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WO2011012654A1 - Composes d'hydroxy-asenapine, leurs derives et les compositions pharmaceutiques les comprenant - Google Patents

Composes d'hydroxy-asenapine, leurs derives et les compositions pharmaceutiques les comprenant Download PDF

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Publication number
WO2011012654A1
WO2011012654A1 PCT/EP2010/060971 EP2010060971W WO2011012654A1 WO 2011012654 A1 WO2011012654 A1 WO 2011012654A1 EP 2010060971 W EP2010060971 W EP 2010060971W WO 2011012654 A1 WO2011012654 A1 WO 2011012654A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
mmol
compounds
hydroxyasenapine
asenapine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2010/060971
Other languages
English (en)
Inventor
Werenfridus Adrianus Faassen
Gerardus Johannes Kemperman
Mohammad Shahid
Maria Louise Petra Stefanie Douglas-Van Iersel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Organon NV
Original Assignee
Organon NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Organon NV filed Critical Organon NV
Publication of WO2011012654A1 publication Critical patent/WO2011012654A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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
    • A61P25/18—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
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the compound of Formula A is known to have activity in the treatment of patients afflicted with central nervous system disorders (CNS disorders).
  • CNS disorders central nervous system disorders
  • CoI. 1 , lines 45 to 50 compounds like the compound of Formula I show in general a marked CNS -depressant activity, which can be used in the treatment of states of tension, excitation and anxiety, and in the treatment of psychotic and schizophrenic conditions and show as well excellent antihistamine and anti serotonin activities.
  • U.S. patent no. 5,763,476 (the '476 patent), filed March 9, 1995 as international application, no. PCT/EP95/00765, in CoI.
  • an asenapine salt for example, an a senapine maleic acid salt
  • an asenapine salt for example, an a senapine maleic acid salt
  • Compounds having atypical antipsychotic properties for providing treatment for many CNS diseases are always of interest, particularly compounds which may be used in injectable compositions or in oral compositions to provide acceptable therapeutic levels of asenapine in patients suffering from schizophrenia, bipolar disorder, or manic, depressive, or mixed episodes associated with bipolar disorder.
  • composition which is stable and provides activity as an atypical antipsychotic when administered to a patient in need of such therapy.
  • the i solated hydroxyasenapine compound is a compound of Formulae I, Il or III.
  • Another aspect of the present inventi on is the provision of isolated and/or purified derivatives of the hydroxyasenapine compounds of Formulae I, Il and III, particularly ester derivatives, wherein the position of the hydroxyl substituent of a compound of Formula I or Il in the ester derivati ve is occupied by an ester functional group, or wherein the position occupied by at least one of the hydroxyl substituents of the compound of Formula III is occupied by an ester functional group in the derivative compound.
  • Another aspect of the present i nvention is a pharmaceutical composition comprising at least one compound of Formula I, Formula II, or Formula III, or a derivative of at least one compound of Formulae I, II, or III, and one or more
  • composition suitable for depot administration for example, depot administration as described in U.S. provisional application no. 61/220027, filed June 24, 2009, which is incorporated by reference as if fully set forth herein.
  • Oxidation metabolites of asenapine and its salts including the compound of Formula II, h ave been noted in small amounts in human clinical studies.
  • Other oxidation products of asenapine and its salts for example the compounds of Formulae I and III, have not been observed but may be produced by metabolic oxidation when asenapine or its salts are administered to a human.
  • the inventors have surprisingly discovered that the hydroxyasenapine compounds of Formulae I, II, and III, and derivatives thereof, have activity as atypical antipsychotic compounds useful in the provision of treatment of CNS diseases in patients in need thereof, for example, in the treatment of schizophrenia, bipolar disorder, or manic, depressive, or mixed episodes associated with bipolar disorder .
  • Hydroxy compounds of Formulae I, II, and III may be prepared by modifying known processes for the preparation of asenapine, for example, the process for preparing asenapine described in U.S. Patent Application No. 12/341281 , filed
  • the compounds of the present invention can be prepared by substituting in the process es described in the '281 application, suitably substituted aryl compounds, for example, the compound of Formula Ma or IMa, which comprise methoxy substituents pendent upon the aryl precursor at the locations in which it is desirable for hydroxyl groups t o be present in the product compound.
  • hydroxyasenapine compounds for example the compound of Formula I, can be prepared by direct oxidation of asenapine, for example by acylating asenapine at the 1 1 -carbon position followed by oxidation of the resulting ketone to an ester, for example, by employing meta -chloroperoxybenzoic acid (m -CPBA), which may be converted to the corresponding alcohol (hydrox yl substituent) using base hydrolysis.
  • m -CPBA meta -chloroperoxybenzoic acid
  • ester functionalized compounds may have advantages in preparing pharmaceutical compositions for the treatment of schizophrenia, bipolar disorder, or manic, depressive, or mixed episodes associated with bipolar disorder .
