WO2001041750A2 - Nouvelles combinaisons therapeutiques de (s)-2-(benzylamino-methyl)-2,3,8,9,-tetrahydro-7h-1,4-dioxino[2,3-e]indol-8-one et neuroleptiques destines au traitement ou a la prevention de troubles psychotiques - Google Patents

Nouvelles combinaisons therapeutiques de (s)-2-(benzylamino-methyl)-2,3,8,9,-tetrahydro-7h-1,4-dioxino[2,3-e]indol-8-one et neuroleptiques destines au traitement ou a la prevention de troubles psychotiques Download PDF

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Publication number
WO2001041750A2
WO2001041750A2 PCT/US2000/033060 US0033060W WO0141750A2 WO 2001041750 A2 WO2001041750 A2 WO 2001041750A2 US 0033060 W US0033060 W US 0033060W WO 0141750 A2 WO0141750 A2 WO 0141750A2
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WO
WIPO (PCT)
Prior art keywords
antipsychotic
methyl
indol
dioxino
tetrahydro
Prior art date
Application number
PCT/US2000/033060
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English (en)
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WO2001041750A3 (fr
Inventor
Karen Lovell Marquis
Original Assignee
Wyeth
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
Priority to NZ519381A priority Critical patent/NZ519381A/en
Priority to IL14966900A priority patent/IL149669A0/xx
Application filed by Wyeth filed Critical Wyeth
Priority to MXPA02005649A priority patent/MXPA02005649A/es
Priority to JP2001543095A priority patent/JP5557409B2/ja
Priority to HU0203309A priority patent/HUP0203309A3/hu
Priority to EP00982461A priority patent/EP1235570A2/fr
Priority to EA200200656A priority patent/EA005002B1/ru
Priority to BR0016168-3A priority patent/BR0016168A/pt
Priority to AU19490/01A priority patent/AU784211B2/en
Priority to KR1020027007286A priority patent/KR100772854B1/ko
Priority to CA002396351A priority patent/CA2396351C/fr
Publication of WO2001041750A2 publication Critical patent/WO2001041750A2/fr
Publication of WO2001041750A3 publication Critical patent/WO2001041750A3/fr
Priority to IL149669A priority patent/IL149669A/en
Priority to NO20022739A priority patent/NO20022739L/no
Priority to HK02107378.5A priority patent/HK1045942A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to therapeutic combinations of (S)-2- (benzylaminomethyl)-2,3,8,9-tetrahydro-7H-l,4-dioxino[2,3-e]indol-8-one, a partial agonist of the dopamine D2/D3 receptors, and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders, to pharmaceutical compositions containing said combinations, and to their use in the treatment or prophylaxis of psychotic disorders.
  • Psychoses are serious mental illnesses characterized by defective or lost contact with reality. These disorders are characterized by a variety of symptoms which are classified as positive symptoms (disordered thought, hallucinations, and delusions), negative symptoms (social withdrawal and unresponsiveness), and cognitive deficits.
  • Neuroleptics or antipsychotics can be used to treat schizophrenia and other related psychotic disorders by blocking the dopaminergic neurotransmission in the central nervous system. Neuroleptics are used widely to treat the "positive" symptoms of schizophrenia. However, many of these drugs are not considered to be effective for the treatment of "negative” symptoms of schizophrenia and may in fact exacerbate these symptoms because of the dopaminergic blockade associated with their mechanism of action. Cognitive deficits associated with schizophrenia, such as distractability, and executive skills such as a working memory and ability to plan, are also believed to be negatively effected by the blockade of dopamine receptors.
  • these neuroleptics have important side effects such as akathisia, dystonia, Parkinsonism dyskinesia and late dyskinesia and the like, which are caused by blocking the dopaminergic neurotransmission.
  • Anticholinergic agents such as Cogentin®, have been used to reduce Parkinson-like side effects, but also cause side effects such as mental and/or physical impairment, tachycardia, dysuria and gastrointestinal symptoms.
  • Some partial dopamine agonists with relatively high intrinsic activity have been shown to have effectiveness against the negative symptoms of schizophrenia. It has been hypothesized that in this respect, some intrinsic activity is desirable to optimize the treatment of negative symptoms while minimizing side effects.
