BE873596A - SUBSTITUTED PROPANOLAMINES AND MORPHOLINES AND METHOD OF PREPARATION. - Google Patents

Description

       

  Propanolamines and substituted morpholines

  
and method of preparation The present invention relates to substituted derivatives of propanolamine and morpholine, a method

  
for the preparation of these compounds and the pharmaceutical compositions which contain them.

  
The compounds in accordance with the present invention correspond to the general structural formula (I)

  
next :

  

 <EMI ID = 1.1>


  
in which :

  
 <EMI ID = 2.1>

  
 <EMI ID = 3.1>

  
 <EMI ID = 4.1>

  
 <EMI ID = 5.1>

  
2 <EMI ID = 6.1>

  
 <EMI ID = 7.1>

  
 <EMI ID = 8.1>

  
or different, represents a hydrogen atom, a group

  
 <EMI ID = 9.1>

  
or else R3 and R4 form with the nitrogen atom to which they are attached, a heteromonocyclic, pentatomic or hexatomic radical, saturated or unsaturated, optionally substituted, optionally containing other heteroatoms chosen from the class formed by atoms of oxygen, sulfur and nitrogen;

  
 <EMI ID = 10.1>

  
as also all their possible isomers and their mixtures, the metabolites of the compounds in question endowed with pharmacological activity, for example anti-depressive, as well as the metabolic precursors of the compounds of

  
formula (I).

  
The alkyl, alkenyl, alkynyl, and alkoxy groups can be straight chain or branched chain.

  
 <EMI ID = 11.1>

  
 <EMI ID = 12.1>

  
have the meanings previously indicated.

  
The aryl radicals are preferably phenyl groups.

  
 <EMI ID = 13.1>

  
 <EMI ID = 14.1>

  
&#65533; 6

  
previously indicated. The same substituents can be

  
 <EMI ID = 15.1>

  
 <EMI ID = 16.1>

  
cations previously indicated.

  
 <EMI ID = 17.1>

  
 <EMI ID = 18.1>

  
the meanings indicated above.

  
 <EMI ID = 19.1>

  
methyl, ethyl or isopropyl radicals.

  
The alkyl groups 0, -0 ,,, are preferably methyl, ethyl, isopropyl or octyl.

  
 <EMI ID = 20.1>

  
benzyloxy radicals.

  
 <EMI ID = 21.1>

  
R6

  
independently, preferably, hydrogen atoms or

  
 <EMI ID = 22.1> isopropyl.

  
 <EMI ID = 23.1>

  
cyclopropyl, cyclopentyl or cyclohexyl radicals.

  
When R3 and R4 together with the nitrogen atom to which they are attached form a substituted heteromonocyclic radical, the substituents are preferably alkyl radicals.

  
 <EMI ID = 24.1>

  
Preferred heteromonocyclics are morpholino, piperidino, N-pyrrolidinyl, N-methyl-piperazinyl and N-phenyl-piperazinyl.

  
When two neighboring R groups or when two groups

  
 <EMI ID = 25.1>

  
preferably, a 3,4-methylenedioxy radical.

  
Due to the presence of at least two asymmetric carbon atoms, there can be for each compound of

  
 <EMI ID = 26.1>

  
from which one can obtain at least four distinct enantiomorphs: both the isolated diastereomers and their mixtures, as also the isolated enantiomorphs and their mixtures form part of the present invention.

  
As examples of pharmaceutically acceptable salts of compounds (I), mention may be made of salts with inor-. ganics, for example hydrochloric acid, hydrobromic acid, sulfuric acid and salts with organic acids, for example citric acid, tartaric acid, methanesulfonic acid, fumaric acid, malic acid, maleic acid and mandelic acid.

  
In accordance with the present invention, the preferred salts of compounds (I) are those in which the group <EMI ID = 27.1>

  
P-4

  
preferably hydrochloric acid.

  
The preferred compounds according to the invention are

  
 <EMI ID = 28.1>

  
feels a hydrogen atom or a methyl radical; one of the

  
 <EMI ID = 29.1>

  
that the other represents a methyl radical, as also the pharmaceutically acceptable salts of the compounds in question.

  
The most particularly preferred compounds in accordance with the invention are the compounds of formula (I) in

  
 <EMI ID = 30.1>

  
 <EMI ID = 31.1>

  
gene, a methoxy or ethoxy radical, a chlorine atom, a trifluoromethyl group, or two neighboring R groups form the

  
 <EMI ID = 32.1>

  
methyl or isopropyl group, as also the pharmaceutically acceptable salts of the compounds in question.

  
As examples of preferred compounds in accordance with the invention, the following substances may be mentioned:

  
 <EMI ID = 33.1> <EMI ID = 34.1>

  
 <EMI ID = 35.1>

  
as also their pharmaceutically acceptable salts.

  
The compounds according to the present invention can be prepared by a process characterized in that:
a) reducing a compound of formula (II)
 <EMI ID = 36.1>
 <EMI ID = 37.1>

  
previously indicated, so as to obtain compounds of

  
 <EMI ID = 38.1>

  
meanings previously indicated; or b) a compound of formula (III) is reduced
 <EMI ID = 39.1>
  <EMI ID = 40.1>

  
fications previously indicated; or c) reducing a compound of formula (IV)
 <EMI ID = 41.1>
 <EMI ID = 42.1>

  
 <EMI ID = 43.1>

  
 <EMI ID = 44.1>

  
 <EMI ID = 45.1> d) reacting a compound of formula (V)
 <EMI ID = 46.1>
 <EMI ID = 47.1>

  
previously indicated, on an amine of the formula HNR3R4 in

  
 <EMI ID = 48.1>

  
indicated, so as to obtain compounds of formula (I)

  
 <EMI ID = 49.1> <EMI ID = 50.1>

  
R2, the radical -CH2-CH2-; or e) reducing a compound of formula (VI)
 <EMI ID = 51.1>
 <EMI ID = 52.1> previously indicated; or else f) a compound of formula (VII) is reductively cyclized
 <EMI ID = 53.1>
 <EMI ID = 54.1>

  
one of the symbols Rb and Rc represents a hydrogen atom, while the other of these symbols represents a group <EMI ID = 55.1> have the meanings previously indicated,

  
 <EMI ID = 56.1>

  
 <EMI ID = 57.1>

  
g) a compound of formula (VIII) is cyclized

  

 <EMI ID = 58.1>


  
 <EMI ID = 59.1>

  
tions indicated above and X represents a hydroxyl group or a halogen atom or the residue of a reactive ester of an alcohol, so as to obtain compounds of

  
 <EMI ID = 60.1>

  
the meanings indicated above; or h) a compound of formula (IX) is reacted

  

 <EMI ID = 61.1>


  
 <EMI ID = 62.1>

  
in which each of the groups Y, whether they are identical or different, represents a halogen atom or the residue of a reactive ester of an alcohol, so as to obtain

  
 <EMI ID = 63.1>

  
and, if desired, converting a compound of formula (I) to another compound of formula (I) and / or, if desired, salifying a compound of formula (I) or a free compound is obtained from a salt and / or, if desired, a mixture of isomers is resolved into the individual isomers.

  
The reduction of a compound of formula (II), as also the reduction of a compound of formula (III) can, in general, be carried out by carrying out the processes usually employed for the reduction of nitriles and 'amides,

  
 <EMI ID = 64.1>

  
a mixture of these solvents, at temperatures which vary

  
 <EMI ID = 65.1>

  
treatment with an alkali borohydride, eg NaBH4, in the presence of alkali metals, as described, eg in Tetr. Lett. 1969, page 4555. The reduction of a compound of formula (II) can also be carried out by catalytic hydrogenation using, for example,

  
Raney nickel or a catalyst consisting of palladium on carbon and operating in the presence of liquid ammonia in a solvent which may be, for example, an aliphatic alcohol

  
 <EMI ID = 66.1> atmospheric pressure and at temperatures that vary from

  
 <EMI ID = 67.1>

  
A salt of a compound of formula (IV) is, for example, the salt of a compound of formula (IV) in which R2 represents a hydrogen atom, with an alkali metal,

  
for example sodium or potassium: this salt can be obtained directly during the preparation of compound (IV) described in the remainder of this specification.

  
The reduction of a compound of formula (IV) or of a salt thereof can be carried out in a conventional manner, for example, using LiAlH4, as described, for example, in the work: J. Org. Chem. 39, page 2852 (1974) or with sodium bis- (2-methoxyethoxy) aluminumdihydride, i.e.

  
 <EMI ID = 68.1>

  
described, for example, in the work: Chem. Comm. 1974,

  
page 307. The reaction of a compound of formula (V) with an amine of formula HNR3R4 can be carried out by carrying out known processes, preferably without solvents, but also in the presence of a solvent, such as as, for example, an aqueous or aqueous alcoholic solvent or dimethylformamide, operating, if necessary, in a stoppered flask, at temperatures which vary from room temperature to approximately 150 [deg.] C.

  
Reduction of a compound of formula (VI) can

  
be carried out using the same process as that described above

  
concerning the reduction of a compound of formula (III) using, for example, the method described in J. Med. Chem., Vol. 19, page 41 (1976), especially when Z in <EMI ID = 69.1>

  
reducing agent of a compound of formula (VII) can be carried out by treatment with a suitable reducing agent, according to:

  
 <EMI ID = 70.1>

  
inert anhydrous, for example an aliphatic ether, for example diethyl ether or tetrahydrofuran, at temperatures

  
 <EMI ID = 71.1>

  
When in the compound of formula (VIII), X represents a halogen atom, the latter is preferably a chlorine or bromine atom and when X represents the residue of a reactive ester of an alcohol, this remainder is, preferably

  
 <EMI ID = 72.1>

  
The cyclization of a compound of formula (VIII) can be carried out in a conventional manner, for example, when X represents a hydroxyl radical, by boiling in a solvent capable of forming an azeotropic mixture with water, for example toluene , in the presence of an acid catalyst,

  
 <EMI ID = 73.1>

  
presence of a dehydrating agent, for example anhydrous CuSO4; or else, when X represents a halogen atom

  
or is the residue of a reactive ester of an alcohol, by treatment with a base, for example, with potassium tert.-butoxide in tert.-butyl alcohol or with sodium hydride in dimethylformamide, tallow dimethyl oxide or dimethylacetamide, or with butyllithium or lithium diisopropylamide and, similarly, in tetrahydrofuran or in an aliphatic ether, for example of

  
 <EMI ID = 74.1> ammonia by implementing methods well known to specialists in organic chemistry.

  
When in the compound of formula (VIII), a

  
 <EMI ID = 75.1>

  
hydroxyl, preferably an amount of base is used which is sufficient for the salification of all the hydroxyl groups present in order to prevent these hydroxyl groups from interfering with the cyclization reaction. The reactivity of salified alcoholic hydroxyl groups is greater than that of salified phenolic hydroxyl groups which, therefore, do not interfere with the reaction in any way.

