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WO2006051410A1 - Azabenzoxazoles pour le traitement de troubles du systeme nerveux central - Google Patents

Azabenzoxazoles pour le traitement de troubles du systeme nerveux central Download PDF

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Publication number
WO2006051410A1
WO2006051410A1 PCT/IB2005/003394 IB2005003394W WO2006051410A1 WO 2006051410 A1 WO2006051410 A1 WO 2006051410A1 IB 2005003394 W IB2005003394 W IB 2005003394W WO 2006051410 A1 WO2006051410 A1 WO 2006051410A1
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Prior art keywords
pyridine
diazabicyclo
compound
oct
oxazolo
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PCT/IB2005/003394
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English (en)
Inventor
Andrei V. Belyankin
Allen Jacob Duplantier
Lei Zhang
Christopher John O'donnell
Bruce Nelsen Rogers
Lawrence Albert Vincent
Sergey I. Sviridov
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Pfizer Inc.
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Publication of WO2006051410A1 publication Critical patent/WO2006051410A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P25/28—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
    • 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
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention relates to ⁇ 7 nicotinic receptor agonists and to a method for treating disorders of the Central Nervous System (CNS) and other disorders in a mammal, including a human, by administering to the mammal an ct7 nicotinic receptor agonist. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and a
  • Nicotinic acetylcholine receptors play a large role in central nervous system (CNS) activity and in different tissue throughout the body. They are known to be involved in functions, including, but not limited to, cognition, learning, mood, emotion, and neuroprotection. There are several types of nicotinic acetylcholine receptors, and each one appears to have a different role. Some nicotinic receptors regulate CNS function, including, but not limited to, attention, learning and memory; some regulate pain, inflammation, cancer, and diabetes by controlling tumor necrosis factor alpha (TNF- ⁇ ). Nicotine affects all such receptors, and has a variety of activities. Unfortunately, not all of the activities are desirable. In fact, undesirable properties of nicotine include its addictive nature and the low ratio between efficacy and safety.
  • Schizophrenia is a complex multifactorial illness caused by genetic and non- genetic risk factors that produce a wide variety of symptoms. Historically, the disease has been characterized by positive and negative symptoms. The positive symptoms include delusions and hallucinations and the negative symptoms include apathy, withdrawal, lack of motivation and pleasure. More recently, deficits in affect, attention, cognition and information processing have been recognized as key pathologies in this complex disorder. No single biological element has emerged as a dominant pathogenic factor in this disease. Indeed, it is likely that schizophrenia is a syndrome that is produced by the combination of many low penetrance risk factors. Pharmacological studies established that dopamine receptor antagonists are efficacious in treating the overt psychotic features (positive symptoms) of schizophrenia such as hallucinations and delusions.
  • Clozapine an "atypical" antipsychotic drug, is novel because it is effective in treating not only the positive symptoms, but also negative, and to some extent the cognitive symptoms of this disease. Clozapine's utility as a drug is greatly limited because continued use leads to an increased risk of agranulocytosis and seizure. No other antipsychotic drug is effective in treating the cognitive symptoms of schizophrenia. This is significant because the restoration of cognitive functioning is the best predictor of a successful clinical and functional outcome of schizophrenic patients (Green, M. F., Am J. Psychiatry, 153:321- 30, 1996).
  • One aspect of the cognitive deficit of schizophrenia can be measured by using the auditory event-related potential (P50) test of sensory gating.
  • P50 auditory event-related potential
  • EEG electroencepholographic
  • Normal individuals respond to the first click with greater degree than to the second click.
  • schizophrenics and schizotypal patients respond to both clicks nearly the same (Cullum, CM.
  • schizophrenics express the same ⁇ 7 nAChR as non-schizophrenics.
  • Selective ⁇ 7 nAChR agonists may be found using a functional assay on FLIPR (see WO 00/73431). FLlPR is designed to read the fluorescent signal from each well of a 96 or 384 well plate as fast as twice a second for up to 30 minutes.
  • This assay may be used to accurately measure the functional pharmacology of ⁇ 7 nAChR.
  • To conduct such an assay one uses cell lines that express functional forms of the cc7 nAChR using the ⁇ 7/5-HT 3 channel as the drug target and cell lines that express functional 5HT 3 R. In both cases, the ligand-gated ion channel was expressed in SH-EP1 cells. Both ion channels can produce robust signal in the FLIPR assay.
  • compositions comprising an ⁇ 7 nicotinic receptor agonist and an antipsychotic drug are described in US Published App. 2003/045540, which is incorporated by reference herein in its entirety.
  • compositions of the present invention that contain an cc7 nicotinic receptor agonist are useful for the treatment of cognitive deficits or impairments in schizophrenia and in Alzheimer's Disease.
  • This invention relates to a compound of the formula Ia or Ib
  • each R 9 and R 10 is independently selected from H 1 (C ⁇ C B )alkyl, (C 2 -C 8 )alkenyl,
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and f-butyl.
  • alkoxy as used herein, unless otherwise indicated, includes an O-alkyl radical, wherein “alkyl” is defined herein.
  • alkenyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.
  • alkynyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above.
  • alkynyl groups include, but are not limited to, ethynyl and 2-propynyl.
  • alkylene includes saturated divalent hydrocarbon radicals having straight or branched moieties.
  • alkyl groups include, but are not limited to, -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -, and -CH 2 - C(CH 3 ),-.
  • cycloalkyl as used herein, unless otherwise indicated, includes non- aromatic saturated cyclic alkyl moieties wherein alkyl is as defined above.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • "Bicycloalkyl” groups are non-aromatic saturated carbocyclic groups consisting of two rings. Examples of bicycloalkyl groups include, but are not limited to, bicyclo-[2.2.2]-octyl and norbornyl.
  • cycloalkenyl and “bicycloalkenyl” refer to non- aromatic carbocyclic cycloalkyl and bicycloalkyl moieties as defined above, except comprising of one or more carbon-carbon double bonds connecting carbon ring members (an “endocyclic” double bond) and/or one or more carbon-carbon double bonds connecting a carbon ring member and an adjacent non-ring carbon (an “exocyclic” double bond).
  • cycloalkenyl groups include, but are not limited to, cyclopentenyl and cyclohexenyl.
  • a non-limiting example of a bicycloalkenyl group is norborenyl.
  • Cycloalkyl, cycloalkenyl, bicycloalkyl, and bicycloalkenyl groups also include groups similar to those described above for each of these respective categories, but which are substituted with one or more oxo moieties.
  • groups with oxo moieties include, but are not limited to oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl, and norcamphoryl.
  • aryl as used herein, unless otherwise indicated, includes an organic radical derivedifrom an aromatic hydrocarbon by removal of one hydrogen atom. Examples of aryl groups include, but are not limited to phenyl and naphthyl.
  • aryloxy as used herein, unless otherwise indicated, includes an O-aryl radical, wherein “aryl” is defined herein.
  • heterocyclic and heterocycloalkyl refer to non-aromatic cyclic groups containing one or more heteroatoms, preferably from one to four heteroatoms, each selected from O, S and N.
  • heterocycloalkyl groups are non-aromatic two-ringed cyclic groups, wherein at least one of the rings contains a heteroatom (O, S, or N).
  • the heterocyclic groups of this invention can also include ring systems substituted with one or more oxo moieties.
  • non-aromatic heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1 ,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imida
  • heteroaryl refers to aromatic groups containing one or more heteroatoms (O, S, or N).
  • a multicyclic group containing one or more heteroatoms wherein at least one ring of the group is aromatic is a "heteroaryl” group.
  • the heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
  • heteroaryl, heterocyclic and heterocycloalkyl groups may be C-attached or N-attached (where such is possible).
