1,2,3,4-Tetrahydroisoquinolines 6.10,7,8 dihydroxy substitute-1-methylanilino and use as smooth muscle relaxants

1,2,3,4-Tetrahydroisoquinolines having the formula: ##STR1## wherein R.sub.1 and R.sub.2 are each hydrogen, lower alkyl, lower alkenyl, acyl, aryl or ar(lower)alkyl, in which aryl and the aryl moiety of the ar(lower)alkyl may contain at least one substituent selected from the group consisting of halogen, lower alkoxy, amino, nitro, hydroxy, acyloxy, ar(lower)alkoxy, lower alkylenedioxy, halo(lower)alkyl, acylamino, ar(lower)alkylamino and aryl, and pharmaceutically acceptable salts thereof, having a relaxant activity on smooth muscles.

BACKGROUND OF THE INVENTION 
Field of the Invention 
The present invention relates to new 1,2,3,4-tetrahydroisoquinolines and 
the pharmaceutically acceptable salts thereof, which have a relaxing 
activity on smooth muscles, and or processes for the preparation thereof. 
SUMMARY OF THE INVENTION 
The new 1,2,3,4-tetrahydroisoquinolines of the present invention are 
represented by the formula: 
##STR2## 
wherein R.sub.1 and R.sub.2 are each hydrogen, lower alkyl, lower alkenyl, 
acyl, aryl or ar(lower)alkyl, in which the aryl groups and the aryl moiety 
of the ar(lower)alkyl may have substituent(s) selected from the group 
consisting of halogen, lower alkoxy, amino, nitro, hydroxy, acyloxy, 
ar(lower)alkoxy, lower alkylenedioxy, halo(lower)alkyl, acylamino, 
ar(lower)alkylamino and aryl. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
In this specification, it is to be understood that the term "lower" as used 
in connection with the moieties derived from alkane or alkene such as 
alkyl or alkenyl is intended to mean a group having 1 to 6 carbon atom(s) 
unless otherwise indicated. 
Suitable lower alkyl groups include those having 1 to 6 carbon atom(s). 
These may be branched. Typical examples are methyl, ethyl, propyl, 
isopropyl, butyl, isobutyl, tertbutyl, pentyl or hexyl. 
Suitable lower alkenyl groups include those having 2 to 6 carbon atoms such 
as vinyl, 1-propenyl, allyl, isopropenyl, 2-butenyl, 3-pentenyl or 
4-hexenyl. 
Suitable acyl groups and acyl moieties of the acyloxy and acylamino groups 
include lower alkanoyl (e.g., formyl, acetyl, propionyl, etc.); mono (or 
di or tri) halo(lower)alkanoyl (e.g., chloro acetyl, trifluoroacetyl, 
etc.); ar(lower)alkanoyl, for example, phenyl(lower)alkanoyl (e.g., 
phenylacetyl, phenylpropionyl, etc.) or the like; ar(lower)alkoxycarbonyl 
which may have suitable substituent(s), for example, 
phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, 
phenethyloxycarbonyl, phenylpropyloxycarbonyl, etc.), 
halophenyl(lower)alkoxycarbonyl (e.g., 2-bromobenzyloxycarbonyl, 
4-chlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, etc.), 
nitrophenyl(lower)alkoxycarbonyl (e.g., 4-nitrobenzyloxycarbonyl, etc.), 
mono(or di)-(lower)alkoxyphenyl(lower)alkoxycarbonyl (e.g., 
4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxy carbonyl, etc.), 
phenylazophenyl(lower)alkoxycarbonyl (e.g., 
4-(phenylazo)benzyloxycarbonyl, etc.), or the like; lower alkoxycarbonyl 
(e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, 
1-cyclopropylethoxycarbonyl, tertbutoxycarbonyl, 
1,1-dimethylpropoxycarbonyl, etc.); mono (or di or tri) 
halo(lower)alkoxycarbonyl (e.g., trichloroethoxycarbonyl, 
tribromoethoxycarbonyl, etc.); aroyl having 7 or 8 carbon atoms (e.g., 
benzoyl, toluoyl, etc.); lower alkanesulfonyl (e.g., mesyl, 
ethanesulfonyl, propanesulfonyl, etc.); arenesulfonyl having 6 or 7 carbon 
atoms (e.g., benzenesulfonyl, tosyl, etc.); 8-quinolyloxycarbonyl; 
2-pyridylmethoxycarbonyl; adamantyloxycarbonyl; and the like. 
Suitable aryl groups include those having 6 to 10 carbon atoms such as 
phenyl, phenyl having lower alkyl (e.g., tolyl, xylyl, mesityl, cumenyl, 
etc.) or naphthyl, and preferably those having 6 or 7 carbon atoms. 
Suitable ar(lower)alkyl groups include those having 7 to 13 carbon atoms 
such as phenyl(lower)alkyl (e.g., benzyl, phenethyl, etc.), tolylmethyl, 
xylylmethyl, cumenylmethyl or diphenylmethyl, and preferably those having 
7 or 8 carbon atoms. 
Suitable halogens include chlorine, bromine, fluorine and iodine. 
Suitable lower alkoxy groups include those having 1 to 6 carbon atom(s) 
such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, 
tert-butoxy, pentyloxy or hexyloxy, and preferably those having 1 to 4 
carbon atom(s), and more preferably those having 1 or 2 carbon atom(s). 
Suitable ar(lower)alkoxy groups include those having 7 to 10 carbon atoms 
such as phenyl(lower)alkoxy (e.g., benzyloxy, phenethyloxy, etc.), 
tolylmethyloxy, xylylmethyloxy or cumenylmethyloxy, and preferably those 
having 7 to 8 carbon atoms. 
Suitable loweralkylenedioxy groups include those having 1 or 2 carbon 
atom(s) such as methylenedioxy or ethylenedioxy. 
Suitable halo(lower)alkyl groups include those having 1 to 6 carbon atom(s) 
such as mono(or di or tri) halo(lower)alkyl (e.g., chloromethyl, 
chloroethyl, bromoethyl, dichloroethyl, trichloromethyl, trifluoromethyl, 
trichloroethyl, iodopropyl, chloropentyl, chlorohexyl, etc.), or the like, 
and preferably those having 1 to 4 carbon atom(s), and more preferably 
those having 1 or 2 carbon atom(s). 
Suitable ar(lower)alkylamino groups include amino groups having the 
aforementioned ar(lower)alkyl groups thereon. 
Sutable acyloxy, acylamino and aryl substituents are as defined above. 
The above-mentioned aryl groups and the aryl moiety of the ar(lower)alkyl 
groups for R.sub.1 and R.sub.2 may have at least one, preferably one to 
three, substituent(s) as mentioned above. When said aryl group or aryl 
moiety has more than two substituents, said substituents may be the same 
or different. When the aforementioned substituents on the aryl and the 
aryl moieties of the ar(lower)alkyl possibilities for R.sub.1 and R.sub.2 
are ar(lower)alkoxy and/or ar(lower)alkylamino, the aryl and the aryl 
moieties of these substituents may further be substituted with the 
aforementioned halogen and/or lower alkoxy groups at desired positions. 
Suitable pharmaceutically acceptable salts include salts with an acid, such 
as an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric 
acid, phosphoric acid, etc.) or an organic acid (e.g., acetic acid, 
tartaric acid, fumaric acid, maleic acid, toluenesulfonic acid, 
camphorsulfonic acid, etc.) 
According to the present invention, the object compounds (I) can be 
prepared by various methods, which are described as follows: 
1. One process is represented by the following scheme: 
##STR3## 
wherein R'.sub.1 and R'.sub.2 are each hydrogen, lower alkyl, lower 
alkenyl, acyl, aryl or ar(lower)alkyl, in which the aryl and the aryl 
moieties of the ar(lower)alkyl may have substituent(s) selected from the 
group consisting of halogen, lower alkoxy, amino, nitro, hydroxy, acyloxy, 
ar(lower)alkoxy, lower alkylenedioxy, halo(lower)alkyl, acylamino, 
ar(lower)alkylamino and aryl, and R.sub.1 and R.sub.2 are each as defined 
above. 
The present reaction can be carried out by reacting the compound (II) or a 
salt thereof with the aldehyde compound (III) or a reactive equivalent 
thereof. 
The compound (II) has two hydroxy groups at any two positions between the 
second and sixth position of the benzene ring, but does not have the two 
hydroxy groups at the second and the sixth positions, simultaneously. 
Suitable salts of the compound (II) include inorganic acid salts (e.g., 
hydrochlorides, hydrobromides, sulfates, carbonates, etc) and organic acid 
salts (e.g., acetates, oxalates, p-toluenesulfonates, tartarates, 
fumarates, maleates, etc.) 
