Note: Descriptions are shown in the official language in which they were submitted.
, AHP-6692/6693
~85i891~
Background of the Invention
__
a) Field of the Invention
This invention relates to aryloxy propylamines having
antidepressant activity, to processes for their preparation, to
in~ermediates used for the process, and to formulations and a
- method of use for these aryloxy propylamines.
b) Prior Art
During the last few decades, psychotherapy has become more
effective due to the adjunct use of new central nervous system
; agents, in particular, the use of tranquilizers and antidepressants.
.
As a consequence, the development of new and useful agents for
~; psychotherapy has been diligently pursued, and the finding of a
potent, well tolerated agent is noteworthy indeed.
- The present invention discloses a group of antidepressant agents
having these attributes. The agents are aryloxy propylamines.
I A number of aryloxy propylamines are known to possess pharmacologic
' properties; for example, l-isopropylamino-3-(1-naphthyloxy)-2-
; propanol, J. W. Black, et al., Lancet, 1, 1080 (1964), a potent
~-blocking agent, and a group of alkyl ethers of 3-amino-l-phenoxy-2-
propanol derivatives, V. Dauksas and L. Pikunaite, Zh. Vses. Khim.
Obshchestva im. D.I. Mendeleeva, 9, 352 (1964); Chem Abstr., 61,
6942c(1964) having a stimulating effect on the central nervous
system. The compounds of the present invention are distinguished
readlly from these latter prior art compounds by having a different
structural relationship with respect to the substituents and a
different pharmacological profile. Another example,
2-isopropylamino-3-(l-naphthyloxy)-l-propanol, having the
same structural rela~ionship respecting the substituents has
been reported, R. How, J. Med. Chem., 13, 398 (1970). The compound
--2--
A~lP-6692/6693
L
was devoid of ~-receptor blocking activity in the only pharma-
cological testing reported therefor. When tested for anti-
depressant activity according to the methods described herein~ the
compound was found to be devoid of or to have marginal activity.
Summary of the Invention
The compounds of this invention are represented by formula I
!
Ar-OCH2CHCH2-Z
: NR R
,
in which Ar is phenyl or l-naphthyl; R and R are either the same
or different selected from the group consisting of hydrogen or lower
alkyl, or Rl and R together with the nitrogen atom to which they
are joined form a heterocyclic amine radical selected from the
group consisting of l-pyrrolidinyl, piperidino, morpholino and
4-(lower alkyl)-l-piperazinyl; and Z is NR R4 wherein R and R
are either the same or different selected from the group consisting
of hydrogen or lower alkyl, or R and R together with the nitrogen
to which they are joined represent a heterocyclic amine radical
selected from the group consisting of l-pyrrolidinyl, piperidino,
morpholino and 4-(lower alkyl)-l-piperazinyl, or Z is oR5 wherein
R5 is hydrogen or lower alkyl; with the provisos that when Ar is
--3--
s A}IP-6693/6693
~5~4~
phenyl, Z must be OR5, and that when Z is OR , Rl and R together
with the nitrogen atom to which they are joined form said hetero-
cyclic amine radical; or a thereapeutically acceptable acid
addition salt thereof.
The compounds of formula I are prepared by process described
hereinafter.
Pharmaceutical compositions comprising the compounds of
formula I, or a therapeutically acceptable acid addition salt
thereof, and a pharmaceutically acceptable carrier are included
within the scope of this invention.
Also included is a method for alleviating the symptoms of
depression in mammals by administering to said animals an anti-
depressant effective amount of the compound of formula I, or a
therapeutically acceptable salt thereof.
A preferred group of compounds are ~he compounds of formula I
in which Ar is l-naphthyl; Rl and R2 together with the nitrogen atom
to which they are joined represent a heterocyclic amine radical
selected from the group consisting of l-pyrrolidinyl, piperidino,
morpholino and 4-(lower alkyl)-l-piperazinyl; and Z is NR3R4 wherein
R3 and R4 are either the same or different selected from the group
consisting of hydrogen or lower alkyl, or Z is oR5 wherein R5 is
hydrogen or lower alkyl; or a therapeutically acceptable acid addition
salt thereof.
Details of the Invention
.
The term "lower alkyl" as used herein contemplates straight
chain alkyl radicals containing from one to six carbon atoms and
branched chain alkyl radicals containing three ~o four carbon atoms
and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl
and the like.
~P-6692/6693
;8~L~
The term "lower alkanoic acid" as used herein contemplates
both straight and branched chain alkanoic acids containing from
one to six carbon atoms and includes formic, acetic, propionic,
t _ -butanoic, pentanoic, hexanoic acids and the like.
The compounds of formula I are capable of forming acid
addition salts wi~h therapeutically acceptable acids. Such acid
addition salts are included within the scope of this invention.
The acid addition salts are prepared by reacting the
corresponding base form of the compound of formula I with at
least one equivalent, or prefe-rably with an excess of the
appropriate acid in an organic solvent, for example, diethyl ether
or an ethanol-diethyl ether mixture. It should be noted that both
mono- and di-acid addition salts can be obtained depending on the
number of equivalents of the acid used and the solubility of a particular
acid addition salt in a particular solvent. These salts, when administered
to mammals, possess the same pharmacologic activities as the corres-
ponding bases. For many purposes it is preferable to administer the
salts rather than the base compounds. Among the acid addition salts
suitable for this purpose are salts such as the sul~ate, phosphate,
lactate, tartratr, maleate, citrate, hydrobromide and hydrochloride.
Both ~he base compounds and the salts have the distinct advantage of
possessing a relatively low order of toxicity.
Also included in this invention are the stereochemical
isomers of the compounds of formula I which result from asymmetric
centers contained therein.
A~ 6692/6693
5~
Individual optical isomers, which might be separated
by fractional crystallization of the diastereoisomeric salts thereof,
for instance, salts with d- or l-tartaric acid or D~ -bromocamphor
sulfonic acid, are also included.
The antidepressant activity of the compounds of ~ormula I
and their acid addition salts with pharmaceutically acceptable acids
is demonstrated in standard pharmacologic tests such as for example,
the tests described by F. Hafliger and V. Burckhart in "Psycho-
pharmacological Agents", M. Gordon, Ed., Academic Press, New York
and London, 1964, pp. 75 - 83.
More specifically, as noted in the latter reference the
antidepressant properties of a compound may be demonstrated by
its capacity to antagonize the depressant effects of reserpine.
Furthermore, it is well documented that reserpine in animals
produces a model depression which can be used for detecting
antidepressant properties. Accordingly, the compounds of the
present invention antagonize reserpine effects in mice at
doses ranging from about 1 to 100 mg/kg.
