WO2011088836A1 - Nouveaux dérivés de 4-(aryl-4-sulfonyl)-6,6a,7,8,9,10-hexahydro-4h-4,8,10a-triaza-acéphénanthrylène et 3-arylsulfonyl-6,6a,7,8,9,10-hexahydro-3h-3,8,10a-triaza-cyclopenta[c]fluorène en tant que ligands de sérotonine 5-ht6 - Google Patents

Nouveaux dérivés de 4-(aryl-4-sulfonyl)-6,6a,7,8,9,10-hexahydro-4h-4,8,10a-triaza-acéphénanthrylène et 3-arylsulfonyl-6,6a,7,8,9,10-hexahydro-3h-3,8,10a-triaza-cyclopenta[c]fluorène en tant que ligands de sérotonine 5-ht6 Download PDF

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WO2011088836A1
WO2011088836A1 PCT/DK2011/050017 DK2011050017W WO2011088836A1 WO 2011088836 A1 WO2011088836 A1 WO 2011088836A1 DK 2011050017 W DK2011050017 W DK 2011050017W WO 2011088836 A1 WO2011088836 A1 WO 2011088836A1
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Prior art keywords
disorder
hexahydro
triaza
compound
acephenanthrylene
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PCT/DK2011/050017
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English (en)
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Jan Kehler
Niels Krogsgaard-Larsen
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H. Lundbeck A/S
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Publication of WO2011088836A1 publication Critical patent/WO2011088836A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • 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

Definitions

  • the present invention provides compounds that are serotonin 5-HT 6 ligands, and as such are useful to treat neurodegenerative and psychiatric disorders.
  • the present invention also provides pharmaceutical compositions comprising
  • Cognitive dysfunction is a feature of various forms of dementia such as Alzheimer's disease (AD) and a core feature of schizophrenia (see e.g. Peuskens, J.; Demily, C; Thibaut, F. Clin. Ther. 2005, 27, S25; BowieChristopher, R.; Jaga, K. Expert Rev. Neurother. 2007, 7, 281 ; Kuperberg, G.; Heckers, S. Curr. Opin.
  • AD Alzheimer's disease
  • schizophrenia see e.g. Peuskens, J.; Demily, C; Thibaut, F. Clin. Ther. 2005, 27, S25; BowieChristopher, R.; Jaga, K. Expert Rev. Neurother. 2007, 7, 281 ; Kuperberg, G.; Heckers, S. Curr. Opin.
  • the 5-HT 6 receptor was first cloned in 1993 and is one of the most recently discovered 5-HT receptor subtypes and is an emerging therapeutic target for cognitive enhancement (Monsma, F. J., Jr.; Shen, Y.; Ward, R. P.; Hamblin, M. W.; Sibley, D. R. Mol. Pharmacol. 1993, 43, 320 ; Ruat, M.; Traiffort, E.; Arrang, J. M.; Tardivel-Lacombe, J.; Diaz, J.; Leurs, R.; Schwartz, J. C. Biochem. Biophys. Res. Commun. 1993, 193, 268).
  • the 5-HT 6 receptor is a member of the G-protein superfamily, and is positively coupled to adenylate cyclase. It is localized almost exclusively in the brain, including areas important for memory and learning e.g. the cerebral cortex and hippocampus and also in the nucleus accumbens, striatum, olfactory tubercle, substantia nigra, and hippocampus of the brain (Ward et al., Neuroscience, 1995, 64:1 105).
  • WO 2008/147812 discloses 4'-substituted compounds having 5-HT 6 receptor affinity with the general formula P1 exemplified with the compound P1 , ex as selective 5-HT 6 receptor ligands for the treatment of certain neurologic and psychiatric disorders.
  • WO 02/102774 discloses 4-piperazinylindole derivatives having 5-HT 6 receptor affinity with the general formula P2 exemplified with the compound P2, ex as selective 5-HT 6 receptor antagonists for the treatment of disorders of the CNS, particularly wherein the disease state comprises psychoses, schizophrenia, manic depressions, neurological disorders, memory disorders, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease.
