BE896927A - ISOQUINOLEIN DERIVATIVES, THEIR PREPARATION PROCESS AND MEDICAMENT CONTAINING THEM - Google Patents

Description

       

  EGYT Gyôgyszervegyészeti Gyar

  
The present invention relates to new derivatives of 4-aryl-2-methyl-1,2,3,4-tetrahydro-isoquinoline, to a process for their preparation and to pharmaceutical compositions containing them.

  
8-amino-4-aryl-2-alkyl-tetrahydro-isoquinoline derivatives the amino group of which is substituted by an acyl group derived from a saturated or unsaturated aliphatic carboxylic acid, containing not more than 6 carbon atoms, a aromatic carboxylic acid or an arylaliphatic carboxylic acid containing 7 to 10 carbon atoms, are described in British Patent n [deg.] 1,164,192. These compounds have a thymoleptic and stimulating effect on the central nervous system. Compounds of similar structure are described in the German Patent Applications published before examination n [deg.] 1,670,848 and 1,795,829.

  
The subject of the present invention is new derivatives of 4-aryl-2-methyl-1,2,3,4-tetrahydro-isoquinoline represented by the general formula I below:

  

  <EMI ID = 1.1>


  
and their pharmaceutically acceptable acid addition salts, wherein:

  
R represents a hydrogen atom, a lower alkyl radical or a halogen atom, and

  
X is a group of general formula below:

  

  <EMI ID = 2.1>
 

  
or

  
R and R2 can be the same or different and represent

  
try a hydrogen atom or an alkyl radical

  
  <EMI ID = 3.1>

  
adjacent nitrogen atom to which they are attached, a pentagonal or hexagonal saturated heterocyclic ring, which may optionally contain another oxygen or sulfur atom, or an imino group optionally substituted by a lower alkyl radical; n is an integer equal to 1, 2, 3 or 4;

  
R <3> is an optionally substituted lower alkyl or phenyl group and

  
R is a lower alkyl, halo-lower alkyl or phenyl-lower alkyl group.

  
A preferred subgroup of the compounds of general formula (I) is represented by the general formula (IA) below:

  

  <EMI ID = 4.1>
 

  
  <EMI ID = 5.1>

  
Preferred representatives of the compounds of general formula (IA) are the following compounds:

  
  <EMI ID = 6.1>

  
tetrahydroisoquinoline;

  
and their pharmaceutically acceptable acid addition salts.

  
Another preferred subgroup of the compounds of general formula (I) is represented by the formula (IB) below.

  

  <EMI ID = 7.1>


  
(where R and R are as defined above).

  
Preferred representatives of the compounds of general formula (IB) are the following derivatives:

  
  <EMI ID = 8.1>

  
tetrahydroisoquinoline;

  
and their pharmaceutically acceptable acid addition salts.

  
Yet another preferred subgroup of the compounds of general formula (I) corresponds to the general formula (IC) below

  

  <EMI ID = 9.1>


  
(where R and R4 are as defined above).

  
A preferred representative of the compounds of general formula (IC) is 8- (ethoxycarbonylamino) -4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline and its addition salts pharmaceutically acceptable acids, in particular its hydrochloride. This compound and its salts have particularly advantageous therapeutic properties.

  
The term "lower alkyl group" used in the present context refers to straight or branched chain aliphatic groups having 1 to 6 and in particular 1 to

  
  <EMI ID = 10.1>

  
n-propyl, isopropyl, n-butyl, isobutyl, etc. The term "halogen atom" includes fluorine, chlorine, bromine and iodine atoms. The saturated heterocyclic nucleus pentago-

  
  <EMI ID = 11.1>

  
hundred to which they are attached, can be, for example, a pyrrolidino, piperidino, morpholino, thiomorpholino, pipérazino or pipérazino group in which the nitrogen atom is substituted
(for example, N-alkyl-, or N-benzyl-piperazino groups, such as N-methyl-piperazino). The symbol n is preferably equal to 1 or 2. The substituent R is preferably fixed in the para position of the phenyl ring.

  
R <3>, as an optionally substituted phenyl group, may carry one or more identical substituents

  
or different, such as one or more halogen atoms (for example chlorine, bromine, iodine) and / or an alkyl group (for example, methyl, ethyl, etc.).

  
Acceptable acid addition salts of the point

  
from the pharmaceutical point of view, the compounds of general formula (I) can be formed with pharmaceutically acceptable organic or mineral acids. Thus, the salts can be formed with mineral acids (for example, with hydrohalic acids such as hydrochlorides,

  
hydrobromides), sulfates, phosphates, etc. or organic acids (such as formates, acetates, propionates, lactates, maleates, tartrates, benzoates, salicylates, etc.).

  
According to another characteristic of the present invention, the subject of the invention is a process for the preparation of the compounds of general formula (I) in which

  
R is a hydrogen atom, a halogen atom, an alkyl radical, and

  
  <EMI ID = 12.1>
-NH-R <3> or -OR4, where

  
R <1> and R2 may be the same or different and represent a hydrogen atom or a lower alkyl group, or else R and R2 form, with the adjacent nitrogen atom to which they are attached, a pentagonal or hexagonal saturated heterocyclic ring which may optionally contain another oxygen or sulfur atom, or an amino group optionally substituted by a lower alkyl radical;

  
n is an integer equal to 1,2,3 or 4;

  
R <3> is an optionally substituted lower alkyl or phenyl radical and

  
R4 is a lower alkyl, halo-lower alkyl or phenyl-lower alkyl group
-and their pharmaceutically acceptable acid addition salts, which process consists of:
a) to prepare compounds of general formula <EMI ID = 13.1>

  
reacting a compound of general formula (II) ci) below.

  

  <EMI ID = 14.1>


  
(in which Hlg represents a halogen atom and R and n are as defined above) or a salt thereof, with an amine of general formula (III) below

NHR <1> R <2> (III)

  
  <EMI ID = 15.1>

  
this one; or b) to prepare compounds of general formula IB (where R and R <3> are as defined above), <EMI ID = 16.1>

  
(IV) below:

  

  <EMI ID = 17.1>


  
(where R is as defined above) with an isocyanate represented by the general formula (V) below:

R <3> _NCO (V)

  
(where R <3> is as defined above), or

  
b2) to submit a compound of general formula (VI) below:

  

  <EMI ID = 18.1>


  
(where R and R <3> are as defined above) to a cyclization; or c) to prepare compounds of general formula
(IC) (where R and R4 are as defined above), <EMI ID = 19.1>

  
(IV) (where R is as defined above) with a haloformate of general formula (VII) below:

  
Hlg-COOR4 (VII)
(where Hlg is a halogen atom, preferably chlorine or bromine, and R4 is as defined above); or

  
c2) to submit a compound of general formula
(VIII) below:

  

  <EMI ID = 20.1>


  
(where R and R4 are as defined above) to a cyclization, and if desired, to convert a compound of general formula (I) into one of its acid addition salts acceptable from the point of view pharmaceutical.

  
According to process a) of the present invention, a compound of general formula (II) or a salt thereof is reacted with an amine of general formula (III) or a salt thereof. This reaction can preferably be carried out in an inert organic solvent. As reaction medium, it is preferably possible to use aliphatic alcohols, in particular methanol or ethanol. The reaction can be carried out at elevated temperature, preferably at the boiling point of the reaction mixture.

  
The starting materials for general formulas (II) and
(III) can also be used in the form of their acid addition salts (for example, hydrochlorides).

  
The reaction mixture can be treated according to methods known in themselves. Thus, one can proceed by removing the solvent by distillation and isolating the product.
- by extraction with an organic solvent.

  
The starting materials of general formula (II) can be prepared from the compounds of general formula (XI) below:

  

  <EMI ID = 21.1>


  
(where R is as defined above) by two methods:

  
In accordance with the first method, a compound of general formula (XI) is subjected to a cyclization and the compound of general formula (IV) thus obtained is reacted with an acid halide of general formula (X) below:

  
  <EMI ID = 22.1>

  
  <EMI ID = 23.1>

  
halogen, preferably a chlorine atom).

  
The cyclization of the compounds of general formula (XI) can be carried out in an inert organic solvent. As the reaction medium, halogenated hydrocarbons (for example methylene chloride, chloroform, etc.) can be used. The reaction can be carried out in the presence of an acid catalyst. Mineral acids can be used for this purpose (for example, sulfuric acid, polyphosphoric acid or polyphosphates, etc.). The reaction already takes place at low temperature, for example at 0 - 5 [deg.] C.

