Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • 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
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
  • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/06—Antimigraine agents
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • 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
  • A61P25/20—Hypnotics; Sedatives
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
  • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
  • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the invention relates to a tetrahydroisoquinoline derivative and its use in therapy.
• the present invention relates to a pharmacologically active substituted tetrahydroisoquinoline derivative.
• This compound acts as a D1 Positive Allosteric Modulator and is accordingly of benefit as a pharmaceutical agent for the treatment of diseases in which D1 receptors play a role.
• the monoamine dopamine acts via two families of GPCRs to modulate motor function, reward mechanisms, cognitive processes and other physiological functions.
• dopamine is acting upon neurons via D1 -like, comprising dopamine D1 and D5, receptors which couple mainly to the Gs G-protein and thereby stimulate cAMP production, and D2- like, which comprise D2, D3 and D4, receptors which couple to Gi/qG-proteins and which attenuate cAMP production.
• D1 receptors are involved in numerous physiological functions and behavioural processes.
• D1 receptors are, for instance, involved in synaptic plasticity, cognitive function and goal-directed motor functions, but also in reward processes.
• D1 receptors Due to their role in several physiological/neurological processes, D1 receptors have been implicated in a variety of disorders including cognitive and negative symptoms in schizophrenia, cognitive impairment related to neuroleptic therapy, Mild Cognitive Impairment (MCI), impulsivity, Attention-Deficit Hyperactivity Disorder (ADHD), Parkinson’s disease and other movement disorders, dystonia, Parkinson’s dementia, Huntington’s disease, dementia with Lewy Body, Alzheimer’s disease, drug addiction sleep disorders, apathy, traumatical spinal cord injury or neuropathic pain.
• MCI Mild Cognitive Impairment
• ADHD Attention-Deficit Hyperactivity Disorder
• Parkinson’s disease and other movement disorders dystonia
• Parkinson’s dementia Huntington’s disease
• dementia with Lewy Body Alzheimer’s disease
• Alzheimer’s disease drug addiction sleep disorders
• apathy traumatical spinal cord injury or neuropathic pain.
• D1 agonists developed so far are generally characterized by a catechol moiety and their clinical use has therefore been limited to invasive therapies. Achieving sufficient selectivity has also been challenging due to the high degree of homology in the ligand binding site between dopamine receptors subtypes (e.g. dopamine D1 and D5). Also, D1 agonists are associated with potentially limiting side effects including but not limited to dyskinesia and hypotension.
• GPCRs represent the largest family of cell-surface receptors and a large number of marketed drugs directly activate or block signaling pathways mediated by these receptors.
• GPCRs e.g. peptide receptors
• Allosteric ligands have a diverse range of activities including the ability to potentiate (positive allosteric modulator, PAM) or attenuate (negative allosteric modulator, NAM) the effects of the endogenous ligand, by affecting affinity and/or efficacy.
• PAM positive allosteric modulator
• NAM negative allosteric modulator
• allosteric modulators may present other potential advantages from a drug discovery perspective such as a lack of direct effect or intrinsic efficacy; only potentiating the effect of the native transmitter where and when it is released; reduced propensity for inducing desensitization arising from constant exposure to an agonist as well as reduced propensity to induce target-related side-effects.
• the compounds according to the present invention potentiates the effect of D1 agonists or of the endogenous ligand on D1 receptors through an allosteric mechanism, and is therefore a D1 Positive Allosteric Modulator (D1 PAM).
• D1 PAM D1 Positive Allosteric Modulator
• the compound in accordance with the present invention being a D1 PAM, is therefore beneficial in the treatment and/or prevention of diseases and disorders in which D1 receptors play a role.
• diseases include cognitive and negative symptoms in schizophrenia, cognitive impairment related to neuroleptic therapy, Mild cognitive impairment (MCI), impulsivity, Attention-Deficit Hyperactivity Disorder (ADHD), Parkinson’s disease and other movement disorders, dystonia, Parkinson’s dementia, Huntington’s disease, dementia with Lewy Body, Alzheimer’s disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.
• International patent application WO2016/055479 discloses substituted 3,4- dihydroisoquinolin-2(1 H)-yl derivatives and analogs thereof which may be useful for the treatment of diseases in which D1 receptors play a role.
