EP1087954A1 - Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents - Google Patents

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

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Publication number
EP1087954A1
EP1087954A1 EP99928648A EP99928648A EP1087954A1 EP 1087954 A1 EP1087954 A1 EP 1087954A1 EP 99928648 A EP99928648 A EP 99928648A EP 99928648 A EP99928648 A EP 99928648A EP 1087954 A1 EP1087954 A1 EP 1087954A1
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Prior art keywords
group
alkyl
ethyl
cyclohexylmethyl
methyl
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EP99928648A
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German (de)
French (fr)
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Wayne Everett Childers
Michael Gerard Kelly
Yvette Latko Palmer
Edward James Podlesny
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American Home Products Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring

Definitions

  • 5-HTIA agonists and antagonists may find use in the treatment of several diseases such as anxiety, depression, schizophrenia, cognitive deficits resulting from neurodegenerative diseases like Alzheimer's Disease, nausea and vomiting, and in the treatment of prostate cancer (for recent references, see: K. Rasmussen and V. P. Rocco, Recent Progress in Serotonin (5-HT) jA Receptor Modulators, in Annual Reports in Medicinal Chemistry, Volume 30, J. A. Bristol, ed., pp. 1-9 (1995)).
  • X is selected from the group consisting of:
  • n is selected from the integers 1 through 5;
  • R 1 is C 6 -C ⁇ o-aryl or mono or bicyclic heteroaryl, optionally substituted by F, Cl, Br, I, -OH, -NH 2 , CO 2 H, -CO 2 -C ⁇ -C 6 alkyl, -CN, -NO 2 , - alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ -C 6 perhaloalkyl, OR 4 , and -CO perhaloalkoxy, with a proviso that heteroaryl is not thiadiazole;
  • R 2 is selected from the group consisting of H and C ⁇ -C 6 alkyl;
  • R 3 is selected from the group consisting of H, COR 5 , COOR 5 , and CONR 5 R 6 ;
  • R 4 is selected from the group consisting of H, C ⁇ -C 6 alkyl, C 2 -C alkenyl, C 2 -C 6 alkynyl, C 6 -C ⁇ o aryl, mono or bicyclic heteroaryl, C -Ci 4 aralkyl, and mono or bicyclic heteroaralkyl, where 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, -NH 2 , -NO 2 , -OH, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ -C 6 perhaloalkyl, C ⁇ -C 6 alkoxy, and C ⁇ -C 6 perhaloalkoxy;
  • R 5 and R 6 are selected independently from the group consisting of H, C ⁇ -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 taken together with the interposed nitrogen atom may form a 5-7 membered azacyclic ring, optionally containing an additional heteroatom selected from O, S, or NR 4 ; the optical isomers; and the pharmaceutically acceptable salts thereof.
  • C 6 -C ⁇ o aryl includes phenyl and naphthyl.
  • Monocyclic heteroaryl means a 5-6 membered heteroaryl group having from 1-3 heteroatoms selected independently from N, O, and S, such as pyridine, pyrrole, thiophene, furan, imidazole, oxazole, pyrimidine, pyridazine, pyrazine, thiazole and oxathiazole.
  • Bicyclic heteroaryl includes phenyl fused to a monocyclic 5-6 membered heteroaryl group or a 5-6 membered heteroaryl group fused to another 5-6 membered heteroaryl group, including, but not limited to indole, quinoline, isoquinoline, benzofuran, benzodioxan, benzothiophene, benzimidazole, naphthyridine, and imidazopyridine.
  • C -Ci 4 aralkyl means a C1-C 4 alkyl group having a phenyl or naphthyl group as a substituent
  • heteroaralkyl means a C 1 -C 4 alkyl group having a mono or bicyclic heteroaryl group as defined above as a substituent
  • Optical isomers of the invention compounds 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 invention compounds include the conventional acid addition salts which are formed from an invention compound and a pharmaceutically acceptable organic or inorganic acid.
  • the acid addition salts include, but is not limited to, the acetate, adipate, alginate, aspartate, benzoate, benzene- sulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, dodecylsulfate, ethanesulfonate, fumarate, glycerophosphate, phosphate, hemisulfate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, nicotinate, oxalate, pamoate, pectinate, pivalate, propionate, succinate, tartrate, and tosylate.
  • the basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, dialkyl sulfates, long chain halides such as lauryl bromide, aralkyl halides like benzyl and phenethyl bromides.
  • 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 a phosgene equivalent such as trichloromethylchloroformate or triphosgene followed by treatment with an appropriate alcohol or amine.
  • a phosgene equivalent such as trichloromethylchloroformate or triphosgene followed by treatment with an appropriate alcohol or amine.
  • 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 reaction mixture was allowed to stir under nitrogen at 0°C for one hour, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine.
  • reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H 2 O 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/hexanes) and then converted to the hydrochloride • hemihydrate salt of the title compound with ethereal HCl to yield 0.82 g
  • Example 11 1-Methyl-cyclohexanecarboxylic acid ⁇ (lR)-l-cyclohexylmethyl-2-[4-(2- methoxyphenyl)-piperidin-l-yl]-ethyl ⁇ -amide
  • Example 13 1-Methyl-cyclohexanecarboxylic acid ⁇ (lR)-l-cyclohexylmethyl-2-[4-(2- methoxyphenyl)-piperidin-l-yl]-ethyl ⁇ -methyl-amide
  • 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 yield 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 yield
  • the reaction mixture was allowed to stir under nitrogen at 0°C for one hour, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine.
  • Affinity for the serotonin 5-HTIA receptor was established by assaying the test compound's ability to displace [ 3 H] 8-OHDPAT from its binding site on the receptor complex in CHO cells stably transfected with the human 5-HTIA receptor following the procedure described by J. Dunlop, Y. Zhang, D. Smith and L. Schechter (Eur. J. Pharmacol., submitted; variation of a procedure described by J. Zgombick et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 354, 226-236 (1996)).
  • the compounds of this invention displayed high affinity for the 5-HTIA receptor, as described in Table 1.
  • Example 16 2.75 nM - 45.5 nM
  • Some of the compounds of this invention displayed 5-HT ⁇ A partial agonist activity, as assessed by the test compound's ability to stimulate the binding of [ 35 S]-GTP ⁇ S to the 5-HTIA receptor-G protein complex in CHO cells stably transfected with the human 5- HT ⁇ A receptor following a variation of the procedure described by Lazareno and Birdsall [Br. J. Pharmacol., 109, 1120 (1993)].
  • 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 5-HT ⁇ A 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-HTIA receptor using a procedure described by J. Dunlop, Y. Zhang, D. Smith and L. Schechter [Eur. J. Pharmacol., submitted; variation of a procedure described by J. Zgombick et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 354, 226-236 (1996)]. Selected compounds of this invention which demonstrated 5-HTIA antagonist activity in this are shown in Table 1.
  • PHARMACEUTICAL COMPOSITION Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or encapsulating materials.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • 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 up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing 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 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 osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g.
  • cellulose derivatives preferable sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols
  • oils e.g. fractionated coconut oil and arachis oil
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
  • the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • 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.
  • the dosage to be used in the treatment of a specific disease must be subjectively determined by the attending physician.
  • the variables involved include the specific disease state and the size, age and response pattern of the patient.

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 C¿6?-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 C¿1?-C6 alkyl; R?3¿ is selected from the group consisting of H, COR?5, COOR5¿, and CONR?5R6; R4, R5 and R6¿ are as defined hereinabove; or an optical isomer; or a pharmaceutically acceptable salt thereof.

Description

CYCLOALKYL-SUBSTITUTED ARYL-PIPERAZINES, PIPERIDINES AND TETRAHYDROPYRIDINES AS SEROTONERGIC AGENTS
Background of the Invention
Compounds having selective partial agonist activity at the 5-HTIA receptor have established a presence in the marketplace as effective anxiolytic agents (buspirone, Buspar®, US Patent 3,717,634). 5-HTIA agonists and antagonists may find use in the treatment of several diseases such as anxiety, depression, schizophrenia, cognitive deficits resulting from neurodegenerative diseases like Alzheimer's Disease, nausea and vomiting, and in the treatment of prostate cancer (for recent references, see: K. Rasmussen and V. P. Rocco, Recent Progress in Serotonin (5-HT)jA Receptor Modulators, in Annual Reports in Medicinal Chemistry, Volume 30, J. A. Bristol, ed., pp. 1-9 (1995)).
Description of the Invention
In accordance with this invention, there is provided a set of novel compounds, including their enantiomers, which have activity as 5-HTi A agonists and antagonists. Compounds of the present invention are described by the generic formula:
where: X is selected from the group consisting of:
n is selected from the integers 1 through 5;
R1 is C6-Cιo-aryl or mono or bicyclic heteroaryl, optionally substituted by F, Cl, Br, I, -OH, -NH2, CO2H, -CO2-Cι-C6 alkyl, -CN, -NO2, - alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cι-C6 perhaloalkyl, OR4, and -CO perhaloalkoxy, with a proviso that heteroaryl is not thiadiazole; R2 is selected from the group consisting of H and Cι-C6 alkyl;
R3 is selected from the group consisting of H, COR5, COOR5, and CONR5R6;
R4 is selected from the group consisting of H, Cι-C6 alkyl, C2-C alkenyl, C2-C6 alkynyl, C6-Cιo aryl, mono or bicyclic heteroaryl, C -Ci4 aralkyl, and mono or bicyclic heteroaralkyl, where 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, -NO2, -OH, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cι-C6 perhaloalkyl, Cι-C6 alkoxy, and Cι-C6 perhaloalkoxy;
R5 and R6 are selected independently from the group consisting of H, Cι-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 may form a 5-7 membered azacyclic ring, optionally containing an additional heteroatom selected from O, S, or NR4; the optical isomers; and the pharmaceutically acceptable salts thereof.
