WO2008149163A2 - Potassium ion channel modulators and uses thereof - Google Patents

Potassium ion channel modulators and uses thereof Download PDF

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Publication number
WO2008149163A2
WO2008149163A2 PCT/GB2008/050423 GB2008050423W WO2008149163A2 WO 2008149163 A2 WO2008149163 A2 WO 2008149163A2 GB 2008050423 W GB2008050423 W GB 2008050423W WO 2008149163 A2 WO2008149163 A2 WO 2008149163A2
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groups
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carbon atoms
pharmacologically acceptable
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WO2008149163A3 (en
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Geoff Lawton
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Lectus Therapeutics Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—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
    • A61P13/00—Drugs for disorders of the urinary system
    • 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]
    • 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 ion channel modulators, and more particularly to heterocyclic compounds which inhibit the interaction between the pore- forming (alpha) subunits of Kv1 voltage-gated potassium channels and accessory (Kvbeta subunit) proteins.
  • Voltage-dependent potassium (Kv) channels conduct potassium ions (K + ) across cell membranes in response to changes in the membrane voltage and thereby can regulate cellular excitability by modulating (increasing or decreasing) the electrical activity of the cell.
  • Kv1.1-Kv1.8 Mammalian homologues (Kv1.1-Kv1.8) of so-called Kv1 potassium channel alpha subunits encoded by the Drosophiia Shaker gene can form tetrameric protein complexes that span the plasma membrane of cells and allow the passage of K + ions. These tetrameric protein complexes of KvLx channels constitute the ion channel pore-forming domain.
  • Functional Kv1 channels consisting of a tetramer of transmembrane spanning KvLx channel subunits may be associated with, and regulated by, accessory (Kvbeta) proteins that are able to modulate the function of ion channel pore- forming domains (for reviews, see: Xu, J. & Li, M., Trends Cardiovasc. Med., 1998, 8, 229-234; Pongs, O., et at., Ann. N.Y. Acad. ScL, 1999, 868, 344- 355).
  • accessory (Kvbeta) proteins that are able to modulate the function of ion channel pore- forming domains
  • Functional Kv1 channels can exist as multimeric structures formed by the association of either identical or dissimilar KvLx and/or Kvbeta proteins. Modulation of functional Kv1 channel complexes by Kvbeta subunits is believed to be Kv subfamily specific (Sewing et a/., Neuron 1996, 15, 455- 463). Kvbeta subunits bind to KvLx channel alpha subunits through an interaction domain known as the T1 domain' or 'tetramerisation domain' located on the N-terminus of KvIx channel alpha subunits.
  • the T1 domain was originally identified as an amino-terminal fragment of KvLx channels that was necessary for alpha subunit assembly (Li et al., Science, 1992, 257, 1225- 1229; Shen et al., Neuron, 1993, 11 , 67-76).
  • the putative sequence of the interaction site between Kv1.x alpha subunits with Kvbeta subunits has been determined and a sequence identified within the so-called T1 domain that is necessary for this interaction (Yu et al., Neuron, 1996, 16, 441-453; Sewing et al. Neuron 1996, 15, 455-463).
  • Kvi .x channels consist of at least 8 members which include one or more of the following mammalian channels: Kv1.1 , Kv1.2, Kv1.3, Kv1.4, Kv1.5, Kv1.6, Kv1.7, Kv1.8 and any mammalian or non-mammalian equivalents or variants (including splice variants) thereof.
  • Kvbeta proteins may include one or more of the following mammalian subunits: KvbetaH , Kvbeta 1.2, Kvbeta1.3, Kvbeta2.1 , Kvbeta2.2, Kvbeta3, Kvbeta3.1 , Kvbeta4 and any mammalian or non-mammalian equivalents or variants (including splice variants) thereof.
  • interactions between Kv1 ,x channels and Kvbeta proteins can confer modulation (increasing or decreasing) of a number of features of functional Kv1 channels including, but not limited to (i) the transport or chaperone of Kv1 ,x channels to the plasma membrane of a given cell type (e.g.
  • Kv beta subunits can also exert effects on other gating properties (see HtIIe, B.
  • Kvbeta subunits may confer differentia! modulation to KvLx channel currents (Bahring et a/., Molecular Membrane Biology, 1994, 21 , 19-
  • Kv1.x channel openers Kv1.x channel opening
  • Kv1.x channel inhibitors KvLx channel inhibition
  • KvLx channel openers or KvLx channel inhibitors have potential utility in the treatment, prevention, inhibition, amelioration or aileviation of symptoms of a number of conditions or disease states including:
  • “Lower Urinary Tract Disorders” this encompasses both painful (any lower urinary tract disorder involving sensations or symptoms that a patient subjectively describes as producing or resulting in pain) and non-painfui lower urinary tract disorders (any lower urinary tract disorder involving sensations or symptoms, including mild or general discomfort, that is subjectively described as not producing or resulting in pain).
  • “Lower urinary tract disorders” also includes any lower urinary tract disorder characterised by overactive bladder with and/or without loss of urine, urinary frequency, urinary urgency, and nocturia.
  • lower urinary tract disorders includes overactive bladder or overactive urinary bladder (including, overactive detrusor, detrusor instability, detrusor hyperreflexia, sensory urgency and the symptoms of detrusor overactivity), urge incontinence or urinary urge incontinence, stress incontinence or urinary stress incontinence, lower urinary tract symptoms including obstructive urinary symptoms such as slow urination, dribbling at the end of urination, inability to urinate and/or the need to strain to urinate at an acceptable rate or irritating symptoms such as frequency and/or urgency.
  • overactive bladder or overactive urinary bladder including, overactive detrusor, detrusor instability, detrusor hyperreflexia, sensory urgency and the symptoms of detrusor overactivity
  • urge incontinence or urinary urge incontinence urge incontinence or urinary urge incontinence
  • stress incontinence or urinary stress incontinence lower urinary tract symptoms including obstructive urinary symptoms
  • Lower urinary tract disorders may also include neurogenic bladder that occurs as the result of neurological damage due to disorders including but not limited to stroke, Parkinson's disease, diabetes, multiple sclerosis, peripheral neuropathy, or spinal cord lesions. Lower urinary tract disorders may also include prostatitis, interstitial cystitis, benign prostatic hyperplasia, and, in spinal cord injured patients, spastic bladder.
  • Anxiety and Anxiety-Related Conditions this includes, but is not limited to, anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, performance anxiety, post-traumatic stress disorder, acute stress reaction, adjustment disorders, hypochondriacal disorders, separation anxiety disorder, agoraphobia and specific phobias.
  • Specific anxiety related phobias include, but are not limited to, fear of animals, insects, storms, driving, flying, heights or crossing bridges, closed or narrow spaces, water; blood or injury, as well as extreme fear of inoculations or other invasive medical or dental procedures.
  • Epilepsy includes, but is not limited to, one or more of the following seizures: simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures.
  • Pain Disorders includes but is not limited to one or more on the following: acute pain such as musculoskeletal pain, post-operative pain and surgical pain; chronic pain such as chronic inflammatory pain (e.g. rheumatoid arthritis and osteoarthritis), neuropathic pain (e. g.
  • post-herpetic neuralgia trigeminal neuralgia and sympathetically-maintained pain
  • pain associated with cancer and fibromyalgia pain associated with migraine; pain (both chronic and acute), and/or fever and/or inflammation of conditions such as rheumatic fever; symptoms associated with influenza or other viral infections, such as the common cold; lower back and neck pain; headache; toothache; sprains and strains; myositis; neuralgia; synovitis; arthritis, including rheumatoid arthritis; degenerative joint diseases, including osteoarthritis; gout and ankylosing spondylitis; tendinitis; bursitis; skin-related conditions, such as psoriasis, eczema, burns and dermatitis; injuries, such as sports injuries and those arising from surgical and dental procedures.
  • Gynaecological Pain for example, dysmenorrhoea, labour pain and pain associated with endometriosis.
  • Cardiac Arrhythmias include, but are not limited to, atrial fibrillation, atrial flutter, atrial arrhythmia and supaventricular tachycardia.
  • Cardiovascular Diseases such as angina pectoris, hypertension and congestive heart failure.
  • Inflammatory and Immunological Diseases include inflammatory bowel disease, rheumatoid arthritis, graft rejection, asthma, chronic obstructive pulmonary disease, multiple sclerosis, cystic fibrosis and atherosclerosis.
  • Gastrointestinal Disorders including reflux oesophagitis, functional dyspepsia, motility disorders (including constipation and diarrhoea), and irritable bowel syndrome.
  • Vascular and Visceral Smooth Muscle Disorders including asthma, pulmonary hypertension, chronic obstructive pulmonary disease, adult respiratory distress syndrome, peripheral vascular disease (including intermittent claudication), venous insufficiency, impotence, cerebral and coronary spasm and Raynaud's disease.
  • Chronic gliomas including those of lower and higher maiignancy.
  • Diabetes including diabetic retinopathy, diabetic nephropathy and diabetic neuropathy
  • insulin resistance/insensitivity obesity
  • “Memory Loss” including Alzheimer's disease and dementia.
  • CNS-Mediated Motor Dysfunction Disorders including Parkinson's disease and ataxia.
  • Opthalamic Disorders such as ocular hypertension.
  • KvIx channel openers and KvLx channel inhibitors for the prophylaxis or treatment of a number of disease states including lower urinary tract disorders, inflammatory and immunological diseases and pain indications.
  • assays based on the interaction between KvLx channel T1 domains and Kvbeta subunits immobilised through an affinity tag a new family of heterocyclic compounds has been found that inhibits the interaction between Kv 1.x channels and Kvbeta proteins.
  • a and B are independently CH 2 or CH 2 CH 2 ;
  • D is CR2 or a nitrogen atom;
  • E is CR3 or a nitrogen atom;
  • G is CR4 or a nitrogen atom; with the proviso that at least one of D, E and G is nitrogen;
  • R1 is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group or a heteroaralkyl group;
  • R2, R3 and R4 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyi groups, hydroxyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, aikylsulphonyl groups, arylsulphonyl groups, aminosulphonyl groups and cyano groups;
  • X is selected from RSSO 2 , R5R7NCO, R5R7NSO 2 and R5SO 2 NR7CO wherein R5 and R7 are as defined below;
  • Y is selected from R6CO, R6SO 2 , R6R7NCO, R6R7NSO 2 , R6SO 2 NR7CO and CO 2 R8 wherein R6, R7 and R8 are as defined below;
  • R5 and R6 are independently selected from hydrogen atoms, alkyl groups, aryl groups, aralkyl groups, heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and heteroaraikyl groups;
  • R7 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; and R8 is an alkyl group, an aryl group, an aralkyl group, an alkoxyalkyl group, a heteroaryl group or a heteroarylalkyl group.
  • Preferred compounds of the present invention include:
  • R1 is a hydrogen atom, an aSkyl group having from 1 to 6 carbon atoms or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from aikyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups;
  • R1 is a hydrogen atom
  • R2 is independently selected from hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxy groups, hydroxyl groups and cyano groups;
  • R2, R3 and R4 are independently selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms and halogen atoms;
  • R2, R3 and R4 are independently selected from hydrogen atoms, methyl groups, ethyl groups, fluorine atoms and chlorine atoms;
  • X is a group of formula R5SO 2 , wherein R5 is: a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, aikoxy groups having from 1 to 6 carbon atoms, aikoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyi group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from al
  • X is a group of formula R5SO 2 , wherein R5 is an alkyl group having from 1 to 4 carbon atoms or an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms;
  • R5 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, aikoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the aikoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalky!
  • R7 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen
  • X is a group of formula R5R7NCO, wherein R5 is a hydrogen atom, an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from aikyl groups having from 1 to 4 carbon atoms, halogen atoms and haloaikyl groups having from 1 to 4 carbon atoms, or an aralkyl group comprising an alky!
  • R7 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms
  • X is a group of formula R5R7NCO, wherein R5 is a hydrogen atom, a pheny! group which may optionally be substituted with at least one substituent selected from methyl groups, ethyl groups, fluorine atoms and chlorine atoms, or benzyl group which may optionally be substituted with at least one substituent selected from methyl groups, ethyl groups, fluorine atoms and chlorine atoms, and R7 is a hydrogen atom, a methyl group or an ethyl group;
  • R5 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haioaikyi groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxy!
  • an aralkyl group comprising an alkyi group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to
  • R7 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloaikyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms
  • Y is a group of formula R6CO, wherein R6 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms; an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to
  • Y is a group of formula R6CO, wherein R6 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms or an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms;
  • (21) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6CO, wherein R6 is a hydrogen atom; a methyl group, a phenyl group, a 4- methylphenyl group, a benzyl group or a phenethyl group;
  • (22) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6SO 2 , wherein R6 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an ary!
  • alkyl groups having from 1 to 6 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups
  • an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyi groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carb
  • R6 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, al
  • R6 is a hydrogen atom, an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from aikyi groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyi groups having from 1 to 4 carbon atoms, or an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms, and R7 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms;
  • Y is a group of formula R6R7NCO, wherein R6 is a hydrogen atom, a phenyl group which may optionally be substituted with at least one substituent selected from methyl groups, ethyl groups, fluorine atoms and chlorine atoms, or a benzyl group which may optionally be substituted with at least one substituent selected from methyl groups, ethyl groups, fluorine atoms and chlorine atoms, and
  • R7 is a hydrogen atom, a methyi group or an ethyl group
  • Y is a group of formula R6R7NCO, wherein R6 is a hydrogen atom, a benzyl group or a phenyl group which is optionally substituted with a methyl group, and R7 is a hydrogen atom.
  • R6 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyi groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an atkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alky!
  • R7 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least
  • alkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups.
  • R6 is an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms, or an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms; and R7 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms.
  • R6SO 2 R7NCO wherein R6 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom; (32) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula CO 2 R8 wherein R8 is an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alky!
  • alkoxyalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an alkoxy group having from 1 to 6 carbon atoms, a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyi groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, , an alkoxyalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an alkoxy group having from 1
  • Y is a group of formula CO 2 R8 wherein R8 is an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyi groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms, or an aralkyl group comprising an aikyl group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at ieast one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms;
  • D is nitrogen and E is nitrogen; or D is nitrogen and G is nitrogen; or E is nitrogen; or
  • E is nitrogen and G is nitrogen;
  • G is nitrogen; or each of D, E and G is nitrogen;
  • D is nitrogen and E is nitrogen;
  • D is nitrogen and G is nitrogen;
  • R1 is a hydrogen atom
  • X is a group of formula R5SO 2 R7NCO, wherein R5 is a phenyl group which may optionally be substituted with an alkyl group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom;
  • Y is a group of formula R6SO 2 R7NCO, wherein R6 is a phenyl group which may optionally be substituted with an alkyl group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom; D is a nitrogen atom;
  • E is CR3, wherein R3 is a hydrogen atom; and G is CR4 wherein R4 is a hydrogen atom; or
  • R1 is a hydrogen atom
  • X is a group of formula R5SO 2 R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
  • Y is a group of formula R6SO 2 R7NCO, wherein R6 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
  • D is a nitrogen atom
  • E is CR3, wherein R3 is a hydrogen atom
  • G is CR4 wherein R4 is a hydrogen atom
  • R1 is a hydrogen atom
  • X is a group of formula R5SO 2 R7NCO, wherein R5 is a phenyl group which may optionally be substituted with an alkyl group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom;
  • Y is a group of formula R6SO 2 R7NCO, wherein R6 is a phenyl group which may optionally be substituted with an alky! group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom;
  • D is a nitrogen atom
  • E is CR3, wherein R3 is a hydrogen atom; and G is a nitrogen atom;
  • R1 is a hydrogen atom
  • X is a group of formula R5SO 2 R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
  • Y is a group of formula R6SO 2 R7NCO, wherein R6 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
  • D is a nitrogen atom
  • E is CR3, wherein R3 is a hydrogen atom
  • G is a nitrogen atom; or (b) R1 is a hydrogen atom;
  • X is a group of formula R5SO 2 R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
  • Y is a group of formula CO 2 R8, wherein R8 is a benzyi group which may optionally be substituted with a methyl group;
  • D is a nitrogen atom
  • E is CR3, wherein R3 is a hydrogen atom
  • G is CR4, wherein R4 is a hydrogen atom
  • R1 is a hydrogen atom
  • X is a group of formula R5SO 2 R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
  • Y is a group of formula R6CO, wherein R6 is a phenyl group which may optionally be substituted with a methyl group;
  • D is a nitrogen atom
  • E is CR3, wherein R3 is a hydrogen atom
  • G is CR4, wherein R4 is a hydrogen atom; or
  • R1 is a hydrogen atom
  • X is a group of formula R5SO 2 R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
  • Y is a group of formula R6SO 2l wherein R6 is a phenyl group which may optionally be substituted with a methyl group;
  • D is a nitrogen atom
  • E is CR3, wherein R3 is a hydrogen atom
  • G is CR4, wherein R4 is a hydrogen atom
  • X is a group of formula R5SO 2 R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyi group, and R7 is a hydrogen atom;
  • Y is a group of formula R6R7NCO, wherein R6 is a benzyl group which may optionally be substituted with a methyl group and R7 is a hydrogen atom;
  • D is a nitrogen atom;
  • E is CR3, wherein R3 is a hydrogen atom; and G is CR4, wherein R4 is a hydrogen atom; or
  • R1 is a hydrogen atom
  • X is a group of formula R5SO 2 R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
  • Y is a group of formula R6R7NSO 2 , wherein R6 is a phenyl group which may optionally be substituted with a methyl group and R7 is a hydrogen atom;
  • D is a nitrogen atom
  • E is CR3, wherein R3 is a hydrogen atom; and G is nitrogen; or
  • X is a group of formula R5SO 2 R7NCO, wherein R5 is a phenyl group which may optionally be substituted with an alkyl group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom;
  • Y is a group of formula R6SO 2 R7NCO, wherein R6 is a phenyl group which may optionally be substituted with an alkyl group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom;
  • D is CR2, wherein R2 is a hydrogen atom; E is a nitrogen atom; and G is CR4, wherein R4 is a hydrogen atom; and
  • a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and an active ingredient, wherein said active ingredient is a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof as an active ingredient thereof.