  • New combination drug therapies may be useful for treatment of patients. It is greatly desired to optimize the beneficial properties of both drugs, while minimizing the side effects associated with the drugs when given alone. Applicants have found useful therapeutic combination for the treatment of psychotic disorders.
  • Figure 1 is a schematic representation of the effect of (S)-2-(benzylamino- methyl)-2,3,8,9-tetrahydro-7H-l,4-dioxino[2,3-e]indol-8-one (agent) on haloperidol- induced catalepsy in rats at 60 minutes after drug treatment, the time point of greatest reversal as measured by seconds spent in catelepsy over a dose range of 0.003 to 3 mg/kg s.c. of agent.
  • the data are means + SEM.
  • Figure 2 is a schematic representation of the ability of (S)-2-(benzylamino- methyl)-2,3,8,9-tetrahydro-7H-l,4-dioxino[2,3-e]indol-8-one (agent) to induce catalepsy in rats as measured by seconds spent in catelepsy over a dose range of 0.003 to 3 mg/kg s.c. of agent.
  • the data are means + SEM.
  • Figure 3 is a schematic representation of the effect of (S)-2-(benzylamino- methyl)-2,3,8,9-tetrahydro-7H-l,4-dioxino[2,3-e]indol-8-one (agent) to reverse d-amphetamine induced hyperactivity in mice.
  • the data are expressed as a percentage of the activity level (horizontal activity counts) observed in mice treated with d-amphetamine alone for eight doses ranging from 0.0001 to 1 mg kg s.c. of agent.
  • the data are presented as means + SEM.
  • composition comprising (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-l,4-dioxino[2,3-e]- indol-8-one, or pharmaceutical salts thereof, and one or more antipsychotic agents.
  • Pharmaceutically acceptable salts include acid addition salts such as hydrochloric, fumaric, maleic, citric or succinic.
  • antipsychotic agent or neuroleptic agent includes those antipsychotics which work as a full antagonist of the dopamine D2 receptor and include both typical and atypical antipsychotics.
  • Representative antipsychotic agents that are commercially available or known to those skilled in the art and include, but are not limited to:
  • Chlorpromazine or 2-chloro-N,N-dimethyl- 1 OH-phenothiazine- 10-propan- amine, is described in U.S. Patent No. 2,645,640, which is incorporated by reference herein in its entirety.
  • Trifluoperazine or 10- [3-(4-methyl- 1 -piperazinyl)-propyl]-2-(trifluoro- methyl)- 1 OH-phenothiazine is described in GB 813,861 which is incorporated by reference herein in its entirety.
  • Perphenazine or 4-[3-(2-chloro-10H-phenothiazin-l-yl)propyl]-l-piperazine- ethanol, is described in U.S. Patent No. 2,766,235, which is incorporated by reference herein in its entirety.
  • Clozapine, or 8-chloro-l l-(4-methyl-l-piperazinyl)-5H-dibenzo[b,e]-[l,4]- diazepine is described in U.S. Patent No. 3,539,573, which is incorporated by reference herein in its entirety.
  • Haloperidol or 4-[4-(4-chlorophenyl)-4-hydroxy-l-piperidinyl]-l-(4-fluoro- phenyl)-l-butanone is described in U.S. Patent No. 3,438,991, which is incorporated by reference herein in its entirety.
  • Thiothixene or N,N-dimethyl-9-[3-(4-methyl- 1 -piperazinyl)-propylidene-9H- thioxanthene-2-sulfanamide is described in U.S. Patent No. 3,310,553, which is incorporated by reference herein in its entirety.
  • Sulphide, or 5-(aminosulfonyl)-N-[(l-ethyl-2-pyrolidinyl)methyl]-2-meth- oxybenzamide is described in U.S. Patent No. 3,342,826, which is incorporated by reference herein in its entirety.
  • Amisulpiride or 4-amino-N-[(l-ethyl-2-pyrrolidin-yl)methyl]-5-(ethyl- sulfonyl)-2-methoxybezamide, is described in U.S. Patent No. 4,401,822, which is incorporated by reference herein in its entirety.
  • Risperidone or 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidino]-ethyl]- imidazolidin-2-one, is described in U.S. Patent No. 4,804,663, which is incorporated by reference herein in its entirety.
  • Seroquel or 1 l-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,f]- [l,4]thiazepine, preparation is described in EP 240228, which is incorporated by reference herein in its entirety.