The antidepressant activity of the compounds of formula I
is also demonstrated by the method of D.F. Bogdanski, et al.,
J, Pharmacol. Exp. Ther., 122, 182 (1958) which measures the effect
of the test compound on the 5-hydroxytryptophan(5-HTP)-induced
syndrome. In this test the degree of intensity of the 5-HTP-
induced syndrome, i.e. extension and abduction of hindlimbs,
lordosis, tremors, head movements and excitation, following the
administration of the test compound to Swiss albino mice, is
~ AIIP-6692/6693
I
indicated by a scale ranging from ~1 (weak effect) to +4 (very
strong effect). A positive score in the test is indicative of
antidepressant agents having desirable mood elevation properties,
see A. Carlsson, et al., Eur. J. Pharmacol., 5, 357 (1969).
Several of the preferred compounds, for example, ~-((1-naphthyloxy)-
methyl)-l-piperidineethanamine hydrochloride, produces a significant
effect (*l to -~4) on the 5-HTP-induced syndrome at doses of 6.25
to 25 mg/kg, i.p., when administered to mice (five per group) 30
minutes prior to the 5-HTP injection (300 mg/kg, i.p.) in the same
test, l-{(l-ethoxymethyl)-2-(1-naphthyloxy))ethyl}piperidine hydro-
chloride, produces a significant effect (+ 1 to +3).
The following table illustrates further a comparative
study of ~ l-naphthyloxy)methyl)-l-piperidineethanamine hydrochloride,
l-{(l-ethoxymethyl)-2-(1-naphthyloxy)ethyl~piperidine hydrochloride,
imipramine hydrochloride and desimipramine hydrochloride in the
potentiation of the 5-HTP-syndrome test.
. _ . _
Compound Dose (mg/kg, i.p.) Behavioral Score
. __ __ . .. _
saline _ O
~-((l-naphthyloxy)methyl)-
l-piperidineethanamine 25 +4
hydrochloride 12.5 +3
(Example 4) 6.25 +1
l-{(l-(ethoxymethyl)-2- 25 +3
~1-naphthyloxy))ethyl}- 12.5 ~1
piperidine hydrochloride 6.25 +1
(Example 18)
imipramine hydrochloride 25 +1
desimipramine 25 +1
hydrochloride
~IP-6692/6693
The 5-~lTP-syndrome test can also be employed to demonstrate
the superiority of the compounds of formula I in which Z is NR3R4
over corresponding analogs in which the l-naphthyl group is replaced
by a phenyl group (cf. Dauksas and Pikunaite, cited above). For example,
under the testing conditions noted above in which ~-((l-naphthyloxy)methyl)-
l-piperidineethanamine hydrochloride, is active, the corresponding phenyl
analog, ~-(phenoxymethyl)-l-piperidineethanamine hydrochloride, is inactive.
When the compounds of formula I are used as antidepressants in
mammals, e.g. rats and mice, they may be used alone or in combination with
pharmacologically acceptable carriers, the proportion of which is deter-
mined by the solubility and chemical nature of the compound, chosen route
of administration and standard biological practice. For example, they
are administered orally in solid form containing such excipients as starch,
milk sugar, certain types of clay and so forth. They may also be admini-
stered orally in the form of solutions or they may be injected parente-
rally. For parenteral administration ~hey may be used in the form of a
sterile solution containing other solutes, for example, enough saline or
glucose to make the solution isotonic.
The dosage of the present therapeutic agents will vary with
the form of administration and the particular compound chosen. Furthermore,
it will vary with the particular host under treatment. Generally, treatment
is initiated with small dosages substantially less than the optimum dose of
the compound. Thereafter, the dosage is increased by small increments until
the optimum effect under the circumstances is reached. In general,
the compounds of this invention are most desirably administered at
a concentration level that will generally afford effective results with-
out causing any harmful or deleterious side effects and preferably at a
A~lP-6692/66g3
1515 4L~l
level that is in a range of from about 0.1 mg to about 100 mg/kg per
day, although as aforementioned variations will occur. However, a
dosage level that is in the range of from about 0.5 mg to about
50 mg/kg per day is most desirably employed in order to achieve
effective results.
The compounds of formula I in which Ar is l-naphthyl J R
and R2 are the same or different selected from the group consisting
of hydrogen or lower alkyl, or Rl and R together with the nitrogen
atom to which they are joined.form a heterocyclic amine radical
selected from the group consisting of l-pyrrolidinyl, piperidino,
morpholino and 4-(lower alkyl)-l-piperazinyl and Z is NR3R4 wherein
R3 and R4 are either the same or different selected from the group
consisting of hydrogen or lower alkyl, or R3 and R4 together with
the nitrogen to which they are joined represent a heterocyclic amine
radical selected from the group consisting of l-pyrrolidinyl, piperi-
dino, morpholino and 4-(lower alkyl)-l-piperazinyl are prepared by
a process represented by the following flow diagram.
~ AIIP-6692/6693
5~
Ar OCH2 ~ H2 ~Ar-OCH2~1HCH2NR R
0 0~1
II III
Ar-OCH2CHCH2NR R Ar-CH2fHCH2-Z
1~1 / NRlR2
IV ~ V
I (Z = NR R )
With reference to the flow diagram, the starting material
of formula II in which Ar is l-naphthyl, 1,2-epoxy-3-(1-naphthyloxy)-
propane, is described by A.F. Crow~her and L.H. Smith, J. Med. Chem.,
11, 1009 (1968), and references therein.
With reference to the preceding flow diagram, the compounds
of formula I in which Ar, R , R , R and R are as defined in the last
instance ~re prepared by a process comprising:
reacting the starting material of formula II with an amine of
formula NHRlR2 in which Rl and R2 are each hydrogen or lower alkyl or
and R together with the ni~rogen atom to which they are joined form a
heterocyclic'amine radical as defined herein to obtain the corresponding
~-hydroxypropylamine of formula III in which Ar, Rl and R2 are as defined
in the last instance; reacting the last-named compound with ~-toluene-
sulfonic acid chloride or thionyl chloride to obtain the corresponding ~-
chloropropylamine of formula IV, and thereafter either reacting the
~-chloropropylamine of formula IV with sodium or potassium azide to
obtain the corresponding compound of formula V in which Z is the
-10-
~85~4~ AHp-6692/669~
azide radical (-N3) and reducing the latter compound either with
hydrogen in the presence of a suitable catalyst or with a suitable
complex metal hydride to obtain the corresponding conpound of
formula I in which Ar is l-naphthyl, Rl and R2 each are hydrogen
or lower alkyl or Rl and R2 together with the nitrogen atom to
which they are joined form a heterocyclic amine as defined herein
and Z is NR3R4 wherein R3 and R4 each are hydrogen, or reacting said
~-chloropropylamine of formula IV with an appropriate amine of formula
NHR3R4 in which R3 is hydrogen or lower alkyl and R4 is lower alkyl, or
R3 and R4 together with the nitrogen atom to which they are joined form
a heterocyclic amine radical as defined herein, to give the
corresponding compound of formula V in which zl is NR3R4 in which R3
is hydrogen or lower alkyl and R is lower alkyl, or R3 and R to~ethe~
with the nitrogen atom to which they are joined form a heterocyclic amine
radical as defined herein, said last-named compound being identical to ~he
compound of formula I in which Ar is l-naphthylJ Rl and R2 each are hydrogen
or lower alkyl or Rl and R2 together with the nitrogen atom to which they
are joined form a heterocyclic amine as defined herein and Z is NR3R4 where~
in R3 is hydrogen or lower alkyl and R4 is lower alkyl, or R3 and R4 together
with the nitrogen atom to which they are joined form a heterocyclic amine
radical as defined herein.
