EP1701954A1 - Derives de piperidine et de piperazine n-substitues - Google Patents

Derives de piperidine et de piperazine n-substitues

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Publication number
EP1701954A1
EP1701954A1 EP04806416A EP04806416A EP1701954A1 EP 1701954 A1 EP1701954 A1 EP 1701954A1 EP 04806416 A EP04806416 A EP 04806416A EP 04806416 A EP04806416 A EP 04806416A EP 1701954 A1 EP1701954 A1 EP 1701954A1
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EP
European Patent Office
Prior art keywords
disorder
mmol
disorders
piperazin
ethanone
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP04806416A
Other languages
German (de)
English (en)
Inventor
S.S.Y. Pfizer Global Res. and Develeopment CHO
T.F. Pfizer Global Res. and Development GREGORY
Peter Robert Guzzo
H.R. Jr. Pfizer Global Res. and Dev. HOWARD
S.S. Pfizer Global Res. and Development NIKAM
Matthew David Surman
M.A. Pfizer Global Res. and Development WALTERS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
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Warner Lambert Co LLC
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Publication date
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of EP1701954A1 publication Critical patent/EP1701954A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/08—Mydriatics or cycloplegics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to N-substituted piperidine and piperazine derivatives, pharmaceutical compositions containing them and their use for the treatment of schizophrenia and other central nervous system (CNS) disorders or conditions.
  • CNS central nervous system
  • N-substituted piperidine and piperazine derivatives of this invention exhibit activity as antagonists of dopamine D2 receptors and of serotonin 2A (5HT2A) receptors.
  • Other heterocyclic piperazine derivatives that are useful for the treatment of schizophrenia are referred to in United States patent 5,350,747, which issued on September 27, 1994, and in United States patent 6,127,357, which issued on
  • M ⁇ D /Ri wherein U is sulfur, oxygen, SO, SO 2 , CH 2 or NR 3 ; V is nitrogen or carbon; Z is nitrogen or carbon; A is -(CH 2 ) m O-; -(CH 2 ) m NR 4 -; or -(CH 2 ) m C(R 5 R 6 )-, wherein R 5 and R 6 are independently selected from hydrogen, (C C ) alkyl optionally substituted with from one to three fluorine atoms, (CrC ) alkoxy optionally substituted with from one to three fluorine atoms, hydroxy, and aminoalkyl; or R 5 and R 6 together form a carbonyl, and wherein m is an integer from one to four; R 1 and R 2 are independently selected from hydrogen, (CrC ) alkyl optionally substituted with from one to three fluorine atoms, (CrC 4 ) alkoxy optionally substituted with from one to three fluorine atoms, hal
  • R 3 and R 4 are independently selected from hydrogen, (C C ) alkyl optionally substituted with from one to three fluorine atoms and (CrC ) alkoxy optionally substituted with from one to three fluorine atoms; or, when U is NR 3 , one of R 1 and R 2 can form, together with the carbon to which it is attached, and together with R 3 and the nitrogen to which it is attached, a heterocyclic ring containing from four to seven ring members of which from one to three ring members can be heteroatoms selected from nitrogen, oxygen and sulfur, and of which the remaining ring members are carbon, with the proviso that when R 3 forms a ring with one of R 1 and R 2 , the other of R 1 and R 2 is absent.
  • X is -[C(R 11 )(R 12 )] 0 -, wherein R 11 and R 12 are independently selected from hydrogen and (CrC 4 ) alkyl optionally substituted with from one to three fluorine atoms, and wherein o is an integer from zero to three, with the proviso that when W is absent, o must be greater than or equal to two; W is -[C(R 13 )(R 14 )] P -, wherein R 13 and R 14 are independently selected from hydrogen and (CrC ) alkyl optionally substituted with from one to three fluorine atoms, and wherein p is an integer from zero to four, with the proviso that when X is absent, p is greater than or equal to two; R 7 and R 8 are independently selected from halo, R 1 and -OR 1 ; or R 7 , when attached to a carbon adjacent to one of the carbon atoms shared by both the phenyl ring to which R 7 is attached and the ring
  • Specific embodiments of the invention include compounds of the formula 1 wherein: U is sulfur; U is sulfur, oxygen or NR 3 ; V is nitrogen; Z is nitrogen; A is -(CH 2 ) m C(R 5 R 8 )-, wherein R 5 and R 6 are hydrogen and m is one or two; A is ethylene or propylene; R 1 and R 2 are independently selected from hydrogen, (C C 4 ) alkyl, (CrC ) alkoxy and halogen; R 1 and R 2 are hydrogen; X is absent; W is [C(R 13 )(R 14 )] P -, wherein R 13 and R 14 are independently selected from hydrogen and (C r C ) alkyl, and wherein p is two to four; W is ethylene or propylene; R 7 and R 8 are independently selected from hydrogen, chloro and methyl; R 8 is chloro or methyl; M is C(O)R 9 and R 9 is (C C 4 ) alkyl; M is ER 9 , E is -
  • Examples of specific embodiments of this invention include the following compounds and their pharmaceutically acceptable salts: 1- ⁇ 5-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-6-chloro-3,3-dimethyl- 2,3-dihydro-indol-1-yl ⁇ -ethanone; 1- ⁇ 5-[2-(4-Benzo[d]isoxazol-3-yl-piperazin-1-yl)-ethyl]-6-chloro-3,3-dimethyI- 2,3-dihydro-indol-1 -yl ⁇ -ethanone; 1- ⁇ 7-[2-(4-Benzo[d]isoxazol-3-yl-piperazin-1-yl)-ethyl]-5,5-dimethyl-2,3,4,5- tetrahydro-benzo[b]azepin-1-yl ⁇ -ethanone; 1 - ⁇ 5-[3-(
  • alkyl unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, iso- sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.
  • alkoxy means “alkyl-O-", wherein “alkyl” is as defined above.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy and pentoxy.
  • alkenyl includes unsaturated hydrocarbon radicals having one or more double bonds connecting two carbon atoms, wherein said hydrocarbon radical may have straight, branched or cyclic moieties or combinations thereof. Examples of “alkenyl” groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl.
  • substituents refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites.
  • halo and halogen, unless otherwise indicated, include, fluoro, chloro, bromo and iodo.
  • the compounds of formula 1 and their pharmaceutically acceptable salts are also referred to herein, collectively, as the “compounds of this invention” and the
  • active compounds of this invention also relates to a pharmaceutical composition comprising a compound of formula 1 and a pharmaceutically acceptable carrier. Additionally, this invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Compounds of formula 1 may contain chiral centers and therefore may exist in different enantiomeric and diastereomeric forms.
