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WO2007017750A1 - Sel de benzoate de 4-(5-methyl-oxazolo[4,5-b]pyridin-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane - Google Patents

Sel de benzoate de 4-(5-methyl-oxazolo[4,5-b]pyridin-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane Download PDF

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Publication number
WO2007017750A1
WO2007017750A1 PCT/IB2006/002219 IB2006002219W WO2007017750A1 WO 2007017750 A1 WO2007017750 A1 WO 2007017750A1 IB 2006002219 W IB2006002219 W IB 2006002219W WO 2007017750 A1 WO2007017750 A1 WO 2007017750A1
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disease
disorder
treating
syndrome
cognitive
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PCT/IB2006/002219
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Allen Jacob Duplantier
Kenneth George Kraus
Bruce Nelsen Rogers
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Pfizer Products Inc.
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Publication of WO2007017750A1 publication Critical patent/WO2007017750A1/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
    • A61P25/00—Drugs for disorders of the nervous system
    • 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

Definitions

  • the present invention relates to a benzoate salt of 4-(5-methyloxazolo[4,5-b]pyridine-
  • Nervous System and other disorders in a mammal, including a human, by administering to the mammal the benzoate salt. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and the benzoate salt.
  • the benzoate salt of the invention is useful in the treatment of schizophrenia and Alzheimer's Disease. It is particularly of use in the treatment of cognitive deficits associated with schizophrenia, cognitive and attention deficit symptoms of Alzheimer's Disease, and neurodegeneration associated with Alzheimer's Disease.
  • 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.
  • 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.
  • 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
  • schizophrenics express the same ⁇ 7 nAChR as non-schizophrenics.
  • Selective al nAChR agonists may be found using a functional assay on FLIPR (see WO 00/73431). FLIPR 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 ⁇ 7 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 al nicotinic receptor agonist are useful for the treatment of cognitive deficits or impairments in schizophrenia and in Alzheimer's Disease.
  • FIG. 1 is the X-ray powder diffraction pattern of 4-(5-methyloxazolo[4,5-b]pyridin-2- yl)-1 ,4-diazabicyclo[3.2.2]nonane benzoate Form A.
  • FIG. 2 is the differential scanning calorimetry trace of 4-(5-methyloxazolo[4,5- b]pyridin-2-yl)-1 ,4-diazabicyclo[3.2.2]nonane benzoate Form A.
  • the present invention provides a benzoate salt of Formula I:
  • Formula I is known as 4-(5-methyloxazolo[4,5-b]pyridine-2-yl)-1,4- diazabicyclo[3.2.2]nonane, or 4-(5-methyl-oxazolo[4,5-b]pyridine-2-yl)-1 ,4-diaza- bicyclo[3.2.2]nonane.
  • the benzoate salt is also known as the benzoic acid salt.
  • the benzoate salt of Formula I of the present invention is crystalline and relatively non- hygroscopic, and exhibits physical properties that render it superior to other salts of Formula I.
  • the benzoate salt of Formula I has been found to exist in polymorphic Form A.
  • the benzoate salt of the invention is useful in the treatment of schizophrenia and Alzheimer's Disease. It is particularly of use in the treatment of cognitive deficits associated with schizophrenia, cognitive and attention deficit symptoms of Alzheimer's Disease, and neurodegeneration associated with Alzheimer's Disease.
  • 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.
  • the benzoate salt of Formula I may exist in different polymorphic forms, all of which are encompassed by the present invention.
  • the benzoate salt of Formula I has been found to exist in crystalline polymorphic Form A.
  • the benzoate salt of Formula I of the present invention encompasses solvates or hydrates thereof.
  • the salt may form solvates or hydrates with solvents such as, but not limited to, water, acetone, and alcohol such as ethanol, propanol, butanol, propylene glycol, etc.
  • the benzoate salt has characteristic X-ray powder diffraction peaks as measured with copper radiation of 2-Theta ⁇ 0.1 ° of 10.6, 12.9, 13.8, 17.6, and 19.3.
