Note: Descriptions are shown in the official language in which they were submitted.
1~51~
The present invention relates to novel, pharmaceuti-
cally active l-substituted-4-(1,2-diphenylethyl)piperazine
derivatives and their pharmaceutically acceptable salts and
the preparation thereof. More particularly, it relates to
l-substituted-4-(1,2-diphenylethyl)piperazine derivatives
of the following formula:
X ~ C~2 ~ -~ ~ N-R [I]
wherein X is hydroxy, methoxy, methyl or trifluoromethyl; and
R is an unsubstituted monocycloalkyl group having 6 to 8 carbon
atoms or 2-methoxyphenyl; provided that when X is hydroxy, R
is cyclohexyl, and when X is trifluoromethyl, R is 2-methoxy-
phenyl,
and their pharmaceutically acceptable salts, and further the
preparation thereof.
Some compounds having an analogous structure to that
of the present compounds have been already described in Japanese
Patent Publication Nos. 6304/1972 and 188/1974 and The Japanese
J~urnal of Pharmacology, Vol. 22, page 88 (April-27, 1972), etc.
These known compounds have been prepared by some of the present
inventors and some compounds have a comparatively excellent
analgesic activity. However, such compounds have a morphine-
like drug dependence liability or too strong toxicity, and
therefore, they can hardly be used as a medicine excepting
the use for a specific purpose.
The present inventors have extensively studied to
find a novel compound having excellent analgesic activity with-
out such undesirable side effect, and then found that the novel
piperazine derivatives of the formula ~I] and their pharmaceuti-
cally acceptable salts exhibit superior pharmacological ac-
- 2 - ~
lVSi433
tivities, such as analgesic, anti-tussive and anti-inflam-
matory activities and are less toxicity and free from narco-
tic ac~tivity, and therefore, they are useful as a medicine.
An object of the present invention is to provide
novel piperazine derivatives and their pharmaceutically ac-
ceptable salts having excellent pharmacological activities
without undesirable side effects.
Another object of the invention is to provide a
process for the preparation ofthe piperazine derivatives
and their pharmaceutically acceptable salts.
A further object of the invention is to provide a
pharmaceutical composition containing the compound as set
forth above as the active ingredient.
Still further object of the invention is to provide
the use of the compound as set forth above as an analgesic.
These and other objects will be apparent from the
description hereinafter.
The compounds of the present invention include
those represented by the formula [IJ as shown hereinbefore
and their pharmaceutically acceptable salts. Suitable com-
pounds of the present invention are as follows:
l-Cyclohexyl-4-~2-(4-methoxyphenyl)-1-phenylethyl]-
piperazine and its pharmaceutically acceptable acid addition
salt
l-Cycloheptyl-4-[2-(4-methoxyphenyl)-1-phenylethyl]-
piperazine and its pharmaceutically acceptable acid addition
~alt
1-(2-Methoxyphenyl)-4-[1-phenyl-2-(4-tolyl)ethyl]-
piperazine and its pharmaceutically acceptable acid addition
salt
-- 3 --
. . .
~: -
lOSi433 :``
The present compounds have an asymmetric carbonin the molecule, and therefore, optical isomers exist. The
present invention includes all these racemic or optically resolved
products. Preferred one is the racemic product.
The compounds of the present invention have the
advantages as summarized as follows:
1. They show superior analgesic activity.
2. They are non-narcotic, i.e. they do not show
any morphine-like drug dependence liability.
3. They show low toxicity.
4. They show superior activities by oral administ-
ration.
5. Some compounds show also excellent anti-tussive
and anti-inflammatory activities.
6. They are u~eful in a racemic form, and there-
fore, no resolution is required for obtaining active substance,
which is economical.
The excellent activities of the present compounds
are demonstrated by the following experimental tests.
(1) Drug dependence liability:
i) Mouse jumping test (Cf. J.K. Saelens, F.R. Granat
and W.K. Sawyer, Arch. int. Pharmacodyn., Vol. 190, page 213,
1971; and H. Nakamura, Y. Yokoyama, S. Motoyoshi and M. Shimizu,
Folia Pharmacologica Japonica, Vol. 69, ~age ~26p, 1973)
Male mice of ddN strain, weighing 19 to 2~ g, were
used. The test compounds were subcutaneously and/or orally
given in increasing increments of 8, 16, 25, 50 and 100 mg/kg
or until a maximally tolerated dose was reached within that
range. Two hours after the last injection, the animals received
lntraperitoneal injections of 50 mg/kg of nalorphine hydrochloride.
-- 4
i~)S1433
The number of jumps and the height of jumps made by each mouse
during the 30 minutes period after the injection of the morphine
antagonist were recorded.
ii) Straub tail index (Cf. Irving Shemano and
Herbert Wendel, Toxicology and Applied Pharmacology, Vol.6,
page 334, 1964)
Graded doses of compounds were rapidly injected
intravenously through the tail vein of male mice of ddN strain,
weighing 18 to 22 g, in a volume of 0.1 ml per 10 g body weight.
The criterion for Straub tail was erection of the tail to 90
degrees or greater within 20 minutes after the injection of
the test compounds. The Straub tail ED50-value!and intravenous
~D50-value for each compound were determined, and the Straub
index, the ratio of ~D50 to Straub tail ED50, was calculated.
iii) Substitution test in morphine-dependent rats
(Cf. O.J. ~orenzetti and ~.F. Sancilio, Arch. int. Pharmacodyn.,
Vol. 183, page 391, 1970; and S. Nurimoto, Japan. J. Pharmacol.,
Vol. 23, page 401, 1973)
Male rats of Wistar strain, weighing 200 to 250 g,
received morphine hydrochloride subcutaneously twice daily.
The initial dose of 20 mg/kg was increased weekly by 20 mg/kg
until a maintenance of 100 mg/kg X 2/day was attained. The
animals received two subcutaneous or oral administrations of
a test compound instead of morphine hydrochloride. The with-
drawal symptoms were determined and the percent reduction of
each withdrawal symptom was calculated from the scores of test
compound and vehicle control groups.
These test results are shown in the following Table 1.
-- 5 --
.. . .. . . . .. .