More specifically, convenient conditions for converting the
starting material of formula II to the corresponding hydroxypropylamine of
formula III include reacting the starting material of formula II with
about one ~o two molar equivalents of the appropria$e amine of formula
NHRlR . An inert solvent, for example, diethyl ether, methanol or tetra-
hydrofuran, may be employed for the reaction. Usual reaction tempera-
tures and times are from 0 to 100C for ten minutes to 24 hours.
A1IP-6692/6693
~al135~
Subsequent transformation of the hydroxypropylamine of
formula III to the corresponding ~--chloropropylamine is conveniently
effected by reacting in an inert organic solvent the hydroxypropylamine
with about one molar equivalent of tosyl chloride or thionyl chloride,
tosyl chloride being preferred, at 10 to 80C for two to 24 hours.
The reaction is preferably carried out in the presence of an excess of
sn organic base, for example, triethylamine or pyridine. Suitable
inert organic solvents include benzene, diethyl ether or tetrahydrofuran.
In one aspect of the process of this invention, the ~-chloro~
propylamine of formula IV is converted to the compound of formula V
in which zl is the azido radical by treating a solution of the ~-chloro-
propylamine in a water-immiscible solvent with an aqueous solution of
1.0 to 1.2 molar equivalents of sodium or potassium azide. Convenient
conditions include the use of dimethylformamide~ acetone or methanol,
temperatures ranging from 20 to lOOGC or the boiling point of the
mixture and a reaction time ranging from one to six hours.
Thereafter, the compound of formula V in which zl is the
azido radical is reduced to yield the corresponding primary amine
of formula I in which Ar, Rl and R2 are as defined in the last
instance and Z is NR3R4 wherein R3 and R4 each is hydrogen. This
reduction is effected by reacting the latter compound of formula V
with gaseous hydrogen in the presence of a noble metal catalyst, for
example, platinum, platinum oxide, palladium or palladium oxide, in
a suitable inert organic solvent, for example, methanol, ethanol or
AIIP-6~92/6693
431
dioxane. Alternatively, the reduction is effected by reaction of said
latter compound of formula V with a sui~able complex metal hydride.
Examples of suitable complex metal hydrides are lithium aluminum
hydride, lithium aluminum hydride-aluminum chloride, aluminum hydride-
aluminum chloride, diborane and sodium borohydride-aluminum chloride.
Lithium aluminum hydride is preferred.
It should be noted that a second produc~ can be isolated from
the aforementioned reaction producing the compound of formula V in which
zl is the azido radical. The second product is the po~itional isomer of the
compound of formula V with respect ~0 zl and NRlR2. The positional isomer,
by catalytic reduction or by reduction with a complex metal hydride, as
described above, gives the corresponding compound of formula I in which
Rl and R2 each are hydrogen. The structures of the first and second
product are determined by nuclear magnetic resonance spectroscopy and
mass spectroscopy.
In another aspect of this process, the ~-chloropropylamine of
formula IV is con~erted to a compound of formula V in which Z is NR3R
wherein R3 is hydrogen or lower alkyl and R4 is lower alkyl, or R3 and R4
together with the nitrogen atom to which they are joined form a hetero-
cyclic amine radical as defined herein, by reacting the ~-chloro-
propylamine with a suitable amine of formula NHR3R4 in which R3 is
hydrogen or lower alkyl and R4 is lower alkyl, or R3 and R4 together
with the nitrogen atom to which they are joined form a heterocyclic
amine radical as defined herein. Examples of suitable amines are
~ 0 ~ A~IP--S692/6693
melhylalllinc> diisopropylaminc, butylaminc, pyrrolidine, piperidine and
the like. Convenient conditions for effecting this reaction include
treating a mixture of the ~-chloropropylamine with at least two molar
equivalents, usually two to ten molar equivalents of the amine, with or
without the use of an inert organic solvent, for example, tetrahydrofuran,
diethyl ether, or benzene as a reaction mediurn, at 20 to 100C or at the
boiling point of the reaction for a period of four to 24 hours. In this
manner the compounds of formula V in which Ar, Rl and R2 are as defined in
the last instance and zl is NR3R4 wherein R is hydrogen or lower slkyl and
R4 is lower alkyl, or R3 and R4 together with the nitrogen atom to which
they are joined form a heterocyclic amine radical as defined herein, are
obtained. The latter compounds are identical to corresponding compounds of
formula I in which R3 is hydrogen or lower alkyl and R4 is lower alkyl, or
R3 and R4 together with the nitrogen atom to which they are joined form a
heterocyclic amine r~dical as defined herein.
In addition, the positional isomer of the compound of formula V
with respect to Z and NR R (i.e. the positional isomer with respect to
Z and NRlR2 of the corresponding cornpounds of formula I) can be isolated
from the preceding reaction as a second product. The second product is
separated from the main product, the compound of formula V, by conventional
methods such as chromatography. The structures of the first and second
product are determined by nuclear magnetic spectroscopy and mass spectro-
s c opy .
-14-
AIIP-6692/66~3
` I ~01~,5t~
The compounds of formula I in which Z is ORS wherein
R5 is hydrogen and Ar is phenyl or l-naphthyl and Rl and R2
together with the nltrogen atom to which they are joined form a
heterocyclic amine radical as defined herein are prepared by a
process represented by the following second flow diagram.