  • the benzoate salt has characteristic X-ray powder diffraction peaks as measured with copper radiation of 2-Theta ⁇ 0.1 ° of 10.6, 17.6, 18.6, 19.3 and 21.3.
  • the benzoate salt has the characteristic X-ray powder diffraction pattern of FIG. 1.
  • the benzoate salt has a melting onset temperature of 174 ⁇ 2°C.
  • the benzoate salt increases in weight by less than 0.2% at 90 ⁇ 2% relative humidity in an isothermal (24.9 + 0.1 0 C) moisture sorption test conducted from approximately 1 % to 90% ( ⁇ 2%) humidity.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the benzoate salt of the Formula I, and a pharmaceutically acceptable carrier.
  • the benzoate salt of the pharmaceutical composition is crystalline.
  • 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 benzoate salt of the Formula I, 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 benzoate salt of the Formula I, 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 ⁇ 7 nicotinic receptor agonizing amount of a benzoate salt of formula I 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 benzoate salt of the formula I.
  • 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 benzoate salt of Formula I effective in treating said disorder or condition.
  • 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 benzoate salt of Formula I 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 I 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.
  • a benzoate salt of Formula I is useful 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, presenile 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, sleep disorders (including narcolepsy), chronic fatigue syndrome, jet lag, 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, gla
  • Some of the conditions that are preferred for treatment in accordance with the present invention are attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, cognitive deficits associated with schizophrenia, 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 bulimia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependent drug cessation, Gilles de Ia Tourette's Syndrome, glaucoma, neurodegeneration associated with glaucoma, and 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 benzoate salt of the Formula I, 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 cx7 nicotinic receptor agonizing amount of a benzoate salt of the Formula I, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition which may be a composition for treating a disorder or condition listed in the previous paragraphs, comprising an cx7 nicotinic receptor agonizing amount of a benzoate salt of the Formula I, 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 benzoate salt of the Formula I.
  • 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 benzoate salt of the Formula I.
  • 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 any of the afore-mentioned indications, 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 bulimia 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
  • the present invention also relates to a method for treating male infertility in a mammal in need thereof comprising administering to the mammal a benzoate salt of Formula 1.
  • 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 benzoate salt of Formula I.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a benzoate salt of the Formula 1, 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 benzoate salt of Formula I, in an amount that is effective in treating schizophrenia, and an antipsychotic drug or pharmaceutically acceptable salt thereof.
  • the benzoate salt of Formula I and the antipsychotic drug may be administered together or separately.
  • the benzoate salt of Formula I and the antipsychotic drug may be administered simultaneously or at separate intervals. When administered simultaneously the benzoate salt of Formula I and the antipsychotic drug may be incorporated into a single pharmaceutical composition.
  • compositions i.e., one containing a benzoate salt of Formula I and the other containing an antipsychotic drug, may be administered simultaneously.
  • the antipsychotic drug may be, for example, Chlorpromazine, Fluphenazine,
  • the antipsychotic drug may also be, for example, Asenapine, Ziprasidone, Olanzapine, Clozapine, Risperidone, Sertindole, Quetiapine, Aripiprazole or Amisuipride.
  • 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 benzoate salt of Formula I.
  • 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 benzoate salt of Formula I 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 -9-
  • 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 ,2-benzisothiazol-3-yl)piperazin-1 -yl]ethyl]-6-chloroindolin- 2-one) is a benzisothiazolyl piperazine atypical antipsychotic with in vitro activity as a 5-HT 1A receptor agonist and an inhibitor of serotonin and norepinephrine reuptake (U.S. Patent No. 4,831 ,031).
  • 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 B2006/002219
  • bioavailability of ziprasidone taken with food is approximately 60%, half-life is approximately 6-7 hours, and protein binding is extensive.
  • 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 7- ⁇ 4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy ⁇ -3- ,4-dihydro carbostyril or 7- ⁇ 4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy ⁇ -3,4-dihydro -2(1 H)- quinolinone.
