N-substituted imide derivatives with serotonergic activity

FIELD OF THE INVENTION

[0002] 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-HT1A receptor, acting as partial agonists and antagonists and are useful for preventing and treating serotonergic neuron-related diseases.

DESCRIPTION OF THE PRIOR ART

[0003] 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)].

[0004] It is also known that compounds acting on a 5-HT1A receptor 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).

[0005] Compounds having selective partial agonist activity at he 5-HT1A receptor 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-HT1A agonists 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-HT1A Receptor Modulators, in Annual Reports in Medicinal Chemistry, Volume 30, J. A. Bristol, ed., pp. 1-9 (1995)).

[0006] A series of naphylpiperazines useful as 5-HT1A receptor ligands having the generic structure:

[0007] 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.

[0008] 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:

[0009] EP 795328-A1 discloses a new use for naphthalene serotonin 5-HT1D receptor antagonists of the generic formula:

[0010] as inhibitors of cell growth in human small cell lung carcinoma, where R1 is a moiety of formulae:

[0011] Reported in GB 2303303-A is a method of using 5HT1A or 5HT2 receptor antagonists of the formulae:

[0012] for preventing or reducing the side effects of serotonin re-uptake inhibitors

[0013] 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.

[0014] 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

[0015] Accordingly, the present invention discloses compounds represented by Formula (I):

[0016] wherein:

[0017] n is an integer of 0 to 5;

[0018] X is a moiety selected from the group consisting of:

[0019] Y is a moiety selected from the group consisting of:

[0020] R1 is 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;

[0021] R2 is 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;

[0022] z is an integer of 1 to 3;

[0023] R4 is independently cycloalkyl or cycloalkenyl of 3 to 10 carbon atoms;

[0024] R4 is 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;

[0025] with the proviso that X is not the radical

[0026] when R5 is H, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and hydroxyl; n is 0; R2 is H; Y is the radical

[0027] and R4 is 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.

[0028] Among the preferred compounds of Formula (I) of this invention are those in the subgroups, and pharmaceutically acceptable salts thereof:

[0029] a) compounds having the general formula:

[0030] wherein:

[0031] R2, R3, X and n are hereinbefore defined;

[0032] b) compounds having the general formula:

[0033] wherein:

[0034] R2, R4, X and n are hereinbefore defined;

[0035] c) compounds having the general formula:

[0036] wherein:

[0037] R2, R3, R4, X and n are hereinbefore defined;

[0038] d) compounds of the general Formula (I)

[0039] wherein:

[0040] R4 is 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;

[0041] e) compounds of the general Formula (I)

[0042] wherein:

[0043] R2 is 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;

[0044] Among the more preferred compounds of Formula (I) of this invention are those in the subgroups, and pharmaceutically acceptable salts thereof:

[0045] a) compounds having the general formula:

[0046] wherein:

[0047] R1, R2, R3, and n are hereinbefore defined;

[0048] b) compounds having the general formula:

[0049] wherein:

[0050] R1, R2, R4 and n are hereinbefore defined;

[0051] c) compounds having the general formula:

[0052] wherein:

[0053] R1, R2, R3, R4, and n are hereinbefore defined;

[0054] d) compounds having the general formula:

[0055] wherein:

[0056] R1 is 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 R2 and n are hereinbefore defined;

[0057] e) compounids having the general formula:

[0058] wherein:

[0059] R1 is 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;

[0060] R4 is 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

[0061] R2 and n are hereinbefore defined;

[0062] wherein:

[0063] R1 is 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;

[0064] R4 is 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

[0065] R2 and n are hereinbefore defined.

[0066] 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:

[0067] Cyclohexanecarboxylic acid cyclohexaniecarbonyl-{2-[4-(2-methoxyphenyl)-piperazin-yl]-ethyl}-amide dihydrochloride;

[0068] Cyclohexanecarboxylic acid cyclohexanecarbonyl-{2-[4-(1H-indol-4-yl)-piperazin-1-yl]-ethyl}-amide dihydrochloride;

[0069] Cyclohexanecarboxylic acid cyclohexanecarbonyl-{2-[4-(2,3-dihydro-benzo[1,4]-dioxin)-5-yl}-piperazin-1-yl]-ethyl}-amide sesquihydrochloride monohydrate;

[0070] (R)-Cyclohexanecarboxylic acid cycloliexanecarbonyl-{1-methyl-2-[4-(2-methoxyphenyl)-pipcrazin-1-yl]-ethyl}-amide fumarate;

