analogous to that described above for the preparation of the compounds of formula Vb. We can also transform

  
 <EMI ID = 137.1>

  
compound is in an unprotected form, for example ortho-brominated derivatives can be obtained simply from the corresponding phenols. Protected compounds

  
 <EMI ID = 138.1>

  
 <EMI ID = 139.1> known methods, for example according to the Williamson reaction.

  
The compounds of formula IVd

  

 <EMI ID = 140.1>


  
in which

  
R. ,, Z, n and Y have the meanings already given, and

  
 <EMI ID = 141.1>

  
 <EMI ID = 142.1>

  
cycloalkyl-alkyl,

  
and their corresponding derivatives containing protective groups, for example compounds in which the hydroxy group is protected by a benzyl, methyl or tetrahydro-pyrannyl group,

  
are new. They are part of the present invention.

  
When the preparation of the starting products is not described, these are known or can be prepared according to known methods, from known products.

  
The following examples illustrate the present invention without in any way limiting its scope. The temperatures are all indicated in degrees Celsius.

Example 1

  
 <EMI ID = 143.1>

  
the solvent, the resulting mixture is stirred for 1 hour at 70 ° C. The resulting mixture is then dissolved in ether in ether and then allowed to crystallize while cooling. After purification by recrystallization from benzene, the title compound is obtained which melts at 95-97 [deg.].

  
The starting material can be obtained as described below:

  
 <EMI ID = 144.1>

  
flux at 98-99 [deg.] [prepared by reaction of 4-benzyloxyphenol with 2-chloroethyl ether of methyl followed by elimination of the benzyl group in 1-

  
 <EMI ID = 145.1>

  
43 [deg.]). by hydrogenation with palladium on carbon]

  
 <EMI ID = 146.1>

  
in chloroform and the whole is stirred for 2 hours. After chromatography on silica gel, reacting

  
 <EMI ID = 147.1>

  
(oil) thus obtained, with a mixture of potassium carbonate, acetone and benzyl bromide. After chromatography on silica gel, the reaction is carried out for 5 hours with cuprous cyanide in dimethylform-

  
 <EMI ID = 148.1>

  
(oil) resulting. The product is then purified by distributing it between an aqueous solution of hydrochloric acid and ethyl acetate, then the benzyl group is eliminated in 2-ben2yloxy-5- (2-methoxyethoxy)

  
 <EMI ID = 149.1>

  
10% palladium on charcoal in methanol. Then reacted at 1000 with epichlorohydrin and a catalytic amount of piperidine 2-hydroxy-S-

  
 <EMI ID = 150.1>

  
in the form of an oil.

  
By proceeding as described in Example 1 and year

  
 <EMI ID = 151.1>

  
 <EMI ID = 152.1>

  
 <EMI ID = 153.1>

  
 <EMI ID = 154.1>

  
after.

  
CC

  
 <EMI ID = 155.1>
 <EMI ID = 156.1>
 
 <EMI ID = 157.1>
 
 <EMI ID = 158.1>
  <EMI ID = 159.1>

  
Physically acceptable lysables and their salts have not been described so far in the literature. In tests carried out on laboratory animals, they stand out for their interesting pharmacodynamic properties.

  
These compounds exert in particular a blocking effect on the p-adrenergic receptors. The inhi-

  
 <EMI ID = 160.1>

  
evidence on the isolated atrium of the spontaneously beating guinea pig. The method used is described by A. Bertholet et al. in Postgrad.Med. 57, Suppl. 1 [1981] 9-18.

  
 <EMI ID = 161.1>

  
positive chronotropic isoprenaline when added

  
 <EMI ID = 162.1>

  
 <EMI ID = 163.1>

  
Some of the compounds of formula I, for example the compounds of examples 12, 14 and 15 also exert a blocking effect on the α-adrenergic receptors, as has been demonstrated by standard tests.

