WO2007124136A1 - Utilisation de 4-amino-piperidines pour le traitement des troubles du sommeil - Google Patents

Utilisation de 4-amino-piperidines pour le traitement des troubles du sommeil Download PDF

Info

Publication number
WO2007124136A1
WO2007124136A1 PCT/US2007/009804 US2007009804W WO2007124136A1 WO 2007124136 A1 WO2007124136 A1 WO 2007124136A1 US 2007009804 W US2007009804 W US 2007009804W WO 2007124136 A1 WO2007124136 A1 WO 2007124136A1
Authority
WO
WIPO (PCT)
Prior art keywords
methylpiperidin
carbamide
methylpropyloxy
phenylmethyl
fluorophenylmethyl
Prior art date
Application number
PCT/US2007/009804
Other languages
English (en)
Inventor
Daniel Van Kammen
David M. Weiner
Mark R. Brann
Robert E. Davis
Original Assignee
Acadia Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Acadia Pharmaceuticals, Inc. filed Critical Acadia Pharmaceuticals, Inc.
Publication of WO2007124136A1 publication Critical patent/WO2007124136A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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

Definitions

  • the present invention relates to treating sleep disorders using compounds that are selective towards monoamine receptors such as serotonin receptors.
  • Compounds that are useful for treating sleep disorders include 4-amino-piperidines.
  • insomnia sleep maintenance insomnia
  • SMI Sleep maintenance insomnia
  • One embodiment described herein includes a method of increasing slow- wave sleep comprising administering N-(l-methylpiperidin-4-yl)-N-(4- fluorophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide to a subject in need of increased slow wave sleep in an amount sufficient to increase slow wave sleep.
  • One embodiment further comprises informing the subject that N-(I -methylpiperidin-4-yl)- N-(4-fluorophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide increases slow wave sleep.
  • the informing comprises providing printed matter that advises that N-(l-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2- methylpropyloxy)phenylmethyl) carbamide increases slow wave sleep.
  • the printed matter is a label.
  • Another embodiment disclosed herein includes a method of treating insomnia comprising administering N-(l-methylpiperidin-4-yl)-N-(4- fluorophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide to a subject suffering from insomnia in an amount sufficient to ameliorate insomnia.
  • One embodiment further comprises informing the subject that N-(l-methylpiperidi ⁇ -4-yl)-N- (4-fluorophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide ameliorates insomnia.
  • the informing comprises providing printed matter that N- (l-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2- methylpropyloxy)phenylmethyl) carbamide ameliorates insomnia.
  • the printed matter is a label.
  • Another embodiment disclosed herein includes a method for decreasing the number of awakenings after sleep onset comprising administering N-(I- methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2- methylpro ⁇ yloxy)phenylmethyl) carbamide to a subject in need of a decreased number of awakenings after sleep onset in an amount sufficient to decrease the number of awakenings after sleep onset.
  • Another embodiment disclosed herein includes a method for decreasing the time awake after sleep onset comprising administering N-(I- methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2- methylpropyloxy)phenylmethyl) carbamide to a subject in need of decreased time awake after sleep onset in an amount sufficient to decrease time awake after sleep onset.
  • Another embodiment disclosed herein includes a method of manufacturing a pharmaceutical composition including obtaining a first dosage form comprising a first amount of N-(l-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4- (2-methylpropyloxy)phenylmethyl) carbamide, obtaining a second dosage form comprising a second amount of N-(l-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'- (4-(2-methylpropyloxy)phenylmethyl) carbamide, and packaging together the first dosage form and the second dosage form.
  • the first dosage form and the second dosage form each comprise an oral dosage form.
  • the first dosage form comprises a higher dose of N-(l-methylpiperidin-4-yl)-N-(4- fluorophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide than the second dosage form.
  • the amount of N-(I- methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2- methylpropyloxy)phenylmethyl) carbamide is in the range of about 0.5 rag to about 50 mg. In one embodiment, the amount is in the range of about 1 mg to about 40 mg. In one embodiment, the amount is in the range of about 2.5 mg to about 30 mg. In one embodiment, the amount is in the range of about 5 mg to about 20 mg.
  • the administration does not affect a sleep parameter selected from the group consisting of sleep period time, total sleep time, sleep onset latency, number of stage shifts, total time awake, early morning wake, sleep efficiency index, microarousal index, and a REM sleep parameter.
  • the REM sleep parameter is selected from the group consisting of REM sleep duration, proportion of REM sleep, REM sleep latency, REM activity and REM density.
  • the amount results in a steady state blood plasma concentration of N-(l-methylpiperidin-4-yl)-N-(4- fluorophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide in the range of about 2 ng/mL to about 60 ng/mL. In one embodiment, the amount results in a steady state blood plasma concentration in the range of about 4 ng/mL to about 50 ng/mL. In one embodiment, the amount results in a steady state blood plasma concentration of in the range of about 6 ng/mL to about 40 ng/mL.
  • the amount results in a steady state blood plasma concentration in the range of about 8.5 ng/mL to about 35 ng/mL.
  • the subject is administered N-(l-methylpiperidin-4-yl)-N-(4- fluorophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide once every day.
  • the subject is administered a first dosage form at least 24 hours prior to administration of a second dosage form.
  • the first dosage form comprises a higher dose than the second dosage form.
  • N-(I- methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2- methylpropyloxy)phenylmethyl) carbamide is administered at a time other than immediately before a sleep period. In one embodiment, it is administered in the morning.
  • Another embodiment disclosed herein includes a packaged pharmaceutical composition, comprising N-(l-methylpiperidin-4-yl)-N-(4- fluorophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide in a container and instructions for using N-(l-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2- methylpropyloxy)phenylmethyl) carbamide to treat insomnia.
  • Another embodiment disclosed herein includes a packaged pharmaceutical composition, comprising N-(l-methylpiperidin-4-yl)-N-(4- fluorophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide in a container and instructions for using N-(l-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2- methylpropyloxy)phenylmethyl) carbamide to increase slow wave sleep, decrease the number of awakenings after sleep onset or decrease the time awake after sleep onset.
  • kits comprising a first dosage form of N-(l-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2- methylpropyloxy) ⁇ henylmethyl) carbamide and a second dosage form of N-(I- methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2- methylpropyloxy)phenylmethyl) carbamide.
  • the first dosage form contains a higher dose of N-(l-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2- methylpropyloxy)phenylmethyl) carbamide than the second dosage form.
  • the kit further comprises instructions for taking the first dosage form at least 24 hours before taking the second dosage form.
  • the instructions are on a label.
  • the instructions further inform a subject that N-(I- methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2- methylpropyloxy)phenylmethyl) carbamide increases slow wave sleep.
  • the instructions further inform a subject that N-(l-methylpiperidin-4-yl)-N- (4-fluorophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide ameliorates insomnia. In one embodiment, the instructions further inform a subject that N-(I- methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2- methylpropyloxy)phenylmethyl) carbamide decreases the number of awakenings after sleep onset.
  • the instructions further inform a subject that N-(I- methylpiperidin-4-yl)-N-(4-f ⁇ uorophenylmethyl)-N'-(4-(2- methylpropyloxy)phenylmethyl) carbamide decreases the time awake after sleep onset.
  • FIGURE 1 is a graph depicting the change in slow wave sleep duration from baseline for placebo and various doses of N-(l-methylpiperidin-4-yl)-N-(4- fluorophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide.
  • FIGURE 2 is a graph depicting the correlation between slow wave sleep duration and blood plasma level of N-(l-methylpiperidin-4-yl)-N-(4- fluorophenylmethyl)-N ' -(4-(2-methylpropyloxy)phenylmethyl) carbamide.
  • FIGURE 3 is a graph depicting the change in number of awakenings from baseline for placebo and various doses of N-(l-methyl ⁇ iperidin-4-yl)-N-(4- fluorophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide.
  • the present application relates to the use of compounds that are inverse agonists or antagonists of a serotonin receptor to treat a sleep disorder.
  • the compounds are inverse agonists or antagonists of a 5-HT2A receptor.
  • the compounds are selective inverse agonists or antagonists.
  • the sleep disorder is insomnia.
  • the insomnia is sleep maintenance insomnia.
  • the sleep maintenance insomnia is caused by other disorders.
  • the sleep maintenance insomnia is comorbid with a psychiatric disorder including, but not limited to, schizophrenia, affective disorders including MDD, bipolar 2 depression, bipolar 1 mania, rapid cyclers, dysthymia, PTSD (e.g., nightmares or arousals), alcoholism, substance abuse, drug withdrawal, and anxiety.
  • a psychiatric disorder including, but not limited to, schizophrenia, affective disorders including MDD, bipolar 2 depression, bipolar 1 mania, rapid cyclers, dysthymia, PTSD (e.g., nightmares or arousals), alcoholism, substance abuse, drug withdrawal, and anxiety.
  • the compounds described herein may be administered in combination with an SSRI or NASR to decrease insomnia, increase efficacy, decrease sexual side effects and akathisia, provide a faster response, and limit treatment resistance.
  • the sleep maintenance insomnia is caused by a neurological disorder, including but not limited to Parkinson's disease, multisystems atrophy, migraines, multiple sclerosis, Huntington's Chorea, "Sun-downing" in DAT and other dementia's, and epilepsy.
  • a neurological disorder including but not limited to Parkinson's disease, multisystems atrophy, migraines, multiple sclerosis, Huntington's Chorea, "Sun-downing" in DAT and other dementia's, and epilepsy.
  • Other disorders that may cause sleep maintenance insomnia that can be treated using the compounds described herein include, but are not limited to, rheumatoid and osteo-arthritis and other chronic disorders with pain, fibro-myalgia, and female menopause.
  • the compounds described herein are administered to a patient to increase slow wave sleep in the patient for any purpose.
  • the compounds decrease the number of awakenings after sleep onset and the time awake after sleep onset.
  • the compounds described herein are administered to a patient to treat other sleep related disorders including periodic limb movement syndrome or obstructive sleep apnea.