  
The reaction of the compound of general formula (IV)

  
  <EMI ID = 24.1>
-general (X) can be carried out in an inert organic solvent. As the reaction medium, it is possible to use preferably aromatic hydrocarbons (for example, benzene, toluene, xylene, etc.). The reaction can advantageously be carried out at elevated temperature, preferably at the boiling point of the reaction mixture. The reaction can be carried out in the presence of an acid fixing agent (for example a tertiary organic base, such as triethylamine, quinoline, etc.).

  
The compound of general formula (II) can be isolated from the reaction mixture by known methods (for example, filtration, crystallization, etc.).

  
The crude compounds of general formula (II) can be directly used for the preparation of the compounds of general formula (I) without purification.

  
According to another method, the starting materials of general formula (II) can be prepared by reacting a compound of general formula (XI) with a halo-acid halide of general formula (X) by subjecting the compound of general formula (IX) below:

  

  <EMI ID = 25.1>


  
thus obtained by cyclization (R, Hlg and n being as defined above).

  
The reaction of the compounds of general formulas (XI) and (X) can be carried out in a manner analogous to that of the compounds of general formulas (IV) and (X). The cyclization of the compound of general formula (IX) can be carried out in a similar manner to that which is carried out for the cyclization of the compounds of general formula (XI).

  
The compounds of general formulas (IV) and (XI) are either known (British patent n [deg.] 1,164,192), or can be prepared according to known methods.

  
  <EMI ID = 26.1>

  
tion, a compound of general formula (IV) is reacted with an isocyanate of general formula (V). The reaction is carried out in an inert organic solvent. As reaction medium, it is possible to use preferably aromatic hydrocarbons (for example benzene, toluene, xylene, etc.).

  
The reaction can be carried out hot, preferably at the boiling point of the reaction mixture.

  
The reaction mixture can be treated according to methods known in themselves. Thus, the solvent can be evaporated and the residue purified by chromatographic methods.

  
The starting materials of general formula (IV) can be prepared by cyclization of the compounds of general formula (XI).

  
In accordance with method b2), a compound of formula
-general (VI) is subject to cyclization. The cyclization is carried out in the presence of an acid catalyst. Mineral acids (for example, sulfuric acid, polyphosporic acid, etc.) or Lewis acids (for example, boron trifluoride, aluminum chloride, chloride can be used for this purpose. zinc, tin chloride, etc. The sulfuric acid is a particularly useful acid catalyst. The reaction is carried out in an organic solvent, preferably in a halogenated hydrocarbon (for example, methylene chloride, chloroform The reaction temperature depends on the activity of the catalyst, if sulfuric acid is used as a catalyst, the reaction takes place quickly already at low temperature, for example at 0 - 6 [deg.] C.

  
The reaction mixture can be treated according to methods known in themselves. If sulfuric acid is used as a catalyst, the acid reaction mixture is poured onto ice, the mixture obtained is made alkaline and the product is isolated by extraction. As extractants, halogenated hydrocarbons can preferably be used
(for example, chloroform).

  
The starting materials of general formula (VI) can be prepared by reacting a compound of general formula (XI) with an isocyanate of general formula (V). The reaction is carried out in a manner analogous to that of

  
  <EMI ID = 27.1>

  
  <EMI ID = 28.1>

  
tion, a compound of general formula (IV) is reacted with a halo-formate of general formula (VII). It is preferred to use compounds of general formula (VII) in which Hlg is a chlorine atom. The reaction is carried out in an inert organic solvent. As reaction medium, aromatic hydrocarbons can preferably be used

  
(for example benzene, toluene, xylene, etc.). The reaction can preferably be carried out at elevated temperature, in particular at the boiling point of the reaction mixture. The reaction can also be carried out in the absence of a solvent. The reaction can preferably be carried out in the presence of an acid-fixing agent, such as tertiary amines, for example, triethylainine. or quinoline.

  
The reaction mixture can be treated according to methods known in themselves. Thus, it is possible to proceed by evaporation of the reaction mixture, alkalization of the residue (for example, with ammonium hydroxide) and extraction of the desired compound of general formula (I) with an organic solvent
(for example, chloroform).

  
The compounds of general formula (IV) used as starting material can be prepared by subjecting a compound of general formula (XII) to cyclization.

  
  <EMI ID = 29.1>

  
a compound of general formula (VIII) is subjected to a cyclization. Cyclization can be carried out in the presence of an acid catalyst, for example mineral acids (such as hydrochloric acid, sulfuric acid, polyphosphoric acid, etc.) or Lewis acids (for example aluminum chloride, boron trifluoride, zinc or tin chloride, etc.). It is particularly advantageous to work in the presence of sulfuric acid as a catalyst.

  
The reaction is carried out in an inert organic solvent. As the reaction medium, halogenated hydrocarbons can be used (for example, methylene chloride, chloroform, etc.). The reaction temperature depends on the activity of the catalyst; the reaction can generally be carried out between 0-80 [deg.] C.

  
The compounds of general formula (I) can be isolated by methods known per se. If sulfuric acid is used as a catalyst, this can preferably be done by pouring the sulfuric acid solution onto ice, basifying the mixture and purifying the compound.

  
of general formula (I) by extraction with an organic solvent (for example chloroform).

  
The starting materials of general formula (VIII) can be prepared by reacting a compound of general formula (XI) with a halogeno-formate of general formula
(VII). The reaction can be carried out in a manner analogous to that of process cI).

  
The compounds of general formula (VIII) thus obtained can be subjected to cyclization after or - preferably - without isolation.

  
The compounds of general formula (I) thus obtained can be converted into their acid addition salts formed with pharmaceutically acceptable acids. Salt formation can be carried out by usual and generally known methods. Thus, it is preferable to proceed by reacting a compound of general formula (I)

  
with the corresponding acid, in a suitable inert organic solvent. The acid is preferably used in a stoichiometric amount. It is also possible to release the compound of general formula (I) from a pharmaceutically unacceptable salt, using a strong base and to react the free base of general formula (I) with the acid. pharmaceutical acceptable correspondent.

  
The new compounds of general formula (I) and their pharmaceutically acceptable acid addition salts have useful pharmaceutical properties and exert particularly beneficial effects on the central nervous system.

  
The compounds according to the present invention are particularly useful as active constituents in antidepressant agents and antiparkinsonn agents.

  
In accordance with another characteristic of the present invention, the subject of the invention is pharmaceutical compositions comprising one or more compounds of general formula (I) or a pharmaceutically acceptable acid addition salt thereof, in admixture with suitable inert pharmaceutical carriers and / or carriers.

  
The pharmaceutical compositions can be put into forms suitable for oral administration (for example, tablets, capsules, pills, sugar-coated pills, dragees, solutions, emulsions, suspensions) or parenteral (for example, injections). The pharmaceutical compositions can contain the usual inert, solid or: liquid supports (for example, talc, starch, magnesium stearate, maize carbonate

  
  <EMI ID = 30.1>

  
passes, etc.). The compositions can also comprise pharmaceutical adjuvants (for example, wetting agents, disintegrating agents, flavoring agents, taste correcting agents, etc.).

  
The pharmaceutical compositions in accordance with the present invention can be prepared by methods known per se from the pharmaceutical industry.

  
In addition to the foregoing provisions, the invention also comprises other provisions, which will emerge from the description which follows.

  
The invention will be better understood with the aid of the additional description which follows, which refers to examples of implementation of the method which is the subject of the present invention.

  
It should be understood, however, that these examples of implementation are given solely by way of illustration of the subject of the invention, of which they do not in any way constitute a limitation.

  
The pharmacological activity of the compounds in accordance with the present invention is determined by the following tests:

  
  <EMI ID = 31.1> <EMI ID = 32.1>

  
96 hours.

  
2.) Dose s.c. which inhibits catalepsy induced by a dose of 13 moles / kg of haloperidol, in 50% of the mice.

  
3.) The lowest i.p. (intraperitoneal) which further increases or decreases the spontaneous mobility of mice.

  
4.) Dose s.c. which inhibits catalepsy induced by a dose of 110 pmol / kg of tetrabenazine, in 50% of the mice.

  
5.) Dose s.c. which inhibits ptosis induced by a dose of 79 pmol / kg of tetrabenazine, in 50% of the mice.

  
6.) The lowest dose s.c. which still prevents the decrease in rectal temperature caused by the administration

  
  <EMI ID = 33.1>

  
7.) The lowest dose s.c. which further increases the blood pressure and the scalloping effect of the membrane in cats.

  
8.) The lowest dose s.c. which still induces stereotypy in rats.

  
9.) The dose which induces the characteristic behavior of movement in circles after the electrolytic lesion of the substantia nigra.

