WO2013127817A1 - Dérivés d'imidazole comme inhibiteurs de l'enzyme pde10a - Google Patents

Dérivés d'imidazole comme inhibiteurs de l'enzyme pde10a Download PDF

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Publication number
WO2013127817A1
WO2013127817A1 PCT/EP2013/053875 EP2013053875W WO2013127817A1 WO 2013127817 A1 WO2013127817 A1 WO 2013127817A1 EP 2013053875 W EP2013053875 W EP 2013053875W WO 2013127817 A1 WO2013127817 A1 WO 2013127817A1
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compound
methyl
disorder
group
triazolo
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PCT/EP2013/053875
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English (en)
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Jan Kehler
Jacob Nielsen
Morten LANGGÅRD
Mikkel JESSING
John Paul Kilburn
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H. Lundbeck A/S
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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
    • C07D487/02—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 two hetero rings
    • C07D487/04—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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • the present invention provides compounds that are PDE10A enzyme inhibitors, and as such are useful to treat neurodegenerative and psychiatric disorders. Especially, the invention provides compounds that are highly selective for PDE10A enzyme over other PDE subtypes. The present invention also provides pharmaceutical compositions comprising compounds of the invention and methods of treating disorders using the compounds of the invention.
  • cyclic-adenosine monophosphate cyclic-adenosine monophosphate
  • cGMP cyclic-guanosine monophosphate
  • Intracellular cAMP and cGMP are generated by adenyl and guanyl cyclases, and are degraded by cyclic nucleotide phosphodiesterases (PDEs) via hydrolysis of the cyclic nucleotides into their respective nucleotide monophosphates.
  • PDEs cyclic nucleotide phosphodiesterases
  • Phosphodieasterase 10A is a dual-specificity phosphodiesterase that can convert both cAMP to AMP and cGMP to GMP (Soderling, S. et al. Proc. Natl. Acad. Sci. 1999, 96, 7071 -7076). PDE10A is primarily expressed in the neurons in the striatum, n. accumbens and in the olfactory tubercle (Kotera, J. et al. Biochem. Biophys. Res. Comm. 1999, 261, 551 -557 and Seeger, T.F. et al. Brain Research, 2003, 985, 1 13-126).
  • MSN medium spiny neurons
  • D 2 D 2 dopamine receptors
  • the Di class of neurons is part of the 'direct' striatal output pathway, which broadly functions to facilitate behavioral responses.
  • the D 2 class of neurons is part of the 'indirect' striatal output pathway, which functions to suppress behavioral responses that compete with those being facilitated by the 'direct' pathway.
  • Dopamine D 2 receptor antagonism is well established in the treatment of schizophrenia. Since the 1950's, dopamine D 2 receptor antagonism has been the mainstay in psychosis treatment and all effective antipsychotic drugs antagonise D 2 receptors. The effects of D 2 are likely to be mediated primarily through neurons in the striatum, nucleus accumbens and olfactory tubercle, since these areas receive the densest dopaminergic projections and have the strongest expression of D 2 receptors (Konradi, C. and Heckers, S. Society of Biological Psychiatry, 2001 , 50, 729-742).
  • PDE10A in this context, has the desired expression profile with high and relatively specific expression in neurons in striatum, nucleus accumbens and olfactory tubercle, PDE10A inhibition is likely to have effects similar to D 2 receptor antagonism and therefore have antipsychotic effects. While PDE10A inhibition is expected to mimic D 2 receptor antagonism in part, it might be expected to have a different profile.
  • the D 2 receptor has signaling components besides cAMP (Neve, K. A. et al. Journal of Receptors and Signal Transduction 2004, 24, 165-205), wherefore interference with cAMP through PDE10A inhibition may reduce the risk of the extrapyramidal side effects that are seen with strong D 2 antagonism.
  • PDE10A inhibition may have some effects not seen with D 2 receptor antagonism.
  • PDE10A is also expressed in Di receptors expressing striatal neurons (Seeger, T. F. et al. Brain Research, 2003, 985, 1 13-126).
  • PDE10A inhibition is likely to also have effects that mimic Di receptor agonism.
  • PDE10A inhibition will not only increase cAMP in cells, but might also be expected to increase cGMP levels, since PDE10A is a dual specificity phosphodiesterase.
  • cGMP activates a number of target protein in cells like cAMP and also interacts with the cAMP signaling pathways.
