Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
M -103 1
~I~Z3~
~-(NAPHTHALENYLOXY)?IPERIDINE DERIVATIVES
FIELD OF THE INVENTION
This invention relates ro novel derivatives of 4-
(naphthalenyloxy)piperidines and methods for their pre-
paration. ~lore particularly it relates to new 4-naphthal-
enyloxypiperidines, useful as chemical intermediates, and
their N-(~-benzoylalkyl) and N-~W-hydroxy-~-phenylalkyl3
derivatives, useful as neuroleptic tranquilizers ~hose use
does not induce slgnificant extrapyramidal side effects.
DESCRIPTION OF THE PR IOR ART
1-Phenyl-w-(1-piperidyl)alkanones constitute an im~or-
tant class of central nervous system depressants. Various
compounds of this class are claimed, -for example, in U.S.
pa.ents 3,438,991; ~,518~-76; ~,~76,810; 3,816,~2~;
3~8~8,867 and ~,907,812. Although compounds of -thi, type
are often found to have potent anripsycho-cic activityJ their
use has been limited by the occurrence of serious extra-
pyramidal side efrects and transient hypotension.
It has now been discovered tha~ the novel w-!~-
naphthalenyloxy-1-piperidyl)-1-phenylalkanones and the
corresponding naphthalenyloxy-r~-phenyl-1-pip2ridinalkanois
of this invention display potent antipsycho~ic ac~ivi~y
without inducin~ significant extrapyramidal side e,fects
and with li~tle ef-fect on blood pressure.
SUMMAR',' OF TrlE I~I~ENTION
Novel compounds of rormula
! . . . : ' ~ , . ; , . . : '
~` ~Ll ~ 8 M-10~1
R ~
O Formula I
(cH2)n-z~Rl
wherein n is an integer Gf from 2 to 5; R is hydrogen,
alkylJ alkoxy, halogen or trifluormethyl; R1 is hydrogen,
alkyl, alkoxy or halogen; and Z is carbonyl or hydroxy-
5 methylene, are useful as antipsychotic agents. These anti-
psychotic compounds may be prepared from inter-
mediates of Formula II
R ~
Formula Il
R2
wherein R2 is hydrogen, lower alkyl or phenyl(lower alkyl)
and R has the meaning defined above. Compounds oF For-
mula II are also novel compounds and are included in this
invention. Included in the invention are the pharmaceu-
tically acceptable acid addition salts of compounds of
Formulas I and II and individual optical isom~rs of the
compounds of Formula I.
DETA!LED DESCRIPTION OF THE INVENTION
Compounds of Formula I include w-~4-(1- and 2-naph-
thalenyloxy-1-piperidyl)~ (4-substituted)phenyl-1-
alkanones of Formula III
~ z34,~ M-1031
R ~
I Formula III
O
(CH 2 ) n-C ~ R1
and 4-(1- and ~-naphthalenyloxy)-~-(4-substituted)phenyl-
1-piperidinealkanols of Formula IV
R ~
Formula IV
N OH
(cH2)n-cH-~)-Rl
wherein n, R and R1 have the meanings defined above,
their individual Opticâl isomers, and their pharmaceuti-
cally acceptable acid addition salts.
As used herein, alkyl is taken to mean straight or
branched chain alkyl groups having from 1 to 4 carbon
atoms. Illustrative examples of alkyl groups are methyl,
ethyl, propyl and tertiary butyl. Lo~ler alkyl is taken
to mean straight chain alkyl of from 1 to 3 carbon atoms.
Alkoxy is taken to mean straight or branched chain alkoxy
groups having from 1 to 4 carbon atoms. illustrative
1~ examples of alkoxy groups are methoxy, ethoxy and isopro-
poxy. Halogen is taken to mean fluorine, chlorine or
bromine.
The substituent R may be located in any posi-tion oF
the naphthalene ring system other than the position occu-
?ied by the (4-piperidyloxy) substituent.
Preferred embodiments of this invention are compounds
of Formula I ~herein Z is carbonyl; also preferred are
embodiments of this invention wherein n is equal to 3.
~: - . - : . . .
, -
- : - . . ~ : : ,. :: :: :, . :
.
3~ M-1031
Further preferred embodiments of this invention are com-
pounds of Formula I wherein R is selected from hydrogen
and halogen. Preferred embodiments of this invention also
include compounds of Formula I wherein R1 is halogen and
especially fluorine.
Exemplary compounds of Formula I are:
4-[4-(1-naphthalenyloxy)-1-pipleridyl]-1-(4-fluorophenyl)
1-butanone,
4-[4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-
1-butanone,
4-[4-(6-chloro-2-naphthalenyloxy)-1-piperidyl]-1-(4-fluoro-
phenyl)-1-butanone,
3-[4-(5-methoxy-1-naphthalenyloxy)-1-piperidyl]-1-(4-
chlorophenyl)-1-propanone,
4-[4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-methylphenyl)-
1-butanone,
5-[4-(1-methyl-2-naphthalenyloxy)-1-piperidyl]-1-(4-ethoxy-
phenyl)-1-pentanone,
4-[4-(8-methoxy-2-naphthalenyloxy)-1-piperidyl]-1-phenyl-
1-butanone,
6-[4-(5-fluoro-1-naphthalenyloxy)-1-piperidyl]-1-(4-fluoro-
phenyl)-1-hexanone,
4-~4-(2-trifluoromethyl-1-naphthalenyloxy)-1-piperidinyl]-
1-(4-bromophenyl)-1-butanone,
4-(1-naphthalenyloxy)-~-(4-f7uorophenyl)-1-piperidir,e-
butanol)
4-(2-naphthalenyloxy)-a-(4-fluorophenyl)-1-piperidine-
butanol,
4-(4-trifluoromethyl-2-naphthalenyloxy)-~-phenyl-1-piperi-
dinebutanol,
4-(o-bromo-2-naphthalenyloxy)-a-~4-bromophenyl)-1-ptperi-
dinepropanol,
4-(7-isopropyl-1-naphthalenyloxy)-a-(4-fluorophenyl)-1-
piperidinepentar,ol,
4-(3-ethoxy-2-naphthalenyloxy)-a-(4-methoxyphenyl)-1-
piperidinebutanol,
,,, ~. , . ,. .
