FR2518087A2 - Aminoalkyl di:hydro-naphthalene, isoquinoline and benzoxazepine cpds. - useful as analgesics and antidepressants - Google Patents

Abstract

Aminoheterocycles of formula (I) and their acid addition salts are new (n is 1-3, A is nitrogen or CH. X is methylene, or provided A is not CH, also methyleneoxy. When A is CH, R is phenyl opt. 2-fluoro substd. and when A is N, R is phenyl (opt. substd. by halo, nitro, 1-4C alkyl or alkoxy, or trifluoromethyl), pyridyl or cyclohexyl. NR1R2 is amino or methylamino (but not when X is CH2O or when A is N, X is CH2 and n is 1), di(1-4C) alkylamino, pyrrolidino, piperidino, morpholino or 4-methylpiperazino. When A is CH, R3 is H and when A is N, R3 is H, halo, 1-4C alkyl or alkoxy or represents two methoxy gps.). (I) have CNS, esp. analgesic and antidepressant activities. Cpds. tested had acute intraperitoneal LD50 in mice 35-170 mg. per kg. and analgesic ED50 (phenylbenzoquinone test) of 1-30mg. per kg. About 60 cpds. e.g. where A is N or CH and X is CH2 or where A is N and X is CH2O; R1R2N is dimethylamino; n is 1 or 2; R is phenyl and R3 is H are specifically claimed.

Description

dans laquelle
- l'enchaînement Ao#Bo représente l'un quelconque des motifs suivants
C-CH, C-N, CH-NH, CH-N-COOEt ;
- Xo représente soit le groupe méthylène (-CH2-), soit le groupe méthylène
oxy (-CH2-0-), l'enchaînement Ao#Bo ne pouvant toutefois dans ce
dernier cas représenter le motif C=CH ;;
-Ro représente soit un groupe phényle, soit, à l'exception du cas où
Ao#Bo représente le motif C=CH, un groupe pyridinique, cyclohexyle
ou phényle substitué par un atome d'halogène, un groupe nitro, un grou
pe alkyle comportant de 1 à 4 atomes de carbone, ou un groupe alkyloxy
comportant de I à 4 atomes de carbone

représente un groupe choisi parmiles suivants : amino, methy
lamino, N, N-dialkylamino dont les groupes allyle comportent chacun de 1 4 atomes de carbone, pyrrolidono, piperidino, morpholino,
(méthyl-4)pipérazino ;NRo1Ro2 ne pouvant toutefois prendre la valeur
amino ou méthylamino quand Ao#Bo represente le motif C=CH, quand
Xo = CH2O ou quand nO = l ; R3 represente :
. soit un atome d'hydrogène,
. soit un atome d'halogene, un groupe alkyle comportant de I a 4
atomes de carbone, un groupe alkyloxy comportant de 1 à 4 atomes
de carbone ou deux groupes methoxy, RO ne pouvant toutefois être
situé en position 8 quand Xo=-CH2- et l'enchaînement Ao#Bo
représente le motif C=CH, C=N ou CH-NH, et en position 9 quand
X=-CH2O- et l'enchaînement Ao#Bo represente le motif C=N ou
CH-NH ; et - n0 prend la valeur 1, 2 ou 3. The main patent application No. 80 27252 relates in particular to new 3,4-dihydro-naphthalene and 3,4-dihydro-isoquinoline derivatives, substituted at the 3-position with an aminoalkyl chain, corresponding to the formula

in which
the sequence Ao # Bo represents any one of the following patterns
C-CH, CN, CH-NH, CH-N-COOEt;
Xo represents either the methylene group (-CH2-) or the methylene group
oxy (-CH2-0-), the sequence Ao # Bo can not however in this
last case represent the C = CH;
-Ro represents either a phenyl group or, with the exception of the case where
Ao # Bo represents the C = CH unit, a pyridine group, cyclohexyl
or phenyl substituted by a halogen atom, a nitro group, a grou
alkyl having 1 to 4 carbon atoms, or an alkyloxy group
having 1 to 4 carbon atoms

represents a group chosen from the following: amino, methy
lamino, N, N-dialkylamino, the allyl groups of which each have 14 carbon atoms, pyrrolidone, piperidino, morpholino,
(methyl-4) piperazino, NRo1Ro2 can not however take the value
amino or methylamino when Ao # Bo represents the C = CH motif, when
Xo = CH2O or when nO = 1; R3 represents:
. either a hydrogen atom,
. a halogen atom, an alkyl group having from 1 to 4
carbon atoms, an alkyloxy group having 1 to 4 atoms
of carbon or two methoxy groups, RO can not, however, be
in position 8 when Xo = -CH2- and the sequence Ao # Bo
represents the C = CH, C = N or CH-NH unit, and in position 9 when
X = -CH2O- and the sequence Ao # Bo represents the pattern C = N or
CH-NH; and - n0 is 1, 2 or 3.

dans laquelle l'enchaînement A = B represente
- soit le motif C - CH,auquel cas R1-R2-CH3, R3 = H et le couple
(R,n) prend l'une quelconque des valeurs suivantes : (phenyle, 3)
(o-fluorophényle, 1), (o-fluorophényle, 2), (o-fluorophényle, 3),
- soit le motif C - N, auquel cas
R1 = R2 = CH3 et l'ensemble (n,R,R3) - (2, phényle, 7-CH3)
(2, o-CF3 phenyle, H) , (2, m-CF3 phényle, H) , (2, phenyle 6,7 - diOCH3) ou

. R1 =R2=C2H5 et l'ensemble (n, R,R3) s (1, phenyle, 7-CH3), . R1 et R2 forment coniointement avec l'atome d'azote auquel ils sont lies, un radial

auquel cas l'ensemble
(n,R,R3) = (1, phenyle, 5-C1), (1, phenyle, 7-CH3)
(1, phényle, 7-OCH3), (2, phenyle, 5-Cl) ou(2, phényle, 7-OCH3),
ou R R et R. forment conjointement avec l'atome d'azote auquel ils sont lies un radical

The subject of the present invention is new derivatives belonging to the family of 3,4-dihydro-naphthalenes and 3,4-dihydroisoquinolines, subsitute in the 3-position by an aminoalkyl chain. These new derivatives have a skeleton identical to that of the derivatives of formula (Io) and more precisely correspond to the general formula:

in which the sequence A = B represents
or the C-CH motif, in which case R1-R2-CH3, R3 = H and the pair
(R, n) takes any of the following values: (phenyl, 3)
(o-fluorophenyl, 1), (o-fluorophenyl, 2), (o-fluorophenyl, 3),
- the C-N pattern, in which case
R1 = R2 = CH3 and the group (n, R, R3) - (2, phenyl, 7-CH3)
(2, o-CF 3 phenyl, H), (2, m-CF 3 phenyl, H), (2, phenyl 6,7-diOCH 3) or

. R1 = R2 = C2H5 and the group (n, R, R3) s (1, phenyl, 7-CH3),. R1 and R2 form together with the nitrogen atom to which they are attached, a radial

in which case the whole
(n, R, R3) = (1, phenyl, 5-Cl), (1, phenyl, 7-CH3)
(1, phenyl, 7-OCH3), (2, phenyl, 5-Cl) or (2, phenyl, 7-OCH3),
or RR and R. together with the nitrogen atom to which they are attached form a radical

 the group (n, R, R3) = (1, phenyl, 7-CH3).

Like the main patent application, the present addition also relates to the pharmaceutically acceptable mineral or organic acid addition salts of the compounds of formula (I).

 In addition, the present invention relates to processes for the preparation of the compounds of formula (I), the methods set out below.

dans laquelle le couple (@@ n) = (phényle, 3) (o-fluorophényle, 2) , (o-fluorophényle, 3).A / The compounds (I) for which the sequence AB represents the unit
C = CH are obtained by a two-stage synthesis which consists of
densing dimethylamine with the mesylate of the compound of formula

wherein the pair (@@ n) = (phenyl, 3) (o-fluorophenyl, 2), (o-fluorophenyl, 3).

- par condensation du dérive lithium du bromo-l fluoro-2 benzène,
de préférence dans le THF, cespectivement avec les composés de formule

The mesylates of the compounds (II) are for their part obtained by the action of mesyl chloride, in the presence of triethylamine and in methylene chloride medium, on the compounds (II)
The compounds (II) are obtained
by condensation of the lithiated derivative of bromobenzene, preferably
in THF, with the compound of formula

by condensation of the lithium derivative of bromo-1-fluoro-2-benzene,
preferably in THF, with the compounds of the formula

 where n = i, 2 or 3.

où n = 1, 2 ou 3.Compounds (IIIa) and (IIIb) are obtained by the action of tert-butyldimethylsilyl chloride in the presence of imidazole and in dimethylformamide medium, respectively, of compounds of formula:

where n = 1, 2 or 3.

dans laquelle m prend la valeur 0, I ou 2, synthèse qui consiste 1) à traiter les composés (V) par méthanol chlorhydrique en milieu
henzènique et éthanolique, 2) a condenser sur le céto-ester ainsi obtenu, l'éthanedithiol en présence
d'étherate de trifluorure de bore, en solution dans le chlorure de
méthylène, 3) a éduire le groupe @ ^ d.- composé ainsi obtenu, en groune
hydroxyméthyle par l'hydrure double de lithiumet d'aluminiam
dans le T.H.F., et enfin
4) à deproteger la fonction cétone par traitement par l'iodure de
méthyle en milieu méthanolaqueux.Compounds (IV) are obtained by a quantum stad synthesis of the compounds of

in which m takes the value 0, I or 2, which synthesis consists of 1) treating the compounds (V) with hydrochloric methanol in a medium
henzene and ethanol, 2) to condense on the keto ester thus obtained, ethanedithiol in the presence
of boron trifluoride etherate in solution in
methylene, 3) to build the group thus obtained, in group
hydroxymethyl by lithium aluminum lithium hydride
in THF, and finally
4) to deprote the ketone function by treatment with iodide
methyl in methanolacous medium.

dans laquelle R11 et R21 et le couple (n1,R5) ont respectivement la même signification que R1 et R2 et le couple (n, R) dans la formule (I) quand l'enchaînement A=B représente le motif C-N, et R31=4-cH3, H, 3,4-diOCH3, 2-C1 ou 4-OCH3. B / The compounds (I) for which 11 sequence A = B represents
the C = N motif are obtained by cyclisation, preferably by
phosphorus oxychloride and in an inert solvent such as
methylene chloride, for example, compounds of formula:

in which R11 and R21 and the pair (n1, R5) have the same meaning respectively as R1 and R2 and the pair (n, R) in formula (I) when the sequence A = B represents the unit CN, and R31 = 4-cH3, H, 3,4-diOCH3, 2-C1 or 4-OCH3.

