WO2009019508A1 - Modulateurs des canaux calciques et leurs utilisations - Google Patents

Modulateurs des canaux calciques et leurs utilisations Download PDF

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WO2009019508A1
WO2009019508A1 PCT/GB2008/050652 GB2008050652W WO2009019508A1 WO 2009019508 A1 WO2009019508 A1 WO 2009019508A1 GB 2008050652 W GB2008050652 W GB 2008050652W WO 2009019508 A1 WO2009019508 A1 WO 2009019508A1
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groups
carbon atoms
group
substituted
atoms
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PCT/GB2008/050652
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Raymond John Boffey
Svenja Burckhardt
Julie Elaine Cansfield
Nawaz Mohammed Khan
Geoff Lawton
David Tickle
Ngoc-Tri Vo
Srinivasan Kanumilli
Jonathan E. H. Buston
Andy Smith
Robert A. J. Wybrow
Roland Zbigniew Kozlowski
Dayle Spencer Hogg
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Lectus Therapeutics Limited
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Publication of WO2009019508A1 publication Critical patent/WO2009019508A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to ion channel modulators, and more particularly to compounds which inhibit the interaction between the pore-forming ( ⁇ ) subunits of Cav voltage-gated calcium channels and accessory (Cav ⁇ subunit) proteins.
  • Voltage-dependent calcium (Cav) channels conduct calcium tons 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.
  • Cavlx channels are involved in both skeletal (Cav1.1) and cardiac smooth muscle contraction (Cav1.2), as well as neuroendocrine release (Cav1.3 and Cav1.4). Cav2.x channels are important in neurotransmitter release (Cav2.1 and Cav2.2) and controlling neuronal excitability (Cav2.3). Cav channels which belong to the Cavi .x and Cav2.x families are defined by their threshold for activation as high threshold and are also known as L- or N-type channels respectively. L-type Cav channels are pharmacologically defined by their sensitivity to inhibition by dihydropyridines. Cav channels which belong to the Cav3.x class (Cav3.1 , Cav3.2, Cav3.3) are activated at much lower membrane voltages and are defined as low threshold or T-type calcium channels.
  • Cav channels are composed of an ⁇ 1 subunit, which forms the pore-region of the channel through which Ca 2+ ions can flow. conserveed transmembrane and pore domains of the ⁇ 1 subunits are less than 40% identical between the related families (Cav1 ,x : Cav2.x : Cav3.x) but greater than 70% identical within a family' which leads to difficulty in identifying compounds that pharmacologically discriminate between these related Cav channel subtypes.
  • Cav channel ⁇ subunits are intracellular proteins endogenously associated with Cav channel ⁇ 1 subunits, which finely tune many of their functional and electrophysiological / kinetic properties".
  • Ten different genes encode voltage-gated Cav channel alpha 1 subunits" 1 .
  • Cav ⁇ subunits (Cav ⁇ i , Cav ⁇ 2, Cav ⁇ 3, Cav ⁇ 4) have been shown to interact and regulate the functional activity of Cav1.x, Cav2.x and Cav3.x channels l( ⁇ V " vl ' v ".
  • Cav ⁇ subunits include altering the threshold for activation and the kinetics for both activation and inactivation, as well as regulating trafficking of the Cav ⁇ i subunit to the cell membrane.
  • the predominant effect of the combined ⁇ - ⁇ interaction is dependent upon the nature of each of the two proteins such that combining one type of Cava subunit with any of the ⁇ (1-4) subunits will lead to differential effects on functional expression and kinetics of the channel.
  • the ⁇ subunit potentially adds a further source of modulation of the final Cav current.
  • Mammalian homologues of Cav channel ⁇ subunits consist of four homologous domains each with six transmembrane segments. These domains can form tetrameric protein complexes that span the plasma membrane of cells and aliow the passage of Ca 2+ ions. These tetrameric protein complexes of Cav channels constitute the ion channel pore-forming domain.
  • Cav channels consisting of a tetramer of transmembrane spanning Cav2 channel subunits may be associated with and regulated by cytosolic accessory (Cav ⁇ ) proteins that are able to modulate the function of ion channel pore-forming domains (for review, see v ⁇ ").
  • cytosolic accessory (Cav ⁇ ) proteins that are able to modulate the function of ion channel pore-forming domains (for review, see v ⁇ ").
  • Cav ⁇ subunits bind to Cav channel ⁇ 1 subunits through an ⁇ interaction domain (AID) located between domains I and Il of the pore-forming ⁇ -1 subunit. Binding of the Cav ⁇ subunit to the AID can increase the trafficking of the Cav channel to the cell membrane and modulate the kinetics of the Cav current.
  • AID ⁇ interaction domain
  • Cav2.2 calcium channels also known as N-type channels, are located at nerve terminals, dendrites and neuroendocrine cells and are involved in neurotransmitter release'. There is substantial evidence for their involvement in pain.
  • ⁇ -Conotoxin -GVlA a specific peptide blocker of Cav2.2 blocks electrically evoked responses of dorsal horn neurons and this is enhanced in nerve-injured rats'*.
  • blockade of the N-type calcium channel with ⁇ -conotoxin-GVIA also abolishes injury-induced wind-up and post-discharge phenomena. It is suggested that nerve injury results in either increased frequency of opening of the N-type calcium channel, or an increase in the population. Blockade of these channels is expected to decrease the enhanced excitatory neurotransmitter release that occurs after nerve injury, thus inhibiting the manifestations of enhanced pain x .
  • Neuronal Cav2.2 channels may bind to any Cav ⁇ subunit whereas cardiac calcium currents are of the Cav1.2 type and their activity appears to be modulated by Cav ⁇ 2 proteins * .
  • the presence of Cav2.2 with Cav ⁇ 2 produces non-inactivating currents in chromaffin cells"" whereas the association of Cav2.2 with Cav ⁇ 3 produces inactivating currents.
  • Cav2.2 would appear to be preferentially co-localised with Cav ⁇ 3 because ⁇ - conotoxin-GVIA binding sites are immunoprecipitated by an antibody to Cav ⁇ 3 in rabbit brain*"'.
  • Mice lacking the N-type Cav ⁇ 3 subunit show reduced levels of Cav2.2 channels with altered sensitivity to inflammatory pain when compared to wild-type x ⁇ v .
  • Cav ⁇ 3 subunits hyperpolarise the voltage-dependence of activation and also hyperpolarise the voltage-dependence of steady-state inactivation of Cav2.2 channels* ViXvl .
  • These channels are located at the presynaptic terminals of nociceptive neurons in dorsal horn of the spinal cord where they regulate the release of the key pro- nociceptive neurotransmitters such as glutamate and substance P.
  • selective blockers of N-type channels can be used to ameliorate chronic painTM'.
  • chronic pain is postherpetic neuralgia (PHN), traditionally defined as the persistence of pain for more than 1 month after the disappearance of the rash associated with shinglesTM".
  • Shingles is caused by the varicella-zoster virus (VZV) and can persist for years in the dorsal root ganglia of cranial or spinal nerves after resolution of the original infection.