• International patent application WO2019/204418 discloses certain pyrazo- tetrahydroisoquinolines derivatives which are D1 positive allosteric modulators and may be useful in the treatment of Parkinson's disease, Alzheimer's disease, schizophrenia, and Attention-Deficit Hyperactivity Disorder (ADHD).
• ADHD Attention-Deficit Hyperactivity Disorder
• the present invention provides 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3- (hydroxymethyl)-5-(1-hydroxy-1 -methyl-ethyl)-1 -methyl-3, 4-dihydro-1 H-isoquinolin-2- yl]ethenone of formula (I),
• the present invention also provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, for use in therapy.
• the present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases and/or disorders in which D1 receptors play a role.
• the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment related to neuroleptic therapy, Mild Cognitive impairment (MCI), impulsivity, Attention-Defficit Hyperactivity Disorder (ADHD), Parkinson’s disease and other movement disorders, dystonia, Parkinson’s dementia, Huntington’s disease, dementia with Lewy Body, Alzheimer’s disease drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.
• MCI Mild Cognitive impairment
• ADHD Attention-Defficit Hyperactivity Disorder
• the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof for use in the treatment of Parkinson’s disease and other movement disorders, Alzheimer’s disease, or cognitive and negative symptoms in schizophrenia. Therefore, in one particular aspect, the present invention provides a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of Parkinson’s disease and other movement disorders.
• the present invention provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment and/or prevention of diseases and/or disorders in which D1 receptors play a role.
• the present invention provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment and/or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment related to neuroleptic therapy, Mild Cognitive Impairment (MCI), impulsivity, Attention-Deficit Hyperactivity Disorder (ADHD), Parkinson’s disease and other movement disorders, dystonia, Parkinson’s dementia, Huntington’s disease, dementia with Lewy Body, Alzheimer’s disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.
• MCI Mild Cognitive Impairment
• ADHD Attention-Deficit Hyperactivity Disorder
• the present invention provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful for the treatment of Parkinson’s disease and other movement disorders, Alzheimer’s disease, or cognitive and negative symptoms in schizophrenia.
• the present invention provides for the use of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of Parkinson’s disease and other movement disorders.
• the present invention also provides a method for the treatment and/or prevention of disorders for which the administration of D1 positive allosteric modulator is indicated, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
• the present invention provides a method for the treatment and/or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment related to neuroleptic therapy, Mild Cognitive Impairment (MCI), impulsivity, Attention-Deficit Hyperactivity Disorder (ADHD), Parkinson’s disease and other movement disorders, dystonia, Parkinson’s dementia, Huntington’s disease, dementia with Lewy Body, Alzheimer’s disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
• MCI Mild Cognitive Impairment
• ADHD Attention-Deficit Hyperactivity Disorder
• Parkinson’s disease and other movement disorders dystonia
• Parkinson’s dementia Huntington’s disease
• dementia with Lewy Body Alzheimer’s disease
• Alzheimer’s disease drug addiction
• sleep disorders sleep disorders
• apathy traumatic spinal cord injury or neuropathic pain
• the present invention provides a method for the treatment of Parkinson’s disease and other movement disorders, Alzheimer’s disease, or cognitive and negative symptoms in schizophrenia, which comprises administering to a patient in need of such treatment of an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
• the present invention provides a method for the treatment of Parkinson’s disease and other movement disorders, which comprises administering to a patient in need of such treatment of an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
• the salts of the compound of formula (I) will be pharmaceutically acceptable salts.
• Other salts may, however, be useful in the preparation of the compound of formula (I) or of its pharmaceutically acceptable salts. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. P.H. Stahl & C.G. Wermuth, Wiley-VCH, 2002.
• Suitable pharmaceutically acceptable salts of the compound of formula (I) include acid addition salts which may, for example, be formed by mixing a solution of the compound of formula (I) with a solution of a pharmaceutically acceptable acid.
• each individual atom present in formula (I), or in the formulae depicted hereinafter may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred.
• each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter may be present as a 1 H, 2 H (deuterium) or 3 H (tritium) atom, preferably 1 H.
