US20020013324A1

US20020013324A1 - N-substituted imide derivatives with serotonergic activity

Info

Publication number: US20020013324A1
Application number: US09/938,016
Authority: US
Inventors: Wayne Childers; Michael Kelly; Gan Zhang; Yvette Palmer; Edward Podlesny
Original assignee: American Home Products Corp
Current assignee: Wyeth LLC
Priority date: 1999-03-02
Filing date: 2001-08-23
Publication date: 2002-01-31
Also published as: US6306859B1

Abstract

Compounds of the Formula (I)

wherein R₂, Y, X and n are as defined in the specification which compounds are useful in the treatment of disorders associated with serotonergic neuron-related diseases.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No. 60/160,089, which was converted from U.S. patent application Ser. No. 09/261,298, filed Mar. 2, 1999 pursuant to a petition filed under 37 C.F.R. 1.53 (c) (2) filed Jun. 8, 1999.[0001]

FIELD OF THE INVENTION

The present invention relates to a series of novel N-substituted imide derivatives and non-toxic salts thereof, which have a high affinity for the serotonin 5-HT _1Areceptor, acting as partial agonists and antagonists and are useful for preventing and treating serotonergic neuron-related diseases.

DESCRIPTION OF THE PRIOR ART

It is known that serotonin [5-hydroxytryptamine (5-HT)] as a neurotransmitter has correlations with various physiological phenomena, such as appetite, memory, thermoregulation, sleep, sexual behavior, anxiety, depression and stress [Glennon, R. A., J. Med. Chem., 30, 1 (1987)].

It is also known that compounds acting on a 5-HT _1Areceptor which is one of the serotonin-susceptive receptors are useful for preventing and treating anxiety, depression, eating disorders, high blood pressure and emesis. Results of studies on various compounds have been reported [see “Nippon Rinsho (Japanese Journal of Clinical Medicine)” vol. 47, special edition. pp. 1241-1248 (1989); J. P. Feighnev, W. F. Boyer, Psychopathology, 22, 21 (1989); P. R. Saxena, C. M. Vilialon,.TIPS, 11, 95 (1990); N. Matsuki, et al., Jpn. J. Pharmacol. Suppl., 58, 313 (1992).

Compounds having selective partial agonist activity at he 5-HT _1Areceptor have established a presence in the marketplace as effective anxiolytic agents (buspirone HCl, 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione monohydrochloride, U.S. Pat. No. 3,717,634). 5-HT_1Aagonists and antagonists are being evaluated in the laboratory and in the clinic for use in the treatment of several diseases such as anxiety, depression, schizophrenia, the cognitive deficits resulting from neurodegenerative diseases like Alzheimer's Disease, and additionally prostate cancer (K. Rasmussen and V. P. Rocco, Recent Progress in Serotonin (5-HT_1A Receptor Modulators, in Annual Reports in Medicinal Chemistry, Volume 30, J. A. Bristol, ed., pp. 1-9 (1995)).

A series of naphylpiperazines useful as 5-HT _1Areceptor ligands having the generic structure:

are described in EPO 434561-A2 andl U.S. Pat. Nos. 5,143,916; 5,162,321; 5,162,324; 5,166,156 and 5,166,157.

Reported in WO 9640136-A1 is a series of N-(piperidinyl or piperazinyl alkyl)phenyl acetamnide derivatives as alpha 1a ardenergic receptor antagonists having the generic formula:

EP 795328-A1 discloses a new use for naphthalene serotonin 5-HT _1Dreceptor antagonists of the generic formula:

as inhibitors of cell growth in human small cell lung carcinoma, where R ₁is a moiety of formulae:

Reported in GB 2303303-A is a method of using 5HT _1Aor 5HT₂receptor antagonists of the formulae:

for preventing or reducing the side effects of serotonin re-uptake inhibitors

Reported in DE 19520499-A1, WO 9608480A1, and U.S. Pat. Nos. 5,696,123 and 5,708,006 is a series of aralkyl amines, amides and ureas as neurokinin antagonists.

The N-substituted imide derivatives or pharmaceutically acceptable salts thereof of the present invention and described herein are useful in the treatment of disorders associated with serotonergic neuron-related diseases such as anxiety, depression, eating disorders, high blood pressure, emesis, schizophrenia, the cognitive deficits resulting from neurodegenerative diseases of Alzheimer's Disease and additionally prostate cancer.

SUMMARY OF THE INVENTION

Accordingly, the present invention discloses compounds represented by Formula (I):

wherein:

n is an integer of 0 to 5;

X is a moiety selected from the group consisting of:

Y is a moiety selected from the group consisting of:

R ¹is aryl of 6 to 12 carbon atoms optionally substituted with one or more substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; heteroaryl having 5 or 6 ring atoms containing 1 to 3 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 substituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen; bicyclic heteroaryl having 8 to 20 ring atoms containing 1 to 3 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur optionally substituted with 1 to 3 substiluents which may be the same or different, selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen;

R ₂is independently H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydroxy, —(CH₂)_z—O—alkyl of 1 to 6 carbon atoms , —(CH₂)_z—S-alkyl of 1 to 6 carbon atoms, —(CH₂)_zOH, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms , —CN, —NO₂, and halogen; aryl of 6 to 12 carbon atoms optionally substituted with one or more substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN,—NO₂, and halogen; heteroaryl having 5 or 6 ring atoms containing 1 to 3 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 substituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen; bicyclic heteroaryl having 8 to 20 ring atoms containing 1 to 3 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur optionally substituted with 1 to 3 substituents which may be the same or different, selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen;

z is an integer of 1 to 3;

R ₄is independently cycloalkyl or cycloalkenyl of 3 to 10 carbon atoms;

R ₄is aryl of 6 to 12 carbon atoms optionally substituted with one or more substituents selected from alkyl of 1 to 6 carbon atoms, cyclolkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perlialoalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; having 5 or 6 ring atoms containing 1 to 3 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 substituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen; bicyclic heteroaryl having 8 to 20 ring atoms containing 1 to 3 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur optionally substituted with 1 to 3 substituents which may be the same or different, selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen;

with the proviso that X is not the radical

when R ₅is H, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and hydroxyl; n is 0; R₂is H; Y is the radical

and R ₄is phenyl substituted with three substituents which are the same or different selected from H, halogen, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.

