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WO2010035032A1 - Modulateurs des canaux ioniques calciques et leurs utilisations - Google Patents

Modulateurs des canaux ioniques calciques et leurs utilisations Download PDF

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Publication number
WO2010035032A1
WO2010035032A1 PCT/GB2009/051242 GB2009051242W WO2010035032A1 WO 2010035032 A1 WO2010035032 A1 WO 2010035032A1 GB 2009051242 W GB2009051242 W GB 2009051242W WO 2010035032 A1 WO2010035032 A1 WO 2010035032A1
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Nawaz Mohammed Khan
Svenja Burckhardt
Julie Elaine Cransfield
Ngoc-Tri Vo
Richard Edward Armer
Raymond John Boffey
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Lectus Therapeutics Ltd
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Lectus Therapeutics Ltd
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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
    • C07D209/12—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system

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 ions 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.
  • Cavi .x 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 (Cavi .x : Cav2.x : Cav3.x) but greater than 70% identical within a family 1 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 Cavi .x, Cav2.x and Cav3.x channels' v ' 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 allow 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 released There is substantial evidence for their involvement in pain.
  • ⁇ -Conotoxin -GVIA a specific peptide blocker of Cav2.2 blocks electrically evoked responses of dorsal horn neurons and this is enhanced in nerve-injured rats x .
  • 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 x ".
  • the presence of Cav2.2 with Cav ⁇ 2 produces non-inactivating currents in chromaffin cells xm 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 x ⁇ v .
  • Mice lacking the N-type Cav ⁇ S subunit show reduced levels of Cav2.2 channels with altered sensitivity to inflammatory pain when compared to wild-typeTM.
  • Cav ⁇ 3 subunits hyperpolarise the voltage-dependence of activation and also hyperpolarise the voltage-dependence of steady-state inactivation of Cav2.2 channels xv ⁇ ' xv ". 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. Consistent with this, selective blockers of N-type channels can be used to ameliorate chronic pain xvm .
  • 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 shingles x ⁇ x .
  • 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.
  • PRIALT the synthetic analogue of ⁇ -conotoxin-MVI!A, is effective in patients with PHN, as well as phantom-limb pain, and HIV-related neuropathic pain who are refractory to opioids xx .
  • Compounds which are believed to inhibit chronic pain by acting at accessory proteins and reducing hyperexcitability of calcium currents have been described.
  • 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.
  • DPN diabetic peripheral neuropathy
  • pregabalin is approved for use as adjunctive therapy for adult patients with partial onset seizuresTM'TM 1 .
  • Pregabalin 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 00 2 - ⁇ .
  • Pregabalin is six-times more potent than gabapentin in binding affinity to the ⁇ , 2 - ⁇ voltage-gated calcium channelTM".
  • 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 nighttime 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.
  • 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 typ e ⁇ v ⁇ , ⁇ v ii, ⁇ v ⁇ i, ⁇ i ⁇ anc j/or ( ⁇ ) gating properties such as channel inactivation ,*XXX
  • 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 (non-conducting state) and inactivated states (non-conducting state) of Cav channels.
  • Cav channel currents e.g. Cav2 xxx ⁇
  • This phenomenon may account for the wide diversity of Cav channels.
  • exact subunit compositions of native Cav channels and the physiologic role that particular channels play are, in most cases, still unclear.
  • 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, post-traumatic stress disorder, acute stress reaction, adjustment disorders, hypochondriacal disorders, separation anxiety disorder, agoraphobia and specific phobias.
  • Specific anxiety related phobias include, but are not limited to, fear of animals, insects, storms, driving, flying, heights or crossing bridges, closed or narrow spaces, water, blood or injury, as well as extreme fear of inoculations or other invasive medical or dental procedures.
  • Epilepsy 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.
  • Cell Proliferative Disorders including restenosis and cancer (including leukemia); treating or preventing 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.
  • Opthalarnic 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, a hydroxyl group or an aralkyl group
  • R2 is an alkyl group, an aryl group or a heteroaryl group, each of which may be unsubstituted or substituted with at least one substituent selected from the group consisting of hydroxyl groups, alkoxyl groups, haloalkoxyl groups, aryl groups, heteroaryl groups, cycloalkyl groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulphonyl groups, alkylsulphinyl groups, alkylsulphonylamino groups, acylamino groups, saturated or partially unsaturated heterocyclic groups and groups of formula COY;
  • Y is a hydroxyl group, an alkoxyl group, a group of formula NR11 R12 or an aminoacid residue
  • R11 and R12 are the same or different and each is
  • alkyl group an alkyl group, an aryl group or a heteroaryl group, each of which may be unsubstituted or substituted with at least one substituent selected from the group consisting of alkoxy groups, haloalkoxy groups, aryloxy groups, alkylsulphonyl groups and alkylsulphinyl groups,
  • a saturated or partially unsaturated heterocyclic group or R11 and R12 together with the nitrogen atom to which they are attached form a nitrogen-containing saturated heterocyclic group (said group optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms);
  • R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen atoms, alkyl groups, aryl groups, heteroaryl groups, halogen atoms, haloalkyl groups, alkoxy groups, haloalkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, hydroxyalkyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups; or
  • any two of R3 to R6 that are adjacent on the ring may together represent the moiety -O-(CH 2 )n-0- wherein n is an integer of from 1 to 3;
  • W is selected from oxygen atoms, sulphur atoms, groups of formula NR7, wherein R7 is a hydrogen atom, an alkyl group, an aryl group or a heteroaryl group and groups of formula CR8R9, wherein R8 and R9 are the same or different and each is a hydrogen atom, an alkyl group, an aryl group or a heteroaryl group; and
  • X is selected from nitrogen atoms and groups of formula CR10, wherein R10 is a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, halogen atoms and haloalkyl groups;
  • R1 is a hydrogen atom and R2 is an alkyl group substituted with a group of formula COY, wherein Y is a hydrogen atom, a methyl group or an ethyl group, then R4 cannot be a hydrogen atom, a halogen atom,
  • R1 is a hydrogen atom or benzyl group
  • R2 cannot be an aralkyl group
  • R1 is a hydrogen atom
  • R2 cannot be a methyl-substituted norbornanyl group
  • Preferred compounds of this first aspect of the present invention include:
  • R1 is a hydrogen atom, a hydroxyl group or an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from 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 wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino 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
  • R1 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms that is substituted with an aryl group having from 6 to 10 carbon atoms, said aryl group optionally being substituted with an aminoalkyl group having from 1 to 4 carbon atoms or an alkyl group having from 1 to 4 carbon atoms;
  • R1 is a hydrogen atom or a (3-aminomethyl)benzyl group;
  • R11 and R12 are the same or different and each is
  • a cycloalkyl group having from 3 to 14 carbon atoms having from 3 to 14 carbon atoms
  • a saturated or partially unsaturated heterocyclic group which is a 4- to 8- membered saturated or partially unsaturated heterocyclic group containing at least one nitrogen, oxygen or sulphur atom which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, alkoxy groups having from 1 to 6 carbon atoms, haloalkyl groups having from 1 to 6 carbon atoms and carbony! groups,
  • R11 and R12 together with the nitrogen atom to which they are attached together form a 4- to 8- membered nitrogen-containing saturated heterocyclic group, said group optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms;
  • alkyl groups having from 1 to 4 carbon atoms which may be unsubstituted or substituted with one or more substituents selected from amino groups, and nitrogen-containing unsaturated 5- or 6- membered heterocyclic groups, said groups optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms,
  • alkyl groups having from 1 to 4 carbon atoms which are substituted with a group of formula COY wherein Y is a group of formula NR11R12, wherein R11 and R12 together with the nitrogen atom to which they are attached form a nitrogen-containing saturated heterocyclic group containing from 4- to 6- members and optionally containing 1 more heteroatoms selected from nitrogen, oxygen and sulphur, and (c) alkyl groups having from 1 to 4 carbon atoms which are substituted with a group of formula COY wherein Y is a group of formula NR11 R12 wherein R11 is selected from hydrogen, alkyl groups having from 1 to 4 carbon atoms and cycloalkyl groups having from 3 to 6 carbon atoms and R12 is selected from unsaturated heterocyclic groups having from 4 to 6 carbon atoms and containing at least one nitrogen, oxygen or sulphur atom, alkoxyalkyl groups comprising alkyl groups having from 1 to 4 carbon atoms that are substituted with alkoxy groups
