CA1100971A - 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline- acetamide derivatives and a process for the preparation thereof and pharmaceutical compositions containing same - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The invention discloses novel 6,7-dimethoxy- and diethoxy-1,2,3,4-tetrahydro-1-isoquinoline derivatives of the general formulae (I) and (VIII) wherein R1 is hydrogen or benzyloxy-carbonyl, R2 is aryl, substituted aryl or heteroaryl, R4 is methyl or ethyl;
and to a process for the preparation thereof. The invention is also directed to pharmaceutical compositions containing these compounds as active ingredi-ent. The compounds of the present invention are effective antiinflammatory agents.

Description

7~L

The presen~ invention is directed to new 6,7-dimethoxy-1,2,3,4~
tetrahydro-l-isoquinoline derivatives of the general formulae ;:. ;

~eO ~ -Rl (I) CH2-CONI-I-R ~ ~ ' ' and to a process for the preparation thereof, and pharmaceutical compositions containing same as active ingredient.
In the formula I and VIII ~ ;~
Rl is hydrogen or benzyloxy-carbonyl and R2 is phenyl, optionally substituted by Cl 4 alkyl, Cl 4 alkoxy halogen or C2 4 alkanoyl o~xis heteroaryl, preferably pyridyl, thiazolyl or quinoxalyl.
The new compounds of the formula I may be prepared by a~ reacting a 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acettc acid of the formulae MeO ~ (II) .

MeO ~ NH

C112-COO~I

:1 , .

- 2 -,, . ~".

~9~1 with benzylo~ycarbonyl hallde and reacting the thus formed 2-benzylo~y~
carbonyl~6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetic acid of the formula M;O XX~ e O[~ ~ ~

or reactiYe acid derivative of the general formula MeO ~ N-3-o ~ (IV~

MeO
¢H2COR

or ':
' '-1 ::
~' ;

~- ~

~L~0~)~7~

wherein R3 is an atom or atom group capable of activating a carboxyl group such as halogen, acyloxy, alkyloxy, aryloxy or substituted a-ryloxy.
with an amine of the general formula R2 _ NH2 .. ;
wherein R2 is as defined above, and if required removin~ the benzyloxycarbonyl `~
group, If required, the product of formula I can be converted to a pharma- ~ ;ceutically acceptable salt or a compound of formula I can be released from its salt. -;~ :
~ .
.
.:

: .

:
;'"

', L ~ ~ ~

~ )C397~L ;

MeO ~ ~ N~ VII) MeO ~ 2 CH2-CONH-R :~

': ' R2 preferably stands for a phenyl, p-toIyl, 4-fluorophenyl, 4-bromophenyl, 4-methoxyphenyl, 3-chloro-4-methyl-phenyl, 2,4-dibromophenyl, 4-acetylphenyl, 3-pyridyl, 1,3-thiazol-2-yl or 2-quinoxalyl group.
If R3 is halogen, it is preferably chlorine or bromine, if i~ is acyl it may be an aromatic or heterocyclic carboxylic acid radical, preferably Cl ~ alkanoyl, benzoyl, alkoxycarbonyl or he~erocyclic carbonyl, R may further stand for Cl 4 alkoxy, aryloxy, preferably phenoxy, wherein phenyl is substituted with Cl 4 alkyl or nitro.
1-(2-benzyloxycarbonyl-6,7-dimethoxy-~ ~ 5 1,2,3,4-tetrahydro~isoquinolyl) and 6,7-dimethoxy-1,2,3,~-tetrahydro-1-isoquinoline~acetamides of the general formula I are new compo~nds. The N~alkyl- and N-aralkyl-acetamide derivatives, which are structurally the most similar to the compounds of the invention, were prepared by Lombardino, J.G.
et al. ~. Med. Chem. 3, 505 /1961/, United States Patenk No. 3~021,331 C.Ao 57, 786 d /1962/) and the compounds were used as starting materials for the preparation of condensed cyclic compounds.
The abovementioned compounds were used as starting materials also according to United States Patent No. 3,654,281 CoAo 77, 19688a (1972). The biological activity of the compounds of the general formula I of this in-vention could not be foreseen on the basis of the references mentioned above.
According to one embodiment of the present invention 6,7-dimethoxy-1,2,3,4~tetrahydro-1-isoquinoline-acetic acid of the general formula II is reacted with benzyloxycarbonyl chloride. The reaction is carried out in a solvent or in the absence of a solvent at a reaction temperature of (-10) to (~100)C. In the course of the reaction hydrochloric acid is released which is bound with an organic or inorganic base. As organic bases preferably tertiary amines, such as trie~hylamine, dimethylamine or pyridine may be used, but an excess of the isoquinoline derivatives may also be used as an acid binding agentO As inorganic bases an alkali-hydroxide, alkali carbonate, alkali earth metal hydroxide or carbonate may be used. The reaction may be l;
carried out in a solvent. As a solvent water, lower alkyl alcohols, ketones, and ethers may be employed. The reaction may be carried out ~ ~ ~ 6 -. . . , ~ " .