Among the preferred compounds of Formula (I) of this invention are those in the subgroups, and pharmaceutically acceptable salts thereof:

a) compounds having the general formula:

wherein:

R ₂, R₃, X and n are hereinbefore defined;

b) compounds having the general formula:

wherein:

R ₂, R₄, X and n are hereinbefore defined;

c) compounds having the general formula:

wherein:

R ₂, R₃, R₄, X and n are hereinbefore defined;

d) compounds of the general Formula (I)

wherein:

R ₄is selected from phenyl optionally substitute with 1 or 2 substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perlhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; 2 or 3-furyl, 2 or 3-thionyl, 2-,3- or 4-pyridyl, indolyl, azaindolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, benzodioxanyl, beinzopyranyl, benzofuranyl, dihydrobenzofuranyl, beenzothiophenyl, benzothiazolyl, benzothiadiazolyl, benzooxazolyl and 2,3-dihydro-benzo[1,4]dioxin; and R₂, R₃, R₄, X and n are hereinbefore defined;

e) compounds of the general Formula (I)

wherein:

R ₂is selected from H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydroxy, —(CH₂)_z—O—alkyl of 1 to 6 carbon atoms, —(CH₂)_z-S-alkyl of 1 to 6 carbon atoms, —(CH₂)_zOH, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; phenyl optionally substituted with 1 or 2 substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, and perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; 2 or 3-furyl, 2 or 3-thienyl, 2-,3- or 4-pyridyl, indolyl, azaindolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzopyranyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, benzothiazolyl, benzothiadiazolyl, benzooxazolyl and 2,3-dihydro-benzo[1,4]dioxin; and R₁, R₃, R₄, Y, X, z and n are hereinbefore defined;

Among the more preferred compounds of Formula (I) of this invention are those in the subgroups, and pharmaceutically acceptable salts thereof:

a) compounds having the general formula:

wherein:

R ₁, R₂, R₃, and n are hereinbefore defined;

b) compounds having the general formula:

wherein:

R ₁, R₂, R₄and n are hereinbefore defined;

c) compounds having the general formula:

wherein:

R ₁, R₂, R₃, R₄, and n are hereinbefore defined;

d) compounds having the general formula:

wherein:

R ₁is phenyl optionally substituted with one or two substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms,, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; indolyl and 2,3-dihydro-beizo[1,4]dioxin; and R₂and n are hereinbefore defined;

e) compounids having the general formula:

wherein:

R ₁is phenyl optionally substituted with one or two substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; indolyl and 2,3-dihydro-benzo[1,4]dioxin;

R ₄is phenyl, optionally substituted with one, two or three substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perlaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; and

R ₂and n are hereinbefore defined;

wherein:

R ₁is phenyl optionally substituted with one or two substituents selected alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; indolyl and 2,3-dihydro-benzo[1,4]dioxin;

R ₄is phenyl, optionally substituted with one, two or three substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; and

R ₂and n are hereinbefore defined.

Among the most particularly preferred compounds of this invention according to general Formula (I) are the following compounds or pharmaceutically acceptable salts thereof for the method of treating disorders associated with serotonergic neuron-related diseases such as anxiety, depression, eating disorders, high blood pressure, emesis, schizophrenia, the cognitive deficits resulting from neurodegenerative diseases of Alzheimer's Disease and additionally prostate cancer:

Cyclohexanecarboxylic acid cyclohexaniecarbonyl-{2-[4-(2-methoxyphenyl)-piperazin-yl]-ethyl}-amide dihydrochloride;

Cyclohexanecarboxylic acid cyclohexanecarbonyl-{2-[4-(1H-indol-4-yl)-piperazin-1-yl]-ethyl}-amide dihydrochloride;

Cyclohexanecarboxylic acid cyclohexanecarbonyl-{2-[4-(2,3-dihydro-benzo[1,4]-dioxin)-5-yl}-piperazin-1-yl]-ethyl}-amide sesquihydrochloride monohydrate;

(R)-Cyclohexanecarboxylic acid cycloliexanecarbonyl-{1-methyl-2-[4-(2-methoxyphenyl)-pipcrazin-1-yl]-ethyl}-amide fumarate;

(R)-Cyclohexaniecarboxylic acid cyclohexanecarbonyl-{1-(4-benzyl)-2-[4-(2-methoxy-phleniyl)-piperazin-1-yl]-ethyl}-amnide fumarate;

(R)-Cyclohexanecarboxylic acid cyclohexanecarbonyl-{1-(4-methoxybenzyl)-2-[4-(2-methoxyphenyl)-piperazini-1-yl]-ethlyl}-amide hydrochloride;

(R)-Cyclohexanecarboxylic acid cyclohexanecarbonyl-{1-[4-(2-methoxyphelnyl)-piperazin-1-ylmethyl]-2-(1-methyl-1H-indol-3-yl)ethyl}-amide hydrochloride monohydrate;

Cyclohexanecarboxylic acid {2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl-]ethyl}-amnide;

Cyclohexanecarboxylic acid benzoyl-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-ylethyl]-amide hydrochloride sesquihydrate;

N-Benzoyl-N-{-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-benzamide hydrochloride hemihydrate; and

(R)-N-Benzoyl-N-{-1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-benzamide semifumarate-heimhydrate.

In particular, the present invention also provides a method of treatment of disorders associated with serotonergic neuron-related diseases such as anxiety, depression, eating disorders, high blood pressure, emesis, schizophrenia, the cognitive deficits resulting from neurodegenerative diseases of Alzheimer's Disease and additionally prostate cancer by acting on a 5-HT _1Areceptor in warm-blooded animals in need thereof, which comprises administering to said warm-blooded animals, preferably mammals, most preferably humans, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

For the compounds defined above and referred to herein, unless otherwise noted, the following terms are defined.

The term halogen may be selected from fluorine, chlorine, bromine and iodine, unless otherwise specified.

The term alkyl means a branched or unbranched, saturated aliphatic hydrocarbon radical. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertbutyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n-heptyl, 2-methylhexyl, and the like unless otherwise specified.

The term alkenyl means a branched or unbranched hydrocarbon radical containing at least one carbon-carbon double bond, each double bond being independently cis, trans or a nongeometric isomer.

The term alkynyl means a branched or unbranched hydrocarbon radical containing at least one carbon-carbon triple bond.

The term alkoxy means a branched or unbranched hydrocarbon radical attached through an oxygen bridge and including for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and the like.

The term perhaloalkyl means a branched or unbranched hydrocarbon radical in which three of more hydrogens are replaced with halogen and encompass groups such as trifluoromethyl, perfluoroethyl and the like.

