1,4-DISUBSTITUTED PIPERIDINES

PIPERIDINES DISUBSTITUEES EN 1,4

English Abstract

ABSTRACT OF THE DISCLOSURE
1,4-bisubstituted piperidines having the formula:
<IMG>
are disclosed wherein R is hydrogen, chlorine, bromine,
fluorine, lower-alkyl, lower-alkoxy, trifluoromthyl or
p-fluorophenyl, R1 is hydrogen, chlorine or fluorine,
A is -C(O)-, -C(NOH)-, -CHOH- or -C(OH)(CH3)-, and B is
-C(O)-, -C(NOH)-, -CHOH-, -C(OH)(CH3)-, or <IMG>.
The pharamceutically acceptable acid addition salts of the
free bases are also disclosed. The compounds have moderate
to strong central nervous system depressant activity.

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 a compound selected from 1,4-
substituted piperidines having the formula:
<IMG>
wherein; R is selected from the group consisting of fluorine and p-fluoro-
phenyl, R1 is fluorine, A is selected from the group consisting of -C(O)-,
-C(NOH)-, -CHOH and -C(OH)(CH3)-, B is selected from the group consisting of
-C(O)-, -CHOH-, -C(NOH)-, -C(OH)(CH3)- and <IMG>, with the provisos
that A and B cannot both be -C(O)-, except when R is p-fluorophenyl, A cannot
be -CHOH when B is -C(O)-, and pharmaceutically acceptable acid addition salts
thereof which comprises either: (a) reducing a compound of the formula:
<IMG> (II)
in which B1 is -CO- or <IMG> to produce a compound of formula I in
which A and B are both -CHOH- groups or A is -CHOH- and B is <IMG>
or (b) reacting a compound of formula II with hydroxylamine to produce a
compound of formula I in which A and B are both <IMG> groups; or (c) reacting
a compound of the formula:
<IMG> (III)
wherein A and R are as hereinbefore defined, with a substituted .gamma.-propyl
halide of the formula:
<IMG> (IV)
22

wherein Hal is chlorine, bromine or iodine and B and R1 are as hereinbefore
defined; or (d) reacting a compound of the formula:
<IMG> (V)
wherein A" is -CO-, -CHOH or <IMG> and B" is -CO-, -CHOH-, <IMG> or
<IMG> and where at least one of A" and B" is a carbonyl group and R
and R1 are as hereinbefore defined, with a methylmagnesium halide and hydro-
lysing the Grignard complex so formed; and where the process may comprise
the additional step of converting a base of formula I obtained into a corres-
ponding pharmaceutically acceptable acid addition salt.
2. A process according to claim 1(a) in which the reduction is effect-
ed by reaction with an alkali metal borohydride.
3. A process according to claim 2 in which the alkali metal boro-
hydride is sodium borohydride.
4. A compound selected from 1,4-substituted piperidines having the
formula:
<IMG>
wherein; R is selected from the group consisting of fluorine and p-fluorophenyl,
R1 is fluorine, A is selected from the group consisting of -C(O)-, -C(NOH)-,
-CHOH and -C(OH)(CH3)-, B is selected from the group consisting of -C(O)-,
-CHOH-, -C(NOH)-, -C(OH)(CH3)- and <IMG> with the provisos that A and
B cannot both be C(O)- except when R is p-fluorophenyl, A cannot be -CHOH
when B is -C(O)-, and pharmaceutically acceptable acid addition salts thereof
whenever prepared by the process of claim 1, 2 or 3 or by an obvious chemical
equiva-
23

lent thereof.
5. A process according to claim 1 (b) in which 4-(.alpha.-hydroxyimino-p-
fluorobenzyl)-1-[3-(.alpha.-hydroxyimino-p-fluorobenzyl)propyl]piperidine is
prepared by reacting 4-(p-fluorobenzoyl)-1-[3-(p-fluorobenzoyl)propyl]piperi-
dine with hydroxylamine.
6. 4-(.alpha.-Hydroxyimino-p-fluorobenzyl)-1-[3-(.alpha.-hydroxyimino-p-fluoro-
benzyl)propyl]piperidine whenever prepared by the process of claim 5 or by
an obvious chemical equivalent thereof.
7. A process according to claim 1 (c) in which 2-(p-fluorophenyl)-2-
{3-[4-(p-fluorobenzoyl)piperidino]propyl}-1,3-dioxolane is prepared by react-
ing 4-(p-fluorobenzoyl)piperidine with 2-(p-fluorophenyl)-2-(3-chloropropyl)-
1,3-dioxolane.
8. 2-(p-fluorophenyl)-2-{3-[4-(p-fluorobenzoyl)piperidino]propyl}-1,3-
dioxolane whenever prepared by the process of claim 7 or by an obvious
chemical equivalent thereof.
9. A process according to claim 1 (a) in which 2-(p-fluorophenyl)-2-
{3-[4-(.alpha.-hydroxy-p-fluorobenzyl)piperidino]propyl}-1,3-dioxolane is prepared
by reducing 2-(p-fluorophenyl)-2-{3-[4-(p-fluorobenzoyl)piperidino]propyl}-
1,3-dioxolane by reaction with sodium borohydride.
10. 2-(p-fluorophenyl)-2-{3-[4-(.alpha.-hydroxy-p-fluorobenzyl)piperidino]
propyl}-1,3-dioxolane whenever prepared by the process of claim 9 or by an
obvious chemical equivalent thereof.
11. A process according to claim 1 (c) in which 4-(.alpha.-hydroxyimino-p-
fluorobenzyl)piperidine is reacted with 2-(p-fluorophenyl)-2-(3-chloropropyl)-
1,3-dioxolane and the resulting isomer separated.
12. Z-2-(p-fluorophenyl)-2-{3-[4-(.alpha.-hydroxyimino-p-fluorobenzyl)piperi-
dino]propyl}-1,3-dioxolane whenever prepared by the process of claim 11 or by
an obvious chemical equivalent thereof.
24