[0071] (R)-Cyclohexaniecarboxylic acid cyclohexanecarbonyl-{1-(4-benzyl)-2-[4-(2-methoxy-phleniyl)-piperazin-1-yl]-ethyl}-amnide fumarate;

[0072] (R)-Cyclohexanecarboxylic acid cyclohexanecarbonyl-{1-(4-methoxybenzyl)-2-[4-(2-methoxyphenyl)-piperazini-1-yl]-ethlyl}-amide hydrochloride;

[0073] (R)-Cyclohexanecarboxylic acid cyclohexanecarbonyl-{1-[4-(2-methoxyphelnyl)-piperazin-1-ylmethyl]-2-(1-methyl-1H-indol-3-yl)ethyl}-amide hydrochloride monohydrate;

[0074] Cyclohexanecarboxylic acid {2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl-]ethyl}-amnide;

[0075] Cyclohexanecarboxylic acid benzoyl-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-ylethyl]-amide hydrochloride sesquihydrate;

[0076] N-Benzoyl-N-{-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-benzamide hydrochloride hemihydrate; and

[0077] (R)-N-Benzoyl-N-{-1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-benzamide semifumarate-heimhydrate.

[0078] 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-HT1A receptor 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.

[0079] For the compounds defined above and referred to herein, unless otherwise noted, the following terms are defined.

[0080] The term halogen may be selected from fluorine, chlorine, bromine and iodine, unless otherwise specified.

[0081] 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.

[0082] 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.

[0083] The term alkynyl means a branched or unbranched hydrocarbon radical containing at least one carbon-carbon triple bond.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] The term cycloalkyl means a saturated monocyclic ring which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0088] 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.

[0089] Phenyl as used herein refers to a 6-membered aromatic ring.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] When R3 and R4 are used multiple times in la moiety such as

[0094] each R3 or R4 may be the same or different.

[0095] It is understood by those practicing the art that the definition of compounds of Formula (I) when R1, R2, R3 and R4 contain 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.

[0096] 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

[0097] Compounds Of Formula I are synthesized a: described in Scheme I from amine intermediate 1 where n, R2 and X are hereinbefore defined by acylation with two equivalents of acid chloride 2 where R3 is hereinbefore defined to give imide 3, where n, R2, R3 and X are hereinbefore defined, and which is isolated as a pharmaceutically acceptable salt.

[0098] Amine intermediate 1 can be further acylated with acid chloride 4 where R4 is hereinbefore defined to give imide 5, where n, R2, R4 and X are hereinbefore defined, and which is isolated as a pharmaceutically acceptable salt.

[0099] As shown in Scheme II, compounds of Formula I are prepared from amine intermediate 1 where n, R2 and X are hereinbefore defined by sequential acylation using acid chlorides 2 and 4. Acylation of amine intermediate 1 with acid chloride 2 where R3 is hereinbefore defined gives amide 6 where n, R2, R3 and X are hereinbefore defined and which is further acylated with acid chloride 4 to give imide 7, where n, R2, R3, R4 and X are hereinbefore defined and which is isolated as a pharmaceutically acceptable salt.

[0100] Alternatively, as described in Scheme III, imide 7 may be prepared by introducing the first acyl group using an appropriate carboxylic acid 8 where R3 is 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, R3 and X are hereinbefore defined. Acylation of amide 6 with acid chloride 4 yields imide 9 where n, R2, R3, R4 and X are hereinbefore defined.

[0101] Amine intermediate 1 can be prepared using two general methods. Using the first general method, as shown in Scheme IV, unsubstituted compounds where R2 is 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 R2 is 11 and n is 0.

[0102] Using the second general method, amine intermediate 1 where R2 and n are hereinbefore defined can be synthesized in three steps as shown in Scheme V. An amino acid 12 where R2 and 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.

[0103] 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.

[0104] 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.

[0105] The compounds of this invention have high affinity for the 5-HT1A receptor and this activity was established using standard pharmacological test procedures with representative compounds of this invention as follows.

[0106] Affinity for the serotonin 5-HT1A receptor 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-HT1A receptor 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-HT1A receptor in place of 5-HT1D receptor; 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-HT1A receptor, as described in Table 1.

1TABLE 1Example5-HT1A Affinity (IC50)Example 6 3.10 nMExample 7 4.55 nMExample 8 4.77 nMExample 9 2.69 nMExample 1061.01 nMExample 11 0.38 nMExample 12 0.78 nMExample 14 5.13 nMExample 1523.45 nMExample 1679.60 nM

[0107] Some of the compounds of this invention displayed 5-HT1A partial agonist activity, as assessed by the test compound's ability to stimulate the binding of [35S]-GTPγS to the 5-HT1A receptor-G protein complex in CHO cells stably transfected with the human 5-HT1A receptor 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-HT1A receptor 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 IC50 values between 1 and 100 nM.

