WO2019180176A1 - Composition pour le traitement de la schizophrénie et/ou de la psychose - Google Patents

Composition pour le traitement de la schizophrénie et/ou de la psychose Download PDF

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WO2019180176A1
WO2019180176A1 PCT/EP2019/057159 EP2019057159W WO2019180176A1 WO 2019180176 A1 WO2019180176 A1 WO 2019180176A1 EP 2019057159 W EP2019057159 W EP 2019057159W WO 2019180176 A1 WO2019180176 A1 WO 2019180176A1
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agent
receptor
pyrrolo
sulfonyl
quinoline
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PCT/EP2019/057159
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English (en)
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Pau CELADA
Francesc ARTIGAS
Anna CASTAÑÉ
Maurizio RIGA
Montserrat Cano Biosca
Luis RUIZ-AVILA
Paweł ZAJDEL
Frederic Lamaty
Piotr POPIK
Original Assignee
Spherium Biomed, S.L.
Uniwersytet Jagielloński
Instytut Farmakologii Polskiej Akademii Nauk
Centre National De La Recherche Scientifique
Université De Montpellier
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Publication of WO2019180176A1 publication Critical patent/WO2019180176A1/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • 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

Definitions

  • composition for the treatment of schizophrenia and/or psychosis Composition for the treatment of schizophrenia and/or psychosis
  • the present invention is encompassed within the field of psychotherapeutics and provides a novel therapy for the treatment and/or prevention of psychosis and/or schizophrenia.
  • Schizophrenia is a serious disease affecting one percent of the entire global population including about three million Americans.
  • the annual cost of this disorder to the United Sates alone due to loss of employment, hospitalizations, medications, and the like exceeds 60 billion dollars annually and its toll in human suffering is shown by the ten to thirteen percent suicide rate for people who have the disease (American Psychiatric Association Public Information Online [1998] http://www.psych.org).
  • Schizophrenia is a chronic, severe mental disorder characterized by positive symptoms (including delusions, hallucinations and disordered thought), negative symptoms (such as apathy, poverty of speech and lack of interest in social interactions) and cognitive dysfunction (Tandon et al 2013, Schizophr Res. 150: 3-10; Leucht et al.2007 Acta Psychiatr Scand. 116: 317-333).
  • a long history of research has demonstrated the efficacy of D2 receptor antagonism in the alleviation of positive and disorganized symptoms (Gray, 1998. Schizophrenia Bull. 24(2): 249-266). Persistence of negative symptoms often continues, even following neuroleptic treatment (Arndt et al., 1995. Arch Gen Psychiatry.
  • 5-HT6R antagonists The role of 5-HT6R antagonists in several neurological disorders has been described over the past two decades and reported as a novel target for cognitive enhancement in Alzheimer’s Disease or Schizophrenia (de Bruin & Kruse, 2015. Curr Pharm Des. 2l(26):3739-59).
  • clinical trials involving the use of 5-HT6R antagonists for the treatment of schizophrenia have resulted in failure.
  • 5-HT3R antagonists for the treatment of cognitive impairment
  • three selective 5-HT3R antagonists are undergoing clinical trials for Schizophrenia.
  • all of these clinical trials use 5-HT3R as a form of adjunctive therapy in combination with, for example, haloperidol or risperidone (Andrade, 2014. J Clin Psychiatry. 75(7):e707-9; Garay el al., 2016. Expert Opin Investig Drugs. 25(2): 159-70).
  • 5-HT3R antagonists or 5-HT6R antagonists have any effect on the positive symptoms of Schizophrenia.
  • 5-HT6R antagonists have been shown to have no effect on the positive symptoms of Schizophrenia.
  • SB-271046, a specific 5-HT6 receptor antagonist, in three models for the positive symptoms of schizophrenia— D-amphetamine-induced hyperactivity, and D-amphetamine- or phencyclidine (PCP)-disrupted prepulse inhibition (PPI) was studied and from the results it is clear that SB-271046 is not expected to have an antipsychotic efficacy, at least when given as monotherapy (Pouzet et al., 2002. Pharmacol Biochem Behav. 7l(4):635-43).
  • Figure 1 Effect of Compound 6 of Table 1 on low frequency oscillations of the medial prefrontal cortex after the rat had been administered PCP.
  • Figure 2 Effect of Ondansetron on low frequency oscillations of the medial prefrontal cortex after the rat had been administered PCP.
  • Figure 3 Effect of SB-399885 on low frequency oscillations of the medial prefrontal cortex after the rat had been administered PCP.
  • Figure 4 Effect of SB-399885 and Ondansetron on low frequency oscillations of the medial prefrontal cortex after the rat had been administered PCP.
  • Figure 5 Preventative effects of Compound 6 on the changes in gamma oscillations and fast oscillations in the prefrontal cortex as well as the changes in the fast oscillation on the nucleus accumbens induced by PCP.