  • WO 02/32863 discloses 2-, 3-, 4- or 5-substituted N1 - (benzenesulfonylindoles) having 5-HT 6 receptor affinity with the general formula P3 exemplified formula P3, ex as 5-HT 6 antagonists for treating obesity and
  • WO 02/32562 discloses 1 -aryl or 1 -alkylsulfonyl-heterocyclylbenzazole derivatives having 5-HT 6 affinity with the general formulas P4A and P4B exemplified with the compound of formula P4, ex as 5-HT 6 ligands for treating 5-HT 6 receptor- mediated central nervous system diseases and neurodegenerative disorders.
  • WO 02/41889 discloses indole sulfonamide compounds having 5-HT 6 affinity with the general formula P5 exemplified with the compound of formula P5, ex as 5- HT li ands for the treatment of CNS disorders.
  • the compounds of the present invention may offer alternatives to current marketed treatments for neurodegenerative and/or psychiatric disorders, which are not efficacious in all patients.
  • novel compounds with potent activity at the 5-HT 6 receptor.
  • novel compounds with improved properties relative to known compounds which are 5-HT 6 ligands. Improvement of one or more of the following parameters is desired: half-life, clearance, selectivity, interactions with other medications, bioavailability, potency, formulability, chemical stability, metabolic stability, membrane permeability, solubility and therapeutic index. The improvement of such parameters may lead to improvements such as:
  • the objective of the present invention is to provide compounds that are serotonin 5-HT 6 ligands.
  • a further objective of the present invention is to provide compounds which have such activity, and which have improved solubility, metabolic stability and/or bioavailability compared to prior art compounds.
  • Another objective of the invention is to provide an effective treatment, in particular long-term treatment, of a human patient, without causing the side effects typically associated with current therapies for neurological and psychiatric disorders.
  • the invention further provides a compound of formula I or II, or a
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or II, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier or excipient.
  • the invention further provides a compound of formula I or II, or a
  • the invention further provides the use of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in the treatment of a neurodegenerative or psychiatric disorder.
  • the present invention provides a method of treating a subject suffering from a neurodegenerative or psychiatric disorder, which method comprises administering a therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • alkyl is intended to indicate a straight, branched and/or cyclic saturated hydrocarbon.
  • d-salkyl is intended to indicate such hydrocarbon having 1 , 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
  • Examples of Ci-salkyl include but are not limited to methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methyl-propyl, tert-butyl, and
  • alkenyl is intended to indicate a non-aromatic, straight, branched and/or cyclic hydrocarbon comprising at least one carbon-carbon double bond.
  • C2-8alkenyl is intended to indicate such hydrocarbon having 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
  • Examples of C2-8alkenyl include ethenyl, 1 - propenyl, 2-propenyl, 1 -butenyl, 2-butenyl, 3-butenyl, and cyclohexenyl.
  • alkynyl is intended to indicate a non-aromatic, straight, branched and/or cyclic hydrocarbon comprising at least one carbon-carbon triple bond and optionally also one or more carbon-carbon double bonds.
  • C2-6alkynyl is intended to indicate such hydrocarbon having 2, 3, 4, 5, or 6 carbon atoms. Examples of C2-6alkynyl include ethynyl, 1 -propynyl, 2-propynyl, 1 - butynyl, 2-butynyl, 3-butynyl and 5-but-1 -en-3-ynyl.
  • Ci-6alkoxy refers to a straight-chain or branched saturated alkoxy group having from one to six carbon atoms, inclusive, with the open valency on the oxygen. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-butoxy, 2-methyl-pentoxy and n-hexyloxy.
  • Ci-6alkylsulfanyl refers to a straight-chain or branched saturated alkylsulfanyl group having from one to six carbon atoms, inclusive.
  • Examples of such groups include, but are not limited to, methylsulfanyl,
  • a pharmaceutically acceptable salt include salts of inorganic acids as well as organic acids.
  • suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8- halotheophyllines, for example 8-bromotheophylline and
  • pharmaceutically acceptable carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • neuropeptide agent refers to drugs, which have the effect on cognition and behaviour of antipsychotic agent drugs that reduce
  • neuroleptic agents include, but are not limited to: typical antipsychotic drugs, including phenothiazines, further divided into the aliphatics, piperidines, and piperazines, thioxanthenes (e.g., cisordinol), butyrophenones (e.g., haloperidol),
  • dibenzoxazepines e.g., loxapine
  • dihydroindolones e.g., molindone
  • diphenylbutylpiperidines e.g., pimozide
  • atypical antipsychotic drugs including benzisoxazoles (e.g., risperidone), sertindole, olanzapine, quetiapine, osanetant and ziprasidone.
  • Particularly preferred neuroleptic agents for use in combination with the compounds of the present invention are sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.
  • 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.
  • the term "therapeutically effective amount" of a compound means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound.
  • An amount adequate to accomplish this is defined as “therapeutically effective amount”.
  • Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.
  • treatment means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder.
  • the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatments are two separate aspects of the invention.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • compounds of the present invention generally have a low intrinsic clearance, which leads to good metabolic stability. Furthermore, compounds of the present invention have a low propensity for side effects related to drug-drug interactions since they are only weak inhibitors of the five most abundant human cytochrome P450 enzymes.
  • R1-R5 is independently selected from hydrogen, halogen, cyano, nitro, -NH 2 , -CONH2, hydroxy, Ci-salkyl, C2-8alkenyl, C2-6alkynyl, Ci-6alkoxy or Ci- 6 alkylsulfanyl wherein said Ci-salkyl, C2-8alkenyl or C2-6alkynyl is optionally
  • the compounds of the invention are defined by formula I, wherein R1-R5 is independently selected from hydrogen, halogen, cyano, nitro, -NH 2 , -CONH2, hydroxy, Ci-salkyl, C2-8alkenyl, C2-6alkynyl, Ci-6alkoxy or Ci- 6 alkylsulfanyl wherein said Ci-salkyl, C ⁇ -salkenyl or C2-6alkynyl is optionally
  • R1-R5 is independently selected from hydrogen, halogen, Ci- 6 alkoxy or Ci-salkyl.
  • At least one of Ri , R2, R3, R 4 and R 5 is Ci-6alkoxy, such as methoxy.
  • At least one of Ri , R2, R3, R 4 and R 5 is halogen, such as chlorine or fluorine.
  • At least one of Ri , R2, R3, R 4 and R 5 is Ci-salkyl, such as methyl.
  • Ri , R2, R 4 and R 5 is not hydrogen and R3 is hydrogen.
  • Ri , R 2 , R3, R 4 and R 5 are all hydrogen.
  • R 2 is methyl. In another specific embodiment, R 2 is fluorine. In another specific embodiment, R 2 is chlorine. In another specific embodiment, R 2 is methoxy.
  • R 3 is methyl. In another specific embodiment, R 3 is fluorine. In another specific embodiment, R 3 is chlorine. In another specific embodiment, R 3 is methoxy.
  • the compounds of the present invention may have one or more asymmetric centers and it is intended that any optical isomers (i.e. enantiomers or
  • Racemic forms can be resolved into the optical antipodes by known methods, for example by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography of an optically active matrix.
  • the compounds of the present invention may also be resolved by the formation of diastereomeric derivatives.
  • Optically active compounds can also be prepared from optically active starting materials.
  • the compounds of the present invention are in the form of a single isomer (enantiomer).
  • geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention.
  • molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.
  • the compounds of the present invention can be used independently as the sole active ingredient for treatment of a disease or they can be used in combination therapy.
  • Table 1 lists compounds of the invention and the corresponding Ki values determined as described in the section "5-HT 6 binding assay".
  • Each of the compounds, in the form of the free base, one or more isomers thereof or a pharmaceutically acceptable salt thereof, constitutes an individual embodiment, of the present invention:
  • the present invention further provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable carrier or excipient.
  • the present invention also provides a
  • composition comprising a therapeutically effective amount of one of the specific compounds disclosed in the Experimental Section herein, or a
  • compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with
  • compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules.
