MXPA00012479A - Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents - Google Patents

Abstract

This invention relates to compounds which have activity as 5-HT1A agonists and antagonists which may be useful for the treatment of anxiety, depression, cognitive deficits, and prostate cancer. Useful compounds are those of formula (I) where:X is selected from the group consisting of (1), (2), (3);n is selected from the integers 1 through 5;R1 is optionally substituted C6-C10-aryl or mono or bicyclic heteroaryl, with a proviso that heteroaryl is not thiadiazole;R2 is selected from the group consisting of H and C1-C6 alkyl;R3 is selected from the group consisting of H, COR5, COOR5, and CONR5R6;R4, R5 and R6 are as defined hereinabove;or an optical isomer;or a pharmaceutically acceptable salt thereof.

Description

ARIL-PIPERAZINES, PIPERIDINES AND TETRAHYDROPYRIDINES, SUBSTITUTED WITH CYCLAL ALCOHOL AS AGENTS SEROTONERGIC Background of the Invention Compounds having selective partial agonist activity to the 5-HT? A receptor have established a presence in the mercantile world as effective anxiolytic agents (buspirone, Buspar®, Patent United States 3,717,634). 5-HT? A agonists and antagonists may find use in the treatment of severe conditions such as anxiety, schizophrenia depression, cognitive deficiencies resulting from neurodegenerative conditions such as Alzheimer's disease, nausea and vomiting, and in the treatment of cancer. prostate (for recent references, see: K. Rasmussen and V.P. Rocco, Recent Progress i n Sero t oni n (5 - TH) ÍA Recept or Modul a t ors, in Annual Reports in Medicinal Chemistry, Volume 30, J.A. Bristol, ed., Pp. 1-9 (nineteen ninety five) ) .

REF. : 125825 Description of the Invention In accordance with this invention, a number of new compounds are provided, including their enantiomers, which have activity as 5-HTn agonists and antagonists. The compounds of the present invention are described by the generic formula: where: X is selected from the group consisting of: n is selected from integers 1 to 5; R1 is arylC6_C? Or mono or bicyclic heteroaryl, optionally substituted by F, Cl, Br, I, -OE., -NH2, -C02H, alkylC? -C6-C02, -CN, -N02, Ci-Ce alkyl, C2 alkenyl -C6 / C2-C6 alkynyl, C6-C6 perhaloalkyl, ORA and C6-C6 perhaloalkoxy, with the proviso that heteroaryl is not thiadiazole; R2 is selected from the group consisting of H and Ci-Ce alkyl; R3 is selected from the group consisting of H, COR5, COOR5 and CONR5R6; R4 is selected from the group consisting of H, C? -C6 alkyl, C2-C6 alkenyl / C2-C6 alkynyl, C6-C? Aryl or mono- or bicyclic heteroaryl, C7-C14 aralkyl, and mono- or bicyclic heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one to three substituents independently selected from the group consisting of F, Cl, Br, I, CN, -NH2, -N02, -OH, alkyl, C2-C6 alkenyl, C2-C2 alkynyl , C 1 -C 6 perhaloalkyl, C 6 -C 6 alkoxy, and C 1 -C 6 perhaloalkoxy; R5 and R6 are independently selected from the group consisting of H, Ci-Cß alkenyl C2-Cd alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl C2-C6 cycloalkenyl, adamantyl, and noradamantyl or R5 and R6 taken together with the interposed nitrogen atom, can form a 5-7 element azacyclic ring, optionally containing an additional heteroatom t selected from 0, S or NR. the optical isomers; and pharmaceutically acceptable salts thereof.

The term "C6-C aryl" includes phenyl and naphthyl. "Monocyclic heteroaryl" means a heteroaryl group of 5-6 elements having from 1-3 heteroatoms independently selected from N, 0 and S, such as pyridine, pyrrole, thiophene, furan, imidazole, oxazole, pyrimidine, pyridazine, pyrazine, thiazole and oxathiazole . Bicyclic heteroaryl includes phenyl fused to a heteroaryl group of 5-6 monocyclic elements or a heteroaryl group of 5-6 elements fused to another heteroaryl group of 5-6 elements, including but not limited to indole, quinoline, isoquinoline, benzofuran, benzodioxane, benzothiophene, benzimidazole, naphthyridine, and imidazopyridine. The term C7-C14 aralkyl means a C? ~C alkyl group having a phenyl or naphthyl group as a substituent, and the term heteroaralkyl means a C? -C alkyl group having a mono or bicyclic heteroaryl group as defined above as a substituent. The optical isomers of the compounds of the invention can be selectively synthesized or separated using conventional procedures known to those skilled in the art of organic synthesis. The pharmaceutically acceptable salts of the compounds of the invention include the conventional acidic addition salts, which are formed of a compound of the invention and a pharmaceutically acceptable organic or inorganic acid. Acidic addition salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorrate, camphorsulfonate, dodecyl sulfate, ethanesulfonate, fumarate, glycerophosphate, phosphate, hemisulfate, hydrochloride, hydrobromide, iodohydrate, lactate, maleate, methanesulfonate, nicotinate, oxalate, pamoate, pactinate, pivalate, propionate, succinate, tartrate and tosylate. Also groups containing basic nitrogen can be quaternized with such agents as lower alkyl halides, dialkylsulfates, long chain halides such as lauryl bromide, aralkyl halides such as benzyl and phenethyl bromides.