  • PDE10A inhibition is likely to mimic D 2 receptor antagonism in part and therefore has antipsychotic effect, but the profile might differ from that observed with classical D 2 receptor antagonists.
  • the PDE10A inhibitor papaverine is shown to be active in several antipsychotic models. Papaverine potentiated the cataleptic effect of the D 2 receptor antagonist haloperidol in rats, but did not cause catalepsy on its own (WO 03/093499). Papaverine reduced hyperactivity in rats induced by PCP, while reduction of amphetamine induced hyperactivity was insignificant (WO 03/093499). These models suggest that PDE10A inhibition has the classic antipsychotic potential that would be expected from the theoretical considerations outlined above.
  • WO 03/093499 further discloses the use of selective PDE10 inhibitors for the treatment of associated neurologic and psychiatric disorders. Furthermore, PDE10A inhibition reverses subchronic PCP-induced deficits in attentional set-shifting in rats (Rodefer et al. Eur. J. Neurosci. 2005, 4, 1070-1076). This model suggests that PDE10A inhibition might alleviate cognitive deficits associated with schizophrenia.
  • the tissue distribution of PDE10A indicates that PDE10A inhibitors can be used to raise levels of cAMP and/or cGMP within cells that express the PDE10A enzyme, especially neurons that comprise the basal ganglia, and the PDE10A inhibitors of the present invention would therefore be useful in treating a variety of associated neuropsychiatric conditions involving the basal ganglia such as neurological and psychiatric disorders, schizophrenia, bipolar disorder, psychosis and obsessive compulsive disorder, and may have the benefit of not possessing unwanted side effects, which are associated with the current therapies on the market.
  • EP 1250923 discloses the use of selective PDE10 inhibitors in general, and papaverine in particular, for the treatment of certain neurologic and psychiatric disorders.
  • Pyrrolodihydroisoquinolines and variants thereof are disclosed as inhibitors of PDE10 in WO 05/03129 and WO 05/02579.
  • Piperidinyl-substituted quinazolines and isoquinolines that serve as PDE10 inhibitors are disclosed in WO 05/82883.
  • WO 06/1 1040 discloses substituted quinazoline and isoquinoline compounds that serve as inhibitors of PDE10.
  • US 20050182079 discloses substituted tetrahydroisoquinolinyl derivatives of quinazoline and isoquinoline that serve as effective phosphodiesterase (PDE) inhibitors.
  • PDE phosphodiesterase
  • US 20060019975 discloses piperidine derivatives of quinazoline and isoquinoline that serve as effective phosphodiesterase (PDE) inhibitors.
  • US 20060019975 also relates to compounds that are selective inhibitors of PDE10.
  • WO 06/028957 discloses cinnoline derivatives as inhibitors of PDE10 for the treatment of psychiatric and neurological syndromes.
  • WO09/152825 and WO10/145668 disclose phenylimidazole derivatives as compounds that serve as inhibitors of PDE10.
  • the present invention provides compounds that are PDE10A enzyme inhibitors and thus useful for treatment for neurodegenerative and/or psychiatric disorders, which are not efficacious in all patients. Hence, there remains a need for alternative methods of treatment. Summary of the Invention
  • 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.
  • HET is a heteroaromatic group of formula II containing from 2 to 4 nitrogen atoms:
  • Y can be N or CH
  • Z can be N or C
  • HET may optionally be substituted with up to three substituents R7, R8 and R9 wherein R7, R8 and R9 independently are selected from the group consisting of H; C1 -C6 alkyl such as Me; halogen such as chlorine and bromine; cyano; halo(Ci -C6)alkyl such as trifluoromethyl; aryl such as phenyl; alkoxy, preferably C1 -C6 alkoxy, such as methoxy, dimethoxy, ethoxy, methoxy-ethoxy and ethoxy- methoxy, and Ci-Ce hydroxyalkyl such as CH 2 CH 2 OH, and wherein * denotes the attachment point,
  • R10, R1 1 , R12 and R13 independently of each other are selected from the group consisting of hydrogen, methyl and fluorine with the limitation that at least one of R10, R1 1 , R12 and R13 is selected from the group consisting of methyl and fluorine;
  • R1 is selected from the groupd consisting of H; C1 -C6 alkyl such as methyl, ethyl, 1 -propyl, 2-propyl, isobutyl; C1 -C6 alkyl (C3-C8)cycloalkyl such as cyclopropylmethyl; C1 -C6 hydroxyalkyl such as hydroxyethyl; CH 2 CN; CH 2 C(O)NH 2 ; Ci-C 6 arylalkyl such as benzyl and 4-chlorobenzyl; and Ci-C 6 alkyl-heterocycloalkyl such as tetrahydropyran-4-yl-methyl and 2-morpholin-4-yl- ethyl;
  • R2-R6 independently of each other are selected from the group consisting of H; C1 -C6 alkoxy such as methoxy; and halogen such as chlorine or fluorine; and a pharmaceutically acceptable acid addition salt of Compound I, a racemic mixture of Compound I, or the corresponding enantiomer and/or optical isomer of Compound I, and polymorphic forms of Compound I as well as tautomeric forms of Compound I.