  
In a compound of formula (X), the groups Y preferably represent both halogen atoms and, in this case, one of them preferably represents a chlorine atom while the 'other represents an iodine atom, or they both represent groups
-O-tosyl, or, preferably, they both represent -O-mesyl groups.

  
Reaction of a compound of formula (IX) with a compound of formula (X) in which the groups Y both represent halogen atoms, in particular, on 1-chloro-2-iodo-ethane, can be carried out, for example, by using equimolecular amounts of the reactants, in the presence of an at least equimolecular amount of a strong base chosen, preferably, from the group formed by alkali hydrides, for example sodium hydride , or a slight excess of a metal bicarbonate or carbonate

  
 <EMI ID = 76.1> <EMI ID = 77.1>

  
The reaction temperature can vary from room temperature to the reflux temperature of the solvent, this temperature being preferably around 50 [deg.] C.

  
The reaction of a compound of formula (IX) on

  
a compound of the formula (X) in which the two groups Y represent residues of a reactive ester of an alcohol, in particular -O-mesyl radicals, can be carried out by treating, under cooling, the mixture containing equimolecular amounts of the reactants in an apolar solvent, for example benzene or an aliphatic ether, for example diethyl ether, by at least two molar equivalents of a strong base, such as, for example, butyllithium, lithium isopropylamide or sodium amide in

  
ammonia.

  
Interference, during the reaction between compounds (IX) and compounds (X), of hydroxyl groups

  
 <EMI ID = 78.1>

  
be avoided by using an excess of the base in a manner analogous to that indicated above in connection with the cyclization of a compound of formula (VIII).

  
When, in the compounds corresponding to the formulas
(II), (III), (IV), (VI) and (VII) indicated above, one or

  
 <EMI ID = 79.1>

  
reducible groups and it is desired to keep these groups in the unchanged state in the final compounds (I), then the reductions indicated above in paragraphs a), b), c), e) and f are preferably carried out ) by choosing selective conditions.

  
Thus, for example, the reduction of compounds of formulas (II), (III), (VI) and (VII) containing halogen atoms or nitro groups, can be carried out selectively with respect to these groups, by operating, for example,

  
 <EMI ID = 80.1>

  
for example diethyl ether, under a nitrogen atmosphere, for

  
 <EMI ID = 81.1>

  
86, 3566 (1964) or also with zinc in ethanol, as described in Experientia 33 (I), 101-102 (1977). The reduction of a compound of formula (IV) in which

  
one or more of the R and IL groups. represents a halogen atom can be carried out selectively vis-à-vis the halogen atom using, for example, aluminum

  
 <EMI ID = 82.1>

  
as a reducing agent. The reduction of compounds of formulas (III) and (VI) in which R or R4 represents a

  
 <EMI ID = 83.1>

  
selectively vis-à-vis these groups using,

  
for example, LiAlH &#65533; under the reaction conditions

  
 <EMI ID = 84.1>

  
and, therefore, compounds (I) in which one or more

  
 <EMI ID = 85.1>

  
 <EMI ID = 86.1>

  
 <EMI ID = 87.1>

  
be prepared by the reduction methods described above.

  
These compounds can be obtained, for example, by the methods given above in paragraphs d), g) or h) or by converting a compound of formula (I) into another compound of formula (I).

  
The same considerations apply to the other reducing methods described herein, whether they relate to the preparation of final compounds or whether they relate to the preparation of intermediates.

  
Both the optional conversion of a compound of formula (I) into another compound of formula (I) and the optional salification or preparation of a free compound of formula
(I) from a salt of such a compound, as also the optional resolution of a mixture of isomers, can be carried out in a conventional manner.

  
For example, a compound of formula (I) in which R3 represents a hydrogen atom and R4 has the aforementioned meanings or form, together with

  
R2, a -CH2-CH2- 'group can be converted into the compound

  
 <EMI ID = 88.1>

  
 <EMI ID = 89.1>

  
customary amine alkylation procedures, for example reductive amination or simple alkylation.

  
Reductive amination involves reacting a

  
 <EMI ID = 90.1>

  
smell hydrogen atoms on the appropriate carbonyl compound i.e. aldehyde or ketone in the presence of a reducing agent which may be hydrogen or, pre- '<EMI ID = 91.1 >

  
 <EMI ID = 92.1>

  
 <EMI ID = 93.1>

  
 <EMI ID = 94.1>

  
 <EMI ID = 95.1>

  
catalyst such as, for example, Raney nickel or palladium on carbon, at atmospheric pressure and at a temperature which varies from room temperature to about

  
50 [deg.] C, according to the method described, for example in Org. Reactions,

  
4, <1> 74 (1948). When the reducing agent is a mixed hydride,

  
for example NaBH3CN or NaBH4, the reductive amination can be carried out in the presence of an excess of the hydride, by operating,

  
preferably, at room temperature according to the methods described in Tetr. Lett., 3, 261 (1963), J. Org. Chem., 37,

  
 <EMI ID = 96.1>

  
reducing agent is carried out with fornic acid according to the Leuckart-Wallach reaction, formic acid may be present in excess and the reaction mixture may preferably be heated for a period which varies from 2 to 12 hours, such as described, for example, in Org. Reactions, 5, 301
(1949).

  
The alkylation reaction can be carried out, for example, by treatment with the appropriate aralkyl halide or alkyl halide, or with a reactive ester, for example a tosylate or mesylate, or the appropriate alcohol. . The alkylation can be carried out in the absence of solvents, or else in a solvent, such as, for example, water, an aliphatic alcohol, for example ethyl alcohol or methyl alcohol, a glycol, for example example ethylene glycol or propylene glycol, benzene or dimethylformamide or a mixture of these solvents, in the presence of an acid acceptor, such as, for example, triethylamine, a bicarbonate or an alkaline carbonate, or an excess of the amine, at temperatures which vary

  
 <EMI ID = 97.1>

  
mement to the methods described, for example in J. Org. Chem. 2, <1> 39 (1938); Org. Synt. Coll., Vol. II, 183 (1943); J. Amer. Chem. Soc., 54, 4457 (1932).

  
The monoalkylation can also be carried out by the methods described, for example, in J. Org. Chem. 40, 23, 3453 (<1> 975); J. Chem. Soc. c 2223 (1969); J. Med. Chem. 17 (1), 654
(1974).

  
Conversion of a compound of formula (I) in which one of the symbols R3 and R4 represents a hydrogen atom, into the corresponding compound of formula (I)

  
in which one of the symbols R3 and R4 represents a methyl radical can be carried out, in particular, also by reaction with ethyl chloroformate in chloroform, in the presence

  
 <EMI ID = 98.1>

  
with an excess of LiAlH4 or of BH3 in anhydrous diethyl ether, at reflux temperature.

  
A compound of formula (I) can be obtained in

  
 <EMI ID = 99.1>

  
C1-C6 alkyl, while the other of these symbols represents a hydrogen atom, in several different ways:
a ') by reacting a compound of formula (I) in

  
 <EMI ID = 100.1>

  
on benzaldehyde, in a solvent, such as, for example, benzene or toluene, at reflux temperature;

  
b ') by reducing the Schiff base obtained, for example by catalytic hydrogenation in an alcoholic solvent, in the presence of Raney nickel or of palladium on carbon,

  
 <EMI ID = 101.1>

  
amine obtained with the appropriate alkyl halide, according to the previously described alkylation process and, finally, d ') by removing the benzyl group, for example, by catalytic hydrogenation, according to the process described in

  
J. Amer. Chem. Soc. 63, 1964 (1941) or, preferably, by carrying out a treatment with ethyl chloroformate,

  
at reflux temperature, according to the process described in

  
J. Med. Chem. 18 (6), 576 (1975). By proceeding in an analogous manner, a compound of the formula (I) can be converted

  
 <EMI ID = 102.1>

  
hydrogen atom. We can convert a compound of the formula

  
 <EMI ID = 103.1> hydrogen atoms, in the corresponding compound of the

  
 <EMI ID = 104.1>

  
feels a hydrogen atom, while the other of these symbols represents a benzyl group, by reaction with benzoyl chloride, in the presence of an aqueous solution of sodium hydroxide in an organic solvent, such as, for example , dichloromethane, preferably at temperatures which vary from 0 [deg.] C to room temperature and then reducing the derivative of the benzoylamino type thus obtained with a mixed hydride, for example a compound of the formula

  
 <EMI ID = 105.1>

  
diethyl ether, at the reflux temperature of the solvent.

  
A compound of formula (I) can be converted into

  
 <EMI ID = 106.1>

  
 <EMI ID = 107.1>

  
commonly employed for the etherification of alcohols, for example, by reacting an alkali salt of 1 [deg.] alcohol, for example the lithium salt or the sodium salt, with the alkyl or aralkyl halide appropriate; we can perform the reaction to a

  
 <EMI ID = 108.1>

  
reflux in an organic solvent which may be, for example, the same solvent as that in which the alkali salt of the alcohol was prepared.

  
 <EMI ID = 109.1>

  
 <EMI ID = 110.1>

  
in an anhydrous inert solvent, such as, for example, tetrahydrofuran; the sodium salt can be obtained by reaction with metallic sodium or with sodium hydride, in an inert anhydrous solvent, such as, for example,

  
 <EMI ID = 111.1>

  
analogue, a compound of formula (I) can be converted

  
in which one of the groups R and IL represents a hydroxyl group, in the corresponding compound of formula CI)

  
 <EMI ID = 112.1>

  
C1-C6 alkoxy or C1-C6 arylalkoxy.

  
A compound of formula (I) in which R2 represents C1-6 alkoxy or C1-C6 arylalkoxy

  
can be converted into the corresponding compound of the

  
 <EMI ID = 113.1>

  
by carrying out customary deetherification processes; for example, one can deetherify a compound of formula (I)

  
 <EMI ID = 114.1>

  
with pyridine hydrochloride or with boron bromide

  
 <EMI ID = 115.1>

  
BBr3 in chloroform, operating under a nitrogen atmosphere

  
 <EMI ID = 116.1>

  
methyl.

  
A compound of formula (I) can be converted

  
 <EMI ID = 117.1>

  
methyl to the corresponding compound of formula (I) in

  
 <EMI ID = 118.1>

  
methyl, while the other of these symbols represents

  
a hydrogen atom, for example, by treatment with ethyl chloroformate in benzene or toluene, at the reflux temperature of the solvent and by subsequent treatment with alcoholic KOH, at the reflux temperature.

  
 <EMI ID = 119.1>

  
wherein one of the substituents R and R. represents a group -NO 2 in the corresponding compound of formula (I)

  
 <EMI ID = 120.1> reduction of nitroaromatic derivatives, for example, by catalytic hydrogenation using, for example, platinum, palladium or Raney nickel, as catalyst, according to methods well known to those skilled in the art of chemistry organic.