  • VZV varicella-zoster virus
  • PRIALT the synthetic analogue of ⁇ -conotoxin-MVIfA, is effective in patients with PHN, as well as phantom-limb pain, and HIV-related neuropathic pain who are refractory to opioids'TM,
  • Pregabalin received Food and Drug Administration (FDA) approval on December 30, 2004, for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN) and PHN. Moreover, pregabalin is approved for use as adjunctive therapy for adult patients with partial onset seizuresTMTM. Pregabaiin is structurally related to gabapentin (Neurontin ® ; Pfizer), These compounds are thought to reduce trafficking of the Cav2 channel subunit by an interaction with another accessory subunit, called ⁇ 2 - ⁇ .
  • Pregabalin is six-times more potent than gabapentin in binding affinity to the ⁇ 2 - ⁇ voltage-gated caicium channel*TM.
  • the manufacturer states that 50 mg of pregabalin is approximately equal to 300 mg of gabapentin.
  • pregabalin and gabapentin alter channel function without complete blockade of the calcium channel resulting in virtually no change in systemic blood pressure or coronary blood flow changes.
  • Overactive bladder is an unmet medical need. Symptoms of overactive bladder include increased urinary frequency, urgency, nocturia (the disturbance of night-time sleep because of the need to urinate) and accidental loss of urine (urge incontinence) due to a sudden and unstoppable need to urinate. Urge incontinence is usually associated with an overactive detrusor muscle, the smooth muscle of the bladder which contracts and causes it to empty. There is no single etiology for overactive bladder. Neurogenic overactive bladder occurs as the result of neurological damage found in a variety of disorders such as stroke, Parkinson's disease, diabetes, multiple sclerosis, peripheral neuropathy, or spinal cord lesions. In these cases, the overactivity of the detrusor muscle is termed detrusor hyperreflexia.
  • Overactive bladder may result from hypersensitivity of sensory neurons of the urinary bladder, arising from inflammatory conditions, hormonal imbalances, and prostate hypertrophy. Destruction of the sensory nerve fibres, either from a crushing injury to the sacral region of the spinal cord, or from a disease that causes damage to the dorsal root fibres as they enter the spinal cord may also lead to overactive bladder. In addition, damage to the spinal cord or brain stem causing interruption of transmitted signals may lead to abnormalities in micturition. Therefore, both peripheral and central mechanisms can contribute to overactive bladder. Carbone et ai. (2003) have previously reported the effects of gabapentin on neurogenic detrusor overactivity"TM 1 . This study demonstrated a positive effect on symptoms and significant improvement in urodynamic parameters after treatment with gabapentin and suggested that the effects of the drug should be explored further in controlled studies in both neurogenic and nonneurogenic detrusor overactivity.
  • Cav2.2 may exert a central role in mediating control of reflex bladder activity by NO through suppressing the excitability and/or the release of transmitters from bladder afferent nerves.
  • novel modulators of the protein-protein interaction between Cav2.2 channels and Cav ⁇ 3 accessory proteins may offer a novel mode of reducing hyperexcitability produced by over-expression of Cav2.2.
  • Such a reduction of hyperactivity in primary afferent neurons is anticipated to lead to an alleviation of pain and of disorders of the lower urinary tract.
  • “Cavx” channels consist of at least 10 members which includes one of the following mammalian channels: Cav1.1 , Cav1.2, Cav1.3, Cav1.4, Cav2.1 , Cav2.2, Cav2.3, Cav3.1 , Cav3.2 or Cav3.3 and any mammalian or non-mammalian equivalents or variants (including splice variants) thereof.
  • “Cav ⁇ ” proteins may include one or more of the following mammalian subunits: Cav ⁇ i, Cav ⁇ 2, Cav ⁇ 3, Cav ⁇ 4 and any mammalian or non-mammalian equivalents or variants (including splice variants) thereof.
  • interactions between each combination of Cavx channel and Cav ⁇ protein may confer modulation (increasing or decreasing) of a number of features of functional Cav channels including, but not limited to (i) the transport or chaperone of Cav channels to the plasma membrane of a given cell type XXVi>MVi )on " i ' xxvl " and/or (ii) gating properties such as channel inactivationTM*.
  • Cav ⁇ subunits can also exert effects on other gating properties by mechanisms which may alter the time and voltage dependency of the open (conducting state), closed (nonconducting state) and inactivated states (non-conducting state) of Cav channels.
  • Cavx channel blockers compounds which inhibit the interaction between Cavx channels and Cav ⁇ proteins and thus reduce either the conducting state of Cavx channels (e.g. though increasing the rate of inactivation) and/ or decreasing the transport of Cavx channels to the plasma membrane.
  • Cavx channel inhibitors have potential utility in the treatment, prevention, inhibition, amelioration or alleviation of symptoms of a number of conditions or disease states including:
  • Lower urinary tract disorders is intended to encompass both painful (any lower urinary tract disorder involving sensations or symptoms that a patient subjectively describes as producing or resulting in pain) and non-painful 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 irritate 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 urinar
  • 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 is intended to include, but is not limited to, anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, performance anxiety, posttraumatic 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 is intended to include, 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 is intended to include 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.
  • Cardiovascular Diseases such as angina pectoris, hypertension and congestive heart failure.
  • Gynaecological Pain for example, dysmenorrhoea, labour pain and pain associated with endometriosis.
  • Gastrointestinal Disorders including reflux esauphagitis, functional dispepsia, 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 malignancy.
  • 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.
  • Cavx channel blockers for the prophylaxis or treatment of a number of disease states including lower urinary tract disorders and pain indications.
  • assays based on the interaction between Cavx channel domains and Cav ⁇ subunits immobilised through an affinity tag we have discovered a new family of compounds which inhibit the interaction between Cavx channels and Cav ⁇ proteins.
  • R1 is a hydrogen atom, an alkyl group, a cycloalkyl group which is a single ring or a bridged ring system, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an aralkyl group comprising an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyi groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carb
  • R2 is a hydrogen atom, an alkyi group which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups, aryl groups (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyi groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), heteroaryl groups (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkyla
  • Y is a hydroxyl group, an alkoxyl group, a group of formula NR40R41 or an aminoacid residue
  • R3 is an alkyl group, a cycloalkyl group which is a single ring or a bridged ring system (said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups), a cycloalkenyl group which is a single ring or a bridged ring system, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, mono
  • R4 and R40 are independently selected from hydrogen atoms, alkyl groups which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups, aryl groups ⁇ which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkyiamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), heteroaryl groups (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamin
  • R4' and R41 are independently selected from hydrogen atoms and alkyl groups; or R4 and R4' together with the nitrogen atom to which they are attached and/or R40 and R41 together with the nitrogen atom to which they are attached may form a nitrogen- containing saturated or partially unsaturated 4- to 14- membered heterocyclic group having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings, said group optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, acyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulfonyl groups and hydroxyl groups);
  • R11 is a hydrogen atom, an alkyl group, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an aralkyl group which comprises an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino
  • R12 is a hydrogen atom, an alkyl group, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups) or an aralkyl group which comprises an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamin
  • R13 is an alkyl group, an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acyiamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups and cyano groups), an aralkyl group which comprises an alkyl group which is substituted with an aryl group (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups, hydroxyalkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, alkoxycarbonyl, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups
  • R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haioalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, acyiamino groups, alkoxycarbonylamino groups, alkyisulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups, or any two adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-(CH 2 ) P -O- wherein p is an integer of from 1 to 3; and
  • X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group.