  • the compounds achieve the desired effect on slow wave sleep, number of awakenings after sleep onset, and the time awake after sleep onset without affecting other sleep parameters.
  • sleep parameters unaffected include sleep period time, total sleep time, sleep onset latency, number of sleep stage shifts, total time awake, early morning wake, sleep efficiency index, microarousal index, and REM sleep parameters (e.g., REM sleep duration, proportion of REM sleep, REM sleep latency, REM activity, and REM density).
  • the compounds are administered at a dose between about 0.5 mg and about 50 mg, between about 1 mg and about 40 mg, between about 2.5 mg and about 30 mg, or between about 1 mg and about 20 mg.
  • the dosage and administration cyst are sufficient to achieve a steady state blood plasma concentration of between about 2 ng/ml and about 60 ng/ml, between about 4 ng/ml and about 50 ng/ml, between about 6 ng/ml and about 40 ng/ml, or between about 8.5 ng/ml and about 35 ng/ml.
  • the dosage is varied over the dosage regimen.
  • the first administration or series of administrations have a higher dosage than subsequent administrations.
  • the compound administered has a relatively high half-life such that after an initial dosage sufficient to raise the blood plasma concentration to a desired level, subsequent dosages sufficient to maintain a desired steady state blood plasma concentration can be lower.
  • pharmaceutical compositions comprising multiple doses are packaged together.
  • a sleep-inducing agent is administered in combination with the compounds described herein.
  • the sleep-inducing agent may be administered to induce onset of sleep in the patient while the inverse agonist or antagonist of a serotonin receptor may be administered to maintain sleep in the patient.
  • the compounds described herein may be administered to maintain slow wave sleep in the patient.
  • suitable sleep-inducing agents include AMBIEN®, indiplon, LUNESTA®, and melatonin.
  • administration in “combination” it is meant that the two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered.
  • the agents are administered simultaneously.
  • administration in combination is accomplished by combining the agents in a single dosage form.
  • the agents are administered sequentially.
  • the agents are administered through the same route, such as orally.
  • the agents are administered through different routes, such as one being administered orally and another being administered intravenously.
  • the pharmacokinetics of the two or more agents are substantially the same.
  • the compounds described herein are long acting (e.g., have a long half-life), allowing them to be given relatively infrequently and at times other than immediately prior to a desired sleep period.
  • the compounds have a half-life long enough so that that they don't need to be administered more often than once a day.
  • the compound may be administered once every 1, 2, 3, 4, or 5 days and still provide sleep maintenance properties during each sleep period.
  • the half-life of the compound is from about 10 hours to about 100 hours, from about 20 hours to about 60 hours, or from about 35 hours to about 55 hours. In some embodiments, the compound is not administered immediately prior to a sleep period.
  • the compound may be administered in the morning or afternoon. In one embodiment, the compound is administered in the morning.
  • the long acting properties of the compounds eliminate or reduce any withdrawal effects experienced by patients as either a co-administered sleep-inducing agent or the inverse agonist or antagonist of a serotonin receptor wears off. For example, many short acting sleep agents cause a patient to wake in the middle of their sleep period and experience a withdrawal effect. In some embodiments, patients taking a compound described herein experience no such withdrawal effect. Definitions
  • constitutive activity is defined as the basal activity of a receptor which is independent of the presence of an agonist. Constitutive activity of a receptor may be measured using a number of different methods, including cellular (e.g., membrane) preparations (see, e.g., Barr &. Manning, J. Biol. Chem.
  • agonist is defined as a compound that increases the activity of a receptor when it contacts the receptor.
  • antagonist is defined as a compound that competes with an agonist or inverse agonist for binding to a receptor, thereby blocking the action of an agonist or inverse agonist on the receptor.
  • an antagonist also known as a “neutral” antagonist
  • inverse agonist is defined as a compound that decreases the basal activity of a receptor (i.e., signaling mediated by the receptor). Such compounds are also known as negative antagonists.
  • An inverse agonist is a ligand for a receptor that causes the receptor to adopt an inactive state relative to a basal state occurring in the absence of any ligand.
  • an antagonist can inhibit the activity of an agonist
  • an inverse agonist is a ligand that can alter the conformation of the receptor in the absence of an agonist.
  • Bond et al. in Nature 374:272 (1995). More specifically, Bond et al.
  • an inverse agonist can additionally manifest its activity in the absence of an agonist by inhibiting the spontaneous conversion of an unliganded receptor to an active conformation.
  • 5-HT2A receptor is defined as a receptor, having an activity corresponding to the activity of the human serotonin receptor subtype, which was characterized through molecular cloning and pharmacology as detailed in Saltzman et al., Biochem. Biophys. Res. Comm. 181:1469-78; and Julius et al., Proc. Natl. Acad. ScL USA 87:928-932.
  • subject refers to an animal, preferably a mammal, most preferably a human, who is the object of treatment, observation or experiment.
  • selective is defined as a property of a compound whereby an amount of the compound sufficient to effect a desired response from a particular receptor type, subtype, class or subclass causes a substantially smaller or no effect upon the activity other receptor types.
  • the terms "selectivity" or “selective,” in relation to an inverse agonist, are understood as a property of a compound of the invention whereby an amount of compound that effectively inversely agonizes the 5 -HT2 A. receptor, and thereby decreases its activity, causes little or no inverse agonistic or antagonistic activity at other, related or unrelated, receptors.
  • certain compounds of the invention have been found not to interact strongly with other serotonin receptors (S-HT IA, IB, ID, IE, IF, 2B, 2C 5 4 A, 6, and 7) at concentrations where the signaling of the 5-HT2 A receptor is strongly or completely inhibited.
  • the compounds of the invention are also selective with respect to other monoamine-binding receptors, such as the dopaminergic, histaminergic, adrenergic and muscarinic receptors.
  • monoamine-binding receptors such as the dopaminergic, histaminergic, adrenergic and muscarinic receptors.
  • Compounds that are highly selective for 5-HT2A receptors may have a beneficial effect in the treatment of psychosis, schizophrenia or similar neuropsychiatric disorders, while avoiding adverse effects associated with drugs hitherto suggested for this purpose.
  • the EC50 for an agonist is intended to denote the concentration of a compound needed to achieve 50% of a maximal response seen in R-SAT.
  • EC50 is intended to denote the concentration of a compound needed to achieve 50% inhibition of an R-SAT response from basal, no compound, levels.
  • aryl is intended to mean a carbocyclic aromatic ring or ring system. Moreover, the term “aryl” includes fused ring systems wherein at least two aryl rings, or at least one aryl and at least one C 3 - 8 -cycloalkyl share at least one chemical bond. Some examples of “aryl” rings include optionally substituted phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl.
  • aryl relates to aromatic, preferably benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from heterocyclyl, heteroaryl, halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci- 6 alkoxy, Ci -6 alkyl, Ci- 6 hydroxyalkyl, Ci -6 aminoalkyl, Ci-e alkylamino, alkylsulfenyl, alkylsulf ⁇ nyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl.
  • the aryl group may be substituted at the para and/or meta positions.
  • aryl groups include, but are not limited to, phenyl, 3-halophenyl, 4-halophenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4- methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl 3- cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, trifluoromethylphenyl, alkoxyphenyl, 4-mo ⁇ holin-4-ylphenyl, 4- pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidin-l- yl)phenyl.
  • heteroaryl is intended to mean a heterocyclic aromatic group where one or more carbon atoms in an aromatic ring have been replaced with one or more heteroatoms selected from the group comprising nitrogen, sulfur, phosphorous, and oxygen.
  • heteroaryl comprises fused ring systems wherein at least one aryl ring and at least one heteroaryl ring, at least two heteroaryl rings, at least one heteroaryl ring and at least one heterocyclyl ring, or at least one heteroaryl ring and at least one C 3 .s-cycloalkyl ring share at least one chemical bond.
  • heteroaryl is understood to relate to aromatic, C 3 - 8 cyclic groups further containing one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom with up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, preferably connected via one of the ring-forming carbon atoms.
  • Heteroaryl groups may carry one or more substituents, selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci-6-alkoxy, C1-6- alkyl, Cj-6-hydroxyalkyl, Ci -6 -aminoalkyl, Ci.
  • heteroaryl groups may be five- and six-membered aromatic heterocyclic systems carrying 0, 1, or 2 substituents, which may be the same as or different from one another, selected from the list above.
  • heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quionoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, which are all preferred, as well as furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4- thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine,
  • the substituents are halo, hydroxy, cyano, O-Ci- 6 -alkyl, Ci ⁇ -alkyl, hydroxy-Ci- ⁇ -alkyl, amino-Ci. 6 -al.cyl.
  • alkyl d- 6 -alkyl
  • alkyl d- 6 -alkyl
  • d- 6 -alkyl are intended to mean a linear or branched saturated hydrocarbon chain wherein the longest chain has from one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl.
  • An alkyl chain may be optionally substituted.
  • “Lower alkyl groups” are Ci -6 cyclic, straight-chained or branched aliphatic substituent groups connected via a carbon atom. Examples include methyl, ethyl, propyl, butyl, methylbutyl, cyclopropyl, cyclohexyl, iso-propyl, tert-butyl.
  • C 2 - 8 -alkenyl is intended to mean a linear or branched hydrocarbon group having from two to eight carbon atoms and containing one or more double bonds.
  • Some examples of C 2 - 8 -alkenyl groups include allyl, homo-allyl, vinyl, crotyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl.
  • C2- 8 -alkenyl groups with more than one double bond include butadienyl, pentadienyl, hexadienyl, heptadienyl, heptatrienyl and octatrienyl groups as well as branched forms of these.
  • the position of the unsaturation (the double bond) may be at any position along the carbon chain.
  • C 2 - 8 -alkynyl is intended to mean a linear or branched hydrocarbon group containing from two to eight carbon atoms and containing one or more triple bonds.
  • Some examples of C 2 - 8 -alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl and octynyl groups as well as branched forms of these.