  
We can convert a compound of formula (I)

  
 <EMI ID = 121.1>

  
amino group to the corresponding compound of formula (I)

  
 <EMI ID = 122.1>

  
hydroxyl, by converting the amine into the corresponding diazonium salt and then hydrolyzing the latter, for example, according to the process described in the book Org. Synth.
23, 11 (1943), or according to the process described in the work J. Org. Chem. 42, 2053 (1977).

  
A compound of the formula (I) in which one of the groups R and IL represents an amino radical can be converted into the corresponding compound of the formula (I) in which one of the groups R and R. represents an radical

  
 <EMI ID = 123.1>

  
by alkylation, as previously indicated. As

  
as mentioned above, it is also possible to carry out the salification of a compound of formula (I), as also the preparation of a free compound from its salt and the separation of the isomers from a mixture , in a classic way. -

  
Thus, for example, the salt of a compound of formula (I) can be obtained with hydrochloric acid by treatment with anhydrous gaseous hydrochloric acid, or with an anhydrous alcoholic solution of hydrochloric acid in a solvent. anhydrous, such as, for example, diethyl ether, benzene, ethyl alcohol and then isolating the hydrochloride by filtration or evaporation of the solvent.

  
The separation of isomers, for example diastereomers, from their mixture can be carried out by fractional crystallization from a suitable solvent or by chromatography.

  
Chromatographic separation can be carried out both by preparative thin-layer chromatography and by column chromatography, using silica gel or magnesium silicate as a support and, for example,

  
benzene, ethyl acetate, cyclohexane, chloroform, methylene chloride, ethyl ether or mixtures thereof as eluting solvents, or by high pressure liquid chromatography.

  
The optional conversions described above

  
with regard to the compounds of formula (I) such as also the sepa-

  
 <EMI ID = 124.1>

  
Mixing can also be carried out, if desired, on the starting materials or on the intermediates.

  
The compounds of formula (II) in which R2 represents a hydrogen atom can be prepared from aldehydes of formula (XI)

  

 <EMI ID = 125.1>


  
where R, IL. , n and &#65533; have the aforementioned meanings, according to the methods usually employed for the conversion of aldehydes to cyanohydrins, for example, by treatment with a metabisulfite, preferably an alkaline metabisulfite, for example sodium metabisulfite, in the presence of a cyanide, preferably, an alkali cyanide, for example sodium or potassium cyanide, working in an appropriate solvent, such as, for example, diethylene glycol, dimethyl ether, water, an aliphatic alcohol, for example ethyl alcohol, or a mixture of these solvents, at temperatures which vary from room temperature

  
 <EMI ID = 126.1>

  
etherification of compounds of formula (II) in which

  
 <EMI ID = 127.1>

  
c, for example, by treating the alkali salt of the alcohol with a suitable aralkyl or alkyl halide, as previously described in connection with analogous conversions on compounds.

  
 <EMI ID = 128.1>

  
according to customary processes for preparing amides, for example

  
 <EMI ID = 129.1>

  
indicated, on a compound of formula (XII)

  

 <EMI ID = 130.1>


  
 <EMI ID = 131.1>

  
previously indicated or, preferably, on a reactive derivative of such a compound, for example, an acid halide or

  
 <EMI ID = 132.1>

  
The reaction can be carried out in the absence of a solvent or in the presence of a suitable solvent, such as, for example,

  
 <EMI ID = 133.1>

  
that in the presence, if necessary, of a condensing agent, for example dicyclohexylcarbodiimide, or of an acid acceptor, for example a bicarbonate or an alkali carbonate, or a tertiary amine, for example the tri -

  
 <EMI ID = 134.1>

  
can be prepared, for example, by cyclization of a compound of formula (XIII)

  

 <EMI ID = 135.1>


  
 <EMI ID = 136.1>

  
previously indicated and X represents a hydroxyl group or a halogen atom or, preferably, the residue of a reactive ester of an alcohol, for example a tosylate or mesylate group, by operating, for example, under the reaction conditions described above in connection with the cyclization of a compound of formula (VIII), preferably when X represents a halogen atom or the residue of a reactive ester of a

  
 <EMI ID = 137.1> tallow dimethyl ether and the like.

  
The compounds of formula (III) in which

  
 <EMI ID = 138.1>

  
can also be obtained from a compound of the formula (XIV)

  

 <EMI ID = 139.1>


  
 <EMI ID = 140.1>

  
previously indicated, by heating at temperatures varying from about 120 [deg.] C to about 180 [deg.] C, in a solvent

  
 <EMI ID = 141.1>

  
triamide, as described, for example, in the book:

  
 <EMI ID = 142.1>

  
The compounds of formula (IV) can be prepared, for example, a reactive derivative of the compound of formula (XII), which can be, for example, one of the reactive derivatives indicated above or, preferably, the amide obtained by reacting

  
 <EMI ID = 143.1>

  
ple, an alkali hydride, for example sodium hydride, in a suitable anhydrous solvent, for example tetrahydrofuran. In this way, compounds of the formula (IV) are obtained in which R2 represents the cation of the base used, which, if desired, can be etherified by conventional methods, for example, the methods indicated above, so as to obtain compounds of formula (IV) in which R2 represents an alkyl group

  
 <EMI ID = 144.1>

  
in C1-C6, or acidified so as to generate the ketone form of the compounds of formula (IV) in which R2 represents a hydrogen atom.

  
The compounds of formula (V) can be prepared

  
by carrying out known methods, for example by oxidizing a compound of formula (XV)

  

 <EMI ID = 145.1>


  
 <EMI ID = 146.1>

  
previously indicated, for example, with a peroxy acid, preferably m-chloro-perbenzoic acid, in an organic solvent, for example, dichloromethane, chloroform, benzene or acetone, or according to the method described in 'work: Tetrahedron 28, 3009 (1972), from the aldehydes of formula (XI).

  
The compounds of formula (VI) can be prepared

  
 <EMI ID = 147.1>

  
cyclizing a compound of formula (XVI)

  

 <EMI ID = 148.1>


  
 <EMI ID = 149.1> tions shown above, using approximately

  
 <EMI ID = 150.1>

  
top about the cyclization of a compound of the formula
(VIII).

  
The compounds of the formula (VI) can be obtained

  
 <EMI ID = 151.1>

  
a compound of the formula (XVII)

  

 <EMI ID = 152.1>


  
 <EMI ID = 153.1>

  
 <EMI ID = 154.1>

  
be the same or different, represents an alkyl group

  
 <EMI ID = 155.1>

  
mentioned above. The reaction is preferably carried out under pressure in a suitable solvent, for example an alcohol.

  
 <EMI ID = 156.1>

  
the reaction is carried out under controlled temperature, time and stoichiometry conditions, a compound of the formula is obtained in which one of the groups -COOR

  
 <EMI ID = 157.1>

  
a compound of formula (VI) can be obtained by boiling, for example, in acetic acid, or by treatment with a strong base, for example NaH, in a suitable solvent, for example dimethylformamide or dimethyl sulfoxide .

  
Compounds (VI) can also be obtained from the imides corresponding to the amides of formula (XIV) by the same process as that described above with regard to the preparation of compounds (III) from compounds (XIV).

  
The compounds of formula (VII) in which

  
 <EMI ID = 158.1>

  
that the other represents a -CsN group, can be prepared according to known methods, for example, by reacting a compound of formula (II) in which R2 represents a

  
 <EMI ID = 159.1>

  
example, an alkali metal carbonate or bicarbonate, for example K2CO3, in an anhydrous solvent, such as, e.g.

  
 <EMI ID = 160.1>

  
wind is obtained, by an analogous way, starting from a compound

  
 <EMI ID = 161.1>

  
example an alkali cation, for example a sodium cation, for

  
 <EMI ID = 162.1>

  
as, for example, tetrahydrofuran, dioxane or one of the aforementioned solvents.

  
The compounds of formula (VIII) can be prepared, for example, from compounds of formula (IX) as described, for example, in the work: Ind. J. Chem. 13, 462
(1975) ,, or by reducing a compound of formula (XVI) to <EMI ID = 163.1>

  
 <EMI ID = 164.1>

  
in an inert anhydrous solvent, such as, for example, tetrahydrofuran or an aliphatic ether, for example diethyl ether.

  
 <EMI ID = 165.1>

  
represents a hydrogen atom can be prepared by the methods indicated above in paragraphs a), b) and c).

  
 <EMI ID = 166.1>

  
is different from a hydrogen atom can be obtained by alkylation according to known methods, for example, those related above in connection with the alkylation of amines, compounds of formula (IX) in which R 1 represents a hydrogen atom or by reduction of compounds of the formula
(III) in which R3 represents a hydrogen atom, carried out as described above.

  
The compounds of formula (X) are known compounds or they can be prepared by carrying out known processes.

  
The aldehydes of formula (XI) can be obtained by carrying out the usual processes for the preparation of aldehydes described in organic chemistry, for example,

  
by oxidizing the corresponding primary alcohols, for example, by treatment with 99% phosphoric acid, in the presence of dicyclohexylcarbodiimide, in a conventional manner, or by reduction of the corresponding acid chlorides according to known methods. This reduction can be carried out, for example, with a mixed hydride, in particular <EMI ID = 167.1>

  
that and the like. The acid chlorides mentioned above can in turn be obtained from the carboxylic acids.

  
 <EMI ID = 168.1>

  
acetic, by conventional methods of organic chemistry, for example by treatment with thionyl chloride

  
or with oxalyl chloride, in the absence of solvents or in an anhydrous organic solvent, for example benzene,

  
toluene and the like, according to known methods.

  
The compounds of the formula (XII), as also the reactive derivatives of the compounds of the formula (XII), can

  
prepare according to known methods, in particular, one

  
 <EMI ID = 169.1>

  
the formula (XII) where R2 represents a hydrogen atom, for example, by reaction of a compound of the formula (XVIII)

  

 <EMI ID = 170.1>


  
 <EMI ID = 171.1>

  
previously indicated, on a compound of formula (XIX)
 <EMI ID = 172.1>
 in which R and n have the meanings indicated above, in the presence of a catalytic amount of a base which may be, for example, an alkali carbonate, for example sodium or a strong base or the salt of the phenol of the formula ( XIX), either in the absence of solvents, or in a suitable solvent, for example an aliphatic alcohol in

  
 <EMI ID = 173.1>

  
Compounds of formula (XIII) can be prepared, for example, by treating a reactive derivative of a compound of

  
 <EMI ID = 174.1>

  
 <EMI ID = 175.1>

  
R3 has the meanings previously indicated and, if desired, the compound of formula (XIII) in which X represents an -OH group, thus obtained, is converted into the halide or the corresponding reactive ester, according to methods known.

  
Compounds of formula (XIV) can be prepared according to known methods, for example, by treating a compound of formula (XX)

  

 <EMI ID = 176.1>


  
 <EMI ID = 177.1>

  
mentioned above, with the appropriate phenyl chloroformate, in the presence of a base, for example pyridine, according to standard methods.