  • the inventors used several in vivo models. The inventors tested classic memory and learning models, but were not able to discriminate between the effects of the dual antagonists or the mono-antagonists. By moving to electrophysiological models, the inventors hoped to observe a difference in the effect of the dual antagonist versus the mono-antagonists.
  • the present invention provides a composition comprising one or more agent(s) for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the one or more agent(s) has or have 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity.
  • the present invention provides an agent with 5-HT6 receptor antagonist activity for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the agent is co administered with a second agent and the second agent has 5-HT3 receptor antagonist activity.
  • the present invention provides an agent with 5-HT3 receptor antagonist activity for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the agent is co administered with a second agent and the second agent has 5-HT6 receptor antagonist activity.
  • the present invention provides a kit comprising one or more agent(s) that has or have 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity, and a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent and/or a pharmaceutically acceptable excipient for use in the manufacture of an anti-psychotic.
  • alkyl denotes a univalent saturated branched or straight hydrocarbon chain. Unless otherwise stated such chains can contain from 1 to 3 carbon atoms. Representative of such alkyl groups are methyl, ethyl, propyl, isopropyl and the like. The same carbon content applies to the patent term “alkane”, and to derivative terms such as“alkoxy”. The carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety.“Alkyl(C r Cy” for example, means methyl, ethyl, n-propyl or isopropyl.
  • aryl encompasses monocyclic or fused bicyclic aromatic or hetero-aromatic groups, including but not limited to furyl, thienyl, pyrroryl, oxazolyl, thiazolyl, imidazolyl, imidazo[2,l- b][l,3]thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pirymidinyl, pyrazinyl, 1,3,5- triazinyl, phenyl, 1 //-indazol-7-yl, 1 //-indazol-6-yl, 1 //-indol-2-yl, 1 //-indol-3-yl, 1 //-indol-6-yl, 1 H- indol-7-yl, indolizinyl, isoindolyl, 1 -benzofuran-2-yl, l-
  • substituted r means that the specified group or moiety bears one or more substituents. Where any group may carry multiple substituents, and a variety of possible substituents is provided, the substituents are independently selected, and need not be the same.
  • unsubstituted means that the specified group bears no substituents.
  • N-oxides of the compounds mentioned in the present document belong to the invention.
  • Tertiary amines may or may not give rise to N-oxide metabolites. The extent to what N-oxidation takes place varies from trace amounts to a near quantitative conversion.
  • N-oxides may be more active than their corresponding tertiary amines, or less active. While N-oxides can easily be reduced to their corresponding tertiary amines by chemical means, in human body this happens to varying degrees.
  • Some N-oxides undergo nearly quantitative reductive conversion to the corresponding tertiary amines, in other cases it is a mere trace reaction, or even completely absent.
  • selective and selectivity refer to compounds that display affinity towards a particular receptor (e.g. a 5-HT6 receptor) without displaying substantial cross-affinity towards another receptor (e.g. other 5-HT receptor sub-types).
  • selective compounds of the present invention may display affinity towards 5-HT6 receptors and/or 5-HT3 receptors without displaying substantial cross-affinity towards other 5-HT receptors (including 5-HT1, 5-HT2, 5-HT4, 5-HT5 and/or 5-HT7) or D receptors (including Dl, D2, D3 or D4 receptor) ln
  • an agent of the present invention has at least about 10 fold selectivity to the 5-HT6 receptor and/or 5-HT3 receptor, at least about 50 fold selectivity to the 5-HT6 receptor and/or 5-HT3 receptor, at least about 100 fold selectivity to 5-HT6 receptor and/or 5-HT3 receptor, at least about 250 fold selectivity to 5-HT6 receptor and/or 5-HT3 receptor, or at least about 500 fold selectivity to the desired target(s).
  • IC50 refers to the half maximal inhibitory concentration (IC50) which is a measure of the potency of a substance in inhibiting a specific biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half.
  • the terms“ individual”,“patient” or“subject” are used interchangeably in the present application to designate a human being and are not meant to be limiting in any way.
  • The“individual” ,“patient” or “subject” can be of any age, sex and physical condition.
  • the animal is selected from a group consisting of cats, dogs, pigs, ferrets, rabbits, gerbils, hamsters, guinea pigs, horses, rats, mice, cows, sheep, goats, alpacas, camels, donkeys, llamas, yaks, giraffes, elephants, meerkats, lemurs, lions, tigers, kangaroos, koalas, bats, monkeys, chimpanzees, gorillas, bears, dugongs, manatees, seals and rhinoceroses.
