4-DIPHENYLMETHYLENE-1-HYDROXYBENZYL-PIPERIDINE COMPOUNDS

TRADUCTION NON-DISPONIBLE

English Abstract

ABSTRACT OF THE DISCLOSURE:
New 4-diphenylmethylene-1-hydroxybenzyl-piperidines
having the formula
<IMG>
wherein A1, A2, A3 and A4, taken separately, each represents
hydrogen, halogen, trifluoromethyl, alkyl containing 1 to 4
carbon atoms or alkoxy containing 1 to 4 carbon atoms, and the
pharmaceutically acceptable acid addition salts thereof possess
valuable pharmacological properties. In particular, they are
blood circulation activating and anticonvulsive.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for the preparation of 4-diphenylmethylene-
1-hydroxybenzyl-piperidines of the general formula
<IMG>
wherein A1, A2, A3 and A4, taken separately, each represents
hydrogen, halogen, trifluoromethyl, alkyl containing 1 to 4 carbon
atoms or alkoxy containing 1 to 4 carbon atoms, and the pharmaceu-
tically acceptable acid addition salts thereof, which comprises
a) condensing a 4-diphenylmethylene-piperidine of the formula
<IMG>
in which A1, A2, A3 and A4 have the meanings given above, with a
benzyl compound of the formula
<IMG>
in which X is a halogen atom or an equivalent reactive group and
A5 is a protective group for the hydroxyl group, which can be easily
eliminated by hydrolysis, in the presence of an acid acceptor and
in solution in an organic solvent and subjecting the resulting
1-benzyl-4-diphenylmethylene-piperidine of the formula
28

<IMG>
in which A1, A2, A3, A4 and A5 have the meanings given above, to
hydrolysis, or
b) condensing an alpha, alpha-diphenyl-4-pyridinemethanol of the
formula
<IMG>
in which A1, A2, A3 and A4 have the meanings given above, with a
benzyl compound of the formula:
<IMG>
in which X and A5 have the meanings given above, catalytically
reducing the resulting 1-benzyl-4-(alpha-hydroxy-diphenylmethyl)-
pyridinium compound of the formula
<IMG>
in which A1, A2, A3, A4, A5 and X have the meanings given above,
dehydrating with a dehydrating agent the resulting 1-benzyl-alpha,
alpha-diphenyl-4-piperidinemethanol of the formula
29

<IMG>
in which A1, A2, A3, A4 and A5 have the meanings given above, and
subjecting the resulting 1-benzyl-4-diphenylmethylene-piperidine of
the formula
<IMG>
in which A1, A2, A3, A4 and A5 have the meanings given above, to
hydrolysis, or
c) condensing a 4-diphenylmethylene-piperidine of the formula
<IMG>
in which A1, A2, A3 and A4 have the meanings given above,with a
hydroxybenzaldehyde in an inert solvent in the presence of catalyti-
cally activated hydrogen, and, if desired,
d) converting the obtained 4-diphenylmethylene-1-hydroxybenzyl-
piperidines into pharmaceuticaily acceptable acid addition salts
thereof.

2. A process according to claim 1, wherein each of A1,
A2, A3 and A4 is hydrogen and the hydroxyl group is in the 4-posi-
tion of the benzyl group.
3. A process according to claim 1, wherein A1 is 2-
chloro, each of A2, A3 and A4 is hydrogen and the hydroxyl group is
in the 4-position of the benzyl group.
4. A process according to claim 1, wherein A1 is 4-
chloro, each of A2, A3 and A4 is hydrogen and the hydroxyl group
is in the 3-position of the benzyl group.
5. A process according to claim 1, wherein A1 is 4-
fluoro, each of A2, A3 and A4 is hydrogen and the hydroxyl group
is in the 4-position of the benzyl group.
6. A process according to claim 1, wherein A1 is 4-
fluoro, each of A2, A3 and A4 is hydrogen and the hydroxyl group is
in the 3-position of the benzyl group.
7. A process according to claim 1, wherein A1 is 4-
trifluoromethyl,each of A2, A3 and A4 is hydrogen and the hydroxyl
group is in the 4-position of the benzyl group.
8. A process according to claim 1, wherein A1 is 2-
trifluoromethyl,each of A2, A3 and A4 is hydrogen and the hydroxyl
group is in the-4-position of the benzyl group.
9. A process according to claim 1, wherein A1 is 4-
chloro, A3 is 4'-fluoro, each of A2 and A4 is hydrogen and the
hydroxyl group is in the 4-position of the benzyl group.
10. A process according to claim 1, wherein A1 is 4-
chloro, A3 is 4'-fluoro, each of A2 and A4 is hydrogen and the
hydroxyl group is in the 3-position of the benzyl group.
31

11. A process according to claim 1, wherein A1 is 4-
fluoro, A3 is 4'-trifluoromethyl, each of A2 and A4 is hydrogen
and the hydroxyl group is in the 4-position of the benzyl group.
12. A process according to claim 1, wherein A1 is 4-
fluoro, A3 is 4'-methoxy, each of A2 and A4 is hydrogen and the
hydroxyl group is in the 4-position of the benzyl group.
13. 4-Diphenylmethylene-1-hydroxybenzyl-piperidines of
the general formula
<IMG>
wherein A1, A2, A3 and A4, taken separately, each represents
hydrogen, halogen, trifluoromethyl, alkyl containing 1 to 4 carbon
atoms or alkoxy containing 1 to 4 carbon atoms,
and the pharmaceutically acceptable acid addition salts thereof,
whenever prepared by a process according to claim 1 or any obvious
chemical equivalent thereof.
14. 4-Diphenylmethylene-1-(4-hydroxybenzyl)-piperidine,
whenever prepared by a process according to claim 2 or any obvious
chemical equivalent thereof.
15. 4-(2-Chloro-diphenylmethylene)-1-(4-hydroxybenzyl)-
piperidine, whenever prepared by a process according to claim 3
or any obvious chemical equivalent thereof.
16. 4-(4-Chloro-diphenylmethylene)-1-(3-hydroxybenzyl)-
piperidine, whenever prepared by a process according to claim 4
or any obvious chemical equivalent thereof.
32