by adding 6,7-dimethoxy-1,2,3~4-tetrahydro-l~isoquinoline-acetic acid to the solution of the equimolar base and benzyloxy-carbonyl chloride is dropped under stirring and cooling. The reaction is complete after stirring for 1 to 8 hours. The product is after acidifying isolated by fil~ration or if desired by evaporation. The solid thus obtained is purified if desired by crystallization or by other physical methods.
T~ obba ned 6~,i7,7dimethoxy-2-benzyloxy-carbonyl-1,2,3,4--tetrahydro-l-isoquinoline-acetic acid is reacted with amines of the general formula V
in the presence of a tertiary amine such as, triethylamine and alkoxy-carbonylchloride such as isobutyloxycarbonyl chloride. The reaction is optionally carried out in a solvent. As a solvent preferably ketones, ethers such as acetone, methylethylketone, tet-rahydrofuran may be employed. The reaction may be carried out at a temperature within the range from ~-15)C
to (~30)C. The tempera*ure is preferably maintained below ~5C during the reaction and completed at 20 to 25C. The product is preferably isolated from the reaction mixture by filtering the formed tertiary amine salt and evaporating tha filtrate. The resildue contains the desired product which is purified, if desired by a physical method, such as crystallization.
According to another embodiment of the present invention an acid chloride is prepared from 6,7-dlmethoxy-2-benzyloxy-carbonyl-1,2,3,4-tetrahydro_isoquinoline- acetic acid of the general formula III or X with an inorganic acid chloride, such as phosphoryl trichloride, or thionyl chloride ; and this acid chloride is ~ - 7 -.. ....~ i 7~

reacted with an amine of the general formula V. The acid chloride is prepared in a solvent such as, benzene, chlorinated solvents, such as chloroform, but the chlorinating agent itself may also be used as a solvent. The acid chlor~
ide is prepared at a t0mperature of 20 to 100 C, preferably at the boiling point of the solvent or the chlorinating agent, as thus the formed hydro-chloric acid gas or sulphur dioxide is removed from the reaction mixture.
After the formation of the acid chloride the excess of the chlorinating agent ;-and the solvent are distilled off and the residual crude acid chloride is employed without purification for the preparation of the amide. The amide ormation is preferably carried out in the presence of an acid binding agent.
As acid binding agents organic and inorganic bases may be used.
The acid chloride or a benzenic solution thereof is simultaneously dropped to the amine or benzenic solution thereof with the aqueous sodium hydroxide or carbonate solutionO According to an alternative solution the acid chloride is added to the mixture or solution of the amine and the organic base, such as triethylamine, In this case the reaction is preferably carried out under anhydrous conditions. The reaction is carried out within 1 to 5 hours at a temperature of -10 to ~100C. The product is isolated by ~iltration or by evaporation of the reaction mixture. The product is, if desired, purified by crystallization or by other physical methods.
According to a further embodiment of the present invention an alkyl or aryl ester of 2-benzyloxy-carbonyl-6,7-dimethoxy-1,2,3,~-tetrahydro-iso-~ .