  • 'pharmaceutically acceptable carrier or“ pharmaceutically acceptable diluent” means any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and, without limiting the scope of the present invention, include: additional buffering agents; preservatives; co-solvents; antioxidants, including ascorbic acid and methionine; chelating agents such as EDTA; metal complexes (e.g., Zn-protein complexes); biodegradable polymers, such as polyesters; salt forming counterions, such as sodium, polyhydric sugar alcohols; amino acids, such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamic acid, and threonine; organic sugars or sugar alcohols, such as lactitol, stachyose, mannose, sorbose, xylose, ribose, ribitol, myoinisitose, myoinis
  • receptor refers to a protein molecule present on the membrane or in the interior of the cell that receives chemical signals (i.e., interacts with endogenous and/or exogenous molecules), leading to: a) the blockade of the said protein molecule (e.g. as caused by receptor antagonists); or b) a cellular response upon binding to the chemical signals (e.g. as caused by receptor agonists, partial agonists, inverse agonists and allosteric modulators).
  • receptor antagonist as used in the present application refers to a type of receptor ligand and/or drug that blocks or dampens agonist- or partial agonist-mediated responses rather than provoking a biological response itself upon binding to a receptor.
  • the term“ receptor antagonist” may also refer to a type of receptor ligand and/or drug that activates the receptor to produce a biological response that is opposed to that produced by a full or partial agonist.
  • these compounds are technically known as “ inverse agonists”, here we use the term“ receptor antagonist” to encompass both antagonists and inverse agonists. Both antagonists and inverse agonists effectively counteract the effects of agonists (full or partial).
  • the term“ 5-HT3R” or“5-HT3 receptor” refers to a receptor belonging to the Cys-loop superfamily of ligand-gated ion channels.
  • the 5-HT3 receptor is made up of five subunits (encoded by the genes HTR3A, ATR3B, HTA3a, HTR3D, and/or HTR3E) arranged around a central ion conducting pore.
  • a functional channel may be composed of either five identical 5-HT3A subunits (homopentameric) or a mixture of 5-HT3A and one of the other four receptor subunits (5-HT3B, 5-HT3C, 5-HT3D, 5-HT3E) (heteropentameric)
  • the 5-HT3R is found in humans and the different subunits of the receptor has been sequenced, characterized and the data have been deposited in the UniProtKB database under the accession number P46098, 095264, A5X5Y0, Q70Z44 and/or Q8WXA8.
  • the term“ 5-HT3R” may also refer to a homologue in another species which has the same function as the 5-HT3R in humans or to any biological combination of receptor subunits to form the pentameric complex.
  • 5-HT6R or“5-HT6 receptor” refers to a G protein-couple receptor which mediates excitatory neurotransmission.
  • the 5-HT6R is found in humans and the receptor has been sequenced, characterized and the data have been deposited in the UniProtKB database under the accession number P50406.
  • the term“ 5-HT6R” may also refer to a homologue in another species which has the same function as the 5-HT6R in humans.
  • D2 receptor refers to a subtype of the dopamine receptor.
  • the D2R is found in humans and the receptor has been sequenced, characterized and the data have been deposited in the UniProtKB database under the accession number P 14416.
  • the term“ D2R” may also refer to a homologue in another species which has the same function as the D2R in humans.
  • treatment and“ therapy” refer to a set of hygienic, pharmacological, surgical and/or physical means used with the intent to cure and/or alleviate a disease and/or symptoms with the goal of remediating the health problem.
  • treatment and therapy include preventive and curative methods, since both are directed to the maintenance and/or reestablishment of the health of an individual or animal. Regardless of the origin of the symptoms, disease and disability, the administration of a suitable medicament to alleviate and/or cure a health problem should be interpreted as a form of treatment or therapy within the context of this application.
  • prevention refers to a set of hygienic, pharmacological, surgical and/or physical means used to prevent the onset and/or development of a disease and/or symptoms.
  • prevention encompasses prophylactic methods, since these are used to maintain the health of an animal or individual.
  • agents or compositions of the present invention are used to treat and/or prevent schizophrenia and/or psychosis.
  • agents or compositions of the present invention are used to treat and/or prevent psychosis in an individual or animal who suffers from schizophrenia.
  • compositions of the present invention are used to treat and/or prevent psychosis in a subject or animal who suffers from Schizophrenia.
  • compositions and agents for use are provided.
  • the present invention provides a composition comprising one or more agent(s) for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the one or more agent(s) has or have 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity.
  • the one or more agent(s) has an IC50 for the D2 receptor that is at least 10 times higher than the IC50 for the 5-HT6 receptor and the 5-HT3 receptor.
  • the present invention provides a composition comprising a first agent that has 5-HT6 receptor antagonist activity and a second agent that has 5-HT3 receptor antagonist activity for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein
  • the first and second agent may be the same or different agents.
  • the composition comprises an agent with 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity.
  • the composition comprises a first agent with 5-HT6 receptor antagonist activity and a second agent with 5-HT3 receptor antagonist activity, wherein, optionally:
  • the agent with 5-HT6 receptor antagonist activity is a selective 5-HT6 receptor antagonist that has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT6 receptor, and
  • the agent with 5-HT3 receptor antagonist activity is a selective 5-HT3 receptor antagonist that has an IC50 for the D2 receptor at least 10 higher than times the IC50 for the 5-HT3 receptor.
