WO2010001185A1 - Thieno [2,3-b] pyridine compounds with mglur activity - Google Patents

Thieno [2,3-b] pyridine compounds with mglur activity Download PDF

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Publication number
WO2010001185A1
WO2010001185A1 PCT/HU2009/000052 HU2009000052W WO2010001185A1 WO 2010001185 A1 WO2010001185 A1 WO 2010001185A1 HU 2009000052 W HU2009000052 W HU 2009000052W WO 2010001185 A1 WO2010001185 A1 WO 2010001185A1
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Prior art keywords
formula
compound
mglurl
disorders
mglur5 receptor
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PCT/HU2009/000052
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French (fr)
Inventor
István Gyertyán
Katalin NÓGRÁDI
Ottília ELEKES
Mónika VASTAG
Amrita Ágnes BOBOK
Katalin Sághy
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Richter Gedeon Nyrt.
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Publication of WO2010001185A1 publication Critical patent/WO2010001185A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to mGluRl and mGluR5 receptor subtype preferring ligands of formula (I) and/or salts and/or hydrates and/or solvates thereof, to the processes for their preparation, to pharmaceutical compositions containing these compounds and to their use in treatment, therapy and/or prevention of a condition related to modulation of mGluRl and mGluR5 receptors.
  • R 1 , R 2 , X, Y and Z are as defined therein.
  • the compounds are stated to be useful in therapy and/or prevention of pathological conditions which require the modulation of mGluRl and mGluR5 receptors such as neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunction of the lower urinary tract and gastrointestinal disorders.
  • Binding affinity of compounds to the target receptor is a crucial and determinant property. The higher the affinity to the target receptor the lower effective concentration of the drug is required for the successful modulation of the receptor function during the course of treatment. However, binding affinity itself does not ensure that a compound can successfully be applied in the therapy. In the majority of diseases oral applicability of the medication is a requirement. Therefore, in vivo activity, specifically oral activity is an essential criteria for putative medicaments in terms of druglike properties and therapeutic applicability. Furthermore, beside oral efficacy and potency, oral bioavailability is also an important property.
  • Low oral bioavailability may amplify individual differences in drug metabolism with the potential consequence of appearance of unwanted side-effects and/or loss of efficacy, hi searching for therapeutically applicable drugs we screened the compounds disclosed in Int. Pat. Appl. WO 2007/072095 for high mGluR5 binding affinity, in vivo efficacy after oral administration and acceptable oral bioavailability.
  • the present invention relates to mGluRl and mGluR5 receptor subtype preferring ligands of formula (I):
  • X is Cl or F and/or hydrates and/or solvates and/or pharmaceutically acceptable salts thereof (i.e. or hydrates, solvates, or pharmaceutically acceptable salts, or combinations thereof).
  • these compounds have particularly desirable properties for therapeutically-applicable drugs useful in one or more of the treatment, therapy, or prevention of conditions relating to modulation of mGluRl and mGluR5 receptors.
  • these compounds have favorable binding affinities to the mGluR5 receptor (Ki values of less than about 10 nM), favorable anxiolytic activity in rats after oral administration (minimal effective doses of less than about 10 mg/kg p.o.), and the degree of oral bioavailability of these compounds in rodents exceeds 10.0%.
  • Other compounds falling within the scope of WO 2007/072095 were not found to meet the above three criteria.
  • This disclosure also provides processes for the synthesis of compounds of formula (I).
  • compositions containing a therapeutically effective amount of at least one of: a compound of formula (I), or salts, hydrates, or solvates thereof (including combinations thereof) as active ingredient and at least one of: pharmaceutically acceptable diluents, excipients or inert carriers (including combinations thereof).
  • a compound of formula (I) or salts, hydrates, or solvates thereof (including combinations thereof) as active ingredient and at least one of: pharmaceutically acceptable diluents, excipients or inert carriers (including combinations thereof).
  • This disclosure also provides for the use of a compound of formula (I) for the prevention, therapy, and/or treatment of mGluR5 receptor mediated disorders, such as neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunction of the lower urinary tract and gastrointestinal disorders.
  • mGluR5 receptor mediated disorders such as neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunction of the lower urinary tract and gastrointestinal disorders.
  • This disclosure also provides for the use of a compound of formula (I) for the manufacture of a medicament for the prevention and/or treatment of mGluR5 receptor- mediated disorders, such as neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunction of the lower urinary tract and gastrointestinal disorders.
  • mGluR5 receptor- mediated disorders such as neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunction of the lower urinary tract and gastrointestinal disorders.
  • the present invention relates to mGluRl and mGluR5 receptor subtype preferring ligands of formula (I)
  • X is Cl or F and/or hydrates and/or solvates and/or pharmaceutically acceptable salts thereof.
  • Appl. WO 2007/072095 has outstandingly high binding affinity to the mGluR5 receptor (Ki values are less than 10 nM) and possesses high anxiolytic activity in rats after oral administration (minimal effective doses are less than 10 mg/kg p.o.). Furthermore, the degree of oral bioavailability of these compounds in rodents exceeds 10.0%. Conformity to these triple criteria represents definite advantage in terms of druglike properties and therapeutic or preventive applicability in conditions which require the modulation of mGluRl and mGluR5 receptors.
  • Compounds of formula (I) may form salts with acids.
  • the invention relates also to the salts of compounds of formula (I) formed with acids, including without limitation the salts formed with pharmaceutically acceptable acids.
  • the phrase " a compound of formula (I)" encompasses both the free base and the salt, even if the salt is not explicitly recited.
  • Both organic and inorganic acids can be used for the formation of acid addition salts.
  • Suitable inorganic acids can be for example hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
  • Representatives of monovalent organic acids can be for example formic acid, acetic acid, propionic acid, and different butyric acids, valeric acids and capric acids.
  • Representatives of bivalent organic acids can be for example oxalic acid, malonic acid, maleic acid, fumaric acid and succinic acid.
  • the acid addition salts are ones in which the acid component itself is physiologically acceptable and does not have therapeutical effect in the applied dose or it does not have unfavorable influence on the effect of the active ingredient.