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • Examples of specific compounds of this invention are the following compounds and their pharmaceutically acceptable salts, hydrates, solvates and optical and other stereoisomers: (R)-(-)- 2-(1,4-diazabicyclo[3.2.1]oct-4-yl)[1,3]oxozolo[4,5-b]pyridine, (R)-(-)-6-chloro-
  • Examples of specific compounds of this invention also include the following compounds and their pharmaceutically acceptable salts, hydrates, solvates and optical and other stereoisomers: (S)-(+)-2-(1 ,4-diazabicyclo[3.2.1]oct-4-yl)[1 ,3]oxozolo[5,4-b]pyridine, (S)-(+)-6-chloro-
  • substituents refers to from one to the maximum number of substituents possible based on the number of available bonding sites.
  • treatment refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such condition or disorder.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • Compounds of formula Ia or Ib may contain chiral centers and therefore may exist in different enantiomeric and diastereomeric forms. Individual isomers can be obtained by known methods, such as resolution, stereoselective reaction, or chromatographic separation in the preparation of the final product or its intermediate. This invention relates to all optical isomers and all stereoisomers of compounds of the formula Ia or Ib , both as racemic mixtures and as individual enantiomers and diastereoismers of such compounds, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment defined above that contain or employ them, respectively.
  • the compounds of formula Ia or Ib of this invention are basic compounds, they are all capable of forming a wide variety of different salts with various inorganic and organic acids. Although 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, Le 1 , salts containing pharmaceutically acceptable anions, such as the chloride, bromide, iodide, 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.
  • pharmaceutically acceptable anions such as the chloride, bromide, iodide, nitrate, sulfate or bis
  • the present invention also includes isotopically labelled compounds, which are identical to those recited in formula Ia or Ib , 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 0, 31 P, 32 P, 35 S, 18 F, and 38 CI, respectively.
  • Isotopically labelled compounds of formula Ia or Ib of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula Ia or Ib , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also relates to a pharmaceutical composition for the treatment of schizophrenia in a mammal, including a human, comprising an amount of a compound of the formula Ia or Ib , or a pharmaceutically acceptable salt thereof, that is effective in treating schizophrenia and a pharmaceutically acceptable carrier.
  • the present invention also relates to a method for treating schizophrenia in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula Ia or Ib , or a pharmaceutically acceptable salt thereof, that is effective in treating schizophrenia.
  • the present invention also relates to a pharmaceutical composition for the treatment of schizophrenia in a mammal, including a human, comprising an ⁇ x7 nicotinic receptor agonizing amount of a compound according to formula Ia or Ib and a pharmaceutically acceptable carrier.
  • the present invention also relates to a method for treating schizophrenia in a mammal, including a human, comprising administering to said mammal an ⁇ 7 nicotinic receptor agonizing amount of a compound of the of formula Ia or Ib , or a pharmaceutically acceptable salt thereof.
  • This invention provides a method of treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of Formula Ia or
  • deficiency in attention and/or cognition refers to a subnormal functioning in one or more cognitive aspects such as memory, intellect, or learning and logic ability, in a particular individual relative to other individuals within the same general age population.
  • Deficiency in attention and/or cognition also refers to a reduction in any particular individual's functioning in one or more cognitive aspects.
  • This invention further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof effective in treating said disorder or condition.
  • a "neurodegenerative disorder or condition” refers to a disorder or condition that is caused by the dysfunction and/or death of neurons in the central nervous system.
  • the treatment of these disorders and conditions can be facilitated by administration of an agent which prevents the dysfunction or death of neurons at risk in these disorders or conditions and/or enhances the function of damaged or healthy neurons in such a way as to compensate for the loss of function caused by the dysfunction or death of at-risk neurons.
  • a neurodegenerative disorder that can be treated according to the present invention includes, but is not limited to, Alzheimer's Disease.
  • the compounds of Formula Ia or Ib are useful to treat, or are useful to make a medicament to treat, a condition in a mammal that may be treated by administration of an ⁇ 7 nicotinic acetylcholine receptor agonist.
  • the compounds of Formula Ia or Ib are useful to treat, or are useful to make a medicament to treat, a mammal where the mammal receives symptomatic relief from activation of an ⁇ 7 nicotinic acetylcholine receptor agonist.
  • the present invention also relates to a pharmaceutical composition for treating a disorder or condition selected from cognitive and attention deficit symptoms of Alzheimer's, neurodegeneration associated with diseases such as Alzheimer's disease, pre ⁇ senile dementia (mild cognitive impairment), senile dementia, schizophrenia or psychosis including the cognitive deficits associated therewith, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson's disease, tardive dyskinesia, Pick's disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependent drug cessation, Tourette's syndrome, glaucoma, neurodegeneration associated with glaucoma, symptoms
  • a condition that is preferred for treatment is attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson's disease, tardive dyskinesia, Pick's disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependent drug cessation, Gilles de Ia Tourette's Syndrome, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.
  • the present invention also relates to a pharmaceutical composition for treating male infertility.
  • the present invention also relates to a pharmaceutical composition for treating inflammation, for example, postoperative ileus.
  • the present invention also relates to a method for treating a disorder or condition listed, comprising administering to a mammal in need of such treatment an amount of a compound of the formula Ia or Ib, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.
  • the present invention also relates to a pharmaceutical composition, which may be a composition for treating a disorder or condition listed in the previous paragraphs, comprising an ⁇ 7 nicotinic receptor agonizing amount of a compound of the formula Ia or Ib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also relates to a method for treating a disorder or condition listed in the previous paragraphs, comprising administering to a mammal in need of such treatment an ⁇ 7 nicotinic receptor agonizing amount of a compound of the formula Ia or Ib, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a method for treating a disease or condition in a mammal in need thereof, wherein the mammal receives symptomatic relief from activation of an ⁇ 7 nicotinic acetylcholine receptor, comprising administering to a mammal in need of such treatment a compound of the formula Ia or Ib, or a pharmaceutically acceptable salt thereof.
  • the disease or condition may be, for example, cognitive and attention deficit symptoms of Alzheimer's, neurodegeneration associated with diseases such as Alzheimer's disease, pre ⁇ senile dementia (mild cognitive impairment), or senile dementia.
  • the disease or condition may also be, for example, schizophrenia or psychosis and related cognitive deficits associated therewith.
  • the disease or condition may also be, for example, attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson's disease, tardive dyskinesia, Pick's disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependent drug cessation, Gilles de Ia Tourette's Syndrome, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.
  • attention deficit disorder attention deficit hyperactivity disorder
  • mood and affective disorders amyotrophic lateral sclerosis
  • borderline personality disorder traumatic brain injury
  • behavioral and cognitive problems associated with brain tumors AIDS dementia complex
  • dementia associated with Down's syndrome
  • the present invention also relates to a method for treating male infertility in a mammal in need thereof comprising administering to the mammal a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a method for treating inflammation such as postoperative ileus, in a mammal in need thereof comprising administering to the mammal a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a pharmaceutical composition comprising a compound of the formula Ia or Ib 1 or a pharmaceutically acceptable salt thereof, and an antipsychotic drug or pharmaceutically acceptable salt thereof.
  • the present invention also relates to a method of treating a mammal suffering from schizophrenia or psychosis, comprising administering a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating schizophrenia, and an antipsychotic drug or pharmaceutically acceptable salt thereof.
  • the compound of formula Ia or Ib and the antipsychotic drug may be administered together or separately.
  • the compound of formula Ia or Ib and the antipsychotic drug may be administered simultaneously or at separate intervals.
  • the compound of formula Ia or Ib and the antipsychotic drug may be incorporated into a single pharmaceutical composition.
  • two separate compositions i.e., one containing a compound of formula Ia or Ib and the other containing an antipsychotic drug, may be administered simultaneously.
  • the antipsychotic drug may be, for example, Chlorpromazine, Fluphenazine, Haloperidol, Loxapine, Mesoridazine, Molindone, Perphenazine, Pimozide, Thioridazine, Thiothixene, or Trifluoperazine. These drugs all have an affinity for the dopamine 2 receptor.