  • Preferred compounds of the present invention include: (2) compounds according to (1) and pharmacologically acceptable salts, isosteres and prodrugs thereof, wherein R1 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycfoalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, an aryl group having from 5 to 14 carbon atoms (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl 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, amino groups, a monoalkylamino group wherein the alkyl group
  • R1 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aminoalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an amino group, a heteroaryl group which is a 5- to 6- membered aromatic heterocyclic group containing 1 to 2 sulfur atoms, oxygen atoms and/or nitrogen atoms which may be unsubstituted or substituted with an alkyl group having from 1 to 4 carbon atoms, and a guanidinoalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with a guanidino group;
  • R1 is a hydrogen atom, a methyl group, a 3-aminopropyl group, a 4-aminobutyl group, a 3-methyl-[1 ,2,4]oxadiazol-5-yl group, a 5-methyl- [1 ,3,4]oxadiazol-2-yl group, a 3-methyl-isoxazol-5-yl group, a 3-guanidinopropyl group or a tetrazol-5-yl group; (5) compounds according to any one of (1) to (4) and pharmacologically acceptable salts, isosteres and prodrugs thereof wherein R2 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to
  • Y is a hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms, a group of formula NR40R41 , or an aminoacid residue, wherein R40 is selected from hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms (said aryl groups being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl 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, amino groups,
  • R41 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haioalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by
  • R11 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyaSkyl 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, amino groups, a monoalkyiamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is
  • R12 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryi group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyi 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, amino groups, a monoalkylamino group wherein the alkyi group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted
  • R13 is an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyi groups having from 1 to 6 carbon atoms, hydroxyalkyi 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, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom
  • R2 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 4 carbon atoms, aryl groups having from 6 to 10 carbon atoms, heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, amino groups, monoalkylamino groups wherein the alkyl substituent has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl substit ⁇ ent is the same or different and has from 1 to 4 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or
  • Y is a hydroxyl group, an alkoxyl group having from 1 to 4 carbon atoms, a group of formula NR40R41, or an aminoacid residue, wherein R40 is selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 4 carbon atoms, aryl groups having from 6 to 10 carbon atoms, heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially uns
  • R41 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (said heterocyclic groups being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups that are substituted by an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted by
  • R11 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aralkyl group comprising an alkyi group having from 1 to 4 carbon atoms which is substituted with one or more aryl groups having from 6 to 10 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 4 carbon atoms which is substituted with one or more heteroaryl groups which are 5- to 7- memberecl aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms;
  • R12 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or aryl groups having from 6 to 10 carbon atoms; and
  • R13 is an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with one or aryl groups having from 6 to 10 carbon atoms, an alkoxyalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an alkoxy group having from 1 to 4 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 4 carbon atoms which is substituted with one or more heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms;
  • R2 is a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 3 carbon atoms, amino groups, monoalkylamino groups wherein the alkyl substituent has from 1 to 3 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom and groups of formula COY 1 or
  • R2 is a group of formula COY, wherein
  • Y is a hydroxyl group, an alkoxyl group having from 1 to 3 carbon atoms, a group of formula NR40R41 , or an aminoacid residue, wherein R40 is selected from hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkoxyl groups having from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and carboxy groups, cycloalkyl groups having from 3 to 6 carbon atoms atoms which are single rings or bridged ring systems and saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom;
  • R41 is a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, or
  • R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur;
  • R2 is a group of formula COY, wherein Y is selected from hydroxyl groups, ethoxy groups, t-butoxy groups, amino groups, methylamino groups, ethylamino groups, i-propylamino groups, dimethylamino groups, 2-(methoxysulphonyl)ethylamino groups, pyrrolidin-1-yi groups, tetrahydropyran-4- ylamino groups, cyclohexylamino groups, piperidin-1-yl groups, cyclopropylamino groups, 2-methoxyethylamino groups, morpholin-4-yl groups, 2-(pyrrolidin-1- yl)ethylamino groups, and amioacid residues selected from ornithine, lysine and glycine, or an aS
  • R3 is an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system
  • said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of 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, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoal
  • R3 is a cycloalkyl group having from 4 to 10 carbon atoms which is a single ring or a bridged ring system
  • said cycloalkyl group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyi groups substituted with an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1
  • R3 is a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4-hydroxycyclohexyl group, a 4,4-dimethylcyclohexyl group, a 4,4-difluorocyclohexyl group, an adamantyl group, a norbornenyl group, a piperidinyl group, a 4-acetylpiperidinyl group or a 4-methylsulfonylpiperidinyl group;
  • R4 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms (said aryl groups may be unsubstituted or be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl 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, amino groups, monoalkylamino groups wherein the alkyl
  • R11 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl 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, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted
  • R12 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl 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, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkyiamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyi is substitute
  • R13 is an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms (said aryl group being unsubstituted or being substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl 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, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkyiamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyi is substituted with a hydrogen
  • R4 is an alkyl group having from 1 to 4 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkoxy groups having from 1 to 4 carbon atoms, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms and dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms which is a single ring or a bridged ring system (said cycloalkyl group being unsubstituted or being substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms and acyl groups having from 1 to 4 carbon atoms), an aryl
  • R4 is a methyl group, an /-propyl group, a f-butyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4,4-difluorocyclohexyl group, an adamantyl group, a phenyl group (which is unsubstituted or is substituted with one or more substituents selected from fluorine atoms, chlorine atoms, hydroxyl groups, methyl groups, acetylamino groups, methoxy groups and diethylamino groups), a benzyl group (which is unsubstituted or is substituted with a methoxy group or a hydroxyl group), a phenethyl group (which is un
  • R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, hydroxyalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, hydroxyl groups, haloalkoxy groups having from 1 to 4 carbon atoms, halogen atoms, cyano groups, or any two adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-(CH 2 ) P -O- wherein p is an integer of from 1 to 2;
  • R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, methyl groups, methoxy groups, fluorine atoms, chlorine atoms, bromine atoms, hyroxymethyl groups, trifluoromethoxy groups, trifluoromethyl groups, i-propyl groups, ethoxy groups, hydroxyl groups, cyano groups, methylsuiphonyl groups, or to adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-CH 2 -;
  • R1 is a hydrogen atom, an alkyl group, a cycSoalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroaralkyl group, an aminoalkyl group or a guanidinoalkyl group;
  • R2 is an alkyl group which is substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups, aryl groups, heteroaryl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic groups, said groups optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, and groups of formula COY 1 or R2 is a group of formula COY;
  • Y is a hydroxyl group, an alkoxyl group, a group of formula NHR40 or an aminoacid residue
  • R3 is an alkyl group, a cycloalkyl group, a cycloaSkenyl group, an aryl group, a heteroaryl group, a nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic group, a cycloalkylalkyl group or an aralkyl group;
  • R4 and R40 are independently selected from hydrogen atoms, alkyl groups which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups, aryl groups, heteroaryl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitrogen-containing unsaturated or partially saturated 4- to 8- membered heterocyclic groups, said groups optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, carboxy groups, aminocarbonyi groups, monoalkylaminocarbonyl groups, dialkylaminocarbonyl groups and alkoxycarbonyigroups, aryl groups, cycloalkyl groups, cycloalkenyl groups, groups of formula COR11 , groups of formula SO 2 RH 1 groups of formula CONR11 R12, groups of formula SO 2 NRI 1R12 , groups of formula CONR12SO 2 R11 and groups of formula CO 2 RI 3 wherein R11 , R12 and R13
  • R11 is a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, a heteroaryl group or a heteroaralkyl group;
  • R12 is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group
  • R13 is an alkyl group, an aryi group, an aralkyl group, an alkoxyalkyl group, a heteroaryl group or a heteroarylalkyi group;
  • R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups; and
  • X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group.