J

  
Compounds of formula (XVI) can be obtained, for example, by reacting a compound of formula (IX)

  
 <EMI ID = 178.1>

  
0

  
 <EMI ID = 179.1>

  
smells of a halogen atom, preferably chlorine, according to known methods, for example in an organic solvent

  
 <EMI ID = 180.1>

  
methylene or methylene chloride and water, in the presence

  
 <EMI ID = 181.1>

  
The compounds of formula (XVII) can be prepared

  
 <EMI ID = 182.1>

  
represents a hydrogen atom and the carboxyl group is esterified, for example as the alkyl ester in

  
 <EMI ID = 183.1>

  
Compounds of formulas (XV), (XVIII), (XIX)

  
and (XX) are known compounds or can respectively be prepared by carrying out known processes, from known compounds. In particular, it is possible to obtain a compound

  
 <EMI ID = 184.1>

  
 <EMI ID = 185.1>

  
 <EMI ID = 186.1>

  
anhydrous, for example tetrahydrofuran, at a temperature which varies from about. -70 ° C to about -50 [deg.] C. In an analogous manner, the compounds of the formula

  
 <EMI ID = 187.1>

  
The compounds of the present invention are active on the central nervous system, in particular, as

  
 <EMI ID = 188.1>

  
Antidepressant activity was evaluated in mice, based on the prevention of hypothermia and reserpine-induced blepharospasm.

  
Reserpine was administered by the endoperitoneal route at a dose of 2.5 mg / kg and the test compounds were administered orally 30 minutes before the administration of reserpine. The record

  
1-blepharospasm evaluated by rating according to the technique described by Rubin B. et al. in J. Pharmacol., 120, 125
(1957) _7 and measurement of body temperature (using a rectal thermocouple) were carried out 1 hour and 4 hours respectively after administration of reserpine.

  
The compounds according to the present invention are preferably administered orally, although they can also be administered by other conventional methods, for example, by injection or rectally.

  
 <EMI ID = 189.1>

  
suitable for oral administration to adult humans preferably ranges from 5 to 30 mg per dose, from two to four times per day. The pharmaceutical compositions containing the compounds in accordance with the invention are prepared according to conventional methods with the usual ingredients.

  
Thus, for administration by the oral route, the pharmaceutical compositions containing the compounds according to the invention are preferably presented in the form of tablets, pills or capsules which contain the active substance at the same time as diluents. ,

  
such as, for example, lactose, dextrose, sucrose,

  
mannitol, sorbitol, cellulose; lubricants,

  
for example, silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols;

  
or else the pharmaceutical compositions in question may also contain binders, such as, for example, starches, gelatin, methyl cellulose, gum arabic,

  
 <EMI ID = 190.1>

  
disintegration, such as, for example, starches, alginic acid, alginates; effervescent agents; of

  
coloring agents; sweetening agents; wetting agents, such as, for example, lecithin, polysorbates,

  
 <EMI ID = 191.1>

  
mentally inactive and non-toxic used in pharmaceutical compositions. The pharmaceutical preparations in question can be produced in a known manner, for example by mixing, granulating, forming into tablets, coating with sugar, that is to say coating or coating with a film.

  
The other pharmaceutical compositions containing the compounds according to the invention can also be prepared according to known methods and these pharmaceutical compositions can be presented, for example, in the form of syrups or drops suitable for administration by the oral route, sterile solutions for injection

  
or suppositories.

  
In the following examples, the abbreviations

  
 <EMI ID = 192.1>

  
dimethyl diethylene glycol.

  
Very wide melting points generally refer to mixtures of diastereomers.

  
The examples which follow illustrate the present invention without, however, limiting the latter. EXAMPLE 1

  
To a well stirred mixture of 2-hydroxy-3- (3,4-methylenedioxy-phenoxy) -3-phenyl-propylamine (2.87 g) in

  
 <EMI ID = 193.1>

  
for about 30 minutes, a solution of ethyl chloroformate (1.58 ml) in

  
 <EMI ID = 194.1>

  
 <EMI ID = 195.1>

  
This oil was dissolved in anhydrous diethyl ether (100 ml) and this solution was added dropwise.

  
 <EMI ID = 196.1>

  
in anhydrous diethyl ether (25 mL). The mixture was stirred at room temperature for 20 hours,

  
cooled and decomposed with water (1 ml), <EMI ID = 197.1>

  
Analogously, it was possible to prepare the compounds

  
following

  
 <EMI ID = 198.1>

  
amine;

  
 <EMI ID = 199.1> amine.

EXAMPLE

  
 <EMI ID = 200.1>

  
(6.23 mL), cooled to 0-5 [deg.] C. 55% NaH was added
(4.36 g). Stirring and cooling was continued for

  
 <EMI ID = 201.1>

  
tional with water, then diluted with full amount of water and extracted with ethyl acetate; we washed the phase

  
 <EMI ID = 202.1> to dryness. The residue was purified by dissolving the latter in methanol and filtering off the insoluble material. The filtrate was evaporated to dryness.

  
 <EMI ID = 203.1>

  
After 48 hours, the reaction mixture was concentrated to dryness, then n-propyl alcohol was added to restore it to its original volume. We boiled it all for
20 hours and evaporated to dryness; the residue was taken up in water and extracted with diethyl ether. The ethereal phase was extracted with 3% hydrochloric acid, the acid extract was basified with NaOH at

  
20% and re-extraction with diethyl ether. The organic phase was washed with water, no. dried it

  
 <EMI ID = 204.1>

  
propylamine, 2.05 g; oil; yield: 81.3%. HC1 M.P. 142-145 [deg.] C.

  
In an analogous manner, the following compounds could be prepared:

  
 <EMI ID = 205.1>

  
 <EMI ID = 206.1>

  
amine EXAMPLE 3

  
At 15 [deg.] C and under a nitrogen atmosphere, was added

  
46.2 ml of a solution of 1.35 M diborane in tetrahydro-

  
 <EMI ID = 207.1>

  
phenoxy) -propionitrile in 110 ml of anhydrous tetrahydrofuran. Stirring was continued at room temperature for

  
 <EMI ID = 208.1>

  
evaporated everything to dryness. The residue was dissolved in ethyl ether, the solution was extracted with HCl.

  
 <EMI ID = 209.1>

  
&#65533; proceeded to a further extraction with ethyl ether. After washing with water, drying over Na2SO4, filtration

  
and evaporating to dryness, 12.45 g of 2-hydroxy- &#65533;

  
 <EMI ID = 210.1>

  
 <EMI ID = 211.1>

  
useful primer for the preparation of the N-methyl derivatives mentioned in Examples 1 and 2. EXAMPLE 4

  
 <EMI ID = 212.1>

  
cooling. The whole was stirred for 16 hours at room temperature and then refluxed for

  
 <EMI ID = 213.1>

  
The insoluble matter was filtered off and was suitably

  
j washed with ethyl acetate with heating.

  
After the solvent evaporated, the

  
 <EMI ID = 214.1>

  
with 3% HCl, the extract was basified with NaOH at
20% and reextracted with ether. After the normal processing, 86.2 g of 2-hydroxy-

  
 <EMI ID = 215.1>

  
mixture of diastereomers in a ratio of approximately 1: 1. The mixture was separated by gel chromatography.

  
 <EMI ID = 216.1>

  
in this way, two distinct diastereomers were obtained having respective melting points of 126-129 [deg.] C (dia-

  
 <EMI ID = 217.1>

  
 <EMI ID = 218.1>

  
Similarly, all the amines suitable for the preparation of the N-methyl derivatives mentioned in Examples 1 and 2 were prepared, with the exception of the chlorinated derivatives. EXAMPLE 5

  
2.69 g of 2-hydroxy-3-phenyl-3- (2-methoxy-

  
 <EMI ID = 219.1>

  
anhydrous amide and 7.1 g of methyl iodide, at 0 [deg.] C. Per fractions, 2.18 g of 55% NaH were added. After the addition, we stirred

  
 <EMI ID = 220.1>

  
Thoroughly decomposed the whole with the aid of water, under a nitrogen atmosphere, a dilution was carried out with a full quantity of water, then an extraction with ethyl acetate and a washing at the water. The organic phase was dried over Na2SO4 and evaporated to dryness, thereby obtaining <EMI ID = 221.1>

  
 <EMI ID = 222.1>

  
In an analogous manner, it was possible to prepare all the derivatives of the 2-methoxy-propionitrile type suitable for the preparation of the 2-methoxy-propylamines listed in Example 2 and obtained according to the reduction described in Example 3.

  
EXAMPLE 6

  
 <EMI ID = 223.1>

  
acetaldehyde dissolved in approximately 1800 ml of diglyme with 176.5 g of sodium metabisulfite in 550 ml of water and
200 ml of ethanol at 50 [deg.] C for 16 hours. The whole was cooled to room temperature and 44.4 g were added.

  
of potassium cyanide in 200 ml of water. We waved it all

  
 <EMI ID = 224.1>

  
to a volume of approximately 800 ml and poured into water. Extraction was carried out with 4 x 750 ml of ethyl ether and the whole was washed with water, dried over Na2SO4 and evaporated to dryness so that

  
 <EMI ID = 225.1>

  
propionitrile in the form of a viscous oil, the yield being 94%.

  
Analogously, all the derivatives of the 2-hydroxy-propionitrile type suitable for the preparation were prepared.

  
 <EMI ID = 226.1>

  
EXAMPLE 7

  
171 g of α- (2-methoxyphenoxy) -phenylacetic acid chloride was dissolved in 1000 ml of anhydrous diglyme, with stirring. At a temperature varying from -60 [deg.] C to -65 [deg.] C, was added, dropwise and over the course of 2 and a half hours, <EMI ID = 227.1>

  
dissolved in 800 ml of anhydrous diglyme. After the addition was complete, the temperature was maintained at -60 [deg.] C for 30 min. The temperature was then allowed to rise to -40 [deg.] C and the mixture was decomposed with 152 g of ammonium sulfate in 228 ml of water. The whole was diluted with 2000 ml of ethyl ether and Celite was added. We filtered it all out

  
 <EMI ID = 228.1>

  
the residue with ethyl ether. The ether was concentrated in vacuo at a temperature below 30 [deg.] C, so that

  
 <EMI ID = 229.1>

  
phenoxy) -phenyl-acetaldehyde in quantitative yield.

  
This solution was used as it was to obtain the propionitrile of Example 6.

  
Similarly, all the aldehydes suitable for the preparation of the propionitrile derivatives obtained in accordance with Example 6 were obtained.