• each individual carbon atom present in formula (I), or in the formulae depicted hereinafter may be present as a 12 C, 13 C or 14 C atom, preferably 12 C.
• the present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed with common organic solvents or water.
• the present invention also includes within its scope co-crystals of the compounds of formula (I) above.
• co-crystal is used to describe the situation where neutral molecular components are present within a crystalline compound in a definite stoichiometric ratio.
• the preparation of pharmaceutical co-crystals enables modifications to be made to the crystalline form of an active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).
• Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention.
• the compound of formula (I) is isolated in the form of a monohydrate as further described in the Examples.
• the invention also includes within its scope pro-drug forms of the compounds of formula (I) and its various sub-scopes and sub-groups.
• Activity in any of the above-mentioned therapeutic indications or disorders can of course be determined by carrying out suitable clinical trials in a manner known to a person skilled in the relevant art for the particular indication and/or in the design of clinical trials in general.
• compound of formula (I) or its pharmaceutically acceptable salts may be employed at an effective daily dosage and administered in the form of a pharmaceutical composition.
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising the compound of formula (I) as depicted above, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable carriers.
• one or more of the compounds of formula (I) or a pharmaceutically acceptable salt thereof is intimately admixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques known to the skilled practitioner.
• Suitable diluents and carriers may take a wide variety of forms depending on the desired route of administration, e.g., oral, rectal, parenteral or intranasal.
• compositions according to the present invention can, for example, be administered orally, parenterally, i.e., intravenously, intramuscularly or subcutaneously, intrathecally, by inhalation or intranasally.
• compositions suitable for oral administration can be solids or liquids and can, for example, be in the form of tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing-gums and the like.
• the active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose.
• these pharmaceutical compositions can also contain a binder such as microcrystalline cellulose, gum tragacanth or gelatine, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, a glidant such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, or colouring agents or a flavouring agent such as peppermint or methyl salicylate.
• a binder such as microcrystalline cellulose, gum tragacanth or gelatine
• a disintegrant such as alginic acid
• a lubricant such as magnesium stearate
• a glidant such as colloidal silicon dioxide
• a sweetener such as sucrose or saccharin
• colouring agents or a flavouring agent such as peppermint or methyl salicylate.
• the invention also contemplate
• these solutions or suspensions can optionally also contain a sterile diluent such as water for injection, a physiological saline solution, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diamine-tetra-acetic acid, buffers such as acetates, citrates or phosphates and agents for adjusting the osmolarity, such as sodium chloride or dextrose.
• a sterile diluent such as water for injection, a physiological saline solution, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diamine-tetra-acetic acid, buffers such as acetates, citrate
• the quantity of a compound of use in the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, the daily dosage may range from 0.05 to 3000 mg, typically from 0.5 mg to 1000 mg for parenteral compositions.
• the compound in accordance with the present invention, or a pharmaceutically acceptable salt thereof may be administered alone (monotherapy) or in combination with L-dopa (combination therapy). Alone or in combination with fractions of the L-dopa doses necessary to ameliorate motor disability in patients, the compounds of formula (I) according to the present invention, or pharmaceutical acceptable salts thereof, may be useful for the treatment of dyskinesia associated with administration of L-dopa.
• a compound of formula (I) in accordance with the present invention is used with fractions of the L-dopa doses given to patient or used alone to replace L-dopa, it is believed that compound of formula(l) according to the present invention will be effective against motor disability without inducing troublesome dyskinesia. Therefore it is believed that the compound according to the present invention may be useful for the treatment of motor deficits and levodopa-induced dyskinesia (LID).
• LID levodopa-induced dyskinesia
• the present invention also provides a compound of formula (I), which is useful for the treatment of levodopa induced dyskinesia (LID).
• LID levodopa induced dyskinesia
• Compound of formula (I) may be prepared by a process involving reacting an intermediate of formula (II) with an intermediate of formula (III), Intermediate (III) may be conveniently reacted with intermediate of formula (II) in the presence of (2-(1 H-benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HBTU) or another coupling agent known to the person skilled in the art, in a suitable solvent, e.g. dimethylformamide, with an excess amount of a base, e.g. N,N-diisopropylethylamine.