  • R1 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, an aryi group having from 5 to 14 carbon atoms (which may be unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon 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, amino groups, a monoalkylamino group wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to
  • R2 is an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms which may be unsubstituted or 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, amino groups, monoalkyiamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon carbon atoms
  • R3 is an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 14 carbon atoms which is a single ring or a bridged ring system, a cycloalkenyl group having from 4 to 14 carbon atoms which is a single ring or a bridged ring system, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or 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, amino groups, monoalkyiamino groups wherein the alkyl group has
  • R4 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, aryl groups having from 5 to 14 carbon atoms which may be unsubstituted or 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 aSkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be
  • R11 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 be unsubstituted or 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, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkyiamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonyiamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms,
  • R12 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 be unsubstituted or 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, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alk
  • R13 is an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may be unsubstituted or 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, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, alkoxycarbonylamino
  • R5, R6, R7, R8 and R9 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 a carbonyl group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, acylamino groups comprising a carbonylamino group in which the carbonyl is substituted with a hydrogen atom or an alkyl group having from 1 to
  • R1 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aminoalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with an amino group, a heteroaryl group which is a 5- to 6-membered aromatic heterocyclic group containing 1 to 2 sulphur atoms, oxygen atoms and/or nitrogen atoms which may be unsubstituted or substituted with an alkyl group having from 1 to 4 carbon atoms, and a guanid ⁇ noalkyl group comprising an alkyl group having from 1 to 4 carbon atoms which is substituted with a guanidino group,
  • R2 is a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 3 carbon atoms, amino groups, monoalkylamino groups wherein the alkyl substituent has from 1 to 3 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom and groups of formula COY, or
  • R2 is a group of formula COY, wherein
  • Y is a hydroxyl group, an alkoxyl group having from 1 to 3 carbon atoms, a group of formula NR40R41 , or an aminoacid residue, wherein
  • R40 is selected from hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from alkoxyl groups having from 1 to 3 carbon atoms, saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and carboxy groups, cycloalkyl groups having from 3 to 6 carbon atoms atoms which are single rings or bridged ring systems and saturated, partially unsaturated or unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atom;
  • R41 is a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, or R40 and R41 together with the nitrogen atom to which they are attached together form a nitrogen-containing saturated or partially unsaturated 4- to 8- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings, said group optionally further containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur,
  • R3 is a cycloalkyl group having from 4 to 10 carbon atoms which is a single ring or a bridged ring system (said cycloalkyi group may be unsubstituted or be substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups comprising carbonyl groups substituted with an alkoxy group having from 1 to 4 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 4 carbon
  • R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, hydroxyalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, hydroxyl groups, haloalkoxy groups having from 1 to 4 carbon atoms, halogen atoms and cyano groups, or any two adjacent ring substituents R5, R6, R7 and R8 may together form the group
  • X is an oxygen atom, a sulphur atom or a group of formula NR10, wherein R10 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms;
  • R1 is a hydrogen atom, a methyl group, a 3-aminopropyl group, a 4-aminobutyl group, a 3-methyl-[1 ,2,4]oxadiazot-5-yl group, a 5-methyl-[1 ,3,4]oxadiazol-2-yl group, a 3-methyl- isoxazol-5-yt group or a 3-guanidinopropyl group;
  • R2 is a group of formula COY, wherein Y is selected from hydroxyl groups, ethoxy groups, t-butoxy groups, amino groups, methylamino groups, ethylamino groups, i- propylamino groups, dimethylamino groups, 2- ⁇ methoxysulphonyi)ethylamino groups, pyrrolidin-1-yl groups, tetrahydropyran-4-yla ⁇ nino groups, cyclohexylamino groups, piperidin-1-yl groups, cyclopropylamino groups, 2-methoxyethylamino groups, morpholin-4-yl groups, 2-(pyrrolidin-1-yl)ethylamino groups, and amioacid residues selected from ornithine, lysine and glycine, or an alkyl group having from 1 to 3 carbon atoms which may be unsubstituted or substituted with a substituent selected from carboxy groups,
  • R4 is a methyl group, an /-propyl group, a f-butyl group, a cyclopropyi group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4,4-difluorocyclohexyl group, an adamantyl group, a phenyl group (which is unsubstituted or is substituted with one or more substituents selected from fluorine atoms, chlorine atoms, hydroxyl groups, methyl groups, acetylamino groups, methoxy groups and diethylamino groups), a benzyl group (which is unsubstituted or is substituted with a methoxy group or a hydroxyl group), a phenethyl group (which is unsubstituted or is substituted with a hydroxyl group), a pyridinyl group, a thiazolyl group,
  • R5, R6, R7, R8 and R9 are independently selected from hydrogen atoms, methyl groups, methoxy groups, fluorine atoms, chlorine atoms, bromine atoms, hyroxymethyl groups, trifluoromethoxy groups, trifluoromethyl groups, i-propyl groups, ethoxy groups, hydroxyl groups, cyano groups, methylsulphonyl groups, or to adjacent ring substituents R5, R6, R7 and R8 may together form the group -O-CH 2 -; and X is a sulphur atom, an amino group or a methySamino group; 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 (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof for use as a medicament there is provided a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof for use as a medicament.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a disease in which Cavx channels are involved.
  • a compound according to any one of (1 ) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel opening.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel inhibition.
  • a seventh aspect of the present invention there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Lower Urinary Tract Disorders.
  • a ninth aspect of the present invention there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Epilepsy.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Pain Disorders.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Gynaecological Pain.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiac Arrhythmias.
  • a thirteenth aspect of the present invention there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Thromboembolic Events.
