1-(hydroxymethyl)-1,6,7,11b-tetrahydro-2H,4H-[1,3]oxazino- or -thiazino-[4,3-a]isoquinoline derivatives and pharmaceutical compositions containing them

The invention relates to 1-(hydroxymethyl)-1,6,7,11b-tetrahydro-2H,4H-[1,3]oxazino- or -thiazino-[4,3-a]isoquinoline derivatives of the formula (I), ##STR1## wherein R.sup.1 and R.sup.2 are alkoxy having from 1 to 6 carbon atoms, PA1 X is oxygen or sulfur, PA1 Y is .dbd.O, .dbd.S or an .dbd.NR.sup.3 group, wherein PA2 R.sup.3 is hydrogen, alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 8 carbon atoms or optionally substituted phenyl, and acid addition and quaternary salts thereof.

The invention relates to new isoquinoline derivatives, process for their 
preparation and pharmaceutical compositions containing them as active 
ingredient. More particularly, the invention concerns new 
1-(hydroxymethyl)-1,6,7,11b-tetrahydro-2H,4H-[1,3]oxazino- or 
-thiazino[4,5-a]isoquinoline derivatives of the formula (I), 
##STR2## 
wherein R.sup.1 and R.sup.2 represent alkoxy having from 1 to 6 carbon 
atoms, 
X is oxygen or sulfur, 
Y is .dbd.O, .dbd.S, or an .dbd.NR.sup.3 group, wherein 
R.sup.2 is hydrogen, alkyl having from 1 to 6 carbon atoms, cycloalkyl 
having from 3 to 8 carbon atoms or optionally substituted phenyl, 
and acid addition and quaternary salts thereof. 
The term "alkyl having from 1 to 6 carbon atoms" in the definition of 
R.sup.3 is used to refer to straight-chained or brached alkyl groups, e.g. 
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, 
tert.-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc. 
The alkoxy groups in the definition of R.sup.1 and R.sup.2 are 
straight-chained or branched, and include methoxy, ethoxy, n- or 
isopropoxy, n-, sec.- or tert.-butoxy, n- or isopentoxy or n- or 
isohexyloxy, etc. 
In the definition of R.sup.3 the preferred substituents of phenyl include 
halogens, preferably chlorine. 
A preferred representative of cycloalkyls having from 3 to 8 carbon atoms 
in the definition of R.sup.3 is cyclohexyl. 
According to the invention compounds of the formula (I), wherein R.sup.1, 
R.sup.2, X, Y and R.sup.3 are as defined above, and acid addition and 
quaternary salts thereof may be prepared by the following processes: 
(a) for preparing compounds of the formula (I), in which X is oxygen and Y 
is an .dbd.NR.sup.3 group (R.sup.1, R.sup.2 and R.sup.3 are as defined 
above), 
(a.sub.1) a bis(hydroxymethyl)-methyl isoquinoline derivative of the 
formula (II), 
##STR3## 
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, is reacted with 
an alkyl halide, and the thiuronium salt obtained is treated with a base, 
after or without isolation; or 
(a.sub.2) a bis(hydroxymethyl)-methyl-isoquinoline derivative of the 
formula (III), 
##STR4## 
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, is treated with 
a dehydrating agent; or 
(b) for preparing compounds of the formula (I), in which X is sulfur, Y is 
an .dbd.NR.sup.3 group, R.sup.1, R.sup.2 and R.sup.3 are as defined above, 
a bis(hydroxymethyl)-methyl-isoquinoline derivative of the formula (II), 
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, is treated with 
an acid; or 
(c) for preparing compounds of the formula (I), in which X is oxygen, Y is 
oxygen or sulfur, R.sup.1 and R.sup.2 are as defined above, a 
bis(hydroxymethyl)-methyl isoquinoline derivative of the formula (IV), 
##STR5## 
wherein R.sup.1 and R.sup.2 are as defined above, or an acid addition salt 
thereof is reacted with a reactive carbonic acid derivative, optionally in 
the presence of an acid or a base, and, if desired, a compound of the 
formula (I) obtained, in which Y is oxygen, is converted into a 
corresponding compound of the formula (I), in which Y is sulfur; 
and, if desired, an oxazino-compound prepared according to any of processes 
(a.sub.1), (a.sub.2) and (c), in which X is oxygen, Y, R.sup.1, R.sup.2 
and R.sup.3 are as defined in the respective process variants, is 
converted into a corresponding thiazino-compound, in which X is sulfur, 
while the other substituents are unchanged; 
and/or, if desired, a compound of the formula (I), in which Y is sulfur, X, 
R.sup.1 and R.sup.2 are as defined above, is converted into a 
corresponding compound of the formula (I), in which Y is an .dbd.NR.sup.3 
group, R.sup.3 is as defined above, while X, R.sup.1 and R.sup.2 remain 
unchanged; 
and/or, if desired, in a compound of the formula (I), in which Y represents 
an .dbd.NR.sup.3 group, X, R.sup.1, R.sup.2 and R.sup.3 are as defined 
above, the group R.sup.3 is replaced by another group within the 
definition of R.sup.3 ; 
and/or, if desired, a compound of the formula (I) is converted into an acid 
addition or quaternary salt thereof. 