13. E-2-(p-fluorophenyl)-2-{3-[4-(.alpha.-hydroxyimino-p-fluorobenzoyl)
piperidino]propyl}-1,3-dioxolane whenever prepared by the process of claim
11 or by an obvious chemical equivalent thereof.
14. A process according to claim 1 (c) in which 4-[4'-(p-fluorophenyl)
benzoyl]-1-[3-(p-fluorobenzoyl)propyl]piperidine hydrochloride is prepared by
reacting 4-[4'-(p-fluorophenyl)benzoyl]piperidine with 2-(p-fluorophenyl)-2-
(3-chloropropyl)-1,3-dioxolane and treating the base so obtained with hydro-
gen chloride.
15. 4-[4'-(p-fluorophenyl)benzoyl]-1-[3-(p-fluorobenzoyl)propyl]piperi-
dine hydrochloride whenever prepared by the process of claim 14 or by an
obvious chemical equivalent thereof.
16. A process according to claim 1 (c) in which 4-(.alpha.-hydroxyimino-p-
fluorobenzyl)-1-[3-(p-fluorobenzoyl)propyl]piperidine is prepared by reacting
4-(.alpha.-hydroxyimino-p-fluorobenzyl)piperidine with p-fluorobenzoyl-propyl
chloride.
17. 4-(.alpha.-hydroxyimino-p-fluorobenzyl)-1-[3-(p-fluorobenzoyl)propyl]
piperidine whenever prepared by the process of claim 16 or by an obvious
chemical equivalent thereof.
18. A process according to claim 1 (a) in which 4-(.alpha.-hydroxy-p-fluoro-
benzyl)-1-[3-(.alpha.-hydroxy-p-fluorobenzyl)propyl]piperidine is prepared by re-
ducing 4-(p-fluorobenzoyl)-1-[p-fluorobenzoyl)propyl]piperidine by reaction
with sodium borohydride.
19. 4-(.alpha.-hydroxy-p-fluorobenzyl)-1-[3-(.alpha.-hydroxy-p-fluorobenzyl)propyl]
piperidine whenever prepared by the process of claim 18 or by an obvious
chemical equivalent thereof.
20. A process according to claim 1 (d) in which 4-(.alpha.-hydroxy-.alpha.-methyl-
p-fluorobenzyl)-1-[3-(p-fluorobenzoyl)propyl]piperidine and its hydrochloride
is prepared by reacting 2-(p-fluorophenyl)-2-{3-[4-(p-fluorobenzoyl)piperid-

ino]propyl}-1,3-dioxolane with methylmagnesium iodide, hydrolysing the
Grignard complex so obtained and isolating the product either as the free
base or hydrochloride.
21. 4-(.alpha.-hydroxy-.alpha.-methyl-p-fluorobenzyl)-1-[3-(p-fluorobenzoyl)propyl]
piperidine and its hydrochloride whenever prepared by the process of claim
20 or by an obvious chemical equivalent thereof.
22. A process according to claim 1 (c) in which 4-(p-fluorobenzoyl)-1-
[3-(.alpha.-hydroxy-.alpha.-methylbenzyl)propyl]piperidine and its oxalate is prepared by
reacting 4-(p-fluorobenzoyl)piperidine with 1-chloro-4-hydroxy-4-(p-fluoro-
phenyl)pentane and isolating the product either as the base or oxalate.
23. 4-(p-fluorobenzoyl)-1-[3-(.alpha.-hydroxy-.alpha.-methylbenzyl)propyl]piperid-
ine and its oxalate whenever prepared by the process of claim 22 or by an
obvious chemical equivalent thereof.
26

