CN1312802A - 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; R<1> is optionally substituted C6-C10-aryl or mono or bicyclic heteroaryl, with a proviso that heteroaryl is not thiadiazole; R<2> is selected from the group consisting of H and C1-C6 alkyl; R<3> is selected from the group consisting of H, COR<5>, COOR<5>, and CONR<5>R<6>; R<4>, R<5> and R<6> are as defined hereinabove; or an optical isomer; or a pharmaceutically acceptable salt thereof.

Description

Cycloalkyl-substituted arylpiperazines, piperidines and tetrahydropyridines as serotonergic drugs

Background of the invention

Compounds with selective partial agonistic activity at the 5-HT1A receptor have been marketed as potent anxiolytics (buspirone, Buspar ^(R) , US Patent 3,717,634). 5-HT _1A agonists and antagonists can be found in the treatment of several diseases such as anxiety, depression, schizophrenia, cognitive impairment caused by neurodegenerative diseases such as Alzheimer's disease, nausea and vomiting , and for the treatment of prostate cancer (latest references in: K. Rasmussen and VPRocco, Recent advances in modulators of the 5-hydroxytryptamine (5-HT) _1A receptor, Annual Reports of Medicinal Chemistry, volume 30, edited by JABristol, vol. pp. 1-9 (1995)).

Description of the invention

其中：X选自下列基团：

n选自1到5的整数；R¹是C₆-C₁₀-芳基或单或双环杂芳基，由F、Cl、Br、I、-OH、-NH₂、According to the present invention, there is provided a novel group of compounds, including their enantiomers, which possess 5-HT _1A agonist and antagonist-like activity. The compounds of the present invention are illustrated by the following general formula:

Wherein: X is selected from the following groups:

n is an integer selected from 1 to 5; R ¹ is C ₆ -C ₁₀ -aryl or mono- or bicyclic heteroaryl, composed of F, Cl, Br, I, -OH, -NH ₂ ,

CO ₂ H, -CO ₂ -C ₁ -C ₆ alkyl, -CN, -NO ₂ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenes

radical, C ₂ -C ₆ alkynyl, C ₁ -C ₆ perhaloalkyl, OR ⁴ and C ₁ -C ₆ perhaloalkoxy optional

Substituted, with the proviso that heteroaryl is not thiadiazole; ^{R2 is} a group selected from H and _C1 - _C6 alkyl; ^R3 is a group selected from H, ^COR5 , ^COOR5 and ^CONR5R6 ; R ⁴ is selected from H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -C ₁₀ aryl,

Mono- or bicyclic heteroaryl, C ₇ -C ₁₄ aralkyl and mono- or bicyclic heteroarylalkyl radicals, which

The aryl or heteroaryl group in said 1 to 3 independently selected from F, Cl, Br, I,

CN, -NH ₂ , -NO ₂ , -OH, alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -

The substituents of C ₆ perhaloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ perhaloalkoxy are optional

R ⁵ and R ⁶ are independently selected from H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆

Cycloalkyl, C ₂ -C ₆ cycloalkenyl, adamantyl and noradamantyl, or R ⁵ and R ⁶

Linked with the nitrogen atom inserted in the middle to form a 5-7 membered nitrogen heterocycle, optionally containing

An additional heteroatom selected from O, S, or NR ⁴ ; optical isomers thereof; and pharmaceutically acceptable salts thereof.

The term C ₆ -C ₁₀ aryl includes phenyl and naphthyl. Monocyclic heteroaryl means a 5-6 membered heteroaryl group having 1-3 heteroatoms independently selected from N, O and S, such as pyridine, pyrrole, thiophene, furan, imidazole, oxazole, pyrimidine, Pyridazines, pyrazines, thiazoles and oxthiazoles. Bicyclic heteroaryl groups include phenyl fused to a monocyclic 5-6 membered heteroaryl group or 5-6 membered heteroaryl groups fused to another 5-6 membered heteroaryl group, including but It is not limited to indole, quinoline, isoquinoline, benzofuran, benzodioxane, benzothiophene, benzimidazole, naphthyridine and imidazopyridine. The term C ₇ -C ₁₄ aralkyl denotes a C 1 -C 4 alkyl group with a phenyl or naphthyl group as a substituent, while the term heteroaralkyl denotes a C ₁ -C ₄ alkyl group with a phenyl or naphthyl group as defined above. A C ₁ -C ₄ alkyl group of a mono- or bicyclic heteroaryl group.

Optical isomers of the compounds of the present invention can be selectively synthesized or separated by conventional methods known to those skilled in the art of organic synthesis.