  • hydroxyasenapine compounds of Formulae I, II, or III, or derivatives t hereof, for example, ester derivatives thereof can be mixed with one or more pharmaceutically acceptable excipients, for example, those described in Remington: The Science and Practice of Pharmacy, for example, the 21 st edition, to provide pharmaceutical compositions suitable for administration of these compounds in the provision of therapy for CNS diseases, for example, schizophrenia, bipolar disorder, or manic, depressive, or mixed episodes associated with bipolar disorder .
  • Salts of the compounds of For mulae I, II, or III, or their derivatives can be formed by ordinary means
  • isolated means that the compound has been obtained in a form which is removed from or separated from any physiological media or environment in which it naturally occurs.
  • purified means that the compound is present in at least about 70 wt.% of the form in which it has been isolated.
  • Trimethylamine ⁇ /-oxide dihydrate (3.12 g, 28.07 mmol) was slowly added to a solution of 18 prepared in Step 1 (7.09 g, 18.57 mmol) in THF (50 ml_), followed by addition of lithium diisopropylamide (2 M in THF/ n-heptane, 71.5 ml_, 143.00 mmol).
  • the mixture was stirred at rt and monitored by TLC (CH 2 CI 2 /EtOH, 9/1 ) and HPLC. After 3.5 h the reaction was quenched by addition of H 2 O (100 mL).
  • the resulting emulsion was treated with 4 M HCI to lower the pH from 1 1.5 to 9 and then extracted twice with AcOEt.
  • HBr (5 ml_) was added to a solu tion of 20 (1.16 g, 3.67 mmol) in acetic acid (18 ml_) and the mixture brought to reflux temperature (100 oC). The reaction was monitored by GC/MS. When no complete conversion was detected additional acetic acid (5 ml_) and HBr (5 ml_) were added. Stirring co ntinued for 16 h, the solvent was evaporated and the residue was coevaporated three times with toluene. The crude product was dissolved in AcOEt/NH 4 OH (1/1 , pH ⁇ 10) and extracted twice with AcOEt. The combined organic layers were dried over MgSO 4 , filtered and evaporated to dryness. Purification was performed by chromatography on silica gel with a gradient of toluene (100%) to toluene/EtOH (8/2) to afford 21 (520 mg, 1.73 mmol, 47%)
  • the compounds of Formulae I and Il were studied in rat models for their ability to inhibit amphetamine -stimulated locomotor activity in comparison to asenapine.
  • This rat model is believed to reflect dopamine receptor antagonism which is predictive of efficacy against CNS diseases, for example, schizophrenia, bipolar disorder, or manic, depressive, or mixed episodes associated with bipolar disorder .
  • Asenapine is a novel psychopharmacologic agent, acting as an antagonist at the dopamine D2 receptor subtype, as well as at multiple seroto nergic and adrenergic receptor subtypes , as described by M. Shadid M and EHF Wong in "Asenapine has unique human receptor binding signature ", World J. Biol Psychiatr 2005;6(suppl 1 ):306 , incorporated herein by reference as if fully set forth herein . As described by Mano and Kapur "Kapur S, Mano D. Haif a century of antipsychotics and still a central role for dopamine D2 receptors .
  • Rats Male Sprague-Dawley rats (Harlan), 130 to 150 g at time of arrival, were used. Rats were housed in groups of 5 for 7 to 10 days prior to testing, and weighed 180 to 200 g at the timeof testing. The housing room was maintained on a 12 -hour light/dark cycle, lights on at 6:00 hours and off at 18:00 hours. Food and water were available ad libitum. Tests occurred between 8:00 and16:00. All rats were food deprived overnight prior to testing. Rats were randomly assign ed to vehicle or drug treatment groups.
  • d-Amphetamine was dissolved in a solution of 0.9% saline.
  • the test or comparison drug (Asenapine, 1 1 -hydroxyasenapine (compound of Formula I), or 7 - hydroxyasenapine (compound of Formula III ) were dissolved or suspended in 1 % cremophor EL, 1 % 1 N HCI, and 0.5% methocel in water, which served as a vehicle control. All test compounds were solutions . Doses were expressed as the active moiety (ie, base) and were administered in a volume of 5 mL/kg.
  • Locomotor activity (LMA) testing in rats was performed using 16 -Beam Digiscan Animal Activity Monitors (Accuscan Electronics, Columbus, Ohio). Each test chamber consisted of a PLEXIGLAS® box measuring 16 x 16 x16 inches, surrounded by an activity monitor which use d the interruption of infrared light beams, 16 -per side, 1 -inch spacing, to measure locomotor activity. Each box was housed inside a stainless steel, ventilated, sound-attenuating chamber (SAC ). Lighting was provided in the chamber by two white incandescent lights and testing was carried out with one rat per chamber .
  • SAC ventilated, sound-attenuating chamber
  • Rats were weighed and dosed in a test room. Rats were dosed orally (PO) with drug or vehicle and then closed into a test chamber. After a n acclimation/absorption period (30 minutes), each rat was injected subcutaneously (SC) with 1 mg/kg d -amphetamine and returned to the chamb er whereupon recording of
  • LMA locomotor activity
  • test consisted of 4 groups, a vehicle control and 3 doses of the test compound. All groups received the same d -amphetamine treatment.
  • LMA was measured as centimeters traveled and expressed as percen t inhibition from the LMA measured with animals injected with vehicle control.
  • Statistical analysis was performed for the total distance traveled (cm) for the full 2-hour experimental period, using a one-way ANOVA followed by a post hoc Dunnett's test using dose as the single factor, significance set at p ⁇ 0.05.
  • Statistical analysis was performed using Jandel SigmaStat, which performs normality and variance testing as part of the ANOVA.
  • a common feature of most atypicals are the properties of dopamine D2 receptor antagonism along with moderate to potent serotonergic, adrenergic, and muscarinic activity, but asenapine and its deri vatives are novel psychopharmacologic agent with dopaminergic, serotonergic, and adrenergic antagonism having a preclinical receptor binding profile of high affinity binding to the dopamine D2 receptor and multiple serotonergic and adrenergic receptors.1 Inhibition of d-amphetamine-stimulated activity is a measure of D2 antagonism and serves as an indicator of antipsychotic potential.