Detailed description of the invention Compounds in which at least one of R2 and R3 is hydrogen, are synthesized in four stages (Scheme 1), starting from cycloalkylalanine which has been protected at the nitrogen atom with the t-butoxycarbonyl group (BOC). This material is coupled to the appropriately substituted heterocycle aryl wherein X is CH, N or carbon having a double bond to an adjacent carbon atom using dicyclohexylcarbodiimide (DCC) to provide compound 1. Removal of the BOC group under acidic conditions followed by reduction using a borane complex, leads the penultimate intermediate 2. Subsequent acylation of 2 with the appropriate acid chloride gives compound 3, which is isolated as an acceptable one.

Scheme 1 The compounds in which both R 2 and R 3 are other than hydrogen, are prepared using two general methods. The reduction of the BOC-protected amide 1 with lithium aluminum hydride (LAH) provides methylamine 4 in one step (Scheme 2). Subsequent acylation using the appropriate acid chloride provides N-methylamide 5.

Scheme 2 Alternatively, acylation of intermediate 2, followed by reduction with an appropriate reducing agent such as borane * dimethylsulfide gives alkylamine 6, which can then be converted with the final acylated product 7 (Scheme 3).

Scheme 3 The carbamates and ureas can be prepared from the intermediate amines 2, 4, and 6 either by treatment with an appropriate isocyanate or by reacting the amine with an equivalent phosgene such as trichloromethylchloroformate or triphosgene followed by treatment with an alcohol or amine appropriate Other synthetic procedures may be apparent to those skilled in the art of organic synthesis.

The compounds of this invention are prepared by conventional methods, which are well known to one skilled in the art of chemistry using chemicals that are either commercially available or readily prepared following standard literature procedures. The following examples are included for illustrative purposes only and are not intended to be considered as limiting this description in any way.

Example 1 . { [(IR) -1-Cyclohexylmethyl-2- [4- (2-methoxy phenyl) -piperazin-1-yl] -ethyl} -cyclohexanecarboxylic acid amide To a solution of 0.31 g (0.94 mmol) of. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxy phenyl) -piperazin-1-yl] -ethyl} -amine and 0.26 L (1.87 mmol) of triethylamine in 10 mL of dichloromethane at 0 ° C, 0.15 g (1.03 mmol) of cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane was added as drops. The reaction mixture was allowed to stir under nitrogen at 0 ° C for one hour, and then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with saturated aqueous NaHCO 3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel (dichloromethane / methanol) and then converted to the dihydrochloride salt. of the title compound with ethanolic HCl to give 0.41 g (85%) as a beige solid; mp = 121-131 ° C; MS (+) ESI m / z = 442 (M + H) A Analysis for C2 H43N302 • 2HC1 Calculated: C: 63.02; H: 8.81; N: 8.17 Found: C: 63.56; H: 9.21; N: 8.07.

Example 2 { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxy phenyl) -piperazin-1-yl] -ethyl} -amide of 1-methyl-cyclohexanecarboxylic acid To a solution of 0.30 g (0.91 mmol) of . { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxy phenyl) -piperazin-1-yl] -ethyl} -amine and 0.25 mL (1.74 mmol) of triethylamine in 10 mL of dichloromethane at 0 ° C, 0.16 g (1.00 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane was added as drops. The reaction mixture was allowed to stir under nitrogen at 0 ° C for one hour, and then concentrated in a rotary evaporator, diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel (dichloromethane / methanol) and then converted to the hydrochloride • salt ae title compound hydrate with ethanolic HCl to give 0.30 g (63%) as a light yellow solid; mp = 119-121 ° C; MS (+) ESI m / z = 456 (M + H) A Analysis for C28H45N302 • HCl • H20 Calculated: C: 65.92; H: 9.48; N: 8.24 Found: C: 65.85; H: 9.26; N: 7.67.

Example 3 { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) piperazin-1-yl] -ethyl} -cyclohexanecarboxylic acid-amide-amide To a solution of 0.30 g (0.87 mmol) of. { [(1 R) -l-cyclohexylmethyl-2- [4- (2-methoxy-phenyl-1) -piperazin-1-yl] -ethyl} -met-il-amide and 0.25 mL (1.74 mmol) of triethylamine in 10 mL of dichloromethane at 0 ° C, 0.19 g (1.31 mmol) of cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane was added as drops. The reaction mixture was allowed to stir under nitrogen overnight at room temperature, and then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with saturated aqueous NaHCO 3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel. (dichloromethane / methanol) and then converted to the hydrochloride salt with ethanolic HCl to give 0.41 g (89%) of the title compound as a white solid; mp = 222-224 ° C; MS (+) ESI m / z = 456 (M + H) A Analysis for C27H43N302 • 2HC1 Calculated: C: 63.02; H: 8.96; N: 7.95 Found: C: 63.11; H: 8.81; N: 7.97.