lOSi4;~3
Table 1
Test * Straub tail Substitution
compound ) Jumping test index test
A (-) (-) (-)
(-) I (-) (-)
C (-) (-) (-)
D (-) ¦ (-) (-)
E (-) (-)
F ~ (-)
G (-) (-) (-)
H (-) ¦ (-) (-)
I
I (-) (-)
- - J _ (-) (-)
Reference
comp~und
1 (+) (+) 7.34 (+)
2 (+) (+) 30 (+)
3 _ (+) (+) ca.44 (+)
4 (+) (+) 3~.1 (+)
(-) (-) (-)
[Note]: *) The test` compounds are as follows:
~ : dl-l-Cyclohexyl-4-[2-(4-methoxyphenyl)-1-
phenylethyl]piperazine 2HCl
B: dl-1-Cyclohexyl-4-[2-(4-hydroxyphenyl)-1-
phenylethyl]piperazine-2H~r
C: dl-l-Cyclohexyl-4-[1-phenyl-2-(4-tolyl)-
-- 6 --
l()Si433
ethyl]piperazine 2HCl
D: dl-l-Cycloheptyl-4-[2-(4-methoxyphenyl)-1-
phenylethyl]piperazine-2HCl
-- E: dl-1-(2-Methoxyphenyl)-4-[2-(4-methoxyphenyl)-
l-phenylethyl]piperazine 2HCl
F: dl-l-Cyclooctyl-4-[2-(4-methoxyphenyl)-1-
phenylethyl]piperazine 2HCl
G: dl-l-Cycloheptyl-4-[1-phenyl-2-(4-tolyl)ethyl]-
piperazine-2HCl
H: dl-1-(2-Methoxyphenyl)-4-[1-phenyl-2-(4-tolyl)-
ethyl]piperazine 2HCl
I: dl-1-(2-Methoxyphenyl)-4-[1-phenyl-2-(4-trifluoro-
methylphenyl)ethyl]piperazine 2HCl
J: dl-l-Cyclooctyl-4-[1-phenyl-2-(4-tolyl)ethyl]-
piperazine 2HCl
1: dl-l-cyclohexyl-4-(l~2-diphenylethyl)pipera-
zine 2HCl (disclosed in Japanese Patent Publication No. 6~04/1972)
2: d-1-Cyclohexyl-4-(1,2-diphenylethyl)pipera-
zine~2HCl (disclosed in Japanese Patent Publication ~o. 188/1974)
3: dl-4-(1,2-Diphenylethyl)-1-(2-methoxyphenyl)pipera-
zine 2HCl (disclosed in Japanese Patent Publication No. 6304/1972)
4: Morphine hydrochloride
5: Aminopyrine (commercially available analgesic)
- (2) Analgesic activity:
i) D'Amour-Smith method (Cf. F.E. D'Amour and D.~.
Smith, J. Pharmacol., Vol. 72, page 74, 1941)
Thermal pain was induced by radiating heat light on
the tail blacked with a black ink of male mice of ddN strain,
weighing 9 to 12 g, using the modified apparatus of D'Amour-
Smith. The analgesic ED50-value ~as calculated from the number
- 7 -
iO51433
of positive animals showing the response time prolonged more
than 100 % compared with each before value.
ii) Haffner method (Cf. E. Haffner, Deut. Med.
Wochschr., Vol. 55, page 731, 1929)
Mechanical pain was induced by pressing the tail of
male rats of Wistar strain9 weighing 90 to 110 g, using the
modified apparatus of Haffner. The analgesic ED50-value was
calculated from the number of positive animals showing pain
threshold of 40 mm or more (normal value is about 20 mm).
iii) Phenylquinone method (Cf. E. Siegmund, R. Cadmus
and G. ~u, Proc. Soc. Exptl. ~iol. Med., Vol. 95, page 792,
1957 ?
Chemical pain was induced by an intraperitoneal
injection of 0.1 ml/10 g body weight of 0.03 ~ phenylquinone
in 5 % aqueous ethanol in female mice, weighing 18 to 22 g of
ddN ~train. Drugs were given 30 minutes before challenge of
phenylquinone.
The test results are shown in the following Table 2.
, . . . . . . . .
lOS1433
~able 2
Phenylquinone Haffner
Test *) D'Amour-~mith method method method
compound _
. p. o. s. c. p. o. p. o.
A 164 74.2 39.0 180
B 84 13.1 58.3 96.3 `
D 137.9 _ 25.8 94.5
. . I .
E 256 _ 1 38.5 29.3
F 48.1 _ 27 _
H 283 ¦ _ 49.4 _
I ca. ~ - _
J 177 ~ _ 48 _
Reference
compound
6 116 50.7 73.3 118.0
> 128G _ 83
8 > 160 46.6 52.3 > 240
.
~ 640 _ 233 53.3 > 2560
[Note]: *) The test compounds A, B, D, E, F, H, I and
J and the Reference compound 5 are as defined in Table 1, and
other Reference compounds are as follows:
` 6: ~-1-Cyclohexyl-4-(1,2-diphenylethyl)piperazine
2HCl (disclosed in Japanese Patent Publication No. 188/1974)
7: dl-4-[2-(4-Chlorophenyl)-l-phenylethyl]-l-
(2-methoxyphenyl)piperazine 2HCl
8: ~-1,2-Diphenyl-l-dimethylaminoethane HCl
(disclosed in German Patent No. 19159,958)
_ g _
.~
lQ5i433 `
(3) Toxicity:
i) Acute lethal toxicity
Male mice of ddN strain, weighing 18 to 26 g, and
male rats of Wistar strain, weighing 200 to 300 g, were used.
The test compounds were dissolved in saline or suspended in
- 0.5 % gum tragacanth aqueous solution, and administered sub-
cutaneously, intraveneously or orally. The value of ~D50
was calculated according to ~itchfield-Wilcoxon method. The
results are shown in the following Table 3.
Table 3
Test *) Mio ~e Rats
compound p.o. i.v. p.o. s.c.
_
A 440 37.0 953 363
477 _ ¦ ca.1000
Cca. 1200 _ ca.1200
D 464 26.0 ! 727 697
~ 3200 _ ¦ ca. 900
i
F 538 _ ¦ ca. 800
i
2987 _ ¦ ca. 1000
H ~ 3200 - ¦ ca.2100
I
Ica. 1600 _ ¦ _
J ~ 3200 _ _
Reference j
compound
6 250 17.9 288 97.7
_.
8 176 _ ca. 300
, . . _
9 246 _ _ 160 1 -
_ _ _ .
-- 10 --
. . .
lOSi433 ;
[Note~: *) The test compounds A to J and the Reference
compounds 6 and 8 are as defined in Table 1 and Table 2, and
other Reference compound 9 is as follows:
9: dl-4-[2-(4-Chlorophenyl)-l-phenylethyl]-l-
cyclohexylpiperazine 2HCl
ii) Subacute toxicity
Male rats of Wistar strain, weighing 140 to 160 g,
were used. The test compound A was orally administered once a
day for 4 weeks in a dose of 100 mg/kg/day. No abnormal symptom
was observed in the test animals.
(4) Anti-tussive activity (Cf. K. Takagi, H. Fukuda
and K. Yano, Yakugakuzasshi, Vol. 80, page 1497, 1960)
Male guinea-pigs, weighing 500 to 600 g, were used.
Coughs were caused by successive mechanical stimulations with
whiskers, and anti-tussive effects were evaluated by all or
none of the cough. The test compounds A and G were intra-
peritoneally injected. As the results, the test compounds
showed excellent anti-tussive activity in a dose of 160 mg/kg
(about 1/4 of codeine phosphate).
(5) Anti-inflammatory activity:
The activity was determined by carrageenin-induced
hind paw oedema (Cf. C.A. Winter, E.A. Risley and G.G. Nuss,
Proc. Soc. Exp. Biol, Med., Vol. 111, page 544, 1962).
Male rats~ of Wistar strain, weighing 100 to 120 g,
were used. `Hind paw oedema was induced by subcutaneous injec-
tion of 0.1 ml of 1 % carrageenin into the right foot pad of
each rat. The value of ED50 was calculated according to
~itchfield-Wilcoxon method using the number of positive rats,
which showed the inhibitory effect of 25 % or more than the
corresponding vehicle control group at ~ hours after the
-- 11 --
1C~5143~
challenge of carrageenin. The test compounds A and B were orally
administered one hour before challenge of carrageenin. As the
results, the test compounds showed excellent anti-inflammatory
activity similar to that of aminopyrine.