  • the present invention provides an agent with 5-HT6 receptor antagonist activity for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the agent is co administered with a second agent and the second agent has 5-HT3 receptor antagonist activity, wherein, optionally
  • the agent with 5-HT6 receptor antagonist activity is a selective 5-HT6 receptor antagonist that has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT6 receptor, and
  • the present invention provides an agent with 5-HT3 receptor antagonist activity for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the agent is co administered with a second agent and the second agent has 5-HT6 receptor antagonist activity, wherein, optionally
  • the agent with 5-HT3 receptor antagonist activity is a selective 5-HT3 receptor antagonist that has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT3 receptor.
  • the 5-HT3 and D2 affinity could be measured, as IC50, according to the methods described in the present application and the 5-HT6 could be measured using the methods described in WO 2015/012704 Al.
  • any of the agents or compositions disclosed herein is used for the treatment and/or prevention of psychosis in an individual or animal who/that suffers from schizophrenia.
  • the agent has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT6 receptor and 5-HT3 receptor.
  • the agent has an IC50 for the D2 receptor at least 20 times higher than the IC50 for the 5-HT6 receptor and 5-HT3 receptor.
  • the agent has an IC50 for the D2 receptor at least 50 times higher than the IC50 for the 5-HT6 receptor and 5-HT3 receptor.
  • the agent has an IC50 for the D2 receptor at least 100 times higher than the IC50 for the 5-HT6 receptor and 5-HT3 receptor.
  • the agent is a compound according to Formula (I):
  • R 1 , R 2 independently represent hydrogen, an unsubstituted alkyl(Ci-C3) group, an alkyl(Ci-C3) group substituted with one or more halogen atoms or an alkoxyl(Ci-C3) group, or independently a group selected from: cyano, nitro, amino or hydroxyl;
  • R 4 represents CO, CH 2 , substituted alkyl(Ci-C 2 ) group, SO or S0 2 ;
  • R 5 represents an (i) unsubstituted or substituted aryl (5-6 membered), (ii) unsubstituted or substituted biaryl (8-10 membered), (iii) unsubstituted or substituted heteroaryl (5-6 membered) having 1-3 heteroatoms independently selected from the group consisting of N, O and S, or (iv) unsubstituted or substituted hetero-biaryl (8-10 membered) having 1-3 heteroatoms independently selected from the group consisting of N, O and S, wherein, optionally the substituted aryl, biaryl, heteroaryl or hetero biaryl is substituted with one or more substituents selected from an alkyl(Ci-C4) group, alkyl(Ci-C3) group substituted with one or more halogen atoms, alkoxy(Ci-C 3 ) group, alkenyl(C 2 -C 4 ), halogen, nitro, hydroxyl, cyano, amino, alkylamino or
  • R 3 represents a substituent consisting of Formula (II):
  • A represents NH, O, CH 2 or NR 6 ;
  • n is selected from 0, 1 or 2; or
  • R 4 represents CO, CH 2 , substituted alkyl(Ci-C 2 ) group, SO or S0 2 , wherein the alkyl(Ci-C 2 ) group is substituted with one or more substituents selected from an alkyl(Cr C 3 ) group, alkyl(Ci-C 3 ) group substituted with one or more halogen atoms, alkoxy(Ci-C 3 ) group, alkenyl(C 2 -C 4 ), halogen, nitro, hydroxyl, cyano, amino, alkylamino or carboxamide ln an alternative embodiment, R 4 represents CO, CH 2 , alkyl(Ci-C 2 ) group, SO or S0 2 . ln a preferred embodiment, the agent is selected from any one of the compounds disclosed in Table 1.
  • Binding data for, inter alia, 5-HT IA , 5-HT 2c , 5-HT 6 , 5-HT 7 and D 2 for some of the above compounds is disclosed in Tables 1-4 of WO 2015/012704 Al .
  • the agent is selected from the group consisting of compounds 6, 18, 34 and 36 of Table 1. More preferably, the agent is selected from the group consisting of compounds 6, 18 and 36 of Table 1.
  • the 1UPAC names may be converted into chemical structures using any means known to the skilled person. Such means include“OPSIN: Open Parser for Systematic IUPAC nomenclature v. 2.3.7” which is able to automatically convert the 1UPAC names into chemical structures (Lowe el al., 201 1. J. Chem. Inf. Model. 5l(3):739-53).
  • the second group comprises arylpiperazine derivatives, containing one or more condensed aromatic rings.
  • PRX-07034 belongs to monoarylpiperazine derivatives modified with sulfonyl moiety.
  • Other arylpiperazine derivatives with planar aromatic systems, e.g. SB-742457 and R-1485 are the subject of clinical trials for cognitive impairment in schizophrenia and Alzheimer's disease.