- représentent chacun un groupe éthyle auquel cas l'ensemble
(R6, R32) = (phényle, 4-CH3), ou - forment avec l'atome d'azote auquel ils sont liés

The compounds (VI) new, for which nl = 1 are obtained by reduction by lithium hydride double and ahminiam suspended in the rIP compounds of formula

- each represent an ethyl group in which case the whole
(R6, R32) = (phenyl, 4-CH3), or - form with the nitrogen atom to which they are bound

où R6 et R32 ont la même signification que dans (VII), les chlorure d'acides intermédiaires ainsi obtenus était soumis à l'action des amines appropriées de formule

où R12 et R22 ont la même signification que dans (VII).The new compounds (VII) are obtained by the action of phosphorus pentachloride, in solution in ether, on the acids of formula

where R6 and R32 have the same meaning as in (VII), the intermediate acid chloride thus obtained was subjected to the action of the appropriate amines of formula

where R12 and R22 have the same meaning as in (VII).

sur les composes appropriés de formule

dans laquelle
- R13 = R23=CH3 auquel cas R33=4-CH3, H ou 3,4-diOCH39 ou - R13 et R23 forment conjointement avec l'atome d'azote auquel ils sont liés un radical

auquel cas R33=2-Cl ou 4-OCH3.
Les composés (XI) sont obtenus par réduction par l'hydrure double de lithium et d'aluminium des composés de formule

où Rl3, R23 et R33 ont la même signification que dans (XI).The compounds (VI) new, for which nl = 2 are obtained by the action of the acid chloride of formula
R5-CO C1 (X) where R5 = phenyl, o-CF3 phenyl, m-CF3 phenyl or

on the appropriate formula compounds

in which
- R13 = R23 = CH3 in which case R33 = 4-CH3, H or 3,4-diOCH39 or - R13 and R23 form together with the nitrogen atom to which they are bonded a radical

in which case R33 = 2-Cl or 4-OCH3.
Compounds (XI) are obtained by reduction with lithium aluminum hydride of compounds of formula

where R13, R23 and R33 have the same meaning as in (XI).

où R13, R23 et R33 ont la même signification que dans (XII).The compounds (XII) are obtained by reduction with sodium borohydride in

where R13, R23 and R33 have the same meaning as in (XII).

obtenus par hydrolyse acide, en milieu acétonique de préférence, des composés de formule

eux-mêmes obtenus par réaction dite de "BOISSONNAS" des composés de formule

où R13 et R23 ont la même signification que dans (XI), avec les acides correspondants de formule

où R33 a la même signification que dans (XI). The compounds (XIIa) are obtained by condensation, in ethanolic medium, of the ammonia with the compounds of formula

obtained by acid hydrolysis, in acetone medium preferably, compounds of formula

themselves obtained by so-called "BOISSONNAS" reaction of compounds of formula

where R13 and R23 have the same meaning as in (XI), with the corresponding acids of formula

where R33 has the same meaning as in (XI).

où R33 a la même signification que dans (XV).The compounds (XV) result from the saponification of the esters of formula:

where R33 has the same meaning as in (XV).

où R33 a la même signification que dans (XVI). Finally, the esters (XVI) are obtained by reaction of ethylene glycol, in the presence of para-toluenesulphonic acid, on the keto esters of formula

where R33 has the same meaning as in (XVI).

où le couple (R5, R34)=(phéanyle, 7-CH3), (o-CF

(m-CF3 phényle, H) , (phényle, 6,7-diOCH3) , Q (phényle, 5-Cl) ou (phényle, 7-OCH3).
Les composés de formule (XVIII) sont obtenus par action du carbonate de sodium ou de potassium en milieu méthanolique sur tes coms

dans laquelle R5 et R34 ont les mêmes significations que dans
Les composés (XIX) sont @btenus par cyclisation par l'oxychlorure de phosphore, des composés de formule

dans laquelle le couple (R5,R33) = (phényle, 4-CH3) , (o-CF3 phényle, H), (m-CF3 phényle, H) , (phényle, 3,4-diOCH3)

(phényle, 2-Cl) ou (phényle, 4-OCH3).
Les composes (XX) sont obtenus par acétylation des composés de formule

dans laquell e R5 et R33 ont les mêmes significations que dans (XX). C / compounds of formula (I) for which the sequence
A = B represent the pattern C = N and n = 2 can also
be obtained by condensation of the amines of formula (IX ')
with the mesylates of the appropriate alcohols, this alcohols
being of formula

where the pair (R5, R34) = (pheinyl, 7-CH3), (o-CF

(m-CF 3 phenyl, H), (phenyl, 6,7-diOCH 3), Q (phenyl, 5-Cl) or (phenyl, 7-OCH 3).
The compounds of formula (XVIII) are obtained by the action of sodium or potassium carbonate in methanolic medium on your coms

in which R5 and R34 have the same meanings as in
The compounds (XIX) are obtained by cyclization with phosphorus oxychloride, compounds of formula

wherein the pair (R5, R33) = (phenyl, 4-CH3), (o-CF3 phenyl, H), (m-CF3 phenyl, H), (phenyl, 3,4-diOCH3)

(phenyl, 2-Cl) or (phenyl, 4-OCH3).
The compounds (XX) are obtained by acetylation of the compounds of formula

in which R5 and R33 have the same meanings as in (XX).

Finally, compounds (XXI) are obtained by reduction with lithium aluminum hydride, compounds of formula

in which R5 and R33 have the same meanings as in
(XXI).

es composés de formule :
(XXIII) dans laquelle R4 a les mêmes significations que dans (II). D / The compounds (II) for which n has the value 3 can
also be obtained by reduction with lithium hydride and aluminum

compounds of formula:
(XXIII) in which R4 has the same meanings as in (II).

dans laquelle R4 a les mêmes significations que dans (XXIII) et les composés (XXIV) sont obtenus par une synthese en deux stades qui consiste a faire réagir le chlorure de mésyle ,en présence de triéthylamine, respectivement sur les composés de formule

où R4 =phényle ou o-F phényle, en solution dans le chlorure de méthylène, puis a traiter les composés intermédiaires ainsi obtenus par le cyanure de sodium en solution dans le diméthylsulfoxyde.The compounds (xXIII) are obtained by the action of ethanol hydrochloric ethanol on the compounds of formula

in which R4 has the same meanings as in (XXIII) and the compounds (XXIV) are obtained by a two-stage synthesis which consists in reacting mesyl chloride, in the presence of triethylamine, respectively on the compounds of formula

where R4 = phenyl or oF phenyl, in solution in methylene chloride, then treat the intermediate compounds thus obtained with sodium cyanide dissolved in dimethylsulfoxide.

The salts of the compounds of formula (I) will preferably be obtained by the action of inorganic or organic acids in solution in a suitable solvent, on said compounds of formula (I) also in solution in a suitable solvent.

 The following examples are given to illustrate the invention.

Example I: (N, N-dimethylamino-2) ethyl-3-dihydro-3,4-orthofluoro maleate
phenyl naphthalene, (I)
Code number: 101
leer stage: (2-hydroxy) ethyl-3-tetrahydro-1,2,3,4-naphthalene-1-one
[(IV), n = 2]
A solution of 28.3 g of acid is refluxed for eight hours.
(1,2,3,4-tetrahydro-naphthalen-1-yl-3-yl) acetic acid (V) in 150 ml
of ethanol, 30 ml of 7N dilaurric ethanol and 150 ml of benzene. Then we
the solvents are evaporated, the residue is taken up in ether, washed with water, dried over
Sodium sulphate, filter and evaporate the filtrate.On get 38 g (rdt # 100 Z)
(1,2,3,4-tetrahydro-naphthalen-1-yl-3-yl) ethyl ester
acetic acid whose NMR spectrum (CDCl3) has the following characteristics: # ppm -7.8 to 8.1, m (aromatic H at 8); 7.2 to 7.6, m (aromatic H at 5.6 and 7);
4.15, q (COO-CH 2); 2.4 è 3, m (7 H: protons in 2,3,4 and CH2-CO-O-); 1.25,
t (CH3).

