WO2009133387A1 - Indole- 3 -glyoxylamide derivatives for use as calcium ion channel modulators - Google Patents

Indole- 3 -glyoxylamide derivatives for use as calcium ion channel modulators Download PDF

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WO2009133387A1
WO2009133387A1 PCT/GB2009/050422 GB2009050422W WO2009133387A1 WO 2009133387 A1 WO2009133387 A1 WO 2009133387A1 GB 2009050422 W GB2009050422 W GB 2009050422W WO 2009133387 A1 WO2009133387 A1 WO 2009133387A1
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groups
group
carbon atoms
indol
pharmacologically acceptable
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PCT/GB2009/050422
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French (fr)
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Nawaz Mohammed Khan
Svenja Burckhardt
Julie Elaine Cansfield
Raymond John Boffey
Richard Edward Armer
Ngoc-Tri Vo
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Lectus Therapeutics Limited
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to ion channel modulators, and more particularly to compounds which inhibit the interaction between the pore-forming ( ⁇ ) subunits of Cav voltage-gated calcium channels and accessory (Cav ⁇ subunit) proteins.
  • Voltage-dependent calcium (Cav) channels conduct calcium 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 (Cavi .2), as well as neuroendocrine release (Cav1 ,3 and Cav1.4). Cav2.x channels are important in neurotransmitter release (Cav2.1 and Cav2.2) and controlling neuronal excitability (Cav2.3). Cav channels which belong to the Cavi .x and Cav2.x families are defined by their threshold for activation as high threshold and are also known as L- or N-type channels respectively. L-type Cav channels are pharmacologically defined by their sensitivity to inhibition by dihydropyridines. Cav channels which belong to the Cav3.x class (Cav3.1 , Cav3.2, Cav3.3) are activated at much lower membrane voltages and are defined as low threshold or T-type calcium channels.
  • Cav channels are composed of an ⁇ 1 subunit, which forms the pore-region of the channel through which Ca 2+ ions can flow. conserveed transmembrane and pore domains of the ⁇ 1 subunits are less than 40% identical between the related families (Cav1.x : Cav2.x : Cav3.x) but greater than 70% identical within a family' which leads to difficulty in identifying compounds that pharmacologically discriminate between these related Cav channel subtypes.
  • Cav channel ⁇ subunits are intracellular proteins endogenously associated with Cav channel ⁇ 1 subunits, which finely tune many of their functional and electrophysiological / kinetic properties".
  • Ten different genes encode voltage-gated Cav channel alpha 1 subunits 1 ".
  • Cav ⁇ subunits (Cav ⁇ i , Cav ⁇ 2, Cav ⁇ 3, Cav ⁇ 4) have been shown to interact and regulate the functional activity of Cavlx, Cav2.x and Cav3.x channels iwi ' vii ' viii .
  • 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 ⁇ x ).
  • cytosolic accessory (Cav ⁇ ) proteins that are able to modulate the function of ion channel pore-forming domains (for review, see ⁇ x ).
  • 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 x ⁇ v 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 xv .
  • Mice lacking the N-type Cav ⁇ 3 subunit show reduced levels of Cav2.2 channels with altered sensitivity to inflammatory pain when compared to wild-type xv ⁇ .
  • Cav ⁇ 3 subunits hyperpolarise the voltage-dependence of activation and also hyperpolarise the voltage-dependence of steady-state inactivation of Cav2.2 channelsTM 1 'TM 1 ". 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 x ⁇ x .
  • 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 ⁇ .
  • 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 1 the synthetic analogue of ⁇ -conotoxin-MVIIA, is effective in patients with PHN, as well as phantom-limb pain, and HIV-related neuropathic pain who are refractory to opioidsTM.
  • Pregabalin received Food and Drug Administration (FDA) approval on December 30, 2004, for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN) and PHN. Moreover, pregabalin is approved for use as adjunctive therapy for adult patients with partial onset seizuresTM 1 '' 0 '" 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 oc 2 - ⁇ .
  • Pregabalin is six-times more potent than gabapentin in binding affinity to the ⁇ , 2 - ⁇ voltage-gated calcium channel*TM.
  • the manufacturer states that 50 mg of pregabalin is approximately equal to 300 mg of gabapentin.
  • pregabalin and gabapentin alter channel function without complete blockade of the calcium channel resulting in virtually no change in systemic blood pressure or coronary blood flow changes.
  • Overactive bladder is an unmet medical need. Symptoms of overactive bladder include increased urinary frequency, urgency, nocturia (the disturbance of 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 t yp e ⁇ v ⁇ , ⁇ v ⁇ n , xx i x , x ⁇ x anc
  • 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.
  • 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.
  • Methodabolic Disorders such as diabetes (including diabetic retinopathy, diabetic nephropathy and diabetic neuropathy), insulin resistance/insensitivity and obesity.
  • Memory Loss including Alzheimer's disease and dementia.
  • CNS-Mediated Motor Dysfunction Disorders including Parkinson's disease and ataxia.
  • Opthalamic Disorders such as ocular hypertension.
  • Cavx channel blockers for the prophylaxis or treatment of a number of disease states including lower urinary tract disorders and pain indications.
  • assays based on the interaction between Cavx channel domains and Cav ⁇ subunits immobilised through an affinity tag we have discovered a new family of compounds which inhibit the interaction between Cavx channels and Cav ⁇ proteins.
  • R1 is 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 guanidinoalkyl group;
  • R2 is an alkyl group, an aryl group or a heteroaryl group which may optionally be substituted with at least one substituent selected from 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 a hydrogen atom, an alkyl group, a cycloalkyl group, saturated or partially unsaturated heterocyclic groups, an alkyl group that is substituted with at least one substituent selected from alkoxy groups, haloalkoxy groups, unsaturated or partially saturated heterocyclic groups, aryloxy groups, alkylsulfonyl groups and alkylsulfinyl groups, 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 hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups;
  • W is selected from oxygen atoms, sulphur atoms, groups of formula NR7, wherein R7 is a hydrogen atom or alkyl, and groups of formula CR8R9, wherein R8 and R9 are the same or different and each is H or alkyl; and
  • X is selected from nitrogen atoms and groups of formula CR10, wherein R10 is H or alkyl;
  • Preferred compounds of the present invention include:
  • R1 is an alkyl group having from 1 to 6 carbon atoms, an aminoalkyl group having from 1 to 6 carbon atoms, 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 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, acy
  • R1 is a cyclopentyl group, a cyclohexyl group, a cyclohexylmethyl group or a 2-cyclohexylethyl group;
  • R2 is an aikyl 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, said group optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, which is optionally substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, haloalkoxyl groups having from 1 to 6 carbon atoms, an aryl groups having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alk
  • Y is a hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms, a group of formula NR11 R12 (wherein R11 and R12 are the same or different and each is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group 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 and 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 carbonyl groups, and alkyl groups having from 1 to 6 carbon atom that are substituted with at least one substituent selected from the group consisting of alkoxy groups having from 1 to 6 carbon atom
  • 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, or R2 is an alkyl group,
  • R2 is an alkyl group having 1 to 4 carbon atoms which is substituted with one or more substituents selected from carboxy groups, amino groups, 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 ⁇ /-(4-tetrahydro-2H- 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, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising a carbonyl group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, nitro groups, amino groups, 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, alkoxycarbon
  • 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 an alkyl group having from 1 to 4 carbon atoms, 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 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, or R2 is an alkyl group,
  • 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;
  • R1 is a cyclopentyl group, a cyclohexyl group, a cyclohexylmethyl group or a 2- cyclohexylethyl group;
  • R2 is an alkyl group having 1 to 4 carbon atoms which is substituted with one or more substituents selected from carboxy groups, amino groups, 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 ⁇ /-(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; and W is a group of formula NH;
  • 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 (17) or a pharmacologically acceptable salt or prodrug thereof.
  • a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof for use as a medicament in a third aspect of the present invention, there is provided use of a compound of general formula (I 1 ) or a pharmacologically acceptable salt or pro-drug thereof, wherein:
  • RV is an alkyl group, a cycloalkyl group, an aryl group, an aralkyl 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 heteroaryl group which may optionally be substituted with at least one substituent selected from 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 NR1 VR12' or an aminoacid residue
  • R1 V and R12' are the same or different and each is a hydrogen atom, an alkyl group, a cycloalkyl group, saturated or partially unsaturated heterocyclic groups, an alkyl group that is substituted with at least one substituent selected from alkoxy groups, haloalkoxy groups, unsaturated or partially saturated heterocyclic groups, aryloxy groups, alkylsulfonyl groups and alkylsulfinyl groups, or R1 V 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 hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups;
  • W is selected from oxygen atoms, sulphur atoms, groups of formula NR7', wherein R7' is a hydrogen atom or alkyl, and groups of formula CR8'R9', wherein R8' and R9' are the same or different and each is H or alkyl; and
  • X' is selected from nitrogen atoms and groups of formula CR10', wherein R10' is H or alkyl,
  • R3' to R12', W, X' and Y' is identical in its definition to R3 to R12, W, X and Y in the compounds of general formula (I).
  • the preferred substituent definitions are also the same.
  • the definitions of R1 ' and R2' are essentially the same as of R1 and R2 but RT can also be aralkyl while in the compounds of formula (I 1 ) R1 and R2 can both be alkyl.
  • the preferred substituent definitions are again the essentially the same.
  • RT is an aralkyl group it is preferably an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, 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 carbonylarnino group in which the carbonyl is substituted with a hydrogen
  • a compound of general formula (I 1 ) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel opening.
  • a compound of general formula (I 1 ) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel inhibition.
  • a compound of general formula (I') or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Lower Urinary Tract Disorders.
  • a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Epilepsy in a ninth aspect of the present invention.
  • a compound of general formula (I') or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Pain Disorders there is provided use of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Pain Disorders.
  • a compound of general formula (I 1 ) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiac Arrhythmias.
  • a compound of general formula (I 1 ) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Thromboembolic Events.
  • a fourteenth aspect of the present invention there is provided use of a compound of general formula (I 1 ) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiovascular Diseases.
  • a compound of general formula (P) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Disorders of the Auditory System.
  • a compound of general formula (T) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Migraine.
  • a seventeenth aspect of the present invention there is provided use of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Inflammatory and Immunological Diseases.
  • a compound of general formula (I 1 ) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders.
  • a compound of general formula (P) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cell Proliferative Disorders.
  • a compound of general formula (I 1 ) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Metabolic Disorders.
  • a compound of general formula (I') or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Memory Loss.
  • a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders.
  • a compound of general formula (I 1 ) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Opthalamic Disorders.
  • a method for the prophylaxis or treatment of a disease in which Cavx is involved comprising administering to a patient in need thereof an effective amount of a compound of general formula (I 1 ) 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 general formula (I 1 ) 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 general formula (I 1 ) 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 general formula (I') 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 according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof.
  • a method for the prophylaxis or treatment of Epilepsy comprising administering to a patient in need thereof an effective amount of a compound of general formula (P) 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 general formula (I 1 ) 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 according to any one of (1) to (17) 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 general formula (I 1 ) 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 according to any one of (1) to (17) 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 general formula (I 1 ) 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 general formula (I 1 ) 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 general formula (I 1 ) 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 according to any one of (1) to (17) 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 general formula (I 1 ) 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 general formula (I 1 ) 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 general formula (I 1 ) 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 according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof.
  • a method for the prophylaxis or treatment of Memory Loss comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof.
  • a method for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof.
  • a method for the prophylaxis or treatment of Opthalamic Disorders comprising administering to a patient in need thereof an effective amount of a compound of general formula (I 1 ) or a pharmacologically acceptable salt or prodrug thereof.
  • a compound of general formula (I) according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof for use in the prophylaxis or treatment of any disease or condition recited in any of the eighth, ninth, seventeenth, eighteenth and twenty-third aspects of the invention recited above.
  • a compound of general formula (I 1 ) or a pharmacologically acceptable salt or prodrug thereof for use in the prophylaxis or treatment of any disease or condition recited in any of the fourth to seventh, tenth to sixteenth, nineteenth to twenty-second and twenty-fourth aspects of the invention recited above.
  • a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and at least two active ingredients, wherein said active ingredients comprise at least one compound of general formula (I) according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof or one compound of general formula (I 1 ) as recited in the fourth aspect of the present invention 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
  • Preferred pharmaceutical combinations according to the present invention 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 of general formula (I) according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof or one compound of general formula (V) as recited in the fourth aspect of the present invention 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 of general formula (I) according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof or one compound of general formula (I') as recited in the fourth aspect of the present invention 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, /V-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor
  • the combinations of preferred option (1) are of particular use in the prophylaxis or treatment of lower urinary tract disorders.
  • the combinations of preferred option (2) are of particular use in the prophylaxis or treatment of pain.
  • a forty-ninth aspect of the present invention there is provided use of at least one compound of general formula (I) according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof or one compound of general formula (I 1 ) as recited in the fourth aspect of the present invention 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,
  • SNRIs norepinephrine reuptake inhibitors
  • a fiftieth aspect of the present invention there is provided use of at least one compound of general formula (I) according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof or one compound of general formula (I 1 ) as recited in the fourth aspect of the present invention 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, /V-methyl- D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anticonvulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing
  • the alkyl groups in the definitions of R1 , R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 , R12, R1 ⁇ R2 ⁇ R3 ⁇ R4', R5 ⁇ R6', R7', R8', R9', R10', R11 ' 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 , R2, R11 , R12, R1 1 , R2', R11' 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 , R2, R1 ' and R2' 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, 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, alkoxycarbonylamin
  • 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 RT 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 R1 , R2, R1 ' and R2' are preferably 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms.
  • Examples include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1 ,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups. Most preferred is pyridyl.
  • heteroaralkyl groups in the definition of R1 and R1' are preferably alkyl groups as defined above which are substituted with heteroaryl groups as defined above.
  • the cycloalkylalkyl groups in the definition of R1 and R1 ' 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.
  • aminoalkyl groups in the definition of R1 and R1' 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 R1 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, R3, R4, R5, R6, R11 , R12, Y, R2 1 , R3 ⁇ R4 ⁇ R5 ⁇ R6 ⁇ R1 V, R12' 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, R3, R4, R5, R6, R11 , R12, R2 ⁇ R3 ⁇ R4 ⁇ R5 J , R6 ⁇ R1 V 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, R3, R4, R5, R6, R2 1 , R3 ⁇ R4', R5' 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, R3, R4, R5, R6, R2', R3 ⁇ R4 ⁇ R5' 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 saturated or partially unsaturated heterocyclic groups in the definitions of R1 , R2, R11 , R12, RT 1 R2 ⁇ R11' and R12' are 4-8 to membered saturated or partially unsaturated heterocylic groups containing at least one nitrogen, oxgen or sulphur atom, and are more preferably preferably morpholinyl, piperazinyl or pyrrolidinyl groups.
  • the nitrogen-containing heterocyclic groups in the definition of R11 and 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 R11 , R12, R11 ' and R12' are aryl groups as defined above attached to an oxygen atom and are preferably phenyloxy groups.
  • the haloalkyl groups in the definitions of R3, R4, R5, R6, R3', R4 ⁇ R5' and R6' 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 group, trichloromethyl groups, trifluoromethyl groups and tetrafluoroethyl groups.
  • the alkoxycarbonyl groups in the definitions of R3, R4, R5, R6, R3', R4', R5' and R6' are preferably carbonyl groups substituted with alkoxy groups as defined, and are more preferably methoxycarbonyl or ethoxycarbonyl groups.
  • the acylamino groups in the definitions of R3, R4, R5, R6, R3', R4', R5' and R6' 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, R4, R5, R6, R3', R4', R5' 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, R3, R4, R5, R6, R11 , R12, R2', R3', R4', R5 ⁇ R6', R11' 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 alkylsulphinyl groups in the definitions of R2, R11 , R12, R2', R11 ' and R12' are preferably sulphinyl groups which are substituted with an alkyl group as defined above and are more preferably a methylsulphinyl or ethylsulphinyl group.
  • the arylsulphonyl groups in the definitions of R3, R4, R5, R6, R3', R4', R5' 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 alkylsulphonylamino groups in the definitions of R2, R3, R4, R5, R6, R2 ⁇ R3', R4', R5' and R6' are preferably sulphonylamino groups which are substituted with an alkyl group as defined above and are more preferably a methylsulphonylamino or ethylsulphonylamino group.
  • the arylsulphonylamino groups in the definitions of R3, R4, R5, R6, R3 ⁇ R4 ⁇ R5' 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.
  • pharmacologically acceptable salts of the compound having the formula (I) or formula (I 1 ) 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, triethylamine salt, dicyclohexylamine salt, ⁇ /
  • the compounds of formula (I) or formula (I 1 ) of the present invention can be administered in the form of prodrugs.
  • Prodrugs are derivatives of the pharmacologically active compound in which one or more of the substituents on said compound are protected by a group which is then removable by a biological process (e.g. hydrolysis) in vivo after administration to the patient.