  • sulfonyl or sulfonamide group may be replaced by its amide or alkyl bioisoster or carboxamide group (US 2003/0232843 Al; WO 2005/030724 Al)
  • arylsulfonyl and arylsulfonamide derivatives remain an important class of 5-HT6 ligands.
  • patent publications e.g. US 8,003,670, US 6,423,717, US 7,960,374 B2, US 2009/0069337 Al, WO 2011/044134 Al, EP 2 069 310 Bl, disclose several classes of arylsulfonamides, and claim their potential application in the treatment of CNS disorders related to disturbance of 5-HT6 receptor functions.
  • the agent with 5-HT6 receptor antagonist activity has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT6 receptor.
  • the agent has an IC50 for the D2 receptor at least 20 times higher than the IC50 for the 5-HT6 receptor. More preferably, the agent has an IC50 for the D2 receptor at least 50 times higher than the IC50 for the 5- HT6 receptor. Most preferably, the agent has an IC50 for the D2 receptor at least 100 times higher than the IC50 for the 5-HT6 receptor.
  • the agent with 5-HT6R antagonist activity is a compound according to Formula (I):
  • R 1 , R 2 independently represent hydrogen, an unsubstituted alkyl(Ci-C3) group, an alkyl(Ci-C3) group substituted with one or more halogen atoms or an alkoxyl(Ci-C3) group, or independently a group selected from: cyano, nitro, amino or hydroxyl;
  • R 4 represents CO, CH 2 , substituted alkyl(Ci-C2) group, SO or S0 2 ;
  • R 5 represents an (i) unsubstituted or substituted aryl (5-6 membered), (ii) unsubstituted or substituted biaryl (8-10 membered), (iii) unsubstituted or substituted heteroaryl (5-6 membered) having 1-3 heteroatoms independently selected from the group consisting of N, O and S, or (iv) unsubstituted or substituted hetero-biaryl (8-10 membered) having 1-3 heteroatoms independently selected from the group consisting of N, O and S, wherein, optionally the substituted aryl, biaryl, heteroaryl or hetero biaryl is substituted with one or more substituents selected from an alkyl(Ci-C4) group, alkyl(Ci-C3) group substituted with one or more halogen atoms, alkoxy(Ci-C3) group, alkenyl(C 2 -C4), halogen, nitro, hydroxyl, cyano, amino, alkylamino or carboxamide
  • R 3 represents a substituent consisting of Formula (11), Formula (111), Formula (IV) or Formula (V):
  • A represents NH, O, CH 2 or NR 6 ;
  • B represents NH, O or NR 7 ;
  • R 6 is an alkyl(Ci-C3) group, benzyl or a carboxyl(Ci-C3) group substituted with an alkyl(Ci-C4) group;
  • R 7 is a hydrogen atom or alkyl(Ci-C3) group;
  • R 8 is an alkyl(Ci-C3) group; m is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2;
  • 1 is selected from 1 or 2; or
  • the agent with 5-HT6R antagonist activity is selected from a list consisting of SB-271046 (CAS No: 209481-24-3), SB-357134 (CAS No: 219963-52-7), SB-399885 (CAS No: 402713-80-8), Ro04-6790 (CAS No: 202466-68-0), Ro65-7l99 (CAS No: 350800-83-8), AVN-211 (CAS No: 1173103-84-8), idalopirdine (CAS No: 467459-31-0), MS-245 (CAS No: 275363-58-1), PF-05212365 (CAS No: 925448-93-7), PRX-07034 (CAS No: 903580-39-2), SB-742457 (CAS No: 607742-69-8), R-1485 (PubChem ID: 90488993) PF-5212377 (Compound ID: CHEMBL3545344), Cerlapirdine (CAS No: 925448-93-7), SUV
  • the agent with 5-HT6R antagonist activity is selected from a list consisting of SB-271046, SB-357134, SB- 399885, Ro04-6790, Ro65-7l99, AVN-211, idalopirdine, MS-245, PF-05212365, PRX-07034, SB- 742457, R-1485, Cerlapirdine, SUVN-502, SYN-120, AVN-101, AVN-322, BVT-5182, BVT-74316, JNJ-39269646 and Ro-4368554. More preferably, the agent with 5-HT6R antagonist activity is SB- 399885.
  • the agent with 5-HT3 receptor antagonist activity has an IC50 for the D2 receptor at least 10 times higher than the IC50 for the 5-HT3 receptor.
  • the agent has an IC50 for the D2 receptor at least 20 times higher than the IC50 for the 5-HT3 receptor. More preferably, the agent has an IC50 for the D2 receptor at least 50 times higher than the IC50 for the 5- HT3 receptor. Most preferably, the agent has an IC50 for the D2 receptor at least 100 times higher than the IC50 for the 5-HT3 receptor.