The tern perhaloalkoxy means a branched or unbranched hydrocarbon radical attached through an oxygen bridge in which three or more hydrogens are replaced with halogen and encompass groups such as trifluoromethoxy, perfluoroethoxy and the like.

The term cycloalkyl means a saturated monocyclic ring which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term cycloalkenyl means a unsaturated monocyclic ring containing at least one carbon-carbon double bond, examples which include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like.

Phenyl as used herein refers to a 6-membered aromatic ring.

The term aryl when used alone means a homocyclic aromatic radical, whether or not fused. Preferred aryl groups include phenyl, alpha-napphthyl and beta-naphthyl and the like optionally substituted with one, two or three substituents.

The term heteroaryl means an optionally substituted monocyclic heteroaromatic ring. Preferred are 2- or 3-furyl, 2- or 3-thienyl, or 2-,3- or 4-pyridyl.

The tern bicyclic heteroaryl means an optionally substituted bicyclic saturated, unsaturated or aromatic ring system. Preferred are: indolyl, azaindolyl, benzinidazolyl, indazolyl, quinolinyl, isoquinohnyl, benzodioxanyl, benzopyranyl, belnzofuraniyl, dihydrobenzofuranyl, benzothiophenyl, benzothiazolyl, benzothiadiazolyl, benzooxazolyl and 2,3-dihydro-benzo[1,4]dioxin.

When R ₃and R₄are used multiple times in la moiety such as

each R ₃or R₄may be the same or different.

It is understood by those practicing the art that the definition of compounds of Formula (I) when R ₁, R₂, R₃and R₄contain asymmetric carbons, encompass all possible stereoisomers, mixtures and regioisomers thereof which possess the activity discussed below. Such regioisomers may be obtained pure by standard separation methods known to those skilled in the art. In particular, the definition encompasses any optical isomers and diastereomers as well as the racemic and resolved enantiomerically pure R and S stereoisomers as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof, which passess the activity discussed below. Optical isomers may be obtained in pure form by standard separation techniques or enantiomer specific synthesis. It is understood that this invention encompasses all crystalline forms of compounds of Formula (I). The pharmaceutically acceptable salts of the basic compounds of this invention are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, fumaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methlanesulfonic and similarly known acceptable acids.

The present invention accordingly provides a pharmaceutical composition which comprises a compound of Formula (I) of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.

DESCRIPTION OF THE INVENTION

Compounds Of Formula I are synthesized a: described in Scheme I from amine intermediate 1 where n, R ₂and X are hereinbefore defined by acylation with two equivalents of acid chloride 2 where R₃is hereinbefore defined to give imide 3, where n, R₂, R₃and X are hereinbefore defined, and which is isolated as a pharmaceutically acceptable salt.

Amine intermediate 1 can be further acylated with acid chloride 4 where R ₄is hereinbefore defined to give imide 5, where n, R₂, R₄and X are hereinbefore defined, and which is isolated as a pharmaceutically acceptable salt.

As shown in Scheme II, compounds of Formula I are prepared from amine intermediate 1 where n, R ₂and X are hereinbefore defined by sequential acylation using acid chlorides 2 and 4. Acylation of amine intermediate 1 with acid chloride 2 where R₃is hereinbefore defined gives amide 6 where n, R₂, R₃and X are hereinbefore defined and which is further acylated with acid chloride 4 to give imide 7, where n, R₂, R₃, R₄and X are hereinbefore defined and which is isolated as a pharmaceutically acceptable salt.

Alternatively, as described in Scheme III, imide 7 may be prepared by introducing the first acyl group using an appropriate carboxylic acid 8 where R ₃is hereinibefore defined in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC) or alternatively using appropriate coupling reagents which include: 1) N,N′-dicyclohexylcarbodiimide plus 1-hydroxybenzotriazole 2) benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP-reagent) 3) N,N′bis[2-oxo-3-oxazolidinyl]phosphorodiamidic chloride (BOP-Cl) 4) diphenylphosphinyl chloride (DPP-Cl) 5) diethoxyphosphoryl cyanide 6) 2-chloro-1-methylpyridinium iodide 7) phenyldichlorophosphate plus imidazole to give amide 6 where n, R₂, R₃and X are hereinbefore defined. Acylation of amide 6 with acid chloride 4 yields imide 9 where n, R₂, R₃, R₄and X are hereinbefore defined.

Amine intermediate 1 can be prepared using two general methods. Using the first general method, as shown in Scheme IV, unsubstituted compounds where R ₂is H and n is 0 are synthesized from appropriate aryl piperazines, piperidines, or tetrahydropyridines 10, where X is hereinbefore defined by condensation with bromoacetonitrile in the presence of a base which include but are not limited to triethylamine, N,N-diisopropylethylamine or pyridine to give nitrile 11 followed by reduction in the presence of palladium-on-carbon and hydrogen or by methods known to those versed in the art to give amine 1 where R₂is 11 and n is 0.

Using the second general method, amine intermediate 1 where R ₂and n are hereinbefore defined can be synthesized in three steps as shown in Scheme V. An amino acid 12 where R₂and n are hereinbefore defined is converted to the protected t-butylcarbamate intermediate 13 which is condensed with an appropriate aryl piperazine, piperidine, or tetrahydropyridine 10 in the presence of a coupling reagent (DCC) or alternatively with coupling reagents herein before defined to give protected amine 14. Removal of the t-butylcarbamate (BOC) protecting group under acid catalysis gives amine 15 which is converted, using an appropriate reducing agent such as lithium aluminum hydride or borane to the desired amine intermediate 1 where R₂, X and n are hereinbefore defined.

Reactions are performed in a solvent appropriate to the reagents mid materials employed and suitable for the transformation being, effected. It is understood by those skilled in the art of organic synthesis that the various functionalities present on the molecule must be consistent with the chemical transformations proposed. This may necessitate judgement as to the order of synthetic steps, protecting groups, if required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions. Such restrictions to the substituents which are compatible with the reaction conditions will be apparent to one skilled in the art. Some of the compounds of the hereinbefore described schemes have centers of asymmetry. The compounds may, therefore, exist in at least two and often more stereoisomeric forms. The present invention encompasses all stereoisomners of the compounds whether free from other steieoisomers or admixed with other stereoisomers in any proportion and thus includes, for instance, racemic mixture of eniantiomers as well as the diastereomeric mixture of isomers. The absolute configuration of any compound may be determined by conventional X-ray crystallography.