The pharmaceutically acceptable salts of the compounds of the present invention include conventional acid addition salts formed from the compounds of the present invention and pharmaceutically acceptable organic or inorganic acids. The acid addition salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, acid sulfate, butyrate, citric acid Salt, camphorate, camphorsulfonate, lauryl sulfate, ethanesulfonate, fumarate, glycerophosphate, phosphate, hemisulfate, hydrochloride, hydrobromide, hydroiodide salt, lactate, maleate, methanesulfonate, nicotine salt, oxalate, pamoate, pectate, pivalate, propionate, succinate, tartrate and Tosylate. Substances such as lower alkyl halides, dialkyl sulfates, long-chain halides (such as lauryl bromide), aralkyl halides (such as benzyl and phenethyl bromide) can also make basic nitrogen-containing groups Group quaternization. Detailed description of the invention

Compounds in which at least one of R ^{and R} is hydrogen are synthesized in four steps (Scheme 1) from cycloalkylalanines that have been replaced with a tert-butoxycarbonyl group on the nitrogen atom (BOC) protection. This material is coupled with dicyclohexylcarbodiimide (DCC) as an appropriately substituted arylheterocycle, where X is CH, N, or has a carbon double-bonded to an adjacent carbon atom to obtain compound 1 . Removal of the BOC group under acidic conditions followed by reduction with a borane complex afforded the penultimate intermediate 2. Acylation of 2 with the appropriate acid chloride then affords compound 3, which is isolated as an acceptable salt. plan 1. Compounds in which neither ^R2 nor ^R3 are hydrogen are prepared using two general methods. Reduction of the BOC-protected amide with lithium aluminum hydride (LAH) afforded the methylamine 4 in one step (Scheme 2). Subsequent acylation with the appropriate acid chloride affords the N-methylamide 5. Scenario 2. Alternatively, after acylation of intermediate 2, reduction with a suitable reducing agent such as borane-dimethylsulfide affords alkylamine 6, which is then converted to the final acylated product 7 (Scheme 3). Option 3. Prepared from intermediate amines 2, 4 and 6 by treatment with the appropriate isocyanate or by reaction of the amine with a phosgene equivalent such as trichloromethyl chloroformate or triphosgene followed by treatment with the appropriate alcohol or amine Urethane and urea. Other synthetic steps will be apparent to those skilled in the art of organic synthesis.

The compounds of the present invention are prepared by conventional methods well known to those skilled in the chemical arts, using commercially available chemicals or those readily prepared following standard literature procedures. The following examples are included for illustrative purposes only and are not meant to limit the invention in any way.

Example 1 Cyclohexanecarboxylic acid {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-amide

{(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-amine (0.31g, 0.94mmol ) and triethylamine (0.26mL, 1.87mmol) in dichloromethane (10mL) was added dropwise a solution of cyclohexanecarbonyl chloride (0.15g, 1.03mmol) in dichloromethane (4mL). The reaction mixture was stirred at 0 °C under nitrogen for 1 h, then concentrated on the 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 obtain a crude product which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted with ethanolic HCl As the dihydrochloride salt of the title compound, 0.41 g (85%) of a beige solid was obtained; mp = 121-131 °C; MS (+) ESI m/z = 442 (M+H) ⁺ . _Anal. Calcd. for _{C27H43N3O2-2HCl} : C: _63.02 ; H: 8.81; N _: 8.17 Found: C: 63.56; H: 9.27; N: 8.07.

Example 21-Methyl-cyclohexanecarboxylic acid {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl} -amide

{(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-amine (0.30g, 0.91mmol ) and triethylamine (0.25mL, 1.74mmol) in dichloromethane (10mL) was added dropwise a solution of 1-methyl-cyclohexanecarbonyl chloride (0.16g, 1.00mmol) in dichloromethane (4mL). The reaction mixture was stirred at 0 °C under nitrogen for 1 h, then concentrated on the 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 obtain a crude product which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted with ethanolic HCl As the hydrated hydrochloride salt of the title compound, 0.30 g (63%) of a pale yellow solid was obtained; mp = 119-121 °C; MS(+)ESI m/z = 456 (M+H) ⁺ . _{Anal. Calcd} . for _C28H45N3O2 ·HCl· _H2O : _C : 65.92; _H : 9.48; N: 8.24 Found: C: 65.85; H: 9.26; N: 7.67.