  • a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof for use as a medicament in a third aspect of the present invention.
  • a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Anxiety and Anxiety-Related Conditions.
  • a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Migraine in the preparation of a medicament for the prophylaxis or treatment of Migraine.
  • a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders there is provided use of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders.
  • a and B are independently CH 2 or CH 2 CH 2 ;
  • D is CR2 or a nitrogen atom;
  • E is CR3 or a nitrogen atom;
  • G is CR4 or a nitrogen atom; with the proviso that at least one of D, E and G is nitrogen;
  • R1 is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group or a heteroaralkyl group;
  • R2, R3 and R4 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxy! groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyi groups, aminosulphonyl groups and cyano groups;
  • X is selected from R5CO, RSSO 2 , R5R7NCO, R5R7NSO 2 , R5SO 2 NR7CO and CO 2 R8 wherein R5, R7 and R8 are as defined below;
  • Y is selected from R6CO, R6SO 2 , R6R7NCO, R6R7NSO 2 , R6SO 2 NR7CO and CO 2 R8 wherein R6, R7 and R8 are as defined below;
  • R5 and R6 are independently selected from hydrogen atoms, alkyl groups, aryl groups, aralkyl groups, heteroaryl groups and heteroaralkyl groups;
  • R7 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group;
  • R8 is an alkyi group, an aryl group, an aralkyl group, an alkoxyalkyl group, a heteroaryl group or a heteroarylalkyl group.
  • a compound of formula (1 a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by KvLx channel opening.
  • a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by KvLx channel inhibition.
  • a thirteenth aspect of the present invention there is provided use of a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Lower Urinary Tract Disorders.
  • a fourteenth aspect of the present invention there is provided use of a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Pain Disorders.
  • a compound of formula (1a) as defined in the tenth aspect of the invention or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiac Arrhythmias there is provided use of a compound of formula (1a) as defined in the tenth aspect of the invention or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiac Arrhythmias.
  • a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Thromboembolic Events.
  • a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiovascular Diseases.
  • a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Disorders of the Auditory System.
  • a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Gastrointestinal Disorders.
  • a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders.
  • a compound of formula (1 a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Cell Proliferative Disorders.
  • a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Metabolic Disorders.
  • a method for the prophylaxis or treatment of Anxiety and Anxiety-Related Conditions comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of Epilepsy comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (40) or a pharmacologically acceptable sait or pro-drug thereof.
  • a method for the prophylaxis or treatment of Migraine comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of Inflammatory and Immunological Diseases comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of Memory Loss comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of a disease in which KvIx channels are involved comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined below or a pharmacologically acceptable salt or pro-drug thereof:
  • a and B are independently CH 2 or CH 2 CH 2 , D is CR2 or a nitrogen atom; E is CR3 or a nitrogen atom; G is CR4 or a nitrogen atom; with the proviso that at (east one of D 1 E and G is nitrogen;
  • R1 is a hydrogen atom, an alkyl group, a cycioalkyl group, an aryl group, an aralkyl group or a heteroaralkyl group;
  • R2, R3 and R4 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, aminosulphonyl groups and cyano groups;
  • X is selected from R5CO, R5SO 2 , R5R7NCO, R5R7NSO 2[ R5SO 2 NR7CO and CO 2 R8 wherein R5, R7 and R8 are as defined below;
  • Y is selected from R6CO, R6SO 2f R6R7NCO, R6R7NSO 2 , R6SO 2 NR7CO and CO 2 R8 wherein R6, R7 and R8 are as defined below;
  • R5 and R6 are independently selected from hydrogen atoms, alkyl groups, aryl groups, aralkyl groups, heteroaryl groups and heteroaralkyl groups;
  • R7 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group
  • R8 is an alky! group, an aryl group, an aralkyl group, an alkoxyalkyl group, a heteroaryl group or a heteroarylalkyl group.
  • a method for the prophylaxis or treatment of a condition or disease ameliorated by KvIx channel opening comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of a condition or disease ameliorated by Kv1.x channel inhibition comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of Lower Urinary Tract Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of Pain Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable sa!t or pro-drug thereof.
  • a method for the prophylaxis or treatment of Gynaecological Pain comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of Cardiac Arrhythmias comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of Thromboembolic Events comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of Cardiovascular Diseases comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of Disorders of the Auditory System comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of Gastrointestinal Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of Cell Proliferative Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of Metabolic Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
  • a method for the prophylaxis or treatment of Opthalamic Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
  • a compound of formula (1) according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of any disease or condition recited in any of the fourth to twenty-fourth aspects of the invention recited above.
  • a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and at least two active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of muscarinic receptor antagonists, ⁇ 3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel ⁇ 2 ⁇ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists, alpha-1 adrenoceptor antagonists, tricyclic antidepressants, N-methyl-D- aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anticonvulsants, aldose reductase inhibitors, opioids,
  • active ingredients comprise at least one compound according to any one of (1)
  • said composition comprises a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of muscarinic receptor antagonists, ⁇ 3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel ⁇ 2 ⁇ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and alpha-1 adrenoceptor antagonists.
  • active ingredients comprise at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of muscarinic receptor antagonists, ⁇ 3 adrenergic receptor agonists,
  • said composition comprises a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel ⁇ 2 ⁇ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators,
  • a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of muscarinic receptor antagonists, ⁇ 3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel ⁇ 2 ⁇ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and alpha-1 adrenoceptor antagonists for use in the prophylaxis or treatment of lower urinary tract disorders.
  • active ingredients comprise at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of muscar
  • a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel ⁇ 2 ⁇ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, aipha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators
  • a fifty-second aspect of the invention there is provided use of at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof and at least one compound selected from the group consisting of muscarinic receptor antagonists, ⁇ 3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel ⁇ 2 ⁇ ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and alpha-1 adrenoceptor antagonists in the manufacture of a medicament for the prophylaxis or treatment of lower urinary tract disorders.
  • muscarinic receptor antagonists ⁇ 3 adrenergic receptor agonists
  • neurokinin K receptor antagonists neurokinin K receptor antagonists
  • vanilloid VR1 agonists calcium channel ⁇ 2 ⁇ ligands
  • potassium channel inhibitors calcium channel inhibitor
  • a fifty-third aspect of the invention there is provided use of at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof and at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel ⁇ 2 ⁇ ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyi-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anticonvulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non
  • a method for the prophylaxis or treatment of lower urinary tract disorders comprising administering to a patient in need thereof an effective amount of a composition according to the first or second preferred aspects of the invention in accordance with the forty-nith aspect of the invention.
  • the alkyl groups in the definitions of R1 , R2, R3, R4, R5, R6, R7 and R8 are preferably alkyl groups having from 1 to 6 carbon atoms, more preferably alkyl groups having from 1 to 4 carbon atoms and most preferably methyl groups.
  • the cycloalkyl groups in the definition of R1 is preferably a cycloalkyl group having from 3 to 8 carbon atoms, more preferably having from 5 to 7 carbon atoms and most preferably cyclohexyl.
  • the aryl groups in the definitions of R1 , R5, R6, R7 and R8 are preferably aryl groups having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, aminosulphonyl groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups and cyano groups.
  • unsubstiuted aryl groups examples include phenyl, indenyi, naphthyl, phenanthrenyl and anthracenyl groups. More preferred aryl groups include phenyl groups which may optionally substituted by 1 or 2 alkyl groups.
  • the aralkyl groups in the definitions of R1 , R5, R6, R7 and R8 are preferably alkyl groups as defined above which are substituted with one or more aryl groups as defined above, and are more preferably benzyl or phenethyl groups.
  • the heteroaryl groups in the definitions of R5, R6 and R8 are preferably 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms.
  • Examples include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazoiyl, isoxazolyl, thiazolyl, isothiazolyl, 1 ,2,3-oxadiazolyi, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyf, pyrimidinyl and pyrazinyl groups.
  • heteroaralkyl groups in the definitions of R5, R6 and R8 are preferably alkyl groups as defined above which are substituted with heteroaryl groups as defined above.
  • the alkoxyalkyl group in the definition of R8 is preferably an aikyl group having as defined above which is substituted by an alkoxy group as defined below, and is more preferably an alkyl group having from 1 to 4 carbon atoms which is substituted with an alkoxy group having from 1 to 4 carbon atoms.
  • the haloalkyl groups in the definitions of R2, R3 and R4 are preferably alkyl groups as defined above which are substituted with one or more halogen atoms. More preferably, they are alkyl groups having from 1 to 4 carbon atoms that are substituted with at least one chlorine or fluorine atom and most preferably they are chloromethyl group, trichloromethyl groups, trifluoromethyl groups or tetrafluoroethyl groups.
  • the alkoxy groups in the definitions of R2, R3 and R4 are preferably alkoxy groups having from 1 to 6 carbon atoms, more preferably alkoxy groups having from 1 to 4 carbon atoms and most preferably methoxy or ethoxy groups.
  • the alkoxycarbonyl groups in the definitions of R2, R3 and R4 are preferably carbonyl groups substituted with alkoxy groups as defined above, and are more preferably methoxycarbonyl or ethoxycarbonyi groups.
  • the monalkylamino groups in the definitions of R2, R3 and R4 are preferably amino groups which are substituted with one alkyi group as defined above, and are more preferably methylamino, ethylamino or t-butylamino groups.
  • dialkylamino groups in the definitions of R2, R3 and R4 are preferably amino groups which are substituted with two alkyl groups as defined above which may be the same or different from each other, and are more preferably dimethyiamino or diethylamino groups.
  • the acylamino groups in the definitions of R2, R3 and R4 are preferably amino groups which are substituted with an acyl group having from 1 to 6 carbon atoms and are more preferably acetylamino or propanoylamino groups.
  • the alkoxycarbonylamino groups in the definitions of R2, R3 and R4 are preferably amino groups which are substituted with an aikoxycarbonyl group as defined above, and are more preferably methoxycarbonylamino or ethoxycarbonylamino groups.
  • the alkylsulphonyl groups in the definitions of R2, R3 and R4 are preferably sulphonyl groups which are substituted with an alkyl group as defined above and are more preferably a methylsulphonyl or ethylsulphonyl group.
  • the arylsulphonyl groups in the definitions of R2, R3 and R4 are preferably sulphonyl groups which are substituted with an aryl group as defined above and are more preferably a phenylsulphonyl group which may be optionally substituted with one or two alkyl groups as defined above or a naphthylsulphonyl group.
  • the compounds of formulae (1) and (1a) and pharmacologically active prodrugs and salts thereof contain some substituents for which there exist isosteres, and compounds containing such isosteres in place of said substituents also form a part of the present invention. For example, where the compounds of formulae (1) and (1a) and pharmacologically active prodrugs or salts thereof contain a carboxyl group, this can be replaced with a tetrazolyl group.
  • Hydrates or solvates of the compounds of formulae (1) and (1a), prodrugs thereof and pharmacologically acceptable salts thereof can also be used and form a part of the invention.
  • Some compounds of formulae (1) and (1a) and their pharmacologically acceptable salts or prodrugs thereof of the present invention may have one or more asymmetric carbons, and optical isomers (including diastereomers) due to the presence of asymmetric carbon atom(s) in the molecule can exist. These isomers are included in the present invention, both as individual isomers and mixtures thereof in all possible ratios.
  • the compounds of formulae (1) and (1a) of the present invention can form pharmacologically acceptable salts and pro-drugs and these form a part of the present invention.
  • salts include inorganic salts such as ammonium salts; organic amine salts such as t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N 1 N'- dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-N-phenethylamine salts, piperazine salts, tetramethylammonium salts and tris(hydroxymethyl)aminemethane salts; hydrohalogenated
  • the compounds of formulae (1) and (1a) of the present invention can be administered in the form of prodrugs.
  • Prodrugs are derivatives of the pharmacologically active compound in which one or more of the substituents on said compound are protected by a group which is then removable by a biological process (e.g. hydrolysis) in vivo after administration to the patient.
  • a biological process e.g. hydrolysis
  • suitable prodrugs are well-known to the person in the art and can be found, for example, in "Greene's Protective Groups in Organic Synthesis", 4 th Edition, 2006, Wiley-VCH, Suitable examples of such prodrugs include pharmacologically acceptable esters of the compound having the formulae (1) or (1a) wherein a carboxyl moiety of the compound having the formula (1) or (1a) is esterified.
  • esters are not particularly restricted, and can be selected by a person with an ordinary skill in the art. In the case of said esters, it is preferable that such esters can be cleaved by a biological process such as hydrolysis in vivo.
  • the group constituting the said esters can be, for example, a CrC 4 alkoxy C 1 -C 4 alkyl group such as methoxyethyl, 1-ethoxyethyl, 1 -methyl- 1-methoxyethyl, 1-(isopropoxy)ethyl, 2- methoxyethyl, 2-ethoxyethyl, 1 ,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; a C 1 -C 4 alkoxylated C- I -C 4 alkoxy Ci-C 4 alkyl group such as 2-methoxyethoxymethyl; a C 6 -Ci 0 aryloxy C1-C4 alkyl group such as phenoxymethyl; a halogenated Cr C 4 alkoxy CrC 4 alkyl group such as 2,2,2-trichlor
  • a C 6 -Ci 0 arylthiomethyl group such as phenylthiomethyl or naphthylthiomethyl
  • a C 1 -C 4 alkylsulfonyl CrC 4 lower alkyl group which may be optionally substituted with a halogen atom(s) such as 2- methanesulfonylethyl or 2-trifluoromethanesulfonylethyl
  • acyloxy CrC 4 aikyl group such as formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyi, 1-acetoxyethyl, 1-propionyioxyethyl, 1-butyry!oxyethyl, 1-pivaloyloxyethyl, 1- valeryloxyethyl, 1-isovaleryloxyethyl, 1»hexanoyloxyethyl, 2-formyloxyethyl, 2- acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-pivaloyloxye
  • muscarinic receptor antagonists include esoxybutynin, oxybutynin [especially the chloride], tolterodine [especially the tartrate], solifenacin [especially the succinate], darifenacin [especially the hydrobromide], temiverine, fesoterodine, imidafenacin and trospium [especially the chloride].
  • ⁇ 3 adrenergic receptor agonists include YM-178 and solabegron, KUC-7483.
  • neurokinin K receptor antagonists include cizolirtine and casopitant.
  • vanilloid VR1 agonists examples include capsaicin, resiniferatoxin and NDG-8243.
  • Examples of calcium channel ⁇ 2 ⁇ ligands include gabapentin and pregabaiin.
  • potassium channel activators include activators of KCNQ, BKCa channels, Kv channels and KATP channels
  • potassium channel activators include KW-7158, NS-8 and retigabine.
  • Examples of calcium channel inhibitors include ziconotide and NMED-160.
  • sodium channel blockers examples include lidocaine, lamotrigine, VX- 409, ralfinamide and carbamazepine.
  • Examples of serotonin and norepinephrine reuptake inhibitors include duloxetine and venlafaxine 10.
  • Examples of 5-HT antagonists including 5-HT1a antagonists and 5HT3 antagonists.
  • Examples of ⁇ -1 adrenoceptor antagonists include tamsulosin.
  • tricyclic antidepressants include amitriptyline, amoxapine, clomipramine, dosulepin (dothiepin), doxepin, imipramine, lofepramine, nortriptyline, and trimipramine.
  • NMDA ⁇ /-methyl-D-aspartate receptor antagonists
  • examples of ⁇ /-methyl-D-aspartate (NMDA) receptor antagonists include ketamine, memantine, amantadine, AVP-923, NP-1 and EVT-101.
  • Examples of cannabinoid receptor agonists include GW-1000 (Sativex) and KDS-2000. 15. Anti-convulsants. Examples include iacosamide, carbamazepine, topiramate, oxcarbazepine and levetiracetam
  • aldose reductase inhibitors include tolrestat, zopolrestat, zenarestat, epalrestat, sorbinil, AS-3201 , fidarestat, risarestat, ponalrestat and alrestatin.
  • opioids e.g. mu opioid agonists
  • examples of opioids include fentany! and tapentadol.
  • ⁇ adrenoceptor agonists include ai-adrenoceptor agonists such as ethoxamine, phenylephrine, oxymetazoline, tetrahydralazine and xylometazoline and a 2 -adrenoceptor agonists such as clonidine, guanabenz, guanfacine and ⁇ -methyldopa.
  • P2X receptor antagonists including P2X2 receptor antagonists and P2X7 receptor antagonists.
  • Examples of acid-sensing ion channel modulators include amiloride.
  • Examples of NGF receptor modulators include trkA.
  • nicotinic acetylcholine receptor modulators include A-85380, tebanicline, ABT-366833, ABT-202, ABT-894, epibatidine analogs and SiB- 1663.
  • synaptic vesicle protein 2A ligands examples include brivaracetam.
  • Examples of the administration form of the combination of the present invention are the same as given above for the compounds of general formula (1) or (1a) and pharmacologically acceptable salts or pro-drugs thereof.
  • the particular form can be chosen depending upon the condition to be treated and the nature of the compounds being administered in combination.
  • a combination of a compound of general formula (I) or (1 a) or a pharmacologically acceptable salt or pro-drug thereof with lidocaine could be administered transdermal ⁇ by means of a patch while a combination with ziconotide could be administered transmucosaliy.
  • Examples of the administration form of a compound having general formulae (1) or (1 a) of the present invention, or a pharmacologically acceptable salt or pro-drug thereof include oral administration by tablets, capsules, granules, powders or syrups, and parenteral administration by injection, patches or suppositories.
  • compounds having the general formula (1) or (1a) or a pharmacologically acceptable salt or pro-drug thereof of the present invention can also be administered by pulmonary administration in the form of a powder, solution or suspension. Preparations for these administrations are produced by known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, corrigents, diluents and so forth.
  • excipients include organic excipients such as sugar derivatives, e.g. lactose, sucrose, glucose, mannitol or sorbitol, starch derivatives, e.g. corn starch, potato starch, ⁇ -starch, dextrin or carboxymethyl starch, cellulose derivatives, e.g. crystalline cellulose, low substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose or internally crosslinked sodium carboxymethyl cellulose, and gum Arabic, dextran or pullulan; and, inorganic excipients such as silicate derivatives, e.g.