  • R2 is an alkyl group having 1 to 4 carbon atoms which is optionally substituted with one or more substituents selected from carboxy groups, amino groups, methoxy groups, ethoxycarbonyl groups, methylsulfonyl groups, tetrahydropyranyl groups, N-Me-piperidin-4-yl groups and pyrrolidinyl groups, or R2 is an alkyl group having from 1 to 4 carbon atoms that is substituted with a pyrrolidine -ylcarbonyl group or R2 is an alkyl group having form 1 to 4 carbon atoms that is substituted with a 2- methoxyethylaminocarbonyl group, a ⁇ /-(4-tetrahydro-2/-/-pyranyl)aminocarbonyl group or a 2-pyrrolidin-1-ylethylaminocarbonyl group
  • R3, R4, R5 and R6 are independently selected from hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms,
  • ⁇ ryl groups having from 5 to 14 carbon atoms which may be unsubstituted or 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 qaving from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, ⁇ Ikoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, Wboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein £ he alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein each jlkyl 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 groups compris
  • heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, said groups optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, halogen atoms,
  • haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, haloalkoxy 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, hydroxyalkyl groups having from 1 to 6 carbon atoms, nitro groups, amino groups, monalkylamino 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 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atom
  • arylsulphonyi groups wherein the ary! moiety has from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino 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 groups comprising a carbonylamino group
  • alkylsulphonylamino groups having from 1 to 6 carbon atoms
  • arylsulphonylamino groups wherein the aryl moiety has from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino 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 groups comprising a carbonylamin
  • R3 to R6 may together represent the moiety -O-(CH 2 ) n - wherein n is an integer of 1 to 3;
  • R3, R4, R5 and R6 are independently selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, fluorine atoms and chlorine atoms;
  • X is a group of formula CR10 wherein R10 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or X is a nitrogen atom;
  • R1 is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms that is substituted with an aryl group having from 6 to 10 carbon atoms, said aryl group optionally being substituted with an aminoalkyl group having from 1 to 4 carbon atoms or an alkyl group having from 1 to 4 carbon atoms;
  • R2 is selected from (a) alkyl groups having from 1 to 4 carbon atoms which are optionally substituted with one or more substituents selected from amino groups, and nitrogen-containing unsaturated 5- or 6- membered heterocyclic groups, said groups optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms,
  • R3, R4, R5 and R6 are independently selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, fluorine atoms and chlorine atoms;
  • X is a group of formula CR10 wherein R10 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or X is a nitrogen atom; and
  • W is an oxygen atom, a sulphur atom, a group of formula NR7, wherein R7 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or a group of formula CR8R9, wherein R8 and R9 are the same or different and each is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms; (16) a compound according to (1) or a pharmacologically acceptable salt or prodrug thereof wherein:
  • R1 is a hydrogen atom or a (3-aminomethyi)benzyl group
  • R2 is an alky! group having 1 to 4 carbon atoms which is optionally substituted with one or more substituents selected from carboxy groups, amino groups, methoxy groups, ethoxycarbonyl groups, methylsulfonyl groups, tetrahydropyranyl groups, N-Me-piperidin-4-yl groups and pyrrolidinyl groups, or R2 is an alkyl group having from 1 to 4 carbon atoms that is substituted with a pyrrolidin-1-ylcarbonyl group or R2 is an alkyl group having form 1 to 4 carbon atoms that is substituted with a 2-methoxyethylaminocarbonyl group, a /V-(4- tetrahydro-2/-/-pyranyl)aminocarbonyl group or a 2-pyrrolidin-1- ylethylaminocarbonyl group;
  • R3, R4, R5 and R6 are independently selected from hydrogen atoms, methyl groups, methoxy groups, fluorine atoms and chlorine atoms;
  • X is a group of formula CH
  • W is a group of formula NH or NMe
  • an N- substituted indole compound selected from the following group, or a pharmacologically acceptable salt or pro-drug thereof:
  • R1' is a cycloalkyl group, an aryl group, a heteroaryl group, a heteroaralkyl group, a saturated or partially unsaturated heterocyclic group, a cycloalkylalkyl group, an aminoalkyl group or a guanidinoalkyl group;
  • R2' is an alkyl group, an aryl group or a heteroary! group, each of which is substituted with at least one substituent of formula COY', wherein Y' is a group of formula NR11'R12';
  • R11 1 and R12' are the same or different and each is
  • an aryl group or a heteroaryi group each of which may be unsubstituted or substituted with at least one substituent selected from the group consisting of alkoxy groups, haloalkoxy groups, aryloxy groups, alkylsulphonyl groups and alkylsulphinyl groups;
  • R3', R4', R5' and R6' are independently selected from the group consisting of hydrogen atoms, alkyl groups, aryl groups, heteroaryi groups, halogen atoms, haloalkyl groups, alkoxy groups, haloalkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, hydroxyalkyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups; or
  • any two of R3' to R6' that are adjacent on the ring may together represent the moiety -O ⁇ (CH 2 ) n -O- wherein n is an integer of from 1 to 3;
  • W is selected from oxygen atoms, sulphur atoms, groups of formula NR7', wherein R7' is a hydrogen atom, an alkyl group, an aryl group or a heteroaryi group and groups of formula CR8'R9', wherein R8' and R9' are the same or different and each is a hydrogen atom, an alkyl group, an aryl group or a heteroaryi group; and
  • X' is selected from nitrogen atoms and groups of formula CR10', wherein R10' is a hydrogen atom, an alkyl group, an aryl group, a heteroaryi group, halogen atoms and haloalkyl groups;
  • Preferred compounds of this third aspect of the present invention include:
  • R1' is a cycloalkyl group having from 3 to 14 carbon atoms, an aryl group having from 5 to 14 carbon atoms which may optionally 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 wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, a monalkylamino 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
  • (21) a compound according to (19) or a pharmacologically acceptable salt or prodrug thereof wherein R1' is a cycloalkyl group having from 3 to 7 carbon atoms or a cycloalkylalkyl group comprising an alkyl group having from 1 to 4 carbon atoms that is substituted with a cycloalkyl group having from 3 to 7 carbon atoms;
  • (22) a compound according to (19) or a pharmacologically acceptable salt or prodrug thereof wherein R1' is a cyclopentyl group, a cyclohexyl group, a cyclohexylmethyl group or a 2-cyclohexylethyl group;
  • R2' is an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 5 to 14 carbon atoms or 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, wherein said group optionally contains one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, wherein said alkyl, aryl or heteroaryl group is substituted with at least one substituent of formula COY', wherein Y' is a group of formula NR11 'R12' (wherein R11' and R12' are as defined below); and
  • R11' and R12' are the same or different and each is an aryl group having from 5 to 14 carbon atoms or a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and each of said aryl or aromatic heterocyclic groups may be unsubstituted or substituted with at least one substituent selected from the group consisting of alkoxy groups having from 1 to 6 carbon atoms, haloalkyl groups having from 1 to 6 carbon atoms, aryloxy groups having from 5 to 14 carbon atoms which may be unsubstituted or 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 wherein the alkoxy group has from 1 to 6 carbon
  • alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, alkylsulphonyl groups having from 1 to 6 carbon atoms and alkylsulphinyl 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 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 wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkyiamino 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 groups comprising a carbonylamino group which is
  • heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, a heteroaralkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, said groups optionally containing one or more further heteroatorns selected from oxygen, nitrogen and sulphur atoms, halogen atoms,
  • haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, haloalkoxy 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, hydroxy!