  • This invention relates to all optical isomers and all stereoisomers of compounds of the formula 1, both as racemic mixtures and as individual enantiomers and diastereoisomers of such compounds, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment defined above that contain or employ them, respectively. Individual isomers can be obtained by known methods, such as optical resolution, optically selective reaction, or chromatographic separation in the preparation of the final product or its intermediate. Individual enantiomers of the compounds of formula
  • the compounds of formula 1 of this invention may have advantages, as compared with the racemic mixtures of these compounds, in the treatment of various disorders or conditions.
  • the compounds of formula 1 of this invention are basic compounds, they are all capable of forming a wide variety of different salts with various inorganic and organic acids.
  • such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the base compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert to the free base compound by treatment with an alkaline reagent and thereafter convert the free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi-tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2- hydroxy-3-naphthoate)) salts.
  • non-toxic acid addition salts i.e., salts containing pharmaceutically acceptable anions, such as the hydrochlor
  • the present invention also includes isotopically labeled compounds, which are identical to those recited in formula 1 , but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 0, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • isotopically labeled compounds of formula 1 of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compounds of formula 1 of this invention have useful pharmaceutical and medicinal properties.
  • treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or preventing one or more symptoms of such condition or disorder.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • This invention also relates to a method of treating a disorder or condition selected from the group consisting of single episodic or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, early morning waking or psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder and pediatric depression; bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; conduct disorder; disruptive behavior disorder; behavioral disturbances associated with mental retardation, autistic disorder, and conduct disorder; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social anxiety, social phobia, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorders; borderline personality disorder; schizophrenia and other psychotic
  • This invention also relates to a pharmaceutical composition for treating a disorder or condition selected from the disorders and conditions as defined in the paragraph directly above, in a mammal in need of such treatment, including a human, comprising an amount of a compound of the formula 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for treating a disorder or condition selected from the disorders and conditions as defined in the paragraph directly above, in a mammal in need of such treatment, including a human, comprising an amount of a compound of the formula 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier.
  • a more specific embodiment of this invention relates to the above method and composition wherein the disorder or condition that is being treated is selected from major depression, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, dysthymia, cyclothymia and bipolar disorder.
  • Another more specific embodiment of this invention relates to the above method and composition wherein the disorder or condition that is being treated is selected from schizophrenia, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, and schizophreniform disorder.
  • Another more specific embodiment of this invention relates to the above method and composition wherein the disorder or condition that is being treated is selected from autism, pervasive development disorder, and attention deficit hyperactivity disorder.
  • Another more specific embodiment of this invention relates to the above method and composition wherein the disorder or condition that is being treated is selected from generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post- traumatic stress disorder, and phobias, including social phobia, agoraphobia, and specific phobias.
  • Another more specific embodiment of this invention relates to the above method and composition wherein the disorder or condition that is being treated is selected from movement disorders such as akinesias, dyskinesias, including familial paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome; and extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour.
  • movement disorders such as akinesias, dyskinesias, including familial paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome
  • extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced
  • the disorder or condition that is being treated is selected from delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, memory disorder, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies.
  • PD Parkinson's disease
  • HD Huntington's disease
  • Alzheimer's disease senile dementia
  • dementia of the Alzheimer's type dementia of the Alzheimer's type
  • memory disorder vascular dementia
  • other dementias for example, due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies.
  • Another more specific embodiment of this invention relates to the above method and composition wherein the compound of formula 1 is administered to a human for the treatment of any two or more comorbid disorders or conditions selected from those disorders and conditions referred to in any of the above methods.
  • the compounds of this invention can be used in conjunction with one or more other antidepressants or anti-anxiety agents.
  • antidepressants examples include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase
  • Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics.
  • Suitable tertiary amine tricyclics and secondary amine tricyclics include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, dothiepin, butripyline, iprindole, lofepramine, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline.
  • Suitable selective serotonin reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine and sertraline. Examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine, and tranylcyclopramine.
  • Suitable reversible inhibitors of monoamine oxidase include moclobemide.
  • Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include venlafaxine.
  • Suitable CRF antagonists include those compounds described in International Patent Application Nos. WO 94/13643, WO 94/13644, WO 94/13661 , WO 94/13676 and WO 94/13677.
  • Suitable atypical anti- depressants include bupropion, lithium, nefazodone, trazodone and viloxazine.
  • Suitable NK-1 receptor antagonists include those referred to in World Patent Publication WO 01/77100.
  • Suitable classes of anti-anxiety agents that can be used in combination with the active compounds of this invention include benzodiazepines and serotonin IA (5- HTIA) agonists or antagonists, especially 5-HT
  • Suitable benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam.
  • a receptor agonists or antagonists include buspirone, flesinoxan, gepirone and ipsapirone.
  • This invention also relates to a method of treating a disorder or condition selected from single episodic or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, early morning waking or psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder and pediatric depression; bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; conduct disorder; disruptive behavior disorder; behavioral disturbances associated with mental retardation, autistic disorder, and conduct disorder; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social anxiety, social phobia, obsessive-compulsive
  • This invention also relates to a pharmaceutical composition for treating a disorder or condition selected from the disorders and conditions as defined in the paragraph directly above, in a mammal in need of such treatment, including a human, comprising: (a) a compound of the formula 1 or a pharmaceutically acceptable salt thereof; (b) another pharmaceutically active compound that is an antidepressant or anti-anxiety agent, or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the active compounds "a” and "b” are present in amounts that render the composition effective in treating such disorder or condition.
  • a more specific embodiment of this invention relates to the above method and composition wherein the disorder or condition that is being treated is selected from major depression, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, dysthymia, cyclothymia and bipolar disorder.
  • Another more specific embodiment of this invention relates to the above method and composition wherein the disorder or condition that is being treated is selected from schizophrenia, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, and schizophreniform disorder.
  • Another more specific embodiment of this invention relates to the above method and composition wherein the disorder or condition that is being treated is selected from autism, pervasive development disorder, and attention deficit hyperactivity disorder.
  • Another more specific embodiment of this invention relates to the above method and composition wherein the disorder or condition that is being treated is selected from generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post- traumatic stress disorder, and phobias, including social phobia, agoraphobia, and specific phobias.