  • (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-l,4- dioxino[2,3-e]indol-8-one in combination with one or more antipsychotic agents is useful for the treatment or prevention of psychotic disorders associated with altered neurotransmission activity of the dopaminergic system in the central nervous system such as schizophrenia, schizoaffective disorder, acute mania, and depression with psychotic features, while eliminating or minimizing certain side affects associated with said antipsychotics when taken alone such as akathisia, dystonia, Parkinsonism dyskinesia and late dyskinesia and the like.
  • This invention also provides a product comprising (S)-2-(benzylamino- methyl)-2,3,8,9-tetrahydro-7H-l,4-dioxino[2,3-e]indol-8-one and an antipsychotic agent as a combined preparation for simultaneous, separate or sequential administration to treat a patient suffering from a psychotic disorder.
  • Combinations of (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-l,4-di- oxino[2,3-e]indol-8-one and one or more antipsychotics hereinafter referred to as "combinations” may be administered simultaneously, in the same or different pharmaceutical formulation, or sequentially.
  • the timing of the sequential administration should preserve the advantageous effects of the combination and said timing can be determined by a skilled practitioner.
  • a therapeutically acceptable amount of the combination will be understood to be an amount which treats, inhibits, prevents or ameliorates one or more symptoms of the psychotic disorder in question, preferably with fewer side effects than those associated with the administration of the antipsychotic agent alone.
  • the dosages of each of the drugs in the combination must be determined by a physician and will depend upon the specific psychotic disorder, as well as the size, age and response pattern of the patient. Dosage guidelines are provided here. For the combination, the dosage guideline for each of the drugs of the combination would be considered.
  • suitable doses of (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro- 7H-l,4-dioxino[2,3-e]indol-8-one range from about 0.5 mg per day to about 100 mg per day, and more preferably from about 1 to about 50 mg per day.
  • a suitable dose of antipsychotic agent will be in the range recommended by the manufacturer. The following guidelines are provided for some preferred antipsychotics of the present invention:
  • Chlorpromazine from about 300 to about 800 mg per day
  • Mesoridazine from about 100 to about 400 mg per day
  • Thioridazine from about 200 to about 600 mg per day; Fluphenazine: from about 2 to about 5 mg per day; Trifluoperazine: from about 6 to about 20 mg per day; Perphenazine: from about 8 to about 40 mg per day; Clozapine: from about 300 to about 600 mg per day:
  • Haloperidol from about 1 to about 20 mg per day; Loxapine: from about 60 to about 100 mg per day; Molindone: from about 15 to about 225 mg per day; Thiothixene: from about 20 to about 30 mg per day; Risperidone: from about 4 to about 20 mg per day;
  • Seroquel from about 15 to about 750 mg per day; and Olanzapine: from about 10 to about 20 mg per day.
  • compositions according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • the carriers must be acceptable in the sense of being compatible with the other ingredients in the formula.
  • a combination of (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-l,4- dioxino[2,3-e]indol-8-one and an antipsychotic agent may conveniently be presented as a pharmaceutical formulation in a unitary dosage form.
  • a convenient unitary dosage formulation contains the active ingredients in amounts from 0.1 mg to 1 g each, for example 5 mg to 100 mg.
  • Typical unit doses may, for example, contain about 0.5 to about 100 mg (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-l,4- dioxino[2,3-e]indol-8-one, and preferably about 1 mg to about 50 mg of (S)-2- (benzylamino-methyl)-2,3,8,9-tetrahydro-7H-l,4-dioxino[2,3-e]indol-8-one .
  • compositions may be prepared as "patient packs" containing the whole course of treatment in a single package, usually a blister pack.
  • Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in traditional prescriptions.
  • the inclusion of a package insert has been shown to improve patient compliance with the physician's instructions.