Reactive equivalents of the compound (III) include all compounds capable of 
serving the same purpose as does compound (III) in this reaction. Suitable 
such reactive equivalents include those having (a) a derivative on the 
formyl group of the compound (III) such as acetal, hemiacetal, 
hydrate(diol), mono or diacylated diol, thioacetal, hemithioacetal, 
Schiff's base, oxime, semicarbazone, thiosemicarbazone, alkoxalyl (e.g., 
methoxalyl, ethoxalyl, etc.) or the like; (b) compounds wherein the 
formylmethylene group of the aldehyde compound (III) is in the form of 
2-acyloxyvinyl (e.g., 2-acetoxyvinyl, 2-propionyloxyvinyl, etc.), 2-lower 
alkoxyvinyl (e.g., 2-methoxyvinyl, 2-ethoxyvinyl, 2-propoxyvinyl, 
2-isopropoxyvinyl, etc.), 2-lower alkylthiovinyl (e.g., 2-methylthiovinyl, 
2-ethylthiovinyl, 2-propylthiovinyl, etc.), 2-aminovinyl; and (c) 
compounds substituted by a carboxy group or a derivative (z) thereof, for 
one hydrogen atom on the methylene group adjacent to the formyl group of 
the compound (III) or reactive equivalents thereof as mentioned in (a) or 
(b) above. 
Suitable such derivatives (z) of the carboxy group include esters such as a 
saturated or unsaturated, cyclic or acyclic aliphatic hydrocarbon esters 
(e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl 
ester, t-butyl ester, cyclohexyl ester, cycloheptyl ester, vinyl ester, 
1-propenyl ester, 2-propenyl ester, 3-butenyl ester, etc.), aryl esters 
(e.g., phenyl ester, xylyl ester, tolyl ester, naphthyl ester, etc.), 
aralkyl esters (e.g., benzyl ester, phenethyl ester, etc.) or the like; 
amides such as N-lower alkyl amide (e.g., N-methyl amide, N-ethyl amide, 
etc.), a N-aryl amide (e.g., N-phenyl amide, etc.), a N,N-di(lower 
alkyl)amide (e.g., N,N-dimethyl amide, N,N-diethylamide, N-ethyl-N-methyl 
amide, etc.), or other amides with imidazole, 4-substituted imidazole, 
etc. or the like; and anhydrides such as a mixed anhydride with a 
dialkylphosphoric acid, dibenzylphosphoric acid, a halogenated phosphoric 
acid, a dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, 
sulfuric acid, an alkylcarbonic acid, an aliphatic carboxylic acid (e.g., 
pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid, 
chloroacetic acid, etc.), or an aromatic carboxylic acid (e.g., benzoic 
acid, etc.); and symmetrical anhydrides. 
The present reaction can be also carried out in the presence of an acid. 
Suitable acids include, for example, an inorganic acid (e.g., hydrochloric 
acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.) and an 
organic acid (e.g., acetic acid, chloroacetic acid, trifluoroacetic acid, 
propionic acid, methanesulfonic acid, etc.). The reaction can be carried 
out with or without a solvent. Suitable solvents include, for example, 
methanol, ethanol, n-butanol, water, benzene, chloroform, dioxane, a 
buffer solution and the like, and mixtures thereof. The reaction 
temperature is not critical. The reaction can be carried out at low or 
elevated temperature, most usually at ambient temperature, or, using 
heating, at a temperature around the boiling point of the solvent. 
When isoquinoline rings are formed in the present reaction, it sometimes 
occurs that the direction of ring closure varies. Consequently, 
occasionally, hydroxy group position isomers of the isoquinoline ring are 
obtained. These products are also included in the scope of the present 
invention. Furthermore, when R'.sub.1 and R'.sub.2 are acyl or when the 
substituents on the aryl and the ar(lower)alkyl alternatives for R'.sub.1 
and R'.sub.2 are acyloxy or acylamino, these substituents may be converted 
into hydrogen, hydroxy and amino, respectively, in the course of the 
reaction. Such products are also included in the scope of the present 
invention. 
2. An alternative process for preparing the compounds of this invention is 
represented by the following scheme: 
##STR4## 
wherein R".sub.1 is hydrogen, lower alkyl, lower alkenyl, a protective 
group for an amino or aryl which may have substituent(s) selected from the 
group consisting of halogen, lower alkoxy, amino, nitro, hydroxy, acyloxy, 
ar(lower)alkoxy, lower alkylenedioxy, halo(lower)alkyl, acylamino, 
ar(lower)alkylamino and aryl, R.sub.3 is a protective group for an amino 
and R'".sub.1 is hydrogen, lower alkyl, lower alkenyl or aryl which may 
have substituent(s) selected from the group consisting of halogen, lower 
alkoxy, amino, nitro, hydroxy, acyloxy, ar(lower)alkoxy, lower 
alkylenedioxy, halo(lower)alkyl, acylamino, ar(lower)alkylamino and aryl. 
In this reaction, the compound (IV) or a salt thereof is subjected to 
elimination of the protective group(s) for the amino to give the compound 
(I'). 
Suitable protective groups for the amino include both protective groups for 
primary amino and secondary amino groups. They include the aforementioned 
acyl group, and further include conventional protective groups for amino 
other than the acyl group such as ar(lower)alkyl (e.g., benzyl, phenethyl, 
trityl, etc.), substituted phenylthio(e.g., 2-nitrophenylthio, 
2,4-dinitrophenylthio, etc.) lower alkoxy- or ar(lower)alkoxy(lower)alkyl 
(e.g., methoxymethyl, benzyloxymethyl, etc.), tetrahydropyranyl, 
substituted or unsubstituted benzylidene (e.g., 2-hydroxybenzylidene, 
benzylidene, 4-nitrobenzylidene, 2-hydroxy-5-chlorobenzylidene, etc.), 
substituted lower alkylene (e.g., 2-hydroxy-1-naphthylmethylene, 
3-hydroxy-4-pyridylmethylene, etc.), acyl substituted lower alkylidene 
(e.g., 1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-propylidene, 
3-ethoxycarbonyl-2-butylidene, 1-acetyl-2-propylidene, 
1-benzoyl-2-propylidene, 1-[N-(2-methoxyphenyl)carbamoyl]-2-propylidene, 
1-[N-(4-methoxyphenyl)carbamoyl]-2-propylidene, etc.), acyl substituted 
cyclo(lower)alkylidene (e.g., 2-ethoxycarbonylcyclohexylidene, 
2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, etc.), 
3,3-dimethyl-4-oxocyclohexylidene (in these groups, for example, 
1-methoxycarbonyl-2-propylidene and 2-ethoxycarbonylcyclohexylidene can 
also be represented as 1-methoxycarbonyl-1-propen-2-yl and 
2-ethoxycarbonyl-1-cyclohexenyl, respectively), di- or 
tri(lower)alkylsilyl or the like. Suitable protective groups for the amino 
in the present reaction are not limited to the groups mentioned above but 
include all conventional protective groups for an amino which are 
eliminable in the present reaction. 
Suitable salts of the compound (IV) include those listed for the compound 
(II). 
The elimination of the protective group(s) for the amino is conducted in a 
conventional manner well known in the art, for example, by hydrolysis 
using an acid or a base, or by reduction of the compound (IV) or a salt 
thereof. Of course, it is to be understood that approximate reaction 
conditions for eliminating the protective groups for the amino will vary 
depending upon the kind of protective group used. When the protective 
groups are, for example, groups such as acetyl, benzyl, 
ar(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl), substituted 
ar(lower)alkoxycarbonyl, lower alkoxycarbonyl, substituted lower 
alkoxycarbonyl, tosyl, adamantyloxycarbonyl, trityl, methoxymethyl, 
substituted phenylthio or the like, the protective groups may be 
eliminated by hydrolysis using an acid, for example, an inorganic acid 
such as hydrohalogenic acid (e.g., hydrobromic acid, hydrochloric acid, 
etc.), or an organic acid such as substituted or unsubstituted lower 
alkanoic acid (e.g., formic acid, acetic acid, trifluoroacetic acid, 
etc.), or a mixture thereof, or the like. The elimination takes place 
easily under reduced pressure. The hydrolysis using an acid can be also 
carried out in a solvent such as water, a hydrophilic organic solvent or a 
mixture thereof. When the protective groups are acyl groups, the 
protective groups may be eliminated by hydrolysis using a base. Suitable 
bases include inorganic bases, for example, alkaline metal hydroxides such 
as alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, 
etc.), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium 
hydroxide, etc.), alkali metal or alkaline earth metal carbonates, or 
alkali metal bicarbonates, and organic bases such as trialkylamines (e.g., 
trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine or 
N-methylmorpholine, and the like. The hydrolysis using a base is 
preferably carried out in a solvent such as water, a hydrophilic solvent 
or a mixture thereof. When the protective group is trifluoroacetyl, it can 
be easily eliminated only by treating the compound (IV) or the salt 
thereof with an aqueous alkaline solution such as sodium bicarbonate 
aqueous solution. When the protective group is for example a group such as 
benzyloxycarbonyl, substituted benzyloxycarbonyl, trichloroethoxycarbonyl, 
2-pyridylmethoxycarbonyl, diphenylmethoxycarbonyl, benzyl, trityl or the 
like, the protective group may be eliminated by reduction. Suitable 
methods of reduction include the use of a metal (e.g., tin, zinc, etc.) or 
a metal compound (e.g., chromous chloride, chromous acetate, etc.) in an 
acidic medium such as an inorganic acid (e.g., hydrochloric acid, etc.) or 
an organic acid (e.g., acetic acid, propionic acid, etc.), and catalytic 
reduction. The catalytic reduction can be carried out by any suitable 
conventional manner known in the art in the presence of a conventional 
catalyst such as palladium carbon or the like. Halogen substituted lower 
alkoxycarbonyl and 8-quinolyloxycarbonyl may be eliminated by treating the 
compound (IV) with a heavy metal (e.g., copper, zinc, etc.), and mesyl and 
tosyl may be eliminated by treating the compound (IV) with an alkali metal 
such as sodium metal in liquid ammonia. It is to be understood that any 
other conventional method for eliminating an amino-protective group may 
also be employed. 