  
10.) The dose which induces a significant decrease in the level of prolactin after a 4-day treatment with a dose

  
  <EMI ID = 34.1>

  
three weeks earlier.

  
The following test compounds are used:
- Compound A = product of Example 4
- Compound B = product of Example 8
- Compound C = product of Example 10
- Compound D = product of Example 11
- Compound E = product of Example 17
- Compound F = product of Example 18
- Compound G = product of Example 13
- Compound H = product of Example 12 - Compound I = product of Example 20
- Nomifensine = reference compound, namely the <EMI ID = 35.1>

  
described in British Patent No. [deg.] 1,164,192.

  
The test results are summarized in Tables I and II below.

  

  <EMI ID = 36.1>


  

  <EMI ID = 37.1>
 

TABLE II

  

  <EMI ID = 38.1>


  
Acute toxicity data are determined in mice. Tests 2 to 6 are also carried out at

  
mice. The doses are expressed in oles moles / kg. The therapeutic index (I.T.) is the quotient of DL / DE.

  
In test 3: "+ = increased mobility and" - = decreased mobility.

  
The sign "> signifies that at the given dose, the compound is inactive.

  
TBZ = Tetrabenazine

  
Tests 7 to 10 are carried out on cats and

  
rats, doses are expressed in & moles / kg.

  
Tests 2,8,9 and 10 are suitable for evaluating the stimulating effect of dopamine formation of the test compounds (potential antiparkinsian agent). Tests 4,5, 6 and 7 provide information on the inhibitory effect of taking catecholamine (potential antidepressant activity).

  
The reference compound, Nomifensine, is a well-known antiparkinsian and antidepressant agent.

  
The new compounds of general formula (I) do not increase the spontaneous mobility of the mouse, unlike Nomifensine which increases it. The absence of this psychomotor stimulating effect analogous to that of amphetamine is favorable from a therapeutic point of view.

  
Compound C outperforms Nomifensin activity in three tests. Compound D is more active than Nomifensine in several tests also and in the anti-reserpine test, it has a more interesting therapeutic index. Compounds G and H have a very high activity and give a good therapeutic index. Compound I has remarkable therapeutic properties. Its toxicity is much lower and its activity is higher than that of Nomifensin; the therapeutic index of compound I is approximately 2 to 6.8 times higher than that of Nomifensine, in the various

  
tests.

  
By comparing the anti-haloperidol test of the dopamine generator type and the anti-tetrabenazine activity being characteristic of the antidepressant effect, it can be established that:

  
The quotient of the ED values in columns 2 and 4 is

  
  <EMI ID = 39.1>

  
that this compound is relatively a stronger antidepressant than it is an antiparkinsian agent. This quotient is high in the case of Nomifensine (1.6), compound D (1.8), compound E (2.7) and compound F (1.7).

  
On the other hand, this quotient is low in the case of compounds G and H, which have a stronger anti-dopamine, antipartkinsonnien activity.

  
EXAMPLE 1

  
  <EMI ID = 40.1>

  
A mixture of 5.3 g (0.015 mole) of 4-phenyl-8- (chloroacetyl-amino) -2-methyl1,2,3,4-tetrahydro-isoquinoline hydrochloride is reacted, 15 ml (10, 4 g, 0.23 mol) of ethylamine and 50 ml of ethanol in a sealed tube at 60 ° C. for 5 hours. The reaction mixture is evaporated, the residual oil (7.1 g) is triturated with 50 ml of water, the mixture is basified by addition of 30 ml of an aqueous solution

  
at 30% sodium hydroxide, with stirring and cooling. The mixture is extracted 10 times each time with a 100 ml portion of ether. The ethereal solution is dried

  
on anhydrous sodium sulfate and evaporated. The residual oil is triturated with petroleum ether. 4.3 g (0.0133 mole) of 8-ethylamino-acetylamino-4phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline are thus obtained in the form of a white-yellowish powder.

  
The base thus obtained is dissolved in 30 ml of ethanol and a solution of 1.6 g (0.01238 mole) of maleic acid and

  
15 ml of ethanol are added to it. The precipitated product is separated by filtration. 5.2 g of the product are thus obtained

  
whose name is indicated in the title, P.F. 169 [deg.] C. By recrystallization from 50 ml of ethanol, 4.7 g of the pure compound are obtained. Yield: 71.2%, m.p. 170 [deg.] C

  
Analysis: C24H29N304 (439,515)

  
Calculated values: C% = 65.60 H% = 6.65 N% = 9.56 Values found: C% = 65.38 H% = 6.74 N% = 9.62

  
8- (ethylamino-acetylamino) -4-phenyl-2-methyl1,2,3,4-tetrahydro-isoquinoline base melts at 111 [deg.] C (from a mixture of benzene and petroleum ether ).

  
  <EMI ID = 41.1>

  
Calculated values: C% = 74.27 H% = 7.79 N% = 12.99 Values found: C% = 74.41 H% = 7.97 N% = 13.13

  
The starting material can be prepared as follows: Dissolve 31.9 g (0.09 mole) of 8 amino-4-phenyl-2- methyl maleate -1,2,3,4- tetrahydro- isoquinoline in 200 ml of water, then 500 ml of ether are added and the mixture is made alkaline by adding 150 ml of a 30% aqueous solution of sodium hydroxide under cooling and stirring. The ethereal phase is separated and the aqueous layer is again extracted three times with successive portions of 300 ml of ether. The combined ethereal solution is dried over anhydrous sodium sulfate and evaporated in vacuo (25 [deg.] C /
20 Torr). The residual yellow oil (22.5 g) is dissolved in
600 ml of anhydrous benzene and a solution of 7.6 ml (11.4 g, 0.101 mole) of chloroacetyl chloride and 40 ml of anhydrous benzene is added dropwise with stirring.

   The reaction mixture is heated at reflux for 2 hours and cooled. The precipitated product is filtered, washed three times with 60 ml portions of anhydrous benzene and three times with 70 ml portions of anhydrous ether. 32 a of a white powder is thus obtained. P.F.217 [deg.] C (decomposition). After recrystallization from 230 ml of ethanol, 25.5 g of the desired product are obtained in the form of a white powder. Yield: 81%; P.F. 222 [deg.] C (decomposition).

  
Analysis: C18H20C12N20 (M = 351.278)

  
Calculated values: C% = 61.54 H% = 5.74 N% = 7.97

  
  <EMI ID = 42.1>

  
Values found: C% = 61.23 H% = 5.66 N% = 8.00

Cl% = 20.41 CI% = 10.17

  
The starting material can also be prepared from

  
as follows: 3.12 g (0.012 mol) of N-L2amino-benzyl7-1-phenyl-2-methylamino-1-ethanol are dissolved in 70 ml of anhydrous ether, then added dropwise 0 , 95 g
(0.012 mole) of anhydrous pyridine and then 1.62 g (0.0144 mole) of chloroacetyl chloride with vigorous stirring and cooling with ice to 3-6 [deg.] C. The white-yellowish reaction mixture containing a precipitate is stirred

  
at room temperature for 30 minutes, poured into

  
100 ml of ice water and extracted three times with 100 ml portions of ether. The ethereal solution is dried over anhydrous sodium sulfate for 30 minutes and evaporated in vacuo without heating. The crude N-chloroacetylated compound thus obtained is immediately subjected to a cyclization.

  
The oily product obtained in the previous paragraph is dissolved in 30 ml of dichloromethane, filtered and poured into 20 ml of concentrated sulfuric acid. The reaction mixture is stirred at 0-3 [deg.] C for 15 minutes and stirring is continued for an additional 20 minutes. The reaction mixture is poured onto 100 g of ice and extracted

  
four times with 200 ml portions of chloroform. The organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo. 3.0 g of an orange powder are thus obtained. The product is washed three times with 30 ml portions of ether. 2.3 g of a beige powder are thus obtained. After recrystallization from ethanol, 1.6 g are obtained.

  
  <EMI ID = 43.1>

  
hydroisoquinoline in the form of a white powder; yield: 42.4%; M.P. 240 [deg.] C (decomposition).

  
  <EMI ID = 44.1>

  
Calculated values: C% = 68.67 H% = 6.08 N% = 8.90 Cl% = 11.26 Values found: C% = 68.42 H% = 5.95 N% = 8.96 Cl% = 11.12

  
1.5 g (0.00475 mole) of the above base are put

  
suspended in 5 ml of ethanol, then 5 ml of ether saturated with hydrochloric acid are added hot and the solution is made cloudy by addition of ether. The precipitated product is filtered cold. 1.5 g of hydrochloride are thus obtained.