Description

104~)~35 ~:
The present invention is concerned with novel
piperidine compounds and is more particularly concerned with 1,4-
disubstituted piperidines, methods for their preparation, com-
positions containing the same as active ingredients, and methods
for employing the compositions.
The novel 1,4-disubstituted piperidines of the
present invention have the formula:
R ~ A ~ N - ~CH2)3- B
Formula I
wherein; R is fluorine or p-fluorophenyl, Rl is fluorine, A
is -CtO)-, -C(NOH)-, -CHOH-, or -C(OH)(CH3)-, B is -C(O~-,
-C(NOH)-, -C~IOH-, -C(OH)(CH3)-, or ~C-O-CH2-CH20, with the
provlsos that A and B cannot both be -C(O)- except when R is
p-fluorophenyl, A cannot be -CHOH- when B is -C(O)-, and the
pharmaceutically acceptable acid addition salts thereof.
The compounds having the foregoing Formula I
when tested using standard pharmacological procedures have
been demonstrated to possess moderate to strong central nervous
sys~em depressant activity. The activity is demonstrable when
the compounds are used in the form of the free bases or as
the pharmaceutically
r~
- 2 ~
- - - -
~ ~ .,' '
.

1040635
acceptable acid addition salts. The aforementioned central nervous
system depressant activity is indicative that the compounds may be
used as tranquilizing agents and, as such, are particularly useful
in inducing an anti-anxiety effect in a living animal body.
The depressant action of these compounds was determined
in aggregated mice to which d-amphetamine was subsequently given
according to a modification of the method of Burn and ~lobbs (Arch.
Intern. Pharmacodyn. 113: 290, 1958).
The pharmaceutically acceptable acid addition salts of
the free bases of Eormula I are included within the scope of the
present invention. The salts are readily prepared by methods
known to the art. The acids which can be used to prepare the acid
addition salts are those whose anions are relatively innocuous to
the animal organism in therapeutic doses of the salts, so that the
beneficial physiological properties inherent in the free bases are
not vitiated by side effects ascribable to the anions. The free
base is reacted with the calculated amount of organic or inorganic
acid in an aqueous miscible solvent such as ethanol or isopropanol
with isolation of the salt by concentration and cooling, or the
base is reacted with an excess of the acid in an aqueous immiscible
solvent such as ethyl ether or isopropyl ether, with the desired
salt separating directly. Exemplary of such organic salts are
those prepared

~040635 ~ ~
with maleic, fumaric, benzoic, ascorbic, citric, malic acid
and the like. Exemplary of such inorganic salts are those -
prepared with hydrochloric, hydrobromic, sulfuric and
sulfamic acid.
The present invention provides novel 1,4- -
disubstituted piperidines. It also provides methods for
their preparation. According to a further feature of this
invention there is provides novel compositions containing
the novel 1,4-disubstituted piperidines as active ingredients
and methods for their use.
The starting materials for the novel compounds of
Formula I are 4-(R-benzoyl)-1-[3-(Rl-benzoyl)propyl]piperidine,
2-(R -phenyl)-2- ~3-[4-(R-benzoyl)piperidino]propyl~-1,3-
, dioxolane and 4-(R-benzoyl)piperidine which can be prepared by
methsds disclosed and described in United States Patent No.
3,576,810 and 4-[4'-(p-fluorophenyl)benzoyl]piperidine and
4-~-hydroxyimino-R-benzyl)piperidine. 4-[4'-(p-Fluorophenyl)
benzoyl]piperidine i5 prepared concomitantly in the synthesis
of 4-(p-fluorobenzoyl)piperidine from which it is separated by ~
fractional crystallization. 4-(~-Hydroxyimino-R-benzyl) :
piperidine is prepared by reacting 4-(R-benzoyl)piperidine
-4-
'' . -: ' '
,

AHR-2'78-CI~
with hydroxylamine. 10 40 6 35
The novel compounds of the invention can be prepared by
processes represented by the following equations wherein the
values of R and Rl are as defined hereinabove.
.