CH2C~CH2 Ar-OCH2fHCH2NR R
OH
II III
Ar-OCH2fHCH2NR R_______________~ Ar-OCH2CHCH2BCR
Cl NRlR2
IV VI
I (Z = OR wherein R is hydrogen)
With reference to the preceding flow diagram, the
~-chloropropylamine of formula IV in which Ar is l-naphthyl is
prepared from 1,2-epoxy-3-(1-naphthoxy)propane of formula II,
via the corresponding hydroxypropylamine of formula III, as
described hereinabove. The ~-chloropropylamine of formula IV
in which Ar is phenyl is prepared by the same process for the
aforementioned ~-chloropropylamine in which Ar is l-naphthyl by
replacing the above noted 1,2-epoxy-3-(1-naphthoxy)propane of
formula II with 1,2-epoxy-3-phenoxy-propane, described by W.
Bradley, J. Forrest and O. Stephenson, J. Chem. Soc., 1589 (1959).
-15-
~5~ A~ 6692/66g3
With reference to the flow diagram, the compounds of
formula I in which Z is oR5 wherein R is hydrogen and Ar, R
and R2 are as defined in the last instance are prepared by a process
comprising:
reacting the starting material of formula II in which Ar is
phenyl or l-naphthyl with an amine of formula NHRlR2 in which Rl and
R together with the nitrogen atom to which they are joined form
a heterocyclic ring as defined herein to obtain the ~-hydroxy-
propylamine of formula III in which Ar, Rl and R2 are as defined
in the last instance; reacting the last-named compound with ~-
toluenesulfonic acid chloride or thionyl chloride to obtain the
corresponding ~-chloropropylamine of formula IV, in which Ar is
phenyl or l-naphthyl, and Rl and R2 together with the nitrogen
atom to which they are joined form a heterocyclic ring as defined
herein, reacting the latter compound with a lower alkanoic acid
of formula R6COOH in which R6 is hydrogen or lower alkyl in the
presence of an alkali salt of the lower alkanoic acid to obtain
the corresponding compound of formula VI in which Ar~ Rl, R2 and R6
are as defined in the last ins~ance, and hydrolyzing the latter
compound with an acid or a base to obtain the corresponding compound
of formula I in which Z is oR5 wherein R5 is hydrogen.
More specifically~ convenient conditions for converting
the starting material of formula II to the hydroxypropylamine of
formula III include reacting the starting material of formula II
with about one molar equivalent of the appropriate amine of formula
NHR R in an inert solvent, for example, diethyl ether, methanol or
~etrahydrofuran, at 0 to 40C for ten minutes ~o four hours.
-16-
51~ 'P-~692/6693
Subsequent trans~ormation of the hydroxypropylamine of
formula III to the corresponding ~-chloropropylamine is conveniently
effected by reacting in an inert organic solvent the hydroxypropylamine
with about one molar equivalent of tosyl chloride or thionyl chloride,
tosyl chloride being preferred, at 10 to 80C for two to 24 hours.
The reaction is preferably carried out in the presence of an excess of
an organic base, for example, triethylamine or pyridine. Suitable
inert organic solvents include benzene, diethyl ether or tetrahydrofuran.
Thereafter the ~-chloropropylamine of formula IV is converted
to the compound of formula VI under mildly acidic oonditions using an
excess of a lower alkanoic acid, preferably acetic acid, in the
presence of one to ten molar equivalents of an alkali salt of the
lower al]canoic acid, preferably sodium or potassium acetate. It has
been found convenient to use the lower alkanoic acid as a solvent for
this reaction, and temperatures and times ranging from 10 to 100C
and one to six hours, respectively; It should benoted that this
reaction involves a rearrangement of the amino radical (NR R ).
Subsequent hydrolysis of the compound of formula VI to the
corresponding compound of formula I in which Z is oR5 wherein R5 is
hydrogen is effected using an acid or a base as the hydrolysis agent.
Hydrolysis is preferably effected with a base. For the basic hydrolysis
a preferred embodiment involves subjecting the compound of formula VI to
the action of a strong base, for example, sodium or potassium hydroxide,
the presence of suficient water to effect hydrolysis. The hydrolysis
-17-
1 ~8~l~4~ AHP-6692/6693
is performed using a suitable solvent, for example, methanol or ethanol
and the reaction mixture is maintained at a temperature of from 25C
to the reflux temperature until hydrolysis occurs. Usually from ten
minutes to six hours is sufficient for this hydrolysis. The reaction
mixture is extracted with an organic solvent, for example diethyl ether,
and the extract worked up in the usual manner to afford the compound
of formula I in which Z is oR5 wherein R5 is hydrogen.
The compound of formula I in which Z is oR5 wherein R5 is
lower alkyl and Ar is phenyl or l-naphthyl, and Rl and R2 together
with the nitrogen atom to which they are attached form a heterocyclic
amine radical as defined herein are prepared by reacting the above-
mentioned P-chloropropylamine of formula IV in which Ar, Rl and R2
are as defined in the last instance with an alcohol of formula R70H
in which R7 is lower alkyl in the presence of sodium or potassium
alkoxide in which the alkyl portion thereof corresponds to the lower
alkyl or R7. Preferably one to ten molar equivalents of alkoxide
is employed. This reaction proceeds readily within about 15 minutes
to two hours at 20 to 80C using an excess of the alcohol as a
reaction medium. When benzyl alcohol is used as the alcohol together
with sodium or potassium phenylmethoxide in this reaction, the corres-
ponding benzyl ether is obtained.
The following examples illustrate further this invention.
-18-
AHP-6692/6693
5~
EXAMPLE 1
3-(1-Pyrrolidinyl~ l-naphthyloxy)-2-propanol
(III; Ar ~ l-naphthyl and NRlR2 - l-pyrrolidinyl)
A solution of 1,2-epoxy-3-(1-naphthyloxy)propane (62.0 g)
and the amine of formula NHRiR , pyrrolidine (23.5 g), in methanol
(250 ml) is heated at reflux for two hours. The reaction mixture
is concentrated to dryness. The oily residue is crystallized from
chloroform and diethyl ether by the addition of hexane to give the
title compound, mp 68-70C.
In the same manner but replacing pyrrolidine with an
equivalent amount of piperidine, morpholine or N-methylpiperazine,
3-piperidino~ 1-naphthyloxy)-2-propanol, ~ nujol 3250 and
2655 cm 1, (the corresponding hydrochloride of the latter
compound has mp 189-l90~C
3-morpholino-1-(1-naphthvloxy)-2-~ro~anol, mp 68-70C, and
3-(~-methyl-1-piperazinyl)-1-(1-naphthyloxy)-2-propanol,
mp 73-74C, are obtained, respectively.
