CZ20002027A3 - Arylpiperazines having effect on 1A serotonin receptor - Google Patents

Abstract

The present invention relates to a number of arylpiperazine compounds which are active pharmaceutical agents for the treatment of conditions related to or affected by serotonin 1A receptors; the compounds are particularly effective as antagonists of this f receptor and are particularly useful for symptom relief, associated with interruption or cessation of nicotine use and tobacco.

Description

Arylpiperazines having an effect on the _1A serotonin receptor

This application claims priority to U.S. Pat. Provisional Applications Nos. 60 / 069,722, filed December 16, 1997, 60 / 069,791, filed December 16, 1997 and 60 / 089,589, filed June 17, 1998.

Technical field

The present invention relates to arylpiperazines having an effect on the serotonin _1A receptor. It concerns pharmacology and medical chemistry. It provides novel pharmaceutical products that are useful for the treatment of diseases that are caused or affected by disorders of serotonin-affected neurological systems, especially those related to the _1A receptor.

BACKGROUND OF THE INVENTION

In recent years, researchers in the pharmaceutical industry have discovered that neurons in the brain that contain monoamines are extremely important for many physiological processes that also strongly affect many psychological and personality-affecting processes. In particular, serotonin (5-hydroxytryptamine; 5-HT) has been found to play a key role in a large number of processes that affect physiological and psychological functions. Drugs that affect the function of serotonin in the brain are therefore of great importance and are now used for a surprisingly large number of different therapies.

Initial generations of serotonin-affecting drugs tended to affect a number of different physiological functions, both mechanistically and medically. Later, it became possible to study the function of drugs at individual receptors in vitro or. ex vivo and it has also become apparent that therapeutic agents with a single mechanism of action are often advantageous to the patient. Accordingly,. The aim of current research was not only the discovery of a substance that affects only serotonin functions, but also substances that affect only one serotonin function at a single identifiable receptor.

SUMMARY OF THE INVENTION

Presented by selective receptors.

invention with activity

1a · relates to compounds which have high serotonin antagonists

The present invention relates to a number of novel arylpiperazine compounds, methods of using them for pharmaceutical purposes, and pharmaceutical compositions through which the compounds can be advantageously administered.

The present invention also relates to methods of antagonizing the 5HT-L _and therapeutic methods which are related to their effect on the _5HT-Ia. Such methods of treatment include, in particular, methods of alleviating symptoms caused by discontinuation or partial discontinuation of tobacco or nicotine use, and include administering to a patient in need thereof a compound of Formula I

fa in which

Ar 1 represents a mono- or bicyclic aryl or heteroaryl radical substituted with one to three substituents selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C 6) alkylthio , (C2-C6) alkenyl, (C2-Cg) .alkinyl, (Ci-Cg) alkylhalo, (C ₃ -C) cycloalkyl, (C ₃ -C _e) cycloalkenyl or halo;

R ¹ represents hydrogen, _(Ci-C6) alkyl, _(Ci-C) alkoxy, (Ci-Cg) alkylthio;

R ² represents phenyl, naphthyl or (C3-C12) cycloalkyl substituted with one or two substituents ·, .zvolenými from the group consisting of hydrogen, a group (Οχ-Cg) alkyl, (Ci-Cg) alkoxy, (Ci-Cg) alkylthio , (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₆ ) alkylhalo, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen;

R ³ is selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (O-C _1-6 ) alkylhalo, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen;

X is -C (= O) -, -CHOH- or -CH ₂ -;

or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof.

Such methods of treatment include methods of treating anxiety,

depression, hypertension, cognitive disorders, psychosis, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, eating disorders and obesity, substance abuse, obsessive-compulsive disease, panic disorder and migraine.

Other methods of treatment of the present invention are methods of potentiating the action of a serotonin reuptake inhibitor, comprising administering to a patient an effective amount of a compound of Formula I in combination with a serotonin reuptake inhibitor.

More particularly, the present invention relates to compounds of formula Ia;

or a pharmaceutically acceptable salt thereof.

Compounds of formula Ia are within the scope of compounds of formula I and are therefore useful in the methods described below for compounds of formula I. For example, the present invention relates to methods of antagonizing 5HT- _1A receptors and methods of treatment related to their effect on the 5HT receptor -1 _A. Such methods of treatment include specifically

methods of alleviating symptoms caused by discontinuation or partial discontinuation of tobacco or nicotine use, including

When administered to a patient in need of such treatment, an effective amount of a compound of Formula Ia. In addition, r

such treatment includes methods of treating anxiety, depression, hypertension, cognitive disorders, psychosis, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, eating disorders and obesity, substance abuse, obsessive-compulsive disease, panic disorder and migraines.

In addition, the present invention relates to a method of potentiating the action of a serotonin uptake inhibitor, comprising i

administering to the patient an effective amount of a compound of Formula Ia in combination with a serotonin uptake inhibitor.

The present invention further relates to a method of assisting a patient in a patient.

interrupting or reducing its use of tobacco or nicotine, comprising administering to the patient an effective amount of a compound of Formula I or Formula Ia.

The present invention. it also encompasses new methods of synthesizing compounds of Formula I and Formula Ia, synthesizing novel intermediates therefor, and further includes novel intermediates as such.

WITH

Description of preferred embodiments

Throughout this document, all descriptions of concentrations, amounts, ratios, and the like are expressed in units of weight,

9 t

«· · Φ ·» 4 4 4 4 4 4 4 4 4 9

unless otherwise stated. All temperatures are in degrees Celsius.

Compounds

It is believed that the general description _of the above compounds is sufficient to explain their nature skill; it is also recommended to pay attention to the enclosed Examples. In addition, additional explanations of some terms will be provided to avoid possible misunderstandings.

In the general description, the general chemical terms have all their normal and usual meanings.

For example, small alkyl and alkoxy groups, such as (C 1 -C 6) alkyl and (C 1 -C ₆ ) alkoxy groups, depending on the size of the groups, include methyl, ethyl, propyl, isopropyl, n-butyl, straight chain butyl, pentyl, 3-methylbutyl, hexyl and branched hexyl groups and the corresponding alkoxy groups which include the individual groups designated by name. When a set of substituents, such as up to three alkyl or alkoxy groups or atoms of the Ar group, is acceptable on a given group, it is understood that substitutions which are possible from one halogen are intended to be permissible only for such electron coatings and steric ratios.

The term alkenyl as used herein represents an unsaturated branched or straight group having at least one double bond. Examples of such groups include residues such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-

-4 9 ·· ·· '9 9 9 9 9 «· « « '9 9 • • «9 • 9 9 • • 9 9 • • • 9 ·· · 999 '9 9 »· • 9 · • ·

hexenyl, 5-hexenyl as well as straight and branched chain dienes and trienes.

The term alkynyl refers to such radicals as ethynyl, er propynyl, butynyl, pentynyl, hexynyl as well as di- and triins.

The term (C 1 -C 6) alkylthio defines a straight or branched alkyl chain having one to six carbon atoms attached to the remainder of the molecule through a sulfur atom. Typical (C 1 -C 8) alkylthio groups include ethylthio, propylthio, butylthio, pentylthio, and the like.

methylthio, hexylthio and

The term (C 1 -C ₆ ) alkylhalo refers to alkyl substituents having one or more independently selected halogen atoms bonded to one or the other. more available carbon atoms. These terms include chloromethyl, bromoethyl, trifluoroethyl, trifluoromethyl, 3-bromopropyl, 2-bromopropyl, and the like. 3-chlorobutyl, 2,3-dichlorobutyl, 3-chloro-2-bromobutyl, trichloromethyl, dichloroethyl, 1,4-dichlorobutyl, 3-bromopentyl, 1,3-dichlorobutyl, 1,1-dichloropropyl and the like. More preferred '(Οχ-Οε) alkylhalo groups are trichloromethyl, trichloroethyl, and trifluoromethyl. The most preferred (C 1 -C ₆ ) alkylhalogen is trifluoromethyl.

The term (C 3 -C 8) cycloalkyl includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term (C 3 -C ₈ ) cycloalkyl includes (C 3 -C ₆ ) cycloalkyl.

Ϊ-7 '<

',' 1-Γ

The term (C 3 -C 8) cycloalkenyl represents an olefinically unsaturated ring having 3 to 8 carbon atoms and includes groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like. The term (C ₃ -C) cycloalkenyl includes (C3-C6) cycloalkenyl.

The term aryl represents phenyl or naphthyl.

The term bicyclic represents either an unsaturated or saturated stable 7- to 12-membered carbon ring bridge or fused ring. The bicyclic ring may be bonded to any carbon atom that provides a stable structure. The term includes, but is not limited to, naphthyl, dicyclohexyl, dicyclohexenyl and the like.

The term mono- or bicyclic heteroaryl radical refers to radicals derived from monocyclic or polycyclic aromatic nuclei having 5 to 14 ring atoms and containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, indolizinyl, isoquinolyl, benzothienyl, isoindolizinyl, oxazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, dibenzofuranyl, thianaphthenyl, indibizothiofenyl, dibenzothiofenyl, dibenzothiofenyl, anthranilyl, purinyl, pyridinyl, phenylpyridinyl, pyrimidinyl, pyrazinyl, quinolinyl.

The terms halogen or halide are used in the general formulas to denote fluorine, chlorine, bromine or iodine atoms.

The term aprotic solvent refers to polar solvents with a medium high dielectric constant that do not contain acidic hydrogen. Examples of common aprotic solvents are dimethylsulfoxide (DMSO), dimethylformamide, sulfolane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether or 1,2-dimethoxyethane.

The term protic solvent refers to a solvent containing a hydrogen atom that is bound to an oxygen atom and therefore. is noticeably acidic. Common protic solvents include such solvents as water, methanol, ethanol, 2-propanol and 1-butanol.

The term inert atmosphere refers to reaction conditions in which the mixture is covered with an inert gas layer such as nitrogen or argon.

As used herein, the term Me refers to the -CH 3 group, the term Et refers to the -CH 2 CH 3 group, and the term Pr refers to the -CH 2 CH 2 CH 3 group.

As used herein, the term stereoisomer refers to compounds that are formed from the same atoms bonded by the same bonds but with a different three-dimensional structure that are not interchangeable. Three-dimensional structures are called configurations. As used herein, the term enantiomer refers to two stereoisomers whose molecules are non-transferable mirror images of each other. As used herein, the term optical isomer is equivalent to the term enantiomer. The terms racemate, racemic mixture, or racemic modification refer to a mixture of equal parts

enantiomers. The term chiral center refers to a carbon atom to which four different groups are attached.

The term enantiomeric enrichment as used herein refers to an increase in the amount of one enantiomer compared to the other. A preferred method of enantiomeric expression

enrichment is the concept of enantiomeric excess (enantiomeric : the following excess) equation: called ee, which, is calculates from ee - E ¹ - E ² x 100 E ¹ + E ² where E ¹ . is the quantity of the first enantiomer and E ² is the quantity second enantiomers. If then initial ratio of two

enantiomers is 50:50, as in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50: 30 is achieved, then the ee is 25% relative to the first enantiomer. However, if the final ratio is 90:10, the ee with respect to the first enantiomers is 80%. ^: An ee of greater than 90% ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric enrichment can be readily determined by one of ordinary skill in the art using standard techniques and procedures such as gas or high performance liquid chromatography with a chiral column. Selection of a suitable chiral column, elution solvent and conditions necessary to effect separation; a pair of enantiomers is within the skill of the art. In addition, the enantiomers of the compounds of formula I or Ia may be separated based on conventional knowledge in the art using standard techniques well known in the art. '' · * · '· · *'>

• · 9 9 9 9 · ^r · «· 9 9 9 9 · ♦ • '9 · 9' · 9 '9 · Φ · (9 9 9 9' 9 9 9 · 9th

to those skilled in the art, such as those described in J. Jacques et al., Enantiomers, Racemates, and Resolutions, John Wiley and Sons, Inc., 1981. Examples of separation include recrystallization techniques or. chiral chromatography.

The compounds of formula (I) and formula (Ia) represent a class of highly active, important and particularly useful compounds in the treatment of the methods of the present invention, but certain classes of compounds are preferred. The following paragraphs describe such preferred classes. It is understood that the description of preferred compounds relates to both the methods of treatment and the novel compounds of the present invention.

It will also be appreciated that preferred classes of compounds may be combined to form additional broader or narrower classes of preferred compounds.

a) Ar 1 is -phenyl or pyridyl;

b) Ar 1 represents naphthyl;

c) Ar 1 represents pyrazinyl, pyrimidinyl, pyrrolyl, furyl, thienyl, indolyl, purinyl, imidazolyl, pyrazolyl, indolizinyl,. benzofuranyl, isoquinolyl, quinolyl, benzothiyl or isoindolizinyl;

d) Ar 1 is optionally substituted with (C 1 -C ₆ ) alkyl, (C 1 -C 6) alkoxy, halogen, (C ₂ -C ₆ ) alkenyl or (C ₂ -C ₆ ) alkynyl;

e) Ar 1 is optionally substituted with (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) alkyl;

C ₄ ) alkoxy or halogen;

f) R ¹ represents a hydrogen atom;

g ¹ R ¹ represents (C 1 -C ₆ ) alkyl or (C 1 -C 6) alkoxy;

• ·· '·· »·· • • J · · 4 4. 4 · · · ·· • · 4 ^r 4 4 · · · «· 4 4

(h) and) R ¹ represents (C 1 -C 2) alkyl or (C 1 -C 2) alkoxy; R ² is phenyl; Ť? (j) to) ^R2 is (C3-C8) cycloalkyl; ^R2 is (C3-C8) cycloalkyl; 1) R ² is cyclohexyl; (m) R ³ represents _(Ci-C6) alkyl, _(Ci-Ce) alkoxy, halo; or atom (n) R ³ represents (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or atom O) halogen; X is -C = O; (p) X is -CHOH; and q). X is -CH 2. (r) Formula Ia with) an enantiomer of formula (Ia) wherein  [ot] ° 20 v

of methanol is (+).

Since the compounds of the present invention are basic in nature, they react with any of the compounds. a variety of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Single and double salts are within the scope of the present invention. The acids commonly used to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts are therefore sulphate, pyrosulphate, hydrogen sulphate, sulphite, hydrogen sulphite, phosphate, monohydrogen phosphate,

- 13 dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, fumarate, sebacate, sebacate, sebacate, sebacate, 1,4-dioate, hexine-1,6dioate, benzoate, chlorobenzoate. methyl benzoate, dinitrobenzoate, methoxybenzoate, phthalate, sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, hydroxybenzoate, xylenesulfonate, citrate, lactate, p-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, Preferred are monohydrochloride, dihydrobromide, general naphthalene-2-sulfonate, mandelated pharmaceutically acceptable salts dihydrochloride, monohydrobromide, formula I / succinate (1: 1), formula Ia / succinate (1: 1), formula I / succinate 2: 1 , formula Ia / succinate 2: 1, phosphate, d-tartrate, 1-tartrate or maleicate. The skilled artisan will appreciate that hydrates of the free base or pharmaceutically acceptable salts are within the scope of the present invention.

Many compounds of formula I, including compounds of formula Ia, are optical isomers. For example, the compounds have an asymmetric center (or chiral center) in the carbon atom to which R ¹ and X are attached. However, when the compound of the present invention is named without giving an asymmetric form, any of the possible asymmetric forms are contemplated. The present invention is not limited to any particular isomer, but encompasses all possible individual isomers and racemates.