  • lubricants include stearic acid and metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as bee gum or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium fatty acid salts; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as silicic anhydride or silicate hydrate; and, starch derivatives.
  • stearic acid and metal stearates such as calcium stearate or magnesium stearate
  • talc colloidal silica
  • waxes such as bee gum or spermaceti
  • boric acid adipic acid
  • sulfates such as sodium sulfate
  • glycol fumaric acid
  • binders include polyvinylpyrrolidone, Macrogol and compounds similar to the aforementioned excipients.
  • disintegrants agents include compounds similar to the aforementioned excipients, and chemically cross-linked starches and celluloses such as cross sodium carmellose, sodium carboxymethyi starch or crosslinked polyvinylpyrrolidone.
  • stabilizers include paraoxybenzoate esters such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzy! alcohol or phenyl ethyl alcohol; benzalkonium chloride; phenols such as phenol or cresoi; thimerosai; dehydroacetic acid; and, sorbic acid.
  • corrigents include ordinarily used sweeteners, sour flavourings and fragrances.
  • said solution or suspension for pulmonary administration of a compound having the general formula (1) or general formula (1a) or pharmacologically acceptable salt or pro-drug thereof of the present invention
  • said solution or suspension can be produced by dissolving or suspending crystals of the present invention in water or in a mixture of water and an auxiliary solvent (e.g., ethanol, propylene glycol or polyethylene glycol).
  • an auxiliary solvent e.g., ethanol, propylene glycol or polyethylene glycol.
  • Such a solution or suspension may also contain an antiseptic (e.g., benzalkonium chloride), solubilizing agent (e.g., a polysorbate such as Tween 80 or Span 80 or surface activator such as benzalkonium chloride), buffer, isotonic agent (e.g., sodium chloride), absorption promoter and/or thickener.
  • an antiseptic e.g., benzalkonium chloride
  • solubilizing agent e.g., a polysorbate such as Tween 80 or Span 80 or surface activator such as benzalkonium chloride
  • buffer e.g., isotonic agent
  • absorption promoter and/or thickener e.g., sodium chloride
  • the suspension may additionally contain a suspending agent (such as microcrystalline cellulose or sodium carboxymethyi cellulose).
  • a composition for pulmonary administration produced in the manner described above is administered directly into the nasal cavity or oral cavity by a typical means in the field of inhalants (using, for example, a dropper, pipette, cannula or atomizer).
  • crystals of the present invention can be atomized as an aerosol in the form of a pressurized pack together with a suitable nebula (for example, a chlorofluorocarbon such as dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or a gas such as carbon dioxide), or they can be administered using a nebulizer.
  • a suitable nebula for example, a chlorofluorocarbon such as dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or a gas such as carbon dioxide
  • the amount of a compound having the general formula (1) or general formula (1a) or pharmacologically acceptable salt or pro-drug thereof of the present invention used varies depending on the symptoms, age, administration method and so forth, and may be administered either in a single dose or by dividing into multiple doses according to the symptoms.
  • Boc anhydride (73g, 336 mmol) was added to a stirred mixture of acid 2 (3Og, 168 mmo! in 1 :1 DCM:MeOH (800 cm 3 ) and triethylamine (70 cm 3 , 505 mmol). The mixture was stirred at room temperature for 3 days. DCM (200 cm 3 ) was then added followed by 10% citric acid (500 cm 3 ). The mixture was stirred for 30 mins before the DCM layer was separated, dried (MgSO 4 ), and evaporated in vacuo.
  • Benzyl chloroformate (32 ⁇ l_, 0.225 mmol) was added to a stirred mixture of 5 ⁇ 50 mg, 0.225 mmol) and K 2 CO 3 (93 mg, 0.675 mmol) in 1 :1 THF/H 2 O (2 cm 3 ). The mixture was stirred for 4 hours before ethyl acetate (5 cm 3 ) and water (5 cm 3 ) was added. The organic layer was separted, dried (MgSO 4 ) and evaporated in vacuo to yield 11 (33 mg, 52%).
  • Benzoyl chloride (26 ⁇ l_, 0.225 mmol) was added to 5 ⁇ 50 mg, 0.225 mmol) and K 2 CO 3 (93 mg, 0.675 mmol) in 1 :1 THF:H 2 O (2 cm 3 ). The mixture was stirred for 4 hours before ethyl acetate (5 cm 3 ) and water (5 cm 3 ) was added and mixed. The organics were separated and concentrated in vacuo to yield 13 (37 mg, 65%).
  • p-Toluenesulfonyl isocyanate (59 ⁇ L, 0.391 mmol) was added to 20 in THF (5 cm 3 ). The mixture was stirred overnight before diethyl ether (-8 cm 3 ) was added. The resultant solid was filtered to yield N-benzyl-2-( ⁇ [(4- methylphenyl)sulfonyl]carbamoyl ⁇ amino)-7 l 8-dihydro-1 l 6 ⁇ naphthyridine-6(5H)- carboxamide 21 as a white solid (85 g, 58%).
  • test compounds dissolved in a suitable vehicle
  • concentrations 100 ⁇ l. Plates were incubated for 30 minutes at room temperature.
  • Kv1.1 alpha subunit T1 domain cleared lysate (diluted 1 in 10 in PBS-Tween) was added to each well and incubated for 60 minutes at room temperature on a shaker. Unbound Kv1.1 alpha subunit T1 domain was removed by washing 3 times in 300 ⁇ l of PBS- Tween. Bound Kv1.1 alpha subunit T1 domain was estimated by using appropriately diluted mouse anti-FLAG antibody and anti-mouse IgG secondary antibody HRP conjugate using standard ELISA procedures. HRP was detected as previously described (Kozlowski et al., patent application WO03078464).
  • test compounds were examined for their ability to inhibit the binding of Kv1.1 alpha subunit T1 domain to Kvbetal subunits to determine inhibition as a percentage of maximal binding in the absence of any test compound. Results are presented as the half maximal inhibitory concentration (IC 50 ) for inhibition of Kv1.1 alpha subunit T1 binding to Kvbetal subunits.
  • IC 50 half maximal inhibitory concentration
  • the tested compounds of Examples of this invention displayed the ability to inhibit the binding of Kv1.1 alpha subunit T1 domain to Kvbetal subunits as measured by determination of the IC 50 .

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Abstract

Compounds of general formula (1) and pharmacologically acceptable salts and pro-drugs thereof: wherein A and B are CH2 or CH2CH2, R1 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl or heteroaralkyl, D, E and G are CR2 or nitrogen, with the proviso that at least one of D, E and G is nitrogen, R2, R3 and R4 are hydrogen, alkyl, halogen, haloalkyl, alkoxy, alkoxycarbonyl, carboxyl, hydroxyl or cyano, X is R5SO2, R5R7NCO, R5R7NSO2or R5SO2NR7CO, Y is R6CO, R6SO2, R6R7NCO, R6R7NSO2, R6SO2NR7CO or CO2R8, R5 and R6 are hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, R7 is hydrogen, alkyl, aryl or aralkyl, and R8 is alkyl, aryl, aralkyl, alkoxyalkyl, heteroaryl or heteroarylalkyl, are of use inthe prophylaxis or treatment of diseases and conditions in which Kv1.x channels are involved, such as lower urinary tract disorders, cardiovascular diseases, inflammatory and immunological diseases and pain.

Description

Potassium Ion Channel Modulators & Uses Thereof
Field of the Invention
The present invention relates to ion channel modulators, and more particularly to heterocyclic compounds which inhibit the interaction between the pore- forming (alpha) subunits of Kv1 voltage-gated potassium channels and accessory (Kvbeta subunit) proteins.
Background to the Invention Voltage-dependent potassium (Kv) channels conduct potassium ions (K+) across cell membranes in response to changes in the membrane voltage and thereby can regulate cellular excitability by modulating (increasing or decreasing) the electrical activity of the cell.
Mammalian homologues (Kv1.1-Kv1.8) of so-called Kv1 potassium channel alpha subunits encoded by the Drosophiia Shaker gene can form tetrameric protein complexes that span the plasma membrane of cells and allow the passage of K+ ions. These tetrameric protein complexes of KvLx channels constitute the ion channel pore-forming domain.
Functional Kv1 channels consisting of a tetramer of transmembrane spanning KvLx channel subunits may be associated with, and regulated by, accessory (Kvbeta) proteins that are able to modulate the function of ion channel pore- forming domains (for reviews, see: Xu, J. & Li, M., Trends Cardiovasc. Med., 1998, 8, 229-234; Pongs, O., et at., Ann. N.Y. Acad. ScL, 1999, 868, 344- 355).
Functional Kv1 channels can exist as multimeric structures formed by the association of either identical or dissimilar KvLx and/or Kvbeta proteins. Modulation of functional Kv1 channel complexes by Kvbeta subunits is believed to be Kv subfamily specific (Sewing et a/., Neuron 1996, 15, 455- 463). Kvbeta subunits bind to KvLx channel alpha subunits through an interaction domain known as the T1 domain' or 'tetramerisation domain' located on the N-terminus of KvIx channel alpha subunits. The T1 domain was originally identified as an amino-terminal fragment of KvLx channels that was necessary for alpha subunit assembly (Li et al., Science, 1992, 257, 1225- 1229; Shen et al., Neuron, 1993, 11 , 67-76). The putative sequence of the interaction site between Kv1.x alpha subunits with Kvbeta subunits has been determined and a sequence identified within the so-called T1 domain that is necessary for this interaction (Yu et al., Neuron, 1996, 16, 441-453; Sewing et al. Neuron 1996, 15, 455-463). More recently, elucidation of the crystal structure of the interaction between the Kv1.1 T1 domain and the Kvbeta2 subunit, has established the current understanding of sequence of the critical interaction site between Kv1.1 channels and Kvbeta subunits (Gulbis et al., Science, 2000, 289, 123-127).
"Kvi .x" channels consist of at least 8 members which include one or more of the following mammalian channels: Kv1.1 , Kv1.2, Kv1.3, Kv1.4, Kv1.5, Kv1.6, Kv1.7, Kv1.8 and any mammalian or non-mammalian equivalents or variants (including splice variants) thereof.
"Kvbeta" proteins may include one or more of the following mammalian subunits: KvbetaH , Kvbeta 1.2, Kvbeta1.3, Kvbeta2.1 , Kvbeta2.2, Kvbeta3, Kvbeta3.1 , Kvbeta4 and any mammalian or non-mammalian equivalents or variants (including splice variants) thereof.
At a functional level, interactions between Kv1 ,x channels and Kvbeta proteins can confer modulation (increasing or decreasing) of a number of features of functional Kv1 channels including, but not limited to (i) the transport or chaperone of Kv1 ,x channels to the plasma membrane of a given cell type (e.g. Shi et al., Neuron, 1996, 16, 843-852) and/or (ii) gating properties such as channel inactivation (for example see Rettig et al., Nature, 1994,369, 289- 294; Heinemann et al., Journal of Physiology, 1996, 493, 625-633; Bahring et al., Molecular Membrane Biology, 1994, 21 , 19-25). In addition to modulation of Kv channel "inactivation", which refers to the closing of the Kv channel by any mechanism such as by N-type inactivation, Kv beta subunits can also exert effects on other gating properties (see HtIIe, B. Ionic Channels of Excitable Membranes, Sunderland, M A, 1992) by mechanisms which may alter the time and voltage dependency of the open (conducting state), closed (non-conducting state) and inactivated states (nonconducting state) of KvIx channels.
Furthermore, the interaction between specific Kvbeta subunits and different KvLx channel compositions may confer differentia! modulation to KvLx channel currents (Bahring et a/., Molecular Membrane Biology, 1994, 21 , 19-
25). This phenomenon may account for the wide diversity of K+ channels.
However, both the exact subunit compositions of native K+ channels and the physiological roie that particular channels play are, in most cases, still unclear,
Compounds which inhibit the interaction between KvLx channels and Kvbeta proteins and thus preserve or enhance either the conducting state of KvLx channels (e.g. though reducing the rate of KvIx channel inactivation) and/ or increase the transport of KvLx channels to the plasma membrane, are defined as "Kv1.x channel openers" (Kv1.x channel opening)
Compounds which inhibit the interaction between KvLx channels and Kvbeta proteins and thus preserve either the closed state of KvLx channels and/or decrease the transport of KvLx channels to the plasma membrane, are defined as "Kv1.x channel inhibitors" (KvLx channel inhibition)
Such KvLx channel openers or KvLx channel inhibitors have potential utility in the treatment, prevention, inhibition, amelioration or aileviation of symptoms of a number of conditions or disease states including:
"Lower Urinary Tract Disorders", this encompasses both painful (any lower urinary tract disorder involving sensations or symptoms that a patient subjectively describes as producing or resulting in pain) and non-painfui lower urinary tract disorders (any lower urinary tract disorder involving sensations or symptoms, including mild or general discomfort, that is subjectively described as not producing or resulting in pain). "Lower urinary tract disorders" also includes any lower urinary tract disorder characterised by overactive bladder with and/or without loss of urine, urinary frequency, urinary urgency, and nocturia. Thus, lower urinary tract disorders includes overactive bladder or overactive urinary bladder (including, overactive detrusor, detrusor instability, detrusor hyperreflexia, sensory urgency and the symptoms of detrusor overactivity), urge incontinence or urinary urge incontinence, stress incontinence or urinary stress incontinence, lower urinary tract symptoms including obstructive urinary symptoms such as slow urination, dribbling at the end of urination, inability to urinate and/or the need to strain to urinate at an acceptable rate or irritating symptoms such as frequency and/or urgency. Lower urinary tract disorders may also include neurogenic bladder that occurs as the result of neurological damage due to disorders including but not limited to stroke, Parkinson's disease, diabetes, multiple sclerosis, peripheral neuropathy, or spinal cord lesions. Lower urinary tract disorders may also include prostatitis, interstitial cystitis, benign prostatic hyperplasia, and, in spinal cord injured patients, spastic bladder.
"Anxiety and Anxiety-Related Conditions", this includes, but is not limited to, anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, performance anxiety, post-traumatic stress disorder, acute stress reaction, adjustment disorders, hypochondriacal disorders, separation anxiety disorder, agoraphobia and specific phobias. Specific anxiety related phobias include, but are not limited to, fear of animals, insects, storms, driving, flying, heights or crossing bridges, closed or narrow spaces, water; blood or injury, as well as extreme fear of inoculations or other invasive medical or dental procedures.
"Epilepsy", includes, but is not limited to, one or more of the following seizures: simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures. "Pain Disorders", includes but is not limited to one or more on the following: acute pain such as musculoskeletal pain, post-operative pain and surgical pain; chronic pain such as chronic inflammatory pain (e.g. rheumatoid arthritis and osteoarthritis), neuropathic pain (e. g. post-herpetic neuralgia, trigeminal neuralgia and sympathetically-maintained pain) and pain associated with cancer and fibromyalgia; pain associated with migraine; pain (both chronic and acute), and/or fever and/or inflammation of conditions such as rheumatic fever; symptoms associated with influenza or other viral infections, such as the common cold; lower back and neck pain; headache; toothache; sprains and strains; myositis; neuralgia; synovitis; arthritis, including rheumatoid arthritis; degenerative joint diseases, including osteoarthritis; gout and ankylosing spondylitis; tendinitis; bursitis; skin-related conditions, such as psoriasis, eczema, burns and dermatitis; injuries, such as sports injuries and those arising from surgical and dental procedures.
"Gynaecological Pain", for example, dysmenorrhoea, labour pain and pain associated with endometriosis.
"Cardiac Arrhythmias", include, but are not limited to, atrial fibrillation, atrial flutter, atrial arrhythmia and supaventricular tachycardia.
"Thromboembolic Events" such as stroke.
"Cardiovascular Diseases" such as angina pectoris, hypertension and congestive heart failure.
"Disorders of the Auditory System" such as tinnitus.
"Migraine"
"Inflammatory and Immunological Diseases" (or a disorder involving immunosuppression) including inflammatory bowel disease, rheumatoid arthritis, graft rejection, asthma, chronic obstructive pulmonary disease, multiple sclerosis, cystic fibrosis and atherosclerosis.
"Gastrointestinal Disorders" including reflux oesophagitis, functional dyspepsia, motility disorders (including constipation and diarrhoea), and irritable bowel syndrome.
"Vascular and Visceral Smooth Muscle Disorders" including asthma, pulmonary hypertension, chronic obstructive pulmonary disease, adult respiratory distress syndrome, peripheral vascular disease (including intermittent claudication), venous insufficiency, impotence, cerebral and coronary spasm and Raynaud's disease.
"Ceil Proliferative Disorders" including restenosis and cancer (including leukemia); treating or preventing gliomas including those of lower and higher maiignancy.
"Metabolic Disorders" such as diabetes (including diabetic retinopathy, diabetic nephropathy and diabetic neuropathy), insulin resistance/insensitivity and obesity.
"Memory Loss" including Alzheimer's disease and dementia.
Other "CNS-Mediated Motor Dysfunction Disorders" including Parkinson's disease and ataxia.
"Opthalamic Disorders" such as ocular hypertension.
Thus, it would be desirable to identify KvIx channel openers and KvLx channel inhibitors for the prophylaxis or treatment of a number of disease states including lower urinary tract disorders, inflammatory and immunological diseases and pain indications. Using assays based on the interaction between KvLx channel T1 domains and Kvbeta subunits immobilised through an affinity tag, a new family of heterocyclic compounds has been found that inhibits the interaction between Kv 1.x channels and Kvbeta proteins.
Description of the Invention
In a first aspect of the present invention, there is provided a compound represented by the general formula (1) or a pharmacologically acceptable salt or pro-drug thereof:
Figure imgf000008_0001
(1)
wherein:
A and B are independently CH2 or CH2CH2; D is CR2 or a nitrogen atom; E is CR3 or a nitrogen atom; G is CR4 or a nitrogen atom; with the proviso that at least one of D, E and G is nitrogen;
R1 is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group or a heteroaralkyl group;
R2, R3 and R4 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyi groups, hydroxyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, aikylsulphonyl groups, arylsulphonyl groups, aminosulphonyl groups and cyano groups;
X is selected from RSSO2, R5R7NCO, R5R7NSO2 and R5SO2NR7CO wherein R5 and R7 are as defined below; Y is selected from R6CO, R6SO2, R6R7NCO, R6R7NSO2, R6SO2NR7CO and CO2R8 wherein R6, R7 and R8 are as defined below;
R5 and R6 are independently selected from hydrogen atoms, alkyl groups, aryl groups, aralkyl groups, heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and heteroaraikyl groups;
R7 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; and R8 is an alkyl group, an aryl group, an aralkyl group, an alkoxyalkyl group, a heteroaryl group or a heteroarylalkyl group.