Example 3 Cyclohexanecarboxylic acid {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-methyl- Amide

To {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-methyl-amine (0.30g , 0.87mmol) and triethylamine (0.25mL, 1.74mmol) in dichloromethane (10mL) was added dropwise a solution of cyclohexanecarbonyl chloride (0.19g, 1.31mmol) in dichloromethane (4mL). The reaction mixture was stirred overnight at room temperature under nitrogen, 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 obtain a crude product which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted with ethanolic HCl As the dihydrochloride salt, 0.41 g (89%) of the title compound was obtained as a white solid; mp = 222-224 °C; MS(+)ESI m/z = 456 (M+H) ⁺ . _Anal. Calcd. for _{C27H43N3O2-2HCl} : C: _63.62 ; H: 8.96; N: 7.95 _Found : C: 63.11; H: 8.81; N: 7.97.

Example 41-Methyl-cyclohexanecarboxylic acid {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl} -Methyl-amide

To {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-methyl-amine (0.30g , 0.87mmol) and triethylamine (0.25mL, 1.74mmol) in dichloromethane (10mL) were added dropwise 1-methyl-cyclohexanecarbonyl chloride (0.21g, 1.31mmol) in dichloromethane (4mL) solution. The reaction mixture was stirred overnight at room temperature under nitrogen, 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 obtain a crude product which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted with ethanolic HCl As the dihydrochloride salt of the title compound, 0.41 g (86%) of a white solid was obtained; mp = 208-210° C.; MS(+)ESI m/z = 470 (M+H) ⁺ . _Anal. Calcd. for _{C29H47N3O2-2HCl} : _C : 64.19; H: 9.10; N: 7.74 _Found : C: 63.89; H: 9.03; N: 7.93.

Example 5 Cyclohexanecarboxylic acid {(1R)-1-cyclohexylmethyl-2-[4-(2,3)-dihydrobenzo[1,4]-dioxin-5-yl)- Piperazin-1-yl]-ethyl}-methyl-amide

To {(1R)-1-cyclohexylmethyl-2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)-piperazin-1-yl ]-Ethyl}-methyl-amine (0.7g, 1.87mmol) and triethylamine (0.5mL, 3.7mmol) in dichloromethane (10mL) solution was added dropwise cyclohexanecarbonyl chloride (0.27g, 1.87mmol ) in dichloromethane solution. The reaction mixture was stirred overnight at room temperature under nitrogen, then concentrated on the 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 obtain a crude product which was purified by flash chromatography on silica gel (ethyl acetate/hexanes) and then converted with ethereal HCl As the hydrochloride hemihydrate of the title compound, 0.82 g (91%) of a white solid was obtained; mp = 147-148 °C; MS(+)ESI m/z = 484 (M+H) ⁺ . _Anal. Calcd. for _{C29H45N3O3.HCl.0.5H2O} : C: _65.82 ; H: _8.95 ; N: _7.94 Found: C: 65.90; H: 9.04; N: 7.98.

Example 61-Methyl-cyclohexanecarboxylic acid {(1R)-1-cyclohexylmethyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5- Base)-piperazin-1-yl]-ethyl}-methylamide

To {(1R)-1-cyclohexylmethyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine-1- 1-methyl-cyclohexanemethanol (0.7 g, 1.87 mmol) and triethylamine (0.5 mL, 3.7 mmol) in dichloromethane (10 mL) were added dropwise Acid chloride (0.3 g, 1.87 mmol) in dichloromethane. The reaction mixture was stirred overnight at room temperature under nitrogen, then concentrated on the 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 obtain a crude product which was purified by flash chromatography on silica gel (ethyl acetate/hexanes) and then converted with ethereal HCl As the hydrochloride salt of the title compound, 0.85 g (91%) of the title compound was obtained as a white solid; mp = 219-220 °C; MS (+) ESI m/z = 498 (M+H) ⁺ . Anal. Calcd. for C ₃₀ H ₄₇ N ₃ O ₃ ·HCl: C: 67.45; H: 9.06; N: 7.87 Found: C: 67.04; H: 9.17; N: 7.88.

Example 7 Cyclohexanecarboxylic acid {(1R)-1-cyclohexylmethyl-2-[4-(1H-indol-4-yl)-piperazin-1-yl]-ethyl}-methyl -amide

To {(1R)-1-cyclohexylmethyl-2-[4-(1H-indol-4-yl)-piperazin-1-yl]-ethyl}-methyl-amine (0.6 g, 1.69 mmol) and triethylamine (0.5 mL, 3.7 mmol) in dichloromethane (10 mL) was added dropwise a solution of cyclohexanecarbonyl chloride (0.25 g, 1.69 mmol) in dichloromethane. The reaction mixture was stirred overnight at room temperature under nitrogen, then concentrated on the 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 obtain a crude product which was purified by flash chromatography on silica gel (ethyl acetate/hexanes) and then converted with ethereal HCl As the hydrochloride salt 0.3 hydrate of the title compound, 0.68 g (87%) of a white solid was obtained; mp=>260 °C; MS(+)ESI m/z=465 (M+H) ⁺ . _Anal. Calcd. for _{C29H44N4O.HCl.0.3H2O} : _C : 68.76; H: 9.07 _; N: 11.06 Found: C: 68.52; H: 9.15; N: 11.18.