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

Abstract

L'invention concerne des composés d'hydroxyasenapine isolés ou purifiés, leurs dérivés, notamment leurs dérivés d'ester, et des compositions pharmaceutiques les comprenant. L'invention concerne également des procédés de traitement les utilisant.
PCT/EP2010/060971 2009-07-29 2010-07-28 Composes d'hydroxy-asenapine, leurs derives et les compositions pharmaceutiques les comprenant Ceased WO2011012654A1 (fr)

Applications Claiming Priority (2)

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US22956009P 2009-07-29 2009-07-29
US61/229,560 2009-07-29

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WO2011012654A1 true WO2011012654A1 (fr) 2011-02-03

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AR (1) AR077429A1 (fr)
TW (1) TW201118102A (fr)
WO (1) WO2011012654A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105566336A (zh) * 2016-01-08 2016-05-11 万特制药(海南)有限公司 一种制备阿塞那平去甲基杂质的新方法
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
US12329862B2 (en) 2018-06-20 2025-06-17 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

Citations (3)

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US4145434A (en) 1976-05-24 1979-03-20 Akzona Incorporated Tetracyclic derivatives and pharmaceutical compositions of matter
US5763476A (en) 1994-03-02 1998-06-09 Akzo Noble N.V. Sublingual or buccal pharmaceutical composition
US20060084692A1 (en) 2004-10-15 2006-04-20 Pfizer Inc. Treatment of bipolar disorders and associated symptoms

Patent Citations (3)

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US4145434A (en) 1976-05-24 1979-03-20 Akzona Incorporated Tetracyclic derivatives and pharmaceutical compositions of matter
US5763476A (en) 1994-03-02 1998-06-09 Akzo Noble N.V. Sublingual or buccal pharmaceutical composition
US20060084692A1 (en) 2004-10-15 2006-04-20 Pfizer Inc. Treatment of bipolar disorders and associated symptoms

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M. SHADID M; EHF WONG: "Asenapine has unique human receptor binding signature", WORLD J. BIOL PSYCHIATR, vol. 6, no. 1, 2005, pages 306
NIEMEGEERS CJE; JANSSEN PAJ: "A systematic study of the pharmacological activities of dopamine antagonists", LIFE SCI, vol. 24, 1979, pages 2201 - 15
ROBERTS DCS; ZIS AP; FIBIGER HC: "Ascending catecholamine pathways and amphetamine-induced locomotor activity: Importance of dopamine and apparent noninvolvement of norepinephrine", BRAIN RESEARCH, vol. 93, 1975, pages 441 - 54
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SERPA KA; MOORE CL; MELTZER LT: "Effects of the Novel Psychopharmacological Ag ent Asenapine on Amphetamine", STIMULATED AND SPONTANEOUS LOCOMOTOR ACTIVITY IN THE RAT, 22 March 2006 (2006-03-22)
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105566336A (zh) * 2016-01-08 2016-05-11 万特制药(海南)有限公司 一种制备阿塞那平去甲基杂质的新方法
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
US12485099B2 (en) 2016-12-20 2025-12-02 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
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
US12329862B2 (en) 2018-06-20 2025-06-17 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

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AR077429A1 (es) 2011-08-24
TW201118102A (en) 2011-06-01

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