• HBTU (2-(1 H-benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate
• Z represents halogen or 1 -hydroxy- 1 -methyl ethyl
• R a represents tert-butyl dimethylsilyl
• R c represents hydrogen or tert-butoxycarbonyl.
• intermediate of formula (IV), wherein Z represents bromo, and R c represents hydrogen, herein after referred to as intermediate (IVa), may be protected with an appropriate protective group, according to methods known to the skilled in the art to afford a compound of formula (IV), wherein Z represents bromo and R c represents tert-butoxycarbonyl, herein after referred to as intermediate (IVb).
• a metal-halogen exchange reaction may be performed e.g. in the presence of n-BuLi, in a suitable solvent, e.g. tetrahydrofuran, at low temperature, in the presence of dry acetone under continuous flow, according to a method described in the accompanying Examples, to afford corresponding intermediate (IV) as described above wherein Z represents 1 -hydroxy- 1 -methyl ethyl, herein after referred to as intermediate (IVc).
• the tert-butoxycarbonyl (Boc) group (R c ) may then first be deprotected according to methods known to the person skilled in the art or as further described in the accompanying Examples, followed by deprotection of the trimethylsilyl group formed during Boc group deprotection and the tert-butyl dimethylsilyl group (R a ) to afford intermediate (III).
• Intermediate of formula (IVa) may be prepared by a process involving reaction of an intermediate of formula (V), wherein Y is a halogen, e.g. bromo, and R a is defined above for intermediate of formula (IV).
• the reaction is conveniently effected in the presence of methyl magnesium chloride, in a suitable solvent e.g. tetrahydrofuran, at low temperature.
• a suitable solvent e.g. tetrahydrofuran
• Intermediate (V) may be prepared by a 2 step process involving reaction of intermediate of formula (VI),
• Y is as defined above for intermediate of formula (V) and R a represents hydrogen or tert-butyl-dimethylsilyl.
• intermediate (VI) wherein R a represents tert-butyl-dimethylsilyl is reacted with N-Chlorosuccinimide (NCS), in a suitable solvent, e.g. THF to afford intermediate (V).
• NCS N-Chlorosuccinimide
• Intermediate (VI) wherein R a represents hydrogen may be prepared by a process involving intermediate of formula (VII), wherein Y is as defined above for intermediate (V).
• the reaction is conveniently effected in the presence of a strong base, e.g. sodium hydroxide, in a suitable solvent, e.g. mixture of ethanol and water, a high temperature.
• Intermediate of formula (VII) may be prepared by a process involving reaction of intermediate (VIII),
• reaction is conveniently effected in the presence of trimethylsilyltriflate and paraformaldehyde, in a suitable solvent e.g. dichloromethane.
• Intermediate (VIII) may be prepared by a 2 steps process involving commercially available intermediate (IX),
• reaction is conveniently effected according to the methods described in the accompanying examples or according to methods known to the person skilled in the art.
• Intermediate of formula (II) may be prepared by a multi-step process involving reaction of intermediates of formula (X), wherein
• R 1 represents chloro, amino or nitro
• R b represents hydrogen or tert-butyl.
• intermediate of formula (X) wherein R 1 represents nitro and R b represents tert-butyl, herein after referred to as intermediate (Xa) is reduced into the corresponding intermediate (X) wherein R 1 represents amino and R b represents tert-butyl, herein after referred to as intermediate (Xb).
• the reaction is conveniently effected by Pd/C catalyzed hydrogenation under high pressure, in a suitable solvent e.g. methanol.
• Intermediate (Xb) is transformed into corresponding intermediate (X) wherein R 1 represents chloro and R b represents hydrogen, herein after referred to as intermediate (Xc), by adding concentrated hydrochloric acid and sodium nitrite, followed by further addition of hydrochloric acid and copper chloride (II). The reaction is conveniently effected at low temperature.
• Intermediate (II) may then obtained directly from intermediate (Xc) by reaction with N- chlorosuccinimide according to the methods describe in the accompanying Examples or according to methods known to the person skilled in the art.