The term C6-Cιo aryl includes phenyl and naphthyl. Monocyclic heteroaryl means a 5-6 membered heteroaryl group having from 1-3 heteroatoms selected independently from N, O, and S, such as pyridine, pyrrole, thiophene, furan, imidazole, oxazole, pyrimidine, pyridazine, pyrazine, thiazole and oxathiazole. Bicyclic heteroaryl includes phenyl fused to a monocyclic 5-6 membered heteroaryl group or a 5-6 membered heteroaryl group fused to another 5-6 membered heteroaryl group, including, but not limited to indole, quinoline, isoquinoline, benzofuran, benzodioxan, benzothiophene, benzimidazole, naphthyridine, and imidazopyridine. The term C -Ci4 aralkyl means a C1-C4 alkyl group having a phenyl or naphthyl group as a substituent, and the term heteroaralkyl means a C1-C4 alkyl group having a mono or bicyclic heteroaryl group as defined above as a substituent.
Optical isomers of the invention compounds 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 invention compounds include the conventional acid addition salts which are formed from an invention compound and a pharmaceutically acceptable organic or inorganic acid. The acid addition salts include, but is not limited to, the acetate, adipate, alginate, aspartate, benzoate, benzene- sulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, dodecylsulfate, ethanesulfonate, fumarate, glycerophosphate, phosphate, hemisulfate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, nicotinate, oxalate, pamoate, pectinate, pivalate, propionate, succinate, tartrate, and tosylate. Also the basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, dialkyl sulfates, long chain halides such as lauryl bromide, aralkyl halides like 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 steps (Scheme 1) starting from cycloalkylalanine which has been protected on the nitrogen atom with the t-butoxycarbonyl group (BOC). This material is coupled to the appropriately substituted aryl heterocycle where X is CH, N, or carbon having a double bond to an adjacent carbon atom using dicyclohexylcarbodiimide (DCC) to afford compound 1. Removal of the BOC group under acidic conditions followed by reduction using a borane complex leads to the penultimate intermediate 2. Subsequent acylation of 2 with the appropriate acid chloride gives compound 3, which is isolated as an acceptable salt.
Scheme 1.
2
Compounds in which both R2 and R3 are other than hydrogen are prepared using two general methods. Reduction of BOC-protected amide 1 with lithium aluminum hydride (LAH) affords methylamine 4 in one step (Scheme 2). Subsequent acylation using the appropriate acid chloride yields N-methylamide 5. Scheme 2.
Alternatively, acylation of intermediate 2 followed by reduction with an appropriate reduction agent such as borane*dimethylsulfide gives alkylamine 6, which can then be converted to the final acylated product 7 (Scheme 3).
Scheme 3.
2 6
7
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 a phosgene equivalent such as trichloromethylchloroformate or triphosgene followed by treatment with an appropriate alcohol or amine. 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 to this disclosure in any way.
Example 1
Cyclohexanecarboxylic acid {(lR)-l-cyclohexylmethyl-2-[4-(2- methoxyphenyl)-piperazin-l-yI]-ethyI}-amide To a solution of 0.31 g (0.94 mmol) of {(lR)-l-cyclohexylmethyl-2-[4-(2- methoxyphenyl)-piperazin-l-yl]-ethyl} -amine and 0.26 mL (1.87 mmol) of triethylamine in 10 mL of dichloromethane at 0°C was added dropwise 0.15 g (1.03 mmol) of cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane. The reaction mixture was allowed to stir under nitrogen at 0°C for one hour, and was 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 yield 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 yield 0.41 g (85%) as a beige solid; mp = 121-131°C;
MS (+) ESI m/z = 442 (M+H)+.
Analysis for C27H43N3O2 • 2HC1
Calculated: C: 63.02; H: 8.81; N: 8.17
Found: C: 63.56; H: 9.27; N: 8.07.
Example 2
1-Methyl-cyclohexanecarboxylic acid {(lR)-l-cyclohexylmethyl-2-[4-(2- methoxyphenyl)-piperazin-l-yl]-ethyl}-amide
To a solution of 0.30 g (0.91 mmol) of {(lR)-l-cyclohexylmethyl-2-[4-(2- methoxyphenyl)-piperazin-l-yl] -ethyl} -amine and 0.25 mL (1.74 mmol) of triethylamine in 10 mL of dichloromethane at 0°C was added dropwise 0.16 g (1.00 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane.
The reaction mixture was allowed to stir under nitrogen at 0°C for one hour, and was 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 yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to the hydrochloride • hydrate salt of the title compound with ethanolic HCl to yield 0.30 g (63%) of a light yellow solid; mp = 119-121°C; MS (+) ESI m/z = 456 (M+H)+. Analysis for C28H45N3O2 • HCl • H2O Calculated: C: 65.92; H: 9.48; N: 8.24 Found: C: 65.85; H: 9.26; N: 7.67.