  • the position of unsaturation (the triple bond) may be at any position along the carbon chain. More than one bond may be unsaturated such that the "C2-8-alkynyl" is a di-yne or enedi-yne as is known to the person skilled in the art.
  • Cs-s-cycloalkyl is intended to cover three-, four-, five-, six-, seven-, and eight-membered rings comprising carbon atoms only.
  • a Ca- ⁇ -cycloalkyl may optionally contain one or more unsaturated bonds situated in such a way, however, that an aromatic ⁇ -electron system does not arise.
  • Ca ⁇ -cycloalkyl are the carbocycles cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene.
  • Cyclic organyl groups are aliphatic, alicyclic groups in which carbon atoms form a ring. In preferred embodiments containing three, four, five, six or seven carbon atoms, the ring, as a substituent, is connected either directly via one of the ring atoms or via one or more appended carbon atoms. Particular examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl groups, and the like.
  • Straight-chained acyclic organyl groups are substituent groups consisting of a linear arrangement of carbon atoms, where accordingly each carbon atom binds a maximum of two other carbon atoms, connected through single, double, or triple bonds.
  • the straight-chained organyl groups may contain none, one, or several multiple bonds, and are, for example, commonly referred to as alkyl, alkenyl or alkynyl, or alkadienyl groups, respectively.
  • straight-chained organyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, propenyl, butenyl, pentadienyl, propargyl, butynyl.
  • Branched acyclic organyl groups are substituent groups consisting of a branched arrangement of carbon atoms, where accordingly one or more carbon atoms may bind more than two other carbon atoms, connected through single, double, or triple bonds.
  • the branched organyl groups may contain none, one, or several multiple bonds. Examples of branched organyl groups include iso-propyl, iso-butyl, tert-butyl, methylbutyl, methylbutenyl, methylbutynyl.
  • C)- 6 alkoxy and "lower alkoxy groups” are understood as C ] . 6 cyclic or acyclic organyl groups connected, as substituents, via an oxygen atom. Examples of lower alkoxy groups include methoxy, ethoxy, iso-propoxy, butoxy, tert- butoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, and cyclobutylmethyl.
  • Ci. 6 alkylamino and “lower alkylamino groups” are understood as lower alkyl groups connected, as substituents, via a nitrogen atom, which may carry one or two lower alkyl groups. Particular examples include methylamino, dimethylamino, iso-propylamino. Optionally, lower aminoalkyl groups may consist of 4-6 membered nitrogen-containing rings, such as pyrrolidino.
  • aminoalkyl and “lower aminoalkyl groups” are understood as lower alkyl groups carrying, as a substituent, an additional amino group. Examples include aminomethyl and aminoethyl.
  • Ci- 6 -hydroxyalkyl and “lower hydroxyalkyl groups” are understood as lower alkyl groups carrying, as a substituent, an additional hydroxy group. Examples include hydroxymethyl, hydroxyethyl, 2-hydroxy-2-propyl, hydroxypentyl.
  • heterocyclyl is intended to mean three-, four-, five-, six-, seven-, and eight-membered rings wherein carbon atoms together with from 1 to 3 heteroatoms constitute the ring.
  • a heterocyclyl may optionally contain one or more unsaturated bonds situated in such a way, however, that an aromatic ⁇ -electron system does not arise.
  • the heteroatoms are independently selected from oxygen, sulfur, and nitrogen.
  • a heterocyclyl may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, and the like.
  • Heterocyclyl rings may optionally also be fused to aryl rings, such that the definition includes bicyclic structures.
  • Preferred such fused heterocyclyl groups share one bond with an optionally substituted benzene ring.
  • benzo-fused heterocyclyl groups include, but are not limited to, benzimidazolidinone, tetrahydroquinoline, and methylenedioxybenzene ring structures.
  • heterocyclyls include, but are not limited to, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4- dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1 ,4-oxathiin, 1,4-oxathiane, tetrahydro- 1 ,4-thiazine, 2//-l,2-oxazine , maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5- triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,
  • Binding to the heterocycle may be at the position of a heteroatom or via a carbon atom of the heterocycle, or, for benzo-fused derivatives, via a carbon of the benzenoid ring.
  • the term "(heterocyclyl)Ci-6-alkyl” is understood as heterocyclyl groups connected, as substituents, via a lower alkylene, each as defined herein.
  • the heterocyclyl groups of (heterocyclyl)Ci- 6 -alkyl groups may be substituted or unsubstituted.
  • (aryl)Ci- 6 -alkyl” and “aralkyl” are intended to mean an aryl group connected, as a substituent, via a lower alkylene, each as defined herein.
  • the aryl groups of (ary ⁇ Ci- ⁇ -alkyl may be substituted or unsubstituted. Examples include benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl.
  • heteroarylCi. 6 -alkyl and “heteroaralkyl” are understood as heteroaryl groups connected, as substituents, via a lower alkylene, each as defined herein.
  • the heteroaryl groups of heteroaralkyl groups may be substituted or unsubstituted. Examples include 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl, and their substituted as well as benzo-fused analogs.
  • (cyclo alky I)C i- ⁇ -alkyl is intended to mean a cycloalkyl groups connected, as substituents, via a lower alkylene, each as defined herein.
  • O-Ci-e-alkyl is intended to mean Ci-g- alkyloxy, or alkoxy, such as methoxy. ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy and hexyloxy.
  • the definition of "O-Ci. 6 -alkyl” is intended to cover cyclic alkoxy groups having a maximum of six carbon atoms. Illustrative non-limiting examples of cyclic alkoxy groups include cyclobutyloxy, cyclopropylmethyloxy, cyclohexyloxy, and the like.
  • lower alkylene means a bivalent hydrocarbon tether, containing from one to six carbon atoms. Additionally, “lower alkylene” tethers may optionally contain one or more substituents selected from Ci- ⁇ alkyl, halogen, hydroxyl, and amino. Non-limiting examples of “lower alkylene” groups are methylene, ethylene, propylene, tetramethylene, hexamethylene.
  • Vinylene groups are ethene-l,2-diyl groups (— CHCH-) having (E) or (Z) configuration.
  • Acyl groups are hydrogen or lower alkyl groups connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl.
  • haloalkyl hydroxyalkyl
  • aminoalkyl are intended to cover Cj-6-alkyl groups, defined above, carrying at least one halogen, hydroxy group, or amino group, respectively.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • the term "optionally substituted” is intended to mean that the group in question may be substituted one or several times, such as 1 to 5 times, or 1 to 3 times, or 1 to 2 times, with one or more groups selected from Ci-e-alkyl, Ci- 6 -alkoxy, oxo (which may be represented in the tautomeric enol form), carboxyl, amino, hydroxy (which when present in an enol system may be represented in the tautomeric keto form), nitro, alkylsulfonyl, alkylsulfenyl, alkylsulf ⁇ nyl,Ci- 6 -alkoxycarbonyl, d- ⁇ -alkylcarbonyl, forrnyl, amino, mono- and di(Ci- 6 -alkyl)amino; carbamoyl, mono- and di(C]- 6 - alkyl)aminocarbonyl
  • salts is intended to mean pharmaceutically acceptable acid addition salts obtainable by treating the base form of a functional group, such as an amine, with appropriate acids such as inorganic acids, for example hydrohalic acids; typically hydrochloric, hydrobromic, hydrofluoric, or hydroiodic acid; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example acetic, propionic, hydroacetic, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethandioic, propanediol, butanedioic, (Z)-2-butenedioic, (E)-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2- hydroxy-l,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs are inactive derivatives of the compounds of this invention that are readily convertible in vivo into the required compound.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985). Metabolites of these compounds include active species that are produced upon introduction of compounds of this invention into the biological milieu.
  • the compounds according to the invention may exist as a racemate or as enantiomers. It should be noted that all such isomers and mixtures thereof are included in the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also included in the scope of this invention.
  • Such isomers may be separated by conventional techniques such as preparative chiral chromatography.
  • the compounds may be prepared in racemic form or individual enantiomers may be prepared by stereoselective synthesis or by resolution.
  • the compounds may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toIuoyl-d-tartaric acid and/or (+)- di-p-toluoyl-1-tartaric acid, followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved using a chiral auxiliary by formation of diastereomeric derivatives such as esters, amides or ketals followed by chromatographic separation and removal of the chiral auxiliary.
  • One embodiment includes the use of N-(l-methylpiperidin-4-yl)-N-(4- fluorophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide, a 5-HT2A inverse agonist which has the structure:
  • R is a hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an aralkyl or heteroaralkyl group; and n can be 0, 1, or 2.
  • X] is methylene, vinylene, or an NH or N(lower alkyl) group
  • X 2 is methylene , or, when X] is methylene or vinylene, X 2 is methylene or a bond; or when Xj is methylene, X 2 is O, S, NH, or N(lower alkyl) or a bond.
  • Y] is methylene and Y 2 is methylene, vinylene, ethylene, propylene, or a bond; or Yj is a bond and Y2 is vinylene; or Yj is ethylene and Y 2 is O, S, NH, or N(lower alkyl).
  • Ari and Ar 2 each independently is unsubstituted or substituted aryl or heteroaryl groups.
  • W is oxygen or sulfur.
  • Yi is methylene and Y 2 is a bond, methylene, ethylene, or vinylene; or Yi is ethylene and Y2 is O or S; and Xj is methylene and X 2 is a bond, methylene, O, or S; or Xi is NH or N(lower alkyl) and X 2 is methylene.
  • Z is
  • Arj and Ar 2 independently are mono- or disubstituted phenyl groups.
  • the R of Formula (I) is a hydrogen, a lower alkyl group, a cyclic organyl group, or a substituted or unsubstituted aralkyl or heteroaralkyl group; n is 1; Yi is methylene, and Y 2 is a bond, methylene, ethylene, or vinylene; Xi is methylene and X2 is a bond, or Xi is NH or N(lower alkyl) and X 2 is methylene; andAri and Ar 2 are phenyl groups, independently / ⁇ -substituted with groups selected from lower alkyl, lower alkoxy and halogen.
  • R N is hydrogen, lower alkyl, aralkyl, or heteroaralkyl
  • Ar L is selected from lower alkyl, lower alkoxy and halogen
  • Ar R is selected from lower alkyl, lower alkoxy and halogen
  • k is 1 or 2
  • a " is a suitable anion.
  • Forma I refers to compounds of Formulae (I) and (Ia).
  • Suitable embodiments of the compounds of Formula I may be selected from the group consisting, of: iV-((4-methylphenyl)methyl)-iV " -(piperidin-4-yl)-7V- phenylmethylcarbamide;
  • 2-(4-ethoxyphenyl)-iV -(4-fluoroben2yl)-//-( 1 -methylpiperidin-4-yl) acetamide; 2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(l-isopropylpiperidin-4-yl)- acetamide;
  • the compound of Formula I is selected from the group consisting of:
  • the compound of Formula I is selected from the group consisting of:
  • the compound of Formula I is 2-(4- methoxyphenyl)-N-(4-methylbenzyl)-N-(8-methyl-8-aza-bicyclo[3.2.1 ]oct-3-yl)- acetamide.