• R 2 represents hydrogen or methyl
• intermediate (Xla) is reacted with methyl iodide in the presence of a strong base, e.g. potassium hydroxide, in a suitable solvent, e.g. dimethylformamide.
• a strong base e.g. potassium hydroxide
• a suitable solvent e.g. dimethylformamide
• the resulting intermediate (XI) wherein R 2 represents methyl, herein after referred to as intermdediate (XI b) is then reacted with tert-butyl 2-chloroacetate in the presence of potassium tert-butoxide, in a suitable solvent, e.g. tetrahydrofuran, at low temperature, to afford intermediate (Xa).
• the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
• the diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
• a racemate of formula (I) may be separated using chiral HPLC.
• a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
• a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode.
• any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999.
• the protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.
• the compounds of formula (I) according to the present invention does not directly activate the dopamine D1 receptor, but potentiates the effect of D1 agonists or the endogenous ligand on D1 receptors, dopamine, through an allosteric mechanism, and is therefore D1 positive allosteric modulator (D1 PAM).
• D1 PAM D1 positive allosteric modulator
• Dopamine and other D1 agonists directly activate the dopamine D1 receptor by themselves.
• activation assay activation assay
• potentiation assay
• the activation assay measures the stimulation of the production of cyclic adenosinemonophosphate (cAMP) in the Homogeneous Time Resolved Fluorescent (HTRF) assay, with the maximum increase in cAMP by increasing concentrations of the endogenous agonist, dopamine, defined as 100% activation.
• cAMP cyclic adenosinemonophosphate
• HTRF Homogeneous Time Resolved Fluorescent
• compounds of formula (I) according to the present invention lacks significant direct agonist-like effects in that it produces less than 20% of activation (compared to dopamine maximal response) when present in a concentration of 10 mM.
• the potentiation assay measures the ability of compounds to increase the levels of cAMP produced by a low-threshold concentration of dopamine.
• concentration of dopamine used [EC20]) is designed to produce 20% stimulation compared to the maximal response (100%) seen with increasing the concentration of dopamine.
• concentrations of the compound with the [EC20] of dopamine are incubated and the potentiation is measured as increases in cAMP production and concentration of compound which produces 50% of the potentiation of the cAMP levels is measured.
• compound of formula (I) according to the present invention When tested in the cAMP HTRF assay, compound of formula (I) according to the present invention has exhibited a value of pEC50 of greater than about 6.5 which shows that it is a D1 Positive Allosteric Modulator.
• GABA A receptor inhibition is known to be intimately linked to seizures and epilepsy. It is therefore desirable to develop compounds which are D1 Positive Allosteric Modulators and which at the same time minimize such effects.
• compound of formula (I) displays a percentage of inhibition of the GABA A receptor of less than or equal to about 20%, ideally less than about 10%, appositely less than about 5%, when measured at a concentration of 10mM of a compound of formula (I).
• a problem which can be faced when developing compounds for use in therapy is the capacity for certain compounds to induce CYP450 enzymes. The induction of such enzymes may impact the exposure of such compounds or of other compounds which could be co administered therewith to a patient, thereby potentially altering their respective safety or efficacy. It is therefore desirable to develop compounds which minimize such potential for induction.
• the CYP450 induction potential of compound of formula (I) according to the present invention has been tested by measuring the potential increase of CYP450 activities in human hepatocytes treated with increasing concentrations of compounds according to the present invention.
• compound of formula (I) according to the present invention exhibits a fold-induction value of at least about 2 times lower, ideally at least about 3 times lower, appositely at least about 4 times lower than the positive control compound (Rifampicin).
• the clearance is a parameter which gives that information because it represents the volume of plasma (or blood) totally cleaned from the compound of interest by time unit. It is usually expressed as ml/min/kg or L/h. It can then be compared to any physiological blood flow (e.g. liver blood flow) to evaluate if the clearance is low, moderate or high.
• physiological blood flow e.g. liver blood flow
• the clearance is generally evaluated by using hepatocyte incubations and scaling calculations, assuming the main elimination pathway is metabolism, according to protocols described herein.
• the intrinsic clearance evaluated from hepatocytes is expressed in pl/min/10 6 cells.