Example 3
Cyclohexanecarboxylic acid {(lR)-l-cycIohexylmethyl-2-[4-(2- methoxyphenyl)-piperazin-l-yl]-ethyl}-methyl-amide
To a solution of 0.30 g (0.87 mmol) of {(lR)-l-cyclohexylmethyl-2-[4-(2- methoxyphenyl)-piperazin-l-yl]-ethyl}-methyl-amine and 0.25 mL (1.74 mmol) of triethylamine in 10 mL of dichloromethane at 0°C was added dropwise 0.19 g (1.31 mmol) of cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and was 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 yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to the dihydrochloride salt with ethanolic HCl to yield 0.41 g (89%) of the title compound as a white solid; mp = 222-
224°C; MS (+) ESI m/z = 456 (M+H)+. Analysis for C27H43N3O2 • 2HC1
Calculated: C: 63.62; H: 8.96; N: 7.95 Found: C: 63.11; H: 8.81; N: 7.97.
Example 4 1-Methyl-cyclohexanecarboxylic acid {(lR)-l-cyclohexylmethyl-2-[4-(2- methoxyphenyl)-piperazin-l-yl]-ethyl}-methyl-amide
To a solution of 0.30 g (0.87 mmol) of {(lR)-l-cyclohexylmethyl-2-[4-(2- methoxyphenyl)-piperazin-l-yl]-ethyl}-methyl-amine and 0.25 mL (1.74 mmol) of triethylamine in 10 mL of dichloromethane at 0°C was added dropwise 0.21 g (1.31 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with aqueous 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 the dihydrochloride salt of the title compound with ethanolic HCl to yield 0.41 g (86%) of white solid; mp = 208-210°C;
MS (+) ESI m/z = 470 (M+H)+ Analysis for C29H47N3O2 • 2HC1 Calculated: C: 64.19; H: 9.10; N: 7.74 Found: C: 63.89; H: 9.03; N: 7.93.
Example 5 Cyclohexanecarboxylic acid {(lR)-l-cyclohexylmethyl-2-[4-(2,3)- dihydrobenzo[l,4]-dioxin-5-yl)-piperazin-l-yl]-ethyl}-methyl-amide
To a solution of 0.7 g (1.87 mmol) of {(lR)-l-cyclohexylmethyl-2-[4-(2,3-dihydro- benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-ethyl}-methyl-amine and 0.5 mL (3.7 mmol) of triethylamine in 10 mL of dichloromethane at 0°C was added dropwise 0.27 g (1.87 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and 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/hexanes) and then converted to the hydrochloride • hemihydrate salt of the title compound with ethereal HCl to yield 0.82 g
(91%) as a white solid; mp = 147-148°C; MS (+) ESI m/z = 484 (M+H)+. Analysis for C29H45N3O3 • HCl • 0.5 H2O Calculated: C: 65.82; H: 8.95; N: 7.94 Found: C: 65.90; H: 9.04; N: 7.98.
Example 6 l-Methyl-cyclohexanecarboxylic acid {(lR)-l-cyclohexylmethyl-2-[4-
(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]ethyl}-methylamide
To a solution of 0.7 g (1.87 mmol) of {(lR)-l-cyclohexylmethyl-2-[4-(2,3-dihydro- benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-ethyl}-methyl-amine and 0.5 mL (3.7 mmol) of triethylamine in 10 mL of dichloromethane at 0°C was added dropwise 0.3 g (1.87 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature and 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/hexanes) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.85 g (91%) of the title compound as a white solid; mp = 219-220°C; MS (+) ESI m/z = 498 (M+H)+. Analysis for C3oH47N3O3 • HCl
Calculated: C: 67.45; H: 9.06; N: 7.87 Found: C: 67.04; H: 9.17; N: 7.88.
Example 7 Cyclohexanecarboxylic acid {(lR)-l-cyclohexylmethyl-2-[4-(lH-indol-
4-yl)-piperazin-l-yI]-ethyl}-methyl-amide
To a solution of 0.6 g (1.69 mmol) of {(lR)-l-cyclohexylmethyl-2-[4-(lH-indol-4-yl)- piperazin-l-yl]-ethyl}-methyl-amine and 0.5 mL (3.7 mmol) of triethylamine in 10 mL of dichloromethane at 0°C was added dropwise 0.25 g (1.69 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and 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/hexanes) and converted to the hydrochloride • 0.3 hydrate salt of the title compound with ethereal HCl yield 0.68 g
(87%) as a white solid; mp = >260°C; MS (+) ESI m/z = 465 (M+H)+. Analysis for C29H44N4O • HCl • 0.3 H2O Calculated: 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 {(lR)-l-cyclohexylmethyl-2-[4-(l- indol-4-yl)-piperazin-l-yl]-ethyI}-methyl-amide
To a solution of 0.6 g (1.69 mmol) of {(lR)-l-cyclohexylmethyl-2-[4-(lH-indol-4-yl)- piperazin-l-yl]-ethyl}-methyl-amine and 0.5 mL (3.7 mmol) of triethylamine in 10 mL of dichloromethane at 0°C was added dropwise 0.27 g (1.69 mmol) of 1-methyl- cyclohexanecarboxylic acid chloride in dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature and 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/hexanes) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.7 g (87%) as a white solid; mp = 253-254°C; MS (+) ESI m/z = 479 (M+H)+ Analysis for Analysis for C30H46N4O • HCl Calculated: C: 69.94; H: 9.20; N: 10.88 Found: C: 69.68; H: 9.21; N: 10.89.