According to a further aspect of the present invention there is provided a series of compounds of Formula (I) or the pharmaceutically acceptable salts thereof as defined hereinbefore for use in a method of treatment of human or animal disease.

The compounds of this invention have high affinity for the 5-HT _1Areceptor and this activity was established using standard pharmacological test procedures with representative compounds of this invention as follows.

Affinity for the serotonin 5-HT _1Areceptor was established by assaying the test compound's ability to displace [3H]8-OHDPAT (dipropylaminotetralin) from its binding site on the receptor complex in CHO cells stably transfected with the human 5-HT_1Areceptor following a variation of a procedure of J. Zgombick et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 354, 226-236 (1996), as described by J. Dunlop, Y. Zhang, D. L. Smith and L. E. Schechter, Journal of Pharmacological and Toxicological Methods 40, 47-55 (1998). The variation includes: the use of cells containing clonal human 5-HT_1Areceptor in place of 5-HT_1Dreceptor; the use of [3H]-8-OH-DPAT (1.5 nM) as radioligand in place of [3H]-LSD; nonspecific binding determined with 10 μM 5-HT; and the test procedure was run at room temperature rather than 37° C. The compounds of this invention displayed high affinity for the 5-HT_1Areceptor, as described in Table 1.

	TABLE 1


	Example	5-HT_1AAffinity (IC₅₀)

	Example 6	3.10 nM
	Example 7	4.55 nM
	Example 8	4.77 nM
	Example 9	2.69 nM
	Example 10	61.01 nM
	Example 11	0.38 nM
	Example 12	0.78 nM
	Example 14	5.13 nM
	Example 15	23.45 nM
	Example 16	79.60 nM

Some of the compounds of this invention displayed 5-HT _1Apartial agonist activity, as assessed by the test compound's ability to stimulate the binding of [35S]-GTPγS to the 5-HT_1Areceptor-G protein complex in CHO cells stably transfected with the human 5-HT_1Areceptor following a variation of the procedure described by Lazareno and Birdsall (Br. J. Pharmacol., 109, 1120 (1993). lhe variation includes: the use of cells containing clonal human 5-HT_1Areceptor rather than muscarinic receptors; the pH of the medium was 8 rather than 7.4; the use of 10 μM GDP; and the test procedure was run at 37° C. rather than 30° C. The compounds of this invention which demonstrated agonist activity in this assay possessed IC₅₀values between 1 and 100 nM.

Some of the compounds of this invention demonstrated 5-HT _1Aantagonist activity, as measured by the test compound's ability to inhibit forskolin-stimulated cAMP turnover in CHO cells stably transfected with the human 5-HT_1Areceptor using a variation of a procedure of J. Zgombick et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 354, 226-236 (1996), as described lay J. Dunlop, Y. Zhang, D. L. Smith and L. E. Schechter, Journal of Pharmacological and Toxicological Methods 40, 47-55 (1998). The variation includes: cAMP formation determined using a Scintillation Proximity Assay (SPA); and centrifugation was unnecessary. The compounds of this invention which demonstrated 5-HT_1Aantagonist activity in this assay possessed IC₅₀values between 1 and100 nM.

Based on the activity in the standard pharmacological test procedures, the compounds of this invention modulate serotonergic activity and therefore are useful in the treatment of disorders associated with serotonergic neuron-related diseases such as anxiety, depression, eating disorders, high blood pressure, emesis, schizophrenia, the cognitive deficits resulting from neurodegenerative diseases of Alzheimer's Disease and additionally prostate cancer.

Thus according to this aspect of this invention there is provided the use of compounds of the Formula (I) or the pharmaceutically acceptable salts thereof in the manufacturing of medicament for use in the production of agonists and antagonists useful as pharmaceutical compositions for preventing and treating serotonergic neuron-related diseases such as anxiety, depression, eating disorders, high blood pressure, emesis, schizophrenia, the cognitive deficits resulting from neurodegenerative diseases of Alzheimer's Disease and additionally prostate cancer in a warm-blooded animal such as a human.

The compounds of this invention may be formulated neat or may be combined with one or more pharmaceutically acceptable carriers for administration. For example, solvents, diluents and the like; and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspension containing from about 0.05 to 5% suspending agent in an isotoniic medium. Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 1000 mg/kg of animal body weight, optionally given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 1 to 1000 mg, preferably from about 2 to 500 mg. Dosage forms suitable for internal use comprise from about 0.5 to 1000 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

The compounds of this invention may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid comnpositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred. In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol.

The compounds of this invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

The following examples are presented to illustrate rather than limit the methods for the production of representative compounds of the invention.

EXAMPLE 1

[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-acetoitrile

A solution of bromoacetonitrile (2.38 g, 19.86 mmol), benzodioxin-5-ylpiperazine (5.1 g, 9.86 mmol) and triethylamine (11.05 mL, 79.4 mmol) in dimethylformamide (50 mL) was stirred under a nitrogen atmosphere at 70° C. for 3 days. Water (300 mL) was added and the produce extracted into ethyl acetate (6×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration on a rotary evaporator gave the desired compound as a light yellow oil which solidified on standing (5.1 g, 99% yield). The compound was isolated is its hydrochloride salt by treatment in ethyl acetate with ethereal HCl to yield a light yellow solid, mp=193-194° C.; MS (+) ESI m/z=260 (M+H)[0118] ⁺.
Analysis for C[0119] ₁₄H₁₇N₃O₂.HCl.0.75 H₂O
Calculated: C: 54.37; H: 6.36; N: 13.59 [0120]
Found: C: 54.55; H: 6.36; N: 15.50. [0121]

EXAMPLE 2

2-[4-(2,3-Dihydro-benzo[1,4]dioxinyl-5-yl)-piperazin-1-yl]-ethylamine

A solution of [4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-acetonitrile (1.55 g, 5.97 mmol) in anhydrous tetrahydrofuran (10 mL) at 0° C. under an atmosphere of nitrogen was treated dropwise with a 1M solution of lithium aluminum hydride in tetrahydrofuran (6.0 mL, 6.0 mmol). The resulting solution was stirred overnight during which time it came up to room temperature. The reaction was quenched by dropwise addition of saturated aqueous ammonium chloride just until foaming ceased. The resulting mixture was filtered through a pad of diatomaceous earth, which was washed throughly with ethyl acetate. The combined organic solution was washed with water (25 mL) and brine (25 mL) and dried over anhydrous sodium sulfate. Filtration and concentration gave the title compound as a white solid, mp=68-69° C.; MS (+) ESI m/z=264 (M+H)[0122] ⁺.
Analysis for C[0123] ₁₄H₁₂N₃O₂
Calculated: C: 63.85; H: 8.04; N: 15.96 [0124]
Found: C: 63.64; H: 8.13; N: 15.36. [0125]