  • These acid addition salts are pharmaceutically acceptable acid addition salts.
  • the acid addition salts may not be pharmaceutically acceptable acid addition salts because, for example they can be advantageous in the purification and isolation of the desired compounds.
  • the compounds of formula (I) can be solvates and/or hydrates of compounds of formula (J).
  • compositions containing the compounds of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof as active ingredient and one or more physiologically acceptable carriers.
  • the compounds of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof may be administered by any convenient method, for example by oral, parenteral (including subcutaneous, intramuscular, and intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • the compounds of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation of the compounds of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof generally include a suspension or solution of the compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in a suitable liquid carrier(s) for example an aqueous solvent, such as water and ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • a suitable liquid carrier(s) for example an aqueous solvent, such as water and ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the solid form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid etc.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a composition in the solid form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then these are filled into a hard gelatine capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then is filled into a soft gelatine capsule.
  • suitable pharmaceutical carrier(s) for example aqueous gums, celluloses, silicates or oils
  • Parenteral compositions may be a solution or suspension of the compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • compositions including one or more compounds according to the present invention may be formulated for nasal administration.
  • a nasal administration formulation may include a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof formulated as aerosols, drops, gels and powders.
  • Aerosol formulations of the present invention may comprise a solution or fine suspension of the compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates in a physiologically acceptable aqueous or non-aqueous solvent and are may be presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device.
  • the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser, it may contain a propellant which can be a compressed gas, such as compressed air or an organic propellant, such as a fiuorochlorohydrocarbon.
  • the aerosol dosages form can also take the form of a pump-atomiser.
  • compositions including one or more compounds according to the invention may be formulated for buccal or sublingual administration.
  • Such compositions may include a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates in the form of, for example, tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier, such as sugar and acacia, tragacanth, or gelatine, glycerin etc.
  • compositions including one or more compounds according to the present invention may be formulated for rectal administration.
  • compositions include a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in the form of suppositories containing a conventional suppository base, such as cocoa butter and other materials commonly used in the art.
  • a conventional suppository base such as cocoa butter and other materials commonly used in the art.
  • the suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • compositions including one or more compounds according to the invention may be formulated for transdermal administration.
  • Such compositions include a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof formulated in ointments, gels and patches.
  • compositions of the present invention including a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof are in the unit dose form, such as tablet, capsule or ampoule.
  • each dosage unit of the present invention for oral administration contains from about 0.1 to about 500 mg of a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof calculated as a free base.
  • each dosage unit of the present invention for parenteral administration contains from about 0.1 to about 500 mg of a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof calculated as a free base.
  • the compounds of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof may be administered in a daily dosage regimen.
  • mGluRl and mGluR5 mediated disorders such as schizophrenia, anxiety, depression, panic, bipolar disorders, and circadian disorders or chronic and acute pain disorders
  • the dosage levels from about 0.01 mg/kg to about 100 mg/kg of body weight per day may be suitable or alternatively about 0.5 mg to about 7 g per patient per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form may vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Unit dosage forms may generally contain between from about 1 mg to about 1000 mg of the active ingredient, for example 25 mg, 50 mg, 100 mg, 200 mg, 250-300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
  • the compounds of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates of the present invention have been found to exhibit biological activity at mGluRl and mGluR5 receptors and are expected to be useful in the treatment of mGluRl and mGluR5 mediated disorders.
  • the compounds according to the present invention or salts thereof exhibit a high degree of potency and selectivity for mGluRl and mGluR5 receptors.
  • the compounds according to the present invention are highly potent (Ki ⁇ 10 nM) ligands of the mGluR5 receptor. Accordingly, the compounds of the present invention are expected to be useful in the prevention and/or treatment of conditions associated with excitatory activation of mGluRl and mGluR5 receptor.
  • the compounds may be used to produce an inhibitory effect of mGluRl and mGluR5, in mammals, including human.
  • the compounds of the present invention are expected to be particularly suitable for oral application in conditions relating to the modulation of mGluRl and mGluR5 receptors.
  • the compounds of the present invention are well suited for the prevention, therapy and/or treatment of mGluRl and mGluR5 receptor-mediated disorders such as acute and chronic neurological and psychiatric disorders, chronic and acute pain disorders and neuromuscular dysfunction of the lower urinary tract and gastrointestinal disorders.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of mGluRl and mGluR5 receptor-mediated disorders.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of neurological disorders.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of psychiatric disorders.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of chronic and acute pain disorders.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of neuromuscular dysfunction of the lower urinary tract and gastrointestinal disorders.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of pain related to migraine, inflammatory pain, neuropathic pain disorders such as diabetic neuropathies, arthritis and rheumatoid diseases, low back pain, post-operative pain and pain associated with various conditions including angina, in renal or biliary colic, menstruation, migraine and gout.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of Alzheimer's disease senile dementia, AIDS-induced dementia Parkinson's disease, amyotrophic lateral sclerosis,
  • Huntington's Chorea migraine, epilepsy, schizophrenia, depression, anxiety, acute anxiety, obesity, obsessive compulsive disorder, attention deficit and hyperactivity disorder, substance abuse and dependence, ophthalmological disorders such as retinopathies, diabetic retinopathies, glaucoma, auditory neuropathic disorders such as tinnitus, chemotherapy induced neuropathies, post-herpetic neuralgia and trigeminal neuralgia, Fragile X, autism, mental retardation, and Down's Syndrome.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, cardiovascular diseases and epilepsy.
  • the one or all of the compounds may be well suited for the treatment of neuromuscular dysfunction of the lower urinary tract, such as urinary urgency, overactive bladder, greater urinary frequency, reduced urinary compliance, cystitis, incontinence, enuresis and dysuria. Furthermore, one or all of the compounds may be well suited for the treatment of gastrointestinal disorders, such as transient lower esophageal sphincter relaxation (TLESR), gastrointestinal reflux disease and irritable bowel syndrome.