The compounds of the formula (I) are pharmaceutically active, for example 
show vasodilating, antispasm and antidiarrhoeic activity. According to 
another aspect of the invention there are provided pharmaceutical 
compositions containing compounds of the formula (I) of pharmaceutically 
acceptable salts thereof as active ingredient, in association with 
pharmaceutical carriers and/or excipients. 
The compounds of the formula (I) can structurally be considered cyclic 
analogues of 3,4-dihydro-2(1H)-isoquinoline carboxamide (U.S. Pat. No. 
3,157,573), which is potent hypotensive agent. 
The compounds of the formulae (II) and (III) used as starting materials in 
process variants (a.sub.1), (a.sub.2) and (b) can be prepared from the 
corresponding N-unsubstituted compounds according to the Hungarian patent 
application 3652/83 (European patent application No. 84112855.6) by 
conventional techniques of N-substitution. 
The N-unsubstituted compounds of the formula (IV) used as starting 
materials in process variant (c) are disclosed in the Hungarian patent 
application 3651/83 (European patent application No. 84112856.4). 
In process variant (a.sub.1) preferably methyl iodide is employed as an 
alkyl halide. The reactant can be used in a molar equivalent amount but 
preferably the reaction is performed with an excess of the alkyl halide, 
e.g. methyl iodide. According to a preferred embodiment of process variant 
(a.sub.1) a compound of the formula (II) is reacted with methyl iodide at 
room temperature but the reaction may be accomplished also at a slightly 
elevated temperature. The methylthiuronium iodide formed, after or without 
isolation, is decomposed with a base, in an organic solvent medium. 
Parallel with the decomposition of thiuronium salt, ring closure takes 
place yielding the desired compound of the formula (I). As a base 
preferably an alkali metal hydroxide or carbonate, most preferably sodium 
hydroxide or potassium hydroxide, is used, preferably in an alkanolic, 
e.g. methanolic or ethanolic medium. 
According to process variant (a.sub.2) ring closure is performed by 
treating a compound of the formula (III) with a dehydrating agent. As a 
dehydrating agent any agent known for this purpose, such as thionyl 
chloride or phosphorus oxychloride can be used. The reaction rate is 
satisfactory already at room temperature, therefore there is no need of 
increasing the temperature. 
In process variant (b) preferably mineral acids such as hydrochloric acid, 
sulfuric acid, phosphoric acid, most preferably hydrochloric acid, is 
employed as an acid. The reaction is carried out in an inert, preferably 
polar organic solvent, most preferably an alkanol having from 1 to 4 
carbon atoms, e.g. ethanol. 
According to process variant (c) the isoquinoline-4-one derivatives of the 
formula (I) are prepared by reacting compounds of the formula (IV) with 
reactive carbonic acid derivatives. As reactive carbonic acid derivatives 
for example phosgene, chloroformic acid methyl or ethyl ester, urea, 
thiourea, etc. can be used. Depending on the nature of carbonic acid 
derivatives, the reaction is performed in the presence of a base or an 
acid. If for example ethyl chloroformate is used, the reaction is carried 
out in the presence of a base, e.g. an alkali metal bicarbonate such as 
sodium bicarbonate. 
The isoquinoline-4-one compounds obtained in process (c) (Y=oxygen) can be 
converted into the corresponding isoquinoline-4-thiones (Y=sulfur) by 
methods known in the art. The conversion is accomplished with a suitable 
sulfur compound, e.g. phosphorus pentasulfide, in an inert apolar organic 
solvent, at a temperature between room temperature and the boiling point 
of the mixture, preferably at elevated temperature. 
The oxazine compounds of formula (I), which contains oxygen as X, can be 
converted into the corresponding thiazino compounds (X=sulfur) in a known 
manner. The reaction is carried out with a suitable sulfur compound, e.g. 
phorphorus pentasulfide, in the absence of solvent, by melting a mixture 
of the starting compound of the formula (I) and phosphorus pentasulfide. 
Compounds of the formula (I), in which Y is sulfur, can be converted, if 
desired, into the corresponding compounds of formula (I), in which Y 
stands for an .dbd.NR.sup.3 group. For example, a compound of the formula 
(I), in which R.sup.3 is phenyl, can be prepared by reacting the 
corresponding isoquinoline-4-thione with aniline, in the presence of 
Hg(II)oxide. The reaction is carried out in an inert organic solvent, 
preferably at room temperature. 