  
This inhibitory effect was determined for example on the inverted aorta of the rat according to the method described by K.K.F. Ng, S. Duffy, W.J. Louis and A.E. Doyle in Proceedings of the Australian Physiological and Pharmacolo-

  
 <EMI ID = 164.1>

  
has been confirmed by linkage studies, for example as described by R.J. Summers, B. Jarrott and W.J. Louis in Neuroscience Letters 20, (1980) p. 347-350.

  
Thanks to these properties, the compounds of formula

  
 <EMI ID = 165.1>

  
 <EMI ID = 166.1>

  
tick and curative of coronary ailments such as angina pectoris, of disorders resulting from a sympathetic hyperstimulation such as nervous cardiac malaise, of myocardial infarction, of hypertension, for the interval treatment of migraine and for the treatment of <EMI ID = 167.1>

  
this fact be used as antiarrhythmic agents for the

  
 <EMI ID = 168.1>

  
supraventricular chycardia. They will be prescribed in daily doses.

  
 <EMI ID = 169.1>

  
appropriately ministrated, for example by oral route, in unit doses each containing approximately 2.5 to 250 mg of active substance at a rate of 2 to 4 times per day, or in delayed form.

  
It appears from tests carried out with the

  
 <EMI ID = 170.1>

  
surprisingly marked pharmacological properties and to-. wider spectrum. In particular, their activity is more cardioselective than that of compounds

  
 <EMI ID = 171.1>

  
evidence in vitro according to standard tests carried out on tissues isolated from the guinea pig. For example, we

  
prepares membranes of the left ventricle and the guinea pig lung using the standard method described by G. Engel et al. in Triangle 19: [1980] p. 69-76 and, to determine the affinity of the substance to be tested

  
 <EMI ID = 172.1>

  
react with a radioactive p-ligand added via

  
12 #

  
 <EMI ID = 173.1>

  
92 -adrenergics is approximately 80 times for the compound of Example 1, approximately 410 times for the compound of Example 2, approximately 170 times for the compound of Example 3 and approximately 640 times for the compound of Example 7.

  
The guinea pig lung and left ventricle membranes can be prepared, for example, as follows:

  
We decapitate adult guinea pigs weighing from 350 to
500 g. The heart and lungs are then put on an infusion with a tris-saline buffer solution (tris-HCl

  
 <EMI ID = 174.1> drawn, the connective tissue and the trachea are eliminated.

  
The membranes of the lungs are prepared by proceeding as described by Kleinstein, J. and Glossmann H. in NaunynSchmiedeberg's Arch.Pharmacol., 305, [1978] p. 191-200, but by modifying the medium A which contains only 20 mM

  
sodium bicarbonate. The final precipitate is suspended in 10 ml (20 mM) of sodium bicarbonate

  
and stored in liquid nitrogen. The preparation of

  
 <EMI ID = 175.1>

  
method described by McNamara, D.B. et al. in J. Biochem., 75, [1974] p. 795-803 until the stage where the fraction of membranes is obtained. These membranes are stored in liquid nitrogen and then diluted just before use to the appropriate concentration as indicated in the text.

  
Added to concentrations between
10 -9 and 10 5 5 M, the compounds of Examples 1 to 18 make

  
 <EMI ID = 176.1>

  
p-adrenergic receptors.

  
The high selectivity of the blocking effect exerted by the compounds of formula I is particularly important for the treatment of cases of hypertension where existing asthmatic disorders can be aggravated by the administration of known drugs.

  
Compounds of formula 1 also demonstrate

  
 <EMI ID = 177.1>

  
this property helps prevent unwanted bradycardia and reduce the frequency of heart failure in people with myocardial disease.

  
The compounds of formula I can be administered in the form of free bases or in the form of their pharmaceutically acceptable salts, the activity of which is of the same order as that of the corresponding free bases. In general, the activity of optical isomers including the carbon atom located in position 2 of

  
the 3-aminopropoxy side chain has the configuration <EMI ID = 178.1>

  
heavy.

  
The compounds of formula 1 are particularly suitable for the treatment of coronary heart conditions and hypertension.

  
 <EMI ID = 179.1>

  
in particular examples 1 and 3 are preferred.