  • Embodiments of the invention in a first embodiment (E1 ) the present invention relates to compounds of formula I (Compound I)
  • HET is a heteroaromatic group of formula II containing from 2 to 4 nitrogen atoms:
  • R10, R1 1 , R12 and R13 independently of each other are selected from the group consisting of hydrogen, methyl and fluorine with the limitation that at least one of R10, R1 1 , R12 and R13 is selected from the group consisting of methyl and fluorine;
  • R1 is selected from the groupd consisting of H; d-Ce alkyl such as methyl, ethyl, 1 -propyl, 2-propyl, isobutyl; C1-C6 alkyl(C3-C8)cycloalkyl such as cyclopropylmethyl; C1-C6 hydroxyalkyl such as hydroxyethyl; CH 2 CN;
  • R2 R3, R4, R5 and R6 independently of each other are selected from the group consisting of H; C1-C6 alkoxy such as methoxy; and halogen such as chlorine or fluorine; and a pharmaceutically acceptable acid addition salt of Compound I, a racemic mixture of Compound I, or the corresponding enantiomer and/or optical isomer of Compound I, and polymorphic forms of Compound I as well as tautomeric forms of Compound I.
  • R1 is selected from the group consisting of H and methyl
  • R2 to R6 are independently of each other selected from the group consisting of H, fluorine and methoxy.
  • R1 is methyl and R2-R6 are H.
  • HET is selected from the group consisting of:
  • R1 -R1 1 and R1 to R1 1 is short notation for the group consisting R1 , R2, R3, R13, R5, R6, R7, R8, R9, R10 and R1 1 .
  • the present invention further provides certain embodiments of the invention, which are described below.
  • the present invention also comprises salts of the compounds, typically, pharmaceutically acceptable salts.
  • Such salts include pharmaceutically acceptable acid addition salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids.
  • 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, from about 0.05 to about 500 mg, or from about 0.5 mg to about 200 mg.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is an acid addition salt of a compound having the utility of a free base.
  • a compound of formula I contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula I with a molar equivalent of a pharmaceutically acceptable acid.
  • suitable organic and inorganic acids are described above.
  • solutions of the compounds of formula I in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed.
  • Suitable pharmaceutical 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 or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • sustained release material such as glyceryl monostearate or glyceryl distearate
  • the pharmaceutical compositions formed by combining the compounds of formula I and a pharmaceutically acceptable carrier are then 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 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 formula I are PDE10A enzyme inhibitors and as such are useful to treat associated neurological and psychiatric disorders.
  • the invention thus provides a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, as well as a pharmaceutical composition containing such a compound, for use in the treatment of a neurodegenerative disorder, psychiatric disorder or drug addiction in humans.
  • the neurodegenerative disorder or condition involves neurodegeneration of striatal medium spiny neurons in a human.
  • the neurodegenerative disorder or condition is Huntington's disease.
  • the disorder is dyskinesia associated with dopamine agonist therapy.
  • the psychiatric disorder is selected from the group consisting of schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type.
  • schizophrenia for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type
  • schizophreniform disorder for example of the delusional type or the depressive type
  • delusional disorder substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine
  • personality disorder of the paranoid type and personality
  • This invention further provides a method of treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a human, which method comprises administering to said human an amount of a compound of formula I effective in treating drug addiction.
  • a drug addiction for example an alcohol, amphetamine, cocaine, or opiate addiction
  • Drug addiction is widely considered a pathological state.