  • 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.
  • 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 benzoate salt of Formula I of the present invention.
  • Hygroscopic drug substances become moist due to their affinity for moisture in the air. Highly hygroscopic or deliquescent compounds cannot be prepared satisfactorily as powders. Nonhygroscopic drug substances are preferable for preparing solid unit dosage forms.
  • crystalline means a material that has an ordered, long range molecular structure. The degree of crystallinity of a crystal form can be determined by many techniques including, for example, powder X-ray diffraction, moisture sorption, differential scanning calorimetry, solution calorimetry, and dissolution properties.
  • Crystalline organic compounds consist of a large number of atoms that are arranged in a periodic array in three-dimensional space.
  • the structural periodicity normally manifests distinct physical properties, such as sharp, explicit spectral features by most spectroscopic probes (e.g., X-ray diffraction, infrared and solid state NMR).
  • X-ray diffraction X-ray diffraction (XRD) is acknowledged to be one of the most sensitive methods to determine the crystallinity of solids.
  • Crystals yield explicit diffraction maxima that arise at specific angles consistent with the lattice interplanar spacings, as predicted by Bragg's law. On the contrary, amorphous materials do not possess long-range order. They often retain additional volume between molecules, as in 19
  • Amorphous solids normally unveil a featureless XRD pattern with broad, diffuse halos because of the absence of the long range order of repeating- crystal lattice.
  • PXRD has reportedly been used to characterize different crystal forms of organic compounds (e.g., compounds useful in pharmaceutical compositions). See, for example, U.S. Pat. Nos. 5,504,216 (Holohan et al), 5,721 ,359 (Dunn et al.), 5,910,588 (Wangnick et al.), 6,066,647 (Douglas et al.), 6,225,474 (Matsumoto et al.), 6,239,141 (Allen et al.), 6,251 ,355 (Murata et al.), 6,288,057 (Harkness), 6,316,672 (Stowell et al.), and 6,329,364 (Groleau).
  • Crystalline materials are preferred in many pharmaceutical applications. Crystalline forms are generally thermodynamically more stable than amorphous forms of the same substance. This thermodynamic stability is preferably reflected in the lower solubility and improved physical stability of the crystalline form.
  • the regular packing of the molecules in the crystalline solid preferably denies the incorporation of chemical impurities. Hence crystalline materials generally possess higher chemical purity than their amorphous counterparts.
  • the packing in the crystalline solid generally constrains the molecules to well defined lattice positions and reduces the molecular mobility that is the prerequisite for chemical reactions.
  • crystalline solids with very few notable exceptions, are chemically more stable than amorphous solids of the same molecular composition.
  • the crystalline form of the crystalline polymorph of the benzoate salt Form A of Formula I of the present invention has the distinct powder X-ray diffraction profile provided in
  • Characteristic diffraction peaks as used herein are peaks selected from the most intense peaks of the observed diffraction pattern.
  • the characteristic peaks are selected from about 20 of the most intense peaks, more preferably from about 10 of the most intense peaks, and most preferably from about 4 to 5 of the most intense peaks in the diffraction pattern.
  • Powder x-ray diffraction pattern was collected for 4-(5-methyloxazolo[4,5-b]pyridin-2- yl)-1 ,4-diazabicyclo[3.2.2]nonane benzoate Form A using a Bruker D5000 diffractometer (Madison Wisconsin) equipped with a copper radiation source, fixed slits (divergence 1.0 mm, antiscatter 1.0 mm, and receiving 0.6 mm) and a Kevex solid-state detector.
  • X-ray tube voltage and amperage were set at 4OkV and 4OmA respectively.
  • Data were collected and analyzed using Bruker DIFFRAC Plus software. Samples were prepared by placing them in a quartz holder.
  • the relative intensity may vary depending on particle size and shape.