  • a fourteenth aspect of the present invention there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiovascular Diseases.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Disorders of the Auditory System,
  • a sixteenth aspect of the present invention there is provided use of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Migraine.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Inflammatory and Immunological Diseases.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Gastrointestinal Disorders.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cell Proliferative Disorders.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Metabolic Disorders.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders.
  • a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Opthalamic Disorders.
  • a method for the prophylaxis or treatment of a disease in which Cavx is involved comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel opening comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel inhibition comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug 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 according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • 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 (29) or a pharmacologically acceptable salt, isostere or prodrug 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 (29) or a pharmacologically acceptable salt, isostere or prodrug 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 according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug 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 according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug 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 according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug 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 according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof
  • a thirty-fifth 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 according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug 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 according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug 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 (29) or a pharmacologically acceptable salt, isostere or prodrug 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 (29) or a pharmacologically acceptable salt, isostere or prodrug 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 according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug 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 according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • a method for the prophylaxis or treatment of Ceil Proliferative Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug 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 according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug 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 (29) or a pharmacologically acceptable salt, isostere or prodrug 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 (29) or a pharmacologically acceptable salt, isostere or prodrug 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 according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof.
  • 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 (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in combination 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, anti-convulsants, aldose reductas
  • 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 (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in combination 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 ⁇ -1 adrenoceptor antagonists; and
  • 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 (29) or a pharmacologically acceptable salt, isostere or prodrug thereof in combination 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, nicotinic acetyl
  • the combinations of preferred option (1) are of particular use in the prophylaxis or treatment of lower urinary tract disorders.
  • the combinations of preferred option (2) are of particular use in the prophylaxis or treatment of pain.
  • a forty-eighth aspect of the present invention there is provided use of at least one compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere 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, caicium channel ⁇ 2 ⁇ deita ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNFUs), 5-HT antagonists and ⁇ -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 caicium channel ⁇ 2
  • a forty-ninth aspect of the present invention there is provided use of at least one compound according to any one of (1) to (29) or a pharmacologically acceptable salt, isostere or prodrug thereof and at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel ⁇ 2 ⁇ delta iigands, potassium channel inhibitors, caicium 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
  • the alkyl groups in the definitions of R1 , R2, R3, R4, R4 J , R40, R41 , R5, R6, R7, R8, R9, R10, R11 , R12 and R13 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, ethyl groups, /-propyl groups and t- butyl groups.
  • the cycloalkyl groups in the definition of R1 , R3, R4 and R40 are preferably cycloalkyl groups having from 3 to 14 carbon atoms which may either be unsubstituted or may be substituted with at least one substituent selected from the group consisting of 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 comprising carbonyl groups substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyl groups comprising a carbonyl group which is substituted with a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, nitro groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different
  • the cycloalkyl groups more preferably have from 5 to 10 carbon atoms, and are most preferably cyclopentyl, cyclohexyl, cycloheptyl and adamantyl groups which may be subsitiuted with one or more substiituents selected from fluorine atoms, hydroxyl groups and methyl groups.
  • the aryl groups in the definitions of R1 , R2, R3, R4, R40, R11 , R12 and R13 are preferably aryl groups having from 5 to 14 carbon atoms in one or more rings which may either be unsubstituted or may be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxyalkyl 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, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups, acylamino groups comprising
  • unsubstituted aryl groups include phenyl, indenyl, naphthyl, phenanthrenyl and anthracenyl groups. More preferred aryl groups include phenyl groups which may optionally substituted by 1 or 2 halogen atoms, alkoxy groups having from 1 to 4 carbon atoms, hydroxyalkyl groups having from 1 to 4 carbon atoms, acylylamtno groups having from 1 to 4 carbon atoms, hydroxyl groups and dialkylamino groups wherein each alkyl group is the same or different and has from 1 to 4 carbon atoms; and most preferred aryl groups are phenyl groups which are unsubstituted or are substituted with a fluorine atom, a hydroxyl group, a methoxy group, a hydroxymethyl group, a diethylamino group, a chlorine atom or a diethoxyamino group.
  • the aralkyl groups in the definitions of R1 , R3, R11 , R12 and R13 are preferably alkyl groups as defined above which are substituted with one or more aryi groups as defined above, and are more preferably benzyl and phenethyl groups which may be unsubstituted or substituted with at least one substituent selected from alkoxyl groups having from 1 to 4 carbon atoms and hydroxyl groups, and most preferably are benzyl and phenethyl groups which may be unsubstituted or substituted with a methoxy group or a hydroxyl group.
  • the heteroaryl groups in the definitions of R1 , R2, R3, R4, R40, R11 and R13 are preferably a heteroaryi group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulphur atoms, oxygen atoms and/or nitrogen atoms atoms which may be unsubstituted or 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, alkoxycarbonyf groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl group may be the same or different and has from 1 to 6 carbon atoms, nitro groups,
  • Examples include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1 ,2,3-oxadiazolyl, triazoiyl, tetrazolyl, thiadiazolyf, pyranyf, pyridyl, pyridazinyl, pyrimidinyl, indazolyl, 1-methylindazolyl and pyrazinyl groups. Most preferred is thiazolyl, indazolyl, 1-methylindazolyl and pyridyl.
  • the heteroaralkyl groups in the definitions of R1 , R11 and R13 are preferably alkyl groups as defined above which are substituted with heteroaryl groups as defined above.
  • the aminoalkyl groups in the definition of R1 are preferably aSkyi groups as defined above which are substituted with an amino group, and most preferred are aminopropyl groups and aminobutyl groups.
  • the guanidinoalkyl groups in the definition of R1 are preferably alkyl groups as defined above which are substituted with a guanidino group, and most preferred are guanidinopropyl groups.
  • the alkoxyl groups in the definitions of R2, R3, R4, R40, R4', R41 , R5, R6, R7, R8, R9 and Y 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 monoalkylamino groups in the definitions of R2, R3, R4, R40, R4 ⁇ R41 , R5, R6, R7, R8 and R9 are preferably amino groups which are substituted with one alkyl group as defined above, and are more preferably methylamtno, ethySamino or t-butylamino groups.
  • dialkylamino groups in the definitions of R2, R3, R4, R40, R4', R41 , R5, R6, R7, R8 and R9 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 dimethylamino or diethylamino groups.
  • the saturated, partially unsaturated or unsaturated heterocyclic 4- to 14- membered heterocyclic groups having one or more rings including bridged saturated or partially unsaturated heterocyclic groups having two or more rings and containing at least one nitrogen, oxygen or sulphur atoms in the definitions of R2, R3, R4, R40, R4' and R41 are 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups having two or more rings which may be unsubstituted or substituted with at (east one substituent selected from the group consisting of 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 that are substituted by an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, acyi groups comprising a carbon
  • Preferred examples include morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 4-acetylpiperidinyl, 4- methylsulphonylpiperidinyl, tetrahydrofuranyl, N-methylpiperidinyl and N- methylpiperazinyl groups.