Example 4 { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxy phenyl) -piperazin-1-yl] -ethyl} -methyl-amide of 1-methyl-cyclohexanecarboxylic acid To a solution of 0.30 g (0.87 mmol) of . { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperazin-1-yl] -ethyl} -methyl-amine and 0.25 mL (1.74 mmol) of triethylamine in 10 mL of dichloromethane at 0 ° C, 0.21 g (1.31 mmol) of 1-methyl-yl-cyclohexanecarboxylic acid chloride was added in drops. 4 mL of dichloromethane. The reaction mixture was stirred under nitrogen overnight at room temperature, and then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel. (dichloromethane / methanol) and then converted to the dihydrochloride salt of the title compound with ethanolic HCl to provide 0.41 g (86%) of a white solid; mp = 208-210 ° C; MS (+) ESI m / z = 470 (M + H) A Analysis for C29H47N302 • 2HC1 Calculated: C: 64.19; H: 9.10; N: 7.74 Found: C: 63.89; H: 9.03; N: 7.93 Example 5 { [(IR) -1-Cyclohexylmethyl-2- [4- (2, 3) -dihydro-benzo [1,4] -dioxin-5-yl) -piperazin-1-yl] -ethyl} - cyclohexanecarboxylic acid methyl-amide To a solution of 0.7 g (1.87 mmol) c'.e. { [(IR) -l-Cyclohexylmethyl-2- [4- ((2,3) -dihydro-benzo [1,4] -dioxin-5-yl) -piperazin-1-yl] -ethyl} -methyl-amine and 0.5 mL (3.7 mmol) of triethylamine in 10 mL of dichloromethane at 0 ° C, 0.27 g (1.87 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane was added dropwise. The reaction mixture was allowed to stir under nitrogen overnight at room temperature, and then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H20 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel (ethyl acetate / hexanes) and then converted to the hydrochloride salt • hemihydrate salt of the title compound with ethereal HCl to give 0.82 g (91%) as a white solid; mp = 147-148 ° C; MS (+) ESI m / z = 484 (M + H) A Analysis for C29H45N303 • HCl • 0.5 H20 Calculated: C: 65.82; H: 8.95; N: 7.94 Found: C: 65.90; H: 9.04; N: 7.98.

Example 6 { [(IR) -l-Cyclohexylmethyl-2- [4- (2,3-dihydrobenzo [1,4] dioxin-5-yl) -piperazin-1-yl] -ethyl} - 1-methyl-cyclohexanecarboxylic acid methylamide To a solution of 0.7 g (1.87 mmol) of. { [(IR) -l-Cyclohexylmethyl-2- [4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -ethyl} -methylamine and 0.5 mL (3.7 mmol) of triethylamine in 10 mL of dichloromethane at 0 ° C0.3 g (1.87 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in dichloromethane was added dropwise. The reaction mixture was allowed to stir under nitrogen overnight at room temperature and then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H20 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel (ethyl acetate / hexanes) and then converted to the hydrochloride salt of the title compound with ethereal HCl to give 0.85 g (91%) of the title compound as a white solid; mp = 219-220 ° C; MS (+) ESI m / z = 498 (M + H) A Analysis for C3oH47N30 • Calculated HCl: C: 67.45; H: 9.06; N: 7.87 Found: C: 67.04; H: 9.17; N: 7.88.

Example 7 { [(IR) -l-Cyclohexylmethyl-2- [4- (1H-indol-4-yl) -piperazin-1-yl] -ethyl} -cyclohexanecarboxylic acid-methyl-amide To a solution of 0.6 g (1.69 mmol) of. { [(IR) -l-Cyclohexylmethyl-2- [4- (lH-indol-4-yl) -piperazin-1-yl] -ethyl} -methyl-amine and 0.5 L (3.7 mmol) of triethylamine in 10 mL of dichloromethane at 0 ° C, 0.25 g (1.69 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane was added dropwise. The reaction mixture was allowed to stir under nitrogen overnight at room temperature, and then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H20 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel (ethyl acetate / hexanes) and converted to the salt. of hydrochloride • 0.3 hydrate salt of the title compound with ethereal HCl to give 0.68 g (87%) as a white solid; pf = > 260 ° C; MS (+) ESI m / z = 465 (M + H) A Analysis for C29H44N402 • HCl • 0.3 H20 Calculated: C: 68.76; H: 9.07; N: 11.06 Found: C: 68.52; H: 9.15; N: 11.18.