Example 8 l-methyl-cyclohexanecarboxylic acid {(1R)-1-cyclohexylmethyl-2-[4-(1-indol-4-yl)-piperazin-1-yl]-ethyl }-methyl-amide

To {(1R)-1-cyclohexylmethyl-2-[4-(1H-indol-4-yl)-piperazin-1-yl]-ethyl}-methyl-amine (0.6 g, 1.69 mmol) and triethylamine (0.5 mL, 3.7 mmol) in dichloromethane (10 mL) was added dropwise a solution of 1-methyl-cyclohexanecarbonyl chloride (0.27 g, 1.69 mmol) in dichloromethane. The reaction mixture was stirred overnight at room temperature under nitrogen, then concentrated on the 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 obtain a crude product which was purified by flash chromatography on silica gel (ethyl acetate/hexanes) and then converted with ethereal HCl As the hydrochloride salt of the title compound, 0.7 g (87%) of a white solid was obtained; mp = 253-254 °C; MS(+)ESI m/z = 479 (M+H) ⁺ . _Anal. Calcd. for _C30H46N4O · _HCl : C: 69.94; H: 9.20; N: 10.88 Found: C: 69.68; H: 9.21; N: 10.89.

Example 9N-{(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-formamide

2.10 mL (23.6 mmol) of glacial acetic acid and 1.23 mL (32.1 mmol) of formic acid were stirred at 60°C for 4 hours to form mixed anhydrides. The resulting solution was slowly added to ice-cold {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}- Amine (1.18g, 3.56mmol) in anhydrous tetrahydrofuran (35mL) solution. The reaction mixture was stirred at room temperature under nitrogen overnight, then poured slowly into 60 mL of saturated aqueous NaHCO ₃ and stirred for 10 min. 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 obtain a crude product which was purified by flash chromatography on silica gel (dichloromethane/methanol) and dissolved in ethanolic HCl. Conversion to the hydrochloride salt 1.5 hydrate of the title compound afforded 1.03 g (80%) of a white solid; mp = 157-159 °C; MS(+)ESI m/z = 360 (M+H) ⁺ . Anal. Calcd. for C ₂₁ H ₃₃ N ₃ O ₂ ·HCl·1.5H ₂ O: C: 59.62; H: 8.81; N: 9.93 Found: C: 59.54; H: 8.63; N: 9.33.

Example 10 Cyclohexanecarboxylic acid {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidin-1-yl]-ethyl}-amide

To potassium carbonate (0.076g, 0.54mmol) in water (1ml) solution was added {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidine-1- [Ethyl]-ethyl}-amine (0.18 g, 0.54 mmol) in dichloromethane (10 mL). The resulting mixture was cooled to 0°C and 0.076 mL of cyclohexanecarbonyl chloride (0.54 mmol) was added. The reaction mixture was stirred overnight at 0 °C, 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 obtain a crude product which was purified by flash chromatography on silica gel (dichloromethane/methanol) and dissolved in isopropanolated HCl. It was converted to the hydrated hydrochloride salt of the title compound to obtain 0.177 g (68%) of a white solid; mp = 100-103 °C; MS (+) ESI m/z = 441 (M+H) ⁺ . _{Anal. Calcd .} for _{C28H44N2O2.HCl.H2O} : C: 67.91; H: 9.56; _N : 5.66 Found: C: 68.15; H: 9.57; N: 5.59.

Example 111-Methyl-cyclohexanecarboxylic acid {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidin-1-yl]-ethyl} -amide

To potassium carbonate (0.076g, 0.54mmol) in water (1ml) solution was added {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidine-1- [Ethyl]-ethyl}-amine (0.18 g, 0.54 mmol) in dichloromethane (10 mL). The resulting mixture was cooled to 0°C and 0.085 g of 1-methyl-cyclohexanecarbonyl chloride (0.54 mmol) was added. The reaction was allowed to stir overnight at 0 °C, 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 obtain a crude product which was purified by flash chromatography on silica gel (dichloromethane/methanol) and dissolved in isopropanolated HCl. This was converted to the hydrochloride salt 0.75 hydrate of the title compound to obtain 0.35 g (55%) of a white solid; mp = 208-210 °C; MS (+) ESI m/z = 455 (M+H) ⁺ . Anal. Calcd. for C ₂₈ H ₄₄ N ₂ O ₂ ·HCl·0.75 H ₂ O: C: 69.01; H: 9.69; N: 5.55 Found: C: 69.03; H: 9.60; N: 5.45.