2,4 a 2,8, m (protons en 2,3,4 et CH2-CO-O) ; 1,35, t (CH3 lanne est ajouté à une suspension refroidie à 0 C de 3,5 g d'hydrure double de lithium et d'aluminium dans 250 ml de T.H.F. On laisse à 0 c pendant 3 heures, puis on hydrolyse a l'aide de sulfate de sodium humide, filtre et évapore le filtration obtient 24 g (99 %) d'[(hydroxy -2) éthyl-3 tétrahydro-1,2,3,4 yl -1] -2 dithiolane1,3 : Spectre de RMN (CDCl3): # ppm-7,8 à 8,

ique en 8) ; 6,8 à 7,3, m (H aromatiques en 5,6 et 7) ; 3,6, ni ; 1,4 à @ 3, m (protons en 2,3,4 et -CH2-CH2-OH).25.2 g of this ester are dissolved in 250 ml of methylene chloride and
14.7 ml of ethane dithiol and 5 ml of boron trifluoride etherate are added, the mixture is left for 36 hours at room temperature and then 350 ml of sodium hydroxide are added.
IN, decant the organic phase, wash it with water, dry on sulphate of soda,
filtered, the filtrate is evaporated and the residue is chromatographed on a column of alumina.By elution with a cyclohexane mixture (90 t) - ethyl acetate
the (10%) yielding 26.8 g (yield = 83%) of (3-ethoxycarbonylmethyl-1,2,3,4-tetrahydro-1-yl) -1,3-dithiolane whose NMR spectrum (CDCl3) has the following characteristics
Sppm = 7.9 at 8.1, m (aromatic H at 8); 6g9 at 7.3, m (aromatic H at 5.6 and 7); 4.2, q (-COO-CH 2 - 3.4 to 3.6, m

2.4 to 2.8, m (protons at 2,3,4 and CH2-CO-O); 1.35, t (CH 3) is added to a suspension cooled at 0 ° C. of 3.5 g of lithium aluminum hydride in 250 ml of THF. It is left at 0 ° C. for 3 hours, then hydrolysed using wet sodium sulfate, filter and evaporate the filtration obtains 24 g (99%) of [(hydroxy -2) ethyl-3-tetrahydro-1,2,3,4-yl -1] -2 dithiolane1,3 NMR spectrum (CDCl3): # ppm-7.8 to 8,

in 8); 6.8 to 7.3, m (aromatic Hs in 5.6 and 7); 3.6, ni; 1.4 to 3 m (protons at 2,3,4 and -CH 2 -CH 2 -OH).

This compound is then dissolved in a solution of 300 ml of methanol (5% water) and 50 ml of methyl iodide. The mixture is brought to reflux for 12 hours, then the solvents are evaporated, the residue is taken up in ether, washed with water, dried over sodium sulphate, filtered, the filtrate is evaporated and the residue is chromatographed on a silica column. ; by elution with a mixture of methyl chloride (9%) and methanol (10%) with ammonia (1%), 13.6 g (rtt = 79%) of the expected compound (oily) are obtained, the NMR spectrum of which (CDCl 3 ) has the following characteristics: ppm = 7.8 è 8.2, m (aromatic H at 8); 7.2 to 7.6, m (aromatic H at 5.6 and 7); 3.8, t (CH 2 -OH); 2.2 to 3, m (H at 2,3,4 and -OH); 1.6 to 1.9om

1,s

2nd stage: tert-butyl dimethyl silyl ether (2-hydroxy)
3-ethyl-1,2,3,4-tetrahydro-naphthalenone-1 (IIIb)
A mixture of 4.5 g of the compound (IV) obtained in the preceding stage, 4.03 g of imidazole and 4.3 g of tert-butyl dimethylsilyl chloride is stirred at room temperature for 12 hours. Then it is diluted with water, extracted with ethyl acetate, dried over sodium sulphate, filtered and the filtrate is evaporated, the residue is taken up in ether and washed with a 5% solution. Z of potassium acid sulphate and then with a solution of sodium chloride. After drying over sodium sulphate, the mixture is filtered and the filtrate is evaporated. 7 g (rdt-97%) of the expected product (oily) are obtained, the NMR spectrum of which (CDCl3) has the following characteristics: # ppm = 8.1, m (1H aromatic in 8); 7.35 to 7.6, m (aromatic H at 5.6 and 7); 3.82, t (CH 2 -O-); 2.4 to 3.1, m (H at 2.3 and 4); 1.7, m

1, s

3rd stage: (2-hydroxyethyl) -3-dihydro-3,4-orthoflurorophenyl-1
napthalene (II)
To a solution cooled to -93 ° C. of 11.7 ml of a 2.4M solution of butyl lithium in hexane, in 20 ml of ether under an argon stream, 3.2 ml of bromo are slowly added. 1-Fluoro-2-benzene. Leave 30 min -930 ° C. and then add a solution of 3 g of compound (IIIb) obtained in the preceding stage in 50 ml of ether in 11 minutes. After 2 hours at -800 ° C., 10 ml of hydrochloric ethanol are added, the solvents are evaporated, the residue is taken up in ether, washed with water, dried over sodium sulphate, filtered, the filtrate is evaporated and the residue is chromatographed on a silica column; by elution with a mixture of ether (70%) and heptane (30%), 1.3 g (yield = 50%) of the expected product (oily) are obtained.

1 (cDCl3): # ppm = 7.6 to 7.4, m (8H aromatics) * 5.95, d 3.7, t (CH2-OH); 2.4 to 3, m (H at 3 and 4 and -OH); 1.7, m
4th stage: (N, N-limethylamino-3-ethyl) maleate
dihydro-, 4-orthofluorophenyl-1 naphthalene (I)
Code number: 101
To a solution of 1.2 g of the compound (II) obtained in the preceding stage in 30 ml of methylene chloride, 1.6.5 ml of triethylamine and 0.75 ml of mesyl chlorate are added. The mixture is left standing for 1 hour at room temperature. then diluted with water, decanted the organic phase, washed with a 1N hydrochloric acid solution, then with water, then with a solution of sodium bicarbonate, dry over sodium sulfate, filter and evaporate the filtrate. The crude product obtained (1.5 g, yield = 93%) is dissolved in 33 ml of a 1.9 M solution of dimethylamine in benzene and the mixture is heated for 17 hours at 40 ° C. in an autoclave. solvent, the residue is taken up in methylene chloride, washed with water, dried over sodium sulfate, filtered, the filtrate is evaporated and the residue is chromatographed on a silica column. Elution with a mixture of methylene chloride (90%) methanol (9.5%) and ammonia (0.5%) gives 0.61 g (rdt = 50%) of an oily product which is dissolved in acetone. An acetic solution of 0.24 g of maleic acid is added, the mixture is diluted with ether and the precipitate obtained is filtered off. 0.62 g of the compound obtained are thus isolated.

F = 134 ° C; C24-H26 FNO4 = 411.46
Elemental analysis. Calc% C 70.0S H 6.37 N 3.40
Tr% 70.15, 6.74, 3.47.

By the same method, but from the corresponding reagents, there is obtained the compound (I) of code number 123 shown in the table below. -
Example 2: Methylpiperazino-3-ethyl-1-phenyl-7-methoxy-3,4-dihydro
isoquinoline, dioxalate hydrate (I)
Code number: 107
1st stage: benzoylamino-3-para-4-methoxyphenylbutanol (XXI)
To a suspension of 6.5 g of lithium aluminum hydride in 300 ml of THF, a solution of 58 g of benzoylamino-3-para-methoxyphenyl-4-butanoic acid ethyl ester (XXII) is slowly added (XXII). ) in 150 ml THF. Stir at room temperature for 12 hours, then hydrolyze with wet sodium sulfate, dilute with ether, filter, and evaporate the filtrate; 48.5 g of the expected compound are obtained (yield = 95%)
Mp = 1270 ° C (C18H21O3N = 299.36).

2nd stage: N- (3-acetyloxy-p-methoxybenzyl-1-propylbenzamide (XX)
A solution of 48 g of compound is left at 0 ° C. for 12 hours.
(XXI) obtained in the preceding stage in 350 ml of pyridine and 60 ml of aquegetic anhydride. The following are repeated in the methylene chloride, washed with water, dried over sodium sulfate, filtered and the filtrate evaporated; 28 g (yield = 50%) of the expected product are obtained.

3,8,s (CH30-) ; 2,9,m et 1,9,m (2-CH2) ; 2,0,s (CH3COO).NMR spectrometer (CDCl3): # ppm = 6.7 to 7.6, m (9H aromatics); 6 to 6.3, m (CONH); 4.1, m

3.8, s (CH 3 O); 2.9, m and 1.9, m (2-CH 2); 2.0, s (CH3COO).

3rd stage: (2-acetyloxy) 3-ethyl-7-methoxy-1-phenyl-3,4-dihydro
isoquinoline (XIX)
A solution of 26 g of compound (XX) obtained in the preceding stage in 250 ml of POCl3 is heated for 24 hours at 100 ° C. Then the solvent is evaporated, the residue is taken up in water, washed with ether, basified with concentrated NaOH, extracted with methylene chloride, washed with water, dried over sodium sulphate, filtered and evaporated. the filtrate. 12 g (yield = 50%) of the expected product (oily) are obtained
NMR spectrum (CDCl 3) δ ppm = 6.8 to 7.8, m (8H aromatics); 4.4, t (CH2-O-CO-); 3.7, s (CH3O); 3.4 to 3.8, m (H at 3); 2.7, m (H at 4) 2.05, s (CH3COO); 2.0, m (-CH 2).