  • Another more specific embodiment of this invention relates to the above method and composition wherein the disorder or condition that is being treated is selected from movement disorders such as akinesias, dyskinesias, including familial paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome; and extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour.
  • movement disorders such as akinesias, dyskinesias, including familial paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome
  • extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced
  • the disorder or condition that is being treated is selected from delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, memory disorder, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies.
  • PD Parkinson's disease
  • HD Huntington's disease
  • Alzheimer's disease senile dementia
  • dementia of the Alzheimer's type dementia of the Alzheimer's type
  • memory disorder vascular dementia
  • other dementias for example, due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies.
  • Another more specific embodiment of this invention relates to the above method and composition wherein the compound of formula 1 and the additional antidepressant or anti-anxiety agent are administered to a human for the treatment of any two or more comorbid disorders or conditions selected from those disorders and conditions referred to in any of the above methods.
  • the compounds of formula 1 of the present invention may be prepared as described in the following reaction schemes. Unless otherwise indicated, in the reaction schemes and discussion that follow, R 1 through R 14 , A, n, m, o, p, q, U, V, L, W, D, E, T, Z and X are defined as above.
  • X 1 is represented by a halogen
  • the reaction is typically carried out in the presence of a Lewis acid such as aluminum bromide (AIBr 3 ), aluminum chloride (AICI 3 ), gallium trichloride (GaCI 3 ), ferric chloride (FeCI 3 ), zinc chloride (ZnCI 2 ), antimony pentachloride (SbCI 5 ), zirconium tetrachloride (ZrCI ), tin tetrachloride (SnCI ) , boron trichloride (BCI 3 ), boron trifluoride (BF 3 ), or antimony trichloride (SbCI 3 ).
  • a Lewis acid such as aluminum bromide (AIBr 3 ), aluminum chloride (AICI 3 ), gallium trichloride (GaCI 3 ), ferric chloride (FeCI 3 ), zinc chloride (ZnCI 2 ), antimony pentachloride (SbCI 5 ), zircon
  • the reaction can be carried out in nonpolar solvents such as chloroform, dichloromethane, dichloroethane, or carbon disulfide, or in polar solvents such as nitrobenzene, or may be run neat in the presence of excess Lewis acid.
  • the reaction is typically carried out at a temperature of 25°C to about 120°C for a period of about 1 hour to 48 hours preferably, 1 hour to 6 hours.
  • X 1 is represented by OH
  • the reaction is typically carried out in the presence of a proton acid such as polyphosphoric acid or sulfuric acid.
  • a proton acid such as polyphosphoric acid or sulfuric acid.
  • reaction illustrated in Scheme A-2 can be carried out using triethylsilane in trifluoroacetic acid at a temperature from about rt to the reflux temperature of the solvent for a period of up to about 24 hours.
  • reaction may be carried out using borane-tert-butylamine in the presence of a Lewis acid such as aluminum chloride or by using borane- dimethylamine in the presence of a Lewis acid such as titanium tetrachloride in an inert solvent such as dichloromethane, chloroform, or nitrobenzene under temperatures described.
  • Inorganic salts such as a sodium or potassium halide (e.g., sodium iodide or potassium iodide) may be employed as catalysts in the reaction.
  • the temperature of the reaction may vary from ambient to reflux temperature of the solvent used, preferably from about 80°C to 120°C, for a period of about 1 hour to about 96 hours, preferably from about 12 hours to 48 hours.
  • This reaction is typically carried out at a temperature from about -78 °C to about the reflux temperature of the solvent, preferably from about -20 °C to about 50 °C, for a period of about 5 minutes to about 48 hours, preferably from about 0.5 to about 16 hours.
  • the reaction is typically quenched with methanol, water, or a dilute base such as sodium carbonate or sodium bicarbonate.
  • the reaction is quenched with methanol or 10% sodium carbonate and the complexes are broken up by heating the reaction mixture to a temperature from about 30 °C to about the reflux temperature of the solvent, preferably to about 90 °C, for about 0.5 to about 20 hours, preferably for about 2 hours.
  • This reaction may be carried out in an inert solvent such as methylene chloride, dichloromethane, dichloroethane, benzene, toluene, tetrahydrofuran, or pyridine, preferably methylene chloride.
  • This reaction is generally performed in the presence of organic base such as diisopropylethylamine, pyridine, or triethylamine, preferably triethylamine, or in the presence of a polymer supported base such as tris-(2- aminoethyl)amine polystyrene.
  • organic base such as diisopropylethylamine, pyridine, or triethylamine, preferably triethylamine, or in the presence of a polymer supported base such as tris-(2- aminoethyl)amine polystyrene.
  • This reaction is typically carried out at a temperature from about -78°C to about the reflux temperature of the solvent, preferably from about -20°C to about 50°C, for a period of about 5 minutes to about 48 hours, preferably from about 0.5 to about 16 hours.
  • the reaction is typically quenched with methanol, water, or a dilute base such as sodium carbonate or sodium bicarbonate.
  • the reaction is quenched with methanol or 10% sodium carbonate and the complexes are broken up by heating the reaction mixture to a temperature from about 30°C to about the reflux temperature of the solvent, preferably to about 90°C, for about 0.5 to about 20 hours, preferably for about 2 hours.
  • This reaction may be carried out in an inert solvent such as methylene chloride, dichloroethane, benzene, toluene, tetrahydrofuran, or pyridine, preferably methylene chloride.
  • This reaction is generally performed in the presence of organic base such as diisopropylethylamine, pyridine, or triethylamine, preferably triethylamine, or in the presence of a polymer supported base such as tris-(2-aminoethyl)amine polystyrene.
  • organic base such as diisopropylethylamine, pyridine, or triethylamine, preferably triethylamine, or in the presence of a polymer supported base such as tris-(2-aminoethyl)amine polystyrene.
  • the above scheme illustrates a method for preparing compounds of the formula 1 wherein A is -(CH 2 ) m CH 2 - by reacting a compound of the formula 9, as described in scheme B-2, with a compound of formula 5.
  • the reaction is typically run in the presence of a base such as potassium carbonate, sodium carbonate, triethylamine, or diisopropylethylamine.
  • the solvent used may be water, acetonitrile, dioxane, benzene, toluene, tetrahydrofuran, methyl isobutyl ketone, or a combination of two of the formerly mentioned solvents.
  • Inorganic salts such as a sodium or potassium halide (e.g., sodium iodide or potassium iodide) may be employed as catalysts in the reaction.