  • the nitrogen-containing saturated or partially unsaturated 4- to 14- membered heterocyclic groups having one or more rings including bridged saturated or partially unsaturated heterocyclic groups having two or more rings formed by R4 and R4' together with the nitrogen atom to which they are attached or R40 and R41 together with the nitrogen atom to which they are attached are nitrogen- containing saturated or partially unsaturated 4- to 14- membered heterocyclic groups having one or more rings, including bridged saturated or partially unsaturated heterocyclic groups and they optionally further contain one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur (said heterocyclic groups may be unsubstituted or be substituted with at least one substituent selected from the group consisting of 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 that
  • aminoacid residues in the definition of Y are the residual moieties obtained after reaction of an amino group with the carboxyl group of an amino acid, and are preferably ornithine, lysine or glycine residues.
  • the monoalkylaminocarbonyl groups in the definitions of R4 and R40 are preferably aminocarbonyl groups which are substituted with one alkyl group as defined above, and are more preferably methylaminocarbonyS, ethylaminocarbonyl or t-butylaminocarbonyl groups.
  • dialkylaminocarbonyl groups in the definitions of R4 and R40 are preferably aminocarbonyl 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 dimethylaminocarbonyl or diethylaminocarbonyl groups.
  • the cycloalkenyl groups in the definition of R3, R4 and R40 are preferably cycloalkenyl groups having from 4 to 14 carbon atoms; the cycloalkyl group can be in a single ring or can be a bridged ring system.
  • the cycloalkenyi groups more preferably have from 5 to 10 carbon atoms, and are most preferably norbomenyl groups.
  • the cycloalkylalkyl groups in the definition of R3 are preferably alkyl groups as defined above which are substituted with a cycloalkyi groups as defined above.
  • the haloalkoxy groups in the definitions of R5, R6, R7, R8 and R9 are preferably alkoxyl groups as defined above which are substituted with one or more halogen atoms. More preferably, they are alkoxyl groups having from 1 to 4 carbon atoms that are substituted with at least one chlorine or fluorine atom and most preferably they are chloromethoxy group, trichloromethoxy groups, trifluoromethoxy groups and tetrafluoroethoxy groups.
  • the haioalkyl groups in the definitions of R2, R3, R4, R4 ⁇ R40, R41 , R5, R6, R7, R8 and R9 are preferably alkyl groups as defined above which are substituted with one or more halogen atoms. More preferably, they are alky] 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 and tetrafluoroethyl groups.
  • the alkoxycarbonyl groups in the definitions of R2, R3, R4, R4 ⁇ R40, R41 , R5, R6, R7, R8 and R9 are preferably carbonyl groups substituted with alkoxy groups as defined, and are more preferably methoxycarbonyl or ethoxycarbonyl groups.
  • the acylamino groups in the definitions of R5, R6, R7, R8 and R9 are preferably carbonylamino groups in which the carbonyl is substituted with an hydrogen atom or an alkyl group having from 1 to 6 carbon atoms and are more preferably acetylamino or propanoylamino groups.
  • the hydroxyalkyl groups in the definitions of R5, R6, R7, R8, R9 are preferably hydroxyalkyl groups having from 1 to 6 carbon atoms, more preferably hydroxyalkyl groups having from 1 to 4 carbon atoms and most preferably hydroxymethyl groups, 2-hydroxyethyl groups, and 3-hydroxypropyl groups groups.
  • the acyl groups in the definitions of R2, R3, R4, R4' ; R40 and R41 are preferably a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, more preferably a carbonyl group which is substituted by a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and most preferably an acetyl or propionyl group.
  • the alkoxycarbonylamino groups in the definitions of R5, R6, R7, R8 and R9 are preferably amino groups which are substituted with an alkoxycarbonyl group as defined above, and are more preferably methoxycarbonylamino or ethoxycarbonylamino groups.
  • the alkylsulphonyl groups in the definitions of R2, R3, R4, R4 ⁇ R40, R41 , R5, R6, R7, R8 and R9 are preferably sulphonyl groups which are substituted with an alkyl group as defined above and are more preferably a methylsulphonyl or ethylsuiphonyl group.
  • the arylsulphonyl groups in the definitions of R5, R6, R7, R8 and R9 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 alkylsulphonylamino groups in the definitions of R5, R6, R7, R8 and R9 are preferably sulphonylamino groups which are substituted with an alkyl group as defined above and are more preferably a methylsulphonylamino or ethylsulphonylamino group.
  • the aryisuiphonylamino groups in the definitions of R5, R6, R7, R8 and R9 are preferably sulphonylamino groups which are substituted with an aryl group as defined above and are more preferably a phenylsulphonylamino group which may be optionally substituted with one or two alkyl groups as defined above or a naphthylsuiphonylamino group.
  • the alkoxyalkyl groups in the definition of R13 are preferably alkyl groups as defined above which are substituted by one or more alkoxy groups as defined above. More preferably they are alkyl groups having from 1 to 4 carbon atoms that are substituted with an alkoxy group having from 1 to 4 carbon atoms and most preferably methoxymethyl and 2-methyoxyethyl groups.
  • pharmacologically acceptable salts of the compound having the formula (1) described above are not specificaijy restricted and these salts can be selected by a person with an ordinary skill in the art.
  • such salts are, for example, basic salts such as an alkaline metal sait such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as calcium salt or magnesium salt; a metal salt such as aluminium salt, iron salt, zinc salt, copper salt, nickel salt or cobalt salt; an amine salt such as an ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N- methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine
  • the compounds of formula (1) 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
  • Many suitable prodrugs would be 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 formula (1) wherein a carboxyl moiety of the compound having the formula (1) 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 C 1 -C 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 1 -C 4 alkoxy C 1 -C 4 alkyi group such as 2-methoxyethoxymethyl; a C 6 -C 10 aryloxy C 1 -C 4 alkyl group such as phenoxymethyl; a halogenated C 1 -C 4 alkoxy C 1 -C 4 alkyl group such
  • the compounds of formula (1) or pharmacologically active prodrugs or 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.
  • isosteres or salts thereof contain a carboxyl group, this can be replaced with a tetrazolyl group.
  • Hydrates or solvates of the compounds of formula (1), isosteres thereof, prodrugs thereof and pharmacologically acceptable salts thereof can also be used and form a part of the invention.
  • Some compounds of formula (1) and their pharmacologically acceptable salts, isosteres or prodrugsthereof 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.
  • some of the compounds of formula (1) and their pharmacologically acceptable saits, isosteres or prodrugs thereof of the present invention may have one or more double bonds, and these can exist in cis and trans isomeric forms. These respective isomers are included in the present invention, both as individual isomers and mixtures thereof in all possible ratios.
  • Examples of the administration form of a compound having the general formula (1) of the present invention, or pharmacologically acceptable salt, isostere or prodrug thereof include oral administration by tablets, capsules, granules, powders or syrups, and parenteral administration by injection, patches or suppositories.
  • a compound having the general formula (1) or a pharmacologically acceptable salt, isostere or prodrug 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 examples include polyvinylpyrrolidone, Macrogol and compounds similar to the aforementioned excipients.