17. 4-(4-Fluoro-diphenylmethylene)-1-(4-hydroxybenzyl)-
piperidine, whenever prepared by a process according to claim 5
or any obvious chemical equivalent thereof.
18. 4-(4-Fluoro-diphenylmethylene)-1-(3-hydroxybenzyl)-
piperidine, whenever prepared by a process according to claim 6
or any obvious chemical equivalent thereof.
19. 1-(4-Hydroxybenzyl)-4-(4-trifluoromethyl-diphenyl-
methylene)-piperidine, whenever prepared by a process according
to claim 7 or any obvious chemical equivalent thereof.
20. 1-(4-Hydroxybenzyl)-4-(2-trifluoromethyl-diphenyl-
methylene)-piperidine, whenever prepared by a process according
to claim 8 or any obvious chemical equivalent thereof.
21. 4-(4-Chloro-4'-fluoro-diphenylmethylene)-1-(4-
hydroxybenzyl)-piperidine, whenever prepared by a process according
to claim 9 or any obvious chemical equivalent thereof.
22. 4-(4-Chloro-4'-fluoro-diphenylmethylene)-1-(3-hydroxy-
benzyl)-piperidine, whenever prepared by a process according to
claim 10 or any obvious chemical equivalent thereof.
23. 4-(4-Fluoro-4'-trifluoromethyl-diphenylmethylene)-1-
(4-hydroxybenzyl)-piperidine, whenever prepared by a process
according to claim 11 or any obvious chemical equivalent thereof.
24. 4-(4-Fluoro-4'-methoxy-diphenylmethylene)-1-(4-
hydroxybenzyl)-piperidine, whenever prepared by a process according
to claim 12 or any obvious chemical equivalent thereof.
33

Description

1101426
The present invention relates to new piperidine deriva-
tives and the pharmaceutically acceptable acid addition salts
thereof, as well as to processes for the preparation of these new
piperidine derivatives. The present inyention relates also to
pharmaceutical compositions containing the new compounds and/or
their salts and to the therapeutic use thereof.
The new piperidine derivatives according to the present
invention are 4-diphenylmethylene-1-hydroxybenzyl-pipeLidines of
the general formula:
A
1~ , .
~ ~ OH
A2 C ~ -CH ~ ~I)
A3
A4
wherein Al, A2, A3 and A4, taken separately, each represents hy-
drogen, halogen, trifluoromethyl, alkyl containing 1 to 4 carbon
atoms or alkoxy containing l to 4 carbon atoms, and the pharma-
ceutically acceptable acid addition salts thereof.
In preferred compoands according to the present invention,
the symbols Al, A2, A3 and A4, which may be the same or different,
are hydrogen, chlorine~or fluorine atoms or trifluoromethyl radi-
cals or alkyl or alkoxy radicals containing up to 4 carbon atoms.
- The compounds according to the present invention in the
form of the free bases or of salts with pharmaceutically acceptable
inorganic or organic acids, have valuable pharmacological proper-
ties. They have a very favourable action on the cerebral,peripheral
and coronary circulations. In addition, they are active on the
central nervous system in general.
The new compounds of general formula (I) according to
the present invention can be prepared by several known chemical
'~

11~14Z6
methods, which may be illustrated by the following three non- .
limiting examples:
1) A 4-diphenylmethylene-piperidine of the general formula:
A
~2
C=~ ~H (II)
~ ' / ~ - ,
~Y
A4 ~ ~~~ ~~~ ~ ;- -~-- -
_ _ ~ , , . . . , _ _

111~14Z6
wherein ~ 2~ ~3 and ~4 have the s~me meanings as above, is
condensed with a benzyl compound of the general formula:
0--~
X-CH2 ~ (III~
wherein x is halogen atom or an equivalent reactive group
and A5 is a protective group for the hydroxyl group which can
be easily eliminated by hydrolysis, for example a benzoyl
radical, in the presence of an acid acceptor and in solution
in an inert solvent, for example xylene, and the l-benzyl-4-
diphenylmethylene-piperidine thus obtained of the general
formula:
A13~
A2 C=~--C~32~o_A5 IIV)
A3
wherein Al, A2, A3, A4 and A5 have the same meanings as above,
is subsequently subjected to hydrolysis.
2) An alpha,alpha-diphenyl-4-pyridinemethanol of the general
formula
A ~ 0
2 H
C ~ N (V)
A
wherein Al, A2, A3 and A4 have the same meanings as above,
is concensed with a benzyl compound of the general formula
X-CH2 ~ O-A5 (III)
--3--
`X~
.

1~14Z6
wherein X and A5 have the same meanings as above, the l-benzyl-
4-(alpha-hydroxy-diphenylmethyl)-pyridinium compound thus
obtained of the general formula
A2 \ OH O-A
C ~ ~ -CH2 ~ X (VI)
10 wherein Al, A2, A3, A4, A5 and X have the same meanings as
above, is reduced catalytically, the corresponding l-benzyl-
alpha,alpha-diphenyl-4-piperidinemethanol thus obtained of
the general formula:
A
\ ' ~ N-CH2 ~ O-A5 (VII~
wherein Xl, A2, A3, A4 and A5 have the same meanings as above,
is dehydrated with a dehydrating agent, for example anhydrous
hydrogen chloride in alcoholic solution, and the resulting
l-benzyl-4-diphenylmethylene-piperidine of the general formula
A ~
C ~ N-CH ~ O-A5 (IV)
A3
A4
wherein Al, A2, A3, A4 and A5 have the same meanings as
above, is finally subjected to hydrolysis.
~ -4-

~Q14~6
3) A 4-diphenylmethylene-piperidine of the general formula
A
C~ NII (II~
A3`~
A4
wherein Al, A2, A3 and A4 have the same meaning as above,
is condensed with a hydroxybenzaldehyde in a inert solvent,
for example ethanol, in the presence of catalytically activated
hydrogen.
The starting material~ of formula II can be prepared
according to the method already described i.n British Patent
Specification No. 1,242,169 by the reduction of an alpha,alpha-
diphenyl-4-pyridinemethanol of the formula:
1~
A2 \ OH
C ~ N (V)
A~
A4
wherein Al, A3, A3 and A4 have the same meanings as above,
to give an alpha,alpha-diphenyl-4-piperidine-methanol of the
formula:
A2><===/\0H
~C_~H (VI I I )
A3~/
A4~X
wherein Al, A2, A3 and A4 have the same meanings as above,
--5--
j.,,