In the .dbd.NR.sup.3 group in the definition of Y R.sup.3 can be converted, 
if desired, into another group within the definition of R.sup.3. For 
example compounds in which R.sup.3 is phenyl can be obtained by reacting 
the corresponding compounds, in which R.sup.3 represents an alkyl group 
having from 1 to 4 carbon atoms, preferably ethyl, with aniline. The 
reaction is performed in an inert organic solvent, preferably alkanol, 
between room and reflux temperature, preferably under reflux. 
The antispasm activity of the compounds was tested by the following 
methods. 
Maximum electroshock (MES) on mice 
The shock was applied through a corneal electrode (20 mA, 0.2 msec, HSE 
Schockgerat typ. 207). The animals which do not show a tonic, extensoric 
spasm as a result of electroshock treatment are considered protected [see 
Swinyard et al.: J. Pharmacol. Exp. Ther. 106, 319 (1952)]. 
Metrazole spasm (MET) on mice 
After pretreatment, the animals were administered 125 mg/kg of 
pentylenetetrazole subcutaneously. The animals which did not show (a) a 
clonic, (b) a tonic extensoric spasm and which survived the experiment 
were regarded protected. 
Observation time: 1 hour [Everett L. M. and Richards R. K.: J. Pharmacol. 
Exp. Ther. 81, 402 (1944)]. 
Test compounds 
Compound "A": 
1-(hydroxymethyl)-4-(iminophenyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H,4 
H-[1,3]oxazino[4,3-a]isoquinoline 
Compound "B": 
1-(hydroxymethyl)-4-(iminophenyl)-9,10-diethoxy-1,6,7,11b-tetrahydro-2H,4H 
-[1,3]thiazino[4,3-a]isoquinoline 
The results are shown in Table I below. 
TABLE I 
______________________________________ 
Antispasm activity (%) 
Compound MES MET 
______________________________________ 
Compound "A" -- 40 
Compound "B" -- 40 
______________________________________ 
Compounds of the formula (I) according to the invention can be converted 
into acid addition salts by reaction with suitable acids. 
Salt formation can be carried out, for example, in an inert organic 
solvent, such as an aliphatic alcohol having from 1 to 6 carbon atoms, by 
dissolving the compound of formula (I) in the solvent and adding the 
selected acid or a solution thereof formed with the same solvent to the 
first solution, until it becomes slightly acidic. Thereafter the acid 
addition salt separates and can be removed from the reaction mixture e.g. 
by filtration. 
The quaternary salts of the compounds of formula (I) are prepared by 
conventional techniques of quaternization. 
If desired, the compounds of the formula (I) or the salts thereof can be 
subjected to further purification, e.g. recrystallization. The solvents 
used for recrystallization are selected depending on the solubility and 
crystallization properties of the compound to be crystallized. 
The new compounds of the formula (I) and their physiologically acceptable 
salts may be formulated for therapeutic purposes. The invention therefore 
relates also to pharmaceutical compositions; comprising as active 
ingredient at least one compound of formula (I) or a physiologically 
acceptable salt thereof, in association with pharmaceutical carriers 
and/or excipients. Carriers conventional for this purpose and suitable for 
parenteral or enteral administration as well as other additives may be 
used. As carriers solid or liquid compounds, for example water, gelatine, 
lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable 
oils, such as peanut oil, olive oil, arabic gum, polyalkylene glycols, and 
vaseline (registered trade mark), can be used. The compounds can be 
formulated as conventional pharmaceutical formulations, for example in 
solid (globular and angular pills, dragees, capsules, e.g. hard gelatine 
capsules) or liquid (injectable oil or aqueous solutions or suspensions) 
form. The quantity of the solid carrier can be varied within wide ranges, 
but preferably is between 25 mg and 1 g. The compositions optionally 
contain also conventional pharmaceutical additives, such as preserving 
agents, wetting agents, salts for adjusting the osmotic pressure, buffers, 
flavouring agents and aroma substances. 
The compositions according to the invention optionally contain the 
compounds of formula (I) in associated with other known active 
ingredients. The unit doses are selected depending on the route of 
administration. The pharmaceutical compositions are prepared by 
conventional techniques including sieving, mixing, granulation, pressing 
or dissolution of the active ingredients. The formulations obtained are 
then subjected to additional conventional treatments, such as 
sterilization.

The invention is elucidated in detail by the aid of the following 
non-limiting Examples. 