  
EXAMPLE 8

  
0.47 g of α- (3-methoxy-phenoxy) phenylacetic acid was dissolved in 20 ml of dry benzene. At room temperature, 1.9 ml of oxalyl chloride diluted with 7 ml of anhydrous benzene were added dropwise. We heated the

  
 <EMI ID = 230.1>

  
Resuming it twice with anhydrous benzene and again concentrating to dryness. In this way, α- (3-methoxy-phenoxy) -phenylacetic acid chloride was obtained in quantitative yield (0.50 g), which was used as it was for reduction to aldehyde in the manner indicated at
-example 7.

  
In an analogous manner, all the acid chlorides suitable for the preparation of the aldehydes mentioned in Example 7 were prepared. EXAMPLE 9

  
 <EMI ID = 231.1>

  
 <EMI ID = 232.1>

  
ambient. The reaction was complete after 20 hours. We eva- ''

  
 <EMI ID = 233.1>

  
taking up with anhydrous benzene and evaporating again; to dryness. In this way, we obtained a yield

  
 <EMI ID = 234.1>

  
phenylacetic which was used as it is to carry out the reduction to aldehyde indicated in Example 7.

  
In an analogous manner, the acid chlorides suitable for the preparation of the aldehydes mentioned were prepared.

  
in example 7.

  
The phenylacetic acids used as starting materials for the preparation of the acid chlorides given in this example and in example 8 were known compounds which can be prepared by carrying out known methods, such as, for example, that described in

  
Bull. Soc. Chem. Fr. 1956, 776.

  
EXAMPLE 10

  
50.3 g of N-methyl-2-hydroxy-3-phenyl- was reduced

  
 <EMI ID = 235.1>

  
anhydrous tetrahydrofuran to the amine by slow addition,

  
at 8 [deg.] C, 340 ml of a molar solution of diborane in tetrahydrofuran. The whole was refluxed for 4 hours, cooled to room temperature, the excess diborane was decomposed with MeOH and then, again at room temperature, carried out. dropwise addition of 400 ml of an ethereal solution of HCl. This was left to stand for 16 hours and then evaporated to

  
 <EMI ID = 236.1>

  
and washing with an aqueous solution of sodium bicarbonate. The organic phase was then washed several times with a saturated aqueous solution of NaCl, one

  
 <EMI ID = 237.1>

  
dryness. The dark oil forming the residue was dissolved in

  
800 ml of ethyl ether and alcoholic hydrochloric acid (18% solution in ethanol) was added, thereby obtaining 50.9 g of N-methyl-2-hydroxy-3- hydrochloride ( 2-nitro-

  
 <EMI ID = 238.1>

  

 <EMI ID = 239.1>


  
Analogously, all of the compounds indicated in Examples 1 and 2 were prepared.

  
EXAMPLE 11

  
40 g of ethyl 2-hydroxy-3-phenyl-3- (2-nitrophenoxy) -propionate were heated in 1 liter of ethyl alcohol

  
 <EMI ID = 240.1>

  
It was dried in vacuo, taken up in 200 ml of absolute ethyl alcohol, evaporated again to dryness and the residue formed was crystallized from isopropanol. In this way,

  
 <EMI ID = 241.1>

  
(2-nitro-phenoxy) -propionamide having a melting point of 162-163 [deg.] C.

  
 <EMI ID = 242.1>

  
 <EMI ID = 243.1>

  
 <EMI ID = 244.1>

  
Analogously, the propionamts suitable for the preparation of the propylamines obtained were prepared in a manner analogous to that described in Example 10.

  
 <EMI ID = 245.1>

  
66 g of ethyl trans-glycidate were dissolved and
48 g of o-nitrophenol in 1 liter of absolute ethyl alcohol

  
 <EMI ID = 246.1>

  
reflux for a further 36 hours, after which it was evaporated to dryness in vacuo, diluted with water and extracted with ethyl acetate, extract which was then washed with 2N NaOH until the total elimination of excess phenol. The whole was then washed with water until neutral,

  
 <EMI ID = 247.1>

  
crystallized the residue from diethyl ether to obtain 67 g (60%) of ethyl 2-hydroxy-3-phenyl-3- (2-nitro-phenoxy) propionate, m.p. 129-131 "C.

  

 <EMI ID = 248.1>


  
In an analogous manner, all the 2-hydroxypropionates suitable for: the synthesis of the 2-hydroxy-propionamides obtained in accordance with Example 11 (including the diastereomers obtained starting from the cis glycidates) were prepared.

  
EXAMPLE 13

  
A 2 g of ethyl 2-hydroxy-3-phenyl-3- (2-nitro-phenoxy) propionate dissolved in 30 ml of dimethylformamide

  
 <EMI ID = 249.1>

  
then we also added, in two additions and to the same

  
 <EMI ID = 250.1>

  
for 1 hour and at room temperature for 1 hour, after which it was poured into 300 ml of water, extracted with ethyl ether which, after washing with saturated water of

  
NaCl and dehydration with sodium sulfate, was evaporated to dryness under reduced pressure. We thus obtained 2 g

  
 <EMI ID = 251.1>

  
ethyl in the form of an oil.

  

 <EMI ID = 252.1>


  
In an analogous manner, all the 2-methoxypropionates suitable for the preparation of the 2-methoxy-propionamides obtained according to Example 11 were prepared.

  
EXAMPLE 14

  
6.9 g of ethyl 3-phenyl-3- (2-nitro-phenoxy) 2-methoxy-propionate, dissolved in 150 ml of absolute ethanol, were hydrogenated (charcoal supporting 5% palladium), at ambient temperature and pressure.

The reaction was completed within 30 minutes.

  
The catalyst was filtered off and removed.

  
the solvent under reduced pressure. To the residual oil, taken up in a small amount of ethanol, was then added 4 ml of 18% HCl in ethanol. The hydrochloride <EMI ID = 253.1> was obtained

  
by dilution with ethyl ether.

  

 <EMI ID = 254.1>


  
EXAMPLE 15

  
 <EMI ID = 255.1>

  
(11.6 ml), water (30 ml) at a temperature of 4 to 5 [deg.] C was added and, still under cooling, a solution of NaNO 2 (NaNO 2) was slowly added dropwise ( 1.73 g) in

  
 <EMI ID = 256.1>

  
so as to obtain an oil which was separated by column chromatography to obtain 4.0 g of ethyl 3- (2-hydroxyphenoxy) -3-phenyl-2-methoxy-propionate (50%).

  
 <EMI ID = 257.1>

  
EXAMPLE 16

  
To a solution of 9.5 g of ethyl 3- (2-hydroxy-phenoxy) 3-phenyl-2-methoxy-propionate in 130 ml of anhydrous dimethylformamide was added 4.8 ml of anhydrous potassium carbonate and then, with stirring, was carried out the dropwise addition of 2.2 ml of methyl iodide in 15 ml of dimethylformamide. After 4.5 hours, the mixture was poured into 1 liter of water, then extracted twice with ethyl acetate. The extracts were combined, washed with water and dried to then concentrate under reduced pressure. Chromatography was carried out on silica gel so as to obtain 8.6 g of ethyl 3-phenyl-3- (2methoxy-phenoxy) -2-methoxy-propionate in a yield of 86.8%.

  

 <EMI ID = 258.1>


  
EXAMPLE 17 '

  
 <EMI ID = 259.1>

  
benzene (100 ml), a solution of methyl iodide (5.5 g) in benzene (20 ml) was added dropwise and

  
at room temperature over 1 hour. Stirring was continued at room temperature for 20 hours, the mixture was separated by filtration and the solvent was evaporated to dryness so as to obtain an oil.

  
 <EMI ID = 260.1>

  
 <EMI ID = 261.1>

  
 <EMI ID = 262.1>

  
EXAMPLE 18

  
 <EMI ID = 263.1>

  
ethyl chloroformate (3.5 ml) was added thereto dropwise over 30 minutes. Stirring and cooling at 0 [deg.] C was continued for 1 hour; the organic phase was separated, washed with water and dried over

  
 <EMI ID = 264.1>

  
gave a colorless oil which was dissolved in ether

  
 <EMI ID = 265.1>

  
anhydrous (200 ml). The mixture was stirred at room temperature for 20 hours; To this were added water (2.5 ml), 15% NaOH (2.5 ml) and water (7.5 ml). After filtration, the ether layer was separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water and dried over

  
anhydrous Na2SO4. After evaporation to dryness of the

  
 <EMI ID = 266.1>

  
yield: 82%).

  
Analogously, all the derivatives were prepared

  
 <EMI ID = 267.1>

  
glacial acetic acid (5.2 ml), acetone was added
(12 ml) and water (8 ml), NaBH4 (6.024 g), in the space <EMI ID = 268.1>

  
to room temperature and, after 30 hours, the reaction mixture was poured into a solution of NaHCO3 in water, then extracted with diethyl ether. The ethereal extracts were washed with water, dried over

  
 <EMI ID = 269.1>

  
Analogously, the following 4-isopropyl-morphcline derivatives were prepared: <EMI ID = 270.1>

  
 <EMI ID = 271.1>

  
EXAMPLE 20

  
 <EMI ID = 272.1>

  
3-one, dissolved in 60 ml of anhydrous tetrahydrofuran, was added, dropwise and with stirring, 16.7 ml of a solution.

  
 <EMI ID = 273.1>

  
all at reflux for 3 hours and then the addition was carried out dropwise and under cold conditions

  
 <EMI ID = 274.1>

  
The solvent was removed under reduced pressure. The residue was diluted with water, basified and extracted with chloroform. The organic extracts were washed until neutral, dried and evaporated to dryness, so as to

  
 <EMI ID = 275.1>

  
 <EMI ID = 276.1>

  

 <EMI ID = 277.1>


  
Analogously, the following compounds were prepared:

  
 <EMI ID = 278.1>

  
 <EMI ID = 279.1>

  
as also all the compounds mentioned in Examples 17 and 19.

  
EXAMPLE 21

  
Has a solution of 4.24 g of N- (2-mesyloxyethyl) -3-

  
 <EMI ID = 280.1>

  
then poured into water and extracted with ethyl acetate. The dehydrated organic extracts were evaporated to dryness and the residue was chronographed on gel.

  
 <EMI ID = 281.1>

  

 <EMI ID = 282.1>


  
Analogously, morpholine-3-one derivatives suitable for the preparation of the compounds mentioned in Examples 17, 19 and 20 were prepared.

  
EXAMPLE 22

  
 <EMI ID = 283.1>

  
The solution was cooled to -10 [deg.] C and, with stirring,

  
a slow dropwise addition of a solution of 1.83 g of mesyl chloride in 30 ml of tetrahydrofuran was carried out. After 45 minutes at -10 [deg.] C, the temperature was allowed to rise to room temperature. The solution was concentrated to a small volume under reduced pressure. The residue was poured into water. The mixture was extracted with chloroform, the extracts were washed until neutral with

  
water and then dried over sodium sulfate.