  • a biological process e.g. hydrolysis
  • Many suitable prodrugs would be well-known to the person in the art and can be found, for example, in "Greene's Protective Groups in Organic Synthesis", 4 th Edition, 2006, Wiley-VCH.
  • Suitable examples of such prodrugs include pharmacologically acceptable esters of the compound having the formula (I) or formula (I') wherein a carboxyl moiety of the compound having the formula (I) or formula (I 1 ) 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 Ci-C 4 alkoxy Ci-C 4 alkyl group such as methoxyethyl, 1- ethoxyethyl, 1-methyl-1 -methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2- ethoxyethyl, 1 ,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; a CrC 4 alkoxylated Ci-C 4 alkoxy Ci-C 4 alkyl group such as 2-methoxyethoxymethyl; a C 6 -Ci 0 aryloxy Ci-C 4 alkyl group such as phenoxymethyl; a halogenated CrC 4 alkoxy CrC 4 alkyl group such as 2,2,2-trichloroethoxymethyl or bis
  • the compounds of formula (I) and compounds of formula (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 formula (I) or formula (I 1 ) 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 formula (I), prodrugs thereof and pharmacologically acceptable salts thereof can also be used and form a part of the invention.
  • Some compounds of formula (I) or formula (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.
  • some of the compounds of formula (I) or formula (!') 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.
  • (I I ) 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.
  • lubricants include stearic acid and metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as bee gum or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium fatty acid salts; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as silicic anhydride or silicate hydrate; and, starch derivatives.
  • stearic acid and metal stearates such as calcium stearate or magnesium stearate
  • talc colloidal silica
  • waxes such as bee gum or spermaceti
  • boric acid adipic acid
  • sulfates such as sodium sulfate
  • glycol fumaric acid
  • binders examples include polyvinylpyrrolidone, Macrogol and compounds similar to the aforementioned excipients.
  • disintegrants agents include compounds similar to the aforementioned excipients, and chemically crosslinked starches and celluloses such as cross sodium carmellose, sodium carboxymethyl starch or crosslinked polyvinylpyrrolidone.
  • stabilizers include paraoxybenzoate esters such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenyl ethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; and, sorbic acid.
  • paraoxybenzoate esters such as methyl paraben or propyl paraben
  • alcohols such as chlorobutanol, benzyl alcohol or phenyl ethyl alcohol
  • benzalkonium chloride phenols such as phenol or cresol
  • thimerosal thimerosal
  • dehydroacetic acid and, sorbic acid.
  • corrigents include ordinarily used sweeteners, sour flavourings and fragrances.
  • said solution or suspension can be produced by dissolving or suspending crystals of the present invention in water or in a mixture of water and an auxiliary solvent (e.g. ethanol, propylene glycol or polyethylene glycol).
  • auxiliary solvent e.g. ethanol, propylene glycol or polyethylene glycol.
  • Such a solution or suspension may also contain an antiseptic (e.g. benzalkonium chloride), solubilizing agent (e.g. a polysorbate such as Tween 80 or Span 80 or surface activator such as benzalkonium chloride), buffer, isotonic agent (e.g. sodium chloride), absorption promoter and/or thickener.
  • the suspension may additionally contain a suspending agent (such as microcrystalline cellulose or sodium carboxymethyl cellulose).
  • a composition for pulmonary administration produced in the manner described above is administered directly into the nasal cavity or oral cavity by a typical means in the field of inhalants (using, for example, a dropper, pipette, cannula or atomizer).
  • crystals of the present invention can be atomized as an aerosol in the form of a pressurized pack together with a suitable nebula (for example, a chlorofluorocarbon such as dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or a gas such as carbon dioxide), or they can be administered using a nebulizer.
  • a suitable nebula for example, a chlorofluorocarbon such as dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or a gas such as carbon dioxide
  • the amount of a compound having the general formula (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.
  • Examples of potassium channel activators include activators of KCNQ, BKCa channels, Kv channels and KATP channels
  • 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 5HT3 antagonists.
  • Examples of ⁇ -1 adrenoceptor antagonists include tamsulosin.
  • tricyclic antidepressants include amitriptyline, amoxapine, clomipramine, dosulepin (dothiepin), doxepin, imipramine, lofepramine, nortriptyline, and trimipramine.
  • NMDA /V-methyl-D-aspartate receptor antagonists
  • examples of /V-methyl-D-aspartate (NMDA) receptor antagonists include ketamine, memantine, amantadine, AVP-923, NP-1 and EVT-101.
  • cannabinoid receptor agonists examples include GW-1000 (Sativex) and KDS-2000.
  • Anti-convulsants examples include lacosamide, carbamazepine, topiramate, oxcarbazepine and levetiracetam
  • aldose reductase inhibitors include tolrestat, 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. 19.
  • 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 formula (I) and pharmacologically acceptable salts thereof.
  • the particular form can be chosen depending upon the condition to be treated and the nature of the compounds being administered in combination.
  • a combination of a compound of general formula (I) or a pharmacologically acceptable salt thereof with lidocaine could be administered transdermal ⁇ by means of a patch while a combination with ziconotide could be administered transmucosally.
  • analogues of the present invention can be synthesised using standard methods and principles as illustrated in the general schemes 1 and 2 below:
  • Secondary amines 2 can be prepared by the reductive amination of aldehydes and ketones 1 with a primary amine. The secondary amines can be subsequently reacted with indole-3-glyoxylyl chlorides to give indole-3- glyoxylamides 3.
  • Scheme 2
  • Esters 4 can be synthesised by the protocol outlined in Scheme 1 , and can be converted to the corresponding acid 5, using standard acid deproction methodology.
  • Amides of structure 6 can be synthesised by conventional amine coupling conditions from the acid 5.
  • 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, ⁇ . ⁇ mmol) 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 1 M 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, ⁇ . ⁇ mmol) was added to a mixture of intermediate 49 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 1 M NaOH (3OmI) 1 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 purified by silica flash chromatography eluting with ethyl acetate and iso-hexane to provide 50 as pale yellow foam (865mg, 42% yield over 2 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 1 M 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.
  • ⁇ -Chloromethyl-S-methylisoxazole (265mg, 2.0mmol) was added to a mixture of cyclohexylmethylamine (175 ⁇ l, 1.4mmol), potassium carbonate (550mg, 4.0mmol) and potassium iodide (225mg, 1.4mmol) in acetonitrile (5ml). The resulting suspension was heated to 50 0 C overnight. The inorganic solids were removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate (30ml) and washed with water (30ml). The organic phase was dried over MgSO 4 , 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), 1M HCI (15ml), water (15ml) and brine (15ml). The organic phase was stirred with activated charcoal and MgSO 4 for 1 hr, filtered and concentrated.
  • Trifluoroacetic acid anhydride (2.8ml, 20mmol) was added to a solution of N- carbamoylmethyl- ⁇ /-cyclohexylmethyl-2-(6-methoxy-1H-indol-3-yl)-2- oxoacetamide (1.46g, 3.9mmol) in tetrahydrofuran (60ml) containing pyridine (2.8ml, 20mmoi). 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 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.
  • Bromocyclohexane (2ml) was added to magnesium (6.53g, 0.27mol) in Et 2 O (5ml) at room temperature. A crystal of iodine was added and the reaction warmed to reflux. The reaction was then left to stir at this temperature for IOmins after the colour had disappeared. Further bromocyclohexane (28ml) was added as a solution in Et 2 O (105ml), maintaining a gentle reflux for 1 hr. On cooling the reaction was added to diethyl oxalate (40ml, 0.29mol) in a 1 :1 tetrahydrofu ran: Et 2 O mixture (60ml) at -78 °C, keeping the temperature below - 60 °C.
  • ferf-Butyl 3-(aminomethyi)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)- benzyl]-[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.
  • Indoleglyoxyl chloride 38mg, 0.18mmol was added to a stirring solution of tert- butyl 3-((1 -(te/t-butylamino)-1 -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 (1 OmI) and the product extracted with EtOAc (3 x 1 OmI). The combined organic layers were dried over Na 2 SO 4 and the concentrated in vacuo to yield an off-white solid.
  • lndole-3-glyoxylyl chloride (284mg) was added to sarcosine (89mg) in 2M NaOH (2ml) and the reaction stirred at room temperature for 16hr. The aqueous layer was extracted with EtOAc (2 x 1OmI) and then acidified to pH 1 using concentrated HCI.
  • 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, 2.83mmoi) 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).
  • 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%).
  • Examples 51 to 61 were prepared according to the general experimental procedure for the formation of amides of structure 14 above.
  • Cyclohexane carboxaldehyde (708mg) was dissolved in MeOH (20ml) at O 0 C. Triethylamine (2.6ml) was added followed by 1-[3-methoxymethyl)-1 ,2,4- oxadiazol-5-yl]methanamine.HCI (1g). The reaction was stirred at O 0 C for 30 minutes and then at room temperature for 2 hours. Sodium triacetoxyborohydride (2.68g) was added to the reaction mixture at O 0 C and the reaction was left to warm to room temperature overnight. The solvent was removed and the residue was dissolved in EtOAc (25ml).
  • Cyclohexane carboxaldehyde (388mg) was dissolved in MeOH (15ml) at O 0 C. Triethylamine (1.9ml) was added followed by (5-methyl-4H-1 ,2,4-triazol-3- yl)methanamine.2HCI (700mg). The reaction was stirred at O 0 C for 30 minutes then at room temperature for 2 hours. Sodium triacetoxyborohydride (1.47g) was added to the reaction mixture at O 0 C and the reaction was left to warm to room temperature overnight. The solvent was removed and the residue was dissolved in EtOAc (25ml). Saturated, aqueous NaHCO 3 solution was added until a pH 9 was reached.
  • Aqueous NaOH (2M; 30ml) was added to 135 (120.4mg, 0.317mmol, 1 eq) and the mixture was left to stir at room temperature over night.
  • the reaction mixture was washed with Et 2 O (50ml) and the aqueous layer was acidified with aqueous HCI (2M). A fine precipitate was formed which was extracted into EtOAc (30ml). The organic extract was dried (MgSO 4 ) and concentrated to a give 136 as a pale yellow solid (87.0mg, 0.274mmol, 78%).
  • Sarcosine t-butyl ester .HCI (1.Og, 5.34mmol, 1eq) was suspended in THF (10ml) at O 0 C. Hunig's base (2.77ml, 16.02mmol, 3eq) was added followed by 6- fluoroindoleglyoxyl chloride (1.81g, 8.01 mmol, 1.5 eq) in THF (20ml). The reaction mixture was left to warm up to room temperature overnight. The solvent was removed and saturated, aqueous NaHCO 3 solution (20ml) was added and the product was extracted into EtOAc.
  • ⁇ /-Benzylglycine ethylester (1.Og, 4.97mmol, 1eq) was suspended in THF (10ml) at O 0 C. Hunig's base (1.72ml, 9.94mmol, 2eq) was added followed by a solution of 6-methoxyindoleglyoxyl chloride (1.77g, 7.452mmol, 1.5 eq) in THF (20ml). The reaction mixture was left to warm up to room temperature overnight. Further 6-methoxyindoleglyoxyl chloride (0.5 eq) was added and the reaction was left to stir at room temperature overnight. The solvent was removed and saturated, aqueous NaHCO 3 solution (20ml) was added and the product was extracted into EtOAc.
  • 6-Trifluoromethoxyindole glyoxylchloride 149 (300 mg) in THF (5ml) was added to 7 (234mg) and Hunig's base (357 ⁇ l) in THF (5ml) at O 0 C. The reaction was then allowed to reach room temperature and stirred for 16 hours. The solvent was removed and saturated, aqueous NaHCO 3 solution (10ml) was added and the product was extracted into EtOAc. The combined organic extracts were dried (Na 2 SO 4 ) and concentrated to give the crude product which was purified by flash column chromatography eluting from 5:1 - 1 :1 hexane:EtOAc to yield 150 as a yellow foam (366mg, 76%).
  • 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 (100 nM).
  • Nitrix oxide modulates Ca(2+) channels in dorsal root ganglion neurons innervating rat urinary bladder J N ⁇ urophysiol 86, 304-311

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Abstract

Compounds of formula (I) are of use in treating a range of conditions, including pain.

Description

INDOLE- 3 -GLYOXYLAMIDE DERIVATIVES FOR USE AS CALCIUM ION CHANNEL MODULATORS
Field of the Invention
The present invention relates to ion channel modulators, and more particularly to compounds which inhibit the interaction between the pore-forming (α) subunits of Cav voltage-gated calcium channels and accessory (Cavβ subunit) proteins.
Background to the Invention
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 (Cavi .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 α1 subunit, which forms the pore-region of the channel through which Ca2+ ions can flow. Conserved transmembrane and pore domains of the α1 subunits are less than 40% identical between the related families (Cav1.x : Cav2.x : Cav3.x) but greater than 70% identical within a family' which leads to difficulty in identifying compounds that pharmacologically discriminate between these related Cav channel subtypes.
Cav channel β subunits (Cavβ) are intracellular proteins endogenously associated with Cav channel α1 subunits, which finely tune many of their functional and electrophysiological / kinetic properties". Ten different genes encode voltage-gated Cav channel alpha 1 subunits1". To date, Cavβ subunits (Cavβi , Cavβ2, Cavβ3, Cavβ4) have been shown to interact and regulate the functional activity of Cavlx, Cav2.x and Cav3.x channelsiwi'vii'viii.
The major functions of Cavβ subunits include altering the threshold for activation and the kinetics for both activation and inactivation, as well as regulating trafficking of the Cavαi subunit to the cell membrane. The predominant effect of the combined α-β interaction is dependent upon the nature of each of the two proteins such that combining one type of Cava subunit with any of the β(1-4) subunits will lead to differential effects on functional expression and kinetics of the channel. Thus the β subunit potentially adds a further source of modulation of the final Cav current.
Mammalian homologues of Cav channel α subunits (Cavi .x, Cav2.x and Cav3.x) 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 Ca2+ ions. These tetrameric protein complexes of Cav channels constitute the ion channel pore-forming domain.
Functional Cav channels consisting of a tetramer of transmembrane spanning Cav2 channel subunits may be associated with and regulated by cytosolic accessory (Cavβ) proteins that are able to modulate the function of ion channel pore-forming domains (for review, see ιx).
Cavβ subunits bind to Cav channel α1 subunits through an α interaction domain (AID) located between domains I and Il of the pore-forming α-1 subunit. Binding of the Cavβ subunit to the AID can increase the trafficking of the Cav channel to the cell membrane and modulate the kinetics of the Cav current.
Cav2.2 channels and Pain
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. ω-Conotoxin -GVIA, a specific peptide blocker of Cav2.2 blocks electrically evoked responses of dorsal horn neurons and this is enhanced in nerve-injured ratsxι. In addition, blockade of the N-type calcium channel with ω-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 painx".
Neuronal Cav2.2 channels may bind to any Cavβ subunit whereas cardiac calcium currents are of the Cav1.2 type and their activity appears to be modulated by Cavβ2 proteinsxι". The presence of Cav2.2 with Cavβ2 produces non-inactivating currents in chromaffin cellsxιv whereas the association of Cav2.2 with Cavβ3 produces inactivating currents. Cav2.2 would appear to be preferentially co-localised with Cavβ3 because ω-conotoxin-GVIA binding sites are immunoprecipitated by an antibody to Cavβ3 in rabbit brainxv. Mice lacking the N-type Cavβ3 subunit show reduced levels of Cav2.2 channels with altered sensitivity to inflammatory pain when compared to wild-typexvι.
Furthermore, Cavβ3 subunits hyperpolarise the voltage-dependence of activation and also hyperpolarise the voltage-dependence of steady-state inactivation of Cav2.2 channels™1'™1". 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 painxιx. One example of 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^. 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. PRIALT1 the synthetic analogue of ω-conotoxin-MVIIA, is effective in patients with PHN, as well as phantom-limb pain, and HIV-related neuropathic pain who are refractory to opioids™.
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. Moreover, pregabalin is approved for use as adjunctive therapy for adult patients with partial onset seizures™1''0'"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 oc2-δ. Pregabalin is six-times more potent than gabapentin in binding affinity to the α,2-δ voltage-gated calcium channel*™. The manufacturer states that 50 mg of pregabalin is approximately equal to 300 mg of gabapentin. Unlike classical pore-forming domain blockers 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.
Cav2.2 channels and Lower Urinary Tract Disorders
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.
The physiology underlying micturition is complex and the exact mechanism causing overactive bladder is unknown. Overactive bladder may result from hypersensitivity of sensory neurons of the urinary bladder, arising from inflammatory conditions, hormonal imbalances, and prostate hypertrophy. Destruction of the sensory nerve fibres, either from a crushing injury to the sacral region of the spinal cord, or from a disease that causes damage to the dorsal root fibres as they enter the spinal cord may also lead to overactive bladder. In addition, damage to the spinal cord or brain stem causing interruption of transmitted signals may lead to abnormalities in micturition. Therefore, both peripheral and central mechanisms can contribute to overactive bladder.