By the same method, but from the corresponding reagents, there is obtained: (2-acetyloxy) -3-ethyl-7-methyl-1-phenyl-3,4-dihydro-isoquinoline (oil): NMR Spectrum (CDCl3) # ppm = 7 to 8, m (8H aromatics); 4.4, t (CH 2 CO); 3.6, m (H at 3); 2.65, m (H at 4); 2.3, s (CH3); 2.05, s (CH3CO); 2.0, m (CH2)
4th stage: (2-hydroxy) 3-ethyl-7-methoxy-1-phenyl-3,4-dihydro
isoquinoline (XVIII)
It is left for 3 hours at room temperature a suspension
Se 12 g of the product (XIX) obtained in the preceding stage and 2 g of potassium carbonate in 250 ml of methanol.Then the mixture is filtered, the filtrate is evaporated, the residue is taken up in methylene chloride, washed with water and evaporated. the organic phase and chromatography the residue on a silica column; eluting with hexane (30%) - ether (70%) gives 6.3 g (yield = 60%) of the expected product (oily)
NMR spectrum (CDCl 3) δ ppm = 6.8 to 7.8, m (8H aromatics); 5.3, s (OH); 4.0, t (CH 2 -O); 3.7, s (CH3O); 3.7, m (H at 3.5, 2.5 to 2.8, m (H at 4), 2.0, m (CH 2).

By the same method but from the corresponding reagents, there is obtained (2-hydroxy-ethyl) 3-methyl-7-methyl-1-phenyl-3,4-dihydro-isoquinoline (oil).

NMR spectrum (CDCl 3) δ ppm = 7 to 7.6, m (8H aromatics); 3.92, t (CH 2 -O); 3.5, m (H 3); 2.2, s (CH3); 2.5 to 2.8, m (H at 4); 1.95, m (CH2)
5th stage: Methyl piperazino ethyl-3-phenyl-1-methoxy-7
3,4-dihydro-isoquinoline, dioxalate hydrate (I)
Code number: 107
To a solution cooled to -100 ° C. of 6.2 g of the compound (XVIII) obtained in the preceding stage in 300 ml of methylene chloride, 7.7 ml of triethylamine and 3.4 ml of mesyl chloride are added. It is then left for 30 minutes at 0 ° C., then washed with water, with 1N hydrochloric acid, then with water, then with a solution of sodium bicarbonate, and then with water. 'water,. The crude product obtained is dissolved in 150 ml of benzene, 5.2 ml of N-methylpiperazine is added, and then the solution is heated at 500 ° C. for 12 hours in an autoclave. The reaction mixture is dried over sodium sulfate, filtered and the filtrate is evaporated. The mixture is evaporated, the residue is taken up in acidic water, washed with ether, basified with concentrated NaOH, extracted with methylene chloride, washed with water several times, dried over sodium sulfate, filtered, evaporated the filtrate and chromatography the residue on a silica column. Elution with a mixture of methylene chloride (88%) -methanol (10%) and ammonia (2%) gives 3.8 g (yield 347%) of oily compound which is dissolved in acetone. An acetonic solution of oxalic acid is added and filters the precipitate formed, which is the expected compound.

. Melting point: 2100 C
. Molecular weight: 556.30
. Gross formula: C27H33N3O9 + 2.3% H2O
. Elemental analysis:

<tb><SEP> C <SEP> H <SEP> N
<tb> Calculated <SEP> (Z) <SEP> 58.29 <SEP> 6.24 <SEP> 7.55
<tb> Found <SEP> (%) <SEP> 58.29 <SEP> 6.07 <SEP> 7.74
<Tb>
By the same method, but from the corresponding reagents, the compounds of formula (I) appearing in Table 1 and of code numbers: 102 to 106 and 108 are obtained.

Example 3 (4-methyl-1-piperazinyl) 3-methyl-7-methoxy-1-phenyl-3,4-dihydro
isoquinoline, dimaleate (I)
Code number: 100
At a temperature of 1000 ° C. for 12 hours, a solution of 2 g of
N - [(4-methyl-1-piperazinyl) -1-methoxybenzyl] ethylbenzamide [(VI), n1 = in 50 ml of POCl3. Then the solvent is evaporated, the residue is taken up in acidic water, washed with ether, basified with concentrated NaOH, extracted with methylene chloride, washed with water, dried over sodium sulphate, filtered, evaporated on filtrate and chromatograph the residue on a column of alumina. Elution with ether gives 0.7 g (yield = 35%) of product which is dissolved in acetone. An acetonic solution of maleic acid is added and the precipitate obtained, which corresponds to the expected compound, is filtered off
Melting Point: 168 C
. Gross formula: C30H35 N309 + 0.7% H2O
. elementary analysis:

<tb><SEP> C <SEP> H <SEP> N
<tb> Calculated <SEP> (%) <SEP> 61.52 <SEP> 6.11 <SEP> 7.18
<tb> Found <SEP> (%) <SEP> 61.29 <SEP> 5.92 <SEP> 7.14
<Tb>
By the same process, but from the corresponding reagents, we obtain
compounds (I) of number, code: 94 to 99 and 102 to 108 appearing in the
table 1.

Example 4 N - [(4-methyl-1-piperazinyl) para-methoxybenzyl-1] -ethyl
benzamide [(VI), n1 = 1]
Code number: 115
worm stage: N - [(methyl-4-piperazinyl) carbonyl-1 para methoxy
phenyl-2] ethyl benzamide (VII) has a suspension of 92 g of &alpha; benzoylamino para methoxyphenyl-3-propionic acid (VIII) in 1000 ml ether is added at 0 ° C., with stirring, 77.5 g.
of PCl5. We leave 1 hour at Oc C then 1 hour at 20 C, diluted using
of petroleum ether, filter, rinse the precipitate formed with petroleum ether,
and dissolved in 300 ml of anhydrous THF. We add this solution
slowly to a cooled solution at 0 ° C of 225 ml of N-methyl piperazine
(IX) in 500 ml of THF, then left for 3 hours at 0 ° C. and 1 hour at 20 ° C.

Then filtered, the filtrate is evaporated, the residue is taken up in chloroform,
washed with a 2N hydrochloric acid solution, then with water, dried over sodium sulphate, filtered and
the filtrate is evaporated to give 41% of the expected product (F =
2nd stage: N - [(4-methyl-1-piperazinyl) para-methoxybenzyl]
ethyl benzamide [(VI), n1 = 1]
To a suspension cooled to -15 ° C. of 5.5 g of double hydride
Lithium and aluminum in 100 ml of THF is added slowly a solution of 44 g of the compound (VII) obtained at a stage crécident. dane 400 ml of fdR, one
@ @@@@ sse at 15 C for @ hours. then bydrolysis with sodium sulphate
of, diluted with ether, filtered and evaporated the yarn. 53% of the expected product is obtained:
(F = 132 C)
C22H29N3O2 = 367.48.

NMR spectrum. (CDCl3) # ppm = 6.7 to 7.8m (9H aromatics); 6.5, m (CONH); 4.4, m (CH); 3.75, # (CH 3 O); 3.0, d (CH 2); 2.4, m

 By the same process, meis from the corresponding reagents, the compounds of formula (VI) of code n: 109 to 114 are obtained in table 2 below.

Example 5: N- [N, N-dimethylamino-3- (3,4-dimethoxy) benzyl-1] n -propylbenzamide
[(VI), n, = 2]
Code number: 120
1st stage: Ethyloxycarbonylmethyl-2 (3,4-dimethoxy) -2-benzyl-1,3-dioxolan () tVt)
A solution of 93 g of (3,4-dimethoxy) phenylacetoacetate (XVII) and 2 g of para-toluenesulfonic acid in 56 ml of ethylene glycol and 1000 ml of benzene is refluxed for 12 hours. . Then washed with water, dried over sodium sulfate filter and evaporated the filtrate; 93 g (yield 86%) of the expected product (oily) are obtained.

3,0,s (CH2) ; 2,6, s (CH2-CO-O) ; 1,25, t (CH3).NMR Spectrum (CDCl3) # ppm = 6.8 to 7, m (3H aromatics); 3.15, q (COO-CH 2 -); 3.8, s (2 cH3 0); 3.5 to 4, m

3.0, s (CH2); 2.6, s (CH2-CO-O); 1.25, t (CH3).

2nd stage: 3,4-Dimethoxy-benzyl-1,3-dioxolanic acid
yl-2] -3 propionic. (XV)
A solution of 90 g of compound (XVI) obtained in the preceding stage and 23.8 g of pelletized sodium hydroxide in 500 ml of water and 500 ml of ethanol is left for 12 hours at room temperature. Then the solvents are evaporated off, the residue is taken up in water, washed with ether, acidified with oxalic acid, the reaction medium is maintained in OOC, extracted with methylene chloride, dried over sodium sulphate, filtered and dried. evaporate the filtrate. 80 g (yield = 97%) of the expected product (Pateux) are obtained.

11,5,s (COOH) ; 6,8 à 7, m (3H aromatiques) ; 3,6 à 4, 3,9,s (2CH3O) ; 3,1,s (CH2); 2,7,s(CH2-CO-O).NMR spectrum

11.5, s (COOH); 6.8 to 7, m (3H aromatics); 3.6 to 4, 3.9, s (2CH3O); 3.1, s (CH 2); 2.7, s, (CH2-CO-O).

3rd stage: N, N-dimethylaminocarbonyl methyl-2 (3,4-dimethoxy)
2-benzyl-1,3-dioxolan (XIV;
To a solution of 80 g of acid (XV) obtained in the preceding stage in 800 ml of THF, cooled with OOC, 43 ml of triethylamine and then 33 ml of ethyl chloroformate are added. OOC is left for 1 hour and then a current of dimethylamine gas is passed. When the reaction is complete (control on TLC), the THF is evaporated, the residue is taken up in methylene chloride, washed with 1N sodium hydroxide solution, and then at 0.degree. water, then with 1N hydrochloric acid, then with water, dried over sodium sulfate, filtered and the filtrate evaporated. 75 g (yield - 85%) of the expected product (oily) are obtained.