  
The solvent was removed under reduced pressure and the residue was crystallized from 95 [deg.] Ethanol, so

  
 <EMI ID = 284.1>

  
(2-nitro-phenoxy) -propionamide, m.p. 122-125 [deg.] C (yield:

  
 <EMI ID = 285.1>

  

 <EMI ID = 286.1>


  
 <EMI ID = 287.1>

  
ethyl) -propionamides suitable for the preparation of the compounds mentioned in Example 2.

  
EXAMPLE 23

  
 <EMI ID = 288.1>

  
ethyl phenoxy) -propionate at reflux with 5.4 ml of ethanolamine in 50 ml of anhydrous ethanol for 20 hours. The solvent was removed under reduced pressure, the residue was taken up with water and the solid was collected by filtration. After crystallization from ethyl acetate, 1.8 g of N- (2-hydroxyethyl) -3-phenyl-2-hydroxy-3- (2-nitro-phenoxy) - were obtained.

  

 <EMI ID = 289.1>


  
In an analogous manner, the N- (2-hydroxy-, ethyl) -propionamides suitable for the preparation of the compounds mentioned in Example 22 were prepared.

  
EXAMPLE 24

  
 <EMI ID = 290.1>

  
all with water and extracted with ethyl acetate. The organic extracts were washed with water, dried over Na2SO4, filtered and concentrated to

  
 <EMI ID = 291.1>

  
3-one.

  
Similarly, all of the morpholine-3-one derivatives necessary for the preparation of the compounds of Example 20 were prepared.

  
EXAMPLE 25

  
Has 0.6 g of 2- (a-hydroxy-benzyl) -morpholin-3-one

  
 <EMI ID = 292.1>

  
dropwise, 0.5 g of phenyl chloroformate. We have

  
stirred at room temperature for 12 hours.

  
 <EMI ID = 293.1>

  
washing with 5% HCl and then with 5% NaOH and finally with water. The organic phase was dried

  
 <EMI ID = 294.1>

  
benzyl) -morpholin-3-one with a yield of 95%.

  
Similarly, all of the analogous intermediate compounds suitable as starting materials for the preparation of the compounds described in Example 24 were prepared.

  
EXAMPLE 26

  
Under a nitrogen atmosphere and in an anhydrous apparatus, a mixture of 2.02 g of morpholin-3-one in 60 ml of anhydrous tetrahydrofuran was stirred. 26.7 ml of 15% butyllithium in hexane were then added dropwise at room temperature over 45 minutes. After 2.5 hours of stirring at room temperature,

  
 <EMI ID = 295.1>

  
of freshly distilled benzaldehyde in 10 ml of anhydrous tetrahydrofuran over 45 minutes. The mixture was kept at -62 [deg.] C for 3 hours, left at temperature.

  
 <EMI ID = 296.1>

  
held at this temperature for an additional 16 hours.

  
A little water was added and everything evaporated to dryness. The residue was taken up with a dilute solution of

  
 <EMI ID = 297.1>

  
filtered and evaporated to dryness. The solid residue was ground with 40 ml of ethyl ether and the mixture was filtered, so as to obtain 2.4 g of 2- (α-hydroxy-benzyl) -morpholin-3-one as the the product was crystallized from ethyl acetate, the product then having a melting point of 130-140 [deg.] C, yield: 58.0%.

  

 <EMI ID = 298.1>


  
Similarly, all suitable intermediates were prepared as starting materials for the preparation of the compounds of Example 25.

  
EXAMPLE 27

  
 <EMI ID = 299.1>

  
in 70 ml of anhydrous tetrahydrofuran. After the addition,

  
&#65533;

  
 <EMI ID = 300.1>

  
 <EMI ID = 301.1>

  
 <EMI ID = 302.1>

  
to dryness. The residue was dissolved in ethyl ether;

  
 <EMI ID = 303.1>

  
with 20% NaOH and back-extracted with ethyl ether. The solution was then washed with water, it was

  
dried over Na2SO4, filtered and evaporated to dryness.

  
A small amount of isopropyl ether was then used to grind the residue to obtain 2-hydroxy-3- (2-

  
 <EMI ID = 304.1>

  
Similarly, all the primary amines suitable for the preparation of the N-methyl derivatives indicated in Examples 1 and 2 were prepared.

  
 <EMI ID = 305.1>

  
EXAMPLE 28 a) To a suspension of 6 g of (2-methoxyphenoxy) -phenylacetic acid in 50 ml of tetrahydrofuran <EMI ID = 306.1>

  
of anhydrous tetrahydrofuran. The whole was heated under reflux for 1 hour. This solution was used as it is in b).

  
b) Under a nitrogen atmosphere, washed three times <EMI ID = 307.1>

  
anhydrous. The whole was covered with 40 ml of anhydrous tetrahydrofuran and 5.7 ml of nitromethane were added dropwise with stirring. After 15 min, we added

  
solution a) to this suspension, over 10 min. It was heated under reflux for 16 hours, cooled

  
and we filtered it. The solid which was the product was washed

  
 <EMI ID = 308.1>

  
dryness, taking up with ethanol at 99 [deg.] hot, then the whole was allowed to cool to room temperature and then filtration was carried out. There was thus obtained 4.1 g of the sodium salt of 2-hydroxy-1-nitro-3-phenyl-3- (2-

  
 <EMI ID = 309.1>

  

 <EMI ID = 310.1>
 

  
Similarly, all the nitro derivatives suitable for the synthesis of the 2-hydroxy-propylamines obtained according to Example 27 were prepared.

  
EXAMPLE 29

  
A solution of 1 g of the sodium salt of

  
 <EMI ID = 311.1>

  
a yield of 92%.

  
Similarly, the compounds obtained according to Example 28 could be methylated.

  
EXAMPLE 30

  
25.6 g of 3- (2-methoxy- 1,2-oxide was dissolved

  
 <EMI ID = 312.1>

  
heated to 120 [deg.] C for 8 hours, excess benzylamine was distilled off and the rest poured into water; the aqueous solution was extracted four times with diethyl ether to make a total of 1000 ml, then washed with a full amount of water and the diethyl ether evaporated to dryness so as to obtain 25.2 g (69.4%) of N-benzyl-2-hydroxy-3- (2-methoxyphenoxy) -3-phenyl-propylamine in the form of a colorless oil.

  
Similarly, all of the primary and secondary 2-hydroxy-propylamines shown in Examples 1, 3 and 4 were prepared.

  
EXAMPLE 31

  
Has a solution of 2.4 g of 3- (2-methoxy-phenoxy) -

  
 <EMI ID = 313.1>

  
room and kept under stirring for approximately 2 hours. M-Chlorobenzoic acid was filtered off, the organic layer was washed with

  
 <EMI ID = 314.1>

  
organic phase over Na2SO4 and evaporated to dryness to obtain 1.6 g (62.5%) of 1,2-oxide.

  
 <EMI ID = 315.1>

  
Similarly, all the 1,2-propylene oxide derivatives suitable for the preparation of the 2-hydroxy-propylamines of Example 30 were prepared.

  
EXAMPLE 32

  
To a solution of 5 g of the sodium salt of guaiacol in 60 ml of dimethylformamide was added 1-phenylallyl chloride (5.22 g) (J.C.S. 1959, p. 2720), under a nitrogen atmosphere. The whole was stirred for 4 hours at room temperature and for 2 hours at 50 [deg.] C, poured into water and extracted with ethyl ether. After conventional treatment, followed by chromatographic separation, 3- (2-methoxy-phenoxy) -3-phenyl-propylene was obtained.
(8.1 g; 98%).

  
In an analogous manner, the propylene derivatives suitable for the preparation of the compounds indicated in Example 31 were prepared.

  
EXAMPLE 33

  
 <EMI ID = 316.1>

  
anhydrous tetrahydrofuran, added dropwise and

  
 <EMI ID = 317.1>

  
MeOH at room temperature and then dropwise addition to the reaction mixture of 50 ml.

  
23% HCl and then stirring for 1 hour

  
 <EMI ID = 318.1>

  
diluted the residue with water, then basifying with NaOH and extracting with CH2Cl2. After normal processing and crystallization from

  
 <EMI ID = 319.1>

  

 <EMI ID = 320.1>


  
Similarly, the morpholine-5-one derivatives obtained in Examples 36, 37 and 38 and all the morpholin-5-one derivatives corresponding to the compounds of Examples 17, 19 and 20 were reduced to corresponding morpholines. EXAMPLE 34

  
3.5 g of 50% NaH in an oil was added.

  
 <EMI ID = 321.1>

  
phenyl-3- (2-nitro-phenoxy) -propylamine dissolved in 300 ml <EMI ID = 322.1>

  
let stand for 16 hours, then poured into

  
2 liters of water so that a brown solid separated which was filtered off and purified by mixing with boiling 95% ethanol. 18 g was thus obtained (yield

  
 <EMI ID = 323.1>

  

 <EMI ID = 324.1>


  
The morpholine-5-one derivatives corresponding to the compounds of Examples 17 were prepared in a similar manner,
19 and 20.

EXAMPLE

  
To 55 g of N-methyl-2-hydroxy-3phenyl-3- (2-nitro-phenoxy) -propylamine hydrochloride, dissolved in 770 ml of distilled water, was added, at room temperature,

  
 <EMI ID = 325.1>

  
16.7 ml of chloroacetyl chloride dissolved in 350 ml of anhydrous CH2C12. The solution was stirred at room temperature for 3 hours. The organic phase was separated and washed with aqueous bicarbonate solution, then with saturated NaCl solution, then dried and evaporated to dryness. There was thus obtained 60 g (yield

  
 <EMI ID = 326.1>

  
(2-nitro-phenoxy) -propylamine.

  

 <EMI ID = 327.1>
 

  
Similarly, analogous intermediates suitable for the preparation of

  
 <EMI ID = 328.1>

  
EXAMPLE 36

  
 <EMI ID = 329.1>

  
formamide, charcoal supporting 5% palladium (0.7 g) was added and the mixture hydrogenated under

  
 <EMI ID = 330.1>

  

 <EMI ID = 331.1>


  
 <EMI ID = 332.1>

  
extraction was carried out with ethyl acetate under cold conditions; the organic phase was washed until neutrality with saturated aqueous NaCl solution, it was

  
 <EMI ID = 333.1> dryness. There was thus obtained a yellow oil which was separated by column chromatography on silica gel (phase: ethyl acetate / cyclohexane 2: 1). We thus obtained 6 g

  
 <EMI ID = 334.1>

  
methyl-morpholine-5-one.

  

 <EMI ID = 335.1>


  
EXAMPLE 32

  
4.8 g of potassium carbonate was added to a

  
 <EMI ID = 336.1>

  
morphcline-5-one in 150 ml of anhydrous dimethylformamide and

  
 <EMI ID = 337.1>

  
 <EMI ID = 338.1>

  
restlessness. The mixture was poured into 1.5 liters of water and extracted with ethyl acetate. The organic extracts were washed with water, dried over Na2SO4 and concentrated under reduced pressure. We thus have

  
 <EMI ID = 339.1>

  
(1.9 g) in 35 ml of tetrahydrofuran. The mixture was heated to reflux with stirring for 6 hours. We have in-

  
 <EMI ID = 340.1> <EMI ID = 341.1>

  
 <EMI ID = 342.1>

  
 <EMI ID = 343.1>

  
The combined filtrates were evaporated to dryness under reduced pressure. The residue was taken up in ethyl ether and

  
 <EMI ID = 344.1>

  
The amorphous hydrochloride precipitated and the product in question was washed several times with fresh ethyl ether.