The temperature employed in the present reaction is not critical and may be 
suitably selected according to the kind of amino-protective group being 
used, the method of elimination employed, and similar considerations. 
During the course of the reaction, depending upon the kind of elimination 
reaction used, some substituent(s) on the aryl group for R".sub.1 may be 
converted: for example, halogen may be converted into hydrogen; lower 
alkoxy, acyloxy, ar(lower)alkoxy, or lower alkylenedioxy may be converted 
into hydroxy; nitro, acylamino or ar(lower)alkylamino may be converted 
into amino; and lower alkenyl (as R".sub.1) may be also converted into 
lower alkyl. These possibilities are also included within the scope of the 
present invention. 
The starting compound (IV) which itself is novel, can be prepared, for 
example, by reacting a compound of the formula: 
##STR5## 
or a salt thereof, with an aldehyde compound of the formula: 
##STR6## 
wherein R".sub.1 and R.sub.3 are both as defined above, or are reactive 
equivalents thereof. 
3. Another suitable alternative method is represented by the following 
scheme: 
##STR7## 
wherein R.sub.4 is a protected hydroxy, R.sub.5 is hydroxy or a protected 
hydroxy, R"".sub.1 and R"".sub.2 are each hydrogen, lower alkyl, lower 
alkenyl, protective groups for amino, aryl or ar(lower)alkyl and 
R""'.sub.1 and R""'.sub.2 are each hydrogen, lower alkyl, lower alkenyl, 
aryl or ar(lower)alkyl, in which the aryl group and the aryl moiety of the 
ar(lower)alkyl for R"".sub.1, R"".sub.2, R""'.sub.1 and R""'.sub.2 may 
contain substituent(s) selected from the group consisting of halogen, 
lower alkoxy, amino, nitro, hydroxy, acyloxy, ar(lower)alkoxy, lower 
alkylenedioxy, halo(lower)alkyl, acylamino, ar(lower)alkylamino and aryl. 
The present reaction may be carried out by subjecting the compound (V) or a 
salt thereof to an elimination reaction for the hydroxy-protective 
group(s). 
Suitable hydroxy-protective groups referred to by the term "protected 
hydroxy" include the aforementioned acyl groups and further include lower 
alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), allyl, 
ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethyl, etc.), 
trityl or the like, tetrahydropyranyl, lower alkoxy- or 
ar(lower)alkoxy(lower)alkyl (e.g., methoxymethyl, benzyloxymethyl, etc.), 
substituted phenylthio(e.g., 2-nitrophenylthio, 2,4-dinitrophenylthio, 
etc.), and the like, and also include the group formed when R.sub.4 and 
R.sub.5 are combined together to form lower alkylenedioxy (e.g., 
methylenedioxy, ethylenedioxy, etc.) when R.sub.4 and R.sub.5 are adjacent 
to each other. Suitable protective groups for hydroxy used in the present 
reaction are not limited to the groups mentioned above but include all 
conventional hydroxy-protective groups which are eliminable in the present 
reaction. 
Suitable salts of the compound (V) include those mentioned for the compound 
(II). 
The elimination reaction of the hydroxy-protective group(s) is carried out 
in a similar manner to that for the amino-protective group(s) mentioned 
above. Further, when R.sub.4 and R.sub.5 are combined together to form a 
lower alkylenedioxy group, hydrolysis using an acid is preferably 
employed. When the protective group(s) for hydroxy is lower alkyl, a 
method using an acid (e.g., hydrochloric acid or hydrobromic acid), boron 
trihalide (e.g., boron trichloride or boron tribromide), aluminum 
chloride, pyridine hydrohalide (e.g., pyridine hydrochloride, pyridine 
hydrobromide, etc.), lithium iodide, lithium tertiary-butyl sulfide or a 
mixture thereof, and the like, can be employed. When these are used in a 
liquid form, the reaction can be carried out without a solvent. Methylene 
chloride is often used as a solvent, but any other solvent which does not 
adversely affect the present reaction can be used. 
The temperature used in the reaction is not critical. It can be suitably 
selected in accordance with the kind of protective group or elimination 
reaction, and the like being employed. 
During the course of the reaction, by a kind of elimination reaction, 
occasionally lower alkenyl and ar(lower) alkyl (as R"".sub.1 and 
R"".sub.2) may be converted into lower alkyl and hydrogen, respectively. 
Also, some substituent(s) on the aryl and the ar(lower)alkyl groups (as 
R"".sub.1 and R"".sub.2) may be converted: for example, halogen may be 
converted into hydrogen; lower alkoxy, acyloxy, ar(lower)alkoxy or lower 
alkylenedioxy may be converted into hydroxy; and nitro, acylamino or 
ar(lower)alkylamino may be converted into amino. These possibilities are 
also included within the scope of the present invention. 
The starting compound (V) which itself is novel, can be prepared, for 
example, 
(a) by reacting a compound of the formula: 
##STR8## 
wherein R.sub.4 and R.sub.5 are each as defined above, or a salt thereof, 
with a compound of the formula: 
##STR9## 
wherein R.sub.6 is hydrogen, lower alkyl, lower alkenyl, an 
aminoprotective group, aryl or ar(lower)alkyl and R.sub.7 is lower alkyl, 
lower alkenyl, an amino-protective group, aryl or ar(lower)alkyl, in which 
the aryl and the aryl moiety of the ar(lower) alkyl for R.sub.6 and 
R.sub.7 may have substituent(s) selected from the group consisting of 
halogen, lower alkoxy, amino, nitro, hydroxy, acyloxy, ar(lower)alkoxy, 
lower alklenedioxy, halo(lower)alkyl, acylamino, ar(lower)alkylamino and 
aryl, or a reactive derivative thereof at the carboxy group, and treating 
the resulting compound of the formula: 
##STR10## 
wherein R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each as defined above, 
with a dehydrating agent, and thereafter reducing the resulting compound 
of the formula: 
##STR11## 
wherein R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each as defined above, 
or a salt thereof; or 
(b) reacting a compound of the formula: 
##STR12## 
wherein R.sub.4 and R.sub.5 are each as defined above, or a salt thereof 
with a compound of the formula: 
##STR13## 
wherein R.sub.7 is as defined above, or a reactive derivative thereof at 
the carboxy group, and subjecting the resulting compound of the formula: 
##STR14## 
wherein R.sub.4, R.sub.5 and R.sub.7 are each as defined above, to a 
reaction for introducing an amino-protective group, and treating the 
resulting compound of the formula: 
##STR15## 
wherein R.sub.3, R.sub.4, R.sub.5, and R.sub.7 are each as defined above, 
with a dehydrating agent, and thereafter reducing the resulting compound 
of the formula: 
##STR16## 
wherein R.sub.3, R.sub.4, R.sub.5 and R.sub.7 are each as defined above, 
or a salt thereof; or 
(c) subjecting the resulting compound obtained in process (b) of the 
formula: 
##STR17## 
wherein R.sub.3, R.sub.4 and R.sub.5 are each as defined above, and 
R'.sub.7 is lower alkyl, lower alkenyl, an amino-protective group, aryl or 
ar(lower)alkyl, in which the aryl and the aryl moiety of the 
ar(lower)alkyl may have substituent(s) selected from the group consisting 
of halogen, lower alkoxy, amino, nitro, hydroxy, acyloxy, ar(lower)alkoxy, 
lower alkylenedioxy, halo(lower) alkyl, acylamino, ar(lower)alkylamino and 
aryl, to a reaction eliminating the amino-protective groups(s). 