  • alkyl groups hydroxyalkyl groups having from 1 to 6 carbon atoms, nitro groups, amino groups, monalkylamino 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 6 carbon atoms, alkoxycarbonylamino groups comprising a carbonylamino group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms,
  • arylsulphonyl groups wherein the aryl moiety has from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino 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 groups comprising a carbonylamino group
  • arylsulphonylamino groups wherein the aryl moiety has from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino 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 groups comprising a carbonylamin
  • R3' to R6' may together represent the moiety -O-(CH 2 ) n - wherein n is an integer of 1 to 3;
  • R3', R4', R5' and R6' are independently selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, fluorine atoms and chlorine atoms;
  • R1' is a cycloalkyl group having from 3 to 7 carbon atoms or a cycloalkylalkyl group comprising an alkyl group having from 1 to 4 carbon atoms that is substituted with a cycloalkyl group having from 3 to 7 carbon atoms;
  • R2' is selected from alkyl groups having from 1 to 4 carbon atoms that are substituted by groups of formula COY', wherein Y' is a group of formula NR11'R12', wherein R11' and R12' are the same or different and each is an aryl group having from 5 to 14 carbon atoms or a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and each of said aryl or aromatic heterocyclic groups may be unsubstituted or substituted with at least one substituent selected from the group consisting of alkoxy groups having from 1 to 6 carbon atoms, haloalkyl groups having from 1 to 6 carbon atoms, aryloxy groups having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms,
  • R3 1 , R4', R5' and R6' are independently selected from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, fluorine atoms and chlorine atoms;
  • X' is a group of formula CR10' wherein R10' is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or X is a nitrogen atom;
  • W is an oxygen atom, a sulphur atom, a group of formula NR7 ⁇ wherein R7' is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or a group of formula CR8'R9', wherein R8' and R9' are the same or different and each is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms;
  • R1' is a cyclopentyl group, a cyclohexyl group, a cyclohexylmethyl group or a 2- cyclohexylethyl group;
  • R2' is selected from alkyl groups having from 1 to 4 carbon atoms that are substituted by groups of formula COY 1 , wherein Y' is a group of formula NR11 'R12', wherein R11' and R12' are the same or different and each is an aryl group having from 5 to 14 carbon atoms or a heteroaryl group which is a 5- to 7- membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and each of said aryl or aromatic heterocyclic groups may be unsubstituted or substituted with at least one substituent selected from the group consisting of alkoxy groups having from 1 to 6 carbon atoms, haloalkyl groups having from 1 to 6 carbon atoms, aryloxy groups having from 5 to 14 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atom
  • R3', R4', R5' and R6' are independently selected from hydrogen atoms, methyl groups, methoxy groups, fluorine atoms and chlorine atoms;
  • X' is a group of formula CH
  • W is a group of formula NH or NMe.
  • an N- substituted indole compound selected from the following group, or a pharmacologically acceptable salt or pro-drug thereof:
  • an N- substituted indole compound selected from the following group, or a pharmacologically acceptable salt or pro-drug thereof:
  • 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 (34) or a pharmacologically acceptable salt or prodrug thereof.
  • R1" is a hydrogen atom, a hydroxyl group or an aralkyl group
  • R2" is an alkyl group, an aryl group or a heteroaryi group, each of which may be unsubstituted or substituted with at least one substituent selected from the group consisting of hydroxyl groups, alkoxyl groups, haloalkoxyl groups, aryl groups, heteroaryi groups, cycloalkyl groups, amino groups, monoalkylamino groups, dialkylamino groups, alkylsulphonyl groups, alkylsulphinyl groups, alkylsulphonylamino groups, acylamino groups, saturated or partially unsaturated heterocyclic groups and groups of formula COY";
  • Y is a hydroxyl group, an alkoxyl group, a group of formula NR11"R12" or an aminoacid residue;
  • R11" and R12" are the same or different and each is
  • alkyl group an alkyl group, an aryl group or a heteroaryi group, each of which may be unsubstituted or substituted with at least one substituent selected from the group consisting of alkoxy groups, haloalkoxy groups, aryloxy groups, alkylsulphonyl groups and alkylsulphinyl groups,
  • a saturated or partially unsaturated heterocyclic group or R11" and R12" together with the nitrogen atom to which they are attached form a nitrogen-containing saturated heterocyclic group (said group optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms);
  • R3", R4", R5" and R6" are independently selected from the group consisting of hydrogen atoms, alkyl groups, aryl groups, heteroaryl groups, halogen atoms, haloalkyl groups, alkoxy groups, haloalkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, hydroxyalkyl groups, nitro groups, amino groups, rnonalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups; or
  • any two of R3" to R6" that are adjacent on the ring may together represent the moiety -O-(CH 2 ) n -O- wherein n is an integer of from 1 to 3;
  • W is selected from oxygen atoms, sulphur atoms, groups of formula NR7", wherein R7" is a hydrogen atom, an alkyl group, an aryl group or a heteroaryl group and groups of formula CR8"R9", wherein R8" and R9" are the same or different and each is a hydrogen atom, an alkyl group, an aryl group or a heteroaryl group; and
  • X is selected from nitrogen atoms and groups of formula CR10", wherein R10" is a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, halogen atoms and haloalkyl groups.
  • R1"' is an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a heteroaralkyl group, a saturated or partially unsaturated heterocyclic group, a cycloalkylalkyl group, an aminoalkyl group or a guanidinoaikyl group;
  • R2"' is an alkyl group, an aryl group or a heteroaryl group, each of which is substituted with at least one substituent of formula COY'", wherein Y'" is a group of formula NRI r 11 RIZ" 1 ;
  • R11" 1 and R12 1 are the same or different and each is
  • an aryl group or a heteroaryl group each of which may be unsubstituted or substituted with at least one substituent selected from the group consisting of alkoxy groups, haloalkoxy groups, aryloxy groups, alkylsulphonyl groups and alkylsulphinyl groups;
  • R3 1 ", R4" 1 , R5" 1 and R6 1 " are independently selected from the group consisting of hydrogen atoms, alkyl groups, aryl groups, heteroaryl groups, halogen atoms, haloalkyl groups, alkoxy groups, haloalkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, hydroxyalkyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups; or any two of R3"' to R6" 1 that are adjacent on the ring may together represent the moiety -0-(CH ⁇ ) n -O- wherein n is an integer of from 1 to 3;
  • W" is selected from oxygen atoms, sulphur atoms, groups of formula NR7"', wherein R7"' is a hydrogen atom, an alkyl group, an aryl group or a heteroaryl group and groups of formula CR8"'R9" ⁇ wherein R8" 1 and R9"' are the same or different and each is a hydrogen atom, an alkyl group, an aryl group or a heteroaryl group; and
  • X"' is selected from nitrogen atoms and groups of formula CR10"', wherein R10 1 " is a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, halogen atoms and haloalkyl groups.
  • R1" is a hydrogen atom and R2" is an alkyl group substituted with a group of formula COY", wherein Y" is a hydrogen atom, a methyl group or an ethyl group, then R4" cannot be a hydrogen atom, a halogen atom, a nitro group or an alkoxy group, and
  • R1"' cannot be an alkyl group.
  • R1" when R1" is a hydrogen atom, R2" cannot be a methyl-substituted norbornanyl group, and for compounds of formula (I'"), R1'" cannot be an alkyl group.
  • R1" is a hydrogen atom
  • R2" cannot be a methyl-substituted norbornanyl group
  • RT cannot be an alkyl group.