  • the compound of Formula I is selected from the group consisting of:
  • the compound of Formula I is selected from the group consisting of:
  • the compound of Formula I is 2-(4- Methoxyphenyl)-N-(4-methylbenzyl)-N-(8-methyl-8-aza-bicyclo[3.2.1]octen-3-yl)- acetamide.
  • R 1 is selected from the group consisting of optionally substituted heterocyclyl, and optionally substituted (heterocyclyl)Ci-6-alkyl.
  • R 2 and R 3 are independently selected from the group consisting of hydrogen, Ci-6-alkyl and halogen or such that R 2 together with R 3 forms a ring.
  • R 2 and R 3 together can form a 3-, A-, S-, 6-, or 7-membered ring system with the atoms of the piperidine ring.
  • m 1 is selected from the group consisting of 0, 1 , and 2.
  • n 1 is selected from the group consisting of 1, 2, and 3;
  • a ⁇ 3 is an optionally substituted aryl or heteroaryl.
  • the aryl or heteroaryl can be optionally substituted with a substituent selected from the group consisting of Ci- ⁇ -alkyl, Ci ⁇ -alkoxy, carboxyl, amino, hydroxy, thiol, nitro, cyano, guanidino, carbamido and halogen.
  • Wi is selected from the group consisting of O and S.
  • X 3 is selected from the group consisting of optionally substituted methylene, optionally substituted ethylene, optionally substituted propylene, optionally substituted vinylene, and CH 2 N(R N1 ), wherein R N1 is selected from hydrogen and Cj-e-alkyl.
  • a ⁇ 4 is an optionally substituted aryl or heteroaryl.
  • the heterocyclyl or (heterocyclyl)C]_ 6 -alkyl of R 1 may be optionally substituted.
  • the substituent may be selected from halogen, hydroxy, alkyl, alkoxy, and amino.
  • the substituent may be on the alkyl chain or the ring system. In further embodiments the substituent is on the ring system.
  • the heterocyclyl ring in R 1 may be selected from the group consisting of tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1 ,4-oxathiin, 1,4-oxathiane, tetrahydro-l,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-l,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrol
  • the azacyclic ring may be a 5, 6, or 7-membered ring as reflected in that m' may be selected from 0, 1 and 2. In certain embodiments, however, the azacyclic ring is a 6-membered ring, wherein m' is 1.
  • the azacyclic ring may be substituted with R 2 and R 3 .
  • R 2 and R 3 may be independently selected from the group consisting of hydrogen, Ci- 6 -alkyl, and halogen, or such that R together with R forms a ring. That is to say that R 2 and R 3 may be biradicals which combine to form a 3-, 4-, 5-, 6-, or 7-membered ring system with the atoms of the azacyclic ring.
  • the azacyclic ring system is selected from wherein R 7 and R 8 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, and Cj. ⁇ alkyl. In certain embodiments R 7 and R 8 are hydrogen.
  • R 2 and R 3 are hydrogen.
  • R 1 is an optionally substituted (heterocyclyl)Ci_ 6-alkyl. In certain of these embodiments, R 1 is an optionally substituted (heterocyclyl)methyl, an optionally substituted (heterocyclyl)ethyl, or an optionally substituted (heterocyclyl)propyl. In other embodiments, R 1 is an optionally substituted (hetero cycly l)ethyl .
  • Ar 3 is linked to a central nitrogen atom via a short aliphatic chain 1, 2, or 3 carbon atoms in length.
  • n' is 1, resulting in a methylene spacer between the central nitrogen atom and Ar 3 .
  • Ar 3 may be an optionally substituted aryl or heteroaryl.
  • Ar 3 is an optionally substituted aryl.
  • the central nitrogen atom is linked to an optionally substituted benzyl group.
  • Ar 3 is an optionally substituted aryl, which may be a 4-substituted aryl.
  • the 4-substituent of the 4-substituted aryl may be any substituent known to the person skilled in the art, such as a C 1 - 6 -alkyl, Q- 6 -alkoxy, carboxyl, amino, hydroxy, thiol, nitro, cyano, guanidino, carbamido and halogen.
  • the halogen is fluoro, while in other embodiments, the halogen is chloro.
  • Ar 3 is selected from the group consisting of alkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, hydroxy- substituted phenyl and amino-substituted phenyl.
  • the substituent may be present 0 to 5 times, or 0 to 4 times, or 0 to 3 times, such as 0, 1 , 2, or 3 times. In certain embodiments, the substituent is present 1 to 2 times.
  • Ar 3 is a 4-substituted aryl selected from the group consisting of 4-halophenyl and 4-alkylphenyl.
  • the phenyl group is 4-fluorophenyl.
  • Ar 3 is an optionally substituted heteroaryl.
  • the heteroaryl may be substituted with substituents known to the person skilled in the art, such as a Ci-g-alkyl, C]_6-alkoxy, carboxyl, amino, hydroxy, thiol, nitro, cyano, guanidino, carbamido and halogen.
  • the central nitrogen is linked to Ar4 via a 2 to 4 carbon spacer unit.
  • This spacer unit comprises a carbonyl or thiocarbonyl function wherein Wi is selected from the group consisting of oxygen and sulfur. In some embodiments Wi is oxygen.
  • X3 may be selected from the group consisting of optionally substituted methylene, optionally substituted ethylene, optionally substituted propylene, optionally substituted vinylene, and CH 2 N(R 1 "").
  • X 3 may extend the spacer unit by 1 to 3 atoms between the central nitrogen and Ar 4 and render the central nitrogen part of an amide or carbamide.
  • X 3 is selected from the group consisting of optionally substituted methylene, optionally substituted ethylene, and CH 2 N(R 1 " 11 ).
  • X 3 is an optionally substituted methylene, or CH 2 N(R N1 ), wherein R Nl may be hydrogen.
  • Ar 4 may be an optionally substituted aryl or heteroaryl. In certain embodiments, Ar 4 is an optionally substituted aryl. In some embodiments, Ai4 is a 4-substituted aryl.
  • Ar 4 may be selected from the group consisting of alkoxy-substituted phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl, amino-substituted phenyl, and heterocyclyl-substituted phenyl.
  • Ar 4 is a 4-substituted aryl wherein the substituent is selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, alkylamino, heterocyclyl, and heteroaryl.
  • the substituent on Ar 4 is selected from chloro, fluoro, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, n- butoxy, sec-butoxy, tert-butoxy, trifluoromethoxy, N-morpholinyl, N-pyrrolidinyl, N- pyrazolyl, N-triazolyl and 2-oxopyrrolidinyl.
  • Suitable embodiments of the compounds of Formula II can be selected from the group consisting of: iV- ⁇ l-[2-(l,3-Dioxolan-2-yl)ethyl]piperidin-4-yl ⁇ -N-(4-fluorobenzyl)-N'-
  • X4 is selected from the group consisting of CH2, CH 2 CH 2 , CH 2 O, OCH 2 , O, CH 2 S 5 SCH 2 , S, CH 2 N(R N2 ), N(R N2 )CH 2 and N(R N2 ); wherein R N2 is selected from hydrogen and C 1 . 6 alkyl.
  • W 2 is selected from the group consisting of O and S.
  • Z 3 is absent or selected from the group consisting of CH and N.
  • R 9 is hydrogen, or an optionally substituted substituent selected from the group consisting of Q-e alkyl, C 2 - 8 alkenyl, C 2 -S alkynyl, C3.8 cycloalkyl, aryl, heteroaryl, aryl(Ci ⁇ alkyl), heteroaryl(Ci. 6 alkyl), heterocyclylCCj- ⁇ alkyl), C3.8 cyc!oalkyl(Ci. 6 alkyl), hydroxy(C]. 6 alkyl), amino(Ci. 6 alkyl), and halo(C 1 . 6 alkyl).
  • m is selected from the group consisting of 0 and 1.
  • R 12 , R 13 , and R 14 are independently hydrogen, or an optionally substituted substituent selected from the group consisting of Ci -6 alkyl, aryl(C
  • R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, hydroxy, and optionally substituted C 1. 6 alkyl or selected such that R 10 and R 1 ' together form a ring system such that is selected from the group consisting of
  • R 15 and R 16 are independently selected from the group consisting of hydrogen, halogen, hydroxy, and Cj. 6 alkyl.
  • R 12 , R 13 , and R 14 may be independently selected from the group consisting of 4-monosubstituted-aryl(Ci -6 alkyl), and 4- monosubstituted-heteroaryl(Ci.6 alkyl).
  • the other of the at least two of R 12 , R 13 , and R 14 independently selected from the group consisting of aryl(Ci- 6 alkyl) and heteroaryl(Ci_6 alkyl) is selected from the group consisting of (O-Ci-6 alkyl)-substituted- aryl(C i-6 alkyl), and (O-Ci ⁇ alkyl)-substituted-heteroaryl(Ci-6 alkyl).
  • At least one of R 12 , R 13 , and R 14 is selected from the group consisting of fluoro-substituted-aryl(Ci- 6 alkyl), and fluoro-substituted- heteroaryl(Ci-6 alkyl).
  • R 12 , R 13 , and R 14 are independently selected from the group consisting of aryl(Ci-6 alkyl), heteroaryl(Ci- 6 alkyl), and heterocycIyl(Ci-6 alkyl) are each substituted 1, 2, or 3 times, with a substituent selected from the group consisting of halogen and optionally substituted O-C L ⁇ -alkyl.
  • the halogen is fluorine.
  • -6 alkyl), heterocyclyl(Ci_6 alkyl) is substituted 1 to 3 times, such as 1, 2, or 3 times with an optionally substituted O-Ci -6 -alkyl, such as a fluorinated O-Ci ⁇ -alkyl.
  • At least two of R 12 , R I3 5 and R 14 are optionally substituted aryl(Ci. 6 alkyl). In a preferred embodiment, at least two of R 12 , R 13 , and R 14 are optionally substituted benzyl.
  • R 12 , R 13 , and R 14 are independently selected from the group consisting of aryl(Ci- 6 alkyl), heteroary ⁇ C ⁇ alkyl), heterocyclyl(Ci. 6 alkyl).
  • the d. 6 alkyl of the aryl(Ci_ 6 alkyl), heteroaryl(C 1-6 alkyl), heterocyclyl(Ci-6 alkyl) is Ci_4 alkyl, such as methylene (Ci alkyl). ethylene (C 2 alkyl), or propylene (C 3 alkyl), or butylene (C 4 alkyl), more typically a Cj alkyl or C 2 alkyl, most typically a C 1 alkyl.
  • the Ci -6 alkyl of the aryl(Ci -6 alkyl), heteroaryl(Cj. 6 alkyl), heterocycly ⁇ C ⁇ alkyl) may be substituted so as to form a branched hydrocarbon.
  • R 12 , R 13 , and R 14 are an optionally substituted benzyl.
  • One of R 12 , R 13 , and R 14 may be a 4-halo-benzyl group and one may be a 4-alkoxy-benzyl group.
  • the 4-halo-benzyl group is typically a 4-fluoro- benzyl.
  • the 4-alkoxy-benzyl group is typically a C 2 - 5 alkoxybenzyl or optionally fluorinated 4-methoxy-benzyl group such as a fluoromethoxy-benzyl, difluoromethoxy- benzyl, trifluoromethoxy-benzyl group, and 2,2,2-trifluorethoxy-benzyl.
  • the compounds of the invention may be selected from the group consisting of (i) l-oxa-4,9-diaza-spiro[5.5]undecan-3-one; (ii) l-oxa-3,8-diaza- spiro[4.5]decan-2-one; (iii) l,3,8-triaza-spiro[4.5]decan-2-one; (iv) 1,2,9-triaza- spiro[5.5]undecan-3-one; (v) l,2,8-triaza-spiro[4.5]decan-3-one; (vi) 1,2, 8-triaza- spiro[4.5]decan-3-one (vii) l,2,4,8-tetraaza-spiro[4.5]decan-3-one; (viii)2,4,9-triaza- spiro[5.5]undecan-3-one; (ix) 2,8-diaza-spiro[4.5]decan-3-one (x)
  • Suitable embodiments of the compounds of Formula III may be selected from the group consisting of:
  • the compounds of Formula I, II, and III exhibit activity at monoamine receptors, specifically serotonin receptors. Certain compounds share the common property of acting as inverse agonists at the 5-HT2A receptor. Thus, experiments performed on cells transiently expressing the human phenotype of the receptor have shown that the compounds of general Formula I, II, and III attenuate the signaling of such receptors in the absence of additional ligands acting upon the receptor. The compounds have thus been found to possess intrinsic activity at this receptor and are able to attenuate the basal, non- agonist-stimulated, constitutive signaling responses that the 5-HT2A receptor displays.
  • some embodiments include use of compounds of Formula I, II, III and the salts and stereoisomers thereof, including compounds that show a relatively high degree of selectivity towards the 5-HT2A subtype of serotonin receptors relative to other subtypes of the serotonin (5-HT) family of receptors as well as to other receptors, most particularly the monoaminergic G-protein coupled receptors, such as dopamine receptors.