  • the agent with 5-HT3R antagonist activity is a compound according to Formula (VI):
  • R 1 represents a C 3.7 cycloalkyl, C 1.4 alkyl group or a C 3.10 alkynyl group
  • R 2 , R 3 and R 4 is a hydrogen atom or a Ci_6 alkyl, C3.7 cycloalkyl, C2-6 alkenyl or phenyl-(Ci_3)alkyl group and each of the other two groups, which may be the same or different represents a hydrogen atom or a Ci_6 alkyl group; or
  • the agent with 5-HT3R antagonist activity is selected from a list consisting of vabicaserin (CAS No: 620948-93-8 or 887258-95-9), ondansetron (CAS No: 99614-01-4, 99614- 02-5 or 103639-04-9), tropisetron (CAS No: 105826-92-4), granisetron (CAS No: 107007-99-8), dolasetron (CAS No: 115956-12-2), palonosetron (CAS No: 135729-62-3), ramosetron (CAS No: 132907-72-3), cilansetron (CAS No: 120635-74-7), vortioxetine (CAS No: 508233-74-7), alsoetron (CAS No: 122852-42-0), DAU 6215 (CAS No: 123258-84-4), GF038032F, WAY 100289 (CAS No: 136013-69-9), TAK-058 (WO 2014/014951 Al), R3487/ME
  • the agent with 5-HT3R antagonist activity is selected from a list consisting of vabicaserin, ondansetron, tropisetron, granisetron, dolasetron, palonosetron, ramosetron, cilansetron, vortioxetine, alsoetron, DAU 6215, WAY 100289, TAK-058, R3487/MEM3454 and EVP-5141. More preferably, the agent with 5-HT3R antagonist activity is ondansetron.
  • a pharmaceutical composition as described herein may also contain other substances. These substances include, but are not limited to, cryoprotectants, lyoprotectants, surfactants, bulking agents, anti-oxidants, and stabilizing agents. In some embodiments, the pharmaceutical composition may be lyophilized.
  • cryoprotectanf includes agents which provide stability to the agents against freezing-induced stresses. Cryoprotectants may also offer protection during primary and secondary drying and long-term product storage.
  • cryoprotectants include sugars, such as sucrose, glucose, trehalose, mannitol, mannose, and lactose; polymers, such as dextran, hydroxyethyl starch and polyethylene glycol; surfactants, such as polysorbates (e.g., PS-20 or PS-80); and amino acids, such as glycine, arginine, leucine, and serine.
  • a cryoprotectant exhibiting low toxicity in biological systems is generally used.
  • a lyoprotectant is added to a pharmaceutical composition described herein.
  • lyoprotectant includes agents that provide stability to the agents during the freeze-drying or dehydration process (primary and secondary freeze- drying cycles. This helps to minimize product degradation during the lyophilization cycle, and improve the long-term product stability.
  • Non-limiting examples of lyoprotectants include sugars, such as sucrose or trehalose; an amino acid, such as monosodium glutamate, non-crystalline glycine or histidine; a methylamine, such as betaine; a lyotropic salt, such as magnesium sulfate; a polyol, such as trihydric or higher sugar alcohols, e.g., glycerin, erythritol, glycerol, arabitol, xylitol, sorbitol, and mannitol; propylene glycol; polyethylene glycol; pluronics; and combinations thereof.
  • the amount of lyoprotectant added to a pharmaceutical composition is generally an amount that does not lead to an unacceptable amount of degradation when the pharmaceutical composition is lyophilized.
  • a bulking agent is included in the pharmaceutical composition.
  • bulking agents may also impart useful qualities in regard to modifying the collapse temperature, providing freeze-thaw protection, and enhancing the stability over long-term storage.
  • Non-limiting examples of bulking agents include mannitol, glycine, lactose, and sucrose.
  • Bulking agents may be crystalline (such as glycine, mannitol, or sodium chloride) or amorphous (such as dextran, hydroxyethyl starch) and are generally used in formulations in an amount from 0.5% to 10%.
  • nontoxic solid carriers may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • the pharmaceutical composition may further comprise cryoprotectants, lyoprotectants, surfactants, bulking agents, anti-oxidants, stabilizing agents and pharmaceutically acceptable carriers.
  • the pharmaceutical compositions are generally supplied in finely divided form along with a surfactant and propellant. The surfactant must, of course, be nontoxic, and is generally soluble in the propellant.
  • esters or partial esters of fatty acids containing from 6 to 22 carbon atoms such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride.
  • Mixed esters, such as mixed or natural glycerides may be employed.
  • a carrier can also be included, as desired, as with, e.g., lecithin for intranasal delivery.
  • traditional binders and carriers may include, for example, polyalkalene glycols or triglycerides.
  • the composition or agent of the present invention is prepared for oral, sublingual, buccal, intranasal, intravenous, intramuscular, intraperitoneal and/or inhalation-mediated administration.
  • the composition or agent of the present invention is administered continuously or discontinuously.
  • the patient may be administered the composition or agent via continuous intravenous infusion or the patient may be administered the composition or agent through several discrete injections.
  • the agent with 5-HT6R antagonistic activity, and the agent with 5-HT3R antagonistic activity are administered together or separately.