Example 9 N-{(lR)-l-cyclohexyImethyl-2-[4-(2-methoxyphenyl)- piperazin-l-yl]ethyI}-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 added slowly to an ice-cooled solution of 1.18 g (3.56 mmol) of {(1R)-1- cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-l-yl]-ethyl}-amine in 35 mL of anhydrous tetrahydrofuran under nitrogen. The reaction mixture was stirred under nitrogen overnight at ambient temperature and was then poured slowly into 60 mL of saturated aqueous NaHCO3 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 yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride • 1.5 hydrate salt of the title compound with ethanolic HCl to yield 1.03 g (80%) of white solid; mp = 157-159°C; MS (+) ESI m/z = 360 (M+H)+. Analysis for C21H33N3O2 • HCl • 1.5 H2O Calculated: C: 59.62; H: 8.81; N: 9.93 Found: C: 59.54; H: 8.63; N: 9.33.
Example 10
Cyclohexanecarboxylic acid {(lR)-l-cyclohexylmethyl-2-[4-(2- methoxyphenyl)-piperidin-l-yl]-ethyl}-amide
To a solution of 0.076 g of potassium carbonate (0.54 mmol) in 1 ml. of water was added a solution of 0.18 g of {(lR)-l-cyclohexylmethyl-2-[4-(2-methoxyphenyl)- piperidin-l-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 was then diluted with 5 mL of water and 20 mL of dichloromethane and the phases 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 yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride • hydrate salt of the title compound with isopropanolic HCl to yield
0.177 g (68%) of white solid; mp = 100-103° C; MS (+) ESI m/z = 441 (M+H)+. Analysis for C28H44N2O2 • HCl • H2O Calculated: C: 67.91; H: 9.56; N: 5.66 Found: C: 68.15; H: 9.57; N: 5.59.
Example 11 1-Methyl-cyclohexanecarboxylic acid {(lR)-l-cyclohexylmethyl-2-[4-(2- methoxyphenyl)-piperidin-l-yl]-ethyl}-amide
To a solution of 0.076 g of potassium carbonate (0.54 mmol) in 1 ml. of water was added a solution of 0.18 g of {(lR)-l-cyclohexylmethyl-2-[4-(2-methoxyphenyl)- piperidin-l-yl]-ethyl} -amine (0.54 mmol) in 10 mL of dichloromethane. 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, and was then diluted with 5 mL of water and 20 mL of dichloromethane and the phases 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 yield 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 yield 0.35 g (55%) as a white solid; mp = 208-210° C; MS (+)
ESI m/z = 455 (M+H)+. Analysis for C28H44N2O2 • HCl • 0.75 H2O Calculated: C: 69.01; H: 9.69; N: 5.55 Found: C: 69.03; H: 9.60; N: 5.45.
Example 12 Cyclohexanecarboxylic acid {(lR)-l-cyclohexylmethyl-2-[4-(2- methoxyphenyl)-piperidin-l-yl]-ethyl}-methyl-amide
To a solution of 0.080 g of potassium carbonate (0.58 mmol) in 1 ml. of water was added a solution of 0.20 g of {(lR)-l-cyclohexylmethyl-2-[4-(2-methoxyphenyl)- piperidin-l-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. The reaction was allowed to stir overnight at 0°C, and was then diluted with 5 mL of water and 20 mL of dichloromethane and the phases 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 yield 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 yield 0.195 g (69%) as a white solid; mp = 135-137° C; MS (+)
ESI m/z = 455 (M+H)+. Analysis for C29H46N2O2 • HCl • 0.75 H2O Calculated: C: 69.01; H: 9.69; N: 5.55 Found: C: 69.07; H: 9.52; N: 5.19.
Example 13 1-Methyl-cyclohexanecarboxylic acid {(lR)-l-cyclohexylmethyl-2-[4-(2- methoxyphenyl)-piperidin-l-yl]-ethyl}-methyl-amide
To a solution of 0.08 g of potassium carbonate (0.58 mmol) in 1 ml. of water was added a solution of 0.18 g of {(lR)-l-cyclohexylmethyl-2-[4-(2-methoxyphenyl)- piperidin-l-yl]-ethyl}-methyl-amine (0.58 mmol) in 10 mL of dichloromethane. The resulting mixture was cooled to 0°C and 0.093 g of 1-methyl-cyclohexanecarboxylic acid chloride (0.58 mmol) was added. The reaction was allowed to stir overnight at 0°C, and was then diluted with 5 mL of water and 20 mL of dichloromethane and the phases 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 yield 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 yield 0.220 g (75%) of white solid; mp = 169-171° C; MS (+)
ESI m/z = 469 (M+H)+ Analysis for C30H48N2O2 • HCl • 0.75 H2O Calculated: C: 69.52; H: 9.82; N: 5.40 Found: C: 69.44; H: 9.61; N: 4.94.