~ 1426
followed by dehydration to give the desired compound of formula
II.
The benzoyloxybenzyl bromides of formuIa III (X=
bromine; A5=benzoyl) can be prepared by the method described
by J.H. B~RNES et al. (J. Chem. Soc. 1953, 773).
It is to be understood that each of the new compounds
according to the present invention can be prepared by any
of the above-described methods or by equivalents thereof.
The present invention also provides pharmaceutical
compositions comprising at least one of the new compounds in
admixture with a solid or liquid pharmaceutical diluent or
carrier.
The following Examples are given for the purpose of
illustrating the present invention:
Preparation of the starting 4-diphenylmethylene-piperidines of
the formula II.
These compounds are prepared by the method described
in British Patent Specification No. 1,242,169. Apart from
the compounds already specifically mentioned in this British
Patent, the following compounds have also been synthetized
(for each compound prepared, there are given by order, the
starting product of formula V, the intermediate product of
formula VIII and the final product of formula II):
- alpha-4-fluoro~henyl-alpha-4'-methoxyphenyl-4-
pyridinemethanol (m.p. 147-150C.); alpha-4-fluorophenyl-alpha-
4'-methoxyphenyl-4-piperidinemethanol (m.p. 174-175C.); 4-(4-
fluoro-4'-methoxy-diphenylmethylene)-piperidine (m.p. 76-77C.);
- alpha-phenyl-alpha-2-trifluoromethylphenyl-4-
pyridinemethanol (m.p. 224-225C.); alpha-phenyl-alpha-2-
trifluoromethylphenyl-4-piperidinemethanol (m.p. 173-174C.);
4-(2-trifluoromethyl-diphenylmethylene)-piperidine (b.p. 128-
130C./0.001 mm.Hg.);
--6--

1101426
.
- alpha-3-fluorophenyl-alpha-phenyl-4-pyridinemethanol
(m.p. 194-195C.); alpha-3-fluorophenyl-alpha-phenyl-4-piperi-
dinemethanol (m.p. 149-150C.); 4-~3-fluoro-diphenylmethylene)-
piperidine (b.p. 142-144C./0.001 mm.Hg.; m.p. 45-46C.);
- alpha-4-fluorophenyl-alpha-4'-trifluoromethylphenyl-4-
pyridinemethanol m.p. 157-158C.); alpha-4-fluorophenyl-alpha-
4'-trifluoromethylphenyl-4-piperidinemethanol (m.p. of HCl
salt: 262-263C.); 4-(4-fluoro-4'-trifluoromethyl-diphenyl-
methylene)-piperidine (b.p. 130-134C./0.001 mm.Hg.);
- alpha,alpha-bis-(4-chlorophenyl)-4-pyridinemethanol
(m.p. 202-205C.); alpha,alpha-bis-(4-chlorophenyl)-4-piperi-
dinemethanol (m.p. 175-177C.); 4-(4,4'-dichlorodiphenyl-
methylene)-piperidine (m.p. 115-117C.);
- alpha-4-isopropylphenyl-alpha-phenyl-4-pyridinemethanol
(m.p.-151-153C); alpha-4-isopropylphenyl-alpha-phenyl-4-piperi-
dinemethanol (m.p. 216-218C.); 4-(4-isopropyl-diphenylmethylene)-
piperidine (m.p. 55-56C.);
- alpha-2-fluorophenyl-alpha-phenyl-4-pyridinemethanol
(m.p. 200-201C.); alpha-2-fluorophenyl-alpha-phenyl-4-piperi-
dinemethanol; dehydrated without isolation to 4-(2-fluorodi-
phenylmethylene)-piperidine (b.p. 122-124C./0.001 mm.Hg.;
m.p. 65-66C.);
- alpha-phenyl-alpha-4-propoxyphenyl-4-pyridinemethanol
(m.p. 138-140C.); alpha-phenyl-alpha-4-propoxyphenyl-4-piperi-
dinemethanol; dehydrated without isolation to 4-(4-propoxydi-
phenylmethylene)-piperidine (m.p. 70-71C.);
- alpha-4-chlorophenyl-alpha-3'-methylphenyl-4-
pyridinemethanol (m.p. 184-185C.); alpha-4-chlorophenyl-alpha-
3'-methylphenyl-4-piperidinemethanol; dehydrated without isolation
to 4-(4-chloro-3'-methyl-diphenylmethylene)-piperidine (b.p.
154-156GC./0.001 mm.Hg.).
~ -7-

11~1426
Preparation of the 4-diphenylmethylene-1-hydroxybenzyl-piperi-
dines accordin~ to the invention.
Example 1. First proc_ss.
1. 4-(4-tert.-sutyl-diphenylmethylene)-1-(4-hydroxybenzyl)-
piperidine .a) A mixture of 18.4 g. of 4-(4-tert.-butyldiphenyl-
methylene)-piperidine, 20 g. of 4-benzoyloxybenzyl bromide
and 9.5 g. anhydrous sodium carbonate in 50 ml. xylene is
heated for 4 hours at 120C. After cooling, the reaction
mixture is filtered to separate the sodium bromide formed and
the filtrate is extracted with dilute hydrochloric acid ~15 ml.
of concentrated hydrochloric acid diluted with 40 ml. of water).
1-(4-Benzoyloxybenzyl)-4-(4-tert.-butyl-diphenylmethylene)-
piperidine, precipitates out in the form of its sparingly
soluble hydrochloride, which is filtered off and recrystallized
from isopropanol; m.p. 259-261C. Yield: 85~.
Y C36 37N02.HC
calculated: Cl 6.42% N 2.53
found : 6.35~ 2.60%
b) A mixture of 10 g. of the compound obtained according
to a) above and 10 g. of potassium hydroxide in 200 ml. of
ethanol is heated under reflux. The ethanol is allowed to
distil off and is progressively replaced by water. After
distillation of the ethanol, dilute hydrochloric a~id (20 ml.
of concentrated hydrochloric acid diluted with 25 ml. of water)
is slowly added. The sparingly soluble hydrochloride precipitates
out and is separated by decanting the reaction mixture. The
precipitate is washed twice with lukewarm water and then re-
crystallized from isopropanol to give 4-(4-tert.-butyl-diphenyl-
methylene)-1-(4-hydroxybenzyl)-piperidine hydrochloride; m.p.
202-204C. (recrystallized from isopropanol).
Yield: 72%