Example 8 { [(IR) -l-Cyclohexylmethyl-2- [4- (1-indol-4-yl) -piperazin-1-yl] -ethyl} 1-Methyl-cyclohexanecarboxylic acid-methyl-amide To a solution of 0.6 g (1.69 mmol) of. { [(IR) -1-Cyclohexymethyl-2- [4- (lH-indol-4-yl) -piperazin-1-yl] -ethyl} -methalamine and 0.5 mL (3.7 mmol) of triethylamine in 10 mL of dichloromethane at 0 ° C, 0.27 g (1.69 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in dichloromethane was added dropwise. The reaction mixture was allowed to stir under nitrogen overnight at room temperature, and then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H20 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel (ethyl acetate / hexanes) and converted to the salt. of hydrochloride of the title compound with ethereal HCl to provide 0.7 g (87%) as a white solid; mp = 253-254 ° C; MS (+) ESI m / z = 479 (M + H) A Analysis for C3oH46N40 • Calculated HCl: C: 69.94; H: 9.20; N: 10.88 Found: C: 69.68; H: 9.21; N: 10.89.

Example 9 N-. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxy phenyl) -piperazin-1-yl] -ethyl} -formamide A mixture of 2.10 mL (23.6 mmol) of glacial acetic acid and 1.23 mL (32.1 mmol) of formic acid was stirred at 60 ° C for 4 hours to form the mixed anhydride. The resulting solution was slowly added to an ice-cooled solution of 1.18 g (3.56 mmol) of. { [(IR) -1-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperazin-1-yl] -ethyl} -amine in 35 mL of tetrahydrofuran under nitrogen. The reaction mixture was stirred under nitrogen at room temperature, and then poured slowly into 60 mL of saturated aqueous NaHCO 3 and stirred for 10 minutes. The layers were separated and the aqueous phase was extracted with two additional portions of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel (dichloromethane / methanol) and converted to the hydrochloride. 1.5 hydrate of the title compound with ethanolic HCl to give 1.03 g (80%) as a white solid, mp = 157-159 ° C, MS (+) ESI m / z = 360 (M + H) A Analysis for C2 H33N302 • HCl • 1.5 H20 Calculated: C: 59.62; H: 8.81; N: 9.93 Found: C: 59.54; H: 8.63; N: 9.33 Example 10 { [(IR) -1-Cyclohexylmethyl-2- [4- (2-methoxy phenyl) piperidin-1-yl] -ethyl} -cyclohexanecarboxylic acid amide To a solution of potassium carbonate 0.076 g (0.54 mmol) in 1 ml of water, a solution of 0.18 g of water was added. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperidin-1-yl] -ethyl} -amine (0.54 mmol) in 10 mL of dichloromethane. The resulting mixture was cooled to 0 ° C and 0.076 mL of cyclohexanecarboxylic acid chloride (0.54 mmol) was added. The reaction was allowed to stir overnight at 0 ° C, and then it was diluted with 5 L of water and 20 mL of dichloromethane, and the phases were separated. The aqueous phase was extracted with three additional portions of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel (dichloromethane / methanol) and converted to the hydrochloride • salt of hydrate of the title compound with isopropanolic HCl to give 0.177 g (68%) of the white solid; mp = 100-103 ° C; MS (+) ESI m / z = 441 (M + H) A Analysis for C28H44N202 • HCl • H20 Calculated: C: 67.91; H: 9.56; N: 5.66 Found: C: 68.15; H: 9.57; N: 5.59.

Example 11 { [(IR) -1-Cyclohexy-lmet-il-2- [4- (2-methoxy-phenyl) -piperidin-1-yl] -ethyl} -amide of 1-methyl-cyclohexanecarboxylic acid To a solution of potassium carbonate 0.076 g (0.54 mmol) in 1 ml of water, a solution of 0.18 g of water was added. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperidin-1-yl] -ethyl} -amine (0.54 mmol) in 10 mL of dichloromethane. The resulting mixture was cooled to 0 ° C and 0.085 mL of 1-methyl-cyclohexanecarboxylic acid chloride (0.54 mmol) was added. The reaction was allowed to stir overnight at 0 ° C, and then diluted with 5 mL of water and 20 mL of dichloromethane, and the phases were separated. The aqueous phase was extracted with three additional portions of dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on a silica gel. silica (dichloromethane / methanol) and converted to the hydrochloride • 0.75 hydrate salt of the title compound with isopropanolic HCl to provide 0.35 g (55%) of the white solid; mp = 208-210 ° C; MS (+) ESI m / z = 455 (M + H) A Analysis for C28H 4N202 • HCl • 0.75 H20 Calculated: C: 69.01; H: 9.69; N: 5.54 Found: C: 69.03; H: 9.60; N: 5.45.