EXAMPLE 1 
Preparation of 
1-(hydroxymethyl)-4-(iminophenyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H,4 
H-[1,3]oxazino[4,3-a]isoquinoline 
Route (A) 
To 4.0 g (0.01 mole) of 
1-[bis(hydroxymethyl)-methyl]-2-(phenylthiocarboxyamido)-6,7-dimethoxy-1,2 
,3,4-tetrahydroisoquinoline 4.3 g (0.03 mole) of methyl iodide are added, 
and the reaction mixture is allowed to stand for 3 to 4 hours. The excess 
of methyl iodide is evaporated, and the reaction mixture is stirred with 3 
moles of abs. methanolic potassium hydroxide until the total amount of 
methyl mercaptane is eliminated (4 to 6 hours). 
The reaction mixture is evaporated to dryness, whereupon a small amount of 
water is added, and the separated crystalline product is filtered off and 
washed to neutral with water. 
Route (B) 
To 4.0 g (0.01 mole) of 
1-[bis(hydroxymethyl)-methyl]-2-(phenylthiocarboxamido)-6,7-dimethoxy-1,2, 
3,4-tetrahydroisoquinoline 4.3 g (0.02 mole) of methyl iodide are added, 
and the reaction mixture is allowed to stand for 3 to 4 hours. The excess 
of methyl iodide is evaporated, whereupon the reaction mixture is stirred 
with 3 moles of abs. methanolic potassium hydroxide until the total 
elimination of methyl mercaptane (4 to 6 hours). The reaction mixture is 
evaporated to dryness, and the residue is extracted with five 30-ml 
portions of hot benzene. The combined benzene phases are evaporated, and 
the residue is triturated with a small amount of ether to yield the 
desired compound in crystalline form. 
The compounds set forth in Table 1 can be prepared in an analogous manner, 
by proper selection of the starting substances. 
TABLE 1 
__________________________________________________________________________ 
1-(Hydroxymethyl)-4-(imino-substituted)-9,10-dialkoxy-1,6,7,11b- 
tetrahydro-2H,4H[1,3]oxazino- 
[4,3-a]isoquinolines of formula (I) 
(X = O; Y = .dbd.NR.sup.3) 
Formula/ 
Melting point Yield (%) 
Molecular 
(.degree.C.) 
Analysis (%) 
Route 
R.sup.1 = R.sup.2 
R.sup.3 
weight Solvent 
C H N A B 
__________________________________________________________________________ 
CH.sub.3 O 
C.sub.2 H.sub.5 
C.sub.17 H.sub.24 N.sub.2 O.sub.4 
110-112 
63.73 
7.55 
8.75 63 
320.38 ethanol 
63.53 
8.00 
8.42 
CH.sub.3 O 
C.sub.6 H.sub.5 
C.sub.21 H.sub.24 N.sub.2 O.sub.4 
202-205 
68.46 
6.57 
7.61 
84 80 
368.42 ethanol 
67.94 
6.82 
8.02 
CH.sub.3 O 
C.sub.6 H.sub.11 
C.sub.21 H.sub.30 N.sub.2 O.sub.4 
175-178 
67.35 
8.08 
7.48 
87 
374.47 ethanol 
67.48 
8.27 
7.71 
C.sub.2 H.sub.5 O 
C.sub.2 H.sub.5 
C.sub.19 H.sub.28 N.sub.2 O.sub.4 
146-148 
65.49 
8.10 
8.04 73 
348.43 ethanol 
65.80 
8.25 
8.66 
C.sub. 2 H.sub.5 O 
C.sub.6 H.sub.5 
C.sub.23 H.sub.28 N.sub.2 O.sub.4 
202-203 
69.67 
7.12 
7.07 
85 
396.47 ethanol 
69.21 
7.31 
7.04 
C.sub.2 H.sub.5 O 
C.sub.6 H.sub.11 
C.sub.23 H.sub.34 N.sub.2 O.sub.4 
185-186 
68.62 
8.51 
6.96 
84 
402.52 ethanol 
68.54 
8.71 
6.90 
__________________________________________________________________________ 
EXAMPLE 2 
Preparation of 
1-(hydroxymethyl)-4-(iminophenyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H,4 
H-[1,3]thiazino[4,3-a]isoquinoline 
Route A 
4.0 g (0.01 mole) of 
1-[bis(hydroxymethyl)-methyl]-2-(phenylthiocarboxamido)-6,7-dimethoxy-1,2, 
3,4-tetrahydroisoquinoline are refluxed in 20 ml of a solution of 
hydrochloric acid in absolute ethanol for 15 minutes. The mixture is 
evaporated to dryness and the residue is taken up in a small amount of 
water, neutralized with a base and extracted with chloroform. The combined 
chloroform extracts are dried and evaporated to yield the desired thiazine 
derivative in crystalline form. 