7~
quinoline~l-acetic acid of the general formula IV (prepared from an acid or acid chloride of the general formula III, by a method known ~er se) is reacted with an amine of the general formula V. The reaction may be carried out in a solvent or in the absence of a solvent by heating the reactants. As a solvent aromatic or aliphatic hydrocarbons~ alcohols, e~hers may be used. The alcohol $ormed during the reaction is preferably distilled off. The reaction mayilbe conducted by using so called active esters such as p-nitro-phenyl-ester, the ester of N-hydroxy-phthalimi~e or 3-hydroxy~4(3H)quinazolinone. The reaction temperature and reaction time depend upon substituent R3, ieO the type of ester used in the reaction~:l In the case of alkyl esters a higher temperature C50 to 150C~ and a longer reaction time is required (2 to 10 hours), than when using aryl esters, particularly active esters~ After th~ reaction is completed the solid is reco~ered by filtration or evaporation. The solid is purified, if desired, by physical methods, such as crystallization.
According to a further alternative method of the present invention . ~b:enzyloxy~carbonyl-6~7-dimethoxy-l~2~3~4-tetrahydro-isoquinoline-l-acetic acid is reacted with amines of the general formula V in the presence of carbodiimides, such as dicyclohexylcarbodiimide. The reaction is preferably performed in a solventO As a solvent preferably aromatic or aliphatic hydrocarbons, such as benzene and homologues thereof, benzine, etc. ketones, such as acetone, acetophenone, ethers, such as ethylether, dioxane, tetra-hydrofuran~ may be employed. The reaction j~ 9 _ .
..

is readily performed, the reaction is thus preferably conducted at a low temperature such as (-20) to (~30)C. In the course of the reaction an urea derivative is formed from the carbodiimide, which precipitates as an in~
soluble solld. After the reaction is complete the insoluble urea derivative is filtered and the filtrate is evaporated in order to recover the product, ~hiChiis~ if desired, purified by crystallization, or by other physical methods.
According to a further alternative method of the invention 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-acetic acid of the general formula III is reacted preferably under heating with amines of the general formula V. The reaction may be performed in the presence or in the absence of a solvent. As a solvent, preferably a solvent immiscible with water is used and the water formed during the reaction is removed by azeotropic distillation. Thus the equilibrium is shifted into the direction of forming the acid amides of formula I. When working without a solvent the !
~ acids of the general formula III are heated together with amines of the ; general formula ~ at lO0 to 200Co The removal of the formed water is desirable in this case too~ This can be achieved by carrying out the reaction in an open vessel, or nitrogen or an other inert gas is passed above the reaction mixture. The reaction may be carried out in vacuo. When using a solvent the solvent is removed by distillation after the reaction is completed and the product thus obtained is, if desired, purified by crystallization.
The benzyloxy_carbonyl ~roup is then removed, if desired, from the obtained 2-benzyloYy-carbonyl-6,7-di-. , ~ ~ - lo -; ,. ,~ ~

97~

methoxy-1,2,3,4~tetrahydro-1-lsoquinoline acetamide derivatives by dissolving the benzyloxy-carbonyl derivative in a concentrated acetic acid containing hydrogen bromide9 and after standing a 6,7-dimethoxy-1,2,3,4-tetrahydro31-isoquinoline-acetamide derivative crystallizes from the solution, and it may be isolated by filtration.
The benzyloxy-carbonyl group may be removed by ca~alytical hydro-genation as well. The benzyloxy-carbonyl derivative is dissolved in a solvent and hydrogenated in the presence of a hydrogen transferring catalyst such as palladium charcoal. The catalyst is filtered off and the product may be re-covered by filtration or evaporation.
The 6,7-dimethoxy-1,2,3~4~tetrahydro-1-isoquinoline-acetamide derivatives of the general formula I - ~wherein Rl = H) - may be prepared by reduci~g the corresponding isoquinoline or dihydro-isoquinoline derivative tooO
The compounds of the present invention are effective antiinflammatory agents. This antiinflammatory activity is higher, than the antiinflammatory activity of the known phenylbutazone and the toxicity of the compounds is also lv~er than that of the phenylbuta~one. Thus N(2-quinoxalyl)-6,7-dimethoxy-1, 253~4-tetrahydro_l-iSoquinoline_acetamide causcs an inhibition of 44 %, in a carrageenine footoedema test in mice in a 25 mg./kg. i.p. dose, and inhibition 20 o~ 30 % in a dose of 2.5 mg./kg. in rats and an inhibition of 47 % in a dose ; of 10 mg./kg. in rats. On administration i.p. of a dose of 80 mg./kg. no death o~ mice i9 observed.