` 1101426
lysis C2sTI33No.Hcl
calculated: Cl 7.91% N 3.13
found : 8.04% 3.30~
The following compounds are prepared in an analogous
manner. The melting points are, unless stated to the contrary,
those of the hydrochlorides. The melting points are often not
very sharp (margin of error 1-5C.) due to the fact that the
compounds prepared frequently contain a small quantity of
solvent.
2. 4-(4-tert.Butyl-diphenylmethylenej-1-(2-hydroxybenzy _ -
piperidine
.
) C36 37 2 HCl calculated: Cl 6.42% N 2.53%
found : 6.55~ 2.64%
m.p. 205-207C. (recrystallized from isopropanol).
b) C29H33NO-HCl calculated: Cl 7.91% N 3.13%
found : 8.13% 3.18%
m.p. 150-152C. (recrystallized from acetonitrile)
3. 4-Diphenylmethylene-1-(4-hydroxybenzyl)-piperidine
) C32 29NO2.HCl calculated: Cl 7.14% N 2.80%
20found : 7.08% 2.78%
m.p. 246-248C. (recrystallized from isopropanol)
bj C25H25NO-HCl calculated: Cl 9.04% N 3.57%
found : 9.20~ 3.56%
m.p. 244-246C. (recrystallized from isopropanol)
4. 4-Diphenylmethylene--l-(3-hydroxy-enzyl)-piperidine
a) C32 29NO2.HCl calculated: Cl 7.14% N 2.80%
found : 7.31% 2.88%
m.p. 249-251C.
b) C25 25NO-HCl calculated: Cl 9.04% N 3.57%
found : 9.05% 3.69%
m.p. 148-150C. (recrystallized from acetonitrile)
5. 4-Diphenylmethylene-1-(2-hydroxybenzyl)-piperidine

` 11~14Z6
a) C32H29N2 HCl calculated: Cl 7.14% N 2.80%
found : 7.12%2.88%
m.p. 214-216C.
) 25 25 Cl calculated: Cl 9.04% N 3.57
Eound : 9.00'~ 3.58~
m.p. 156-158C. (recrystallized from acetonitrile) (softened
at 132C.).
6. 4-(2-Chloro-dipheny_methylenej~ 4-hydroxybenzyl)-
piperidine.
a) C32H28ClNO2.HCl
calculated: Cl 13.36% C1 6.68% N 2.64%
found : 13.25~ 6.75% 2.63%
m.p~ 264-266C. (recrystallized from isopropanol)
b) C25H24ClN0-HCl
calculated: Cl 16.63~ Cl 8.31% N 3.28%
found : 16.30% 8.36~ 3.34%
m.p. 248-250C. (recrystallized from isopropanol); 193-194C.
(free base)
7. 4-(2-Chloro-diphenylmethylene)-1-(3-hydroxybenzyl)-piperidine.
a) C32H28ClN02.HCl
calculated: Cl 13.36% Cl 6.68~ N 2.64%
fo~nd : 13.50% 6.72% 2.72%
m.p. 254-256C. (recrystallized from isopropanol)
b) C25 24ClNO.HCl
calculated: Cl 16.63% Cl 8.31~ N 3.28%
found : 16.75% 8.25% 3.39%
m.p. 242-244C.
8. 4-(2-Chloro-diphenylmethylene)-1-(2-hydroxybenzyl)-piperidine.
a) C32H28ClNO2.HCl
calculated: Cl 13.36~ Cl 6.68% N 2.64%
found : 13.10~ 6.85% 2.86%
m.p. 200-202C.
--10--

~" 11(~14Z6
~`
) C25H24ClNO.HCl
calculated: Cl 16.63~ Cl 8.31% N 3.28%
found : 16.28% 8.20% 3.23%
m.p . 240-242c.
9. 4-(3-Chloro-diphenylmethyiene)-1-14-hydroxybenzyl~-piperidine.
a) C32H28ClNO2.HCl
calculated: Cl 13.36% Cl 6.68% N 2.64%
found : 12.92~ 6.85% 2.70
m.p. 242-244C. (recrystallized from isopropanol)
' ) C25 24ClNO HCl
calculated: Clttal 16.63% Cl 8 31% N 3 28%
found : 16.57% 8.30~ 3.36%
m.p. 234-236C. (recrystalllzed from isopropanol)
10. 4-(3-Chloro-diphenylmethylene)-1-~3-hydroxybenzyl)-
piperidine.
a) C32H28.ClNo2.HCl
calculated: Cl 13.36% Cl 6.68% N 2.64%
found : 13.18% 6.55% 2.67%
m.p. 221-223C.
) C25 24ClNO.HCl
calculated: Cl 16.63~ Cl 8.31% N 3.28%
found : 16.53% 8.31% 3.22
m.p. 156-157C. (recrystallized from isopropanol)
11. 4-(4-Chloro-diphenylmethylene)-1-(4-hydcoxybenzyl)-
piperidine.
a) C32H28ClNO2-E~Cl
calculated: Cl 13.36% Cl 6068% N 2.64~
found : 13.10% 6.95~ 2.73%
m~p. 244-246C.
) C25 24ClNO HCl
calculated: Cl 16.63~ Cl 8.31% N 3.28%
found : 16.40~ 8.35% 3.33
-11-

11(~1426
m.p. 232-233C. (recrystallized from isopropanol)
12. 4-(4-Chloro-diphenylmethylene)-1-(3-hydroxybenzyl)-
piperidine.
a) C32H28ClNO2.HCl
calculated: Cl 13.36% Cl 6.68% N 2.64%
found :13.10~ 6.75%2.68%
m.p. 192-194C.
) C25 24ClNO-HCl
calculated: Cl 1 14.16%Cl 7.08% N 2.79~
(for 1/2 molecuIe of benzene of crystallization)
found : 14.50% 7.20% 3.00%
m.p. 143-145C. (benzene)
13. 4-(4-Chloro-diphenylmethylene)-1-(2-hydroxybenzyl)-
piperidine.
a) C32H28ClNO2.HCl
calculated: Cl 12.04~ Cl 6~02% N 2.37%
(for 1 molecule of acetone of crystallization)
found :12.00% 6.05%2.39%
m.p. 112-114C (acetone)
) 25 24ClNO.HCl
calculated: Cl 16.63% Cl 8.31% N 3.28~
found :16.55% 8.42%3.28%
m.p. 240-241C.
14. 4-(4-Fluoro-diphenylmethylene)-l-(4-hydroxybenzyl)
pi~eridine.
a) C32H28FNo2.HCl calculated: Cl 6.90~ N 2.72%
found : 7.00% 2.72%
m.p. 233-234C. (recrystallized from isopropanol)
) C25 24 NO-HCl calculated: Cl 8.65% N 3.41%
found : 8.72% 3.42%
m.p. 230-232C. (recrystallized from benzene)
~ -12-
" ,