Example 14 N-{(lR)-l-cyclohexylmethyI-2-[4-(2-methoxyphenyl)-piperidin-l-yl]- ethyl}-2,2-dimethyl-propionamide
To a solution of 0.076 g of potassium carbonate (0.54 mmol) in 1 ml. of water was added a solution of 0.18 g of {(lR)-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 0.066 g of trimethylacetyl chloride (0.54 mmol) was added. The reaction was allowed to stir overnight at 0°C, and was then diluted with 5 mL of water and 20 mL of dichloromethane and the phases 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 yield 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 yield
0.137 g (56%) of white solid; mp = 97-99° C; MS (+) ESI m/z = 415 (M+H)+ Analysis for C26H42N2O2 • HCl • 0.75 H2O Calculated: C: 67.22; H: 9.65; N: 6.02 Found: C: 66.91; H: 9.68; N: 5.90. Example 15
N-{(lR)-l-cyclohexylmethyI-2-[4-(2-methoxyphenyl)-piperidin-l-yl]- ethyl}-2,2,N-trimethyl-propionamide
To a solution of 0.08 g of potassium carbonate (0.58 mmol) in 1 ml. of water was added a solution of 0.20 g of {(lR)-l-cyclohexylmethyl-2-[4-(2-methoxyphenyl)- piperidin-l-yl]-ethyl}-methyl-amine (0.58 mmol) in 10 mL of dichloromethane. 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, and was then diluted with 5 mL of water and 20 mL of dichloromethane and the phases 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 yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride • 0.25 hydrate salt of the title compound with isopropanolic HCl to yield 0.157 g (58%) of white solid; mp = 233-236° C; MS (+) ESI m/z = 429 (M+H)+. Analysis for C27H44N2O2 • HCl • 0.25 H2O Calculated: 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 {(lR)-l-cyclohexylmethyl-2-[4-(2- methoxyphenyl)-3,6-dihydro-2H-pyridin-l-yl]-ethyl}-amide
To a solution of 0.25 g (0.76 mmol) of {(lR)-l-cyclohexylmethyl-2-[4-(2- methoxyphenyl)-3,6-dihydro-2H-pyridin-l-yl]-ethyl} -amine and 0.21 mL (1.52 mmol) of triethylamine in 10 mL of dichloromethane at 0°C was added dropwise 0.13 g (0.84 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane. The reaction mixture was allowed to stir under nitrogen at 0°C for one hour, and was 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 yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/- methanol) and then converted to the hydrochloride • hemihydrate salt of the title compound with ethanolic HCl to yield 0.15 g (41%) of yellow solid; mp = 93-95°C;
MS (+) ESI m/z = 453 (M+H)+. Analysis for C29H44N2O2 • HCl • 0.5 H2O Calculated: C: 69.92; H: 9.31; N: 5.62 Found: C: 69.92; H: 9.03; N: 5.23.
PHARMACOLOGY
Affinity for the serotonin 5-HTIA receptor was established by assaying the test compound's ability to displace [3H] 8-OHDPAT from its binding site on the receptor complex in CHO cells stably transfected with the human 5-HTIA receptor following the procedure described by J. Dunlop, Y. Zhang, D. Smith and L. Schechter (Eur. J. Pharmacol., submitted; variation of a procedure described by J. Zgombick et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 354, 226-236 (1996)). The compounds of this invention displayed high affinity for the 5-HTIA receptor, as described in Table 1.
Table 1
5-HT1A Affinity Agonist Activity Antagonist Activity
Example (IC50) GTPγS (EC50) 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 displayed 5-HTΪA partial agonist activity, as assessed by the test compound's ability to stimulate the binding of [35S]-GTPγS to the 5-HTIA receptor-G protein complex in CHO cells stably transfected with the human 5- HTΪA receptor following a variation of the procedure described by Lazareno and Birdsall [Br. J. Pharmacol., 109, 1120 (1993)]. 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 5-HTΪA 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-HTIA receptor using a procedure described by J. Dunlop, Y. Zhang, D. Smith and L. Schechter [Eur. J. Pharmacol., submitted; variation of a procedure described by J. Zgombick et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 354, 226-236 (1996)]. Selected compounds of this invention which demonstrated 5-HTIA antagonist activity in this are shown in Table 1.
PHARMACEUTICAL COMPOSITION Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or encapsulating materials. 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 up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers may be used in preparing 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 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 osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g. cellulose derivatives, preferable sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. 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.
The dosage to be used in the treatment of a specific disease must be subjectively determined by the attending physician. The variables involved include the specific disease state and the size, age and response pattern of the patient.