  • disintegrants agents include compounds similar to the aforementioned excipients, and chemically crosslinked starches and celluloses such as cross sodium carmellose, sodium carboxymethyl starch or crosslinked polyvinylpyrrolidone.
  • stabilizers include paraoxybenzoate esters such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenyl ethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; and, sorbic acid.
  • paraoxybenzoate esters such as methyl paraben or propyl paraben
  • alcohols such as chlorobutanol, benzyl alcohol or phenyl ethyl alcohol
  • benzalkonium chloride phenols such as phenol or cresol
  • thimerosal thimerosal
  • dehydroacetic acid and, sorbic acid.
  • corrigents include ordinarily used sweeteners, sour flavourings and fragrances.
  • 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. ethanof, propylene glycol or polyethylene glycol).
  • 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.
  • the suspension may additionally contain a suspending agent (such as microcrystalline cellulose or sodium carboxymethyl 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 pharmacologically acceptable salt, isostere or prodrug 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.
  • 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 examples 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 pregabalin.
  • potassium channel activators include KW-7158, NS-8 and retigabine,
  • Examples of calcium channel inhibitors include ziconotide and NMED-160.
  • Examples of sodium channel blockers include lidocaine, lamotrigine, VX-409, ralfinamide and carbamazepine.
  • Examples of serotonin and norepinephrine reuptake inhibitors (SNRIs) include duloxetine and venlafaxine
  • 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.
  • N-methyl-D-aspartate (NMDA) receptor antagonists include ketamine, memantine, amantadine, AVP-923, NP-1 and EVT-101.
  • cannabinoid receptor agonists examples include GW-1000 (Sativex) and KDS- 2000.
  • Anti-convulsants examples include lacosamide, carbamazepine, topiramate, oxcarbazepine and levetiracetam
  • aldose reductase inhibitors include tolrestat, zopoirestat, zenarestat, epalrestat, sorbinil, AS-3201 , fidarestat, risarestat, ponalrestat and alrestatin.
  • opioids e.g. mu opioid agonists
  • opioids include fentanyl and tapentadol.
  • alpha adrenoceptor agonists include a r 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.
  • acid-sensing ion channel modulators include amiloride.
  • NGF receptor modulators examples include trkA.
  • nicotinic acetylcholine receptor modulators inciude A-85380, tebanicline, ABT-366833, ABT-202, ABT-894, epibatidine analogs and S1B-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) and pharmacologically acceptable salts 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 (1) or a pharmacologically acceptable salt thereof with lidocaine could be administered transdermal ⁇ by means of a patch while a combination with ziconotide could be administered transmucosally.
  • test compounds dissolved in a suitable vehicle such as DMSO
  • a suitable vehicle such as DMSO
  • Cav2.2 ⁇ subunit AID After incubation with test compounds, 10 ⁇ l of Cav2.2 ⁇ subunit AID at 10x Kd was added to each well and incubated for 60 minutes at room temperature on a shaker. Unbound Cav2.2 ⁇ subunit AID domain was removed by washing 3 times in 300 ⁇ l of PBS-Tween. Bound Cav2.2 ⁇ subunit AID domain was estimated by using appropriately diluted mouse anti-FLAG antibody HRP conjugate using standard ELISA procedures. HRP was detected by addition of colourmetric HRP substrate 2,2'-azino-bis(3-ethylbenzthiazoline- 6-sulfonic acid) and microtitre plates were read in a Biotek Synergy HT microtitre plate reader equipped with a 405nm absorbance filter.
  • Test compounds were examined for their ability to inhibit the binding of Cav2.2 ⁇ subunit AID domain to Cav ⁇ 3 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 Cav2.2 ⁇ subunit AID binding to Cav ⁇ 3 subunits.
  • IC 50 half maximal inhibitory concentration
  • the tested compounds of Examples 2, 4, 6, 18, 27, 41 to 44, 48 to 51 and 53 to 55 of this invention displayed excellent ability to inhibit the binding of Cav2.2 ⁇ subunit AID domain to Cav ⁇ 3 subunits as measured by determination of the IC 50 (see Table 1).
  • the rat Cav ⁇ i , ⁇ 2, ⁇ 3 and ⁇ 4 subunits cDNA were ligated into an E.coli expression vector downstream of sequence coding for a poly Histidine-tag and the BCCP domain of the E.coli AccB gene.
  • the ligation mix was transformed into chemically competent
  • Colonies of Rosetta2 cells containing Cav subunit plasmids were inoculated in 5ml of LB medium containing ampicillin and chloramphenicol in 20m! tubes and grown overnight at 37°C in a shaking incubator. 2ml of overnight culture was used to inoculate another 200ml of LB containing ampicil ⁇ n and chloramphenicol in 500ml flasks and grown at 37°C until an OD600 of 0.7AU was reached. IPTG was then added to a final concentration of 1mM and induction continued at 30°C for 4 hours. Cells were then harvested by centrifugation, cell pellets were washed in PBS and stored in aliquots at - 80°C.
  • lysis buffer PBS containing 0.1% Tween 20, 1mg/ml lysozyme and 1 ⁇ g/ml DNAse I
  • Lysis was aided by incubation on a rockerat room temperature for 30min before cell debris was collected by centrifugation at 13000rpm for 10mins at 4°C. The cleared supernatant of soluble protein was removed and used immediately.
  • the cDNA for the alpha interacting domain (amino acids 357-399 Accession number NP_671482) was cloned downstream of sequences coding for GST-tag and a FLAG-tag in an E.coli expression vector. Plasmids were checked by sequencing for correct sequence and induction of E.coli cultures showed expression of a GST and FLAG-tagged soluble protein of the expected size.
  • binding reactions were assembled containing 10 ⁇ l Cav ⁇ subunit cleared lysated, 10 ⁇ l anti-FLAG agarose in the presence and absence of 10 ⁇ l purified AID protein in 250 ⁇ l phosphate buffered saline containing 300mM NaCI, 0.1% Tween20, 0.01% Triton 100 and 1% (w/v) bovine serum albumin. Reactions were incubated on a rocker at room temperature for 1 hour and FLAG bound complexes harvested by centrifugation at 700rpm for 10min. After extensive washing in PBS-T ween, FLAG bound complexes were denatured in SDS sample buffer and Western blotted. Presence of biotinylated Cav ⁇ subunits were detected by Streptavidin/HRP conjugate.

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Abstract

La présente invention porte sur des modulateurs de canaux ioniques, et plus particulièrement sur des composés qui inhibent l'interaction entre les sous-unités de formation de pore (α) de canaux calciques dépendants d'un potentiel d'action de type Cav et des protéines accessoires (Cavβ). Les composés sont d'utilité dans le traitement et la prévention d'un nombre de maladies et d'états comprenant la douleur et les troubles des voies urinaires inférieures, et ont la Formule suivante (I).