Example 12 { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxy phenyl) -piperidin-1-yl] -ethyl} cyclohexanecarboxylic acid-methyl-amide To a solution of potassium carbonate 0.080 g (0.58 mmol) in 1 ml of water, a solution of 0.20 g of. { [(IR) -l-Cyclohexylmethyl-2- [- (2-methoxyphenyl) -piperidin-1-yl] -ethyl} -methyl-amine (0.58 mmol) in 10 mL of dichloromethane. The resulting mixture was cooled to 0 ° C and 0.090 g of cyclohexanecarboxylic acid chloride (0.58 mmol) was added thereto. The reaction was allowed to stir overnight at 0 ° C, and then diluted with 5 mL of water and 20 mL of dichloromethane, and the phases were separated. The aqueous phase was extracted with three additional portions of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel (dichloromethane / methanol) and converted to the hydrochloride • salt. of hydrate 0.75 of the title compound with isopropanolic HCl to give 0.195 g (69%) as a white solid; mp = 135-137 ° C; MS (+) ESI m / z = 455 (M + H) A Analysis for C29H4eN202 • HCl • 0.75 H20 Calculated: C: 69.01; H: 9.69; N: 5.55 Found: C: 69.07; H: 9.52; N: 5.19.

Example 13 { [(IR) -1-Cyclohexylmethyl-2- [4- (2-methoxy phenyl) -piperidin-1-yl] -ethyl} -methyl-amide of 1-methyl-cyclohexanecarboxylic acid To a solution of potassium carbonate 0.08 g (0.58 mmol) in 1 ml of water, a solution of 0.18 g of water was added. { [(IR) -l-Cyclohexylmethyl-2- [- (2-methoxyphenyl) -piperidin-1-yl] -ethyl} -methyl-amine (0.58 mmol) in 10 mL of dichloromethane. The resulting mixture was cooled to 0 ° C and 0.093 mL of 1-methyl-cyclohexanecarboxylic acid chloride (0.58 mmol) was added. The reaction was allowed to stir overnight at 0 ° C, and then diluted with 5 mL of water and 20 mL of dichloromethane, and the phases were separated. The aqueous phase was extracted with three additional portions of dichloromethane and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel. (dichloromethane / methanol) and converted to the hydrochloride • 0.75 hydrate salt of the title compound with isopropanolic HCl to provide 0.223 g (75%) of a white solid; mp = 169-171 ° C; MS (+) ESI m / z = 469 (M + H) A Analysis for C30H48N2O2 • HCl • 0.75 H20 Calculated: C: 69.52; H: 9.82; N: 5.40 Found: C: 69.44; H: 9.61; N: 9.94.

Example 14 N-. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperidin-1-yl] -ethyl} -2, 2-dimethyl-propionamide To a solution of potassium carbonate 0.076 g (0.54 mmol) in 1 ml of water, a solution of 0.18 g of water was added. { [(IR) -1-Cyclohexymethyl-2- [4- (2-methoxyphenyl) -piperidin-1-yl] -ethyl} -amine (0.54 mmol) in 10 mL of dichloromethane. The resulting mixture was cooled to 0 ° C and 0.066 g of trimethylacetyl chloride (0.54 mmol) was added thereto. The reaction was allowed to stir overnight at 0 ° C, and then diluted with 5 mL of water and 20 mL of dichloromethane, and the phases were separated. The aqueous phase was extracted with three additional portions of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel (dichloromethane / methanol) and converted to the hydrochloride • salt hydrate 0. 75 of the title compound with isopropanol HCl to provide 0.137 g (56%) of a white solid; mp = 97-99 ° C; MS (+) ESI m / z = 415 (M + H) A Analysis for C26H42N202 • HCl • 0.75 H20 Calculated: C: 67.22; H: 9.65; N: 6.02 Found: C: 66.91; H: 9.68; N: 5.90.

Example 15 N-. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxy phenyl) -piperidin-1-yl] -ethyl} -2, 2, N-trimethyl-propionamide To a solution of potassium carbonate 0.08 g (0.58 mmol) in 1 ml of water, a solution of 0.20 g of. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperidin-1-yl] -ethyl} -methyl-amine (0.58 mmol) in 10 mL of dichloromethane. The resulting mixture was cooled to 0 ° C and 0.075 mL of trimethylacetyl chloride (0.62 mmol) was added. The reaction was allowed to stir overnight at 0 ° C, and then diluted with 5 mL of water and 20 mL of dichloromethane, and the phases were separated. The aqueous phase was extracted with three additional portions of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel (dichloromethane / methanol) and converted to the hydrochloride • salt of hydrate 0.25 of the title compound with isopropanoic HC1 to provide 0.157 g (58%) of the white solid; mp = 233-236 ° C; MS (+) ESI m / z = 429 (M + H) A Analysis for C27H44N202 • HCl • 0.25 H20 Calculated: C: 69.05; H: 9.77; N: 2.97 Found: C: 69.28; H: 9.96; N: 5.90.

