CA1051433A - 1-substituted-4-(1,2-diphenylethyl)piperazine derivatives and their salts and the preparation thereof - Google Patents

Abstract

1-SUBSTITUTED-4-(1,2-DIPHENYLETHYL)-PIPERAZINE DERIVATIVES AND THEIR
SALTS AND THE PREPARATION THEREOF

Abstract of the Disclosure:
1-Substituted-4-(1,2-diphenylethyl)piperazine deriv-atives of the formula:

[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-methoxyphenyl, and their pharmaceutically acceptable salts, which have ex-cellent analgesic, anti-tussive and anti-inflammatory activi-ties, without undesirable side effect such as narcotic activ-ity, and a process for the preparation thereof.

Description

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 . . .
~: -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.

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.

.. . .. . . . .. .

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)-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 -_ _ _ .

. . .

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 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

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 ~

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

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:

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.

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

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]

wherein X is as defined above, with a compound of the following formula:

N-R [VII ]

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 .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]

~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.

~$

~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~-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 - .
''' '` - . '' '` " ' ' ' ~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).

~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 . ., ~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 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:
, .

~(~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 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 ~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 ':

~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 ... . . . . .. .... .. . . . . . . . . ...

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 .

.

.. . .. ... . .. . .. .. .... . . . . .
, . ... . .. . . . .

. .

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 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-.

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.

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.

, . ~ ,, ., , ....... , ~ '

Claims (48)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the formula:

[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-methoxyphenyl, or a pharmaceutically acceptable salt thereof, which comprises (a) reacting a compound of the formula:

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:

wherein R is as defined above, (b) reacting a compound of the formula:

wherein X is as defined above, with a compound of the formula:

wherein R and Z are as defined above, or a salt thereof, (c) reacting a compound of the formula:

wherein R and X are as defined above, or a salt thereof, with a halogenating agent to give a compound of the formula:

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:

wherein R is as defined above, with a compound of the formula:

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:

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.

2. A compound of the formula [I] or a pharmaceu-tically acceptable salt thereof as set forth in claim 1, whenever produced by the process of claim 1 or by an obvious chemical equivalent of that process.

3. A process for preparing a compound of the for-mula:

[I]

wherein X is hydroxy, methoxy, methyl or trifluoromethyl; and R is an unsubstituted monocycloakyl 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, or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of the formula:

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:

wherein R is as defined above, and 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.

4. A compound of the formula [I] or a pharma ceutically acceptable salt thereof as set forth in claim 3, whenever produced by the process of claim 3 or by an obvious chemical equivalent of that process.

5. A process according to claim 3, wherein X is methoxy and R is cyclohexyl.

6. 1-Cyclohexyl-4-[2-(4-methoxyphenyl)-1-phenylethyl]-piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 5 or by an obvious chemical equivalent of that process.

7. A process according to claim 3, wherein X is methoxy and R is cycloheptyl.

8. 1-Cycloheptyl-4-[2-(4-methoxyphenyl)-1-phenyl-ethyl]piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 7 or by an obvious chemical equivalent of that process.

9. A process according to claim 3, wherein X is methyl and R is 2-methoxyphenyl.

10. 1-(2-Methoxyphenyl)-4-[1-phenyl-2-(4-tolyl)ethyl]-piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 9 or by an obvious chemical equivalent of that process.

11. A process according to claim 3, wherein X is hydroxy and R is cyclohexyl.

12. 1-Cyclohexyl-4-[2-(4-hydroxyphenyl)-I-phenylethyl]]-piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 11 or by an obvious chemical equivalent of that process.

13. A process according to claim 3, wherein X is methyl and R is cyclohexyl.

14. 1-Cyclohexyl-4-[1-phenyl-2-(4-tolyl)ethyl]piperaziine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 13 or by an obvious chemical equivalent of that process.

15. A process according to claim 3, wherein X is methoxy and R is 2-methoxyphenyl.

16. 1-(2-Methoxyphenyl)-4-[2-(4-methoxyphenyl)-1-phenylethyl]piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 15 or by an obvious chemical equivalent of that process.

17. A process according to claim 3, wherein X is methoxy and R is cyclooctyl.

18. 1-Cyclooctyl-4-[2-(4-methoxyphenyl)-1-phenylethyl]]-piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 17 or by an obvious chemical equivalent of that process.

19. A process according to claim 3, wherein X is methyl and R is cycloheptyl.

20. 1-Cycloheptyl-4-[1-phenyl-2-(4-tolyl)ethyl]-piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 19 or by an obvious chemical equivalent of that process.