, - , .
: . . -. ~. , . :, .. . . -ç . . . .
- - . ~ - ,
~ ~ z 3 ~ ~ M-1031
--5-
4-(2-naphthalenyloxy-~-(4-ethylphenyl)-1-piperidine-
hexanol,
4-(8-fluoro-1-naphthalenyloxy)-~-(4-fluorophenyl)-1-
piperidinebutanol, and
4-(2-methyl-1-naphthalenyloxy)-c-(phenyl)-1-piperidine-
butanol.
The invention also includes the pharmaceutically
acceptable acid addition salts of compounds of Formula 1,
which are also active as antipsychotics. Suitable salts
include those of inorganic acids, such as hydrochloric,
hydrobromic, sulfuric and phosphoric acids; carboxylic
acids, such as acetic, propionic, glycolic, lactic,
pyruvic, malonic, succinic, fumaric, malic, tartaric,
citric, ascorbic, maleic, hydroxymaleic, dihydroxymaleic,
benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic,
anthranilic, cinnamic~ salicylic, aminosalicylic, 2-
phenoxybenzoic, 2-acetox~ybenzoic and mandelic acids; and
sulfonic acids, such as methanesulfonic, 2-hydroxy-
ethanesulfonic and p-toluenesulfonic acids.
Novel intermediates for the preparation of compounds
of Formula I are compounds of Formula ll
R ~
1 1
~N)
R2
wherein R has the meaning defined above, and R2 is hydro-
gen, lower alkyl or phenyl(lower alkyl) and acid addition
salts thereof. Preferred embodiments of Formula ll are
compounds wherein R2 is hydrogen, methyl or phenylmethyl
and those wherein R is hydrogen or halogen.
Exemplary compounds of Formula ll include:
4-(~-naphthalenyloxy)piperidine,
4-(2-naphthalenyloxy)piperidine,
4-(6-chloro--2-naphthalenyloxy)piper~dine,
~.,.
... . .
- , - : ~ - :: : - : , :
- :~lZ3~ ~ M-1031
:
-6-
4-(5-methoxy-1-naphthalenyloxy)piperidine,
4-(1-methyl-2-naphthalenyloxy)piperidine,
4-(8-methoxy-2-naphthalenyloxy)piperidine,
4-(5-fluoro-1-naphthalenyloxy)piperidine,
4-(2-trifluoromethyl-1-naphthalenyloxy)piperidine~
4-(6-bromo-2-naphthalenyloxy)piperidine,
4-(7-isopropyl-1-naphthalenyloxy)piperidine,
4-(4-trifluoromethyl-2-naphthalenyloxy)piper;dine,
4-(3-ethoxy-2-naphthalenyloxy~piperidine,
4-(8-fluoro-1-naphthalenyloxy)piperidine,
4-(2-methyl-1-naphthalenyloxy)piperidine
1-methyl-4-(1-naphthalenyloxy)piperidine,
1-methyl-4-(6-chloro-2-naphthalenyloxy)piperidine,
1-methyl-~-(1-methyl-2-naphthalenyloxy)piperidine,
1-methyl-4-(~-trifluoromethyl-2-naphthalenyloxy)piperidine,
1-ethyl-4-(5-fluoro-1-naphthalenyloxy)piperidine,
1-methyl-4-(7-isopropyl-1-naphthalenyloxy)piperidine,
1-propyl-4-(8-methoxy-2-naphthalenyloxy)piperidine,
1-(phenylmethyl)-4-(2-naphthalenyloxy)piperidine,
1-(2-phenylethyl)-4-(5-methoxy-l-naphthalenyloxy)piper
dine,
1-(phenylmethyl)-4-(2-trifluoromethyl-1-naphthalenyloxy)-
piperidine,
1-(phenylmethyl)-4-(6-bromo-2-naphthalenyloxy)piperidine, ;
2~ 1-(pnenylmethyl)-4-(3-ethoxy-2-naphthalenyloxy)piperidi~ne,
1-(3-phenylpropyl)-4-(8-fluoro-1-naphthalenyloxy)piperi-
dine, and their acid addition salts.
The novel compounds of Formula I are antipsychotic
agents useful when administered alone or in the form of
pharmaceutical preparations contalning the novel compounds
in combination ~ith a pharmaceutical carrier as neuro-
leptic tranquilizers in warm blooded animals. Neuroleptic
tranquil7zers are useful for treatment of patients showing
symptoms of psychoses, such as schizophrenia, or of
severe anxiety, agitation or aggressiveness. Such agents
have a tranquilizing effect on psychomotor activity, induc-
ing a state of general quiescence in the patient without
inducing sleep. Patients suitable for treatment with
M-1031
3 4 ~O
antipsychotic compositions containing compounds of Formula i
inc1ude warm blooded animals such as birds, for example
turkeys and chickens, and mammals, for example mice, rats,
dogs, cats, horses, pi95, cattle, sheep and humans.
Pharmaceutical compositions containing compounds of
Formula I may be in solid or liquid form, such as
tablets, capsules, powders, solutions, suspensions or
emulsions, and may be administered orally, parenterally,
for example, intraperitoneally, intramuscularly or sub-
cutaneously, or topically, for example, transdermally or
transmucosally. The quantity comprising an effective
amount of the novel compound provided in a unit dosage
and the nature and quantity of the pharmaceutical carrier
will vary widely according to the type of pharmaceutical
composition and the body weight of members of the patient
population to be treated. The treatment of a patient
in need of tranquilizing will provide from 0.002 to 100
mg/kg of body weight of the patient per day to achieve
the desired tranquilizing effect. For a human pattent
this degree of tranquilization may be achieved by means
of an antipsychotic composition in the form of tablets con-
taining from 0.2 to 200 mg of the active compound and an
appropriate pharmaceutical carrier taken from 1 to 4
times a day. Small unit dosages will be required to
2~ achieve a comparable neuroleptic effect in smaller species
of animals.