• the compound of formula (I) in accordance with the present invention advantageously exhibit a clearance of less than about 10 pl/min/10 6 cells.
• Cells were cultured at 37°C in a humidified atmosphere of 5% CO2. Cells were grown in DMEM-F12+GlutaMAXTM-l medium (GIBCO ® , Invitrogen, Merelbeke, Belgium) containing 10% fetal bovine serum (BioWhittaker ® , Lonza, Verviers, Belgium), 400 pg/mL Geneticin (GIBCO ® ), 100 lll/mL Penicillin and 100 lll/mL Streptomycin (Pen-Strep solution, BioWhittaker ® ).
• LMtk Ltk- mouse fibroblast cells expressing the dopamine D1 receptor (BioSignal Inc, Montreal, Canada, now Perkin Elmer) were used as they have been shown to couple efficiently and give robust functional responses (Watts et al, 1995).
• cyclic adenosinemonophopshpate was determined using the HTRF cAMP dynamic assay kit from CisBio (Codolet, France). Using homogenous time-resolved fluoresence technology, the assay is based on competition between native cAMP produced by cells and cAMP labelled with the dye d2. The tracer binding is determined by an anti-cAM P antibody labeled with cryptate.
• the effects of the compound alone (agonism) was determined by performing the assay in the absence of dopamine, whilst the effect of the compound as a positive allosteric modulator (PAM) was determined in the presence of an EC20 concentration of dopamine.
• PAM positive allosteric modulator
• Cells (20,000 per well) are incubated in 384 plates for 1 hour at room temperature in a final volume of 20 pLHBSS (Lonza, with calcium, magnesium and HEPES buffer 20 mM, pH 7.4) containing: isobutyl methylxanthine (Sigma, 0.1 mM final), varying concentrations of test compound (typically 10 9 5 M to 10 4 5 M) in the presence and absence of dopamine (1.1 nM final).
• the reaction is then terminated and the cells lysed by adding the d2 detection reagent in lysis buffer (10 microL) and the cryptate reagent in lysis buffer (10 microl) according to manufacturer’s instructions.
• compound of formula (I) When tested in the above assay, compound of formula (I) exhibits a value of pEC50 of about 8.1 and an Erel value of about 68%.
• CHO-K1 cells stably expressing human GABA A receptor a1 ,b2 and g2 subunits were used. The cells were harvested using trypsin and maintained in serum-free medium at room temperature. The cells were washed and re-suspended in extracellular solution before testing.
• the internal pipette solution contained potassium fluoride 70mM, potassium chloride 60mM, sodium chloride 70mM, HEPES 5mM, EGTA 5mM, and Magnesium ATP 4mM.
• the final concentration of vehicle used to dilute compounds was 0.33% DMSO in each well.
• Bicuculline (0.032 to 100pM) was used as positive control inhibitor.
• GABA (15mM) was used as agonist. All recordings were obtained from a holding potential of -60mV.
• the compound addition sequence was the following: one addition of the ECso concentration of GABA was added to establish baseline response. Each concentration of compound was applied for 30 seconds followed by the addition of 15mM GABA in the presence of the compound for 2 seconds. The process was repeated with the next ascending concentration of compound. Peak inward currents in response to the GABA additions in the presence of a single concentration of compound were measured. All compound data have been normalized to the baseline peak current induced by addition of 15mM GABA for 2 seconds.
• the following assays are aimed at determining the potential of the compound according to the present invention to induce CYP3A4 enzyme.
• the objective of the human hepatocyte assay is to characterize the induction potential of Compound of formula (I) by measuring the CYP3A4 activities after 3-days of hepatocytes treatment with culture medium alone or culture medium containing increasing concentration of NCE.
• cryopreserved human hepatocytes from a single donor are seeded on a 48 well collagen coated plate so that the final seeding density is 0.2 x 10 6 cells/well (final volume per well 0.25 ml_).
• the cells are then incubated in seeding medium at 37 °C, 95 % humidity, 5 % CO2 to allow the cells to attach.
• the seeding medium is replaced with 0.25 ml_ of pre warmed serum free Williams E medium containing 100 lll/mL penicillin, 100 pg/mL streptomycin, 10 pg/mL insulin, 2 mM L glutamine and 0.1 pM hydrocortisone.