The compounds [I] and their pharmaceutically acceptable
salts of the present invention may be used as medicines, for
example, in the form of pharmaceutical preparations containing
the compound in admixture with an organic or inor~anic, solid or
liquid pharmaceutical adjuvants suitable for oral or parenteral
administration. Pharmaceutically acceptable adjuvants are
substances that do not react with the compounds, for example,
water, gelatin, lactose, starch, cellulose, preferably micro-
crystalline cellulose, sodium carboxymethyl cellulose, calcium
carboxymethyl cellulose, methyl cellulose, sorbitol, magnesium
stearate, talc, vegetable oils, benzyl alcohol, gums, propylene
glycol, polyalkylene glycols, methylparaben and other known
medicinal adjuvants. The pharmaceutical preparations may be,
for example, powder, tablets, suppositories, or capsules, or
in liquid form as solutions, suspensions, or emulsions. They
may further contain other therapeutically valuable substances.
The preparations are prepared by conventional methods.
A clinical dosage of the compound [I] or its pharma-
ceutically acceptable salt depends on body weight, age and ad-
ministration routes, but it is generally in the range of 10 to
500 mg/day, preferably of 50 to 200 mg/day.
According to the invention there is provided a process
for preparing a compound of the formula:
1~1
~ ~ [I]
X~CH -CH-~-R
- 12 -
wherein X is hydroxy, methoxy, methyl or trifluoromethyl; and
R is an unsubstituted monocycloalkyl group having 6 to 8 carbon
atoms or 2-methoxyphenyl; provided that when X is hydroxy, R is
cyclohexyl, and when X is trifluoromethyl, R is 2-methoxyphenyl,
or a pharmaceutically acceptable salt thereof, which comprises
(a) reacting a compound of the formula:
X e~.CH2--CH-N ~
S H2C 2
wherein Z is a residue of a reactive ester of alcohol, and X
is as defined above, or a salt thereof, with a compound of the
formula:
. H2N-R
wherein R is as defined above,
(b) reacting a compound of the formula:
X~H2 CH NH2
wherein X is as defined above, with a compound of the formula:
ZCH2CH2~
~ ~N-R
ZCH2CH2
wherein R and Z are as defined above, or a salt thereof,
(c) reacting a compound of the formula:
-CH(C6H5)-N ~ -R
OH
wherein R and X are as defined above, or a salt thereof, with
a halogenating agent to give a compound o. the formula:
33
CH-CH(C6H5)-N N-R
halogen
wherein R and X are as defined above, or a salt thereof, and then
subjecting the resulting compound, or a salt thereof, to a
reductive dehalogenation,
(d) when X is methoxy, methyl or trifluoromethyl,
reacting a compound of the formula:
~ A
NC- H-N N-R
wherein R is as defined above, with a compound of the formula:
X '_~--CH2MgZ
wherein Z' is a halogen atom and X' is methoxy, methyl or
trifluoromethyl, or
(e) when X is hydroxy, subjecting a compound of the
formula:
YO ~ CH~-CH-N N ~
wherein Y is an alkyl group having 1 to 7 carbon atoms or benzyl,
or a salt thereof, to cleavage of the ether linkage, and
(f) if desired, when the compound so obtained is
: in the form of a free base, reacting it with an appropriate acid
to provide a salt thereof, or when the compound so obtained is
in the form of a salt, converting it by known means to provide
the corresponding free base.
33
As will be understood, the compoun~smay be prepared,
according to process (a), by reacting a compound of the following
formula:
~ / 2 2 [II]
X ~ CH2- H-N
CH2CH2Z
wherein Z is a residue of reactive ester of alcohol, such as
halogen (e.g. chlorine or bromine), arylsulfonyloxy (e.g. p-
toluenesulfonyloxy or benzenesulfonyloxy) or alkanesulfonyloxy
(e.g. methanesulfonyloxy), X is as defined above, or a salt
thereof, with a compound of the formula: H2N-R [III]
wherein R is as defined above.
The reaction of process (a) may be carried out by
heating a mixture of the compound [II] with an equimolar or
excess amount of the compound [III] in the presence or absence
of a solvent, such as an aliphatic alcohol (e.g. aqueous or
anhydrous ethanol or isopropanol), an aromatic hydrocarbon (e.g.
toluene or xylene), a ketone (e.g. methyl ethyl ketone), an ether
! ` (e.g. dioxane), a halogenated hydrocarbon (e.g. ethylene dichlo-
ride), dimethylformamide, or dimethyl sulfoxide. Suitable
i reaction temperature may be 60 to 170C, and the reaction may
~ 20 usually be carried out at a reflux temperature.
7 The reaction may be also carried out in the presence
of a basic material, such as an alkali metal hydrogen carbonate
(e.g. sodium hydrogen carbonate or potassium hydrogen carbonate),
an alkali metal carbonate (e.g. sodium carbonate or potassium
carbonate~, or an organic base (e.g. triethylamine). The
reactant of the formula [III] may also be utilized as the basic
material by using in an excess amount.
The starting material [II] in the above process (a)
may be prepared, for example, by the following process,
l(~S1~3;~
3-t2-Hydroxyethyl)-2-phenyloxazolidine is reacted with
a compound of the formula:
X' ~ H2MgCl [IV]
wherein X' is methoxy, methyl or trifluoromethyl, in an inert
solvent to give a compound of the formula:
~ CH2CH20H
X' ~ 2 CH ~ ~ CH2CH2OH [V]
wherein X' is as defined above, or its salt. Subsequently, the
compound [V] or its salt thus obtained is reacted with a con-
ventional halogenating agent, such as thionyl chloride, or with
a conventional sulfonating agent, such as p-toluenesulfonyl
chloride, benzenesulfonyl chloride or methanesulfonyl chloride,
to give the desired compound ~II] wherein X is X', i.e. methoxy,
methyl or trifluoromethyl. When the compound [II] thus obtained
(X is methoxy) is subjected to cleavage of the ether linkage by
treating it with a cleavage agent for splitting ether, the
desired compound [II] wherein X is hydroxy can be obtained.
Examples of the cleavage agents for splitting ethers include
Lewis acids (e.g. aluminum chloride, aluminum bromide or boron
tribromide) and hydrohalogenic acid (e.g. hydrobromic acid,
hydroiodic acid or hydrochloric acid).
The compounds [I] and their pharmaceutically acceptable
salts may be prepared according to process (b) by reacting a
compound of the following formula:
~3
X ~ CH2 H-NH2 [VI]
- 16 -
wherein X is as defined above, with a compound of the following
formula:
ZCH2CH2
N-R [VII ]
ZCH2CH2/
wherein R and Z are as defined above, or a salt thereof.
The reaction of process (b) may be carried out by
heating a mixture of the compound [VII] with an equimolar or
excess amount of the compound [VI] in the presence or absence
of a solvent in the similar manner as described in process (a).
The starting material [VI] in the above process (b)
can be prepared in the similar manner as described in Archiv
der Pharmazie, Vol. 274, page 153, 1936. Besides, the other
starting material [VII] can be prepared in the similar manner
as described in Journal of American Chemical Society, Vol. 73,
page 3635, 1951, for instance, by reacting N-cyclohexyldiethano-
lamine with a halogenating or sulfonating agent as described in
the process (a).