The compounds of general Formula I, together with
suitable pharmaceutical carriers, can be in the form of
solid unit dosage forms such as tablets, capsules and
powders, in the form of a suppository, or embedded in a
polymeric matrix. In the preparation of solid unit dosage
forms it may be desirable to micronize the compound to be
employed. In solid unit dosage forms the compounds can
be combined with conventional carriers, for example,
binders~ such as acacia, corn starch or gelatin; disinte-
grating agents, such as corn starch. guar gum or alginic
acid; lubricants, such as stearic acid or magnesium
.. . . ., . ~ ;
: '.`: `
~- 10~1
3~a~0
-8-
stearate: and inert fillers, such as lactose, sucrose or
corn starch.
The compounds of general Formula I may also be ad-
ministered as liquid suspensions or solutions using a
sterile liquid, such as an oil, water, an alcohol or mix-
tures thereof, with or without the addition of a pharmaceu-
tically suitable surfactant, suspending agent, or emulsify-
ing agent, for oral, topical or paren-teral aclministration.
For liquid preparations, the compounds of Formula I
can be formulated suitably with oils, for example, fixed
oils, such as peanut oil, sesame oil and olive oil; fatty
acids, such as oleic acid and isostearic acid; and fatty
acid esters, such as isopropyl myristate and fatty acid
gl~cerides; with alcohols, such as ethanol, isopropanol
and propylene glycol; with water; or with mixtures
thereof.
Peanut oil and sesame oil are particularly useful in
preparation of formulations for intramuscular injection.
Oils can also be employed in the preparation of formula-
tions of the soft gelatin type and suppositories. Water,saline, aqueous dextrose and related sugar solutions and
glycerols, such as polyethyleneglycol, may be employed
in the preparation of liquid formulations which may suit-
ably contain suspending agents, such as pectin, carbomers,
methyl cellulose, hydroxypropyl cellulose or carboxy-
methyl celluloseJ as well as buffers and preservatives.
Illustratively, when 4-r4-(2-naphthalenyloxy)-1-
piperidyl]-1-(4-fluorophenyl)-1-butanone hydrochloride
was administered intraperitoneally to mice at a dosage
of o.o6 mg/kg the aggregate toxicity o-F d-amphetamine
was inhibited in 50~ of the mice tested according to the
procedures disclosed by J. Burn et al., Arch. Int.
Pharmacodyn. 113~ 290-5 !1955), thus demonstrating anti-
psychotic effectiveness, whereas a dosage level of o.g8
~5 mg/kg of the known tranquilizer chlorprom~zine is required
to attain a similar level of response. Similarly, com-
pounds of this invention evince neuroleptic activity
~ ' M-1031
~lZ3~`~0
through the inhibition of pernicious preening in mice
tested according to the method disclosed by A. Kandel et
al., Fed. Proc., 19 (1, Pt. 1), 24 (1960).
The neuroleptic potency of these compounds is accom-
panied by a reduced tendency to produce extrapyramidalside effects in patients treated wiih a neuroleptically
effective dosage as compared with known antipsychotic
agents. Indicative of the reduced extrapyramidal effect
of the compounds of this invention, when 4-[4-(2-naphtha-
lenyloxyj-1-piperidyl~-1-(4-fluorophenyl)-1-butanone hydro-
chloride was administered intraperitoneally to mice, a
dosage of 34.0 mg/kg was required to counteract the
behavioral effects of apomorphine in 50~ of the mice
tested according to the general method disclosed by
P. A. J. Janssen et al.~ in Arzneim-Forsch. 10, 1003 (1960),
whereas only 1.~ mg/kg of chlorpromazine was required to
attain a similar effect.
Compounds of Formula I are prepared by alkylation
of intermediate compounds of Formula IIa,
o
I Formula IIa
H
which represent compounds of Formula II wherein R2 is
hydrogen and R has the above-identified meaning. Com-
pounds of Formula IIa are themselves prepared by dealkyla-
tion or debenzylation of compounds of Formula IIb,
R ~
~ Formula IIb
N
R3
- l . , . . .. ~ .... . . . .. . ..
M-~0~1
ll'h34~0
-9a-
wherein R3 is lower alkyl or phenyl(lower alkyl) and R
has the above-defined meaning, which represent compounds
of Formula ll wherein R2 is lower alkyl or phenyl(lower
alkyl). It is thus apparent that all of the compounds
of Formula ll are useful intermediates for the pharmaceu-
tically useful compounds of Formula 1. Compounds of
Formula ll are also new and represent a part of this
invention.
Compounds of Formula llb are prepared by reaction
of an N-substituted-4-piperidinol salt of Formula V
O-M+
Formula V
R3 .
wherein R3 is lower alkyl or phenyl(lower alkyl) and M
is an alkali metal cation, such as potassium, sodium or
lithium, with a naphthalene fluoride of Formula Vl -
R ~ F Formula Vl
:
,:
,~ ,.
;..
`: : i . . !, ` . `; . ` .,
. M-1031
Z3~ ~
-10-
wherein R has the meaning defined above, to produce a
1-(low2r alkyl) or 1-phenyl(lower alkyl)-4-naphthalenyloxy-
piperidine of Formula llb. The compounds of Formula lla,
wherein R2 is hydrogen, are prepared by dealkylation o~
N-substituted compouncis of Formuia llb by means of a chloro-
formic acid ester of Formula R40C-C1, wherein R4 is 2,2,2-
trichloroethyl, vinyl, substituted vinyl, benzyl, substi-
tuted benzyl or cycloalkyl, which is reacted with the com-
pound of Formula llb in the presence of a proton scavenger,
to produce a 1-(R4-oxycarbonyl)-4-(naphthanlenyloxy)piper-
idine of Formula Vll
R
O
Formula Vil
IN
O=C-O-R4
:~
wherein R and R4 have the meanings defined above, and
removal of the R4-oxycarbonyl groùp by means of a mild
15 reducing agent, such as zinc dust in acetic acid or ;
methanol, or by acid hydrolysis, as illustrated by the
following:
O M+ R ~ R
F > O ~:
N
R3 V Vl llb N ~ :
R3 :
R ~ reduction R ~ ~ R~OCCl
< hydrolysis
lla ~ Vll
H O=C-OR4
M -10~ 1
-11 -
Naphthalene fluorides of Formula Vl are well known
and may be prepared by methods well known in the art, -For
example by the methods described by W. Adcock et al., in
J. Am. Chem. Soc. 89(2), 386-390 (1967) and in J. Am. Chem.
Soc. 98(7), 1701-1711 (1976).