The intermediates and final products may be isolated and purified by conventional purification techniques such as' ♦ · · ^(Φ 'Φ *' · 9 ý®: ® φ · · φ / φ φ φ φ

ΙΦΦΦ Φ'ΦΦ. (φΦ Φ ¹ · φ '· Φ φ''φφ' φφ

chromatography using silica gel or recrystallization of crystalline isolates.

It will be readily apparent to those skilled in the art that the starting materials not described are either commercially available or can be readily prepared from commercially available starting materials by known methods. All other reactants used to prepare the compounds of the present invention are commercially available.

The compounds of the present invention are generally prepared according to the following reaction schemes.

44 4

· 4 4 '44 4 »'·!' . '4 «4 '4 ^{| r} 4' 4 i4 4 · '· 4 • 4 ^γ · 4 • 44 • 4 4 _v 4 4 4 ·  4 4

Scheme, 1

(3)

(7)

The starting material (1) is treated with a base, preferably potassium tert-butoxide, followed by. alkylation with 2-bromomethyl-1,3-dioxolane. Other suitable bases include sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate and the like.

I, '<* 9 • ··' ··, 9 · 9

The reaction is preferably carried out in a solvent such as dimethylsulfoxide at a temperature of from 15 ° C to reflux temperature, with a temperature of 45-55 ° C being most preferred and essentially complete in 1 to 24 hours to prepare intermediate (2).

Treatment of compound (2) with an acid such as hydrochloric acid or p-toluenesulfonic acid in a suitable organic solvent affords the aldehyde (3). Generally, the reaction is carried out in a protic solvent such as a mixture of aqueous acid and acetone at temperatures from about 50 to 75 ° C, preferably at ambient temperature.

The aldehyde (3) is coupled with the desired arylpiperidine (-4) by reductive amination to prepare compound (5). The reaction is preferably carried out at ambient temperature in a non-reacting solvent such as dichloroethane or methylene chloride in the presence of sodium triacetoxyborohydride and is essentially complete in one to 24 hours. See, for example, A.F. AbdelMagid et al., J. Org. Chem., 61, 3849 (1996).

The reduction (5) is readily accomplished using a reducing agent such as sodium borohydride or, preferably, diisobutylaluminum hydride to prepare the hydroxy compound (6). The reaction is preferably carried out in an organic solvent such as methylene chloride at temperatures from about -20 ° C to 0 ° C.

Further reduction of compound (6) to yield product (7) may be achieved by treatment with a reducing agent such as triethylsilane or boron trifluoride (where -R ² represents phenyl

fit (·· ve * ·· '4' · ^l 4'4 <4 <4 4 <· <4 ^y 4 <· F ·. · • · ··· (· · · '* 4

or substituted phenyl) or treatment with an acid such as hydrochloric acid or trifluoroacetic acid, in an aprotic solvent such as tetrahydrofuran, at ambient temperature, to form a double bond, followed by hydrogenation with, for example, hydrogen and palladium carbon.

The starting material (1) is either commercially available or can be prepared by coupling (8) [see Nahm and Weinreb, Tetrahedron Lett., 22, 3815, (1981)] and (9) as described in Scheme II below.

Scheme II

M is a metal salt such as a lithium or magnesium halide. The reaction is preferably carried out under an inert atmosphere preferably. nitrogen, in an aprotic solvent such as tetrahydrofuran, at ambient temperature.

More specifically, compounds of Formula Ia can be prepared according to the procedure described in Scheme III. All substituents, unless otherwise indicated, are as defined above. Reagents and starting materials are readily available to those skilled in the art.

4 99 <• 4 - 4 · - · · • 4 • 4 ’4 • > 4 f · • Í4 ♦ z · <· • ‘4 '· • '4 O·· <· · 4 9 . ·. · ··

Scheme III

co ₂ ch ₃ (9)

Step A

Italy (11)

(13)

Step E (+) enantiomer of Formula Ia

Step F (+) enantiomer of a pharmaceutical salt of a compound of formula Ia

In Scheme III, Step A, an ester of formula (10) is treated with benzylmagnesium chloride or benzylmagnesium bromide under standard conditions well known to those skilled in the art for obtaining the ketone of formula (11). For example, about 1.05 to about 1.1 equivalents of a suitable amine, such as dimethylamine, is dissolved in a suitable organic solvent, such as tetrahydrofuran (cooled to about -5 ° C) under an inert atmosphere. Warm the solution to ambient temperature while adding 1.0 equivalents of ester (10) with stirring. Then approximately 1.0% of the solution is slowly added to the solution. 9919 <<® <U,,,,, 9,,, (, ((ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ (((ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ 1,0 ΦΦΦ ΦΦΦ 1,0 1,0 1,0 1,0 1,0 1,0 1,0 After addition, the reaction mixture is stirred at ambient temperature for about 1-2 hours, then cooled to less than 0 ° C and then carefully quenched with a suitable acid such as HCl. then extracted with a suitable organic solvent such as tert-butyl methyl ether (hereinafter MTBE), the organic layers are combined, dried over anhydrous magnesium sulfate, filtered and concentrated to afford the ketone (11) .Ketone (11) can be purified by techniques well known to those skilled in the art. , such as flash chromatography on silica gel with a suitable eluting solvent such as ethyl acetate / hexane to give the purified material Alternatively, the crude ketone (11) can be used in step B. In Scheme III, Step B, ketone (11) is alkylated with bromoacetaldehyde with diethyl acetal and then with iodomethane under conditions well known to those skilled in the art to obtain a compound of formula (12). For example, ketone (11) is dissolved in a suitable organic solvent such as methyl sulfoxide and treated with about 1.05 to about 1.1 equivalents of a suitable base such as potassium tert-butoxide. The reaction mixture is stirred for about 15 to 30 minutes and about 1.0 to about 1.05 equivalents of bromoacetaldehyde diethyl acetal is added dropwise to the reaction mixture. One skilled in the art will readily appreciate that bromoacetaldehyde dimethyl acetal, bromoacetaldehyde ethylene acetal and the like may be used in place of the corresponding diethyl acetal. The reaction mixture is then heated to about 50 ° C for about 2 to 2.5 hours. The reaction mixture was then quenched with ice / water and cooled.

Τ ·. · ··· · · · · · · · «

• · · · · · ·

9.9 9 9 about 2.2 equivalents of a suitable base such as potassium tert-butoxide are added. The reaction mixture is stirred for about 15 to 30 minutes with continued cooling and then about 1.5 to about 1.8 equivalents of iodomethane are added dropwise to the reaction mixture, maintaining the temperature of the mixture below 41 ° C, preferably below 21 ° C. After the addition is complete, the reaction mixture is warmed to ambient temperature and stirred for about 1 to 4 hours. The reaction mixture is then partitioned between water and a suitable organic solvent such as MTBE. Separate the layers and wash the organic phase with water, brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to afford compound (12).

In Scheme III, Step C, compound (12) is hydrolyzed under acidic conditions to afford aldehyde (13) in a manner analogous to that described in Scheme I. More specifically, for example, compound (12) is dissolved in a suitable organic solvent such as acetone and treated with a suitable acid such as is hydrochloric acid. The reaction mixture is stirred for about 1 to 3 hours at ambient temperature. The reaction mixture is then extracted with a suitable organic solvent such as ethyl acetate or methylene chloride, the organic extracts are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. recovering the aldehyde (13). The aldehyde (13) can be purified by methods well known to those skilled in the art, such as flash chromatography on silica gel with a suitable eluting solvent such as ethyl acetate / hexane. Alternatively, the crude aldehyde (13) can be used directly in step D.

In Scheme III, Step D, the aldehyde (13) is reductively aminated

and· i * · ·· • '9 8 • 4 ·· '· 9 9 9 «4« · '· · ··. ·· • 9

under conditions well known to those skilled in the art of piperazine (14) to obtain the compound of formula (Ia) in a manner analogous to that described in Scheme I. . To this solution is added approximately 1.1 equivalents of piperazine (14). Optionally, acetic acid may be added to facilitate the dissolution of piperazine (14). Approximately 1.2 to 1.3 equivalents of sodium triacetoxyborohydride are then added and the reaction mixture is stirred at ambient temperature for 1 hour. for about 3-5 hours. The reaction is then quenched by addition of a suitable base such as aqueous sodium hydroxide to achieve a pH of about 10 to about 12. then extracted with a suitable organic solvent such as methylene chloride. Combine the organic extract, wash with brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to afford the compound of Formula Ia. This material can be purified by methods well known to those skilled in the art, such as flash chromatography on silica gel with a suitable eluting solvent such as ethyl acetate / hexane.

The free base of Formula Ia can be converted to the corresponding pharmaceutically acceptable salts under standard conditions well known to those skilled in the art. For example, the free base of Formula Ia is dissolved in a suitable organic solvent, such as methanol, treated with one equivalent, for example. maleic acid or oxalic acid or, for example, two equivalents of hydrochloric acid, and then concentrated under reduced pressure to afford the corresponding pharmaceutically acceptable salt. The residue can then be purified by recrystallization from an appropriate

« • »* · « · <· '· 1 · • ·· · · 4 • »'· • • 4 4 4 4 .4 4 • • • • · •. · • 4 ·· · ··· · « ·· ·· • ·

an organic solvent or a mixture of organic solvents such as methanol / diethyl ether.

In Scheme III, Step E, the (+) enantiomer of Formula Ia can be separated from the (-) enantiomer using techniques and procedures well known to those skilled in the art, such as those described in J. Jacques et al., Enantiomers, Racemates, and Resolutions. , John Wiley and Sons, Inc., 1981. For example, it may be. for. chiral chromatography with a suitable organic solvent such as ethanol / acetonitrile and a Chiralpak AD column, 20 microns, was used to separate enantiomers.

In Scheme III, Step F, the (+) enantiomer of Formula Ia is converted to a pharmaceutically acceptable salt thereof such as monohydrochloride, dihydrochloride, monohydrobromide, dihydrobromide, compound Ia / succinate (1: 1), compound Ia / succinate-2: 1 , phosphate, d-tartrate, 1-tartrate or maleate in a manner analogous to the procedure described at the end of step D above.

Alternatively, compounds of formula (5) can be prepared according to the procedure described in Scheme IV. All substituents, unless otherwise indicated, are as previously described. as defined above. Reagents and starting materials are readily available to those skilled in the art.

• • tttt ·· tttt «Tt tttt • tt • • • 'tt tt • • • (tt tt ·· • • tt tt • • ♦ tt tt tt  · • • • tt · · ··· tt * • tt • tt ··

with*

Scheme IV

(5)

In Scheme IV, Step A, the aldehyde (15) is combined, with a suitable organometallic reagent (16) under conditions well known to those skilled in the art for obtaining alcohol (17). Examples of suitable organometallic reagents include Grignard reagent, alkyl lithium reagents, alkyl zinc reagents and the like.

· - - «« «« «« «................ • • • • • • • · Η η η · ».» »» »» »

Grignard reagents are preferred. For examples of typical Grignard reagents and reaction conditions, see J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 2nd Edition, McGraw-Hill, pp. 836-841 (1977). More specifically, the aldehyde (15) is dissolved in a suitable organic solvent such as. is tetrahydrofuran or toluene, cooled to about -5 ° C and treated with about 1.1 to 1.2 equivalents of the Grignard reagents of formula (16) wherein M is MgCl or MgBr. The reaction mixture is stirred for about 0.5 to 2 hours, then the reaction is stopped and the alcohol (17) is isolated. For example, the reaction mixture is poured into ice cold. IN HCl, extract with a suitable organic solvent such as toluene, dry the organic extracts either azeotropically or over a suitable drying agent such as anhydrous magnesium sulfate, filter and concentrate under reduced pressure to obtain the alcohol, (17).

In Scheme IV, Step B, the alcohol (17) is oxidized to. standard conditions well known to those skilled in the art, such as those described in J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and. Structure, 2nd Edition, McGraw-Hill, pp. 1082-1084 (1977), for. obtaining a ketone (1).

[Ketone (1) is the starting material used in Scheme I above.]

For example, alcohol (17) is dissolved in a suitable organic solvent such as methylene chloride, cooled with an ice-acetone bath and treated with 2.5 to 3.0 equivalents of dimethylsulfoxide. After stirring for about 30 minutes, the reaction mixture was treated with about 1.8 equivalents of P2O5. The reaction mixture is stirred for about 3 hours and then preferably

treated with about 3.5 equivalents of a suitable amine such as triethylamine for about 30 minutes. The cooling bath was then added

Λ discard and the reaction mixture is stirred for about 8 to 16 hours. The ketone (1) is then isolated by standard extraction techniques well known to those skilled in the art. The above oxidation is also carried out using Swern oxidation conditions which are well known to those skilled in the art.

In Scheme IV, Step C, the ketone (1) is treated with a suitable base followed by addition of an alkene (18) in which X represents a suitable leaving group to give compound (19). For example, ketone (1) is combined with an excess of alkene (18) in a suitable organic solvent such as tetrahydrofuran and cooled with an ice-acetone bath. Examples of suitable leaving groups are Cl, Br, I, tosylate, mesylate and the like. Preferred leaving groups are Cl and Br. About 1.1 equivalents of the appropriate base is added and the reaction mixture is stirred for about 2 hours at ambient temperature. Examples of suitable bases are potassium tert-butoxide, sodium hydride, NaN (Si (CH ₃ ) 3) 2, LDA, KN (Si (CH 3) 3) 2, NaNH ₂ , sodium ethoxide, sodium methoxide and the like. Potassium tert-butoxide is the preferred base. The reaction is then quenched with aqueous acid and compound (19) is isolated by extraction with a suitable organic solvent such as heptane. . The heptane extracts were washed <

Sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford the compound. (19).

In Scheme IV, Step D, compound (19) is treated with a suitable oxidizing agent to yield the aldehyde (3). [Aldehyde (3) is also prepared in Scheme 1]. Examples of suitable oxidation

The 9 reagents are ozone, NaIO ₄ / oemium catalyst and the like. Ozone is a preferred oxidizing agent. Examples of suitable oxidizing reagents and conditions are described in J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 2nd Edition, McGraw-Hill, pp. 1090-1096 (1977).

For example, compound (19) is dissolved in a suitable organic solvent such as methanol, a small amount of Sudan III is added, and the solution is cooled to about -20 ° C. Ozone was bubbled into the solution for about 4 hours until the pink color turned pale yellow. Me ₂ S was then added to the reaction mixture and the cooling bath was removed.

Concentration of the reaction mixture under reduced pressure gives the intermediate aldehyde dimethylacetal (3). This dimethylacetal was. easily hydrolyses under standard acidic conditions. to obtain the aldehyde (3). Alternatively, direct acid treatment of the crude reaction mixture affords the aldehyde (3). Alternatively, the aldehyde (3) can be obtained directly by ozonolysis (19) in a non-acetal-forming solvent such as methylene chloride.

In Scheme IV, Step E, the aldehyde (3) is reductively aminated under conditions analogous to those described above in Scheme III, Step D, to obtain compound (5). [Compound 5 is also prepared in Scheme I.]

Scheme V provides an alternative synthesis for the preparation of compound (5). All substituents, unless otherwise indicated, are as described above. Reagents and starting materials are readily available to those skilled in the art.