EXAMPLE 3

(R)-{1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid-tert-butyl ester

To a solution of D-N-(tert-butoxycarbonyl)-alanine (4.0 g, 21.1 mmol) and 1-(2-methyxophenyl)-piperazine (4.47 g, 23.3 mmol) in dimethylformamide (40 mL) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.05 g, 21.1 mmol), 1-hydroxybenzotriazole hydrate (3.71 g, 27.5 mmol) and 1-methyl morpholine (3.4 mL, 31.7 mmol). The resulting mixture was stirred overnight, during which time it came up to room temperature. The reaction mixture was then diluted with water (100 mL) and ethyl acetate (150 mL) and the layers separated. The aqueous layer was extracted with three additional 30 mL portions: of ethyl acetate. The combined organic layers were washed with 1N aqueous HCl (50 mL) and saturated aqueous NaHCO[0126] ₃and then dried over anhydrous sodium sulfate. Filtration and concentration on a rotary evaporator yielded the crude product which was purified by flash chromatography on silica gel (ethyl acetate/hexane) to afford the desired (R)-{1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid-tert-butyl ester (7.24 g, 95%) as a yellow oil.

EXAMPLE 4

(R)-{1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-amino-propane-2-1-one

The (R)-{1-methyl-2-[4-(2-methoxyphenyi)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid-tert-butyl ester (7.24 g, 19.9 mmol) was dissolved in a 1:1 mixture of 4N aqueous HCl/dioxane (100 mL) and stirred overnight at room temperature. Concentration of the mixture on a rotary evaporator yielded the required (R)-{1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-amino-propan-2-1-one (5.90 g, 99%) as a hydrochloride salt. [0127]

EXAMPLE 5

(R)-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]-1-methyl-ethyl}-amine

The above mentioned (R)-{1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-amino-propan-2-1-one hydrochloride (5.90 g, 19.7 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) at room temperature. Triethylamine (6.3 mL, 45 mmol) was added, followed by dropwise addition of a 1M solution of borane in tetrahydrofuran (77.5 mL, 45 mmol). The resulting mixture was refluxed for 18 hours. After cooling the reaction mixture to room temperature, ethyl acctate (60 mL) and 2N aqueous HCl were added and the resulting mixture was stirred it room temperature for one hour. The layers were separated and the aqueous layer was made basic by careful addition of 50% aqueous NaOH. The resulting basic mixture was extracted with three 50 mL portions of ethyl acetate. The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration on a rotary evaporator yielded 4.62 g (94%) of the desired of 2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethylamine as a colorless oil which was used without further purification. [0128]

EXAMPLE 6

Cyclohexanecarboxylic acid cyclohexanecarbonyl-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-amide dihydrochloride

To a solution of 2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethylamine (0.40 g, 1.7 mmol) and triethylamine (0.95. mL, 6.8 mmol) in dichloromethane (20 mL) at 0° C. was added cyclohexanecarboxylic acid chloride (0.56 g, 3.8 mmol). The reaction mixture was allowed to stir under nitrogen for eighteen hours, during which time the reaction came up to room temperature. The reaction mixture was then concentrated oil a rotary evaporator, diluted with ethyl acetate and washed with sat. aq. NaHCO[0129] ₃and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to its dihydrochloride salt with ethanolic HCl to yield 0.77 g (86%) of the title compound as a white solid; mp=159-160° C.; MS (+) ESI m/z=456 (M+H)⁺.
Analysis for C[0130] ₂₇H₄₁N₃O₂.2HCl
Calculated: C: 61.35; H: 8.20; N: 7.95 [0131]
Found: C: 61.16H: 8.29; N: 8.04. [0132]

EXAMPLE 7

Cyclohexanecarboxylic acid cyclohexanecarbonyl-{2-[4-(1H-indol-4-yl)-piperazin-1-yl]-ethyl}-amide dihydrochloride

To a solution of 2-[4-(1H-indol-4-yl)-piperazin-1-yl]-ethylamine (0.16 g, 0.66 mmol) and triethylamninie (0.137 mL, 2.64 mmol) in dichloromethane (10 mL) at 0° C. was added cyclohexanecarboxylic acid (0.22 g, 1.49 mmol). The reaction mixture was allowed to stir under nitrogen for eighteen hours, during which time the reaction came up to room temperature. The reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with sat. aq. NaHCO[0133] ₃and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to its dihydrochloride salt with ethanolic HCl to yield 0.22 g (81%) of the title compound as an off-white solid; mp=144-146° C.; MS (+) ESI m/z=465 (M+H)⁺.
Analysis for C[0134] ₂₈H₄₀N₄O₂. 2HCl
Calculated: C: 62.56; H: 7.88; N: 10.42 [0135]
Found: C: 62.32; H: 8.01; N: 10.27. [0136]

EXAMPLE 8

Cyclohexanecarboxylic acid cyclohexanecarbonyl-{2-[4-(2,3-dihydro-benzo[1,4]-dioxin)-5-yl}-piperazin-1-yl]-ethyl}-amide sesquihydrochloride monohydrate

To a solution of 2-[4-(2,3-dihydro-benzo[1,4]-dioxin)-5-yl}-piperazin-1-yl]-ethylamine (0.20 g, 0.76 mmol) and triethylamine (0.31 mL, 2.28 mmol) in (dichloromethane (10 mL) at 0° C. was added cyclohexanecarboylic acid chloride (0.33 g, 2.28 mmol). The reaction mixture was allowed to stir under nitrogen for eighteen hours, during which time the reaction came up to room temperature. The reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with sat. aq. NaHCO[0137] ₃and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrate, on a rotary evaporator to yield die crude product, which was purified by flash chromotography on silica gel (ethyl acetate/hexane) and then converted to its 1.5 hydrochloride monohydrate salt in ethyl acetate to yield 0.28. g (67%) of the title compound as a white solid; mp=148-149° C.; MS (+) ESI m/z=484 (M+H)⁺.
Analysis for C[0138] ₂₈H₄₁N₃O₄.1.5HCl.H₂O
Calculated: C: 60.45; H: 8.06; N: 7.55 [0139]
Found: C: 60.45; H: 7.92; N: 7.56. [0140]