~7 - 11 -,. . .. ~

1~0~97:~L

N-(p-methoxy-phenyl)-6,7-dimethoxy-1 J 2,3,4-tetrahydro-1--isoquinoline-acetamide causes an inhibition of 25 % in a carrageenine foot-oedema test of rats administered i.p. in a dose o 10 mg./kg., and an inhibition of 57 % in a dose of 25 mg./kg.
The toxicity administered to mice i.p. is 280 mg./kg. ~;
l-(p Chlorobenzoyl)-2~methyl-5-methoxy-2-indolylacetic acid: the known indomethacine causes an inhibition of 50 % in the carrageenine foot oedema test of rats administered i.p. in a dose of 10 mg./kg. and the toxicity is 33 mg./kg. administered per os.
The phenylbutazone (~-n-butyl-1,2-diphenyl-pyrazolidine-

-3,5-dione) causes an inhibition o~ 22 % in a carrageenine foot oedema test of rats in a dose of 30 mg./kg. and the toxicity administered p.o. to mice is 660 mg./kg.
The pharmaceutical compositions according to the inven-tion may be prepared in the form for oral, parenteral or local route of administration. Dosage unit forms as tablets, capsules or drgees, solutions for injection, salves, talcs, or spray etc.
may be prepared. The pharmaceutical compositions may contain inorganic or organic solid or liquid carriers, such as water, polyethyleneglycol, talc, starch, calcium carbonate, magnesium stearate, cacao butter, vaseline etc.
The usual excipients may also be added such as stabil-izers, disintegrating agents etc. The compositions are prepared by methods known per se.
The further details of the present invention are illustrated by the following Examples without limiting the scope of the inven~ion to the Examples.
' :~

`' . .. - ..... ,., .. " , .. . . .

7~

Example 1 28.7 g. (0.1 mole) of 6,7-dimethoxy-1,2,3,4-tetrahydro--l-isoquinoline-acetic acid is dissolved in a 50 ml. aqueous solu-tion of 4 g. of sodium hydroxide. The solution is cooled to (-10) to (-15)C and 17 g. (0.1 mole) of benzyloxycarbonyl chloride is dropped to the solution under cooling in 30 minutes. The cooled reaction is stirred for a further 3 hours, whereafter it is acid-ified with 40 ml. of 20 % hydrochloric acid. The precipitated crystals are filtered, washed with water, dried and recrys-tallized.
32.5 g. of 2-benzyloxy-carbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro--l-isoquinoline-acetic acid is obtained.
M.p.: 153-154C

Analysis for the formula C21H26N06 calculated: C 65.44 % H 6.01 % N 3.63 %
found: C 65.26 % H 5.90 % N 3.46 %
Example 2 0.02 mole of 2-benzyloxy-carbonyl-6,7-dimethoxy-1,2,3,4--tetrahydro-l-isoqu moline-acetic acid is dissolved in 80 ml. of anhydrous tetrahydrofuran, the solution is cooled to ~-10) to (-15)C and simultaneously 0.02 mole of triethylamine and 0.02 mole o isobutyloxy-carbonyl chloride are dropped in 5 ml. of tetrahydrofuran within S minutes to the solution ~mder stirring.
After stirring for another 5 minutes 0.02 moles of the correspond-ing amine is added dropwise to the reaction mixture in 20 ml. of tetrahydrofuran, the mixture is stirred for 5 hours and allowed to stand overnight. The precipitated triethylammonium chloride is filtered and washed with tetrahydrofuran. The tetrahydrofuran solutions are evaporated. The residue is dissolved in 70 ml. of ~ .