Scheme V

(3)

(5)

In Scheme V, Step A, the aldehyde (3) is condensed with piperidine (4) under standard conditions well known to those skilled in the art for obtaining the enamine (20). For example, approximately 1.05 equivalents of aldehyde (3) dissolved in a suitable organic solvent such as isopropyl acetate or isopropanol is added to the anhydrous piperazine (4), free base. Additional organic solvent was added to obtain a slurry, and the reaction mixture was stirred, for about 1 to about 3. 2 hours. Enamine (20) is then isolated by standard techniques such as collection by filtration.

In Scheme V, Step B, the enamine (20) is hydrogenated to

conditions well known to those skilled in the art for obtaining compound (5). For example, the enamine (20) is charged in a suitable organic solvent such as isopropanol and a catalytic amount of 5% palladium on carbon in a Parr bottle. The mixture is placed under 50 psi of hydrogen and shaken for about 2 days at ambient temperature. The suspension is then filtered to remove the catalyst and the filtrate is concentrated to give compound (5).

DETAILED DESCRIPTION OF THE INVENTION

The following examples are typical examples of the synthesis of compounds of Formula I and Formula Ia as generally described above. These examples are illustrative only and are not intended to limit the scope of the present invention in any way. Reagents and starting materials are readily available to one of ordinary skill in the art.

As used herein, the following terms have the meanings indicated:

aq means aqueous; eq means equivalent; G means gramme; mg means milligram; 1 means liter; ml means milliliters; μΐ means microliter; mol. means mol; mmol means milimol; 'dogs means pounds per square inch; 'min means minute;

h means hour; Noc: 2 ° C means degree Celsius; TLC means thin layer chromatography; HPLC ' means high performance liquid chromatography; R _f means retention factor; nn ii <- »in \ —i m / n in *» o of ΛΠ · Z_ i i ClXLiC · i X Ů A - t. F δ means parts per million tetramethylsilane; THF means tetrahydrofuran; DMF means N, N-dimethylformamide; IPA means isopropyl alcohol; iPrOAc means isopropyl acetate; ACOH means acetic acid; HRMS means high mass spectrometry

resolution;

Et ₃ N means triethylamine; LDA means lithium diisopropylamide; RT means ambient temperature; SRI means a serotonin uptake inhibitor; aq means aqueous; and

MTBE means tert-butyl methyl ether.

IN

1- (2-methoxyphenyl) -4- [3- (benzoyl) -3- (phenyl) propyl] piperazine oxalate

A. Preparation of 2- (2'-benzoyl-2'-phenyl) ethyl-1,3-dioxolane:

To a stirred suspension of sodium hydride (61.25 mmol) in 150 mL

V., 14.4, -3.1 4-x-s v, Ί z-x 4-X

U-Lll'S L-iiy -L -L VJ.iUCUUJ.UU pXX CCp-LUOU v-iz-sr-l / ^ ηςι Ι / λτταπ + - m o A v »i ί

Ρ »UU UUO X. In U LA UiLtV O J-Cj. For U, a solution of deoxybenzoin (50.96 mmol) in 150 mL of tetrahydrofuran was added dropwise. The mixture was stirred at 0 ° C for 1 hour and at ambient temperature for 1 hour. To the mixture were added 2-bromomethyl-1,3-dioxolane (60.55 mmol) and potassium iodide catalyst (6.0 mmol). The mixture was heated to reflux for 13 hours. After cooling, diethyl ether (300 mL) and water (300 mL) were added. The organic layer was separated and washed with water (150 mL x 2). Purification by flash chromatography using hexanes and ethyl acetate gave 2- (2'-benzoyl-2'-phenyl) ethyl-1,3-dioxolane (8.18 g; 57%).

B; Preparation of 3-benzoyl-3-phenylpropionaldehyde.

To 100 ml of acetone was added 2- (2 ^{1-benzoyl-2'-phenyl)} ethyl1,3-dioxolane (8.85 mmol). 100 ml of 2N hydrochloric acid. After stirring the mixture at ambient temperature for 7 hours, 100 mL of 2N sodium hydroxide was added. The acetone was evaporated and the residue was extracted with diethyl ether and hexanes (1: 1, 100 mL x 3). The combined organic layers were dried (sodium sulfate), filtered and concentrated. It was found that the residue was a substantially pure material (3-benzoyl-3-phenylpropionaldehyde) and was therefore used in the next step.

C. Preparation of 1- (2-methoxyphenyl) -4- [3- (benzoyl) -331

(Phenyl) propyl] piperazine. ;

• ť

The 3-benzoyl-3-phenylpropionaldehyde residue obtained in Step. B above (approximately 8.85 mmol) was dissolved in 110 mL of methylene chloride. To this solution was added 2-methoxyphenylpiperazine (10.61 mmol) and sodium triacetoxyborohydride, NaBH (OAc) ₃ , (10.61 mmol). The mixture was stirred at ambient temperature for 3 hours. Aqueous work-up followed by flash chromatography gave the pure product 1- (2-methoxyphenyl) -4- [3- (benzoyl) -3- (phenyl) propyl] piperazine (3.48)

g) with 95% yield in the last two steps. One equivalent of oxalic acid was added to the free base dissolved in methanol. The solvent was evaporated and the product was dried under reduced pressure to form the oxalate salt. Mp = 161-163 ° C;

MS (m / e): 414 (M ^& lt ^{; +} & gt ^; ). '

Example 2

1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) propyl] piperazine oxalate

A. Preparation of cyclohexylbenzyl ketone.

To a stirred solution of N-methyl-N-methoxy cyclohexanecarboxamide (7.42 mmol). in 30 mL of tetrahydrofuran • 4 at 0 ° C under a nitrogen atmosphere was added a solution of benzylated magnesium chloride (2.0 M in tetrahydrofuran, 4.5 mL, 9.0 mmol). The mixture was stirred at 0 ° C for 30 minutes and at ambient temperature for 1 hour. Diethyl ether (50 mL) and water (20 mL) were added. The organic layer was separated, dried, filtered and concentrated. Purification of the residue by flash chromatography using hexanes and ethyl acetate gave cyclohexylbenzyl ketone (1.05'g) in 70% yield as an oil.

B. Preparation of 2- (2'-Cyclohexanecarbonyl-2'-phenyl) -ethyl-1,3-dioxolane.

Following the procedures described in Example 1, Step A, reaction of cyclohexylbenzyl ketone (5.09 mmol) and 2-bromomethyl-1,3-dioxolane (7.63 mmol) in the presence of sodium hydride (5.60 mmol) gave 2- (2'-). cyclohexanecarbonyl-2'-phenyl) ethyl 1,3-dioxolane (0.86 g) in 59% yield.

C. Preparation of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde. Following the procedures described in Example 1, Step. B, treatment of 2- (2'-cyclohexanecarbonyl-2'-phenyl) ethyl-1,3-dioxolane (2.98 mmol) with 1N hydrochloric acid gave 3cyclohexanecarbonyl-3-phenylpropionaldehyde as a crude product in 100% yield.

D. Preparation of 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) propyl] piperazine.

Following the procedures described in Example 1, Step C, reaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.39 mmol) and 2-methoxyphenylpiperazine (1.39 mmol) with sodium triacetoxyborohydride (1.80 mmol) gave pure product

-φ · β-c-e -e- «· · · · · · · ···

1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) propyl] piperazine (464 mg) in 79% yield. The oxalate salt was prepared as described above.

Mp = 149-151 ° C;

MS (m / e): 420 (M ^& lt ^{; +} & gt ^; ).

Example 3

1- (2-pyridyl) -4- [3- (cyclohexanecarbonyl) -3-, (phenyl) propyl] piperazine oxalate

Following the procedures described in Example 1, Step C, reaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.55 mmol) a. 1- (2-pyridyl) piperazine (1.55 mmol). with sodium triacetoxyborohydride (2.0 mmol) gave the pure product 1- (2-pyridyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) propyl] piperazine (475 mg) in 78% yield. The oxalate salt was prepared as described above.

Mp = 185-187 ° C;

MS (m / e): 391 (M ^& lt ^{; +} & gt ^; ).

-04 \

Example 4

1- (2-ethoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) propyl] piperazine dihydrochloride

Following the procedures described in Example 1, Step C, reaction of 3-cyclohexanecarbonyl-3-phenylpropionaldehyde (1.02 mmol) and 1- (2-ethoxyphenyl) piperazine. (1.13 mmol) with sodium triacetoxyborohydride (1.33 mmol) gave the pure product 1- (2-ethoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) propyl] piperazine (270 mg) in 52% yield. A solution of hydrochloric acid in diethyl ether was added to a solution of the free base in methanol, the solvents were removed under reduced pressure, and the product was dried under reduced pressure to obtain the dihydrochloride salt.

Mp = 180-183 ° C; . .

MS (m / e): 434 (M ^& lt ^{; +} & gt ^; ).

- 35 ’

·· <> *

Example 5

1- (2-methoxyphenyl) -4- [3- (benzoyl) -3- (phenyl) butyl] piperazine oxalate ^; A. Preparation of 2- (2'-Benzoyl-2'-phenyl) propyl-1,3-dioxolane. Following the procedures described in Example 1, Step A, reaction of 2- (2'-benzoyl-2'-phenyl) ethyl-1,3-dioxolane (3.54 mmol) and iodomethane (10.62 mmol) in the presence of a hydride sodium (4.25 mmol) gave 2- (2'-benzoyl-2'-phenyl) propyl-1,3-dioxolane (0.60 g).

B. Preparation of 3-benzoyl-3-phenylbutyraldehyde.

Following the procedures described in the Example ^; Step B, reaction of 2- (2'-benzoyl-2'-phenyl) propyl-1,3-dioxolane (0.60 g) with 3N hydrochloric acid gave 3-benzoyl-3-phenylbutyraldehyde as a crude product (0.32 G).

C. Preparation of 1- (2-methoxyphenyl) -4- [3- (benzoyl) -3 (phenyl) butyl] piperazine. .

Following the procedures described in Example 1, Step C, reaction of 3-benzoyl-3-phenylbutyraldehyde (0.32 g) and 1- (2-methoxyphenyl) piperazine I (0.23 g) (with triacetoxyborohydride)

Λ> '’

φ- 99 9 9 '9 9 9 9  - IN 9 '9 9 9 • • · · · 9 9 9 φφ φ 'Φ · φ 9 • 9 · ·

sodium (0.33 g) gave the pure product 1- (2-methoxyphenyl) -4- [3- (benzoyl) -3- (phenyl) butyl] piperazine (0.12 g). The oxalate salt was prepared as described above.

Mp = 192-193 ° C;

MS (m / e): 428 (M ^& lt ^{; +} & gt ^; ).

Example 6

1- (2-methoxyphenyl) -4- [3- (cycloheptanecarbonyl) -3 (phenyl) propyl] piperazine, dihydrochloride

Following the procedures described in Example 1, Step C, reaction of 3-cycloheptanecarbonyl-3-phenylpropionaldehyde (2.52 mmol) and 1- (2-methoxyphenyl) piperazine. (2.52 mmol) with sodium triacetoxyborohydride (3.28 mmol) gave the pure product 1- (2-methoxyphenyl) -4- [3- (cycloheptanecarbonyl) -3 (phenyl) propyl] piperazine (770 mg) in 70% yield. . The dihydrochloride salt was prepared. as described above.

Mp = 193-194 ° C;

MS (m / e): 434 (M ^& lt ^{; +} & gt ^; ).

Example 7

-. 37 Φ φ φ • · · · φ φ φ φ

1- (2-methoxyphenyl) -4- [3- (cyclopentanecarbonyl) -3 (phenyl) propyl] piperazine dihydrochloride

Following the procedures described in Example 1, Step C, Reaction of 3-cyclopentanecarbonyl-3-phenylpropionaldehyde. .. (1.36 mmol) and _1- (2-methoxyphenyl) piperazine. (1.49 mmol) with sodium triacetoxyborohydride (1.77 mmol) gave the pure product 1- (2-methoxyphenyl) -4- [3- (cyclopentanecarbonyl) -3 (phenyl) propyl] piperazine (370 mg) in 67% yield. the salt was prepared as described above.

Mp = 210-212 ° C;

MS (m / e): 406 (M ^& lt ^{; +} & gt ^; ). '

Example 8

• ··

1- (2-methoxyphenyl) -4- [4- (cyclohexyl) -4- (hydroxy) -3 (phenyl) butyl] piperazine oxalate

To a stirred solution of 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3- (phenyl) propyl] piperazine (0.11 g, 0.20 mmol) in methylene chloride (10 mL) at -78 ° C Dibal-HTM solution (0.89 mmol) was added under nitrogen. The mixture was stirred at -78 ° C for 1 hour and then slowly warmed to ambient temperature over 16 hours. Workup followed by flash chromatography purification gave pure 1- (2-methoxyphenyl) -4- [4- (cyclohexyl) -4- (hydroxy) -3 (phenyl) butyl] piperazine (0.086 g), in 78% yield. The oxalate salt was prepared as described above.

Mp = 100-102 ° C;

MS (m / e): 422 (M ^& lt ^{; +} & gt ^; ).

Example 9

1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine.

• · · φ ·· "·· 9 9 (99 · ·· · 'ί® ·. · •' ·: ·· · ^· · · ··

-9 · · 9. ('· · · · 9 (9 9 9 (99 9 9 9 99 9 9' 9 9)

Preparation of 2-phenyl-1-cyclohexane-ethan-1-one.

Scheme III, Step A: A 5 L reaction vessel was charged with tetrahydrofuran (1.05 L) under a nitrogen atmosphere. The solution was cooled to about -5 ° C with an acetone / ice bath. Liquid dimethylamine (115.9 g, 2.57 mol) was then added via a Teflon addition tube. The cooling bath was removed and the solution was allowed to warm to about 15-20. Deň: 32 ° C. Methylcyclohexanecarboxylate (341.7 g, 2.40 mol) was then added resulting in a tea-colored solution. Benzylmagnesium chloride (2.52 L of a 2.0 M solution in THF, 246 mol) was then slowly added at such a rate as to add. it took about 1.8 to about 2.2 hours. A cooling bath was used to maintain the temperature of the reaction mixture at about 15-20 ° C during the addition. After addition of the benzylmagnesium chloride solution, the resulting slurry was stirred at ambient temperature for about 1-2 hours. The reaction mixture was then cooled to less than 0 ° C. Concentrated HCl (709.7 g, 7.2 mol) was combined with water (3.08 L) and the solution was cooled to less than 5 ° C. The diluted acid mixture was added to a 22 L reaction vessel with an ice bath applied to the vessel. The above cold reaction mixture was then slowly poured into the cooled dilute acid solution with stirring. There was an extreme .exothermy (proceed very carefully!). The rate of addition to the reaction mixture should be controlled to keep the solution temperature below 45 ° C. After

- 4Π -

• ·· ’« ·· . -9 ". í í: -s -s'i • (4 • · <· (··· '· · · ♦ · · ^Γ · • ·

Add the reaction mixture to the dilute acid solution, cool the reaction mixture to ambient temperature, and adjust the pH to about 6.5 to 7.5 with a sufficient amount of concentrated HCl. The poured reaction mixture was extracted with MTBE (1.71 L). The layers were separated and the organic layer was washed. water / MTBE (1.03 L / 1.37 L) followed by a second wash with water / MTBE (1.03 L / 1.03 L). The organic layers were combined, washed with brine (683 mL), dried over anhydrous magnesium sulfate (167 g), filtered, and concentrated under reduced pressure. The crude oil was dried under vacuum for a period of time. 5-16 hours to give the crude 2-phenyl-1-cyclohexane-ethan-1-one (522.3 g). This crude material was used in the next reaction without further purification.