  • the antipsychotic drug may also be, for example, Asenapine, Ziprasidone, Olanzapine, Clozapine, Risperidone, Sertindole, Quetiapine, Aripiprazole or Amisulpride.
  • Certain combinations of this invention include at least two active components: an atypical antipsychotic, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of said prodrug, and a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof.
  • the combinations of this invention also include a pharmaceutically acceptable vehicle, carrier or diluent.
  • the combinations may result in synergistic action allowing a lower dose of the atypical antipsychotic to be administered while achieving at least the same psychotropic effect as achieved with a standard dose of the atypical antipsychotic.
  • the dosage of the atypical antipsychotic may be reduced by about 25-90%, for example, about 40-80% and typically about 50-70%.
  • the reduction in amount of antipsychotic required will be dependent on the amount of the compound of Formula Ia or Ib given.
  • the selection of the dosage of each therapeutic agent is that which can provide relief to the patient as measured by a reduction or amelioration of symptoms associated with the disorder or condition of the patient.
  • the dosage of each component depends on several factors such as the potency of the selected specific compound, the mode of administration, the age and weight of the patient, the severity of the condition to be treated, and the like. Determining a dose is within the skill of the ordinary artisan. To the extent necessary for completeness, the synthesis of the components of the compositions and dosages are as described in the listed patents above or the Physicians' Desk Reference, 57th ed., Thompson, 2003 which are expressly incorporated herein by reference. Desirably, when ziprasidone is selected as the active agent, the daily dose contains from about 5 mg to about 460 mg.
  • each dose of the first component contains about 20 mg to about 320 mg of the ziprasidone, and even more preferably, each dose contains from about 20 mg to about 160 mg of ziprasidone.
  • Pediatric dosages may be less such as for example in the range of about 0.5 mg to about 40 mg daily. This dosage form permits the full daily dosage to be administered in one or two oral doses, for example.
  • Olanzapine from about 0.25 to about 100 mg, once/day; preferably, from about 1 to about 30 mg, once/day; and most preferably about 1 to about 25 mg once/day;
  • Clozapine from about 12.5 to about 900 mg daily; preferably, from about 150 to about 450 mg daily; Risperidone: from about 0.25 to about 16 mg daily; preferably, from about 2-8 mg daily;
  • Sertindole from about 0.0001 to about 1.0 mg/kg daily;
  • Quetiapine from about 1.0 to about 40 mg/kg given once daily or in divided doses;
  • Asenapine from about 0.005 to about 60 mg total per day, given as a single dose or in divided doses;
  • Paliperidone from about 0.01 mg/kg to about 4 mg/kg body weight, more preferably from about 0.04 to about 2 mg/kg body weight;
  • the presently preferred atypical antipsychotic used according to the invention is ziprasidone.
  • Ziprasidone (5-[2-[4-(1 ⁇ -benzisothiazol-S-ylJpiperazin-i-yllethyll- ⁇ -chloroindolin-
  • 2-one is a benzisothiazolyl piperazine atypical antipsychotic with in vitro activity as a 5-HTi A receptor agonist and an inhibitor of serotonin and norepinephrine reuptake (U.S. Patent No.
  • the postsynaptic 5-HT 1A receptor has been implicated in both depressive and anxiety disorders (NM Barnes, T Sharp, 38 Neuropharmacology 1083-152,1999). Oral bioavailability of ziprasidone taken with food is approximately 60%, half-life is approximately
  • Ziprasidone is efficacious for the treatment of patients with schizophrenia and schizomood disorders, refractory schizophrenia, cognitive impairment in schizophrenia, affective and anxiety symptoms associated with schizoaffective disorder and bipolar disorder.
  • the drug is considered a safe and efficacious atypical antipsychotic (Charles Caley &
  • the present invention is useful in treating mental disorders and conditions, the treatment of which is facilitated by the administration of ziprasidone.
  • the present invention has application where ziprasidone use is indicated as, e.g., in U.S. Patent Nos.
  • atypical antipsychotics which can be used include, but are not limited to: Olanzapine, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.
  • Olanizapine is a known compound and is described in U.S. Patent No. 5,229,382 as being useful for the treatment of schizophrenia, schizophreniform disorder, acute mania, mild anxiety states, and psychosis.
  • U.S. Patent No. 5,229,382 is herein incorporated herein by reference in its entirety;
  • Clozapine 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1 ,4]diazepine.
  • Clozapine is described in U.S. Patent No. 3,539,573, which is herein incorporated by reference in its entirety. Clinical efficacy in the treatment of schizophrenia is described (Hanes, et al., Psychopharmacol. Bull., 24, 62 (1988));
  • Risperidone 3-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)piperidino]ethyl]-2-methyl-6,7,8,9 - tetrahydro-4H-pyrido-[1 ,2-a]pyrimidin-4-one.
  • Risperidone and its use in the treatment of psychotic diseases are described in U.S. Patent No. 4,804,663, which is herein incorporated by reference in its entirety; Sertindole, 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1 H-indol-3-yl]-1- piperidinyl]ethyl]imidazolidin-2-one.
  • Sertindole is described in U.S. Patent No. 4,710,500. Its use in the treatment of schizophrenia is described in U.S. Patent Nos. 5,112,838 and 5,238,945. U.S. Patent Nos. 4,710,500; 5,112,838; and 5,238,945 are herein incorporated by reference in their entireties; Quetiapine, 5-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl -1-piperazinyl)ethoxy]ethanol.
  • Quetiapine and its activity in assays which demonstrate utility in the treatment of schizophrenia are described in U.S. Patent No. 4,879,288, which is herein incorporated by reference in its entirety.
  • Quetiapine is typically administered as its (E)-2-butenedioate (2:1) salt.
  • Aripiprazole is an atypical antipsychotic agent used for the treatment of schizophrenia and described in U.S. Patent No. 4,734,416 and U.S. Patent No. 5,006,528, which are herein incorporated by reference in their entireties. Amisulpride, which is described in U.S. Patent No. 4,401,822. U.S. Patent No.
  • Bifeprunox 2-[4-[4-(5-fluoro-1 H-indol-3-yl)-3,6-dihydro-1 (2H)-pyridinyl]butyl] -1 H- isoindole-1,3(2H)-dione.
  • Preparation and use of bifeprunox is described in U.S. Patent 6,225,312, which is incorporated in its entirety herein.
  • a preferred combination is ziprasidone with a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof of the present invention.
  • the compounds of the formulas Ia and Ib may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art.
  • B, E, R 1 , R 3 , R 4 , R 6 , and R 7 are defined as above in the definition of compounds of formulas Ia and Ib.
  • Exemplary methods include, but are not limited to, those described below.
  • reaction conditions may be those conditions that are standard for that reaction, as would be readily recognized by one of skill in the art. Alternate methods that are known in the literature may also be used.
  • inert reaction solvent refers to a solvent system in which the components do not interact with starting materials, reagents, or intermediates of products in a manner which adversely affects the yield of the desired product.
  • a compound of the formula Ia or Ib may be prepared, for example, as illustrated in Scheme 1.
  • the amine of formula Il is reacted with a compound of the formula III wherein L is a leaving group (e.g., choride, bromide, methyl sulfide, alkyl sulfide, aryl sulfide, alkyl sulfoxide, or aryl sulfoxide) in the presence or absence of base (e.g., triethylamine, diisopropylamine, pyridine, 2,6-lutidine, sodium or potassium hydroxide, sodium or potassium or cesium carbonate, sodium or potassium tert-butoxide, diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene) in the presence or absence of an inert reaction solvent such as water, methanol, ethanol, isopropanol, acetonit
  • an inert reaction solvent such as water
  • This reaction is typically carried out at a temperature from about -10°C to about 15O 0 C.
  • L is methylsulfide and the reaction is carried out in the absence of solvent at a temperature from about 70 0 C to about 120 0 C.
  • L is chloride and the reaction is carried out in the presence of triethylamine, diisopropylethylamine, or sodium terf-butoxide in a solvent selected from chloroform, methylene chloride and toluene at a temperature from about O 0 C to about 5O 0 C.