Carbone et al. (2003) have previously reported the effects of gabapentin on neurogenic detrusor overactivity*™. This study demonstrated a positive effect on symptoms and significant improvement in urodynamic parameters after treatment with gabapentin and suggested that the effects of the drug should be explored further in controlled studies in both neurogenic and nonneurogenic detrusor overactivity.
Further support for a pivotal role for Cav2.2 channels in the innervation of the urinary bladder comes from the finding that nitric oxide(NO), which is released by afferent nerves, acting via a cGMP signalling pathway can modulate N-type Ca2+ channels in DRG neurons innervating the urinary bladder*00". Thus 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.
Together, these studies indicate that modulation of N-type calcium channels offers a novel approach to reducing the hyperexcitability of bladder afferents in conditions of detrusor overactivity leading to overactive bladder and urinary incontinence.
Thus novel modulators of the protein-protein interaction between Cav2.2 channels and Cavβ3 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.
"Cavβ" proteins may include one or more of the following mammalian subunits: Cavβi , Cavβ2, Cavβ3, Cavβ4 and any mammalian or non-mammalian equivalents or variants (including splice variants) thereof. At a functional level, interactions between each combination of Cavx channel and Cavβ protein may confer modulation (increasing or decreasing) of a number of features of functional Cav channels including, but not limited to (i) the transport or chaperone of Cav channels to the plasma membrane of a given cell type χχvιι,χχvιn,xxix,xχx anc|/or (jj) gating properties such as channel inactivation***'.
Cavβ 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.
Furthermore, the interaction between specific Cavβ subunits and different Cav channel compositions may confer differential modulation to Cav channel currents (e.g. Cav2 xxx"). This phenomenon may account for the wide diversity of Cav channels. However, exact subunit compositions of native Cav channels and the physiologic role that particular channels play are, in most cases, still unclear.
As such, compounds which inhibit the interaction between Cavx channels and Cavβ 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, are defined as "Cavx channel blockers" (Cav2 channel block).
Such 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". 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. Thus, lower urinary tract disorders includes overactive bladder or overactive urinary bladder (including, overactive detrusor, detrusor instability, detrusor hyperreflexia, sensory urgency and the symptoms of detrusor overactivity), urge incontinence or urinary urge incontinence, stress incontinence or urinary stress incontinence, lower urinary tract symptoms including obstructive urinary symptoms such as slow urination, dribbling at the end of urination, inability to urinate and/or the need to strain to urinate at an acceptable rate or irritate symptoms such as frequency and/or urgency. Lower urinary tract disorders may also include neurogenic bladder that occurs as the result of neurological damage due to disorders including but not limited to stroke, Parkinson's disease, diabetes, multiple sclerosis, peripheral neuropathy, or spinal cord lesions. Lower urinary tract disorders may also include prostatitis, interstitial cystitis, benign prostatic hyperplasia, and, in spinal cord injured patients, spastic bladder.
"Anxiety and Anxiety-Related Conditions". 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". 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 Disorders". 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. post herpetic neuralgia, trigeminal neuralgia and sympathetically maintained pain) and pain associated with cancer and fibromyalgia; pain associated with migraine; pain (both chronic and acute), and/or fever and/or inflammation of conditions such as rheumatic fever; symptoms associated with influenza or other viral infections, such as the common cold; lower back and neck pain; headache; toothache; sprains and strains; myositis; neuralgia; synovitis; arthritis, including rheumatoid arthritis; degenerative joint diseases, including osteoarthritis; gout and ankylosing spondylitis; tendinitis; bursitis; skin-related conditions, such as psoriasis, eczema, burns and dermatitis; injuries, such as sports injuries and those arising from surgical and dental procedures.
"Cardiovascular Diseases" such as angina pectoris, hypertension and congestive heart failure.
"Gynaecological Pain", for example, dysmenorrhoea, labour pain and pain associated with endometriosis.
"Disorders of the Auditory System" such as tinnitus.
"Migraine".
"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.
"Metabolic Disorders" such as diabetes (including diabetic retinopathy, diabetic nephropathy and diabetic neuropathy), insulin resistance/insensitivity and obesity. "Memory Loss" including Alzheimer's disease and dementia.
Other "CNS-Mediated Motor Dysfunction Disorders" including Parkinson's disease and ataxia.
"Opthalamic Disorders" such as ocular hypertension.
Thus, it would be desirable to identify Cavx channel blockers for the prophylaxis or treatment of a number of disease states including lower urinary tract disorders and pain indications. Using assays based on the interaction between Cavx channel domains and Cavβ subunits immobilised through an affinity tag, we have discovered a new family of compounds which inhibit the interaction between Cavx channels and Cavβ proteins.
Description of the Invention
In a first aspect of the present invention, there is provided a compound represented by the general formula (I) or a pharmacologically acceptable salt or pro-drug thereof, wherein:
Figure imgf000010_0001
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 guanidinoalkyl group;
R2 is an alkyl group, an aryl group or a heteroaryl group which may optionally be substituted with at least one substituent selected from 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 a hydrogen atom, an alkyl group, a cycloalkyl group, saturated or partially unsaturated heterocyclic groups, an alkyl group that is substituted with at least one substituent selected from alkoxy groups, haloalkoxy groups, unsaturated or partially saturated heterocyclic groups, aryloxy groups, alkylsulfonyl groups and alkylsulfinyl groups, 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 hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups;
W is selected from oxygen atoms, sulphur atoms, groups of formula NR7, wherein R7 is a hydrogen atom or alkyl, and groups of formula CR8R9, wherein R8 and R9 are the same or different and each is H or alkyl; and
X is selected from nitrogen atoms and groups of formula CR10, wherein R10 is H or alkyl;
PROVIDED THAT when R1 is an alkyl group, R2 cannot also be an alkyl group.
Preferred compounds of the present invention include:
(2) compounds according to (1) and pharmacologically acceptable salts and prodrugs thereof, wherein R1 is an alkyl group having from 1 to 6 carbon atoms, an aminoalkyl group having from 1 to 6 carbon atoms, 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 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 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, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, 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, 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 carbonyl groups, a cycloalkylalkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a cycloalkyl group having from 3 to 14 carbon atoms, an aminoalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one amino group, and a guanidinoalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with a guanidino group; (3) compounds according to (1) and pharmacologically acceptable salts and prodrugs thereof wherein R1 is an alkyl group having from 1 to 4 carbon atoms, 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;
(4) compounds according to (1) and pharmacologically acceptable salts and prodrugs thereof wherein R1 is a cyclopentyl group, a cyclohexyl group, a cyclohexylmethyl group or a 2-cyclohexylethyl group;
(5) compounds according to any one of (1) to (4) and pharmacologically acceptable salts and prodrugs thereof wherein R2 is an aikyl 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, said group optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, which is optionally substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, haloalkoxyl groups having from 1 to 6 carbon atoms, an aryl groups having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, 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 which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, heteroaryl groups which are 5- to 7- membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, cycloalkyl groups having from 3 to 14 carbon atoms, amino groups, alkylamino groups wherein the alkyl substituent has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphinyl groups having from 1 to 6 carbon atoms, alysulphonylamino groups having from 1 to 6 carbon atoms, saturated or partially unsaturated heterocyclic groups which are 4- to 8- membered saturated or partially unsaturated heterocyclic groups 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 carbonyl groups, and groups of formula COY,
wherein Y is a hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms, a group of formula NR11 R12 (wherein R11 and R12 are the same or different and each is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group 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 and 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 carbonyl groups, and alkyl groups having from 1 to 6 carbon atom that are substituted with at least one substituent selected from the group consisting of alkoxy groups having from 1 to 6 carbon atoms, haloalkoxy groups having from 1 to 6 carbon atoms, saturated or partially unsaturated heterocyclic groups which are 4- to 8- membered saturated or partially unsaturated heterocyclic groups 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 carbonyl groups, aryloxy groups comprising a an aryl groups having from 5 to 14 carbon atoms which is attached to an oxygen atom, alkylsulfonyl groups having from 1 to 6 carbon atoms and alkylsulfinyl groups having from 1 to 6 carbon atoms, or 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), or an aminoacid residue;
(6) compounds according to any one of (1) to (4) and pharmacologically acceptable salts and prodrugs thereof wherein 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, or R2 is an alkyl group,
(b) 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 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 having from 1 to 4 carbon atoms, and alkyl groups having from 1 to 4 groups that are substituted with unsaturated heterocyclic groups having from 4 to 6 carbon atoms and containing at least one nitrogen, oxygen or sulphur atom;
(7) compounds according to any one of (1) to (4) and pharmacologically acceptable salts and prodrugs thereof wherein R2 is an alkyl group having 1 to 4 carbon atoms which is substituted with one or more substituents selected from carboxy groups, amino groups, 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 Λ/-(4-tetrahydro-2H- pyranyl)aminocarbonyl group or a 2-pyrrolidin-1-ylethylaminocarbonyl group;
(8) compounds according to any one of (1) to (7) and pharmacologically acceptable salts and prodrugs thereof wherein R3, R4, R5 and R6 are independently selected from hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising a carbonyl group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, nitro groups, amino groups, 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 which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, 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 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, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, aminosulphonyl groups and cyano groups;
(9) compounds according to any one of (1) to (7) and pharmacologically acceptable salts and prodrugs thereof wherein 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;
(10) compounds according to any one of (1) to (7) and pharmacologically acceptable salts and prodrugs thereof wherein R3, R4, R5 and R6 are independently selected from hydrogen atoms, methyl groups, methoxy groups, fluorine atoms and chlorine atoms;
(11) compounds according to any one of (1) to (10) and pharmacologically acceptable salts and prodrugs thereof wherein 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;
(12) compounds according to any one of (1) to (10) and pharmacologically acceptable salts and prodrugs thereof wherein X is a group of formula CH; (13) compounds according to any one of (1) to (12) and pharmacologically acceptable salts and prodrugs thereof wherein 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;
(14) compounds according to any one of (1) to (12) and pharmacologically acceptable salts and prodrugs thereof wherein W is a group of formula NH;
(15) compounds according to (1) and pharmacologically acceptable salts and prodrugs thereof wherein:
R1 is an alkyl group having from 1 to 4 carbon atoms, 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
(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, or R2 is an alkyl group,
(b) 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 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 having from 1 to 4 carbon atoms, and alkyl groups having from 1 to 4 groups that are substituted with unsaturated heterocyclic groups having from 4 to 6 carbon atoms and containing at least one nitrogen, oxygen or sulphur atom;
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) compounds according to (1) and pharmacologically acceptable salts and prodrugs thereof wherein:
R1 is a cyclopentyl group, a cyclohexyl group, a cyclohexylmethyl group or a 2- cyclohexylethyl group;
R2 is an alkyl group having 1 to 4 carbon atoms which is substituted with one or more substituents selected from carboxy groups, amino groups, 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 Λ/-(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; and W is a group of formula NH;
(17) compounds according to (1) selected from the following, and pharmacologically acceptable salts and prodrugs thereof:
{cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo-acetyl]amino} acetic acid tert-butyl ester,
{cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo-acetyl]amino} acetic acid,
{cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo-acetyl]amino} acetic acid methyl ester,
Λ/-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-N-(3-methyl-[1 ,2,4]oxadiazol-5- ylmethyl)-2-oxo-acetamide,
2-{cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetyl]amino}-2- methylpropionic acid,
(R)-2-{cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetyl]amino}- propionic acid,
(S)-2-{cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetyl]amino}- propionic acid,
Λ/-cyclohexylmethyl-Λ/-(2-methoxyethyl)-2-(6-methoxy-1 H-indo!-3-yl)-2- oxoacetamide,
Λ/-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-Λ/-(3-methylisoxazol-5-ylmethyl)- 2-oxoacetamide,
Λ/-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-Λ/-(5-methyl-isoxazol-3- ylmethyl)-2-oxo-acetamide,
Λ/-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-Λ/-(5-methyl-isoxazol-3-ylmethyl)-2- oxo-acetamide,
Λ/-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-Λ/-(1 H-tetrazol-5- ylmethyl)acetamide, 3-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]amino} propionic acid,
4-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino} butyric acid,
{cyclohexylmethyl-[2-(6-fluoro-1 H-indol-3-yi)-2-oxo-acetyl]amino} acetic acid tert- butyl ester,
{cyclohexylmethyl-[2-(6-fluoro-1 H-indol-3-yl)-2-oxo-acetyl]-amino} acetic acid,
Λ/-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-Λ/-pyridin-2-ylmethyl- acetamide,
Λ/-cyclohexylmethyl-2-(6-methoxy-1 H-indoi-3-yl)-2-oxo-Λ/-pyridin-3-ylmethyl- acetamide,
Λ/-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-Λ/-pyridin-4-ylmethyl- acetamide,
Λ/-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-Λ/-pyridin-2-ylmethyl- acetamide,
Λ/-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-Λ/-pyridin-3-ylmethyl- acetamide,
Λ/-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-Λ/-pyridin-4-ylmethyl- acetamide,
{[3-(tert-butoxycarbonylamino-methyi)-benzyl]-[2-(1 H-indol-3-yl)-2-oxo-acetyl]- aminojcyclohexyl acetic acid,
[3-({(1-tert-butylcarbamoylethyl)-[2-(1 H-indol-3-yl)-2-oxo-acetyl]amino}- methyl)benzyl]carbamic acid tert-butyl ester,
4-(2-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}ethyl)-piperazine-1- carboxylic acid tert-butyl ester,
Λ/-cyclohexylmethyl-2-(1 H-indol-3-yl)-2-oxo-Λ/-(2-piperazin-1-ylethyl) acetamide,
(4-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}-butyl)carbamic acid tert-butyl ester, (4-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}butyl)carbamic acid tert-butyl ester,
{2-(1 H-indol-3-yl)-2-oxo-acetyl]methylamino} acetic acid,
[3-({cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]amino}methyl)benzyl] carbamic acid tert-butyl ester,
3-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]amino} propionic acid,
4-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]amino} butyric acid,
(S)-5-amino-2-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]amino} pentanoic acid,
(S)-6-amino-2-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino} hexanoic acid,
Λ/-cyclohexyl-2-(1 H-indol-3-yl)-A/-methyl-2-oxoacetamide,
Λ/-cyclohexyl-Λ/-[1 H-indol-3-yl(oxo)acetyl]glycine,
Λ/-cyclohexyl-2-(1 H-indol-3-yl)-2-oxo-Λ/-(3-pyrrolidin-1-ylpropyl)acetamide,
Λ/-(cyclohexylmethyl)-2-(1 H-indol-3-yl)-Λ/-methyl-2-oxoacetamide,
Λ/-(cyclohexylmethyl)-Λ/-[1 H-indol-3-yl(oxo)acetyl]glycine,
Λ/-(cyclohexylmethyl)-2-(1 H-indol-3-yl)-2-oxo-Λ/-(3-pyrrolidin-1- ylpropyl)acetamide,
Λ/-cyclohexyl-2-(6-methoxy-1 H-indol-3-yl)-Λ/-methyl-2-oxoacetamide,
Λ/-cyclohexyl-Λ/-[(6-methoxy-1 H-indol-3-yl)(oxo)acetyl]glycine,
Λ/-cyclohexyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-Λ/-(3-pyrrolidin-1- ylpropyl)acetamide,
Λ/-(cyclohexylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-Λ/-methyl-2-oxoacetamide,
Λ/-(cyclohexylmethyl)-Λ/-[(6-methoxy-1 H-indol-3-yl)(oxo)acetyl]glycine, Λ/-(cyclohexylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-Λ/-(3-pyrrolidin-1- ylpropyl)acetamide,
Λ/2-(cyclohexylmethyl)-Λ/2-[(6-methoxy-1 H-indol-3-yl)(oxo)acetyl]-L-ornithine,
N-cyclohexylmethyl-N-{[(2-methoxy-ethyl)-methyl-carbamoyl]-methyl}-2-(6- methoxy-1 H-indol-3-yl)-2-oxo-acetamide,
N-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-N-{[methyl-(2-pyrrolidin-1-yl- ethyl)-carbamoyl]-methyl}-2-oxo-acetamide,
N-cyclohexylmethyl-N-[(4-methoxy-cyclohexylcarbamoyl)-methyl]-2-(6-methoxy- 1 H-indol-3-yl)-2-oxo-acetamide,
N-cyclohexylmethy[-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-({[(S)-1-(tetrahydro- furan-2-yl)methyl]-carbamoyl}-methyl)-acetamide,
N-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-N-[2-((R)-2-methoxymethyl- pyrrolidin-1-yl)-2-oxo-ethyl]-2-oxo acetamide,
N-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-N-(2-oxo-2-pyrrolidin-1-yl- ethyl)-acetamide,
N-cyclohexylcarbamoylmethyl-N-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2- oxo-acetamide,
N-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-N-[(tetrahydro-pyran-4- ylcarbamoyl)-methyl]-acetamide,
N-cyclohexylmethyl-N-dimethylcarbamoylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo- acetamide,
N-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-N-[(2-methoxy-ethylcarbamoyl)- methyl]-2-oxo-acetamide,
N-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-N-[(2-pyrrolidin-1-yl- ethylcarbamoyl)-methyl]-acetamide, N^cyclohexylmethyO^^Θ-fluoro-I H-indol-S-yO-N^CS-^ethoxymethyO-i ^^- oxadiazol-5-yl)methyl)-2-oxoacetamide,
N-(cyclohexylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-N-((3-(methoxymethyl)-1 ,2,4- oxadiazol-5-yl)methyl)-2-oxoacetamide,
N-(cyclohexylmethyl)-2-(6-fluoro-1 H-indol-3-yl)-N-((5-methyl-4H-1 ,2,4-triazol-3- yl)methyi)-2-oxoacetamide,
N-(cyclohexylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-N-((5-methyl-4H-1 ,2,4-triazol- 3-yl)methyl)-2-oxoacetamide,
ethyl 2-(2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-phenylacetamido)acetate,
2-(2-(6-Methoxy-1 H-indol-3-yl)-2-oxo-N-phenylacetamido)acetic acid,
ethyl 2-(N-(cyclohexylmethyl)-2-(6-fluoro-1 H-indol-3-yl)-2-oxoacetamido)acetate,
ethyl 2-(2-(6-fluoro-1 H-indol-3-yl)-N-methyl-2-oxoacetamido)acetate,
ethyl 2-(2-(6-fluoro-1 H-indol-3-yl)-2-oxo-N-phenylacetamido)acetate,
2-(2-(6-fluoro-1 H-indol-3-yl)-2-oxo-N-phenylacetamido)acetic acid,
ethyl 2-(N-benzyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetamido)acetate,
ethyl 2-(N-benzyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxoacetamido)acetate, and
2-(N-(cyclohexylmethyl)-2-oxo-2-(6-(trifluoromethoxy)-1 H-indol-3- yl)acetamido)acetic acid.