Preparation of 1,1-diethpxy-3-phenyl-3-cyclohexanecarbonylbutane.

Scheme III, step B .; .

2-Phenyl-1-cyclohexan-ethan-1-one. (8.26 g, 40.8 mmol) was placed in a 250 mL three-necked round bottom flask equipped with a magnetic stirrer, a thermocouple digital thermometer unit and an additional funnel, along with DMMS (45 mL). Potassium tert-butoxide (5.04 g, 44.9 mmol) was added to the stirred solution. 16 ° C was observed

exothermia and the yellow solution turned dark brown. The reaction mixture was stirred for an additional 15 minutes after completion of the addition, and then bromoacetaldehyde diethyl acetal (8.26 g, 41.9 mmol) was added dropwise via addition funnel over approximately 10 minutes. The reaction mixture was then heated to 50 ° C for 2 to 2.5 hours during which the reaction mixture turned yellow. The reaction mixture was then cooled with an ice-water bath to about 9.5 ° C and potassium tert-butoxide (10.07 g, 89.7 mmol) was added resulting in an exothermic reaction and a change from yellow to brown . Still using the cooling bath, the reaction mixture was stirred for an additional 15 minutes followed by dropwise addition of iodomethane (10.26 g, 72.3 mmol, without solvent). The temperature of the reaction mixture was maintained at or below 21 ° C. Any exothermia during addition of iodomethane should be kept below 41-43 ° C, which is the boiling point of iodomethane. After the addition was complete, the reaction mixture was stirred for 1 to 4 hours at ambient temperature. The reaction mixture was then partitioned between MTBE (100 mL) and water (100 mL).

The organic phase was washed with water (3 X 50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, vacuum filtered and concentrated under reduced pressure to give crude 1,1-diethoxy-3-phenyl-3-cyclohexanecarbonylbutane ( 13.6 g) as a yellow oil. This crude material was used in the next reaction without further purification.

CHO

• 4 4 4 4 4 ' ..4 4 '4 • 4 4 · 4 4 4 * '4 4 4 4 4 <4, * 4 '4 4; 4 4 4 14.4.4 4 4 4 4 4 4 4 4 4 4 4 4 4

4

Preparation of 1-cyclohexyl-2-phenyl-butan-1-one-4-alu.

Scheme III, Step C;

1,1-Diethoxy-3-phenyl-3-cyclohexanecarbonylbutane (74.4 g, 224 mmol) was dissolved in acetone (800 mL) followed by the addition of 3.0 N HCl (800 mL). The reaction mixture was stirred for one hour at ambient temperature. It was then concentrated under reduced pressure to less than 1/2 of the original volume and then extracted with methylene chloride (800 mL). The organic extract was then washed with brine (300 mL), dried over anhydrous magnesium sulfate, vacuum filtered, and concentrated under reduced pressure to give crude 3-phenyl-3-cyclohexanecarbonyl-butan-1-alu (57.8 g). Alternatively, the dry and filtered methylene chloride solution can be used directly in the next step without concentration.

Preparation of the title compound, 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3- (phenyl) butyl] piperazine.

Scheme III, Step-D;

3-Feethyl-3-cyclohexanecarbonyl-butan-1-al (57.8 g, 224 mmol) was dissolved in methylene chloride (1650 mL) followed by the addition of 1- (2-methoxyphenyl) piperazine hydrochloride (56.3 g, 246 mmol). Acetic acid (41 mL) may optionally be added to convert the slurry into a solution. To the stirred solution was. sodium triacetoxyborohydride (60.3 g, 284 mmol) was added slowly. There was a slight exotherm and a slurry formed. The reaction mixture was stirred for an additional 3 hours at ambient temperature. The reaction was then quenched by the addition of 2.0 N sodium hydroxide (1050 mL) resulting in a pH of about 10 for the resulting reaction mixture. The mixture was then extracted with methylene chloride (twice, 11 and 300 mL). The organic extracts were combined, (washed sequentially with 1.0 N HCl (600 mL), 1.0 N sodium hydroxide (600 mL), brine (600 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. to obtain the title compound as a thick oil.

UV (MeOH):

Λmax = 24 3 nm, ε ₂₄₃ = 7110;

Λ max = 281 nm, ε ₂₈ ι = 3200

IR (CDCl ₃ , cm ^-1 ) 2937, 28.56, 2836, 1698, 1499, 1451, 1377,

1316, 1242, 1029.

¹ H NMR (300 MHz, DMSO) δ · 7.75 (2H; -n), 7.55 (2H, η), 6.93 '(3H, η), 6.85 (2H, n), 3 75 (3H, s), 2.90 (4H, η), 2.43 (4H, n), 2.08 (5H, n), 1.5 (10H, η), 1.05 (3H, n), m).

¹³ C NMR (300 MHz, DMSO) δ 214.18, 151.94, 141.25, 141.23, 128.45, 126.85, 126.74, 122.22, 120.79. 117.81, 111.97, 55.28, 54.54, 53, 67, 53.13, · 50.01, - 45.30, 33.75, 30.44,

30.12, 25.21, 24.98, 24.93, 19, 94.

Elementary analysis:

Calcd for C ₂₈ H ₃₈ N ₂ O ₂ : C, 77.38; H, 8.81; N, 6.45.

Found: C, 76.44; H, 8.89; N, 6.01.

Preparation of 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3- (phenyl) butyl] piperazine maleate.

1- (2-Methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine (prepared above) was dissolved in hot methanol (50 mL) followed by the addition of β acid.

· Ζ • · · · · · · ·

Maleic acid (26.8 g) and MTBE (200 mL). This mixture was concentrated to a paste and then redissolved by adding methanol (approximately 15 mL) and MTBE (200 mL). The mixture was seeded and an additional amount of MTBE (300 mL) was added as crystallization started. The mixture was vacuum filtered and the solid was rinsed with MTBE and vacuum dried for 5 hours at 40 ° C to give the title compound (122 g).

In addition, one of ordinary skill in the art can prepare 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine in a manner analogous to that described above starting from 3-cyclohexanecarbonyl-3-phenylbutyraldehyde and 1- (2- methoxyphenyl) piperazine as generally described in Scheme V.

Preparation of 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine.2 HCl.

The title compound is prepared in a manner conventional in the art by analogous to the preparation of the above maleic acid salt from the free base and hydrochloric acid to give a white solid; Melting point (DSC) = 192.81 ° C

Preparation of (+) -1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine and (-) - 1- (2-methoxyphenyl) -4- [3 (cyclohexanecarbonyl) - 3- (phenyl) butyl] piperazine.

Scheme III, Step E:

Materials:

Chiralpak AD Bulk Kit, 20 microns

Acetonitrile

3A alcohol

Prochrom column 8 cm

Prochrom DC-80 system / sampling system

Column Preparation: ProChem LC-80 Automated System with 8 X 19 cm Column Prochrom (ProChem, 5622 West 73rd Street, Indianapolis, IN 46278) was filled with a slurry of approximately 500 g Chiralpak AD (Chiral Technologies, 730 Springdale Drive, Exton, PA 19341) ) in propanol (1 L). A wash solvent containing approximately 5% 3A alcohol and acetonitrile was prepared. The column flow was 155 ml / min and the detector was set at 280 nm. Racemic 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3- (methyl) -3- (phenyl) propyl] piperazine (25 g) was dissolved. in acetonitrile (50 mL). About 3 g of this solution was weighed into a flask and dissolved with acetonitrile (50 mL). This solution was then pumped into the column to begin separation of the (+) and (-) enantiomers of 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine. Fractions were collected and the (-) enantiomer eluted first. The approximate total cycle time was 15 minutes.

The enantiomeric excess of the two separated isomers was determined under the following conditions;

Column: 46X15 cm Chiralcel OH-H Washing solvent: 3% ethanol in heptane dimethylamine Flow: 0.6 ml / min Temperature: Surroundings UV: 280 nm % ee for (-) enantiomer: 96.4%.

containing

0.2% jfr

% ee for the (+) enantiomer: 96.6%.

Preparation of (+) -1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine, dihydrochloride.

Scheme III, Step F:

(+) - 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine (15.0 g, 34.5 mmol, prepared above) was diluted with methanol (40 mL). To this solution was added HCl (9.58 g of a 26.3% solution in methanol, 69.0 mmol). The mixture began to form gelatinously. looking crystals and gave a solid over minutes. To this mixture was added diethyl ether (100 mL) with vigorous stirring. The white solid was collected by suction filtration and then dried under reduced pressure at 45 ° C for two days to give the title compound (13.4 g, 76%) as a white solid;

Melting point (DSC) = 195.58 ° C

IR (CDCl ₃ , cm ^-1 ) 2976, 2939, 1700, 1502, 1462, 1451, 1267,

1243, .1021;

¹ H NMR (300MHz, DMSO) δ 7.40 (2H, η), 73.1 (3H, n) 7.03 (3H, M) 6.90 (1H, m) 3.78 (3H, s) 3.49 (4H, m) 3.16 (5H, m) 2.64 (1H, m) 2.40 (3H, n) 1.56 (3H, s) 1.46 (4H, n) 1, 11 (5H, m) 0.86 (1 H, m);

¹³ C NMR (300 MHz, DMSO) δ 213.46, 151.84, 139.56, 138.12, 128.72, 127.37, 126.86, 124.29, 120.85, 118.71, 112.29, 55.48, 54.06, 52.20, 50.78, 50.57, 46.93, 45.14, 30.31,

30.16, 25.15, 24.91, 24.89, 19.15;

HRMS:

· ♦. <· »· · Β β '·' · · · · · · · · ·

Calcd. For C 28 H 39 N 2 O 2 (MH ⁺ ) 435.3012.

Found 435.3018.

[α] ²⁵ D = +76.530 (c = 1, MeOH), ee 99.3% (Chiral HPLC).

Preparation of (+) -1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine, monohydrochloride.

Scheme III, Step F:

(+) - 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine (6.05 g, 13.9 mmol) was diluted with MTBE (120 mL) followed by addition of HCl solution. (2.2 M in isopropanol, 6.3 mL, 13.9 mmol, prepared from 0.80 g HCl gas in 10 mL isopropanol). The mixture formed an oil / solid mixture which, while stirring, gave a uniformly crystalline material. The mixture was vacuum filtered and rinsed with MTBE to give a white solid, which was dried under reduced pressure at 45 ° C (5.774 g, 96.2% ee).

(+) - 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3- (phenyl) butyl] piperazine monohydrochloride can be prepared in a similar manner as above from the equivalent of concentrated aqueous HCl instead of gaseous HCl.

Φ © φ φ φ φ

Alternative preparation of 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3- (phenyl) butyl] piperazine.

Preparation of 1-cyclohexyl-2-phenylpropanol.

Scheme IV, Step A:

To a solution of cyclohexylmagnesium chloride (50 / mmol) in 25 mL of Et ₂ O and 40 mL of THF at -5 ° C was added a solution of 2-phenylpropanaldehyde (5.36 g, 40 mmol) in 10 mL of THF. The reaction mixture was exothermic to 5 ° C. After stirring at ambient temperature for 75 minutes, the solution was poured into ice cold 1 N HCl, extracted with toluene, dried over MgSO ₄ and concentrated to give the title compound as a colorless oil (6.15 g, 70%):

¹ H NMR (d ⁶ -DMSO): δ 7.23-7.30 (m, 2H, phenyl CH), 7.15-7.22 (m, 3H, phenyl CH), 4.17-4.51 (br s, 1H, OH), 3.23 to 3.33 (m, 1H, R ₂ CHOH), 2.78 (dq, J = 7.0 Hz, J = 7.1 Hz, 1H, CH (CH 3) Ph), 1.23-1.83 (m, 6H, cyclohexyl CH), 1.20 (d, J = 6.9 Hz, 3H, -CH (CH ₃ ) Ph), 0.88- 1.18 (m, 5H, cyclohexyl CH).

λΛ

w · 9 9 '' »... - 8. · Β • · 9 ·· 9 9 9 · 9 9 9 '9 9 9 9 - 9 · · ·· «<* · ··

Preparation of cyclohexyl 1-phenylethyl ketone.

Scheme IV, Step 'B:

DMSO (118 mL, 1.6774 mol) was added dropwise to a solution of 126.42 g (0.579 mol) of 1-cyclohexyl-2-phenylpropanol in 1737 mL of CH ₂ Cl ₂ (cooled in an acetone ice bath). After 29 minutes, 147.93 g (1.0422 mol) of P2O5 was added. After 11 minutes, the cooling bath was removed. An aliquot in which the reaction was stopped with Et ₃ N showed completion of the reaction at 3 hours at reflux. The reaction mixture was cooled in an ice-acetone bath. Et ₃ N (282 mL, 2.0265 mol) was added dropwise to the cooled reaction mixture over 30 minutes. The cooling bath was removed and the mixture was stirred at reflux overnight. The reaction was stopped by dropwise addition of 500 mL of 3 N HCl (aq) (pH = 0). After shaking in a separatory funnel, the aqueous phase was removed. The organic phase was washed with 500 mL of 3 N HCl (aq) (pH = 0), washed twice with 1 L of 10% K ₂ CO ₃ (aq) (pH = 12; 12), washed three times with 500 mL of NaOCl, (aq), washed with 1 L of water, washed with 1 L of 25%. NaCl (aqueous), dried over MgSO ₄ , gravity filtered and concentrated under reduced pressure to collect Me ₂ S with dry ice. An amber oil of the title compound was obtained (107.01 g, 85.437%);

¹ H NMR (d ⁶ -DMSO): δ 7.30-7.37 (m, 2H, phenyl CH), 7.21-7.28 (m, 3H, phenyl CH), 4.08 (q, J) = 6.9 Hz, 1H, -CH _(CH3) Ph), 2.40-2.49 (m, 1H, cyclohexyl CH), 1.82-1.84 (m, 1H, cyclohexyl _-CH2) , 1.67-1.69 (m, 1H, cyclohexyl _-CH2), 1521.63 (m, 1H, cyclohexyl _-CH2), 1,34-1, 43 (m, 1H, cyclohexyl

-CH ₂ ), 1.26 (d, J = 6.9 Hz, 3H, -CH (CH ₃ ) Ph), 1.01-1.24 (m,

4H, cyclohexyl _-CH2).

.1 ·· '· «·· ··»' · · · · ♦ β

Preparation of 2-phenyl-2-methyl-4-pentenoylcyclohexane.

Scheme IV, Step C;

A solution of 31.39 g (0.2797 mol) t-BuOK in 100 ml THF was added dropwise to a solution of 55.00 g (0.2543 mol) cyclohexyl 1-phenylethyl ketone and 26.4 ml (0.3052 mol) allyl bromide in 136 ml of THF (cooled in an ice bath and acetone). THF (16 mL) was added to the reaction mixture. After the addition, the cooling bath was removed. After completion of the reaction (2 hours), the reaction was quenched with 300 mL of 1 N HCl (pH = 0) and the reaction mixture was extracted with 300 mL of heptane. The heptane extract was washed with 10% NaHCO ₃ (aq) (pH = 9), dried over MgSO ₄ , gravity filtered and concentrated under reduced pressure to yield 59.70 g (91.58%) of the title compound as a Amber oil:

^{Σ Η} NMR (d ⁶ -DMSO): δ 7.32-7.42 (m, 2H, phenyl CH), 7.24-7.31 (m, 3H, phenyl CH), 5,34-5, 47 (m, 1H, -CH = _CH2), 5.02 (dd, J =

17.1 Hz, d = 2.1 Hz, 1H, -CH-CH-H (trans)), 4.97 (ddd, d =

10.2 Hz, d = 2.2 Hz, d = 1.0 Hz, 1H, -CH = CH-H (cis, W-coupling)), 2.66 (ddd, J = 14.2 Hz, J = 6.9 Hz, d = _r 0 Hz, 1H, -CH ₂ CH = CH _2), 2.59 (ddd, d = 14.2 Hz, d = 7.3 Hz, J = 1.0 Hz, 1H, - CH ₂ CH = CH ₂ ), 2.38-2.49 (m, 1H, cyclohexyl CH), 1.48.1.69 (m, 4H, cyclohexyl-CH ₂ ), 1.46 (s, 3H, -CH (CH. ₃ ) Ph), 1.36-1.44 (m, 1H, cyclohexyl-CH ₂ ), 0.82-1.36 (m _from 1H, m / _z, 1H). 99 cyclohexyl - (¾) · φ 99 cyk cyk cyk cyk cyk cyk cyk

. Preparation of 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde.