  • Liquid dosage forms for oral administration include solutions, emulsions,
  • compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • suppositories suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.
  • Typical dosages range from about 0.001 to about 100 mg/kg body weight per day such as from about 0.01 to about 50 mg/kg body weight per day preferably from about 0.05 to about 10 mg/kg body weight per day.
  • Oral dosages are usually administered in one or more dosages, typically, one to three dosages per day. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg such as from about 0.05 to about 500 mg such as from about 0.5 mg to about 200 mg.
  • the present invention also provides a process for making a pharmaceutical composition
  • a pharmaceutical composition comprising mixing a therapeutically effective amount of a compound of the present invention and at least one pharmaceutically acceptable carrier.
  • the compound used in the aforementioned process is one of the specific compounds disclosed in the Experimental Section herein.
  • the pharmaceutical compositions formed by combining the compounds of the present invention and a pharmaceutically acceptable carrier are readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. Such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula I or II with an equivalent of a pharmaceutically acceptable acid. Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
  • solutions of the compounds of the present invention in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or in oily solutions such as sesame or peanut oil may be employed.
  • Aqueous solutions might be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal
  • the compounds of the present invention may be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and optionally a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in- water or water-in-oil liquid emulsion.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per dosage unit.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • compositions of the invention may be prepared by conventional methods in the art.
  • tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine prepare tablets.
  • adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colorings, flavorings, preservatives etc. may be used provided that they are compatible with the active ingredients.
  • the compounds of the present invention are 5-HT 6 ligands and as such are useful to treat associated neurological and psychiatric disorders.
  • the invention thus relates to a compound of the present invention, as well as a pharmaceutical composition containing such a compound, for use in the treatment of a neurodegenerative or psychiatric disorder, alone or in combination with one or more neuroleptic agents such as sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease; multi-infarct dementia; alcoholic dementia or other drug-related dementia; dementia associated with intracranial tumors or cerebral trauma; dementia associated with Huntington's disease or Parkinson's disease; AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder; a learning disorder selected from reading disorder, mathematics disorder or a disorder of written expression;
  • neuroleptic agents such as sertindole, olanzapin
  • the psychiatric disorder is selected from the group consisting of schizophrenia;
  • schizophrenia of the paranoid, disorganized, catatonic, undifferentiated or residual type schizophreniform disorder; schizoaffective disorder; a schizoaffective disorder selected from the delusional type or a schizoaffective disorder from the depressive type; delusional disorder; bipolar disorder; bipolar I disorder; bipolar II disorder; cyclothymic disorder; substance-induced psychotic disorder; substance-induced psychotic disorder induced by alcohol, amphetamine, cannabis, cocaine,
  • the invention relates to the use of a compound of the present invention, for the preparation of a medicament for the treatment of a neurodegenerative or psychiatric disorder, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease; multi-infarct dementia; alcoholic dementia or other drug-related dementia; dementia associated with intracranial tumors or cerebral trauma; dementia associated with Huntington's disease or Parkinson's disease; AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder; a learning disorder selected from reading disorder, mathematics disorder or a disorder of written expression; attention-deficit/hyperactivity disorder and age-related cognitive decline, and the psychiatric disorder is selected from the group consisting of schizophrenia; schizophrenia of the paranoid, disorganized, catatonic,
  • schizophreniform disorder schizoaffective disorder
  • schizoaffective disorder a schizoaffective disorder selected from the delusional type or a
  • schizoaffective disorder from the depressive type delusional disorder; bipolar disorder; bipolar I disorder; bipolar II disorder; cyclothymic disorder; substance- induced psychotic disorder; substance-induced psychotic disorder induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids or phencyclidine; personality disorder of the paranoid type and personality disorder of the schizoid type.
  • the treatment of psychiatric disorders comprises co-administration of one or more neuroleptic agents such as sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.
  • neuroleptic agents such as sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.