Preferred compounds of the present invention include:
(2) a compound according to (1) or pharmacologically acceptable salt or prodrug thereof wherein R1 is a hydrogen atom, an aSkyl group having from 1 to 6 carbon atoms or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from aikyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups;
(3) a compound according to (1) or a pharmacologically acceptable salt or pro-drug thereof wherein R1 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms;
(4) a compound according to (1) or a pharmacologically acceptable salt or pro-drug thereof wherein R1 is a hydrogen atom; (5) a compound according to any one of (1) to (4) or a pharmacologically acceptable salt or pro-drug thereof wherein R2, R3 and R4 are independently selected from hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxy groups, hydroxyl groups and cyano groups;
(6) a compound according to any one of (1) to (4) or a pharmacologically acceptable salt or pro-drug thereof wherein R2, R3 and R4 are independently selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms and halogen atoms;
(7) a compound according to any one of (1) to (4) or a pharmacologically acceptable sait or pro-drug thereof wherein R2, R3 and R4 are independently selected from hydrogen atoms, methyl groups, ethyl groups, fluorine atoms and chlorine atoms;
(8) a compound according to any one of (1) to (4) or a pharmacologically acceptable salt or pro-drug thereof wherein each of R2, R3 and R4 is a hydrogen atom;
(9) a compound according to any one of (1) to (8) or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5SO2, wherein R5 is: a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, aikoxy groups having from 1 to 6 carbon atoms, aikoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyi group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, aikoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the aikoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms;
(10) a compound according to any one of (1) to (8) or a pharmacologically acceptable sait or pro-drug thereof wherein X is a group of formula R5SO2, wherein R5 is an alkyl group having from 1 to 4 carbon atoms or an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms;
(11) a compound according to any one of (1) to (8) or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula RSSO2, wherein R5 is a phenyl group which may optionally be substituted with at least one substituent selected from methyl groups, ethyl groups, chlorine atoms and fluorine atoms;
(12) a compound according to any one of (1) to (8) or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula
R5R7NCO, wherein
R5 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, aikoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the aikoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalky! groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups and cyano groups, a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an aikyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and R7 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups and cyano groups, or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the aikoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups and cyano groups;
(13) a compound according to any one of (1 ) to (8) or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5R7NCO, wherein R5 is a hydrogen atom, an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from aikyl groups having from 1 to 4 carbon atoms, halogen atoms and haloaikyl groups having from 1 to 4 carbon atoms, or an aralkyl group comprising an alky! group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyi groups having from 1 to 4 carbon atoms, halogen atoms and haioaikyi groups having from 1 to 4 carbon atoms, and R7 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms;
(14) a compound according to any one of (1) to (8) or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5R7NCO, wherein R5 is a hydrogen atom, a pheny! group which may optionally be substituted with at least one substituent selected from methyl groups, ethyl groups, fluorine atoms and chlorine atoms, or benzyl group which may optionally be substituted with at least one substituent selected from methyl groups, ethyl groups, fluorine atoms and chlorine atoms, and R7 is a hydrogen atom, a methyl group or an ethyl group;
(15) A compound according to any one of (1) to (8) or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5R7NCO, wherein R5 is a hydrogen atom, a benzyl group or a phenyl group which is optionally substituted with a methyl group, and R7 is a hydrogen atom;
(16) a compound according to any one of (1) to (8) or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5SO2R7NCO, wherein
R5 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haioaikyi groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxy! groups and cyano groups, an aralkyl group comprising an alkyi group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and
R7 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloaikyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups;
(17) a compound according to any one of (1) to (8) or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5SO2R7NCO, wherein R5 is an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms, or an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryi group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms, and R7 is a hydrogen atom or an alkyi group having from 1 to 4 carbon atoms;
(18) a compound according to any one of (1) to (8) or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom.
(19) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6CO, wherein R6 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms; an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyi groups, hydroxyl groups and cyano groups, a heteroaryi group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 suifur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryi group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms;
(20) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6CO, wherein R6 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms or an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms;
(21) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6CO, wherein R6 is a hydrogen atom; a methyl group, a phenyl group, a 4- methylphenyl group, a benzyl group or a phenethyl group;
(22) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6SO2, wherein R6 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an ary! group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyi groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms; (23) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6SO2, wherein R6 is an alkyl group having from 1 to 4 carbon atoms or an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms;
(24) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6SO2, wherein R6 is a phenyl group which may optionally be substituted with at least one substituent selected from methyl groups, ethyl groups, chlorine atoms and fluorine atoms;
(25) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula
R6R7NCO, wherein
R6 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the aikoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaraikyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and R7 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups;
(26) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6R7NCO, wherein
R6 is a hydrogen atom, an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from aikyi groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyi groups having from 1 to 4 carbon atoms, or an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms, and R7 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms;
(27) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6R7NCO, wherein R6 is a hydrogen atom, a phenyl group which may optionally be substituted with at least one substituent selected from methyl groups, ethyl groups, fluorine atoms and chlorine atoms, or a benzyl group which may optionally be substituted with at least one substituent selected from methyl groups, ethyl groups, fluorine atoms and chlorine atoms, and
R7 is a hydrogen atom, a methyi group or an ethyl group;
(28) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug wherein Y is a group of formula R6R7NCO, wherein R6 is a hydrogen atom, a benzyl group or a phenyl group which is optionally substituted with a methyl group, and R7 is a hydrogen atom.
(29) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6SO2R7NCO, wherein
R6 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyi groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an atkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alky! groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyi groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and R7 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, or an aralky! group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups.
(30) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6SO2R7NCO, wherein
R6 is an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms, or an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms; and R7 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms.
(31) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula
R6SO2R7NCO, wherein R6 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom; (32) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula CO2R8 wherein R8 is an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alky! group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyi groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, , an alkoxyalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an alkoxy group having from 1 to 6 carbon atoms, a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms;
(33) a compound according to any one of (1) to (18) or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula CO2R8 wherein R8 is an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyi groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms, or an aralkyl group comprising an aikyl group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at ieast one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms;
(34) a compound according to any one of (1) to (33) or a pharmacologically acceptable salt or pro-drug thereof wherein: either:
D is nitrogen; or
D is nitrogen and E is nitrogen; or D is nitrogen and G is nitrogen; or E is nitrogen; or
E is nitrogen and G is nitrogen; or
G is nitrogen; or each of D, E and G is nitrogen;
(35) a compound according to any one of (1) to (33) or a pharmacologically acceptable salt or pro-drug thereof wherein either:
D is nitrogen; or
D is nitrogen and E is nitrogen; or
D is nitrogen and G is nitrogen;
(36) a compound according to (1) or a pharmacologically acceptable salt or pro-drug thereof wherein:
(a) R1 is a hydrogen atom;
X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with an alkyl group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom;
Y is a group of formula R6SO2R7NCO, wherein R6 is a phenyl group which may optionally be substituted with an alkyl group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom; D is a nitrogen atom;
E is CR3, wherein R3 is a hydrogen atom; and G is CR4 wherein R4 is a hydrogen atom; or
(b) R1 is a hydrogen atom; X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
Y is a group of formula R6SO2R7NCO, wherein R6 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
D is a nitrogen atom;
E is CR3, wherein R3 is a hydrogen atom; and
G is CR4 wherein R4 is a hydrogen atom; or
(c) R1 is a hydrogen atom;
X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with an alkyl group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom; Y is a group of formula R6SO2R7NCO, wherein R6 is a phenyl group which may optionally be substituted with an alky! group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom;
D is a nitrogen atom;
E is CR3, wherein R3 is a hydrogen atom; and G is a nitrogen atom;
(37) A compound according to (1) or a pharmacologically acceptable salt or pro-drug thereof wherein: (a) R1 is a hydrogen atom; X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
Y is a group of formula R6SO2R7NCO, wherein R6 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
D is a nitrogen atom;
E is CR3, wherein R3 is a hydrogen atom; and
G is a nitrogen atom; or (b) R1 is a hydrogen atom;
X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom; Y is a group of formula CO2R8, wherein R8 is a benzyi group which may optionally be substituted with a methyl group;
D is a nitrogen atom;
E is CR3, wherein R3 is a hydrogen atom; and
G is CR4, wherein R4 is a hydrogen atom;
(38) a compound according to (1) or a pharmacologically acceptable salt or pro-drug thereof wherein:
(a) R1 is a hydrogen atom;
X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
Y is a group of formula R6CO, wherein R6 is a phenyl group which may optionally be substituted with a methyl group;
D is a nitrogen atom; E is CR3, wherein R3 is a hydrogen atom; and
G is CR4, wherein R4 is a hydrogen atom; or
(b) R1 is a hydrogen atom;
X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
Y is a group of formula R6SO2l wherein R6 is a phenyl group which may optionally be substituted with a methyl group;
D is a nitrogen atom; E is CR3, wherein R3 is a hydrogen atom; and
G is CR4, wherein R4 is a hydrogen atom;
(39) a compound according to (1) or a pharmacologically acceptable salt or pro-drug thereof wherein: (a) R1 is a hydrogen atom;
X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyi group, and R7 is a hydrogen atom; Y is a group of formula R6R7NCO, wherein R6 is a benzyl group which may optionally be substituted with a methyl group and R7 is a hydrogen atom; D is a nitrogen atom;
E is CR3, wherein R3 is a hydrogen atom; and G is CR4, wherein R4 is a hydrogen atom; or
(b) R1 is a hydrogen atom;
X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom; Y is a group of formula R6R7NSO2, wherein R6 is a phenyl group which may optionally be substituted with a methyl group and R7 is a hydrogen atom;
D is a nitrogen atom;
E is CR3, wherein R3 is a hydrogen atom; and G is nitrogen; or
(c) X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with an alkyl group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom; Y is a group of formula R6SO2R7NCO, wherein R6 is a phenyl group which may optionally be substituted with an alkyl group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom;
D is CR2, wherein R2 is a hydrogen atom; E is a nitrogen atom; and G is CR4, wherein R4 is a hydrogen atom; and
(40) a compound according to (1) or a pharmacologically acceptable salt or pro-drug thereof selected from the group consisting of: N-[(4-methy!phenyl)sulfonyl]-2-({[(4-methylphenyl)sulfonyl]carbamoyl}amino)-
7,8-dihydro-1 ,6-naphthyridine-6(5H)-carboxamide;
N-[(4-methy[pheny!)sulfonyl]-2-({[{4-methylphenyl)sulfonyl]carbamoyl}amino)-
5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide; N-(phenylsulfonyl)-7-{[(phenylsulfonyl)carbamoyl]amino}~1 ,2,4,5-tetrahydro-
3H-3-benzazepine-3-carboxamide; benzyl 2-({[(4-methylphenyl)su!fonyl3carbamoyl}amino)-7,8-dihydro-1 ,6- naphthyridine-6(5H)-carboxylate;
N-[(6~benzoyl~5,6,7,8-tetrahydro»1 ,6-naphthyridin-2-yl)carbamoyl]-4- methylbenzenesuifonamide;
4-methyl-N-{[6-(4-methylbenzoyl)-5,6,7,8-tetrahydro-1 ,6-naphthyridin-2- yl]carbamoyl}benzenesulfonamide;
4~methyi-N-({6-[(4-methyiphenyl)sulfonyl]-5,6,7,8-tetrahydro-1 ,6-naphthyridin-
2-y[}carbamoyl)benzenesulfonamide; 4-methyl-N-({6-[(4-methy!phenyl)sulfonyl]-5,6,7,8-tetrahydro-1 ,6-naphthyridin-
2-y[}carbamoyi)benzenesuifonamide ammonium sait;
N-benzyl-2-({[(4-methylphenyl)sulfonyl3carbamoyl}amino)-7,8-dihydro-1 ,6- naphthyridine-6(5H)-carboxamide;
N-[(4-methylphenyl)sulfonyl]-2-({[(4-methyiphenyl)sulfonyl]carbamoyi}- amino)5,6,7,8-tetrahydro-pyrido[4,3-d]pyhmidinyl-carboxamide; and
N-[(4-methylphenyl)sulfonyl]-3-({[(4-methy!phenyl)sulfonyl]carbamoyl}-amino)-
7,8-dihydro-1 ,6-naphthyridine-6(5H)-carboxamide.
In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and an active ingredient, wherein said active ingredient is a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof as an active ingredient thereof.
In a third aspect of the present invention, there is provided a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof for use as a medicament. In a fourth aspect of the present invention, there is provided use of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Anxiety and Anxiety-Related Conditions.
In a fifth aspect of the present invention, there is provided use of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Epilepsy.
In a sixth aspect of the present invention, there is provided use of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Migraine.
in a seventh aspect of the present invention, there is provided use of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Inflammatory and Immunological Diseases.
in an eighth aspect of the present invention, there is provided use of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Memory Loss.
in a ninth aspect of the present invention, there is provided use of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders.
In an tenth aspect of the present invention, there is provided use of a compound of formula (1 a) as defined below or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of a disease in which Kv1.x channels are involved:
Figure imgf000028_0001
(la)
wherein:
A and B are independently CH2 or CH2CH2; D is CR2 or a nitrogen atom; E is CR3 or a nitrogen atom; G is CR4 or a nitrogen atom; with the proviso that at least one of D, E and G is nitrogen;
R1 is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group or a heteroaralkyl group;
R2, R3 and R4 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxy! groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyi groups, aminosulphonyl groups and cyano groups;
X is selected from R5CO, RSSO2, R5R7NCO, R5R7NSO2, R5SO2NR7CO and CO2R8 wherein R5, R7 and R8 are as defined below;
Y is selected from R6CO, R6SO2, R6R7NCO, R6R7NSO2, R6SO2NR7CO and CO2R8 wherein R6, R7 and R8 are as defined below;
R5 and R6 are independently selected from hydrogen atoms, alkyl groups, aryl groups, aralkyl groups, heteroaryl groups and heteroaralkyl groups; R7 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; and
R8 is an alkyi group, an aryl group, an aralkyl group, an alkoxyalkyl group, a heteroaryl group or a heteroarylalkyl group.
In a eleventh aspect of the present invention, there is provided use of a compound of formula (1 a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by KvLx channel opening.
In a twelfth aspect of the present invention, there is provided use of a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by KvLx channel inhibition.
!n a thirteenth aspect of the present invention, there is provided use of a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Lower Urinary Tract Disorders.
In a fourteenth aspect of the present invention, there is provided use of a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Pain Disorders.
In a fifteenth aspect of the present invention, there is provided use of a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Gynaecological Pain. In a sixteenth aspect of the present invention, there is provided use of a compound of formula (1a) as defined in the tenth aspect of the invention or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiac Arrhythmias.
In a seventeenth aspect of the present invention, there is provided use of a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Thromboembolic Events.
In a eighteenth aspect of the present invention, there is provided use of a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiovascular Diseases.
In a nineteenth aspect of the present invention, there is provided use of a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Disorders of the Auditory System.
In a twentieth aspect of the present invention, there is provided use of a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Gastrointestinal Disorders.
In a twenty-first aspect of the present invention, there is provided use of a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders.
In a twenty-second aspect of the present invention, there is provided use of a compound of formula (1 a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Cell Proliferative Disorders.
In a twenty-third aspect of the present invention, there is provided use of a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Metabolic Disorders.
in a twenty-fourth aspect of the present invention, there is provided use of a compound of formula (1a) as defined in the tenth aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Opthalamic Disorders.
In a twenty-fifth aspect, there is provided use according to any one of the eleventh to twenth-fourth aspects of the invention wherein said compound or a pharmacologically acceptable salt or pro-drug thereof is a compound as defined in any one of (1) to (40).
In a twenty-sixth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Anxiety and Anxiety-Related Conditions comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof.
In a twenty-seventh aspect of the present invention, there is provided a method for the prophylaxis or treatment of Epilepsy comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (40) or a pharmacologically acceptable sait or pro-drug thereof.
In a twenty-eighth aspect of the present invention, there is a method for the prophylaxis or treatment of Migraine comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof. In a twenty-ninth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Inflammatory and Immunological Diseases comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof.
In a thirtieth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Memory Loss comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof.
In a thirty-first aspect of the present invention, there is provided a method for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof.
In an thirty-second aspect of the present invention, there is provided a method for the prophylaxis or treatment of a disease in which KvIx channels are involved comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined below or a pharmacologically acceptable salt or pro-drug thereof:
Figure imgf000032_0001
(Ia)
wherein:
A and B are independently CH2 or CH2CH2, D is CR2 or a nitrogen atom; E is CR3 or a nitrogen atom; G is CR4 or a nitrogen atom; with the proviso that at (east one of D1 E and G is nitrogen;
R1 is a hydrogen atom, an alkyl group, a cycioalkyl group, an aryl group, an aralkyl group or a heteroaralkyl group;
R2, R3 and R4 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, aminosulphonyl groups and cyano groups;
X is selected from R5CO, R5SO2, R5R7NCO, R5R7NSO2[ R5SO2NR7CO and CO2R8 wherein R5, R7 and R8 are as defined below;
Y is selected from R6CO, R6SO2f R6R7NCO, R6R7NSO2, R6SO2NR7CO and CO2R8 wherein R6, R7 and R8 are as defined below;
R5 and R6 are independently selected from hydrogen atoms, alkyl groups, aryl groups, aralkyl groups, heteroaryl groups and heteroaralkyl groups;
R7 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; and
R8 is an alky! group, an aryl group, an aralkyl group, an alkoxyalkyl group, a heteroaryl group or a heteroarylalkyl group.