NMR Spectrum (CDCl3) # ppm = 6.8 to 7, m (3H aromatics)

4th stage: (3,4-dimethoxy-phenylacetyl-2N, N-dimethylacetamide
(XIII)
A solution of 75 g of compound (XIV) obtained in the preceding stage in 30 ml of concentrated hydrochloric acid and 1000 ml of acetone is left for 12 hours at room temperature. When the reaction is complete by TLC control), neutralize with sodium carbonate, filter, evaporate the filtrate, dilute the residue in water, extracted with ether,
Wash with water, dry over sodium sulfate, filter and evaporate the filtrate. 63 g (yield 98%) of the expected product are obtained (oily)
RMW spectrum (CDCl3): # ppm = 6.8, aromatic m S3H); 3.8, s

3,9,s (20CH3 et NH2) ; 3,4, s (CH2-C=) ; 2,9,s
N

6ème stade : amino-3(diméthoxy-3,4) phényl-4 N,N diméthyl butanamide (XII).2 amide (XIIa)
A stream of ammonia gas is passed for 6 hours in a solution of 99 g of compound (XIII) obtained in the preceding stage in 1000 ml of ethanol. When the reaction is complete (TLC control), the solvent is evaporated, the residue is taken up in methylene chloride, washed with water, dried over sodium sulphate, filtered and the filtrate is evaporated. 95 g (yield 96%) of the expected product (oily)
NMR Spectrum (CDCl3): # ppm = 6.8, m (3H aromatics)

3.9, s (20CH3 and NH2); 3.4, s (CH2-C =); 2.9, s
NOT

6th stage: 3-amino-3- (3,4-dimethoxy) -4-phenyl-N, N-dimethylbutanamide (XII).

(2CH3O) ; 3,8, m (CH2) ; 3,2 à 3,6, m (CH22,3 à 2,8,m(-NH2).To 600 ml of acetic acid cooled to 0 ° C., 13.3 g of sodium borohydride are added, then 46.6 g of compound (XIIa) obtained in the preceding stage in 50 ml of acetic acid are slowly added. Then left for 3 hours at room temperature, cooled to 0 ° C., basified with concentrated sodium hydroxide, extracted with methylene chloride, washed with water, dried over sodium hydroxide, filtered and the filtrate evaporated; 35.8 g (yield 76%) of the expected product (oily) are obtained
NMR spectrum;
CDCl3) # ppm = 6.6 to 6.9, m (3H aromatics);

(2CH3O); 3.8, m (CH 2); 3.2 to 3.6, m (CH22.3 to 2.8, m (-NH2).

7th stage: amino-3 (3,4-dimethoxy) 4-phenyl-N, N-dimethyl-amino
1 butane (XI)
Code number: 121
To a suspension cooled at 0 ° C. of 11.4 g of lithium aluminum hydride in 200 ml of THF, a solution of 40 g of compound (XII) obtained in the preceding stage in 300 ml of THF It leaves 1 hour at 0 C then 2 hours at 250C. Then neutralized with wet sodium sulfate, filtered, evaporated the filtrate and chromatography the residue on a column of silica.Parution with methylene chloride, then with mixtures of methyl chloride - methanol containing up to 20% methanol, 35 g (yield = 92%) of the expected product (oily) are isolated: Crude formula: C1 4H4N2O2 Molecular weight: 252.35
NMR spectrum: (CDCln ppm = 6.8, s

By the same method, but from the corresponding reagents, there is obtained 3-amino-4-chloro-4-phenyl [(4-methyl) piperazin-1-yl] butane (XI) (Code No. 122) ( oil): NMR spectrum (CDCl3) (ppm = 7.2,

Stage 8: N- [N, N-dimethylamino-3 (3,4-dimethoxy) benzyl] 1n
propyl benzamide [(VI), n1 = 2].

N of code 120
To a cooled solution at 0 ° C. of 21.2 g of compound (XI) obtained in the preceding stage, in 250 ml of methylene chloride, 15.2 ml of triethylamine and then 10.8 ml of benzoyl chloride are added slowly. It is left for 30 minutes at 0 ° C. and then for 3 hours at room temperature. The mixture is then filtered, the filtrate is evaporated, the residue is taken up in acidic water, washed with ether, basified with concentrated sodium hydroxide, extracted with ethyl acetate, washed with water and dried over sulfate. of sodium, filter, evaporate the filtrate and crystallize the residue in ethyl acetate (70%) - hexane (30%). 25 g (yield = 75%) of the expected product are obtained. Melting point = 115 ° C.
Crude formula = C21H28N203 Molecular weight = 356.45
NMR Spectrum (CDCl3) # ppm = 9, m (CONH); 7.8, 7.4 and 6.8,

 By the same method but from the corresponding reagents, the compounds of formula (VI) appearing in table 2 and of code number 116 to 119 are obtained.

Example 8: (3-hydroxypropyl) -3-dihydro-3,4-orthophthalophenyl-1-naphthyl
[(II), nr 3]
1st stage: (2-cyanoethyl) -3-dihydro-3,4-orthofluorophenyl-1
naphthyl (XXIV)
To a solution of 17.2 g of (2-hydroxy-ethyl) -3-dihydro-1-orthofluorophenyl-naphthyl [(II), n1 = 2] obtained in the third stage of the above example, in 200 ml of methylene chloride, cooled to -100 ° C., 22.3 ml of triethylamine and then 10 ml of mesyl chloride are added. It is left at -10 ° C. and when the reaction is finished (TLC control), it is diluted with water washed with a dilute hydrochloric acid solution, then with water, then with a dilute solution of sodium bicarbonate, then with water, dried over magnesium sulphate, filtered and the filtrate evaporated the crude product (22, 2 g) is dissolved in 100 ml of DMSO and 25 g of sodium cyanide are added. The mixture is left overnight at room temperature, then diluted with water, extracted with chloroform, washed with water, dried over magnesium sulfate, filtered and the filtrate evaporated. 18 g of the expected product (oily) are obtained.

IR spectrum (microcell) CN band at 2 240 cml
2nd stage: (2-ethoxycarbonyl-ethyl) -3-dihydro-3,4-orthofluorophenyl-1-naphthyl (XXIII)
A solution of 18 g of the compound (XXIV) obtained in the preceding stage in 200 ml of 7N hydrochloric ethanol and 200 ml of ethanol is refluxed for 36 hours. Then the solvent is evaporated, the residue is taken up.

in methylene chloride, washed with a sodium bicarbonate solution, then with water, dried over magnesium sulfate, filtered and the filtrate evaporated. 15 g of the expected product (oil) are obtained
Spectrum @R (myocell) hande CD @ And at 1730 cm-1.

NMR Spectrum (CDCl 3) δppm = 6.8 at 7.8, m: 8 aromatic protons 5.92, d (H at 2) 4. 1, q (-COOCH 2 -)

2.2 to 3.1, m (CH2-COO and H at 3 and 4); 1.8, m (CH2)
3rd stage: (3-hydroxypropyl) -3-dihydro-3,4-orthofluoro phenyl
1 naphthyl [(II); n = 3]
To a suspension of 1.7 g of lithium aluminum hydride in 50 ml of THF, cooled to 0 ° C., is added over 5 minutes. a solution of 14.8 g of compound (XXIII) obtained in the preceding stage in 100 ml of THF. After 1 hour, the mixture is hydrolyzed with sodium sulfate, diluted with ether, filtered and evaporated. The filtrate is chromatographed and the residue is chromatographed on a silica column. Elution with heptane (60%) -ethyl acetate (40%) gives 12.1 g of the expected compound (oily).
NMR spectrum (CDCl3) # ppm
6.7 to 7.8, m (aromatic 8H)
6, d (H in
3.6, m
2.42, s (-OH)
2.6 to 3.1, m (H in 3 and 4)
1.6, m (-CH2-CH2-) TABLE-1

<SEP> ANALYSIS <SEP> ELEMENTARY
<tb><SEP> Formula <SEP> Weight <SEP> Point <SEP> (OR <SEP> R. <SEP> M. <SEP> N)
<tb> N <SEP> of <SEP> A = B <SEP> R <SEP> n <SEP>#<SEP> R3 <SEP> Raw <SEP> form <SEP> molecular- <SEP> of
<tb> code <SEP> laire <SEP> merge
<tb><SEP> (C) <SEP>% <SEP> C <SEP> H <SEP> N
<tb><SEP> Cal. <SEP> 59.43 <SEP> 5.50 <SEP> 7.17
<tb> 94 <SEP> C = N <SEP>#<SEP> 1 <SEP>#<SEP> 5-Cl <SEP> dimaleate <SEP> C29H32ClN3O8 <SEP> 586.03 <SEP> 209
<tb><SEP> Tr. <SEP> 58.93 <SEP> 5.52 <SEP> 7.28
<tb><SEP> Cal. <SEP> 64.67 <SEP> 6.36 <SEP> 5.20
<tb> 95 <SEP>"<SEP>"<SEP>"<SEP>#<SEP> 7-CH3 <SEP>"<SEP> C29H34N2O8 <SEQ> 538.58 <SEP> 114
<tb><SEP> Tr. <SEP> 64.43 <SEP> 6.41 <SEP> 5.23
<tb><SEP> Cal. <SEP> 64.91 <SEP> 6.01 <SEP> 5.22
<tb> 96 <SEP>"<SEP>"<SEP>"<SEP>#<SEP>"<SEP>"<SEP> C29H32N2O8 <SEP> 536.56 <SEP> 134
<tb><SEP> Tr. <SEP> 64.71 <SEP> 6.01 <SEQ> 5,12
<tb> TABLE 1 (continued)