  • the invention relates to a method of treating a subject suffering from a neurodegenerative or psychiatric disorder, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease; multi-infarct dementia; alcoholic dementia or other drug-related dementia; dementia associated with intracranial tumors or cerebral trauma; dementia associated with Huntington's disease or Parkinson's disease; AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder; a learning disorder selected from reading disorder, mathematics disorder or a disorder of written expression; attention- deficit/hyperactivity disorder and age-related cognitive decline, and the psychiatric disorder is selected from the group consisting of schizophrenia; schizophrenia of the paranoid, disorganized, catatonic, undifferentiated or residual type;
  • schizophreniform disorder schizoaffective disorder; a schizoaffective disorder selected from the delusional type or a schizoaffective disorder from the depressive type; delusional disorder; bipolar disorder; bipolar I disorder; bipolar II disorder; cyclothymic disorder; substance-induced psychotic disorder; substance-induced psychotic disorder induced by alcohol, amphetamine, cannabis, cocaine,
  • a therapeutically effective amount of a compound of the present invention comprises administering a therapeutically effective amount of a compound of the present invention, alone or in combination with one or more neuroleptic agents such as sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.
  • neuroleptic agents such as sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.
  • the invention relates to a compound of the present invention for use in therapy.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present invention have utility. Additionally, the compounds of the present invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the present invention. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or
  • compositions of the present invention include those that contain one or more other active ingredients, in addition to the compounds of the present invention.
  • the combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen.
  • psychiatric disorders such as schizophrenia.
  • the combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are resistant to other known treatments.
  • This invention also provides a method of treating drug addiction a subject wherein the drug addiction is an alcohol, amphetamine, cocaine, or opiate addiction, which method comprises administering to said mammal a therapeutically effective amount of a compound of the present invention.
  • This invention further provides a method of treating a subject suffering from a disorder comprising as a symptom a deficiency in attention and/or cognition in a subject which method comprises administering to said subject an amount of a compound of the present invention effective in treating said disorder.
  • disorders that can be treated according to the present invention are obsessive/compulsive disorders; mood disorders and mood episodes such as major depressive disorder or minor depressive disorder; movement disorders such as dyskinesia associated with dopamine agonist therapy; restless leg syndrome;
  • Tourette's syndrome and other tic disorders are examples of Tourette's syndrome and other tic disorders.
  • the invention relates to a method of treatment, said method comprising the administration of a therapeutically effective amount of a compound of the present invention to a patient in need thereof.
  • This reaction is typically carried out in a solvent such as e.g. diethylether or dichloromethane, containing an acid like e.g. trifluoracetic acid or hydrochloric acid.
  • the reaction can be performed at a temperature ranging from about 0° C to about 200° C, but preferably at room temperature.
  • the product compounds of formula I might conveniently be isolated as a salt e.g. a hydrochloride salt.
  • the intermediates IMA can be prepared from commercially available 4-(1 H- indol-4-yl)piperazine-1 -carboxylic acid tert-butyl ester VA (Beta Pharma, Inc., catalog number AB153541 ) by the reaction sequence shown in scheme 2.
  • the introduction of the protecting group -C(O)O-PG is performed by standard reactions using methods well known to chemists skilled in the art.
  • This reaction is typically carried out in a solvent such as e.g. diethylether or dichloromethane, containing an acid like e.g. trifluoracetic acid or hydrochloric acid.
  • a solvent such as e.g. diethylether or dichloromethane
  • the reaction can be performed at a temperature ranging from about 0° C to about 200° C, but preferably at room temperature.
  • the product compounds of formula I might conveniently be isolated as a salt e.g. a hydrochloride salt.
  • the intermediates XIA can be prepared from commercially available 4- piperazino indole IV by the reaction sequence shown in scheme 2 and scheme 4.
  • the introduction of the protecting group -C(O)O-PG is performed by standard reactions using methods well known to chemists skilled in the art.
  • This reaction is typically carried out in a suitable solvent, such as ethanol, methanol, dioxane, dimethylformamide, dimethylacetamide, or acetonitrile, in the presence of a suitable catalyst such as a palladium on charcoal or platinum, at a temperature ranging from about 0° C to about 100° C.