  
 <EMI ID = 345.1>

  

 <EMI ID = 346.1>


  
Similarly, all of the compounds mentioned in Examples 17, 19 and 20 were prepared with the exception of the chlorinated derivatives. We realized the same reaction as that

  
described in Example 39 with diborane using the process of Example 20: in this way all of the compounds mentioned in Examples 17, 19 and 20. EXAMPLE 40 were also prepared.

  
 <EMI ID = 347.1>

  
ethyl phenyl-3- (2-methoxyphenoxy) -propionate, dissolved in
30 ml of ethanol, in an autoclave, at 150 [deg.] C, for 20 hours

  
 <EMI ID = 348.1>

  
The mixture was allowed to cool and the solvent was removed under reduced pressure. The residue was crystallized from

  
 <EMI ID = 349.1>

  
Yield: 64 96.

  

 <EMI ID = 350.1>
 

  
Analogously, morpholine-3,5-dione derivatives suitable as intermediates for the preparation of the compounds of Example 39 were prepared.

  
EXAMPLE 41

  
A solution of 3.85 g of 2-hydroxy-3- was heated.

  
 <EMI ID = 351.1>

  
with 5.34 ml of ethyl bromacetate and 3.2 g of anhydrous potassium carbonate. The mixture was then poured into water, extracted with ethyl acetate, and the organic extracts were washed until neutral with water, then extracted.

  
a dehydrated, concentrated under reduced pressure and the residue thus obtained was chromatographed on silica gel
(phase: ethyl acetate / cyclohexane 1: 1), so as to obtain

  
 <EMI ID = 352.1>

  
ethyl phenoxy) -propionate with a yield of 67%.

  

 <EMI ID = 353.1>


  
Similarly, analogous intermediates suitable for the preparation of

  
compounds of Example 40. EXAMPLE 42

  
 <EMI ID = 354.1>

  
 <EMI ID = 355.1>

  
of anhydrous tetrahydrofuran, this solution being cooled to 10 [deg.] C under a nitrogen atmosphere, was slowly added, dropwise and with stirring, 15 ml of a molar solution of diborane in tetrahydrofuran. The mixture was then stirred at room temperature for 16 hours, <EMI ID = 356.1>

  
purified the residue by dissolving it in 3% HCl, basifying with sodium bicarbonate and extracting with ethyl ether.

  
The whole was evaporated to dryness so as to obtain 2.8 g of an oil which was dissolved in 30 ml of

  
 <EMI ID = 357.1>

  
naked at reflux for 4 hours. After cooling to

  
 <EMI ID = 358.1>

  
cautiously decomposed the reaction mixture with HCl

  
at 3%; the tetrahydrofuran was removed in vacuo at room temperature!

  
 <EMI ID = 359.1>

  
times with ethyl ether, then basified with NaHCO3 and back-extracted with ethyl ether. The organic phase was washed with water, dried over

  
 <EMI ID = 360.1>

  
crystallized from isopropanol and a small amount of ethyl ether. There was thus obtained 2.2 g of hydrochloride

  
 <EMI ID = 361.1>

  
BCOOH - 160/30/20), thus obtaining two distinct diastereomers having respective boiling points of

  
 <EMI ID = 362.1>

  
 <EMI ID = 363.1>

  
Similarly, all the morpholines unsubstituted in position 4 mentioned in Example 20 were prepared.

  
EXAMPLE 43

  
2.69 g of 2-hydroxy-3-phenyl-.3- (2-methoxyphenoxy) -propionitrile was stirred in 25 ml of anhydrous dimethylacetamide with 6.68 g of ethyl bromacetate in the presence of 2.76 g of anhydrous potassium carbonate. The mixture was heated at 50 [deg.] C for 16 hours, poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and concentrated to dryness to obtain 3.55 g of 2-ethoxycarbonyl-.

  
 <EMI ID = 364.1>

  
yield: 100%), which was used as it was for the reaction described in the previous example.

  
Analogously, the 2-ethoxycarbonylmethyloxy-propionitriles suitable as intermediates for the synthesis of the compounds described in Example 42 were prepared.

  
EXAMPLE 44

  
 <EMI ID = 365.1>

  
35 ml of anhydrous tetrahydrofuran, with stirring, over approximately 2 hours. After the addition, the mixture was refluxed for 2 hours, cooled and treated with water, then with 15% sodium hydroxide and then.

  
again with water. After filtration, the solid was washed with tetrahydrofuran and the solvent was evaporated to.

  
 <EMI ID = 366.1>

  
 <EMI ID = 367.1>

  
ethyl as a solvent. The residual oil was converted from the concentration to the hydrochloride which was crystallized at

  
 <EMI ID = 368.1>

  
 <EMI ID = 369.1>

  
with respective melting points of 211-214 [deg.] C and

  
175-178 [deg.] C.

  
Analogously, all the morpholines unsubstituted in position mentioned in Example 20 were prepared,

  
with the exception of chlorinated compounds.

  
EXAMPLE 45

  
 <EMI ID = 370.1>

  
mixing at room temperature for 48 hours. The mixture was poured into water and extracted with ethyl acetate. The organic extracts were washed with water,

  
they were dried over Na2SO4 and concentrated to dryness. The residue was separated by column chromatography.

  
 <EMI ID = 371.1>

  
(oil). Yield: 70%.

  
Analogously, all the nitro-propene-type derivatives suitable as intermediates for the preparation of the compounds of Example 44 were prepared.

  
EXAMPLE 46

  
3.35 g of N- (2-chloro-ethyl) -2-hydroxy- was dissolved

  
 <EMI ID = 372.1>

  
To the mixture, dropwise added 6.07 ml of 15% butyllithium in hexane. After approximately

  
2 hours at -10 [deg.] C, the temperature was allowed to slowly return to room temperature and the whole was stirred for

  
 <EMI ID = 373.1>

  
concentrated to dryness. The residue was dissolved in ethyl ether, filtered, and the filtrate was again concentrated to dryness. The residue was converted to the hydrochloride by treatment with HCl gas in ethyl ether. After crystallization from a mixture of isopropanol and a very small amount of ethyl ether,

  
 <EMI ID = 374.1>

  
isomers. By chromatographic separation, carried out as described in Examples 42 and 44, two distinct cliastereoisomers were obtained having melting points of 211-214 [deg.] C and 175-178 [deg.] C respectively.

  
Analogously, all of the compounds mentioned in Examples 17, 19 and 20 were prepared.

  
EXAMPLE 47

  
Has a solution of N-chloro-acety.l-3-phenyl-2-

  
 <EMI ID = 375.1>

  
Anhydrous tetrahydrofuran (35 ml), slowly added,

  
 <EMI ID = 376.1>

  
 <EMI ID = 377.1>

  
again stirred the mixture under cold conditions for 2 hours and then for 16 hours at room temperature. The mixture was carefully decomposed with a small amount of 990 ethanol and used. concentrated it

  
 <EMI ID = 378.1>

  
phenoxy) -propylamine (3.35 g; 100%) (oil).

  
The product as such was immediately used to carry out the conversion described in the previous example.

  
Analogously, all the N- (2-chlorethyl) -propylamines serving as intermediates for the preparation of the compounds described in Example 46 were prepared. EXAMPLE 43

  
A mixture of 2.73 g of 3-phenyl-2-hydroxy- was stirred.

  
 <EMI ID = 379.1>

  
of chloroacetyl chloride in 2 ml of methylene chloride.

  
 <EMI ID = 380.1> and evaporated to dryness. We thus obtained. 3.49 g

  
 <EMI ID = 381.1>

  
Analogously, all suitable internals were prepared as starting materials for the preparation of the compounds of Example 47.

  
EXAMPLE 49

  
 <EMI ID = 382.1>

  
and vigorous stirring, one then proceeded to the dropwise addition to the suspension of 3.65 ml of butyl-lithium at

  
 <EMI ID = 383.1>

  
2 hours and then at room temperature for 20 hours. A few drops of water were carefully added to the mixture which was then evaporated to dryness. A small amount of water was added to the residue and then the whole was extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and followed. evaporated it to dryness. The residue dissolved in

  
 <EMI ID = 384.1>

  
alcoholic acid and, after two crystallizations from a mixture of isopropanol and a: small amount of ethyl ether, we have

  
 <EMI ID = 385.1>

  
line having a melting point of 140-170 ° C. Denial:
49.4%.

  
Analogously, all of the compounds mentioned in Examples 17, 19 and 20 were prepared.

  
EXAMPLE 50

  
 <EMI ID = 386.1>

  
 <EMI ID = 387.1>

  
(150 mL), 55% NaH (1.75 g) was added at room temperature. After stirring for 1 hour, a solution of 2-chloro-1-iodo-ethane (7 g) in dimethylformamide (50 ml) was added all at once. We kept the temperature

  
 <EMI ID = 388.1>

  
 <EMI ID = 389.1>

  
traction with ethyl acetate. After a classical treatment

  
 <EMI ID = 390.1>

  
All of the compounds mentioned in Examples 17, 19 and 20 were prepared in a similar manner.

  
EXAMPLE 51

  
 <EMI ID = 391.1>

  
morpholine dissolved in 30 ml of acetonitrile, 4 ml of a 37% aqueous solution of formaldehyde was added and then 1 g

  
of NaBH3CN. The whole was stirred for 30 min at room temperature and then glacial acetic acid was added until neutral. The mixture was stirred for 3 hours at

  
Room temperature. The solvent was removed in vacuo,

  
 <EMI ID = 392.1>

  
The chloroform solution was washed with water until

  
 <EMI ID = 393.1>

  
scaled down. The residual oil was taken up in ethanol to which 2 ml of an 18% alcoholic HCl solution had been added.

  
Dilution with ethyl ether caused precipitation.

  
 <EMI ID = 394.1>

  
0.7 g of charcoal supporting 5% palladium was added and the mixture was hydrogenated at 2.5 atm for 0.5 hour. The catalyst was filtered off, the solution was evaporated to dryness and the residual oil was converted to the hydrochloride with an alcoholic HCl solution. Crystallization from a mixture of ethyl acetate and ethanol gave 5.1 g

  
 <EMI ID = 395.1>

  
dropwise and at room temperature, 1 ml of methyl iodide. After the addition, the whole was stirred for

  
 <EMI ID = 396.1>

  
cold and the whole was extracted with ethyl acetate. After washing with saturated aqueous NaCl solution and drying with sodium sulfate, the ethereal extracts were concentrated to a small volume. To the residue was added an 18% alcoholic solution of HCl, so as to <EMI ID = 397.1>

  
76%).