104(1 635
= ~ o ~o ~o
n=o ~ ] i~
o -æ
~=o I~J ~bJ ~7J
-o ~=0 ~O] ~
~3 Q ~P $ ~ ~

AHR-27~3-CIP
~04(~635
Process A - In process A, a suspension of 4-(R-benzoyl)-
(Rl-benzoyl)propyl]piperidine in a lower alkanol solvent
such as absolute ethanol is warmed to a temperature of from
about 40C. to about 60 C. while an excess of sodium borohydride
is added in small portions. The reaction is continued at the
elevated temperature for a period of from about one hour to
about three hours, and then the excess metallic hydride is
decomposed by the addition of dilute hydrochloric acid. The
bis-hydroxy compound prepared in this manner is isolated from
the reaction mixture by standard acid-base extraction procedures.
Process B - A basic aqueous solution of 4-(R-benzoyl)-l-
~-(Rl-be~zoyl)propyl]piperidine and hydroxylamine is reacted
together at a temperature of from about 50 C. to about 75C.
for a perLod of from about four hours to about eight hours.
The cooled reaction mixture is diluted with approximately four
volumes o water and the bis-hydroxyimino compound which separates
from the dilute solution is collected by filtration.
Process C - In process C, an ether solution of 2-(R-phenyl)-
2-{~-~4-(R -benzoyl)piperidino]propyl}-1,3-dioxolane is added
dropwise to an ethereal solution of methyl magnesium iodide at a
rate sufficient to maintain mild refluxing conditions. Subsequent
to the addition the mixture is stirred for a period of from about
one hour to about three hours. The reaction mixture is decomposed
by adding it to crushed ice. The product is extracted from the
~old mixture by solvent extraction and the dried extracts concen-
trated to a residual oil which is reflux~d briefly in alcohol
containing a mineral acid to hydrolyze the ketal. 4-(~-Hydroxy-
:

- AI~-278-CI~'
104C~635
~-methyl-R-benzyl)~ 3-(Rl-benzoyl)propyl]piperidine is isolated
by acid base extraction. The 2-(Rl-phenyl)-2-{3-[4-(R-benzoyl)
piperidino~propyl}-1,3-dioxolane is also reduced as in process A,
using sodium borohydride to give 2-(Rl-phenyl)-2-{3-[4-(~-hydroxy-
R-benzyl)piperidino]propyl}-1,3-dioxolane.
Process D - In process D, a mixture of 4-(~-hydroxyimino-
R-benzyl)piperidine and 2-(Rl-phenyl)-2-(3-chloropropyl)-1,3-
dioxolane in a lower alkanol solvent such as l-butanol is refluxed
for a period of from about 60 to ahout 80 hours. The reaction
furnishes the two spatial isomers of 2-(Rl-phenyl)-2-{3-[4-(~-
hydroxyimino-R-benzoyl)piperidino~propyl-1,3-dioxolane which
have been designated the Z-isomer and the E-isomer and which are
separated from each other by fractional crystallization.
Process E - In E, the foregoing process D is essentially
followed using the same solvent and reaction conditions. The
4-(a-hydroxyimino-R-benzyl)-l-~3-(Rl-benzoyl)propyl]piperldine
is isolated from the reaction mixture and purified from a suitable
solvent system such as provided by benzene-isooctane.
Process F - In process F, a mixture of 4-(R-benzoyl)
piperidine and 1-chloro-4-hydroxy-4-(Rl-phenyl)pentane is reacted
together in a lower alkanol solvent such as l-butanol at reflux
` temperature for a period of from about 20 hours to about 30
hours in the presence of sodium bicarbonate. The crude product
is placed on a column of aluminum silicate and by using in^reasing
portion~ of acetone in benzene followed by increasing portions
of methanol in acetone, several products are separated among
which is the main product of process F, 4-(R-benzoyl)-1-[3-
.' ' ' ~

AHR-278-CIP
104(~635
(~-hydroxy~x-methyl-Rl-benzyl)propyl~piperidine.
Process G - In process G~ 4-[4 -(p-fluorophenyl)benzoyl]-
~ -(p-fluorobenzoyl)propyl]piperidine is prepared using the
same conditions as given in process F. The product is isolated
from the reaction mixture by conventional means and is recrystal-
}ized from a suitable solvent such as isopropanol.
: ~ - g _
. .

1041)635
In summary therefore the compounds of this invention are prepared
by a process for the preparation of a compound selected from 1,4-substituted :
piperidines having the formula:
` ~ ~ ~ N -(CH ) - B ~ ~
wherein; R is selected from the group consisting of fluorine and p-fluoro-
phenyl, Rl is fluorine, A is selected from the group consisting of -C(O)-,
-C(NOH)-, -CHOH and -C(OH)(CH3)-, B is selected from the group consisting of
-C(O)-, -CHOH-, -C~NOH)-, -C(OH)(CH3)- and =C-OCH2CH20, with the provisos
that A and B cannot both be -C~OH)- except when R is p-fluorophenyl, A cannot
be -CHOH when B is -C(O)-, and pharmaceutically acceptable acid addition
salts thereof which comprises either: (a) reducing a compound of the formula:
R O Rl
~ (CH2)3 - Bl ~ (II)
in which Bl is -CO- or =C-O-CH2-CH2-0 to produce a compound of formula I in
which A and B are both -CHOH- groups or A is -CHOH- and B is =C-O-CH2-CH2-0
or (b) reacting a compound of formula II with hydroxylamine to produce a
compound of formula I in which A and B are both ,N,OH groups; or (c) reacting
a compound of the formula: -C-
~3 A NH (111)
wherein A and R are as hereinbefore defined, with a substituted ~-propyl
halide of the formula:
Rl
Hal- (CH2)3 - B ~ (IV)
~ ~' - 9a -
.. . .