  • TLESR transient lower esophageal sphincter relaxation
  • the present invention relates also to the use of a compound of formula (I) as defined hereinbefore, in the manufacture of a medicament for therapy, prevention and/or treatment of mGluRl and mGluR5 receptor-mediated disorders and any disorder listed above.
  • the invention also provides a method of therapy, treatment and/or prevention of mGluRl and mGluR5 receptor mediated disorders and any disorder listed above, in a patient suffering from, or at risk of, said condition, which comprises administering to the patient an effective amount of a compound of formula (I), as hereinbefore defined.
  • the term “antagonist” means a compound that by any means, partly or completely blocks the transduction pathway leading to the production of a response by the ligand.
  • disorder means any condition or disease associated with metabotropic glutamate receptor activity.
  • the disclosure provides a process for the preparation of a compound of formula (I)
  • X is Cl or F; and/or hydrates and/or solvates and/or pharmaceutically acceptable salts thereof, illustrated schematically below for the production of a compound of formula (I) in which X is F.
  • a similar scheme can be used to produce a compound of formula (I) in which X is Cl by using a compound of formula (II) (shown below) wherein the F is replaced by Cl.
  • a compound of formula (I) can be prepared from the precursor compound of formula (II) by nitration, followed by reduction and Suzuki coupling.
  • salts and/or hydrates and/or solvates of compounds of formula (I) can be formed.
  • Intermediate (I) was prepared from the corresponding N-oxide (II) (WO 2007/072095) by a selective nitration reaction using aq. nitric acid in acetic acid. The reaction was carried out in the range of 100-130 0 C temperature by the method of Klemm, L.H ( J. Heterocycl. Chem., 7, 1970, 81).
  • MGluR5 receptor binding was determined according to Gasparini et.al. (Bioorg. Med.
  • Rat cerebro-cortical membrane preparation was used to determine the binding characteristics of reference compounds and novel compounds to the rat mGluR5.
  • the Al 8 cell line expressing hmGluR5a (purchased from Euroscreen) was used to determine binding characteristics of the chemical compounds to the human mGluR5a receptor.
  • radioligand [3H]-M-MPEP (2 nM) was used. The nonspecific binding was determined in the presence of 10 ⁇ M M-MPEP.
  • the compounds were formulated freshly as microemulsion for intravenous dosing and as suspension for oral dosing.
  • a dose of 3 mg/kg of the compounds was administered intravenously in the tail vein by a dosing volume of 2.5 ml/kg.
  • Blood samples ( ⁇ 1 ml) were drawn from the retroorbital sinus at 0.083, 0.333, 1.0, 5.0 h post dose into heparinized tubes.
  • a dose of 10 mg/kg of the compounds were administered orally to rats by a dosing volume of 5 ml/kg by gavage.
  • Blood samples ( ⁇ 1 ml) were drawn from the retroorbital sinus at 0.4, 1.0, 2.0, 5.0 h post dose into heparinized tubes.
  • Plasma samples were obtained by immediate centrifugation of blood samples and were stored at -2O 0 C until HPLC-UV analysis. Plasma samples were extracted with chlorobutane and then analysed on 150x4.6mm, 5 ⁇ m, Zorbax Eclipse XDB-C 18 column (Agilent) using gradient elution with binary mobile phase containing 0.1 M ammonium acetate and acetonitrile. Analysis were performed at 4O 0 C. The column eluent was monitored at 245nm (Compound 2) and 250nm (Compound 1). The pharmacokinetic parameters (AUC, Cmax, tmax were calculated by non-compartmental analysis using Kinetica Version 4.4.1 Program. The absolute oral bioavailability was calculated as AUC oral /AUC j v • Dose; v / Dose ora i.. Results
  • Compound 1 and Compound 2 bind with high affinity to both human and rat mGlu5 receptors.
  • the compounds showed remarkable anxiolytic activity after oral administration and their oral bioavailability exceeds 10.0 %.
  • These pharmacological properties represents definite advantage in terms of drug-like properties and treatment, therapeutic or preventive applicability and renders Compound 1 and Compound 2 particularly suitable for oral application in conditions which require the modulation of mGluRl and mGluR5 receptors.
  • the tablets made according to the method described above were coated by a layer consisting of entero- or gastrosolvent film, or of sugar and talc.
  • the dragees were polished by a mixture of beeswax and carnuba wax.
  • nipasol 0.005-0.02 % of nipasol, 0.01-0.5 % of carbopol (polyacrilic acid), 0.1-5 % of 96 % ethanol,
  • a 5 % solution of mannitol or lactose was made with bidistilled water for injection use, and the solution was filtered so as to have sterile solution.
  • a 0.01-5 % solution of the active ingredient of formula (I) was also made with bidistilled water for injection use, and this5 solution was filtered so as to have sterile solution.
  • These two solutions were mixed under aseptic conditions, filled in 1 ml portions into ampoules, the content of the ampoules was lyophilized, and the ampoules were sealed under nitrogen. The contents of the ampoules were dissolved in sterile water or 0.9 % (physiological) sterile aqueous sodium chloride solution before administration. 0

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Abstract

A compound of formula (I), wherein X is Cl or F or hydrates, solvates, or salts thereof for use treating of mGluR1 and mGluR5 receptor-mediated disorders.

Description

Thieno [2,3-b] pyridine compounds with mGluR activity
FIELD OF THE INVENTION
The present invention relates to mGluRl and mGluR5 receptor subtype preferring ligands of formula (I) and/or salts and/or hydrates and/or solvates thereof, to the processes for their preparation, to pharmaceutical compositions containing these compounds and to their use in treatment, therapy and/or prevention of a condition related to modulation of mGluRl and mGluR5 receptors.
BACKGROUND OF THE INVENTION
Int. Pat. Appl. WO 2007/072095 discloses thieno-pyridine derivatives that are mGluRl and mGluR5 receptor subtype preferring ligands, having the formula:
Figure imgf000002_0001
wherein R1, R2, X, Y and Z are as defined therein.