In the same manner but replacing pyrrolidine with an equivalent
amount of ethylamine, butylamine or diisopropylamine,
3-(ethylamino)-1-(1-naphthyloxy)-2-propanol,
3-(butylamino)-1-(1-naphthyloxy)-2-propanol, and
3-(diisopropylamino)-1-(1-naphthyloxy)-2-propanol, mp 173-174~C,
after recrystallization from methanol-diethyl e~her, are obtained, respec-
tively.
In the same manner but replacing 1,2-epoxy-3-(1-naphthyloxy)-
propane with an equivalent amount o~ 1,2-epoxy-3-phenoxy-propane and
using pyrrolidine, piperidine, morpholine, or l-methylpiperazine as the
amine of formula NHR R ,
-19 -
3~L AHP-6692/6693
3-tl-pyrrolidinyl)-1-phenoxy-2-propanol,
3-piperidino-1-phenoxy-2-propanol, mp 52 - 54C,
3-morpholino-1-phenoxy-2-propanol, and
3-(4-methyl-1-piperazinyl)-1-phenoxy-2-propanol, are
obtained, respectively.
-20-
IP-6692/6693
EXAMPLE 2
.
1-{(2-Chloro-3-(1- a ~ opyl}pyrrolidine
(IVi _r = l-nap].thyl and NRlR2 = l-pyrrol dinyl~
A solution of 3-(1-pyrrolidinyl)-1-(1-naph~hyloxy)-2-
propanol (56 g), described in Example 1, and tosyl chloride ~43 g)
in benzene (500 ml) is heated at reflux for 18 hours. The mixture
is cooled, washed with dilute sodium bicarbonate ~nd extracted with
dilute hydrochloric acid. The dilute hydrochloric acid extract
is washed with ether, rendered neutral with dilute sodium hydroxide
and extracted with chloroform (CHC13). The CHC13 extract is dried and
concentrated. The residue is subjected to chromatography using silica
gel as the absorbent. Elution with die~hyl ether-methanol (9:1) yields
unchanged starting material. Subsequent elution with diethyl e~her-
methanol (7:3) yields the title compound.
In the same manner but replacing 3-~1-pyrrolidinyl)-1-(1-
naphthyloxy)-2-propanol with an equivalent amount of
3-piperidino-1-(1-naphthyloxy)-2-propanol,
3-morpholino-1-(1-naphthyloxy)-2-propanol,
3-(4-methyl-1-piperazinyl)-1-~1-naphthyloxy)-2-propanol,
3-(ethylamino)-1-(1-naphthyloxy)-2-propanol,
3-(butylamino)-1-(1-naph~hyloxy)-2-propanol, or
3-(diisopropylamino)-1-(1-naphthyloxy)-2-propanol,
3-(1-pyrrolidinyl)-1-phenoxy-2-propanol,
3-piperidino-1-phenoxy-2-propanol,
3-morpholino-1-phenoxy-2-propanol,
3-~4-methyl-1-piperazinyl)-1-phenoxy-2-propanol,
-21-
84 ~ A~IP-6692/6693
the following ~-chloropropylamines of formula IV,
1-{~2-chloro-3-(1-naphthyloxy))propyl}piperidine, mp 45-48C,
1-{(2-chloro-3-(1-naphthyloxy))propyl}morpholine, bp 158-
160C/0.02 mm/Hg,
1-{(2-chloro-3-(1-naphthyloxy))propyl}-4-methylpiperazine,
. 2-chloro-N-ethyl-3-(1-naphthyloxy)propylamine,
2-chloro-N-butyl-3-(1-naphthyloxy)propylamine~ and
2-chloro-N,N-diisopropyl-3-(1-naph~hyloxy)propylamine,
AmaOXll 319 nm (c ~ 1850), 305 nm (c ~ 3420), 288 nm (~ ~ 6380) and
. 229 nm (~ = 31,400), the hydrochloric acid addition salt of the latter
compound has mp 149 - 152C, after recrystallization from methanol-diethyl
ether.
~, 1-((2-chloro-3-phenoxy)propyl)pyrrolidine,
1-((2-chloro-3-phenoxy)propyl)piperidine (reported by Dauksas
and Pikunaite, cited above),
2-chloro-3-phenoxy)propyl)morpholine, and
1-((2-chloro-3-phenoxy)propyl)-4-me~hylpiperazine, are
obtained, respectively.
~ 5~ A~IP-6692/6693
EXAMPLE 3
Azidometh-yl)-2-(l-naphthyloxy)~ethylJpyrrolidine
~V; Ar ~ l-naphthyl, NRIR2 - l-pyrrolidinyl and zI - N3
A solution of sodium azide (3.3 g~ in water (15 ml) is
added ~o a solution of l-{~2--chloro-3-(1-naphthyloxy))propyl}pyrrolidine
(14 g), described in Example 2, in dimethylformamide (45 ml). The
mixture is heated on a steam bath for 2 hours. The mixture is extracted
with diethyl ether. The ex~ract is washed with water, dried and evaporated.
The residue is subjected to chromatography on silica gel. Elution with
hexane-diethyl ether (1:1) yields the title compound, nmr (CDC13) ~ 1.80
(m, 4H), 2.8 (mJ 4H), 3.1 (m, lH), 3.74 ~d, J ~ 5.5, 2H), 4.32 (d, J ~ 5.5,
2H), 6.8 - 8.4 (m, 7H~.
Gontinued elution with the same solvent gives the positional
isomer, l-{r2-azido-3-(1-naphthyloxy))propyl}pyrrolidine, nmr (CDCl)
1.50 (m, 6H), 2.54 (m, 6H), 4.20 (m, 3H) and 6.70-8.50 (m, 7H).
In the same manner but replacing 1-{~2-chloro-3-(1-
naphthyloxy))propyl}pyrrolidine with an equivalent amount of
1-{(2-chloro-3-(1-naphthyl~xy))propyl}piperidine,
1-{(2-chloro-3-(1-naphthyloxy~)propyl}morpholine, or
1-{(2-clIloro-3-(l-naphthyloxy))propyl}-4-methylpiperazine,
the following compounds of formula V in which zl is the azide radical,
l-{(l-(azidome~hyl)-2-(1-naphthyloxy))ethyl}piperidine,
nmr (CDC13) ~1.50 (m, 6H), 2.77 (m, 4H), 3.25 (m, lH), 3.55 (m, 2H),
4,23 (m, 2H), 6.70-8.50 (m, 7H).
AHP-6692/6693
EXAMPL~ 3 (Continued)
l-{(l-(azidomethyl)-2-(1-naphthyloxy))ethyl}morpholine, and
l-~(l-(azidomethyl)-2-(1-naphthyloxy))ethyl}-4-methylpiperazine,
are obtained, respectively.