  • Compounds of the formula Il can be prepared using methods analogous to those reported in the literature, as described in Rubstov, M.V.; Mikhlina, E.E.; Vorob'eva, V. Ya.; Yanina, A. Zh. Obshch. Khim. (1964), V34, 2222-2226, and in WO 2004/024729, which is incorporated by reference herein in its entirety.
  • Compounds of formula III can also be prepared by methods analogous to those reported in the literature, see: Lok, R.; Leone, R.E.; Williams, A.J. J. Org. Chem.
  • Scheme 2 illustrates an alternative preparation of compounds of the formula Ia or Ib (referred to as formula I in Scheme 2).
  • a halogenating reagent such as but not limited to Cl 2 , Br 2 , I 2 , N- bromosuccinimide, N-chlorosuccinimide, or N-iodosuccinimide in an inert reaction solvent such as water, acetic acid, methanol, ethanol, tetrhydrofuran, carbon tetrachloride, chloroform, acetonitrile or mixtures thereof in the presence or absence of a base such as potassium acetate, sodium acetate, cesium acetate, sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, cesium fluoride n-butyllithium, lithium diisopropyl amide at -78°C to 100 0 C; preferable Br 2 in water and acetic acid with sodium acetate at
  • a compound of the formula I can be prepared from a compound of formula XIII wherein Z is chloro, bromo, iodo or triflate (OTf) by first reacting it with bis(pinacolato)diboron and a palladium catalyst such as palladium (0) tetrakis(triphenylphosphine), palladium (II) acetate, allyl palladium chloride dimer, tris(dibenzylideneacetone)dipalladium (0), tris(dibenzylidene-acetone)dipalladium (0) chloroform adduct, palladium (II) chloride or dichloro[1,1'- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct, preferably dichloro[1 ,1'-bis(diphenylphosphino)-ferrocene]palladium (II) dichlorome
  • this reaction is carried out in a reaction inert solvent such as 1,4-dioxane, acetonitrile, methyl sulfoxide, tetrahydrofuran, ethanol, methanol, 2-propanol, toluene, preferably methyl sulfoxide, at a temperature from about from O 0 C to about 200 0 C, preferably from about 8O 0 C to about 120 0 C.
  • a reaction inert solvent such as 1,4-dioxane, acetonitrile, methyl sulfoxide, tetrahydrofuran, ethanol, methanol, 2-propanol, toluene, preferably methyl sulfoxide
  • a compound of the formula XIII wherein Z is Br or I with an alkyl lithium reagent such as, but not limited to n-butyl lithium, sec butyl lithium or tert-butyl lithium, in a solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, hexane, toluene, dioxane or a similar reaction inert solvent, at a temperature from about -100 0 C to about 25 0 C will afford the corresponding compound of the formula XIV wherein M is Li.
  • an alkyl lithium reagent such as, but not limited to n-butyl lithium, sec butyl lithium or tert-butyl lithium
  • a solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, hexane, toluene, dioxane or a similar reaction inert solvent, at a temperature from about -100
  • 1,1'-bis(diphenylphosphino)ferrocene and in the presence or absence of a base such as potassium phosphate, potassium acetate, sodium acetate, cesium acetate, sodium carbonate, lithium carbonate, potassium carbonate, cesium fluoride or cesium carbonate, preferably potassium phosphate, affords a compound of formula I.
  • a base such as potassium phosphate, potassium acetate, sodium acetate, cesium acetate, sodium carbonate, lithium carbonate, potassium carbonate, cesium fluoride or cesium carbonate, preferably potassium phosphate
  • This reaction is typically carried out in a reaction inert solvent such as 1,4-dioxane, acetonitrile, methyl sulfoxide, tetrahydrofuran, ethanol, methanol, 2-propanol, or toluene, preferably 1,4-dioxane, in the presence or absence of from about 1%-about 10% water, preferably about 5% water, at a temperature from about 0 0 C to about 200 0 C, preferably from about 6O 0 C to about 100 0 C.
  • a reaction inert solvent such as 1,4-dioxane, acetonitrile, methyl sulfoxide, tetrahydrofuran, ethanol, methanol, 2-propanol, or toluene, preferably 1,4-dioxane, in the presence or absence of from about 1%-about 10% water, preferably about 5% water, at a temperature from about 0 0 C to about 200 0 C
  • a compound of the formula XIII can be reacted with a compound of the formula R 3 M, wherein M is a boronic acid, boronic acid ester, borane pinacol ester or trialkylstannane group, in the presence of a palladium catalyst such as palladium (0) tetrakis(triphenylphosphine), palladium (II) acetate, allyl palladium chloride dimer, tris(dibenzylideneacetone)dipalladium (0), tris(dibenzylideneacetone)dipalladium (0) chloroform adduct, palladium (II) chloride or dichloro[1 ,1 '- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct, preferably palladium (II) acetate, in the presence or absence of a phosphine ligand such
  • This reaction is typically carried out in a reaction inert solvent such as 1,4-dioxane, 1 ,2-dimethoxyethane, acetonitrile, methyl sulfoxide, tetrahydrofuran, ethanol, methanol, 2-propanol, or toluene, preferably 1,2-dimethoxyethane, in the presence or absence of from about 1% to about 10% triethylamine, preferably about 1% triethylamine, at a temperature from about 0 0 C to about 200 0 C, preferably from about 60°C to about 100°C.
  • a scheme analogous to Scheme 2 can be envisioned wherein R 4 is introduced after R 3 by analogous procedures to those described above.
  • the amine 1,4-diaza-bicyclo[3.2.1]octane (formula II) can be prepared as illustrated in Scheme 3.
  • the preparation of compound Ilia is known in the literature [Saunders, et al. J. Chem. Soc, Chem. Commun. 1988, 1618-9].
  • Oxime IVa can be prepared from compound MIa by reaction with hydroxyl amine in a polar solvent such as methanol and / or water.
  • Compound IVa can be converted to a lactam of the formula Va by reaction with an acid such as sulfuric acid; this reaction is well known to those skilled in the art as a Beckmann rearrangement.
  • This reaction is typically carried out at a temperature of about -1O 0 C to about 100 0 C.
  • One preferred set of conditions is benzyl bromide in ethanol in the absence of base at room temperature over a period of 15 hours.
  • Single enantiomers of Vila [(+) Vila or (-) Vila] can be obtained by high pressure liquid chromatography using a chiral column.
  • a preferred set of conditions for separating the enantiomers of Vila is to use a Chiralcel OD column and elute with an 85/15 mixture of heptane and isopropyl alcohol at a flow rate of about 275 ml/min.
  • the single enantiomers of compound Vila are reacted with a hydride- transfer reagent such as lithium aluminum hydride in an aprotic solvent such as tetrahydrofuran or ethyl ether at a temperature of about -1O 0 C to about 70 0 C to give the corresponding single enantiomer of the formula Villa.
  • a hydride- transfer reagent such as lithium aluminum hydride in an aprotic solvent such as tetrahydrofuran or ethyl ether at a temperature of about -1O 0 C to about 70 0 C to give the corresponding single enantiomer of the formula Villa.
  • a preferred condition is lithium aluminum hydride in tetrahydrofuran at 7O 0 C for 3 hours.
  • the single enantiomers of Villa are converted to the corresponding single enantiomers of IXa by a reaction known to those skilled in the art as a Mitsunobu Reaction.
  • the single enantiomers of Villa are reacted with either diethyl azodicarboxylate or diisopropyl azodicarboxylate and triphenylphosphine in an aprotic solvent such a tetrahydrofuran or ethyl ether at a temperature from about -2O 0 C to about 7O 0 C.
  • aprotic solvent such as a tetrahydrofuran or ethyl ether
  • a preferred set of conditions is diethyl azodicarboxylate and triphenylphosphine in tetrahydrofuran at O 0 C to 2O 0 C for 1 hour.