Claims

WE CLA :
1. A compound according to the formula
where:
X is selected from the group consisting of: n is selected from the integers 1 through 5;
R1 is Ce- o-aryl or mono or bicychc heteroaryl having 5-10 atoms, 1 to 3 of which are heteroatoms selected independently from N, S or O, wherein the aryl or heteroaryl group is optionally substituted by F, Cl, Br, I, -OH, -NH2, CO2H, -CO2-C╬╣-C6 alkyl, -CN, -NO2, C╬╣-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C6 perhaloalkyl, OR4, and C╬╣-C6 perhaloalkoxy, with a proviso that heteroaryl is not thiadiazole; R2 is selected from the group consisting of H and -C6 alkyl; R3 is selected from the group consisting of H, COR5, COOR5, and CONR5R6; R4 is selected from the group consisting of H, -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C╬╣o aryl or mono or bicychc heteroaryl as defined above, C7-Ci4 aralkyl, and mono or bicychc heteroaralkyl, where the aryl or mono or bicyclic 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, -NO2, -OH, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C6 perhaloalkyl, Cj-C6 alkoxy, and C]-C6 perhaloalkoxy;
R5 and R6 are selected independently from the 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 may form a 5-7 membered azacyclic ring, optionally containing an additional heteroatom selected from O, S, or NR4; or an optical isomer; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 having the formula
where:
X is selected from the group consisting of:
FlHsj N- - R1— N- - n is selected from the integers 1 through 5; R1 is Cό- o-aryl or mono or bicyclic heteroaryl, optionally substituted by F, Cl, Br, I, CO2H, -CO2-Cι-C6 alkyl, -CN, -NO2, -Q- alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C--C6 perhaloalkyl, OR4, and -C6 perhaloalkoxy, with a proviso that heteroaryl is not thiadiazole; R2 is selected from the group consisting of H and Cι-C6 alkyl; R3 is selected from the group consisting of H, COR5, COOR5, and CONR5R6;
R4 is selected from the group consisting of H, Cι-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cό-Cio aryl, mono or bicychc heteroaryl, C -C!4 aralkyl, and mono or bicychc heteroaralkyl, where 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, -NO2, Cι-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cι-C6 perhaloalkyl, Cι-C6 alkoxy, and -C6 perhaloalkoxy; R5 and R6 are selected independently from the 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 forms piperidine, morpholine, or piperazine substituted at the 4 position by a substituent selected from R4; or an optical isomer; or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 which is:
cyclohexanecarboxylic acid { ( 1 R)- 1 -cyclohexylmethyl-2- [4-(2-methoxyphenyl)- piperazin- 1 -yl]-ethyl } -amide,
1-methyl-cyclohexanecarboxylic acid { (IR)- l-cyclohexylmethyl-2-[4-(2-methoxy- phenyl)-piperazin- 1 -yl]-ethyl } -amide,
cyclohexanecarboxylic acid { ( 1 R)- 1 -cyclohexylmethyl-2- [4-(2-methoxyphenyl)- piperazin- 1 -yl]-ethyl } -methyl-amide,
1 -methyl-cyclohexanecarboxylic acid { ( 1 R)- 1 -cyclohexylmethyl-2- [4-(2-methoxy- phenyl)-piperazin- 1 -yl]-ethyl } -methyl-amide,
cyclohexanecarboxylic acid { ( IR)- 1 -cyclohexylmethyl-2-[4-(2,3)-dihydrobenzo[ 1 ,4]- dioxin-5-yl)-piperazin- 1 -yl]-ethyl } -methyl-amide,
1 -methyl-cyclohexanecarboxylic acid { ( 1 R)- 1 -cyclohexylmethyl-2-[4-(2,3-dihydro- benzo[ 1 ,4]dioxin-5-yl)-piperazin- 1 -yl]ethyl } -methyl-amide,
cyclohexanecarboxylic acid { ( 1 R)- 1 -cyclohexylmethyl-2- [4-( 1 H-indol-4-yl)-piperazin- 1 -yl]-ethyl } -methyl-amide,
1 -methyl-cyclohexanecarboxylic acid { ( 1 R)- 1 -cyclohexylmethyl-2- [4-) 1 -indol-4-yl)- piperazin- 1 -yl]-ethyl } -methyl-amide,
N- { ( 1 R)- 1 -cyclohexylmethyl-2- [4-(2-methoxyphenyl)-piperazin- 1 -yl]ethyl } - formamide,
cyclohexanecarboxylic acid {(lR)-l-cyclohexylmethyl-2-[4-(2-methoxyphenyl)- piperidin- 1 -yl] -ethyl } -amide,
1-methyl-cyclohexanecarboxylic acid { ( IR)- 1 -cyclohexylmethyl-2- [4-(2- methoxyphenyl)-piperidin- 1 -yl]-ethyl } -amide, cyclohexanecarboxylic acid { ( 1 R)- 1 -cyclohexylmethyl-2- [4-(2-methoxyphenyl)- piperidin- 1 -y 1] -ethyl } -methyl-amide,
1 -methyl-cyclohexanecarboxylic acid { ( 1 R)- 1 -cyclohexylmethyl-2- [4-(2- methoxyphenyl)-piperidin- 1 -yl]-ethyl } -methyl-amide,
N- { ( 1 R)- 1 -cyclohexylmethyl-2- [4-(2-methoxyphenyl)-piperidin- 1 -y 1] -ethyl } -2,2- dimethyl-propionamide,