Example 12 Cyclohexanecarboxylic acid {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidin-1-yl]-ethyl}-methyl- Amide

Add {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidine-1- [Ethyl]-ethyl}-methyl-amine (0.20 g, 0.58 mmol) in dichloromethane (10 mL). The resulting mixture was cooled to 0°C and 0.090 g of cyclohexanecarbonyl chloride (0.58 mmol) was added. The reaction was allowed to stir overnight at 0 °C, 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 obtain a crude product which was purified by flash chromatography on silica gel (dichloromethane/methanol) and dissolved in isopropanolated HCl. This was converted to the hydrochloride salt 0.75 hydrate of the title compound to obtain 0.195 g (69%) of a white solid; mp = 135-137 °C; MS (+) ESI m/z = 455 (M+H) ⁺ . Anal. Calcd. for C ₂₉ H ₄₆ N ₂ O ₂ ·HCl·0.75 H ₂ O: C: 69.01; H: 9.69; N: 5.55 Found: C: 69.07; H: 9.52; N: 5.19.

Example 131-Methyl-cyclohexanecarboxylic acid {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidin-1-yl]-ethyl} -Methyl-amide To a solution of potassium carbonate (0.08g, 0.58mmol) in water (1ml) was added {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)- A solution of piperidin-1-yl]-ethyl}-methyl-amine (0.18 g, 0.58 mmol) in dichloromethane (10 mL). The resulting mixture was cooled to 0°C and 0.093 g of 1-methyl-cyclohexanecarbonyl chloride (0.58 mmol) was added. The reaction mixture was stirred overnight at 0 °C, 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 obtain a crude product which was purified by flash chromatography on silica gel (dichloromethane/methanol) and dissolved in isopropanolated HCl. This was converted to the hydrochloride salt 0.75 hydrate of the title compound to obtain 0.220 g (75%) of a white solid; mp = 169-171 °C; MS (+) ESI m/z = 469 (M+H) ⁺ . Anal. Calcd. for C ₃₀ H ₄₈ N ₂ O ₂ ·HCl·0.75 H ₂ O: C: 69.52; H: 9.82; N: 5.40 Found: C: 69.44; H: 9.61; N: 4.94.

Example 14N-{(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidin-1-yl]-ethyl}-2,2-dimethyl -Propanamide To a solution of potassium carbonate (0.076g, 0.54mmol) in water (1ml) was added {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidine -1-yl]-ethyl}-amine (0.18 g, 0.54 mmol) in dichloromethane (10 mL). The resulting mixture was cooled to 0°C and 0.066 g of trimethylacetyl chloride (0.54 mmol) was added. The reaction was allowed to stir overnight at 0 °C, 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 obtain a crude product which was purified by flash chromatography on silica gel (dichloromethane/methanol) and dissolved in isopropanolated HCl. This was converted to the hydrochloride salt 0.75 hydrate of the title compound to obtain 0.137 g (56%) of a white solid; mp = 97-99°C; MS (+) ESI m/z = 415 (M+H) ⁺ . Anal. Calcd. for C ₂₆ H ₄₂ N ₂ O ₂ ·HCl·0.75 H ₂ O: C: 67.22; H: 9.65; N: 6.02 Found: C: 66.91; H: 9.68; N: 5.90.

Example 15 N-{(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidin-1-yl]-ethyl}-2,2,N-tri Methyl-propionamide

Add {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidine-1- [Ethyl]-ethyl}-methyl-amine (0.20 g, 0.58 mmol) in dichloromethane (10 mL). The resulting mixture was cooled to 0°C and 0.075 g of trimethylacetyl chloride (0.62 mmol) was added. The reaction was allowed to stir overnight at 0 °C, 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 obtain a crude product which was purified by flash chromatography on silica gel (dichloromethane/methanol) and dissolved in isopropanolated HCl. This was converted to the hydrochloride salt 0.25 hydrate of the title compound to obtain 0.157 g (58%) of a white solid; mp = 233-236 °C; MS (+) ESI m/z = 429 (M+H) ⁺ . _Anal. Calcd. for _{C27H44N2O2.HCl.0.25H2O} : C: 69.05; H _{: 9.77 ;} N: 5.97 Found: C: 69.28; H: 9.96; N: 5.90.