  • these compounds act as inverse agonists and/or antagonists at the 5-HT2A subtype of serotonin receptors.
  • the compounds of Formulae I and II may in general be prepared by routes such as those summarized below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc, and will be obvious to those skilled in the art.
  • compounds of the Formula C may be synthesized from the corresponding ketone A by reductive animation utilizing any primary amine.
  • the reaction is conveniently carried out by stirring the reactants in an inert solvent such as methanol or ethanol containing acetic acid.
  • an inert solvent such as methanol or ethanol containing acetic acid.
  • reducing agent NaBH 4 , NaCNBHb, BH 3 -pyridine or any related reagent may be used including solid-supported reagents.
  • the reaction is typically carried out at room temperature.
  • the ketone A as exemplified by the piperidone, may be chosen from a list of compounds corresponding to the Z and Zi- groups listed in Formulae I and II.
  • the ketones can either be obtained commercially or synthesized by methodology disclosed in Lowe et al. J. Med.
  • the protecting group P includes groups such as those described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, 3. Ed. John Wiley & Sons, 1999, and they should be chosen in such a way, that they are stable to the reaction conditions applied and readily removed at a convenient stage using methodology known from the art.
  • Typical protecting groups are N-Boc, N-Cbz, N-Bn.
  • the amine C can be synthesized from the primary amine B by reductive amination with any aldehyde.
  • the reaction is conveniently carried out by stirring the reactants in an inert solvent such as methanol or ethanol containing acetic acid.
  • an inert solvent such as methanol or ethanol containing acetic acid.
  • reducing agent NaBH 4 , NaCNBHa, BH 3 -pyridine or any related reagent may be used including solid-supported reagents.
  • the reaction is typically carried out at room temperature.
  • the primary amine B as exemplified by the 4-aminopiperidine, may be chosen from a list of compounds corresponding to the Z and Zi-groups listed in Formulae I and II.
  • the amines can either be obtained commercially or synthesized from the corresponding ketones.
  • the protecting group P may be chosen as stated above.
  • the amine C can be synthesized from the primary amine B by alkylation with any alkylating agent (R-L 1 ).
  • the leaving group Li is suitably a halogen atom, e.g., bromine or iodine, or a sulfonate, e.g. tosylate or mesylate, or another leaving group favoring the reaction.
  • the reaction is conveniently carried out by stirring the reagents under basic conditions in an inert solvent, e.g., diisopr ⁇ pylethylamine in acetonitrile, or K2CO3 in ⁇ N-dimethylformamide.
  • the reaction is typically carried out at temperatures between room temperature and 8O 0 C.
  • the primary amine B as exemplified by the 4-aminopiperidine, may be chosen from a list of compounds corresponding to the Z and Zl -groups listed in Formulae I and II.
  • the amines can either be obtained commercially or synthesized from the corresponding ketones.
  • the protecting group P may be chosen as stated above.
  • R and R* are defined in agreement with Formulae I and II, and P represents a suitable protecting group, and Li represents a suitable leaving group.
  • the reaction is typically carried out by stirring the reactants, using an excess of isocyanate or isothiocyanate in an inert solvent, e.g., dichloromethane at a temperature between 0 0 C and room temperature and under dry conditions.
  • the reaction is typically carried out using an excess of the acylating agent and a suitable base, e.g., triethylamine or diisopropylethylamine in an inert solvent, e.g., dichloromethane, at a temperature between O 0 C and room temperature and under dry conditions.
  • a suitable base e.g., triethylamine or diisopropylethylamine in an inert solvent, e.g., dichloromethane
  • the amine C may be acylated using a carboxylic acid (Q 2 COOH) and a suitable coupling reagent e.g. PyBroP, DCC or EDCI.
  • the reaction is typically carried out using an excess of the acylating agent and the coupling reagent in an inert solvent, e.g., dichloromethane at a temperature between O 0 C and room temperature and under dry conditions.
  • an inert solvent e.g., dichloromethane
  • the compounds of the general structure (E) may be converted into the corresponding thioamides using methodology disclosed in Varma et al., Org. Lett. 1: 697-700 (1999); Cherkasov et al. Tetrahedron 41:2567 (1985); or Scheibye et al, Bull. Soc. Chim. BeIg. 87:229 (1978).
  • R, Qi, Q 2 , W and Wi are defined in agreement with Formulae I and II, P represents a suitable protecting group, and X represents a halide.
  • the substituent T on the ring nitrogen in compounds F or G can be introduced by a two step procedure.
  • the protecting group on the urea D or the amide E is removed using well-known methods.
  • the N-Boc group is removed by treating the protected compound with 4 M HCl in dioxane or trifluoroacetic acid in dichloromethane.
  • the reaction is conveniently carried out by stirring the reactants in an inert solvent such as methanol or ethanol.
  • solid-supported borohydride NaBH 4 , NaCNBH 3 , BH 3 -pyridine, H2/Pd-C or any related reagent may be used, including solid-supported reagents.
  • the reaction is typically carried out at room temperature.”
  • the compounds F and G can be synthesized from the secondary amine obtained from D or E as described above by alkylation with any alkylating agent (T- Lj).
  • the leaving group Li is suitably a halogen atom, e.g., bromine or iodine, or a sulfonate, e.g., tosylate or mesylate, or another leaving group favoring the reaction.
  • the reaction is conveniently carried out by stirring the reagents under basic conditions in an inert solvent, for example diisopropylethylamine in acetonitrile, or K. 2 CO 3 in NjN-dimethylforrnamide.
  • the reaction is typically carried out at temperatures between room temperature and 8O 0 C.
  • the T-group can be introduced in the first step of the synthetic sequence leading to the compounds in accordance with the present invention by JV-alkylation of compound H with any alkylating agent (T- Li).
  • the leaving group L 1 is suitably a halogen atom, e.g., bromine or iodine, or a sulfonate, e.g., tosylate or mesylate, or another leaving group favoring the reaction.
  • the reaction is conveniently carried out by stirring the reagent under basic conditions in an inert solvent, e.g., diisopropylethylamine in acetonitrile, or K 2 C ⁇ 3 in N,N-dimethylformamide.
  • the reaction is typically carried out at temperatures between room temperature and 8O 0 C.
  • the reaction is conveniently carried out by stirring the reactants in an inert solvent such as methanol or ethanol.
  • an inert solvent such as methanol or ethanol.
  • solid-supported borohydride, NaBH 4 , NaCNBH3, BH 3 -pyridine, H 2 ZPd-C or any related reagent may be used, including solid-supported reagents.
  • the reaction is typically carried out at room temperature, but less reactive carbonyl compounds may require higher temperatures and/or the preformation of the corresponding imine under water removal before addition of the reducing agent. Removal of the protecting group gives the desired compound J.
  • the secondary amine H and H 1 as exemplified by 4-piperidone and its protected derivative, may be chosen from a list of compounds corresponding to the Z and Zl -groups listed in Formulae I and II.
  • the amines can either be obtained commercially or synthesized from methodology disclosed in Lowe et al., J. Med. Chem. 37:2831-40 (1994); and Carroll et al., J. Med. Chem. 35:2184-91 (1992).
  • compounds of the general structure J may be synthesized starting from K using the method disclosed in: Kuehne et al., J. Org. Chem. 56:2701 (1991); and Kuehne et al., J. Org. Chem. (1991), 56:513.
  • R, Q 1 , Q 2 , W, and T are defined in agreement with Formulae I and II, and Li is a suitable leaving group.
  • Heterocyclylalkyl alkylating agents such as T-Li may be commercially available or are typically obtained by alkylation of a heterocycle with a bifunctional alkyl- linker, as shown below.
  • the leaving groups Li and L 2 are suitably a halogen atom, e.g., chlorine, bromine or iodine, or a sulfonate, e.g., tosylate or mesylate, or another leaving group favoring the reaction.
  • the reaction is conveniently carried out by stirring the reagent under basic conditions in an inert solvent, e.g., diisopropylethylamine in acetonitrile, or K 2 CO 3 in NvN-dimethylformamide.
  • the reaction is typically carried out at temperatures between room temperature and 8O 0 C.
  • the alkylating agent hence obtained can be either reacted in situ in the next step with the secondary amine (i.e. deprotected D/E, or H) or isolated from the reaction mixture before its further use.
  • Heterocyclylalkyl alcohols such as T + -CH 2 OH or T-OH may also be converted into suitable alkylating agents T-Li by transforming the hydroxyl into a leaving group, e.g. by tosylation, mesylation or halogenation.
  • a ⁇ 4 may either be obtained commercially or synthesized from methodology disclosed in the literature.
  • the introduction of substituents on Ari, Ar 2> A r3 and/or Ar 4 may be performed from a suitable precursor at any appropriate stage of the preparation of the compounds.
  • compounds containing an alkoxy substituents may be typically prepared by Williamson ether synthesis from the corresponding hydroxyaryl derivatives.
  • Structures bearing an amine substituent on Ari, Ar 2, A r3 and/or Ar 4 may be obtained from a suitable halo- or pseudohalo precursor (e.g. Br, I-, Cl-, triflate-, nonaflate-, tosylate-substituted aryl derivatives) by metal-catalyzed amination chemistries, such as Pd- or Ni- (Hartwig, Angew. Chem. Int. Ed., 1998, 37, 2046-2067; Yang & Buchwald, J.
  • a suitable halo- or pseudohalo precursor e.g. Br, I-, Cl-, triflate-, nonaflate-, tosylate-substituted aryl derivatives
  • metal-catalyzed amination chemistries such as Pd- or Ni- (Hartwig, An
  • the structures bearing an amide substituent on Arj, Ar 2 , A r 3 and/or Ar 4 may be obtained from a suitable halo- or pseudohalo precursor either by Pd catalyzed (Yin & Buchwald, J. Am. Chem. Soc, 2002, 124, 6043-6048) or by Cu catalyzed (Buchwald et al, J. Am. Chem. Soc, 2002, 124, 7421-7428) amidation chemistries.
  • these compounds may also be obtained from the corresponding aniline precursors either by acylation (Wolf, Liebigs Ann. Chem., 1952, 576, 35; Yasukara et al, J. Chem. Soc.
  • Compounds that carry an alkylsulfanyl substituent on Arj, Ar ⁇ A r 3 and/or Ar 4 be obtained from a suitable halo- or pseudohalo precursor by Pd catalyzed (Li, J. Org. Chem., 2002, 67, 3643-3650), or Cu catalyzed (Kwong & Buchwald, Org. Lett., 2002, 4, 3517-3520) thioetherification chemistry.
  • these compounds may be prepared by alkylation of corresponding benzenethiol precursors (Vogel, J. Chem. Soc, 1948, 1809; Landini & Rocca, Synthesis, 1974, 565-566; Bun-Hoi et al, J.
  • alkylarylsulfanyls may be obtained by irradiation of benzenethiols and alkenes (Screttas & Micha-Screttas, J. Org. Chem., 1978, 43, 1064- 1071).
  • Compounds that bear an acyl group on An, Ar 2, A ⁇ and/or Ar 4 may be prepared from corresponding aryl iodides by Pd catalyzed (Cacchi et al, Org. Lett, 2003, 5, 289-293) acylation chemistry.