  • Single enantiomers of IXa are converted to the corresponding single enantiomers of Il by removal of the benzyl protecting group using various methods known to those skilled in the art as described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999.
  • One preferred method is palladium catalyzed hydrogenation.
  • a set of preferred conditions for the conversion of a single enantiomer of IXa to its corresponding single enantiomer of Il is to shake vigorously a mixture of a compound of the formula IXa and catalytic 5% palladium on carbon, in ethanol and concentrated hydrochloric acid under hydrogen at 50 psi at room temperature over a period of 20 hours.
  • the first reaction of Scheme 5 is performed in a mixture of water and an organic solvent such as ether, benzene, toluene or THF in the presence of a base such as sodium bicarbonate, sodium carbonate, or triethylamine at a temperature from about O 0 C to about 100 0 C for a time period from about 15 min to about 16 h.
  • a base such as sodium bicarbonate, sodium carbonate, or triethylamine
  • One preferred set of conditions is a mixture of aqueous sodium bicarbonate and ether at room temperature for 1 h.
  • the second reaction of Scheme 5 is performed in a mixture of water and an organic solvent such as DMSO, DMF or THF at a temperature from about O 0 C to about 100 0 C for a time period from about 10 min to about 16 h.
  • One preferred set of conditions is a mixture of water and DMSO at 7O 0 C for 10 min.
  • the third reaction of Scheme 5 is performed in an organic solvent such as ether, THF, toluene, dioxane or DMF at a temperature from about O 0 C to about 100 0 C for a time period from about 1h to about 48 h.
  • One preferred set of conditions is ether at room temperature for 20 h.
  • the fourth reaction of Scheme 5 is performed in water or a mixture of water and an organic solvent such THF, dioxane, DMSO or DMF at a temperature from about 25 0 C to about 15O 0 C for a time period from about 15 min to about 16 h.
  • One preferred set of conditions is a mixture of water and THF at 100 0 C for 2 h.
  • the fifth reaction of Scheme 5 is analogous to the reduction of Vila to Villa as illustrated in scheme 4.
  • This reaction utilizes a hydride-transfer reagent such as lithium aluminum hydride in an aprotic solvent such as tetrahydrofuran or ethyl ether at a temperature of about -10 0 C to about 7O 0 C to give the corresponding single enantiomer of the formula Villa.
  • a preferred set of conditions is lithium aluminum hydride in tetrahydrofuran at 7O 0 C for 3 hours.
  • One preferred set of conditions is catalytic hydrogenation using palladium on carbon as a catalyst in ethanol at ambient temperature and 50 psi of hydrogen.
  • the compound of formula XXIV can then be treated with a compound of formula XXV, wherein F and G are defined as R 6 and R 7 above, and a reducing agent such as, but not limited to sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, catalytic hydrogenation or transfer hydrogenolysis in the presence or absence of an acid such as but not limited to acetic acid, hydrochloric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid or nitric acid in an inert reaction solvent such as chloroform, dichloromethane, 1 ,2-dichloroethane, acetonitrile, toluene, benzene, ethanol, methanol or water at 0°C to 100 0 C to afford a compound of formula XXVI,
  • a compound of formula XXIV can be reacted with a compound of formula R 6 L in which R 6 is as defined above, except that R 6 may not be hydrogen, and L is a leaving group (e.g., Cl, Br, I, OSO 2 alkyl, OSO 2 aryl) in the presence or absence of base (e.
  • a compound of formula XXIV can undergo a transformation to replace a diazonium group derived from an aryl amine with a fluoride to yield a compound of formula XXVII.
  • the most commonly used procedure for diazotization of an aryl amine involves sodium nitrite in aqueous hydrochloric acid or sulfuric acid.
  • Fluoro- containing counter ions may be then introduced into the reaction mixture to convert the diazonium ion to a fluoride.
  • Commonly used counter-ions include, but not limited to BF 4 ' , PF 6 ' , AsF 6 ' and SbF 6 " .
  • Hydrogen fluoride may also be used as a fluoride source.
  • a compound of formula III is prepared from a compound of formula XVIII.
  • a compound of Formula XVIII is treated with carbon disulfide in the presence of potassium hydroxide (for analogous procedure in literature, see: Katz, L; Cohen, M. S. J. Org. Chem. 1954, 19, 758-766; Supin, G. S. et al.; J. Gen. Chem. USSR (EN) 1975, 45, 363-367; Sugimoto, H, Makino, I.; Hirai, K. J. Org. Chem. 1988, 53, 2263-2267) or with ethyl potassium xanthate (Van Allan, J. A.; Deacon, B. D.
  • a compound of Formula XIX is prepared by treating a compound of formula XVIII with thiophosgene (Zinner, H. et al.; Chem. Ber.
  • a inert reaction solvent such as but not limited to tetrahydrofuran (THF), 1 ,4-dioxane, ethyl ether or dimethoxyethane (DME) at a reaction temperature ranging from 0 0 C to 30 0 C.
  • THF tetrahydrofuran
  • DME dimethoxyethane
  • the compound of formula XIX is then converted to a compound of formula III upon treatment with alkyl-X wherein X is a good leaving group such as halogen, mesylate or triflate in the presence of a base (suitable bases include but not limited to sodium or potassium or cesium carbonate, sodium or potassium tert-butoxide, sodium or potassium acetate, where sodium or potassium carbonate is preferred).
  • the reaction is carried out in an inert solvent such as tetrahydrofuran (THF), 1,4-dioxane, ethyl ether or dimethoxyethane
  • a compound of the Formula XV(a), wherein R 4 is alkyl, alkenyl, C 6 -C 11 aryl or 5-12 membered heteroaryl group is prepared using benzyl ether XXI and a reagent of formula R 4 -M, wherein M is defined as a boronic acid, boronic ester, trialkylstanane, magnesium halogen, or zinc, with a palladium catalyst such as but not limited to palladium(O) tetrakis(triphenylphosphine), palladium(ll) acetate, tris(dibensylideneacetone)dipalladium(0), dichloro[1 ,1 '- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct, in the presence of a phosphine ligand such as but not limited to triphenylphosphine, tri-o-
  • This reaction is typically carried out in an inert solvent such as 1,4-dioxane, ethyl ether, tetrahydrofuran (THF), benzene, toluene, DMF, DMSO in the presence or absence of 1 %-10% water at a temperature from 0 0 C to 200 0 C.
  • an inert solvent such as 1,4-dioxane, ethyl ether, tetrahydrofuran (THF), benzene, toluene, DMF, DMSO
  • THF tetrahydrofuran
  • the reaction is typically carried out with a palladium catalyst such as palladium (0) tetrakis(triphenylphosphine), palladium (II) acetate, allyl palladium chloride dimer, tris(dibenzylideneacetone)dipalladium (0), tris(dibenzylidene-acetone)dipalladium (0) chloroform adduct, palladium (II) chloride or dichloro[1,1'- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct, in the presence or absence of a copper salt such as CuI, in the presence of a large excess base such as, but not limited to, triethylamine, diisopropylethylamine, diisopropylamine as solvent, or a mixed solvent of a base and a suitable solvent such as 1,4-dioxane, benzene, toluene at
  • a compound of the Formula XV(c) is prepared by treating benzyl ether XXI with an amine of Formula NHR 6 R 7 using the conditions well-described in the literature (Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240; Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217).
  • the reaction is typically carried out with a palladium catalyst such as palladium(ll) acetate, tris(dibensylideneacetone)dipalladium(0), dichloro-[1,1'-bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct, in the presence of a phosphine ligand such as BINAP, 1,3-bis(diphenylphsphino)-propane, or 1,1'- bis(diphenylphsophino)ferrocene, in the presence of a base such as sodium tert-butoxide in a suitable solvent such as toluene at a temperature from 6O 0 C to 110 0 C.