  • a patient pack comprising at least one active ingredient of the combination of the invention and an information insert containing directions on the use of the combination of the invention.
  • Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the formulations may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al., Remington's Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and their Manufacture).
  • Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • accessory ingredients include those conventional in the art, such as, fillers, binders, diluents, disintegrants, lubricants, colorants, flavouring agents and wetting agents.
  • Formulations suitable for oral administration may be presented as discrete units such as pills, tablets or capsules each containing a predetermined amount of active ingredient; as a powder or granules; as a solution or suspension.
  • the active ingredient may also be present as a bolus or paste, or may be contained within liposomes.
  • Formulations for rectal administration may be presented as a suppository or enema.
  • suitable formulations include aqueous and non- aqueous sterile injection.
  • the formulations may be presented in unit-dose or multi- dose containers, for example, sealed vials and ampoules, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water prior to use.
  • Formulations suitable for administration by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurized aerosols, nebulisers or insufflators.
  • side effects caused by treatment with haloperidol are influenced by concommitant treatment with (S)-2-(benzylamino- methyl)-2,3,8,9-tetrahydro-7H-l,4-dioxino[2,3-e]indol-8-one.
  • Tests for reversal of haloperidol-induced catalepsy in rats were conducted according to a variation of the methods of Svensson et al., Neuropharmacology, 1993, 32: 1037-1045. Rats (200 - 250g) were transported from the colony room to the experimental room and held there for the duration of the experiment. Haloperidol, dissolved in 0.25% Tween 80®, was administered to all animals at a dose of 3 mg/kg i.p.
  • Figure 1 is a schematic representation of the effect of (S)-2-(benzylamino- methyl)-2,3,8,9-tetrahydro-7H-l,4-dioxino[2,3-e]indol-8-one (agent) on haloperidol- induced catalepsy in rats at 60 minutes after drug treatment, the time point of greatest reversal.
  • the data are means + SEM.
  • a dose-dependent decrease in time spent in catalepsy position was observed.
  • a MED of 0.3 mg/kg and an ED 50 of 0.08 mg/kg were calculated from these results.
  • FIG. 1 is a schematic representation of the ability of (S)-2-(benzylamino- methyl)-2,3,8,9-tetrahydro-7H-l,4-dioxino[2,3-e]indol-8-one (agent) to induce catalepsy in rats.
  • the data are means + SEM.
  • mice 25 - 30g were transported from the colony room to the experimental room and held there for the duration of the experiment. The animals were habituated in the locomotor test chambers (an open field 8 X 8 in.) for 60 min prior to testing. Following the habituation period, d-amphetamine (2.5 mg/kg i.p., dissolved in distilled water) was administered to all animals. Fifteen minutes later, test compounds dissolved in 0.25% Tween 80® were administered s.c. at 8 dose levels to 8 mice per dose level. Control groups, assessed simultaneously with drug-treated groups, received vehicle at equal volumes (10 ml/kg). Immediately after administration of the test compound, animals were placed individually into the locomotor activity chambers. Activity was monitored for
  • Figure 3 is a schematic representation of the effect of (S)-2-(benzylamino- methyl)-2,3,8,9-tetrahydro-7H-l,4-dioxino[2,3-e]indol-8-one (agent) to reverse d-amphetamine induced hyperactivity in mice.
  • the data are expressed as a percentage of the activity level observed in mice treated with d-amphetamine alone and are presented as means + SEM.
  • a dose-dependent decreased in d-amphetamine-induced hyperactivity was observed.
  • An ED 50 of 0.002 mg/kg was calculated from these results.
  • compositions of the present invention reduce side effects induced by haloperidol as modeled by catelepsy, while not diminishing the ability of haloperidol to treat positive symptoms of schizophrenia as modeled by the amphetamine-induced hyperactivity.