The object compounds (I), (I') and (") obtained by the above methods may, 
if necessary, be converted into the pharmaceutically acceptable salt 
mentioned above. 
The new 1,2,3,4-tetrahydroisoquinolines (I) of the present invention and 
the pharmaceutically acceptable salts thereof have a relaxant activity of 
smooth muscles, especially on vascular- and visceral-smooth muscles. 
Accordingly, they show vasodilating, intestinal-contraction inhibiting and 
bladder-contraction inhibiting activities, showing less bronchodilating 
activity, and are useful as vasodilating, intestinal-contraction 
inhibiting and bladder-contraction inhibiting agents. Thus, the compound 
(I) of the present invention and the pharmaceutically acceptable salts 
thereof can be used as a medicine for treating spasmodic disorder of 
visceral organs, e.g., colonic irritability, chronic cholecystitics and 
the like, in mammals. 
The new 1,2,3,4-tetrahydroisoquinolines (I) and the pharmaceutically 
acceptable salts thereof can be administered by conventional methods, in 
conventional types of unit dosages or with conventional pharmaceutical 
carriers in order to produce a relaxing effect on smooth muscles. 
Thus, they can be used in the form of conventional pharmaceutical 
preparations, wherein they are contained in admixture with a 
pharmaceutical organic or inorganic carrier material suitable for enteral 
or parenteral applications. Oral administration by the use of tablets, 
capsules or in a liquid form such as a suspension, solution or emulsion is 
particularly advantageous. When formed into tablets, conventional binding 
and disintegrating agents used in therapeutic unit dosages can be 
employed. Suitable binding agents include glucose, lactose, gum acacia, 
gelatin, mannitol, starch paste, magnesium trisilicate and talc. Suitable 
disintegrating agents include corn starch, keratin, colloidal silica and 
potato starch. When administered as liquids, conventional liquid carriers 
can be used. 
The unit dosage or therapeutically effective quantity of the compounds (I) 
and the pharmaceutically acceptable salts thereof for human beings can 
vary over wide limits such as from 0.01 milligram to about 100 milligrams. 
The upper limit is limited only by the degree of the effect desired and 
economical considerations. For oral administration, it is preferred to 
employ from about 1 milligram to about 100 milligrams of the therapeutic 
agent per unit dosage. It is indicated from animal experiments that 
dosages from about 0.1 to about 10 milligrams administered orally three 
times daily as needed, will provide a preferred daily dosage. Of course, 
the suitable dosage of the particular therapeutic agent used can vary 
considerably dependent upon the age of the patient and the degree of 
therapeutic effect desired. Each unit dosage form of these novel 
therapeutic compounds can contain from about 0.5 to about 99.5% of the 
novel therapeutic agents by weight of the entire composition with the 
remainder comprising conventional pharmaceutical carriers. The term 
pharmaceutical carriers includes non-therapeutic materials which are 
conventionally used within a unit dosage and include fillers, diluents, 
binders, lubricants, disintegrating agents and solvents, i.e., the pure 
compounds, without the use of a pharmaceutical carrier. It is also 
possible to administer the new 1,2,3,4-tetrahydroisoquinolines (I) and the 
pharmaceutically acceptable salts thereof in the form of a mixture with 
other agents useful as relaxants for smooth muscles and especially 
vascular-smooth and visceral-smooth muscles. 
The relaxing activity on smooth muscles of typical compounds which fall 
within the category of the compounds of the formula (I) of this invention 
can be illustrated by reference to a test in which the individual active 
ingredients employed were the following numbered compounds. 
Compound No. 1 
1-(p-Fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
d-camphor-10-sulfonate 
Compound No. 2 
1-(p-Chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
hydrochloride 
Compound No. 3 
1-(p-Hydroxyanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride. 
Test 
Intestinal Motility in Dogs 
Method: Mongrel dogs weighing 8 to 16 kg which were withheld from any food 
and water for 24 hours were anesthetized with a combination of urethane 
(1.5g/kg) and morphine (15 mg/kg). A balloon was placed at the jejunum of 
the dog, compressed at a pressure of 10 cm. H.sub.2 O and connected to a 
strain gauge. Changes in the motility were principally recorded in terms 
of the amplitude of the movements, but the number of movements occurring 
were also taken into account. The maximum change in all the determinations 
served as the basis for calculations of the 50% inhibition dose 
(ED.sub.50). Results are shown in the following table. 
______________________________________ 
Compound No. ED.sub.50 (g/kg) 
______________________________________ 
1 3 
2 1.5 
3 4 
______________________________________ 
Having generally described the invention, a more complete understanding can 
be obtained by reference to certain specific examples, which are included 
for purposes of illustration only and are not intended to be limiting 
unless otherwise specified.

EXAMPLE 1 
(A) N-benzyloxycarbonyl-p-toluidinoacetaldehyde diethyl acetal (6 g) and 
3,4-dihydroxyphenethylamine hydrochloride (2.5 g) were added to a mixture 
of n-butyl alcohol (60 ml) and water (8.5 ml) and then the mixture was 
refluxed for 9.5 hours in a stream of nitrogen. In the course of the 
reaction, the above-mentioned acetal (0.6 g) was twice added to the 
mixture, after 5 hours and after 7.5 hours from the beginning of the 
reaction. The reaction mixture was concentrated and the residue was washed 
with ether and dissolved in hot water (300 ml). After the insoluble 
material was filtered off, the filtrate was washed with ethyl acetate and 
treated with activated charcoal. The aqueous layer was concentrated to 
dryness to give amorphous 
1-(N-benzyloxycarbonyl-p-toluidinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydro 
isoquinoline hydrochloride (3.8 g), mp 125.degree. C. (dec). 
(B) N-benzyloxycarbonyl-p-fluoroanilinoacetaldehyde diethyl acetal (6 g) 
and 3,4-dihydroxyphenethylamine hydrochloride (2.5 g) were added to a 
mixture of n-butyl alcohol (60 ml) and water (8.5 ml). The mixture was 
then refluxed for 11 hours in a stream of nitrogen. In the course of the 
reaction, amounts of the above-mentioned acetal (0.6 g and 1.2 g) were 
added to the mixture after 4.5 hours and 6 hours, respectively, from the 
beginning of the reaction. The reaction mixture was concentrated to 
dryness and the residue was washed with ether and dissolved in water. The 
solution was washed with ether and concentrated to dryness to given 
amorphous 
1-(N-benzyloxycarbonyl-p-fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrah 
ydroisoquinoline hydrochloride (2.7 g), mp 122.degree. C. (dec.). 
(C) N-benzyloxycarbonyl-3,4,5-trimethoxyanilinoacetaldehyde diethyl acetal 
(21 g) and 3,4-dihydroxyphenethylamine hydrochloride (8.3 g) were added to 
a mixture of n-butyl alcohol (210 ml) and water (30 ml) and then the 
mixture was refluxed for 11 hours in a stream of nitrogen. In the course 
of the reaction, amounts of the above-mentioned acetal (2.1 g, 2.1 g and 
4.2 g) were added to the mixture after 5 hours, 6 hours and 7 hours, 
respectively, from the beginning of the reaction, respectively. The 
reaction mixture was concentrated to dryness under reduced pressure and 
the residue was washed with ether and acetone to give 
1-(N-benzyloxycarbonyl-3,4,5-trimethoxyanilinomethyl)-6,7-dihydroxy,1,2,3, 
4-tetrahydroisoquinoline hydrochloride (16.3 g). The product was 
recrystallized from a mixed solvent of ethanol and ether to give a pure 
product, mp 197.degree. to 199.degree. C. (dec). 
(D) N-benzyloxycarbonyl-p-chloroanilinoacetaldehyde diethyl acetal (10 g) 
and 3,4-dihydoxyphenethylamine hydrochloride (4.2 g) were added to a 
mixture of n-butyl alcohol (100 ml) and water (14 ml) and then the mixture 
was refluxed for 4 hours. The above-mentioned acetal (1 g) was added to 
the mixture and the resultant mixture was refluxed for 4 hours. The 
reaction mixture was concentrated to dryness under reduced pressure and 
the residue was washed with ethyl acetate and collected by filtration. The 
crystals were recrystallized from a mixture of methanol and ether to give 
1-(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrah 
ydroisoquinoline hydrochloride (7.0 g), mp 210.degree. to 212.degree. C. 
(dec). 