  
The compounds of formula I, their physiologically acceptable hydrolyzable derivatives and their pharmaceutically acceptable salts, can be used as medicaments, as such or in the form of pharmaceutical compositions in combination with excipients, vehicles and suitable diluents. As examples of suitable compositions; mention may be made, for example, of solutions or tablets.


    

Claims (1)

CLAIMS <EMI ID = 180.1> characterized in that they correspond to the formula  <EMI ID = 181.1> in which R signifies a phenyl group optionally carrying a, two or three substituents chosen from halogen atoms having an atomic number from 9 to 35 and alkyl and alkoxy groups each containing from 1 to 4 carbon atoms,  <EMI ID = 182.1>  <EMI ID = 183.1> carbon, a cycloalkyl group containing from 3 to 7 carbon atoms, an alkanoyl group. containing 1 to 5 carbon atoms, a trifluoromethyl, 1pyrrolyl, cyano or carbamoyl group, or an alkenyl group containing 2 to 5 carbon atoms or alkenyloxy containing 3 to 5 carbon atoms, the double  <EMI ID = 184.1> adjacent 3 the oxygen atom, R2 signifies an alkyl group containing from 1 to 4 atoms of carbon, a cycloalkyl group containing from 3 to 7 carbon atoms, a cycloalkylalkyl group whose  <EMI ID = 185.1>  <EMI ID = 186.1>  <EMI ID = 187.1> 10 carbon atoms, this phenyl group or the phenyl residue of the phenylalkyl group possibly optionally bearing one, two or three substituents chosen from halogen atoms having an atomic number of 9 to 35 and the alkyl groups and alkoxy each containing from 1 to 4 carbon atoms, A represents an alkylene group containing from 2 to 5 atoms of carbon, X signifies a direct bond or an oxygen atom or sulfur,  <EMI ID = 188.1> Z means an oxygen atom and, in this case, n means 2 or 3, or Z represents a direct bond and, in this case, n means 1, 2 or 3, with the conditions that <EMI ID = 189.1> oxygen atom and the residue -NH-A-X-R has a meaning other than the residues of formula  <EMI ID = 190.1>  b) when R2 signifies an alkyl group and X represents a bond or an oxygen atom, Y signifies a  <EMI ID = 191.1> <EMI ID = 192.1> or monosubstituted, that X signifies a bond, and that Z represents an oxygen atom or when R2 represents a cycloalkyl or cycloalkylalkyl group and that X  <EMI ID = 193.1> hydrogen, and their physiologically acceptable hydrolyzable derivatives in which the hydroxy group located in position 2  <EMI ID = 194.1>  <EMI ID = 195.1> characterized in that they correspond to formula E  <EMI ID = 196.1> in which  <EMI ID = 197.1> claim 1, and Re represents an alkyl group containing from 1 to 12 carbon atoms, cycloalkyl containing from 3 to 7 carbon atoms, or a phenyl or phenylalkyl group containing from 7 to 12 carbon atoms, this phenyl group or the phenyl residue of the phenylalkyl group possibly being monosubstituted by an alkyl group  <EMI ID = 198.1> disubstituted by halogen having an atomic number of 9 to 35, or monosubstituted, disubstituted or trisubstituted by alkoxy groups containing from 1 to 4 carbon atoms. 3.- New derivatives of 3-aminopropoxybenzene, characterized in that they correspond to the formula la (formula see next page)  <EMI ID = 199.1>  in which  <EMI ID = 200.1> dication 1,  <EMI ID = 201.1> carbon atoms, a cycloalkylalkyl group in which the cycloalkyl residue contains from 3 to 7 carbon atoms and the alkyl residue contains from 1 to 4 carbon atoms, or a phenyl or phenylalkyl group containing from 7 to 10 carbon atoms, this phenyl group or the phenyl residue of the phenylalkyl group possibly optionally having one, two or three substituents chosen from halogen atoms having an atomic number from 9 to 35 and the alkyl and alkoxy groups each containing from 1 to 4 carbon atoms,  <EMI ID = 202.1> carbon atoms, and means an oxygen or sulfur atom, and their physiologically acceptable hydrolysable derivatives, in which the hydroxy group located in position 2 of the 3-aminopropoxy side chain is in esterified form. 4.