  • RT cannot be an alkyl group.
  • 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 of formula (I") as defined in (37), a compound of formula (I"') as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt 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 of formula (I") as defined in (37), a compound of formula (I"') as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt 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 of formula (I") as defined in (37), a compound of formula (I 1 ") as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt 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 of formula (I") as defined in (37), a compound of formula (I 1 ") as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt 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 of formula (I") as defined in (37), a compound of formula (I 1 ") as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt or prodrug thereof,
  • R1" when R1" is a hydrogen atom and R2" is an alkyl group substituted with a group of formula COY", wherein Y" is a hydrogen atom, a methyl group or an ethyl group, then R4" cannot be a hydrogen atom, a halogen atom, a nitro group or an alkoxy group, and for compounds of formula (I'"), R1"' cannot be an alkyl group.
  • a method for the prophylaxis or treatment of Epilepsy comprising administering to a patient in need thereof an effective amount of a compound of formula (I") as defined in (37), a compound of formula (I"') as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt 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 of formula (I") as defined in (37), a compound of formula (I 1 ") as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt 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 of formula (I") as defined in (37), a compound of formula (I 1 ") as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt 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 of formula (I") as defined in (37), a compound of formula (I"') as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt 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 of formula (I") as defined in (37), a compound of formula (I"') as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt or prodrug thereof.
  • a method for the prophylaxis or treatment of Cardiovascular Diseases comprising administering to a patient in need thereof an effective amount of a compound of formula (I") as defined in (37), a compound of formula (I'") as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt 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 of formula (I") as defined in (37), a compound of formula (C") as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt 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 of formula (I") as defined in (37), a compound of formula (I 1 ") as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt 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 of formula (I") as defined in (37), a compound of formula (I 1 ") as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt 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 of formula (I") as defined in (37), a compound of formula (I 1 ") as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt 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 of formula (I") as defined in (37), a compound of formula (I"') as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt or prodrug thereof.
  • a method for the prophylaxis or treatment of Cell Proliferative Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (I") as defined in (37), a compound of formula (I"') as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt 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 of formula (I") as defined in (37), a compound of formula (I 1 ") as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt or prodrug thereof,
  • R2" when RT' is a hydrogen atom, R2" cannot be a methyl-substituted norbomanyl group, and
  • RT cannot be an alkyl group.
  • a method for the prophylaxis or treatment of Memory Loss comprising administering to a patient in need thereof an effective amount of a compound of formula (I") as defined in (37), a compound of formula (I 1 ") as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt or prodrug thereof
  • R1" is a hydrogen atom
  • R2" cannot be a methyl-substituted norbornanyl group
  • R1"' cannot be an alkyl group.
  • 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 of formula (I") as defined in (37), a compound of formula (I 1 ") as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt or prodrug thereof,
  • Rf cannot be an alkyl group.
  • a method for the prophylaxis or treatment of Opthalamic Disorders comprising administering to a patient in need thereof an effective amount of a compound of formula (I") as defined in (37), a compound of formula (I" 1 ) as defined in (38) or a compound according to any one of (2) to (18) and (20) to (34) or a pharmacologically acceptable salt 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 (2) to (18) and (20) to (34), a compound of formula (I") as defined in (37), a compound of formula (I'") as defined in (38) or a pharmacologically acceptable salt 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 (SNRIs), 5-HT antagonists, alpha-1 adren
  • Preferred pharmaceutical combinations include:
  • 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 (2) to (18) and (20) to (34), a compound of formula (I") as defined in (37), a compound of formula (F") as defined in (38) or a pharmacologically acceptable salt 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 (2) to (18) and (20) to (34), a compound of formula (I") as defined in (37), a compound of formula (T") as defined in (38) or a pharmacologically acceptable salt 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, ⁇ /-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonist
  • the combinations of preferred option (83) are of particular use in the prophylaxis or treatment of lower urinary tract disorders.
  • the combinations of preferred option (84) are of particular use in the prophylaxis or treatment of pain.
  • a fifty-first aspect of the present invention there is provided use of at least one compound according to any one of (2) to (18) and (20) to (34), a compound of formula (I") as defined in (37), a compound of formula (I"') as defined in (38) or a pharmacologically acceptable salt or prodrug thereof and at least one compound selected from the group consisting of muscarinic receptor antagonists, ⁇ 3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel ⁇ 2 ⁇ delta ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 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
  • a fifty-second aspect of the present invention there is provided use of at least one compound according to any one of (2) to (18) and (20) to (34), a compound of formula (I") as defined in (37), a compound of formula (I"') as defined in (38) or a pharmacologically acceptable salt or prodrug thereof and at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel ⁇ 2 ⁇ delta ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, ⁇ /-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,
  • the alkyl groups in the definitions of R1', Rf", R2, R2 ⁇ R2", R2" ⁇ R3, R3 ⁇ R3", R3"', R4, R4 ⁇ R4", R4" ⁇ R5, R5 ⁇ R5", R5'", R6, R6 ⁇ R6", R6" ⁇ R7, R7 1 , R7", R7"', R8, R8', R8", R8'", R9, R9', R9", R9 m , R10, R10 ⁇ R10", R10'", R11 , R11', R11", R11'", R12, R12', R12" and R12'” 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, /- propyl groups and f-butyl groups.
  • the cycloalkyl groups in the definition of R1 ⁇ Rr", R2, R2", R11 , R11", R12 and R12" are preferably cycloalkyl groups having from 3 to 14 carbon atoms; the cycloalkyl group can be in a single ring or can be a bridged ring system.
  • the cycloalkyl groups more preferably have from 5 to 10 carbon atoms, and are most preferably cyclopentyl, cyclohexyl, cycloheptyl and adamantyl groups.
  • the aryl groups in the definitions of R1', RT 1 R2, R2 1 , R2", R2 1 ", R3, R3 ⁇ R3", R3" ⁇ R4, R4 ⁇ R4", R4'", R5, R5', R5", R5'", R6, R6', R6", R6'", R7, R7 1 , R7", R7"', R8, R8 1 , R8", R8'", R9, R9', R9", R9'", R10, R10 1 , R10", R10"', R11 , R11 1 , R11", R1 T, R12, R12', R12" and R12'" are preferably aryl groups which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms,
  • 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, 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 or a diethoxyamino group.
  • the aralkyl groups in the definitions of R1 and R1" are preferably alkyl groups as defined above which are substituted with one or more aryl groups as defined above, and are more preferably benzyl and phenethyl groups which may optionally be 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 optionally be substituted with a methoxy group or a hydroxyl group.
  • the heteroaryl groups in the definitions of RT, RV", R2, R2 ⁇ R2", R2" ⁇ R3, R3 ⁇ R3", R3"', R4, R4', R4", R4'", R5, R5', R5", R5"', R6, R6 ⁇ R6", R6" ⁇ R7, R7', R7", R7" ⁇ R8, R8', R8", R8" ⁇ R9, R9 ⁇ R9", R9" 1 , R10, R10', R10", R10"', R11 , R11 ⁇ R11", R1 f", R12, R12 1 , R12" and R12"' are preferably 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms.
  • Examples include fury I, thienyl, pyrrolyl, azepinyi, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1 ,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups. Most preferred is pyridyl.
  • the cycloalkylalkyl groups in the definition of RV and RV" are preferably alkyl groups as defined above which are substituted with cycloalkyl groups as defined above. More preferably, they are alkyl groups having from 1 to 4 carbon atoms which are substituted with cycloalkyl groups having from 3 to 7 carbon atoms.