9i7~

ethyl acetate and washed with 2.6 ml. of water and 1 % sodium-hydroxide solu~ion, and again with water to neutral. The ethyl acetate is dried on sodium sulphate and evaporated in vacuo. The residue is crystallized. The data of the obtained compounds are to be found in Table I.
Example 3 7.7 g. (0.02 moles) of 2-b0nzyloxy-carbonyl-6,7-di-methoxy-1,2,3,4-tetrahydro-1-isoquinDline acetic acid are dis- -solved in 30 ml. chloroform, and the solution is heated with 2.83 g. (0.02~ moles) thionylchloride under reflux for 1 hour.
The reaction mixture is then evaporated in vacuo and the residual acid chloride is dissolved in 10 ml. of benzene.
2.9 g. ~0.02 moles) of 2-amino-quinoxaline is dissolved in 10 ml. of benzene and simultaneously the solution of 2-benzyl-oxy-carbonyl-6,7-dimethoxy-1~2,3,4-tetrahydro-isoquino~lyl-acetyl chloride prepared as described above and 15 ml., of 2 N sodium hydroxide are added dropwise to the mixture at 0C. After the addition is completed the mixture is allowed to warm up and it is stirred at room temperature for 3 hours. After separation the benzenic layer is washed with 2 N sodium hydroxide and water. The benzenic solution is dried and evaporated. 9.4 g. of 2-(2-benzyl-oxy-carbonyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolyl-acetamido)-quinoxaline is obtained. M.p.: 166-167C (from ethanol and ether).
Example 4 10.12 g. (0.02 moles) of p-nitrophenyl-~2-benzyloxy-carbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline)-acetate and 2.14 g. ~0.02 moles) of p-toluidine are heated in 50 ~nl. of toluene under reflux for 3 hours. The reaction mixture is cooled and washed with 1 N sodium hydroxide and with water. The toluene solution is dried on anhrdrous sodium sulphate and evaporated.
9.2 g. of N-tolyl-(2-benzyloxy-carbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-l-isoquinolyl)-acetamide is obtained. M.p. 167-169C
(ethanol).
Example 5 7.7 g. ~0.02 moles) of 2-benzyloxy-carbonyl-6,7-dirnethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid and 1.86 g. ~0.02 moles) of aniline are dissolved in ~0 ml. of tetrahydrofuran and at 0C 4.52 g. ~0.022 moles) of dicyclohexyl-carbodiimide dissolved in 20 ml. ot tetrahydrofuran is added dropwise under stirring. This mixture is stirred at 0C for 1 hour and at room tem~erature for 2 hours. The precipitated dicyclohexyl-urea is filtered, washed with tetrahydrofuran and the filtrate is evaporated.
9.2 g. of 2-benzrloxr-carbonrl-6,7-dimethoxy-1,2,3,4-tetra-hydro-l-isoquinolyl-acetanilide is o~tained. M.p.: 104-106C ~benzene:
ether).
Example 6 7.7 g. (0.02 moles) of 2-benzylo~y-carbonyl-6,7-dimethoxy-1,2,3,~-tetrahydro-1-isoquinoline-acetic acid and 2.9 g. (0.02 moles) of 2-amino-quinoxaline are mixed together and the mixture is heated at 170-180C for 3 hours in under mild nitrogen current. Upon cooling 8.2 g. of 2-(2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolyl-acetamido)-quinoxaline are obtained. M.p. 165-166C
~ethanol:ether) ?
..~.,.

. . -- ~

0~7~

.

:
Example 7 0.02 moles of 2-~enzylox~-carbonyl-6,7-dimethoxy-1,2 f~ t~7~r~h~ o -~O~ 3,4~isoquinoline-acetamide is dissolved in a solution of 4 - 5 eq.
30 % hydrogen bromide solution in glacial acetic acid. After 30 to S0 minutes crystals are precipitated from the solution and the solution gets solid. After adding ether the precipitation of crystals will be complete, the solid is fil~ered and washed with ether. After drying recrystallization follows. The data o:f the obtained products are summarized in Table II.

- ' '.~.

~Y' ~.

99'~

Table I
Physical and chemical constants of the compounds of the formula I
prepared according to ~xample 2 R = benzyloxy-carbonyl R2 M.p. Cryst. Yield Analysis solvent calculated/found C H N
phenyl M.p. 104-106C 86 70.41 6.13 6.08 ~ j benzene-ether 69.9 6.05 6.17 p-tolyl M.p. 168-169C 66 70.86 6.37 5.90 ethanol 70.81 6.41 6.16