  • a suitable solvent such as ethanol, methanol, dioxane, dimethylformamide, dimethylacetamide, or acetonitrile
  • NMR spectra were recorded on a Bruker Avance AV-500 (500 MHz) using deuterated chloroform (CDCI 3 ), DMSO ((CD 3 ) 2 SO), methanol (CD 3 OD) or water (D 2 O) with TMS as internal reference standard in the chloroform and DMSO.
  • Biosystems consisting of the following equipment: Applied Biosystems API150ex single quadrupole mass spectrometer with atmospheric pressure photo ionization (APPI) ionsource, Gilson 333 pump (master), Gilson 334 pump (slave), Gilson GX 281 autosampler/fraction collector, Shimadzu LCI OADvp pump (x2), Gilson UVA/IS 155 UV detector, Gilson 506C system interface, water bath for column and solvent heating, passive flowsplitter (approx. 1 :1000), The MS and fraction collector are controlled by Masschrom software. Method: Duration: app: 7.5 min. pr.
  • Biosystems with the following equipment Applied Biosystems API300 triple quadrupole mass spectrometer with atmospheric pressure photoionization (APPI) ionsource, Shimatsu LCI OADvp LC pumps (3X), acquity UPLC core system w/column manager (including UPLC binary solvent manager), acquity UPLC sampler organizer, acquity UPLC PDA detector with an analytical flow cell, acquity UPLC ELS detector.
  • APSI atmospheric pressure photoionization
  • the HRMS performed were generated on an Agilent/Bruker Daltonics LC- SPE-MS consisting of the following components: Agilent 1 100 quaternary pump with degasser, Agilent 1 100 automatic sample injector, Agilent 1 100 variable wavelength detector (VWD), Agilent diode-array detector (DAD), Agilent 1200 column oven, Spark Prospectll automatic cartridge exchanger (ACE) and high-pressure dilutor (HPD) for peak trapping on solid-phase-exchange (SPE) cartridges.
  • Agilent 1 100 quaternary pump with degasser Agilent 1 100 automatic sample injector
  • Agilent 1 100 variable wavelength detector (VWD) Agilent diode-array detector
  • ACE Spark Prospectll automatic cartridge exchanger
  • HPD high-pressure dilutor
  • benzyltriethylammonium chloride (20 mg, 0.09 mmol) were dissolved in 10 mL toluene and added 5 mL water and 5 mL NaOH (28 %). The mixture was stirred vigorously for 45 min at room temperature. The mixture was added EtOAc and poured into water. The organic phase was washed with brine, dried with MgSO 4 , filtered, concentrated in vacuo on celite® (545 coarse) and purified by flash chromatography (FM) to yield 563 mg (92 %) of clear colorless oil/white foam.
  • FM flash chromatography
  • Benzyl 4-(Toluene-4-sulfonyl)-4,6,6a,7,9,10-hexahydro-4,8,1 Oa-triaza- acephenanthrylene-8-carboxylate (0,245 g, 0.49 mmol) was dissolved in 3 mL DMSO and added 1 .5 mL 20 % KOH. The mixture was microwaved at 150 °C for 4 minuts and then added a large amount of EtOAc. The organic phase was washed with a combination of NH CI and sat. NaHCO3, then twice with brine, dried over MgSO 4 , filtered and concentrated in vacuo.
  • Benzyl 4-(5-Formyl-1 H-indol-4-yl)-piperazine-1 -carboxylate (1 .338 g, 3.68 mmol), tosyl chloride (813 mg, 4.26 mmol) and benzyltriethylammonium chloride (60 mg, 0.26 mmol) were dissolved in 20 mL toluene and added 10 mL water and 10 mL NaOH (28 %). The mixture was stirred vigorously for 45 min at room temperature. The mixture was added EtOAc and poured into water.
  • the mixture was removed several times from the sonification and placed in the ice-bath for short periods of time due to a raise in the temperature that caused refluxing of the solvent.
  • the mixture was filtered through celite and concentrated in vacuo to yield a white gel.