  • the aminoalkyl groups in the definition of RV and RV are preferably alkyl 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 RV and RV" 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, R2", R3, R3 ⁇ R3", R3 J ", R4, R4 1 , R4", R4"', R5, R5 ⁇ R5", R5'", R6, R6 ⁇ R6", R6"', R11 , R1 V, R1 V, R1 V", R12, R12', R12", R12'", Y 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 haloalkoxyl groups in the definitions of R2, R2", R3, R3 ⁇ R3", R3"', R4, R4 ⁇ R4", R4'", R5, R5 ⁇ R5", R5"', R6, R6 ⁇ R6", R6" ⁇ R11 , R1 V, R1 V, R1 V", R12, R12 ⁇ R12" and R12'" are preferably alkoxy groups having from 1 to 6 carbon atoms that are substituted with at least 1 halogen atom, more preferably alkoxy groups having from 1 to 4 carbon atoms with from 1 to 6 fluorine or chlorine atoms and most preferably trifluoromethoxy or 1 ,1 ,2,2-tetrachloroethoxy groups.
  • the monoalkylamino groups in the definitions of R2, R2", R3, R3 ⁇ R3", R3" ⁇ R4, R4', R4", R4" ⁇ R5, R5', R5", R5"', R6, R6', R6" and R6"' are preferably amino groups which are substituted with one alkyl group as defined above, and are more preferably methylamino, ethylamino or t-butylamino groups.
  • dialkylamino groups in the definitions of R2, R2", R3, R3 1 , R3", R3" ⁇ R4, R4 ⁇ R4", R4" ⁇ R5, R5', R5", R5 1 ", R6, R6', R6" and R6"' 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 nitrogen-containing heterocyclic groups formed from R11 or R12 or R11" and R12" together with the nitrogen atom to which the groups are attached are 4- to 8- membered saturated or partially unsaturated heterocylic groups containing at least one nitrogen atoms, said groups optionally containing one or more nitrogen, oxgen or sulphur atoms, and are more preferably preferably morpholinyl, piperazinyl or pyrrolidinyl groups.
  • the aminoacid residues in the definition of Y and 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 aryloxy groups in the defintinion Of RH 1 R11', R11", R11" ⁇ R12, R12 1 , R12" and R12 1 " are aryl groups as defined above attached to an oxygen atom and are preferably phenyloxy groups.
  • the haloalkyl groups in the definitions of R3, R3 ⁇ R3", R3" 1 , R4, R4 ⁇ R4", R4"', R5, R5 ⁇ R5", R5"', R6, R6', R6", R6" ⁇ R10, R10', R10" and R10'” are preferably alkyl groups as defined above which are substituted with one or more halogen atoms.
  • they are alkyl groups having from 1 to 4 carbon atoms that are substituted with at least one chlorine or fluorine atom and most preferably they are chloromethyl groups, trichloromethyl groups, trifluoromethyl groups and tetrafluoroethyl groups.
  • the alkoxycarbonyl groups in the definitions of R3, R3 1 , R3", R3"', R4, R4', R4", R4" ⁇ R5, R5', R5", R5" ⁇ R6, R6', R6" and R6"' are preferably carbonyl groups substituted with alkoxy groups as defined, and are more preferably methoxycarbonyl or ethoxycarbonyl groups.
  • the hydroxyalkyl groups in the definitions of R3, R3', R3", R3" ⁇ R4, R4 ⁇ R4", R4'", R5, R5 ⁇ R5", R5 1 ", R6, R6', R6" and R6"' are preferably alkyl groups as defined above which are substituted with one or more hydroxyl groups. More preferably, they are alkyl groups having from 1 to 4 carbon atoms that are substituted with at least one hydroxyl groups and most preferably they are hydroxymethyl groups, and 2-hydroxyethyl groups.
  • the acylamino groups in the definitions of R2, R2 R3, R3', R3", R3"', R4, R4 ⁇ R4", R4"', R5, R5', R5", R5" ⁇ R6, R6', R6” and R6 1 " 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 alkoxycarbonylamino groups in the definitions of R3, R3', R3", R3"', R4, R4 1 , R4", R4"', R5, R5', R5", R5'", R6, R6', R6" and R6'” 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, R2", R3, R3', R3", R3"', R4, R4 1 , R4", R4"', R5, R5', R5", R5" ⁇ R6, R6', R6", R6'", R11 , R11 ', R11", R11'", R12, R12', R12" and R12'” are preferably sulphonyl groups which are substituted with an alkyl group as defined above and are more preferably a methylsulphonyl or ethylsulphonyl group.
  • the alkylsulphiny! groups in the definitions of R2, R2", R11 , R11 ⁇ R11", R11 1 ", R12, R12', R12" and R12'” are preferably sulphinyl groups which are substituted with an alkyi group as defined above and are more preferably a methylsulphinyl or ethyisulphinyl group.
  • the arylsulphonyl groups in the definitions of R3, R3', R3", R3" ⁇ R4, R4 ⁇ R4", R4" ⁇ R5, R5', R5", R5'", R6, R6', R6" and R6"' 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 arylsulphonylamino groups in the definitions of R3, R3 ⁇ R3", R3" 1 , R4, R4', R4", R4"', R5, R5', R5", R5" 1 , R6, R6', R6" and R6"' 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 naphthylsulphonylamino group.
  • salts of the compound having the formulae (I), (I 1 ), (I") and (V") described above are not specifically 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 salt 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, triethyl
  • the compounds of formulae (I), (I'), (I") and (I"') 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 formulae (I), (I 1 ), (I") and (I 1 ") wherein a carboxyl moiety of the compound having the formulae (I), (I 1 ), (I") and (T") is esterified.
  • the pharmacologically acceptable esters are not particularly restricted, and can be selected by a person with an ordinary skill in the art. In the case of said esters, it is preferable that such esters can be cleaved by a biological process such as hydrolysis in vivo.
  • the group constituting the said esters can be, for example, a C 1 -C 4 alkoxy C 1 -C 4 alky! 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 CrC 4 alkoxy C 1 -C 4 alkyl group such as 2-methoxyethoxymethyl; a C 6 -Ci 0 aryloxy Ci-C 4 alkyl group such as phenoxymethyl; a halogenated C 1 -C 4 alkoxy C 1 -C 4 alky! group such as methoxyethyl, 1- ethoxye
  • the compounds of formulae (I), (I'), (I") and (I"') 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.
  • substituents for which there exist isosteres
  • compounds containing such isosteres in place of said substituents also form a part of the present invention.
  • the compounds of formulae (I), (I 1 ), (I") and (I"') or pharmacologically active prodrugs or salts thereof contain a carboxyl group, this can be replaced with a tetrazolyl group.
  • Hydrates or solvates of the compounds of formulae (I), (l ( ), (I") and (I'"), prodrugs thereof and pharmacologically acceptable salts thereof can also be used and form a part of the invention.
  • Some compounds of formulae (I), (I 1 ), (I") and (I 1 ") and their pharmacologically acceptable salts or prodrugs thereof of the present invention may have one or more asymmetric carbons, and optical isomers (including diastereomers) due to the presence of asymmetric carbon atom(s) in the molecule can exist. Furthermore, some of the compounds of formulae (I), (I'), (I") and (I 1 ") and their pharmacologically acceptable salts 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 formulae (I), (P), (I") and (I 1 ") of the present invention, or pharmacologically acceptable salt 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 formulae (I), (I 1 ), (I") and (I 1 ") or a pharmacologically acceptable salt 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. light anhydrous silicic acid, synthetic aluminium silicate or magnesium aluminium metasilicate, phosphates, e.g. calcium phosphate, carbonates, e.g. calcium carbonate, or sulfates, e.g. calcium sulfate.
  • silicate derivatives e.g. light anhydrous silicic acid
  • synthetic aluminium silicate or magnesium aluminium metasilicate phosphates, e.g. calcium phosphate
  • carbonates e.g. calcium carbonate
  • sulfates e.g. calcium sulfate.