(E) N-ethoxycarbonyl-p-chloroanilinoacetaldehyde diethyl acetal (3.0 g) and 
3,4-dihydroxyphenethylamine hydrochloride (1.5 g) were added to a mixture 
of n-butyl alcohol (30 ml), water (5 ml) and 10% hydrochloric acid (0.5 
ml), and then the mixture was refluxed for 4 hours in a stream of 
nitrogen. Above mentioned acetal (0.8 g) was further added to the mixture 
and the resultant mixture was refluxed for 4 hours. The solvent was 
distilled off from the reaction mixture and the residue was washed with 
ethyl acetate and then recrystallized from water to give 
1-(N-ethoxycarbonyl-p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydr 
oisoquinoline hydrochloride, mp 208.degree. to 210.degree. C. and mp 
214.degree. to 215.degree. C. Analysis: Calcd. for C.sub.19 H.sub.21 
N.sub.2 O.sub.4 Cl.HCl.3/10H.sub.2 O: C 54.50, H 5.44, N 6.69, Cl 16.93. 
Measured: C 54.29, H 5.57, N 6.70, Cl 16.69. 
(F) N-benzyloxycarbonyl-N-isopropylaminoacetaldehyde diethyl acetal (9 g) 
and 3,4-dihydroxyphenethylamine hydrochloride (4.5 g) were added to a 
mixture of n-butyl alcohol (100 ml) and water (15 ml) and then the mixture 
was refluxed for 6 hours. The above-mentioned acetal (2 g) was added 
thereto and the resultant mixture was refluxed for 1.5 hours. The solvent 
was distilled off from the reaction mixture. To the residue was added a 
mixed solvent of isopropyl alcohol, methanol and ether. The crystals 
obtained was recrystallized from the same mixed solvent to give 
1-(N-benzyloxycarbonyl-N-isopropylaminomethyl)-7,8-dihydroxy-1,2,3,4-tetra 
hydroisoquinoline hydrochloride (1.6 g), mp 200.degree. to 205.degree. C. 
(dec). The mother liquor was concentrated and allowed to stand to give 
1-(N-benzyloxycarbonyl-N-isopropylaminomethyl)-6,7-dihydroxy-1,2,3,4-tetra 
hydroisoquiniline hydrochloride (4.4 g), colorless crystals, mp 207.degree. 
to 210.degree. C. (dec). 
(G) N-benzyloxycarbonyl-m-fluoroanilinoacetaldehyde diethyl acetal (15 g) 
and 3,4-dihydroxyphenethylamine hydrochloride (5.75 g) were added to a 
mixture of n-butyl alcohol (150 ml) and water (20 ml) and then the mixture 
was refluxed for 11 hours in a stream of nitrogen. The reaction mixture 
was concentrated to dryness and the residue was in turn washed with ether 
and with a mixture of ether: ethyl acetate (2:1) and then crystallized 
with acetone. The crystals were collected by filtration to give 
1-(N-benzyloxycarbonyl-m-fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrah 
ydroisoquinoline hydrochloride (11.27 g), mp 184.degree. to 186.degree. C. 
(dec). 
(H) N,N-diphenylaminoacetaldehyde diethyl acetal (3.5 g) and 
3,4-dihydroxyphenethylamine hydrochloride (2.1 g) were added to a mixture 
of n-butyl alcohol (35 ml), water (5 ml) and conc. hydrochloric acid (2 
drops) and then the mixture was refluxed for 6.5 hours in a stream of 
nitrogen. The reaction mixture was concentrated to dryness and the residue 
was washed with acetone and collected by filtration to recover the 
starting material, 3,4-dihydroxyphenethylamine (1.2 g). The filtrate was 
concentrated to give 
1-(N,N-diphenylaminomethyl)6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
hydrochloride (1.5 g), oil. 
(I) p-Chloroanilinoacetaldehyde diethyl acetal (486 mg) and 
3,4-dihydroxyphenethylamine hydrochloride (378 mg) were added to a mixture 
of n-butyl alcohol (4 ml) and water (0.4 ml) and then the mixture was 
refluxed for 3.5 hours. The above-mentioned acetal (0.24 g) was further 
added thereto and the resultant mixture was refluxed for 3 hours. The 
reaction mixture was treated in a conventional manner to give 
1-(p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
hydrochloride. This product was identified by thin-layer chromatography on 
silica gel [Developing solvent: (n-butyl alcohol:acetic acid:water=8:1:1)] 
with an authentic sample, mp 91.degree. to 93.degree. C., which was 
obtained by reacting 
1-(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrah 
ydroisoquinoline hydrochloride obtained in Example 1(D) with conc. 
hydrochloric acid and acetic acid. 
(J) 3,4-Dihydroxyphenethylamine hydrochloride (41.4 g) and 
N-benzyloxycarbonyl-p-benzyloxyanilinoacetaldehyde diethyl acetal (147 g) 
were added to a mixture of n-butyl alcohol (1 l.) and water (130 ml) and 
then the mixture was refluxed overnight with stirring. N-Butyl alcohol was 
distilled from the reaction mixture under reduced pressure and the residue 
was pulverized by adding diisopropyl ether (500 ml). The powder was 
collected by filtration and dried by allowing it to stand overnight at 
ambient temperature to produce a powder (169 g). To the powder were added 
a saturated sodium bicarbonate aqueous solution (500 ml) and ethyl acetate 
(500 ml) and the mixture was shaken. The ethyl acetate layer was separated 
and the aqueous layer was further extracted with ethyl acetate (200 ml). 
Both ethyl acetate layers were mixed together, washed with a saturated 
sodium chloride aqueous solution (300 ml) and dried over magnesium 
sulfate. After drying, activated charcoal (3 g) was added to the solution 
and the mixture was filtered. The filtrate was concentrated under reduced 
pressure to give an oil (150 g). The oil was dissolved in ethyl acetate 
(600 ml) and p-toluenesulfonic acid monohydrate (50 g) was added thereto. 
The mixture was stirred at ambient temperature in order to precipitate 
crystals. After stirring for 2 hours, the precipitated crystals were 
collected by filtration, washed with ethyl acetate (100 ml) and dried by 
allowing them to stand overnight to give 
1-(N-benzyloxycarbonyl-p-benzyloxyanilinomethyl)-6,7-dihydroxy-1,2,3,4-tet 
rahydroisoquinoline p-toluenesulfonate (70.6 g), mp 203.degree. to 
206.degree. C. (dec). A portion of the crystals was recrystallized from 
95% ethanol to give a pure product, mp 219.degree. -220.degree. C. (dec). 
Analysis: Calcd. for C.sub.38 H.sub.38 N.sub.2 O.sub.8 S: C, 66.84; H, 
5.61; N, 4.10. Measured: C, 66.96; H, 5.58; N, 4.07. 
(K) A solution of 3,4-dihydroxyphenethylamine hydrochloride (2.17 g) and 
N-benzyloxycarbonylaminoacetaldehyde diethyl acetal (4.0 g) in a mixture 
of n-butyl alcohol (20 ml) and water (3.5 ml) was refluxed for 4.5 hours. 
After the reaction, the solvent was distilled off under reduced pressure. 
To the residue were added water (15 ml) and sodium acetate. A 
precipitating oil was separated from the aqueous layer and chloroform was 
added thereto. The mixture was allowed to stand to give crystals. The 
crystals were collected by filtration, washed with chloroform and 
recrystallized twice from a mixture of methanol and ether to give 
1(N-benzyloxycarbonylaminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquino 
line acetate (1.2 g), mp 158.degree. to 162.degree. C. (dec). 
Analysis: Calcd. for C.sub.20 H.sub.24 N.sub.2 O.sub.6 : C, 61.84; H, 6.23; 
N 7.21. Meausred: C, 61.68; H, 6.16; N, 7.11. 
Infrared Absorption Spectrum (Nujol) 1704, 1275 cm.sup.-1. 
Nuclear Magnetic Resonance Spectrum (d.sub.6 -DMSO,.delta.), ppm 7.40 (5H, 
s), 6.60 (1H, s), 6.50 (1H, s), 5.12 (2H, s), 3.90 (1H, m), 3.22 (2H, m), 
3.00 (2H, m), 2.63 (2H, m), 1.90 (3H, s). 
The product was converted into its hydrochloride (oil) in a conventional 
manner. 
(L) A mixture of N-acetyl-p-nitroanilinoacetaldehyde diethyl acetal (1 g), 
3,4-dihydroxyphenethylamine hydrochloride (1 g), n-butyl alcohol (10 ml) 
and water (1.5 ml) was refluxed for 7 hours. In the course of the 
reaction, the above-mentioned acetal (2.5 g) was added to the mixture, 
twice in 0.5 g portions and five times in 0.3 g portions, one every hour. 
The reaction mixture was filtered and the filtrate was concentrated to 
dryness. The residue was pulverized by adding ether and the powder was 
collected by filtration, washed with ethyl acetate and water and dried to 
give 1-(p-nitroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
hydrochloride (1 g), mp 238.degree. to 239.degree. C. (dec). 