In a thirty-third aspect of the present invention, there is provided a method for the prophylaxis or treatment of a condition or disease ameliorated by KvIx channel opening comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
In a thirty-fourth aspect of the present invention, there is provided a method for the prophylaxis or treatment of a condition or disease ameliorated by Kv1.x channel inhibition comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
In a thirty-fifth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Lower Urinary Tract Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
In a thirty-sixth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Pain Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable sa!t or pro-drug thereof.
In a thirty-seventh aspect of the present invention, there is provided a method for the prophylaxis or treatment of Gynaecological Pain comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
in a thirty-eighth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Cardiac Arrhythmias comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof. In a thirty-ninth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Thromboembolic Events comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
In a fourtieth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Cardiovascular Diseases comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
In a forty-first aspect of the present invention, there is provided a method for the prophylaxis or treatment of Disorders of the Auditory System comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
In a forty-second aspect of the present invention, there is provided a method for the prophylaxis or treatment of Gastrointestinal Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
In a forty-third aspect of the present invention, there is provided a method for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
In a forty-fourth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Cell Proliferative Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
In a forty-fifth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Metabolic Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
In a forty-sixth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Opthalamic Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) as defined in the thirty-second aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof.
In one preferred aspect of the present invention, there is provided a method according to any one of the thirty-second to forty-sixth aspects of the invention wherein said compound or a pharmacologically acceptable salt or pro-drug thereof is a compound as defined in any one of (1) to (40).
In a forty-seventh aspect of the present invention, there is provided a compound of formula (1) according to any one of (1) to (40) or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of any disease or condition recited in any of the fourth to twenty-fourth aspects of the invention recited above.
In a forty-eighth aspect of the present invention, there is provided a compound of formula (1a) as defined in the eleventh aspect of the invention or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of any disease or condition recited in any of the tenth to twenty-fourth aspects of the invention recited above.
In a forty-ninth aspect of the present invention there is provided a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and at least two active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of muscarinic receptor antagonists, β3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists, alpha-1 adrenoceptor antagonists, tricyclic antidepressants, N-methyl-D- aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anticonvulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs),
In one preferred aspect of the pharmaceutical composition of the forty-ninth aspect of the invention, said composition comprises a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of muscarinic receptor antagonists, β3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and alpha-1 adrenoceptor antagonists.
In another preferred aspect of the pharmaceutical composition of the forty- ninth aspect of the invention, said composition comprises a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs).
In a fiftieth aspect of the invention, there is provided a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of muscarinic receptor antagonists, β3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and alpha-1 adrenoceptor antagonists for use in the prophylaxis or treatment of lower urinary tract disorders.
In a fifty-first aspect of the invention, there is provided a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, aipha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs) for use in the prophylaxis or treatment of pain.
in a fifty-second aspect of the invention, there is provided use of at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof and at least one compound selected from the group consisting of muscarinic receptor antagonists, β3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and alpha-1 adrenoceptor antagonists in the manufacture of a medicament for the prophylaxis or treatment of lower urinary tract disorders.
In a fifty-third aspect of the invention, there is provided use of at least one compound according to any one of (1) to (40) or a pharmacologically acceptable salt or prodrug thereof and at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyi-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anticonvulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs) in the manufacture of a medicament for the prophylaxis or treatment of pain.
In a fifty-fourth aspect of the invention, there is provided a method for the prophylaxis or treatment of lower urinary tract disorders comprising administering to a patient in need thereof an effective amount of a composition according to the first or second preferred aspects of the invention in accordance with the forty-nith aspect of the invention.
Detailed Description of the Invention
In the compounds of the present invention, the alkyl groups in the definitions of R1 , R2, R3, R4, R5, R6, R7 and R8 are preferably alkyl groups having from 1 to 6 carbon atoms, more preferably alkyl groups having from 1 to 4 carbon atoms and most preferably methyl groups.
In the compounds of the present invention, the cycloalkyl groups in the definition of R1 is preferably a cycloalkyl group having from 3 to 8 carbon atoms, more preferably having from 5 to 7 carbon atoms and most preferably cyclohexyl.
In the compounds of the present invention, the aryl groups in the definitions of R1 , R5, R6, R7 and R8 are preferably aryl groups having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, aminosulphonyl groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups and cyano groups. Examples of the unsubstiuted aryl groups include phenyl, indenyi, naphthyl, phenanthrenyl and anthracenyl groups. More preferred aryl groups include phenyl groups which may optionally substituted by 1 or 2 alkyl groups.
In the compounds of the present invention, the aralkyl groups in the definitions of R1 , R5, R6, R7 and R8 are preferably alkyl groups as defined above which are substituted with one or more aryl groups as defined above, and are more preferably benzyl or phenethyl groups. !n the compounds of the present invention, the heteroaryl groups in the definitions of R5, R6 and R8 are preferably 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms. Examples include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazoiyl, isoxazolyl, thiazolyl, isothiazolyl, 1 ,2,3-oxadiazolyi, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyf, pyrimidinyl and pyrazinyl groups.
In the compounds of the present invention, the heteroaralkyl groups in the definitions of R5, R6 and R8 are preferably alkyl groups as defined above which are substituted with heteroaryl groups as defined above.
In the compounds of the present invention, the alkoxyalkyl group in the definition of R8 is preferably an aikyl group having as defined above which is substituted by an alkoxy group as defined below, and is more preferably an alkyl group having from 1 to 4 carbon atoms which is substituted with an alkoxy group having from 1 to 4 carbon atoms.
In the compounds of the present invention, the haloalkyl groups in the definitions of R2, R3 and R4 are preferably alkyl groups as defined above which are substituted with one or more halogen atoms. More preferably, they are alkyl groups having from 1 to 4 carbon atoms that are substituted with at least one chlorine or fluorine atom and most preferably they are chloromethyl group, trichloromethyl groups, trifluoromethyl groups or tetrafluoroethyl groups.
In the compounds of the present invention, the alkoxy groups in the definitions of R2, R3 and R4 are preferably alkoxy groups having from 1 to 6 carbon atoms, more preferably alkoxy groups having from 1 to 4 carbon atoms and most preferably methoxy or ethoxy groups.
In the compounds of the present invention, the alkoxycarbonyl groups in the definitions of R2, R3 and R4 are preferably carbonyl groups substituted with alkoxy groups as defined above, and are more preferably methoxycarbonyl or ethoxycarbonyi groups.
In the compounds of the present invention, the monalkylamino groups in the definitions of R2, R3 and R4 are preferably amino groups which are substituted with one alkyi group as defined above, and are more preferably methylamino, ethylamino or t-butylamino groups.
In the compounds of the present invention, the dialkylamino groups in the definitions of R2, R3 and R4 are preferably amino groups which are substituted with two alkyl groups as defined above which may be the same or different from each other, and are more preferably dimethyiamino or diethylamino groups.
In the compounds of the present invention, the acylamino groups in the definitions of R2, R3 and R4 are preferably amino groups which are substituted with an acyl group having from 1 to 6 carbon atoms and are more preferably acetylamino or propanoylamino groups.
In the compounds of the present invention, the alkoxycarbonylamino groups in the definitions of R2, R3 and R4 are preferably amino groups which are substituted with an aikoxycarbonyl group as defined above, and are more preferably methoxycarbonylamino or ethoxycarbonylamino groups.
In the compounds of the present invention, the alkylsulphonyl groups in the definitions of R2, R3 and R4 are preferably sulphonyl groups which are substituted with an alkyl group as defined above and are more preferably a methylsulphonyl or ethylsulphonyl group.
in the compounds of the present invention, the arylsulphonyl groups in the definitions of R2, R3 and R4 are preferably sulphonyl groups which are substituted with an aryl group as defined above and are more preferably a phenylsulphonyl group which may be optionally substituted with one or two alkyl groups as defined above or a naphthylsulphonyl group. The compounds of formulae (1) and (1a) and pharmacologically active prodrugs and salts thereof contain some substituents for which there exist isosteres, and compounds containing such isosteres in place of said substituents also form a part of the present invention. For example, where the compounds of formulae (1) and (1a) and pharmacologically active prodrugs or salts thereof contain a carboxyl group, this can be replaced with a tetrazolyl group.
Hydrates or solvates of the compounds of formulae (1) and (1a), prodrugs thereof and pharmacologically acceptable salts thereof can also be used and form a part of the invention.
Some compounds of formulae (1) and (1a) and their pharmacologically acceptable salts or prodrugs thereof of the present invention may have one or more asymmetric carbons, and optical isomers (including diastereomers) due to the presence of asymmetric carbon atom(s) in the molecule can exist. These isomers are included in the present invention, both as individual isomers and mixtures thereof in all possible ratios.
The compounds of formulae (1) and (1a) of the present invention can form pharmacologically acceptable salts and pro-drugs and these form a part of the present invention. Examples of such salts include inorganic salts such as ammonium salts; organic amine salts such as t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N1N'- dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-N-phenethylamine salts, piperazine salts, tetramethylammonium salts and tris(hydroxymethyl)aminemethane salts; hydrohalogenated salts such as hydrofluoric acid salts, hydrochlorides, hydrobromides and hydroiodides; inorganic acid salts such as nitrates, perchlorates, sulfates and phosphates; lower alkanesulfonate salts such as methanesulfonates, trifluoromethanesulfonates and ethanesulfonates; arylsulfonate salts such as benzensulfonates and p-toluenesulfonates; organic acid salts such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates and maleates; and amino acid salts such as ornithinates, glutamates and aspartates. Of these, organic amine salts are more preferred and triethylamine salts are most preferred.
The compounds of formulae (1) and (1a) of the present invention can be administered in the form of prodrugs. Prodrugs are derivatives of the pharmacologically active compound in which one or more of the substituents on said compound are protected by a group which is then removable by a biological process (e.g. hydrolysis) in vivo after administration to the patient. Many suitable prodrugs are well-known to the person in the art and can be found, for example, in "Greene's Protective Groups in Organic Synthesis", 4th Edition, 2006, Wiley-VCH, Suitable examples of such prodrugs include pharmacologically acceptable esters of the compound having the formulae (1) or (1a) wherein a carboxyl moiety of the compound having the formula (1) or (1a) is esterified. The pharmacologically acceptable esters are not particularly restricted, and can be selected by a person with an ordinary skill in the art. In the case of said esters, it is preferable that such esters can be cleaved by a biological process such as hydrolysis in vivo. The group constituting the said esters (the group shown as R when the esters thereof are expressed as - COOR) can be, for example, a CrC4 alkoxy C1-C4 alkyl group such as methoxyethyl, 1-ethoxyethyl, 1 -methyl- 1-methoxyethyl, 1-(isopropoxy)ethyl, 2- methoxyethyl, 2-ethoxyethyl, 1 ,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; a C1-C4 alkoxylated C-I-C4 alkoxy Ci-C4 alkyl group such as 2-methoxyethoxymethyl; a C6-Ci0 aryloxy C1-C4 alkyl group such as phenoxymethyl; a halogenated Cr C4 alkoxy CrC4 alkyl group such as 2,2,2-trichloroethoxymethyl or bis(2- chloroethoxy)methyi; a C1-C4 alkoxycarbonyl CrC4 alkyl group such as methoxycarbonylmethyl; a cyano CrC4 alkyl group such as cyanomethyl or 2- cyanoethyl; a CrC4 alkylthiomethyl group such as methylthiomethy! or ethylthiomethyi; a C6-Ci0 arylthiomethyl group such as phenylthiomethyl or naphthylthiomethyl; a C1-C4 alkylsulfonyl CrC4 lower alkyl group, which may be optionally substituted with a halogen atom(s) such as 2- methanesulfonylethyl or 2-trifluoromethanesulfonylethyl; a Cs-Cio arylsulfonyl Ci-C4 alky! group such as 2-benzenesulfonylethyl or 2-toluenesulfonylethyl; a C1-C7 aliphatic acyloxy CrC4 aikyl group such as formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyi, 1-acetoxyethyl, 1-propionyioxyethyl, 1-butyry!oxyethyl, 1-pivaloyloxyethyl, 1- valeryloxyethyl, 1-isovaleryloxyethyl, 1»hexanoyloxyethyl, 2-formyloxyethyl, 2- acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-pivaloyloxyethyl, 2- valeryloxyethyl, 2-isovaieryloxyethyl, 2-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1- pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1- hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1- pivaloyloxybutyl, 1-acetoxypθntyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1- pivaloyloxypentyl or 1-pivaloyloxyhexy!; a C5-C6 cycloalkylcarbonyloxy Ci-C4 alkyl group such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyioxymethyl, 1-cyclopentyicarbonyloxyethyl, 1- cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1- cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl or 1- cyclohexylcarbonyioxybutyl; a C6-Ci0 arylcarbonyloxy CrC4 alkyl group such as benzoyloxymethyl; a CrC6 alkoxycarbonyloxy Ci-C4 alkyl group such as methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethy!, 1- (methoxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)buty!, 1- (methoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl, ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, 1- (ethoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)butyl, 1- (ethoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)hexyi, propoxycarbonyloxymethyl, 1-(propoxycarbonyloxy)ethyl, 1- (propoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)butyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyloxy)ethyl, 1- (isopropoxycarbonyloxy)butyl, butoxycarbonyloxymethyl, 1~ (butoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)propyl, 1- (butoxycarbonyloxy)butyl, isobutoxycarbonyloxymethyl, 1- (isobutoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)propyl, 1- (isobutoxycarbonyloxy)butyl, t-butoxycarbonyloxymethyl, 1-(t- butoxycarbonyloxy)ethy[, pentyloxycarbonyloxymethyl, 1- (pentyloxycarbony!oxy)ethyi, 1-(pentyloxycarbonyloxy)propyl, hexyloxycarbonyloxymethyl, 1-(hexyloxycarbonyloxy)ethyl or 1- (hexyloxycarbonyloxy) propyl; a C5-C6 cycloalkyloxycarbonyloxy C1-C4 alkyl group such as cyclopentyloxycarbonyloxymethyl, 1-
(cyclopentyloxycarbonyloxy)ethyl, 1-{cyclopentyloxycarbonyloxy)propyl, 1- (cyclopentyloxycarbonyloxy)butyl, cyclohexyloxycarbonyloxymethyl, 1 - (cyclohexyloxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)propyl or 1- (cyclohexyloxycarbonyloxy)butyl; a [5-(Ci-C4 alkyi)-2-oxo-1 ,3-dioxolen-4- yl]methyl group such as (5-methyl-2-oxo-1 ,3-dioxolen-4-yl)methyl, (5-ethyl-2- oxo-1 ,3-dioxolen-4~yl)methyl, (5-propyl-2-oxo-1 ,3-dioxolen-4-yl)methyl, (5- isopropyl-2-oxo-1 ,3-dioxolen-4-yl)methyl or (5-buty!-2-oxo-1 ,3-dioxolen-4- yl)methy; a [5-(phenyl, which may be optionally substituted with a Ci-C4 alkyl, Ci-C4 alkoxy or halogen atom(s))-2-oxo-1 ,3-dioxolen-4-yl]methyl group such as (5-phenyl-2-oxo-1 ,3-dioxoien-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1 ,3- dioxolen-4-yl3methyl, [5-(4-methoxyphenyl)-2-oxo-1 ,3-dioxolen-4-yl]methyl, [5- (4-fluorophenyl)-2-oxo-1 ,3-dioxolen-4-yl]methyl or [5-(4-chlorophenyl)-2-oxo- 1 ,3~dioxolen-4-yl3methyl; or a phthalidyl group, which may be optionally substituted with a Ci-C4 alkyl or CrC4 alkoxy group(s), such as phthalidyl, dimethylphthalidyl or dimethoxyphthalidyl, and is preferably a pivaloyloxymethyl group, phthalidyl group or (5-methyl-2-oxo-1 ,3-dioxolen-4- yl)methyl group, and more preferably a (5-methyl-2-oxo-1 ,3-dioxolen-4- yl)methyl group.
in the combinations according to the forty-ninth aspect of the present invention, typical examples of each of the classes of compounds that can be used in combination with the compounds having the general formula (1) or (1a) or a pharmacologically acceptable salt or prodrug thereof of the present invention are as follows:
1. Examples of muscarinic receptor antagonists (including but not limited to selective M3 antagonists) include esoxybutynin, oxybutynin [especially the chloride], tolterodine [especially the tartrate], solifenacin [especially the succinate], darifenacin [especially the hydrobromide], temiverine, fesoterodine, imidafenacin and trospium [especially the chloride]. 2. Examples of β3 adrenergic receptor agonists include YM-178 and solabegron, KUC-7483. 3. Examples of neurokinin K receptor antagonists (including selective NK-1 antagonists) include cizolirtine and casopitant.
4. Examples of vanilloid VR1 agonists include capsaicin, resiniferatoxin and NDG-8243.
5. Examples of calcium channel α2 δ ligands include gabapentin and pregabaiin.
6. Examples of potassium channel activators (including activators of KCNQ, BKCa channels, Kv channels and KATP channels) include KW-7158, NS-8 and retigabine.
7. Examples of calcium channel inhibitors (including Cav2.2 channel inhibitors) include ziconotide and NMED-160.
8. Examples of sodium channel blockers include lidocaine, lamotrigine, VX- 409, ralfinamide and carbamazepine.
9. Examples of serotonin and norepinephrine reuptake inhibitors (SNRIs) include duloxetine and venlafaxine 10. Examples of 5-HT antagonists including 5-HT1a antagonists and 5HT3 antagonists.
11. Examples of α-1 adrenoceptor antagonists include tamsulosin.
12. Examples of tricyclic antidepressants include amitriptyline, amoxapine, clomipramine, dosulepin (dothiepin), doxepin, imipramine, lofepramine, nortriptyline, and trimipramine.
13. Examples of Λ/-methyl-D-aspartate (NMDA) receptor antagonists include ketamine, memantine, amantadine, AVP-923, NP-1 and EVT-101.
14. Examples of cannabinoid receptor agonists include GW-1000 (Sativex) and KDS-2000. 15. Anti-convulsants. Examples include iacosamide, carbamazepine, topiramate, oxcarbazepine and levetiracetam
16. Examples of aldose reductase inhibitors include tolrestat, zopolrestat, zenarestat, epalrestat, sorbinil, AS-3201 , fidarestat, risarestat, ponalrestat and alrestatin. 17. Examples of opioids (e.g. mu opioid agonists) include fentany! and tapentadol.