  • composition or agent of the present invention is administered intravenously, intraperitoneally or via inhalation.
  • the composition or agent may be aerosolized and administered via an, for example, an anesthesia mask.
  • composition or agent of the present invention is administered intravenously, subcutaneously, orally or via inhalation.
  • the present invention provides a kit comprising one or more agent(s) that has or have 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity, and a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent and/or a pharmaceutically acceptable excipient for use in the manufacture of an anti-psychotic and/or a medicament for the treatment and/or prevention of schizophrenia.
  • the one or more agent(s) that has or have 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity may be any one of the agents discussed in the present document.
  • the pharmaceutically acceptable carrier, pharmaceutically acceptable diluent and/or pharmaceutically acceptable excipient may be any one of the carriers diluents and excipients already discussed in the present document.
  • the kit may be used to prepare a liquid, gaseous or solid pharmaceutical composition as already discussed in the present document.
  • composition for use according to [1], wherein the composition treats and/or prevents psychosis in an individual or animal who suffers from schizophrenia.
  • composition for use according to any one of [1] to [2], wherein the composition comprises an agent with 5-HT6 receptor antagonist activity and 5-HT3 receptor antagonist activity.
  • R 1 , R 2 independently represent hydrogen, an unsubstituted alkyl(Ci-C3) group, an alkyl(Ci-C3) group substituted with one or more halogen atoms or an alkoxyl(Ci-C3) group, or independently a group selected from: cyano, nitro, amino or hydroxyl;
  • R 4 represents CO, CH 2 , substituted alkyl(Ci-C2) group, SO or S0 2 ;
  • R 5 represents an (i) unsubstituted or substituted aryl (5-6 membered), (ii) unsubstituted or substituted biaryl (8-10 membered), (iii) unsubstituted or substituted heteroaryl (5-6 membered) having 1 -3 heteroatoms independently selected from the group consisting of N, O and S, or (iv) unsubstituted or substituted hetero-biaryl (8-10 membered) having 1-3 heteroatoms independently selected from the group consisting of N, O and S, wherein, optionally the substituted aryl, biaryl, heteroaryl or hetero biaryl is substituted with one or more substituents selected from an alkyl(Ci-C4) group, alkyl(Ci-C3) group substituted with one or more halogen atoms, alkoxy(Ci-C3) group, alkenyl(C 2 -C4), halogen, nitro, hydroxyl, cyano, amino, alkylamino or carbox
  • R 3 represents a substituent consisting of Formula (11):
  • A represents NH, O, CH 2 or NR 6 ;
  • R 6 is an alkyl(Ci-C3) group, benzyl or a carboxyl(Ci-C3) group substituted with an alkyl(Ci-C4) group;
  • m is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2; or
  • the second agent is selected from a list consisting of vabicaserin, ondansetron, tropisetron, granisetron, dolasetron, palonosetron, ramosetron, cilansetron, vortioxetine, alsoetron DAU 6215, GF038032F, WAY 100289, TAK-058, R3487/MEM3454 and EVP-5141.
  • composition for use according to [6], wherein the first agent and second agent are ondansetron and SB-399885;
  • composition for use according to [5], wherein the agent is selected from the list consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 and 52 of Table 1.
  • composition for use according to any one of [1] to [11], wherein the composition is administered intravenously, subcutaneously, orally or via inhalation.
  • kit comprising :
  • An agent with 5-HT6 receptor antagonist activity for use in the treatment and/or prevention of schizophrenia and/or psychosis, wherein the agent is co-administered with a second agent and the second agent has 5-HT3 receptor antagonist activity.
  • Example 1A In vitro characterization of Compound 6 of Table 1.
  • Boess F6 Steward LJ, Steele JA, Liu D, Reid J, Glencorse TA and Martin IL (1987)
  • Salmeterol a long-acting pi-adrenoceptor agonist mediating cyclic AMP accumulation in a neuronal cell line Br J Pharmacol HO 619-626
  • Ascorbic Acid 0.001% BSA, 150 mM
  • Structural subtypes of the dopamine receptor are functionally distinct Expression of the cloned D;> and D;e subtypes in a heterologous cell line Mol Endocrinol 6(6) 920-926
  • pHJnitrendipine-Iabeled calcium channels discriminate inorganic calcium agonists and antagonists Proc Natl Acad Sci USA 79(11):3656- 3660.
  • Serotonin S-HT ⁇ - and 5-BT n receptors form homodimers when expressed alone and heterodimers when co-expressed.
  • Human mu opiate receptor cDNA and genomic clones, pharmacologic characterization and chromosomal assignment. FEBS Lett. 338:217-222.
  • Kappa-opioid receptor in humans cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. Proc Natl Acad Sci USA. 92(15): 7006-7010.
  • DAT Dopamine
  • Table 2 demonstrates that Compound 6 of Table 1 also has 5-HT 3 antagonist activity.