Analysis: Calcd. for C.sub.16 H.sub.17 N.sub.3 O.sub.4.HCl.H.sub.2 O: C, 
51.96; H, 5.45; N, 11.36. Measured: C, 52.56; H, 5.18; N, 11.24. 
(M) The following compounds were obtained by a method similar to that used 
in Examples 1(A) through 1(L). 
(1) 1-(p-Toluidinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrobromide, mp 211.degree. to 213.degree. C. 
(2) 1-(p-Fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
d-camphor-10-sulfonate, mp 213.degree. to 215.degree. C. 
(3) 
1-(3,4,5-Trimethoxyanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquino 
line hydrochloride, mp 232.degree. to 225.degree. C. 
(4) 1-(N-isopropylaminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydrosioquinoline 
dihydrochloride, mp 268.degree. to 270.degree. C. (dec). 
(5) 1-(N-isopropylaminomethyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride, mp 255.degree. to 258.degree. C. 
(6) 1-(m-Fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
hydrochloride, powder. 
(7) 1-Aminomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride, mp 142.degree. to 147.degree. C. (dec). 
(8) 1-(p-Hydroxyanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride, mp 170.degree. to 184.degree. C. (dec). 
(9) 
1-(m-Trifluoromethylanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquin 
oline p-toluenesulfonate, mp 211.degree. to 214.degree. C. 
(10) 
1-(N-Benzyloxycarbonyl-n-trifluoromethylanilinomethyl)-6,7-dihydroxy-1,2,3 
,4-tetrahydroisoquinoline p-toluene-sulfonate, mp 218.degree. to 
220.degree. C. (dec). 
(11) 
1-(3,4-Dichloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
p-toluenesulfonate, mp 204.degree. to 208.degree. C. (dec). 
(12) 
1-(N-Benzyloxycarbonyl-3,4-dichloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-te 
trahydroisoquinoline p-toluenesulfonate, mp 227.degree. to 229.5.degree. C. 
(dec). 
(13) 
1-[N-(p-Chlorobenzyl)aminomethyl]-6,7-dihydroxy-1,2,3,4-tetrahydroisoquino 
line dihydrochloride, mp 235.degree. to 238.degree. C. (dec). 
Infrared Absorption Spectrum (Nujol) 1615, 1572 1450, 1375 cm.sup.-1. 
Nuclear Magnetic Resonance Spectrum (d6-DMSO,.delta.) ppm 7.60 (4H, m), 
6.86 (1H, s), 6.62 (1H, s), 4.94 (1H, m), 4.22 (2H, broad s), 3.0-4.0 (4H, 
m), 2.70 (2H, m). 
(14) 
1-[N-Benzyloxycarbonyl-N-(p-chlorobenzyl)aminomethyl]-6,7-dihydroxy-1,2,3, 
4-tetrahydroisoquinoline hydrochloride, mp 214.degree. to 217.degree. C. 
(dec). 
The following are other compounds suitable for preparation in this manner. 
(15) 1-(p-Aminoanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride. 
(16) 
1-(p-Mesylaminoanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride. 
(17) 
1-(N-Acetyl-p-aminoanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquino 
line hydrochloride. 
(18) 
1-(N-Acetyl-p-mesylaminoanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroiso 
quinoline hydrochloride. 
EXAMPLE 2 
(A) A mixture of 
1-(N-benzyloxycarbonyl-p-toluidinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydro 
isoquinoline hydrochloride (3 g), 48% hydrobromic acid (30 ml) and acetic 
acid (30 ml) was stirred for 3 hours at 80.degree. C. The reaction mixture 
was concentrated to dryness and the residue was crystallized with acetone 
to give 1-(p-toluidinomethyl)-6,7-hydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrobromide (1.5 g). The product was recrystallized from a mixture of 
isopropyl alcohol and ether to give a pure product, mp 211.degree. to 
213.degree. C. 
Analysis: Calcd. for C.sub.17 H.sub.20 N.sub.2 O.sub.2.2HBr: C, 45.76; H, 
4.97; N, 6.28; Br, 35.82. Measured: C, 45.56; H, 4.94; N, 6.23; Br, 35.55. 
(B) A mixture of 
1-(N-benzyloxycarbonyl-p-fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrah 
ydroisoquinoline hydrochloride (4.6 g), conc. hydrochloric acid (46 ml) and 
acetic acid (46 ml) was refluxed for 2 hours. The reaction mixture was 
concentrated to dryness and the residue was dissolved in water and washed 
with a mixture of ether and ethyl acetate (1:1). The aqueous layer was 
treated with activated charcoal and concentrated to dryness to give 
1-(p-fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
hydrochloride (3.1 g). The product (2.5 g) was converted into its 
d-camphor-10-sulfonate in a conventional manner and the crystals obtained 
were recrystallized from water to give the d-camphor-10-sulfonate of the 
above-mentioned product, mp 213.degree. to 215.degree. C. 
Analysis: Calcd. for C.sub.26 H.sub.33 N.sub.2 O.sub.6 SF: C, 59.98; H, 
6.39; N, 5.38; S, 6.16. Measured: C, 59.67; H, 6.43; N, 5.32; S, 6.36. 
(C) A mixture of 
1-(N-benzyloxycarbonyl-3,4,5-trimethoxyanilinomethyl)-6,7-dihydroxy-1,2,3, 
4-tetrahydroisoquinoline hydrochloride (4.4 g), conc. hydrochloric acid (45 
ml) and acetic acid (45 ml) was refluxed for 1.5 hours in a stream of 
nitrogen. The reaction mixture was concentrated to dryness and the residue 
was washed with ether and acetone and crystallized with methanol to give 
1-(3,4,5-trimethoxyanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquino 
line hydrochloride (2.3 g). The product was recrystallized from water to 
give a pure product, mp 223.degree. to 225.degree. C. 
Analysis: Calcd. for C.sub.19 H.sub.24 N.sub.2 O.sub.5.HCl.1/7H.sub.2 O: C, 
57.13; H, 6.38; N, 7.01; Cl, 8.87. Measured: C, 57.39; H, 6.38; N, 6.99; 
Cl, 9.05. 
(D) A mixture of 
1(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahy 
droisoquinoline hydrochloride (5.1 g), conc. hydrochloric acid (51 ml) and 
acetic acid (51 ml) was refluxed for 3 hours. The reaction mixture was 
concentrated to dryness under reduced pressure and the residue was 
dissolved in water. The aqueous layer was washed with ethyl acetate, 
treated with activated charcoal and concentrated to dryness to give crude 
1-(p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
hydrochloride (2.8 g). The product was converted into its 
p-toluenesulfonate and then again converted into its hydrochloride by 
conventional techniques. The salt was recrystallized from water containing 
a small amount of hydrochloric acid to give pure 
1-(p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
hydrochloride, mp 91.degree. to 93.degree. C. 
Analysis: Calcd. for C.sub.16 H.sub.17 N.sub.2 O.sub.2 Cl.HCl: C, 56.31; H, 
5.32; N, 8.21; Cl, 20.78. Measured: C, 56.03; H, 5.26; N, 8.11; Cl, 20.73. 
(E) A mixture of 
1-(N-benzyloxycarbonyl-N-isopropylaminomethyl)-6,7-dihydroxy-1,2,3,4-tetra 
hydroisoquinoline hydrochloride (3.5 g), conc. hydrochloric acid (20 ml) 
and acetic acid (20 ml) was refluxed for 1 hour. The reaction mixture was 
concentrated to dryness under reduced pressure and the residue was 
crystallized with a mixture of acetone and water. The crystals were 
recrystallized from a mixture of methanol and ether to give 
1-(N-isopropylaminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride (1.15 g), mp 268.degree. to 270.degree. C. (dec). 
Analysis: Calcd. for C.sub.13 H.sub.20 N.sub.2 O.sub.2.2HCl: C, 50.49; H, 
7.17; N, 9.06; Cl, 22.93. Measured: C, 50.44; H, 7.21; N, 8.94; Cl, 23.09. 
(F) A mixture of 
1-(N-benzyloxycarbonyl-N-isopropylaminomethyl)-7,8-dihydroxy-1,2,3,4-tetra 
hydroisoquinoline hydrochloride (1.1 g), acetic acid (11 ml) and conc. 
hydrochloric acid (11 ml) was refluxed for 1.5 hours. The reaction mixture 
was concentrated to dryness under reduced pressure and the residue was 
washed with acetone, followed by recrystallization from a mixture of 
methanol and ether to give 
1-(N-isopropylaminomethyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride, colorless crystals, mp 255.degree. to 258.degree. C. 
Analysis: Calcd. for C.sub.13 H.sub.20 N.sub.2 O.sub.2.2HCl: C, 50.49; H, 
7.17; N, 9.06; Cl, 22.93. Measured: C, 50.09; H, 7.03; N, 8.87; Cl, 22.60. 