EXAMPLE 9

(R)-Cyclohexanecarboxylic acid cyclohexanecarbonyl-{1-methyl-2-[4-(2-methoxyphenyl)-piperazin-2-yl]-ethyl}-amide fumarate

To a solution of (R)-1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethylamine (0.48 g, 1.9 mmol) and triethylamine (2.0 mL, 14.4 mmol) in dichloromethane (20 mL) at 0° C. was added cyclohexanecarboxylic acid chloride (1.04 g, 7.2 mmol). The reaction mixture was allowed to stir under nitrogen for eighteen hours, during which time the reaction came up to room temperature. The reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with sat. aq. NaH[0141] ₄CO₃and brine. The organic phase was dried over and anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (ethyl acetate/hexane) and then converted to its monofumarate salt in ethanol to yield 0.87 g (78%) of the title compound as an off-white solid; mp=127-130° C.; MS (+) ESI m/z=470 (M+H)⁺.
Analysis for C[0142] ₂₈H₄₃N₃O₃.C₄H₄O₄
Calculated: C: 65.62; H: 8.09; N: 7.17 [0143]
Found: C: 65.54; H: 8.12; N: 7.07. [0144]

EXAMPLE 10

(R)-Cyclohexanecarboxylic acid cyclohexanecarbonyl-{1-benzyl)-2-[4-(2-methoxy-phenyl)-piperazin-1yl]-ethyl}-amide fumarate

To a solution of (R)-1-(4-benzyl)-2-[4-(2-metlioxyplieniyl)-piperazin-1-yl]-ethyl-amine (0.49 g, 1.5 mmol) and triethylaimine (0.84 mL, 6.0 mmol) in dichloromethane (10 mL) at 0° C. was added of cyclohexanecarboxylic acid chloride (0.66 g, 4.5 mmol). The reaction mixture was allowed to stir under nitrogen for eighteen hours, during which time the reaction came up to room temperature. The reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with sat. aq. NaHCO[0145] ₃and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (ethyl acetate/hexane) and then converted to its fumarate salt in ethyl acetate to yield 0.79 g (80%) of the title compound as an off-white solid; mp=146-147° C.; MS (+) ESI mn/z 546 (M+H)⁺.
Analysis for C[0146] ₃₄H₄₇N₃O₃.C₄H₄O₄
Calculated: C: 68.96; H: 7.77; N: 6.35 [0147]
Found: C: 68.62; H: 7.80; N: 6.29. [0148]

EXAMPLE 11

(R)-Cyclohexanecarboxylic acid cyclohexanecarbonyl-{1-(4-methoxybenzyl)-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-etlyl}-amide hydrochloride

To a solution of (R)-1-(4-methoxybenzyl)-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethylamine (0.21 g, 0.59 mmol) and triethylamine (0.33 mL, 2.36 mmol) in dichloromethane (10 mL) at 0° C. was added cycloliexanecarboxylic acid chloride (0.19 g, 1.33 mmol). The reaction mixture was allowed to stir under nitrogen for eighteen hours, during which time the reaction came up to room temperature. The reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with sat. aq. NaHCO[0149] ₃and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to its dihydrochloride salt with ethanolic HCl to yield 0.30 g (84%) of the title compound as an off-white solid; mp=106-108° C.; MS (+) ESI m/z=576 (M+H)⁺.
Analysis for C[0150] ₃₅H₄₉N₃O₄.HCl
Calculated: C: 68.66; H: 8.23; N: 6.86 [0151]
Found: C: 68.57; H: 7.87; N: 6.95. [0152]

EXAMPLE 12

(R)-Cyclohexanecarboxylic acid cyclohexanecarbonyl-{1-[4-(2-methoxyphenyl)-piperazin-1-ylmethyl]-2-(1-methyl-1H-indol-3-yl)ethyl}-amide hydrochloride monohydrate

To a solution of (R)-1-[4-(2-methloxyphenyl)-piperazin-1-ylmethyl]-2-(1-methyl-1-H-indol-3-yl)ethylamine (0.21 g, 0.56 mmol) and triethylamine (0.31 mL, 2.24 mmol) in dlichloromethane (10 mL) at 0° C. was added cyclohexanecarboxylic acid chloride (0.18 g, 1.26 mmol). The reaction mixture was allowed to stir under nitrogen for 18 hours, during which time it came up to room temperature. The reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H[0153] ₂O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to its hydrochloride•monohlydrate salt with ethanolic HCl yield 0.28 g (77%) of the title compound as a white solid; mp=136-138° C.; MS (+) ESI m/z=599 (M+H)⁺.
Analysis for C[0154] ₃₇H₅₀N₄O₃.HCl.H₂O
Calculated: C: 68.02; H: 8.17; N: 8.57 [0155]
Found: C: 67.29; H: 7.77; N: 8.31. [0156]

EXAMPLE 13

Cyclohexanecarboxylic acid {2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl-]ethyl}-amide

A solution of 2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl-]ethlylamine (0.20 g, 0.76 mmol) in dichloromethane (5 mL) was treated with cyclohexanecarbonyl chloride (0.11 g, 0.76 mmol) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred overnight, during which time it came up to room temperature. The product was precipitated by the addition of hexane to yield the hydrochloride semihydrate salt of the titled compound (0.25 g, 80%) as a white solid; mp=165-166° C.; MS (+) ESI mn/z=374 (M+H)[0157] ⁺.
Analysis for C[0158] ₂₁H₃₁N₃O₃.HCl.0.5 H₂O
Calculated: C: 60.20; H: 7.94; N: 10.03 [0159]
Found: C: 60.19; H: 7.88; N: 9.83. [0160]

EXAMPLE 14

Cyclohexanecarboxylic acid benzoyl-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-1-piperazin-1-ylethyl]-amide hydrochloride sesquihydrate

To a solution of cyclohexanecarboxylic acid {2-[4-(2,3-dihydro-benzo[1,4]dionin-5-yl)-piperazin-1-yl-]ethyl}-amide hydrochloride semihydrate (0.14 g, 0.34 mmol) and triethylamine (0.14 mL, 1.02 mmol) in dichloromethane (5 mL) at 0° C. was added benzoyl chloride (0.096 g, 0.68 mmol). The reaction mixture was allowed to stir under nitrogen for 18 hours, during which time it came up to room temperature. The reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H[0161] ₂O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (ethyl acetate/hexane) and converted to its hydrochloride•sesquihydrate salt with ethereal HCl to yield 0.08 g (45%) of the title compound as a white solid; mp=169-171° C.; MS (+) ESI m/z=478 (M+H)⁺.
Analysis for C[0162] ₂₈H₃₅N₃O₄.HCl.1.25 H₂O
Calculated: C: 62.68; H: 7.23; N: 7.83 [0163]
Found: C: 62.27; H: 6.82; N: 7.54. [0164]