The compounds are stated to be useful in therapy and/or prevention of pathological conditions which require the modulation of mGluRl and mGluR5 receptors such as neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunction of the lower urinary tract and gastrointestinal disorders.
Int. Pat. Appl. WO 2007/072095 does not disclose further biological data on the compounds in addition to their binding affinity and functional activity at the mGluRl and mGluR5 receptors, and does not specify the exact mGluR5 binding affinities of the compounds having binding affinity at the mGluR5 receptor less than 500 nM.
Binding affinity of compounds to the target receptor is a crucial and determinant property. The higher the affinity to the target receptor the lower effective concentration of the drug is required for the successful modulation of the receptor function during the course of treatment. However, binding affinity itself does not ensure that a compound can successfully be applied in the therapy. In the majority of diseases oral applicability of the medication is a requirement. Therefore, in vivo activity, specifically oral activity is an essential criteria for putative medicaments in terms of druglike properties and therapeutic applicability. Furthermore, beside oral efficacy and potency, oral bioavailability is also an important property. Low oral bioavailability (<10%) may amplify individual differences in drug metabolism with the potential consequence of appearance of unwanted side-effects and/or loss of efficacy, hi searching for therapeutically applicable drugs we screened the compounds disclosed in Int. Pat. Appl. WO 2007/072095 for high mGluR5 binding affinity, in vivo efficacy after oral administration and acceptable oral bioavailability.
SUMMARY OF THE INVENTION
The present invention relates to mGluRl and mGluR5 receptor subtype preferring ligands of formula (I):
Figure imgf000003_0001
Wherein X is Cl or F and/or hydrates and/or solvates and/or pharmaceutically acceptable salts thereof (i.e. or hydrates, solvates, or pharmaceutically acceptable salts, or combinations thereof).
Surprisingly, it has been found that these compounds have particularly desirable properties for therapeutically-applicable drugs useful in one or more of the treatment, therapy, or prevention of conditions relating to modulation of mGluRl and mGluR5 receptors. For example, these compounds have favorable binding affinities to the mGluR5 receptor (Ki values of less than about 10 nM), favorable anxiolytic activity in rats after oral administration (minimal effective doses of less than about 10 mg/kg p.o.), and the degree of oral bioavailability of these compounds in rodents exceeds 10.0%. Other compounds falling within the scope of WO 2007/072095 (including struturally close analogues) were not found to meet the above three criteria.
This disclosure also provides processes for the synthesis of compounds of formula (I).
This disclosure also provides intermediates useful in the preparation process. This disclosure also provides pharmaceutical compositions containing a therapeutically effective amount of at least one of: a compound of formula (I), or salts, hydrates, or solvates thereof (including combinations thereof) as active ingredient and at least one of: pharmaceutically acceptable diluents, excipients or inert carriers (including combinations thereof). For purposes of this disclosure, the phrase: "at least one of: a, b, or c" and the like also encompasses combinations of the listed selections, whether or not combinations is explicitly recited.
This disclosure also provides for the use of a compound of formula (I) for the prevention, therapy, and/or treatment of mGluR5 receptor mediated disorders, such as neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunction of the lower urinary tract and gastrointestinal disorders.
This disclosure also provides for the use of a compound of formula (I) for the manufacture of a medicament for the prevention and/or treatment of mGluR5 receptor- mediated disorders, such as neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunction of the lower urinary tract and gastrointestinal disorders.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to mGluRl and mGluR5 receptor subtype preferring ligands of formula (I)
Figure imgf000004_0001
Wherein X is Cl or F and/or hydrates and/or solvates and/or pharmaceutically acceptable salts thereof.
When X is F, the compound may be called:
S-Amino-Z-CS-cyano-S-fluoro-benzenesulfonylJ-S-CS-fluorophenyO-thienoP.S-bl-pyridine (Compound 1)
When X is Cl, the compound may be called:
5-Amino-2-(3-cyano-5-fluoro-benzenesulfonyl)-3-(3-chlorophenyl)-thieno[2,3-b]-pyridine (Compound 2)
Surprisingly, it was found that a unique subset of the compounds disclosed in hit. Pat.
Appl. WO 2007/072095 has outstandingly high binding affinity to the mGluR5 receptor (Ki values are less than 10 nM) and possesses high anxiolytic activity in rats after oral administration (minimal effective doses are less than 10 mg/kg p.o.). Furthermore, the degree of oral bioavailability of these compounds in rodents exceeds 10.0%. Conformity to these triple criteria represents definite advantage in terms of druglike properties and therapeutic or preventive applicability in conditions which require the modulation of mGluRl and mGluR5 receptors.
Compounds of formula (I) may form salts with acids. The invention relates also to the salts of compounds of formula (I) formed with acids, including without limitation the salts formed with pharmaceutically acceptable acids. The phrase " a compound of formula (I)" encompasses both the free base and the salt, even if the salt is not explicitly recited.
Both organic and inorganic acids can be used for the formation of acid addition salts. Suitable inorganic acids can be for example hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid. Representatives of monovalent organic acids can be for example formic acid, acetic acid, propionic acid, and different butyric acids, valeric acids and capric acids. Representatives of bivalent organic acids can be for example oxalic acid, malonic acid, maleic acid, fumaric acid and succinic acid. Other organic acids can also be used, such as without limitation hydroxy acids for example citric acid, tartaric acid, or aromatic carboxylic acids for example benzoic acid or salicylic acid, as well as aliphatic and aromatic sulfonic acids for example methanesulfonic acid, naphthalenesulfonic acid and p-toluenesulfonic acid, hi some embodiments, the acid addition salts are ones in which the acid component itself is physiologically acceptable and does not have therapeutical effect in the applied dose or it does not have unfavorable influence on the effect of the active ingredient. These acid addition salts are pharmaceutically acceptable acid addition salts. In some embodiments, the acid addition salts may not be pharmaceutically acceptable acid addition salts because, for example they can be advantageous in the purification and isolation of the desired compounds.
In some embodiments, the compounds of formula (I) can be solvates and/or hydrates of compounds of formula (J).