18. Examples of α adrenoceptor agonists include ai-adrenoceptor agonists such as ethoxamine, phenylephrine, oxymetazoline, tetrahydralazine and xylometazoline and a2-adrenoceptor agonists such as clonidine, guanabenz, guanfacine and α-methyldopa.
19. Examples of P2X receptor antagonists including P2X2 receptor antagonists and P2X7 receptor antagonists.
20. Examples of acid-sensing ion channel modulators include amiloride. 21. Examples of NGF receptor modulators include trkA.
22. Examples of nicotinic acetylcholine receptor modulators include A-85380, tebanicline, ABT-366833, ABT-202, ABT-894, epibatidine analogs and SiB- 1663.
23. Examples of synaptic vesicle protein 2A ligands include brivaracetam.
Examples of the administration form of the combination of the present invention are the same as given above for the compounds of general formula (1) or (1a) and pharmacologically acceptable salts or pro-drugs thereof. The particular form can be chosen depending upon the condition to be treated and the nature of the compounds being administered in combination. For example, a combination of a compound of general formula (I) or (1 a) or a pharmacologically acceptable salt or pro-drug thereof with lidocaine could be administered transdermal^ by means of a patch while a combination with ziconotide could be administered transmucosaliy.
Synthesis of Compounds of the Invention
To prepare the compounds of formulae (1) and (1a) of the present invention, corresponding compounds in which "X" and "Y" are hydrogen or one of "X" and "Y" is H and the other is a suitable protecting group are reacted with electrophiies such as acyl chlorides, anhydrides, sulphonyl chlorides, chloroformates, isocyanates or sulfonylisocyanates to give the compounds of the invention after removal of the protecting group if appropriate. Two suitable reaction schemes are given below. Reaction Scheme 1 where Y+ is a suitable electrophile
Figure imgf000049_0002
where X+ is a suitable electrophile
Reaction Scheme 2
Figure imgf000050_0001
where PC+] is a suitable electrophile
wher
Figure imgf000050_0002
Examples of the administration form of a compound having general formulae (1) or (1 a) of the present invention, or a pharmacologically acceptable salt or pro-drug thereof, include oral administration by tablets, capsules, granules, powders or syrups, and parenteral administration by injection, patches or suppositories. Moreover, compounds having the general formula (1) or (1a) or a pharmacologically acceptable salt or pro-drug thereof of the present invention can also be administered by pulmonary administration in the form of a powder, solution or suspension. Preparations for these administrations are produced by known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, corrigents, diluents and so forth.
Examples of excipients include organic excipients such as sugar derivatives, e.g. lactose, sucrose, glucose, mannitol or sorbitol, starch derivatives, e.g. corn starch, potato starch, α-starch, dextrin or carboxymethyl starch, cellulose derivatives, e.g. crystalline cellulose, low substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose or internally crosslinked sodium carboxymethyl cellulose, and gum Arabic, dextran or pullulan; and, inorganic excipients such as silicate derivatives, e.g. light anhydrous silicic acid, synthetic aluminium silicate or magnesium aluminium metasilicate, phosphates, e.g. calcium phosphate, carbonates, e.g. calcium carbonate, or sulfates, e.g. calcium sulfate.
Examples of lubricants include stearic acid and metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as bee gum or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium fatty acid salts; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as silicic anhydride or silicate hydrate; and, starch derivatives.
Examples of binders include polyvinylpyrrolidone, Macrogol and compounds similar to the aforementioned excipients. Examples of disintegrants agents include compounds similar to the aforementioned excipients, and chemically cross-linked starches and celluloses such as cross sodium carmellose, sodium carboxymethyi starch or crosslinked polyvinylpyrrolidone.
Examples of stabilizers include paraoxybenzoate esters such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzy! alcohol or phenyl ethyl alcohol; benzalkonium chloride; phenols such as phenol or cresoi; thimerosai; dehydroacetic acid; and, sorbic acid.
Examples of corrigents include ordinarily used sweeteners, sour flavourings and fragrances.
In the case of producing a solution or suspension for pulmonary administration of a compound having the general formula (1) or general formula (1a) or pharmacologically acceptable salt or pro-drug thereof of the present invention, for example, said solution or suspension can be produced by dissolving or suspending crystals of the present invention in water or in a mixture of water and an auxiliary solvent (e.g., ethanol, propylene glycol or polyethylene glycol). Such a solution or suspension may also contain an antiseptic (e.g., benzalkonium chloride), solubilizing agent (e.g., a polysorbate such as Tween 80 or Span 80 or surface activator such as benzalkonium chloride), buffer, isotonic agent (e.g., sodium chloride), absorption promoter and/or thickener. !n addition, the suspension may additionally contain a suspending agent (such as microcrystalline cellulose or sodium carboxymethyi cellulose).
A composition for pulmonary administration produced in the manner described above is administered directly into the nasal cavity or oral cavity by a typical means in the field of inhalants (using, for example, a dropper, pipette, cannula or atomizer). In the case of using an atomizer, crystals of the present invention can be atomized as an aerosol in the form of a pressurized pack together with a suitable nebula (for example, a chlorofluorocarbon such as dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or a gas such as carbon dioxide), or they can be administered using a nebulizer.
The amount of a compound having the general formula (1) or general formula (1a) or pharmacologically acceptable salt or pro-drug thereof of the present invention used varies depending on the symptoms, age, administration method and so forth, and may be administered either in a single dose or by dividing into multiple doses according to the symptoms.
Synthesis of the Compounds of the Invention
Examples
In these Examples, the following abbreviations are used:
DCM dichioromethane
THF tetrahydrofuran
(BoC)2O tert-butoxy carboxylic acid anhydride
DPPA diphenyl phosphoryl azide
Example 1
N-[(4-methylphenyl)suifonyl]"2-({I(4- methylphenylJsulfonyljcarbamoylϊaminoJ-T.δ-dihydro-i jG-naphthyridine- 6(5H)-carboxamide (6)
Figure imgf000054_0001
Figure imgf000054_0002
1 ,6-naphthyridine-2-carboxylic acid 1 (25g, 141.91 mmol) was added to a solution of sodium hydroxide (6.24g, 156.1 mmol) in water (500 cm3). When this was dissolved 5% Pt/C (2.5 g) catalyst was added. This was charged in a 1 L autoclave with 50 atm of hydrogen and stirred overnight at room temperature. The mixture was then filtered through celite and concentrated in vacuo. The resultant solid was further dried in a vacuum oven and used crude in the next step.
Boc anhydride (73g, 336 mmol) was added to a stirred mixture of acid 2 (3Og, 168 mmo!) in 1 :1 DCM:MeOH (800 cm3) and triethylamine (70 cm3, 505 mmol). The mixture was stirred at room temperature for 3 days. DCM (200 cm3) was then added followed by 10% citric acid (500 cm3). The mixture was stirred for 30 mins before the DCM layer was separated, dried (MgSO4), and evaporated in vacuo. The resultant yellow solid was stirred in a slurry with hexane, filtered and then dried to yield 6-(tert-butoxycarbonyl)-5,6,7,8- tetrahydro-1,6-naphthyridine-2-carboxylic acid 3 as a yellow solid (12.14g,
31 % over 2 steps).
1H NMR (CDCI3) 8.8 (1 H, d, ArH), 7.65 (1 H, d, ArH), 4.68 (2H, s, CH2), 3.80 (2H, t, CH2), 3.55 (2H, t, CH2) 1.5 (9H, s, 3 x CH3) ppm.
3 (12.14g, 43.6 mmol) was dissolved in toluene (300 cm3) and f-butanol (50 cm3). Triethylamine (12.1 cm3, 87.2 mmol) and DPPA (13.0 cm3, 61.1 mmol) were then added and the mixture was refluxed overnight. After cooling, ethyl acetate (300 cm3) and NaHCO3 (100 cm3) were added. This was mixed for 10 mins before the organic layer was separated, washed with water (200 cm3) and brine (200 cm3), dried (MgSO4), and evaporated in vacuo. The resultant solid was washed with hexane and dried to yield tert-butyl 2-[(tert- butoxycarbonyl)amino]-7, 8-dihydro-i, 6-naphthyridine-6(5H)-carboxylate 4 as a brown solid (12.4g, 82%). 1H NMR (CDCI3) 7.74 (1 H, d, ArH), 7.4 (1 H, d, ArH), 4.5 (2H, s, CH2), 3.66 (2H, t, CH2), 2.82 (2H, t, CH2), 1.5 (9H, s, 3 x CH3), 1.48 (9H, s, 3 x CH3) ppm.
4 (12.Og, 0.034 mol) was dissolved in dioxane (200 cm3) and then HCI/dioxane 4M (150 cm3) was added. The mixture was stirred overnight. The resultant solid was filtered and washed with hexane and then dried to yield δ^Jβ-tetrahydro-ifi-naphthyridin^-amine 5 as a brown solid (5.58g, 73%). 1H NMR (DMSO-dβ) 9.8 (2H, br S1 NH2), 8.0 (1 H1 br S1 NH)1 7.72 (1 H1 d, ArH)1 6.88 (1 H, d, ArH), 4.45 (2H, br s, CH2), 3.3 (2H, br s, CH2), 3.0 (2H, t, CH2) ppm.
5 (270mg, 1.21 mmol) was stirred in DCM (10 cm3) and 2M NaOH (2 cm3) was added. After stirring for 10 mins the DCM layer was separated and evaporated in vacuo. The free base (67 mg, 0.44 mmol) was re-suspended in THF (1.5 cm3) and p-toluenesulfonyl isocyanate (136 μl_, 0.96 mmol) was then added dropwise. After stirring overnight the resultant solid was filtered to yield the title compound N-[(4-methylphenyl)sulfonyl]-2-({[(4- methylphenyl)sυlfonyl]carbamoyl}amino)-7,8-dihydro~1,6-naphthyridine-6(5H)- carboxamide 6 as a white solid (109 mg, 17%). 1H NMR (DMSO-de) 7.82 (2H, d, ArH), 7.78 (2H, d, ArH), 7.50 (1 H, d, ArH), 7.4-7.35 (4H1 m, ArH)1 7.21 (1 H, d, ArH), 4.40 (2H, s, CH2), 3.62 (2H, t, CH2), 2.75 (2H, t, CH2), 2.38 (3H, s, CH3), 2.36 (3H, s, CH3) ppm. LCMS [M+H]+ 544 in 94.2% purity, retention time 11.12 mins.
Example 2
N-(phenylsulfonyl)-7-{[(phenylsulfonyl)carbamoyl]amino}-1 , 2,4,5- tetrahydro-3H-3-benzazepine-3-carboxamide (8)
Figure imgf000057_0001
5 <250mg, 1.12 mmol) was stirred in DCM (10 cm3) and 2M NaOH (2 cm3) was added. After stirring for 10 mins the DCM layer was separated and evaporated in vacuo. The free base (67 mg, 0.44 mmol) was re-suspended in THF (6 cm3) and benzenesulfonyl isocyanate (112μl_, 0.838 mmol) was then added dropwise. After stirring overnight the resultant solid was filtered to yield the title compound N-(phenylsulfonyl)-7-{[(phenyisulfonyl)carbamoyl]amino}- 1,2,4, 5-tetrahydro-3H-3-benzazepine-3-carboxamide 8 as a white solid (82 mg, 14%).
1H NMR (DMSO-de) 9.52 (1 H, br s, NH), 7.93 (2H, d, ArH), 7.86 (2H1 d, ArH)1 7.8-7.5 (7H, m, ArH), 7.22 (1 H, d, ArH), 4.40 (2H, s, CH2), 3.55 (2H, t, CH2), 2.75 (2H, t, CH2) ppm. LCMS [M+Hf 516 in 89.6% purity, retention time 9.59 mins.
Example 3
N-[(4-methylphenyl)sulfonyl]-2-({[(4-methylphenyl)sulfonyl]carbamoyl}- amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide (10)
Figure imgf000058_0001
9 (400 mg, 1.913 mmol) was stirred in DCM (15 cm3) and 2M NaOH (2 cm3) was added. After stirring for 20 mins the DCM layer was separated and evaporated in vacuo. The free base (29 mg, 0.213 mmol) was re-suspended in THF (3 cm3) and p-toluenesulfonyl isocyanate (81 μl_, 0.532 mmol) was then added dropwise. After 2 hours stirring at room temperature, diethyl ether (~ 10 cm3) was added dropwise. The resultant solid was filtered, washed with small volumes of ether and dried to yield the title compound N-[(4- methylphenyl)sulfonyl]-2-({[(4-methylphenyl)sulfonyl]carbamoyl}amino)-5, 7- dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide 10 as a white solid (89 mgs, 9%).
1H NMR (DMSO-de) 10.62 (1 H, s, NH), 8.60 (1 H, s, ArH), 7.89-7.78 (4H, m, ArH), 7.42-7.38 (4H, m, ArH), 4.70 (2H, br s, CH2), 4.48 (2H, br s, CH2), 2.48 (3H, s, CH3), 2.46 (3H, s, CH3) ppm.
LCMS [M÷H]+ 531 in 96.0% purity, retention time 10.85 mins.
Example 4
Benzyl 2-({[(4-methylphenyl)sulfonyl]carbamoyl}amino)-7,8-dihydro-1,6- naphthyridine-6{5H)-carboxylate (12)
Figure imgf000059_0001
pTsNCO THF
48%
Figure imgf000059_0002
12
Benzyl chloroformate (32 μl_, 0.225 mmol) was added to a stirred mixture of 5 {50 mg, 0.225 mmol) and K2CO3 (93 mg, 0.675 mmol) in 1 :1 THF/H2O (2 cm3). The mixture was stirred for 4 hours before ethyl acetate (5 cm3) and water (5 cm3) was added. The organic layer was separted, dried (MgSO4) and evaporated in vacuo to yield 11 (33 mg, 52%).
1H NMR (DMSO-de) 7.38 (5H7 m, ArH), 7.15 (1 H, d, ArH), 6.23 (1 H, d, ArH), 5.78 (2H, s, NH2), 5.08 (2H, s, OCH2), 4.38 (2H, br s, CH2), 3.64 (2H, br s, CH2), 2.6 (2H, br s, CH2) ppm.
To 11 (33 mg, 0.116 mmol) in THF (1 cm3) was added p-toluenesulfonyl isocyanate (25 μL, 0.151 mmol). The mixture was stirred for 1 hr before diethyl ether (~ 5 cm3) was added. The resultant solid was filtered to yield 12. 1H NMR (DMSO-de) 7.82 (2H1 d, ArH), 7.58 (1 H, d, ArH), 7.4-7.25 (8H, m, ArH), 5.1 (2H, s, OCH2), 4.52 (2H, br s, CH2), 3.7 (2H, br s, CH2), 2.78 (2H, t, CH2), 2.38 (3H, s, CH3) ppm. LCMS [M+H]+ 481 in 100.0% purity, retention time 12.68 mins. Example 5
N-[(6-benzoyl-5,6,7,8-tetrahydro-1 ,6-naphthyridin-2-yl)carbamoyl]-4- methylbenzenesulfonamide (14)
Figure imgf000060_0001
Benzoyl chloride (26 μl_, 0.225 mmol) was added to 5 {50 mg, 0.225 mmol) and K2CO3 (93 mg, 0.675 mmol) in 1 :1 THF:H2O (2 cm3). The mixture was stirred for 4 hours before ethyl acetate (5 cm3) and water (5 cm3) was added and mixed. The organics were separated and concentrated in vacuo to yield 13 (37 mg, 65%).
To 13 (37 mg, 0.146 mmol) in THF (2 cm3) was added p-toluenesulfonyl isocyanate (31 μl_, 0.219 mmol). The mixture was stirred for 1 hour before diethyl ether (~5 cm3) was added. The resulant solid was filtered to yield N- [(β-benzoyl-5, δ, 7, 8-tetrahydro-1,6-naphthyridin-2-yl)carbamoyl]-4- methylbenzenesulfonamide 14 as a white solid (32 mg, 48%). 1H NMR (DMSO-de) 7.82 (2H, d, ArH), 7.48 (9H, m, ArH), 4.7 (2H, br s, CH2), 3.57 (2H, t, CH2), 3.85 (2H, t, CH2), 2.38 (3H, s, CH3) ppm. LCMS [M+H]+ 451 in 96.5% purity, retention time 10.79 mins.
Example 6
4-methyl-N-{[6-(4-methylbenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2- yl]carbamoyl}benzenesulfonamide (16)
Figure imgf000061_0001
To 5 (100 mg, 0.450 mmol) and K2CO3 {186 mg, 1.35 mmol) in 1:1 THF:H2O
(3 cm3) was added p-toluoyl chloride (62 /vl_, 0.472 mmol). This was stirred for 1 hour before ethyl acetate (5 cm3) and water (5 cm3) was added. After mixing the organic layer was separated, washed with aqueous sodium bicarbonate
(10 cm3), dried (MgSO4) and concentrated in vacuo to yield 15 as a white solid (70 mg, 58%).
1H NMR (CDCI3) 7.35 (5H, m, ArH), 5.70 (1 H, s, NH), 4.5 (2H, br s, CH2), 3.5 (2H, br s, CH2), 2.66 (2H, t, CH2), 2.35 (3H, s, CH3) ppm.
LCMS [M+H]+ 268 in 89.1 % purity, retention time 1.70 mins.
p-Toluenesulfonyl isocyanate (51 μL, 0.340 mmoi) was added to 15 (70 mg,
0.261 mmol) in THF (5 cm3). After 30 mins, diethyl ether (4 cm3) was added and the resultant solid was filtered to yield 4-methyl-N-{[6-(4-methylbenzoyl)-
5, 6, 7, 8-tetrahydro~1,6-naphthyridin-2-yl]carbamoyl}benzenesulfonamide 16 as a white solid (95 mg, 78%).
1H NMR (DMSO-d6) 9.45 (1 H, br s, NH), 7.82 (2H, d, ArH), 7.42-7.25 (8H, m,
ArH), 4.6 (2H, br s, CH2), 3.6 (2H, br s, CH2), 2.83 (2H, t, CH2), 2.39 (3H, s, CH3), 2.32 (3H, s, CH3) ppm.