  
  <EMI ID = 45.1>

  
hydro-isoquinoline in the form of a white powder. Yield: 38.2%; P.F.222 [deg.] C '(decomposition). EXAMPLE 2

  
  <EMI ID = 46.1>

  
A mixture of 4.27 g (0.0122 mole) of 4-phenyl-8- (chloroacetylamino) -2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, 50 ml of ethanol and 15 ml (10.4 g, 0.176 mole) of isopropylamine is heated to boiling for 5 hours.

  
The reaction mixture is evaporated and the sticky residue (6.5 g) is dissolved in 100 ml of water; then, the solution is made alkaline by addition of 10 ml of a 30% sodium hydroxide solution, with stirring and cooling. The aqueous layer is extracted five times with portions of

  
200 ml of ether and the combined ethereal solutions are dried over anhydrous sodium sulfate and evaporated in vacuo. The residual yellow oil (4.4 g) is dissolved in 50 ml of ethanol and a solution of 3.5 g (0.03 mole) of maleic acid and

  
10 ml of ethanol is added with stirring. The precipitated product is filtered cold, washed twice with 10 ml portions of ethanol (6 g) and recrystallized from 45 ml of ethanol. 5.3 g of dimaleate are thus obtained; P.F. 170 [deg.] C.

  
The above dimaleate is dissolved in 30 ml

  
of water and added with 100 ml of ether. The solution is made alkaline by adding 10 ml of a 30% aqueous solution of sodium hydroxide, with stirring and cooling. The ethereal phase is separated, the aqueous layer is extracted

  
twice in 100 ml portions and twice in 50 ml portions of ether. The combined ethereal extracts are dried over anhydrous sodium sulfate and the ether is evaporated in vacuo. This gives 3.15 g (9.35 millimoles)

  
of the raw base (P.F. 89 [deg.] C). This crude base is dissolved in 47 ml of ethanol and a solution of 1.1 g (9.45 millimoles) of maleic acid and 30 ml of ether is added. A white powder (4.1 g) is obtained which is recrystallized from
40 ml of ethanol to obtain 3.45 G of the product whose name is indicated in the title. Yield: 62.6%; M.P. 134 [deg.] C

  
  <EMI ID = 47.1>

  
Calculated values: C% = 66.22 H% = 6.89 N% = 9.29 Values found: C% = 66.23 H% = 7.03 N% = 9.33

  
The free base forms white-yellowish crystals melting at 91 [deg.] C (from a mixture of benzene and petroleum ether).

  
Analysis: C21H27N30

  
Calculated values: C% 74.74 H% = 8.07 N% = 12.45 Values found: C% = 74.68 H% = 8.21 N% = 12.49 EXAMPLE 3

  
  <EMI ID = 48.1>

  
isoquinoline, 50 ml of ethanol and 10 ml (7.39 g, 0.1 mole) of butylamine is heated at reflux for 5 hours. The reaction mixture is evaporated in vacuo and the residue is washed 10 times with 50 ml portions of anhydrous ether. The ethereal washing liquid is evaporated in vacuo until dry, the residue

  
is stirred three times with 10 ml portions of benzene, the benzene being evaporated in each case. 3.3 g of a yellowish oil are thus obtained. This oil is dissolved in 30 ml of ethanol and a solution of 1.2 g (0.01 mole) of maleic acid and 10 ml of ethanol are added. The precipitate (2.9 g; m.p. 172 [deg.] C) is recrystallized from ethanol. 2.3 g of the pure compound are thus obtained, the name of which is indicated in the title; Yield: 49.2%; P.F. 174 [deg.] C.

  
  <EMI ID = 49.1>

  
Calculated values: C% = 66.79 H% = 7.11 N% = 8.99 Values found: C% = 66.80 H% = 7.10 N% = 9.24 EXAMPLE 4

  
  <EMI ID = 50.1>

  
A mixture of 7.0 g (0.02 mole) of 4phenyl-8- (chloroacetylamino) -2-methyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride, 70 ml of ethanol and 20 ml (17.0 g, 0.24 mol) of pyrrolidine is heated at reflux for 5 hours. The reaction mixture is evaporated in vacuo, the residue is dissolved

  
in a mixture of 100 ml of water and 100 ml of ether and the mixture is made alkaline by addition of 30 ml of a 30% aqueous solution of sodium hydroxide, with cooling and stirring.

  
The layers are separated, the aqueous phase is extracted

  
5 times in 100 ml portions of ether, the organic phase is dried over anhydrous sodium sulphate, clarified using active charcoal and evaporated. The residue is dissolved in 100 ml of hot ethanol and a solution of 6.6 g (0.057 mole) of maleic acid and 40 ml of ethanol are added. The product is precipitated by adding 1000 ml of ether. The sticky solid dimaleate is dissolved in 100 ml of water and the solution is made alkaline by adding 60 ml of a 30% aqueous solution of sodium hydroxide, with cooling and stirring. The aqueous layer is extracted once with 200 ml and four times with 100 ml portions of ether. The ethereal phases are combined, dried over anhydrous sodium sulfate and clarified using active charcoal.

   The ether is evaporated and the residue is washed with a mixture of ether and petroleum ether. 5.4 g of 4-phenyl-2-methyl-8- / pyrro- are thus obtained.

  
  <EMI ID = 51.1>

  
the form of white crystals (0.0154 mole); P.F. 130 [deg.] C.

  
The free base thus obtained is suspended in 100 ml of ethanol and a solution of 3.6 g is added.
(0.0315 mole) of maleic acid and 36 ml of ethanol. After dissolving the base, the solution is diluted with 150 ml of ether, the precipitate is filtered cold (9 g) and recrystallized from ethanol and ether. 7.3 g of the compound are thus obtained, the name of which is indicated in the title; yield:
2.9%; P.F. 120 [deg.] C.

  
  <EMI ID = 52.1>

  
Calculated values: C% = 61.95 H% = 6.07 N% = 7.22 Values found: C% = 61.64 H% = 6.40 N% = 6.93

  
The free base forms white crystals, melting at 130 [deg.] C.

  
  <EMI ID = 53.1>

  
Calculated values: C% = 75.61 H% = 7.81 N% = 12.02 Values found: C% = 75.77 H% = 8.02 N% = 12.16 EXAMPLE 5

  
  <EMI ID = 54.1>

  
A mixture of 4.3 g (0.0122 mole) of 4-phenyl-8- (chloroacetylamino) -2-methyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride, 70 ml of ethanol and 15 ml (12.9 g, 0.15 mole) of piperidine is heated at reflux for 5 hours. The reaction mixture is evaporated, the residue is dissolved in 100 ml of water and basified by addition of 15 ml of a 30% aqueous solution of sodium hydroxide, with stirring and cooling. The aqueous solution is extracted once with 200 ml and four times with 100 ml portions of benzene, the benzene extracts are combined, dried over anhydrous sodium sulfate and evaporated. The oily residue

  
(5.6 g) is dissolved in 50 ml of ethanol and a solution of 3.5 g (0.08 mole) of maleic acid and 10 ml of ethanol is added. The precipitate is separated by filtration (5.9 g) and recrystallized from ethanol. 5.0 g of the dimaleate are thus obtained.

  
The dimaleate is dissolved in 30 ml of water and 100 ml of ether are added, then the solution is basified by addition of 10 ml of a 30% aqueous solution of sodium hydroxide, with stirring and cooling. The layers are separated, the aqueous phase is extracted once per 100 ml and twice with 50 ml portions of ether, the ethereal solutions are combined and dried over anhydrous sodium sulfate and evaporated. 3.2 g (0.0085 mole) is thus obtained.

  
of 4-phenyl-2-methyl-8- (piperidino-acetylamino) -1,2,3,4tetrahydro-isoquinoline in the form of a yellowish-white product.

  
The free base thus obtained is dissolved in 38 ml of ethanol and 2.03 g (0.0175 mole) of maleic acid is added. The solution is diluted with 20 ml of ether. The precipitated product is filtered cold. The white powder (4.1 g) is recrystallized from ethanol. 3.55 g of the product are thus obtained, the name of which is indicated in the title: yield:
61%. The product has a prolonged non-characteristic melting point.