PCT/GB2008/050652 2007-08-03 2008-08-01 Modulateurs des canaux calciques et leurs utilisations WO2009019508A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009133387A1 (fr) * 2008-04-29 2009-11-05 Lectus Therapeutics Limited Dérivés d’indole-3-glyoxylamide destinés à être utilisés comme modulateurs des canaux calciques
WO2010035032A1 (fr) * 2008-09-25 2010-04-01 Lectus Therapeutics Limited Modulateurs des canaux ioniques calciques et leurs utilisations
WO2015002230A1 (fr) * 2013-07-03 2015-01-08 武田薬品工業株式会社 Composé amide
WO2016118902A1 (fr) * 2015-01-22 2016-07-28 Brown University Contrôle de cellules excitables peu invasif et dépendant de l'activité
US9834520B2 (en) 2013-03-14 2017-12-05 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10053468B2 (en) 2013-07-03 2018-08-21 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10149986B2 (en) 2012-08-13 2018-12-11 Brown University Optogenetic control of endothelial cells
EP3666769A1 (fr) * 2018-12-12 2020-06-17 Rijksuniversiteit Groningen Nouveaux inhibiteurs de la caspase
WO2020198637A1 (fr) * 2019-03-28 2020-10-01 The Trustees Of Columbia University In The City Of New York Compositions et méthodes pour des bloqueurs de canaux calciques dépendants du voltage à haut seuil encodés génétiquement à l'aide de ligases d'ubiquitine modifiées
WO2021003389A1 (fr) * 2019-07-02 2021-01-07 The Trustees Of Columbia University In The City Of New York Nouvelle approche pour augmenter la contractilité chez des patients atteints d'une insuffisance cardiaque systolique

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0545845A1 (fr) * 1991-12-03 1993-06-09 Neurosearch A/S Composés d'imidazole, leur préparation et utilisation comme inhibiteurs du canal calcique
WO1999051224A1 (fr) * 1998-04-02 1999-10-14 Asta Medica Aktiengesellschaft Derives d'acide indolyl-3-glyoxylique a action antitumorale
US20040116504A1 (en) * 2002-12-10 2004-06-17 Wyeth Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
WO2005000285A2 (fr) * 2003-06-13 2005-01-06 Dynogen Pharmaceuticals, Inc. Methodes de traitement de troubles non inflammatoires de l'appareil gastro-intestinal au moyen de modulateurs du canal calcique contenant des sous-unites cav2.2
WO2005077082A2 (fr) * 2004-02-11 2005-08-25 Univertsity Of Virginia Patent Foundation Inhibition d'isoformes de cav3 et variants d'epissage $g(d)25b pour diagnostic et traitement de cancers
WO2006015867A1 (fr) * 2004-08-10 2006-02-16 Laboratorios Del Dr. Esteve, S.A. Composes d'indole substitues, leurs preparation et utilisation dans des medicaments
WO2006052712A1 (fr) * 2004-11-08 2006-05-18 Baxter International Inc. Compositions nanoparticulaires d'inhibiteurs de la tubuline
WO2006136580A2 (fr) * 2005-06-21 2006-12-28 Neurosearch A/S Nouveaux derives de 2-(phenylamino)benzimidazole et utilisation de ceux-ci en tant que modulateurs de canaux de potassium actives par le calcium a faible conductance

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0545845A1 (fr) * 1991-12-03 1993-06-09 Neurosearch A/S Composés d'imidazole, leur préparation et utilisation comme inhibiteurs du canal calcique
WO1999051224A1 (fr) * 1998-04-02 1999-10-14 Asta Medica Aktiengesellschaft Derives d'acide indolyl-3-glyoxylique a action antitumorale
US20040116504A1 (en) * 2002-12-10 2004-06-17 Wyeth Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
WO2005000285A2 (fr) * 2003-06-13 2005-01-06 Dynogen Pharmaceuticals, Inc. Methodes de traitement de troubles non inflammatoires de l'appareil gastro-intestinal au moyen de modulateurs du canal calcique contenant des sous-unites cav2.2
WO2005077082A2 (fr) * 2004-02-11 2005-08-25 Univertsity Of Virginia Patent Foundation Inhibition d'isoformes de cav3 et variants d'epissage $g(d)25b pour diagnostic et traitement de cancers
WO2006015867A1 (fr) * 2004-08-10 2006-02-16 Laboratorios Del Dr. Esteve, S.A. Composes d'indole substitues, leurs preparation et utilisation dans des medicaments
WO2006052712A1 (fr) * 2004-11-08 2006-05-18 Baxter International Inc. Compositions nanoparticulaires d'inhibiteurs de la tubuline
WO2006136580A2 (fr) * 2005-06-21 2006-12-28 Neurosearch A/S Nouveaux derives de 2-(phenylamino)benzimidazole et utilisation de ceux-ci en tant que modulateurs de canaux de potassium actives par le calcium a faible conductance

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009133387A1 (fr) * 2008-04-29 2009-11-05 Lectus Therapeutics Limited Dérivés d’indole-3-glyoxylamide destinés à être utilisés comme modulateurs des canaux calciques
WO2010035032A1 (fr) * 2008-09-25 2010-04-01 Lectus Therapeutics Limited Modulateurs des canaux ioniques calciques et leurs utilisations
US10149986B2 (en) 2012-08-13 2018-12-11 Brown University Optogenetic control of endothelial cells
US9834520B2 (en) 2013-03-14 2017-12-05 Takeda Pharmaceutical Company Limited Heterocyclic compound
US11053262B2 (en) 2013-07-03 2021-07-06 Takeda Pharmaceutical Company Limited Heterocyclic amide compounds having RORyT inhibitory action
WO2015002230A1 (fr) * 2013-07-03 2015-01-08 武田薬品工業株式会社 Composé amide
JPWO2015002230A1 (ja) * 2013-07-03 2017-02-23 武田薬品工業株式会社 アミド化合物
US10053468B2 (en) 2013-07-03 2018-08-21 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10472376B2 (en) 2013-07-03 2019-11-12 Takeda Pharmaceutical Company Limited Amide compound
US11851449B2 (en) 2013-07-03 2023-12-26 Takeda Pharmaceutical Company Limited Heterocyclic amide compounds having an RORvt inhibitory action
WO2016118902A1 (fr) * 2015-01-22 2016-07-28 Brown University Contrôle de cellules excitables peu invasif et dépendant de l'activité
US11242374B2 (en) 2015-01-22 2022-02-08 Brown University Minimally-invasive and activity-dependent control of excitable cells
EP3666769A1 (fr) * 2018-12-12 2020-06-17 Rijksuniversiteit Groningen Nouveaux inhibiteurs de la caspase
WO2020198637A1 (fr) * 2019-03-28 2020-10-01 The Trustees Of Columbia University In The City Of New York Compositions et méthodes pour des bloqueurs de canaux calciques dépendants du voltage à haut seuil encodés génétiquement à l'aide de ligases d'ubiquitine modifiées
WO2021003389A1 (fr) * 2019-07-02 2021-01-07 The Trustees Of Columbia University In The City Of New York Nouvelle approche pour augmenter la contractilité chez des patients atteints d'une insuffisance cardiaque systolique

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