  • 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 chloroblitanol, 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 chloroblitanol, 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. ethanol, propylene glycol or polyethylene glycol).
  • an auxiliary solvent e.g. ethanol, propylene glycol or polyethylene glycol.
  • Such a solution or suspension may also contain an antiseptic (e.g. benzalkonium chloride), solubilizing agent (e.g.
  • 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 formulae (I), (I'), (I") and (I'") or pharmacologically acceptable salt 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 activators of KCNQ, BKCa channels, Kv channels and KATP channels
  • potassium channel activators include KW-7158, NS-8 and retigabine.
  • Examples of calcium channel inhibitors include ziconotide and NMED-160.
  • sodium channel blockers examples include lidocaine, lamotrigine, VX-409, ralfinamide and carbamazepine.
  • SNRIs serotonin and norepinephrine reuptake inhibitors
  • 5-HT antagonists including 5-HT1a antagonists and 5-HT3 antagonists.
  • Examples of ⁇ -1 adrenoceptor antagonists include tamsulosin.
  • tricyclic antidepressants include amitriptyline, amoxapine, clomipramine, dosulepin (dothiepin), doxepin, imipramine, lofepramine, nortriptyline, and trimipramine.
  • Examples of /V-methyi-D-aspartate (NMDA) receptor antagonists include ketamine, memantine, amantadine, AVP-923, NP-1 and EVT-101.
  • Examples of cannabinoid receptor agonists include GW-1000 (Sativex) and KDS-2000.
  • Anticonvulsants examples include lacosamide, carbamazepine, topiramate, oxcarbazepine and levetiracetam
  • aldose reductase inhibitors include tolrestat, zopolrestat, zenarestat, epalrestat, sorbinil, AS-3201 , fidarestat, risarestat, ponalrestat and alrestatin.
  • opioids e.g. mu opioid agonists
  • opioids include fentanyl and tapentadol.
  • alpha adrenoceptor agonists include ai-adrenoceptor agonists such as ethoxamine, phenylephrine, oxymetazoline, tetrahydralazine and xylometazoline and a 2 -adrenoceptor agonists such as clonidine, guanabenz, guanfacine and ⁇ -methyldopa.
  • ai-adrenoceptor agonists such as ethoxamine, phenylephrine, oxymetazoline, tetrahydralazine and xylometazoline
  • 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 include A-85380, tebanicline, ABT-366833, ABT-202, ABT-894, epibatidine analogs and SIB-1663.
  • synaptic vesicle protein 2A ligands examples include brivaracetam.
  • Examples of the administration form of the combination of the present invention are the same as given above for the compounds of general formulae (I), (I 1 ), (I") and (I 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 formulae (I), (I 1 ), (I") and (I"') or a pharmacologically acceptable salt thereof with lidocaine could be administered transdermally by means of a patch while a combination with ziconotide could be administered transmucosally.
  • analogues of the present invention can be synthesised using standard methods and principles as illustrated in the general schemes below:
  • Method B Oxalyl chloride (1.0eq) was added to the required indole (1.0eq) in Et 2 O (1.5ml/mmol) at 0 0 C. The reaction was allowed to reach room temperature and stirred for 4hr after which time the precipitate was isolated by filtration. The solid was dissolved in 2 M aqueous NaOH solution (1.5ml/mmol) and the reaction mixture was stirred at room temperature for 16hr. The basic solution was washed with Et 2 O (1.5ml/mmol) and acidified to pH 1 using 6 M aqueous HCI solution.
  • Oxalyl chloride (1.0eq) was added to the required indole (1.0eq) in Et 2 O (1.5ml/mmol) at 0 0 C. The reaction was allowed to reach room temperature and stirred 4hr after which time the desired indole-3-glyoxyl chloride was either isolated by filtration or by concentration of the reaction mixture followed by trituration of the residue with Et 2 O.
  • Esters (Ia) can be synthesised by the protocol outlined in the first step of Reaction Scheme 3 below, and can be converted to the corresponding acid (IB), using standard acid deproction methodology.
  • Amides of structure (IC) can be synthesised by conventional amine coupling conditions from the acid (IB).
  • Method D The required amine (1.0 - 5.0eq) and if required a tertiary base (2.0 - 3.0eq) were added to the required indole-3-glyoxyl chloride (1.0eq) in tetrahydrofuran (5ml/mmol) at 0 0 C and the reaction was allowed to reach room temperature and stirred for 16hr. The solvent was removed under reduced pressure, and the residue was dissolved in EtOAc (20ml/mmol).
  • Method E The required amine (1.0 - 1.5eq) and saturated aqueous NaHCO 3 solution (30ml/mmol) were added to a suspension of the required indole-3- glyoxyl chloride (1.0eq) in toluene (30ml/mmol) at 0 0 C and the reaction mixture was allowed to reach room temperature and stirred vigorously for 16hr. The phases were separated and the aqueous phase was extracted with EtOAc (3 x 30ml/mmol). The combined organic layers were washed with brine (30ml/mmol), dried over MgSO 4 and concentrated under reduced pressure to provide the desired amide. If required the product was purified by either trituration with an appropriate solvent, flash column chromatography or by preparative HPLC.
  • Method F The required amine (1.5eq) and a tertiary base (3.0eq) were added to the required indole-3-glyoxyl chloride (1.0eq) in CH 2 Cb (3 - 5ml/mmol) at 0 0 C and the reaction was allowed to reach room temperature and stirred for 16hr.
  • the reaction mixture was diluted with CH 2 CI 2 (30ml/mmol) and washed with 1 M aqueous HCI solution (15ml/mmol), saturated aqueous NaHCO 3 solution (15ml/mmol) and brine (10ml/mmol).
  • the organic phase was dried over MgSO4 and concentrated under reduced pressure to provide the desired amide. If required the product was purified by either trituration with an appropriate solvent, flash column chromatography or by preparative HPLC.
  • Method G 2 M Aqueous NaOH solution (25ml/mmol) was added to the desired ethyl ester (IA) (1.0eq) and the reaction mixture was stirred at room temperature for 16hr. The reaction mixture was washed with Et 2 O (50ml/mmol) and the aqueous phase was acidified to pH 1 using 6 M aqueous HCI solution. The product was extracted with EtOAc (3 x 20ml/mmol) and the combined organic extracts were dried over Na 2 SO 4 and concentrated under reduced pressure to provide the crude product. Purification by preparative HPLC provided the desired pure acid (IB). Reaction Scheme 4
  • Secondary amines 2 can be prepared by the reductive amination of aldehydes and ketones 1a, 1b or 1c with a primary amine. The secondary amines can be subsequently reacted with indole-3-glyoxylyl chlorides to give indole-3- glyoxylamides (Ia).
  • 6-Methoxy-indoleglyoxyl chloride (3.95g, 0.017mol), aqueous sodium bicarbonate (290ml) were added to intermediate 7 (0.106mol), in toluene (290ml).
  • the reaction was stirred at room temperature for 1 hr.
  • the product was extracted with ethyl acetate.
  • the organic layers were combined, and washed with brine.
  • the solution was stirred with activated charcoal (5g) for 20 minutes before being filtered through celite and concentrated in vacuo.
  • the aqueous phase was further extracted with dichloromethane (2 x 50ml) and the combined organic extracts were and the organic layers were combined and dried over MgSO 4 and filtered. The solvent was removed in vacuo and the crude intermediate 43 was used without further analysis or purification.
  • 6-Methoxy-indole-3-glyoxylyl chloride (1.5g, 6.5mmol) was added to a mixture of intermediate 43 in toluene (20ml) and aqueous sodium bicarbonate (saturated, 20ml). The reaction mixture was stirred overnight at room temperature. Ethyl acetate (100ml) was added and any remaining solids were removed by filtration. The phases were separated and the organic phase was successively washed with 1M NaOH (30ml), water (30ml), 1 M HCI (30ml), water (30ml) and brine (30ml). The organic phase was stirred with activated charcoal and MgSO 4 for 1 hr, filtered and concentrated. The residue was crystallised using dichloromethane and methanol to provide intermediate 42 as pale yellow crystals (834mg, 37% yield over two steps).