EXAMPLE 15

N-Benzoyl-N-{-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-benzamide hydrochloride hemihydrate

To a solution of 2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethylamine (0.50 g, 2.12 mmol) and triethylamine (1.2 mL, 8.48 mmol) in dichloromethane (20 mL) at 0° C. was added benzoyl chloride (0.75 g, 6.36 mmol). The reaction mixture was allowed to stir under nitrogen for eighteen hours, during which time the reaction came up to room temperature. The reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with sat. aq. NaHCO[0165] ₃and brine. The organic phase was It dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (ethyl acetate/hexane) and then converted to its hydrochloride hemihydrate salt with ethereal HCl to yield 0.38 g (37%) of the title compound as a white solid mp 208-209° C.; MS (+) ESI m/z=444 (M+H)⁺.
Analysis for C[0166] ₂₇H₂₉N₃O₃.HCl.0.25 H₂O
Calculated: C: 66.93; H: 6.35; N: 8.67 [0167]
Found: C: 66.59; H: 6.45; N: 8.61. [0168]

EXAMPLE 16

(R)-N-Benzoyl-N-{1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-benzamide semifumarate-hemihydrate

To a solution of (R)-1-metlyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethylamine (0.57 g, 2.3 mmol) and triethylamine (1.3 mL, 9.1 mmol) in dichloromethane (20 mL) at 0° C. was added benzoyl chloride (0.45. mL, 3.9 mmol). The reaction mixture was allowed to stir under nitrogen for eighteen hours, during which time it came to room temperature. The reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with sat. aq. NaHCO[0169] ₃and brine.
The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (ethyl acetate/hexane) and then converted to its semifumarate salt in ethanol to yield 0.29 g (24%) of the title compound as a tan solid; mp=115-120° C.; MS (+) ESI m/z=458 (M+H)[0170] ⁺.
Analysis for C[0171] ₂₈H₃₁N₃O₃.0.5 C₄H₄O₄.0.70 H₂O
Calculated: C: 68.21; H: 6.57; N: 7.95 [0172]
Found: C: 68.29; H: 6.29; N: 7.62. [0173]

Claims

What is claimed is:

1. A compound having the Formula (I)

wherein:

n is an integer of 0 to 5;

X is a moiety selected from the group consisting of:

Y is a moiety selected from the group consisting of:

R¹is aryl of 6 to 12 carbon atoms optionally substituted with one or more substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; heteroaryl having 5 or 6 ring atoms containing 1 to 3 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 substituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen; bicyclic heteroaryl having 8 to 20 ring atoms containing 1 to 3 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur optionally substituted with 1 to 3 substituents which may be the same or different, selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen;

R₂is independently H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydroxy, —(CH₂)_z-O-alkyl of 1 to 6 carbon atoms, —(CH₂)_z-S-alkyl of 1 to 6 carbon atoms, —(CH₂)_zOH, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; aryl of 6 to 12 carbon atoms optionally substituted with one or more substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 of to 10 carbon atoms, —CN, —NO₂, and halogen; heteroaryl having 5 or 6 ring atoms containing 1 to 3 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 substituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen; bicyclic heteroaryl having 8 to 20 ring atoms containing 1 to 3 heteroatomns which may be the same or different selected from nitrogen, oxygen and sulfur optionally substituted with 1 to 3 substituents which may be the same or different, selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen;

z is an integer of 1 to 3;

R₃is independently cycloalkyl or cycloalkenyl of 3 to 10 carbon atoms;

R₄is aryl of 6 to 12 carbon atoms optionally substituted with one or more substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; heteroaryl having 5 or 6 ring atoms containing 1 to 3 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 substituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen, bicyclic heteroaryl having 8 to 20 ring atoms containing 1 to 3 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur optionally substituted with 1 to 3 substituents which may be the same or different, selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen;

with the proviso that X is not the radical

when R₅is H, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and hydroxyl; n is 0; R₂is H; Y is the radical

and R₄is phenyl substituted with three substituents which are the same or different selected from H, halogen, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein Y is the moiety

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 wherein Y is the moiety

or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1 wherein Y is the moiety

or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1 wherein

R₁is phenyl optionally substituted with one or two substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; 2 or 3-furyl, 2 or 3-thienyl, 2,3- or 4-pyridyl; indolyl, azaindolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzopyranyl, benzofuranyl, dihydrobenzofuranyl, benzothioplicnyl, benzothiazolyl, benzothiadiazolyl, benzooxazolyl and 2,3-dihydro-benzo[1,4]dioydn; or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 wherein:

R₂is selected from 1H, alkyl of 1 to 6 carbos atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydroxy, —(CH₂)_z-O-alkyl of 1 to 6 carbon atoms, —(CH₂)_z-S-alkyl of 1 to 6 carbon atoms, —(CH₂)_zOH, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; phenyl optionally substituted with 1 or 2 subtituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; 2 or 3-furyl, 2 or 3-thienyl, 2-,3- or 4-pyridyl; indolyl, azaindolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzopyranyl, benzofuranyl, diliydrobenzoforanyl, benzothiophenyl, benzothiazolyl, benzothiadiazolyl, benzooxazolyl and 2,3-dihydro-betizo[1,4]dioxin;

or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 wherein X is the moiety

Y is the moiety

or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 wherein X is the moiety Y is the moiety

or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 wherein X is the moiety

Y is the moiety

or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1 wherein X is the moiety

Y is the moiety

R₁is phenyl optionally substituted with one or two substituents selected front alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; indolyl and 2,3-dihydro-benzo[1,4]dioxin;

or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1 wherein X is the moiety Y is the moiety

R₁is phenyl optionally substituted with one or two substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; indolyl and 2,3-dihydro-benzo[1,4]dioxin;

R₄is phenyl, optionally substituted with one, two or three substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloakoxy of 1 to 10 carbon atoms,

—CN, —NO₂, and halogen;

or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1 wherein X is the moiety

R₁is phenyl optionally substituted with one or two substituent selected alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; indolyl and 2,3-dihydro-benzo[1,4]dioxin;

R₄is phenyl, optionally substituted with one, two or three substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen;