In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and an active ingredient, wherein said active ingredient is a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof.
In a third aspect of the present invention, there is provided a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof for use as a medicament. In a fourth aspect of the present invention, there is provided use of a compound of general formula (I1) or a pharmacologically acceptable salt or pro-drug thereof, wherein:
Figure imgf000025_0001
RV is an alkyl group, a cycloalkyl group, an aryl group, an aralkyl 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 heteroaryl group which may optionally be substituted with at least one substituent selected from 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 NR1 VR12' or an aminoacid residue;
R1 V and R12' are the same or different and each is a hydrogen atom, an alkyl group, a cycloalkyl group, saturated or partially unsaturated heterocyclic groups, an alkyl group that is substituted with at least one substituent selected from alkoxy groups, haloalkoxy groups, unsaturated or partially saturated heterocyclic groups, aryloxy groups, alkylsulfonyl groups and alkylsulfinyl groups, or R1 V 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 hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups;
W is selected from oxygen atoms, sulphur atoms, groups of formula NR7', wherein R7' is a hydrogen atom or alkyl, and groups of formula CR8'R9', wherein R8' and R9' are the same or different and each is H or alkyl; and
X' is selected from nitrogen atoms and groups of formula CR10', wherein R10' is H or alkyl,
in the preparation of a medicament for the prophylaxis or treatment of a disease in which Cavx channels are involved.
Each of R3' to R12', W, X' and Y' is identical in its definition to R3 to R12, W, X and Y in the compounds of general formula (I). The preferred substituent definitions are also the same. The definitions of R1 ' and R2' are essentially the same as of R1 and R2 but RT can also be aralkyl while in the compounds of formula (I1) R1 and R2 can both be alkyl. The preferred substituent definitions are again the essentially the same. In addition, however, when RT is an aralkyl group it is preferably an aralkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, 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 carbonylarnino 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, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, more preferably 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 aminalkyl group having from 1 to 4 carbon atoms or an alkyl group having from 1 to 4 carbon atoms and most preferably a (3-aminomethyl)benzyl group,
In a fifth aspect of the present invention, there is provided use of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel opening.
In a sixth aspect of the present invention, there is provided use of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel inhibition.
In a seventh aspect of the present invention, there is provided use of a compound of general formula (I') or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Lower Urinary Tract Disorders.
In an eighth aspect of the present invention, there is provided use of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Anxiety and Anxiety-Related Conditions.
In a ninth aspect of the present invention, there is provided use of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Epilepsy. In a tenth aspect of the present invention, there is provided use of a compound of general formula (I') or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Pain Disorders.
In an eleventh aspect of the present invention, there is provided use of a compound of general formula (I') or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Gynaecological Pain.
In a twelfth aspect of the present invention, there is provided use of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiac Arrhythmias.
In a thirteenth aspect of the present invention, there is provided use of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Thromboembolic Events.
In a fourteenth aspect of the present invention, there is provided use of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiovascular Diseases.
In a fifteenth aspect of the present invention, there is provided use of a compound of general formula (P) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Disorders of the Auditory System.
In a sixteenth aspect of the present invention, there is provided use of a compound of general formula (T) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Migraine.
In a seventeenth aspect of the present invention, there is provided use of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Inflammatory and Immunological Diseases.
In an eighteenth aspect of the present invention, there is provided use of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Gastrointestinal Disorders.
In a nineteenth aspect of the present invention, there is provided use of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders.
In a twentieth aspect of the present invention, there is provided use of a compound of general formula (P) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cell Proliferative Disorders.
In a twenty-first aspect of the present invention, there is provided use of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Metabolic Disorders.
In a twenty-second aspect of the present invention, there is provided use of a compound of general formula (I') or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Memory Loss.
In a twenty-third aspect of the present invention, there is provided use of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders.
In a twenty-fourth aspect of the present invention, there is provided use of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Opthalamic Disorders. In an twenty-fifth aspect of the present invention, there is provided 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 general formula (I1) or a pharmacologically acceptable salt or prodrug thereof.
In a twenty-sixth aspect of the present invention, there is provided 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 general formula (I1) or a pharmacologically acceptable salt or prodrug thereof.
In a twenty-seventh aspect of the present invention, there is provided 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 general formula (I1) or a pharmacologically acceptable salt or prodrug thereof.
In a twenty-eighth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Lower Urinary Tract Disorders comprising administering to a patient in need thereof an effective amount of a compound of general formula (I') or a pharmacologically acceptable salt or prodrug thereof.
In a twenty-ninth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Anxiety and Anxiety-Related Conditions comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof.
In a thirtieth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Epilepsy comprising administering to a patient in need thereof an effective amount of a compound of general formula (P) or a pharmacologically acceptable salt or prodrug thereof.
In a thirty-first aspect of the present invention, there is provided a method for the prophylaxis or treatment of Pain Disorders comprising administering to a patient in need thereof an effective amount of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof. In a thirty-second aspect of the present invention, there is provided a method for the prophylaxis or treatment of Gynaecological Pain comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof.
In a thirty-third aspect of the present invention, there is provided a method for the prophylaxis or treatment of Cardiac Arrhythmias comprising administering to a patient in need thereof an effective amount of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof.
In a thirty-fourth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Thromboembolic Events comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof.
In a thirty-fifth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Cardiovascular Diseases comprising administering to a patient in need thereof an effective amount of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof.
In a thirty-sixth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Disorders of the Auditory System comprising administering to a patient in need thereof an effective amount of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof.
In a thirty-seventh aspect of the present invention, there is provided a method for the prophylaxis or treatment of Migraine comprising administering to a patient in need thereof an effective amount of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof.
In a thirty-eighth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Inflammatory and Immunological Diseases comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof. In a thirty-ninth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Gastrointestinal Disorders comprising administering to a patient in need thereof an effective amount of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof.
In a fortieth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders comprising administering to a patient in need thereof an effective amount of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof.
In a forty-first aspect of the present invention, there is provided a method for the prophylaxis or treatment of Cell Proliferative Disorders comprising administering to a patient in need thereof an effective amount of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof.
In a forty-second aspect of the present invention, there is provided a method for the prophylaxis or treatment of Metabolic Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof.
In a forty-third aspect of the present invention, there is provided a method for the prophylaxis or treatment of Memory Loss comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof.
In a forty-fourth aspect of the present invention, there is provided a method for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof.
In a forty-fifth aspect of the present invention, there is provided a method for the prophylaxis or treatment of Opthalamic Disorders comprising administering to a patient in need thereof an effective amount of a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof. In a forty-sixth aspect of the present invention, there is provided a compound of general formula (I) according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof for use in the prophylaxis or treatment of any disease or condition recited in any of the eighth, ninth, seventeenth, eighteenth and twenty-third aspects of the invention recited above.
In a forty-seventh aspect of the present invention, there is provided a compound of general formula (I1) or a pharmacologically acceptable salt or prodrug thereof for use in the prophylaxis or treatment of any disease or condition recited in any of the fourth to seventh, tenth to sixteenth, nineteenth to twenty-second and twenty-fourth aspects of the invention recited above.
In a forty-eighth aspect of the present invention there is provided a pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and at least two active ingredients, wherein said active ingredients comprise at least one compound of general formula (I) according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof or one compound of general formula (I1) as recited in the fourth aspect of the present invention or a pharmacologically acceptable salt or prodrug thereof in combination at least one compound selected from the group consisting of muscarinic receptor antagonists, β3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists, alpha-1 adrenoceptor antagonists, tricyclic antidepressants, N- methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs).
Preferred pharmaceutical combinations according to the present invention include:
(1) 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 of general formula (I) according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof or one compound of general formula (V) as recited in the fourth aspect of the present invention or a pharmacologically acceptable salt or prodrug thereof in combination at least one compound selected from the group consisting of muscarinic receptor antagonists, β3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and α-1 adrenoceptor antagonists; and
(2) 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 of general formula (I) according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof or one compound of general formula (I') as recited in the fourth aspect of the present invention 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 α2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, /V-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal antiinflammatory drugs (NSAIDs).
The combinations of preferred option (1) are of particular use in the prophylaxis or treatment of lower urinary tract disorders. The combinations of preferred option (2) are of particular use in the prophylaxis or treatment of pain.
In a forty-ninth aspect of the present invention there is provided use of at least one compound of general formula (I) according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof or one compound of general formula (I1) as recited in the fourth aspect of the present invention or a pharmacologically acceptable salt or prodrug thereof and at least one compound selected from the group consisting of muscarinic receptor antagonists, β3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ delta ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and α-1 adrenoceptor antagonists in the manufacture of a medicament for the prophylaxis or treatment of lower urinary tract disorders,
In a fiftieth aspect of the present invention there is provided use of at least one compound of general formula (I) according to any one of (1) to (17) or a pharmacologically acceptable salt or prodrug thereof or one compound of general formula (I1) as recited in the fourth aspect of the present invention or a pharmacologically acceptable salt or prodrug thereof and at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α2 δ delta ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, /V-methyl- D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anticonvulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs) in the manufacture of a medicament for the prophylaxis or treatment of pain.
Detailed Description of the Invention
In the compounds of the present invention, the alkyl groups in the definitions of R1 , R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 , R12, R1\ R2\ R3\ R4', R5\ R6', R7', R8', R9', R10', R11 ' 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.
In the compounds of the present invention, the cycloalkyl groups in the definition of R1 , R2, R11 , R12, R11, R2', R11' 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.
In the compounds of the present invention, the aryl groups in the definitions of R1 , R2, R1 ' and R2' 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, 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 which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups. Examples of the 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.
In the compounds of the present invention, the aralkyl groups in the definitions of RT 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. In the compounds of the present invention, the heteroaryl groups in the definitions of R1 , R2, R1 ' and R2' are preferably 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms. Examples include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1 ,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups. Most preferred is pyridyl.
In the compounds of the present invention, the heteroaralkyl groups in the definition of R1 and R1' are preferably alkyl groups as defined above which are substituted with heteroaryl groups as defined above.
In the compounds of the present invention, the cycloalkylalkyl groups in the definition of R1 and R1 ' 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.
In the compounds of the present invention, the aminoalkyl groups in the definition of R1 and R1' are preferably alkyl groups as defined above which are substituted with an amino group, and most preferred are aminopropyl groups and aminobutyl groups.
In the compounds of the present invention, the guanidinoalkyl groups in the definition of R1 and RV are preferably alkyl groups as defined above which are substituted with a guanidino group, and most preferred are guanidinopropyl groups.
In the compounds of the present invention, the alkoxyl groups in the definitions of R2, R3, R4, R5, R6, R11 , R12, Y, R21, R3\ R4\ R5\ R6\ R1 V, R12' 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.
In the compounds of the present invention, the haloalkoxyl groups in the definitions of R2, R3, R4, R5, R6, R11 , R12, R2\ R3\ R4\ R5J, R6\ R1 V 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.
In the compounds of the present invention, the monoalkylamino groups in the definitions of R2, R3, R4, R5, R6, R21, R3\ R4', R5' 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.
In the compounds of the present invention, the dialkylamino groups in the definitions of R2, R3, R4, R5, R6, R2', R3\ R4\ R5' 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.
In the compounds of the present invention, the saturated or partially unsaturated heterocyclic groups in the definitions of R1 , R2, R11 , R12, RT1 R2\ R11' and R12' are 4-8 to membered saturated or partially unsaturated heterocylic groups containing at least one nitrogen, oxgen or sulphur atom, and are more preferably preferably morpholinyl, piperazinyl or pyrrolidinyl groups.
In the compounds of the present invention, the nitrogen-containing heterocyclic groups in the definition of R11 and 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.
In the compounds of the present invention, 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.
In the compounds of the present invention, the aryloxy groups in the defintinion of R11 , R12, R11 ' and R12' are aryl groups as defined above attached to an oxygen atom and are preferably phenyloxy groups. In the compounds of the present invention, the haloalkyl groups in the definitions of R3, R4, R5, R6, R3', R4\ R5' and R6' are preferably alkyl groups as defined above which are substituted with one or more halogen atoms. More preferably, they are alkyl groups having from 1 to 4 carbon atoms that are substituted with at least one chlorine or fluorine atom and most preferably they are chloromethyl group, trichloromethyl groups, trifluoromethyl groups and tetrafluoroethyl groups.
In the compounds of the present invention, the alkoxycarbonyl groups in the definitions of R3, R4, R5, R6, R3', R4', R5' and R6' are preferably carbonyl groups substituted with alkoxy groups as defined, and are more preferably methoxycarbonyl or ethoxycarbonyl groups.
In the compounds of the present invention, the acylamino groups in the definitions of R3, R4, R5, R6, R3', R4', R5' and R6' 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.
In the compounds of the present invention, the alkoxycarbonylamino groups in the definitions of R3, R4, R5, R6, R3', R4', R5' and R6' are preferably amino groups which are substituted with an alkoxycarbonyl group as defined above, and are more preferably methoxycarbonylamino or ethoxycarbonylamino groups.
In the compounds of the present invention, the alkylsulphonyl groups in the definitions of R2, R3, R4, R5, R6, R11 , R12, R2', R3', R4', R5\ R6', R11' 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.
In the compounds of the present invention, the alkylsulphinyl groups in the definitions of R2, R11 , R12, R2', R11 ' and R12' are preferably sulphinyl groups which are substituted with an alkyl group as defined above and are more preferably a methylsulphinyl or ethylsulphinyl group.
In the compounds of the present invention, the arylsulphonyl groups in the definitions of R3, R4, R5, R6, R3', R4', R5' 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.
In the compounds of the present invention, the alkylsulphonylamino groups in the definitions of R2, R3, R4, R5, R6, R2\ R3', R4', R5' and R6' are preferably sulphonylamino groups which are substituted with an alkyl group as defined above and are more preferably a methylsulphonylamino or ethylsulphonylamino group.
In the compounds of the present invention, the arylsulphonylamino groups in the definitions of R3, R4, R5, R6, R3\ R4\ R5' 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.
The pharmacologically acceptable salts of the compound having the formula (I) or formula (I1) described above are not specifically restricted and these salts can be selected by a person with an ordinary skill in the art. As pharmacologically acceptable salts of the compound having the formula (I) or formula (T) described above, 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, triethylamine salt, dicyclohexylamine salt, Λ/,Λ/'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, Λ/-benzyl-phenethylamine salt, piperazine salt, tetramethylammonium salt or tris(hydroxymethyl)aminomethane salt, but not restricted to these salts (preferably alkaline metal salts can be used, and particularly preferably the sodium salt can be used); or acidic salts such as a hydrohalogenic acid salt such as a hydrofluoride, hydrochloride, hydrobromide or hydroiodide; a nitrate; a perchlorate; a sulfate; a phosphate; a Ci-C4 alkanesulfonic acid salt, which may be optionally substituted with a halogen atom(s) such as a methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; a C6-Ci0 arylsulfonic acid salt, which may be optionally substituted with a C1-C4 alkyl group(s), such as a benzenesulfonate or p- toluenesulfonate; a Ci-C6 aliphatic acid salt such as an acetate, malate, fumarate, succinate, citrate, tartrate, oxalate or maleate; or an amino acid salt such as a glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt or aspartic acid salt (preferably hydrochlorides, nitrates, sulfates or phosphates can be used, and particularly preferably hydrochlorides).