Positional isomers of the latter four compounds also are
isolated; for example~ the positional isomer 1-{(2-azido-3-(1-naPhthyloxy))-
propyl~piperidine, nmr (CDC13) 6 1.50 (m, 6H), 2.54 tm, 6H), 4.20 (m, 3H)
and 6.70-8.50 (m, 7H).
In the same manner but replacing 1-{(2-chloro-3-(1-naphthyloxy))-
propyl}pyrrolidine with an equivalent amount of
2-chloro-N-ethyl-3-(l-napht}lyloxY)propylamine~
2-chloro-N-butyl-3-(1-naphthyloxy)propylamine, or
2-chloro-N,N-diisopropYl-3-(1-naphthyloxv)propYlamine,
the following compounds of formula V in which zl is the azide radical,
l-(azidomethyl)-N-ethyl-2-(1-nanhthyloxy)ethylamine,
l-(azidomethYl)-N-butyl-2-(1-naphthyloxv)ethylamine. and
l-(azidomethyl)-N,N-diisopropyl-2-(1-naphthyloxy)ethylamine,
are obtained, respectively.
;~ -24-
.,
Al~P-6692/66~3
EXAMPLE 4
Naphthyloxy~methyl-l-pyrrolidineethanamine
(I; Ar = l-naphthyl, NRlR2 - l-pyrrolidinyl and Z ~ NH2)
A solution of l-{~l-(azidomethyl)_2-(1-naphthyloxy))ethyl}-
pyrrolidine (9.4 g), described in Example 3, in methanol (150 ml) is
subjected to hydrogenation in the presence of platinum oxide (940 mg)
at about one atmosphere at 25~C (absorption of hydrogen is complete
after 4 hours). Thereafter, the catalyst is removed by filtration and
the filtrate concentrated. The residue is purified by chromatography
on silica gel. Elution with diethyl ether and methanol-diethyl ether
(3:17) ~ives the title compound, nmr (CDC13) 6 1.4 (2H), 1.75 (m, 4H),
2~75 and 3.05 (m, 7H), 4.3 (d, j = 5Hz, 2H) and 6.8-8.9 (n, 7H).
The hydrochloric acid addition salt (hydrochloride) of the
above compound has mp 183-184C, after recrystallization from methanol-
diethyl ether.
In the same manner but replacing l-{~l-(azidomethyl)-2-
(l-naphthyloxy))ethyl}pyrrolidine with an equivalent amount of
l-{(l-(azidomethyl)-2-(1-naphthyloxy))ethyl}piperidine, described
in Example 3, ~-((l-naphthyloxy)methyl)-l-piperidineethanamine
(I; Ar ~ l-naphthyl, NRlR2 ~ piperidino and Z - NH2), nmr (CDC13) 6
1.52 (m, 6H), 2.40-3.30 (m, 7H), 3.23 (2H), 4.22 (m, 2H) and 6.70-8.50
(m, 7H), is obtained. The hydrochloric acid addition salt (hydrochloride)
of the latter compound has mp 202-208C, after recrystallization from
methanol-diethyl ether.
-25
~ A~IP-6692/6693
~85i~
EXAMPLE 4 (Continued)
In the same manner but replacing l-{(l-aæidomethyl)-2-(1-
naphthyloxy~ethyl}pyrrolidine with an equivalent amount of the positional
isomer noted in Example 3, i.e., l ~t2-azido-3-(1-naphthyloxy))propyl}-
pyrrolidine, ~-((l-naph~hyloxy)methyl)-l-pyrrolidineethanamine (l; Ar =
l-naphthyl, NRlR2 = NH2 and Z a l-pyrrolidinyl), nmr (CDC13~ ~ 1.53
(m, 6H), 1.92 (2H), 2.47 (d, j - 6Hz ~ m, 6H), 3.54 ~m, lH), 4.13
(m, 2H) and 6.70-8.50 (m, 7H), is obtained.
In the same manner but replacing l-{(l-(azidomethyl)-2-(1-
naphthyloxy))ethyl}pyrrolidine with an equivalent amount of the
positional isomer noted in Example 3, i.e., 1-{(2-azido-3-(1-naphthyloxy))-
propyl}piperidine, ~-((l-naphthyloxy)methyl)-l-piperidineethanamine
(I; Ar = l-naphthyl, NRlR2 ~ NH2 and Z = piperidino), nmr (CDC13) ~ 1.53
(m, 6H), 1.92 (2H), 2.47 (ld, j = 6Hz and m, 6H), 3.54 (m, lH), 4.13
(m, 2H) and 6.70-8.50 (m, 7H) is obtained. The hydrochloric acid
addition salt (dihydrochloride) of the latter compound has mp 225-230C,
after recrystallization from methanol-diethyl ether.
In the same manner but replacin~ l-{(l-(aiidomethyl)-2-
(l-naphthyloxy))e~hyl}pyrrolidine with an equivalent amount of
l-{(l-(azidomethyl)-2-(1-naphthyloxy))ethyl}morpholine, or
l-{(l-(azidomethyl~-2-(1-naphthyloxy))ethyl}-4-methylpiperazine,
the following compounds of formula I
~ -((l-naphthyloxy)methyl)-4-morpholineethanamine, and
` ~-((l-naphthyloxy)methyl)-4-methyl-1-piperaæineethanamine,
are obtained respectively.
-26-
~ ~IP-6692/6693
~ S~
EXAMPLE 4 (Continued)
Similarly, replacement with
l-~azidomethyl~-N-ethyl-2-(1-naphthyloxy)ethylamine,
l-(azidomethyl)-N-butyl-2-(l naphthyloxy)ethylamine~ or
l-(azidomethyl)-N,N-diisopropyl-2-(1-naphthyloxy)ethylamine,
gives
~-(N-ethylamino)-~-((l-naphthyloxy)methyl)ethanamine,
~-(N-butylamino)-~-((l-naphthyloxy)methyl)ethanamine, and
~-(N,N-diisopropylamino)-~-((l-naphthyloxy)methyl)ethanamine,
respectively.
-27-
t ~8~ A~IP~669~/6693
EXAMPLE 5
-Ethyl- ~ ~l-naphthyloxy~methyl)-l-piperidineethanamine
(I; Ar = l-naphthyl J NRlR2 - piperidino and Z = NHCH2CH3)
A suspension of the compound of formula IV, 1-{(2-chloro-3-
(l-naphthyloxy))propyl3piperidine (15.0 g), described in Example 2,
in aqueous ethylamine (30%, 60 ml) is stirred for 18 hours.
Excess ethylamine is removed by evaporation. The mixture
is extracted with diethyl ether. The ether extract is washed, dried
and evaporated to dryness. The residue is subjected to chromatography
using silica gel. Elution with methanol-diethyl ether (3:17) gives
the ti~le compound, mp 134-136C, after recrystallization from ethyl
acetate-diethyl ether.