(G) A mixture of 
1(N-benzyloxycarbonyl-m-fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahy 
droisoquinoline hydrochloride (0.3 g), conc. hydrochloric acid (3 ml) and 
acetic acid (3 ml) was refluxed for 1.5 hours in a stream of nitrogen. The 
reaction mixture was concentrated and the residue was pulverized with 
ether to give 
1-(m-fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
hydrochloride (0.2 g), powder. 
(H) A mixture of 
1-(N-benzyloxycarbonylaminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquin 
oline hydrochloride (5.3 g), conc. hydrochloric acid (6 ml) and acetic acid 
(6 ml) was refluxed for 1 hour and 20 minutes. The reaction mixture was 
cooled and concentrated under reduced pressure. The residue was 
crystallized by adding methanol and acetone. The crystals were collected 
by filtration, washed with a mixture of methanol and acetone and 
recrystallized twice from a mixture of water, methanol and acetone to give 
1-aminomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride 
(1.2 g), mp 142.degree. to 147.degree. C. (dec). 
Infrared Absorption Spectrum (Nujol) 1604, 1552 cm.sup.-1. 
Nuclear Magnetic Resonance Spectrum (d.sub.6 -DMSO,.delta.), ppm 6.73 (1H, 
s), 6.55 (1H, s), 4.80 (1H, m), 3.40 (4H, m), 2.82 (2H, m). 
Analysis: Calcd. for C.sub.10 H.sub.16 N.sub.2 O.sub.2 Cl.sub.2 : C, 44.96; 
H, 6.04; N, 10.48; Cl, 26.54. Measured: C, 44.21; H, 5.90; N, 10.45; Cl, 
26.77. 
(I) To 
1-(N-benzyloxycarbonyl-p-benzyloxyanilinomethyl)-6.7-dihydroxy-1,2,3,4-tet 
rahydroisoquinoline p-toluenesulfonate (10.0 g) was added a saturated 
sodium bicarbonate aqueous solution and then the mixture was extracted 
with ethyl acetate. The extract was washed with water, dried and the 
solvent was distilled off to give 
1-(N-benzyloxycarbonyl-p-benzyloxyanilinomethyl)-6,7-dihydroxy-1,2,3,4-tet 
rahydroisoquinoline (8.2 g). To this residue (8.2 g) were added conc. 
hydrochloric acid (50 ml) and ethanol (50 ml) and the mixture was refluxed 
for 4 hours with stirring. The reaction mixture was concentrated to 
dryness under reduced pressure and the residue was pulverized with ether 
to give a powder of 
1-(p-hydroxyanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride (5.8 g), mp 170.degree. to 184.degree. C. (dec). 
Analysis: Calcd. for C.sub.16 H.sub.18 N.sub.2 O.sub.3.2HCl.H.sub.2 O: C, 
50.93; H, 5.88; N, 7.43. Measured: C, 51.09; H, 5.60; N, 7.15. 
(J) The following compounds were obtained by a similar technique to that 
used in Examples 2(A) through 2(I). 
(1) 1-(p-Nitroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
hydrochloride, mp 238.degree. to 239.degree. C. (dec). 
(2) 
1-(m-Trifluoromethylanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquin 
oline p-toluenesulfonate, mp 211.degree. to 214.degree. C. 
(3) 
1-(3,4-Dichloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
p-toluenesulfonate, mp 204.degree. to 208.degree. C. (dec). 
The following are other compounds suitable for preparation in this manner. 
(4) 1-(p-Aminoanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride. 
(5) 
1-(p-Mesylaminoanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride. 
PREATION OF THE STARTING COMPOUNDS (1)-(3) 
(1) 1-(p-Toluidinomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride 
(i) N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(p-toluidino)acetamide 
3,4-Dimethoxyphenethylamine (14.4 g) and p-toluidinoacetic acid (13.1 g) 
were heated for 1.5 hours at 190.degree. C. in a stream of nitrogen. After 
cooling, the reaction mixture was dissolved in ethyl acetate and the 
solution was washed with a cooled 1 N sodium hydroxide solution and water 
and then dried. The solvent was distilled off and the oily residue was 
crystallized by adding ether to give 
N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(p-toluidino)acetamide (18.6 g), mp 
87.degree. to 88.5.degree. C. 
(ii) 
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(N-benzyloxycarbonyl-p-toluidino)acetam 
ide 
A mixture of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(p-toluidino)acetamide (3.6 
g) and anhydrous potassium carbonate (2.5 g) was added to anhydrous 
dimethylformamide (25 ml). The mixture was vigorously stirred under ice 
cooling and to the solution was dropwise added over 20 minutes an 
anhydrous chloroform solution (5 ml) containing benzyl chloroformate (2.04 
g). The reaction mixture was poured into ice-water and extracted with 
chloroform. The extract was washed with water, dried and the solvent was 
distilled off. The residue was crystallized by treating with ether to give 
N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(N-benzyloxycarbonyl-p-toluidino)-aceta 
mide (4.3 g), mp 81.degree. to 85.degree. C. 
(iii) 
1-(N-Benzyloxycarbonyl-p-toluidinomethyl)-6,7-dimethoxy-3,4-dihydroisoquin 
oline hydrochloride and phosphate 
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(N-benzyloxycarbonyl-p-toluidino)acetami 
de (3.5 g) and phosphorus oxychloride (1.33 g) were added to anhydrous 
acetonitrile (45 ml) and the mixture was refluxed for 4 hours. The 
reaction mixture was concentrated to dryness under reduced pressure to 
give a crude mixture of hydrochloride and phosphate of 
1-(N-benzyloxycarbonyl-p-toluidinomethyl)-6,7-dimethoxy-3,4-dihydroisoquin 
oline (4.6 g). 
(iv) 
1-(N-Benzyloxycarbonyl-p-toluidinomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydro 
isoquinoline hydrochloride 
A mixture of hydrochloride and phosphate of 
1-(N-benzyloxycarbonyl-p-toluidinomethyl)-6,7-dimethoxy-3,4-dihydroisoquin 
oline (4.6 g) was dissolved in 99% ethanol (45 ml). To the solution was 
added sodium borohydride (0.8 g) with stirring under ice cooling, and the 
mixture was stirred for 1.5 hours. The reaction mixture was concentrated 
to dryness under reduced pressure and to the residue was added water. The 
mixture was saturated with sodium chloride and extracted with ethyl 
acetate. The extract was dried and the solvent was distilled off. The oil 
obtained was treated with ethanol containing hydrochloric acid to give 
1-(N-benzyloxycarbonyl-p-toluidinomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydro 
isoquinoline hydrochloride (2.3 g), mp 189.degree. to 190.degree. C. 
(v) 1-(p-Toluidinomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride 
A mixture of 
1-(N-benzyloxycarbonyl-p-toluidinomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydro 
isoquinoline hydrochloride (470 mg), acetic acid (4.7 ml) and conc. 
hydrochloric acid (4.7 ml) was heated for 1 hour at 100.degree. C. The 
reaction mixture was concentrated to dryness under reduced pressure and 
the residue was dissolved in methanol. To the solution was added ethyl 
acetate and the precipitating crystals were collected by filtration to 
give 1-(p-toluidinomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride (270 mg), mp 180.degree. to 184.degree. C. 
(2) 
1-(N-Benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dibenzyloxy-1,2,3,4-tetr 
ahydroisoquinoline hydrochloride 
(i) N-[2-(3,4-Dibenzyloxyphenyl)ethyl]-2-(p-chloroanilino)acetamide 
A mixture of 3,4-dibenzyloxyphenethylamine (36.2 g) and 
p-chloroanilinoacetic acid (20 g) was stirred for 3 hours at 190.degree. 
C. The reaction mixture was dissolved in benzene. The solution was washed 
with a diluted potassium carbonate aqueous solution and dried. The solvent 
was distilled off from the benzene solution and the residue obtained was 
purified by column chromatography on silica gel to give 
N-[2-(3,4-dibenzyloxyphenyl)ethyl] -2-(p-chloroanilino)acetamide (27.2 g), 
mp 121.degree. C. 
(ii) 
N-[2-(3,4-Dibenzyloxyphenyl)ethyl]-2-(N-benzyloxycarbonyl-p-chloroanilino) 
acetamide 
A mixture of 
N-[2-(3,4-dibenzyloxyphenyl)ethyl]-2-(p-chloroanilino(acetamide (13.4 g) 
and anhydrous potassium carbonate (7.5 g) was added to anhydrous 
dimethylformamide (100 ml). To the solution was added dropwise over 30 
minutes benzyl chloroformate (9.2 g) with stirring and ice-cooling. The 
reaction mixture was poured into ice-water and extracted with ethyl 
acetate. The extract was washed with water and dried. The solvent was 
distilled off from the solution and the residue obtained was 
recrystallized from a mixture of benzene and petroleum ether to give 
N-[2-(3,4-dibenzyloxyphenyl)ethyl]-2-(N-benzyloxycarbonyl-p-chloroanilino) 
acetamide (9.0 g) mp 114.degree. to 116.5.degree. C. 