LCMS [M+H]+ 465 in 97.4% purity, retention time 11.50 mins. Example 7
4-Methyl-N-({6-[(4-methylphenyl)sulfonyl]-5,6,7,8-tetrahydro-1 ,6- naphthyridin-2-yl}carbamoyl)benzenesulfonamide (18)
Figure imgf000062_0001
5 (150 mg, 0.675 mmol) and K2CO3 (280 mg, 2.026 mmol) were stirred together in 1 :1 THF/H2O (6 cm3). This was cooled to 0 0C and p- toluenesulfonyi chloride (128 mg, 0.675 mmol) was added. The mixture was allowed to warm to RT for 1 hour before ethyl acetate (20 cm3) and aqueous sodium bicarbonate (10 cm3) were added. After mixing, the organic layer was separated, washed with brine (10 cm3), dried (MgSO4) and evaporated in vacuo to yield 17 as a red solid (170 mg, 83%).
1H NMR (DMSO-d6) 7.68 (2H, d, ArH), 7.42 (2H, d, ArH), 7.13 (1 H1 d, ArH), 6.25 (1 H, d, ArH), 5.86 (2H, br s, NH2), 3.92 (2H1 s CH2), 3.22 (2H, t, CH2), 2.64 (2H, t, CH2), 2.33 (3H, s, CH3) ppm.
17 (170 mg, 0.56 mmol) was stirred in THF (3 cm3) and p-toluenesulfonyl isocyanate (102 μL, 0.67 mmol) was then added. This was stirred for 1.5 hours before diethyl ether (-8 cm3) was added dropwise. The resultant solid was filtered to yield 4-methyl-N-({6-[(4-methylphenyl)sulfonyl]-5,6,7,8- tetrahydro-1,6-naphthyridin-2-yl}carbamoyl)benzenesulfonamide 18 as a white solid (178 mg, 63%). 1H NMR (DMSO-ds) 9.43 (1H1 br s, NH), 7.82 (2H, d, ArH), 7.68 (2H, d, ArH), 7.52 (1 H, d, ArH), 7.45-7.39 (5H1 m, ArH), 7.22 (1 H, br d, ArH), 4.08 (2H, s, CH2), 3.26 (2H, t, CH2), 2.78 (2H, t, CH2), 2.34 (6H, s, 2 x CH3) ppm. LCMS [M+Hf 501 in 94.7% purity, retention time 12.42 mins.
Example 8
4-Methyl-N-({6-[{4-methylphenyl)sulfonyl]-5,6,7,8-tetrahydro-1 ,6- naphthyridin-2-yl}carbamoy!)benzenesulfonamide ammonium salt (19)
Figure imgf000063_0001
18 (50 mg, 0.09 mmol) was dissolved in DCM (1 cm3) and 20% methanolic ammonia (4 cm3) was added. This was stirred for 5 mins before being concentrated in vacuo. This material was then dissolved in THF (<1 cm3) and triturated with diethyl ether (~ 4 cm3). The resultant solid was filtered and dried to yield 4-methyl-N~({6-[(4-methylphenyl)sulfonyl]-5,6, 7,8-tetrahydro-1,6- naphthyridin-2-yl}carbamoyl)benzenesulfonamide ammonium salt 19 as a white solid (54mg, 100%). 1H NMR (DMSO-d6) 7.70 (5H, m, ArH), 7.40 (2H, d, ArH), 7.3 (1 H, d, ArH), 7.15 (1 H, d, ArH), 4.02 (2H, s, CH2), 3.26 (2H, t, CH2), 2.68 (2H, t, CH2), 2.38 (3H, s, CH3), 2.29 (3H1 s, CH3) ppm. LCMS [M+H]+ 501 in 94.0% purity, retention time 12.64 mins.
Example 9
N-benzyl-2-({[(4-methylphenyl)suifonyl]carbamoyl}amino)-7,8-dihydro- 1 ,6-naphthyridine-6(5H)-carboxamide (21)
Figure imgf000064_0001
pTsNCO
THF 58%
Figure imgf000064_0002
To 5 (100 mg, 0.450 mmol) and K2CO3 {186 mg, 1.351 mmol) in 1 :1 THF:H2O (3 cm3) was added benzyl isocyanate (56 μL, 0.450 mmol). This was stirred overnight and then ethyl acetate (10 cm3) and water (5 cm3) was added and mixed. The organic layer was separated, washed with brine (5 cm3), dried (MgSO4) and then evaporated in vacuo to yield 20 as a white solid (85 mg, 67%).
1H NMR (DMSO-de) 7.28- 7.08 (6H, m, ArH), 6.25 (1 H, d, ArH), 5.72 (2H, s, NH2), 4.30 (2H, s, CH2), 4.24 (2H, d, CH2), 3.59 (2H, t, CH2), 3.15 (1 H, d, NH), 2.58 (2H, t, CH2) ppm. LCMS [M+H]+ 283 in 85.1 % purity, retention time 1.63 mins.
p-Toluenesulfonyl isocyanate (59 μL, 0.391 mmol) was added to 20 in THF (5 cm3). The mixture was stirred overnight before diethyl ether (-8 cm3) was added. The resultant solid was filtered to yield N-benzyl-2-({[(4- methylphenyl)sulfonyl]carbamoyl}amino)-7l8-dihydro-1l6~naphthyridine-6(5H)- carboxamide 21 as a white solid (85 g, 58%).
1H NMR (DMSO-de) 9-42 (1 H, br s, NH), 7.82 (2H, d, ArH), 7.50 (1 H, d, ArH), 7.38 (2H, d, ArH), 7.28-7.15 (6H, m, ArH), 4.43 (2H, s, CH2), 4.25 (2H, d, CH2), 3.65 (2H, t, CH2), 3.74 (2H, t, CH2), 2.38 (3H, s, CH3) ppm. LCMS [M+H]+ 480 in 95.3% purity, retention time 10.76 mins. Example 10
N-[(4-Methylphenyl)sulfonyt]-2-({[(4-methylphenyl)suIfonyl]carbamoyl}- amino)5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl-carboxamide (23)
Figure imgf000065_0001
p-Toluenesulfonyl isocyanate (227 μL, 1.50 mmol) was added to 22 in THF (30 cm3) containing triethylamine (214 μL, 1.50 mmol). The reaction mixture was stirred for 30 mins and then concentracted in vacuo. The resultant solid was purified by flash column chromatography (CH2CI2:Me0H 19:1 , 0.5%
Et3N) and the resulting solid was dissolved in CH2CI2 (5 cm3) and washed with 1 M citric acid solution (2 x 10 cm3) and concentrated in vacuo to yield N-[(4- methylphenyl)sulfonyl]-2-({[(4-methylphenyl)$ulfonyl]carbarnoyl}amino)- 5,6,7, 8-tetrahydropyrido[4,3-d]pyrimidinyt-carboxamide 23 as a white solid (70 mgs, 17%).
LCMS [M+H]+ 545 in 97% purity, retention time 7.17 mins.
Example 11
N-[(4-Methylphenyl)sulfonyl]-3-{{[(4-methylphenyl)sulfonyl]carbamoyl}- amino)-7,8-dihydro-1 ,6-naphthyridine-6(5H)-carboxamide (26)
Figure imgf000066_0001
To a stirred solution of 24 in CH2CI2 (5 cm3) was added trifluoroacetic acid (0.5 cm3). After stirring for 1 hour the reaction was concentrated to give the crude product 25 as a brown solid which was used directly in the next step. p-Toluenesulfonyl isocyanate (227 μL, 1.50 mmol) was added to 25 in THF (5 cm3) containing triethyiamine (214 μL, 1.50 mmol). The reaction mixture was stirred for 5 min and then concentrated in vacuo. The resultant solid was purified by reverse phase C-18 preparative HPLC to yield N-[(4- methylphenyl)sulfonyl]-3-({[(4-methylphenyl)sulfonyl]carbamoyl}amino)-7,8- dihydro-1,6-naphthyridine-6(5H)-carboxamide 26 as a white solid (9.3 mgs, 4.7% over 2 Steps). LCMS [M+H]+ 544 in 97% purity, retention time 5.82 mins.
Test Example 1
KvLx T1 - Kvbeta subunit interaction assays
Compounds of Examples 1 to 11 were examined for their ability to inhibit the interaction between Kv1 ,x channels and Kvbeta subunits using a protein- protein interaction assay.
Cloning of rat His- and biotin- tagged Kvbetal subunit cDNA, expression of Kvbetal subunits in E. coli and lysis of E. coli containing Kvbetal subunits were carried out as previously described (Kozlowski et al., patent application WO03078464).
Cloning of His- and FLAG- tagged Kv1.1 alpha subunit T1 domain cDNA, expression of Kv1.1 alpha subunit T1 domains in E. coli and lysis of E. coli containing Kv1.1 alpha subunit T1 domains were carried out as previously described (Kozlowski et al., patent application WO03078464).
To 96-weli streptavidin coated microtitre plates, 100μl of optimized concentrations of Kvbetal subunit cleared iysates (typically 1 in 10 dilutions in PBS-Tween) were added to each well. Plates were incubated at room temperature for 1 hour prior to use. Each well was then washed 3 times with 300μl of PBS-Tween. Following the final wash, 80μl of PBS-Tween was added to each well.
The test compounds (dissolved in a suitable vehicle) were added to the wells of a prepared 96-well microtitire plate to achieve a range of concentrations to maintain a final assay volume of 100μl. Plates were incubated for 30 minutes at room temperature.
After incubation with test compounds, 100μl of Kv1.1 alpha subunit T1 domain cleared lysate (diluted 1 in 10 in PBS-Tween) was added to each well and incubated for 60 minutes at room temperature on a shaker. Unbound Kv1.1 alpha subunit T1 domain was removed by washing 3 times in 300μl of PBS- Tween. Bound Kv1.1 alpha subunit T1 domain was estimated by using appropriately diluted mouse anti-FLAG antibody and anti-mouse IgG secondary antibody HRP conjugate using standard ELISA procedures. HRP was detected as previously described (Kozlowski et al., patent application WO03078464).
Data were analysed using standard software packages. The test compounds were examined for their ability to inhibit the binding of Kv1.1 alpha subunit T1 domain to Kvbetal subunits to determine inhibition as a percentage of maximal binding in the absence of any test compound. Results are presented as the half maximal inhibitory concentration (IC50) for inhibition of Kv1.1 alpha subunit T1 binding to Kvbetal subunits. The tested compounds of Examples of this invention displayed the ability to inhibit the binding of Kv1.1 alpha subunit T1 domain to Kvbetal subunits as measured by determination of the IC50.
Table of lC50's for Example Compounds
Figure imgf000068_0001

Claims

Claims
1. A compound represented by the general formula (1) or a pharmacologically acceptable salt or pro-drug thereof:
Figure imgf000069_0001
(D wherein:
A and B are independently CH2 or CH2CH2; D is CR2 or a nitrogen atom; E is CR3 or a nitrogen atom; G is CR4 or a nitrogen atom; with the proviso that at least one of D, E and G is nitrogen;
R1 is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group or a heteroaralkyl group;
R2, R3 and R4 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, aminosulphonyl groups and cyano groups;
X is selected from RSSO2, R5R7NCO, R5R7NSO2 and R5SO2NR7CO wherein R5 and R7 are as defined below;
Y is selected from R6CO, R6SO2, R6R7NCO, R6R7NSO2, R6SO2NR7CO and CO2R8 wherein R6, R7 and R8 are as defined below; R5 and R6 are independently selected from hydrogen atoms, alkyl groups, aryl groups, aralkyl groups, heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and heteroaralkyl groups;
R7 is a hydrogen atom, an alky] group, an aryl group or an aralkyl group; and R8 is an alkyi group, an aryl group, an aralkyl group, an aikoxyalkyl group, a heteroaryl group or a heteroarylalkyl group.
2. A compound according to claim 1 or pharmacologically acceptable sait or pro-drug thereof wherein R1 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or an araSkyl group comprising an aikyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alky! groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups.
3. A compound according to claim 1 or a pharmacologically acceptable salt or pro-drug thereof wherein R1 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms.
4. A compound according to claim 1 or a pharmacologically acceptable salt or pro-drug thereof wherein R1 is a hydrogen atom.
5. A compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt or pro-drug thereof wherein R2, R3 and R4 are independently selected from hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxy groups, hydroxyl groups and cyano groups.
6. A compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt or pro-drug thereof wherein R2, R3 and R4 are independently selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms and halogen atoms.
7. A compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt or pro-drug thereof wherein R2, R3 and R4 are independently selected from hydrogen atoms, methyl groups, ethyl groups, fluorine atoms and chlorine atoms.
8. A compound according to any one of claims 1 to 4 or a pharmacologically acceptable sait or pro-drug thereof wherein each of R2, R3 and R4 is a hydrogen atom.
9. A compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5SO2, wherein R5 is: a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloaikyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alky! groups having from 1 to 6 carbon atoms, halogen atoms, haloaikyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms.
10. A compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5SO2, wherein R5 is an alkyl group having from 1 to 4 carbon atoms or an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloaikyl groups having from 1 to 4 carbon atoms.
11. A compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula RSSO2, wherein R5 is a phenyl group which may optionally be substituted with at least one substituent selected from methyl groups, ethyl groups, chlorine atoms and fluorine atoms.
12. A compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5R7NCO, wherein
R5 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloaikyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloaikyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxy! groups, hydroxyl groups and cyano groups, a heteroaryl group which is a 5» to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and R7 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryi group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloaikyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloaikyl groups having from 1 to 6 carbon atoms, aikoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups.
13. A compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5R7NCO, wherein R5 is a hydrogen atom, an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyi groups having from 1 to 4 carbon atoms, halogen atoms and haloaikyl groups having from 1 to 4 carbon atoms, or an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryi group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloaikyl groups having from 1 to 4 carbon atoms, and R7 is a hydrogen atom or an alkyi group having from 1 to 4 carbon atoms.
14. A compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5R7NCO, wherein R5 is a hydrogen atom, a phenyl group which may optionally be substituted with at least one substituent selected from methyl groups, ethyl groups, fluorine atoms and chlorine atoms, or benzyl group which may optionally be substituted with at least one substituent selected from methyl groups, ethyl groups, fluorine atoms and chlorine atoms, and R7 is a hydrogen atom, a methyl group or an ethyl group.
15. A compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5R7NCO, wherein R5 is a hydrogen atom, a benzyl group or a phenyl group which is optionally substituted with a methyl group, and R7 is a hydrogen atom.
16. A compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5SO2R7NCO, wherein
R5 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the aikoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, aikoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and
R7 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloaikyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, or an aratkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloaikyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxy! groups and cyano groups.
17. A compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5SO2R7NCO, wherein R5 is an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloaikyl groups having from 1 to 4 carbon atoms, or an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloaikyl groups having from 1 to 4 carbon atoms, and R7 is a hydrogen atom or an aikyl group having from 1 to 4 carbon atoms.
18. A compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt or pro-drug thereof wherein X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom.
19. A compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6CO, wherein R6 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms; an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloaikyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, a heteroaryi group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryi group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms.
20. A compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6CO, wherein R6 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms or an aralkyl group comprising an alky! group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alky! groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms.
21. A compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6CO, wherein R6 is a hydrogen atom; a methyl group, a phenyl group, a 4-methylphenyl group, a benzyl group or a phenethyl group.
22. A compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6SO2, wherein R6 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from aikyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms.
23. A compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula RBSO2, wherein R6 is an alkyl group having from 1 to 4 carbon atoms or an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms.
24. A compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6SO2, wherein R6 is a phenyl group which may optionally be substituted with at least one substituent selected from methyl groups, ethyl groups, chlorine atoms and fluorine atoms.
25. A compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6R7NCO, wherein R6 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the aikoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and R7 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyi groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, aikoxycarbonyi groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxy! groups and cyano groups, or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, aikoxycarbonyi groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxy! groups and cyano groups.
26. A compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6R7NCO, wherein R6 is a hydrogen atom, an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms, or an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms, and R7 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms.
27. A compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6R7NCO, wherein
R6 is a hydrogen atom, a phenyl group which may optionally be substituted with at least one substituent selected from methyl groups, ethyl groups, fluorine atoms and chlorine atoms, or a benzyl group which may optionaliy be substituted with at least one substituent selected from methyl groups, ethyl groups, fluorine atoms and chlorine atoms, and R7 is a hydrogen atom, a methyl group or an ethyl group.
28. A compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt or pro-drug wherein Y is a group of formula R6R7NCO, wherein R6 is a hydrogen atom, a benzyl group or a phenyl group which is optionaliy substituted with a methyl group, and R7 is a hydrogen atom.
29. A compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6SO2R7NCO, wherein R6 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the aikoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, a heteroaryi group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryi group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and R7 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryi group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, hafoalkyi groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the aikoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups.
30. A compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6SO2R7NCO, wherein
R6 is an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from afkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms, or an araikyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyi groups having from 1 to 4 carbon atoms; and R7 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms.
31. A compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula R6SO2R7NCO, wherein R6 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom.
32. A compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt or pro-drug thereof wherein Y is a group of formula CO2R8 wherein R8 is an aikyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups and cyano groups, , an alkoxyaikyi group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an alkoxy group having from 1 to 6 carbon atoms, a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a heteroaraSkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms.
33. A compound according to any one of claims 1 to 18 or a pharmacologically acceptable sait or pro-drug thereof wherein Y is a group of formula CO2R8 wherein R8 is an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms, or an aralkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an aryl group having from 6 to 10 carbon atoms which may optionally be substituted with at least one substituent selected from alky! groups having from 1 to 4 carbon atoms, halogen atoms and haloalkyl groups having from 1 to 4 carbon atoms.
34. A compound according to any one of claims 1 to 33 or a pharmacologically acceptable salt or pro-drug thereof wherein: either:
D is nitrogen; or
D is nitrogen and E is nitrogen; or D is nitrogen and G is nitrogen; or E is nitrogen; or
E is nitrogen and G is nitrogen; or
G is nitrogen; or each of D, E and G is nitrogen.