4-fluoro- M.p. 142-144C 72 67.77 6.69 5.86 phenyl benzene-ether 67.47 5.75 6.00 4-bromo- M.p. 152-154C 64 60.11 5.04 5.10 phenyl ethanol-ether 59.86 5.00 5.09 4-methoxy- M.p. 145C 86 68.55 6.16 5.71 phenyl benzene-petrol- 68.87 6.55 5.85 ether 3-chloro- M~p. 185-186C 82 69.30 6.02 5.58 4-methyl- benzene 69.64 6.63 6.02 phenyl 2,4-dibromo- M.p. 125~126C 84 66.07 5.74 5.51 phenyl benzene-ether 66.40 6.01 5.74 ~ "
4-acetyl- M.p. 168-169C 76 52.44 4.24 4.53 phenyl benzene 52.55 4.46 4.41 3-pyridyl M.p. 113-115C 89 61.66 5.90 9.11 benzene-ether 67.32 6.15 8.92 1,3-thia- oil 78 51.66 5.39 8.99 zol-2-yl 62.02 5.56 8.75 2-quinox- M.p. 166-167C 70 67.91 5.50 10.93 alyl ethanol-ether 67.89 5.95 10.85 9'7~ `:

Table II
Physical and chemical constants of the compounds of the formula I
prepared according to ~xample 7 R = hydrogen R M.p. cryst. Yield Analysis solvent calculated/found C H N Br phenyl M.p. 232-233C 74 56.02 5.69 6.88 ethanol-water 55.92 5.67 6.49 3:2 ion p-tolyl M.~. 253-254C 84 57.01 5.98 18.97 ethanol-water 57.25 6.10 18.67 3:2 ion 4 fluor- M.p. 232-234C 72 53.65 5.21 6.59 18.19 phenyl ethanol-water 54.02 5.35 6.14 18.18 4:1 ion 4-bromo- M.p. 234-236C 82 46.93 4.56 32.87 phenyl ethanol-water 46.804.50 covalents 3:2 32.90 ~-methoxy- M.p. 238-239 C 90 54.92 5.76 6.40 phenyl ethanol-water 55.125.69 6.63 2:3 ion 3-ehloro- M.p. 224-225C 94 52.705.31 17.53 4-methyl- ethanol-water 53.015.48 17.40 phenyl 4.1 ion 2,4-di- M.p. 207-208C 95 40.38 3.75 4,96 14.13 bromo- ethanol-water 40.79 3.93 4,91 14.57 phenyl 9:1 4-aeetyl- M.p. 206-208C 86 56.13 5.61 6,24 phenyl ethanol-water 55.98 5.85 6.17 7:3 3-pyri- M.p. 224-226C 88 42.61 4.96 8.28 31.51 dyl ethanol-water 42.36 5.12 8.66 30.98 9:1 with 1 mole water ion 1,3-thia- M.p. 238-240C 72 46.39 4.87 19.29 zol-2-yl ethanol-water 46.53 5,03 19.12 1: 1 2-quinoxa- M.p. 192-194C 84 52.83 5.28 11.74 16.76 lyl ethanol-water 52.83 5.23 11.38 16,48 7:3 ' ~ ~

Claims (28)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetamide derivatives and pharmaceutically acceptable salts thereof of the general formula (I) wherein R1 is hydrogen or benzyloxycarbonyl and R2 is phenyl, optionally substituted by C1-4 alkyl, C1-4 alkoxy, halogen or C2-4 alkanoyl or is heteroaryl, which comprises a) reacting a 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid with benzyloxycarbonyl halide and reacting the obtained 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid of the general formula (IV) or a reactive derivative thereof, wherein R3 is an atom or atom group which activates a carboxy group, with an amine of the general formula R2 - NH2 (V) wherein R2 is as defined above, and, if required removing the benzyloxycarbonyl group and, if required, converting a compound of formula I into a pharmaceuti-cally acceptable salt or releasing a compound of formula I from a salt thereof.

2. A process according to claim 1 wherein R2 is pyridyl, thiazolyl or quinoxalyl.

3. A process according to claim 1 wherein R3 is a halogen atom, or an acyloxy, alkyloxy, aryloxy or substituted aryloxy group.

4. A process according to claim 1 which comprises forming a mixed an-hydride from 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetamide with isobutyloxy-carbonyl-chloride and reacting the obtained compound with an amine of the general formula V.

5. A process according to claim 1, which comprises reacting the 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetyl-chloride with an amine of the general formula V.

6. A process according to claim 1, which comprises reacting 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid ester with an amine of the general formula V.

7. A proce.ss according to claim 1, which comprises reacting 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid with an amine of the general formula V in the presence of dicyclohexyl-carbodiimide.