^`` 11al1426
15. 4-(4-Fluoro-diphenylmethylene)-1-~3-hydroxybenzyl)-
piperidine.
a) C32H28FNO2.HCl calculated: C1 6.90% N 2.72%
found : 6.95~ 2.79%
m.p. 227-228C. (recrystallized from benzene)
b) C25H24FNO-HCl calcuIated: Cl 8.65% N 3.41%
found : 8.54% 3.30%
m.p. 125-126C. (recrystallized from benzene)
.
16. 4-(4-Fluoro-diphen~lmethylene)-1-(2-hydroxybenzyl)-
piperidine.
a) C32H28FN2 HCl calculated: Cl 6.90% N 2.72%
found : 6.85% 2.50%
m.p. 100-102C. (recrystallized from benzene)
) 25 24 - Cl calculated: Cl 8.65% N 3.41%
found : 9.00% 3.30%
m.p. 211-213C.
.
17. 4-(3-Fluoro-diphenylmethylene)-1-(4-hydroxybenzyl)-
piperidine.
a) C32H28FN2'HCl calculated: Cl 6.90% N 2.72%
found : 6.9S% 2.74%
m.p. 254-256C. (recrystallized from benzene)
b) C25H24FNO'HCl calculated: Cl 8.65% N 3.41%
found : 8.84% 3.52%
m.p. 242-246C. ~recrystallized from isopropanol)
18. 4-(3-Fluoro-diphenylmethylene)-1-(3-hydroxybenzyl)-
piperidine.
a) C32H28FNO2.HC1 calculated: Cl 6.90% N 2.72%
found : 7.00% 2.80%
m.p. 241-243C. (recrystallized from xylene)
30b) C25 24 Cl calculated: Cl 8.65%N 3.41~
found : 8.91% 3.44%
m.p. 145-147C. (recrystallized from acetonitrile)
-13-

11014Z6
19. 4-(2-Fluoro-diphenylmethylene)-1-(4-hydroxybenzyl)-
piperidine.
a) C32H28FNO2.Hcl calculated: Cl 6.90% N 2.72%
found : 7.07% 2.84%
m.p. 267-269C. (recrystallized from isopropanol)
b) C25H24FNO'HCl calculated: Cl 8.65% N 3.41%
found : 8.87% 3.52%
m.p~ 245-247C.
20. 1-(4-Hydroxybenzyl)-4-(4-trifluoromethyl-diphenylmethylene)-
piperidine.
a) C33H28F3NO2.HCl calculated: Cl6.28% N 2.48%
found : 6.53% 2.56%
m.p. 242-244C.
b) C26H24F3N'HCl calculated: Cl 7.70% N 3.06%
found : 7.75% 3.08%
m.p. 228-229C (recrystallized from ethyl acetate)
21. ~(3-Hydroxybenzyl)-4-(4-trifluoromethyl-diphenylmethylene)-
piperidine.
a) C33H28F3NO2.HCl calculated: Cl 6.28% N 2.48%
found : 6.48% 2.54%
m.p. 201-203C. (recrystallized from ethyl acetate)
b) C26 24 3 calculated: Cl 7.70% N 3.06%
found : 7.44% 2.92%
m.p. 129-131C.
22. 1-(4-Hydroxybenzyl)-4-(3-trifluoromethyl-diphenylmethylene)-
piperidine
a) C33H28F3No2-Hcl calculated: Cl 6.28% N 2.48%
found : 6.35% 2.61%
m.p. 229-231C. (recrystallized from methanol)
) 26 24 3 calculated: Cl 7.70% N 3.06%
found : 7.65% 3.17%
m.p. 229-230C. (recrystallized from ethyl acetate)
~-14-

1163 14Z6
23. 1-(3-~ydroxybenzyl)-4-(3-trifluoromethyl-diphenylmethylene)
piperidine.
a) C33H28F3NO2.HCl calculated: Cl 6.28~ N 2.48%
found : 6.34% 2.55%
m.p. 215-217C.
b) C26 24F3NO.HCl calculated: Cl 7.70% N 3.06%
found- : 7.58% 3.01%
m.p. 148-150C.
24. 1-(2-Hydroxybenzyl)-4-(3-trifluoromethyl-diphenylmethylene)-
piperidine.
The benzoyloxy derivative was hydrolyzed without isolation.
b) C26 24F3NO.HCl calculated: Cl 7.70% N 3.06%
found : 7.40% 2.92%
m.p. 158-160C. (recrystallized from isopropanol)
25. 1-(4-Hydroxybenzyl)-4-(2-trifluoromethyl-diphenylmethylene)-
piperidine.
a) C33H28F3NO2.HCl calculated: Cl 6.28% N 2.48%
found : 6.18% 2.49%
m.p. 242-244C.
b) C26 24F3NO.HCl calculated: Cl 7.70% N 3.06%
found : 7.95% 3.l4%
m.p. 250-252C. (recrystallized from methanol)
26. 1-(2-Hydroxybenzyl)-4-(2-trifluoromethyl-diphenylmethylene)-
piperidine.
a) C33H28F3NO2~HCl calculated: Cl 6.28% N 2.48%
found : 6.04% 2.51%
m.p. 125-127C.
b) C26 24 3NO HCl calculated: Cl 7.70% N 3.06%
found : 7.75% 3.05%
m.p. 132-134C.
27. 1-(4-Hydroxybenzyl)-4-(4-methoxy-diphenylmethylene)-
piperidine.
-15-

~10~4Z~i
a) C33H31~3-HCl calculated: Cl 6.73% N 2.65%
found : 6.82~ 2.68
m.p. 243-245C.
26 27 2 calculated: Cl 8.40% N 3.31%
found : 8.45% 3.29
m.p. 222-223C.
28. 1-(2-Hydroxybenzyl)-4-(4-methoxy-diphenylmethylene)-
pi~eridine.
a) C33H31N3-HCl calculated: Cl 6.73% N 2.65%
found : 6.55% 2.51%
m.p. 115-120C. (approximate) (recrystallized from ethyl
acetate)
b) C26H27N2 HCl calculated: Cl 8.40% N 3.31
~ found : 8.54% 3.32
m.p. 223-224C.
29. 1-~4-Hydroxybenzyl)-4-(2-methoxy-diphenylmethylene)-pi-
_eridine.
a) C33H31N3-HCl calculated: Cl 6.73% N 2.65~
found : 6.35~ 2.49%
m.p. 242-423C. (recrystallized from isopropanol)
b) C26H27N2'HCl calculated: Cl 8.40% N 3.31%
found : 8.45~ 3.30
m.p. 251-252C.
30. 1-(3-llydroxybenzyl)-4-(2-methoxy-diphenylmethylene)-
piperidine.
a) C33H31N3'HCl calculated: Cl 6.73% N 2.65%
found : 6.85% 2.64%
m.p. 210-212C. (recrystallized from benzene)
) C26 27 2 Cl calculated: Cl 8.40% N 3.31%
found : 8.45% 3.31
m.p. 220-222C. (recrystallized from isopropanol)
31. 1-(2-Hydroxybenzyl)-4-(2-methoxy-diphenylmethylene)-
-16-
~.