  • a palladium catalyst such as palladium(ll) acetate, tris(dibensylideneacetone)dipalladium(0), dichloro-[1,1'-bis(diphenylphos
  • compound of formula I can also be synthesized as illustrated in Scheme 9.
  • a reducing reagent such as, but not limited to, zinc, iron, SnCI 2 , sodium hydrosulfite in an inert reaction solvent such as water, methanol, ethanol, isopropanol to yield a compound of formula XVI, which is then converted to a compound of formula XVII following the procedures detailed in Schemes 1 and 7.
  • a compound of formula I can be generated by treating a compound of formula XVII with a reagent of formula R 4 -M, wherein M is defined as a boronic acid, boronic ester, trialkylstanane, magnesium halogen, or zinc, with a palladium catalyst such as but not limited to palladium(O) tetrakis(triphenylphosphine), palladium(ll) acetate, tris(dibensylideneacetone)dipalladium(0), dichloro[1 ,1 '- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct, in the presence of a phosphine ligand such as but not limited to triphenylphosphine, tri-o-tolylphosphine, tri-tert- butylphosphine, 1 , 1 '-bis(diphenylphsophin
  • This reaction is typically carried out in an inert solvent such as 1,4-dioxane, ethyl ether, tetrahydrofuran (THF), benzene, toluene, DMF, DMSO in the presence or absence of 1%-10% water at a temperature from 0 0 C to 200 0 C.
  • an inert solvent such as 1,4-dioxane, ethyl ether, tetrahydrofuran (THF), benzene, toluene, DMF, DMSO in the presence or absence of 1%-10% water at a temperature from 0 0 C to 200 0 C.
  • the reaction is usually carried out in the presence of a copper salt such as, but not limited to, copper(l) chloride (CuCI), copper(ll) triflate and copper(l) iodide (CuI), in the presence or absence of a ligand such as, but not limited to, 2,2,6,6-tetramethylheptane-3,5-dione (TMHD), 1,10- phenanthroline, 8-hydroxyquinoline, 2-aminopyridine and pentane-2,4-dione (acac), and in the presence or absence of a base such as cesium carbonate, potassium phosphate, potassium acetate, sodium acetate, cesium acetate, sodium carbonate, lithium carbonate, potassium carbonate, preferably cesium carbonate, using the reacting alcohol as solvent or in an inert solvent such as, but not limited to, benzene, toluene, xylene, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) and N
  • a compound of formula I is prepared by treating a compound of formula XVII, wherein X is chloro or bromo, with amine NHR 6 R 7 .
  • the reaction is carried out in the presence or absence of a palladium catalyst such as palladium(ll) acetate, tris(dibensylideneacetone)dipalladium(0), dichloro-[1 ,1 '-bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct, in the presence or absence of a phosphine ligand such as BINAP, 1,3-bis(diphenylphsphino)-propane, or 1 ,1'-bis(diphenylphsophino)ferrocene, in the presence of a strong base such as sodium tert-butoxide in a suitable solvent such as toluene at a temperature from 6O 0 C to 11O 0 C
  • pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 5 atmospheres are generally acceptable, with ambient pressure, Le 1 , about 1 atmosphere, being preferred as a matter of convenience.
  • the compounds of the formula Ia or Ib and their pharmaceutically acceptable salts can be administered via either the oral, transdermal (e.g.. through the use of a patch), intranasal, sublingual, rectal, parenteral or topical routes.
  • Transdermal and oral administration are preferred.
  • These compounds are, most desirably, administered in dosages ranging from about 0.25 mg up to about 1500 mg per day, preferably from about 0.25 to about 300 mg per day in single or divided doses, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen.
  • a dosage level that is in the range of about 0.01 tng to about 10 mg per kg of body weight per day is most desirably employed.
  • Variations may nevertheless occur depending upon the weight and condition of the persons being treated and their individual responses to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out.
  • 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 larger doses are first divided into several small doses for administration throughout the day.
  • the active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the several routes previously indicated. More particularly, the active compounds can be administered in a wide variety of different dosage forms, ejj..
  • inert carriers in the form of tablets, capsules, transdermal patches, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, 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.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the active compounds are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
  • 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 (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 (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 can be used for tabletting purposes.
  • Solid 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 and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • a solution of an active compound in either sesame or peanut oil or in aqueous propylene glycol can be employed.
  • the 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 intraarticular, intramuscular 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.
  • the compounds of the invention may show advantageous potency as measured by functional activation of the ⁇ 7/5-HT 3 chimeric receptor, or high selectivity over other ion channels, such as 5-HT 3 or the IKr channel, or a combination thereof.
  • advantageous properties may be present in the (*) enantiomer and not in the (+) enantiomer of the compounds of the invention, or may be present to a greater extent in the (- ) enantiomer relative to the (+) enantiomer of the compounds of the invention.
  • the high selectivity over the IKr channel is an exemplary advantage of the compounds of the invention.
  • the effectiveness of the active compounds in suppressing nicotine binding to specific receptor sites can be determined by the following procedure, which is a modification of the methods of Lippiello, P. M. and Fernandes, K. G. (in "The Binding of L-f H]Nicotine To A Single Class of High-Affinity Sites in Rat Brain Membranes", Molecular Pharm., 29, 448-54, (1986)) and Anderson, D. J. and Arneric, S. P. (in "Nicotinic Receptor Binding of 3 H-Cystisine, 3 H-Nicotine and 3 H-Methylcarmbamylcholine In Rat Brain", European J. Pharm., 253, 261-67 (1994)).
  • mice Male Sprague-Dawley rats (200-300 g) from Charles River were housed in groups in hanging stainless steel wire cages and were maintained on a 12 hour light/dark cycle (7 a.m.- 7 p.m. light period). They received standard Purina Rat Chow and water ad libitum. The rats were killed by decapitation. Brains were removed immediately following decapitation. Membranes were prepared from brain tissue according to the methods of Lippiello and Fernandez (Molec. Pharmacol., 29, 448-454, (1986)) with some modifications.
  • the membranes were resuspended in assay buffer at a concentration of 1.0g/100mL
  • the composition of the standard assay buffer was 50 mM Tris HCI, 120 mM NaCI, 5 mM KCI, 2 mM MgCI 2 , 2 mM CaCI 2 and had a pH of 7.4 at room temperature.
  • Routine assays were performed in borosilicate glass test tubes.
  • the assay mixture typically consisted of 0.9 mg of membrane protein in a final incubation volume of 1.0 mL Three sets of tubes were prepared wherein the tubes in each set contained 50 ⁇ L of vehicle, blank, or test compound solution, respectively.
  • Incubations were terminated by rapid filtration under vacuum through Whatman GF/BTM glass fiber filters (Brandel Biomedical Research & Development Laboratories, Inc., Gaithersburg, MD) using a BrandelTM multi- manifold tissue harvester (Brandel Biomedical Research & Development Laboratories, Inc., Gaithersburg, MD).
  • filters were washed two times with ice-cold assay buffer (5 ml each). The filters were then placed in counting vials and mixed vigorously with 20 ml of Ready SafeTM (Beckman, Fullerton, CA) before quantification of radioactivity. Samples were counted in a LKB Wallac RackbetaTM liquid scintillation counter (Wallac Inc., Gaithersburg, MD) at 40-50% efficiency. All determinations were in triplicate.
  • % Inhibition (1-((E)/(C)) times 100.
  • the compounds of the invention that were tested in the above assay preferably exhibit IC 50 values of less than 10 ⁇ M.
  • f 125 n-Bunqarotoxin binding to oc7 nicotinic receptors in GHACI cells Membrane preparations were made for nicotinic receptors expressed in GH 4 CI cell line. Briefly, one gram of cells by wet weight were homogenized with a polytron in 25 mis of buffer containing 20 mM Hepes, 118 mM NaCI, 4.5 mM KCI, 2.5 mM CaCI 2 , 1.2 mM MgSO 4 , pH 7.5.