  • the temperature of the reaction may vary from ambient to reflux temperature of the solvent used, preferably from about 80°C to 120°C, for a period of about 1 hour to about 96 hours, preferably from about 12 hours to 48 hours.
  • This reaction is generally performed in the presence of organic base such as diisopropylethylamine, pyridine, or triethylamine, preferably triethylamine, or in the presence of a polymer supported base such as tris-(2-aminoethyl)amine polystyrene.
  • organic base such as diisopropylethylamine, pyridine, or triethylamine, preferably triethylamine, or in the presence of a polymer supported base such as tris-(2-aminoethyl)amine polystyrene.
  • X 1 CO(CH 2 )mQ X 1 is either a halogen or OH and Q is either a halogen, mesylate, or tosylate.
  • X 1 is represented by a halogen
  • the reaction is typically carried out in the presence of a Lewis acid such as aluminum bromide (AIBr 3 ), aluminum chloride (AICI 3 ), gallium trichloride (GaCI 3 ), ferric chloride (FeCI 3 ), zinc chloride (ZnCI 2 ), antimony pentachloride (SbCI 5 ), zirconium tetrachloride (ZrCI 4 ),tin tetrachloride (SnCI 4 ) , boron trichloride (BCI 3 ), boron trifluoride (BF 3 ), or antimony trichloride (SbCI 3 ).
  • a Lewis acid such as aluminum bromide (AIBr 3 ), aluminum chloride (AICI 3 ), gallium t
  • the reaction can be carried out in nonpolar solvents such as chloroform, dichloromethane, dichloroethane, or carbon disulfide, or in polar solvents such as nitrobenzene, or may be run neat in the presence of excess Lewis acid.
  • the reaction is typically carried out at a temperature of 25°C to about 120°C for a period of about 1 hour to 6 hours.
  • X is represented by OH
  • the reaction is typically carried out in the presence of a proton acid such as polyphosphoric acid or sulfuric acid.
  • the above scheme illustrates a method for preparing compounds of formula 13, by reacting a compound of the formula 12 with a compound of formula 5 ⁇ CL
  • the reaction is typically run in the presence of a base such as potassium carbonate, sodium carbonate, triethylamine, or diisopropylethylamine.
  • the solvent used may be water, acetonitrile, dioxane, benzene, toluene, tetrahydrofuran, methyl isobutyl ketone, or a combination of two of the formerly mentioned solvents.
  • Inorganic salts such as a sodium or potassium halide (e.g., sodium iodide or potassium iodide) may be employed as catalysts in the reaction.
  • the temperature of the reaction may vary from ambient to reflux temperature of the solvent used, preferably from about 80°C to 120°C, for a period of about 1 hour to about 96 hours, preferably from about 12 hours to 48 hours.
  • the above scheme illustrates a method for preparing compounds of the formula 15 by reacting compounds of the formula 14.
  • the reaction is typically run in the presence of a chlorinating reagent such as toluenesulfonyl chloride, methanesulfonyl chloride, carbon tetrachloride, or hydrogen chloride.
  • the solvent used may be methylene chloride, dichloroethane, toluene, tetrahydrofuran, chloroform, or a combination of two of the formerly mentioned solvents.
  • the temperature of the reaction may vary from -20°C to reflux temperature of the solvent used, preferably from about 0°C to ambient, for a period of about 1 hour to about 96 hours, preferably from about 2 hours to 12 hours.
  • the above scheme illustrates a method for preparing compounds of the formula 16 by reacting compounds of the formula 15.
  • the reaction is typically run in the presence of a reducing reagent such as trialkyltin hydride, or triaryltin hydride.
  • the reaction is typically run in the presence of a radical initiator such as 2,2- azobisisobutyronitrile or light.
  • the solvent used may be benzene, toluene, tetrahydrofuran, or a combination of two of the formerly mentioned solvents.
  • the temperature of the reaction may vary from 0°C to reflux temperature of the solvent used, preferably from about 40°C to reflux, for a period of about 1 hour to about 96 hours, preferably from about 1 hour to 4 hours.
  • the preparation of other compounds of the formula 1 not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art. In each of the reactions discussed or illustrated above, pressure is not critical unless otherwise indicated.
  • the compounds of the formula 1 , and the intermediates shown in the above reaction schemes can be isolated and purified by conventional procedures, such as recrystallization or chromatographic separation.
  • the compounds of the formula 1 and their pharmaceutically acceptable salts can be administered to mammals via either the oral, parenteral (such as subcutaneous, intraveneous, intramuscular, intrasternal and infusion techniques), rectal, buccal or intranasal routes.
  • these compounds are most desirably administered in doses ranging from about 3 mg to about 600 mg per day, in single or divided doses (i.e., from 1 to 4 doses per day), although variations will necessarily occur depending upon the species, weight and condition of the patient being treated, the patient's individual response to said medicament, the nature and severity of the particular disorder being treated, as well as on the type of pharmaceutical formulation chosen and the overall time period and intervals over which such administration is carried out.
  • a dosage level that is in the range of about 25 mg to about 100 mg per day is most desirably employed.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such higher dose levels are first divided into several small doses for administration throughout the day.
  • the compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes previously indicated, and such administration may be carried out in single or multiple doses.
  • the therapeutic agents of this invention can be administered in a wide variety of different dosage forms, L , they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, suppositories, jellies, gels, pastes, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the weight ratio of the compounds of this invention to the pharmaceutically acceptable carrier will be in the range from about 1 :6 to about 2:1 , and preferably from about 1 :4 to about 1:1.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • This invention relates to methods of treating anxiety, depression, schizophrenia and the other disorders referred to in the description of the methods of the present invention, wherein a compound of this invention and one or more of the other active agents referred to above (e.g., an NK1 receptor antagonist, tricyclic antidepressant, 5HT1 D receptor antagonist, or serotonin reuptake inhibitor) are administered together, as part of the same pharmaceutical composition, as well as to methods in which such active agents are administered separately as part of an appropriate dose regimen designed to obtain the benefits of the combination therapy.
  • the appropriate dose regimen, the amount of each dose of an active agent administered, and the specific intervals between doses of each active agent will depend upon the subject being treated, the specific active agent being administered and the nature and severity of the specific disorder or condition being treated.
  • the compounds of this invention when used as a single active agent or in combination with another active agent, will be administered to an adult human in an amount from about 3 mg to about 600 mg per day, in single or divided doses, preferably from about 25 to about 100 mg per day.