Example 16 1-methyl-cyclohexanecarboxylic acid {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-3,6-dihydro-2H-pyridine- 1-yl]-ethyl}-amide

To {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl} at 0°C -Amine (0.25g, 0.76mmol) and triethylamine (0.21mL, 1.52mmol) in dichloromethane (10mL) solution was added dropwise 1-methyl-cyclohexanecarbonyl chloride (0.13g, 0.84mmol) di Chloromethane (4 mL) solution. The reaction mixture was stirred at 0 °C under nitrogen for 1 h, then concentrated on the 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 obtain a crude product which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted with ethanolic HCl As the hydrochloride hemihydrate of the title compound, 0.15 g (41%) of a yellow solid was obtained; mp = 93-95 °C; MS(+)ESI m/z = 453 (M+H) ⁺ . _Anal. Calcd. for _{C29H44N2O2.HCl.0.5H2O} : C: 69.92; H: _{9.31 ;} N: 5.62 Found: _C : 69.92; H: 9.03; N: 5.23.

Pharmacology followed the procedure described by J. Dunlop, Y. Zhang, D. Smith and L. Schechter (Eur. J. Pharmacol., submitted; modified from the procedure described by J. Zgombick et al., Naunyn-Schmiedeberg's Arch. Pharmacol.,354,226-236(1996)), by detecting the ability of the test compound to displace [3H]8 _- OHDPAT from its binding site on the receptor complex of CHO cells The affinity of the body, the CHO cells are stably transfected with the human 5-HT _1A receptor. As Table 1 illustrates, the compounds of the present invention exhibit high affinity for the 5-HT _IA receptor.

Table 1

5-HT _1A Affinity Agonist Activity Antagonist Activity Example (IC ₅₀ ) GTPγS (EC ₅₀ ) cAMP (IC ₅₀ ) Example 1 0.57nM 0.9nM - Example 2 1.23nM - 14.6nM Example 3 1.46nM - 4.0 nM Example 4 2.82nM - 10.2nM Example 5 2.37nM - 4.6nM Example 6 6.92nM - 7.3nM Example 7 8.84nM - 10.5nM Example 8 32.68nM - - Example 9 1.49nM - 17.3nM Example 10 1.08nM 3.9nM - Example 11 5.97nM - 46.0nM Example 12 1.69nM - 91.5nM Example 13 5.33nM - 97.5nM Example 14 2.19nM - 40.0nM Example 15 5.00nM - - Example 16 2.75nM - 45.5nM

Certain compounds of the present invention exhibit partial 5-HT _1A agonistic activity as assessed by evaluating the test compound following a modified procedure described by Lazareno and Birdsall [Br.J.Pharmacol., 109, 1120 (1993)]. As shown by the ability to stimulate [ ³⁵ S]-GTPγS binding to the 5-HT _1A receptor-G protein complex in CHO cells stably transfected with the human 5-HT _1A receptor. Table 1 presents selected compounds of the invention which demonstrated agonistic activity in this assay.

Using the procedure described by J. Dunlop, Y. Zhang, D. Smith and L. Schechter [Eur.J.Pharmacol., submitted; modification of the procedure described by J.Zgombick et al., Naunyn-Schmiedeberg's Arch.Pharmacol. , 354,226-236(1996)], by measuring the ability of the test compound to inhibit forskolin-stimulated cAMP metabolism in CHO cells stably transfected by human 5-HT _1A receptors, it was demonstrated that this Certain compounds of the invention possess 5-HT _1A antagonistic activity. Table 1 presents selected compounds of the invention which demonstrated 5-HT _1A antagonistic activity in this assay.

pharmaceutical composition

Suitable solid carriers include those which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, gidants, compression aids, binders or tablet disintegrating agents or encapsulating material. or multiple substances. In 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 proportions and compacted in the shape and size desired. The powders and tablets preferably contain more than 99% active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low-melting waxes, and ion exchange resins.

Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient in the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of the two or pharmaceutically acceptable oil or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmotic agents. Conditioner. Suitable examples of liquid carriers for oral and parenteral administration include water (especially containing the above-mentioned additives, such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, such as ethylene glycol) and its derivatives and oils (such as 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 are useful in sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be employed, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be in the form of liquid or solid compositions.

Preferably the pharmaceutical compositions are in unit dosage form, such as tablets or capsules. In such form, the composition is subdivided in unit dosage containing appropriate quantities of the active ingredient; the unit dosage form can be a packaged composition, for example, a packet of powder, a vial containing a liquid, an ampoule, a pre-packaged composition. filled syringe or sachet. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

Dosages for the treatment of a particular disease must be determined subjectively by the treating physician. Variables involved include the specific disease state as well as the patient's weight, age, and response pattern.