The compounds [I] and their pharmaceutically acceptable
salts may be prepared, according to process (c), by reacting a
compound of the following formula~
X ~ C~H CH(C6 5) \___/ [VIII]
whexein R and X are as defined above, or a salt thereof, with a
halogenating agent to give a compound of the following formula:
X ~ CH-CH(C6H5)-N N-R [IX]
halogen
wherein R and X are as defined above, or a salt thereof, and then
subjecting the resulting compound [IX], or a salt thereof, to
a reductive dehalogenation.
The reaction of the above process (c) may be carried
out by heating a mixture of the compound [VIII] and an equimolar
- 17 -
.105~
or excess amount of the halogenating agent, such as thionyl
chloride, thionyl bromide, phosphorus pentachloride or phosphorus
pentabromide, in the presence or absence of an inert solvent,
such as a halogenated hydrocarbon (e.g. chloroform or ethylene
dichloride), an aromatic hydrocarbon (e.g. benzene or toluene),
methyl ethyl ketone, dioxane or dimethylformamide. Suitable
reaction temperature may be 30 to 150C, and the reaction may
usually be carried out at a reflux temperature.
The reductive dehalogenation of the compound [IX] may
be carried out by catalytically reducing the compound [IX], i.e.
by contacting the compound [IX] with an equimolar or slightly
excess amount of hydrogen in an inert solvent, such as aqueous
or anhydrous methanol, ethanol, water or dioxane, in the presence
of a catalyst, such as platinum oxide, platinum black, palladium-
carbon or Raney nickel, at room temperature or an elevated temp-
erature. The reductive dehalogenation may be also carried out
by other reduction methods, for instance, it may be reduced by
using a metal and an acid or an alkali, e.g. a combination of
a metal such as iron, tin or zinc and an acid such as hydro-
chloric acid or sulfuric acid, in a solvent such as water,dilute alcohol or acetic acid, or by using a metal sodium in an
alcohol.
The starting material [VIII] in the above process (c)
may be prepared as follows:
A compound of the following formula:
X ~ CO-CH-halogen ~X]
~051~3~
wherein X is as defined above, is reacted under heating with a
compound of the following formula:
HN N-R [XI ]
wherein R is as defined above, or its salt, in an inert solvent,
such as ethanol or xylene, in the presence of a basic condensing
agent, such as triethylamine or potassium carbonate, to give a
compound of the following formula:
X~CO H--N N--R [XII ]
wherein R and X are as defined above, or its salt, and subse-
quently, the resulting compound [XII] or its salt is reacted
with a complex metal hydride, such as sodium borohydride or
lithium aluminum hydride, at room temperature or an elevated
temperature in a solvent, such as an alcohol (e.g. methanol or
ethanol) or an ether (e.g. tetrahydrofuran or dioxane), to give
the desired compound [VIII].
The compounds [I] wherein X is methoxy, methyl or
trifluoromethyl and their pharmaceutically acceptable salts
may be prepared according to process (d), by reacting a com-
pound of the following formula:
2 0 NC -CH -N N - R [ XI I I ]
wherein R is as defined above, with a compound of the following
formula:
X' ~ CH2MgZ' [XIV]
-- 19 --
~05i9L33
wherein Z' is a halogen atom and X' is as defined above.
The reaction of the above process (d) may be carried
out by heating a mixture of the compound [XIII] and an excess
amo~mt of the compound [XIV] in an inert solvent, such as ether,
tetrahydrofuran, n-butyl ether, benzene, or a mixture thereof.
Suitable reaction temperature may be from room temperature to
130C, and the reaction may usually be carried out at a reflux
temperature~
The starting material [XIII] in the above process (d)
may be prepared, for example, by reacting under heating a salt
of the compound of the formula [XI] as mentioned hereinbefore
with benzaldehyde and sodium cyanide or potassium cyanide in
water or an aqueous solvent.
The compound [I] wherein X is hydroxy, i.e. the com-
pound of the following formula:
HO ~ ~2~C~- ~ ~ [I']
and its pharmaceutically acceptable salt may be prepared, according
to process (e), by subjecting a compound of the following formula:
~S~
YO ~ C ~ N N ~ ~XV]
wherein Y is an alkyl group having 1 to 7 carbon atoms or benzyl,
or a salt thereof, to cleavage of the ether linkage by treating
it with a cleavage agent for splitting ethers at an elevated
temperature in the presence or absence of a solvent, such as
water, acetic acid, toluene, xylene, nitrobenzene or chlorobenzene.
The reaction may usually be carried out at a reflux temperature.
~$
- 20 -
~V~ 3~3
The cleavage agents for splitting ethers include Iewis
acids (e.g. aluminium chloride, aluminium bramide or boron tri-
bra~ide) and hydrohalogenic acid (e.g. hydrobromic acid, hydro-
iodic acid or hydrochloric acid).
Besides, when Y in the compound [XV] is benzyl, the
cleavage of the ether linkage may be carried out by catalytically
reducing it, i.e. by contacting it with an equimolar or slightly
excess amount of hydrogen in an inert solvent, such as aqueous
or anhydrous methanol, ethanol, water, acetic acid or dioxane,
in the presence of a catalyst such as palladiumc æ bon, platinum
black or Raney nickel, at room temperature or an elevated temperature.
The starting material [XV] in the above process (e) may
be prep æed in the simil æ manner as described in the above
process (b).
In the above processes of the preparation of the present
invention, the starting materials and the intermediates may be
either in the racemic form or in the optically resolved form when
they have an asymmetric c æbon in the molecule.
According to the above processes, the desired compounds
[I] may be obtained in a form of free base or salt ~r hydrate
depending on the kinds of the starting materials and the reaction
conditions. When they æ e obtained in a form of free base, they
may be converted into their ph æmaceutically acceptable salts of
various inorganic or organic acid. Suitable acids include in-
organic acids (e.g. hydrochloric acid, hydrobromic acid, hydro-
iodic acid, sulfuric acid or phosphoric acid) and organic acids
(e.g. citric acid, maleic acid, fumaric acid, tart æic acid, acetic
acid, benzoic acid, lactic acid, methanesulfonic acid, 2-naphthalene-
sulfonic acid, salicylic acid or acetylsalicylic acid).
The preparation of the present compounds [I] and their
ph æmaceutically acceptable salts and further the ccmpositions
thereof æ e illustrated by the following Examples but not limited
thereto. In the Examples, percentages are by weight unless
otherwise specified.
-2n~-
1051433
Exam~le 1
Preparation of dl-l-cyclohexyl-4-[2-(4-methoxyphenyl)-
l-phenylethyl]piperazine
(1) In dimethylformamide (50 ml) is dissolved N,N-
bis(2-chloroethyl)-2-(4-methoxyphenyl)-1-phenylethylamine hydro-
chloride (18.5 g) and thereto is added cyclohexylamine (19.5 g).
The mixture is heated under reflux for 6 hours under stirring.
After distilling off the solvent and the excess cyclohexylamine,
the residue is dissolved in 10 % hydrochloric acid and the
mixture is allowed to cool~ The precipitated crystals are
collected by filtration and washed with a small amount of cooled
water and then with acetone and dried. The product is recrystal- `
lized from methanol to give the desired compound as dihydro-
chloride (16 g), colorless needles, m.p. 243 - 245C (decomp).