  • Thermal phase transition data was collected using a Mettler Toledo DSC 822. Crimped Aluminum sample pans with a pinhole in the lid were loaded with one to two milligrams of sample and then scanned from room temperature to 300°C at 5 c C/minute. Onset temperatures are determined by baseline tangent - peak tangent method. Onset temperatures may vary depending on particle size, sample size, sample pan configuration, and heating rate.
  • Hygroscopicity was assessed using a dynamic vapor sorption technique in which an accurately weighed sample is subjected to progressively changing water vapor pressure while simultaneously recording the weight change. The experiment is conducted isothermally at 25°C.
  • a solution of counter ion (acid) at from about 20 0 C to 50 0 C is dissolved in a suitable solvent and added to a solution of the free base of Formula I at from about 20°C to about 50 0 C in a suitable solvent.
  • the mixture is stirred while cooling to room temperature followed by concentration under reduced pressure. Solids are removed by filtration. 19
  • L-lactate salts of Formula I demonstrated undesirable hygroscopicity. Findings also included that the sulfate, phosphate, acetate, succinate, and besylate salts did not meet rational stoichiometry upon preparation.
  • a benzoate salt of the Formula I of the present invention 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.
  • the active 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. However, a dosage level that is in the range of about 0.01 mg 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, exL, they may be combined with various pharmaceutically acceptable 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 solutions, 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 com, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like 19
  • 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 a pharmaceutically acceptable oily or aqueous vehicle such as but not limited to sesame oil, peanut oil or aqueous propylene glycol, can be employed.
  • the aqueous solutions should be suitably buffered, if necessary, and the liquid diluent first rendered isotonic.
  • the preparation of the solutions is under sterile conditions and is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • Parenteral administration may be by injection, including the intravenous, intraarticular, intramuscular, and subcutaneous forms.
  • the aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. It is also possible to administer the active compounds topically and this can be done by way of creams, a patch, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
  • the benzoate salt of the invention shows potency as measured by functional activation of the ⁇ 7/5-HT 3 chimeric receptor, or selectivity over other ion channels, such as 5- HT 3 or the IKr channel, or a combination thereof.
  • 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 ⁇ [ 3 HJNicotine 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.
  • Membranes were prepared from brain tissue according to the methods of Lippiello and Fernandez (Molec. Pharmacol., 29, 448-454, (1986)) with some modifications. Whole brains were removed, rinsed with ice-cold buffer, and homogenized at 0° in 10 volumes of buffer (w/v) using a Brinkmann PolytronTM (Brinkmann Instruments Inc., Westbury, NY), setting 6, for 30 seconds.
  • the buffer consisted of 50 mM Tris HCI at a pH of 7.5 at room temperature. The homogenate was sedimented by centrifugation (10 minutes; 50,000 x g; 0° to 4°C).
  • the supernatant was poured off and the membranes were gently resuspended with the Polytron and centrifuged again (10 minutes; 50,000 x g; 0 0 C to 4 0 C). After the second centrifugation, 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 KCl, 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.
  • To each tube was added 200 ⁇ L of [ 3 H]- nicotine in assay buffer followed by 750 ⁇ L of the membrane suspension.
  • the final concentration of nicotine in each tube was 0.9 nM.
  • the final concentration of cytisine in the blank was 1 ⁇ M.
  • the vehicle consisted of deionized water containing 30 ⁇ l_ of 1 N acetic acid per 50 mL of water.
  • the test compounds and cytisine were dissolved in vehicle.
  • Assays were initiated by vortexing after addition of the membrane suspension to the tube. The samples were incubated at 0° to 4° C in an iced shaking water bath. 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). Following the initial filtration of the assay mixture, 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.
  • 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
  • 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
  • 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.
  • PBS phosphate buffered saline
  • 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.
  • Pellets fresh or frozen - 250 mgs per 96 well plate
  • the homogenate is centrifuged for ten minutes at 40,000 x g.
  • 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). After an hour incubation at 37 0 C in a water bath, 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).
  • 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 oc7- 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-glutamine, 100 units/ml penicillin/streptomycin, 250 ng/mg fungizone, 400 ⁇ g/ml hygromycin B 1 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.
