This invention relates to obtaining 
2,5-dimethyl-benzo[b]thiene[3,2-f]morphan (I), an intermediate for its 
preparation 
2-(2-benzo[b]thienylmethyl)-1,4-dimethyl-1,2,3,6-tetrahydropyridine (II) 
and the addition salts thereof with pharmacologically acceptable acids, 
for example hydrochlorides. 
##STR1## 
The cited compounds are new substances of possible interest as analgesics, 
and are prepared according to the following reaction sequence: 
##STR2## 
In the first part of the process, 2-chloromethyl-benzo[b]thiophene 
magnesiane (A) is obtained in conditions of high dilution and in inert 
atmosphere, and is made to react at reflux temperature with 
1,4-dimethylpyridinium iodide (B) in anhydrous ether, thus obtaining the 
unstable 2-(2-benzo-[b]thienylmethyl-1,4-dimethyl-1,2-dihydropyridine (C) 
intermediate. 
Said intermediate, without subsequent purification, is reduced in basic 
medium with sodium borohydride in aqueous methanolic solution. The organic 
layer provides a mixture from which isolation can be made, by 
distillation, of the compound II, 
2-(2-benzo[b]thienylmethyl)-1,4-dimethyl-1,2,3,6-tetrahydropyridine, from 
which the corresponding hydrochloride is obtained. 
In a second step of the process the previously obtained raw mixture is 
heated at 135.degree. C. for 14 hours in a strong acid, such as for 
example 48% aqueous hydrobromic acid. It is poured over ice and water, 
alkalinized with ammonium hydroxide and extracted with ether, thus 
producing the 2,5-dimethyl-benzo[b]thiene [3,2-f]morphan (I).

The following examples are given only as illustrations, and must not be 
considered in any way limitative of the scope of the invention. 
EXAMPLE 1. 
Obtaining 
2-(2-benzo[b]thienylmethyl)-1,4-dimethyl-1,2,3,6-tetrahydropyridine. (II). 
To obtain 2-benzo[b]thienylmethylmagnesium chloride use has been made of 
the "modified cyclic reactor" embodying a continuous flow column provided 
with a separation funnel, coolant and reaction flask. 
The reactor column is packed with 70 g of magnesium in chips alternated 
with thin layers of mercuric chloride, and is covered with a saturated 
solution of mercuric chloride in anhydrous ether. Following 48 hours of 
repose, 250 ml of anhydrous ether are introduced in the flask and are made 
to reflux for 2 hours. The flask is substituted by another equipped for 
mechanical stirring in which 49.3 g of 1,4-dimethylpyridinium iodide are 
introduced in suspension with 500 ml of anhydrous ether. 36 g of 
2-chloromethylbenzo[b]thiophene dissolved in 400 ml of anhydrous ether are 
placed in a separation funnel, some ml of the halogenide solution are 
added to the magnesium column and when it is seen that the reaction has 
begun the flask is heated to reflux temperature, the addition continuing 
slowly for 6 hours. During the entire process a nitrogen atmosphere is 
maintained in the system. 
When addition is concluded reflux is continued for 4 hours; the resulting 
ether solution is poured over 500 ml of aqueous solution of ammonium 
chloride and ice; the mixture is alkalinized with ammonium hydroxide and 
is extracted with ether. The ether solution is extracted with 10% 
hydrochloric acid; the aqueous layer is alkalinized with concentrated 
ammonium hydroxide and is extracted with ether. The ether extract dried 
with magnesium sulfate and evaporated provides 42.5 g of the unstable 
2-(2-benzo[b]thienylmethyl)-1,4-dimethyl-1,2-dihydropyridine intermediate. 
To the 42.5 g of said intermediate dissolved in 275 ml of methanol are 
added 166 ml of 1 N sodium hydroxide and 6.8 g of boron tetrahydride and 
sodium. The mixture is heated at reflux temperature and is stirred for 12 
hours. The resulting product is extracted with ether and is dried with 
magnesium sulfate. Once the ether has evaporated, 22.6 g of a 
tetrahydropyridine mixture are obtained. The yield of the process is 45%. 
From said mixture the 2-(2-benzo[b] 
thienylmethyl)-1,4-dimethyl-1,2,3,6-tetrahydropyridine (II) can be 
isolated by distillation (b.p. 113-130/0.03 mm Hg) followed by 
crystallization of the corresponding hydrochloride. An analytical sample 
recrystallized from ether-acetone has a melting point of 
214.degree.-18.degree. C. 
Calculated analysis for C.sub.16 H.sub.20 ClNS: C, 65.40; H, 6.85; N, 4.76; 
S, 10.91; Cl, 12.06. 
Found: C, 65.49; H, 6.88; N, 4.49; S, 10.70; Cl. 12.15. 
EXAMPLE 2. 
Obtaining 2,5-dimethyl-benzo[b]thiene-[3,2-f]morphan (I). 