Pharmaceutical formulations In some embodiment, the invention provides pharmaceutical compositions containing the compounds of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof as active ingredient and one or more physiologically acceptable carriers.
The compounds of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof may be administered by any convenient method, for example by oral, parenteral (including subcutaneous, intramuscular, and intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
The compounds of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
A liquid formulation of the compounds of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof generally include a suspension or solution of the compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in a suitable liquid carrier(s) for example an aqueous solvent, such as water and ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
A composition in the solid form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid etc. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques. A composition in the solid form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then these are filled into a hard gelatine capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then is filled into a soft gelatine capsule.
Parenteral compositions may be a solution or suspension of the compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
In some embodiments, compositions including one or more compounds according to the present invention may be formulated for nasal administration. For example, a nasal administration formulation may include a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof formulated as aerosols, drops, gels and powders. Aerosol formulations of the present invention may comprise a solution or fine suspension of the compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates in a physiologically acceptable aqueous or non-aqueous solvent and are may be presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. If the dosage form comprises an aerosol dispenser, it may contain a propellant which can be a compressed gas, such as compressed air or an organic propellant, such as a fiuorochlorohydrocarbon. The aerosol dosages form can also take the form of a pump-atomiser.
In some embodiments, compositions including one or more compounds according to the invention may be formulated for buccal or sublingual administration. Such compositions may include a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates in the form of, for example, tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier, such as sugar and acacia, tragacanth, or gelatine, glycerin etc. In some embodiments, compositions including one or more compounds according to the present invention may be formulated for rectal administration. Such compositions include a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in the form of suppositories containing a conventional suppository base, such as cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
In some embodiments, compositions including one or more compounds according to the invention may be formulated for transdermal administration. Such compositions include a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof formulated in ointments, gels and patches. hi some embodiments, compositions of the present invention including a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof are in the unit dose form, such as tablet, capsule or ampoule. hi some embodiments, each dosage unit of the present invention for oral administration contains from about 0.1 to about 500 mg of a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof calculated as a free base.
In some embodiments, each dosage unit of the present invention for parenteral administration contains from about 0.1 to about 500 mg of a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof calculated as a free base.
The compounds of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof may be administered in a daily dosage regimen. In the treatment of mGluRl and mGluR5 mediated disorders, such as schizophrenia, anxiety, depression, panic, bipolar disorders, and circadian disorders or chronic and acute pain disorders the dosage levels from about 0.01 mg/kg to about 100 mg/kg of body weight per day may be suitable or alternatively about 0.5 mg to about 7 g per patient per day.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form may vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms may generally contain between from about 1 mg to about 1000 mg of the active ingredient, for example 25 mg, 50 mg, 100 mg, 200 mg, 250-300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg. It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Medical use
The compounds of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates of the present invention have been found to exhibit biological activity at mGluRl and mGluR5 receptors and are expected to be useful in the treatment of mGluRl and mGluR5 mediated disorders.
It has been found that the compounds according to the present invention or salts thereof, exhibit a high degree of potency and selectivity for mGluRl and mGluR5 receptors. In particular, the compounds according to the present invention are highly potent (Ki<10 nM) ligands of the mGluR5 receptor. Accordingly, the compounds of the present invention are expected to be useful in the prevention and/or treatment of conditions associated with excitatory activation of mGluRl and mGluR5 receptor. The compounds may be used to produce an inhibitory effect of mGluRl and mGluR5, in mammals, including human.
Furthermore, compounds of the present invention showed favorable bioavailability
(>10.0%) and potent in vivo activity (MED<10 mg/kg p.o.) after oral administration in animal assays. Accordingly, the compounds of the present invention are expected to be particularly suitable for oral application in conditions relating to the modulation of mGluRl and mGluR5 receptors. Thus, it is expected that the compounds of the present invention are well suited for the prevention, therapy and/or treatment of mGluRl and mGluR5 receptor-mediated disorders such as acute and chronic neurological and psychiatric disorders, chronic and acute pain disorders and neuromuscular dysfunction of the lower urinary tract and gastrointestinal disorders.
The dose required for the therapeutic or preventive treatment of a particular disorder may be varied depending on the host treated and the route of administration. In some embodiments, the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy. hi some embodiments, the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of mGluRl and mGluR5 receptor-mediated disorders. hi some embodiments, the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of neurological disorders. hi some embodiments, the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of psychiatric disorders. hi some embodiments, the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of chronic and acute pain disorders. hi some embodiments, the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of neuromuscular dysfunction of the lower urinary tract and gastrointestinal disorders. In some embodiments, the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of pain related to migraine, inflammatory pain, neuropathic pain disorders such as diabetic neuropathies, arthritis and rheumatoid diseases, low back pain, post-operative pain and pain associated with various conditions including angina, in renal or biliary colic, menstruation, migraine and gout. hi some embodiments, the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of Alzheimer's disease senile dementia, AIDS-induced dementia Parkinson's disease, amyotrophic lateral sclerosis,
Huntington's Chorea, migraine, epilepsy, schizophrenia, depression, anxiety, acute anxiety, obesity, obsessive compulsive disorder, attention deficit and hyperactivity disorder, substance abuse and dependence, ophthalmological disorders such as retinopathies, diabetic retinopathies, glaucoma, auditory neuropathic disorders such as tinnitus, chemotherapy induced neuropathies, post-herpetic neuralgia and trigeminal neuralgia, Fragile X, autism, mental retardation, and Down's Syndrome.
In some embodiments, the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy, prevention and/or treatment of stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, cardiovascular diseases and epilepsy.
The one or all of the compounds may be well suited for the treatment of neuromuscular dysfunction of the lower urinary tract, such as urinary urgency, overactive bladder, greater urinary frequency, reduced urinary compliance, cystitis, incontinence, enuresis and dysuria. Furthermore, one or all of the compounds may be well suited for the treatment of gastrointestinal disorders, such as transient lower esophageal sphincter relaxation (TLESR), gastrointestinal reflux disease and irritable bowel syndrome.