  • Assay of the activity of the chimeric ⁇ 7-5HT 3 receptor To assay the activity of the ⁇ 7-5HT 3 ion channel, cells expressing the channel were plated into each well of either a 96 or 384 well dish (Corning #3614) and grown to confluence prior to assay. On the day of the assay, the cells were loaded with a 1 :1 mixture of 2 mM Calcium Green 1 , AM (Molecular Probes) dissolved in anhydrous DMSO and 20% pluronic F- 127 (Molecular Probes). This solution was added directly to the growth media of each well to achieve a final concentration 2 ⁇ M.
  • AM Molecular Probes
  • the cells were incubated with the dye for 60 min at 37° C and is washed with a modified version of Earle's balanced salt solution (MMEBSS) as described in WO 00/73431.
  • MMEBSS Earle's balanced salt solution
  • 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 ⁇ 7-5HT 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 intracellular 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 termed the EC 50 .
  • the benzoate salt of Formula I was tested and analyzed on FLIPR.
  • the EC 50 was determined to be between 10 nM and 1000 nM.

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Abstract

La présente invention concerne un sel de benzoate de formule (I), également, connu en tant que 4-(5-méthyloxazolo[4,5-b]pyridine-2-yl)-1,4- diazabicyclo[3.2.2]nonane. Ledit sel de benzoate de l'invention est utilisé dans le traitement de la schizophrénie et de la maladie d'Alzheimer. Il est, notamment, utilisé dans le traitement de troubles cognitifs associés à la schizophrénie, de symptômes de déficits d'attention et cognitifs de la maladie d'Alzheimer, et de la neurodégénération liée à cette même maladie.
PCT/IB2006/002219 2005-08-08 2006-08-07 Sel de benzoate de 4-(5-methyl-oxazolo[4,5-b]pyridin-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane WO2007017750A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009113950A1 (fr) * 2008-03-10 2009-09-17 Astrazeneca Ab Polythérapies (a) d’un antipsychotique et (b) d’un agoniste du récepteur nicotinique neuronal alpha-4/bêta-2 (a4b2)
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
EP3632918A4 (fr) * 2017-05-27 2020-07-29 Beijing Normal University Composé ligand d'un récepteur nicotinique de l'acétylcholine 7 et son application
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1219622A2 (fr) * 2000-12-29 2002-07-03 Pfizer Products Inc. Compositions pharmaceutiques pour le traitement du SNC et d'autres troubles
WO2005063296A2 (fr) * 2003-12-23 2005-07-14 Pfizer Products Inc. Combinaison therapeutique d'amelioration neuro-cognitive et de traitement de troubles psychotiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1219622A2 (fr) * 2000-12-29 2002-07-03 Pfizer Products Inc. Compositions pharmaceutiques pour le traitement du SNC et d'autres troubles
WO2005063296A2 (fr) * 2003-12-23 2005-07-14 Pfizer Products Inc. Combinaison therapeutique d'amelioration neuro-cognitive et de traitement de troubles psychotiques

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009113950A1 (fr) * 2008-03-10 2009-09-17 Astrazeneca Ab Polythérapies (a) d’un antipsychotique et (b) d’un agoniste du récepteur nicotinique neuronal alpha-4/bêta-2 (a4b2)
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
EP3610890A1 (fr) 2012-11-14 2020-02-19 The Johns Hopkins University Procédés et compositions de traitement de la schizophrénie
US10624875B2 (en) 2012-11-14 2020-04-21 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US10980753B2 (en) 2016-12-20 2021-04-20 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US12138353B2 (en) 2016-12-20 2024-11-12 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
EP3632918A4 (fr) * 2017-05-27 2020-07-29 Beijing Normal University Composé ligand d'un récepteur nicotinique de l'acétylcholine 7 et son application
JP2020523292A (ja) * 2017-05-27 2020-08-06 ベイジン ノーマル ユニバーシティ α７ニコチン性アセチルコリン受容体のリガンド化合物及びその応用
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

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