  
Analysis: C31H37N309 (M = 609.66)

  
Calculated values: C% = 62.51 H% = 6.26 N% = 7.05 Values found: C% = 62.28 H% = 6.29 N% = 7.20

  
The analytical data for the oily base are as follows:

  
Analysis: C23H29N30

  
Calculated values: C% = 75.99 H% = 8.04 N% = 11.56 Values found: C% = 75.60 H% = 8.08 N% = 11.67 EXAMPLE 6

  
  <EMI ID = 55.1>

  
A mixture of 7 g (0.02 mole) of 4-phenyl-8- (chloroacetylamino) -2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, 70 ml of ethanol and 20 ml (20 , 0 g, 0.23 mol) of morpholine is heated at reflux for 5 hours. The reaction mixture is evaporated under vacuum, the residue is dissolved in a mixture of 200 ml of water and 200 ml of ether,

  
30 ml of a 30% aqueous solution of sodium hydroxide are added, the layers are separated and the aqueous phase is extracted four times with 200 ml portions of ether. The combined ethereal solutions are dried over anhydrous sodium sulfate and evaporated. The oily residue
(6.7 g) is dissolved in 100 ml of ethanol and a solution

  
6.6 g (0.057 mole) of maleic acid and 30 ml of methanol are added. The precipitated product is filtered cold. The beige-colored dimaleate (10.7 g) is dissolved in 100 ml of water, the solution is basified by adding 60 ml of a 35% aqueous solution of sodium hydroxide and extracted once with 200 ml and four times in portions

  
100 ml of ether. The ethereal phases are combined, dried over anhydrous sodium sulfate, clarified using activated carbon and dried. The ether is evaporated and the residue is crystallized from a mixture of ether and petroleum ether. 5.1 g (0.014 mole) of 4-phenyl-2-methyl-8- are thus obtained
(white morpholino-acetylamino) -1,2,3,4-tetrahydro-isoquinoline; P.F. 120 [deg.] C.

  
The above free base is dissolved in 70 ml of ethanol and a solution of 3.3 g (0.0284 mole) of maleic acid and 30 ml of ethanol are added to it. The solution is diluted by
15 ml of ether. The precipitated crystals are filtered cold.

  
8.0 g of a white powder are thus obtained. After recrystallization from ethanol, 6.9 g of the compound are collected,

  
the name is indicated in the title, in the form of white crystals. Yield: 58%; P.F. 176 [deg.] C (decomposition).

  
  <EMI ID = 56.1>

  
Calculated values: C% = 60.29 H% = 5.90 N% = 7.03 Values found: C% = 60.11 H% = 5.83 N% = 7.02 The base forms white crystals melting at 120 [deg.] C (petroleum ether ether).

  
  <EMI ID = 57.1>

  
Calculated values: C% = 72.30 H% = 7.45 N% = 11.50 Values found: C% = 72.45 H% = 7.49 N% = 11.58 EXAMPLE 7

  
  <EMI ID = 58.1>

  
A mixture of 4.8 g (0.013 mole) of 4-phenyl-8- (3'-chloro-propionyl) -amino-2-methyl-1,2,3,4- hydrochloride

  
  <EMI ID = 59.1>

  
0.23 mol) of ethylamine is heated in a sealed tube to
60 [deg.] C, for 5 hours. The reaction mixture is evaporated, the residual yellow oil is triturated with 50 ml of water, the solution is basified by addition of 20 ml of a 30% aqueous solution of sodium hydroxide and extracted five times in portions 100 ml and three times with 200 ml portions of benzene. The organic layers are combined, dried over anhydrous sodium sulfate and evaporated in vacuo. 3.5 g of a yellowish-white powder are thus obtained (0.0104 mole of the raw base).

  
The crude base thus obtained is dissolved in 35 ml of ethanol and added with a solution of 1.2 g (0.010 mole) of maleic acid and 5 ml of ethanol. The solution is diluted

  
per 100 ml of ether and cooled. The precipitated product is separated by filtration. This product (4.0 g) is recrystallized from ethanol. 2.8 g of the product are thus obtained, the name of which
-is indicated in the title; yield: 47.4%. The white crystals melt at 162 [deg.] C.

  
Analysis: C25H31N305 (M = 453.54)

  
Calculated values: C% = 66.22 H% - 6.89% N% = 9.29 Values found: C% = 66.13 H% = 7.07 N% = 9.47

  
The starting material can be prepared as follows: 39 g (0.11 mole) of 8-amino4-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline is dissolved in

  
200 ml of water and 500 ml of ether are added thereto. The solution is made alkaline by adding 150 ml of a 30% aqueous solution of sodium hydroxide, with cooling and stirring. The ethereal layer is separated and the aqueous phase is extracted

  
three times with 300 ml portions of ether each time. The combined ethereal solutions are dried over anhydrous sodium sulfate and evaporated in vacuo. The residual yellow oil (24.3 g) is dissolved in 600 ml of anhydrous benzene, then a solution of 14.2 g (0.112 mole) of 3-chloropropionic acid and 50 ml of benzene are added. space of

  
20 minutes and the reaction mixture is heated to boiling for 2 hours. The mixture is cooled, the precipitated product is filtered, washed with ether and air dried. 32.0 g of a white powder are thus obtained. The product is recrystallized from ethanol after dilution with 50 ml of hot ether.

  
22.5 g of the desired compound are thus obtained, yield: 60.4%. The white crystals melt at 220 [deg.] C (decomposition).

  
Analysis: C19H22N20C12 (M = 365.305)

  
Calculated values: C% = 62.47 H% = 6.07 N% = 7.67

  
Cl% = 19.63 CI% = 9.81 Values found: C% = 62.72 H% = 6.17 N% = 7.68

Cl% = 19.33 Ci% = 9.60

  
EXAMPLE 8

  
  <EMI ID = 60.1>

  
A mixture of 4.8 g (0.013 mole) of 4-phenyl-8- (3'-chloro-propionyl) -amino-2-methyl-1,2,3,4tetrahydro-isoquinoline hydrochloride, 50 ml of ethanol and 15 ml (10.4 g, 0.176 mole) of isopropylamine is heated at reflux for

  
5 hours, then the reaction mixture is evaporated in vacuo. The residue is dissolved in 50 ml of water, basified by addition of 20 ml of a 30% aqueous solution of sodium hydroxide, under cooling and stirring, and extracted six times with 150 ml portions of benzene. The benzene solution is dried over anhydrous sodium sulfate and evaporated in vacuo. The residual white oil (5.3 g) is dissolved in 50 ml of ethanol and 1.5 g (0.013 mole) of maleic acid are added thereto. The solution is diluted with 50 ml of ether, cooled and the precipitate is separated by filtration. The white powder (5.6 g) is recrystallized from ethanol. 5.0 g of the compound, the name of which is given in the title, are thus obtained; yield: 77.2%. The white crystals melt at 158 [deg.] C.

  
  <EMI ID = 61.1>

  
Calculated values: C% = 66.79 H% = 7.11 N% = 8.99 Values found: C% = 66.77 H% = 7.32 N% = 8.93

  
  <EMI ID = 62.1>

  
isoquinoline, 50 ml of ethanol and 15 ml (11.0 g, 0.15 mole of butylamine) is heated at reflux for 5 hours. The reaction mixture is evaporated in vacuo; the residue is suspended in 50 ml of water, basified by addition of 20 ml of a 30% by weight aqueous solution of sodium hydroxide and extracted six times with 150 ml portions of ether. The ethereal solutions are combined, dried over

  
anhydrous sodium sulfate and evaporated in vacuo. The residual colorless oil (5.3 g) is dissolved in 60 ml of ethanol and reacted with 1.3 g (0.0112 mole) of maleic acid. The solution is diluted with 100 ml of ether and cooled. The precipitated product is filtered (5.6 g) and recrystallized from ethanol. 4.5 g of the product are thus obtained, the name of which is indicated in the title. Yield: 71.8%. The white crystals melt at 147 [deg.] C.

  
Analysis: C27H35N305 (M 481.60)

  
Calculated values: C% = 67.34 H% = 7.33 N% = 8.72 Values found: C% = 67.49 H% = 7.60 N% = 8.67 EXAMPLE 10

  
  <EMI ID = 63.1>

  
  <EMI ID = 64.1>

  
'is heated in a sealed tube at 60 [deg.] C for 5 hours. The reaction mixture is evaporated, the residual oil is suspended in 50 ml of water and basified by addition of 30 ml of a 35% aqueous solution of sodium hydroxide, then extracted with ether. The ethereal solution is dried over anhydrous sodium sulfate and evaporated. 8.1 g of a yellow oil are thus obtained which is dissolved in 30 ml of ethanol and reacted with a solution of 2.3 g (0.02 mole)

  
of maleic acid in 5 ml of ethanol. The solution is diluted

  
per 40 ml of ether. The precipitate is separated by filtration and dried (10 g), then recrystallized from ethanol. 6.2 g of the compound are thus obtained, the name of which is indicated in the title, yield: 65.2%. White microcrystals melt at 189 [deg.] C
(decomposition).