~04~635
wherein Hal is chlorine, bromine or iodine and B and Rl are as hereinbefore
defined; or (d) reacting a compound of the formula: : -
R ~ A~ ~ N - (CH2)3 - B" ~ R (V)
OH IOH
wherein A" is -CO-, -CHOH or -C- and B" is -CO-, -CHOH-, -C- or
CH3 3
,"C-O;CH2CH2-O and where at least one of A" and B" is a carbonyl group and R
and R are as hereinbefore defined, with a methylmagnesium halide and hydro-
lysing the Grignard complex so formed; and where the process may comprise
the additional step of converting a base of formula I obtained into a corre-
sponding pharmaceutically acceptable acid addition salt.
. :'
-9b-
., : , . . .

1040635
Example l
4-(~-hydroxyimino-p-fluorobenzyl~-l-[3-(~-hydroxy-
imino-p-fluorobenzyl)propyllpiperidine.
A mixture of 4-(p-fluorobenzoyl)-1-[3-(p-fluoro-
benzoyl)propyl]piperidine hydrochloride 20.4 g. (0.05 mole),
100 ml. of water, 400 ml. of ethanol and 92 ml. of 6N sodium
hydroxide was warmed at 65C. until a clear solution was obtain-
ed. A solution of 35 g. (0.5 mole) of hydroxylamine hydro-
chloride in 100 ml. of water was added to the reaction mixture.
The reaction mixture was heated at 65C. for 6 hrs. The
reaction mixture was diluted to about a 4 liter volume with
water and the product which separated was collected by filtra-
tion. The collected solid weighed 11 g. (53.2%). Recrystalli-
zation from ethanol- water gave a light tan product melting at
182-183C.
Analysis:
Calculated for C22 25N32 2 C~ 5-8 ; ~ 6- ; ~ 4
Found : C, 65.79; H, 6.36; N, 10.37
Example 2
2-~p-~luorophenyl)-2-{3-[4-~p-fluorobenzoyl)piperi
dinolpropyl}-1,3-dioxolane.
A mixture of 24.4 g. (0.1 mole) of 4-~p-fluoro-
benzoyl)piperidine hydrochloride, 24.5 g. ~0.1 mole) of 2-(p~
fluorophenyl)-2-~3-chloropropyl)-1,3-dioxolane and 33.6 g. ~0.4
mole) of sodium bicarbonate in 450 ml. of l-butanol was heated
at reflux for 17 hr. The mixture was filtered and the filtrate
was concentrated under reduced pressure. The crude residue was
dissolved in benzene and placed on a magnesium silicate column.
Elution with a benzene-acetone gradient gave 16.0 g. (24%) of pure
- 10 -
. .. -
.: . .

~04~35
product which crystallized. Recrystallization from isooctane
gave the pure product melting at 62-64C. -
Analysis~
Calculated for c24H27F2N03: C~ 69-38; H~ 6-55;
Found : C, 69.51; H, 6.55; N, 3.16
Example 3
2-(P-Fluorophenyl)-2-{3-[4-(~-hydroxy-p-fluorobenzyl)
piperidinolpropyl}-1,3-dioxolane
A mixture of 3.78 g. (0.1 le) of sodium borohydride
in 25 ml. of anhydrous ethanol was stirred at room temperature.
A solution of 8.16 g. ~0.02 mole) of 2-(p-fluorophenyl)-2-
{3-[4-(p-fluorobenzoyl)piperidino]propyl}-1,3-dioxolane in
10 ml. of anhydrous ethanol was slowly added dropwise so as to
maintain a controlled evolution of gas. After the addition was
complete, the mixture was allowed to stir at room temperature
for 16 hr. A large excess of water was added and the mixture
was extracted several times with benzene. The benzene ext~acts
were dried with anhydrous sodium sulfate and filtered. The
filtrate was concentrated under reduced pressure and a glasslike
residue was obtained. The residue was dissolved in benzene and
placed on a magnesium silicate column. Using a benzene-acetone
gradient solution, the product was obtained. Recrystallization
of the solid product from methanol-isooctane gave 6.5 g. (78%) :
of white solid melting at 114-116C.
Analysis:
Calculated for 24 29 2 3
Found : C, 69.07, H, 7.08; N, 3O33
- 11 -