Continued elution with the same solvent gives the positional
isomer, N-ethyl-~-((l-naphthyloxy)methyl)-l-piperidineethanamine (I;
Ar = l-naphthyl, NR R = NHCH2CH3 and Z - piperidino), nmr CDC13) 6 .-;
1.15 (t, J = 7,3H), 1.5 (m, 6H), 2.18 (s, lH), 2.35-3.45 (m, 9H),
4.5 (m, 2H), 6.8-8.4 (m, 7H).
In the same manner but replacing the ethylamine with
isopropylamine, piperidine or morpholine,
~; N-isopropyl-~-((l-naphthyloxy)methyl~-l-piperidineethanamine
nmr (CDC13) ~1.12 (3, 9H), 1.5 (m, 6H), 2.08 (s, lH), 2.85 (m, 7H),
4.25 (m, 21~) and 6.8-8.4 (m, 7H), the corresponding hydrochloric acid
addition salt (hydrochloride) of the latter compound has mp 182-184C,
after recrystallization from ethyl acetate-methanol-diethyl ether,
1-(3-(1-naphthyloxy)-2-(1-piperidinyl)propyl)piperidine,
and
4-(3-(1-naphthyloxy~-2-(1-piperidinyl)propyl)morpholine,
are obtained, respectively.
-28-
A~IP-6692/6693
EXAMPLE 5 ~Continued)
By following the procedure of Example 5 and using an
appropriate ~-chloropropylamine of formula IV together with an
appropria~e amine of formula NHR3R4 in which R3 is hydrogen or
lower alkyl and R4 is lower alkyl, then corresponding compounds
of formula I are obtained.
For example, by using the ~-chloropropylamine, 2-chloro-N,N-
diisopropyl-3-(1-naphthyloxy)propylamine, described in Example 2, and
piperidine, N,N-diisopropyl-~-((l-naphthyloxy)methyl)-l-piperidine-
ethanamine, (I; Ar ~ l-naphthyl, NRlR2 = N(CH(CH3)2)2 and Z ~
piperidino), mp 48-50C, after recrystallization from isopropanol,
is obtained. The sulfuric acid addition salt (sulfate) Df the latter
compound has mp 134-13~ C, after recrystallization from methanol-diethyl
ether.
Examples of other compounds of formula I prepared by following
the pr~cedure of Example S are illustrated in the f~IIowing table.
., .
,~
. , .
-29-
:' .
AIIP-6~92/6~93
5~4~
_ ,
b ~
h O
h h ~ ~ X X --
h P~ O o
~ h , I ~ I h .C .~: h
~ 4
O ~ 4 0 0
~ ~ 'I ~ ~' h ~ , I ~ E E3
E~ o h
:~ ~ ~ o o
C7 ~ o t~
C~ O ,_~ I r I ~ 3 h
~ .C rl _ ~ E ~ ~
X~ X~ ~ .
~ ~ o ~a ~d O ~ ~ O ~ >~ a) o o
O ~ ~
R- td ~ I I ~
O S~ eD ~ .C
~) _ .C ~
I ~ I ~ 1 01 0 I ~rlI ~
- e ~ ~ ~ e ~ rl
,C ~: I hO ~: O ~ I h .C h`----.~ ~.C ~ I '' I O
cd ~ a> h ~dh c~ ~ .S ~ ~ t~ h
.s ~~ ~. P..-C ~..~: ~-- P, a~ ~. ~,c Q> ~' Q~ ~ --' h '--h
. Z C~ Z ~ Z ~ _ ~Z P~ z ~Z R ~ E3 --I ~ L
_ ____ ... ... .- _ . . ._.
U~ '~f ~ 'R .~ 13 e
cl O ~ tl~ d ~ R ~1 El
T' ~ '~ ~ ~ '~ ~ ~ ~ C~ O
~:: c~ z :,~ h ~ :~ h~1 o ~1 ~ ,C o
E~ ~: S ~ 0~ 0 P~ S h ~ ;~ ~ h
~ _ ~ -~ h h ~ ~ o ~.
~; ¢ P~ 4 0 ~ a~ ~ e
Z
~i 0 U
~; ~ h ~ O
0 ~ _~
~ ~ ~rD ,~
O 0 ~ O O ~ ~ ~ I ~ O O O O
h ~ ~ ~ ,~ S
0 3 ~~ ,1 O ~ ~ O O ~ N ~ N E R
h ~ $~ rl h h.C t~ C
O h S h h h h h ~ h ~ h ~ ~
p~ CR~ ~ E ~ S
1 4~ 1 ~ ~ Cl ,0 ,D
o _ ,~
_ - I
u~
~ ~ ~ O
__.- . _ , ...... _ _._._._. _ . ___ . . ... _._ _.. _
-30-
AHP-6692/5693
EXAMPLE 17
?-Piperidino-3~ naphthyloxy?-1-propanol
(I; Ar - l-naphthyl, NRlR2 ~ piperidino and Z ~ OHl
A mixture of the compound of formula IY, 1-{(2-chloro-3-
(l-naphthyloxy)~propyl}piperidine (10.0 g), described in Example 2,
and sodium acetate (5.4 g) in acetic acid (50 g) is heated at reflux
for two hoursO The mixture is cooled and ether added to the mixture.
The resulting solid is collected on a filter. The filtrate is con-
centrated to dryness. The residue is dissolved in diethyl ether. The
solution is washed with dilute NaHC03, dried and poured onto a col D
of silica gel. Elution with ethyl acetate-benzene (1:4) gives 2-piperidino-
3-(1-naphthyloxy)-1-propanol acetate (Vl; Ar = l-naphthyl, NRlR2 -
piperidino and R ~ CH3~, ~ max 318 nm (c ~ l640), 304 nm (c = 3130),
287 nm (e- 6360), 229 nm (c = 29,700), 2l3 nm (c = 42,900).
(Continued elution with ethyl acetate-benzene (1:4) gives the positional
isomer, l-piperidino-3-(1-naphthyloxy)-2-propanol acetate). The hydro-
chloric acid addition salt of 2-piperidino-3-(1-naphthyloxy)-1-propanol
acetate has mp 151-15~ C.
The 2-piperidino-3-(l-naphthyloxy)-1-propanol acetate so
obtained is hydrolyzed in the following manner:
`
. .