<SEP> ANALYSIS <SEP> ELEMENTARY
<tb><SEP> Formula <SEP> gross <SEP> Weight <SEP> Point <SEP> (OR <SEP> R. <SEP> M. <SEP> N)
<tb> N <SEP> of <SEP> A = B <SEP> R <SEP> n <SEP>#<SEP> R3 <SEP> Form <SEP> molecular- <SEP> of
<tb> code <SEP> laire <SEP> merge
<tb><SEP> (C) <SEP>% <SEP> C <SEP> H <SEP> N
<tb><SEP> Cal. <SEP> 67.51 <SEP> 7.21 <SEP> 7.16
<tb> 97 <SEP> C = N <SEP>#<SEP> 1 <SEP>#<SEP> 7 = CH3 <SEP> diHCl <SEP> C22H28Cl2N2 <SEP> 391.37 <SEP> 190
<tb><SEP> Tr. <SEP> 67.34 <SEP> 7.25 <SEP> 7.25
<tb><SEP> Cal. <SEP> 64.12 <SEP> 6.66 <SEP> 7.12
<tb> 98 <SEP>"<SEP>"<SEP>"<SEP>#<SEP>"<SEP>"<SEP> C21H26Cl2N2O <SEP> 393.35 <SEP> 215
<tb><SEP> Tr. <SEP> 64,36 <SEP> 6,86 <SEP> 7,11
<tb><SEP> Cal. <SEP> 63.70 <SEP> 6.24 <SEP> 7.43
<tb> 99 <SEP>"<SEP>"<SEP>"<SEP>#<SEP>"<SEP> diMa- <SEP> C3-N35N3O8 <SEP> 565.60 <SEP> 170
<tb><SEP> Late <SEP> Tr. <SEP> 63.40 <SEP> 6.33 <SEP> 7.48
<tb><SEP> diMa
<SEP> Late <SEP> C30H35N3O9 <SEP> Cal. <SEP> 61.52 <SEP> 6.11 <SEP> 7.18
<tb> 100 <SEP>"<SEP>"<SEP>"<SEP>"<SEP> 7-CH3O <SEP> + 0.7% <SEP> 585.70 <SEP> 168
<tb><SEP> H2O <SEP> +0.7 <SEP>% <SEP> H2O <SEP> Tr. <SEP> 61.29 <SEP> 5.92 <SEP> 7.14
<tb> TABLE 1 (continued)

<SEP> ANALYSIS <SEP> ELEMENTARY
<tb><SEP> Formula <SEP> gross <SEP> Weight <SEP> Point <SEP> (OR <SEP> R. <SEP> M. <SEP> N)
<tb> N <SEP> of <SEP> A = B <SEP> R <SEP> n <SEP>#<SEP> R3 <SEP> Form <SEP> molecular- <SEP> of
<tb><SEP> of <SEP> laire <SEP> merge
<tb> code <SEP> (C) <SEP>% <SEP> C <SEP> H <SEP> N
<tb><SEP> Cal. <SEP> 70.05 <SEP> 6.37 <SEP> 3.40
<tb> 101 <SEP> C = CH <SEP>#<SEP> 2 <SEP>#<SEP> H <SEP> Maleate <SEP> C24H26FNO4 <SEP> 411.46 <SEP> 134
<tb><SEP> Tr. <SEP> 70.15 <SEP> 6.74 <SEP> 3.47
<tb><SEP> Cal. <SEP> 62.46 <SEP> 7.37 <SEP> 7.29
<tb> 102 <SEP> C = N <SEP>#<SEP>"<SEP>"<SEP> 7-CH3 <SEP> diHCl <SEP> C20H26Cl2N2 <SEP> 384.57 <SEP> 235
<tb><SEP> +5 <SEP>% <SEP> + <SEP> 5 <SEP>% <SEP> H2O <SEP> Tr. <SEP> 62.15 <SEP> 7.34 <SEP> 7, 21
<tb><SEP> H2O
<tb><SEP> diHCL <SEP> Cal. <SEP> 51.84 <SEP> 6.06 <SEP> 6.05
<tb> 103 <SEP>"<SEP>#<SEP>"<SEP>"<SEP> H <SEP> + 9.5% <SEP> C20H23Cl2P3N2 <SEP> 463.33 <SEP> 170
<tb><SEP> H2O <SEP> + <SEP> 9.5 <SEP> 5 <SEP> H2O <SEP> Tr. <SEP> 51.86 <SEP> 5.07 <SEP> 6.01
<tb><SEP> dioxa
<SEP> late <SEP> Cal. <SEP> 53.93 <SEP> 4.89 <SEP> 5.24
<tb> 104 <SEP>"<SEP>#<SEP>"<SEP>"<SEP>"<SEP> + 1.5% <SEP> C24H25F3N2O4 <SEP> 534.47 <SEP> 143
<tb><SEP> H2O <SEP> + <SEP> 1.5 <SEP>% <SEP> H2O <SEP> Tr. <SEP> 53.93 <SEP> 4.59 <SEP> 5.03
<tb> TABLE - (continued)

<SEP> ANALYSIS <SEP> ELEMENTARY
<tb><SEP> Formula <SEP> gross <SEP> Weight <SEP> Point <SEP> (OR <SEP> R. <SEP> M. <SEP> N)
<tb> N <SEP> of <SEP> A = B <SEP> R <SEP> n <SEP>#<SEP> R3 <SEP> Form <SEP> molecular- <SEP> of
<tb><SEP> of <SEP> laire <SEP> merge
<tb> code <SEP> (C) <SEP>% <SEP> C <SEP> H <SEP> N
<tb><SEP> dioxo- <SEP> Cal. <SEP> 55.58 <SEP> 6.05 <SEP> 5.18
<tb> 105 <SEP>## EQU1 ##
<tb><SEP> + <SEP> 4 <SEP>% <SEP> Tr. <SEP> 55.64 <SEP> 5.63 <SE> 5.34
<tb><SEP> H2O <SEP> + <SEP> 4 <SEP>% <SEP> H2O
<tb><SEP> diMa- <SEP> Cal. <SEP> 60.04 <SEP> 5.71 <SEP> 7.00
<tb> 106 <SEP>"<SEP>"<SEP>"<SEP>#<SEP> 5-Cl <SEP> Late <SEP> C30H34ClN3O8 <SEP> 600.05 <SEP> 200
<tb><SEP> Tr. <SEP> 50.84 <SEP> 5.77 <SEP> 6.98
<tb><SEP> dioxa107 <SEP>"<SEP>"<SEP>"<SEP>"<SEP> 7-OCH3 <SEP> late <SEP> C27H33N3O9 <SEP> Cal. <SEP> 58.29 <SEP > 6.24 <SEP> 7.35
<tb><SEP> + 2.3% <SEP> 556.30 <SEP> 210
<tb><SEP> H2O <SEP> + <SEP> 2,3 <SEP>% <SEP> H2O <SEP> Tr. <SEP> 58,29 <SEP> 6,07 <SEP> 7,74
<tb><SEP> 1,7
<tb><SEP> oxalate <SEP> C18H21N3 + 1.7 <SEP> oxala- <SEP> Cal. <SEP> 58.60 <SEP> 5.77 <SEP> 9.58
<tb> 108 <SEP>"<SEP>#<SEP>"<SEP>#<SEP> H <SEP> te <SEP> 438.57 <SEP> 129
<tb><SEP> + 1.4% <SEP><SEP> + <SEP> 1.4 @ <SEP>% <SEP> H2O <SEP> Tr. <SEP> 58.27 <SEP> 5, 73 <SEP> 9.50
<tb><SEP> H2O
<tb> TABLE 1 (continued)

<SEP> ANALYSIS <SEP> ELEMENTARY
<tb><SEP> Formula <SEP> gross <SEP> Weight <SEP> Point <SEP> (OR <SEP> R. <SEP> M. <SEP> N)
<tb> N <SEP> of <SEP> A = B <SEP> R <SEP> n <SEP>#<SEP> R3 <SEP> Form <SEP> molecular- <SEP> of
<tb><SEP> of <SEP> laire <SEP> merge
<tb> code <SEP> (C) <SEP>% <SEP> C <SEP> H <SEP> N
<tb><SEP> NMR <SEP> (CDCl3) <SEP>#<SEP> ppm <SEP> = 6.7 <SEP> to <SEP> 7.4,
<tb><SEP> m <SEP> (8 <SEP> H <SEP> aromatic) <SEP>;<SEP> 5.95,
## EQU1 # <SEP> in <SEP> 2) <SEP>;<SEP> 2.20, <SE> s <SEP>(#
<tb><SEP> 2.6 <SEP> to <SEP> 3.1, <SEP> m <SEP> (CH2-N # <SEP> and
<tb><SEP> H <SEP> in <SEP> 3 <SEP> and <SEP>4);<SEP> 1.5, m <SEP> (CH2-CH2-)
<tb><SEP> Cal.
<Tb>