Example 16 { (IR) -l-Cyclohexylmethyl-2- [4- (2-methyl-phenyl) -3,6-dihydro-2H-pyridin-1-yl] ethyl} 1- methyl-cyclohexanecarboxylic acid amide To a solution of 0.25 g (0.76 mmol) of. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxy-phenyl-1) -3,6-dihydro-2H-pyridin-1-yl] -ethyl} -amine and 0.21 mL (1.52 mmol) of triethylamine in 10 mL of dichloromethane at 0 ° C, 0.13 g (0.84 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane was added dropwise. The reaction mixture was allowed to stir under nitrogen at 0 ° C for one hour, and then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with saturated aqueous NaHCO 3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica gel (dichloromethane / methanol) and then converted to the sodium salt. hydrochloride • hemihydrate salt of the title compound with ethanolic HCl to provide 0.15 g (41%) of a yellow solid; mp = 93-95 ° C; MS (+) ESI m / z = 453 (M + H) A Analysis for C29H4 N2? 2 • HCl • 0.5 H20 Calculated: C: 69.92; H: 9.31; N: 5.62 Found: C: 69.92; H: 9.03; N: 5.23.

PHARMACOLOGY The affinity for the 5-HT? A receptor for serotonin was established by testing the ability of the test compounds to displace [3H] 8-OHDPAT from its binding site in the receptor complex in stably transfected CHO cells. with the human 5-HT? A receptor following the procedure described by J. Dunlop, Y. Zhang, D. Smith and L. Schechter (Eur. J. Pharmacol., establishing: variation of a procedure described by J. Zgombick et al. al., Naunyn-Schmiedeberg's Arch. Pharmacol., 354, 226-236 (1996)). The compounds of this invention exhibit high affinity for the 5-HTiA receptor as described in Table 1.

Table 1 Example Affinity Activity Activity 5-HT? A antagonist agonist (IC50) GTP? S (ECso) cAMP (IC50) Example 1 0.57 nM 0.9 nM Example 2 1.23 nM 14.6 nM Example 3 1.46 nM 4.0 nM Example 4 2.82 nM 10.2 nM Example 5 2.37 nM 4.6 nM Example 6 6.92 nM 7.3 nM Example 7 8.84 nM 10.5 nM Example 8 32.68 nM Example 9 1.49 nM 17.3 nM Example 10 1.08 nM 3.9 nM Example 11 5.97 nM 46.0 nM Example 12 1.69 nM 91.5 nM Example 13 5.33 nM 97.5 nM Example 14 2.19 nM 40.0 nM Example 15 5.00 Nm Example 16 2.75 nM 45.5 nM Some of the compounds of this invention exhibited partial 5-HT 1A agonist activity, as verified by the ability of the test compounds to stimulate the binding of [35 S] -GTPγS to the G-protein receptor complex of 5-HT? A in CHO cells stably transfected with the human 5-HTiA receptor, following a variation of the procedure described by Lazareno and Birdsall [Br. J. Pharmacol., 109, 1120 (1993)]. The selected compounds of this invention, which demonstrated agonist activity in this assay are shown in Table 1. Some of the compounds of this invention demonstrated the 5-HT ?A antagonist activity as measured by the ability of the test compounds to inhibit the cAMP change stimulated by forskolin in CHO cells stably transfected with the human 5HTiA receptor using the procedure described by J. Dunlop, Y. Zhang, D. Smith and L. Schechter (Eur. J. Pharmacol., establishing: variation of a procedure described by J. Zgombick et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 354, 226-236 (1996)). The selected compounds of this invention which demonstrated 5-HTiA antagonist activity in this are shown in Table 1 PHARMACEUTICAL COMPOSITION Applicable solid carriers may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, binders, compression aids, binders or tablet disintegrating agents or encapsulating materials. In the powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable portions and compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting waxes, and ion exchange resins.

Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs. The active ingredient in this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils and fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers and osmo-regulators. Examples of liquid carriers for oral and parenteral administration include water (particularly contain additives as above, for example, cellulose derivatives, preferably a solution of sodium carboxymethylcellulose), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and their derivatives, and oils (for example, fractionated coconut oil) and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers can also be used in compositions in sterile liquid form for parenteral administration.

Preferably, the pharmaceutical composition is in unit dosage form, for example, tablets or capsules. In such forms, the composition is subdivided into a unit dose containing appropriate amounts of the active ingredient; the unit dosage forms can be packaged compositions, for example packaged powders, flasks, ampoules, prefilled syringes or fluid-containing syringes. The unit dosage form can be for example, a capsule or a tablet itself, or it can be the appropriate number of any such compositions in the packaged form.