- New derivatives of 3-aminopropoxybenzene, characterized in that they correspond to formula Ib (formula Ib see next page)  <EMI ID = 203.1>  in which  <EMI ID = 204.1> tion 1,  <EMI ID = 205.1> of carbon,  <EMI ID = 206.1>  <EMI ID = 207.1> nb means 2 or 3, and their hydrolyzable derivatives, acceptable from the point of physiological view, in which the hydroxy group located in position 2 of the 3-aminopropoxy side chain is in esterified form.  <EMI ID = 208.1> characterized in that they meet the formula Is  <EMI ID = 209.1> in which  <EMI ID = 210.1> with 1 or 2 alkoxy groups each containing 1 to 4 carbon atoms, T - & 5  <EMI ID = 211.1>  <EMI ID = 212.1>  <EMI ID = 213.1> carbon or cycloalkyl atoms containing 5 or 6 carbon atoms,  <EMI ID = 214.1> phenylalkyl group containing 7 or 8 carbon atoms, the phenyl residue of which is optionally substituted by 1 or 2 alkoxy groups each containing from 1 to 4 carbon atoms,  <EMI ID = 215.1> a direct bond or an oxygen atom, and ns means 2 or 3, Z signifying an oxygen atom when R. represents an s alkyl group, and  <EMI ID = 216.1> has a cyclopropylsnethyl group and X s signifies a direct bond, and their physiologically acceptable hydrolyzable derivatives in which the hydroxy group located in position  <EMI ID = 217.1> <EMI ID = 218.1> their physiologically acceptable hydrolysable derivatives in which the hydroxy group located in position 2 of the 3-aminopropoxy side chain is in esterified form.  <EMI ID = 219.1> benzene. 9. The 3-aminopropoxybenzene derivatives specified in claim 7 and 8, in the form of hydrolysable derivatives which are acceptable from the physiological point of view in which the hydroxy group located in position 2 of the 3-aminopropoxy side chain is in esterified form.  <EMI ID = 220.1> specified in any one of claims 1 to 9, characterized in that they are in the form of optical isomers or racemates. 11.- The 3-aminopropoxybenzene derivatives specified in any one of claims 1 to 9 in the form of free base or of an acid addition salt. 12.- A process for the preparation of the 3-aminopropoxybenzene derivatives of formula I, specified in claim 1, and their salts, characterized in that a corresponding compound of formula II is reacted  <EMI ID = 221.1>  <EMI ID = 222.1> with an appropriate compound of formula III  <EMI ID = 223.1> in which A, X and R have the meanings already given in claim 1, the. if necessary, it is esterified. suitably position 2 of the 3-aminopropoxy side chain in the compounds of formula I thus obtained, and optionally, the compounds thus obtained are transformed into their salts by reaction with mineral or organic acids.  <EMI ID = 224.1> 3-aminopropoxybenzene specified in any one of claims 1 to 10, in the free base state or in the form of a pharmaceutically acceptable salt, as active pharmaceutical ingredients. 14.- A medicament, characterized in that it contains, as active principle, a 3-aminopropoxybenzene derivative of formula I  <EMI ID = 225.1>  in which R signifies a phenyl group optionally carrying a, two or three substituents chosen from halogen atoms having an atomic number from 9 to 35 and alkyl and alkoxy groups each containing from 1 to 4 carbon atoms,  <EMI ID = 226.1> atomic number from 9 to 35, an alkyl, alkoxy or alkylthio group each containing from 1 to 4 carbon atoms, a cycloalkyl group containing from 3 to 7  <EMI ID = 227.1> 5 carbon atoms, a trifluoromethyl group, 1-  <EMI ID = 228.1> containing 2 to 5 carbon atoms or alkenyloxy containing 3 to 5 carbon atoms, the double bond of the alkenyloxy group having to be fixed on a carbon atom other than the carbon atom adjacent to the oxygen atom,  <EMI ID = 229.1> carbon atoms, a cycloalkylalkyl group the  <EMI ID = 230.1>  <EMI ID = 231.1> or a phenyl or phenylalkyl group containing from 7 to 10 carbon