  • the disorder of addiction involves the progression of acute drug use to the development of drug-seeking behavior, the vulnerability to relapse, and the decreased, slowed ability to respond to naturally rewarding stimuli.
  • DSM-IV The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) has categorized three stages of addiction: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect. These stages are characterized, respectively, everywhere by constant cravings and preoccupation with obtaining the substance; using more of the substance than necessary to experience the intoxicating effects; and experiencing tolerance, withdrawal symptoms, and decreased motivation for normal life activities.
  • NIDDM non-insuline demanding diabetes mellitus
  • ADHD Attention Deficit/Hyperactivity Disorder
  • the compounds of formula I or pharmaceutically acceptable salts thereof may be used in combination with one or more other drugs (including typical and atypical antpsychotic agent) in the treatment of diseases or conditions for which the compounds of the present invention have utility, where the combination of the drugs together are safer or more effective than either drug alone. 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.
  • 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.
  • 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.
  • neuroleptic agent refers to drugs, which have the effect on cognition and behaviour of antipsychotic agent drugs that reduce confusion, delusions, hallucinations, and psychomotor agitation in patients with psychoses.
  • 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), and atypical antipsychotic drugs, including benzisoxazoles (e.g., risperidone), sertindole, olan
  • neurotrophic agent refers to a substance or agent that has some or all of these properties. All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety (to the maximum extent permitted by law). Headings and sub-headings are used herein for convenience only, and should not be construed as limiting the invention in any way.
  • Hydroxycompounds of formula V can be prepared by standard reactions described in the art like reduction of the corresponding ketone by e.g. sodium borohydride or by addition of an appropriately substituted organometallic reagent to the appropriately substituted heteroaromatic carbaldehyde or can be prepared by standard methods as described in standard works like and Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart and Organic Reactions, John Wiley & Sons, Inc. New York.
  • Hydroxycompounds of formula VI can be prepared by standard reactions described in the art like reduction of the corresponding ketone by e.g. sodium borohydride or by addition of an appropriately substituted organometallic reagent to the appropriately substituted heteroaromatic imidazo carbaldehyde or can be prepared by standard methods as described in standard works like and Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart and Organic Reactions, John Wiley & Sons, Inc. New York.
  • Compounds of formula I where R12 and R13 can be geminal fluorine can be prepared by conversion of a keto group as in compounds of formula VII using an electrophilic flurorinating reagent like e.g. Diethyiaminosulfur trifluoride (DAST) as described in scheme 4.
  • DAST Diethyiaminosulfur trifluoride
  • Ketones of fomula VII can be prepared by standard reactions described in the art like oxidation of the corresponding alhohol of formula VI by e.g. er periodinate oxidation reagent or by addition of an appropriately substituted organometallic reagent to the appropriately substituted heteroaromatic imidazo ester or weinreb amide or can be prepared by standard methods as described in standard works like and Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme- Verlag, Stuttgart and Organic Reactions, John Wiley & Sons, Inc. New York.
  • Compounds of formula I where R10 and R1 1 can be geminal fluorine can be prepared by conversion of a keto group as in compounds of formula VIII using an electrophilic flurorinating reagent like e.g. Diethyiaminosulfur trifluoride (DAST) as described in scheme 5.
  • DAST Diethyiaminosulfur trifluoride
  • a PE Sciex API 150EX instrument equipped with atmospheric pressure photo ionisation and a Shimadzu CBM-20A system may be used.
  • Method: Linear gradient elution with A:B 83:17 to 0:100 in 2.4 minutes and with a flow rate of 3.0 mL/minute.
  • reaction mixture is stirred at 25 °C for 24 h, and then the reaction is quenched by the slow addition of aqueous NaHCO3 solution until effervescence is completed.
  • the dichloromethane layer is separated, dried over anhydrous Na2CO3, and filtered.
  • a PDE10A assay may for example, be performed as follows: The assay is performed in 60 micro L samples containing a fixed amount of the relevant PDE enzyme (sufficient to convert 20-25% of the cyclic nucleotide substrate), a buffer (50 mM HEPES7.6; 10mM MgCI 2 ; 0.02% Tween20), 0.1 mg/ml BSA, 225 pCi of 3 H-labelled cyclic nucleotide substrate, tritium labeled cAMP to a final concentration of 5 nM and varying amounts of inhibitors.