Abstract

L'invention concerne des combinaisons thérapeutiques, utiles dans le traitement ou la prévention de troubles psychotiques; elle concerne également des compositions pharmaceutiques contenant ces combinaisons, ainsi que l'utilisation de celles-ci dans le traitement ou la prophylaxie de troubles psychotiques.
PCT/US2000/033060 1999-12-10 2000-12-07 Nouvelles combinaisons therapeutiques de (s)-2-(benzylamino-methyl)-2,3,8,9,-tetrahydro-7h-1,4-dioxino[2,3-e]indol-8-one et neuroleptiques destines au traitement ou a la prevention de troubles psychotiques WO2001041750A2 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
AU19490/01A AU784211B2 (en) 1999-12-10 2000-12-07 Combinations of (S)-2(benzylamino-methyl)-2,3,8,9,- tetrahydro-7H-1,4-dioxino(2,3)-E indol-8-one and neuroleptics
BR0016168-3A BR0016168A (pt) 1999-12-10 2000-12-07 Combinações terapêuticas de (s)-2-(benzilaminometil)-2,3,8,9tetrahidro-7h-1,4-dioxi no[2,3 -e]indol-8-ona e neurolépticos para o tratamento ou prevenção de distúrbios psicóticos
MXPA02005649A MXPA02005649A (es) 1999-12-10 2000-12-07 Nuevas combinaciones terapeuticas de (s)-2 -(bencilamino -metil)-2, 3, 8, 9-tetrahidro-7h -1, 4-dioxino(2-3 -e]indol-8 -ona y agentes neurolepticos para el tratamiento o prevencion de trastornos psicoticos.
IL14966900A IL149669A0 (en) 1999-12-10 2000-12-07 NEW THERAPEUTIC COMBINATIONS OF (S) -2-(BENZYLAMINO-METHYL)-2,3,8,9-TETRAHYDRO-7H-1,4-DIOXINO[2,3-e] INDOL-8-ONE AND NEUROLEPTICS FOR THE TREATMENT OR PREVENTION OF PSYCHOTIC DISORDERS
HU0203309A HUP0203309A3 (en) 1999-12-10 2000-12-07 Therapeutic combinations of (s)-2-(benzylamino-methyl)-2,3,8,9,-tetrahydro-7h-1,4-dioxino(2,3)-e indol-8-one and neuroleptics for treatment or prevention of phychotic disorders and pharmaceutical compositions containing them
EP00982461A EP1235570A2 (fr) 1999-12-10 2000-12-07 Nouvelles combinaisons therapeutiques de (s)-2-(benzylamino-methyl)-2,3,8,9,-tetrahydro-7h-1,4-dioxino 2,3-e]indol-8-one et neuroleptiques destines au traitement ou a la prevention de troubles psychotiques
KR1020027007286A KR100772854B1 (ko) 1999-12-10 2000-12-07 (Ｓ)-2-(벤질아미노-메틸)-2,3,8,9-테트라하이드로-7Ｈ-1,4-디옥시노[2,3-ｅ]인돌-8-온 및 항정신병 제제의 배합물
NZ519381A NZ519381A (en) 1999-12-10 2000-12-07 New therapeutic combinations of (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one and neuroleptics for the treatment or prevention of psychotic disorders
JP2001543095A JP5557409B2 (ja) 1999-12-10 2000-12-07 （ｓ）−２−（ベンジルアミノメチル）−２，３，８，９−テトラヒドロ−７ｈ−１，４−ジオキシノ（２，３）ｅインドール−８−オンと神経遮断薬との組合せ
EA200200656A EA005002B1 (ru) 1999-12-10 2000-12-07 НОВЫЕ ТЕРАПЕВТИЧЕСКИЕ КОМБИНАЦИИ (S)-2-(БЕНЗИЛАМИНОМЕТИЛ)-2,3,8,9-ТЕТРАГИДРО-7H-1,4-ДИОКСИН [2,3-e]ИНДОЛ-8-ОНА И НЕЙРОЛЕПТИКОВ ДЛЯ ЛЕЧЕНИЯ ИЛИ ПРЕДОТВРАЩЕНИЯ ПСИХОТИЧЕСКИХ РАССТРОЙСТВ
CA002396351A CA2396351C (fr) 1999-12-10 2000-12-07 Nouvelles combinaisons therapeutiques de (s)-2-(benzylamino-methyl)-2,3,8,9,-tetrahydro-7h-1,4-dioxino[2,3-e]indol-8-one et neuroleptiques destines au traitement ou a la prevention de troubles psychotiques
IL149669A IL149669A (en) 1999-12-10 2002-05-15 Combinations of (S) - 2) Benzylamino – methyl) 2,9,8,3,2 –– Tetrahydro-H7–1, 4 – Dioxino] E – 3,2 [Indole-8 – on and neuroleptic for the treatment or prevention of Psychotic arrangements
NO20022739A NO20022739L (no) 1999-12-10 2002-06-07 Nye terapeutiske kombinasjoner av (S)-2-(benzylamino-metyl)-2,3,8,9-tetrahydro-7H-1,4-dioksino[2,3-e]indol-8-on og nevroleptika for behandling eller forhindring av psykotiske lidelser
HK02107378.5A HK1045942A1 (zh) 1999-12-10 2002-10-09 結合(s)-2-(苄胺甲基)-2，3，8，9，-四氫-7h-1，4-二氧(2，3)吲-8-酮及精神抑制藥