[0108] Some of the compounds of this invention demonstrated 5-HT1A antagonist activity, as measured by the test compound's ability to inhibit forskolin-stimulated cAMP turnover in CHO cells stably transfected with the human 5-HT1A receptor 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-HT1A antagonist activity in this assay possessed IC50 values between 1 and100 nM.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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

[0118] 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)+.

[0119] Analysis for C14H17N3O2.HCl.0.75 H2O

[0120] Calculated: C: 54.37; H: 6.36; N: 13.59

[0121] Found: C: 54.55; H: 6.36; N: 15.50.

EXAMPLE 2

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

[0122] 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)+.

[0123] Analysis for C14H12N3O2

[0124] Calculated: C: 63.85; H: 8.04; N: 15.96

[0125] Found: C: 63.64; H: 8.13; N: 15.36.

EXAMPLE 3

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

[0126] 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 NaHCO3 and 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

[0127] 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.

EXAMPLE 5

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

[0128] 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.

EXAMPLE 6

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

[0129] 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. NaHCO3 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 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)+.

[0130] Analysis for C27H41N3O2.2HCl

[0131] Calculated: C: 61.35; H: 8.20; N: 7.95

[0132] Found: C: 61.16H: 8.29; N: 8.04.

EXAMPLE 7

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

[0133] 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. NaHCO3 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 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)+.

[0134] Analysis for C28H40N4O2. 2HCl

[0135] Calculated: C: 62.56; H: 7.88; N: 10.42

[0136] Found: C: 62.32; H: 8.01; N: 10.27.

EXAMPLE 8

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

[0137] 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. NaHCO3 and 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)+.

[0138] Analysis for C28H41N3O4.1.5HCl.H2O

[0139] Calculated: C: 60.45; H: 8.06; N: 7.55

[0140] Found: C: 60.45; H: 7.92; N: 7.56.

EXAMPLE 9

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

[0141] 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. NaH4CO3 and 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)+.

[0142] Analysis for C28H43N3O3.C4H4O4

[0143] Calculated: C: 65.62; H: 8.09; N: 7.17

[0144] Found: C: 65.54; H: 8.12; N: 7.07.

EXAMPLE 10

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

[0145] 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. NaHCO3 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 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)+.

[0146] Analysis for C34H47N3O3.C4H4O4

[0147] Calculated: C: 68.96; H: 7.77; N: 6.35

[0148] Found: C: 68.62; H: 7.80; N: 6.29.

EXAMPLE 11

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

[0149] 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. NaHCO3 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 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)+.

[0150] Analysis for C35H49N3O4.HCl

[0151] Calculated: C: 68.66; H: 8.23; N: 6.86

[0152] Found: C: 68.57; H: 7.87; N: 6.95.

EXAMPLE 12

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

[0153] 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 H2O 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)+.

[0154] Analysis for C37H50N4O3.HCl.H2O

[0155] Calculated: C: 68.02; H: 8.17; N: 8.57

[0156] Found: C: 67.29; H: 7.77; N: 8.31.

EXAMPLE 13

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

[0157] 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)+.

[0158] Analysis for C21H31N3O3.HCl.0.5 H2O

[0159] Calculated: C: 60.20; H: 7.94; N: 10.03

[0160] Found: C: 60.19; H: 7.88; N: 9.83.

EXAMPLE 14

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

[0161] 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 H2O 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)+.

[0162] Analysis for C28H35N3O4.HCl.1.25 H2O

[0163] Calculated: C: 62.68; H: 7.23; N: 7.83

[0164] Found: C: 62.27; H: 6.82; N: 7.54.

EXAMPLE 15

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

[0165] 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. NaHCO3 and 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)+.

[0166] Analysis for C27H29N3O3.HCl.0.25 H2O

[0167] Calculated: C: 66.93; H: 6.35; N: 8.67

[0168] Found: C: 66.59; H: 6.45; N: 8.61.

EXAMPLE 16

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

[0169] 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. NaHCO3 and brine.

[0170] 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)+.

[0171] Analysis for C28H31N3O3.0.5 C4H4O4.0.70 H2O

[0172] Calculated: C: 68.21; H: 6.57; N: 7.95

[0173] Found: C: 68.29; H: 6.29; N: 7.62.

	Number	Date	Country
Parent	09516137	Mar 2000	US
Child	09938016	Aug 2001	US

N-substituted imide derivatives with serotonergic activity

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