  • the homogenate was centrifuged at 40,000 x g for 10 min at 4 0 C, the resulting pellet was homogenized and centrifuged again as described above. The final pellet was resuspended in 20 mis of the same buffer.
  • Radioligand binding was carried out with [ 125 I] alpha-bungarotoxin from New England Nuclear, specific activity about 16 uCi/ ug, used at 0.4 nM final concentration in a 96 well microtiter plate. The plates were incubated at 37 0 C for 2 hours with 25 ⁇ l drugs or vehicle for total binding, 100 ⁇ l [ 125 I] Bungarotoxin and 125 ⁇ l tissue preparation.
  • Nonspecific binding was determined in the presence of methyllycaconitine at 1 ⁇ M final concentration.
  • the reaction was terminated by filtration using 0.5% Polyethylene imine treated Whatman GF/BTM glass fiberfilters (Brandel Biomedical Research & Development Laboratories, Inc., Gaithersburg, MD) on a Skatron cell harvester (Molecular Devices Corporation, Sunnyvale, CA) with ice-cold buffer, filters were dried overnight, and counted on a Beta plate counter using Betaplate Scint. (Wallac Inc., Gaithersburg, MD).
  • Data are expressed as IC50's (concentration that inhibits 50% of the specific binding) or as an apparent Ki, IC50/1+[L]/KD.
  • [L] ligand concentration
  • KD affinity constant for [ 125 I] ligand determined in separate experiment.
  • the compounds of the invention that were tested in the above assay preferably exhibit IC 50 values of less than 10 ⁇ M. f 125 n-Bunqarotoxin binding to alphal nicotinic receptors in Torpedo electroplax membranes:
  • Frozen Torpedo electroplax membranes (100 ⁇ l) were resuspended in 213 mis of buffer containing 20 mM Hepes, 118 mM NaCI, 4.5 mM KCI, 2.5 mM CaCI 2 , 1.2 mM MgSO 4 , pH 7.5 with 2 mg/ml BSA.
  • Radioligand binding was carried out with [ 125 I] alpha-bungarotoxin from New England Nuclear, specific activity about 16 uCi/ ug, used at 0.4 nM final concentration in a 96 well microtiter plate.
  • the plates were incubated at 37 0 C for 3 hours with 25 ⁇ l drugs or vehicle for total binding, 100 ⁇ l [ 125 I] Bungarotoxin and 125 ⁇ l tissue preparation.
  • Nonspecific binding was determined in the presence of alpha-bungarotoxin at 1 ⁇ M final concentration.
  • the reaction was terminated by filtration using 0.5% Polyethylene imine treated GF/B filters on a Brandel cell harvester with ice-cold buffer, filters were dried overnight, and counted on a Beta plate counter using Betaplate Scint. Data are expressed as IC50's (concentration that inhibits 50% of the specific binding) or as an apparent Ki, IC50/1+[L]/KD.
  • [L] ligand concentration
  • KD affinity constant for [ 125 I] ligand determined in separate experiment.
  • the compounds of the invention that were tested in the above assay preferably exhibit IC 50 values of greater than 10 nM, more preferably greater than 100 nM.
  • 5-HTr, Receptor Binding in NG-108 Cells Using 3H-LY278584 NG-108 cells endogenously express 5-HT 3 receptors. Cells are grown in DMEM containing 10% fetal bovine serum supplemented with L-glutamine (1:100).
  • Cells are grown to confluence and harvested by removing the media, rinsing the flasks with phosphate buffered saline (PBS) and then allowed to sit for a 2-3 minutes with PBS containing 5 mM EDTA. Cells are dislodged and poured into a centrifuge tube. Flasks are rinsed with PBS and added to centrifuge tube. The cells are centrifuged for ten minutes at 40,000 x g (20,000 rpm in Sorvall SS34 rotor(Kendro Laboratory Products, Newtown, CT)). The supernatant is discarded (into chlorox) and at this point the remaining pellet is weighed and can be stored frozen (-80 degrees C) until used in the binding assay.
  • PBS phosphate buffered saline
  • Pellets fresh or frozen - 250 mgs per 96 well plate
  • Pellets are homogenized in 50 mM Tris HCI buffer containing 2 mM MgCI 2 (pH 7.4) using a Polytron homogenizer (setting 15,000 rpm) for ten seconds.
  • the homogenate is centrifuged for ten minutes at 40,000 x g.
  • the supernatant is discarded and the pellet resuspended with the Polytron in fresh ice-cold 50 mM Tris HCl containing 2 rnM MgCI 2 (pH 7.4) buffer and centrifuged again.
  • the final pellet is resuspended in assay buffer (50 mM Tris HCI buffer (pH 7.4 at 37 0 C degrees) containing 154 mM NaCI,) for a final tissue concentration of 12.5 mg per mL buffer (1.25 X final concentration).
  • assay buffer 50 mM Tris HCI buffer (pH 7.4 at 37 0 C degrees) containing 154 mM NaCI,
  • tissue concentration 12.5 mg per mL buffer (1.25 X final concentration
  • Incubations were initiated by the addition of tissue homogenate to 96 well polypropylene plates containing test compounds that have been diluted in 10% DMSO/50 mM Tris buffer and radioligand (1 nM final concentration of 3H-LY278584).
  • Nonspecific binding was determined using a saturating concentration of a known potent 5-HT 3 antagonist (10 ⁇ M ICS-205930).
  • the incubation is ended by rapid filtration under vacuum through a fire-treated Whatman GF/B glass fiber filter (presoaked in 0.5% Polyethylene imine for two hours and dried) using a 96 well Skatron Harvester (3 sec pre-wet; 20 seconds wash; 15 seconds dry). Filters are dried overnight and then placed into Wallac sample bags with 10 mLs BetaScint. Radioactivity is quantified by liquid scintillation counting using a BetaPlate counter (Wallac, Gaithersburg, MD). The percent inhibition of specific binding is calculated for each concentration of test compound.
  • IC50 value the concentration which inhibits 50% of the specific binding
  • the compounds of the invention that were tested in the above assay preferably exhibit IC 50 values of greater than 10 nM, more preferably greater than 100 nM.
  • the cDNA encoding the N-terminal 201 amino acids from the human ⁇ 7 nAChR that contain the ligand binding domain of the ion channel was fused to the cDNA encoding the pore forming region of the mouse 5HT 3 receptor as described by Eisele JL, et al., "Chimaeric nicotinic-serotonergic receptor combines distinct ligand binding and channel specificities," Nature (1993), Dec. 2;366(6454):479-83, and modified by Groppi, et al., WO 00/73431.
  • the chimeric ⁇ 7-5HT 3 ion channel was inserted into pGS175 and pGS179 which contain the resistance genes for G-418 and hygromycin B, respectively. Both plasmids were simultaneously transfected into SH-EP1 cells and cell lines were selected that were resistant to both G-418 and hyrgromycin B. Cell lines expressing the chimeric ion channel were identified by their ability to bind fluorescent ⁇ -bungarotoxin on their cell surface. The cells with the highest amount of fluorescent ⁇ -bungarotoxin binding were isolated using a Fluorescent Activated Cell Sorter (FACS).
  • FACS Fluorescent Activated Cell Sorter
  • Cell lines that stably expressed the chimeric cc7- 5HT 3 were identified by measuring fluorescent ⁇ -bungarotoxin binding after growing the cells in minimal essential medium containing nonessential amino acids supplemented with 10% fetal bovine serum, L-glutan ⁇ ine, 100 units/ml penicillin/streptomycin, 250 ng/mg fungizone, 400 ⁇ g/ml hygromycin B, and 400 ⁇ g/ml G-418 at 37° C with 6% CO 2 in a standard mammalian cell incubator for at least 4 weeks in continuous culture.
  • the ion conditions of the MMEBSS was adjusted to maximize the flux of calcium ion through the chimeric ⁇ 7-5HT 3 ion channel as described in WO 00/73431.
  • the activity of compounds on the chimeric ⁇ 7-5HT 3 ion channel was analyzed on FLIPR.