Piperidtnol salts of Formula V are prepared by react-
ing the corresponding 1-lower alkyl- or 1-phenyl(lower-
alkyl)-4-piperidinol with a strong base, such as an
alkali metal hydride, an alkali metal amide or alkyl
lithium according to generally known procedures. The
piperidinol salt is reacted with the naphthalene fluoride -~
of Formula Vl in the presence of a polar, aprotic solvent
at a temperature of from about 50 to about 200C or at the
boiling temperature of the solvent for from about 1 to
about 24 hours. Suitable solvents include tetrahydrofuran,
dimethoxyethane, diglyme, dioxane, hexamethylphosphorus
triamide, dimethylacetamide, dimethylsulfoxide, 1-methyl-
2-pyrrolidone, sulfolane and, especially~dimethyl formamide.
The reaction is quenched and the resulting N-substitu-
ted compound of Formula llb or its acid addition salt isisolated by conventional means, for example, the reaction
mixture may be filtered and the solvent removed, isolating
the product, which is purified by recrystallization and
dried. Suitable solvents for recrystallization are, for
exam?le, lower aliphatic alcohols, such as methanol,
ethanol and isopropanoli ketones, such as acetone and but-
anone; esters, such as ethyl acetate; hydrocarbons, such as
` hexane; and combinations thereof.
The thus prepared 1-lower alkyl- or 1-phenyl(lower-
alkyl)-4-(naphthalenyloxy)piperjdine of Formula llb is then
reacted with an ester of chloroformic acid in the presence
of an aprotic solvent and, preferably, an acid scavenger to
form a carbamate oF Formula Vll, which is subsequently
cleaved to yield the corresponding 1-unsubstituted-4-(naph-
thalenyloxy)piperidine oL Formula lla. Suitable chloro-
formic acid esters are those which yield R4-oxycarbonyl
. ~ . .
M -10:~ 1
~lZ3~40
-12-
substituents which may be cleaved from the nitrogen atom
of the compound of Formula Vll hydrolytically or by reduc-
ing conditions under which the naphthalene ring is not
hydrogenated. Such chloroformic acid esters include the
2,2,2-trichloroethyl ester, which may be cleaved by reduc-
tion with zinc dust or by electrolysis; the benzyl ester,
benzyl esters subst7tuted by phenyl, methoxy, methyl,
phenylazo, cyano, bromo or chloro, vinyl esters, and cyclo-
alkyl esters, such as the cyctohexyl, cyclopentyl, ada-
mantyl and isobornyl esters, which may be cleaved by acidhydrolysis by means of strong acids, such as hydrochloric
or hydrobromic acids, or by means of mild acids~ such as
trifluoroacetic acid, in suitable solvents. Chloroformic
acid esters suitable for displacing alkyl and benzyl sub-
stituents from tertiary amines and methods suitable for
the cleavage of the various R4-oxycarbonyl groups from the
nitrogen atoms are described by M. Bodanszky et al., in
Peptide Synthesis, 2nd Edition ~ohn Wiley & Sons) p. 21-
37 (1976) and by R. Olofson et al. in U.S. patent
3,905,981, which are hereby incorporated by reference.
The preferred chloroformic acid ester for the dealkylation
of compounds of Formula il wherein R2 is lower alkyl or
phenyl(lower alkyl) is 2,2,2-trichloroethyl chloroformate.
Suitable solvents for the reaction of an N-substituted
compound of Formula llb with a chloroformic acid ester are
aprotic organic solvents, for example, ethers, such as
diethyl ether and tetrahydrofuran, aromatic hydrocarbons,
such as toluene and benzene, chlorinated hydrocarbons,
such as chloroform, dichloroethane and methylene chloride,
or mixtures thereof. The preferred solvent is methylene
chloride. The reaction may be carried out in the presence
of a small amount, for example, 1~-5~ by weight of the
amount of the compound of Formula llb, of a proton
scavenger, which may be an inorganic base, such as sodium
or potassium carbonate, a strong organic base, such as
triethylamine, or a mixture thereof. The reaction
t~ :
,~. . ', ' ' ' ~ '' ' . ` ". " ' ' , ., ' ' , " ' . ':, ' `: ,. ' ', ', "' ', ','"', ' '
~lZ34~ M-10~1
mixture is maintained at a temperature between about 0C
and the reflux temperature of the solvent for from about
1 to about 96 hours. The thus obtained 1-(R~-oxycarbonyl)-
4-(naphthalenyloxy)piperidine of Formula Vll is isolated,
5 for example, by extraction into an organic solvent and -
evaporation of the solvent,according to generally known
procedures, and the R4-oxycarbonyl group cleaved by an
appropriate method.
In the preferred embodiment of this invention, an
N-lower alkyl- or N-phenyl(lower alkyl)-substituted com-
pound of Formula llb is refluxed in methylene chloride with
a slight excess, for example, from 1.01 to 1.3 equivalents,
preferably about 1.1 equivalents, of 2,2,2-trichloroethyl
chloroformate in the presence of a trace amount of a
proton scavenger for from about 6 to about 24 hours at
a temperature of from about 15 to about 40C, preferably
at room temperature. The product is extracted into ether,
washed with dilute acid and concentrated In vacuo. The re-
sulting 1-(2,2,2-trichloroethoxycarbonyl)-4-(naphthaleny-
loxy)piperidine is dissolved in a solvent selected fromacetic acid, aqueous acetic acid, a lower alkanol, such as
methano1, an aqueous lower alkanol, and, preferably, a mix-
ture of acetic acid, water and an ether, such as tetrahydro-
furan. At a temperature of from about 0 to 50C, preferably
at room temperature, from 1 to 5 equivalents, preferably
about 2 equivalents, of 7inc dust is added gradually
with stirring, and the reaction allowed to proceed for
from about 1 to about 6 hours until gas evolution ceases.