The dosage to be used in the treatment of specific conditions may be subjectively determined by the specialist physician. The variables involved include the specific condition and size, age and patient response model.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (10)

1. A compound in accordance with the formula characterized in that: X is selected from the group consisting of n is selected from integers 1 to 5; R1 is arylCi-Cio or mono- or bicyclic heteroaryl, having 5-10 atoms, 1 to 3 of which sor. heteroatoms selected independently of N, S or O, wherein the aryl or heteroaryl group is optionally substituted by F, Cl, Br, I, -OH, -NH2, -C02H, C alquilo-C6-C02 alkyl, -CN, -N02, Ci-Cß alkyl C2-C6 alkynyl C2-C6 alkynyl / C6-C6 perhaloalkyl / OR4, and C6-C6 perhaloalkoxy with the proviso that heteroaryl is not thiadiazole; R 2 is selected from the group consisting of H and C 1 -C 6 alkyl; R3 is selected from the group consisting of H, COR5, R4 is selected from the group consisting of H, C2-C6 Ci-Cß alkenyl, C2-C6-C2-C2 alkynyl, mono- or bicyclic heteroaryl as defined above, C7-C14 aralkyl, and mono- or bicyclic heteroaralkyl, wherein the mono- or bicyclic aryl or heteroaryl group is as defined above and optionally substituted with one to three substituents independently selected from the group consisting of F, Cl, Br, I, CN , -NH2, -N02, -OH, alkyl, C2-C6 alkenyl, C2-C6 alkynyl / perhaloalkyl Ci-Cß, alkoxy C? -C6, and perhaloalkoxy d-C6; R5 and R6 are independently selected from. group consisting of H, C? -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl / C3-C6 cycloalkyl, C2-C6 cycloalkenyl, adamantyl, and noradamantyl or R5 and R6 taken together with the interposed nitrogen atom, can forming an azacyclic ring of 5-7 elements, optionally containing an additional heteroatom selected from 0, S or NR4. or an optical isomer; or the pharmaceutically acceptable salt thereof.
2. 2. A compound according to claim 1 having the formula characterized in that: X is selected from the group consisting of n is selected from integers 1 to 5; R1 is arylCd-Cio or mono- or bicyclic heteroaryl, optionally substituted by F, Cl, Br, I, C02H, C alquilo-C5-C02 alkyl, -CN, -N02, C alquilo-C6 alkyl, C2-C6 alkenyl, C2-alkynyl C6 / perhaloalkyl C? -C6 / OR4, and perhaloalkoxy C? -C6 / with the proviso that heteroaryl is not thiadiazole; R 2 is selected from the group consisting of H and C 1 -C 6 alkyl; R3 is selected from the group consisting of H, COR5 ', R4 is selected from the group consisting of H, C? -C6 alkyl / C2-C6 alkenyl, C2-C6 alkynyl, C aryl (-cyclo, mono- or bicyclic heteroaryl, C-C14 aralkyl, and mono- or bicyclic heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one to three substituents independently selected from the group consisting of F, Cl, Br, I, CN, -N02, Ci- Cβ, C2-C6 alkenyl, C2-C2 alkynyl, Ci-Cß perhaloalkyl, C?-C6 alkoxy, and C?-C6 perhaloalkoxy, R5 and R6 are independently selected from the group consisting of H, Ci-Cß alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Ce cycloalkyl, C2-C6 cycloalkenyl, adamantyl, and noradamantyl or R5 and R6 taken together with the interposed nitrogen atom, form piperidine, morpholine or piperazine substituted at position 4 by a substituent selected from R4 or an optical isomer, or the pharmaceutically acceptable salt thereof
3. 3. A compound according to claim 1 characterized in that it is. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperazin-1-yl] -ethyl} - cyclohexanecarboxylic acid amide,. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperazin-1-yl] -ethyl} -amide of 1-methyl-cyclohexanecarboxylic acid,. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperazin-1-yl] -ethyl} -methyl amide of cyclohexanecarboxylic acid,. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperazin-1-yl] -ethyl} -methyl-amide of 1-methyl-cyclohexanecarboxylic acid,. { [(IR) -l-Cyclohexylmethyl-2- [4- (2, 3) -dihydro-benzo [1,4] -dioxin-5-yl) -piperazin-1-yl] -ethyl} -cyclohexanecarboxylic acid-methyl-amide,. { [(IR) -l-Cyclohexylmethyl-2- [4- (2, 3-dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -ethyl} -methyl-1-methyl-cyclohexanecarboxylic acid amide,. { [(IR) -l-Cyclohexylmethyl-2- [4- (lH-indol-4-yl) -piperazin-1-yl] -ethyl} - cyclohexanecarboxylic acid methylamide,. { [(IR) -l-Cyclohexylmethyl-2- [4- (l-indol-4-yl) -piperazin-1-yl] -ethyl} -methyl-amide of 1-methyl-cyclohexanecarboxylic acid, N-. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperazin-1-yl] -ethyl} -formam,. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperidin-1-yl] -ethyl} - cyclohexanecarboxylic acid amide,. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperidin-1-yl] -ethyl} -amide of 1-methyl-1-cyclohexanecarboxylic acid,. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperidin-1-yl] -ethyl} - cyclohexanecarboxylic acid methylamide,. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperidin-1-yl] -ethyl} -methyl-amide of 1-methyl-cyclohexanecarboxylic acid, N-. { [(IR) -1-Cyclohexylmethyl-2- [4- (2-methoxy phenyl) -piperidin-1-yl] -ethyl} -2, 2-dimethyl-propionamide, N-. { [(IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -piperidin-1-yl] -ethyl} -2, 2, N-trimethyl-propionamide, or. { (IR) -l-Cyclohexylmethyl-2- [4- (2-methoxyphenyl) -3,6-2H-pyridin-1-yl] ethyl} 1-methyl-cyclohexanecarboxylic acid amide, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