atoms, this phenyl group or the phenyl residue of the phenylalkyl group possibly optionally bearing one, two or three substituents chosen from <EMI ID = 232.1> alkyl and alkoxy groups each containing from 1 to 4 carbon atoms,  <EMI ID = 233.1> of carbon, X signifies a direct bond or an oxygen atom or sulfur,  <EMI ID = 234.1> Z means an oxygen atom and, in this case, n means 2 or 3, or Z represents a direct bond and, in this case, n means 1, 2 or 3, with the conditions that <EMI ID = 235.1> oxygen atom and the residue -NH-A-X-R has a meaning other than the residues of formula  <EMI ID = 236.1>  b) when R2 signifies an alkyl group and X represents a bond or an oxygen atom, Y signifies a oxygen atom, and <EMI ID = 237.1> or monosubstituted, that X signifies a bond, and that Z  <EMI ID = 238.1> a cycloalkyl or cycloalkylalkyl group and that X signifies a bond, R1 has a different meaning from hydrogen, optionally in the form of hydrolysable derivatives which are acceptable from the physiological point of view in which the hydroxy group located in position 2 of the 3-aminopropoxy side chain is in esterified form, in the free base state or in the form of an acceptable salt pharmaceutical perspective. 15.- A medicament, characterized in that it contains, as active principle, a derivative of 3-aminopropoxybenzene specified in any one of the claims  <EMI ID = 239.1> pharmaceutically acceptable salt.  <EMI ID = 240.1> ethcxy) benzonitrile, in the free base state or in the form of a pharmaceutically acceptable salt. 17.- A medicine, characterized in that it  <EMI ID = 241.1> in the free base state or in the form of a pharmaceutically acceptable salt. 18. A medicament according to claim 16 and 17, characterized in that the active principle is in the form of a hydrolysable derivative acceptable from the physiological point of view, in which the hydroxy group located in position 2 of the side chain 3- aminopropoxy is in esterified form. 19.- A drug according to any one of  <EMI ID = 242.1> active is in the form of an optical or racemic isomer. 20. A medicament according to claim 19, characterized in that the active principle is in the form of an optical isomer in which the carbon atom in position 2 of the 3-aminopropoxy side chain has the S configuration. 21. A pharmaceutical composition, characterized in that it contains a 3-aminopropoxybenzene derivative specified in any one of the claims 1 to 10, in the free base state or in the form of a pharmaceutically acceptable salt, in combination with pharmaceutically acceptable excipients and vehicles. 22.- New phenolic compounds, characterized in that they correspond to formula IVd  <EMI ID = 243.1> in which  <EMI ID = 244.1> atomic number from 9 to 35, an alkyl or alkoxy group or alkylthio each containing from 1 to 4 carbon atoms, a cycloalkyl group containing from 3 to 7 carbon atoms, an alkanoyl group containing from 1 to  <EMI ID = 245.1> pyrrolyl, cyano or carbamoyl, or an alkenyl group containing from 2 to 5 carbon atoms or alkenyloxy  <EMI ID = 246.1>  <EMI ID = 247.1> on a carbon atom other than the carbon atom adjacent to the oxygen atom, Y represents an oxygen or sulfur atom, Z. signifies an oxygen atom and, in this case, n signifies 2 or 3, or Z represents a direct bond and, in this case, n means 1, 2 or 3, and R "signifies an alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl group containing from 3 to 7 carbon atoms, or a phenyl or phenylalkyl group containing from 7 to 10 carbon atoms, this phenyl group or the phenyl residue of the phenylalkyl group possibly optionally carrying one, two or three substituents chosen from halogen atoms having a  <EMI ID = 248.1>  <EMI ID = 249.1> and their derivatives in which the hydroxy group is protected by a protective group. 23.- Products and processes in substance above described described with reference to the examples cited.