1~014Z6
piperidine.
) C33 31NO3.HCl calculated: Cl 6.73% N 2.65%
found : 6.70% 2.62%
m.p. 181 182C.
b) C26ll27NO2-llCl calculated: Cl 8.40~ N 3.31
found : 8.58% 3.38%
m.p. 128-130C. (recrystallized-from benzene)
32. 4-(3t4-Dimethy~-diphenylmethylene)-l-(4-hydroxybenzyl)
piperid-lne~
10) C34 33NO2.HCl calculated: Cl 6.76% N 2.72%
found : 6.72% 2.71%
m.p. 267-268C. (recrystallized from methanol)
) 27 29 -HCl calculated: Cl 8.44% N 3.33%
found : 8.80% 3.36%
m.p. 248-250C.
33. 4-(3,4-Dimethyl-diphenylmethylene)~ 3-hydroxybenzyl)
piperidine .
a) C34H33N2 HCl calculated: Cl 6.76% N 2.72%
found : 6.89% 2.71%
20m.p. 235-236C. (recrystallized from isopropanol)
b) C27H29NO-HCl calculated: Cl 8.44% N 3.33%
found : 8.33% 3.35%
m.p. 147-149C. (recrystallized from benzene)
34. 4-(3,4-Dimethyl-diphenylmethylene)-1-(2-hydroxybenzyl)-
piperidine.
) 34 33 O2.HCl calculated: Cl 6.76% N 2.72~
found : 6.55%2.60%
m.p. 162-164C.
) 27 29NO.HCl calculated: Cl 8.44% N 3.33%
found : 8.68%3.34
m.p. 203-205C. (recrystallized from ethyl acetate)
35. 4-(4-Chloro-4'-fluoro-diphenylmethylene3-1-(4-hydroxy-
- -17-

110~4Z6
benzyl)-piperidine.
a) C32H27ClFNO2.HCl
calculated: Cl 12.92~ Cl 6.46% N 2.55%
found : 13.18~ 6.57% 2.52%
m.p. 221-222C. (recrystallized from benzene)
b) C25H23ClFNO-HCl
calculated: Cl 13~58% Cl 6.78% N 2.70
(for 1 molecule of benzene of crystallization)
found : 13~30% 6.88% 2.72%
m.p. 134-316C. (benzene)
36. 4-(4-Chloro-4'-f]uoro-diphenylmethylene)-1-(3-hydroxy-
benzyl)-piperidine.
a) C32H27ClFNo2.HCl
calculated: Cl 12.92% Cl 6.46% N 2.55%
found : 12.54% 6.57~ 2.54%
m.p. 236-238C. (recrystallized from isopropanol)
b) C25H23ClFNo.HCl
calculated: Cl 15.95% Cl 7.97% N 3.15%
found : 16.30% 8.10% 3.21
m.p. 229-230C.
37. 4-(4-Fluoro-4'-trifluoromethyl-diphenylmethylene)-1-(4-
hydroxybenzyl)-piperidine.
a) C33H27F4NO2.HCl calculated: Cl 6.49% N 2.40~
found : 6.50% 2.39%
m.p. 228-229C. (recrystallized from isopropanol)
) 26 23 4 C calculated: Cl 7.41% N 2.93
found : 7.35% 2.98
m.p. 223-225C. (recrystallized from benzene)
38. 4-(4-Fluoro-4'-trifluoromethyl-diphenylmethylene)-1-(3-
hydroxybenzyl)-piperidine.
Thebenzoyloxy derivative was hydrolyzed without isolation.
-18-

14Z6
b) C26H23F4NO-HCl calculated: Cl 7.41% N 2.93~
found : 7.20~ 2.88%
m.p. 134-315C. (rccrystallized from acctonitrilc)
39. 4-(4-Fluoro-3'-trifluoromethyl-diphenylmcthylene) 1-(4-
hydro~ybcnzyl)-pip~ridin~.
a) C~3H27F4NO2.HCl calculated: Cl 6.49% N 2.40%
found : 6.20~ 2.47%
m.p. 216-218C. (recrystallized from benzene)
b) C26H23F4NO-HCl calculated: Cl 7.41% N 2.93%
found : - 7.84% 3.11%
m.p. 234-235C.
40. 4-(4-Fluoro-3'-trifluoromethyl-diphenylmethylene)-1-(3-
hydrozybenzyl)-piperidine.
a) C33H27F4NO2.HCl calculated: Cl 6.49% N 2.40%
found : 6.15% 2.50%
m.p. 174-176C. (recrystallized from ethyl acetate)
b) C26H23F4NO-HCl calculated: Cl 7.41% N 2.93%
found : 7.44% 2.94%
m.p. 133-135C.
41. 4-(4-Fluoro-4'-methoxy-diphenylmethylene)-1-(4-hydroxy-
benzyl)-piperidine.
a) C33H30FNO3-HCl calculated: Cl 6.53~ N 2.57%
found : 6.25% 2.66%
m.p. 223-225C. (recrystallized from ethyl acetate)
b) C26H26FN2 HCl calculated: Cl 8.05% N 3.18%
found : 8.50% 3.22%
m.p. 219-220C. (recrystallized from isopropanol)
42. 4-(4-Fluoro-4'-methoxy-diphenylmethylene)-1-(3-hydroxy-
benzyl)-piperidine.
a) C33H30FNO3-HCl calculated: Cl 6.53% N 2.57%
found : 6.68% 2.66%
m.p. 195-197C. (recrystallized from ethyl acetate)
,~," . --1 9--