A solution of 6.5 g of the tetrahydropyridines mixture previously obtained 
in 87.3 ml of 48% aqueous hydrobromic acid is heated at 
130.degree.-5.degree. C. for 14 hours. The mixture is allowed to cool, is 
poured over ice and water, is alkalinized with ammonium hydroxide and is 
extracted with ether. The ether extract, dried with magnesium sulfate and 
evaporated, provides 5.47 g of an oil which is purified by distillation, 
the distilling fraction collecting between 125.degree.-270.degree. C./0.08 
mm Hg. Yield is 68%. The hydrochloride is precipitated and is purified by 
recrystallization from ether-acetone thus obtaining a solid having a 
melting point of 135.degree.-8.degree. C. 
Calculated analysis for: C.sub.16 H.sub.20 ClNS. H.sub.2 O: C, 61.65; H, 
7.09; N, 4.49. Found: C, 61.34; H, 7.29; N, 4.31. 
PHARMACOLOGY OF THE PRODUCTS OF THE INVENTION 
Products 
I-2,5-dimethyl-benzo[b]thiene[3,2-f]morphan. 
II-2-(2-benzo[b]thienylmethyl-1,4-dimethyl-1,2,3,6-tetrahydropyridine. 
These are products of analgesic activity. Their activity has been studied 
in comparison with that of dextropropoxyphene. 
A--ACUTE TOXICITY Acute toxicity studies have been made in I.C.R. Swiss 
albino mice of both sexes of a weight of 30.+-.2 g, kept without food for 
24 hours prior to the experiment. Ambient temperature and relative 
humidity were held constant. The products were administered 
intraperitoneally, with the number of deaths noted 48 hours from the 
moment of treatment. Calculation of the lethal dose 50 (LD.sub.50) was 
made by the Litchfield-Wilcoxon test. The following are the results 
obtained: 
TABLE I 
______________________________________ 
Product LD.sub.50 (mg/kg) 
______________________________________ 
I 90.8 
II 916.3 
Dextropropoxyphene 140 
______________________________________ 
B--ANALGESIC ACTIVITY 
1. Thermal analgesia 
The thermal analgesic effect has been studied in I.C.R. Swiss albino mice. 
The 55.degree. C. "hot plate" technique was used. Batches of 10 mice were 
made. The products in study were administered intraperitoneally and after 
30 minutes the mice were placed on the hot plate and note was made, in 
seconds, of the time it took them to jump. Batches were made of control 
animals injected only with distilled water. The results are shown in 
Tables 2 and 3. 
TABLE II 
______________________________________ 
Jumping time 
in sec. Significance of Diff. 
Treatment 
Dose -x .+-. S.E.M. 
Dextroprop. 
Control 
______________________________________ 
Control -- 30.9 .+-. 5.016 
-- -- 
Dextropro- 
poxyphene 
25mg/kg 70.8 .+-. 13.592 
-- p&lt;0.02 
Prod. I 25mg/kg 48.9 .+-. 8.956 
N.S. N.S. 
______________________________________ 
Product I lacks any thermal analgesic activity. 
TABLE III 
______________________________________ 
Jumping 
time in sec. 
Significance of Diff. 
Treatment 
Dose -x .+-. S.E.M. 
Dextroprop. 
Control 
______________________________________ 
Control -- 48.8 .+-. 5.033 
-- -- 
Dextropro- 
poxyphene 
50mg/kg 91.3 .+-. 7.894 
-- p&lt;0.00005 
Prod. II 
50mg/kg 63 .+-. 8.368 
p&lt;0.05 N.S. 
______________________________________ 
Product II lacks any thermal analgesic activity. 
2. Chemical analgesia The analgesic effect has been studied in I.C.R. Swiss 
albino mice, employing the acetic acid writhing technique. Batches of 10 
mice were made. 
The products studied were administered intraperitoneally, and after 30 
minutes the mice were injected intraperitoneally with 0.25 ml of 1% acetic 
acid. A batch of control animals received only the acetic acid. Note was 
made of the number of writhes in each mouse 20 minutes following injection 
of the acetic acid. The results are shown in Tables 4 and 5. 
TABLE IV 
______________________________________ 
No. of 
writhes Significance of Differences 
Treatment 
Dose -x .+-. S.E.M. 
Control Dextroprop. 
______________________________________ 
Control -- 122.1 .+-. 9.15 
-- -- 
Dextropro- 
poxyphene 
30mg/kg 24 .+-. 6.03 
p&lt;0.00005 
-- 
Prod. I 30mg/kg 44.3 .+-. 6.14 
p&lt;0.00005 
p&lt;0.05 
______________________________________ 
Product I has analgesic activity, but of lesser intensity than that of 
dextropropoxyphene. 
TABLE V 
______________________________________ 
No. of 
writhes Significance of Diff. 
Treatment 
Dose -x .+-. S.E.M. 
Control Dextroprop. 
______________________________________ 
Control -- 109.9 .+-. 6.362 
-- -- 
Dextropro- 
poxyphene 
25mg/kg 27.8 .+-. 8.365 
p&lt;0.00005 
-- 
Prod. II 
25mg/kg 41.2 .+-. 6.024 
p&lt;0.00005 
N.S. 
______________________________________ 
The analgesic activity of Product II is not significantly different from 
that of dextropropoxyphene.