The compounds of formula (I) or formula (I1) of the present invention can be administered in the form of prodrugs. Prodrugs are derivatives of the pharmacologically active compound in which one or more of the substituents on said compound are protected by a group which is then removable by a biological process (e.g. hydrolysis) in vivo after administration to the patient. Many suitable prodrugs would be well-known to the person in the art and can be found, for example, in "Greene's Protective Groups in Organic Synthesis", 4th Edition, 2006, Wiley-VCH. Suitable examples of such prodrugs include pharmacologically acceptable esters of the compound having the formula (I) or formula (I') wherein a carboxyl moiety of the compound having the formula (I) or formula (I1) is esterified. The pharmacologically acceptable esters are not particularly restricted, and can be selected by a person with an ordinary skill in the art. In the case of said esters, it is preferable that such esters can be cleaved by a biological process such as hydrolysis in vivo. The group constituting the said esters (the group shown as R when the esters thereof are expressed as -COOR) can be, for example, a Ci-C4 alkoxy Ci-C4 alkyl group such as methoxyethyl, 1- ethoxyethyl, 1-methyl-1 -methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2- ethoxyethyl, 1 ,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; a CrC4 alkoxylated Ci-C4 alkoxy Ci-C4 alkyl group such as 2-methoxyethoxymethyl; a C6-Ci0 aryloxy Ci-C4 alkyl group such as phenoxymethyl; a halogenated CrC4 alkoxy CrC4 alkyl group such as 2,2,2-trichloroethoxymethyl or bis(2-chloroethoxy)methyl; a Ci-C4 alkoxycarbonyl Ci-C4 alkyl group such as methoxycarbonylmethyl; a cyano Ci-C4 alkyl group such as cyanomethyl or 2-cyanoethyl; a Ci-C4 alkylthiomethyl group such as methylthiomethyl or ethylthiomethyl; a C6-Ci0 arylthiomethyl group such as phenyithiomethyl or naphthylthiomethyl; a CrC4 alkylsulfonyl CrC4 lower aikyl group, which may be optionally substituted with a halogen atom(s) such as 2- methanesulfonylethyl or 2-trifluoromethanesulfonylethyl; a C6-C10 arylsulfonyl C1- C4 alkyl group such as 2-benzenesulfonylethyl or 2-toluenesulfonylethyl; a C1-C7 aliphatic acyloxy C1-C4 alkyl group such as formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1- propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1- isovaleryloxyethyl, 1-hexanoyloxyethyl, 2-formyloxyethyl, 2-acetoxyethyl, 2- propionyloxyethyl, 2-butyryloxyethyl, 2-pivaloyloxyethyl, 2-valeryloxyethyl, 2- isovaleryloxyethyl, 2-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1- propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1- butyryloxypentyl, 1-pivaloyloxypentyl or 1-pivaloyloxyhexyl; a C5-C6 cycloalkylcarbonyloxy C1-C4 alkyl group such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1- cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1- cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl or 1- cyclohexylcarbonyloxybutyl; a C6-C1O arylcarbonyloxy C1-C4 alkyl group such as benzoyloxymethyl; a C1-C6 alkoxycarbonyloxy C1-C4 alkyl group such as methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-
(methoxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)butyl, 1-
(methoxycarbonyloxy)pentyl, 1 -(methoxycarbonyloxy)hexyl, ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, 1-
(ethoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)butyl, 1-
(ethoxycarbonyloxy)pentyl, 1 -(ethoxycarbonyloxy)hexyl, propoxycarbonyloxymethyl, 1-(propoxycarbonyloxy)ethyl, 1-
(propoxycarbonyloxy)propyl, 1 -(propoxycarbonyloxy)butyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-
(isopropoxycarbonyloxy)butyl, butoxycarbonyloxymethyl, 1-
(butoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)propyl, 1-
(butoxycarbonyloxy)butyl, isobutoxycarbonyloxymethyl, 1-
(isobutoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)propyl, 1- (isobutoxycarbonyloxy)butyl, t-butoxycarbonyloxymethyl, 1-(t- butoxycarbonyloxy)ethyl, pentyloxycarbonyloxymethyl, 1-
(pentyloxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy)propyl, hexyloxycarbonyloxymethyl, 1-(hexyloxycarbonyloxy)ethyl or 1-
(hexyloxycarbonyloxy)propyl; a C5-C6 cycloalkyloxycarbonyloxy Ci-C4 alkyl group such as cyclopentyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl, cyclohexyloxycarbonyloxymethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1- (cyclohexyloxycarbonyloxy)propyl or 1-(cyclohexy!oxycarbonyloxy)butyl; a [5-(Cr C4 alkyl)-2-oxo-1 ,3-dioxolen-4-yl]methyl group such as (5-methyl-2-oxo-1 ,3- dioxolen-4-yl)methyl, (5-ethyl-2-oxo-1 ,3~dioxolen-4-yl)methyl, (5-propyl-2-oxo- 1 ,3-dioxolen-4-yl)methyl, (5-isopropyl-2-oxo-1 ,3-dioxolen-4-yl)methyl or (5-butyl- 2-0X0-1 , 3-dioxolen-4-yl)methy; a [5-(phenyl, which may be optionally substituted with a Ci-C4 alkyl, Ci-C4 alkoxy or halogen atom(s))-2-oxo-1 ,3-dioxolen-4- yl]methyl group such as (5-phenyl-2-oxo-1 ,3-dioxolen-4-yl)methyl, [5-(4- methylphenyl)-2-oxo-1 ,3-dioxolen-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1 ,3- dioxolen-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1 ,3-dioxolen-4-yl]methyl or [5-(4- chlorophenyl)-2-oxo-1 ,3-dioxolen-4-yl]methyl; or a phthalidyl group, which may be optionally substituted with a Ci-C4 alkyl or Ci-C4 alkoxy group(s), such as phthalidyl, dimethylphthalidyl or dimethoxyphthalidyl, and is preferably a pivaloyloxymethyl group, phthalidyl group or (5-methyl-2-oxo-1 ,3-dioxolen-4- yl)methyl group, and more preferably a (5-methyl-2-oxo-1 ,3-dioxolen-4-yl)methyl group.
The compounds of formula (I) and compounds of formula (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. For example, where the compounds of formula (I) or formula (I1) 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 formula (I), prodrugs thereof and pharmacologically acceptable salts thereof can also be used and form a part of the invention. Some compounds of formula (I) or formula (I1) 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 formula (I) or formula (!') 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 formula
(I) or formula (I1) 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. Moreover, a compound having the general formula (I) or formula
(II) 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.
Examples of excipients include organic excipients such as sugar derivatives, e.g. lactose, sucrose, glucose, mannitol or sorbitol, starch derivatives, e.g. corn starch, potato starch, α-starch, dextrin or carboxymethyl starch, cellulose derivatives, e.g. crystalline cellulose, low substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose or internally crosslinked sodium carboxymethyl cellulose, and gum Arabic, dextran or pullulan; and, inorganic excipients such as silicate derivatives, e.g. light anhydrous silicic acid, synthetic aluminium silicate or magnesium aluminium metasilicate, phosphates, e.g. calcium phosphate, carbonates, e.g. calcium carbonate, or sulfates, e.g. calcium sulfate.
Examples of lubricants include stearic acid and metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as bee gum or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium fatty acid salts; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as silicic anhydride or silicate hydrate; and, starch derivatives.
Examples of binders include polyvinylpyrrolidone, Macrogol and compounds similar to the aforementioned excipients.
Examples of disintegrants agents include compounds similar to the aforementioned excipients, and chemically crosslinked starches and celluloses such as cross sodium carmellose, sodium carboxymethyl starch or crosslinked polyvinylpyrrolidone.
Examples of stabilizers include paraoxybenzoate esters such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenyl ethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; and, sorbic acid.
Examples of corrigents include ordinarily used sweeteners, sour flavourings and fragrances.
In the case of producing a solution or suspension for pulmonary administration of a compound having the general formula (I) or pharmacologically acceptable salt or prodrug thereof of the present invention, for example, said solution or suspension can be produced by dissolving or suspending crystals of the present invention in water or in a mixture of water and an auxiliary solvent (e.g. ethanol, propylene glycol or polyethylene glycol). Such a solution or suspension may also contain an antiseptic (e.g. benzalkonium chloride), solubilizing agent (e.g. a polysorbate such as Tween 80 or Span 80 or surface activator such as benzalkonium chloride), buffer, isotonic agent (e.g. sodium chloride), absorption promoter and/or thickener. In addition, 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). In the case of using an atomizer, crystals of the present invention can be atomized as an aerosol in the form of a pressurized pack together with a suitable nebula (for example, a chlorofluorocarbon such as dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or a gas such as carbon dioxide), or they can be administered using a nebulizer.
The amount of a compound having the general formula (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.
In the combinations according to the forty-seventh aspect of the present invention, typical examples of each of the classes of compounds that can be used in combination with the compounds having the general formula (I) or a pharmacologically acceptable salt or prodrug thereof of the present invention are as follows:
1. Examples of muscarinic receptor antagonists (including but not limited to selective M3 antagonists) include esoxybutynin, oxybutynin [especially the chloride], tolterodine [especially the tartrate], solifenacin [especially the succinate], darifenacin [especially the hydrobromide], temiverine, fesoterodine, imidafenacin and trospium [especially the chloride].
2. Examples of β3 adrenergic receptor agonists include YM-178 and solabegron, KUC-7483.
3. Examples of neurokinin K receptor antagonists (including selective NK-1 antagonists) include cizolirtine and casopitant.
4. Examples of vanilloid VR1 agonists include capsaicin, resiniferatoxin and NDG-8243.
5. Examples of calcium channel α2 δ ligands include gabapentin and pregabalin.
6. Examples of potassium channel activators (including activators of KCNQ, BKCa channels, Kv channels and KATP channels) include KW-7158, NS-8 and retigabine. 7. Examples of calcium channel inhibitors (including Cav2.2 channel inhibitors) include ziconotide and NMED-160.
8. Examples of sodium channel blockers include lidocaine, lamotrigine, VX-409, ralfinamide and carbamazepine.
9. Examples of serotonin and norepinephrine reuptake inhibitors (SNRIs) include duloxetine and venlafaxine
10. Examples of 5-HT antagonists including 5-HT1a antagonists and 5HT3 antagonists.
11. Examples of α-1 adrenoceptor antagonists include tamsulosin.
12. Examples of tricyclic antidepressants include amitriptyline, amoxapine, clomipramine, dosulepin (dothiepin), doxepin, imipramine, lofepramine, nortriptyline, and trimipramine.
13. Examples of /V-methyl-D-aspartate (NMDA) receptor antagonists include ketamine, memantine, amantadine, AVP-923, NP-1 and EVT-101.
14. Examples of cannabinoid receptor agonists include GW-1000 (Sativex) and KDS-2000.
15. Anti-convulsants. Examples include lacosamide, carbamazepine, topiramate, oxcarbazepine and levetiracetam
16. Examples of aldose reductase inhibitors include tolrestat, zopolrestat, zenarestat, epalrestat, sorbinil, AS-3201 , fidarestat, risarestat, ponalrestat and alrestatin.
17. Examples of opioids (e.g. mu opioid agonists) include fentanyl and tapentadol.
18. Examples of alpha adrenoceptor agonists include ai-adrenoceptor agonists such as ethoxamine, phenylephrine, oxymetazoline, tetrahydralazine and xylometazoline and a2-adrenoceptor agonists such as clonidine, guanabenz, guanfacine and α-methyldopa. 19. Examples of P2X receptor antagonists including P2X2 receptor antagonists and P2X7 receptor antagonists.
20. Examples of acid-sensing ion channel modulators include amiloride.
21. Examples of NGF receptor modulators include trkA.
22. Examples of nicotinic acetylcholine receptor modulators include A-85380, tebanicline, ABT-366833, ABT-202, ABT-894, epibatidine analogs and SIB-1663.
23. Examples of synaptic vesicle protein 2A ligands include brivaracetam.
Examples of the administration form of the combination of the present invention are the same as given above for the compounds of general formula (I) 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. For example, a combination of a compound of general formula (I) or a pharmacologically acceptable salt thereof with lidocaine could be administered transdermal^ by means of a patch while a combination with ziconotide could be administered transmucosally.
Synthesis of the Compounds of the Invention
The analogues of the present invention can be synthesised using standard methods and principles as illustrated in the general schemes 1 and 2 below:
Scheme 1
Figure imgf000048_0001
Secondary amines 2 can be prepared by the reductive amination of aldehydes and ketones 1 with a primary amine. The secondary amines can be subsequently reacted with indole-3-glyoxylyl chlorides to give indole-3- glyoxylamides 3. Scheme 2
Figure imgf000049_0001
Esters 4 can be synthesised by the protocol outlined in Scheme 1 , and can be converted to the corresponding acid 5, using standard acid deproction methodology. Amides of structure 6 can be synthesised by conventional amine coupling conditions from the acid 5.
Examples
Example 1 {Cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo-acetyl]- amino}-acetic acid tert-butyl ester 8
Figure imgf000049_0002
Cyclohexanecarboxaldehyde (1.9ml, 0.016mol), glycine te/f-butyl ester.HCI (0.016mol) and triethylamine (4.3ml, 0.031mol) were stirred in methanol (85ml) at O °C for 1 hr. Sodium triacetoxyborohydride (STAB) (6.57g, 0.031 mol) was added to the reaction. The reaction mixture was stirred at room temperature for 18hr. The reaction was filtered, concentrated and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was collected, washed with brine, and the organic layers were combined and dried over MgSO4 and concentrated in vacuo to yield intermediate 7 as a clear liquid. 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 residue was purified by silica flash column chromatography eluting with isohexane and increasing the polarity to 100% ethylacetate to yield {cyclohexylmethyl-[2-(6- methoxy-1 H-indol-3-yl)-2-oxo-acetyl]-amino}-acetic acid tert-butyl ester 8 a yellowish oil (3.9g, 86% yield).
Example 2 {Cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo-acetyl]- amino}-acetic acid 9
Method 1
Figure imgf000050_0001
{Cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo-acetyl]-amino}-acetic acid tert-butyl ester 8 (3.9g, 9.11mmol) was dissolved in 4M HCI in dioxane (50ml) and the reaction was stirred at room temperature for 18hr. The residue was concentrated in vacuo to yield {cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2- oxo-acetyl]-amino}-acetic acid 9 as an off-white solid (2.52g, 75% yield). Example 2 {Cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo-acetyl]- aminoj-acetic acid 9
Method 2
Figure imgf000051_0001
Cyclohexanecarboxaldehyde (1.2mmol) and glycine ethyl ester.HCL (1 mmol) were stirred in dichloromethane (10ml) at room temperature for 30 minutes. STAB (2mmol) and acetic acid (2mmol) were added to the reaction. The reaction mixture was stirred at room temperature for 24hr. The reaction was quenched with 2M NaOH (20ml) and the product extracted with dichloromethane (3 x 10cm). The organic layers were combined, dried over Na2SO4 and the solvent removed in vacuo to yield intermediate 10 as a brown oil.
To a stirred mixture of 10 (230mg, 1.26mmol) and triethylamine (524μl, 3.76mmol) in tetrahydrofuran (25ml) was added 6-methoxy-indole-3-glyoxylyl chloride (297mg, 1.26mmol) in tetrahydrofuran (10ml) at O0C. The mixture was warmed to room temperature and stirred overnight. The mixture was concentrated and partitioned between ethyl acetate (30ml) and water (30ml). The organic layer was separated, dried (MgSO4) and evaporated in vacuo before being purified by column chromatography eluting with DCM 8:2 MeOH/NH3 to yield {Cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo-acetyl]-amino}-acetic acid ethyl ester 11 (220 mg, 43%). {Cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo-acetyl]-amino}-acetic acid ethyl ester 11 (220mg, 0.549mmol) was stirred in 2M NaOH (5ml) overnight. Diethyl ether (8ml) was added and stirred for 5 minutes. The aqueous layer was collected and acidified with cone. HCI before partitioning between ethyl acetate (20ml). The organic layer was collected, dried (MgSO4) and evaporated in vacuo to yield {Cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3~yl)-2-oxo-acetyl]-amino}- acetic acid 9 as a white solid (128mg, 63%).