4. 4. A method of treating conditions in mammals, modulated by the 5-HTiA receptors of serotonin in the central nervous system in the body, which is characterized in that it comprises administering to a mammal having such condition, a therapeutically effective amount of a compound in accordance with the formula where: X is selected from the group consisting of n is selected from integers 1 to 5; R1 is arylC6-C ?o or mono- or bicyclic heteroaryl, having from 5-10 atoms, 1 to 3 of which are heteroatoms independently selected from N, S or O, wherein the aryl or heteroaryl group is optionally substituted by F, Cl, Br, I, OH, -NH2, -C02H, C -C6-C02 alkyl, -CN, -N02, Ci-C alquilo alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C?-C6 perhaloalkyl, OR 4, and perhaloalkoxy C? -C6, with the proviso that heteroaryl is not thiadiazole; R 2 is selected from the group consisting of H and C 1 -C 6 alkyl; R3 is selected from the group consisting of H, COR, COOR5 and CONR5R6; R 4 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 2 alkynyl, C 6 -Cy aryl, mono or bicyclic heteroaryl as defined above, C 7 -C 4 aralkyl, and mono heteroaryl or bicyclic, wherein the aryl group D mono or bicyclic heteroaryl is as defined above and optionally substituted with one to three substituents independently selected from the group consisting of F, Cl, Br, I, CN, -NH2, -N02, - OH, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, perhaloalkyl Ci-Cß, alkoxy Ci-Ce, and perhaloalkoxy Ci-Cß, "R5 and R6 are independently selected from the group consisting of H, Ci-Cß alkyl , C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl C2-C6 cycloalkenyl, adamantyl, and noradamantyl or R5 and R6 taken together with the interposed nitrogen atom, can form a 5-7 element azacyclic ring, which optionally contain an additional heteroatom selected from O, S or NR4, or an optical isomer, or the salt of the same pharmaceutically acceptable.
5. 5. The method according to claim 4, characterized in that the condition treated is the depression.
6. 6. The method according to claim 4, characterized in that the condition treated is anxiety.
7. 7. The method according to claim 4, characterized in that the condition treated is the loss of memory and / or learning. result of neurodegenerative diseases ta L such as Alzheimer's disease.
8. 8. The method according to claim 4, characterized in that the condition treated is the prostate.
9. 9. The method according to claim 4, characterized in that the condition treated is nausea and vomiting.
10. 10. A pharmaceutical composition, which is characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the formula where: X is selected from the group consisting of n is selected from integers 1 to 5; R1 is arylCd-Cio or mono- or bicyclic heteroaryl, having 5-10 atoms, 1 to 3 of which are heteroatoms independently selected from N, S or O, wherein the aryl or heteroaryl group is optionally substituted by F, Cl , Br, I, -OH, -NH2, -C02H, alkyl? C? -C6-C02, -CN, -N02, C? -C6 alkyl, C2-Cd alkenyl, C2-Ce alkynyl,? -Ci-C? Perhaloalkyl, OR4, and perhaloalkoxy Ci-C *, with the proviso that heteroaryl is not thiadiazole; R 2 is selected from the group consisting of H and C 1 -C 6 alkyl; R3 is selected from the group consisting of H, COR5, COOR5 and CONR5R6; R4 is selected from the group consisting of H, C? -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl Cedo, mono or bicyclic heteroaryl as defined above, C -C? Aralkyl, and mono- or bicyclic heteroaryl , wherein the aryl or heteroaryl group is as defined above and optionally substituted with one to three substituents independently selected from the group consisting of F, Cl, Br, I, CN, -NH2, -N02, -OH, alkyl, alkenyl C2-C6, C2-C6 alkynyl, perhaloalkyl Ci-Cß, alkoxy Ci-Cß, and perhaloalkoxy Ci-Ce; R5 and R6 are independently selected from the group consisting of H, C?-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C ciclo cycloalkyl, C2-C ciclo cycloalkenyl, adamantyl, and noradamantyl or R5 and Rd taken together with the interposed nitrogen atom, they can form an azacyclic ring of 5-7 elements, which optionally contain an additional heteroatom selected from 0, S or NR4 .. or an optical isomer; or the pharmaceutically acceptable salt thereof.