  

 <EMI ID = 398.1>


  
EXAMPLE 54

  
 <EMI ID = 399.1>

  
stirring, a solution of 3.45 g of sodium nitrite in
20 ml of water. After 20 min, the temperature was allowed to rise to room temperature. We heated everything in

  
 <EMI ID = 400.1>

  
nitrogen. The extraction was carried out with chloroform in order to adjust the pH to 9. The organic extracts were dried and evaporated to dryness and the residue was dissolved in

  
 <EMI ID = 401.1>

  
20% HCl nol. Dilution with a small amount of ethyl ether caused precipitation of the hydrochloride

  
 <EMI ID = 402.1>

  

 <EMI ID = 403.1>


  
EXAMPLE 55

  
 <EMI ID = 404.1>

  
Methyl morpholine dissolved in 70 ml of dry toluene, 3 ml of ethyl chlorocarbonate was added and the mixture was heated under reflux for 24 hours. It was then evaporated to dryness and there was thus obtained 5.9 g of an oil which was taken up with 15 ml of an aqueous alcoholic solution.

  
 <EMI ID = 405.1>

  
4 hours. After evaporating to dryness, the

  
 <EMI ID = 406.1>

  
ethyl ether .. After washing with saturated solution

  
 <EMI ID = 407.1>

  
Yield: 68%.

  

 <EMI ID = 408.1>


  
The compounds of Example 20 were prepared in a similar manner.

  
EXAMPLE 56

  
 <EMI ID = 409.1>

  
99% (150 ml) and HCl (6 ml) (catalyst consisting of charcoal supporting palladium), for 4 hours, at room temperature. The mixture was then filtered, dried in vacuo and separated on a column of.

  
 <EMI ID = 410.1>

  
Analogously, the morpholine derivatives mentioned in Example 20 were prepared, except for

  
 <EMI ID = 411.1>

  
EXAMPLE 57

  
 <EMI ID = 412.1>

  
(70 mL) with ethyl chloroformate (1.23 mL) at reflux for 5 hours. The solvent was evaporated and heated

  
the residue at reflux for 2 days with a 10% solution

  
of KOH (70 mL) in methanol. The whole was evaporated to dryness and the residue was partitioned between ethyl ether and water. The water was extracted with fresh ether. Acid-base purification was performed using ether

  
as an extraction solvent. Drying over Na2SO4, the wire

  
 <EMI ID = 413.1>

  
Similarly, all of the compounds listed in Example 20 could be prepared.

  
 <EMI ID = 414.1>

  
 <EMI ID = 415.1>

  
dissolved in 100 ml of anhydrous ethyl ether and 30 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred for 2 days at room temperature and allowed to

  
 <EMI ID = 416.1> the filtrate on Na2SO4 and then brought to complete dryness in vacuo, thereby obtaining

  
 <EMI ID = 417.1>

  
compounds of Examples 17, 19 and 20, with the exception of the chlorinated derivatives.

  
EXAMPLE 59

  
 <EMI ID = 418.1>

  
(60ml), NaOH (0.6g) and water (16ml) were added,

  
at 0 [deg.] C. The whole was cooled to -50 [deg.] C and chloroacetyl chloride (1.1 ml) diluted in CH 2 Cl 2 (10 ml) was added dropwise. The organic extracts were combined and washed with saturated NaCl solution,

  
 <EMI ID = 419.1>

  
amine (4.0 g; yield: 93%) as an oil, chromatographically pure, which was used as it was.

  
2.5 g of this product was dissolved in dimethyl sulfoxide (10 mL) and then 55% NaH was added.
(0.275 g). After 1.5 hours at room temperature, we have

  
 <EMI ID = 420.1>

  
ethyl.

  
The organic extract was washed several times with

  
 <EMI ID = 421.1> <EMI ID = 422.1>

  
94%).

  
Similarly, 4-benzyl-

  
 <EMI ID = 423.1>

  
4-benzyl derivatives suitable for the preparation of the compounds of Example 20, in accordance with the procedure described in Examples 56 and 57.

  
: EXAMPLE 60 <EMI ID = 424.1> A solution of NaOH (1.3 g) and water (40 ml) was added dropwise. Benzoyl chloride (3.6 ml), dissolved in sodium chloride, was then added dropwise.

  
 <EMI ID = 425.1>

  
separated the organic layer and the aqueous phase was extracted with CH2Cl2; the combined organic extracts were washed with saturated aqueous NaCl solution, followed by a

  
 <EMI ID = 426.1>

  
yield: 98%) as an oil.

  
b) To a solution of LiAlH4 (16.3 g) in anhydrous ethyl ether (1000 ml) was added a solution of the oil obtained by carrying out the process described in a) of the present example (8 , 1 g) in anhydrous ethyl ether
(1500 ml) and kept under reflux for 12 hours. After normal treatment and acid-base purification with ethyl ether as a solvent and after evaporating to dryness, N-benzylamino-2-hydroxy-3- was obtained.

  
 <EMI ID = 427.1>

  
45%) in the form of a mixture of diastereoisomers (colorless oil).,

  
 <EMI ID = 428.1>

  
also the derivatives of the N-benzylamino type suitable for the preparation of the compounds of Example 59.

  
EXAMPLE 61

  
Tablets, each weighing 200 mg and each containing 25 mg of active ingredient, were prepared as described below:

  

 <EMI ID = 429.1>


  
 <EMI ID = 430.1>

  
the lactose and half of the corn starch were mixed, sifted through a 0.55mm mesh sieve. We dispersed
30 g of corn starch in 300 ml of water. The mixture of powders was granulated with the obtained starch mucilage. We dried

  
the granule and passed through a 1.4 mm mesh screen. The rest of the starch was added, as well as the

  
talc and magnesium stearate. Thorough mixing was carried out and the mass was compressed into tablets using punches with a diameter of 8 mm.

  
EXAMPLE 62

  
Tablets, each weighing 200 mg and each containing 25 mg of active ingredient were prepared:
Composition (for 10,000 tablets)

  
 <EMI ID = 431.1>

  

 <EMI ID = 432.1>


  
The tablets were prepared as described in Example 61.


    

Claims (1)

1. Compounds corresponding to the structural formula general (I) following: <EMI ID = 433.1> where: <EMI ID = 434.1> <EMI ID = 435.1> optionally substituted C1-C12, or an aryl-C1-C6 alkyl radical; <EMI ID = 436.1> or different, represents a hydrogen atom, a group <EMI ID = 437.1> or else R3 and R4, together with the nitrogen atom to which they are attached, form a heteromonocyclic, pentatomic or hexatomic radical, saturated or unsaturated, optionally substituted. <EMI ID = 438.1> in the class formed by the atoms of oxygen, sulfur and nitrogen; <EMI ID = 439.1> as well as their pharmaceutically acceptable salts. 2. Compounds corresponding to formula (I) as defined in claim 1, in which n and <EMI ID = 440.1> <EMI ID = 441.1> a methoxy or ethoxy radical, chlorine, a trifluoromethyl group, or two neighboring R groups form a radical -0-CH2-0-; R2 represents a hydrogen atom or the radical <EMI ID = 442.1> hydrogen, while the other represents the methyl radical, as well as their pharmaceutically acceptable salts. 3.such as <EMI ID = 443.1> <EMI ID = 444.1> <EMI ID = 445.1> a methoxy or ethoxy radical, a chlorine atom, a trifluoromethyl group, or else two neighboring R groups form <EMI ID = 446.1> <EMI ID = 447.1> of hydrogen, the methyl or isopropyl radical, as well as their pharmaceutically acceptable salts. compounds selected from the group formed by the following substances: <EMI ID = 448.1> <EMI ID = 449.1> as well as their pharmaceutically acceptable salts. 5. Compounds selected from the group formed by the following substances: <EMI ID = 450.1> as also their pharmaceutically acceptable salts. 6. Compounds selected from the group formed by the following substances: <EMI ID = 451.1> as also their pharmaceutically acceptable salts. 7. Compounds selected from the group consisting of the following substances: <EMI ID = 452.1> as also their pharmaceutically acceptable salts. 8. Compounds selected from the group consisting of the following substances; <EMI ID = 453.1> <EMI ID = 454.1> 9. A process for preparing a compound according to any one of the preceding claims, characterized in that- : a) reducing a compound of formula (II) <EMI ID = 455.1> in which <EMI ID = 456.1> of claim 1: how to obtain -compounds- of <EMI ID = 457.1> <EMI ID = 458.1> meanings previously indicated; or b) reducing a compound of formula (III) <EMI ID = 459.1> <EMI ID = 460.1> fications indicated in claim 1; or c) reducing a compound of formula (IV) <EMI ID = 461.1> <EMI ID = 462.1> as indicated and R and R, have the pre- <EMI ID = 463.1> of such a compound, so as to obtain compounds of formula (I) in which n, .il and R2 have the meanings <EMI ID = 464.1> <EMI ID = 465.1> d) reacting a compound of formula (V) <EMI ID = 466.1> <EMI ID = 467.1> <EMI ID = 468.1> <EMI ID = 469.1> indicated, so as to obtain compounds of formula (I) <EMI ID = 470.1> <EMI ID = 471.1> a <EMI ID = 472.1> e) reducing a compound of formula (VI) <EMI ID = 473.1> <EMI ID = 474.1> previously indicated; or f) a compound of formula (VII) is reductively cyclized <EMI ID = 475.1> <EMI ID = 476.1> <EMI ID = 477.1> however the other of these symbols represents a group <EMI ID = 478.1> have the meanings previously indicated, <EMI ID = 479.1> g) a compound of formula (VIII) is cyclized <EMI ID = 480.1> <EMI ID = 481.1> tions indicated above and X represents a hydroxyl group or a halogen atom or the residue of a reactive ester of an alcohol, so as to obtain compounds of formula (I) in which R2 and R4, taken together, <EMI ID = 482.1> the meanings indicated above; or h) a compound of formula (IX) is reacted <EMI ID = 483.1> <EMI ID = 484.1> previously indicated tions &#65533; on a compound of the formula (X) <EMI ID = 485.1> in which each of the groups Y, whether they are identical or different, represents a halogen atom or the residue of a reactive ester of an alcohol, so as to obtain compounds of the formula (I) in which R2 and R4, consider <EMI ID = 486.1> <EMI ID = 487.1> and, if desired, converting a compound of formula (I) to another compound of formula (I) and / or, if desired, salifying a compound of formula (I) or a free compound is obtained from a salt and / or, if desired, a mixture of isomers is resolved into the individual isomers. 10. Pharmaceutical compositions, characterized in that they contain at least one compound according to any one of claims 1 to 8 and a pharmaceutically acceptable diluent and / or excipient.