• test compound in assay medium at 1 pM (final DMSO concentration 0.1 %). Positive control inducer, rifampicin (10 pM) is incubated alongside the test compound. Negative control wells are included where the test compound is replaced by vehicle solvent (0.1 % DMSO in assay medium). Each test compound is dosed in triplicate. The cells are exposed to the culture medium for 72h with medium changes every 24 hr.
• solution of the CYP3A4 probe substrate, midazolam (final concentration 2.5 pM) is prepared in pre warmed assay medium.
• the media is replaced with the CYP3A4 probe substrate.
• the hepatocytes are incubated for 30 min. An aliquot is removed at the end of the incubation period and placed into an equal volume of methanol containing internal standard. The samples are centrifuged at 2500 rpm at 4 °C for 20 min. An aliquot of supernatant is diluted with deionised water and levels of 1-hydroxymidazolam is quantified using generic LC MS/MS methods.
• hepatocytes are solubilised in 0.1 M sodium hydroxide at room temperature and protein content in each well determined using PierceTM BCA Protein Assay Kit (Thermo Scientific) using bovine serum albumin as a standard. Data analysis
• the fold-induction (increase in CYP activity) is obtained by taking the ratio of the measured enzymatic activity obtained in hepatocytes treated with Compound of formula (I), over the one obtained in control hepatocytes treated with vehicle.
• the fold-induction is calculated in the same way for positive control (Rifampicin).
• the induction potential of the Compound of formula (I) is compared to that of rifampicin by calculating the ratio of the fold-induction seen with rifampicin over the fold-induction seen with Compound of formula (I).
• compound of formula (I) When tested in the CYP3A4 induction assay at 1 mM concentration according to the protocols hereabove, compound of formula (I) according to the present invention exhibits a fold- induction value of at least about 7 times lower than the positive control compound (Rifampicin) at a concentration of 10mM.
• test compound in assay medium at a range of concentrations from 0.03 to 10 mM (final DMSO concentration 0.1 %).
• Positive control inducer, rifampicin is incubated alongside the test compound at a concentration range between 0.1 to 30 pM.
• compound of formula (I) When comparing the highest fold-induction values coming from the protocol mentioned above, i.e. those obtained at the highest soluble concentration (3 pM) of compound of formula (I) according to the present invention and at 10 pM of the positive control (Rifampicin), compound of formula (I) exhibits an induction potential of about 4 times lower than that of the positive control compound (Rifampicin).
• Cryopreserved human hepatocytes (pool of 20 donors, BSU batch from Celsis/IVT/Bioreclamation) were thawed accordingly the provider’s information. Viability (trypan blue exclusion) was higher than 75%.
• Pre-incubations 250 pL of hepatocytes suspension at 2x10 6 hepatocytes/mL were carried out with William’s medium, containing 2 mM of glutamine and 15 mM of Hepes, in 48-well plates at +37°C, in an incubator (5% CO2), under gentle agitation (vibrating agitator, Titramax 100, ca 300 rpm) during 30 min.
• the incubation was initiated by adding to hepatocytes, 250 pL of culture medium (see composition above) containing UCB compound (1 pM) or midazolam (positive control) with or without azamulin (6 pM - specific CYP3A4/5 inhibitor).
• UCB compound 1 pM
• midazolam positive control
• azamulin 6 pM - specific CYP3A4/5 inhibitor
• Final concentrations of UCB compound and azamulin in the incubates are 0.5 pM and 3 pM, respectively.
• the cell suspensions was rapidly re-homogenized by 2 in-out pipetting.
• the intrinsic clearance (Clint) of the compound of formula (I) according to the present invention is equal to 2.1 ⁇ 0.6 pl/min/10 6 cells.
• cAMP cyclic adenosinemonophosphate
• Crude materials could be purified by normal phase chromatography, (acidic or basic) reverse phase chromatography, chiral separation or recrystallization.
• the compounds were studied in DMSO-d 6 , CDCL or MeOH-cL solution at a probe temperature of 300 K and at a concentration of 10 mg/mL.