The solvents are evaporated and the N-unsubstituted com-
pound of Formula lla separated from the residual zincsalts by basification, extraction into an organic solvent,
washing to remove water soluble impurities, conversion
to a water-soluble acid addition salt, washing with or-
ganic solvents to lemove neutral organic impurities and
rebasification. The ,~J-unsubstituted compound is recrys-
tallized by conventional methods, preferably in the form
of its acid addition salt, from suitable solvents,
~ '
~,
. ~ :
M -103 1
;Z344
-14-
such as lower aliphatic alcohols, ketones, esters and
combinations thereof.
Free bases of Formula ll prepared by the above-men-
tioned method may be converted to the acid addition salts
by reaction with a suitable acid according to generally
known procedures.
The compounds of Formula I are prepared by reacting a
piperdine derivative of Formula lla, wherein R2 is hydro- -
ger~ with a small excess of an w-haloalkyl phenyl ketone
or an w-halo-1-phenyl-1-alkanol of structure Vlll in the
presence of an excess of an acid acceptor, such as, for
example, sodium bicarbonate, potassium bicarbonate, sodium
carbonate or potassium carbonate, and optionally a small
amount of potassium iodide, in a suitable solvent. If
desired, 2 or more equivalents of the piperidine deriva-
tive of Formula ll relative to compound Vlll may be used
instead of the mineral base acid acceptor. The compounds
of Formula I may also be prepared from the acid addition
salt of the compound of Formula !la by reacting the acid
addition salt with a compound of structure Vlll in the
presence of at least 2 equivalents of the mineral base
acid acceptor. The reaction mixture may be reacted over
a wide range of temperatures. Generally, a reaction
temperature of from about 20 to 180C is employed. The
reaction is conducted over a period of from 1 to 4 days,
during which time any evolved water may be collected.
As examples of suitable solvents for this reaction,
there may be mentioned toluene~ xylene, chlorobenzene,
methyl isobutyl ketone and lower aliphatic alcoholsJ such
as ethanol, propanol and butanol.
After completion of the reaction, the product is
isolated by conventional means, for example, the reaction
mixture may be riltered and the solvent removed, isolating
the product. AlternatelyJ the filtrate may be treated
~5 with an ethereal solution of a suitable mineral or organic
acid to give the corresponding salt of the product. The
M - 10
3 ~'~
-15-
crude product is filtered off, purified by recrystalliza-
tion and dried. Suitable solvents for recrystallization
are, for example, lower aliphatic alcohols, such as
methanol, ethanol and isopropanol; ketones, such as ace-
tone and butanone; nitriles, such as acetonitrile; andcombinations thereof.
The general method for the preparation of the com-
pounds of Formula I can be represented by the following
reaction scheme
R ~
O + ha l o- ( CH2 ) n~Z~ R 1 ----
lla ~ Vlll
H
0
. '
(CH2)n-Z- ~ -R1
wherein n, R, R1 and Z are as hereinabove defined and
halo is a reactive halogen, such as bromine, chlorine or
iodine. ~ -
Compounds of Formula Vlll are commercially available
or may be prepared by methods well known in the art.
Compounds of Formula Vlll wherein Z is C=O may, for example,
be prepared by reacting the appropriate w-haloalkanoyl
halide and a (substituted)benzene in the presence of a
Lewis acid, such as aluminum chloride, or by reacting a
(4-substituted)phenyl Grianard reagent with an appropriate
w-haloalkylnitrile. Compounds of Formula Vlll wherein Z ;
is CHOH may be prepared by reduction by means of chemical
reducing agents or catalytic hydrogenation of the corres-
ponding 1-(4-substituted)phenyl-W-haloalkanones of Formula
- 10~ 1
3~
-16-
VIII prepared as descr7bed above or by reaction of a (4-
substituted)phenyl Grignard reagent with an appropriate
w-haloalkanaldehyde.
3-(4-Naphthalenyloxy-1-piperidyl)-1-phenylpropanones,
compounds of Formula III wherein n is equal to 2, may also
be prepared by reacting compounds of Formula II wherein
R2 is hydrogen with an appropriate acetophenone and form-
aldehyde.
~-(Naphthylenyloxy)-1-piperidinealkanols of Formula
IV may be prepared by reduction of alkanones of Formula III.
Suitable methods for reducing ketones to alcohols are
well known in the art, and include catalytic hydrogenation
and reduction by chemical reducing agents.
For catalytic reduction, a ketone of Formula III may,
for example, be dissolved in a solvent, such as acetic
acid, ethyl acetate, or a lower aliphatic alcohol, such as
methanol or isopropanol, and the solution agitated in the
presence of hydrogen at from about 1 to about 4 atmos-
pheres of pressure and room temperature, that is about
20-25C, in the presence of a suitable catalyst, such as
platinum, platinum oxide or rhodium, until one equivalent
of hydrogen is consumed.
Alternatively, the ketone of Formula III may be
reduced by reaction with a suitable chemical reducing ~
25 agent. For example, the ketone may be refluxed in ether -
for from 1 to 5 hours with a metal hydride, for example,
lithium aluminum hydride or diborane, or reacted for
from about 1/2 to 8 hours at a temperature of from 0C
to the reflux temperature of a lower aliohatic alcohol
solvent, such as methanol or ethanol, with a metal boro-
hydride, such as sodium borohydride or potassium boro-
hydride, to yield an alcohol of Formula IV. Additional
reagents suitable for the reduction of a ketone to an
alcohol will be obvious to one skilled in the art.
Compounds of Formula I prepared in the form of free
bases may be converted to their acid addition salts by
reaction with a pharmaceutically acceptable acid.
M-lO~il
~lLlZ3~'~V
The optical isomers of optically active compounds of
Formula I may be separated by means of any suitable resolv-
ing agent. For example, the optical isomers of compounds
of Formula I wherein Z is hydroxymethylene may be sepa-
rated by using a (+)- or (-)-binaphthylphosphoric acid ;
derivative or a salt of said derivative and an optically
active base by the method described by R. Viterbo et al.,
in Tetrahedron Letters 1971 (48), pp. 4617-20.