  • the instrument was set up with an excitation wavelength of 488 nanometers using 500 milliwatts of power. Fluorescent emission was measured above 525 nanometers with an appropriate F-stop to maintain a maximal signal to noise ratio.
  • Agonist activity of each compound was measured by directly adding the compound to cells expressing the chimeric oc7-5HT 3 ion channel and measuring the resulting increase in intracellular calcium that is caused by the agonist-induced activation of the chimeric ion channel.
  • the assay is quantitative such that concentration-dependent increase in intracelluar calcium is measured as concentration-dependent change in Calcium Green fluorescence.
  • the effective concentration needed for a compound to cause a 50% maximal increase in intracellular calcium is terme
  • the compounds of the invention that were tested in the above assay preferably exhibit IC 50 values of less than 10 ⁇ M, more preferably less than 1 ⁇ M.
  • IC 50 values of less than 10 ⁇ M, more preferably less than 1 ⁇ M.
  • Carbon-13 nuclear magnetic resonance ( 13 C NMR) spectra were recorded on a Varian INOVA400 (100 MHz). Chemical shifts are reported in ppm ( ⁇ ) relative to the central line of the 1:1:1 triplet of deuterochloroform ( ⁇ 77.00), the center line of deuteromethanol ( ⁇ 49.0) or deuterodimethylsulfoxide ( ⁇ 39.7). The number of carbon resonances reported may not match the actual number of carbons in some molecules due to magnetically and chemically equivalent carbons and may exceed the number of actual carbons due to conformational isomers.
  • Mass spectra (MS) were obtained using a Waters ZMD mass spectrometer using flow injection atmospheric pressure chemical ionization (APCI) (Waters Corporation, Milford, Mass).
  • GCMS Gas chromatography with mass detection
  • Triphenylphosphine (2.36 g, 9 mmol) was added to a stirred solution of 2-[(2R)-1- benzylpiperazin-2-yl]ethanol (1.3 g, 5.9 mmol) in THF (90 mL) under argon. The mixture was cooled to 0 0 C, and a solution of DIAD (1.67 mL, 7.8 mmol) in THF (5 mL) was added dropwise under vigorous stirring for 15 min. The mixture was stirred for 12 h at room temperature and evaporated. The residue was dissolved in ether (50 mL). Water (25 mL) and
  • triphenylphosphine (6.7 g, 0.0255 mol) was added to the obtained solution, and the mixture was stirred for 20 h at room temperature. The mixture was evaporated to dryness, and THF (30 mL) and water (3 mL) were added. The resulting mixture was heated at reflux for 2 h, concentrated under reduced pressure, dioxane was added and the solution was concentrated once more. The residue was purified by chromatography (200 g of silica gel, CCI 4 ⁇ CHCI 3 - ⁇ CHCI 3 /Me0H 9:1) to furnish 4.0 g of a light-yellow solid. MS m/z (M + H) + 277.1.

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Abstract

L'invention concerne des agonistes vis-à-vis du récepteur nicotinique α7 de formule (la) ou (lb), selon la description, et un procédé de traitement de troubles du système nerveux central et d'autre troubles chez le mammifère, y compris l'homme, par administration de ce type d'agoniste, ainsi que des compositions pharmaceutiques renfermant à la fois un vecteur pharmaceutiquement acceptable et le type d'agoniste en question pénétrant le système nerveux central.
PCT/IB2005/003394 2004-11-15 2005-11-04 Azabenzoxazoles pour le traitement de troubles du systeme nerveux central WO2006051410A1 (fr)

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Cited By (8)

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WO2007091106A3 (fr) * 2006-02-10 2008-03-06 Summit Corp Plc Traitement de la dystrophie musculaire de duchenne
WO2009082698A1 (fr) * 2007-12-21 2009-07-02 Abbott Laboratories Compositions pour le traitement de troubles cognitifs
WO2012153796A1 (fr) * 2011-05-10 2012-11-15 協和発酵キリン株式会社 Composé pyrimido-diazépinone
US8383657B2 (en) 2007-12-21 2013-02-26 Abbott Laboratories Thiazolylidine urea and amide derivatives and methods of use thereof
US8501713B2 (en) 2007-08-03 2013-08-06 Summit Corporation Plc Drug combinations for the treatment of duchenne muscular dystrophy
WO2020207941A1 (fr) * 2019-04-09 2020-10-15 F. Hoffmann-La Roche Ag Composés hétérocycliques en tant qu'inhibiteurs de la monoacylglycérol lipase (magl)
US11608347B2 (en) 2018-01-08 2023-03-21 Hoffmann-La Roche Inc. Octahydropyrido[1,2-alpha]pyrazines as MAGL inhibitors
US11981661B2 (en) 2020-09-03 2024-05-14 Hoffmann-La Roche Inc. Heterocyclic compounds

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WO2003044024A1 (fr) * 2001-11-23 2003-05-30 Sanofi-Synthelabo Derives de 4-(oxazolopyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane, leur preparation et leur application en therapeutique
US20030119837A1 (en) * 2000-12-29 2003-06-26 Pfizer Inc. Pharmaceutical composition for the treatment of CNS and other disorders
US20030153574A1 (en) * 2000-05-31 2003-08-14 Frederic Galli 1,4-diazabicyclo[3.2.2]nonabenzoxazole, -benzothiazole and benzimidazole derivatives, preparation and therapeutic use thereof

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US20030153574A1 (en) * 2000-05-31 2003-08-14 Frederic Galli 1,4-diazabicyclo[3.2.2]nonabenzoxazole, -benzothiazole and benzimidazole derivatives, preparation and therapeutic use thereof
US20030119837A1 (en) * 2000-12-29 2003-06-26 Pfizer Inc. Pharmaceutical composition for the treatment of CNS and other disorders
WO2003044024A1 (fr) * 2001-11-23 2003-05-30 Sanofi-Synthelabo Derives de 4-(oxazolopyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane, leur preparation et leur application en therapeutique

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8518980B2 (en) 2006-02-10 2013-08-27 Summit Corporation Plc Treatment of Duchenne muscular dystrophy
AU2007213451B2 (en) * 2006-02-10 2013-02-07 Summit (Oxford) Limited Treatment of Duchenne muscular dystrophy
WO2007091106A3 (fr) * 2006-02-10 2008-03-06 Summit Corp Plc Traitement de la dystrophie musculaire de duchenne
US8501713B2 (en) 2007-08-03 2013-08-06 Summit Corporation Plc Drug combinations for the treatment of duchenne muscular dystrophy
WO2009082698A1 (fr) * 2007-12-21 2009-07-02 Abbott Laboratories Compositions pour le traitement de troubles cognitifs
US8383657B2 (en) 2007-12-21 2013-02-26 Abbott Laboratories Thiazolylidine urea and amide derivatives and methods of use thereof
WO2012153796A1 (fr) * 2011-05-10 2012-11-15 協和発酵キリン株式会社 Composé pyrimido-diazépinone
JPWO2012153796A1 (ja) * 2011-05-10 2014-07-31 協和発酵キリン株式会社 ピリミドジアゼピノン化合物
US9453021B2 (en) 2011-05-10 2016-09-27 Kyowa Hakko Kirin Co., Ltd. Pyrimidodiazepinone compound
JP6110787B2 (ja) * 2011-05-10 2017-04-05 協和発酵キリン株式会社 ピリミドジアゼピノン化合物
US11608347B2 (en) 2018-01-08 2023-03-21 Hoffmann-La Roche Inc. Octahydropyrido[1,2-alpha]pyrazines as MAGL inhibitors
WO2020207941A1 (fr) * 2019-04-09 2020-10-15 F. Hoffmann-La Roche Ag Composés hétérocycliques en tant qu'inhibiteurs de la monoacylglycérol lipase (magl)
US11981661B2 (en) 2020-09-03 2024-05-14 Hoffmann-La Roche Inc. Heterocyclic compounds

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