1040635
Example 4
Z-2-(p-Fluorophenyl-2-{3-[4-(~-hydroxyimino-p-fluoro-
benzyl)piperidinolpropyl}-1,3-dioxolane.
A mixture of 15 g. (0.058 mole) of 4-( -hydroxyimino-p-
fluorobenzoyl)piperidine, 18.2 g. (0.0743 mole) of 2-(p-fluoro-
phenyl)-2-(3-chloropropyl)-1,3-dioxolane, and 16,8 g. (0.2 mole)
of sodium bicarbonate in 500 ml. of l-butanol was heated at
reflux for 72 hr. Upon cooling, the reaction mixture solidified.
Trituration of the solid with methanol, followed by filtration,
gave 11 g. of solid. The filtrate was concentrated to give a
gummy residue which was triturated with ligroin to give a
crystalline solid. The solid was collected by filtration and
weighed 7.3 g. The filtrate was concentrated and the residue
was recrystallized from benzene-isooctane to give 5.1 g. of
impure product. A total yield of crude product was 2304 g.
(93.5%). The 11 g. sample and the 7.3 g. sample were combin0d
and recrystallized from isopropanol to give 5.6 g. of product
melting at 191 - 192C. This compound was the Z-isomer.
Analysis:
Calculated for C24H28F2N203: C, 66-96~ H~ 6~56; N~ 6-51
Found : C 66.97; H, 6.55; N, 6.42
Example 5
E~2-(p-Fluorophenyl)-2-{3-[4-(a-hydroxyimino-p-fluoro-
benzyl)piF~eridinolpropyl}-1,3-doxolane
The remaining solid from Example 4 was dissolved in
benzene and placed on a magnesium silicate column to obtain pure
product (0.5 g.) melting at 161-161.5C. This compound is the E-
isomer.
,
- :

iO4~635
Analysis:
24 28 2 2 3 , . ;, . ; N, 6.51
Found : C, 67.03; H, 6.59; N, 6.42
Example 6 ~ ~
4-[4'-(p-Fluorophenyl)benzoyll-1-[3-(p-fluorobenzoyl) -' '
propyllpiperidine Hydrochloride.
A mixture of 9.6 g. (0.03 mole) of 4-[4'-~p-fluorophenyl)
benzoyl]piperidine hydrochloride, 7.35 g. (0.03 mole) of 2-(p-
fluorophenyl)-2-(3-chloropropyl)-1~3-dioxolane and 10 g. (0.12
mole) of sodium bicarbonate in 150 ml. of l-butanol was heated
at reflux for 16 hrs. The mixture was filtered and the filtrate
was concentrated under reduced pressure. The residue was
dissolved in benzene and extracted with dilute hydrochloric
acid. A solid precipitate was obtained which was collected by
filtration. The solid was recrystallized from isopropanol and
a white solid was obtained weighing 11.7 g. (81%) and melting
at 250-260C.
Analysis:
Calculated for C28H28ClF2N02: C, 69-48; H, 5-83; N~ .9
Found : C, 69.09; H, 5.84; N, 2.67
Example 7
4-(~-Hydroxyimino-p-fluorobenzyl)-1-[3-(p-fluorobenzoyl)
propyl]piperidine.
A mixture of 5.5 g. (0.0213 mole) of 4-(a-hydroxyimino-
p-fluorobenzyl)piperidine, 9.0 g. (0.045 mole) of p-fluorobenzoyl-
propyl chloride and 8.4 g. (0.01 mole) of sodium bicarbonate in
100 ml. of l-butanol was heated at reflux for 24 hrs. The reaction
mixture was cooled and filtered to remove solids. The collected
solid was triturated in water and filtered. The collected
.

AHR-278-ClI'
104C~635
product was combined with product filtered from the butanol
solution and the combined weight was ~.1 g. The crude product
(38%) was a solid material melting at 158-160 C. Recrystallization
from benzene-isooctane gave a product melting at 167-168 C.
The material wa3 combined with product collected from another
run and recrystallization o~ the combined materials gave ~.6 g.
of product melting at 168.5-172c.
Analysis: Calculated for C2zH24F2N202: C,68.~8; H,6.26; ~,7.25
Found : c,68.63: H,6.37: N,7.30
Example 8
4-(~-Hydroxy-p-fluorobenzyl)~ 3-(~-hydroxy-p-fluorobenzyl)
propvllplperidine.
To a 3tlrring auepen~ion of 4.3 g. (0.0116 mole) of 4-(p-
fluoroboneoyl)~ p-~luorobenzoyl)propyl~plperldine in 100 ml.
sf aboolute otl~anol At 50C. w~ ~dded in ~mall porti~n~J 1.9 g.
~0.05 mole) o~ ~odlum borohydrldo. A~ter ell the so~lum boro-
hyt~rlde had been added, ~tlrring wae contlnued at 50 C. for one
hou~. About 20 ml. of ~N hydrochloriti ~cltl wa~ 810wly Added
~ropwl~o to ths mixture. Th8 reaction mlxture was t~lut0t9 to
~bou~ 400 ml. o~ wator antl mado ~lightly b~slc wlth ~odium
hydroxid~. Tho mlxture wa0 extracted with chloro~orm and the
chloroform extracts ware drieti over anhydrou~ magnesium ~ulfate.
~hi~ mixtuxe wa~ filte~0d and the ~iltrate wa~ concentrated
unt~er reduced vacuum to get 4.8 g o~ oil which cry~tallizad
upon trlturetion in teooctane. The crude product weighed 4.1 g.
(94-95%) and melted ~t 115-117t~C. Recrystallization from
i~ooctane-ben~ene gave ~.6 g. melting at 115-117C.
- 14 -

