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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P25/00—Drugs for disorders of the nervous system
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• • 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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • 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
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/32—Alcohol-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • 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
  • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
  • C07D211/70—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

• US 4,882,432 teaches adamantyl and noradamantyl piperazine carbamates and ureas with high 5-HT1A receptor affinities. These compounds, as well as those disclosed in U.S. patent number 4,797.489 are useful for the treatment of CNS disorders.
• EP 661266- A 1 describes piperidino and piperazino 5-HT2 receptor antagonists and blood platelet aggregation inhibitors.
• WO 9504042 describes 4-phenyl-4-phenylpropyl(enyl) piperidine tachykinin antagonists for treating pain or inflammation or emesis.
• This invention relates to novel arylpiperidine urea and aryl- 1,2, 5,6- tetrahydropyridine urea derivatives.
• novel arylpiperidine urea and aryl- 1,2,5,6 tetrahydropyridine urea derivatives which are antagonists of the 5HT1A receptor subtype.
• compounds of the present invention are useful for the treatment of central nervous system (CNS) disorders such as depression, anxiety, panic, obsessive- compulsive disorder (OCD), sleep disorders, sexual dysfunction, alcohol and drug addiction, cognition enhancement, Alzheimer's disease, Parkinson's disease, obesity and migraine.
• CNS central nervous system
• R 0 and Ri are independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl alkylcycloalkyl, alkylheterocycloalkyl, aryl or heteroaryl, or taken together R 0 and Rj form a heterocycloalkyl, provided that R Q and Ri are not both hydrogen;
• R2 is hydrogen, alkyl or R3 is hydrogen or alkyl;
• R4 is aryl or heteroaryl;
• R5 is alkyl, alkenyl or alkynyl;
• X is hydrogen, halogen, perhaloalkyl, hydroxy, alkoxy, perhaloalkoxy; n is an integer from 1 to 3; and the dotted line is an optional double bond, or a pharmaceutical salt thereof.
• X is preferably halogen substituted at positions 4- or 5-, more preferably is 4-fluoro or 5-fluoro and most preferably is 5-fluoro-.
• R2 is an alkyl group
• R2 is preferably a straight chain alkyl of 1 to 5 carbon atoms
• R3 is preferably a straight chain alkyl of 1 to 4 carbon atoms.
• R 0 and Ri are independently hydrogen or cycloalkyl or taken together are heterocycloalkyl. More preferably R Q and Rj are independently hydrogen or cyclohexyl or taken together are morpholino.
• R 0 and Ri are independently hydrogen or cyclohexyl, or taken together are morpholino, X is 5-fluoro, and R4 is phenyl.
• Alkyl as used herein means a branched or straight chain having from 1 to 6 carbon atoms and more preferably from 1 to 5 carbon atoms.
• exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
• alkenyl as used herein means a branched or straight chain alkyl having from 2 to 6 carbon atoms.
• exemplary alkenyl groups include ethylene and propylene. In some embodiments of the present invention the alkenyl group may be substituted.
• Alkynyl as used herein means a branched or straight chain alkyl of 2 to 6 carbon atoms and at least one carbon-carbon triple bond.
• exemplary alkynyl groups include ethynyl and propynyl.
• the alkynyl group may be substituted with one or more substituents.
• Alkoxy as used herein means an alkyl-O group in which the alkyl group is as previously described.
• exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
• Aryl as used herein means mono or bicyclic aromatic ring having from 6 to 10 carbon atoms. Monocyclic rings preferably have 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring structures.
• Exemplary aryl groups include phenyl and naphthyl In some preferred embodiments aryl is phenyl, 1-naphthyl or 2-naphthyl. In still more preferred embodiments aryl is phenyl.
• the aryl group may be substituted with one or more substituents. Substituted aryl groups preferably have one to three substituents.
• Cycloalkyl as used herein means a monocyclic alkyl group having from 3 to 8 carbon atoms. In some preferred embodiments cycloalkyl may be substituted with from 1 to 3 substituents.
• Heterocycloalkyl as used herein means a monocyclic alkyl group having from
• heterocycloalkyl groups include piperidinyl, piperazinyl and morpholino.