  • 6-Methoxy-indole-3-glyoxylyl chloride (1.5g, 6.5mmol) was added to a mixture of intermediate 51 in toluene (20ml) and aqueous sodium bicarbonate (saturated, 20ml). The reaction mixture was stirred overnight at room temperature. Ethyl acetate (100ml) was added and any remaining solids were removed by filtration. The phases were separated and the organic phase was successively washed with 1M NaOH (30ml), water (30ml), 1 M HCI (30ml), water (30ml) and brine (30ml). The organic phase was stirred with activated charcoal and MgSO 4 for 1hr, filtered and concentrated.
  • Residual starting amine was removed from the desired intermediate 54 and bis-alkylated amine by silica flash column chromatography using dichloromethane and methanol.
  • Intermediate 54 was used as a mixture with the bis-alkylated by-product in the next step.
  • 6-Methoxy-indole-3-glyoxylyl chloride (384mg, 1.6mmol) was added to a mixture of intermediate 54 in toluene (5ml) and aqueous sodium bicarbonate (saturated, 5ml). The reaction mixture was stirred overnight at room temperature. Ethyl acetate (50ml) was added and any remaining solids were removed by filtration. The phases were separated and the organic phase was successively washed with 1 M NaOH (15ml), water (15ml), 1 M HCI (15ml), water (15mi) and brine (15ml). The organic phase was stirred with activated charcoal and MgSO 4 for 1hr, filtered and concentrated.
  • Trifluoroacetic acid anhydride (2.8ml, 20mmo!) was added to a solution of N- carbamoylmethyl- ⁇ /-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetamide (1.46g, 3.9mmol) in tetrahydrofuran (60ml) containing pyridine (2.8ml, 20mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was triturated with dichloromethane. The nitrile 58 was isolated by filtration to provide a beige solid (850mg, 62% yield) which was used without further purification.
  • 6-Fluoroindoleglyoxyl chloride (8g, 35.6mmol) in tetrahydrofuran (100ml) was added to intermediate 9 (5.4g, 17.8mmol) and DIPEA (12.5ml, 71.3mmol) in tetrahydrofuran (100ml) at 0 °C. This was then left to warm to room temperature and stirred for 16hr. The solvent was removed in vacuo and quenched with NaHCO 3 (saturated, 200ml) and EtOAc (200ml) was then added. The resulting emulsion was filtered through celite and the product was extracted with EtOAc (3 x 100ml). The combined organics were dried over Na 2 SO 4 and concentrated in vacuo.
  • the crude product was purified by silica flash column chromatography eluting with 5:1 Hexane: EtOAc, and increasing the polarity to EtOAc to yield the product, ⁇ cyclohexylmethyl-t2-(6-fluoro-1 H-indol-3-yl)-2-oxo-acetyl]-amino ⁇ -acetic acid tert-butyl ester 63 (5.76g, 78% yield).
  • terf-Butyl 3-(aminomethyl)benzylcarbamate 74 (641 mg, 2.71 mmol) was added to ethyl 2-cyclohexyl-2-oxoacetate 75 (500mg, 2.71 mmol) in DCM (5ml) with some 4A MS. The reaction was left to stir at room temperature for 16hr. Acetic acid (233 ⁇ l_, 4.07mmol) was then added and the reaction left to stir for 4hr. STAB (690mg, 4.07mmol) was then added and the reaction left to stir at room temperature for 16hr. The reaction was quenched with NaHCO 3 (saturated, 10ml) and the product extracted with DCM (3 x 15ml).
  • CDI (59mg, 0.36mmol) was added to ⁇ [3-(tert-butoxycarbonylamino-methyl)- benzyi]-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino ⁇ -cyclohexyl-acetic acid 77 (180mg, 0.33mmol) in DMF (3ml) at 50 0 C. The reaction was stirred for 30 minutes and then cooled to room temperatute before adding aqueous ammonia (20ml) dropwise. The reaction was stirred for a further 16hr. The solvent was removed in vacuo to yield a brown oil. DCM (4ml) was added followed by the addition of TFA (1ml) at room temperature.
  • Indoleglyoxyl chloride 38mg, 0.18mmol was added to a stirring solution of tert- butyl 3-((1 -(ferf-butylamino)-i -oxopropan-2-ylamino)methyl)benzylcarbamate 81 (55mg, 0.15mmol) and triethylamine (42 ⁇ L, 0.30mmol) in tetrahydrofuran (1 ml).
  • the reaction was stirred at room temperature for 16hr before being quenched with 2M NaOH (10ml) and the product extracted with EtOAc (3 x 10ml). The combined organic layers were dried over Na 2 SO 4 and the concentrated in vacuo to yield an off-white solid.
  • ferf-butyl (3- ⁇ [(cyclohexylmethyl)amino]methyl ⁇ benzyl)carbamate 89 (440mg, 2.12mmol) was added to a solution of indole-3-glyoxylyl chloride (470mg, 1.41mmol) and triethylamine (400 ⁇ l, 2.83mmol) in tetrahydrofuran (10ml). The reaction was stirred at room temperature overnight before being quenched with 2M NaOH (20ml). The product was extracted with EtOAc (3 x 50ml) and the combined organic layers were dried over Na 2 SO 4 , and concentrated in vacuo to yield a yellow solid.
  • the brown oil was dissolved in DCM (10ml) before the addition of triethylamine (560 ⁇ l, 2mmol) and indole-3-glyoxylyl chloride (415mg, 2mmol). The reaction was stirred at room temperature for 24hr. The solvent was removed in vacuo and the reaction quenched with water (20ml). The product was extracted with EtOAc (3 x 20ml), and the combined organic layers were dried over Na 2 SO 4 , and concentrated in vacuo to yield a brown oil which was dissolved in MeOH (5ml) and 2M NaOH (5ml) added. The reaction was stirred at room temperature for 16hr. The solvent was removed from the reaction before adding water (10ml).
  • the crude reaction mixture was purified by a column chromatography eluting with DCM/MeOH (8:2) to yield N- (cyclohexylmethyl)-2-(1 H-indol-3-yl)- ⁇ /-methyl-2-oxoacetamide (254mg, 47%) 104.
  • the product was purified by column chromatography eluting with DCM 9:1 MeOH/NH 3 and further chromatography eluting with hexane:ethyl acetate (1 :1) to yield ⁇ /-cyclohexyl-2-(6-methoxy-1 H-indol-3-yl)- ⁇ /-methyl-2-oxoacetamide 110 (145mg, 26%).
  • H-Om(Z)-O 1 Bu HCI (638mg, 1.78mmol) and triethylamine (495 ⁇ l, 3.56mmol) in methanol (1OmI) was added to cyclohexane carboxaldehyde (199mg, 1.78mmol) at O 0 C. The reaction was warmed to room temperature and stirred for 3hr before adding STAB (752mg, 3.56mmol) portion-wise. The reaction was stirred overnight before being concentrated in vacuo. The reaction mixture was partitioned between ethyl acetate (60ml) and water (60ml). The organic layer was collected and washed with aqueous sodium bicarbonate (40ml), brine (40ml), dried (MgSO 4 ) and concentrated in vacuo to yield 116 (700mg, 94%).
  • PBS Ca 2+ /Mg 2+ free phosphate-buffered saline
  • Ganglia were washed in culture medium, Dulbecco's Minimum essential medium (DMEM), supplemented with fetal calf serum (10%, Gibco), penicillin/strepromycin and glutamine (Glutamax, Gibco). Cells were dispersed by trituration and plated on poly-L- lysine-coated 35-mm dishes (BD Bioscience). Cells were kept in culture in a humidified atmosphere (37 0 C, 5% CO 2 ) for up to 4 days for electrophysiological recordings. Unless otherwise noted, all reagents were purchased from Sigma-Aldrich.