  
  <EMI ID = 65.1>

  
Calculated values: C% = 60.82 H% = 5.95 N% = 7.48 Values found: C% = 60.98 H% = 6.04 N% = 7.56 The starting material can be prepared from as follows: a solution of 10.9 g (0.04 mole) of 8-amino-4-
(p-chloro-phenyl) -2-methyl-1,2,3,4-tetrahydro-isoquinoline and of 220 ml of anhydrous benzene is added a solution of 5.4 g (0.047 mole, 3.6 ml ) chloroacetyl chloride and 30 ml of anhydrous benzene, with stirring. When the addition is complete, the reaction mixture is heated to boiling for 2.5 hours. The mixture is cooled and

  
the precipitated product is separated by filtration, washed with benzene, acetone and ether, then dried. 14 g of 8- (chloroacetylamino) -4- (pchlorophenyl) -2-methyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride are thus obtained. Yield: 90.9%. The white powder melts at 220 [deg.] C (decomposition).

  
  <EMI ID = 66.1>

  
Calculated values: C% = 56.05 H% = 4.96 N% = 7.26

CI% = 27.25 CI% = 9.08

  
Values found: C% = 56.21 H% = 5.12 N% = 7.42

CI% = 27.32 CI% = 9.12

  
EXAMPLE 11

  
  <EMI ID = 67.1>

  
A mixture of 6.2 g (0.016 mole) of 8- (chloroacetylamino) -4- (p-chloro-phenyl) -2-methyl-1,2,3,4tetrahydro-isoquinoline hydrochloride, 120 ml of ethanol and 20 ml (14.78 g 0.2 mol) of butylamine is heated at reflux for 5 hours. The reaction mixture is evaporated in vacuo, then the residue is taken up in 50 ml of water and basified with 25 ml of a 30% aqueous solution of sodium hydroxide, with stirring and cooling. The mixture is extracted six times with 150 ml portions of benzene; the benzene solutions are combined, dried over anhydrous sodium sulfate and the solvent is distilled off. The yellow residue (7.3 g) is dissolved in 200 ml of ethanol and a solution of 1.9 g (0.064 mole) of maleic acid and 5 ml of ethanol are added to it. The solution is diluted with 400 ml of ether, the precipitate is <EMI ID = 68.1>

  
in ethanol. 4.6 g of the compound, the name of which is given in the title, are thus obtained; yield 57.5%. The white microcrystals melt at 154 [deg.] C.

  
  <EMI ID = 69.1>

  
Calculated values.

  
C% = 62.21 H% = 6.43 N% = 8.37 Cl% = 7.06 Values found:

  
C% = 62.36 H% = 6.70 N% = 8.38 Cl% = 7.04 EXAMPLE 12

  
  <EMI ID = 70.1>

  
A mixture of 5.2 g (0.0145 mole) of 8- (chloroacetylamino) -2-methyl-4- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride, 100 ml ethanol and 30 ml (20.8 g,

  
0.45 mol) of ethylamine is heated in a sealed tube to
70 [deg.] C for 5 hours. The reaction mixture is evaporated, the orange residual oil is dissolved in 50 ml of ethanol and it is reacted with 1.8 g (0.0155 Mole) of maleic acid. The solution is diluted with 150 ml of ether poured in fractions, cooled and the precipitated product is separated by filtration, then washed with a mixture of acetone and ether. The product
(5.7 g, white powder, m.p .: 157 [deg.] C with decomposition) is recrystallized from a mixture of ethanol and ether. 4.3 g of the product are thus obtained, the name of which is indicated in the

  
title. Yield: 66%; M.P. = 176 [deg.] C (decomposition).

  
  <EMI ID = 71.1>

  
Calculated values: C% = 66.20 H% = 6.89 N% = 9.26 Values found: C% = 66.10 H% = 7.39 N% = 9.25

  
The starting material can be prepared from the

  
as follows: a solution of 7.6 g (0.03 mole) of 8-amino2-methyl-4- (p-tolyl) -1,2,3,4-tetrahydroxy-isoquinoline and
100 ml of anhydrous benzene are added to a solution of 4.05 g (0.035 mol, 2.7 ml) of chloroacetyl chloride and 30 ml of anhydrous benzene, poured dropwise, with stirring. The reaction mixture is heated to boiling for 5 hours and cooled. The precipitated product is separated by filtration, washed with ether and dried. 10.1 g of 8- (chloroacetylamino) -2-methyl-4- (p-tolyl) 1,2,3,4-tetrahydro & isoquinoline hydrochloride are thus obtained. yield: 92.6 The white powder melts at 228 [deg.] C (decomposition).

  
Analysis: C19H22C12N20 (M = 365.3)

  
Calculated values:

  
C% = 62.47 H% = 6.07 N% = 7.67 Cl% = 19.41 CI% = 9.70

  
Values found:

  
C% = 62.69 H% = 6.45 N% = 7.58 CI% = 19.64 CI% = 9.73

  
EXAMPLE 13

  
  <EMI ID = 72.1>

  
hydroisoquinoline, 300 ml of ethanol and 20 ml (14.78 g, 0.12 mole) of butylamine is heated to boiling for

  
5 hours. The reaction mixture is evaporated to dryness, the residue is taken up in 50 ml of water and basified by addition of 25 ml of a 30% aqueous solution of sodium hydroxide, with stirring and cooling. The mixture is extracted five times with 150 ml portions of ether,

  
the organic layers are combined, dried and the solvent

  
is removed by vacuum distillation. The residual yellowish-white oil is taken up in 50 ml of ethanol and reacted

  
  <EMI ID = 73.1>

  
melanqe is added with 50 ml of ether. After cooling, the precipitated product is separated by filtration and washed with

  
a mixture of acetone and ether, then dried. We thus obtain

  
6 q of the compound whose name is indicated in the title; yield: 92.0%. The white powder melts at 172 [deg.] C (decomposition).

  
  <EMI ID = 74.1>

  
Calculated values: C% = 67.34 H% = 7.33 N% = 8.73 Values found: C% = 67.60 H% = 7.50 N% = 8.47 EXAMPLE 14

  
  <EMI ID = 75.1>

  
A mixture of 3.6 g (0.015 Mole) of 8-amino-4-phenyl2-methyl-1,2,3,4-tetrahydro-isoquinoline, 1.17 g (0.0165 mole) of isocyanate ethyl and 40 ml of anhydrous benzene is heated at reflux for 2 hours. The reaction mixture is evaporated under vacuum, the residue is dissolved in 40 ml of chloroform, the solution is subjected to chromatography on a column of silica gel, then eluted successively with 250 ml of chloroform containing 10% ethanol and 250 ml of chloroform containing 20% ethanol. The combined eluates are evaporated, the residue (3.8 g) is treated with petroleum ether. The solid product is reacted with a solution of 3.5 g (0.029 mole) of maleic acid in 60 ml of ethanol. The reaction mixture is diluted with 200 ml of ether and cooled.

   The precipitated product is separated by filtration (5.0 g) and recrystallized from a mixture of ethanol and ether. 4.5 g of

  
compound whose name is given in the title. P.F.: 137-
139 [deg.] C (decomposition). After recrystallization from ethanol, 3.7 g of the purified compound sought are obtained. Yield: 77%
140 [deg.] C (decomposition).

  
Analysis: C23H27N305 (425.49)

  
Calculated values: C% = 64.93 H% = 6.40 N% = 9.88 Values found: C% = 65.13 H% = 6.49 N% = 9.92 EXAMPLE 15

  
  <EMI ID = 76.1>

  
The procedure is as in Example 14, except that n-propyl isocyanate is used in place of ethyl isocyanate. 3.5 g of the compound, the name of which is indicated in the title, are thus obtained in the form of white-yellowish crystals. Yield: 53.0%; M.P. 149-150 [deg.] C

  
  <EMI ID = 77.1>

  
Calculated values: C% = 65.59 H% = 6.65 N% = 9.56 Values found: C% = 65.80 H% = 7.08 N% = 9.48 EXAMPLE 16

  
  <EMI ID = 78.1>

  
The procedure is as in Example 14, except that n-butyl isocyanate is used in place of ethyl isocyanate. 1.9 g of the compound, the name of which is indicated in the title, are thus obtained in the form of a powder.

  
  <EMI ID = 79.1>

  
  <EMI ID = 80.1>

  
Calculated values: C% = 66.20 H% = 6.89 N% = 9.26 Values found: C% = 66.32 H% = 6.37 N% = 9.44 EXAMPLE 17

  
  <EMI ID = 81.1>

  
The procedure is described in Example 14, except that 8-amino-4- (p-chloro-phenyl) -2methyl-1,2,3,4-tetrahydro-isoquinoline and isocyanate are used. of n-butyl as starting materials. 7.8 g of the compound are thus obtained, the name of which is indicated in the title, in the form of a white-yellowish powder, yield 32%; M.P .: 134 [deg.] C
(decomposition).