21. A process according to claim 3, wherein X is trifluoromethyl and R is 2-methoxyphenyl.

22. 1-(2-Methoxyphenyl)-4-[1-phenyl-2-(4-trifluoromethyl-phenyl)ethyl]piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 21 or by an obvious chemical equivalent of that process.

23. A process according to claim 3, wherein X is methyl and R is cyclooctyl.

24. 1-Cyclooctyl-4-[1-pheny1-2-(4-tolyl)ethyl]-piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 23 or by an obvious chemical equivalent of that process.

25. A process for preparing a compound of the formula:

[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-methoxyphenyl, or a pharmaceutically acceptable salt thereof, which com-prises reacting a compound of the formula:

wherein X is as defined above, with a compound of the formula:

wherein Z is a residue of a reactive ester of alcohol, and R is as defined above, or a salt thereof, and 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.

26. A compund of the formula [I] or a pharma ceutically acceptable salt thereof as set forth in claim 25, whenever produced by the process of claim 25 or by an obvious chemical equivalent of that process.

27. A process according to claim 25, wherein X is methoxy and R is cyclohexyl.

28. 1-Cyclohexyl-4-[2-(4-methoxyphenyl)-1-phenylethyl]-piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 27 or by an obvious chemical equivalent of that process.

29. A process according to claim 25, wherein X is methoxy and R is cycloheptyl.

30. 1-Cycloheptyl-4-[2-(4-methoxyphenyl)-1-phenyl-ethyl]piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 29 or by an obvious chemical equivalent of that process.

31. A process according to claim 25, wherein X is methyl and R is 2-methoxyphenyl.

32. 1-(2-Methoxyphenyl)-4-[1-phenyl-2-(4-tolyl)ethyl]-piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 31 or by an obvious chemical equivalent of that process.

33. A process according to claim 25, wherein X is hydroxy and R is cyclohexyl.

34. 1-Cyclohexyl-4-[2-(4-hydroxyphenyl)-1-phenylethyl]-piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 33 or by an obvious chemical equivalent of that process.

35. A process according to claim 25, wherein X is methoxy and R is 2-methoxyphenyl.

36. 1-(2-Methoxyphenyl)-4-[2-(4-Methoxypheny1)-1-phenylethyl]piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 35 or by an obvious chemical equivalent of that process.

37. A process for preparing a compound of the formula:

[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-methoxyphenyl, or a pharmaceutically acceptable salt thereof, which com-prises reacting a compound of the formula:

wherein R and X are as defined above, or a salt thereof, with a halogenating agent to give a compound of the formula:

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, and 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 corre-sponding free base.

38. A compound of the formula [I] or a pharmaceu-tically acceptable salt thereof as set forth in claim 37, whenever produced by the process of claim 37 or by an obvious chemical equivalent of that process.

39. A process according to claim 37, wherein X is methoxy and R is cyclohexyl.

40. 1-Cyclohexyl-4-[2-(4-methoxyphenyl)-1-phenyl-ethyl]piperazine, or a pharmaceutically acceptable salt there-of, whenever produced by the process of claim 39 or by an obvious chemical equivalent of that process.

41. A process according to claim 37, wherein X is methoxy and R is 2-methoxyphenyl.

42. 1-(2-Methoxyphenyl)-4-[2-(4-methoxyphenyl)-1-phenylethyl]piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 41 or by an obvious chemical equivalent of that process.

43. A process for preparing a compound of the for-mula:
[I']

wherein X' is 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 trifluoromethyl, R is 2-methoxyphenyl, or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of the formula:

wherein R is as defined above, with a compound of the formula:

wherein Z' is a halogen atom and X' is as defined above, and 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 corre-sponding free base.

44. A compound of the formula [I'] or a pharma-ceutically acceptable salt thereof as set forth in claim 43, whenever produced by the process of claim 43 or by an obvious chemical equivalent of that process.

45. A process according to claim 44, wherein X1 is methoxy and R is cyclohexyl.

46. 1-Cyclohexyl-4-[2-(4-methoxyphenyl)-1-phenyl-ethyl]piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 45 or by an obvious chemical equivalent of that process.

47. A process for preparing 1-cyclohexyl-4-[2-(4-hydroxphenyl)-1-phenylethyl]piperazine, or a pharmaceutically acceptable salt thereof, which comprises subjecting a com-pound of the formula:

wherein Y is an alkyl group having 1 to 7 carbon atoms or benzyl, or a salt thereof, to cleavage of the ether likage, and 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 corre-sponding free base.

48. 1-Cyclohexyl-4-[2-(4-hydroxyphenyl)-1-phenyl-ethyl]piperazine, or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 47 or by an obvious chemical equivalent of that process.