AnalysiB for C25H34N2 2
Calcd (~0): C,66.51; H,8.04; N,6.21; Cl,15.71
Found (%): C,66.28; H,8.30; N,6.14; Cl,15.98
The free base of the compound is prepared by treating
the dihydrochloride obtained above with diluted aqueous potassium
carbonate solution by a conventional method, m.p. 96 - 97C (re-
crystallized from n-hexane).
Analysis for C25H34N20:
Calcd (%): C,79.32; H,9.05; N,7.40
Found (%): C,79.45; H,8.95; N,7.38
The maleate o~ the compound is prepared by treating the
compound obtained above with equimolar maleic acid in ethanol by
conventional method, m.p. 172 - 175C (recrystallized from
ethanol).
Analysis for C25H34N2 C4H404 3/2H2
Calcd (%): C,66.78; H,7.92; N,5.37
- 21 -
- .
''' '` - . '' '` " ' ' '
~051433
Found (%): C,66.52; H,7.69; N,5.02
The salicylate of the compound has a melting point of
124 - 126C (recrystallized from ethanol-n-hexane).
Y 25 34 2 7 6 3
~Calcd (%): C,71.54; H,7.08; N,4.28
Found (%): C,71.74; H,7.06; N,4.58
(2) In dimethylformamide (50 ml) are dissolved N,N-
bis(2-chloroethyl)-2-(4-methoxyphenyl)-1-phenylethylamine hydro-
chloride (17.7 g) and cyclohexylamine (7.9 g) and thereto is added
1~ sodium hydrogen carbonate (15 g). The mixture is heated under
reflux for 6 hours under stirring. After cooling, the inorganic
materials are filtered off and the filtrate is distilled to
remove the solvent. The resulting residue is treated in the
similar manner as described in (1) to give the desired compound
as dih~drochloride (11.4 g), m.p. 243 - 245C (decomp).
~xample 2
Preparation of dl-l-cycloheptyl-4-[2-(4-methoxyphe~yl)-
l-phenylethyl]piperazine
To a solution of N,N-bis(2-chloroethyl)-2-(4-methoxy-
phenyl)-l-phenylethylamine hydrochloride (19.3 g) in chloroform
is added cycloheptylamine (21 g). After chloroform is distilled
off, the resulting mixture is heated at 135 - 140C for 4 hours.
The excess cycloheptylamine is distilled off under a reduced
pressure, and the residue is dissolved in 10 % hydrochloric acid
and the mixture is allowed to cool. The precipitated crystals
are collected by filtration and washed with acetone and then
recrystallized from methanol to give the desired compound as
dihydrochloride (15.5 g), m.p 241 - 244C.
~nalysis for C26H36 2 2 Cl
Calcd (%): C,67.09; H,8.23; N,6.02; Cl,15.23
- 22 -
. .,
1051433
~ound (~0): C,66.95; H,8.33; N,6.20; Cl,15.30
The free base of the compound has a ~elting point of
82 - 83C (recrystallized from n-hexane).
Analysis for C26H36N20:
Calcd (~0): C,79.55; H,9.24; N,7.14
Found (%): C,79.52; H,9.20; N,7.01
Example ~
Preparation of dl-l-cyclohexyl-4-[2-(4-hydroxyphenyl)-
l-phenylethyl]piperazine
In ethanol (30 ml) are dissolved N,N-bis(2-chloroethyl)-
2-(4-hydroxyphenyl)-1-phenylethylamine hydrochloride (1.9 g)
and cyclohexylamine (0.7 g), and thereto is added sodium hydro-
gen carbonate (1.4 g). The mixture is heated under reflux for
-- , .
30 hours under stirring. After the reaction, the solvent is
distilled off and to the residue is added diluted aqueous potas-
sium carbonate. Illhe mixture is extracted with chloroform, and
the chloroform layer is washed with water, dried over anhydrous
sodium sulfate and then distilled to remove the solvent. The
crystalline residue is recrystallized from benzen2-n-hexane to
20 give the desired compound (1.0 g), m.p. 197 - 199C.
Analysis for C24H32N20:
Calcd (%): C,79.08; H,8.85; N,7.68
~ound (%): C,79.40; H,9.02; N,7.71
The above free base is dissolved in a small amount of
methanol and the mixture is acidified with 25 % hydrobromic acid-
acetic acid. The precipitated crystals are recrystallized from
methanol to give dihydrobromide of the compound, colorless needles,
m.p. 267 - 268.5~C.
~nalysis for C24 ~2 2 .2HBr
Calcd (%): C,54.76; H,6.51; N,5.32; ~r,30.37
- 23 -
1051433 : `
~ound (%): C,54.66; H,6.66; N,5.25; Br,30.35
The monohydrobromide of the compound (colorless prisms)has a melting point of 272 - 274C (recrystallized from methanol).
nalysiS for C24 32 2 r
Calcd (%): C,64.71; H,7.47; N,6.29; ~r,17.94
Found (%): C,64.72; H,7.68; N,6.27; ~r,17.75
Example 4
Preparation of dl-1-(2-methoxyphenyl)-4-[2-(4-methoxy-
phenyl)-l-phenylethyl]piperazine
In dimethylformamide (50 ml) is dissolved N,N-bis-
(2-chloroethyl)-2-(4-methoxyphenyl)-1-phenylethylamine hydro-
chloride (9.0 g) and thereto is added o-anisidine (11.7 g).
The mixture is heated under reflux for 5 hours under stirring.
,_ ,
After the reaction, the solvent is distilled off under a reduced
; pressure, and to the residue is added concentrated aqueous
ammonia. The mixture is extracted with ether, and the ether
; layer is dried over anhydrous potassium carbonate and distilled
to remove the solvent. The residual oil is distilled under a
reduced pressure to remove the excess o-anisidine. The resulting
residue is dissolved in methanol and thereto is added methanolic
hydrochloric acid. The crystals thus obtained are recrystallized
from methanol to give the desired compound as dihydrochloride
monohydrate (6.8 g), m.p. 233 - 236C.
Analysis for 26 30 2 2 2
Calcd (%): C,63.28; H,6.94; N,5.68; Cl,14.37
~ound (%): C,63.31; H,6.77; N,5.78; Cl,14.36
i Mass spectrum: m/e 402 (M+)
The free base of the compound has a melting point of
109 - 110C (recrystallized from ethanol).
` 30 Analysis for C26H30N202:
,
- 24
.
~(~5i433 ; `
Calcd (%): C,77.58; H,7.51; N,6.96
Found (%): C,77.74; H,7.81; N,6.88
~xamPle 5
Preparation of dl-1-(2-methoxyphenyl)-4-[1-phenyl-
2-(4-tolyl)ethyl]piperazine
In dimethylformamide (100 ml) is dissolved N,N-bis-
(2-chloroethyl)-1-phenyl-2-(4-tolyl~ethylamine hydrochloride
(29 g) and thereto is added o-anisidine (38 g). The mixture
is heated under reflux for 5 hours under stirring. The reaction
mixture is treated in the similar manner as described in Example
4 and resulting crystals are recrystallized from methanol to
give the-desired compound as dihydrochloride hemihydrate (22.6
g), m,p 2~4 - 238C,
Analysis for C26H30N20 2HCl l/2H20:
Calcd (%): C,66.66; H,7.10; N,5.98; Cl,15.14
Found (~): C,66.33; H,7.23; N,5.97; Cl,14.85
Mass spectrum: m/e 386 (M+)
The free base of the compound has a melting point of
129 - 130C (recrystallized from ethanol).