Example 3 {Cyclohexylmethyl-[2-(6-methoxy-1 H-indoI-3-yl)-2-oxo-acetyl]- amino}-acetic acid methyl ester 12
Figure imgf000052_0001
{Cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo-acetyl]-amino}-acetic acid 9 (218mg, 0.59mmol) was dissolved in dichloromethane (4ml) and (trimethylsilyl)diazomethane (2.OM in Et2O) (700μl, OJmmol) was added. The reaction was stirred at room temperature for 16hr. The reaction was concentrated in vacuo and methanol added to give the product {cyclohexylmethyl-[2-(6- methoxy-1 H-indol-3-yl)-2-oxo-acetyl]-amino}-acetic acid methyl ester 12 as a beige solid (37mg, 16% yield).
General Experimental for the Formation of Amides of Structure 14
Figure imgf000052_0002
13 14 Acid 13 (0.27mmol), Amine (0.4mmol), and 2-(1 H-7-Azabenzotriazol-1-yl)- 1 ,1 ,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (0.41 mmol) were dissolved in DCM:DMF (1 :1 , 2ml), then DIPEA (134μl, 0.81 mmol) was added and the reaction was stirred at room temperature for 18hr. The reaction mixture was diluted with dichloromethane and washed with 1 M HCI, aqueous sodium bicarbonate, and the organic layers were combined and dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to yield amides 15-39, Table 1.
Table 1 :
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Example 4 W-Cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-Λ/-(3-methyl- [1 ,2,4]oxadiazol-5-ylmethyl)-2-oxo-acetamide 41
Figure imgf000060_0001
10 40
Figure imgf000060_0002
41
Λ/-(cyclohexylmethyl)-Λ/-[1 H-indol-3-yl(oxo)acetyl]glycine 10 (0.81 mmol), acetamide oxime (0.81 mmol), and HATU (370mg, 0.97mmol) were dissolved in DCM:DMF (5:2, 7ml), then DIPEA (325μl, 1.97mmol) was added and the reaction was stirred at room temperature for 18hr. The reaction mixture was diluted with dichloromethane and washed with 1 M HCI, aqueous sodium bicarbonate, and the organic layers were combined and dried over MgSO4 and concentrated in vacuo. The residue was purified by silica flash column chromatography eluting with dichloromethane and increasing the polarity to 10% methanol to yield intermediate 40.
Intermediate 40 (0.81 mmol) was dissolved in MeOH (10ml) and subjected to microwave irradiation at 140 0C for 4hr. The residue was concentrated in vacuo and purified by preparative HPLC to yield Λ/-cyclohexylmethyl-2-(6-methoxy-1 H- indol-3-yl)-Λ/-(3-methyl-[1 ,2,4]oxadiazol-5-ylmethyl)-2-oxo-acetamide 41 as an off-white solid (30mg, 10% yield). Example 5 2-{Cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetyl]- amino}-2-methylpropionic acid 44
Figure imgf000061_0001
NaHCO3, toluene
Figure imgf000061_0002
43
Figure imgf000061_0003
42 44
To a stirred mixture of 2~amino-2~methylpropionic acid tert-butyl ester hydrochloride (0.98g, δ.Ommol) in dichloromethane (50ml) was added cyclohexanecarboxaldehyde (730μl, δ.Ommol). This was stirred for 30min before STAB (2.1g, lO.Ommol) and acetic acid (575 μl, lO.Ommol) were added. The mixture was stirred at room temperature overnight. Aqueous sodium hydroxide solution (1 M, 50ml) was added, the biphasic mixture was stirred for 5min and the phases were separated. 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 MgSO4 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, δ.δmmol) 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 1 M NaOH (30ml), water (30ml), 1 M HCI (30ml), water (30ml) and brine (30ml). The organic phase was stirred with activated charcoal and MgSO4 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).
Intermediate 42 (834mg, 1.83mmoi) was dissolved in a 4M HCI solution in dioxane (10ml) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was dissolved in 1 M NaOH (50ml) and the aqueous solution was washed with ethyl acetate (25ml). The aqueous phase was acidified using cone. HCI and the resulting precipitate was isolated by filtration. The solid was successively washed with water and diethyl ether and concentrated in vacuo to provide 2-{cyclohexylmethyl-[2-(6- methoxy-1 H-indol-3-yl)-2-oxo-acetyl]-amino}-2-methylpropionic acid 44 as an off- white solid (190mg, 26% yield).
Example 6 (R)-2-{Cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetyl]-amino}-propionic acid 45
Figure imgf000062_0001
47 45 Synthesised according to procedure for Example 5 using (R)-alanine tert-butyl ester hydrochloride (910mg, δ.Ommol) as a starting material. (R)-2- {cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetyl]-amino}-propionic acid 45 was obtained as a pale grey solid (650mg, 34% yield over 3 steps).
Example 7 (S)-2-{Cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetyl]-amino}-propionic acid 48
Figure imgf000063_0001
To a stirred mixture of (S)-alanine tert-butyl ester hydrochloride (0.98g, δ.Ommol) in dichloromethane (50ml) was added cyclohexanecarboxaldehyde (730μl, δ.Ommol). This was stirred for 30min before STAB (2.1g, l O.Ommol) and acetic acid (575 μl, lO.Ommol) were added. The mixture was stirred at room temperature overnight. Aqueous sodium hydroxide solution (1 M, 50ml) was added, the biphasic mixture was stirred for 5min and the phases were separated. The aqueous phase was further extracted with dichloromethane (2 x 50ml) and the combined organic extracts were dried over MgSO4 and filtered. The solvent was removed in vacuo and the crude intermediate 49 was used without further analysis or purification.
6-methoxy-indole-3-glyoxylyl chloride (1.5g, δ.δmmol) was added to a mixture of intermediate 49 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 1 M NaOH (3OmI)1 water (30ml), 1 M HCI (30ml), water (30ml) and brine (30ml). The organic phase was stirred with activated charcoal and MgSO4 for 1 hr, filtered and concentrated. The residue purified by silica flash chromatography eluting with ethyl acetate and iso-hexane to provide 50 as pale yellow foam (865mg, 42% yield over 2 steps).
Intermediate 50 (865mg, 2.1 mmol) was dissolved in tetrahydrofuran (10ml) and 0.5M LiOH (5ml) was added. The mixture was stirred at room temperature for two days. The organic volatiles were removed under reduced pressure and the remaining aqueous solution was washed with ethyl acetate (5ml), acidified using 1 M HCI and the resulting precipitate was collected by filtration. The solid was successively washed with water and diethyl ether and the organic layers were combined and dried under reduced pressure at 40°C to provide (S)-2- {cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetyl]-amino}-propionic acid 48 as a colourless solid (600mg, 74% yield).
Example 8 Λ/-Cyclohexylmethyl-Λ/-(2-methoxyethyl)-2-(6-methoxy-1 H-indoI- 3-yl)-2-oxoacetamide 52
Figure imgf000064_0001
51 52
To a stirred solution of 2-methoxyethylamine (440μl, δ.Ommol) in dichloromethane (50ml) was added cyclohexanecarboxaldehyde (730μl, δ.Ommol). The solution was stirred for 30min before STAB (2.1g, lO.Ommol) and acetic acid (575μl, lO.Ommol) were added. The mixture was stirred at room temperature overnight. Aqueous sodium hydroxide solution (1 M1 50ml) was added, the biphasic mixture was stirred for 5min and the phases were separated. The aqueous phase was further extracted with dichloromethane (2 x 50ml) and the combined organic extracts were dried over MgSO4 and filtered. The solvent was removed in vacuo and the crude intermediate 51 was used without further analysis or purification.
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 1 M NaOH (30ml), water (30ml), 1 M HCI (30ml), water (30ml) and brine (30ml). The organic phase was stirred with activated charcoal and MgSO4 for 1 hr, filtered and concentrated. The residue was purified by silica flash chromatography using dichloromethane and methanol as an eluent followed by crystallisation from acetonitrile/water to provide Λ/-cyclohexylmethyl-Λ/-(2- methoxyethyl)-2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetamide 52 as colourless needles (135mg, 7% yield over two steps).
Example 9 /V-Cyclohexylmethyl-2-(6-methoxy-1H-indol-3-yl)-/V-(3- methylisoxazol-5-ylmethyl)-2-oxoacetamide 53
Figure imgf000065_0001
53
δ-Chloromethyl-S-methylisoxazole (265mg, 2.0mmol) was added to a mixture of cyclohexylmethylamine (175μl, 1.4mmol), potassium carbonate (550mg, 4.0mmol) and potassium iodide (225mg, 1.4mmol) in acetonitrile (5ml). The resulting suspension was heated to 500C overnight. The inorganic solids were removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate (30ml) and washed with water (30ml). The organic phase was dried over MgSO4, 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), 1M HCI (15ml), water (15ml) and brine (15ml). The organic phase was stirred with activated charcoal and MgSO4 for 1 hr, filtered and concentrated. The crude product was triturated with dichloromethane, filtered and concentrated in vacuo to provide Λ/- cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-/V-(3-methylisoxazol-5-ylmethyl)-2- oxoacetamide 53 as a beige solid (120mg, 21 % yield over 2 steps).
Example 10 Λ/-Cyclohexylmethyl-2-(6-methoxy-1H-indol-3-yl)-Λ/-(5-methyl- isoxazol-3-ylmethyl)-2-oxo-acetamide 55
Figure imgf000066_0001
Synthesised according to procedure for Example 9 using 3-(chloromethyl)-5- methylisoxazole (1g, 7.6mmol) as a starting material. Λ/-Cyclohexylmethyl-2-(6- methoxy-1 H-indol-3-yl)-Λ/-(5-methyl-isoxazol-3-ylmethyl)-2-oxo-acetamide 55 (44mg, 3% yield over 2 steps) was obtained as an off-white solid after purification by preparative HPLC. Example 11 Λ/-CyclohexylmethyI-2-(6-fluoro-1 H-indol-3-yl)-W-(5-methyI- isoxazol-3-ylmethyl)-2-oxo-acetamide 56
Figure imgf000067_0001
Synthesised according to procedure for Example 9 using 3-(chloromethyl)-5- methylisoxazole (1g, 7.6mmol) as a starting material. Λ/-Cyclohexylmethyl-2-(6- fluoro-1H-indol-3-yl)-Λ/-(5-methyl-isoxazol-3-ylmethyl)-2-oxo-acetamide 56
(321 mg, 25% yield over 2 steps) was obtained as an off-white solid after purification by preparative HPLC.
Example 12 Λ/-Cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-/V-(1 H- tetrazol-5-ylmethyl)acetamide 57
Figure imgf000067_0002
Trifluoroacetic acid anhydride (2.8ml, 20mmol) was added to a solution of N- carbamoylmethyl-Λ/-cyclohexylmethyl-2-(6-methoxy-1H-indol-3-yl)-2- oxoacetamide (1.46g, 3.9mmol) in tetrahydrofuran (60ml) containing pyridine (2.8ml, 20mmoi). 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.
Sodium azide (195mg, 3.0mmol) was added to a mixture of the nitrile 58 (210mg, 0.60mmol) in dimethylformamide (3ml) and NH4CI (saturated, 3ml). The reaction mixture was heated to 1200C overnight. The reaction mixture was concentrated in vacuo and the residue was triturated with water, the solid was isolated by filtration and dried under reduced pressure at 600C overnight. N- CyclohexyImethyl-2-(6-methoxy~1 H-indol-3-yl)-2-oxo-/V-(1 H-tetrazol-5- ylmethyl)acetamide 57 was obtained as a beige solid (135mg, 57% yield).
Example 13 3-{Cyclohexylmethyl-[2-(1 H-indoI-3-yl)-2-oxo-acetyl]-amino}- propionic acid 59
1. Et3N, DCM
Figure imgf000068_0001
61
60
Figure imgf000068_0002
59
Cyclohexanecarboxaldehyde (145μL, 1.2mmol) and β-alanine ethyl ester (154mg, 1 mmol) were stirred in dichloromethane (10ml) at room temperature for 3hr, followed by the addition of NaBH4 (76mg, 2mmol). The reaction was then left to stir at room temperature for 24hr.
The reaction was quenched with NaHCO3 (saturated, 20ml) and the product extracted with dichloromethane (3 x 10ml). The organics were combined, dried over Na2SO4, and concentrated in vacuo to yield intermediate 60 as brown oil.
Intermediate 60 was dissolved in dichloromethane (10ml), followed by the addition of triethylamine (560μL, 2mmol) and indoleglyoxyl chloride (415mg, 2mmol). The reaction was allowed to stir 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 organic layers were combined and dried over Na2SO4, and concentrated in vacuo to yield intermediate 61 as a brown oil.
The intermediate 61 dissolved in MeOH (5ml) and 2M NaOH (5ml) added. The reaction was then left to stir at room temperature for 16hr. The solvent was removed from the reaction and water (10ml) added. The aqueous layer was washed with Et2O (10ml) then acidified with 2M HCI until pH 1. The product was then extracted with EtOAc (3 x 20ml), and the organic layers were combined and dried over Na2SO4, and concentrated in vacuo to yield a brown solid.
Purification by preparative HPLC yielded the product, 3-{cyclohexylmethyl-[2- (1 H-indol-3-yl)-2-oxo-acetyl]-amino}-propionic acid 59, as an off-white solid (27.6mg, 8% yield over 3 steps).
Example 14 4-{Cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}- butyric acid 62
Figure imgf000069_0001
Synthesised according to procedure for Example 13 using GABA ethyl ester (131mg, 1 mmol) as a starting material. 4-{Cyclohexylmethyl-[2-(1 H-indol-3-yl)-2- oxo-acetyl]-amino}-butyric acid 62 (79mg, 21% yield over 3 steps) was obtained as an off-white solid after purification by preparative HPLC.
Example 15 {Cyclohexylmethyl-[2-(6-fluoro-1 H-indol-3-yl)-2-oxo-acetyl]- amino}-acetic acid tert-butyl ester 63
Figure imgf000070_0001
63
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 0C. This was then left to warm to room temperature and stirred for 16hr. The solvent was removed in vacuo and quenched with NaHCO3 (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 Na2SO4 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-[2-(6-fluoro-1 H-indol-3-yl)-2-oxo-acetyl]-amino}-acetic acid tert-butyl ester 63 (5.76g, 78% yield). Example 16 {Cyclohexylmethyl-[2-(6-f luoro-1 H-indol-3-yl)-2-oxo-acetyl]- amino}-acetic acid 64
HCl, dioxane
Figure imgf000071_0001
Figure imgf000071_0002
63 64
4M HCI in dioxane (40ml) was added to {Cyclohexylmethyl-[2-(6-fluoro-1 H-indol- 3-yl)-2-oxo-acetyl]-amino}-acetic acid tert-butyl ester 63 (5.76g, 13.9mmol) and left to stir at room temperature for 16hr. The solvent was removed in vacuo and 10:1 Hexane: EtOAc was added (50ml) to the resulting solid. The solid was then filtered and washed with 10:1 Hexane:EtOAc (2 x 50ml). The solid was dried in vacuo to yield the product, {cyclohexylmethyl-[2-(6-fluoro-1 H-indol-3-yl)-2-oxo- acetyl]-amino}-acetic acid 64 as an off white solid (4.43g, 89% yield).
Example 17 Λ/-CyclohexylmethyI-2-(6-methoxy-1H-indol-3-yl)-2-oxo-
Λ/-pyridin-2-ylmethyl-acetamide 66
Figure imgf000071_0003
65
DIPEA, THF
Figure imgf000071_0004
66 To a solution of cyclohexane carboxaldehyde (1.5g, 13.4mmol) in MeOH (20ml) at 0 0C was added Et3N (3.77ml, 26,8mmol) followed by 2-aminomethylpyridine (1.45ml, 14.0mmol). The mixture was stirred at 0 0C for 30 minutes then warmed to room temperature for 1.5hr. The reaction mixture was then cooled to 0 0C and STAB (5.68g, 26.8mmol) was added. The reaction was stirred for 48hr. The MeOH was removed in vacuo and the residue dissolved in ethyl acetate (10ml). NaHCO3 (saturated) was added until pH 9 and the mixture extracted with EtOAc (3 x 10ml). The combined organics were dried over MgSO4 and concentrated in vacuo and the residue purified by silica flash column chromatography eluting with DCM, and increasing the polarity to 5% MeOH(NH3)/DCM to yield the product, cyclohexylmethyl-pyridin-2-ylmethyl-amine 65, as a yellow oil (500mg, 18% yield).
To a solution of cyclohexylmethyl-pyridin-2-ylmethyl-amine 65 (250mg, 1.22mmol) in tetrahydrofuran (10ml) at 0 0C was added DIPEA (0.4ml, 2.45mmol) followed by a solution of 6-methoxyindoleglyoxyl chloride (290mg, 1.22mmol) in tetrahydrofuran (5ml). The reaction was stirred at room temperature for 16hr. The solvent was then removed in vacuo and the residue quenched with NaHCO3 (saturated, 30ml). This was then extracted with ethyl acetate (3 x 30ml). The combined organics were dried over MgSO4 and concentrated to give the product which was purified by preparative HPLC to yield the product, /V- cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-Λ/-pyridin-2-ylmethyl- acetamide 66, as a solid (15mg, 3% yield).