. Scheme IV, Step D:

Ozone was bubbled through a turbid mixture of 56.50 g (0.2204 mol) of 2-phenyl-2-methyl-4-pentenoylcyclohexane and a small amount (about 10 mg) of Sudan III in 220 ml of MeOH (cooled in an acetone-dry ice bath at temperature). -20 ° C) for 4 hours until the pink color turned pale yellow. After all the oil had been consumed, it was added to the reaction mixture with Me2S (50 mL). The cooling bath was removed. The exotherm rose to 38 ° C and the mixture was cooled in a cooling bath until the temperature ceased. Then the cooling bath was removed and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure by trapping excess Me2S with dry ice to give 83.65 g of crude 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde dimethyl acetal as a pink oil:

^{Χ Η} NMR (d ⁶ -DMSO) δ 7.34-7.39 (m, 2H, phenyl CH3, 7.24-7.30 (m, 3H, phenyl CH), 3.99 (dd, J = 4.2 Hz, J = 5.9 Hz, 1H, CH (OCH ₃ ) ₂ ), 3.14 (s, 3H, CH _(OCH3) 2), 3.06 (s, 3H, CH _(OCH3) 2) r 2.34-2.43 (m, 1H, cyclohexyl CH), 2.10-2.20 (m, 2H, - CH ₂ CH (OCH ₃ ) ₂ ), 1 55-1.67 (m. 1H, cyclohexyl -CH 2), 1.53 (WITH,

3H, R ₂ C (CH ₃ ) Ph), 0 80-1.52 (m, 9H, cyclohexyl-CH ₂ ).

To a solution of 82.65 g (66.29 g, 0.2177 mol) of 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde dimethyl acetal in 539 mL of acetone was added 539 mL of 3 N HCl (aq) at reflux temperature . After completion of the reaction (2 h), the mixture was concentrated to 426.5 g (or 1/3 volume) of the residue (reflux 40 ° C). The residue contained mainly water (pH = 0) and was extracted twice with 300 ml MTBE. The MTBE extract was washed with 300 mL of 25% NaCl (aqueous), dried over MgSO 4, gravity filtered and concentrated to give 54.92 g (97.65%) of the title compound as a pink oil:

¹ H NMR (d ⁶ -DMSO): δ 9.54 (t, J = 2.0 Hz, 1H, -CHO), 7.36-7 / 45 (m, 2H, phenyl CH), 7.28 7.35 (m, 3H, phenyl CH), 2.95 (dd, J = 16.6 Hz, J = 1.9. Hz, 1H, CH ₂ CHO), 2.85 (dd, J = 16 6 Hz, J = 1.7 Hz, -1H, CH ₂ CHO), 2.41-2.49 (m, 1H, cyclohexyl CH), 1.72 (s, 3H, R ₂ C (CH ₃₎ (Ph), 0.85-1.66 (m, 10H, cyclohexyl CH2).

Preparation of the final title compound 1- (2-methoxyphenyl) -4- (3 (cyclohexanecarbonyl) -3- (phenyl) butyl] piperazine.

TV Scheme, Step E: .... ------ ...... _______

To a slurry of 13.72 g (0.05310 mol) of 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde and 11.57 g (0.05058 mol) of 1 (2'-methoxyphenyl) piperazine hydrochloride in 391 ml of CH ₂ C1 ₂ was added 9.7 mL of AcOH to form a homogeneous reaction mixture. 14.63 g (0.06904 mol) of NaBH (OAc) ₃ was added slowly to the reaction solution. After stirring for 4 days (the reaction should be completed within 2-5 hours) 200 mL of 1N HCl (aq) was added to stop the reaction (pH = 1). The mixture was extracted with 200 ml CH ₂ C1 _2nd The CH ₂ Cl ₂ extract was washed again with 200 mL 1 N HCl (aq) (pH = 1). Both HCl (aq). the washes were combined and stored. The organic extract was washed with 200 ml of 1N NaOH β: Φ ť · ·. tt · tttttt;

tt tt »» · 9 · 9) 9. . 9 9 tttttt ·

-'M · .- ·. Tt 9.9 (tt) tt ** (aqueous) (pH = 14). An emulsion was formed and was separated by adding 100 ml of water and 100 ml of MTBE. The organic phase was washed again with 200 mL of 1 N NaOH (aq) (pH = 14) and washed with 200 mL of 25% NaCl (aq), dried over MgSO 4. gravity filtered and concentrated to give 22.74 g of the crude title compound as an amber oil. HPLC analysis against a pure standard showed that the crude oil product contained 13.66 g (61.71%) of the title compound.

To the combined HCl washes was added 28.44 g NaOH (s) to basify the mixture (pH = 14). The cloudy mixture was extracted twice. 100 mL CH 2 Cl 2. The CH 2 Cl 2 extracts were combined, washed with 25% NaCl (aqueous), dried over MgSO ₄ , gravity filtered and concentrated to give 1.86 g of the amber oil oily residue it contained.

0.0969 (total = 62.15%) of the compound of %) 1- (2'-methoxyphenyl) piperazine. title and 1.05 g (10.8 ¹ H NMR (d ⁶ -DMSO): δ 7.35-7.43 (m,  2H, phenyl CH), 7.2 6-7.32 (m, 3H, phenyl CH), 6.89-6.96 (m, 2H, phenyl CH), 6.83-6.88 (m, 2H, * phenyl CH), 3.7 6- (s, . 3 .H, . OCH3) 2.80-3.03 (m, 4H, piperazine _CH2), 2,34-2, 49 (m, 4H, piperazine CH ₂ ), 1.91-2.24

(m, 4H), 1,52-1, 62 (m, 2H, cyclohexyl _CH2), 1.51 (s, 3H,

R ₂ C (CH ₃ ) Ph), 1.34-1.48 (m, 2H, cyclohexyl-CH ₂ ), 1.13-1.27 (m, 4H, cyclohexyl-CH ₂ ), 1.00- 1.10 (m, 2H, cyclohexyl _-CH2), 0.83-1.00 (m, 1H, cyclohexyl _-CH2).

· '· · ····· 9 9 · · · · ·

Φ 9 99 '· · Φ · j · 9 9 9 9'. 9

9 9. W «- ν?

Alternative preparation of the final title compound.

Preparation of enamine.

Scheme V, Step A:

To a solution of 1- (2'-methoxyphenyl) piperazine hydrochloride (25.00 g, 0.1093 mol) in water (42 mL) was added concentrated (29.4%) NH ₄ OH (aq.) ( pH = 9). The mixture was extracted twice with 250 mL of 1: 1. (v / v) THF: toluene. . The organic extracts were combined, dried over MgSO ₄ , gravity filtered and concentrated to give 20.17 g (96.00%) of 1- (2'-methoxyphenyl] piperazine as a pale green oil: - ......

1 H NMR (d ⁶ -DMSO): δ 6.90-6.97 (m, 2H, phenyl CH), 6.83-6.90 (m, 3H, phenyl CH), 3.77 (s, 3H) OCH ₃ ), 2.77-2.91 (xn, 8H, piperazine CH 2), 2.49-2.53 (m, 1H, NH).

A solution of 9.55 g- (0.0370 mol) of 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde in 10 ml of iPrOAc was added to 6.77 g (0.0352 mol) of 1- (2'-methoxyphenyl) piperazine without solvent. The mixture became cloudy and then converted to a solid after addition of 10 mL iPrOAc. The solid was suspended in 45 mL iPrOAC. After 1.5 hours the reaction was complete. The solid was vacuum filtered and washed with 10 mL iPrOAc and air dried to give 9.81 g (64.4%) of pure enamine as: '· Φ' Φ? *>. Φ · »Φ- <<'• · · · ··. ^: 'ι φ φ'

Φ Φ Ι · Φ φ ΦΦΦ · φ φ

·. Φ, '· · ·, * - - = - Τ • Φ'φ'φ. · '· Φ φ......... · · · · · · · · · <<<· · · · The filtrate was concentrated to give 6.40 g of crude enamine;

NMR (d ⁶ -DMSO): δ 7.31-7.43 (m, 2H, phenyl CH), 7.20-7.31 (m, 3H, phenyl CH), 6.82-7.04 (m 4H, phenyl CH), 6.06 (d, =

14.2 Hz, 1H, CR ₃ CH = CHNR ₂ (trans)), 4.98 (d, d = 14.2 Hz, 1H,

CR ³ CH = CHNR ² (trans)), 3.80 (s, 3H, OCH ₃ ), 2.93-3.15 (m, 8H, piperazine CH ₂ ), 2.38-2.49 (m, 1H, cyclohexyl CH), 1.59-1.72 (m, 2H, cyclohexyl _CH2), 1.47-1.59 (m, 2H, cyclohexyl _-CH2), 1.40 (s, 3H, R ₂ C (CH ₃₎ Ph), 1.21-1.34 (m, 3H, cyclohexyl _-CH2), 1.03-1.21 (m, 2H, cyclohexyl _-CH2), 0,83-1 03 (m, 1H, cyclohexyl _-CH2).

Preparation of the final title compound.

Scheme V, Step B:

To 5.35 g (0.00101 mol) of 5% Pd / C in a 500 ml ice-cooled Parr bath was added 8.68 g (0.0201 mol) of the enamine formed above. 40 ml of refrigerated IPA (-22 ° C) was added to the solid mixture. H ₂ 'was fed at 50 psi and the mixture was shaken for 2 days at reflux to terminate the reaction. The black slurry was vacuum filtered and concentrated to give 8.70 g of a colorless oil. The Pd / C catalyst was washed with 50 mL IPA with stirring. The black slurry was vacuum filtered. The filtrate was combined with 8.70 g of residue and concentrated to give 10.03 g of the title compound as a colorless oil.

Other compounds within the scope of the present invention that can be prepared by one skilled in the art by a method analogous to the procedures described above are as follows:

; · Ι *. · I i i i i i i i. I.... · * * · · · · · · · · ·

10) (+) -1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine, dihydrobromide;

11) (+) - 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine, monohydrobromide;

12) (+) - 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine, succinate, 1: 1;

13) (+) - 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine succinate 2: 1;

14) (+) - 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine, phosphate;

15) (+) - 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine, d-tartrate;

16) (+) -1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine, 1-tartrate;

17) (+) - 1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine, maleic acid;

Serotonin _1A receptor activity

Compounds of the present invention are selective antagonists of _A 1 receptor .serotoninu. Previously known Compounds with the .alpha. _1A receptor activity typically have the disadvantage of having other central nervous system effects. It is now well known to pharmacologists and physicians that pharmaceuticals that have a single physiological activity or that are far more effective in their desired manner than in their other activities are far more desirable for therapy than compounds (e.g., pindolol) that have multiple activities with approximately the same level.

Many other known serotonin receptor antagonists

_1A typically also has α-adrenergic, β-adrenergic or α-adrenergic activity

99 9 9 9 9 · · *. · · '9 9 9 9 · · “Φ * * * * * * * * * * *

9 99 9 9 9 · 9 9 9 99 · to dopamine-2 and therefore are not selective for _1A activity.

5-ΗΤχ _Α receptor binding capacity of the compounds of the invention was measured by modifying the binding assay described by Taylor et al. (J. Pharmacol. Exp. Ther., 236. 118-125,1986); and Wong et al., Pharm. Biochem. Behav. 46: 173-77 (1993). Binding assay membranes were prepared from male Sprague-Dawley rats. (150-250 g). Animals were sacrificed by decapitation and brains were rapidly cooled and dissected to obtain hippocampus. The hippocampus membranes were either prepared the same day or the hippocampes were stored frozen (-70 ° C) until the bottom of the preparation. Membranes were prepared by homogenizing tissue in 40 volumes of ice-cold Tris-HCl buffer (50 mM, pH 7.4 at 22 ° C) using a homogenizer for 15 seconds, and the homogenate was centrifuged at 39800xg for 10 minutes. The resulting pellet was then resuspended in the same buffer, and centrifugation and resuspension were repeated three more times to wash the membranes. Between the second and third washes, the resuspended membranes were incubated for 10 minutes at 37 ° C to facilitate removal of endogenous ligands. The resulting pellet was resuspended in 67 mM Tris-HCl, pH 7.4 to a concentration of 2 mg of the original wet tissue at 200 μΐ. This homogenate was stored frozen (-70 ° C) until the bottom of the binding assays. Each binding assay tube had a final volume of 800 μΐ and contained the following;

Tris-HCl (50 mM), pargylline (10 μΜ), CaCl ₂ (3 mM), [ ³ H] 8-OHDPAT (1.0 nM), appropriate dilutions of the test substance and equivalent resuspended membranes of 2 mg original wet tissue weight, with a final pH of 7.4. The test tubes were incubated for either 10 minutes or 15 minutes at 37 ♦ Φ. φφ 'φφ' φφ φ »♦ · '·· ·' 9 ·· 9 Φ t | ·

The contents were then rapidly filtered through GF / B filters (pre-moistened with 0.5% polyethyleneimine), followed by four washes with 1 ml ice-cold buffer. The radioactivity trapped on the filters was measured by liquid scintillation spectrometry and the specific [ ³ H] 8-OH-DPAT binding to the 5HT 1 sites was defined as the difference between [ ³ H] 8-OH-DPAT bound in the presence and absence of 10 µΜ 5-HT.

IC ₅₀ values, i.e., concentrations necessary to inhibit 50% binding, were determined from 12-point competition curves using non-linear regression (SYSTAT, SYSTAT, Inc., Evanston, II.). IC ₅₀ values were converted to Ki values using the Cheng-Prusoff equation. (Biochem. Pharmacol., 22, 3099-3108 (1973). All experiments were performed in triplicate.

Additional binding assays of some of the compounds of the invention were performed using an assay method that uses cloned cell lines that express the serotonin _1A receptor, instead of hippocampal membranes. Such cloned cell lines have been described by Fargin et al. J. Bio. Chem. , 264. 14848-14852 (1989), Aune et al., J. Immunology. 151, 1175-1183 (1993), and Raymond et al., Naunyn-Schmiebeberg's Arch. Pharmacol. _Λ 346, 127-137 (1992). The results from the cell line assay were basically in agreement with the results of the hippocampal membrane tests.