AEIR-27~-CIP
1040635
A~alysis: Calculated for C22I~7F2NO2: C,70.38; H,7.25; N,~.7~ `
Found : C,70.42; HJ7.35; N,3.74
Example 9
4~ Hydroxy-~-methyl-p-fluorobenzyl)-l-[~-(p-fluorobenzoyl)-
propyl~pi~eridine Hydrochloride.
A Grignard reagent was prepared by slowly adding 7.1 g.
(0.05 mole) of methyl iodide to a stirring mixture of 1.2 g.
(0.05 mole) of magnesium metal in 20 ml. of ether. After reaction
had begun, the volume of ether was increased to 200 ml. Following
the addition of the methyl iodide, a solution of 10.3 g. ~0.025
mole) of 2-(p-fluorophenyl)-2-~3-LIt-(p-fluorobenzoyl)piperidino]
propyl}-1,3-dioxolane in 100 ml. ~f ether was added to the
mixture at a rate 90 as to maintain a mild reflux. After the
addition was complete the mixture ~as stirred for 2 hrs. at room
temperature. Tlle mixLure was poured oltO cru3hed ice and
extracted with ether followed by an extraction with ~enzene.
The combined extract~ were dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The residue was
dissolved in 10 ml. of ethanol and 20 ml. of dilute hydrochloric
acid. The mixture was stirred and heated for 15 min. The
mixture was cooled and made basic with sodium hydroxide solution.
The froe base wa~ extracted into benzene and the collective
extracts were dried over anhydrous sodium sulfate. The mixture
was Eil~ered and the filtrate was concentrated under reduced
.pressure. The residue was dissolved in anhydrous ether and an
excess of ethereal hydrogen chloride wa~ added. The hydrochloride
~alt which separated was treated with charcoal and recrystallized
- 15 -

AHR-278-CIP
:~04~635
from isopropanol-isopropyl ether. The salt obtained weighed
5.3 g. (510 and melted at 147-149C.
Analysis: calculated for C2~H28clF2No2: C,64.15; H,6.85; N,~.40
Found : C,64.30; H,6.59; N,3.24
Example 10
4-(p-Fluorobenzoy~ 3-(~-hydroxy-~-meth~l-p-fluorobenzyl)
opylJpiperidine Oxalate.
A mixture of 10.7 g. (0.044 mole) of 4-(p-fluorobenzoyl)
piperidine, 9.5 g. (0.044 mole) of 1-chloro-4-hydroxy-4-(p-
fluorophenyl)pentane and 8.4 g. (0.1 mole) of sodium bicarbonate
in 200 ml. of 1-butanol was stirred at reflux for 24 hrs. The
mixture was filtered and the filtrate was concentrated under
reduced pressure. The crude product which weighed 11 g. sh~wed
several components on thin layer chromatography. The oil ~as
di~olved in benzene and placed on a 200 g. column of magns~ium
~llicate. Using increasing portion~ of acetone in benzene and
then increasing portions of methanol in acetone, several products
were separated. The title compound was isolated as 1 g. (5.9%).
~he free base wa~ treated with 0.32 g. of oxalic acid dihydrate
and the oxalate ~alt which was obtained weighed 1 g. and melted
at 127-129C. The salt was recrystallized from isopropanol-
isopropyl ether to give 0.7 g. of product melting at 133-135C.
Analysi~: calculated for C25H2~F2NO~: C,62.88; H,6.12; N,2.93
Found : C,63.10; H,5.28; ~,2.98

1040635
Effective quantities of any of the foregoing pharma-
cologically active compounds may be administered internally to
animals, including humans, in any one of various ways, for
example, orally as in capsules or tablets, parenterally in the
form of sterile solutions or suspensions, and in some cases
intraveneously in the form of sterile solutions. The basic
amino compounds, while effective, are preferably formulated and
administered in the form of their pharmaceutically acceptable
acid addition salts for purposes of convenience of crystalliza-
tion, increased solubility and the like,
Although very small quantities of the active materials
; of the present invention are effective when minor therapy is
involved or in cases of administration to animals, including
humans, having a relatively low body weight, unit dosages are
usually 5 mg. or above and can be preferably 10, 25 and 50 mg.
and 500 mg. depending, of course, in the emergency of the
situation; 5 mg. to 25 mg. appears optimum per unit dose. The
active agents may be combined with other pharmacologically
active agents, or with buffers, antacids or the like, for adminis-
tration. It is only necessary that the active ingredient
constitute an effective amount, i.e., such that a suitable -
effective dosage will be obtained consistently with the dosage
form employed. Obviously, several unit dosages may be adminis-
tered at about the same time.
Pharmaceutical carriers which can be used in the novel
compositions of the present invention can be solids and liquids.
Solid carriers can include, but are not limited to, lactose,
~ - 17 -
: ,