EXAMPLE 1
4-(2-NaphthalenYloxy)-1-(phenylmethyl)piperidine hydro-
chloride
To a stirred suspension of 1.80 9 (37.5 mmole) of pen-
tane washed 50~ sodium hydride dispersion in 50 ml of dry
dimethylformamide under argon is added a solution of 4.75 g
(25.0 mmole) of 1-phenylmethyl-~-piperidinol in 20 ml of
dry dimethylformamide followed by a solution of 3.83 g
(26.2 mmole, 1.05 eq.) of 2-fluoronaphthalene in 20 ml `
of dimethylformamide. The mixture is heated at 75C for
23 hours, cooled, poured into ice water and extracted twice
with ether. The extracts are washed with water and brine,
dried over magnesium sulfate and filtered. The filtrate
is treated with HCl/methanol and the resulting 4-(2-
naphthalenyloxy)-1-(phenylmethyl)piperidine hydrochloride
recrystalli~ed from butanone/methanol. M.P. 242-244C. -
EXAMPLE 2
4-(1-Naphthalenyloxy)-1-phenylmethylpiperidine hydrochloride
When in the procedure of Example 1, 1-fluoronaphtha- i~
lene is substituted for 2-fluoronaphthalene, 4-(1-
naphthalenyloxy)-1-(phenylmethyl)piperidine hydrochloride
is produced. M.P. 222-224C.
EXAMPLE 3 -
4-(5-Methoxy-1-naphthalenyloxy)-1-(phenylmethyl)piperidine
hydrochloride
When in the procedure of Example 1, 5-methoxy~
fluoronaphthalene is substituted for 2-fluoronaphthalene,
4-(5-methoxy-1-naphthalenyloxy)-1-(phenylmethyl)piperidine
hydrochloride is produced.
.';. :
M-1031
3440
-18-
EXAMPLE 4
4-(1-~lethy1-2-naphthalenyloxy)-1-methylpiperidine hydro-
chloride
-:
When in the procedures of Example 1, 1-methyl-2-
fluoronaphthalene is substituted for 2-fluoronaphthalene
5 and 1-methyl-4-piperidinol is substituted for 1-phenyl-
methyl-4-piperidinol, 4-(1-methyl-2-naphthalenyloxy)-1-
methylpiperidine hydrochloride is produced.
EXAMPLE 5
4-(4-Trifluoromethyl-2-naphthalenyloxY)-l-methylpiperidinol
hydrochlor~de
When in the procedure of Example 1J 4-trifluoromethyl-
2-fluoronaphthalene is substituted for 2-fluoronaphthalene
and 1-methyl-4-piperidinol is substituted for 1-phenyl-
methyl-4-piperidinol, 4-(4-trifluoromethyl-2-naphthalenyl-
oxy)-1-methylpiperidine hydrochloride is produced.
EXAMPLE 6
4-(5-Fluoro-1-naphthalenyloxy)-1-ethylpiperidine hydro-
chloride
When in the procedure of Example 1, 1,5-difluoro-
naphthalene is substituted for 2-fluoronaphthalene and 1-
ethyl-4-piperidinol is substituted for 1-phenylmethyl-4-
piperidinol, 4-(5-fluoro-1-naphthalenyloxy)-1-ethylpiperi-
dine hydrochloride is produced.
EXAMPLE 7
4-(2-Naphthalenyloxy)piperidine hydrochloride
To a stirred solution of 64.6 9 (0.204 mole) of 4-
(2-naphthalenyloxy)-1-phenylmethylpiperidine in 500 ml
of methylene chloride is added ~7.0 ml (.268 mole) of
2,2,2-trichloroethyl chloroformate and about 200 mg.
of potassium carbonate. The mixture is stirred at room
temperature for 48 hours and poured into a volume of
ether and water. The organic phase is washed with dilute
hydrochloric acid and aqueous potassium carbonate, dried
over magnesium sulfate, and concentrated In vacuo.
The resulting 1-(2,2,2-trichloroethoxycarbonyl)-4-
(2-naphthalenyloxy)piperidine is dissolved in a mixture
of 250 ml of ace-tic acid, 250 ml of tetrahydrofuran and
M-1031
, ~ .
~lZ3~40
-19-
125 ml of water. ~8.5 9 (.436 mole) of zinc dust is added
in portions with stirring and the exothermic reaction
allowed to proceed for 2-1/2 hours. The mixture is fil-
tered and the solvents are removed in vacuo. The residue
is partitioned between ether and aqueous sodium hydroxide
and the organic phase washed with water and extracted ;
with dilute aqueous hydrochloric acid. The acid extracts
are washed with ether, made basic with sodium hydroxide
and extracted into ether and toluene and the organic solu-
tion washed~ dried over magnesium sulfate and concentrated
in vacuo to yield 4-(2-naphthalenyloxy)piperidine, which -
is redissolved in ethanol/ether and treated with dry HCl,
and the hydrochloride salt recrystallized from butanone/
methanol. M.P. 229.5-231.5C.
EXAMPLE 8
~-(1-Naphthalenyloxy)piperidine hydrochloride
When in the proceudre of Example 7, 4-(1-naphtha-
lenyloxy)-1-phenylmethyl)piperidine is substituted for
4-(2-naphthalenyloxy)-1-phenylmethyl)piperidine, 4-(1-
naphthalenyloxy)piperidine hydrochloride is produced.
EXAMPLE 9
4-(4-Trifluoromethyl-2-naphthalenyloxy)piperidine hydro-
chloride
When in the procedure of Example 7, 4-(4-trifluoro- ~ `
methyl-2-naphthalenyloxy)-1-methylpiperidine is substi-
tuted fGr 4-(2-naphthalenyloxy-1-(phenylmethyl)-piper-
idine, 4-(4-trifluoromethyl-2-naphthalenyloxy)piperidine
hydrochloride is produced.