Route B 
4.0 g (0.01 mole) of 
1-[bis(hydroxymethyl)-methyl]-2-(phenylthiocarboxamido)-6,7-dimethoxy-1,2, 
3,4-tetrahydroisoquinoline are refluxed for 15 minutes in 20 ml of absolute 
ethanol containing 25% of dry hydrochloric acid gas. The mixture is 
evaporated to dryness and, after addition of a small amount of water, 
neutralized with sodium bicarbonate. The crystalline product is filtered 
off and washed with water. 
The compounds shown in Table 2 are prepared in an analogous manner, by 
proper selection of the starting substances. 
TABLE 2 
__________________________________________________________________________ 
1-(Hydroxymethyl)-4-(imino-substituted)-9,10-dialkoxy-1,6,7,11b-tetrahydro 
2H,4H--[1,3]thiazino[4,3-a]- 
isoquinolines of the formula (I) (X = S; Y = .dbd.NR.sup.3) 
Formula/ 
Melting point Yield (%) 
Molecular 
(.degree.C.) 
Analysis (%) 
Route 
R.sup.1 = R.sup.2 
R.sup.3 
weight Solvent 
C H N Cl A B 
__________________________________________________________________________ 
CH.sub.3 O 
C.sub.2 H.sub.5 
C.sub.17 H.sub.24 N.sub.2 O.sub.3 S 
164-166 
60.68 
7.18 
8.32 80 70 
336.45 ethanol 
60.27 
7.47 
7.94 
CH.sub.3 O 
C.sub.6 H.sub.5 
C.sub.21 H.sub.24 N.sub.2 O.sub.3 S 
188-190 
65.60 
6.29 
7.29 85 
384.49 ethanol 
65.82 
6.29 
7.35 
CH.sub.3 O 
C.sub.6 H.sub.11 
C.sub.21 H.sub.30 N.sub.2 O.sub.3 S 
189-191 
64.58 
7.74 
7.17 90 
390.54 ethanol 
64.08 
7.68 
7.08 
C.sub.2 H.sub.5 O 
C.sub.2 H.sub.5 
C.sub.19 H.sub.28 N.sub.2 O.sub.3 S 
141-143 
62.60 
7.74 
7.69 
364.50 ethanol 
62.26 
7.97 
7.70 
C.sub.2 H.sub.5 O 
C.sub.6 H.sub.5 
C.sub.23 H.sub.28 N.sub.2 O.sub.3 S 
190-191 
66.96 
6.84 
6.79 83 
412.54 ethanol 
67.42 
7.14 
6.42 
C.sub.2 H.sub.5 O 
C.sub.6 H.sub.11 
C.sub.23 H.sub.34 N.sub.2 O.sub.3 S 
207-209 
65.99 
8.19 
6.69 85 
418.59 ethanol 
65.32 
8.04 
6.42 
CH.sub.3 O 
p-Cl--C.sub.6 H.sub.5 
C.sub.21 H.sub.23 N.sub.2 O.sub.3 SCl 
210-213 
55.33 
5.05 
6.15 
15.57 
82 
455.43 ethanol 
55.73 
5.31 
6.17 
15.25 
CH.sub.3 O 
C.sub.4 H.sub.9 
C.sub.19 H.sub.28 N.sub.2 O.sub.3 S 
149-152 
62.60 
7.74 
7.69 70 
364.50 ethanol 
62.96 
8.08 
8.10 
__________________________________________________________________________ 
EXAMPLE 3 
Preparation of 
1-(hydroxymethyl)-4-(iminophenyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H,4 
H-[1,3]oxazino[4,3-a]isoquinoline 
To 3.9 g (0.01 mole) of 
1-[bis(hydroxymethyl)-methyl]-2-phenylcarboxamido-6,7-dimethoxy-1,2,3,4-te 
trahydroisoquinoline 10 ml of thionyl chloride are added, whereupon the 
reaction mixture is allowed to stand overnight. The excess of thionyl 
chloride is evaporated, the residue is taken up in a small amount of water 
while cooling, neutralized with sodium bicarbonate and extracted with 
chloroform. The chloroform phase is dried and evaporated, the residue is 
crystallized from a mixture of ethanol and ether. 
The aimed compound obtained melts at 202.degree. to 205.degree. C. after 
recrystallization from ethanol. Yield: 17%. The physical and 
spectroscopical data of the compound obtained are identical with the 
corresponding parameters of the product obtained in Example 1, and the two 
products give no melting point depression when admixed. 
EXAMPLE 4 
Preparation of 
1-(hydroxymethyl)-4-(iminophenyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H,4 
H-[1,3]thiazino[4,3-a]isoquinoline 
3.68 g (0.01 mole) of 
1-(hydroxymethyl)-4-iminophenyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H,4H 
-[1,3]oxazino[4,3-a]isoquinoline are thoroughly homogenized with 4.4 g 
(0.02 mole) of phosphorus pentasulfide. The mixture is kept at 150.degree. 