• heterocycloalkyl groups may be substituted with from 1 to 3 substituents.
• Halogen as used herein means fluorine, chlorine, iodine and bromine.
• Heteroaryl means 5 to 10 membered mono or bicyclic aromatic ring having from 1 to 3 heteroatoms selected from N, O and S. Monocyclic rings preferably have 5 or 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring structures. Exemplary heteroaryls include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl and benzodioxanyl.
• Preferred heteroaryl groups include thienyl, pyridyl, and furyl. More preferred are heteroaryl groups including 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, and 3-furyl.
• the heteroaryl group may be substituted with one or more substituents. Suitable substituents, unless otherwise noted, include halogen, alkyl, hydroxy, alkoxy, amino, amido, nitro, alkylamino, alkylamido, perhaloalkyl, carboxyalkyl, carboxy, carbamide, dialkylamino and aryl.
• Carbon number refers to the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituents such as an alkyl or alkoxy substituents.
• alkylcycloalkyl is an alkyl-cycloalkyl group in which alkyl and cycloalkyl are as previously described.
• Pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
• a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
• the compounds of this invention contain a chiral center, providing for various seteroisomeric forms of the compounds such as racemic mixtures as well as the individual optical isomers.
• the individual isomers can be prepared directly or by asymmetric or stereospecific synthesis or by conventional separation of optical isomers from the racemic mixture.
• the compounds A and intermediate 4-(halo-2-methoxy-phenyl)-piperidines F or 4-(halo-2-methoxy-phenyl)-l,2,5,6-tetrahydropyridines H of the present invention can be prepared by conventional methods by those skilled in the organic synthesis.
• metal-halogen exchange of an appropriately substituted aryl halide B with a base, such as butyllithium forms a carboanion, and treatment of the resulting mixture with an N-protected-4-piperidone C affords a tertiary alcohol D.
• An example of the nitrogen protecting group Rx of the 4-piperidone C is benzyl, which can be removed by hydrogenation of D to afford amine G.
• Dehydration of G with an acid, such as sulfuric acid can provide the desired 4-(halo-2-methoxy-phenyl)- 1,2,5,6- tetrahydropyridine H.
• Dehydration of the tertiary alcohol D, removal of the nitrogen protecting group, Rx and hydrogenation of the double bond can afford 4-(halo-2- methoxy-phenyl)-piperidine F.
• the protecting group R is of the urethane type, preferably tert-butyloxycarbonyl which may be removed by the action of an acid. After deprotection, the amide may be reduced to an amine M with a reducing reagent such as lithium aluminum hydride (LAH) or diborane, and subsequently acylated to afford the urea A.
• LAH lithium aluminum hydride
• diborane a reducing reagent
• the reaction mixture was diluted with water (50 mL) and EtOAc (50 mL) and the layers separated.
• the aqueous layer was washed with HCl (IN), saturated NaHCO 3 , and the combined aqueous layers were extracted three times with EtOAc.
• the combined organic layers were dried over Na 2 SO 4 and concentrated.
• Compounds of the present invention bind with very high affinity to the 5-HT1 A receptor and consequently, they are useful for the treatment of primary disorders of the central nervous system such as depression, anxiety and panic, as well as secondary attending problems such as sleep disorders and sexual dysfunction. Compounds of the present invention are also useful for other disorders of the central nervous system including alcohol and drug addiction, obesity and migraine. Cognition enhancement may be achieved by use of compounds of the present invention and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease may be treated.
• High affinity for the serotonin 5-HTIA receptor was established by testing a compound's ability to displace [ 3 H] 8-OH-DPAT binding in CHO cells stably transfected with human 5HT1A receptor.
• Stably transfected CHO cells are grown in DMEM containing 10% heat inactivated FBS and non-essential amino acids. Cells are scraped off the plate, transferred to centrifuge tubes, and washed twice by centrifugation (2000 rpm for 10 min., 4°C) in buffer (50 mM Tris pH 7.5). The resulting pellets are aliquoted and placed at -80°C. On the day of assay, the cells are thawed on ice and resuspended in buffer.