  • Such compounds may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day, especially 2 times per day and most especially once daily. Variations may nevertheless occur depending on the species, weight and condition of the patient being treated, the patient's individual response to said medicament, the nature and severity of the particular disorder being treated, as well as on the type of pharmaceutical formulation chosen and the overall time period and intervals over which such administration is carried out.
  • a proposed daily dose of a 5HT reuptake inhibitor, preferably sertraline, in the combination methods and compositions of this invention, for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above, is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the 5HT reuptake inhibitor per unit dose, which could be administered, for example, 1 to 4 times per day.
  • a proposed daily dose of a 5HT1 D receptor antagonist in the combination methods and compositions of this invention, for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above, is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the 5HT1 D receptor antagonist per unit dose, which could be administered, for example, 1 to 4 times per day.
  • the compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container 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.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • Formulations of the active compounds of this invention for treatment of the conditions referred to above in the average adult human are preferably prepared so that each metered dose or "puff" of aerosol contains 20 ⁇ g to 1000 ⁇ g of active compound.
  • the overall daily dose with an aerosol will be within the range 100 ⁇ g to 10 mg.
  • Administration may be several times daily, for example 2, 3,
  • the ability of the compounds of this invention to bind to the dopamine D2 and serotonin 2A (5HT2A) receptors can be determined using conventional radioligand receptor binding assays. All receptors can be heterologously expressed in cell lines and experiments conducted in membrane preparations from the cell lines using procedures outlined below. IC 50 concentrations can be determined by nonlinear regression of concentration-dependent reduction in specific binding. The Cheng- Prussoff equation can be used to convert the IC 50 to Ki concentrations.
  • Dopamine D2 Receptor Binding [ 3 H]Spiperone binding to a membrane preparation from CHO-hD2L cells is carried out in 250 ⁇ l of 50 mM Tris-HCI buffer containing 100 mM NaCI, 1 mM MgCI 2 and 1% DMSO at pH 7.4. Duplicate samples containing (in order of addition) the test compounds, 0.4 nM [ 3 H]spiperone and approximately 12 g protein are incubated for 120 minutes at rt. Bound radioligand is separated by rapid filtration under reduced pressure through Whatman GF/B glass fiber filters previously treated with 0.3% polyethyleneimine. Radioactivity retained on the filter is determined by liquid scintillation spectrophotometry. Certain of the title compounds of Examples 1-164 were tested using the above assay, in which specific binding determined in the presence of 1 mM haloperidol was 95%. The results of the testing are shown in Table A below.
  • Serotonin 2A Binding [ 3 H] Ketanserin binding to Swiss-h5HT2A cell membranes can be carried out in 250 ⁇ l of 50 mM Tris-HCI buffer pH 7.4. Duplicate samples containing (in order of addition) test compounds, 1.0 nM [ 3 H]ketanserin, and approximately 75 ⁇ g protein are incubated for 120 minutes at rt. Bound radioligand is separated by rapid filtration under reduced pressure through Whatman GF/B glass fiber filters previously treated with 0.3% polyethyleneimine. Radioactivity retained on the filter is determined by liquid scintillation spectrophotometry. Certain of the compounds of Examples 1-164 were tested using the above assay, in which specific binding determined in the presence of 1 mM ketanserin was 90%. The results of the testing are shown in Table A below.
  • the reaction was warmed to reflux for 1 hour.
  • the reaction was cooled and treated with a 10% aqueous solution of sodium carbonate (10 mL) and warmed to reflux for 20 hours.
  • the reaction was cooled and the layers were separated.
  • the aqueous layers were extracted with ethyl acetate (2 x 20 mL).
  • the combined organics were dried over magnesium sulfate, filtered and the filtrate concentrated.
  • the crude product was eluted through a flash column (silica gel 40, 230-400 mesh, methylene chloride
  • polystyrene-N-Methyl morpholine resin PS-N-Methylmorpholine resin
  • lsoxazole-4-fluoro-benzoyl chloride 0.40 mmol
  • Polyamine scavenging resin (0.5 mmol) was added. The solution was shaken overnight at rt, then filtered into an 8 mL vial. The filtrate was evaluated by MS, then concentrated via HT-12 GeneVac. Crude was purified by HPLC (30x100 mm ODS-A C(18) 5u column).
  • reaction mixture was then quenched carefully into 300 mL of iced water and extracted with 400 mL of CH 2 CI 2 .
  • the aqueous layer was extracted with an additional 200 mL CH 2 CI 2 , dried over MgSO 4 and concentrated in vacuo to give 11 g of a semi-solid.
  • This material was triturated with 200 mL of 1 :1 diethylether:hexanes and the resulting solid dried in vacuo to give 4.68 g (86 % yield) of the desired material as a pale yellow solid.
  • CDCIs ⁇ 7.89 (bs, 1 H), 7.81 (s, 1 H), 7.67 (s, 1 H), 4.65 (s, 2H), 2.52 (s, 2H), 2.32 (s, 3H), 1.36 (s, 6H).
  • sodium carbonate (1.158 g, 10.924 mmole, 1.25 eq)
  • EXAMPLE 54 f6-r2-(4-Benzord1isothiazol-3-yl-piperazin-1-yl)-ethvn-7-chloro-4.4.8-trimethyl- 3,4-dihvdro-2H-quinolin-1-yl)-cvclopropylmethanone
  • 6-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-7- chloro-4,4,8-trimethyl-1 ,2,3,4-tetrahydro-quinoline (0.4496g, 0.988 mmol) in THF (10 mL) under a nitrogen atmosphere was added cyclop ropanecarbonyl chloride (98.8 ⁇ L, 1.089 mmol).
  • the mixture was heated to reflux for 1 h, allowed to cool, and then made basic (pH 8) with solid sodium hydroxide (NaOH) and a 1 N NaOH solution.
  • the biphasic mixture was diluted with H 2 O (50 mL) and extracted with CH 2 CI 2 (3 x 50 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and the solvent was removed in vacuo.