C. for 2.5 hours. The melt is allowed to cool to room temperature, then it 
is powdered, 25 ml of a 10% sodium hydroxid solution are added, and the 
mixture is extracted with water. The ethereal phase is dried, evaporated 
to dryness and the residue is crystallized from a small amount of a 
mixture of n-hexane and ether. The desired compound obtained melts at 
187.degree. to 190.degree. C. after recrystallization from a mixture of 
n-hexane and ethanol. Yield: 34%. 
The physical and spectroscopical parameters of the compound obtained are 
identical with the corresponding data of the product prepared according to 
Example 2, and the two products give no melting point depression when 
admixed. 
EXAMPLE 5 
Preparation of 
1-(hydroxymethyl)-4-(iminophenyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H,4 
H-[1,3]thiazino[4,3-a]isoquinoline 
3.4 g (0.01 mole) of 
1-(hydroxymethyl)-4-(iminoethyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H,4H 
-[1,3]thiazino[4,3-a]isoquinoline are refluxed with 1.86 g (0.02 mole) of 
aniline in 30 ml of ethanol for 5 hours. The excess of ethanol and aniline 
is distilled off and crystallized from ethanol to yield the desired 
compound, melting at 187.degree. to 189.degree. C. Yield: 62%. 
The physical data of the compound obtained are identical with those of 
Example 2, and the two products give no melting point depression when 
admixed. 
EXAMPLE 6 
Preparation of 
1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 
-N-thiocarboxamide 
2.67 g (10.1 mmoles) of 
1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 
are suspended in 10 ml of water. To the suspension 1.16 g (0.012 mole) of 
potassium rhodanide are added, whereupon the reaction mixture is boiled 
for 6 hours. The substance obtained is cooled, extracted with four 50-ml 
portions of ethyl acetate, and the combined organic phases are dried over 
sodium sulfate and evaporated. The oily product is triturated with ether 
to yield the desired compound in crystalline form. Yield 39%. 
Melting point: 146.degree. to 148.degree. C. (ethanol). 
______________________________________ 
Analysis for C.sub.15 H.sub.22 N.sub.2 O.sub.4 S (326.42): 
______________________________________ 
calculated: 
C % = 55.19, 
H % = 6.79, 
N % = 8.58, 
S % = 
9.82; 
found: C % = 54.91, 
H % = 6.69, 
N % = 8.23, 
S % = 
10.30. 
______________________________________ 
EXAMPLE 7 
Preparation of 
1-[bis(hydroxymethyl)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline- 
N-thiocarboxamide 
Following the procedure described in Example 6 but starting from the 
corresponding diethoxyisoquinoline derivative the desired compound is 
obtained in a yield of 35%. 
Melting point: 115.degree. to 117.degree. C. (ethanol). 
______________________________________ 
Analysis for C.sub.17 H.sub.26 N.sub.2 O.sub.4 S (354.46): 
______________________________________ 
calculated: 
C % = 57.60, 
H % = 6.82, 
N % = 7.90, 
S % = 9.05; 
found: C % = 57.13, 
H % = 6.35, 
N % = 7.61, 
S % = 9.50 
______________________________________ 
EXAMPLE 8 
Preparation of 
1-(hydroxymethyl)-4-imino-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[1,3]oxaz 
ino[4,3-a]isoquinoline 
3.26 g (0.01 mole) of 
1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 
-N-thiocarboxamide prepared according to Example 6 are reacted with 1.42 g 
(0.1 mole) of methyl iodide. The reaction mixture is allowed to stand at 
room temperature for 24 hours. The excess of methyl iodide is evaporated 
and the residue is stirred in 3n methanolic potassium hydroxide for three 
hours, i.e. until the total elimination of methyl mercaptane. The methanol 
is then evaporated and the residue is extracted with hot benzene. After 
evaporation of the solvent the crystalline product obtained is 
recrystallized from a mixture of diisopropyl ether and ethanol. 
Yield: 50%. 
Melting point: 124.degree. to 127.degree. C. 
______________________________________ 
Analysis for C.sub.15 H.sub.20 N.sub.2 O.sub.4 (292.33): 
______________________________________ 
calculated: 
C % = 61.63, 
H % = 6.89, N % = 9.58; 
found: C % = 62.03, 
H % = 6.04, N % = 8.78. 