Example 18 Λ/-Cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-
Λ/-pyridin-3-ylmethyl-acetamide 68
Figure imgf000073_0001
67
DIPEA, THF
Figure imgf000073_0002
68
To a solution of cyclohexane carboxaldehyde (1.5g, 13.4mmol) in MeOH (20ml) at 0 0C was added Et3N (3.77ml, 26.8mmol) followed by 3-aminomethylpyridine (1.43ml, 14.0mmol). The mixture was stirred at 0 °C for 30 minutes then warmed to room temperature for 1.5hr. The reaction mixture was then cooled to 0 °C and STAB (5.68g, 26.8mmol) was added. The reaction was stirred for 48hr. The MeOH was removed in vacuo and the residue dissolved in ethyl acetate (10ml). NaHCO3 (saturated) was added until pH 9 and the mixture extracted with EtOAc (3 x 10ml). The combined organics were dried over MgSO4 and concentrated in vacuo and the residue purified by silica flash column chromatography eluting with DCM, and increasing the polarity to 5% MeOH(NH3)/DCM to yield the product, cyclohexylmethylpyridin-3-ylmethyl-amine 67, as a clear colourless oil (1.3g, 48% yield).
To a solution of cyclohexylmethyl-pyridin-3-ylmethyl-amine 67 (650mg, 3.181 mmol) in tetrahydrofuran (10ml) at 0 0C was added DIPEA (1.1ml, 3.363mmol) followed by a solution of 6-methoxy-indole-3-glyoxylyl chloride (756mg, 3.181mmol) in tetrahydrofuran (5ml). The reaction was stirred at room temperature for 16hr. The solvent was then removed in vacuo and the residue quenched with NaHCO3 (saturated, 30ml). This was then extracted with ethyl acetate (3 x 30ml). The combined organics were dried over MgSO4 and concentrated to yield the product which was purified by preparative HPLC to give the product, Λ/-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-Λ/-pyridin-3- ylmethyl-acetamide 68, as a solid (7mg, 0.5% yield).
Example 19 N-CyclohexylmethyI-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-
W-pyridin-4-ylmethyl-acetamide 70
Figure imgf000074_0001
69
DIPEA, THF
Figure imgf000074_0002
70
To a solution of cyclohexane carboxaldehyde (1.5g, 13.4mmol) in MeOH (20ml) at 0 0C was added Et3N (3.77ml, 26.8mmol) followed by 4-aminomethylpyridine (1.52g, 14.0mmol). The mixture was stirred at 0 °C for 30 minutes then warmed to room temperature for 1.5hr. The reaction mixture was then cooled to 0 °C and STAB (5.68g, 26.8mmol) was added. The reaction was stirred for 48hr. The MeOH was removed in vacuo and the residue dissolved in ethyl acetate (10ml). NaHCO3 (saturated) was added until pH 9 and the mixture extracted with EtOAc (3 x 10ml). The combined organics were dried over MgSO4 and concentrated in vacuo and the residue purified by silica flash column chromatography eluting with DCM, and increasing the polarity to 5% MeOH(NH3)/DCM to yield the product, cyclohexylmethyl-pyridin-4-ylmethyl-amine 69, as a clear colourless oil (948mg, 35% yield).
To a solution of cyclohexylmethyl-pyridin^-ylmethyl-amine 69 (474mg, 2.32mmol) in tetrahydrofuran (10ml) at 0 0C was added DIPEA (0.80ml, 4.64mmol) followed by a solution of 6-methoxy-indole-3-glyoxylyl chloride (551 mg, 2.32mmol) in tetrahydrofuran (5ml). The reaction was stirred at room temperature for 16hr. The solvent was then removed in vacuo and the residue quenched with NaHCO3 (saturated, 30ml). This was then extracted with ethyl acetate (3 x 30ml). The combined organics were dried over MgSO4 and concentrated to yield the product which was purified by preparative HPLC to yield the product, Λ/-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-Λ/-pyridin-4- ylmethyl-acetamide 70, as a solid (13mg, 1.3% yield).
Example 20 W-CycIohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo~Λ/-pyridin- 2-ylmethyl-acetamide 71
DlPEA1 THF
Figure imgf000075_0001
65 71
To a solution of cyclohexylmethyl-pyridin^-ylmethyl-amine 65 (250mg, 1.22mmol) in tetrahydrofuran (10ml) at 0 0C was added DIPEA (0.4ml, 2.45mmol) followed by a solution of 6-fluoro-indole-3-glyoxylyl chloride (276mg, 1.22mmol) in tetrahydrofuran (5ml). The reaction was stirred at room temperature for 16hr. The solvent was then removed in vacuo and the residue quenched with NaHCO3 (saturated, 30ml). The reaction was extracted with ethyl acetate (3 x 30ml). The combined organics were dried over MgSO4 and concentrated to give the product which was purified by preparative HPLC to yield the product, N- cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-Λ/-pyridin-2-ylmethyl-acetamide 71 , as a solid (83mg, 17% yield). Example 21 Λ/-Cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-iV-pyridin- 3-ylmethyl-acetamide 72
DlPEA, THF
Figure imgf000076_0001
67 ?2
To a solution of cyclohexylmethyl-pyridin-S-ylmethyl-amine 67 (650mg, 3.18mmol) in tetrahydrofuran (10ml) at 0 0C was added DIPEA (1.1ml, 3.36mmol) followed by a solution of 6-fluoro-indole-3-glyoxylyl chloride (718mg, 3.18mmol) in tetrahydrofuran (5ml). The reaction was stirred at room temperature for 16hr. The solvent was then removed in vacuo and the residue quenched with NaHCO3 (saturated, 30ml). The reaction was extracted with ethyl acetate (3 x 30ml) and the combined organics were dried over MgSO4 and concentrated to give the product which was purified by preparative HPLC to yield the product, N- cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-Λ/-pyridin-3-ylmethyl-acetamide 72, as a solid (494mg, 39% yield).
Example 22 Λ/-Cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-Λ/-pyridin- 4-ylmethyl-acetamide 73
DlPEA, THF
Figure imgf000076_0002
69 73
To a solution of cyclohexylmethyl-pyridin^-ylmethyl-amine 69 (474mg,
2.32mmol) in tetrahydrofuran (10ml) at 0 0C was added DIPEA (0.80ml,
4.64mmol) and a solution of 6-fluoro-indole-3-glyoxylyl chloride (523mg, 2.32mmol) in tetrahydrofuran (5ml). The reaction was stirred at room temperature for 16hr. The solvent was then removed in vacuo and the residue quenched with NaHCO3 (saturated, 30ml). The reaction was extracted with ethyl acetate (3 x 30ml) and the combined organic layers were dried over MgSO4 and concentrated to yield the product which was purified by preparative HPLC to give the product, Λ/-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-Λ/-pyridin-4-ylmethyl- acetamide 73, as a solid (358mg, 39% yield).
Example 23 {[3-(tert-Butoxycarbonylamino-methyl)-benzyl]-[2-(1H- indol-3-yl)-2-oxo-acetyl]-amino}-cyclohexyl-acetic acid 77
Figure imgf000077_0001
75 1. 2M, NaOH1 MeOH
2. indoleglyoxylyl Chloride
Figure imgf000077_0002
(BoC)2O (5g, 22.91 mmol) was added slowly to m-xylylenediamine (1 Og, 73.43mmol) and triethylamine (20ml, 137.5mmol) in dichloromethane (75ml) at O 0C. The reaction was then left to warm to room temperature and stir for 16hr. The reaction was quenched with NaHCO3 (saturated, 100ml) and the product extracted with DCM (3 x 100ml). The organics were combined, dried over Na2SO4 and concentrated in vacuo to yield a yellow oil. Purification by silica flash column chromatography, eluting with DCM, and increasing the polarity to 10% MeOH(NH3)/DCM yielded the product, ferf-butyl 3-
(aminomethyl)benzylcarbamate 74, as a yellow oil (2.5g, 46% yield).
Bromocyclohexane (2ml) was added to magnesium (6.53g, 0.27mol) in Et2O (5ml) at room temperature. A crystal of iodine was added and the reaction warmed to reflux. The reaction was then left to stir at this temperature for IOmins after the colour had disappeared. Further bromocyclohexane (28ml) was added as a solution in Et2O (105ml), maintaining a gentle reflux for 1 hr. On cooling the reaction was added to diethyl oxalate (40ml, 0.29mol) in a 1 :1 tetrahydrofu ran: Et2O mixture (60ml) at -78 °C, keeping the temperature below - 60 °C. Once the addition was complete, the reaction was stirred at 60 0C temperature for 1 hr. The reaction was quenched with 2M HCI (200ml) and the product extracted with Et2O (3 x 200ml). The organic layers were combined, dried over Na2SO4, and concentrated in vacuo to yield a yellow oil. Purification by distillation (110-120 0C at 6 mmHg) yielded the product, ethyl 2-cyclohexyl-2- oxoacetate 75, as a yellow oil (6Og).
ferf-Butyl 3-(aminomethyi)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 μl_, 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 NaHCO3 (saturated, 10ml) and the product extracted with DCM (3 x 15ml). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to yield a yellow oil. Purification by silica flash column chromatography, eluting with 10:1 Hexane: EtOAc, and increasing the polarity to EtOAc to yield the product, ethyl 2- (3-((te/f-butoxycarbonylamino)methyl)benzylamino)-2-cyclohexylacetate 76, as a yellow oil (413mg, 91% yield). 2M NaOH (δOOmg, 10.22mmol) was added to 2-(3-((fe/f- butoxycarbonylamino)methyl)benzylamino)-2-cyclohexylacetate (413mg,
1.022mmol) in MeOH (5ml). The reaction was warmed to 70 0C and left to stir at this temperature for 24hr. The reaction was cooled to room temperature and indole-3-glyoxylyl chloride (1g, 5.12mmol) was added. The reaction was then left to stir for 16hr. The reaction was acidified to pH 1 using 2 M HCI (20ml) and then product extracted with DCM (3 x 50ml). The organics were combined, dried over Na2SO4, and concentrated in vacuo to yield a yellow solid. Purification by silica flash column chromatography, eluting with DCM, and increasing the polarity to 20% MeOH (AcOH)/DCM, to yield the product, {[3~(tert-butoxycarbonylamino- methyl)-benzyl]-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}-cyclohexyl-acetic acid 77, as an off-white foam (239mg, 43% yield).
1H NMR (CDCI3): 0.6 - 2.0 (2OH, m, Cy), 3.9 - 5.0 (5H, m, CH2), 6.95 - 8.1 (9H, m, Ar)1 8.2 - 8.4 (1 H1 br s, NH).
Example 24 {(3-Aminomethyl-benzyl)-[2-(1 H-indol-3-yl)-2-oxo-acetylJ- amino}-cyclohexyl-acetic acid 78
Figure imgf000079_0001
TFA (1ml) was added to {[3-(tert-Butoxycarbonylamino-methyl)-benzyl]-[2-(1 H- indol-3-yl)-2-oxo-acetyl]-amino}-cyclohexyl-acetic acid 77 (50mg, 0.091 mmol) in DCM (4ml) at room temperature. The reaction was left to stir at room temperature for 16hr. The solvent was removed in vacuo and the resulting oil, basified with 2M NaOH (10ml). The aqueous layer was washed with EtOAc (3 x 10ml), and the organic layers were combined and dried over Na2SO4, and concentrated in vacuo to yield a brown oil. Purification by preparative HPLC yielded the product, {(3-aminomethyl-benzyl)-[2-(1 H-indol-3-yl)-2-oxo-acetyl]- aminoj-cyclohexyl-acetic acid 78 (24mg, 59% yield). Example 25 2-{(3-Aminomethyl-benzyl)-[2-(1 H-indol-3-yl)-2-oxo-acetyl]- amino}-2-cycIohexyl-acetamide 79
Figure imgf000080_0001
CDI (59mg, 0.36mmol) was added to {[3-(tert-butoxycarbonylamino-methyl)- benzyl]-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}-cyclohexyl-acetic acid 77 (180mg, 0.33mmol) in DMF (3ml) at 50 0C. 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 (1 ml) at room temperature. The reaction was stirred at room temperature for 16hr. The solvent was removed in vacuo and the resulting oil, basified with 2M NaOH (10ml). The aqueous layer was washed with EtOAc (3 x 10ml), and the combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield a brown oil. Purification by preparative HPLC yielded the product, 2-{(3- aminomethyl-benzyl)-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}-2-cyclohexyl- acetamide 79 (12mg, 22% yield).
Example 26 [3-({(1 -tert-Butylcarbamoyl-ethyl)-[2-(1 H-indol-3-yl)-2-oxo- acetyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester 82
Figure imgf000081_0001
81
Figure imgf000081_0002
'Butylamine (3.65ml, 34.74mmol) was added slowly to 2-bromopropionyl bromide (5g, 23.16mmol) in tetrahydrofuran (70ml) at 0 0C. The reaction was warmed to room temperature and stirred for 16hr. The solvent was removed in vacuo, followed by addition of EtOAc (50ml) and quenching with NaHCO3 (saturated, 50ml). The product was extracted using EtOAc (3 x 20ml), the combined organic layers were dried over Na2SO4, before being concentrated in vacuo to yield the product, 2-bromo-Λ/-fe/f-butylpropanamide 80, as a white solid (4.55 g, 95% yield).
3-((1 -(te/t-Butylamino)-1 -oxopropan-2-ylamino)methyl)benzylcarbamate 80
(200mg, 0.97mmol) was added to (tert-butyl 3-(aminomethyl)benzylcarbamate 74 (251 mg, 1.06mmol) and K2CO3 (200mg, 1.45mmol) in tetrahydrofuran (3ml) at room temperature. The reaction was heated to reflux and left to stir for 16hr. The solvent was removed in vacuo, followed by addition of EtOAc (10ml) and quenching with 2M NaOH (10ml). The product was extracted using EtOAc (3 x 20ml) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield a yellow oil. Purification by silica flash column chromatography, eluting with 5:1 Hexane: EtOAc, and increasing the polarity to EtOAc to yield the product, ferf-butyl 3-((1-(ferf-butylamino)-1-oxopropan-2- ylamino)methyl)benzylcarbamate 81 (55mg, 16% yield).
Indoleglyoxyl chloride (38mg, 0.18mmol) was added to a stirring solution of tert- butyl 3-((1 -(te/t-butylamino)-1 -oxopropan-2-ylamino)methyl)benzylcarbamate 81 (55mg, 0.15mmol) and triethylamine (42μL, 0.30mmol) in tetrahydrofuran (1 ml). The reaction was stirred at room temperature for 16hr before being quenched with 2M NaOH (1 OmI) and the product extracted with EtOAc (3 x 1 OmI). The combined organic layers were dried over Na2SO4 and the concentrated in vacuo to yield an off-white solid. Purification by silica flash column chromatography, eluting with 9:1 Hexane: EtOAc, and increasing the polarity to EtOAc to yield the product, fe/f-butyl [3-({(1-tert-butylcarbamoyl-ethyl)-[2-(1 H-indol-3-yl)-2-oxo- acetyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester 82, as a yellow oil (59mg, 73% yield).
1H NMR (CDCI3): 1.0 - 1.5 (21 H, m, 1Bu, Boc and MeCHN), 2.2 - 2.4 (1 H, q, CH3H(N)CO), 3.5 - 5.0 (4H, NCH2Ar and BocNCH2Ar), 7.0 - 8.4 (9H, m, Ar), 10.3 and 10.6 (1 H, br s, NH).
Example 27 2-{(3-Aminomethyl-benzyl)-[2-(1 H-indol-3-yl)-2-oxo-acetyl]- amino}-/V-tert-butyl-propionamide 83
4M HCI, Dioxane
Figure imgf000082_0001
Figure imgf000082_0002
4M HCI in dioxane (4ml) was added to [3-({(1-tert-butylcarbamoyl-ethyl)-[2-(1 H- indol-S-yO^-oxo-acetylJ-aminoJ-methyO-benzylJ-carbamic acid tert-butyl ester 82 (59mg, O.Hmmol) and the reaction was stirred at room temperature for 16hr. The residue was concentrate in vacuo and the resulting oil, basified with 2M NaOH (1OmI). The aqueous layer was washed with EtOAc (3 x 1OmI), and the combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield a brown oil. Purification by preparative HPLC yielded the product, 2-{(3- aminomethyl-benzyl)-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}-Λ/-tert-butyl- propionamide 83 (20mg, 39% yield).