11~1426
) C26H26FNO2.HCl calculated: Cl 8.05~ N 3.18
found : 7.95% 3.24
m.p. 140-141C. (recrystallized from isopropanol)
43. 1-(4-Hydroxybenzyl)-4-(4-propoxy-diphenylmethylene)-
piperidine.
) 35 35 3 calculated: Cl 6.39% N 2.52
found : 6.41% 2.64
m.p. 204-206C. (recrystallized from acetonitrile)
b) C28 31 O3 HCl calculated: Cl 7.87% N 3.11%
~ found : 7.81% 3.20
m.p. 225-227C. (recrystallized from acetonitrile)
Example 2. Second process.
44. 4-Diphenylmethylene-1-(4-hydroxybenzyl)-piperidine.
a) 26.3 g. of alpha,alpha-diphenyl-4-pyridinemethanol in
60 ml. of dioxan are boiled under reflux and treated dropwise,
while stirring mechanically, with a solution of 29.5 g of 4-
benzoyloxybenzyl bromide in 50 ml. of dioxan. When the addltion
of this solution is finished, the reaction mixture is further
heated under reflux for 1.5 hours, whereafter excess solvent
is evaporated off under vacuum and the 1-(4-benzoyloxybenzyl)-
4-(alpha-hydroxy-diphenylmethyl)-pyridinium bromide thus ob-
tained is crystallized from benzene; m.p. 210-213C. Yield:
69.5%.
~nalysis: C32ll26~rNO3 calculated: Br 14.46% N 2.53%
found : 14.21~ 2.70%
b) 33 g. of the compound obtained under a) above is subse-
quently reduced catalytically in 1 liter of ethanol in the presence
of 1 g. of platinum oxide under a hydrogen pressure of 4 kg.
in a Parr bomb at 3~C. The reduction product, 1-(4-benzoyloxy-
benzyl)-alpha,alpha-diphenyl-4-piperidinemethanol (not isolated)
obtained after filtering off the platinum oxide and evaporating
the solvent, i5 subsequently dehydrated in 500 ml. of a solution
' "'5 `' -20-
,

11(;~1426
of ethanol saturated in the cold with gaseous hydrogen chloride.
After heating the reaction mixture under reflux for 3 hours
and ~vaporatin~ under vacuum to remove the solvent and exc~ss
hydrogen chloride, the evaporation residue, dissolved in 250 ml.
oE cthanol wiLI~ ~he addikion oE 15 g. r~o~assiu~n hydroxlde, ls
treated and isolated in the same manner as in step b) of Example
1 (firs~ process). ~Eter r~crystallization ~rom lsopropanol,
4-diphenylmethylene-1-(4-hydroxybenzyl)-piperidine hydrochloride
is obtained; m.p. 245-246C. Yield: 82.5~.
Analysis C25H25NO-HCl calculated: Cl 9.04% N 3.57~
found : 9.28% 3.70%
There is no melting point depression when this product is mixed
with the same compound of Example 1 (compound 3).
The following compounds were prepared in the same
manner.
45. 4-Diphenylmethylene-1-(3-hydroxybenzyl)-piperidine.
; a) 1-(3-Benzoyloxybenzyl)-4-(alpha-hydroxy-diphenylmethyl)-
pyridinium bromide melts at 219-221C., after recrystallization
from dioxan.
C32H26BrN3 calculated: Br 14.46% N 2.53~
found : 14.19% 2.57%
b) After reduction 1-(3-benzoyloxybenzyl)-alpha,alpha-
diphenyl-4-piperidine-methanol hydrobromide is obtained, which
melts at 218-219C., after recrystallization from acetonitrile.
C32H31NO3.HBr calculated: Br 14.31% N 2.50~
found : 14.60% 2.64%
4-Diphenylmethylene-1-(3-hydroxybenzyl)-piperidine hydro-
chloride, obtained after dehydration and hydrolysis, melts
at 148-150C. It does not show a melting point depression
when mixed with the same compound prepared according to
Example 1 (compound 4).
C25H25N HCl calculated: Cl 9.04% N 3.57%
found : 8.95% 3.57
-21-
.

11~14Z6
46. 4-Diphenylmethylene-1-(2-hYdroxybenzyl)-piperidine.
a) l-(2-Benzoyloxybenzyl)-4 (alpha-hydroxy-diphenylmethyl)-
pyridinium bromide melts at 197-198C., after recrystallization
from benzene.
C32ll26~rNO3 calculated: Br 14.46~ N 2.53%
found : 13.90% 2.44%
b) ~fter reduction, dehydration and hydrolysis, there
is obtained 4-diphenylmethylene-1-(2-hydroxybenzyl)-piperidine
hydrochloride, which melts at 156-158C., after recrystallization
from acetonitrile. It is to be noted that this compound already
softens at 132-134C., as does the same compound (compound 5)
prepared according to Example 1. The free base, after liberation
from the hydrochloride, melts at 149-150C.
C25H25NO.HCl calculated: Cl 9.04% N 3.57%
found : 9.11% 3.54%
Example 3. Third_process.
47. 4-Diphenylmethylene-1-(4-hydroxybenzyl)-piperidine.
A solution of 12.5 g. of 4-diphenylmethylene-piperidine
and of 20 g. of 4-hydroxybenzaldehyde in 120 ml. of ethanol
is reduced in the presence of 1 g. of platinum oxide in a Parr
bomb under a hydrogen pressure of 4 kg. at a temperature of
30-35C. After filtering the reaction mixture, 4-diphenyl-
methylene-l-(4-hydroxybenzyl)-piperidine crystallizes in the
form of the base upon concentration of the filtrate. After
recrystallization from ethanol, it has a melting point of 189-
190C.
25 25 calculated: N 3.94%
found : 4.03%
The corresponding hydrochloride, after recrystallization
from isopropanol, melts at 244-246C. and does not show any
melting point depression when mixed with the same compound
prepared according to the two other Examples (compounds 3 and
44)-
-22-