  • Reactions are initiated by addition of the cyclic nucleotide substrate, and reactions are allowed to proceed for one hr at room temperature before being terminated through mixing with 15 micro L 8 mg/mL yttrium silicate SPA beads (Amersham). The beads are allowed to settle for one hr in the dark before the plates are counted in a Wallac 1450 Microbeta counter. The measured signal can be converted to activity relative to an uninhibited control (100 %) and IC 5 o values can be calculated using the Xlfit extension to EXCEL.
  • the assay is performed in 60 micro L assay buffer (50 mM HEPES pH 7.6; 10mM MgCI 2 ; 0.02% Tween20) containing enough PDE10A to convert 20-25% of 10 nM 3 H-cAMP and varying amounts of inhibitors. Following a 1 hour incubation the reactions are terminated by addition of 15 micro L 8 mg/mL yttrium silicate SPA beads (Amersham). The beads are allowed to settle for one hr in the dark before the plates are counted in a Wallac 1450 Microbeta counter. IC 5 o values are calculated by non linear regression using XLfit (IDBS).
  • mice Male mice (NMRI, Charles River) weighing 20-25g are used. Eight mice are used in each group receiving the test compound (5 mg/kg) plus PCP (2.3 mg/kg) including the parallel control groups receiving the vehicle of the test compound plus PCP or vehicle injections only. The injection volumen is 10 ml/kg. The experiment is made in normal light conditions in an undisturbed room. The test substance is injected per oss 60 min before injection of PCP, which is administered subcutaneous.
  • mice Immediately after injection of PCP the mice are placed individually in special designed test cage (20 cm x 32 cm). The activity is measured by 5X8 infrared light sources and photocells spaced by 4 cm. The light beams cross the cage 1 .8 cm above the bottom of the cage. Recording of a motility count requires interruption of adjacent light beams, thus avoiding counts induced by stationary movements of the mice.

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Abstract

La présente invention concerne des composés (I), qui sont des inhibiteurs de l'enzyme PDE10A. L'invention concerne une composition pharmaceutique comprenant une quantité thérapeutiquement efficace d'un composé de l'invention et un support pharmaceutiquement acceptable. La présente invention concerne également des procédés de préparation des composés selon la formule. La présente invention concerne en outre un composé de formule (I) destiné à être utilisé dans le traitement d'un sujet souffrant d'un trouble neurodégénératif, d'une addiction à des médicaments ou d'un trouble psychiatrique. Dans la formule I, HET représente un groupe hétéroaromatique de formule II contenant 2 à 4 atomes d'azote.
PCT/EP2013/053875 2012-02-27 2013-02-27 Dérivés d'imidazole comme inhibiteurs de l'enzyme pde10a WO2013127817A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017504648A (ja) * 2014-01-31 2017-02-09 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ 神経学的障害の処置のための（ヘテロ）アリールイミダゾール類／ピラゾール類

Citations (14)

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EP1250923A2 (fr) 2001-04-20 2002-10-23 Pfizer Products Inc. Utilisation des inhibiteurs sélectifs de PDE10 pour le traitement des maladies du système nerveux central
WO2003093499A2 (fr) 2002-05-03 2003-11-13 Pfizer Products Inc. Utilisation therapeutique d'inhibiteurs selectifs de pde10
WO2005003129A1 (fr) 2003-06-30 2005-01-13 Altana Pharma Ag Pyrrolodihydroisoquinolines comme inhibiteurs de pde10
WO2005002579A1 (fr) 2003-06-30 2005-01-13 Altana Pharma Ag Derives de pyrrolo-dihydroisoquinoline comme inhibiteurs de pde10
WO2005012485A2 (fr) 2003-07-31 2005-02-10 Bayer Pharmaceuticals Corporation Procedes pour traiter le diabete, et les troubles associes, au moyen d'inhibiteurs des pde10a
US20050182079A1 (en) 2004-02-18 2005-08-18 Pfizer Inc Tetrahydroisoquinolinyl derivatives of quinazoline and isoquinoline
WO2005120514A1 (fr) 2004-06-07 2005-12-22 Pfizer Products Inc. Inhibition de la phosphodiesterase 10 dans le traitement des etats pathologiques associes a l'obesite et au syndrome metabolique
US20060019975A1 (en) 2004-07-23 2006-01-26 Pfizer Inc Novel piperidyl derivatives of quinazoline and isoquinoline
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