Y is the moiety

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 which is selected from the group consisting of cyclohexanecarboxylic acid cyclohexanecarbonyl-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethyl}-amide dihydrocliloride, cyclolioxanearboxylic acid cyclohexanecarbonyl-{2-[4-(1H-indol-4-yl)-piperazin-1-yl]-ethyl}-amide dihydrochloride, cyclohexanecarboxylic acid cyclohexanecarbonyl-{2-[4-(2,3-dihydrobenzo[1,4-dioxin)-5-yl)-piperazin-1-yl]-ethyl}-amide sesquihydrochloride monolydrate,(R)-cyclohexanecarboxylic acid cyclohexanecarbonyl-{1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-amide furmarate,(R)-cyclohexanecarboxylic acid cyclohexanecarbonyl-{1-(4-benzyl)-2-[4(2-methoxy-phenyl)-piperazin-1-yl]-ethyl}-amide fumarate,

(R)-cyclohexanecarboxylic acid cyclohexanecarbonyl-{1-(4-methoxybenzyl)-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-amide hydrochloride,

(R)-cyclohexanecarboxylic acid cyclohexanecarbonyl-{1-(2-methoxyphenyl)-piperazin-1-ylmethyl]-2-(1-methyl-1H-indol-3-yl)ethyl}-amide hydrochloride monohydrate,cyclohexanecarboxylic acid {2-[4]-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl-ethyl}-amide,cyclohexanecarboxylic acid benzoyl-{2-[4-(2,3-dihydro-benzo[1 ,4]dioxin-5-yl)-piperazin-1-ylethyl}-amide hydrochloride sesquihydrate,

N-benzoyl-N-{-2-(4-(2-methoxyphenyl)-piperaizin-1-yl]-ethyl}-benzamide hydrochloride hemihydrate, and

(R)-N-benzoyl-N-{1-methyl-2-[4(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-benzamide semifumarate-hemihydrate;

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition for treating disorders associated with serotonergic neuron-related diseases, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I)

wherein:

n is an integer of 0 to 5;

X is a moiety selected from the group consisting of:

Y is moiety selected from the group consisting of:

R¹is aryl of 6 to 12 carbon atones optionally substituted with one or more substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen, heteroaryl having 5 or 6 ring atoms containing 1 to 3 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 substituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen; bicyclic heteroaryl having 8 to 20 ring atoms containing 1 to 3 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur optionally substituted with 1 to 3 substituents which may be the same or different, selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen;

R₂is independently 4 alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkonyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydroxy, —CHO₂)_z-O-alkyl of 1 o 6 carbon atoms , —(CH₂)_z-S-alkyl of 1 to 6 carbon atoms, —(CH₂)_zOH, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; aryl of 6 to 12 carbon atoms optionally substituted with one or more substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkxy of 1 to 10 carbon atoms, —CN,—NO₂, and halogen; heteroaryl having 5 or 6 ring atoms containing 1 to 3 heteratoms which may be the same or different, selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 substituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen; bicyclic heteroaryl having 8 to 20 ring atoms containing 1 to 3 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur optionally substituted with 1 to 3 substituents which may be the saine or different, selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen;

z is an integer of 1 to 3;

R₃is independently cycloalkyl or cycloalkenyl of 3 to 10 carbon atoms;

R₄is aryl of 6 to 12 carbon atoms optionally substituted with one or more substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen, heteroaryl having 5 or 6 ring atoms containing 1 to 3 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 stibstituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen, bicyclic heteroaryl having 8 to 20 ring atoms containing 1 to 3 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur optionally substituted with 1 to 3 substituents which may be the same or different, selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen;

with the proviso that X is not the radical

when R₅is H, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and hydroxyl; n is 0;R₂is H; Y is the radical

and R₄is phenyl substituted with three substituents which are the same or different selected from is , halogen, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers.

15. A method of treating serotonergic neuron-related diseases in warm-blooded animals in need thereof, which comprises administering to said warm-blooded animals preferably mammals, most preferably humans an effective amount of a compound of Formula (I)

wherein:

n is an integer of 1 to 5;

X is a moiety selected from the group consisting of:

Y is a moiety selected from the group consisting of:

R¹is aryl of 6 to 12 carbon atoms optionally substituted with one, or more substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen, heteroalyl having 5 or 6 ring atoms containing 1 to 3 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 substituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen; bicyclic heteroaryl having 8 to 20 ring atoms containing 1 to 3 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur optionally substituted with 1 to 3 substituents which may be the same or different, selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen;

R₂is independently H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydroxy, —(CH₂)_z-O-alkyl of 1 to 6 carbon atoms , —(CH₂)_z-S-alkyl of 1 to 6 carbon atoms, —(CH₂)_zOH, perhaloalklyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; aryl of 6 to 12 carbon atoms optionally substituted with one or more substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; heteroaryl is a 5- or 6-numbered monocyclic heteroaromatic ring which contains 1 to3 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 substituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen; bicyclic heteroaryl is a bicyclic saturated, unsaturated or aromatic ring system having 8 to 20 ring atoms containing 1 to 3 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur optionally substituted with 1 to 3 substituents which may be the same or different, selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen;

z is an integer of 1 to 3;

R₃is independently cycloalkyl or cycloalkenyl of 3 to 10 carbon atoms;

R₄is aryl of 6 to 12 carbon atoms optionally substituted with one or more substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, —CN, —NO₂, and halogen; heteroaryl having 5 or 6 ring atoms containing 1 to 3 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 substituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen, bicyclic heteroaryl having, 8 to 20 ring atoms containing 1 to 3 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur optionally substituted with 1 to 3 substituents which nay be the same or different, selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, —CN, —NO₂, and halogen;

with the proviso that X is not the radical

when R₅is X, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and hydroxyl; n 1is 0; R, is H; Y is the radical

and R₄is phenyl substituted with three substituents which are the same or different selected from A, halogen, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thererof.

16. The method of claim 15 wherein the serotonergic neuron-related disease in warm-blooded animals is selected from the group consisting of anxiety, depression, eating disorders, high blood pressure, emesis, schizophrenia, the cognitive deficits resulting from neurodegenerative diseases of Alzheimer's Disease and prostate cancer.

17. The method of claim 16 wherein the serotonergic neuron-related disease in warm-blooded animals is depression.

18. The method of claim 16 wherein the serotonergic neuron-related disease in warm-blooded animals is anxiety.

19. The method of claim 16 wherein the serotonergic neuron-related disease in warm-blooded animals is the neurodegenerative diseases of Alzheimer's Disease.