  • benzenes may be obtained from the corresponding benzenes by Friedel-Crafts chemistry (Read, J. Am. Chem. Soc, 1922, 44, 1746-1755), or by addition of aryl-Grignard reagents to nitriles (Whitmore et al, J. Am. Chem. Soc, 1947, 69, 235-237) or to acyl chlorides (Whitmore & Lester, J. Am. Chem. Soc, 1942, 64, 1247), or by either Pd-catalyzed (Goo ⁇ en & Ghosh, Angew. Chem. Int. Ed. Engl., 2001, 40, 3458-3460) or Rh-catalyzed acylation of arylboronic acids.
  • Friedel-Crafts chemistry Read, J. Am. Chem. Soc, 1922, 44, 1746-1755
  • aryl-Grignard reagents to nitriles
  • the compounds of Formula III may in general be prepared by routes such as those summarized below, or by modification of these methods. Cyclization of the appropriate intermediates may be generally achieved with phosgene or its analogues such as CDI, with chloroacetylchloride or equivalents thereof or by treatment with carbondisulf ⁇ de and subsequent oxidation.
  • 4,5-disubstituted or 3,4,5-trisubstituted spirocycles may be prepared from an appropriate ⁇ -ketoester by reaction with a halide to introduce the 5-substituent, reductive amination (with a primary amine for the 3- substituent), treatment with allyl magnesium bromide, cyclisation as described above, oxidative cleavage of the double bonds (e.g. by ozonolysis) and formation of the piperidine ring by reductive amination.
  • the nitrile may be transformed into an ester, which is reacted with allyl magnesium bromide, followed by oxidative cleavage of the two olefins, formation of the piperidine by reductive amination.
  • Alkylation, deprotection of the hydrazide and cyclisation gives the desired spirocycles.
  • these steps may be inversed and additional protection steps of functional groups may be required.
  • the compounds may be obtained from an appropriate ⁇ - ketoester by reaction with a bis(2-chloroethyl) amine derivative to form the piperidine ring. Reductive amination, saponification and Curtius rearrangement lead to the cyclic urea derivative.
  • a nitroaldol reaction may be used to obtain the desired intermediate 1,2-aminoalcohol after reduction of the nitro-group, followed by cyclisation.
  • the compounds may be prepared by epoxidation of an appropriate olefin, obtained by Wittig or Homer- Wads worth-Emmons reactions from suitably protected 4-piperidone.
  • an enantioselective modification may include an asymmetric epoxidation method of the olefin as described in the literature, e.g. Jacobsen or others.
  • Sharpless asymmetric dihydroxylation method may be used followed by epoxide ring formation.
  • suitably protected 4-methoxycarbonyl- methylenepiperidine may be reduced to the allyl alcohol which is subjected to Sharpless asymmetric epoxidation according to literature procedure. Epoxide opening with a metallorganic reagent and oxidation of the resulting primary alcohol leads to the ⁇ - hydroxy carboxylic acid, which is converted into the desired spirocyclic enantiomer as described in herein.
  • suitably protected 4-methoxycarbonyl- methylenepiperidine may be converted to an enantiomerically pure epoxide by Jacobsen epoxidation, followed by ring opening with ammonia or an appropriate amine, reaction with a metallorganic reagent with the ester group, reduction, cyclisation, alkylation if required and introduction of the piperidine substituent.
  • the stereocenter may be introduced by using an appropriate ⁇ -amino acid ester as the chiral template.
  • compositions comprising a compound as described above, and a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.
  • composition refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, intramuscular, intraocular, intranasal, intravenous, injection, aerosol, parenteral, and topical administration.
  • compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • physiologically acceptable defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s).
  • suitable carriers or excipient(s) include butylene glycol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, s thereof.
  • Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA 3 18th edition, 1990, which is hereby incorporated by reference in its entirety.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, intraocular injections or as an aerosol inhalant.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
  • compositions for use in accordance with the present disclosure thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., as disclosed in Remington's Pharmaceutical Sciences, cited above.
  • the agents disclosed herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination disclosed herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increases the solubility of the compounds to allow for the preparation of highly, concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for the hydrophobic compounds disclosed herein is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water- miscible organic polymer, and an aqueous phase.
  • a common co-solvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • VPD co-solvent system which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80TM; the fraction size of polyethylene glycol may be varied; and other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone.
  • other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • salts may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acids or base forms.
  • compositions suitable for use in the methods disclosed herein include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a “therapeutically effective amount” means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Chapter 1, which is hereby incorporated by reference in its entirety).
  • the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight, or 1 to 500 mg/kg, or 10 to 500 mg/kg, or 50 to 100 mg/kg of the patient's body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. Where no human dosage is established, a suitable human dosage can be inferred from ED 5 0 or ID 5 0 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions disclosed herein or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day.
  • compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day.
  • the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • N-((4-Methylphenyl)methyl)-N-( 1 -(phenylmethyl)piperidin-4-yl)-N'- phenylmeth ylcarbamide was prepared as described in example 9 above. A sample was precipitated as the oxalate and recrystallized from ethyl acetate to give the title compound.
  • N-((4-Methylphenyl)methyl)-N-(l-(tert-butyloxycarbonyl)piperidin-4-yl)-4- methoxyphenylacetamide was dissolved in ether (2 ml) and HCl (3 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2 h, water (5 ml) was added, and the mixture was extracted with HCl (0.1 N, 3 X 30 ml). The combined aqueous layers were treated with NaOH (0.2 N) until basic (pH >8). The aqueous layer was extracted with diethyl ether (2 X 20 ml).
  • N-(3-Phenyl ⁇ ropyl)-N-(l-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyph enylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2 X 15 ml), dried (Na 2 SO-O, filtered to give a clear solution.
  • N-(2-Phenylethyl)-N-(l-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphe nylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2 X 15 ml), dried (Na 2 SO 4 ), filtered to give a clear solution.
  • N-((2-Methoxyphenyl)methyl)-N-(l-(tert-butyloxycarbonyl)piperidin-4-yl)-4- methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2 X 15 ml), dried (Na 2 SO 4 ), filtered to give a clear solution.
  • N-((2-Chlorophenyl)methyl)-N-(l-(tert- butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2 X 15 ml), dried (Na 2 SO 4 ), filtered to give a clear solution.
  • N-((3 ,4-Di-methoxyphenyl)methyl)-N-( 1 -(tert-butyloxycarbonyl)piperidin-4-yl)-4- methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2 X 15 ml), dried (Na 2 SO 4 ), filtered to give a clear solution.
  • N-((4-Fluorophenyl)methyl)-N-(l-(tert- butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichioromethane (10 ml). The mixture was extracted with water (2 X 15 ml), dried (Na 2 SO 4 ), filtered to give a clear solution.
  • Example 26 N-ff2.4-Di-chlorophenvDmethyl)-N-Cpiperidin-4-vD-4- methoxyphenylacetamide f26HCH80-8)
  • N-((2,4-Di-chlorophenyl)methyl)-N-(l-(tert-butyloxycarbonyl)piperidin-4-yl)-4- methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml. 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2 X 15. ml), dried (Na 2 SO 4 ), filtered to give a clear solution.
  • N-((3-Methylphenyl)methyl)-N-(l-(tert- butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2 X 15 ml), dried (Na 2 SO 4 ), filtered to give a clear solution.
  • N-((3-Bromophenyl)methyl)-N-(l-(tert- butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2 X 15 ml), dried (Na 2 SO 4 ), filtered to give a clear solution.
  • Example 34 N-((4-Methylphenyl>methyl)-N- ⁇ -piperidin-4-vn-f 4- chlorophenox y”) acetamide f26HCH78-5') [0232] To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBHa in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature.
  • the mixture was sequentially extracted with HCl (0.2 N, 2 X 15 ml), NaOH (0.2 N, 2 X 15 ml), and H 2 O (10 ml), dried (Na 2 SO 4 ), filtered and concentrated.
  • the crude material was dissolved in diethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2 X 10 ml), dried (Na2SO4), and filtered to give a clear solution.
  • N-((4-Methylphenyl)methyl)amino-l-phenylmethylpyrrolid ⁇ ne 35 mg, 0.125 mmol was dissolved in dichloromethane (1.5 ml), and benzylisocyanate (0.09 ml, 0.3 mmol) was added. The reaction mixture was stirred at room temperature. After 48 h, the crude reaction mixture was added on to a column carrying strongly acidic cation exchange resin, which was washed with methanol (3 X 6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound.
  • R-SAT Receptor Selection and Amplification Technology
  • All receptor and G-protein constructs used were in the pSI mammalian expression vector (Promega Inc) as described in U.S. Pat. No. 5,707,798.
  • the 5HT2A receptor gene was amplified by nested PCR from brain cDNA using the oligodeoxynucleotides based on the published sequence (see Saltzman et. al. Biochem. Biophys. Res. Comm. 181 :1469-78 (1991)). Large-scale transfections, cells were transfected for 12-16 hours, then trypsinized and frozen in DMSO. Frozen cells were later thawed, plated at 10,000-40,000 cells per well of a 96 well plate that contained drug.
  • the graph shown in Figure 1 represents the data obtained from a dose response analysis of 26HCH17 and ritanserin as 5-HT2A receptor inverse agonists. Briefly, the 5-HT2A receptor, and the alpha subunit of the guanine nucleotide binding protein Gq were transiently transfected into NIH3T3 cells and assayed using the functional receptor assay, Receptor Selection and Amplification Technology (R-SAT) essentially as disclosed in U.S. Pat. No. 5,707,798. Each compound was screened at seven serially diluted concentrations in triplicate. Data were analyzed using least squares fit analysis with GraphPad Prism (San Diego, Calif.), and are reported normalized to percent response.
  • R-SAT Receptor Selection and Amplification Technology
  • 26HCH16D is a highly selective 5-HT2A inverse agonist.
  • Method A Agilent HPl 100 HPLC/MSD.
  • Reaction-Step 1 4-(4-Trifluoromethylbenzylamino)-l-methyl ⁇ iperidin (50ELH2).
  • Reaction-Step 2 2-(4-Fluorophenyl)-N-(4-trifluoromethylbenzyl)-N- (l-methylpiperidin-4-yl)a cetamide (50ELH14c).
  • Reaction-Step 2 2-(4-Trifluoromethylphenyl)-N-(4- trifluoromethylbenzyl)-N-(l-methylpiperid in-4-yl)acetamide (50ELH14a).
  • Reaction-Step 1 4-(4-Fluorobenzylamino)-l-methylpiperidine (50ELH4).
  • Reaction-Step 2 2-(Phenyl)-N-(4-fluorobenzyl)-N-(l-methylpiperidin- 4-yl)acetamide (50ELH10).
  • Reaction-Step 2 2-(4-Trifluoromethlphenyl)-N-(4-fluorobenzyl)-N-(l- methylpiperidin-4-yl)ac etamide (50ELH1 22).