  • Barium currents carried by calcium channels were recorded using the whole- cell configuration of the patch-clamp technique. All experiments were carried out at room temperature. Cells were bathed in an external solution containing, in mM: TEA-CI, 140; BaCI 2 , 5; MgCI 2 , 1; HEPES, 10; pH 7.3 adjusted with TEA-OH. Ba 2+ was used as a charge carrier to prevent the run-down caused by Ca 2+ -activated inactivation of Ca 2+ channels. Patch pipettes had a resistance of 2-4 M ⁇ , when filled with a solution containing, in mM: CsCI, 140; EGTA, 5; MgCI 2 , 2; HEPES, 10; pH adjusted to 7.3 with CsOH.
  • Electrophysiological recordings were generated and acquired with a patch- clamp amplifier (Axopatch 200B, or Multiclamp 7; Molecular devices) connected to a personal computer. Online and offline analysis was carried out using the pClamp software suite (v.9, Molecular Devices). Compounds were all prepared from 100 mM stocks in 100% dimethyl sulfoxide (DMSO) and further diluted in external solution to achieve the desired final concentration. Final DMSO concentration was always ⁇ 0.1 %. For the assessment of activity of the compounds, only cells with a membrane capacitance (Cm) ⁇ 40 pf were used, as the Ca2+ current in these cells is carried mostly through N- type/Cav2.2 channels.
  • DMSO dimethyl sulfoxide
  • Cell membrane potential was held at -70 mV and currents were elicited by a series of 100-ms steps to 0 mV, at a frequency of 0.1 Hz. After the establishment of a steady baseline current, the compound was applied to the bath. When the block induced by the compound reached a steady level, the frequency was then increased to 0.5 Hz, to assess use- dependence.
  • step depolarizations were stopped and cell membrane potential was kept at -70 mV for 100-120 s, after which 0.1 Hz stimulation (100 ms, 0 mV) was elicited, to assess recovery of the block, ⁇ -conotoxin GVIA (100 nM; Alomone labs) was added at the end of the experiment to quantify the remaining N-type current. Selectivity of the compounds over non-N-type currents was studied using similar stimulation protocols, in a bath solution containing ⁇ -conotoxin GVIA (I OO nM).
  • Nitrix oxide modulates Ca(2+) channels in dorsal root ganglion neurons innervating rat urinary bladder J Neurophysiol 86, 304-311

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Abstract

L'invention porte sur des composés représentés par la formule (I), dans laquelle R1 représente hydrogène, hydroxyle ou aralkyle; R2 représente un alkyle, un aryle ou un hétéroaryle facultativement substitué (lesdits substituants sont choisis parmi hydroxyle, alcoxyle, haloalcoxyle, aryle, hétéroaryle, cycloalkyle, amino, monoalkylamino, dialkylamino, alkylsulfonyle, alkylsulfinyle, alkylsulfonylamino, acylamino, les groupes hétérocycliques saturés ou partiellement insaturés et les groupes représentés par la formule COY); W est choisi parmi l'oxygène, le soufre, les groupes représentés par la formule NR7, dans laquelle R7 représente hydrogène, alkyle, aryle ou hétéroaryle et des groupes représentés par la formule CR8R9, dans laquelle R8 et R9 représentent hydrogène, alkyle, aryle ou hétéroaryle; et X est choisi parmi l'azote et les groupes représentés par la formule CR10, dans laquelle R10 représente hydrogène, alkyle, aryle, hétéroaryle, halogène ou haloalkyle. Lesdits composés inhibent l'interaction entre les canaux Cavx et les protéines Cavβ et s’utilisent dans le traitement et la prévention d'un certain nombre de maladies et d’affections dont la douleur et les troubles des voies urinaires inférieures.
PCT/GB2009/051242 2008-09-25 2009-09-23 Modulateurs des canaux ioniques calciques et leurs utilisations Ceased WO2010035032A1 (fr)

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
US8846951B2 (en) 2009-05-22 2014-09-30 Abbvie Inc. Modulators of 5-HT receptors and methods of use thereof
US9212139B2 (en) 2010-06-16 2015-12-15 Purdue Pharma, L.P. Aryl substituted indoles and their use as blockers of sodium channels
US9879033B2 (en) 2009-05-22 2018-01-30 AbbVie Deutschland GmbH & Co. KG Modulators of 5-HT receptors and methods of use thereof
US10227323B2 (en) 2013-09-20 2019-03-12 Biomarin Pharmaceutical Inc. Glucosylceramide synthase inhibitors for the treatment of diseases
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity

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EP0490263A1 (fr) * 1990-12-07 1992-06-17 Syntex (U.S.A.) Inc. Dérivés d'alpha-oxoacétamides
US20030096825A1 (en) * 2001-04-25 2003-05-22 Tao Wang Indole, azaindole and related heterocyclic amidopiperazine derivatives
WO2006052712A1 (fr) * 2004-11-08 2006-05-18 Baxter International Inc. Compositions nanoparticulaires d'inhibiteurs de la tubuline
WO2006099256A2 (fr) * 2005-03-11 2006-09-21 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison a l'atp
WO2007044560A2 (fr) * 2005-10-06 2007-04-19 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison à l’atp
WO2008019357A2 (fr) * 2006-08-07 2008-02-14 Ironwood Pharmaceuticals, Inc. Composés d'indole
WO2009019508A1 (fr) * 2007-08-03 2009-02-12 Lectus Therapeutics Limited Modulateurs des canaux calciques et leurs utilisations
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

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Publication number Priority date Publication date Assignee Title
EP0490263A1 (fr) * 1990-12-07 1992-06-17 Syntex (U.S.A.) Inc. Dérivés d'alpha-oxoacétamides
US20030096825A1 (en) * 2001-04-25 2003-05-22 Tao Wang Indole, azaindole and related heterocyclic amidopiperazine derivatives
WO2006052712A1 (fr) * 2004-11-08 2006-05-18 Baxter International Inc. Compositions nanoparticulaires d'inhibiteurs de la tubuline
WO2006099256A2 (fr) * 2005-03-11 2006-09-21 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison a l'atp
WO2007044560A2 (fr) * 2005-10-06 2007-04-19 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison à l’atp
WO2008019357A2 (fr) * 2006-08-07 2008-02-14 Ironwood Pharmaceuticals, Inc. Composés d'indole
WO2009019508A1 (fr) * 2007-08-03 2009-02-12 Lectus Therapeutics Limited Modulateurs des canaux calciques et leurs utilisations
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

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8846951B2 (en) 2009-05-22 2014-09-30 Abbvie Inc. Modulators of 5-HT receptors and methods of use thereof
US9879033B2 (en) 2009-05-22 2018-01-30 AbbVie Deutschland GmbH & Co. KG Modulators of 5-HT receptors and methods of use thereof
US9212139B2 (en) 2010-06-16 2015-12-15 Purdue Pharma, L.P. Aryl substituted indoles and their use as blockers of sodium channels
US10202344B2 (en) 2010-06-16 2019-02-12 Purdue Pharma L.P. Aryl substituted indoles and the use thereof
US10227323B2 (en) 2013-09-20 2019-03-12 Biomarin Pharmaceutical Inc. Glucosylceramide synthase inhibitors for the treatment of diseases
US10927092B2 (en) 2013-09-20 2021-02-23 Biomarin Pharmaceutical Inc. Glucosylceramide synthase inhibitors for the treatment of diseases
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
US11944622B2 (en) 2018-10-05 2024-04-02 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity

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