(iii) 
1-(N-Benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dibenzyloxy-3,4-dihydroi 
soquinoline 
A mixture of 
N-[2-(3,4-dibenzyloxyphenyl)ethyl]-2-(N-benzyloxycarbonyl-p-chloroanilino) 
acetamide (7.3 g), phosphorus oxychloride (2.3 g) and anhydrous benzene (73 
ml) was refluxed for four hours. The reaction mixture was concentrated to 
dryness under reduced pressure and to the residue was added a diluted 
aqueous ammonia solution, and then the mixture was extracted with ethyl 
acetate. The extract was washed with water and dried, and the solvent was 
distilled off to give 
1-(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dibenzyloxy-3,4-dihydroi 
soquinoline (7.0 g). 
(iv) 
1-(N-Benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dibenzyloxy-1,2,3,4-tetr 
ahydroisoquinoline hydrochloride 
1-(N-Benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dibenzyloxy-3,4-dihydrois 
oquinoline (7.0 g) was added to 99% ethanol (160 ml) and to the solution 
was gradually added sodium borohydride (2.2 g) under ice cooling. The 
reaction temperature of the mixture was elevated to ambient temperature 
and the mixture was stirred for 3 hours. An insoluble material was 
filtered off from the reaction mixture and the filtrate was concentrated 
under reduced pressure. After water was added to the residue, the mixture 
was extracted with ethyl acetate. The extract was washed with water and 
dried. The solvent was distilled off from the solution and the residue was 
subjected to column chromatography on silica gel, washed with benzene and 
eluted with a mixture of chloroform and ethyl acetate. The eluate was 
concentrated and the residue was treated with ethanol containing 
hydrochloric acid. The crystals obtained were recrystallized from a 
mixture of 99% ethanol and ether to give 
1-(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dibenzyloxy-1,2,3,4-tetr 
ahydroisoquinoline hydrochloride (1.4 g), mp 139.degree. to 142.degree. C. 
(3) 
1-(N,N-Diphenylaminomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 
(i) N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(N,N-diphenylamino)acetamide 
3,4-Dimethoxyphenethylamine (8.05 g) and N,N-diphenylglycine (10 g) were 
heated for 2 hours at 190.degree. C. After cooling, the reaction mixture 
was dissolved in ethylacetate. The resulting solution was washed with a 5% 
sodium bicarbonate aqueous solution and water and then dried. The solvent 
was distilled off from the solution to give crystals of 
N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(N,N-diphenylamino)acetamide (11.5 g), 
mp 88.degree. to 93.degree. C. 
(ii) 1-(N,N-Diphenylaminomethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline 
hydrochloride and phosphate 
A mixture of 
N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(N,N-diphenylamino)acetamide (2 g), 
phosphorus oxychloride (0.79 g) and anhydrous acetonitrile (25 ml) was 
refluxed for 4 hours. Acetonitrile was removed from the reaction mixture 
and phosphorus oxychloride was completely removed from the residue by 
adding dry benzene to the residue and thereafter removing it to give a 
mixture of 
1-(N,N-diphenylaminomethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline 
hydrochloride and phosphate, amorphous form. 
(iii) 
1-(N,N-Diphenylaminomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 
To the amorpohous substance obtained in the above preparation of compound 
(3) (ii) was added 99% ethanol (30 ml) and to the solution was added 
sodium borohydride (0.4 g) with stirring and ice cooling. The mixture was 
stirred for 16 hours at ambient temperature. The precipitate was filtered 
off and the filtrate was concentrated. To the residue were added ethyl 
acetate and water, and the mixture was sufficiently shaken. The ethyl 
acetate layer was separated, washed with water, dried and the solvent was 
distilled off. The residual oil (1.3 g) was purified by column 
chromatography on silica gel (50 g) using chloroform as the developing 
solvent to give 
1-(N,N-diphenylaminomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 
(0.82 g). 
EXAMPLE 3 
(A) 1-(p-Toluidinomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride (260 mg) was converted into the free amine compound by 
conventional methods. The amine compound was dissolved in anhydrous 
dichloromethane (10 ml) and to the solution was dropwise added at 
-50.degree. C. anhydrous dichloromethane (5 ml) containing boron 
tribromide (340 mg). The mixture was stirred for 14 hours at the same 
temperature and the reaction temperature was gradually elevated to 
8.degree. C. The reaction mixture was concentrated to dryness under 
reduced pressure and the residue obtained was crystallized with acetone. 
The crystals were further recrystallized from a mixture of isopropyl 
alcohol and ether to give 
1-(p-toluidinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrobromide, mp 211.degree. to 213.degree. C. The product was 
identified by means of comparison with an authentic sample prepared by 
another process by its infrared absorption spectrum and nuclear magnetic 
resonance spectrum. 
(B) A mixture of 
1-(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dibenzyloxy-1,2,3,4-tetr 
ahydroisoquinoline hydrochloride (1.1 g), acetic acid (11 ml) and conc. 
hydrochloric acid (11 ml) was heated for 2 hours at 100.degree. C. The 
reaction mixture was concentrated to dryness under reduced pressure and 
the residue was washed with ethyl acetate and ether and pulverized to give 
crude 
1-(p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
hydrochloride. The product was converted into its p-toluenesulfonate and 
then again converted into its hydrochloride to give a pure product, mp 
91.degree. to 93.degree. C. The product was identified by means of 
comparison with an authentic sample prepared by another process by its 
infrared absorption spectrum and nuclear magnetic resonance spectrum. 
(C) To a solution of 
1-(N,N-diphenylaminomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 
(0.38 g) in anhydrous dichloromethane (15 ml) was dropwise added a 
solution of boron tribromide (0.75 g) in anhydrous dichloromethane (5 ml) 
at -60.degree. C. with stirring. The mixture was stirred for 2.5 hours at 
the same temperature and the reaction temperature was elevated to ambient 
temperature over 19 hours. Dichloromethane was removed and to the residue 
were added methanol and a small amount of water. The mixture was warmed 
and concentrated to dryness. The residue was crystallized with a mixture 
of acetone and ether and the crystals were collected by filtration to give 
1-(N,N-diphenylaminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
hydrobromide (0.33 g). 
(D) The following compounds were obtained according to similar techniques 
used in Examples 3(A) through 3(C). 
(1) 1-(p-Fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
d-camphor-10-sulfonate, mp 213.degree. to 215.degree. C. 
(2) 
1-(3,4,5-Trimethoxyanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquino 
line hydrochloride, mp 223.degree. to 225.degree. C. 
(3) 1-(N-Isopropylaminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride, mp 268.degree. to 270.degree. C. (dec). 
(4) 1-(N-Isopropylaminomethyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride, mp 255.degree. to 258.degree. C. 
(5) 1-(m-Fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
hydrochloride, powder. 
(6) 1-Aminoethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride, mp 142.degree. to 147.degree. C. (dec). 
(7) 1-(p-Hydroxyanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroiosquinoline 
dihydrochloride, mp 170.degree. to 184.degree. C. (dec). 
(8) 1-(p-Nitroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
hydrochloride, mp 238.degree. to 239.degree. C. (dec). 
(9) 
1-(m-Trifluoromethylanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquin 
oline p-toluenesulfonate, mp 211.degree. to 214.degree. C. 
(10) 
1-(3,4-Dichloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
p-toluenesulfonate, mp 204.degree. to 208.degree. C. (dec). 
(11) 
1-[N-(p-Chlorobenzyl)aminomethyl]-6,7-dihydroxy-1,2,3,4-tetrahydroisoquino 
line dihydrochloride, mp 235.degree. to 238.degree. C. (dec). 
Infrared Absorption Spectrum (Nujol) 1615, 1572, 1450, 1375 cm.sup.-1. 
Nuclear Magnetic Resonance Spectrum (d.sub.6 -DMSO,.delta.), ppm 7.60 (4H, 
m), 6.86 (1H, s), 6.62 (1H, s), 4.94 (1H, m), 4.22 (2H, broad s), 3.0-4.0 
(4H, m), 2.70 (2H, m). 
The following are other compounds suitable for preparation in this manner. 
(12) 1-(p-Aminoanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride. 
(13) 
1-(p-Mesylaminoanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
dihydrochloride. 
Having now fully described the invention, it will be apparent to one of 
ordinary skill in the art that many changes and modifications can be made 
thereto without departing from the spirit or scope of the invention as set 
forth herein.