5HT1A antagonism, in vivo assays

a) 5HT _ia antagonism subcutaneous test

The compounds were tested in a wide range of subcutaneously administered doses for activity in blocking 8-OH-DPAT-induced behaviors and hypothermia. Lower lip tightening

»» > ·. ·. · · '·

(lower lip retraction - LLR) and fiat body posture - FBPj were recorded in male Sprague Dawley rats (approximately 250 grams, from Harlan Sprague Dawleyj. Both LLR and FBP were measured on a 0-3 scale (Wolff et al. In the LLR behavior test, 0 indicated normal lip position; 1 indicated slight lip retraction; 2 indicated that the muzzle was open with some teeth visible; 3 indicated that the muzzle was fully open with all front teeth exposed. An FBP score of 0 indicated normal ^: posture; 1 indicated that the stomach was at the floor and the butt was in its normal rounded position; 2 indicated that the stomach was at the floor and the butt was leveled and lifted from the shoulders to the hips; that the stomach was pressed to the floor and the butt was flattened and aligned with the shoulders and hips. Body temperature was recorded by a rectal probe inserted 5.0 cm immediately after the behavioral measurements. subcutaneous injection of compound (at doses of 0, 0.3, 1.0 and 3.0 mg / kg) 35 minutes before the score was determined and 8-OH-DPAT (0.1 mg / kg subcutaneously) was injected 20 minutes before determining the score.

b) · _la subcutaneous test 5HT agonism

The compounds were also tested at a high dose of 10 mg / kg subcutaneously on their own to determine if they induce hypothermia of the 5HT 1 _and agonist type.

The potent effect on the _1A serotonin receptors of the compounds of the invention gives them a variety of pharmaceutical and therapeutic applications. One such application is a method of helping people addicted to tobacco or nicotine use to break this habit.

V 'V «/ ·' '» »' '•• I · · ι ι! Ι' '' I I I β β β β β β β · · «·

Discontinuation of tobacco or nicotine use

It is well known that chronic administration of nicotine leads to tolerance and ultimately addiction. Tobacco use has become extremely widespread in all countries, despite the well-known adverse effects of tobacco use in all its forms. It is therefore clear that the use of tobacco is extremely addictive, if not addictive, and that its use brings the user feelings that are pleasant and welcome, even if the user is fully aware of the drastic long-term adverse consequences of using it.

Quite recently there have been strong campaigns against tobacco use and it is now widely known that smoking cessation brings a number of unpleasant withdrawal symptoms including irritation, anxiety, restlessness, lack of concentration, dizziness, insomnia, tremor, increased hunger and weight gain and naturally craving with tobacco.

Presently, nicotine replacement is the most widespread therapy to help stop tobacco use, using nicotine chewing gums or nicotine delivery transdermal patches. However, it is generally known that nicotine replacement is less effective without psychological treatment and exercise for changing habits.

The method of the present invention is widely applicable to assist persons intending to stop or reduce the use of tobacco or nicotine. Smoking is the most common form of tobacco use; cigarettes are the most common form of smoking.

11;

• ^f ·· . · * ·· _M '· <· ·' · '· •. í * · * · =: 9 '-99 4 · · · ^w 'l ·''* Λ *' · <0Φ · '* · · • · i4 · ·  ·· ‘94 <9 ·

However, the present invention also helps to break the habit of all types of tobacco smoking as well as taking tobacco by chewing, sniffing and the like. The method of the present invention also assists those who have replaced or partially substituted tobacco use by the use of nicotine in replacement therapy. Thus, such patients may be helped to reduce or even eliminate their nicotine dependence in all forms.

It will be appreciated that the present invention is useful for preventing or relieving withdrawal symptoms affecting patients who attempt to eliminate or reduce the use of tobacco or nicotine. Common withdrawal symptoms of such persons include at least irritability, anxiety, restlessness, lack of concentration, drowsiness, nervous tremor, increased hunger and weight gain, dizziness and craving for tobacco or nicotine. The prevention or alleviation of such symptoms when caused or related to discontinuation or reduction of the patient's use of tobacco or nicotine is a desirable outcome of the method of the present invention and its important aspect.

The present invention is practiced by administering an effective amount of a compound of Formula I or Formula Ia to a patient in need thereof, or by discontinuing or reducing the use of tobacco or nicotine.

As used herein, the term patient refers to a warm-blooded animal such as a mammal. The term patient includes human, dog, rat, mouse, and the like. Obviously, the preferred patient is human.

. .9 * 9 9'r * · - <

(··! «·> + ·>> • ♦ ♦ * * * * * - '-''''''''''''' ./ » '>*'^Φ;?S>··!>'·» ·· "··

An effective amount of a compound of formula (I); of formula Ia is the amount or dose of a compound that produces the desired effect in a patient diagnosed or in treatment. A compound of Formula I or Formula Ia, for administration, is effective over a wide dosage range and is generally in the range of about 1 to about 200 mg / day; as usual, the daily dose may be administered in one dose or in divided doses, depending on the judgment of the attending physician. A more preferred dosage range is from about 5 to about 5. about 100 mg / day; other dosage ranges that may be preferred in certain circumstances are from about 10 to about 50 mg / day; from about 5 to about 50 mg / day; from about 10 to about 25 mg / day; and a particularly preferred range is from about 20 to about 25 mg / day. Obviously, the dose for a given patient will always be determined by the attending physician and will vary depending on the size of the patient, whether the patient is lean or fat, the properties of the particular compound selected, the patient's tobacco addiction, the patient's withdrawal intensity symptoms and psychological factors that may affect the patient's physiological response.

The effect of the compounds in relieving the symptoms of nicotine discontinuation was evaluated in rats using the auditory startle test, which was performed as follows.

Study of nicotine discontinuation procedures

Animals: Male Long Evans rats were individually housed in a controlled environment with a 12-hour light-dark cycle. · T <· φ · · · ♦ ·· '·' ·· 9 • * '* - ·, ·· ·'. ♦ · · · · <. · '9 ·' »- '» - «ν ν ν 999 99 99 -99 '99 and were given free access to food (Purina Rodent Chow) and water, all containing 8-10 rats.

Chronic nicotine administration: Rats were anesthetized with halothane and implanted subcutaneously with an Alzet ™ osmotic minipump (Alza Corporation, Palo Alto, CA, Model 2ML2). Nicotine ditartrate was dissolved in saline. The pumps were filled with either nicotine ditartrate (6 mg / kg / day) or saline. Twelve days after implantation, the rats were anesthetized with halothane and the pumps were removed.

Auditory startle response: Sensory motor response [auditory startle response (peak amplitude Vmax)] of individual rats was recorded using San Diego Instruments lesson chambers (San Diego, CA). The session consisted of a five-minute adaptation period - with a background noise level of 70 + 3 dBA, immediately followed by 25 repetitions of auditory stimuli (noise '120 ± 2 dBA, duration 50 ms) presented at 8-second intervals ------- .. Then, the mean peak amplitude of response was determined for all 25 stimulus replicates in each series. Auditory startle response was evaluated at daily 24 hour intervals on days 1-4 after nicotine discontinuation. '

Combination with uptake inhibitors

A further application of compounds of formula I or formula Ia is their use in combination with serotonin reuptake inhibitors to further enhance the effect of these compounds by increasing the availability of serotonin as well as

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

®. »I. Ul®. ®._ ®. 99 * milnacipran, when increasing norepinephrine and dopamine, in the brain of the patient receiving the combination. Typical and suitable serotonin reuptake inhibitors (SRIs) are fluoxetine, duloxetine Accordingly, the present invention provides a method of potentiating the action of a serotonin uptake inhibitor, in particular an inhibitor selected from the group consisting of fluoxetine, duloxetine, venlafaxine, citalopram, fluvoxamine, and paroxetine, norepinamine, serotonin, and serotonin. The present invention also relates to pharmaceutical compositions comprising a serotonin reuptake inhibitor in combination with a compound of formula I or formula Ia and a method of treatment of the invention.pathological conditions that are caused or depend on a decrease in the availability of serotonin, dopamine or norepinephrine, the method comprising administering the same adjunctive therapy to a patient in need of such treatment.

Fluoxetine ,. N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine, is marketed as the hydrochloride salt and as a racemic mixture of its two enantiomers. U.S. Patent 4,314,081 is an initial reference to a compound. Robertson et al., J. Med. Chem., 31, 1412 (1988), describe the separation of the R and S enantiomers of fluoxetine and show that their activity as serotonin uptake inhibitors is similar in both. As used herein, the word fluoxetine is used for any acid addition salt or free base and includes both the racemic mixture and any of the R and S enantiomers.

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Duloxetine, N-methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine, is generally administered as the hydrochloride salt and (+) enantiomer. It was first disclosed in U.S. Pat. No. 4,956,388, which showed their strength.

The word duloxetine is used herein to refer to any acid addition salt or free base.

Venlafaxine is known in the literature and its method of synthesis and its activity as. serotonin and norepinephrine reuptake inhibitors are disclosed in U.S. Pat. Venlafaxine is described herein as Compound A.

Milnacipran (N, N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide) is described in U.S. Pat. No. 4,478,836, in which milnacipran is described in Example 4. The patent describes compounds referred to therein as antidepressants. Moret et al., Neuropharmacology 24, 1211-19 (1985), describes its pharmacological effects.

Citalopram, 1- [3- (dimethylaminolpropyl) -1- (4-fluorophenyl) 1,3-dihydro-5-isobenzofurancarbonitrile, is disclosed in U.S. Pat. No. 4,136,193 as a serotonin uptake inhibitor. Its pharmacology has been described by Christensen et al., Eur. J. Pharmacol., 41, 153 (1977) and a description of its clinical efficacy at. depression can be found in Dufour et al., Int. Clin. Psychopharmacol., 2 225 (1987) and Timmerman et al., Ibid., 239.

Fluvoxamine, 5-methoxy-1- [4- (trifluoromethyl) phenyl] -1-pentanone

66 - • • 99 99 99 9 9 • • 9 9 9 ...., f> 9: 9 '9.9 9 ’* '' · · ~ · · 9 Ί9 · 9 • e β , e · e ce ce θ ιφ β O

O- (2-aminoethyl) oxime is disclosed in U.S. Pat. No. 4,085,225. Scientific articles on this substance have been published by Claassen et al., Brit. J. Pharmacol., 60, 505 (1977); and De Wilde et al., J. Affective Disord., 4,249 (1982); and Benfield et al., Drugs. 32, 313 (1986).

Paroxetine, trans - (-) - 3 - ((1,3-benzodioxol-5-yloxy) methyl] -4 (4-fluorophenyl) piperidine, can be found in U.S. Patents 3,912,743 and 4,007,196.

Lassen, Eur. J. Pharmacol., 47. 351 (1978) ; Hassan a. kol., Briton. J. Clin. Pharmacol., 19. 705 (1985); Laursen and kol., Acta Psychiat. Scand., 71. 249 (1985); and Battegay and kol.,

Neuropsychobiologý. 13, 31 (1985).

All U.S. Pat. The patents mentioned above in connection with the compounds used according to the present invention are incorporated by reference. Generally, combinations and methods of treatment using fluoxetine or duloxetine as SRI are preferred.

One of skill in the art will recognize that all compounds used according to; of the present invention can form salts and that salts as a compound form are commonly used in pharmacy, often because they are easier to crystallize and purify than the free base. In any event, the use of the pharmaceutical agents set forth above is included within the scope of the invention, and many are preferred, and pharmaceutically acceptable salts of the compounds are included.

The dosage of the compounds included in the described combinations must ultimately be determined by the attending physician at i

Al) • 41 * 99 · 4 · 4 · 4 · 4 · 4 · · · · χ · χ · _ ·. .-. 5 ·· »• · _C '· -' 4 4 to 4 .9 ~ - '· · · Based on knowledge of the material properties of the substance in combination as determined in clinical trials, and the characteristics of the patient, including including diseases other than those for which the patient is being treated by the physician. General dosing principles and some preferred dosages are provided. The dosing principles of some of these agents are first administered separately; to create dosing principles for any desired combination, dosages for each component should be selected.

Fluoxetine: from about 1 to about 80 mg, once daily; preferably from about 10 to about 40 mg once daily; preferably for bulimia and obsessive-compulsive disease from about 20 to about 80 mg once daily;

Duloxetine: from about 1 to about 30 mg once daily; preferably from about 5 to about 20 mg once daily;

Venlafaxine: from about 10 to about 150 mg one to three times daily; preferably from about 25 to about 125 mg three times a day; _____.______ _______________________

Milnacipran: from about 10 to about 100 mg once to twice daily; preferably from about 25 to about 50 mg twice daily;

Citalopram: from about 5 to about 50 mg once daily; preferably from about 10 to about 30 mg once daily;

Fluvoxamine: from about 20 to about 500 mg once daily; preferably from about 50 to about 300 mg once daily;

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Paroxetine: from about 5 to about 100 mg once daily; preferably from about 50 to about 300 mg once daily.

More generally, the combinations of the present invention may be formed by selecting the dosage of SRI according to the spirit of the above formulas. I ranges.

base and select the dosage or formula Ia of the compound of the above

Complementary therapy of the present invention is performed by administering SRI together with a compound of Formula I or Formula Ia in any manner that delivers effective levels of both compounds in the body simultaneously. All contemplated compounds can be administered orally, and are normally administered orally, such that oral administration of a complementary combination. is preferred. The compounds may be administered together in a single dosage form or may be administered separately.

Oral administration, however, is not the only route or even the only preferred route. For example, transdermal administration may. be very desirable for patients who are forgetful or inaccessible when taking oral medicine. One may be administered by one route, such as the oral route, and the other may be administered transdermally, percutaneously, intravenously, intramuscularly, intranasally, or intrarecally in particular situations. The route of administration may vary in any manner, limited by the physical properties of the agent and the benefit to the patient and the caregiver.

• • •

However, additional combinations that are administered as a single pharmaceutical composition are particularly preferred and therefore pharmaceutical compositions containing both SRI and a compound of Formula I or Formula Ia are important embodiments of the present invention. Such compositions may take any physical form that is pharmaceutically acceptable, but orally useful pharmaceutical compositions are particularly preferred. Such supplementary pharmaceutical compositions comprise an effective amount of each of the compounds, the effective amount being based on the amount of the compound to be administered. Each supplemental dosage unit may contain a daily dose of both compounds or may comprise a portion of a daily dose, such as one-third of the daily dose.

Alternatively, each dosage unit may comprise the entire dose of one of the compounds and a portion of the dose of the other of the compounds. In such a case, the patient takes one dose unit of the combination and one or more units containing the other compound daily. The amount of each agent contained in each dosage unit depends on the dose selected for the therapy and other factors such as the indication for the adjunctive therapy. '

As mentioned above, the benefit of adjunctive therapy lies in its ability to enhance the availability of serotonin, norepinephrine and dopamine due to SRI compounds, resulting in increased efficacy in the treatment of various conditions, which are described in more detail below. The increase in serotonin availability is particularly significant and constitutes a further object of the present invention. The present invention is. further concerns

• a faster onset of action than occurs when administering SRI alone.

Preferred pathological conditions for treatment by the disclosed methods of adjunctive therapy include depression, bulimia, obsessive-compulsive disease, and obesity. Another preferred condition, which is more specific for combinations containing preferably duloxetine but also venlafaxine and milnacipran, is non-linear incontinence.

Depression in its many variations has recently become more visible to the general public than it was before. It is now recognized that this is an extremely damaging disorder that affects a surprisingly large proportion of the population. Suicide is the most extreme symptom of depression, but millions of people who are not so drastically affected live in poor conditions and in partial or total worthlessness and also affect the families of those affected. The introduction of fluoxetine has been a breakthrough in the treatment of depression, and depressive states are now more likely to be diagnosed and treated than just a decade ago.