In some embodiments, the present invention relates also to the use of a compound of formula (I) as defined hereinbefore, in the manufacture of a medicament for therapy, prevention and/or treatment of mGluRl and mGluR5 receptor-mediated disorders and any disorder listed above.
In some embodiments, the invention also provides a method of therapy, treatment and/or prevention of mGluRl and mGluR5 receptor mediated disorders and any disorder listed above, in a patient suffering from, or at risk of, said condition, which comprises administering to the patient an effective amount of a compound of formula (I), as hereinbefore defined.
In this specification, the term "about" is intended to encompass the range of experimental error associated with a particular measurement.
In this specification, unless stated otherwise, the term "antagonist" means a compound that by any means, partly or completely blocks the transduction pathway leading to the production of a response by the ligand.
The term "disorder", unless stated otherwise, means any condition or disease associated with metabotropic glutamate receptor activity. Methods of preparation
The disclosure provides a process for the preparation of a compound of formula (I)
Figure imgf000012_0001
wherein X is Cl or F; and/or hydrates and/or solvates and/or pharmaceutically acceptable salts thereof, illustrated schematically below for the production of a compound of formula (I) in which X is F. A similar scheme can be used to produce a compound of formula (I) in which X is Cl by using a compound of formula (II) (shown below) wherein the F is replaced by Cl.
Scheme:
Figure imgf000012_0002
(π) Intermediate (I)
Figure imgf000012_0003
Intermediate (II) (D
a.) aq. HNO3-acetic acid, 100-130 0C, 4-6 hrs; b.) Fe powder-acetic acid, 60-70 °C, 1 h; c.) 3-Cl or 3-F -phenylboronic acid, toluene-ethanol / 2M NaCO3 aq. solution, reflux, Ih. In some embodiments, a compound of formula (I) can be prepared from the precursor compound of formula (II) by nitration, followed by reduction and Suzuki coupling.
In some embodiments, salts and/or hydrates and/or solvates of compounds of formula (I) can be formed. Intermediate (I) was prepared from the corresponding N-oxide (II) (WO 2007/072095) by a selective nitration reaction using aq. nitric acid in acetic acid. The reaction was carried out in the range of 100-1300C temperature by the method of Klemm, L.H ( J. Heterocycl. Chem., 7, 1970, 81).
Intermediate (II) was selectively reduced with iron used in combination with acid ( HCl or preferably acetic acid) by the method of Org. Synth. Coll., 5, 346, 1973.
Compounds of formula (I) were synthesised by the well known methods of Suzuki coupling reactions using the appropriate boronic acid, base and palladium catalyst as described e.g. A Suzuki & H.C Brown: Organic Syntheses via Boranes Vol. 1-3.
Biological test methods
MGluR5 receptor binding tests
MGluR5 receptor binding was determined according to Gasparini et.al. (Bioorg. Med.
Chem. Lett. 2000, 12:407-409) with modifications. Rat cerebro-cortical membrane preparation was used to determine the binding characteristics of reference compounds and novel compounds to the rat mGluR5. The Al 8 cell line expressing hmGluR5a (purchased from Euroscreen) was used to determine binding characteristics of the chemical compounds to the human mGluR5a receptor. As radioligand, [3H]-M-MPEP (2 nM) was used. The nonspecific binding was determined in the presence of 10 μM M-MPEP.
Measurement of anxiolytic activity in the punished drinking test
The method described by Vo gel et al. (Psychopharmacology (Berl.) 1971, 21 :1-7) was used with modifications. On the day preceding the test day male Wistar rats (180-220 g) were placed into the test chambers which were equipped with a metal water spout mounted on the wall of the chamber and a metal grid floor for delivering electric shocks. During a 5-min adaptation period the animals had free access to the drinking spout. Following the adaptation session rats were deprived of drinking water for 24h prior to test. On the day of the measurement, the animals were orally treated with the test compounds and 60 min later were placed into the test chambers where they had access to the drinking water. In the test session drinking was punished by delivering electric shocks (ImA, 1 sec) through the drinking spout following every 10 licks during a 270-s punished period. Number of licks and shocks delivered were recorded and stored in a computer. Anxiolytic activity is reflected by the increased number of accepted shocks. Minimum effective doses (MED, defined as the dose which increased the number of accepted shocks above 35) were determined and used to characterize the anxiolytic potency of the tested compounds.
Determination of oral bioavailability
The oral bioavailability study was performed in male Wistar rats (200-220 g, n=4) fasted overnight. The compounds were formulated freshly as microemulsion for intravenous dosing and as suspension for oral dosing. A dose of 3 mg/kg of the compounds was administered intravenously in the tail vein by a dosing volume of 2.5 ml/kg. Blood samples (~1 ml) were drawn from the retroorbital sinus at 0.083, 0.333, 1.0, 5.0 h post dose into heparinized tubes. A dose of 10 mg/kg of the compounds were administered orally to rats by a dosing volume of 5 ml/kg by gavage. Blood samples (~1 ml) were drawn from the retroorbital sinus at 0.4, 1.0, 2.0, 5.0 h post dose into heparinized tubes.
Plasma samples were obtained by immediate centrifugation of blood samples and were stored at -2O0C until HPLC-UV analysis. Plasma samples were extracted with chlorobutane and then analysed on 150x4.6mm, 5μm, Zorbax Eclipse XDB-C 18 column (Agilent) using gradient elution with binary mobile phase containing 0.1 M ammonium acetate and acetonitrile. Analysis were performed at 4O0C. The column eluent was monitored at 245nm (Compound 2) and 250nm (Compound 1). The pharmacokinetic parameters (AUC, Cmax, tmax were calculated by non-compartmental analysis using Kinetica Version 4.4.1 Program. The absolute oral bioavailability was calculated as AUCoral/AUC jv • Dose;v/ Doseorai.. Results
Figure imgf000015_0002
Compound 1 and Compound 2 bind with high affinity to both human and rat mGlu5 receptors. The compounds showed remarkable anxiolytic activity after oral administration and their oral bioavailability exceeds 10.0 %. These pharmacological properties represents definite advantage in terms of drug-like properties and treatment, therapeutic or preventive applicability and renders Compound 1 and Compound 2 particularly suitable for oral application in conditions which require the modulation of mGluRl and mGluR5 receptors.