EXAMPLE 10 ;
' . ,
4-(5-Fluoro-1-naphthalenyloxy)piperldine hydrochloride
When in the procedure of Example 7, 4-(5-fluoro-1-
naphthalenyloxy)-1-ethylpiperidine is substituted for
4-(2-naphthalenyloxy)-1-(phenylmethyl)piperidine, 4-
(5-fluoro-1-naphthalenyloxy)piperidine is produced.
M-1031
3~Z3~
-20-
EXAMPLE 11
4-(~-Methoxy-1-n3phthalenyloxy)piperidine hydrochloride
A solution of 18.4 9 (50 mmole) of 4-(5-methoxy-1-
naphthalenyloxy)-1-(phenylmethyl)piperidine in 10 ml
of 1,2-dichloroethane is added gradually to a chilled
solution of 65 mmole of vinyl chloroformate in 50 ml
of 1,2-dichloroethane and the mixture stirred at room
temperature for 4 hours and concentrated in vacuo.
The thus obtained 4-(5-methoxy-1-naphthalenyloxy)-
1-(vinyloxycarbonyl)piperidine is stirred for 2 hours
with 2N HCl in methanol to yield 4-(5-methoxy-1-naph-
thalenyloxy)piperidine hydrochloride.
EXAMPLE 12
4-(1-Methyl-2-naphthalenyloxy)piperidine hydrochloride
When in the procedure of Example 11 4-(1-methyl-2-
naphthalenyloxy)-1-methylpiperidine is reacted with
benzyl chloroformateJ the resulting 4-(1-methyl-2-naph-
thalenyloxy)-1-(phenylmethoxycarbonyl)piperidine yields
upon hydrolysis 4-(1-methyl-2-naphthalenyloxy)piperidine
hydrochloride.
EXAMPLE 1~
4-~4-(2-Naphthalenyloxy)-1-piperidyll-1-phenyl-1-butanone
hydrochloride
A solution of 5.~7 g (25 mmoles) of 4-(2-naphtha-
lenyloxy)piperidine, 5.0 9 (27.4 mmole) of 4-chloro-1-
phenyl-1-butanone, 0.1 g of potassium iodide and 4.5 g
potassium bicarbonate in 100 ml of toluene is heated for
48 hours with stirring on a steam bath. The mixture is
partitioned between 100 ml portions of methylene chloride/
ether and water and the organic phase dried over ~gS04.
A solution of an excess of HCl in ether is added and the
resulting precipitate recrystallized from methanol/
butanone to yield 4-(2-naphthalenyloxy-1-piperidyl)-1
phenyl-1-butanone hydrochloride.
. . . .. ..... ...... .
M-10~1
34~
-21-
EXAMPLE 14
4-[4-(2-Naphthalenyloxy)-1-piperidyll-1-(4-fluorophenyl)-
1-butanone hydrochloride
When in the procedure of Example 13, 4-chloro-1-(4-
fluorophenyl)-1-butanone is substituted for 4-chloro-1-
phenyl-1-butanone; 4-[4-(2-naphthalenyloxy)-1-piperidyl]-
1-(4-fluorophenyl)-1-butanone hydrochloride is produced.
M.P. 219-221.5C.
EXAMPLE 15
4-r4-(1-Naphthalenyloxy)-1-piperidyl1-1-(4-fluorophenyl)-
1-butanone hydrochloride
When in the procedure of Example 13, 4-chloro-1-(4-
fluorophenyl)-1-butanone is substituted for 4-chloro-1-
phenyl-1-butanone and 4-(1-naphthalenyloxy)piperidine
hydrochloride is substituted for 4-(2-naphthalenyloxy)-
piperidine hydrochloride, 4-[4-(1-naphthalenyloxy)-1-
piperidyl]-1-(4-fluorophenyl)-1-butanone hydrochloride
is produced. M.P. 220-222.5 C.
EXAMPLE 16
3-~4-(5-Methoxy-1-naphthalenyloxy)-1-piperidyl1-1-(4-
chlorophenyl ~ 1-propanone hydrochloride
When in the procedure of Example 1~, 4-(5-methoxy-1-
naphthalenyloxy)piperidine hydrochloride is substitutedfor 4-(2-naphthalenyloxy)piperidine hydrochloride and ~-
chloro-1-(4-chlorophenyl)-1-propanone substituted for 4-
chloro-1-phenyl-1-butanone, 3-[4-(5-methoxy-1-naphthalenyl-
oxy)-1-piperidyl]-1-(4-chlorophenyl)-1-propanone hydro-
chloride is produced.
EXAMPLE 17
5-r4-(2-Naphthalenyloxy)-1-piperidyll-1-(4-methylphenyl)-
1-pentanone hydrochloride
When in the procedure of Example 1~, 5-chloro-1-(4-
methylphenyl)-1-pentanone is substituted for 4-chloro-
1-phenyl-1-butanone, 5-~4-(2-naphthalenyloxy-1-piperidyl]-
1-(4-methylphenyl)-1-pentanone hydrochloride is produced.
~ " ": ~
,; - ...... : . .
M-1031
~Z3~
22-
EXAMPLE 18
4-[4-(l-Methyl-2-naphthalenyloxy)-l-piperidy~ (4
fluorophenyl)-1-butanone
A solution of 3.47 9 (12.5 mmole) of 4-(1-methyl-
2-naphthalenyloxy)piperidine, ~.63 9 (13.1 mmole)
o-F 4-chloro-1-(4-fluorophenyl)-1-butanone, 5.2 9
(52 mmole) of potassium bicarbonate and a pinch of
potassium iodide in 60 ml of toluene is heated at reflux
for 80 hours. The mixture is partitioned between toluene
and water and the organic phase washed with brine, dried
over magnesium sul-fate, and concentrated In vacuo to
yield 4-[4-(1-methyl-2-naphthalenyloxy)-1-piperidyl]-1-
(4-fluorophenyl)-1-butanone.