  
  <EMI ID = 82.1>

  
Calculated values:

  
C% = 61.53 H% = 6.20 N% = 8.61 Cl% = 7.27 Values found:

  
C% = 60.97 H% = 6.30 N% = 8.64 Cl% = 7.51

Example 18

  
  <EMI ID = 83.1>

  
The procedure is as described in Example 14, except that 8-amino-2-methyl-4- (p-tolyl) -1,2,3,4- is used.

  
  <EMI ID = 84.1>

  
the name is indicated in the title, in the form of a white-yellowish powder. P.F .: 169 [deg.] C (decomposition). Yield: 41.5%.

  
  <EMI ID = 85.1>

  
Calculated values: C% = 66.79 H% = 7.11 N% = 8.99 Values found: C% = 66.30 H% = 7.30 N% = 8.89

Example 19

  
  <EMI ID = 86.1>

  
of n-butyl isocyanate and 100 ml of anhydrous benzene, is heated under reflux for 2 hours, then the reaction mixture is evaporated under vacuum. 7.2 g of an oil are obtained which solidifies on standing and consists of

  
  <EMI ID = 87.1>

  
amino-1-ethanol.

  
7.2 g of the crude product prepared in accordance with the preceding paragraph are dissolved in 100 ml of methylene chloride, the solution is added dropwise to 4.4 ml of concentrated sulfuric acid, at 2-6 [deg. ] C over 45 minutes and the reaction mixture is stirred at 6 [deg.] C for half an hour. It is poured into 100 g of ice, it is made alkaline with a 30% aqueous solution of sodium hydroxide and it is extracted four times with 100 ml portions of chloroform. The combined chloroform extracts are dried over anhydrous sodium sulfate and evaporated in vacuo. 5.4 g of a yellowish-white solid are thus obtained. The product is dissolved in 30 ml of ethanol and 2.75 g (0.0235 mol) of maleic acid are added.

   The reaction mixture is diluted with 300 ml of ether added in portions, cooled and the precipitated product is separated by filtration and recrystallized from a mixture of ethanol and ether. 6.0 g of the compound are thus obtained, the name of which is indicated in the title; yield 61.6%, M.P .: 145 [deg.] C. The white powder obtained is identical to the product prepared in accordance with Example 16.

Example 20

  
  <EMI ID = 88.1>

  
and 300 ml of anhydrous benzene is mixed with a solution of 6.8 q (0.0625 mole, 6 ml) of ethyl chloroformate and 60 ml of anhydrous benzene. The reaction mixture is heated at reflux for 2.5 hours and the benzene is removed by vacuum distillation. The residue is dissolved in 10 ml of water and basified with 10 ml of a concentrated ammonium hydroxide solution, then extracted

  
three times with 100 ml portions of chloroform. The chloroform extracts are combined, dried over anhydrous sodium sulfate, evaporated and the residue is recrystallized twice from ethanol. 7.3 g of the compound are thus obtained, the name of which is indicated in the title in the form of white crystals, yield: 45.6% P.F .: 155 [deg.] C.

  
  <EMI ID = 89.1>

  
Calculated values:

  
C% = 66.19 H% = 6.14 N% = 8.12 Cl% = 10.28 Values found:

  
C% = 66.79 H% = 5.89 N% = 8.42 Cl% = 10.56

Example 21

  
  <EMI ID = 90.1>

  
7.3 g (0.0212 mole) of the base prepared in accordance with Example 20, are suspended in 50 ml of ethanol and 10 ml of ethanol saturated with hydrochloric acid are added, under cooling. The mixture is made cloudy by adding 200 ml of ether and the precipitation of the product is completed by scraping the wall of the flask. The precipitated product is filtered and washed with ether. 8.1 g of the compound, the name of which is given in the title, are thus obtained in the form of a white powder. Yield: almost
100%. M.P .: 145-150 [deg.] C (decomposition).

  
  <EMI ID = 91.1>

  
Calculated values:

  
C% = 59.85 H% = 5.82 N% = 7.35 Cl% = 18.60

  
  <EMI ID = 92.1>

  
Values found:

  
C% = 59.74 H% = 6.06 N% = 7.17 Cl% = 18.54 CI% = 9.21.

Example 22

  
  <EMI ID = 93.1>

  
A solution of 5.5 g (0.023 mole) of 8-amino4-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline and

  
50 ml of anhydrous benzene are added with a solution of 3.4 g (0.031 mole) of ethyl chloroformate and 30 ml of anhydrous benzene. The reaction mixture is heated

  
at the boil for 3 hours, then the benzene is removed by vacuum distillation. The residue is dissolved in

  
5 ml of water, basified with a 30% aqueous solution of sodium hydroxide and extracted three times with 50 ml portions of chloroform. The chloroform extracts are combined, dried over sodium sulfate and evaporated. The residue is washed with a little cold ethanol and recrystallized from ethanol. 3.0 g of the compound, the name of which is indicated in the title, are thus obtained in the form of white crystals. Yield: 37.5%.

  
P.F.: 178 [deg.] C.

  
  <EMI ID = 94.1>

  
Calculated values: C% = 73.84 H% = 7.15 N% = 9.02 Values found: C% = 73.96 H% = 7.51 N% = 8.95

Example 23

  
  <EMI ID = 95.1>

  
2.6 g (0.01 mole) of N- (2-amino-benzyl) -1-phenyl-2methyl-amino-1-ethanol are dissolved in 30 ml of ether. To this solution is added 0.79 g (0.01 mole) of anhydrous pyridine, then 1.3 g (0.012 mole) of ethyl chloroformate, with vigorous stirring and cooling and the reaction is carried out at 15 [deg. ]VS. The reaction mixture, which contains a white precipitate, is stirred

  
at room temperature for 330 minutes, poured into 30 ml of ice water, the aqueous phase is extracted three times with 100 ml portions of ether; the ethereal extracts are combined and dried over anhydrous sodium sulfate and evaporated in vacuo. We thus obtain

  
  <EMI ID = 96.1>

  
methyl-amino-1-ethanol in the form of a yellowish-white oil, which can be subjected to a subsequent reaction without purification.

  
2.8 g of the oily residue obtained in accordance with the preceding paragraph, are dissolved in 40 ml of dichloromethane and the solution is poured into 15.4 ml of concentrated sulfuric acid at 5-6 [deg.] C in the space of half an hour, with stirring and cooling. The reaction mixture is stirred at this temperature for an additional 20 minutes and poured onto 60 g of ice. The mixture is basified with a 30% aqueous solution of sodium hydroxide, with stirring and cooling, then extracted six times with 80 ml portions of chloroform. The organic phases are combined, dried over anhydrous sodium sulfate and evaporated, under vacuum. 2.3 g of a yellowish-white solid are thus obtained.

   After recrystallization from ethanol, 2.0 g of the compound, the name of which is given in the title, are obtained in the form of white crystals. : 174 [deg.] C. Yield: 64.5%.

Example 24

  
  <EMI ID = 97.1>

  
A solution of 2.4 g (0.01 mole) of 8-amino4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline and
100 ml of anhydrous benzene, is mixed with a solution of 1.4 g (0.012 mole) of butyl chloroformate and

  
10 ml of anhydrous benzene and the reaction mixture is heated to boiling for 2 hours. After cooling, the mixture is diluted with 50 ml of ice water, the pH is adjusted to 9 by adding a concentrated solution of ammonium hydroxide, the benzene phase is separated and extracted twice by portions of 20 ml of benzene, dried over anhydrous sodium sulfate and evaporated in vacuo. 3.6 g of an orange oil are thus obtained. The product is recrystallized twice from ethanol and provides 1.8 g of the product, the name of which is indicated in the title, yield: 52.9%. M.P .: 106 [deg.] C
(White powder) .

  
Analysis: C21H26N202 (M = 338.454)

  
Calculated values: C% = 75.43 H% = 6.63 N% = 8.37 Values found: C% = 75.19 H% = 6.44 N% = 8.57.