  • the reaction mixture was transferred to a separation funnel containing 0.1 M HCI and Et 2 O.
  • the aqueous phase was extracted 3 times with Et 2 O.
  • the combined organic phases were washed with sat.
  • the combined organic phases were pooled, washed with brine and the aqueous phase extracted with toluene.
  • the combined organic phases were dried over MgSO 4 , filtered and concentrated in vacuo.
  • the product was purified by flash chromatography (FM) and concentrated in vacuo to yield a clear oil.
  • the oil was redissolved in 1 .5 ml_ Et 2 O and 1 .5 MeOH before 1 .5 ml_ 2M HCI in Et 2 O was added.
  • the mixture was stirred at room temperature for 24 h.
  • the mixture was concentrated in vacuo, dissolved in water and added 2M NaOH and EtOAc.
  • the organic phase was isolated and the aqueous phase extracted with EtOAc.
  • the combined organic phases were washed with brine and after extraction of the aqueous phase with EtOAc the combined organic phases were dried over MgSO 4 , filtered and concentrated in vacuo.
  • the BHK cells were maintained at 37°C in a humidified 5% CO2 incubator in culture medium [Dulbecco's Modified Eagle Medium supplemented with penicillin (100 U/ml), streptomycin (100 pg/ml) and 10 % FetaClonel serum].
  • the cells were split into 14 cm tissue culture dishes and the following day transfected with h5-HT 6 -pCR4-TOPO (Guthrie HTR0600000- 01 ) using Lipofectamine 2000 ® (InVitrogen, Carlsbad, CA) as a DNA carrier according to the manufacturer's protocol. 4-6 h later the culture medium was changed. Cells were grown to 90-95% confluence, and harvested using a cell scraper.
  • [ 3 H]LSD Binding Competition binding to membranes of BHK-h5-HT 6 cells transiently expressing the human 5-HT 6 receptor using [ 3 H]LSD ([/V-methyl- 3 H]Lysergic acid deithylamide, 81 .0 Ci/mmol, GE Healthcare, Buckinghamshire, UK) was performed. Cells were harvested and scraped into d-PBS, homogenized using an UltraTurrax for 20 sec, centrifuged 40 min @ 40000 x g and frozen.
  • Intracellular cAMP levels were measured using 24-well plates containing the human 5-HT 6 receptor stabily transfected into HELA cells. Upon initiation of the assay, the media from the cell maintenance was aspirated and the cells were preincubated at 37°C for 15 min in KREBS buffer. Following this primary incubation, the buffer was aspirated and an additional incubation was performed at 37°C for 5 min in KREBS buffer containing 500 ⁇ IBMS (3-isobutyl-1 -methylxanthine).
  • the cells were incubated with the test compound at concentrations ranging from 10-5 to 10-10 M for 10 min at 37°C (antagonist assay required a second incubation with the addition of 100 nM 5-HT). The assay was terminated by the addition of 0.5 M percloric acid. Intracellular cAMP levels were determined by radioimmunoassay through the cAMP SPA screening kit. Data were analyzed graphically with GraphPad Prism (GraphPad Software, San Diego, CA).
  • the metabolic stability has been determined by incubation of the test compound at 1 ⁇ with human and rat microsomes (BD Biosciences) for 60 min, using NADPH as co-factor.
  • NADPH NADPH regenerating system containing NADP+, glucose-6-phosphate dehydrogenase, glucose-6-phosphate, sodium citrate and MgC (co-factor mix) was used as a source of NADPH.
  • the microsomes were stored in -80°C, and test tubes with prepared co-factor mix were stored in the freezer until use.
  • the incubation was performed using a liquid handling robot (LHR, Tecan) and the analysis using liquid-chromatography coupled to a tandem mass spectrometer (LC-MS/MS, Waters QuattroMicro, Manchester, UK)
  • Cytochrome P450 (CYP) inhibition was performed using recombinant enzymes (SupersomesTM, Gentest) expressing individual CYP enzymes (CYP1A2, CYP3A4, CYP2C9, CYP2C19 and CYP2D6).