EXAMPLE 19
6-~4-(4-Trifluoromethyl-2-naphthalenyloxy)-1-plperidyll-
1-~Ll-methoxyphenY1,-1-hexanone
When in the procedure of Example 18, 4-(4-trifluoro-
methyl-2-naphthalenyloxy)piperidine is substituted for
4-(1-methyl-2-naphthalenyloxy)piperidine and 6-bromo-
1-~4-methoxyphenyl)-1-hexanone substituted for 4-chloro-
1-(4-fluorophenyl)-1-butanone, 6-[4-(4-trifluoromethyl-
2-naphthalenyloxy)-1-piperidyl]-1-(4-methoxyphenyl)-
1-hexanone is obtained.
EXAMPI E 20
a-(4-Fluorophenyl)-4-(1-methyl-2-naphthalenyloxy)-1-
piperidinebutanol
When in the procedure of Example 18, 4-chloro-1-
(4-fluorop'nenyl)butanol substituted for 4-chloro-1-(4-
fluorophenyl)-1-butanone, G-(4-fluorophenyl)-4-(1-methyl-
2-naphthalenyloxy)-1-piperidinebutanol is produced.
EXA~IPLE 21
2-Phenyl-4-(5-fluoro-1-naphthalenyloxY)-1-piperidine-
propanol
When in the procedure or Example 18, 4-(5- fluoro-1-
naphthalenyloxy)piperidine is substituted for (1-methyl-
2-naphthalenyloxy)piperidine and ~-bromo-1-phenyl-
propanol substituted for 4-chloro-1-(4-fluorophenyl)-1-
butanone, a-phenyl-4-(5-fluoro-1-naphthalenyloxy)-1-
piperidinepropanol is obtained.
-- . ~ - ~, . ,
., -
,.: . ~ . . . ~ . :: :
.. . , ., .. ,~ , ^ , .
M-lO~il
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-23-
EXAMPLE 22
3-L4-(5-Methoxy-1-naphthalenyloxy~-1-piperidyll-1-(4-
fluorophenyl)-1-propanone
A mixture of 25.5 9 (0.1 mole) of 4-(5-methoxy-1-
naphthalenyloxy)piperidine, 9 9 (0.3 mole) of paraform-
aldehyde and 13.8 9 (0.1 mole) of 4'-fluoroacetophenone
in 100 ml of isopropyl alcohol containing 2 drops of
concentrated hydrochloric acid is refluxed for 24 hours.
The mixture is filtered and the filtrate concentrated to
about 100 ml and cooled. The resulting precipitate is
recrystallized from ethanol to give 3-[4-(5-methyl-1-
naphthalenyloxy)piperidyl-1-(4-fluorophenyl)-1-propanone.
EXAMPLE 23
a-(4-Fluorophenyl)-4-(2-naphthalenyloxy)-1-piperidine-
butanol
To 8.o g (0.02 mole) of 4-[4-(2-naphthalenyloxy)-
1-piperidyl]-1-(4-fluorophenyl)-1-butanone HCl in 50 ml
of methanol is added 1.1 9 (0.02 mole) of sodium methoxide
and then 2.7 9 (0.05 mole) of potassium borohydride and
the mixture stirred at room temperature for 2 hours.
The methanol is removed at reduced pressure on a steam
bath after which 50 ml of 10~ sodium hydroxide solution is
added. The mixture is stirred for 15 minutes and 100 ml
of chloroform is added. Stirring is continued for 1/2
hour. The chloroform layer is separated and combined with
two 25 ml chloroform extracts of the aqueous phaseJ
washed with water and with brine, dried over MgS04~ fil-
tered and concentrated to a solid. The solid material
is recrystallized from ethanol/water to give z-(4-fluoro-
phenyl)-4-(2-naphthalenyloxy)-1-piperidinebutanol.
CXAMPLE 24
~-(4-Methoxyphenyl)-4-~4-trifluoromethyl-2-naphthalenYl-
oxy)-1-piperidinehexanol
When in the procedure of ~xample 23~ 6-[4-(4-tri-
fluoromethyl-2-naphthalenyloxy)-1-piperidyl]-1-(4-methoxy-
phenyl)-1-hexanone hydrochloride is substituted for 4-r4-
(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-
M-1031
~3 ~
-24-
butanone, ~-(4-methoxyphenyl)-~-(4-trifluoromethyl-1-
naphthalenyloxy)-1-piperidinehexanol is obtained.
EXAMPLE 25
Tablet Formulation
An illustration of a representative tablet formula-
tion of an active compound of this invention is as follows:
Per Tablet
(a) 4-[(2-naphthalenyloxy)-1- 25.0 mg
piperidyl~-1-(4-fluorophenyl)-
1-butanone hydrochloride
(b) Wheat starch 3.5 mg
10 (c) Lactose 10.0 mg
(d) Magnesium stearate 0.5 mg
A granulation obtained upon mixing lactose with the
starch and granulated starch paste is dried, screened and
mixed with the active ingredient and magnesium stearate.
The mixture is compressed into tablets weighing 39.0 mg
each.
EXAMPLE 26
Gelatin Capsule Formulation
An illustrative composition for hard gelatin capsules
20 is as fol10ws:
Mq
(a) 4-~4-(2-naphthalenyloxy)-1- 10
piperidyl~ (4-fluorophenyl)-1-
butanone hydrochloride
(b) Talc 5
(c) Lactose 100
The formulation is prepared by passing the dry powders
of (a) and (b) through a fine mesh screen and mixing them
well. The powder is then filled into hard gelatin cap-
sules at a net fill of 115 mg per capsules.
EXAM~LE 27
Injectable SusDension Formulation
An illustrative composition for an injectable sus-
pension is the following 1 ml ampul for an intramuscular
injection.
- - . , . . . : . : . . . .
, M-1031
~` ~ Z 3 ~ ~3
-25-
Weiqht Percent
(a) 4-[4-(2-naphthalenyloxy)-1- 1.0
piperidyl]-1-(4--fluorophenyl)-
1-butanone (particle size <10~)
(b) Polyvinylpyrrolidone (M.W. 25000) 0.5
(c) Lecithin 0.25
(d) Water for injection ~o make 100.0
The materials (a)-(d) are mixedJ homogenized, and
filled into 1 ml ampules which are sealed and autoclaved
20 minutes at 121C. Each ampul contains 10 mg per ml
of novel compound (a).