~0~0635
starch, magnesium stearate, corn starch, dicalcium phosphate,
gelatin and calcium stearate. Liquid carriers can include,
but are not limited to, peanut oil, olive oil, sesame oil, and
water.
The following are examples of compositions formed in
accordance with this invention:
(1) CAPSULES
Capsules of 5 mg., 25 mg., and 50 mg. of active
ingredient per capsule are prepared. With the higher amounts of
active ingredien~, reduction may be made in the amount of lacto~e.
Typical blend for Per capsule
encapsulation mg.
Active ingredient, as salt ......... 5.0
Lactose .......................... 296.7
Starch ........................... 129.0
Magnesium stearate ................. 4.3
Total ............. 435.0
Additional capsule formulations preferably contain a
higher dosage of active ingredient and are as follows:
100 mg. 250 mg. 500 mg.
per per per
Ingredients capsule capsule capsule
Active ingredient,
as salt ... u........... 100.0 250.0 500.0
Lactose ................... 231.5 126.5 31.1
Starch .................... 99.2 54.2 13.4
Magnesium stearate......... 4.3 4~3 5.5
~ Total milligrams
- magnesium ...... 435.0 435.0 550.0
In each case, uniformly blend the selected active
ingredient with lactose, starch, and magnesium stearate and
encapsula~ed the blend.
~ 18 -
-. : :
:. .

1040635
(2) TABLETS
A typical formulation for a tablet containing 5.0 mg.
of active ingredient per tablet follows. The formulation may
be used for other strengths of active ingredient by adjustment -
of weight of dicalcium phosphate.
Per tablet, mg.
(1) Active ingredient,
as salt .................... 5.0
(2) Corn starch .................... 13.6
(3) Corn starch (paste) ............ 3.4
(4) Lactose ~ 79.2
(5) Dicalcium phosphate ............ 68.0
(6) Calcium stearate ............... 0.9
Total .............. 170.1
Uniformly blend 1, 2, 4 and 5. Prepare 3 as a 10 per-
cent paste in water. Granulate the blend with starch paste
and pass the wet mass through an eight mesh screen. The wet
granulation is dried and sized through a twelve mesh screen.
The dried granules are blended with the calcium stearate and
compressed.
Additional tablet formulations preferably contain a
higher dosage of the active ingredient and are as follows:
(A) 50 mg. TABLET
- Ingredients Per tablet, mg.
Active ingredient, as salt ........ 50.0
Lactose .... ~......................... 90.0
Dicalcium phosphate ............... 95.0
- Milo starch ....................... 20.0
Corn starch ....................... 38.0
Calcium stearate .................. 2.2
Total .. ~..... O........ 295.2
- 19 -

104~i3S
Uniformly blend the active ingredient, lactose, milo
starch and the corn starch. This blend is granulated using
water as a granulating medium. The wet granules are passed
through an eight mesh screen and dried at 140 to 160 degrees
Fahrenheit overnight. The dried granules are passed through
a number ten mesh screen and blended with the proper amount of
calcium stearate and this blend is then converted into tablets
on a suitable tablet press.
(B) 100 mg. TABLET
Ingredients: Per tablet, mg.
Active ingredient, as salt......... 100.0
L~ctose .. ~ 190.0
Dicalcium phosphate ............... 172.0
Starch ...~................. 54.0
Milo starch ....................... 2106
Calcium stearate .................. 2.2
Total ................ 540.0
Uniformly blend the active ingredient, lactose, dical-
cium phosphate, starch and milo starch. lhis blend is granulated
with water and the wet mass is passed through a number eight
mesh screen. The wet granules are dried at 140 - 160 degrees
Fahrenheit overnight. The dried granules are passed through a
number ten mesh screen. These dried granules are blended with
the proper weight of calcium stearate and the lubricated granules
; are then converted into tablets on a suitable tablet press.
Various modifications and equivalents will be apparent to
one skilled in the art and may be made in the compolmds,
compositions, methods, and procedures of the present invention
without departing from the spirit or scope thereof, and it is -
- 20 -
.:
.
:
~ .

R-2 l~ -CIP
104063S
therefore und~rstood that the invention is to be limited only
by t~le scol~e o~ the app~nded claims.
-- 21 --
.
. '' , ' ~