AHP-6692/66g2
~0~
EXAMPLe 17 (Continued)
A suspension of 2-piperidino-3-(1-naphthyloxy)-1-propanol
acetate ~6 4 g), 15% KOII in methanol (10 ml), methanol (10 ml) and
water (20 ml) is heated at reflux for one hour. The reaction
mix~ure is concentrated dryness. The residue is taken up in
diethyl ether. The ether extract is washed with water and concentrated
to give the title compound as an oil, ~ ma~l 319 nm (~ = 1780),
305 nm (~ : 3330), 2~8 nm (~ = 6~40), 230 nm (~ - 30,600), 212
nm (~ a 44~18~).
The hydrochloric acid addition salt (hydrochloride) of the
~i~le compound has mp 165-170C, after recrystallization from methanol-
diethyl ether.
In the same manner but replacing 1-{(2-chloro-3-(1-naphthyloxy))-
propyl}piperidine with another compound of formula IV described in
Example 2, other corresponding compounds of formula I in which Z is OR
wherein R5 is hydrogen is obtained. For instance, replacement with
1-{(2-chloro-3 (l-naphthyloxy))propyl}pyrrolidine,
1-{(2-chloro-3-(1-naphthyloxy))propyl~morpholine,
1-~(2-chloro~3-(1-naphthyloxy))propyl}-4-methylpiperazine,
1-((2-chloro-3-phenoxy)propyl)pyrrolidine,
1-((2-chloro-3-phenoxy)propyl)piperidine,
1-((2-chloro-3-phenoxy)propyl)morpholine, or
1-((2-chloro-3-phenoxy)propyl)-4-methylpiperazine,
-32-
5~ IP-6692/6693
EXAMPLB 17 (Continued)
lves
2-(1 pyrrolidinyl)-3~ naphthyloxy)-1-propanol,
2-morpholino-3-(1-naphthyloxy)-1-propanol,
2-(4-methyl-1-pipera~inyl)-3-(1-naphthyloxy)-1-propanol,
2-(1-pyrrolidinyl)-3-phenoxy-1-propanol,
2-piperazino-3-phenoxy-1-propanol,
2-morpholino-3-phenoxy-1-propanol, and
2-~4-methyl-1-piperazinyl)-3-phenoxy-1-propanol, respectively.
-33-
~ 1 A~IP-6692/6693
S~
EXAMPLE 18
l-L(l-~_t oxymethyl)-2-~1-na~hthyloxy)~et~Lpiperid;ne
(I; Ar = l-naphthyl, NRlR ~ piperidino and Z = OC2~15)
The compound of formula IV, l-f(2-chloro-3-(1-naphthyloxy)~-
propyl}piperidine ~7.0 g), is added to a solution of sodium ~0.54 g)
in ethanol ~70 ml), i.e. the alcohol of formula R70H in which R7
is ethyl. The mixture is heated at reflux for one hour and cooled.
Precipitated sodium chloride is collected on a filter and the
filtrate is evaporated to yield an oil. The oil is subjected to
chromatography on silica gel. Elution with diethyl ether-hexane
1) gives the title compound, ~ max 319 nm (c ~ 1710), 304 nm
(~ = 3290), 289 nm ~c - 6400), 223 nm ~c = 31,100), 212 nm (c = 44,300).
The corresponding hydrochloric acid addition sal~ of the
title compound has mp 151-156~C, after recrystallization from
methanol-diethyl ether.
In the same manner but replacing 1-{(2-chloro-3-(1-naphthyloxy))-
propyl~piperidine with another compound of formula IY, described in
Example 2 and using the appropriate alcohol of formula R70~1, other
corresponding compounds of formula I in which Z is oR5 wherein R5 is lower
alkyl is obtained. For instance, replacement with
1-{~2-chloro-3-(1-naphthyloxy))propyl}pyrrolidine,
1-{(2-chloro-3-(1-naphthyloxy))propyl}morpholine,
1-{~2-chloro-3-(1-naphthyloxy))propyl}-4-methylpiperazine,
-34-
IP-6692/6693
EXAMPLE 18 (Continued)
1-~(2-chloro-3-phenoxy)propyl)pyrroli~ine,
; 1-((2-chloro-3-phenoxy)propyl)piperidine,
1-((2~chloro-3-phenoxy)propyl)morpholine, or
1-((2-chloro-3-phenoxy)propyl)-4-methylpiperazine, and
using ethanol as the alcohol of formula R 011, gives
l-{(l-(eth~xymethyl)-2-(1-naphthyloxy))ethyl}pyrrolidine,
~ m~aIcxl3 1595, 1580, 1460, 1245 and 1270 cm 1, ~he corresponding hydro-
chloric acid addition salt of the latter compound has mp 168-170C,
l-{(l-~ethoxymethyl) 2-(1-naphthyloxy))ethyl~morpholine,
l-{(l-(ethoxymethyl)-2-(1-naphthyloxy))e~hyl~-4-methylpiperazine,
~ m~aC13 1595, 1580, 1460, 1238 and 1270 cm 1, the corresponding hydro-
chloric acid addition sal~ (dihydrochloride) of the latter compound has
mp 160-165~.
~ l-(ethoxymethyl)-2-phenoxy)ethyl}pyrrolidine,
l-{(l-(ethoxymethyl)-2-phenoxy)ethyl~piperidine,
3 1595, 1577, 1450 and 1220 cm 1, the corresponding hydrochloric
aicd addition salt of the latter compound has mp 85-90C,
l-{~l-(ethoxymethyl)-2-phenoxy)ethyl}morpholine, or
l-{(l-~ethoxymethyl)-2-phenoxy)ethyl}-4-methylpiperazine,
respectively.
A~P-6692/6693
EXAMPLF 18 (Continued
Furthermore, in the same manner and using the appropriate
compound of formula IV and benzyl alcohol as the alcohol, corres-
ponding benzyl ethers are obtained. For example, 1-{~2-chloro-3-
(l-naphthyloxy))propyl}piperidine and benzyl alcohol gives 1-{(2-(1-
naphthyloxy)-l-(phenylmethoxymethyl~)e~hyl3piperidine, the hydrochloric
acid addition salt of the latter compound has mp 145-148C, after
recrystallization from methanol and ether.
1-{(2-chloro-3-(1-naphthyloxy))propyl}r,lorpholine and
benzyl alcohol give 1-{(2-(1-naphthoxy)-1-(phenylmethoxymethyl))ethyl}-
- morpholine, the hydrochloric acid addition salt of the latter compound
has mp 130-145C, after recrystallization from methanol and ether.
~ (2-chloro-3-phenoxy)propyl)piperidine and benzyl alcohol
! give l-f(2-phenoxy-l-(phenylmethoxymethyl))ethyl}piperidine, the
~ hydrochloric acid addition salt of the latter compound has mp 86-9~ C,
I after recrystallization from isopropanol and diethyl ether.
-36-