Analysis for C26~ oN20
Calcd (~): C,80.79; H,7.82; N,7.25
Found (~): C,81.04; H,8.00; N,7.00
Example 6
Preparation of dl-1-(2-methoxyphenyl)-4-[1-phenyl-
2-(4-trifluoromethylphenyl)ethyl]piperazine
In dimethylformamide (5 ml) is dissolved N,N-bis(2-
chloroethyl)-l-phenyl-2-(4-trifluoromethylphenyl)ethylamine
hydrochloride (0.8 g) and thereto is added o-anisidine (1.0 g).
The mixture is heated under reflux for 5 hours under stirring.
~he reacticn mixture is treated in the similar manner as described
- 25 -
1~)51433
in Example 4 and the resulting crystals are recrystallized from
methanol to give the desired compound as dihydrochloride (0.5 g),
m.p. 222 - 225C.
nalysis for 26 27 2 3
Calcd (%): C,60.82; H,5.69; N,5.46; Cl,13.81
Found (~): C,60.75; H,5.98; N,5.75; Cl,13.62
Example 7
~ he following compounds are prepared in the similar
manner as described in Example 1.
dl-1-Cyclohexyl-4-[1-phenyl-2-(4-tolyl)ethyl]pipera-
zine dihydrochloride, m.p. 252 - 256C
nalysis for C25H34N2-2HCl
Calcd (%): C,68.96; H,8.33; N,6.43; Cl,16.28
Found (%): C,68.85; H,8.43; N,6.46; Cl,16.41
dl-l-Cyclooctyl-4-[2-(4-metho~yphenyl)-1-phenylethyl]-
piperazine dihydrochloride, m.p. 241 - 245C
nalysis for 27 38 2
Calcd (%): C,67.63; H,8.41; N,5.84; Cl,14.79
~ound (%): C,67.45; H,8.36; N,6.09; Cl,15.00
dl-1-Cycloheptyl-4-[1-phenyl-2-(4-tolyl)ethyl]pipera-
zine dihydrochloride, m.p. 253 - 256C
AnalySis for C26H36N2-2HCl
Calcd (%): C,69.47; H,8.52; N,6.23; C1,15.77
. . .
Found (%): C,69.37; H,8.63; N,6.28; Cl,15.96
dl-l-Cyclooctyl-4-[1-phenyl-2-(4-tolyl)ethyl]pipera-
zine dihydrochloride, m.p. 249 - 253C
nalysis o 27 38 2
Calcd (%): C,69.96; H,8.70; N,6.04; Cl,15.30
~ound (%): C,69.90; H,8.92; N,5.97; Cl,15.53
Example 8
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~OSi~33 .
Preparation of dl-l-cyclohexyl-4-[2-(4-methoxyphenyl)-
l-phenylethyl]piperazine
(1) In dimethylformamide (30 ml) are dissolved 2-(4-
methoxyphenyl)-l-phenylethylamine (6.8 g) and N-cyclohexyl-2,2'-
dichlorodiethylamine hydrochloride (2.6 g), and the mixture is
heated under reflux for 6 hours under stirring. The solvent is
distilled off under a reduced pressure, and the residue is dis-
solved in 10 % hydrochloric acid and the mixture is allowed to
cool, The precipitated crystals are collected by filtration,
washed with a small amount of cooled water and then with acetone
and dried. The crystals are recrystallized from methanol to
give the desired compound as dihydrochloride (2.6 g), colorless
needles 9 m.p. 243 - 245C (decomp).
(2) In dimethylformamide (30 ml) are dissolved 2-(4-
methoxyphenyl)-l-phenylethylamine (4.5 g) and N-cyclohexyl-di-
ethanolamine di-p-toluenesulfonate hydrochloride (2.7 g), and
thè mixture is heated under reflux for 5 hours under stirring.
The æolvent is distilled off under a reduced pressure, and to
the residue is added diluted aqueous sodium carbonate solution
to make it alkaline. The mixture is extracted with ether, and
the ether layer is washed with water, dried over anhydrous
sodium sulfate and then distilled to remove the solvent. The
i resulting residue is treated with ethanolic hydrochloric acid.
. ..
The resulting crystals are recrystallized from methanol to give
the desired compound as dihydrochloride (0.4 g), m.p. 243 -
245C (decomp).
~xample 9
Preparation of dl-l-cycloheptyl-4-[2-(4-methoxyphenyl)-
l-phenylethyl]piperaæine
To 2-(4-methoxyphenyl)-1-phenylethylamine (6.8 g) is
':
- 27 -
~05~433
added a solution of N-cycloheptyl-2,2'-dichlorodiethylamine
hydrochloride (2.7 g) in chloroform, and then the chloroform is
distilled off. The resulting mixture is heated at 135 - 140C ~-
for 4 hours. The reaction mixture is treated in the similar
manner~as described in Example 8, (1), and the resulting crystals
are recrystallized from methanol to give the desired compound as
dihydrochloride (2.3 g), m.p. 241 - 244C.
Example 10
Preparation of dl-l-cyclohexyl-4-[2-(4-hydroxyphenyl)-
10 l-phenylethyl]piperazine
In ethanol (60 ml) are dissolved 2-(4-hydroxyphenyl)-
l-phenylethylamine (3.0 g) and N-cyclohexyl-2,2'-dichlorodiethyl-
amine hydrochloride (2.6 g), and thereto is added sodium hydro-
gen carbonate (2.8 g). The mixture is heated under reflux for
20 hours under stirring. The solvent is distilled off under a
reduced pre~sure, and to the residue is added 10 % hydrochloric
acid (20 ml) and the mixture is allowed to cool. The resulting
crystals are recrystallized from methanol to give the desired
compound as dihydrochloride (2.5 g), m.p. 263 - 265C.
Analysis for C24H32 2 2HCl
Calcd (%): C,65.90; H,7.83; N,6.40; Cl,16.21
Found (%): C,65.86; ~,7.63; N,6.28; Cl,15.99
Example 11
Preparation of dl-1-(2-methoxyphenyl)-4-[2-(4-methoxy-
phenyl)-l-phenylethyl]piperazine
In dimethylformamide (40 ml) are dissolved 2-(4-methoxy-
phenyl)-l-phenylethylamine (2.3 g) and N,N-bis(2-bromoethyl)-
o-anisidine hydrobromide (4.2 g), and thereto :is added sodium
hydrogen carbonate (2.7 g). The mixture is heated under reflux
~or 10 hours under stirring. After cooling, the inorganic materi-
.. , . . . : ... .
iO51433
als are filtered off and the filtrate is distilled to remove the
solvent. To the residue is added concentrated aqueous ammonia
and the mixture is extracted with ether. The ether layer is
dried over anhydrous sodium sulfate and then the solvent is
distilled off. The resulting residue is treated with methanolic
hydrochloric acid, and the resulting crystals are recrystallized
from methanol to give the desired compound as dihydrochloride
monohydrate (2.7 g), m.p. 233 - 236~C.