  • PREPARATIONS 26A and 26B 7-f2-r4-(5-Fluoro-benzord1isothiazol-3-v ⁇ -piperazin-1-vn-ethylM .3.4.5- tetrahvdro-benzorblazepin-2-one (Prep. 26A)
  • EXAMPLE 56 1-(7-(2-r4-(5-Fluoro-benzord1isothiazol-3-yl)-piperazin-1-vn-ethyll-2.3.4.5- tetrahvdro-benzorb1azepin-1-yl)-ethanone: compound with methane sulfonic acid
  • step A Into a 1-L round- bottom flask was placed the tetralone from step A (8.94 g, 51.4 mmol), hydroxylamine hydrochloride (4.29 g, 61.7 mmol), sodium acetate (8.43 g, 103 mmol), and 50% aqueous ethanol (350 mL). The mixture was refluxed for 16 h, cooled to rt and made alkaline by the addition of 10% aqueous NaHCO 3 . The reaction was extracted with CH 2 CI 2 (3 x 100 mL) and the combined organic layers were dried over Na SO 4 and concentrated under vacuum to produce the title oxime (8.37 g, 84%) as an orange solid.
  • polyphosphoric acid 90 g
  • the reaction was heated to 125°C, the title compound from step B (8.37 g, 44.3 mmol) was added in one portion, and the reaction was stirred for 5 min.
  • the mixture was poured into ice water (300 mL), stirred until the polyphosphoric acid was dissolved and extracted with CH 2 CI 2 (3 x 100 mL).
  • step D Into a 100-mL round-bottom-flask was placed the ketone from step D (2.23 g, 8.4 mmol) and TFA (16 mL). The solution was cooled to 0°C and triethylsilane (4.07 mL, 25.2 mmol) was added dropwise over a 5 min period. The reaction was warmed to 50°C and stirred for 15 h. The mixture was cooled to rt, diluted with H 2 O (100 mL) and extracted with ethyl acetate (3 x 50 mL).
  • the residue was purified by column chromatography (silica gel (100 g), eluting with 800 mL of 10% EtOAc/hexanes to remove the triethylsilane (Et 3 SiH) (collected as a single fraction), then eluting with 1.5 L of 40% EtOAc/hexanes to elute the product) to give the title compound (1.93 g, 40%) as an off-white amorphous solid. Due to the low mass recovery, the initial column wash was examined and determined to contain more of the product. The initial column wash was concentrated in vacuo to give a mixture of solid and liquid. The liquid was decanted, and the solid washed and decanted twice with hexanes.
  • Acetic anhydride (1.0 mL, 11 mmol) was added to a stirred solution from step B (918 mg, 3.56 mmol) and EtsN (1.5 mL, 11 mmol) in anhyd CH 2 CI 2 (10 mL) under N 2 .
  • Methanesulfonyl chloride (0.80 mL, 10 mmol) was added to a stirred solution of the title compound of Example 69 (2.92 g crude, 6.35 mmol theoretical) and triethylamine (2.0 mL, 14 mmol) in anhydrous CH 2 CI 2 (200 mL) at 0°C under N 2 . After stirring for 10 min, the ice-water bath was removed. After stirring for 2 h, TLC analysis indicated that no starting material was remaining.
  • EXAMPLE 72 1 - ⁇ 5-r2-(4-Benzorcnisoxazol-3-ylpiperazin-1 -yl VI -chloroethyll-l .3- dihvdroisoindol-2-yllethanone
  • Methanesulfonyl chloride (0.17 g, 1.50 mmol) was added slowly. The reaction mixture was warmed to rt and stirred for 2 h, 50 mL of CH 2 CI 2 was added. The solution was washed with water, dried over sodium sulphate and concentrated. The crude residue was subjected to chromatography (MeOH/CH 2 CI 2 , 2/98) to provide the title compound (0.32 g, 58 %) as a light yellow oil, which was treated with 5 mL of 2 M solution of hydrogen chloride in ether to provide the title compound as hydrochloride salt, mp 179 °C (dec).
  • step F A stirred solution of the product of step F (2.74 g, 6.21 mmol) and Bu 3 SnH (2.5 mL, 9.3 mmol) in anhyrous toluene (170 mL) was degassed by bubbling argon through the solution for 30 min.
  • AIBN (0.15 g, 0.91 mmol) was added and the flask was heated with a preheated 80 °C oil bath for 1 h. After allowing to cool, H 2 O (10 mL) was added. After stirring for 20 min, the solvents were removed in vacuo.
  • step G The product of step G (6.6 g, 1.60 mmol) was dissolved in 630 mL of EtOH and 630 mL of cone. HCl and refluxed for 77 h. After reaction, the solvent was removed to afford 3- ⁇ 4-[3-(2,3-Dihydro-1 H-isoindol-5-yl)-propyl]-piperazin-1 -yl ⁇ - benzo[d]isothiazole (7.4 g) as a light brown solid. MS m/z 379 [M+1].
  • Acetic anhydride (0.62 mL, 6.6 mmol) was added to a solution containing 3- ⁇ 4-[2- (2,3-Dihydro-1 H-isoindol-5-yl)-propyl] ⁇ piperazin-1 -yl ⁇ -benzo[d]isothiazole (1.0 g, 2.6 mmol), triethylamine (1.62 mL, 11.6 mmol), 4-dimethylamino- pyridine (0.08 g, 0.65 mmol), and anhydrous dichloromethane (40 mL) at rt.
  • Step B Lithium hydroxide monohydrate (0.1 g, 2.4 mmol) was added to a solution containing ⁇ 5-[3-(4-Benzo[d]isothiazol-3-yl-piperazin-1 -yl)-propyl]-1 ,3-dihydro-isoindol-2-yl ⁇ - acetic acid methyl ester (0.6 g, 1.3 mmol), tetrahydrofuran (30 L), and water (4 mL), and stirred overnight. The solution was evaporated to dryness and the residue was dissolved in 3 L of water, and pH was adjusted to 6 using 1 M HCl.
  • the resulting suspension was diluted with 100 mL of chloroform, washed with brine, dried over Na 2 SO 4 , and evaporated.
  • the residue thus obtained was purified over silica gel column (230 - 400 mesh, 2.5 x 14 cm), using ethyl acetate:methanol:acetic acid (88:10:2) solvent mixture as eluent to obtain the title compound.