• the instrument is locked on the deuterium signal of DMSO-d 6 , CDCL or CD 3 OD.
• Chemical shifts are given in ppm downfield from TMS (tetramethylsilane) taken as internal standard.
• the mixture is warmed up to 15-30°C and stirred for 5h.
• the reaction is quenched by the addition of a saturated ammonium chloride solution (9 L) and water (2 L) is added.
• the organic layer is separated and the aqueous layer is extracted with ethyl acetate (2 x 5 L).
• the organic phases are combined, washed with brine (2 L), dried over Na2SC>4, filtered and concentrated under vacuum.
• the crude product is purified by recrystallization with ethyl acetate (5 L). This overall procedure is carried out on 2 batches of the same size in parallel.
• reaction mixture is stirred at 0-10°C for 1 h then washed with water (50.0 L) twice, dried with anhydrous sodium sulfate and filtered to give (4R)-4-[(2-bromophenyl)methyl]oxazolidin- 2-one a7 as a solution in dichloromethane which is used directly in the next step.
• Ethanol (120 L) and water (60.0 L) are mixed into a reactor.
• (10aR)-9-bromo-1 ,5,10, 10a- tetrahydrooxazolo[3,4-b]isoquinolin-3-one a8 (29.7 kg, 1 11 mol) is added then sodium hydroxide (13.3 kg, 332 mol) is slowly added at 15-20°C.
• the reaction mixture is stirred at 90°C for 2h then cooled down to room temperature.
• Water (300 L) is added into the mixture which is centrifugated.
• N-Chlorosuccinimide (NCS) (1.17 kg, 8.73 mol) is slowly added at room temperature and the mixture is stirred at 25°C for 30 min.
• a solution of KOH (1.52 kg, 27.1 mol) in dry methanol (7.00 L) is slowly added at room temperature and the reaction is stirred at 25°C for 1 h.
• the mixed flow stream was pumped through the reaction zone 1 of the microchip (0.3 ml_) and was then combined with a solution of dry acetone (13.5 M) pumped at 6.0 mL/min (27 equiv.). The resulting stream was then passed through the reaction zone 2 of the microchip (0.7 ml_) at -40 °C. Finally, the global flow stream exiting the reactor was collected and quenched at room temperature in a saturated solution of aqueous ammonium chloride. When all the feed solutions were consumed, a bilayer reaction mixture was obtained. The aqueous layer was separated from the organic layer, and then extracted twice with ethyl acetate.
• Trimethylsilyl trifluoromethanesulfonate (154 g, 129 ml_, 692 mmol) is added over 40 min via an addition funnel. Two hours after the start of addition, the reaction is quenched by adding 650 ml_ of an aqueous citric acid solution (1 M) and the temperature of the mixture is brought back to 20°C. One hour after the start of the quench, the layers are separated. The organic layer is washed twice with 350 ml_ of an aqueous solution of citric acid (1 M). The organic layer is stirred with 750 ml_ of aqueous sodium carbonate (10% w/w) for 10 min before separation of the layers. The organic layer is dried over anhydrous sodium sulfate.
• N,N- diisopropylethylamine (9.5 ml_, 54 mmol) is added.
• (2-(1 H-benzotriazol-1-yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate (6.4 g, 17 mmol) is added in four portions over 1 hour.
• the mixture is stirred for 1 h 45 before setting the jacket temperature at 15°C.
• 16 ml_ of water are then added over the course of a few minutes. 15 min later, 30 mg of solid product are added as seeds to initiate the crystallization.
• the jacket temperature is set at 20°C. Half an hour later, 16 ml_ of water are added over 17 min.
• a recristallization is carried out on 5.00 g of the crude material obtained by first suspending in 50 ml_ acetonitrile.
• the jacket temperature is set to 70°C. Once the solid has dissolved and the mass temperature has reached 66°C, 720 pi of water are added. The mass temperature is then cooled to 59°C and 125 mg of solid product is added as seeding material. The mass temperature is then decreased to 55°C over 25 min at which stage crystallization is occurring. The jacket temperature is then decreased over two hours from 58°C down to 20°C. After 50 min, the suspension is filtered and the filtercake is washed with 7.5 ml_ acetonitrile.

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