11(~1426
48. 4-Diphenylmethylene-l-t2-hydroxybenzyl)-piperidine.
This compound is obtained in an analogous manner.
After recrystallization from ethanol, it has a melting point
of 148-149C. (free base). When mixed with the same compound
prepared according to Example 2 (compound 46), it does not
show any melting point depression.
25 25 calculated: N 3.94~
found : 3.90%
The corresponding hydrochloride, after recrystallization
from acetonitrile, melts at 156-158C. but already softens at
about 132-134C., as aLready observed for the same compound
prepared according to the other Examples (compounds 5 and 46).
49. 1-(4-Hydroxybenzyl)-4-(4-isopropyl-diphenylmethylene)-
piperidlne .
A solution of 15 g. of 4-(4-isopropanol-diphenyl-
methylene)-piperidine and of 20 g. of 4-hydroxybenzaldehyde
in 100 ml. of ethanol is reduced in the same manner as des-
cribed above. After the reaction, the reaction mixture is
filtered and excess solvent evaporated off under vacuum on a
waterbath. The evaporation residue is taken up in 100 ml.
of benzene, filtered and extracted with dilute hydrochloric
acid (15 ml. of concentrated hydrochloric acid diluted with
50 ml. of water). 1-(4-Hydroxybenzyl)-4-(4-isopropyldiphenyl-
methylene)-piperidine hydrochloride thus obtained, after crystal-
lization from ethanol, melts at 253-254C. Yield: 60%.
28 3lNo.Hcl calculated: Cl 8.17~ N 3.22%
found : 8.43~ 3.27~
The following two compounds are prepared in the same
manner as compound 49:
50. 4-(4-Chloro-3'-methyl-diphenylmethylene)~1-(4-h~droxy-
benzyl)-piperidine.
C26H26ClNo.HCl
-23-

11(1 14Z6
calculated: Cl 16.10~ Cl 8.05% N 3.18~
found : 15.87% 8.32% 3.26%
A~ter recrystallization from ethyl acetate, it melts
at 221-223C.
51. 4-(4,4'-Dichloro-diphenyl~ethylene)-1-~4-hydroxybenzyl)-
piperidine.
C25 23cl2No-llcl
calculated: Cl 23.08% Cl 7.69% N 3.03%
found : 23.29~ 7.93% 3.10%
After recrystallization from isopropanol, the product
melts at 166-168C.
Salts of compound 6 mentioned above can also be
prepared:
52. 4-(2-Chloro-diphenylmethylene)-1-(4-hydroxybenzyl)-
piperidine fumarate.
c25H24ClNo~c4H4o4 calculated: N 2.76% Cl 7.00%
found : 2.74~ 7.07%
m.p. 130-140C.
53. 4-(2-Chloro-diphenylmethylene)-1-(4-hydroxybenzyl)-
piperidine maleate.
c25H24ClNo~c4H4o4 calculated: N 2.76% Cl 7.00%
found : 2.76% 7.4%
m.p. 110-112C.
Pharmacological properties.
1. Activity on the blood circulation.
_______ _________________________
The hemodynamic effects of compounds of general formula
1 were studied on the anesthetized dog subjected to artificial
respiration under the experimental conditions described by
D. WELLENS and E. WAUTERS (Arch. Int. Pharmacodyn., 171, (1968),
245-250). The measurement of the musculo-cutaneous, cardiac
and cerebral outputs, carried out by means of probes places
around the femoral (A), carotid (B), coronary (C) and vertebral
(D) arteries, showed that the compounds of general formula I
~ -24-

11~14Z6
considerably increase the blood circulation.
In these experiments, the maximum score " 2" is
assigned to a compound that brings about an increase of
circulation of at least 20~ for at least 20 minutes. The
maximum score per experiment carried out on two dogs is " 4" ,
with the possibility of the intermediates form " 0" to " 4" .
For the purpose of comparison, the corresponding values for
two known compounds,~papaverine (X) andtheophylline (Y) are
also given. The results obtained are given in the following
Table I:
TABLE I
Output scores
CompoundDoses in mg/kg (i.v.) A B C D
X 2 1.5 2 2 1.5
Y 20 0 1.5 1 4
6 2 2.0 2.8 3.10 3.0
14 2 1.10 2.20 3.0 4
2 1.2 2.2 3.2 3.2
2 1 2 2.5 2.5
37 Z 1.2 1 3.2 4
44 2 0.8 1.6 2.6 3.2
In this Table I, when the output scores for each
of the tested compound are added up, it can be seen that the
total vasodilatatory activity of the compounds according
to the invention is markedly superior to that of the reference
compounds (X) and (Y); they also show a certain specificity of
action where the reference compounds are deficient.
The compounds according to the invention are thus
useful in the treatment of diseases resulting from central
or peripheral circulatory deficiencies.
2. Activity on the central nervous system.
.
Some of the compounds of general formula I were
-25- -

11014Z6
tested for their anti-convulsive activity using the method
described by M.A. DAVIS et al. (J. Med. Chem. 7, (1964), 88-94).
The object of the test was to provide evidence of antagonism
to convulsions caused by the administration of a convulsive
agent (pentetrazol) which makes it possible to determine a
possible anti-epileptic potentiality of the tested compounds.
'l'he convulsive agcn~ was administered intraperitoneally
to mice (body weight 18-30 g.) in an amount which was sufficient
to induce convulsions in 90 to 100~ of the experimental anima~ls:
in the case of pentetrazol, this is 125 mg./kg. The compound
to be tested was administered orally one hour before administra-
tion of the convulsive agent, using groups of 10 experimental
animals. The ED50 was measured, this being the amount of
tested compound which inhibits tonic crises in 50~ of the
animals. The compound used for comparison was meprobamate.
The results obtained are given in the following Table II:
TABLE II
Compound ED in mg./kg.
- 50
0.24
0.30
36 0.18
37 0.10
41 0.18
12 0.032
meprobamate (comparison) 0.62
In the case of this compound, it is not the ED50 but rather
the active dose for 3 animals out of 8. Consequently, the
ED50 is somewhat greater than this value.
As can be seen from the preceding Table II,the anti-
convulsive activity of the compounds according to the inventionis markedly superior to that of meprobamate.
3. Toxicology.
-26-
~,~

The -toxicity of the compounds of the invention is
relatively low. As an examp]e, for compound 6, r4-(2-chloro-
diphenylmethylene)~ 4-hydroxybenzyl)-piperidine hydrochloride~
the LD 50 in the rat is:
41 mg./]cg~ intravenously
1,230 mg./kg. intraperitioneally,
5,423 mg./kg. orally.
. Posolo~y.
The compounds according to the invention may be
administered orally, reaetally or parenterally in unit doses
of 10 to 50 mg. aceording to the mode of administration, in
admixture with the usual pharmaceutieal liquid or solid
excipients.
~ -27-