  • the inhibitions by the test items were assessed by incubating each enzyme with its substrate alone or in presence of the test items at 8 different concentrations (40 ⁇ -0.02 ⁇ ).
  • the substrate 7-ethoxy-3-cyanocoumarin was used for CYP1A2 (10 ⁇ ) and CYP2C19 (50 ⁇ ).
  • CYP2C9, CYP3A4, and CYP2D6 dibenzylfuorescein (2 ⁇ ), resorufin benzyl ether (100 ⁇ ) and 3-[2-(N,N-diethyl-N-methylamino)ethyl]-7- methoxy-4-methylcoumarin (3 ⁇ ) were used, respectively.
  • the amount of metabolite formed was measured using a fluorescence spectrophotometer.
  • the excitation and emission wavelengths in nanometers are 450 (Ex) and 465 (Em) for CYP1A2, CYP2C19 and CYP2D6; 485 (Ex) and 535 (Em) for CYP2C9, 530 (Ex) and 590 (Em) for CYP3A4.
  • Inhibitions were expressed relative to controls (without inhibitors) and IC50 were calculated using Excel (Microsoft ® ) software.

Abstract

L'invention concerne des composés de formule I ou II, qui sont des ligands de sérotonine 5-HT 6. L'invention concerne une composition pharmaceutique comprenant une quantité thérapeutiquement efficace d'un composé de l'invention et un véhicule pharmaceutiquement acceptable. La présente invention concerne également des procédés de préparation des composés de formule I ou II, ou un de leurs sels pharmaceutiquement acceptables. La présente invention concerne également un procédé de traitement d'un sujet souffrant d'un trouble neurodégénératif comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un composé de formule I ou II, ou d'un de leurs sels pharmaceutiquement acceptables. La présente invention concerne également un procédé de traitement d'un sujet souffrant d'un trouble psychiatrique comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un composé de formule I ou II, ou d'un de ses sels pharmaceutiquement acceptables.
PCT/DK2011/050017 2010-01-25 2011-01-20 Nouveaux dérivés de 4-(aryl-4-sulfonyl)-6,6a,7,8,9,10-hexahydro-4h-4,8,10a-triaza-acéphénanthrylène et 3-arylsulfonyl-6,6a,7,8,9,10-hexahydro-3h-3,8,10a-triaza-cyclopenta[c]fluorène en tant que ligands de sérotonine 5-ht6 WO2011088836A1 (fr)

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WO2016004882A1 (fr) * 2014-07-08 2016-01-14 Sunshine Lake Pharma Co., Ltd. Dérivés hétérocycliques aromatiques et leurs applications pharmaceutiques
CN114835709A (zh) * 2021-02-01 2022-08-02 上海科技大学 氮杂麦角林类衍生物及其制备方法和应用
WO2023036177A1 (fr) 2021-09-07 2023-03-16 中国科学院分子细胞科学卓越创新中心 Composé cyclique thiophène, son procédé de préparation et son application

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Publication number Priority date Publication date Assignee Title
WO2016004882A1 (fr) * 2014-07-08 2016-01-14 Sunshine Lake Pharma Co., Ltd. Dérivés hétérocycliques aromatiques et leurs applications pharmaceutiques
AU2015286049B2 (en) * 2014-07-08 2018-03-01 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic derivatives and pharmaceutical applications thereof
US9974785B2 (en) 2014-07-08 2018-05-22 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic derivatives and pharmaceutical applications thereof
CN114835709A (zh) * 2021-02-01 2022-08-02 上海科技大学 氮杂麦角林类衍生物及其制备方法和应用
WO2022161493A1 (fr) 2021-02-01 2022-08-04 上海科技大学 Dérivé d'aza-ergoline, son procédé de préparation et son application
CN114835709B (zh) * 2021-02-01 2023-10-20 上海科技大学 氮杂麦角林类衍生物及其制备方法和应用
WO2023036177A1 (fr) 2021-09-07 2023-03-16 中国科学院分子细胞科学卓越创新中心 Composé cyclique thiophène, son procédé de préparation et son application

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