  • the product was dissolved in 20 mL of anhydrous ethyl acetate and to which was added 1 M hydrogen chloride solution in ether (5.0 mL, 5 mmol) with stirring. A white precipitate of hydrogen chloride salt was obtained, which was filtered off, washed with ether (2 x
  • EXAMPLE 88 1 - ⁇ 5-r3-(4-Benzord1isothiazol-3-yl-piperazin-1 -yl)-propyl1-1 ,3-dihydro-isoindol-2- yl)-2-r(2-dimethylamino-ethyl)-methyl-amino1-ethanone
  • Methanesulfonylchloride (0.16 mL, 2.2 mmol) was added to a solution containing 3- ⁇ 4-[2-(2,3-Dihydro-1 H-isoindol-5-yl)-propyl]-piperazin-1 -yl ⁇ -benzo[d]isothiazole (0.8 g, 1.8 mmol), triethylamine (4.0 mL, 28.7 mmol) and anhydrous chloroform (50 mL) at
  • Benzenesulfonylchloride (0.14 mL, 1.06 mmol) was added to a solution containing 3- ⁇ 4-[2-(2,3-Dihydro-1 H-isoindol-5-yl)-propyl]-piperazin-1-yl ⁇ -benzo[d]isothiazole (0.4 g, 0.88 mmol), triethylamine (0.43 mL, 3.1 mmol) and anhydrous dichloromethane (40 mL) at 5 °C. After 2 h stirring at rt, the reaction mixture was evaporated to obtain a residue, which was washed with hexane (3 x 10 mL), and dried.
  • Benzoic anhydride (0.50 g, 2.2 mmol) was added to a solution containing 3- ⁇ 4-[2- (2,3-dihydro-1 H-isoindol-5-yl)-propyl]-piperazin-1 -yl ⁇ -benzo[d]isothiazole (0.4 g, 0.88 mmol), triethylamine (0.43 mL, 3.1 mmol), 4-dimethyl-aminopyridine (0.001 g, 0.008 mmol), and anhydrous dichloromethane (40 mL) at rt. The reaction mixture was stirred overnight at rt. The resulting solution was washed with NaHCO 3 , dried over Na 2 SO , and evaporated. The residue thus obtained was purified over silica gel column (230 - 400 mesh, 2.5 x 12 cm), using ethyl acetate:methanol solvent mixture
  • Triethylsilane (7.0 mL, 44 mmol) was added portionwise over 10 min to a stirred solution of the product of Step C (5.03 g, 15.2 mmol) in trifluoroacetic acid (20 mL) under N 2 . The mixture was heated to 50 °C for 17 h, then allowed to cool. The mixture (a dark brown solution) was poured into a stirred mixture of 1 M NaOH (300 mL) and ice (100 mL).
  • the two-phase mixture was stirred for 1 h, during which time the dark oil turned into a brown solid.
  • the mixture was extracted with EtOAc (200 mL), which dissolved the brown solid.
  • the organic phase was washed with H 2 O (200 mL) and saturated NaCI (100 mL), dried over Na 2 SO , filtered, and the solvent was removed in vacuo.
  • the mixture was diluted with EtOAc (300 mL), then washed twice with H 2 O (300 mL).
  • the organic phase was diluted with more EtOAc (200 mL) to dissolve some solid particles, then washed with saturated NaCI (100 mL), dried over Na 2 SO , filtered, and the solvent was removed in vacuo.
  • the residue was dissolved in hot 10% MeOH/EtOAc (220 mL), then allowed to cool with stirring. After stirring for 4 h, no precipitate had formed.
  • the mixture was diluted portionwise with hexanes (200 mL) over the next 2 h to promote precipitation of the product.
  • PREPARATION 46 1 -(4-Fluoro-2.3-dihvdro-indol-1 -yl)-ethanone
  • a 10 mL flask equipped with a magnetic stir bar was charged with 4-fluoro- 1 H-indole (1.0g, 7.4 mmol).
  • the solid was dissolved in glacial acetic acid (10mL).
  • Sodium cyanoborohydride (932 mg, 14.8 mmol) was added portion-wise, and the reaction stirred at ambient temperature while being monitored by TLC. After 72 hours, the reaction was quenched by drop-wise addition of H 2 O and the pH was adjusted to ⁇ 8 with 1 N NaOH.
  • the aqueous layer was extracted with CH 2 CI 2 (3x).
  • the flask was fitted with a nitrogen bubbler, purged with nitrogen gas and cooled to 0 °C in an ice water bath. Chloro-acetyl chloride (242 ⁇ L, 3.0 mmol) was added drop-wise to the stirring solution, and the reaction was allowed to gradually warm to ambient temperature. The reaction stirred at rt for two hours, and was then fitted with a condenser and heated to reflux. After an additional two hours, an additional 1.5 equivalents of AICI (400 mg) were added and the reaction stirred overnight at reflux. When all starting material had disappeared by TLC, the reaction was quenched by drop-wise addition of H 2 O. The contents of the flask were extracted with CH 2 CI (3x) and the combined organic extracts were dried over MgSO , filtered, and concentrated in vacuo to yield 368 mg of a brown solid that was shown to be the desired product (66%).
  • the combined organic extracts were dried over MgSO 4 , filtered, and concentrated in vacuo to yield 367 mg of a crude brown solid.
  • the solid was purified on a column of silica gel (15g) using a slow elution gradient of CH 2 CI 2 to 100:8:1 CH 2 CI 2 :ethanol:NH OH over the course of an hour.
  • the isolated brown solid weighed 148 mg (73%).
  • EXAMPLE 100 1-f5-r2-(4-Benzord1isothiazol-3-yl-piperazin-1-yl)-ethvn-4-fluoro-2.3-dihvdro- indol-1 -v -ethanone 1- ⁇ 5-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-4-fluoro-2,3-dihydro- indol-1-yl ⁇ -ethanone was prepared in a similar fashion as decribed above in Example 99 starting with 1-[5-(2-chloro-ethyl)-4-fluoro-2,3-dihydro-indol-1-yl]-ethanone and 3- piperazin-1-yl-benzo[d]isothiazole.
  • Example 99 starting with 1-[5-(2-chIoro-ethyl)-4-fluoro-2,3-dihydro-indol-1-yl]- ethanone and 5-fluoro-3-piperazin-1-yl-benzo[d]isoxazole. Yield: 50 mg (40%), Isolated in 100% purity @ 254 nm; LCMS (APCI) 427.1 [M+H] + .
  • PREPARATION 49 1 -(4-Chloro-2,3-dihydro-indol-1 -yl)-ethanone 1-(4-Chloro-2,3-dihydro-indol-1-yl)-ethanone was prepared in a similar fashion as decribed above in Preparation 46 for 1-(4-fluoro-2,3-dihydro-indol-1-yl)-ethanone starting with 4-chloroindole yield: 923 mg (71%).