N- { ( 1 R)- 1 -cyclohexylmethyl-2-[4-(2-methoxyphenyl)-ρiperidin- 1 -yl]-ethyl } -2,2,N- trimethyl-propionamide, or
1 -methyl-cyclohexanecarboxylic acid { ( 1 R)- 1 -cyclohexylmethyl-2- [4-(2- methoxyphenyl)-3 ,6-dihydro-2H-pyridin- 1 -yl]-ethyl } -amide,
or an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
4. A method of treating conditions in mammals modulated by serotonin 5-HT╬╣ A receptors in the central nervous system and in the body which comprises administration to a mammal having such a condition a therapeutically effective amount of a compound according to the formula
T X/IChyn
R- 3 where:
X is selected from the group consisting of: RL CH RUΛ-__H n is selected from the integers 1 through 5; R1 is C6-Cιo-aryl or mono or bicychc heteroaryl having 5-10 atoms, 1 to 3 of which are heteroatoms selected independently from N, S or O, wherein the aryl or heteroaryl group is optionally substituted by F, Cl, Br, I, -OH, -NH2, CQ2H,
-CO2-C1-C6 alkyl, -CN, -NO2, C╬╣-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cj-Cg perhaloalkyl, OR4, and C╬╣-C6 perhaloalkoxy, with a proviso that heteroaryl is not thiadiazole;
R2 is selected from the group consisting of H and C╬╣-C6 alkyl;
R3 is selected from the group consisting of H, COR5, COOR5, and CONR5R6; R4 is selected from the group consisting of H, Cj-C╬▓ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C╬╣o aryl or mono or bicychc heteroaryl as defined above, C7-C14 aralkyl, and mono or bicychc heteroaralkyl, where the aryl or mono or bicychc 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, -NO2, -OH, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C╬╣-C6 perhaloalkyl, Cj-C6 alkoxy, and -C6 perhaloalkoxy;
R5 and R6 are selected independently from the 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 may form a 5-7 membered azacyclic ring, optionally containing an additional heteroatom selected from O, S, or NR4; or an optical isomer; or a pharmaceutically acceptable salt thereof.
5. The method according to claim 4 wherein the condition treated is depression.
6. The method according to claim 4 wherein the condition treated is anxiety.
7. The method according to claim 4 wherein the condition treated is impaired memory and/or learning resulting from neurodegenerative diseases such as Alzheimer's disease.
8. The method according to claim 4 wherein the condition treated is prostate cancer.
9. The method according to claim 4 wherein the condition treated is nausea and vomiting.
10. A pharmaceutical composition which 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 the integers 1 through 5; R1 is C6-C╬╣o-aryl or mono or bicychc heteroaryl having 5-10 atoms, 1 to 3 of which are heteroatoms selected independently from N, S or O, wherein the aryl or heteroaryl group is optionally substituted by F, Cl, Br, I, -OH, -NH2, CO2H, -CO2-C╬╣-C6 alkyl, -CN, -NO2, C╬╣-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cj-C6 perhaloalkyl, OR4, and C╬╣-C6 perhaloalkoxy, with a proviso that heteroaryl is not thiadiazole;
R2 is selected from the group consisting of H and - alkyl; R3 is selected from the group consisting of H, COR5, COOR5, and CONR5R6; R4 is selected from the group consisting of H, alkyl, C2-C6 alkenyl, C2- alkynyl, Cβ-Cio aryl or mono or bicychc heteroaryl as defined above, C7-Cj4 aralkyl, and mono or bicychc heteroaralkyl, where the aryl or mono or bicyclic 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, -NO2, -OH, alkyl, C -C6 alkenyl, C2-C6 alkynyl, Cι-C6 perhaloalkyl, Cι-C6 alkoxy, and Cι-C6 perhaloalkoxy; R5 and R6 are selected independently from the group consisting of H, Cj-Cό alkyl, C2-C6 alkenyl, C2-C alkynyl, C3-C6 cycloalkyl, C2-C6 cycloalkenyl, adamantyl, and noradamantyl or R5 and R6 taken together with the interposed nitrogen atom may form a 5-7 membered azacyclic ring, optionally containing an additional heteroatom selected from O, S, or NR4; or an optical isomer; or a pharmaceutically acceptable salt thereof.
EP99928648A 1998-06-15 1999-06-14 Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents Withdrawn EP1087954A1 (en)

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US6696450B2 (en) 2001-04-04 2004-02-24 Wyeth Serotonergic agents with long-acting in vivo effects
US7067518B2 (en) 2002-09-05 2006-06-27 Wyeth Pyridinyl-methyl-ethyl cyclohexanecarboxamides as serotonergic agents
EP2338873A1 (en) 2009-12-22 2011-06-29 Gmeiner, Peter New aminotetraline derivatives
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