Duloxetine is in a clinical trial for the treatment of depression.

Depression is often associated with, or caused by, other conditions and conditions. For example, it is related to Parkinson's disease; HIV; Alzheimer's disease; and abuse of anabolic steroids. Depression may also be related to substance abuse or may be related to behavioral problems arising or occurring in combination with head injuries, mental retardation or stroke. Depression in all its forms. is a preferred target of treatment according to the method of adjunctive therapy and compositions of the invention.

Settlement, cleaning and need or necessity

It appears that obsessive-compulsive disease has a large number of degrees and symptoms, generally associated with the patient's uncontrollable urge to perform useless ritualistic activities. Similarly, gripping activities beyond the rational represent a clear characteristic of the disease. Severely affected patients may be unable to perform anything other than the rituals imposed by the disease. Fluoxetine is approved in the United States and other countries for the treatment of obsessive-compulsive disease and has been found to be effective.

Obesity is a common condition that occurs in the American population. Fluoxetine has been found to allow an obese patient to lose weight, resulting in a beneficial effect on the patient's blood circulation and heart condition as well as on the general condition.

Urinary incontinence is generally classified as stress or urge to incontinence, depending on the main cause of the inability of the clamping muscle to control excretion or overactivity of the bladder muscles. -Duloxetine controls both types of incontinence or both at the same time and is therefore important for many people who suffer. this unpleasant and incapacitating disorder.

The combinations of the present invention are also useful in the treatment of many of the other diseases, disorders and conditions set forth below. In many cases, the diseases that are listed herein are classified. in the International Classification Diseases, 9th Edition (ICD), or in the Diagnostic and Statistical Manual of Mental Disorders, 3rd Revised Edition, published by the American Psychiatry Association (DSM) '. In such cases, ICD or DSM disease codes are given below.

Depression, ICD 296.2 & 296.3, DSM 296, 294.80, 293.81, 293.82,

293.83, 310.10, 318.00, 317.00

Migraine

Pain, especially neuropathic pain Bulimia, ICD 307/51, DSM 307.51

Premenstrual or Luteal Phase Syndrome, DSM 307.90 7 ·

Alcoholism, ICD 305.0, DSM 305.00 & 303.90 Tobacco Abuse, ICD 305.1, DSM 305.10 & 292.00 Panic Disorder, ICD 300.01, DSM 300.01 & 300.21 Anxiety, ICD 300.02, DSM 300.00 posttraumatic syndrome, DSM 309.89 memory loss, ..DSM .294.00 ___ dementia related to aging, ICD 290 .. social phobia, ICD 300.23, DSM 300.23 lack of concentration and hyperactivity, ICD 314.0 disruptive behavior, ICD 312 impulsive behavior, ICD 312, DSM 312.39 & 312.34 indeterminate personality, ICD 301.83, DSM 301.83 chronic fatigue syndrome premature ejection, DSM 302.75 erectile dysfunction, DSM 302.72 anorexia nervosa, ICD 307.1, DSM 307.10 sleep disorders, ICD 307.4

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autism mutism trichothilomania

In addition, the compounds of Formula I or Formula Ia are particularly useful for relieving symptoms of smoking cessation or nicotine use when administered in combination with a serotonin uptake inhibitor. The SRIs for use in the method and methods of administration and the formulations used have been described above. The use of the compounds of the invention in conjunction with SRI patients seeking to discontinue use of tobacco or nicotine provides surprisingly complete relief of usually painful and damaging symptoms in such patients including nervousness, irritability, craving, excessive appetite, anxiety, depression in many. forms, inability to concentrate and the like.

Therapeutic applications of the compound of Formula I or Formula Ia are useful for other important therapeutic purposes in addition to being used in combination with SRI and to stop nicotine or smoking. In particular, the compounds are useful for antagonizing them to the _1A serotonin receptors and are accordingly used to treat or prevent conditions caused or affected by excessive activity of this receptor.

Even more particularly, the compounds of Formula I or Formula Ia are useful for treating anxiety, depression, hypertension, cognitive disorders, psychosis, sleep disorders, gastric motility disorders, sexual dysfunction, cerebral

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trauma, memory loss, appetite and obesity disorders, substance abuse, obsessive-compulsive disease, panic disorder and migraine.

Anxiety and its frequent companion, panic disorder, may particularly be mentioned in connection with the compounds of the invention. This subject is explained in detail in the manual

Diagnostic and Statistical Manual of Mental Disorders, published by the American Psychiatry Association, where anxiety is classified in the 300.02 category. Another particularly mentioned disorder is depression and a group of depression-related disorders mentioned above in the discussion of adjunctive therapy together with SRI.

Pharmaceutical compositions

It is usual that the pharmaceutical agents have been administered in the form of pharmaceutical preparations for gaining control over the dosage and stability of the product during shipping and storing and _If conventional methods of ^- forming p-t-IP-ra-aged to Daj-í__plně__ apply compounds of formula I and formula Ia. Such compositions comprising at least one pharmaceutically acceptable carrier are valuable and novel due to the presence of the novel compounds of Formula I or Formula Ia. Although pharmaceutical chemists are aware of a number of effective methods for making pharmaceutical preparations whose

technology is applicable to the compounds of the invention, some discussion of this issue will be given below for the convenience of the reader.

Conventional methods of making pharmaceutical preparations which:

Are used in pharmacy and the usual types of compositions that can be used include tablets, chewable tablets, capsules, solutions, parenteral solutions, intranasal sprays or powders, lozenges , suppositories, transdermal patches and suspensions. Compositions generally comprise from about 0.5% to about 50% of the compound, depending on the desired dose and the type of composition to be used. However, the amount of a compound of Formula I or Formula Ia is best defined as an effective amount, i.e., that amount of compound that delivers the desired dose to a patient in need of such treatment. The activity of the compounds does not depend on the nature of the composition, so that the composition is selected and formulated as a pharmaceutical composition, preferably for convenience and economy. Any compound may be formulated as a preparation in any type of composition. Some discussion of the various compositions will be given, followed by some typical examples of preparations.

Capsules are prepared by mixing the compound with a suitable diluent and filling the capsules with an appropriate amount of the mixture. Conventional diluents include inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, cereal flour and the like edible powders.

Tablets are prepared by direct compression, wet granulation or dry granulation. Such compositions typically include diluents, binders, lubricants and disintegrants, and in addition a compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, phosphate or calcium sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as gelatin and sugars such as lactose, fructose, and the like. Natural and synthetic gums including gum arabic, polyvinylpyrrolidine and

Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

is starch, glucose, and preferably methylcellulose, are also alginates, like.

A lubricant is required in the tablet formulation to prevent sticking of the tablets and punches to the mold. The lubricant is selected from sliding solids such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

t

Tablet disintegrants are substances which swell when wetted and disrupt the tablet to release the compound. They include starches, clays, celluloses, algins and gums. More specifically, for example, corn and potato starches may be used. · Citrus pulp, and carboxymethylcellulose as well as sodium lauryl sulfate.

Enteric preparations are often used to protect the active ingredient from strongly acidic stomach contents.

Such formulations are formed by coating the dosage form with a thin layer of a polymer which is insoluble in acidic medium and soluble in basic medium. Examples of such materials are cellulose acetate phthalate, polyvinyl

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acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.

Tablets are often coated with sugars to impart taste and seal the tablet or with a film-forming preservative to alter the properties of the tablets with respect to dissolution. The compounds may also be prepared in the form of chewable tablets using a plurality of pleasant tasting agents such as mannitol, which is not currently a common practice. Instant soluble tablet formulations are now also frequently used to ensure that the patient ingests the dosage form and avoids the difficulty of swallowing a solid object, which makes it difficult for some patients.

If it is desired to administer the combinations as suppositories, conventional bases may be used. Cocoa butter is a traditional suppository base that can be modified by adding wax to slightly increase its melting point. Water-miscible suppository bases, including in particular polyethylene glycols of various oil and fat masses, are also widely used. _

Transdermal patches have also recently become widespread. Typically, they comprise a resinous composition in which the active ingredient is dissolved or partially and which is maintained in contact with the skin by a film that protects the composition. Many patents have recently appeared in this field. Other, more complicated compositions in the form of patches are also used, especially those whose membrane is interwoven with innumerable pores through which the active substance is pumped by osmotic action.

- · £ · • ·. . 4 »‘ 'R.

The following typical preparations are provided for the interest and information of the pharmacist.

Preparation 1

Hard gelatin capsules were prepared using the following ingredients:

Quantity (mg / capsule)

Example 1 20 May mg Dry starch .200 mg Magnesium stearate 10 mg Total 230 mg

Preparation 2

Tablets were prepared using the following ingredients:

Quantity (mg / capsule)

Example 2: —'- Cellulose, microcrystalline · Silica Stearic acid Total 10 mg___________ 400 mg 10 mg 5 mg 425 mg The ingredients were mixed and pressed to create weight 425 mg.

Preparation 3

Tablets containing 10 mg of active ingredient each were manufactured

as follows:

Example 3 10 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as a 10% solution in water) 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total 100 mg

The active ingredient, starch and cellulose were sieved through a No. 45 U.S. sieve. mesh and thoroughly mixed. The aqueous solution containing polyvinylpyrrolidone was mixed with the resulting powder and then sieved through a No. 14 U.S. sieve. Mesh. The granules so formed were dried at 50 ° C and passed through a No. 18 U 'sieve. S. mesh. Sodium carboxymethyl starch, lithium stearate, and tert-butyl pre-sieved through sulfur with a mesh size of U.S. Pat. they were then added to the granules which were compressed after mixing on a tabletting machine to obtain tablets weighing 100 mg.

Preparation 4 ’

Capsules, each containing 30 mg of active ingredient, were prepared as follows:

Example 4 Starch mg 59 mg> φ φ φ φ φ φ φ

Microcrystalline cellulose 59 mg

Magnesium stearate 2 mg

Total. 150 mg

The active ingredient, cellulose, starch, and magnesium stearate were mixed, sieved through a No. 45 U.S. sieve. and filled into hard gelatin capsules in an amount of 150 mg.

•and

Preparation 5.

Suppositories containing each 5 mg of active ingredient were produced as follows:

Example 5 5 mg Saturated fatty acid glycerides · 2,000. mg Total 2,005 mg

The active ingredient was sieved through a No. 60 U.S. sieve. The mixture of b-y-1-a then poured into the tics of a nominal capacity of 2 g was allowed to cool.

Preparation 6,

Suspensions, each containing 10 mg of active ingredient per 5 ml dose, were prepared as follows:

mg mg

Example β

Carboxymethylcellulose sodium Syrup

Benzoic acid solution

Flavoring

Dye

Purified water to volume

1.25 ml 0.10 ml

q.v.

q.v.

ml

The active ingredient was sieved through a No. 45 U.S. sieve. and mixed with carboxymethylcellulose sodium and syrup to form a fine paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added with stirring. The remaining water was then added to reach the desired volume.

Preparation 7

An intravenous formulation can be prepared as follows:

Example 7 ——-—---------—---- 10 mg_________ ______ ________

Isotonic solution 1,000 ml

Preparation 8

Hard gelatin capsules were prepared in an analogous manner

Formulation 1 using the following ingredients:

Amount (mg / capsule) of (+) -1- (2-Methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine. HCI mg ·· '4 ·

Dry starch 200 mg Magnesium stearate 10 mg Total 230 mg

Preparation 9

Tablets were prepared using the following ingredients:

Amount (mg / tablet) (+) - 1- (2-Methoxyphenyl) -4- [3; (cyclohexanecarbonyl) -3-

(phenyl) butyl] piperazine HCl .10 mg Cellulose, microcrystalline 400- mg Silica 10 mg Stearic acid 5 mg. Total 425 mg The ingredients were mixed and pressed for creation

weight 425 mg in a manner analogous to Preparation 2.

Preparation 10

Tablets, each containing 10 mg of active ingredient, were prepared as follows:

{+) - 1- (2-Methoxyphenyl) -4- [3 (cyclohexanecarbonyl) -3-

(phenyl) butyl] piperazine. HCl 10 mg Starch 45 mg Microcrystalline cellulose · 35 mg PolyvinyIpýrrolidon (as a 10% solution in water) 4 mg

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Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total 100 mg

The active ingredient, starch and cellulose were sieved through a No. 45 U.S. sieve. mesh and thoroughly mixed. The aqueous solution containing polyvinylpyrrolidone was mixed with the resulting powder and then sieved through a No. 14 U.S. sieve. Mesh. The granules so formed were dried at 50 ° C and passed through a No. 18 mesh U.S. sieve. 'mesh. Sodium carboxymethyl starch, magnesium stearate and talc, pre-sieved. were then added to the granules that were. after mixing, compressed on a tabletting machine to obtain tablets weighing 100 mg.

Preparation 11

Capsules, each containing 30 mg of the active ingredient, were prepared by the following formulation: - -: - (+) - 1- (2-) Methoxyphenyl) -4- [3-cyclohexanecarbonyl) -3-

(phenyl) butyl] piperazine. HCl 30 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 150 mg Represented by: dr. 0. Švorčík

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Claims (44)