<SEP> Tr.
<Tb>

<SEP> Cal.
<Tb>

<SEP> Tr.
<Tb>

<SEP> Cal.
<Tb>

<SEP> Tr.
<Tb>

TABLE 2

<SEP> ANALYSIS <SEP> ELEMENTARY
<tb><SEP> Formula <SEP> Weight <SEP> Point <SEP> (OR <SEP> R. <SEP> M. <SEP> N)
<tb> N <SEP> R31 <SEP> n1 <SEP>#<SEP> R1 <SEP> Form <SEP> Raw <SEP> Molecule <SEP> of
<tb><SEP> of <SEP> laire <SEP> merge
<tb> Code <SEP> (C) <SEP>% <SEP> C <SEP> H <SEP> N
<tb><SEP> NMR <SEP> (CDCl3 + DMSO) <SEP>#<SEP> ppm = 6.6 <SEP> to <SEP> 7.8, m
<tb><SEP> (9 <SEP> H <SEP> ar
<tb> 109 <SEP> 2Cl <SEP> 1 <SEP>#<SEP>#<SEP> Base <SEP> C21H26ClN3O <SEP> 371.89 <SEP> 180 <SEP>(> CH # <SEP>;<SEP> 3.2, <SEP> m <SEP>(-CH2-);<SEP> 2.2 <SEP> to <SEP> 2.65, m
<tb><SEP>#<SEP>;<SEP> 2,2, s <SEP> (N-CH3)
<tb> TABLE 2 (continued)

N <SEP> Formula <SEP> Weight <SEP> Point
<tb> of <SEP> R31 <SEP> n1 <SEP>#<SEP> R1 <SEP> Form <SEP> molecule <SEP> of <SEP> ANALYSIS <SEP> ELEMENTARY <SEP> (OR <SEP> NMR )
<tb> raw <SEP> code <SEP> laire <SEP> susion
<tb><SEP> (C)
<tb><SEP> NMR <SEP> (CDCl3) <SEP>#<SEP> ppm <SEP> = <SEP> 7 <SEP> to <SEP> 7.8, <SEP> m <SEP> (9 <SEP> H <SEP> aromatics) <SEP>;
<tb><SEP> 6.5, <SEP> m <SEP> (CONH) <SEP>;<SEP> 4.2, <SEP> m <SEP> (CH-) <SEP>;<SEP> 2, <SEP> m <SEP> (-CH2-) <SEP>;
<tb> 110 <SEP> 4CH3 <SEP> 1 <SEP>#<SEP>#<SEP> Base <SEP> C21H28N2O <SEP> 324.45 <SEP> 117
<tb><SEP> 2.5, <SEP> q <SEP>(#)<SEP>;<SEP> 2.6, <SEP> d <SEP> (CH2-N #) <SEP>;<SEP> 2.45, <SEP> s
<tb><SEP>(-CH3);<SEP> 1.92, <SEP> t <SEP> (2 <SEP> CH3)
<tb><SEP> NMR <SEP> (CDCl3) <SEP>#ppm<SEP> = <SEP> 7 <SEP> to <SEP> 7.8, <SEP> m <SEP> (9 <SEP> H <SEP> aromati
<SEP> ques) <SEP>;<SEP> 6.4, <SEP> m <SEP> (CONH) <SEP>;<SEP> 4.3, <SEP> m <SEP> (CH-) <SEP>;<SEP> 3, m
<tb> 111 <SEP>"<SEP>"<SEP>#<SEP>"<SEP>"<SEP> C21H26N2O <SEP> 322.43 <SEP> 134
<tb><SEP> (-CH2-) <SEP>;<SEP> 2.5, <SEP> m <SEP>(#);<SEP> 2.3, s <SEP>(CH3);
<tb><SEP> 1.7, <SEP> m <SEP>(#)
<tb><SEP> NMR <SEP> (CDCl3) <SEP>#<SEP> ppm <SEP> = <SEP> 7 <SEP> to <SEP> 7.8, <SEP> m <SEP> (9 <SEP> H <SEP> aromati
<SEP>ques);<SEP> 6.5, <SEP> m <SEP> (CONH) <SEP>;<SEQ> 4.38, <SEP> m <SEP> (CH -); 3, <SEP> m
<tb> 112 <SEP>"<SEP>"<SEP>#<SEP>"<SEP>"<SEP> C22H28N2O <SEP> 336.46 <SEP> 162
<tb><SEP> (CH2) <SEP> 2.28, <SEP> s <SEP> (CH3) <SEP> @ <SEP> 2.38, <SEP> m <SEP>(#)<SEP>
<tb><SEP> 1.5, m <SEP>(#).
<Tb>

<SEP> NMR <SEP> (CDCl3) <SEP>#ppm<SEP> = <SEP> 7 <SEP> to <SEP> 7.8, m <SEP> (9 <SEP> H <SEP> aromatics) <SEP>;
<tb><SEP> 6.6, <SEP> m <SEP> (CONH) <SEP>;<SEP> 4.42, <SEP> m <SEP>(#CH)<SEP>;<SEP> 3.64, <SE> t
<tb> 113 <SEP>"<SEP>"<SEP>#<SEP>"<SEP>"<SEP> C21H26N2O2 <SEP> 338.43 <SEP> 195
<tb><SEP>(#)<SEP>;<SEP> 3, d <SEP>(-CH2-);<SEP> 2.44, m
<tb><SEP>(#)<SEP>;<SEP> 2,3, <SEP> s <SEP> (CH3).
<Tb>

TABLE 2 (continued)

N <SEP> Formula <SEP> Weight <SEP> Point
<tb> of <SEP> R31 <SEP> n1 <SEP>#<SEP> R1 <SEP> Form <SEP> molecule <SEP> of <SEP> ANALYSIS <SEP> ELEMENTARY <SEP> (OR <SEP> NMR )
<tb> raw <SEP> code <SEP> laire <SEP> susion
<tb><SEP> (C)
<tb><SEP> NMR <SEP> (CDCl3) <SEP>#<SEP> ppm <SEP> = <SEP> 7 <SEP> to <SEP> 7.8, m <SEP> (9 <SEP> H <SEP> aromati
<SEP> ques) <SEP>;<SEP> 6.45, <SEP> m <SEP> (CONH) @; <SEP> 4.4, <SEP> m <SEP> (CH-) <SEP>;<SEP> 3, <SEP> d
<tb> 114 <SEP> 4-CH3 <SEP> 1 <SEP>#<SEP>#SEP> Base <SEP> C22H29N3O <SEP> 351.48 <SEP> 147
<tb><SEP> (CH2) <SEP>;<SEP> 3.42, <SEP> m <SEP>(#)<SEP>;<SEP> 2.38, <SEP> s <SEP> (CH3)
<tb><SEP> 2.20, <SEP> s <SEP> (N-CH3)
<tb><SEP> NMR <SEP> (CDCl3) <SEP>#<SEP> ppm <SEP> = <SEP> 6.7 <SEP> to <SEP> 7.8, <SEP> m <SEP> ( 9 <SEP> H <SEP> aromati
<SEP>cs);<SEP> 6.5, <SEP> m <SEP> (CONH): <SEP> 4.4, <SEP> m <SEP> (-CH-) <SEP>;<SEP> 3.75 <SEP> s
<tb> 115 <SEP> 4-CH3O <SEP>"<SEP>"<SEP>"<SEP>"<SEP> C22H29N3O2 <SEP> 367.48 <SEP> 132
<tb><SEP> (CH3O) <SEP>;<SEP> 3. <SEP> d <SEP> (cH2) <SEP>;<SEP> 2,4, <SEP> m <SEP>(#);
<tb><SEP> 2.22, <SEP> s <SEP> (@H-CH3)
<tb><SEP> NMR <SEP> (CDCl3) <SEP>#<SEP> ppm <SEP> = <SEP> 7 <SEP> to <SEP> 7.8, <SEP> m <SEP> (9 <SEP> H <SEP> aromati
<SEP> ques <SEP> and <SEP> CONH) <SEP>;<SEP> 4.30, <SEP> m <SEP> (-CH) <SEP>;<SEP> 3, <SEP> d <SEP> (CH2)
<tb> 116 <SEP> H <SEP> 2 <SEP>#<SEP>#<SEP>"<SEP> C20H23F3N2O <SEP> 364.40 <SEP> 76 <SEP> 2.4, <SEP> m <MS> (CH2-N #) <SEP>;<SEP> 2.4, <SEP> s
<tb><SEP>(#)<SEP>;<SEP> 1.65, <SEP> m <SEP>(#)
<tb><SEP> NMR <SEP> (CDCl3) <SEP>#<SEP> ppm <SEP> = <SEP> 9.65, <SEP> m <SEP> (CONH) <SEP>;<SEP> 7.2 <SEP> to <SEP> 8, m
<tb><SEP> (9 <SEP> H <SEP> aromatic) <SEP>;<SEP> 4.4, <SEP> m <SEP> (-CH) <SEP>;<SEP> 2.25, <SEP> s
<tb> 117 <SEP>"<SEP>"<SEP>"<SEP>#<SEP>"<SEP> C20H23F3H2O <SEP> 364.40 <SEP> 100
<tb><SEP>(#)<SEP>;<SEP> 2.2 <SEP> to <SEP> 3.2, <SEP> m <SEP>(#)<SEP>;<SEP> 1.6,
<tb><SEP> m <SEP>(#)
<tb> TABLE 2 (continued)