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des agonistes inverses et des antagonistes des récepteurs sérotoninergiques utilisables pour le traitement de troubles du sommeil tels que l'insomnie et plus spécifiquement l'insomnie avec éveils nocturnes. Le composé augmente les phases de sommeil à ondes lentes tout en diminuant le nombre et la durée des éveils après l'endormissement.
PCT/US2007/009804 2006-04-19 2007-04-18 Utilisation de 4-amino-piperidines pour le traitement des troubles du sommeil WO2007124136A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US79374106P 2006-04-19 2006-04-19
US60/793,741 2006-04-19

Publications (1)

Publication Number Publication Date
WO2007124136A1 true WO2007124136A1 (fr) 2007-11-01

Family

ID=38328553

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2007/009804 WO2007124136A1 (fr) 2006-04-19 2007-04-18 Utilisation de 4-amino-piperidines pour le traitement des troubles du sommeil

Country Status (1)

Country Link
WO (1) WO2007124136A1 (fr)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2699546A1 (fr) * 2011-04-18 2014-02-26 Commonwealth Scientific & Industrial Research Organisation Procédé de capture de gaz
CN105481757A (zh) * 2015-12-25 2016-04-13 北京康立生医药技术开发有限公司 一种哌马色林的制备方法
CN105859608A (zh) * 2016-05-27 2016-08-17 成都百裕制药股份有限公司 一种制备哌马色林半酒石酸盐晶型b的方法
CN105906551A (zh) * 2016-04-27 2016-08-31 东南大学 5-ht2a反向激动剂acp-103的制备方法
CN106008323A (zh) * 2016-05-30 2016-10-12 成都百裕制药股份有限公司 一种制备哌马色林半酒石酸盐晶型c的方法
JP2017516819A (ja) * 2014-06-02 2017-06-22 ラボラトリオス・デル・デエレ・エステベ・エセ・ア 疼痛に対する多様な活性を有する１−オキサ−４，９−ジアザスピロウンデカン化合物のアルキルおよびアリール誘導体
JP2018522012A (ja) * 2015-07-20 2018-08-09 アカディア ファーマシューティカルズ インコーポレーテッド Ｎ−（４−フルオロベンジル）−ｎ−（１−メチルピペリジン−４−イル）−ｎ’−（４−（２−メチルプロピルオキシ）フェニルメチル）カルバミドならびにその酒石酸塩および多形形態ｃを調製する方法
CN109111385A (zh) * 2017-06-23 2019-01-01 上海翰森生物医药科技有限公司 5-ht2a受体抑制剂及其制备方法和应用
IT201800003736A1 (it) * 2018-03-19 2019-09-19 Lundbeck Pharmaceuticals Italy S P A Processo per la produzione di Pimavanserin
US10449185B2 (en) 2017-08-30 2019-10-22 Acadia Pharmaceuticals Inc. Formulations of pimavanserin
US10517860B2 (en) 2016-03-25 2019-12-31 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
WO2020048831A1 (fr) 2018-09-03 2020-03-12 Bayer Aktiengesellschaft Composés 5-aryl-3,9-diazaspiro[5.5]undécan-2-one
WO2020048828A1 (fr) 2018-09-03 2020-03-12 Bayer Pharma Aktiengesellschaft Composés du 5-hétéroaryl-3,9-diazaspiro[5.5]undécane
WO2020048829A1 (fr) 2018-09-03 2020-03-12 Bayer Aktiengesellschaft Composés de 3,9-diazaspiro[5.5]undécane
WO2020048826A1 (fr) 2018-09-03 2020-03-12 Bayer Aktiengesellschaft Composés de la 1-oxa-3,9-diazaspiro[5.5]undécan-2-one substituée en position 5
WO2020048827A1 (fr) 2018-09-03 2020-03-12 Bayer Aktiengesellschaft Composés de la 1,3,9-triazaspiro[5.5]undécan-2-one
WO2020048830A1 (fr) 2018-09-03 2020-03-12 Bayer Aktiengesellschaft Composés 5-aryl-3,9-diazaspiro[5.5]undécan-2-one
US10689398B2 (en) 2015-10-23 2020-06-23 Esteve Pharmaceuticals, S.A. OXA-Diazaspiro compounds having activity against pain
US10953000B2 (en) 2016-03-25 2021-03-23 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
WO2021193790A1 (fr) * 2020-03-26 2021-09-30 塩野義製薬株式会社 Dérivé aromatique hétérocyclique présentant une activité de liaison de récepteur de sérotoninergique
US11135211B2 (en) 2017-04-28 2021-10-05 Acadia Pharmaceuticals Inc. Pimavanserin for treating impulse control disorder
US11464768B2 (en) 2016-12-20 2022-10-11 Acadia Pharmaceuticals Inc. Pimavanserin alone or in combination for use in the treatment of Alzheimer's disease psychosis