Claims (10)

1. the compound of following formula or its optically active isomer or its pharmacy acceptable salt

Wherein: X is selected from following groups:

N is selected from 1 to 5 integer;

R ¹Be C with 5-10 atom ₆-C ₁₀-aryl or list or bicyclic heteroaryl, its 1-3 atom is the heteroatoms that is independently selected from N, S or O, wherein said aryl or heteroaryl groups by F, Cl, Br, I ,-OH ,-NH ₂, CO ₂H ,-CO ₂-C ₁-C ₆Alkyl ,-CN ,-NO ₂, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Perhaloalkyl radical, OR ⁴And C ₁-C ₆The perhalogeno alkoxyl group is optional to be replaced, and condition is that heteroaryl is not a thiadiazoles;

R ²Be selected from H and C ₁-C ₆Alkyl;

R ³Be selected from H, COR ⁵, COOR ⁵And CONR ⁵R ⁶

R ⁴Be selected from H, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C as defined above ₆-C ₁₀Aryl or list or bicyclic heteroaryl, C ₇-C ₁₄Aralkyl and list or dicyclo heteroaralkyl, wherein said aryl or list or bicyclic heteroaryl group as defined above and by 1 to 3 be independently selected from F, Cl, Br, I, CN ,-NH ₂,-NO ₂,-OH, alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Perhaloalkyl radical, C ₁-C ₆Alkoxyl group and C ₁-C ₆The substituting group of perhalogeno alkoxyl group is optional to be replaced;

R ⁵And R ⁶Be independently selected from H, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₃-C ₆Cycloalkyl, C ₂-C ₆Cycloalkenyl group, adamantyl and noradamantyl, perhaps R ⁵And R ⁶The nitrogen-atoms that inserts with the centre is joined together to form 5-7 unit nitrogen heterocyclic, and optional containing is selected from O, S or NR ⁴Other heteroatoms.

2. according to the compound with following formula or its optically active isomer or its pharmacy acceptable salt of claim 1

Wherein: X is selected from following groups:

N is selected from 1 to 5 integer;

R ¹Be C ₆-C ₁₀-aryl or list or bicyclic heteroaryl are by F, Cl, Br, I, CO ₂H ,-CO ₂-C ₁-C ₆Alkyl ,-CN ,-NO ₂, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Perhaloalkyl radical, OR ⁴And C ₁-C ₆The perhalogeno alkoxyl group is optional to be replaced, and condition is that heteroaryl is not a thiadiazoles;

R ²Be selected from H and C ₁-C ₆Alkyl;

R ³Be selected from H, COR ⁵, COOR ⁵And CONR ⁵R ⁶

R ⁴Be selected from H, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₆-C ₁₀Aryl, list or bicyclic heteroaryl, C ₇-C ₁₄Aralkyl and list or dicyclo heteroaralkyl, wherein said aryl or heteroaryl groups by 1 to 3 be independently selected from F, Cl, Br, I, CN ,-NO ₂, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Perhaloalkyl radical, C ₁-C ₆Alkoxyl group and C ₁-C ₆The substituting group of perhalogeno alkoxyl group is optional to be replaced;

R ⁵And R ⁶Be independently selected from H, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₃-C ₆Cycloalkyl, C ₂-C ₆Cycloalkenyl group, adamantyl and noradamantyl, perhaps R ⁵And R ⁶The nitrogen-atoms that inserts with the centre is joined together to form No. 4 positions by being selected from R ⁴The substituting group piperidines, morpholine or the piperazine that replace.

3. the compound according to claim 1 is:

Hexahydrobenzoic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl }-acid amides,

1-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl }-acid amides,

Hexahydrobenzoic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl }-methyl-acid amides,

1-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl }-methyl-acid amides,

Hexahydrobenzoic acid (1R)-1-cyclohexyl methyl-2-[4-(2,3)-dihydrobenzo [1,4]-dioxin (dioxinyl)-5-yl)-piperazine-1-yl]-ethyl }-methyl-acid amides,

1-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(2,3-dihydro-benzo [1,4] dioxin-5-yl)-piperazine-1-yl]-ethyl }-methyl nitrosourea,

Hexahydrobenzoic acid (1R)-1-cyclohexyl methyl-2-[4-(1H-indoles-4-yl)-piperazine-1-yl]-ethyl }-methyl-acid amides,

1-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(1H-indoles-4-yl)-piperazine-1-yl]-ethyl }-methyl-acid amides,

N-{ (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl }-methane amide,

Hexahydrobenzoic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-acid amides,

1-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-acid amides,

Hexahydrobenzoic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-methyl-acid amides,

1-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-methyl-acid amides,

N-{ (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-2,2-dimethyl-propionic acid amide,

N-{ (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-2,2, N-trimethylammonium-propionic acid amide, or

1-methyl-cyclohexyl alkane carboxylic acid (1R)-and 1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-yl]-ethyl }-acid amides,

Or its optically active isomer,

Or its pharmacy acceptable salt.