N <SEP> Formula <SEP> Weight <SEP> Point
<tb> of <SEP> R31 <SEP> n1 <SEP>#<SEP> R1 <SEP> Form <SEP> molecule <SEP> of <SEP> ANALYSIS <SEP> ELEMENTARY <SEP> (OR <SEP> NMR )
<tb> raw <SEP> code <SEP> laire <SEP> susion
<tb><SEP> (C)
<tb><SEP> NMR <SEP> (CDCl3) <SEP>#<SEP> ppm <SEP> = <SEP> 9.3, <SEP> m <SEP> (CONH) <SEP>;<SEP> 9.25, <SEP> 8.95
<tb><SEP> and <SEP> 8,20, <SEP> m <SEP> (3H <SEP> pyridine) <SEP>;<SEP> 7,3, <SE> m <SEP> (5 <SEP > H
<tb> 119 <SEP> H <SEP> 2 <SEP>#<SEP>#<SEP> Base <SEP> C18H23N3O <SEP> 297,39 <SEP> 100 <SEP> aromatic <SEP> and <SEP> 1 <SEP> H <SEP> pyridine) <SEP>;<SEP> 4.4, <SEP> m
<tb><SEP> (CH) <SEP>;<SEP> 2,3, <SEP> s <SEP>(#)<SEP>;<SEP> 2.2 <SEP> to <SEP> 3.4, <SEP> m
<tb><SEP>(#)<SEP>;<SEP> 3 <SEP> 1.75, <SEP> m <SEP>(#).
<Tb>

<SEP> NMR <SEP> (CDCl3) <SEP>#<SEP> ppm <SEP> = <SEP> 9, <SEP> m <SEP> (CONH) <SEP>;<SEP> 7.8, <SEP> 7.4, <SEP> sets
<tb><SEP> 6.8, <SEP> s <SEP> (8 <SEP> H <SEP> Aromatic) <SEP>;<SEP> 4.4, <SEP> m <SEP> (CH) <SEP>;<SEP> 3.8,
<tb> 120 <SEP> 3,4-di <SEP>"<SEP>"<SEP>#<SEP>"<SEP> C21H28N2O3 <SEP> 356.45 <SEP> 115
<tb><SEP> OCH3 <SEP> s <SEP> (2CH3O) <SEP>;<SEP> 2.22, <SEP> s <SEP>(#)<SEP>;<SEP> 2.3 <SEP> to <SEP> 3.2, <SEP> m
<tb><SEP>(#)<SEP>;<SEP> 1.65, <SEP> m <SEP>(#)
<tb><SEP> NMR <SEP> (CDCl3) <SEP>#<SEP> ppm <SEP> = <SEP> 8.2 <SEP> to <SEP> 8.5, <SEP> m <SEP> ( H <SEP> aromatic
<tb><SEP> in <SEP>&alpha;<SEP> of <SEP> Cl) <SEP>;<SEP> 7 <SEP> to <SEP> 8, <SEP> m <SEP> (8 <SEP> H <SEP> aromatic <SEP> and
<tb> 118 <SEP> 2-Cl <SEP>"<SEP>#<SEP>#<SEP>"<SEP> C22H28N3ClO <SEP> 385.92 <SEP> 180 <SEP> CONH) <SEP>;<SEP> 4.45, <SEP> m <SEP> (CH) <SEP>;<SEP> 3.15, <SEP> m <SEP> (CH2) <SEP>;<SEP> 2.2 <SEP> to
<tb><SEP> 2.8, <SEP> m <SEP> (10 <SEP> H <SEP>;<SEP>#)<SEP>;<SEP> 2.2, <SEP> s <SEP>(#)<SEP>;
<tb><SEP> 1.8, <SEP> m <SEP>(#)
<Tb>
The compounds of formula (I) have been studied in experimental animals and have shown activities in the field of the central nervous system, particularly as analgesics and antidepressants.

The analgesic activity was demonstrated in the mouse (by ip administration of the compounds of formula (I)) using the test of phenyibenzoquinone according to the protocol described by E. SIEGMUND in
Procedé. Soc. Exp. Biol. and Med., 95, 729, (1957).

 The antidepressant activity was demonstrated in the mouse by the ptosis antagonist test observed one hour after an intravenous injection (2 mg / kg) of reserpine in the mouse according to the protocol described by C. GOURET and J. THOMAS in J. Pharmacol. (Paris) (1973), 4, 401.

 To illustrate the invention, the results obtained in these two tests and the acute toxicity (LD50) of some compounds of formula (I) are summarized in Table 3 below.

TABLE 3

<tb><SEP> LD50mouse <SEP> (mg / kg / <SEP> Prop. <SEP> analgesics <SEP> Prop. <SEP> antidepressants
<tb> N <SEP> of <SEP> code <SEP> ip) <SEP> DE50 <SEP> (mg / kg / ip) <SEP> sive <SEP> DE50 <SEP> (mg / kg / ip)
<tb><SEP> 94 <SEP> 140 <SEP> 22
<tb><SEP> 100 <SEP> 140 <SEP> 30 <SEP> 9
<tb><SEP> 103 <SEP> 70 <SEP> - <SEP> 3.8
<tb><SEP> 104 <SEP> 62 <SEP> 4.3 <SEP>
<tb><SEP> 105 <SEP> 165 <SEP> 12 <SEP> 30
<tb><SEP> 108 <SEP> 90 <SEP> 7.6 <SEP> 12
<Tb>
The difference between the toxic doses and the active doses allows the therapeutic use of the compounds of formula (I). They will be used in particular as analgesics and as antidepressants and will be administered in the form of compositions containing at least one of said compounds of fonmile (I), in combination with a pharmaceutically acceptable carrier, for example:
- orally, in the form of tablets, dragèes, capsules, etc.

at doses up to 200 mg / day in 3 or 4 doses,
- intravenously, in the form of injectable ampoules to
doses up to 60 mg / day in 3 or 4 doses,
- intramuscularly, in the form of injectable ampoules to
doses up to 90 mg / day in 3 or 4 doses, or
in the form of suppositories at doses up to
200 mg / day in 3 or 4 doses.

Claims (11)

 1. Novel heterocyclic aminoalkyl derivatives, characterized in that they correspond to the formula

 in which the sequence A = B represents:  or the C = CH motif, in which case R1 = R2 = CH3, R3 = H and the pair  (R, n) takes any of the following values: (phenyl, 3)  (o-fluorophenyl, 1), (o-fluorophenyl, 2), (o-fluorophenyl, 3),  - the reason C = N, in which case  R 1, R 2 -CH 3 and the group (n, R, R 3) - (2, phenyl, 7-CH 3) (2, o-CF 3 phenyl, H), (2, m-CF 3 phenyl, H), ( 2, phenyl 6,7-doOCH 3) or

 or .R. and R form together with the nitrogen atom to which they are attached a radical  (1, phenyl, 7-OCH3), (2, phenyl, 5-Cl) or (2, phenyl, 7-OCH3),  (n, R, R3) = (1, phenyl, 5-Cl), (1, phenyl, 7-CH3)  in which case the whole

R1 = R2 = C2Hs and the group (n, R, R3) = (1> phenyl, 7-CH3), R1- and R2 together with the nitrogen atom to which they are attached, a radial  the group (n, R, R3) = (1, phenyl, 7-CH3), as well as their acid addition salts.  2. New derivatives and salts according to claim 1, characterized in that the sequence A = B represents the C = CH unit; R1 and R2 each denote a methyl group and R3 = H.  3. New derivatives and salts according to claim 2, characterized in that the pair (R, n) = (o-fluorophenyl, 2) or (o-fluorophenyl, 3).  4. Medicaments useful in particular for its analgesic and antidepressant properties, the compounds according to any one of claims 1 to 3.  5. Pharmaceutical composition, characterized in that it comprises at least one drug according to claim 4, in association with a pharmaceutically acceptable component.  6. Process for the preparation of the compounds of formula (I) for which the chain A = B represents the C = CH unit and corresponding salts, characterized in that it consists in conducing the dimethylamine with the mesylate of the compounds of formula

 in which the pair (R4, n) @ (phenyl, 3), (o-fluorophenyl, 1), (ofluorophenyl, 2) or (o-fluorophenyl, 3), and then optionally to salify the products thus obtained, with an acid mineral or organic.  the sequence A = B represents the C = N unit, and R31 = 4-CH3, H, 3,4-diOCH3, then optionally to salify the resulting products with a mineral or organic acid.  in which R11 and R21 and of torque (n1, R5) respectively have the same meaning as R1 and R2 and the pair (n, R) in the formula (I) according to claim 1, when

 7. Process for the preparation of compounds of formula (I) for which the chain A = B represents the C = N unit and corresponding salts, characterized in that it consists in cyclizing the compounds of formula;  8. Process according to claim 7, characterized in that the cyclization is carried out by phosphorus oxychloride in an inert solvent.  9. Process for the preparation of the compounds of formula (I) for which the chain A T B represents the C = N unit and the corresponding salts, characterized in that it consists in condensing the amines of formula

 in which  - R13 = R23 = CH3 or - R13 and R23 together with the nitrogen atom to which they are attached form a radical CH3

 with the mesylates of the appropriate alcohols of the formula

 where the pair (R5, R34) = phenyl, 7

 phenyl, H), (m-CF 3 phenyl, H), (phenyl, 6,7-di OCH 3), (phenyl, 5-Ci) or (phenyl, 7-OCH 3), and then optionally to salify the products obtained, by a organic or mineral acid.  10. As synthetic intermediates necessary for the preparation of the compounds of formula (I), the compounds of formula (II), of formula (VI) and of formula (XVIII), respectively defined in claims 6, 7 and 9 .  11. As synthetic intermediates necessary for the preparation of the compounds of formula (I)  compounds of formula

 and,  compounds of formula

 formulas in which:  . R13 = R23 = CH3 in which case R33 = 4-CH3, H or 3,4-di OCH3, or. R13 and R23 together with the nitrogen atom to which they are attached form a radical

 in which case R33 = 2-Cl or 4-OCH3.