  • PREPARATION 52 1 -(6-Fluoro-2.3-dihvdro-indol-1 -yl)-ethanone 1-(6-Fluoro-2,3-dihydro-indol-1-yl)-ethanone was prepared in a similar fashion as decribed above in Preparation 46 for 1-(4-fluoro-2,3-dihydro-indol-1-yl)-ethanone starting with 6-fluoroindole yield: 1.85 g (70%).
  • PREPARATION 53 1 -(1 -Acetyl-6-f luoro-2.3-dihvdro-1 H-indol-5-yl)-2-chloro-ethanone 1 -(1 -Acetyl-6-fluoro-2,3-dihydro-1 H-indol-5-yl)-2-chloro-ethanone was prepared in a similar fashion as decribed above in Preparation 47 for 1 -(1 -acetyl-4- fluoro-2,3-dihydro-1 H-indol-5-yl)-2-chloro-ethanone starting with 1 -(6-fluoro-2,3- dihydro-indol-1-yl)-ethanone yield: 665 mg (52%).
  • EXAMPLE 105 1-f5-r2-(4-Benzord1isoxazol-3-yl-piperazin-1-yl)-ethvn-6-fluoro-2,3-dihvdro- indol-1 -yl)-ethanone 1- ⁇ 5-[2-(4-Benzo[d]isoxazol-3-yl-piperazin-1-yl)-ethyl]-6-fluoro-2,3-dihydro- indol-1-yl ⁇ -ethanone was prepared in a similar fashion as decribed above in Example 99 starting with 1 -[5-(2-chloro-ethyl)-6-fluoro-2,3-dihydro-indol-1-yl]-ethanone and 3- piperazin-1-yl-benzo[d]isoxazole.
  • EXAMPLE 106 1-(6-Chloro-5-f2-r4-(6-fluoro-benzord1isothiazol-3-yl)-piperazin-1-vn-ethylV2.3- dihvdro-indol-1 -yl)-ethanone 1-(6-Chloro-5- ⁇ 2-[4-(6-fluoro-benzo[d]isothiazol-3-yl)-piperazin-1-yl]-ethyl ⁇ -2,3- dihydro-indol-1-yl)-ethanone was prepared in a similar fashion as decribed above in Example 99 starting with 1-[6-chloro-5-(2-chloro-ethyl)-2,3-dihydro-indol-1-yl]- ethanone and 6-fluoro-3-piperazin-1-yl-benzo[d]isothiazole.
  • PREPARATION 58 1 -(2,3-Dihvdro-indol-1 -yl)-ethanone
  • indoline commercially available from Aldrich Chemical company
  • THF 200mL
  • triethyl amine 15.33 mL, 0.11 mol
  • acetyl chloride 7.82 mL, 0.11 mol
  • the reaction was stirred at room temperature for 20 hours, quenched with water (50 mL) followed by concentration in vacuo. White solid was collected and washed with water. Yield: 15.7 g (97.5%).
  • PREPARATION 59 1 -(1 -Acetyl-2,3-dihydro-1 H-indol-5-yl)-2-chloro-ethanone 1-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-2-chloro-ethanone was prepared in a similar fashion as decribed above in Preparation 47 starting with 1-(2,3-dihydro- indol-1-yl)-ethanone] yield: 11.85 g (100%).

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Abstract

L'invention concerne des composés représentés par la formule 1, dans laquelle R1, R2, R7, R8, R9, U, V, Z, A, W, X, M, E, L, T et D sont tels que définis dans la spécification, des compositions pharmaceutiques contenant ces composés et leur utilisation dans le traitement, entre autres, de maladies du système nerveux central.
EP04806416A 2003-12-31 2004-12-20 Derives de piperidine et de piperazine n-substitues Withdrawn EP1701954A1 (fr)

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WO2008020306A2 (fr) * 2006-08-18 2008-02-21 Pfizer Products Inc. Dérivés d'isoindole
US20080186971A1 (en) * 2007-02-02 2008-08-07 Tarari, Inc. Systems and methods for processing access control lists (acls) in network switches using regular expression matching logic
US8686009B2 (en) 2009-06-25 2014-04-01 Alkermes Pharma Ireland Limited Prodrugs of NH-acidic compounds
LT2445502T (lt) 2009-06-25 2017-09-25 Alkermes Pharma Ireland Limited Heterocikliniai junginiai, skirti neurologinių ir fiziologinių susirgimų gydymui
KR101756495B1 (ko) * 2010-03-11 2017-07-10 다이닛본 스미토모 세이야꾸 가부시끼가이샤 Ｎ-아실 시클릭 아민 유도체 또는 이의 의약상 허용되는 염
AU2011270701B2 (en) 2010-06-24 2015-05-14 Alkermes Pharma Ireland Limited Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives
CA2830511C (fr) 2011-03-18 2021-09-14 Alkermes Pharma Ireland Limited Compositions pharmaceutiques refermant de l'aripiprazole lauroxil et du sorbitan laurate
JP5715605B2 (ja) * 2011-09-14 2015-05-07 大日本住友製薬株式会社 Ｎ−アシル環状アミン誘導体またはその医薬上許容される塩からなる医薬
NZ722096A (en) 2011-12-15 2016-11-25 Alkermes Pharma Ireland Ltd Prodrugs of secondary amine compounds
CA2867121C (fr) 2012-03-19 2021-05-25 Alkermes Pharma Ireland Limited Compositions pharmaceutiques comprenant des esters d'acides gras
US9999670B2 (en) 2012-03-19 2018-06-19 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising benzyl alcohol
US9993556B2 (en) 2012-03-19 2018-06-12 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising fatty glycerol esters
EP3718536A1 (fr) 2012-09-19 2020-10-07 Alkermes Pharma Ireland Limited Compositions pharmaceutiques présentant une stabilité améliorée au stockage
WO2015074064A2 (fr) 2013-11-18 2015-05-21 Bair Kenneth W Compositions de tétrahydroquinoline utilisées comme inhibiteurs de protéines à bromodomaine et domaine extraterminal (bet)
EP3071205B1 (fr) 2013-11-18 2020-02-05 Forma Therapeutics, Inc. Compositions de benzopipérazine en tant qu'inhibiteurs de bromodomaines bet
MA39495A (fr) 2014-03-20 2015-09-24 Alkermes Pharma Ireland Ltd Formulations d'aripiprazole présentant des vitesses d'injection plus élevées
EP3761983A1 (fr) 2018-03-05 2021-01-13 Alkermes Pharma Ireland Limited Stratégie de dosage d'aripiprazole
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