Example 12
Preparation of dl-1-(2-methoxyphenyl)-4-[1-phenyl-2-
(4-tolyl)ethyl]piperazine
In dimethylformamide (40 ml) are dissolved l-phenyl-
2-(4-tolyl)ethylamine (2.1 g) and N,~-bis(2-chloroethyl)-o-
anisidine hydrochloride (2.8 g), and thereto is added sodium
hydrogen carbonate (2.7 g). The mixture is heated under reflux
for 10 hours under stirring. The reaction mixture is treated
in the similar manner as described in Example 11 to give the
desired compound as dihydrochloride hemihydrate (2.6 g), m.p.
234 - 238C.
Example 13
Preparation of dl-l-cyclohexyl-4-[2-(4-methoxyphenyl)-
l-phenylethyl]piperazine
In chloroform (30 ml) is dissolved 1-cyclohexyl-4-
[2-hydroxy-2-(4-methoxyphenyl)-1-phenylethyl]piperazine (1.5 g),
and th~r~to is added dropwise thionyl chloride (15 ml) under
cooling and stirring. ~he mixture is heated under reflux for
1,~ hours After cooling, the solvent is distilled off under
a reduced pressure. The residue is dissolved in lN hydrochloric
acid, and the mixture is made alkaline with sodium carbonate and
extracted with chloroform. The chloroform layer is dried over
- 29 -
... . . . . .. .... .. . . . . . . . . ...
lOSi433 `
anhydrous sodium sulfate and then the solvent is distilled off
to give a crude 2-chloro derivative (0.8 g). The 2-chloro deri-
vative is dissolved in ethanol (40 ml) and thereto is added
platinum oxide (0.3 g), and the mixture is subjected to catalytic
reduction at room temperature and under atmospheric pressure.
When a calculated amount of hydrogen is absorbed, the reaction
i~ stopped and the catalyst is filtered offO The filtrate is
distilled to remove the solvent, and the resulting residue is
treated with methanolic hydrochloric acid. The resulting crystals
are recrystallized from methanol to give the desired compound as
dihydrochloride (0.4 g), m.p. 243 - 245C (decomp).
~xample 14
Preparation of dl-1-(2-methoxyphenyl)-4-[2-(4-methoxy-
phenyl)-l-phenylethyl~piperazine
In chloroform (30 ml) is dissolved 1-(2-methoxyphenyl)-
4-~2-hydroxy-2-(4-methoxyphenyl)-1-phenylethyl]piperazine (1.0 g),
and thereto is added dropwise thionyl chloride (15 ml) under
cooling and stirring. The mixture is heated under reflux for
2 hours. After cooling, the solvent is distilled off under a
reduced pressure. To the residue is added aqueous sodium carbon-
ate solution, and the mixture is extracted with chloroform. The
chloroform layer is dried over anhydrous sodium sulfate and then
the solvent is distilled off to give a crude 2-chloro derivative.
~he 2-chloro derivative thus obtained is dissolved in ethanol
(40 ml) and thereto is added platinum oxide (0.2 g), and the
mixture is subjected to catalytic reduction. When a calculated
~mount of hydrogen is absorbed, the reaction is stopped and the
catalyst is filtered off. The filtrate is distilled to remove
the solvent, and the resulting residue is treated with methanolic
hydrochloric acid. The resulting crystals are recrystallized
.
-- 30 --
.
.. . .. ... . .. . .. .. .... . . . . .
, . ... . .. . . . .
. .
1051433
from methanol to give the desired compound as dihydrochloride
monohydrate (0.2 g), m.p. 233 - 236C.
Example 15
Preparation of dl-l-cyclohexyl-4-[2-(4-methoxyphenyl)-
l-phenylethyl]piperazine
To a Grignard reagent prepared from magnesium turnings
(2.3 g), magnesium powder (2.3 g) and p-methoxybenzyl chloride
(6.3 g) in absolute ether (83 ml) is added dropwise a solution
of -(4-cyclohexylpiperazin-1-yl)phenylacetonitrile (2.8 g) in
absolute ether (10 ml) under stirring. The mixture is heated
under reflux for 1.5 hours. The reaction mlxture is poured onto
ice water by decantation and then acidified with hydrochloric
acid. The aqueous layer is separated and made alkaline with
aqueous ammonia. The mixture is extracted with ether, and the
ether layer is washed with water, dried over anhydrous sodium
sulfate and then distilled to remove the solvent. The residue
is treated with ethanolic hydrochloric acid, and the resulting
crystals are recrystallized from methanol to give the desired
compound as dihydrochloride (3.0 g), colorless needles, m.p.
243 - 245C (decomp).
~xample 16
Preparation of dl-l-cyclohexyl-4-[2-(4-hydroxyphenyl)-
l-phenylethyl]piperazine
(1) A mixture of dl-l-cyclohexyl-4-[2-(4-methoxy-
phenyl)-l-phenylethyl]piperazine dihydrochloride (50 g), 48 %
hydrobromic acid (500 ml) and glacial acetic acid (250 ml) is
heated under reflux for 4 hours and then allowed to cool. The
precipitated crystals are collected by filtration, washed with
a small amount of ethanol and then recrystallized from methanol
to give the desired compound as dihydrobromide (52 g), colorless
- 31 -
1051433
needles, m.p. 267 - 268.5~C.
(2) A mixture of dl-l-cyclohexyl-4-[2-(4~ethoxyphenyl)-
l-phenylethyl}piperazine dihydrochloride (1.5 g) and anhydrous
aluminum chloride (4.0 g) is mashed well with dehumidification.
The mixture is heated at 110 - 125C for about 15 minutes under
stirring under nitrogen gas. After cooling, to the reaction
mixture is added ice, and the hardly soluble materials are
collected by filtration and washed with a small amount of cooled
diluted hydrochloric acid and further washed with acetone and
ether. ~he materials are dissolved in water, and the mixture
is made alkaline with potassium carbonate and extracted with
chloroform. ~he chloroform layer is washed with water, dried
over anhydrous sodium sulfate and then distilled to remove the
solvent. The residue is treated with ethanolic hydrochloric
acid and the resulting crystals are recrystallized from methanol
to give the desired compound as dihydrochloride (0.8 g), m.p.
263 - 265C.
(3) In ethanol-acetic acid (1 : 1, 50 ml) is dissolved
dl-l-cyclohexyl-4-[2-(4-benzyloxyphenyl)-1-phenylethyl]pipera-
zine dihydrochloride monohydrate (0.55 g), and thereto is added10 % palladium-charcoal (0.5 g). The mixture is subjected to
catalytic reduction. When about one molar equivalent of hydrogen
is absorbed, the reaction is stopped, and the catalyst is fil-
tered off. The filtrate is distillted under a reduced pressure
to remove the solvent. The resulting crystals are recrystallized
from methanol to give the desired compound as dihydrochloride
(0,35 g), m.p. 263 - 265C.
~ he starting materials used in the above Examples are
prepared as follows:
3~ (A) Preparation of N,N-bis(2-chloroethyl)-2-(4-
.