______________________________________ 
EXAMPLE 9 
Preparation of 
1-(hydroxymethyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[1,4]oxazino[4,3- 
a]-isoquinoline-4-one 
To 2.67 g (0.01 mole) of 
1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 
0.84 g (0.01 mole) of sodium bicarbonate dissolved in 10 ml of water and 
1.08 g (0.01 mole) of chloroformic acid ethyl ester are added, and the 
mixture obtained is boiled for one hour under stirring. After cooling the 
reaction mixture is extracted with four 100-ml portions of ether, the 
combined ethereal phase is dried over sodium sulfate and evaporated to 
dryness. 0.10 g of sodium methylate are added to the residue and it is 
heated at 120.degree. C. for 30 minutes. The melt is extracted with four 
50-ml portions of hot ethyl acetate and it is then evaporated to 50 ml. 
Upon cooling needle crystals are precipitated. 
Yield: 60%. 
Melting point: 125.degree. to 128.degree. C. (ethyl acetate). 
______________________________________ 
Analysis for C.sub.15 H.sub.19 NO.sub.5 (293.31): 
______________________________________ 
calculated: 
C % = 61.42%, 
N % = 6.52, N % = 4.78; 
found: C % = 60.96%, 
N % = 6.46, N % = 6.45. 
______________________________________ 
EXAMPLE 10 
Preparation of 
1-(hydroxymethyl)-9,10-diethoxy-1,6,7,11b-tetrahydro-2H-[1,3]oxazino[4,3-a 
]-isoquinoline-4-one 
Following the procedure described in Example 9 but starting from the 
corresponding diethoxy analogue the compound given in the title is 
obtained. 
Yield: 58%. 
Melting point: 119.degree. to 121.degree. C. (ethyl acetate). 
______________________________________ 
Analysis for C.sub.17 H.sub.23 NO.sub.5 (321.36): 
______________________________________ 
calculated: 
C % = 63.53, 
H % = 7.21, N % = 4.36; 
found: C % = 63.10, 
H % = 7.08, N % = 4.17. 
______________________________________ 
EXAMPLE 11 
Preparation of 
1-(hydroxymethyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[1,3]-oxazino-[4, 
3-a]isoquinoline-4-thione 
To a solution of 2.67 g (0.01 mole) of 
1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 
in 150 ml of absolute chloroform a solution of 2.0 g (0.02 mole) of 
triethyl amine in 10 ml of absolute chloroform is added, and to the 
mixture 1.15 g (0.01 mole) of thiophosgene are added dropwise with 
stirring, under cooling with ice. The reaction mixture is stirred for 10 
minutes, then it is washed to neutral with 15 ml of a 5% hydrochloric acid 
solution and subsequently water. The chloroformic phase is dried over 
sodium sulfate and evaporated to dryness. The residue is taken up in 15 to 
20 ml of ethanol, and ether is added to the mixture until slight 
turbidity. The desired compound is obtained in crystalline form. 
Yield: 19%. 
Melting point: 139.degree. to 141.degree. C. (ethanol/ether). 
______________________________________ 
Analysis for C.sub.15 H.sub.19 NO.sub.4 S (309.37): 
______________________________________ 
calculated: 
C % = 58.23, 
H % = 6.19, 
N % = 4.53, 
S % = 
10.36, 
found: C % = 57.96, 
H % = 6.36, 
N % = 4.55, 
S % = 
10.60. 
______________________________________ 
EXAMPLE 12 
Preparation of 
1-(hydroxymethyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[1,3]oxazino[4,3- 
a]-isoquinoline-4-thione 
2.93 g (0.01 mole) of 
1-hydroxymethyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[1,3]oxazino[4,3-a 
]isoquinoline-4-one and 3.33 g (0.015 mole) of phosphorus pentasulfide are 
boiled in 50 ml of absolute pyridine for two hours. The reaction mixture 
is cooled and poured onto ice and is extracted with three 50-ml portions 
of chloroform. The combined organic phases are dried and evaporated to 
dryness under reduced pressure. The obtained oily residue is passed 
through a neutral aluminium(III)oxide column. The solution leaving the 
column is evaporated, and the crystalline residue obtained is 
recrystallized from a mixture of ethanol and ether. 
Yield: 21%. 
Melting point: 139.degree. to 141.degree. C. 
The characteristics of the crude product obtained are identical with those 
of the product of Example 11. 
EXAMPLE 13 
Preparation of 
1-(hydroxymethyl)-4-(methylthio)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[1 
,3]oxazino[4,3-a]isoquinolinium iodide 
To a solution of 3.09 g (0.01 mole) of 
1-(hydroxymethyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[1,3]oxazino[4,3- 
a]isoquinoline-4-thione in acetone 1.94 g (0.02 mole) of methyl iodide are 
added. The reaction mixture is allowed to stand at room temperature for 24 
hours. The crystalline product is filtered off, washed and recrystallized 
from a mixture of acetone and ether. Yield: 70% (decomposition). 