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US45860799A 1999-12-10 1999-12-10
US09/458,607 1999-12-10

Publications (2)

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WO2001041750A2 true WO2001041750A2 (fr) 2001-06-14
WO2001041750A3 WO2001041750A3 (fr) 2002-02-14

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PCT/US2000/033060 WO2001041750A2 (fr) 1999-12-10 2000-12-07 Nouvelles combinaisons therapeutiques de (s)-2-(benzylamino-methyl)-2,3,8,9,-tetrahydro-7h-1,4-dioxino[2,3-e]indol-8-one et neuroleptiques destines au traitement ou a la prevention de troubles psychotiques

Country Status (20)

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EP (1) EP1235570A2 (fr)
JP (1) JP5557409B2 (fr)
KR (1) KR100772854B1 (fr)
CN (1) CN1230164C (fr)
AR (1) AR026756A1 (fr)
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US10292966B2 (en) 2003-10-29 2019-05-21 Wyeth Llc Sustained release pharmaceutical compositions

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WO1998029415A1 (fr) * 1996-12-27 1998-07-09 Knoll Aktiengesellschaft Derives de heteroarylsulfamide et compositions pharmaceutiques les contenant

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
US10292966B2 (en) 2003-10-29 2019-05-21 Wyeth Llc Sustained release pharmaceutical compositions
US10463648B2 (en) 2003-10-29 2019-11-05 Wyeth, Llc Sustained release pharmaceutical compositions
US11179369B2 (en) 2003-10-29 2021-11-23 Wyeth Llc Sustained release pharmaceutical compositions
US7297704B2 (en) 2005-02-17 2007-11-20 Wyeth Cycloalkyfused indole, benzothiophene, benzofuran and idene derivatives

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EP1235570A2 (fr) 2002-09-04
IL149669A0 (en) 2002-11-10
NZ519381A (en) 2004-04-30
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AU784211B2 (en) 2006-02-23
CA2396351C (fr) 2009-11-10
KR20030016207A (ko) 2003-02-26
WO2001041750A3 (fr) 2002-02-14
EA200200656A1 (ru) 2002-12-26
CN1409633A (zh) 2003-04-09
TWI222864B (en) 2004-11-01
MXPA02005649A (es) 2004-09-10
CA2396351A1 (fr) 2001-06-14
HUP0203309A3 (en) 2004-12-28
CN1230164C (zh) 2005-12-07
HK1045942A1 (zh) 2002-12-20
AU1949001A (en) 2001-06-18
HUP0203309A2 (hu) 2003-01-28
NO20022739L (no) 2002-06-07
AR026756A1 (es) 2003-02-26
BR0016168A (pt) 2002-08-20
JP2003516350A (ja) 2003-05-13
KR100772854B1 (ko) 2007-11-02
EA005002B1 (ru) 2004-10-28

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