Example 25

  
  <EMI ID = 98.1>

  
3.5 g (0.015 mole) of 8-amino-2-methyl-4-phenyl1,2,3,4-tetrahydro-isoquinoline are dissolved in 100 ml of anhydrous benzene, 1.28 g (0.016 mole) of anhydrous pyridine are added and a solution of 2.14 g (0.015 mol) of chloroformate of -chloroethyl and 10 ml of anhydrous benzene is introduced dropwise with stirring and cooling to room temperature. The reaction mixture is stirred at room temperature for one hour, poured into 50 ml of ice water, the organic phase is separated and the aqueous layer is extracted

  
three times with 30 ml portions of benzene. The combined organic solutions are dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. 4.5 g of a yellowish-white substance are thus obtained. The product is recrystallized twice from ethanol to provide 2.7 g of the compound whose name is given in the title. Yield: 52%. The white crystals melt at 154 [deg.] C.

  
  <EMI ID = 99.1>

  
Calculated values:

  
C% - = 66.18 H% = 6.14 N% = 8.12 Cl% = 10.28 Values found:

  
C% = 66.29 H% = 6.24 N% = 8.10 Cl% = 10.38

Example 26

  
  <EMI ID = 100.1> 4.6 g (0.02 mole) of 8-amino-4-phenyl-2-

  
  <EMI ID = 101.1>

  
100 ml of anhydrous benzene.

  
6.2 g of benzyloxycarbonyl chloride 90% (5.2 ml, 0.03 mole) are added to this solution. The reaction mixture is decomposed with 150 ml of water and basified by addition of a 30% aqueous solution of sodium hydroxide, under cooling with ice. The benzene phase is separated and the aqueous layer is extracted twice with portions of
150 ml of benzene and evaporated. The residue is stirred with
150 ml of ether and cooled, then the precipitated product is filtered and washed with cold ether. We thus obtain

  
  <EMI ID = 102.1>

  
recrystallization from ethanol, 3.6 g of the compound whose name is given in the title are obtained; yield:
49%. The white crystals melt at 147-148 [deg.] C.

  
  <EMI ID = 103.1>

  
Calculated values: C% = 77.39 H% = 6.49 N% = 7.50 Values found: C% = 77.50 H% = 6.78 N% = 7.70

  
2.4 g (0.0064 mole) of the above base are suspended in 70 ml of ether and a solution of 0.75 g (0.0064 mole) of maleic acid, and 5 ml of ethanol is added with stirring. The reaction mixture is stirred for 10 minutes and cooled to 0 [deg.] C. The precipitated product is filtered, washed with a mixture of ethanol and ether, then with ether and recrystallized from ethanol. 2.4 g of 8- (benzyloxycarbonyl-amino) -4-phenyl-2-methyl-1,2,3,4tetrahydro-isoquinoline maleate are thus obtained. Yield: 79%. The white powder melts at: 166-167 [deg.] C.

  
Analysis: C28H28N206 (M = 488.544)

  
Calculated values: C% = 68.84 H% = 5.98 N% = 5.73 Values found: C% = 68.76 H% = 5.95 N% = 5.82

  
As is apparent from the above, the invention is in no way limited to. Those. Of its modes of implementation, embodiment and application which have just been described more explicitly; on the contrary, it embraces all the variants which may come to the mind of the technician in the matter, without departing from the framework, or the scope, of the present invention.


    

Claims (11)

1,2,3,4-tetrahydroisoquinoline and their pharmaceutically acceptable acid addition salts. 1 / Derivatives of '4-aryl-2-methyl-1,2,3,4-tetrahydro-isoquinoline characterized in that they are represented by the general formula 1 below:  <EMI ID = 104.1> in which R is a hydrogen atom, a halogen atom or a lower alkyl radical and X represents a group of general formula below: <EMI ID = 105.1> R <1> and R2 may be the same or different and represent a hydrogen atom or a lower alkyl radical, or else R <1> and R2 form, together with the nitrogen atom to which they are attached, a saturated heterocyclic ring pentagonal or hexagonal which may optionally contain another oxygen or sulfur atom, or an imino group optionally substituted by a lower alkyl radical; n is an integer equal to 1, 2, 3 or 4; R <3> is a lower alkyl group or a phenyl group possibly substituted and R is a lower alkyl, halo-alkyl group lower or phenyl-lower alkyl, as well as pharmaceutically acceptable acid addition salts thereof. 2 / Compounds according to Claim 1, characterized in that they are represented by the general formula (I A) below:  <EMI ID = 106.1> and their acid addition salts acceptable from the point of view <EMI ID = 107.1> high). 3 / Compounds according to Claim 1, characterized in that they are represented by the general formula (IB) below  <EMI ID = 108.1> and their pharmaceutically acceptable acid addition salts (where R and R <3> are as defined in Claim 1). 4 / Compounds according to Claim 1, characterized in that they are represented by the general formula (IC) below:  <EMI ID = 109.1> and their pharmaceutically acceptable acid addition salts (where R and R4 are as defined in Claim 1). 4- (p-chloro-phenyl) - 2-methyl-1,2,3,4-tetrahydro-isoquinoline 5 / Compounds according to Claim 1, characterized in that it is 8- (ethylamino-acetylamino) -4-  <EMI ID = 110.1> isoquinoline, de.la 8- (ethylamino-acetylamino) -4- (p-tolyl) -2-methyl-1,2,3,4-tetrahydro-isoquinoline,  <EMI ID = 111.1> 6 / Compounds according to Claim 1, characterized  <EMI ID = 112.1> (p-chloro-phenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline, 8- (n-butyl-carbamoylamino) -4- (p-tolyl) 2-methyl-1,2,3 , 4-tetrahydro-isoquinoline, and their pharmaceutically acceptable acid addition salts. 7 / Compounds according to Claim 1, characterized in  <EMI ID = 113.1> pharmaceutically acceptable acid addition salts. 8 / Compounds according to Claim 1, characterized in  <EMI ID = 114.1> 9 / Process for the preparation of the compounds of general formula (I) according to Claim 1, in which R represents a hydrogen atom, a halogen atom or a radical lower alkyl and  <EMI ID = 115.1> -OR, where R and R2 can be the same or different and represent a hydrogen atom or an alkyl radical, or alternatively R <1> and R2 form, together with the adjacent nitrogen atom to which they are attached, a saturated pentagonal or hexagonal heterocyclic ring which may optionally contain another oxygen atom or sulfur, or an imino group optionally substituted by a lower alkyl radical; n is an integer equal to 1, 2, 3 or 4; R3 is an optionally substituted lower alkyl or phenyl radical and R4 is a lower alkyl, halo-lower alkyl or phenyl-lower alkyl group, and their pharmaceutically acceptable acid addition salts, characterized in that: a / to prepare compounds of general formula (IA) (where R, R <1> -and R2 and n are as defined above.) reacting a compound represented by the general formula (II) below:  <EMI ID = 116.1> (where Hlg is a halogen atom and R and n are as defined above) or a salt thereof, with an amine of general formula (III) below;  <EMI ID = 117.1>  <EMI ID = 118.1> this one; or b) pour.prepare compounds of general formula (IB) (where R and R <3> are as defined above), <EMI ID = 119.1> below (IV):  <EMI ID = 120.1>  (where R is as defined above) with an isocyanate of general formula (V) below  <EMI ID = 121.1> (where R <3> is as defined above) or b2) subject a compound represented by the general formula (VI) below:  <EMI ID = 122.1> (or R and R <3> are as defined above) to a cyclization; or c) to prepare compounds of general formula (IC), (where R and R4 are as defined above), <EMI ID = 123.1> general (IV) (where R is as defined above) with a halo-formate represented by the general formula (VII) below: Hlg - COOR4 (VII) (where Hlg is a halogen atom, preferably chlorine  <EMI ID = 124.1> or  <EMI ID = 125.1> the (VIII) below:  <EMI ID = 126.1> (where R and R4 are as defined above) to a cyclization; and optionally, we convert a compound of general formula (I) into a pharmaceutically acceptable acid addition salt thereof. 10) Process for the preparation of 8- (ethoxycarbonylamino) -4- (p-chloro-phenyl) -2-methyl-1,2,3,4-tetrahydro-  <EMI ID = 127.1> characterized in that the starting materials are used, compounds represented by the general formulas (IV), (VII) and (VIII) where R is a chlorine atom in the para position, R4 is an ethyl group and Hlg a halogen atom, preferably chlorine, and optionally the 8- (ethoxycarbonylamino) -4 is converted - (p-chloro-phenyl) -2-methyl-1,2,3,4-tetrahydro-isoquinoline thus obtained in its hydrochloride. 11) Pharmaceutical compositions characterized in that they comprise, as active ingredient, at least one compound of general formula (I) (where X and R are as defined in Claim 1) or an addition salt of acceptable acids of from a pharmaceutical point of view, mixed with carriers and / or pharmaceutical excipients  <EMI ID = 128.1>