The following examples are intended to illustrate but not to limit the invention in any manner, shape, or form, either explicity or implicity.
Examples:
Intermediate 1 S-Bromo^-CS-cyano-S-fluoro-benzenesulfoπyO-S-nitro-thieno^^-blpyridin-N-oxide
Figure imgf000015_0001
3-Bromo-2-(3-cyano5-fluorobenzenesulfonyl)-thieno[2,3-b]pyridin-N-oxide (prepared as described in WO 2007/072095) (7.97 g, 19.3mmol) was boiled at 12O0C with 66% nitric acid (1.22ml) in acetic acid (25ml) for 4 hours. The reaction mixture was evaporated and the residue was purified by chromatography (Kieselgel 60, chloroform : methanol = 5 : 0.1). First the starting material was isolated (3.7 g, 47%), than a yelow solid , which was treated with ether (5ml). After filtration the title compound was isolated (0.72 g, 8.3%). LC-MS: (M+H)+ 459.1.
Intermediate 2 5-Amino 3-bromo-2-(3-cyano-5-fluoro-benzenesulfonyl)- thieno[2,3-b]pyridine
Figure imgf000016_0001
3-Bromo-2-(3-cyano-5-fluoro-benzenesulfonyl)-5-nitro-thieno[2,3-b]pyridin-N-oxide (1.0 g, 2.18 mmol) was suspended in acetic acid (12 ml) and Fe powder was added (0,73 g, 13 mmol). The reaction mixture was stirred at 60-70 0C for 60 minutes. Chloroform (45ml) was added and after filtration through celite the filtrate was evaporated, the crude residue was treated with methanol (3 ml). The product was filtered, washed with methanol. It was obtained 0.69g (76.7%) yellow powder. LC-MS: (M+H)+413.1.
Example 1 5-Amino-2-(3-cyano -5-fluoro -benzenesulfonyl)-3-(3-fluorophenyl)-thieno[2,3-b]- pyridine
Figure imgf000016_0002
5-Amino-3-bromo-2-(3-cyano-5-fluoro-benzenesulfonyl)-thieno[2,3-b]pyridine (1.2 g, 29 mmol) was dissolved in toluene (16 ml) and ethanol (18 ml) under argon atmosphere. To the solution Pd(PPh3)4 (157mg, O.Hmmol), 3-fluoroρhenylboronic acid (0.5Og, 35.8 mmol) and 2M solution OfNa2CO3 (14 ml) was added. The reaction mixture was refluxed for 1 hour then it was filtered through celite, and washed with toluene. The filtrate was tightened in vacuum, water (13 ml) and ethyl acetate (13 ml) were added to the residue. It was separated and the water phase was extracted with ethylacetate (2x5 ml). The organic phase was washed with water (5.0 ml), dried over Na2SO4, filtered, and contcentrated in vacuo. The crude product was purified by column chromatography (Kieselgel 60, ethylacetate : hexane= 2 : 1) to yield 0.94 g (76 %) of the title compound. The crude product can be purified by stirring with methanol to give a yelow amorphous material. LC-MS: (M+H)+ 428.2.
1H NMR (500 MHz, DMSO-^5, 25 0C): 5.67 (s, 2H); 6.81 (d, J= 2.6 Hz, IH); 7.00-7.07 (m, 2H); 7.35-7.43 (m, IH); 7.50-7.60 (m, 2H); 7.60-7.64 (m, IH); 8.20-8.25 (m, IH); 8.27 (d, J= 2.6 Hz, IH).
Example 2
5-Amino-2-(3-cyano -5-fluoro -benzenesulfonyl)-3-(3-chlorophenyl) -thieno[2,3-b]- pyridine
Figure imgf000017_0001
5-Amino-3-bromo-2-(3-cyano-5-fluoro-benzenesulfonyl)-thieno[2,3-b]pyridine (1.25 g, 30 mmol) was dissolved in toluene (18 ml) and ethanol (20 ml) under argon atmosphere. To the solution Pd(PPh3)4 (175mg, 0.15mmol), 3-chlorophenylboronic acid (0.58g, 37 mmol) and 2M solution OfNa2CO3 (15 ml) was added. The reaction mixture was refluxed for 1 hour then it was filtered through celite, and washed with toluene (2x5ml). The filtrate was tightened in vacuum, water (13 ml) and ethyl acetate (13 ml) were added to the residue. It was separated and the water phase was extracted with ethyl acetate (2x5 ml). The organic phase was washed with water (5.0 ml), dried over Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by column chromatography (Kieselgel 60, ethyl acetate : hexane = 2 : 1) to yield the title compound which was purified by stirring with methanol (5ml) to give 0.84g (63%) yellow amorphous material. LC-MS: (M+H)+ 444.2.
1H NMR (400 MHz, DMSO-J6, 25 0C): 5.68 (s, 2H); 6.80 (d, J= 2.6 Hz, IH); 7.13-7.22 (m, 2H); 7.53 (t, J= 7.9 Hz, IH); 7.56-7.65 (m, 3H); 8.24 (dm, J= 8.4 Hz, IH); 8.27 (d, J= 2.6 Hz, IH).
1H NMR spectra were obtained on a Varian V-500 or a Varian V-400 spectrometer.
Chemical shifts are reported in parts per million relative to TMS as internal standard.