35. A compound according to any one of claims 1 to 33 or a pharmacologically acceptable salt or pro-drug thereof wherein either:
D is nitrogen; or
D is nitrogen and E is nitrogen; or
D is nitrogen and G is nitrogen.
36. A compound according to claim 1 or a pharmacologically acceptable salt or pro-drug thereof wherein:
(a) R1 is a hydrogen atom;
X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with an alkyl group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom;
Y is a group of formula R6SO2R7NCO, wherein R6 is a phenyl group which may optionally be substituted with an alkyl group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom; D is a nitrogen atom;
E is CR3, wherein R3 is a hydrogen atom; and G is CR4 wherein R4 is a hydrogen atom; or
(b) R1 is a hydrogen atom; X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
Y is a group of formula R6SO2R7NCO, wherein R6 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
D is a nitrogen atom;
E is CR3, wherein R3 is a hydrogen atom; and
G is CR4 wherein R4 is a hydrogen atom; or
(c) R1 is a hydrogen atom;
X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with an alkyl group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom; Y is a group of formula R6SO2R7NCO, wherein R6 is a phenyl group which may optionally be substituted with an alkyl group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom;
D is a nitrogen atom;
E is CR3, wherein R3 is a hydrogen atom; and G is a nitrogen atom.
37. A compound according to claim 1 or a pharmacologically acceptable salt or pro-drug thereof wherein: (a) R1 is a hydrogen atom; X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
Y is a group of formula R6SO2R7NCO, wherein R6 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
D is a nitrogen atom;
E is CR3, wherein R3 is a hydrogen atom; and
G is a nitrogen atom; or (b) R1 is a hydrogen atom;
X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyi group, and R7 is a hydrogen atom; Y is a group of formula CO2R8, wherein R8 is a benzyl group which may optionally be substituted with a methyl group;
D is a nitrogen atom;
E is CR3, wherein R3 is a hydrogen atom; and
G is CR4, wherein R4 is a hydrogen atom.
38. A compound according to claim 1 or a pharmacologically acceptable salt or pro-drug thereof wherein:
(a) R1 is a hydrogen atom;
X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
Y is a group of formula R6CO, wherein R6 is a phenyl group which may optionally be substituted with a methyl group;
D is a nitrogen atom; E is CR3, wherein R3 is a hydrogen atom; and
G is CR4, wherein R4 is a hydrogen atom; or
(b) R1 is a hydrogen atom;
X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom;
Y is a group of formula R6SO2, wherein R6 is a phenyl group which may optionally be substituted with a methyl group;
D is a nitrogen atom; E is CR3, wherein R3 is a hydrogen atom; and
G is CR4, wherein R4 is a hydrogen atom.
39. A compound according to claim 1 or a pharmacologically acceptable salt or pro-drug thereof wherein: (a) R1 is a hydrogen atom;
X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom; Y is a group of formula R6R7NCO, wherein R6 is a benzyl group which may optionally be substituted with a methyl group and R7 is a hydrogen atom; D is a nitrogen atom;
E is CR3, wherein R3 is a hydrogen atom; and G is CR4, wherein R4 is a hydrogen atom; or
(b) R1 is a hydrogen atom;
X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with a methyl group, and R7 is a hydrogen atom; Y is a group of formula R6R7NSO2, wherein R6 is a phenyl group which may optionally be substituted with a methyl group and R7 is a hydrogen atom;
D is a nitrogen atom;
E is CR3, wherein R3 is a hydrogen atom; and G is nitrogen; or
(c) X is a group of formula R5SO2R7NCO, wherein R5 is a phenyl group which may optionally be substituted with an alkyi group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom; Y is a group of formula R6SO2R7NCO, wherein R6 is a phenyl group which may optionally be substituted with an alkyl group having from 1 to 4 carbon atoms, and R7 is a hydrogen atom;
D is CR2, wherein R2 is a hydrogen atom; E is a nitrogen atom; and G is CR4, wherein R4 is a hydrogen atom.
40. A compound according to claim 1 or a pharmacologically acceptable salt or pro-drug thereof selected from the group consisting of: N-[(4-methyiphenyl)sulfonyl]-2-({[(4-methylphenyl)sulfonyl3carbamoyl}annino)-
7,8-dihydro-1 ,6-naphthyridine-6(5H)-carboxamide;
N-[(4-methylphenyl)suIfonyl]-2-({[(4-methylphenyl)sulfonyl]carbamoyl}amino)-
5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide; N-(phenylsulfonyl)-7~{[(phenylsulfonyl)carbamoyl]amino}-1 ,2,4,5-tetrahydro-
3H-3-benzazepine-3-carboxamide; benzyl 2-({[(4-methylphenyl)sulfonyl]carbamoyl}amino)-7,8-dihydro-1 ,6- naphthyridine-6(5H)-carboxylate;
N-[(6-ben2oyl-5,6,7,8-tetrahydro-1 ,6-naphthyridin-2-yl)carbamoyl]-4- methylbenzenesulfonamide;
4-methyl-N-{[6-(4-methylbenzoyl)-5,6,7,8-tetrahydro-1 ,6-naphthyridin-2- yl]carbamoyl}benzenesulfonamide;
4-methyl-N-({6-[(4-methylphenyl)sulfonyl3-5,6,7,8-tetrahydro-1 ,6-naphthyridin-
2-yl}carbamoyl)benzenesulfonamide; 4-methy!-N-({6-[(4-methylphenyl)sulfonyl]-5,6I7,8-tetrahydro-1 ,6-naphthyridin-
2-yt}carbamoyl)benzenesuIfonamide ammonium salt;
N-benzyl-2-({[(4-methylphenyl)sulfonyl]carbamoyl}amino)-7,8-dihydro-1 ,6- naphthyridine-6(5H)-carboxamide;
N-[(4-methylphenyl)sulfonyl]-2-({[(4-methylphenyl)sulfonyl]carbamoyl}- amino)5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinyl-carboxamide; and
N-[(4-methylphenyi)sulfonyi]-3-({[(4-methyIphenyl)sulfonyl]carbamoy!}-amino)-
7,8-dihydro-1 ,6-naphthyridine-6(5H)-carboxamide.
41. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and an active ingredient, wherein said active ingredient is a compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof as an active ingredient thereof.
42. A compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof for use as a medicament.
43. Use of a compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Anxiety and Anxiety-Related Conditions.
44. Use of a compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Epilepsy.
45. Use of a compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Migraine,
46. Use of a compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Inflammatory and Immunological Diseases.
47. Use of a compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Memory Loss.
48. Use of a compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders.
49. Use of a compound of formula (1 a) as defined below or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of a disease in which KvLx channels are involved:
Figure imgf000089_0001
(Ia)
wherein:
A and B are independently CH2 or CH2CH2; D is C R2 or a nitrogen atom; E is CR3 or a nitrogen atom; G is CR4 or a nitrogen atom; with the proviso that at least one of D, E and G is nitrogen;
R1 is a hydrogen atom, an aikyl group, a cycloalkyl group, an aryl group, an araikyl group or a heteroaralkyl group;
R2, R3 and R4 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsuiphonyl groups, aminosulphonyi groups and cyano groups;
X is selected from R5CO, R5SO2, R5R7NCO, R5R7NSO2, R5SO2NR7CO and CO2R8 wherein R5, R7 and R8 are as defined below;
Y is selected from R6CO, R6SO2, R6R7NCO, R6R7NSO2, R6SO2NR7CO and CO2R8 wherein R6, R7 and R8 are as defined below;
R5 and R6 are independently selected from hydrogen atoms, alkyl groups, aryl groups, araikyl groups, heteroaryi groups and heteroaralky! groups; R7 is a hydrogen atom, an alkyl group, an aryi group or an aralkyl group; and
R8 is an alkyl group, an aryl group, an aralkyl group, an alkoxyalkyl group, a heteroaryl group or a heteroarylatky! group.
50. Use of a compound as defined in claim 49 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by KvIx channel opening.
51. Use of a compound as defined in claim 49 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by KvIx channel inhibition.
52. Use of a compound as defined in claim 49 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Lower Urinary Tract Disorders.
53. Use of a compound as defined in claim 49 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Pain Disorders.
54. Use of a compound as defined in claim 49 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Gynaecological Pain.
55. Use of a compound as defined in claim 49 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiac Arrhythmias.
56. Use of a compound as defined in claim 49 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Thromboembolic Events.
57. Use of a compound as defined in claim 49 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiovascular Diseases.
58. Use of a compound as defined in claim 49 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Disorders of the Auditory System.
59. Use of a compound as defined in claim 49 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Gastrointestinal Disorders.
60. Use of a compound as defined in claim 49 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders.
61. Use of a compound as defined in ciaim 49 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Cell Proliferative Disorders.
62. Use of a compound as defined in claim 49 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Metabolic Disorders.
63. Use of a compound as defined in claim 49 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Opthalamic Disorders.
64. Use according to any one of claims 49 to 63 wherein said compound or a pharmacologically acceptable salt or pro-drug thereof is a compound as defined in any one of claims 1 to 40.
65. A method for the prophylaxis or treatment of Anxiety and Anxiety- Related Conditions comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof.
66. A method for the prophylaxis or treatment of Epilepsy comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof.
67. A method for the prophylaxis or treatment of Migraine comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof.
68. A method for the prophylaxis or treatment of Inflammatory and Immunological Diseases comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof.
69. A method for the prophylaxis or treatment of Memory Loss comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof.
70. A method for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof.
71. A method for the prophylaxis or treatment of a disease in which Kv 1.x channels are involved comprising administering to a patient in need thereof an effective amount of a compound of formula (1a) or a pharmacologically acceptable salt or pro-drug thereof:
Figure imgf000093_0001
(Ia) wherein;
A and B are independently CH2 or CH2CH2; D is CR2 or a nitrogen atom; E is CR3 or a nitrogen atom; G is CR4 or a nitrogen atom; with the proviso that at least one of D, E and G is nitrogen;
R1 is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group or a heteroaralkyi group;
R2, R3 and R4 are independently selected from hydrogen atoms, alky! groups, halogen atoms, haloaikyl groups, alkoxy groups, alkoxycarbonyi groups, carboxyl groups, hydroxy! groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, aikylsulphonyl groups, arylsulphonyl groups, aminosulphonyl groups and cyano groups;
X is selected from R5CO, R5SO2, R5R7NCO, R5R7NSO2, R5SO2NR7CO and CO2R8 wherein R5, R7 and R8 are as defined below;
Y is selected from R6CO, R6SO2, R6R7NCO, R6R7NSO2, R6SO2NR7CO and CO2R8 wherein R6, R7 and R8 are as defined below;
R5 and R6 are independently selected from hydrogen atoms, alkyl groups, aryl groups, aralkyl groups, heteroaryl groups and heteroaraikyl groups; R7 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; and
R8 is an alkyl group, an aryl group, an aralkyl group, an alkoxyalkyl group, a heteroaryl group or a heteroarylalkyl group.
72. A method for the prophylaxis or treatment of a condition or disease ameliorated by KvLx channel opening comprising administering to a patient in need thereof an effective amount of a compound as defined in claim 71 or a pharmacologically acceptable salt or pro-drug thereof.
73. A method for the prophylaxis or treatment of a condition or disease ameliorated by KvLx channel inhibition comprising administering to a patient in need thereof an effective amount of a compound as defined in claim 71 or a pharmacologically acceptable salt or pro-drug thereof.
74. A method for the prophylaxis or treatment of Lower Urinary Tract Disorders comprising administering to a patient in need thereof an effective amount of a compound as defined in claim 71 or a pharmacologically acceptable salt or pro-drug thereof.
75. A method for the prophylaxis or treatment of Pain Disorders comprising administering to a patient in need thereof an effective amount of a compound as defined in claim 71 or a pharmacologically acceptable salt or pro-drug thereof.
76. A method for the prophylaxis or treatment of Gynaecological Pain comprising administering to a patient in need thereof an effective amount of a compound as defined in claim 71 or a pharmacologically acceptable salt or pro-drug thereof.
77. A method for the prophylaxis or treatment of Cardiac Arrhythmias comprising administering to a patient in need thereof an effective amount of a compound as defined in claim 71 or a pharmacologically acceptable salt or pro-drug thereof.
78. A method for the prophylaxis or treatment of Thromboembolic Events comprising administering to a patient in need thereof an effective amount of a compound as defined in claim 71 or a pharmacologically acceptable salt or pro-drug thereof.
79. A method for the prophylaxis or treatment of Cardiovascular Diseases comprising administering to a patient in need thereof an effective amount of a compound as defined in claim 71 or a pharmacologically acceptable salt or pro-drug thereof.
80. A method for the prophylaxis or treatment of Disorders of the Auditory System comprising administering to a patient in need thereof an effective amount of a compound as defined in claim 71 or a pharmacologically acceptable salt or pro-drug thereof.
81. A method for the prophylaxis or treatment of Gastrointestinal Disorders comprising administering to a patient in need thereof an effective amount of a compound as defined in claim 71 or a pharmacologically acceptable sait or pro-drug thereof.
82. A method for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders comprising administering to a patient in need thereof an effective amount of a compound as defined in claim 71 or a pharmacologically acceptable salt or pro-drug thereof.
83. A method for the prophylaxis or treatment of Cell Proliferative Disorders comprising administering to a patient in need thereof an effective amount of a compound as defined in claim 71 or a pharmacologically acceptable salt or pro-drug thereof.
84. A method for the prophylaxis or treatment of Metabolic Disorders comprising administering to a patient in need thereof an effective amount of a compound as defined in claim 71 or a pharmacologically acceptable salt or pro-drug thereof.
85. A method for the prophylaxis or treatment of Opthalamsc Disorders comprising administering to a patient in need thereof an effective amount of a compound as defined in claim 71 or a pharmacologically acceptable salt or pro-drug thereof.
86. A method according to any one of claims 71 to 85 wherein said compound or a pharmacologically acceptable salt or pro-drug thereof is a compound as defined in any one of claims 1 to 40.
87. A compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof for use in the the prophylaxis or treatment of Anxiety and Anxiety-Related Conditions.
88. A compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of Epilepsy.
89. A compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of Migraine.
90. A compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of Inflammatory and Immunological Diseases.
91. A compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drugfor use in the prophylaxis or treatment of Memory Loss.
92. A compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders.
93. A compound of formula (1a) as defined below or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of a disease in which Kv1.x channels are involved:
Figure imgf000097_0001
(Ia)
wherein:
A and B are independently CH2 or CH2CHb; D is CR2 or a nitrogen atom; E is CR3 or a nitrogen atom; G is CR4 or a nitrogen atom; with the proviso that at least one of D, E and G is nitrogen;
R1 is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group or a heteroaralkyl group;
R2, R3 and R4 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haloalkyi groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkyisulphonyl groups, arylsulphonyl groups, aminosulphonyi groups and cyano groups; X is selected from R5CO, R5SO2, R5R7NCO, R5R7NSO2, R5SO2NR7CO and CO2R8 wherein R5, R7 and R8 are as defined below;
Y is selected from R6CO, R6SO2, R6R7NCO, R6R7NSO2, R6SO2NR7CO and CO2R8 wherein R6, R7 and R8 are as defined below;
R5 and R6 are independently selected from hydrogen atoms, alkyl groups, aryl groups, aralkyl groups, heteroaryl groups and heteroaralkyl groups;
R7 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; and
R8 is an alkyl group, an aryl group, an aralky! group, an alkoxyalkyl group, a heteroaryl group or a heteroarylalkyl group.
94. A compound as defined in claim 93 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of a condition or disease ameliorated by KvLx channel opening.
95. A compound as defined in claim 93 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of a condition or disease ameliorated by KvLx channel inhibition.
96. A compound as defined in claim 93 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of Lower Urinary Tract Disorders.
97. A compound as defined in claim 93 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of Pain Disorders.
98. A compound as defined in claim 93 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of Gynaecological Pain.
99. A compound as defined in claim 93 or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiac Arrhythmias.
100. A compound as defined in claim 93 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of Thromboembolic Events.
101. A compound as defined in claim 93 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of
Cardiovascular Diseases.
102. A compound as defined in claim 93 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of Disorders of the Auditory System.
103. A compound as defined in claim 93 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of Gastrointestinal Disorders.
104. A of a compound as defined in claim 93 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders.
105. A compound as defined in claim 93 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of Cell Proliferative Disorders.
106. A compound as defined in claim 93 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of Metabolic Disorders.
107. A compound as defined in claim 93 or a pharmacologically acceptable salt or pro-drug thereof for use in the prophylaxis or treatment of Opthalamic Disorders.
108. A compound according to any one of claims 93 to 107 wherein said compound or a pharmacologically acceptable salt or pro-drug thereof is a compound as defined in any one of claims 1 to 40.
109. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and at least two active ingredients, wherein said active ingredients comprise at least one compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of muscarinic receptor antagonists, /?3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel dl δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists, alpha-1 adrenoceptor antagonists, tricyclic antidepressants, N- methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anticonvulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal antiinflammatory drugs (NSAIDs).
1 10. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of muscarinic receptor antagonists, /?3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel o2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and alpha-1 adrenoceptor antagonists.
111. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel σ2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs).
112. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of muscarinic receptor antagonists, £3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel σ2 6 ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and alpha-1 adrenoceptor antagonists for use in the prophylaxis or treatment of lower urinary tract disorders.
113. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or prodrug thereof in combination with at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ Ngands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs) for use in the prophylaxis or treatment of pain.
114. Use of at least one compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or prodrug thereof and at least one compound selected from the group consisting of muscarinic receptor antagonists, /?3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel a2 δ ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and alpha-1 adrenoceptor antagonists in the manufacture of a medicament for the prophylaxis or treatment of lower urinary tract disorders.
115. Use of at least one compound according to any one of claims 1 to 40 or a pharmacologically acceptable salt or prodrug thereof and at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel a2 δ ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs) in the manufacture of a medicament for the prophylaxis or treatment of pain.
116. A method for the prophylaxis or treatment of lower urinary tract disorders comprising administering to a patient in need thereof an effective amount of a composition according to claim 110.
117. A method for the prophylaxis or treatment of pain comprising administering to a patient in need thereof an effective amount of a composition according to claim 111.
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