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6815458B2 (en) * 2000-03-06 2004-11-09 Acadia Pharmaceuticals, Inc Azacyclic compounds
WO2005112927A1 (fr) * 2004-05-21 2005-12-01 Acadia Pharmaceuticals Inc. Agonistes inverses de récepteur de sérotonine sélectifs comme éléments thérapeutiques pour les maladies
WO2006036874A1 (fr) * 2004-09-27 2006-04-06 Acadia Pharmaceuticals Inc. Sels de n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide et leur preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6815458B2 (en) * 2000-03-06 2004-11-09 Acadia Pharmaceuticals, Inc Azacyclic compounds
WO2005112927A1 (fr) * 2004-05-21 2005-12-01 Acadia Pharmaceuticals Inc. Agonistes inverses de récepteur de sérotonine sélectifs comme éléments thérapeutiques pour les maladies
WO2006036874A1 (fr) * 2004-09-27 2006-04-06 Acadia Pharmaceuticals Inc. Sels de n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide et leur preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"ACP-103", DRUGS OF THE FUTURE, vol. 31, no. 11, 2006 - 2006, pages 939 - 943, XP002446571 *

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2699546A1 (fr) * 2011-04-18 2014-02-26 Commonwealth Scientific & Industrial Research Organisation Procédé de capture de gaz
EP2699546A4 (fr) * 2011-04-18 2014-09-24 Commw Scient Ind Res Org Procédé de capture de gaz
US9409122B2 (en) 2011-04-18 2016-08-09 Commonwealth Scientific And Industrial Research Organisation Gas capture process
JP2017516819A (ja) * 2014-06-02 2017-06-22 ラボラトリオス・デル・デエレ・エステベ・エセ・ア 疼痛に対する多様な活性を有する１−オキサ−４，９−ジアザスピロウンデカン化合物のアルキルおよびアリール誘導体
US10703765B2 (en) * 2014-06-02 2020-07-07 Esteve Pharmaceuticals, S.A. Alkyl and aryl derivatives of 1-oxa-4,9-diazaspiro undecane compounds having multimodal activity against pain
JP2018522012A (ja) * 2015-07-20 2018-08-09 アカディア ファーマシューティカルズ インコーポレーテッド Ｎ−（４−フルオロベンジル）−ｎ−（１−メチルピペリジン−４−イル）−ｎ’−（４−（２−メチルプロピルオキシ）フェニルメチル）カルバミドならびにその酒石酸塩および多形形態ｃを調製する方法
US10981870B2 (en) 2015-07-20 2021-04-20 Acadia Pharmaceuticals Inc. Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form
US11840515B2 (en) 2015-07-20 2023-12-12 Acadia Pharmaceuticals Inc. Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form c
US10981871B2 (en) 2015-07-20 2021-04-20 Acadia Pharmaceuticals Inc. Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form C
US10689398B2 (en) 2015-10-23 2020-06-23 Esteve Pharmaceuticals, S.A. OXA-Diazaspiro compounds having activity against pain
CN105481757A (zh) * 2015-12-25 2016-04-13 北京康立生医药技术开发有限公司 一种哌马色林的制备方法
US10517860B2 (en) 2016-03-25 2019-12-31 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
US10953000B2 (en) 2016-03-25 2021-03-23 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
US11191757B2 (en) 2016-03-25 2021-12-07 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
CN105906551A (zh) * 2016-04-27 2016-08-31 东南大学 5-ht2a反向激动剂acp-103的制备方法
CN105859608A (zh) * 2016-05-27 2016-08-17 成都百裕制药股份有限公司 一种制备哌马色林半酒石酸盐晶型b的方法
CN106008323B (zh) * 2016-05-30 2018-11-23 成都百裕制药股份有限公司 一种制备哌马色林半酒石酸盐晶型c的方法
CN106008323A (zh) * 2016-05-30 2016-10-12 成都百裕制药股份有限公司 一种制备哌马色林半酒石酸盐晶型c的方法
US11464768B2 (en) 2016-12-20 2022-10-11 Acadia Pharmaceuticals Inc. Pimavanserin alone or in combination for use in the treatment of Alzheimer's disease psychosis
US11135211B2 (en) 2017-04-28 2021-10-05 Acadia Pharmaceuticals Inc. Pimavanserin for treating impulse control disorder
CN109111385B (zh) * 2017-06-23 2023-06-30 上海翰森生物医药科技有限公司 5-ht2a受体抑制剂及其制备方法和应用
CN109111385A (zh) * 2017-06-23 2019-01-01 上海翰森生物医药科技有限公司 5-ht2a受体抑制剂及其制备方法和应用
US10849891B2 (en) 2017-08-30 2020-12-01 Acadia Pharmaceuticals Inc. Formulations of pimavanserin
US10646480B2 (en) 2017-08-30 2020-05-12 Acadia Pharmaceuticals Inc. Formulations of pimavanserin
US11452721B2 (en) 2017-08-30 2022-09-27 Acadia Pharmaceuticals Inc. Formulations of pimavanserin
US10449185B2 (en) 2017-08-30 2019-10-22 Acadia Pharmaceuticals Inc. Formulations of pimavanserin
WO2019179920A1 (fr) * 2018-03-19 2019-09-26 Lundbeck Pharmaceuticals Italy S.P.A. Procédé de fabrication de pimavansérine
IT201800003736A1 (it) * 2018-03-19 2019-09-19 Lundbeck Pharmaceuticals Italy S P A Processo per la produzione di Pimavanserin
WO2020048830A1 (fr) 2018-09-03 2020-03-12 Bayer Aktiengesellschaft Composés 5-aryl-3,9-diazaspiro[5.5]undécan-2-one
WO2020048827A1 (fr) 2018-09-03 2020-03-12 Bayer Aktiengesellschaft Composés de la 1,3,9-triazaspiro[5.5]undécan-2-one
WO2020048826A1 (fr) 2018-09-03 2020-03-12 Bayer Aktiengesellschaft Composés de la 1-oxa-3,9-diazaspiro[5.5]undécan-2-one substituée en position 5
WO2020048829A1 (fr) 2018-09-03 2020-03-12 Bayer Aktiengesellschaft Composés de 3,9-diazaspiro[5.5]undécane
WO2020048828A1 (fr) 2018-09-03 2020-03-12 Bayer Pharma Aktiengesellschaft Composés du 5-hétéroaryl-3,9-diazaspiro[5.5]undécane
WO2020048831A1 (fr) 2018-09-03 2020-03-12 Bayer Aktiengesellschaft Composés 5-aryl-3,9-diazaspiro[5.5]undécan-2-one
WO2021193790A1 (fr) * 2020-03-26 2021-09-30 塩野義製薬株式会社 Dérivé aromatique hétérocyclique présentant une activité de liaison de récepteur de sérotoninergique

Similar Documents

Publication Publication Date Title
WO2007124136A1 (fr) Utilisation de 4-amino-piperidines pour le traitement des troubles du sommeil
RU2320646C2 (ru) N-замещенные производные пиперидина в качестве агентов серотонинового рецептора
US7538222B2 (en) N-substituted piperidine derivatives as serotonin receptor agents
US7351707B2 (en) Spiroazacyclic compounds as monoamine receptor modulators
US7253186B2 (en) N-substituted piperidine derivatives as serotonin receptor agents
US20080051429A1 (en) Use of 4-amino-piperidines for treating sleep disorders
US20030220316A1 (en) Azacyclic compounds
EA021755B1 (ru) ПИРАЗИНОВЫЕ ПРОИЗВОДНЫЕ В КАЧЕСТВЕ ENaC БЛОКАТОРОВ
KR20230002483A (ko) Bcl-2 단백질 억제제
EP1444200B1 (fr) Azetidinyl-diamines des plus utiles comme ligands du recepteur orl-1 de la nociceptine
AU2007203444B2 (en) N-substituted piperidine derivatives as serotonin receptor agents
AU2002361872C1 (en) Spiroazacyclic compounds as monoamine receptor modulators
EP1787984B1 (fr) Composes azacycliques utilises dans le traitment de maladies liees a la serotonine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07755888

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07755888

Country of ref document: EP

Kind code of ref document: A1