4. method for the treatment of mammalian diseases, this disease is by the central nervous system intravital serotonin 5-HT that unifies _1AAcceptor is regulated, and this method comprises following formula: compound or its optically active isomer or its pharmacy acceptable salt of suffering from significant quantity on this sick Mammals therapeutics Wherein: X is selected from following groups:

N is selected from 1 to 5 integer;

R ¹Be C with 5-10 atom ₆-C ₁₀-aryl or list or bicyclic heteroaryl, its 1-3 atom is the heteroatoms that is independently selected from N, S or O, wherein said aryl or heteroaryl groups by F, Cl, Br, I ,-OH ,-NH ₂, CO ₂H ,-CO ₂-C ₁-C ₆Alkyl ,-CN ,-NO ₂, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Perhaloalkyl radical, OR ⁴And C ₁-C ₆The perhalogeno alkoxyl group is optional to be replaced, and condition is that heteroaryl is not a thiadiazoles;

R ²Be selected from H and C ₁-C ₆Alkyl;

R ³Be selected from H, COR ⁵, COOR ⁵And CONR ⁵R ⁶

R ⁴Be selected from H, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C as defined above ₆-C ₁₀Aromatic base or list or bicyclic heteroaryl, C ₇-C ₁₄Aralkyl and list or dicyclo heteroaralkyl, wherein said aryl or list or bicyclic heteroaryl group as defined above and by 1 to 3 be independently selected from F, Cl, Br, I, CN ,-NH ₂,-NO ₂,-OH, alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Perhaloalkyl radical, C ₁-C ₆Alkoxyl group and C ₁-C ₆The substituting group of perhalogeno alkoxyl group is optional to be replaced;

R ⁵And R ⁶Be independently selected from H, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₃-C ₆Cycloalkyl, C ₂-C ₆Cycloalkenyl group, adamantyl and noradamantyl, perhaps R ⁵And R ⁶The nitrogen-atoms that inserts with the centre links together and can form 5-7 unit nitrogen heterocyclic, and optional containing is selected from O, S or NR ⁴Other heteroatoms.

5. according to the method for claim 4, wherein Zhi Liao described disease is a dysthymia disorders.

6. according to the method for claim 4, wherein Zhi Liao described disease is an anxiety disorder.

7. according to the method for claim 4, wherein Zhi Liao described disease is memory and/or the learning disorder that is caused by neurodegenerative disease such as Alzheimer.

8. according to the method for claim 4, wherein Zhi Liao described disease is a prostate cancer.

9. according to the method for claim 4, wherein Zhi Liao described disease is to feel sick and vomiting.

10. medicinal compositions, it comprises following formula: compound or its optically active isomer or its pharmacy acceptable salt of significant quantity on pharmaceutically acceptable carrier and the therapeutics Wherein: X is selected from following groups:

N is selected from 1 to 5 integer;

R ¹Be C with 5-10 atom ₆-C ₁₀-aryl or list or bicyclic heteroaryl, its 1-3 atom is the heteroatoms that is independently selected from N, S or O, wherein said aryl or heteroaryl groups by F, Cl, Br, I ,-OH ,-NH ₂, CO ₂H ,-CO ₂-C ₁-C ₆Alkyl ,-CN ,-NO ₂, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Perhaloalkyl radical, OR ⁴And C ₁-C ₆The perhalogeno alkoxyl group is optional to be replaced, and condition is that heteroaryl is not a thiadiazoles;

R ²Be selected from H and C ₁-C ₆Alkyl;

R ³Be selected from H, COR ⁵, COOR ⁵And CONR ⁵R ⁶

R ⁴Be selected from H, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C as defined above ₆-C ₁₀Aryl or list or bicyclic heteroaryl, C ₇-C ₁₄The group of aralkyl and list or dicyclo heteroaralkyl, wherein said aryl or list or bicyclic heteroaryl group as defined above and by 1 to 3 be independently selected from F, Cl, Br, I, CN ,-NH ₂,-NO ₂,-OH, alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Perhaloalkyl radical, C ₁-C ₆Alkoxyl group and C ₁-C ₆The substituting group of perhalogeno alkoxyl group is optional to be replaced;

R ⁵And R ⁶Be independently selected from H, C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₃-C ₆Cycloalkyl, C ₂-C ₆Cycloalkenyl group, adamantyl and noradamantyl, perhaps R ⁵And R ⁶The nitrogen-atoms that inserts with the centre can be joined together to form 5-7 unit nitrogen heterocyclic, and optional containing is selected from O, S or NR ⁴Other heteroatoms.