1051433
methoxyphenyl)-l-phenylethylamine
tl) To a Grignard reagent prepared from magnesium
turnings (6 7 g), magnesium powder (6.7 g) and p-methoxybenzyl
chloride (18.1 g) in absolute ether (240 ml) is added dropwise
a solution of 3-(2-hydroxyethyl)-2-phenyloxazolidine (9.6 g) in
absolute ether (24 ml) under stirring, and the mixture is heated
under reflux for 3 hours. The reaction mixture is poured onto
ice water (100 ml) containing ammonium chloride under vigorously
stirring by decantation, and the mixture is made alkaline with
ammonia. The ether layer is separated and extracted with an
excess amount of 10 % hydrochloric acid. The hydrochloric acid
layer is made alkaline with sodium hydroxide and extracted with
chloroform. The chloroform layer is dried over anhydrous sodium
~ulfate and then the solvent is distilled off to give an oily
substance of crude N,N-bis(2-hydroxyethyl)-2-(4-methoxyphenyl)_
l-phenylethylamine (10.2 g).
(2) In chloroform (16 ml) is dissolved N,N-bis(2-
hydroxyethyl)-2-(4-methoxyphenyl)-1-phenylethylamine (12.6 g),
and thereto is added one or two drops of dimethylformamide and
further added dropwise a solution (18 ml) of thionyl chloride
(12 ml) in chloroform. The mixture is heated under reflux for
hours and then distilled under reduced pressure to remove the
solvent and the excess thionyl chloride. The resulting residue
is recrystallized from acetone to give the desired compound as
hydrochloride (1~.4 g), m.p. 121 - 124C.
(B) Preparation of l-cyclohexyl-4-[2-hydroxy-2-(4-
metho~yphenyl)-l-phenylethyl]piperazine
(1) In ethanol (30 ml) are dissolved 2-bromo-2-phenyl-
4'-methoxyacetophenone (~.0 g) and N-cyclohexylpiperazine (1.7
g), and thereto is added triethylamine (1.0 g), and the mixture
1~5i433
is heated under reflux for 6 hours under stirring. After cooling,
the precipitated triethylamine hydrobromide is filtered off and
the filtrate is distilled to remove the solvent. To the residue
are added water and ethyl acetate, and the mixture is shaken
and the precipitated crystals are filtered off. The ethyl acetate
layer is washed with water, dried over anhydrous sodium sulfate
and distilled to remove the solvent. The resulting residue is
dissolved in acetone and thereto is added ether-hydrochloric acid.
The precipitated crystals are collected by filtration and re-
crystallized from ethanol-ether to give 2-(4-cyclohexylpiperazin-
l-yl)-2-phenyl-4'-methoxyacetophenone dihydrochloride sesquihyd
rate (2.0 g), m.p. 210 - 218C.
The free base of the above compound has a melting
point of 135 - 136C (recrystallized from aqueous ethanol).
(2) In ethanol (20 ml) is dissolved 2-(4-cyclohexyl-
piperazin-l-yl)-2-phenyl-4'-methoxyacetophenone (1.4 g), and there-
to is added one or two drops of 5 ~ aqueous sodium hydroxide solu-
tion to make it alkaline and further is added sodium borohydride
(0.5 g). The mixture is heated under reflux for 5 hours. After
the reaction, the solvent is distilled off under a reduced pres-
sure and the residue is extracted with chloroform. The chloro-
form layer is dried over anhydrous potassium carbonate and the
chloroform is distilled off. lhe oily residue is chromatographed
on silica-gel. The crystals obtained from the eluate by 2 %
methanol-chloroform are recrystallized from aqueous ethanol to
give threo-l-cyclohexyl-4-r2-hydroxy-2-(4-methoxyphenyl)-1-
phenylethyl]piperazine hemihydrate (0.20 g), m p. 140 - 142C.
Separately~ the crystals obtained from the eluate by 4 ~ metha-
nol-chloroform are recrystallized from ethanol to give erythro
isomer (0.53 g), m.p. 165 - 166C.
- 34 -
1~)51433
In the same manner as described above, 2-bromo-2-
phenyl-4'-methoxyacetophenone (12 g) is reacted with N-(2-methoxy-
phenyl)piperazine (8.7 g) to give 2-[4-(2-methoxyphenyl)piperazin-
l-yl]-2-phenyl-4'-methoxyacetophenone (12.5 g), m.p. 153 - 155C,
and subsequently, the compound thus obtained is reduced by sodium
borohydride to give a crude free base of 1-(2-methoxyphenyl)-4-
[2-hydroxy-2-(4-methoxyphenyl)-1-phenylethyl]piperazine (11.5 g),
m.p. 183 - 185C (threo isomer hemihydrate), m.p. 178 - 180C
(erythro isomer).
(C) Preparation of -(4-cyclohexylpiperazin-1-yl)-
phenylacetonitrile
. To concentrated hydrochloric acid (5.9 g) are added
N-cyclohexylpiperazine (5.1 g) and then benzaldehyde (3.2 g)
under cooling, and to the mixture is added dropwise a solution
of potas~ium cyanide (2.2 g) in water (4 ml) under stirring,
The mixture is heated at 90C for one hour under stirring, by
which the mixture is solidified. The reaction mixture is dissolved
in ethyl acetate and thereto is added aqueous sodium hydroxide
solution to make it alkaline. After the mixture is shaken, the
organic layer is separated, washed with water, dried over an-
hydrous sodium sulfate and then distilled under a reduced pres-
sure to remove the solvent. The residual crystals are washed
with petroleum ether, dried and recr~stallized from n-hexane to
give the desired compound (7.5 g), colorless needles, m.p. 79 -
81C.
` (D) Preparation of dl-l-cyclohexyl-4-[2-(4-benzyloxy-
phenyl)-l-phenylethyl]piperazine
In dimethylformamide (30 ml) are dissolved 2-(4-
benzyloxyphenyl)-l-phenylethylamine (9.1 g) and N-cyclohexyl-
2,2'-dichlorodiethylamine hydrochloride (2.6 g), and the mixture
- ~5 -
.., , . . - - - ~- . ,. - .
'
iO514~
is heated under reflux for 6 hours under stirring. The solvent
is distilled of~ under a reduced pressure. ~o the residue is
added 10 % hydrochloric acid and the resulting solution is allowed
to cool. The resulting crystals are collected by filtration,
washe~l with a small amount of cooled water and then acetone, dried
and recrystallized from ethanol-ether to give the desired com-
pound as dihydrochloride monohydrate (3.1 g), m.p. 236 - 243C
(decomp).
In the same manner as described above, the following
0 compound is prepared.
dl-l-Cyclohexyl-4-[2-(4-ethoxyphenyl)-1-phenylethyl]-
piperazine, free base: m.p. 80 - 81C, dihydrochloride: m.p.
246 - 249C (decomp).
~xample 17
dl-l-Cyclohexyl-4-[2-(4-methoxyphenyl)-
l-phenylethyl]piperazine dihydrochloride ..... 50 g
Starch ...................................... 110 g
Calcium carboxymethyl cellulose .............. 30 g
Hydroxypropyl cellulose ....................... 9 g
Magnesium stearate ............................ 1 g
The above components are blended, granulated and made
into tablets in accordance with the conventional method. The
1000 tablets each weighing 200 mg are formed.
~xample 18
dl-l-Cyclohexyl-4-~2-(4-methoxyphenyl)-
. .
l-phenylethyl]piperazine dihydrochloride ..... 25 g
Starch ....................................... 20 g
~actose ...................................... 50 g
~alc .......................................... 5 g
~he above components are blended and granulated and
filled into 1,000 capsules in accordance with the conventional
method.
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, . ~ ,, ., , ....... , ~ '