PATENT CLAIMS A compound of the general formula in which,, Ar 1 'represents a mono or bicyclic aryl or heteroaryl radical substituted with one to three substituents selected from the group consisting of hydrogen, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio, (C C ₂ -C ₆ alkenyl, (C ₂ -C ₆ ) alkynyl, (C 1 -C ₆ ) alkylhalo, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen; R ¹ represents, a hydrogen atom, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, (C 1 -C ₆ ) alkylthio; R ² represents phenyl, naphthyl or. (C ₃ -C ₁₂ ) cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen, (C 1 -C 6) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio, (C ₂ -) C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C 1 -C ₆ ) alkylhalo, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or, halogen; R ³ is selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio, (C ₂ -C ₆ ) alkenyl, (C ₂ -C 6) alkynyl, (C 1 -C 8) alkylhalogen, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen; X represents - (C = O) -, -CHOH- or -CH ₂ -; • Φ φ φφ '> · · φφ φφ ^♦: · φ,' φ φ φ · · '. · • · _ · © · •' · φφφ φ Or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof. ' The compound of claim 1, wherein Ar 1 is phenyl or pyridine. The compound of claim 2, wherein Ar 1 is phenyl substituted with (C 1 -C 8) alkoxy. The compound of claim 3, wherein R ² is phenyl or (C 3 -C 12) cycloalkyl. A compound according to claim 4, wherein R ¹ represents a hydrogen atom. ^J The compound of claim 5, wherein X is -C = O. 7. A method of antagonizing a serotonin _1A receptor comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, racemate, optical isomer, or solvate thereof. . ' . 8. A method of alleviating symptoms caused by discontinuation or partial discontinuation of tobacco or nicotine use, comprising administering to a patient in need of such treatment an effective amount of a compound of formula (86). *. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Ar 1 represents a mono or bicyclic aryl or heteroaryl residue substituted with one to three substituents selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C 1 -C ₆ ) alkylhalo, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen; R ¹ represents a hydrogen atom, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkyl; Β) alkylthio; R ² represents phenyl, naphthyl or (C ₃ -C ₁₂ ) cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) and alkoxy, -C _1-6 alkylthio, _______ (C ₂ -C ₆ ) and 1 kenyl, _________ (C ₂ - ^: ------------- C ₆ ) alkynyl, (C 1 -C ₆ ) alkyl halide, (C ₃ -C ₈₎ cycloalkyl, (C ₃ -C ₈₎ cycloalkenyl or halo; R ³ is selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) ₆ ) alkynyl,. _(Ci-C6) alkylhalo, (C ₃ -C ₈₎ cycloalkyl, (C ₃ -C ₈₎ cycloalkenyl or halo; X represents - (C = O) -, -CHOH- or -CH ₂ -; or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof. The method of claim 8, wherein the compound tt is tt 1- (2-methoxyphenyl) -4- [3- (benzoyl) -3- (phenyl) propyl] piperazine; 1- (2-pyridyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) propyl] piperazine; 1- (2-ethoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) propyl] piperazine hydrochloride; 1- (2-methoxyphenyl) -4- [3- (benzoyl) -3- (phenyl) butyl] piperazine oxalate; l ^ (2-methoxyphenyl meth ^about «t ^ 4 ^r 3 - ^{'(fGykl-cyclohepta; ankarboriyl,')} = ^ ^5: *** ^ * ~ * ~ ^{,, **, ***,} **** ^{:;:; i} (phenyl) propyl] piperazine hydrochloride; 1- (2-methoxyphenyl) -4- [3- (cyclopentanecarbonyl) -3- (phenyl) propyl] piperazine Hydrochloride; and 1- (2-methoxyphenyl) -4- [4- (cyclohexyl) -4- (hydroxy) -3 (phenyl) butyl] piperazine oxalate. 10. A method of treating anxiety comprising administering to a patient in need of such treatment an effective amount of a compound of the formula wherein: Ar 1 represents a mono or bicyclic aryl or heteroaryl residue substituted with one to three substituents selected from the group consisting of. hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C 1 -C ₆ ) alkylhalo, (C ₃ -C 6) cycloalkyl. (C ₃ -C ₈ ) cycloalkenyl or halogen; R ¹ represents hydrogen, _(Ci-C6) alkyl, _(Ci-C6) alkoxy, (C ~ 0 _δ) alkylthio; R ² represents phenyl, naphthyl or (C ₃ -C ₁₂ ) cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (- _δ 0) alkylthio, (C ₂ -C ₆₎ alkenyl, _(C2 ^ alkynyl ^^ Ge-lT-S ^^^ ^ er ^ CfJ TkýlíiSlogěn, "(" C ₃ -C ₈₎ cycloalkyl, (C ₃ C ₈ ) cycloalkenyl or halogen; R ³ is selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio, (C ₂ -C ₆ ) alkenyl, (C ₂ - _C6) alkynyl, _(Ci-C6) alkylhalo, (C ₃ -C ₈₎ cycloalkyl, _{(C3. G)} cycloalkenyl or. a halogen atom; X represents -, (G-O) -, -CHOH- or -CH ₂ -; or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof. 11. A method of treating depression, hypertension, cognitive disorders, psychosis, disorders. sleep, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, appetite disorders - food, obesity, substance abuse, obsessive-compulsive disease, panic disorder or migraine, characterized in that it comprises administration to a patient in need of such treatment,. an effective amount of a compound of formula 9 46 46 9 9 · · 9 4 · 9 99 4 4 4 4 9 9 9 9 s' e. «· 9 * * 4 * · - · · ♦ · · 9/9 · · · · 4. · · 9 .9 · 9 4 4 β 9 9 9 9 Wherein the heteroaryl residue is substituted with one to three substituents selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C 1 -C ₆ ) alkylhalo, - (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen; R ^{* 1} represents a hydrogen atom, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio; R ² represents phenyl, naphthyl or (C ₃ -C ₁₂ ) cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, and C ₁ -C ₆ alkyl; ..... (Ch _F-C.) Alkylthio, -------- (C ₂ -C ₆₎ alkenyl?, --------- (C ₂ -C ₆₎ alkynyl, ( _Ci-C6) alkylhalo, (C ₃ -C ₈₎ cycloalkyl, (C ₃ .. _C8) cycloalkenyl or halo; i 3 R is selected from the group consisting of hydrogen, (C 1 -C 6) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆₎ alkynyl, (C 1 -C ₆ ) alkylhalogen, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen; X represents - (C = O) -, -CHOH- or -CH ₂ -; or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof. ) 12. A method of potentiating the action of an uptake inhibitor, serotonin, by increasing the availability of serotonin, norepinephrine, and Dopamine in the brain, characterized in that it comprises administering to a patient in need of such treatment a serotonin reuptake inhibitor. in combination with an effective amount of a compound of the formula wherein: Ar '. represents a mono or, bicyclic aryl or heteroaryl radical substituted with one to three substituents selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio, (C ₂ -) Cg) alkenyl, (C ₂ -C ₆₎ .alkinyl,. (C 1 -C ₆ ) alkylhalo, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen; __R ¹ idea is. and leads to it. (Χ C - _C6) alkyl and 1 1, - (C -Cg) and 1 ko xy (C χ Cg) alkylthio; R ² represents phenyl, naphthyl or (C ₃ -C ₁₂ ) cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₂ -C ₆₎ alkenyl, _(C2 Cg) alkynyl, (Οχ-Cg) alkylhalo, (C ₃ -C ₈₎ cycloalkyl, (C ₃ -C ₈₎ cycloalkenyl or halo; R ³ is selected from the group consisting of hydrogen, a group (C-Cg) alkyl, (Cx-Cg) alkoxy, (Οχ-Cg) alkylthio, _(C2 -Cg) alkenyl, (C ₂ -C ₆₎ alkynyl, (C 1 -C ₆ ) alkylhalo, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen; - 91 · g 91, 91 91 91 g g g g g g * T _# <* * φ · «··· ··· o © β β e ο β β X represents - (C = O) -, -CHOH- or -CH ₂ -; or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof. ‘ 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1. 14. The method of claim 8, wherein the effective amount of Serotonin ⁴ is effective. 15. The method of claim 14 wherein the serotonin uptake inhibitor is fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram, fluvoxamine. or paroxetine. 16. A method of assisting a patient in stopping or reducing the use of tobacco or nicotine, comprising administering to the patient an effective amount of a compound of formula. . <, in which Ar 1 represents a mono or bicyclic aryl or heteroaryl radical substituted with one to three substituents selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio, 92 (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C 1 -C ₆ ) alkylhalogen, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen; R ¹ is hydrogen, (C ₁ -C ₆₎ alkyl, _(Ci-C6) alkoxy, _(Cl-C6) alkylthio; R ² represents phenyl, naphthyl or (C ₃ -C ₁₂ ) cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) ₆₎ alkylthio, (C ₂ -C ₆₎ alkenyl, (C ₂ G ^ o ^ 1 t al křny **** (j-C ^ C ^^ kýlte ógéhT CCI ^^^ ^ e ^ l ^ aiy klb alkyl 17 * (** C 3 -C ₈ ) cycloalkenyl or halogen; R ³ is selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio, (C ₂ -C ₆ ) alkenyl, (C ₂ - C ₆ ) alkynyl, (C 1 -C ₆ ) alkylhalo, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen; X represents - (C = O) -, -CHOH- or -CH ₂ -; or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof. A compound of the formula:. or a pharmaceutically acceptable salt thereof. A compound which is (+) -1- (2-methoxyphenyl) -4- [3cyclohexanecarbonyl) -3- (phenyl) butyl] piperazine and its Pharmaceutically acceptable salts. The compound of claim 18, wherein the acceptable salt is a dihydrochloride salt which is pharmaceutically The compound of claim 18, the acceptable salt being the oxalate salt. in which pharmaceutically ^H!, Compound ^'1' '' ^ ** pddl iiáTPku ^w '* ^ * 8T ^ ve ^ * Msfeeré armaceufci £ IKI> acceptable salt is a maleate salt. The compound of claim 18, wherein the pharmaceutically acceptable salt is a phosphate salt. A compound which is a monohydrochloride. (+) -1- (2-methoxyphenyl) -4- [3- (cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine. - ¹ · 24. A method of alleviating the symptoms of discontinuation or partial discontinuation of tobacco or nicotine comprising administering to a patient in need of such treatment an effective amount of a compound of the formula: CH Or a pharmaceutically acceptable salt thereof. 25. A method of alleviating the symptoms of discontinuation or partial discontinuation of tobacco or nicotine use comprising administering to a patient in need of such treatment an effective amount of (+) - 1- (2-methoxyphenyl) -4- [3-cyclohexanecarbonyl) - 3 (phenyl) butyl] piperazine nébcr * ^j'ehd, fármaeeut4-Gky «« »at-.jatelné. salts. 26. A method of potentiating the action of a serotonin reuptake inhibitor by increasing the availability of serotonin, norepinephrine and dopamine in the brain, comprising administering to a patient in need of such treatment a serotonin reuptake inhibitor in combination with an effective amount of a compound of formula or a pharmaceutically acceptable salts. 27. A method of potentiating the action of a serotonin reuptake inhibitor by increasing the availability of serotonin, norepinephrine and dopamine in the brain, comprising administering to a patient in need of such treatment a serotonin reuptake inhibitor in combination with an effective amount of (+) 1- (2-). methoxyphenyl) -4- [3-cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine or a pharmaceutically acceptable salt thereof. 28. The method of claim 27, wherein the serotonin reuptake inhibitor is fluoxetine. ......... I ¹¹¹ 'Ί li 29. A method of antagonizing receptor 1 _and serotonin, comprising administering to a patient in need of such treatment an effective amount of (+) - 1- (2-methoxyphenyl) -4- (3-cyclohexanecarbonyl) -3- ( phenyl) butyl] piperazine or a pharmaceutically acceptable salt thereof. 30. A method of treating anxiety comprising administering to a patient in need of such treatment an effective amount of (+) - 1- (2-methoxyphenyl) -4- [3cyclohexanecarbonyl) -3- (phenyl) butyl] piperazine or pharmaceutically acceptable salts thereof. '' ' A method of treating depression, hypertension, cognitive disorders, psychosis, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, appetite disorders, obesity, substance abuse, obsessive-compulsive disease, panic disorder or migraine, characterized by comprising administering to a patient in need of such treatment an effective amount of (+) - 1- (2-methoxyphenyl) -4 [3-cyclohexanecarbonyl) -3- (phenyl) butyl] piperazine or a pharmaceutically acceptable salt thereof. Υ. ⁹ . ⁶ 32. A method of assisting a patient in interrupting or reducing the use of tobacco or nicotine, comprising administering to the patient an effective amount of a compound of formula or a pharmaceutically acceptable salt thereof. 33. A method of assisting a patient in interrupting or reducing tobacco or nicotine use, comprising administering to the patient an effective amount of (+) -1- (2-methoxyphenyl) -4- [3-cyclohexanecarbonyl) -3 (phenyl) butyl] piperazine. or a pharmaceutically acceptable salt thereof. 34. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and (+) - 1- (2-methoxyphenyl) -4 [3-cyclohexanecarbonyl) -3- (phenyl) butyl] piperazine or a pharmaceutically acceptable salt thereof. 35. A process for preparing a compound of formula II: AND R ¹ represents a hydrogen atom, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, (C 1 -C 8) alkylthio; R ² represents phenyl, naphthyl or (C ₃ -C ₁₂ ) cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, (C 1 -C 8) alkylthio,. (C ₂ -C ₆ ) alkenyl, (C ₂ -C 6) alkynyl, (C ₁ -C ₆ ) alkylhalo, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen; R ³ is selected from the group consisting of hydrogen, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, (C 1 -C 8) alkylthio, (C ₂ -C 8) alkenyl, (C ₂ -C 8) alkynyl, J C ₁ -C 8 cg) alkylhalo, (C ₃ -C ₈₎ cycloalkyl. (C ₃ C ₈ ) cycloalkenyl or halogen, which comprises treating the compound of formula III III Wherein R ¹ , R ² and R ³ are as defined above, with a suitable base and a compound of formula IV: IV wherein X is a suitable leaving "group, for ^'1 j - ¹ *.]' - ·. .f -. ιι --- ί; ή,> ιΐι. -—. ---- .- 1.- r-i » ¹ -1. · - ...................... ----- <obtaining a compound of the general formula in ***? - · ή ....... and oxidizing a compound of formula V with a suitable oxidizing agent to obtain a compound of formula II. 36. The method of claim 35, wherein: R ¹ represents CH 3; R ² is cyclohexyl; and R ³ represents a hydrogen atom. The method of claim 36, wherein X is Br or Cl. 38. The method of claim 37, wherein the suitable oxidizing agent is ozone. 39. The process of claim 38 wherein the suitable base is potassium tert-butoxide. 40. A compound of the formula: in which "·.··. R ¹ represents a hydrogen atom, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C 6) alkylthio; R ² represents phenyl, naphthyl or (C3-C12) cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen, _(Ci-C6) alkyl, (C, -C ₆₎ alkoxy, (C ₆ -C ) alkylthio, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, (CH-Cg). halogen, a '(C ₃ -C ₈₎ cycloalkyl, (C ₃ C _8). cycloalkenyl or halo; R ³ is selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) ₆ ) alkynyl, (C 1 -C 8) alkylhalo, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen. The compound of claim 40, wherein R ¹ is CH ₃ ; R ² is cyclohexyl; and R ³ represents a hydrogen atom. - ιυυ 42. A compound of the formula: R ¹ represents a hydrogen atom, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, (C 1 -C 6) alkoxy, C ₆ ) alkylthio; · R ² is phenyl, naphthyl. or (C 3 -C 12) cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen, (C 1 -C 6) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio, (C ₂ -) j C ₆ alkenyl, (C ₂ Οβ) alkynyl, _(Ci-C6) alkylhalo, (C ₃ -C ₈₎ cycloalkyl, (C ₃ -C ₈₎ cycloalkenyl or halo; R ³ is selected from hydrogen, groups (C, ₆₎ alkyl, _(Ci-C6) alkoxy, _(Ci-C6) alkylthio, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₆ ) alkynyl, (C 1 -C ₆ ) alkylhalo, (C ₃ -C ₈ ) cycloalkyl, (C ₃ , C ₈ ) cycloalkenyl or halogen. A compound according to claim 42, wherein R ¹ is methyl R ² is cyclohexyl; and R ³ represents a hydrogen atom. 44. A compound of the formula: -_101 tttt ·· ·· • tt tttt tttttt 9 tt tttttt · «'•“ tt- tt · • · · tttt 1 «tt '· tttttt ·· 9 9 tttt tttt in which“ ^ ™ ^Γ , Λ * ^Λ · ^ι ' ρ S ú ú ú ú ú ú ú ú ú ú ú ú ú ** ** ** ** a heteroaryl radical substituted with one to three substituents selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C 1 -C ₆ ) alkylhalo, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen; R ¹ represents a hydrogen atom, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio; R ² represents phenyl, naphthyl or (C ₃ -C _i2) cycloalkyl substituted with one 'or two substituents selected from the group consisting of hydrogen, _(Ci-C6) alkyl, (C-Cg) alkoxy, --- d C ₁ -C ₆ alkylthio, ---------- (C ₂ -C ₆ ) alkenyl,. . (C ₂ -C ₆ ) alkynyl, (C 1 -C ₆ ) alkylhalo, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen; R ³ is selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) ₆ ) alkynyl, (C 1 -C ₆ ) alkylhalogen, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl or halogen; or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof. The compound of claim 44, wherein Ar 1 is - 102 L, »vj> O-CH, ·· »· f ······················ R ¹ represents methyl ^^^ introduc AVU e ^ ^'u'? 1 <L ^"Kex, characterized R" and "R ³ represents hydrogen.