  • WO 2015/012704 Al already demonstrated that Compound 6 has 5-HT 6 antagonist activity (WO
  • Compound 6 has 5-HT 3 and 5-HT6 antagonist activity.
  • Compound 6 has the following inhibition of Dopamine Dl, Dopamine D2L, and Dopamine D2S at 10 mM:
  • S41 , S42, and S54 are compounds encompassed by WO 2015/012704 Al. Thus, it is shown in this Example that not all compounds disclosed in WO 2015/012704 Al are dual antagonists.
  • Example 2 Effects of 5-HT j and 5-HTg R antagonists on PCP-induced disruption of cortical activity
  • PCP phencyclidine
  • LFO low frequency oscillations
  • rats were anesthetized (chloral hydrate 400 mg/kg i.p.) and positioned in a stereotaxic apparatus. Thereafter, chloral hydrate was continuously administered i.p. at a dose of 50-70 mg/kg-h using a perfusion pump. Body temperature was maintained at 37 °C throughout the experiment with a heating pad. All wound margins and points of contact between the animal and the stereotaxic apparatus were infiltrated with lidocaine solution (5%). In order to minimize pulsation, the atlanto- occipital membrane was punctured to release some CSF.
  • Compound 6 reverts the PCP-disturbed power of low frequency (LFO, 0.1-4 Hz) in the mPFC of anesthetized rats (Fig. 1). This effect is also reversed by classical (haloperidol, chlorpromazine, perphenazine) and atypical (clozapine, olanzapine ...) antipsychotic drugs and not by antidepressant drugs like citalopram. Similar effect, although less robust, is attained by simultaneous administration of the 5-HT3R antagonist Ondansetron and the 5-HT6R antagonist SB-399885 (Fig. 4). This effect was not achieved when Ondansetron and SB-399885 were administered on their own (Fig.2-3).
  • Example 3 Effect of 5-HT j and 5-HTg R antagonists on the oscillatory activity in conscious rats
  • Rats were implanted with Plastics One electrodes (Virgina, USA) under isoflurane anesthesia (induction: 5% isoflurane, O 0.6%; maintenance: 2-3 % isoflurane, O 0.6%). Animals were pretreated (30 minutes before anesthesia inhalation) with an analgesic (Buprenorfme: 0.05 mg/kg s.c.).
  • Stereotaxic coordinates were taken from bregma and brain surface (mm) according to the rat brain atlas: (Paxinos and Watson, 2005) medial prefrontal cortex (mPFC) AP + 3.4, L-0.7, DV-2.1; Nucleus accumbens (NAc) AP+1.7, L-1.6, DV-6.8; ventral HPC (vHPC) (AP-5.3, L-6.0, DV-6.0). A ground screw and three stabilizer screws were also implanted. The implant is fixed with dental cement.
  • Buprenorfme (0.05 mg/kg s.c.) and a prophylactic antibiotic (Enrofloxacina 7.5 mg/kg s.c.) was given during 2-3 consecutive days after surgery.
  • Recordings were made in an open-field consisting of a metal box (50 cm x 50 cm x 40 cm height) placed inside a larger noise-isolated box. Recordings were performed with a digital Lynx system and Cheetah software (Neuralynx, Montana, USA) using an electrical swivel (also from Neuralynx) to allow multiple electrode recording during rat movement. The signal was obtained at 3.2kHz sampling rate and filtered between 0.1 and lOOHz. All recordings were posteriorly downsampled 10 times before analysis. Recordings were made once a week starting one week after surgery. All rats were habituated to the experimental setting for 4-5 days before recordings. On the recording day, drugs (or vehicle) is injected 15-30 minutes after the beginning of the recording.
  • rats were euthanatized by an anesthetic overdose. Histological localization of electrodes was performed by passage of current (intensity: 0.15 mA; duration: 10 s). Brain sections were stained according to standard procedures, to verify recordings sites.
  • Compound 6 prevents the increase in power of gamma and fast oscillations induced by PCP in awake animals in key brain areas involved in behavior control, addiction, cognition and executive function, thereby acting as a potential antipsychotic (Fig. 5).

Abstract

La schizophrénie est une maladie grave affectant 1 % de la totalité de la population mondiale. Même si les effets néfastes de la schizophrénie sur l'individu et la société au sens large sont connus et bien documentés, il est communément admis dans la communauté médicale qu'un des principaux besoins non satisfaits dans le traitement de la schizophrénie est une composition qui pourrait traiter une déficience cognitive tout en empêchant ou en traitant la psychose déclenchée par la schizophrénie. La présente invention concerne par conséquent des compositions et des agents pour répondre à ce besoin non satisfait. L'invention concerne en particulier des agents qui sont des antagonistes de 5-HT3R et/ou de 5-HT6R.
PCT/EP2019/057159 2018-03-21 2019-03-21 Composition pour le traitement de la schizophrénie et/ou de la psychose WO2019180176A1 (fr)

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