8. A process according to claim 1 which comprises heating 2-benzyloxy-carbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid with an amine of the general formula V.

9. A process according to claim 1, 4 or 5 wherein the benzyloxy-carbonyl group is removed by reacting the benzyloxycarbonyl-1,2,3,4-tetrahydro-1-isoquinoline-acetic amide derivative of formula I with hydrogen bromide in glacial acetic acid.

10. A process according to claim 6, 7 or 8 wherein the benzyloxy-carbonyl group is removed by reacting the benzyloxycarbonyl-1,2,3,4-tetrahydro-1-isoquinoline-acetic amide derivative of formula I with hydrogen bromide in glacial acetic acid.

11. A process as claimed in claim 1, 4 or 5 wherein the benzyloxycarbonyl group is removed by catalytically hydrogenating the 2-benzyloxycarbonyl-1,2, 3,4-tetrahydro-isoquinoline-acetamide derivative of formula I.

12. A process as claimed in claim 6, 7 or 8 wherein the benzyloxycarbonyl group is removed by catalytically hydrogenating the 2-benzyloxycarbonyl-1,2,3,4-tetrahydro-isoquinoline-acetamide derivative of formula I.

13. Compounds of the general formula (I) and pharmaceutically acceptable salts thereof, wherein R1 is hydrogen or benzyloxycarbonyl and R2 is phenyl, optionally substituted by C1-4 alkyl, C1-4 alkoxy, halogen or C2-4 alkanoyl or is heteroaryl, when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.

14. A process according to claim 1 wherein R2 is a phenyl, p-tolyl, 4-fluorophenyl, 4-bromophenyl, 4-methoxyphenyl, 3-chloro-4-methyl-phenyl, 2,4-dibromophenyl, 4-acetylphenyl, 3-pyridyl, 1,3-thiazol-2-yl or 2-quinoxalyl group .

15. A process according to claim 14 wherein R1 is hydrogen.

16. A process according to claim 14 wherein R1 is benzyloxycarbonyl.

17. A process according to claim 1 wherein R1 is hydrogen and R2 is a quinoxalin-2-yl group.

18. A process for preparing N-(2-quinoxalyl)-2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinaline acetamide which comprises reacting 2-amino-quinoxaline with a mixed anhydride formed by reaction between 2-benzyl-oxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isooquinoline and isobutyloxy-carbonyl chloride.

19. A process for preparing N-(2-quinoxalyl)-2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinaline acetamide which comprises reacting 2-amino-quinoxaline with 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoly-acetyl chloride.

20. A process for preparing N-(2-quinoxalyl)-2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinaline acetamide which comprises reacting 2-amino-quinoxaline with2-benzyloxycaxbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetic acid.

21. A process for preparing N-(2-quinoxalyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinaline acetamide which comprises reacting N-(2-quinoxalyl)-2-benzyloxycarbonyl6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetamide with hydrogen bromide in glacial acetic acid to remove the benzyloxycarbonyl group.

22. A process for preparing N-(2-quinoxalyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-l-isoquinaline acetamide which comprises reacting N-(2-quinoxalyl)-2-benzyloxycarbonyl-6,7 dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetamide prepared by a process according to claim 18, 19 or 20 with hydrogen bromide in glacial acetic acid to remove the benzyloxycarbonyl group.

23. N-(2-quinoxalyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-acetamide when prepared by a process according to claim 21 or an obvious chemical equivalent thereof.

24. A process according to claim 1 wherein R1 is hydrogen and R2 is a p-methoxy-phenyl group.

25. A process fox preparing N-(p-methoxy-phenyl)-2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetamide which comprises reacting 4-methoxyaniline with a mixed anhydride formed by reaction between 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetic acid and isobutyloxycarbonyl chloride.

26. A process for preparing N-(p-methoxy-phenyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetamide which comprises reacting N-(p-methoxy-phenyl)-2-benzyloxycarbonyl-6,7 dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-1-acetamide with hydrogen bromide in glacial acetic acid to remove the benzyloxycarbonyl group.

27, A process according to claim 26 wherein the N-(p-methoxy-phenyl)-2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-1-acetamide is prepared by a process according to claim 25.

28. N-(p-methoxy-phenyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetamide when prepared by a process according to claim 26 or an obvious chemical equivalent thereof.