______________________________________ 
Analysis for C.sub.16 H.sub.22 INO.sub.4 S (451.31): 
______________________________________ 
calculated: 
C % = 42.58, 
H % = 4.69, N % = 3.10; 
found: C % = 43.01, 
H % = 4.18, N % = 2.97. 
______________________________________ 
EXAMPLE 14 
Preparation of 
1-(hydroxymethyl)-4-(iminophenyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[ 
1,3]oxazino[4,3-a]isoquinoline 
To a solution of 4.51 g (0.01 mole) of 
1-(hydroxymethyl)-2-(methylthio)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[1 
,3]oxazino[4,3-a]isoquinoline iodide in ethanol 9.3 g (0.10 mole) of 
aniline are added, and the reaction mixture is boiled for 3 hours. Upon 
cooling the product separates from the mixture in crystalline form. 
Yield: 53%. 
Melting point: 201.degree. to 203.degree. C. 
The physico-chemical properties of the product obtained are identical with 
those of the product of Examples 1 and 3, respectively. 
EXAMPLE 15 
Preparation of 
1-(hydroxymethyl)-4-(iminophenyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[ 
1,3]oxazino[4,3-a]isoquinoline 
To a solution of 3.09 g (0.01 mole) of 
1-(hydroxymethyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[1,3]oxazino[4,3- 
a]isoquinoline-4-thione in 200 ml of dioxane 0.015 mole of HgO are added, 
and the mixture is reacted with 9.3 g (0.1 mole) of aniline. The reaction 
mixture is allowed to stand at room temperature for 24 hours, whereupon 
the HgS is filtered off, and the solvent and the excess of aniline are 
distilled off. The aimed compound is obtained in a yield of 45%. 
Melting point: 201.degree. to 209.degree. C. 
The compound obtained is identical with the products of Examples 1, 3 and 
14. 
EXAMPLE 16 
Preparation of 
1-(hydroxymethyl)-4-(iminophenyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H,4 
H-[1,3]oxazino[4,3-a]isoquinoline 
Following the procedure of Example 1 the amount of methyl iodide used is 
reduced to 0.012 mole, using 20 ml of methanol as solvent. The reaction is 
further performed as described in Example 1. The physical and 
spectroscopical data of the compound obtained are identical with those of 
the product prepared according to Example 1. 
EXAMPLE 17 
Preparation of 
1-(hydroxymethyl)-4-(iminomethyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[ 
1,3]thiazino[4,3-a]isoquinoline 
The compound is prepared following the procedure described in Example 1, 
Route A, starting from 
1-[bis(hydroxymethyl)-methyl]-2-(N'-methyl-thiocarboxamido)-6,7-dimethoxy- 
1,2,3,4-tetrahydroisoquinoline. Melting point: 149.degree. to 151.degree. 
C. (ethanol/ether). 
Yield: 65%. 
______________________________________ 
Analysis for C.sub.16 H.sub.22 NO.sub.3 S (308.41): 
______________________________________ 
calculated: 
C % = 62.31, 
H % = 7.29, N % = 4.54; 
found: C % = 62.73, 
H % = 7.45, N % = 4.18. 
______________________________________ 
EXAMPLE 18 
Preparation of 
1-(hydroxymethyl)-4-(iminomethyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[ 
1,3]thiazino[4,3-a]isoquinoline 
To a solution of 3.68 g (0.01 mole) of 
1-(hydroxymethyl)-4-(iminophenyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[ 
1,3]thiazino[4,3-a]isoquinoline in ethanol a 20% solution of 3.1 g (0.1 
mole) of methyl amine in methanol is added. The mixture is kept in a 
sealed tube at 70.degree. C. for three hours, whereupon it is evaporated 
to dryness under reduced pressure. The oily residue is crystallized by 
trituration with ether. 
Melting point: 149.degree. to 151.degree. C. (ethanol/ether). 
Yield: 45% 
The physical and spectroscopical data of the product are identical with 
those of the substance prepared from N'-methyl-thiocarboxamide according 
to Example 17. 
EXAMPLE 19 
Preparation of 
1-(hydroxymethyl)-4-imino-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[1,3]oxaz 
ino[4,3-a]isoquinoline 
This compound is prepared according to Example 1, Route A from 
1-[bis(hydroxymethyl)-methyl]-2-thiocarboxamido-6,7-dimethoxy-1,2,3,4-tetr 
ahydroisoquinoline. 
Yield: 57%. 
Melting point: 125.degree. to 127.degree. C. (ethanol). 
______________________________________ 
Analysis for C.sub.15 H.sub.20 N.sub.2 O.sub.4 (292.33): 
______________________________________ 
calculated: 
C % = 61.63, 
H % = 6.89, N % = 9.58; 
found: C % = 61.90, 
H % = 6.34, N % = 9.18. 
______________________________________