Example 3
Preparation of pharmaceutical compositions:
a) Tablets:
0.01-50 % of active ingredient of formula (I), 15-50 % of lactose, 15-50 % of potato starch, 5-15 % of polyvinyl pyrrolidone, 1-5 % of talc, 0.01-3 % of magnesium stearate, 1-3 % of colloid silicon dioxide and 2-7 % of ultraamylopectin were mixed, then granulated by wet granulation and pressed to tablets. b) Dragέes, film coated tablets:
The tablets made according to the method described above were coated by a layer consisting of entero- or gastrosolvent film, or of sugar and talc. The dragees were polished by a mixture of beeswax and carnuba wax.
c) Capsules:
0.01-50 % of active ingredient of formula (I), 1-5 % of sodium lauryl sulfate, 15-50 % of starch, 15-50 % of lactose, 1-3 % of colloid silicon dioxide and 0.01-3 % of magnesium stearate were thoroughly mixed, the mixture was passed through a sieve and filled in hard gelatin capsules. d) Suspensions:
Ingredients: 0.01-15 % of active ingredient of formula (I), 0.1-2 % of sodium hydroxide, 0.1-3 % of citric acid, 0.05-0.2 % of nipagin (sodium methyl 4-hydroxybenzoate),
0.005-0.02 % of nipasol, 0.01-0.5 % of carbopol (polyacrilic acid), 0.1-5 % of 96 % ethanol,
5 0.1-1 % of flavoring agent, 20-70 % of sorbitol (70 % aqueous solution) and 30-50 % of distilled water.
To solution of nipagin and citric acid in 20 ml of distilled water, carbopol was added in small portions under vigorous stirring, and the solution was left to stand for 10-12 h. Then the sodium hydroxide in 1 ml of distilled water, the aqueous solution of sorbitol and finally0 the ethanolic raspberry flavor were added with stirring. To this carrier the active ingredient was added in small portions and suspended with an immersing homogenizator. Finally the suspension was filled up to the desired final volume with distilled water and the suspension syrup was passed through a colloid milling equipment. 5 e) Suppositories:
For each suppository 0.01-15% of active ingredient of formula (I) and 1-20% of lactose were thoroughly mixed, then 50-95% of adeps pro suppository (for example Witepsol ' 4) was melted, cooled to 35 0C and the mixture of active ingredient and lactose was mixed in it with homogenizator. The obtained mixture was mould in cooled forms. 0 f) Lyophilized powder ampoule compositions:
A 5 % solution of mannitol or lactose was made with bidistilled water for injection use, and the solution was filtered so as to have sterile solution. A 0.01-5 % solution of the active ingredient of formula (I) was also made with bidistilled water for injection use, and this5 solution was filtered so as to have sterile solution. These two solutions were mixed under aseptic conditions, filled in 1 ml portions into ampoules, the content of the ampoules was lyophilized, and the ampoules were sealed under nitrogen. The contents of the ampoules were dissolved in sterile water or 0.9 % (physiological) sterile aqueous sodium chloride solution before administration. 0

Claims

Claims:
1. A compound of formula (I):
Figure imgf000020_0001
wherein X is Cl or F or hydrates, solvates, or salts thereof.
2. A compound selected from:
5-Amino-2-(3-cyano-5-fluoro-benzenesulfonyl)-3-(3-fluorophenyl)-thieno[2,3-b]-pyridine, and 5-Amino-2-(3 -cyano-5 -fluoro-benzenesulfonyl)-3 -(3 -chlorophenyl)-thieno [2,3 -b] -pyridine.
3. A process for the preparation of a compound of formula (I) :
Figure imgf000020_0002
wherein X is Cl or F or hydrates, or solvates, or salts thereof, comprising: nitration of a compound of formula (II);
Figure imgf000020_0003
followed by a reduction and then a Suzuki coupling reaction to obtain a compound of formula (I); and, optionally forming salts, hydrates,or solvates of compounds of formula (I), or combinations thereof.
4. A process according to claim 3, wherein the nitration produces an intermediate of formula (I):
Figure imgf000021_0001
the reduction reaction reduces the intermediate of formula (I) to produce an intermediate of formula (II):
Figure imgf000021_0002
and the Suzuki coupling reaction is of the intermediate of formula (II) to produce the compound of formula (I).
5. A pharmaceutical formulation, comprising: a therapeutically-effective amount of a compound of formula (I)
Figure imgf000021_0003
wherein X is Cl or F or hydrates, solvates, or pharmaceutically acceptable salts thereof, or combinations thereof; and at least one of physiologically acceptable diluents, excipients or inert carriers.
6. Compound of formula (I) for use treating of mGluRl and mGluR5 receptor-mediated disorders, comprising adrninistering a pharmaceutical composition according to claim 5 to a mammal in need of the treatment.
7. A use according to claim 6, wherein said mGluRl and mGluR5 receptor-mediated disorders are psychiatric disorders.
8. A use according to claim 6, wherein said mGluRl and mGluR5 receptor-mediated disorders are neurological disorders.
9. A use according to claim 6, wherein said mGluRl and mGluR5 receptor-mediated disorders are chronic and acute pain.
10. A use according to claim 6, wherein said mGluRl and mGluR5 receptor-mediated disorders are neuromuscular dysfunction of the lower urinary tract and gastrointestinal disorders.
11. Compound of formula (I) for use treating mGluRl and mGluR5 receptor-mediated disorders, comprising: administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of formula (I) :
Figure imgf000022_0001
wherein X is Cl or F or hydrates, solvates, or pharmaceutically acceptable salts thereof, or combinations thereof.
12. A use according to claim 11 wherein said mammal is a human.
13. A use according to claim 11 wherein said mGluRl and mGluR5 receptor-mediated disorders are psychiatric disorders.
14. A use according to claim 11 wherein said mGluRl and mGluR5 receptor-mediated disorders are neurological disorders.
15. A use according to claim 11 wherein said mGluRl and mGluR5 receptor-mediated disorders are chronic and acute pain disorders.
16. A use according to claim 11 wherein said mGluRl and mGluR5 receptor-mediated disorders are neuromuscular dysfunction of the lower urinary tract and gastrointestinal disorders.
PCT/HU2009/000052 2008-06-30 2009-06-25 Thieno [2,3-b] pyridine compounds with mglur activity WO2010001185A1 (en)

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HUP0800407 2008-06-30

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007072095A1 (en) * 2005-12-20 2007-06-28 Richter Gedeon Nyrt. New compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007072095A1 (en) * 2005-12-20 2007-06-28 Richter Gedeon Nyrt. New compounds

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