• the binding assay is performed in a 96 well microtiter plate in a total volume of 250 ⁇ L. Non-specific binding is determined in the presence of 10 mM 5-HT, final ligand concentration is 1.5 nM. Following a 30 minute incubation at room temperature, the reaction is terminated by the addition of ice cold buffer and rapid filtration through a GF/B filter presoaked for 30 minutes in 0.5% PEL Compounds are initially tested in a single point assay to determine percent inhibition at 1, 0.1, and 0.01 mM, and Ki values are determined for the active compounds.
• the intrinsic activity of compounds of the present invention was established by testing the claimed compounds ability to reverse the stimulation of cyclic adenosinemonophosphate (cAMP) in CHO cells stably transfected with the human 5-HT 1 A receptor.
• cAMP cyclic adenosinemonophosphate
• Stably transfected CHO cells were grown in DMEM containing 10% heat inactivated FBS and non-essential amino acids. The cells are plated at a density of ? xlO 6 cells per well in a 24 well plate and incubated for 2 days in a CO 2 incubator. On the second day, the media is replaced with 0.5 mL treatment buffer (DMEM + 25 mM HEPES, 5 mM theophylline, 10 ⁇ M pargyline) and incubated for 10 minutes at 37°C. Wells are treated with forskolin (1 ⁇ M final concentration) followed immediately by the test compound (0.1 and 1 ⁇ M for initial screen) and incubated for an additional 10 minutes at 37°C.
• DMEM + 25 mM HEPES 5 mM theophylline, 10 ⁇ M pargyline
• compounds of the present invention exhibit high affinity for the 5HT1 A receptor subtype and exhibit intrinsic activity as evidenced by their ability to reverse stimulation of cyclic adenosinemonophosphate (cAMP). Accordingly, compounds of the present invention are useful for treatment of disorders of the central nervous system and may be administered to a patient suffering from one or more of said disorders. Treatment, as used herein, refers to alleviation or amelioration of symptoms of a particular disorder in a patient. In addition, compounds of the present invention may be administered as part of a treatment regime that includes other agents which act on the central nervous system. In some preferred embodiments, compounds of the present invention are part of a combination therapy including a serotonin reuptake inhibitor.
• Serotonin reuptake inhibitors useful in combination therapies of the present invention fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine. Said agents may be administered at the same time, where they may be combined into a single dosage form, or at a different time, as compounds of the present invention, while still being part of the regime of the combination therapy.
• Compounds of the invention may be administered to a patient either neat or with a convention pharmaceutical carrier.
• 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 an encapsulating material.
• 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 of 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 preferably 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 therapeutically effective dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician.
• the variables involved include the specific psychosis or state of anxiety and the size, age and response pattern of the patient.
• the novel method of the invention for treating conditions related to or are affected by the 5-HT 1 A receptor comprise administering to warm-blooded animals, including humans, an effective amount of at least one compound of Formula A and its non-toxic, pharmaceutically acceptable addition salts.
• the compounds may be administered orally, rectally, parenterally or topically to the skin and mucosa.
• the usual daily dose is depending on the specific compound, method of treatment and condition treated.
• the usual daily dose is 0.01 - 1000 mg/Kg for oral application, preferably 0.5 - 500 mg/Kg, and 0.1 - 100 mg/Kg for parenteral application, preferably 0.5 - 50 mg/Kg.

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Citations (4)

• 1999
  • 1999-12-16 BR BR9916220-2A patent/BR9916220A/pt not_active IP Right Cessation
  • 1999-12-16 EP EP99965286A patent/EP1140831A1/en not_active Withdrawn
  • 1999-12-16 JP JP2000588137A patent/JP2002532472A/ja active Pending
  • 1999-12-16 WO PCT/US1999/029907 patent/WO2000035875A1/en not_active Application Discontinuation
  • 1999-12-16 CA CA002351400A patent/CA2351400A1/en not_active Abandoned
  • 1999-12-16 CN CN99814560A patent/CN1335835A/zh active Pending
  • 1999-12-16 AU AU31235/00A patent/AU3123500A/en not_active Abandoned

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