Example 28 4-(2-{Cyclohexylmethy!-[2-(1 H-indoI-3-yl)-2-oxo-acetyl]- amino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester 84
Figure imgf000083_0001
Cyclohexanecarboxaldehyde (145μL, 1.2mmol) and Boc-aminoethylpiperazine (229mg, 1 mmol) were stirred in DCM (10ml) at room temperature for 30mins before the addition of STAB (424mg, 2mmol) and acetic acid (114μL, 2mmol). The reaction was stirred at room temperature for 24hr before being quenched with 2M NaOH (20ml) and the product extracted with DCM (3 x 10ml). The combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield a brown oil. The brown oil was dissolved in DCM (10ml) before the addition of triethylamine (278μl, 2mmol) and indole-3-glyoxylyl chloride (414mg, 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 Na2SO4, and concentrated in vacuo to yield the product, 4-(2- {cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}-ethyl)-piperazine-1- carboxylic acid tert-butyl ester 84, as a brown oil which was carried through to the next step without further purification. Example 29 W-Cyclohexylmethyl-2-(1 H-indol-3-yl)-2-oxo-Λ/-(2-piperazin-1 - yl-ethyl) acetamide 85
Figure imgf000084_0001
TFA (0.5ml) was added to 4-(2-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo- acetyl]-amino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester 84 (1 mmol) in DCM (5ml) at room temperature. The reaction was stirred for 16hr. The residue was concentrated in vacuo and the reaction quenched with NaHCO3 (saturated, 20ml). The product was extracted with DCM (3 x 20ml), and the combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield the product as a brown oil which was purified by preparative HPLC yielding the product, Λ/-cyclohexylmethyl-2-(1 H-indol-3-yl)-2-oxo-Λ/-(2-piperazin-1-yl-ethyl)- acetamide 85, as an off white solid (64.1 mg, 16% yield over 2 steps).
Example 30 (4-{Cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}- butyl)-carbamic acid tert-butyl ester 86
then ,
Figure imgf000084_0002
Figure imgf000084_0003
Cyclohexanecarboxaldehyde (145μl_, 1.2mmol) and Boc-butanediamine (188mg, 1mmoi) were stirred in DCM (10ml) at room temperature for 30mins before the addition of STAB (424mg, 2mmol) and acetic acid (114 μL, 2mmol). The reaction was stirred at room temperature for 24hr. The reaction was quenched with 2M NaOH (20ml) and the product extracted with DCM (3 x 10ml). The combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield a brown oil. This was dissolved in DCM (10ml) before the addition of triethylamine (278μL, 2mmol) and indole-3-glyoxylyl chloride (414mg, 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). The combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield the product, (4-{cyclohexylmethyl-[2-(1H-indol-3- yl)-2-oxo-acetyl]-amino}-butyl)-carbamic acid tert-butyl ester 86, as a brown oil which was carried through to the next step without further purification.
Example 31 (4-{Cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}- butyl)-carbamic acid tert-butyl ester 87
Figure imgf000085_0001
TFA (0.5ml) was added to (4-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]- amino}-butyl)-carbamic acid tert-butyl ester 86 (1mmol) in DCM (5ml) at room temperature. The reaction was stirred for 16hr. The solvent was removed in vacuo and the reaction quenched with NaHCO3 (20ml). The product was extracted with DCM (3 x 20ml), and the combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield a brown oil. The product was purified by preparative HPLC yielding the product, (4-{cyclohexylmethyl-[2-(1 H-indol-3- yl)-2-oxo-acetyl]-amino}-butyl)-carbamic acid tert-butyl ester 87, as an off white solid (31.7mg, 9% yield over 2 steps). Example 32 {2-(1H-lndol-3-yl)-2-oxo-acetyl]-methyl-amino}-acetic acid 88
Figure imgf000086_0001
88
lndole-3-glyoxylyl chloride (284mg) was added to sarcosine (89mg) in 2M NaOH (2ml) and the reaction stirred at room temperature for 16hr. The aqueous layer was extracted with EtOAc (2 x 1OmI) and then acidified to pH 1 using concentrated HCI. The product was extracted with EtOAc (3 x 20ml), and the combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield a yellow solid which was purified by preparative HPLC to yield the product, {[2-(1 H-indol-3-yl)-2-oxo-acetyl]-methyl-amino}-acetic acid 88, as an off-white solid (55.3mg, 21 % yield).
Example 33 [3-({Cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}- methyl)-benzyl]-carbamic acid tert-butyl ester 90
Figure imgf000086_0002
Cyclohexanecarboxaldehyde (231 μl, 1.90mmol) was added to terf-butyl [3- (aminomethyl)benzyl]carbamate 74 (500mg, 2.12mmol) and 4A molecular sieves (~10mg) in DCM (3ml) at room temperature. The reaction was stirred at room temperature overnight. The reation mixture was concentrated in vacuo. The resulting oil was dissolved in DCM (3ml). Acetic acid (242μl, 4.23mmol) was added and the reaction stirred for 4hr before adding STAB (897mg, 4.23mmol). The reaction was stirred at room temperature overnight before being quenched with NaHCO3 (saturated, 10ml). The product was extracted with DCM (3 x 15ml) and the combined organic layers were dried over Na2SO4 and the concentrated in vacuo to yield a yellow oil. Purification by silica flash column chromatography, eluting with DCM, and increasing the polarity to 20% MeOH to yield the product, ferf-butyl (3-{[(cyclohexylmethyl)amino]methyl}benzyl)carbamate 89, as a colourless oil which solidified on standing (470mg, 67% yield).
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 (400μl, 2.83mmoi) 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 Na2SO4, and concentrated in vacuo to yield a yellow solid. Purification by silica flash column chromatography, eluting with 10:1 Hexane: EtOAc, and increasing the polarity to EtOAc to yield the product [3-({cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}-methyl)- benzyl]-carbamic acid tert-butyl ester 90, as a white foam (630mg, 89% yield).
1H NMR (CDCI3): 0.6 - 1.8 (2OH, m, cHex and 1Bu), 3.0 - 3.3 (2H, m, NH2CH2 0HeX), 4.1 - 5.0 (4H, s, NH2CH2ArCH2NHBoC), 5.2 (1 H, br s, NH(Boc)), 7.0 - 8.4 (9H, m, Ar), 9.9 - 10.1 (1 H, m, NH)
Example 34 W-(3-Aminomethyl-benzyl)-W-cyclohexylmethyl-2-(1 H-indol-3- yl)-2-oxo-acetamide 91
91
Figure imgf000087_0001
TFA (2ml) was added to [3-({cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]- amino}-methyl)-benzyl]-carbamic acid tert-butyl ester 90 (630mg, 1 ,25mmol) in DCM (8ml) at room temperature. The reaction was stirred at room temperature for 16hr, The solvent was removed in vacuo and the resulting oil, basified with 2M NaOH (1OmI). The aqueous layer was washed with EtOAc (3 x 10ml), and the combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield an off-white foam. Purification by silica flash column chromatography, eluting with DCM, and increasing the polarity to 10% MeOH (10% NH3) to yield the product, Λ/-(3-aminomethyl-benzyl)-Λ/-cyclohexylmethyl-2-(1 H-indol-3-yl)-2- oxo-acetamide 91 (154mg, 31% yield).
Example 35 3-{Cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}- propionic acid 92
Figure imgf000088_0001
Cyclohexanecarboxaldehyde (145μl, 1.2mmol) and β-alanine ethyl ester (154mg, 1mmol) were stirred in DCM (10ml) at room temperature for 3hr before the addition of NaBH4 (76mg, 2mmol). The reaction was stirred at room temperature for 24hr before being quenched with NaHCO3 (saturated, 20ml). The product was extracted with DCM (3 x 10ml) and the combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield a brown oil. The brown oil was dissolved in DCM (10ml) before the addition of triethylamine (560μl, 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 Na2SO4, 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 aqueous layer was washed with Et2O (10ml) and acidified with 2M HCI until pH 1. The reaction was then extracted with EtOAc (3 x 20ml), and the combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield a brown solid. Purification by preparative HPLC yielded the product 3-{cyclohexylmethyl-[2-(1 H-indol-3-yl)- 2-oxo~acetyl]-amino}-propionic acid 92, as an off-white solid (27,6mg, 8% yield over 3 steps).
Example 36 4-{Cyclohexylmethyl-[2~(1 H-indol-3-yl)-2-oxo-acetyl]-amino}~ butyric acid 93
1. cHexCHO, DCM, then NaBH
Figure imgf000089_0002
Figure imgf000089_0001
Cyclohexanecarboxaldehyde (145μl, 1.2mmol) and GABA ethyl ester (131 mg, 1 mmol) were stirred in DCM (10ml) at room temperature for 3hr before the addition of NaBH4 (76mg, 2mmol). The reaction was stirred at room temperature for 24hr. The reaction was quenched with NaHCO3 (saturated, 20ml) and the product extracted with DCM (3 x 10ml). The combined organics were dried over Na2SO4, and concentrated in vacuo to yield a brown oil which was dissolved in DCM (10ml) before the addition of triethylamine (560μl, 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 reaction was extracted with EtOAc (3 x 20ml), and the combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield a brown oil. The brown oil was dissolved in MeOH (5ml) and 2M NaOH (5ml). The reaction was stirred at room temperature for 16hr. The solvent was removed from the reaction before adding water (10ml). The aqueous layer was washed with Et2O (10ml) and acidified with 2M HCI until pH 1. The reaction was extracted with EtOAc (3 x 20ml), and the combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield a brown solid. Purification by preparative HPLC yielded the product, 4-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2- oxo-acetyl]-amino}-butyric acid 93, as an off-white solid (78.8mg, 21 % yield over 3 steps) Example 37 (S)-5-Amino-2-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo- acetyl]-amino}-pentanoic acid 94
NaBH4
Figure imgf000090_0002
Figure imgf000090_0001
Cyclohexanecarboxaldehyde (145μl, 1.2mmol) and L-Om-(Z)-CbZ-O1Bu-HCI (322mg, 1 mmol) were stirred in DCM (10ml) at room temperature for 3hr before the addition of NaBH4 (76mg, 2mmol). The reaction was stirred at room temperature for 24hr. The reaction was quenched with NaHCO3 (saturated, 20ml) and extracted with DCM (3 x 10ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield a brown oil which was dissolved in DCM (10ml) before the addition of triethylamine (560μl, 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) before being extracted with EtOAc (3 x 20ml). The combined organic layers were dried over Na2SO4, and concentrated in vacuo to yield a brown oil. HBr in acetic acid (5ml) was added to the brown oil and the reaction left to stir at room temperature for 16hr. The solvent was removed in vacuo to yield the product, (S)-5-amino-2-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo- acetyl]-amino}-pentanoic acid 94, as an off-white solid (71.8mg, 18% yield over 3 steps).
Example 38 (S)-6-Amino-2-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo- acetyl]-amino}-hexanoic acid 95
NaBH4
Figure imgf000091_0001
Figure imgf000091_0002
Cyclohexanecarboxaldehyde (145μl, 1.2mmol) and H-LyS-(BoC)-O1Bu. HCI (302mg, 1 mmol) were stirred in DCM (10ml) at room temperature for 3hr before the addition of NaBH4 (76mg, 2mmol). The reaction was stirred at room temperature for 24hr before being quenched with NaHCO3 (saturated, 20ml) and extracted with DCM (3 x 10ml), The combined organics were dried over Na2SO4, and concentrated in vacuo to yield a brown oil which was dissolved in DCM (10ml) before the addition of triethylamine (560μl, 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) and extracted with EtOAc (3 x 20ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield a brown oil. TFA (1 ml) was added to the brown oil in DCM (5ml) and the reaction was stirred at room temperature for 16hr. The solvent was removed in vacuo and purification by preparative HPLC yielded the product, (S)-6-amino-2-{cyclohexylmethyl-[2-(1 H- indol-3-yl)-2-oxo-acetyl]-amino}-hexanoic acid 95, as an off-white solid (72.5mg, 18% yield over 3 steps).
Example 39 W-Cyclohexyl-2-(1H-indol-3-yl)-/V-methyl-2-oxoacetamide 96
Figure imgf000091_0003
lndole-3-glyoxylyl chloride (393mg, 1.89mmol) in tetrahydrofuran (4ml) was added to Λ/~methylcyclohexylamine (250μl, 1.89mmol) and triethylamine (882μl, 5.69mmol) in tetrahydrofuran (10ml) at O0C. The mixture was warmed to room temperature and stirred for 2hr before concentrated in vacuo. The resulting reaction mixture was dissolved in ethyl acetate (15ml) and washed with 2M HCI (1OmI)1 brine (10ml). The organic layer was dried (MgSO4) and concentrated in vacuo to yield Λ/-cyclohexyl-2-(1 H-indol-3-yl)-Λ/-methyl-2-oxoacetamide 96 as a brown solid (324mg, 60%).
Example 40 Λ/-Cyclohexyl-W-[1 H-indol-3-yl(oxo)acetyl]glycine 99
Figure imgf000092_0001
97 98
Figure imgf000092_0002
99
To a stirred mixture of glycine ethyl ester hydrochloride (1.49g, 10.18mmol) and triethylamine (2.9ml, 21.43mmol) in methanol (25ml) was added cyclohexanone (1g, 10.18mmol). The reaction was stirred for 6hr before being cooled to 0 0C. STAB (4.31g, 20.37mmol) was added portion wise. The mixture was warmed to room temperature and stirred overnight. The solvent was removed in vacuo and partitioned between ethyl acetate (25m!) and water (25ml). The pH of the mixture was adjusted to pH 9 with sodium bicarbonate. The organic layer was dried (MgSO4) and concentrated in vacuo to yield intermediate 97 (1.2g, 63%).
lndole-3-glyoxylyl chloride (178mg, 0.86mmol) in tetrahydrofuran (3ml) was added to intermediate 97 and triethylamine (378μl, 2.70mmol) in tetrahydrofuran (8cm) at 0 0C. The reaction was warmed to room temperature and stirred for 1.5hr before being concentrated in vacuo. The reaction was partitioned between dichloromethane (1 OmI)) and 2M HCI (2ml). The organic layer was collected and concentrated in vacuo. The reaction was purified by flash column chromatography eluting with 9:1 dichioromethane:methanol to yield intermediate
98 (100 mg, 33%).
Intermediate 98 (100mg, 0.28mmol) was stirred in 2M NaOH (5ml) overnight. Diethyl ether (5ml) was added and the reaction stirred for 5mins. The aqueous layer was separated and acidified with cone HCI before extracting with ethyl acetate (2 x 10ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo to yield Λ/-cyclohexyl-Λ/-[1 H-indol-3-yl(oxo)acetyl]glycine
99 as a brown solid (70 mg, 76%).
Example 41 Λ/-Cyclohexyl-2-(1 H-indol-3-yl)-2-oxo-Λ/-(3-pyrrolidin-1 - ylpropyl)acetamide 101
Figure imgf000093_0001
Cyclohexanone (2g, 20.37mmol) was added to 1-(3-Aminopropyl)pyrrolidine (2.61g, 20.37mmol) and sodium cyanoborohydride (1.28g, 20.37mmol) in methanol (40ml). The mixture was stirred for 3 days before cone HCI (2ml) was added. After stirring for 1 hr the reaction mixture was concentrated in vacuo. The crude mixture was dissolved in water (30ml), basified with aqueous NaHCO3, and extracted with ethyl acetate (3 x 50ml). The combined organic layers were washed with brine (50ml), dried (MgSO4) and concentrated in vacuo to yield intermediate 99 (2.4g, 56%) which was used in the next step without purification.
lndole-3-glyoxylyl chloride (235mg, 1.14mmol) in tetrahydrofuran (1 ml) was added to intermediate 100 (299mg, 1.42mmol) and triethylamine (594μl, 4.27mmol) in tetrahydrofuran (10ml) at 0 0C. The mixture was stirred overnight at room temperature and then concentrated in vacuo before partitioning between dichloromethane (6ml) and 2M HCI (6ml). The organic layer was collected and concentrated in vacuo. The crude reaction mixture was purified by column chromatography eluting with 9:1 DCM:MeOH/NH3) to yield Λ/-cyclohexyl-2-(1 H- indol-3-yl)-2-oxo-Λ/-(3-pyrrolidin-1-ylpropyl)acetamide 101 (104 mg, 24%).
Example 42 W-(Cyclohexylmethyl)-2-(1 H-indol-3-yl)-Λ/-methyl-2- oxoacetamide 104
MeNH21 THF
Figure imgf000094_0002
Figure imgf000094_0001
Methylamine in tetrahydrofuran (34ml of 2M solution, 68mmol) was cooled to O0C. Cyclohexane carbonyl chloride (5g, 34.1mmol) in tetrahydrofuran (40ml) was added slowly. The reaction mixture was warmed to room temperature and stirred overnight before being concentrated in vacuo and partitioned between aqueous sodium bicarbonate (75ml) and ethyl acetate (100ml). The organic layer was collected and washed with brine (75ml), dried (MgSO4) and concentrated in vacuo to yield intermediate 102 (4.81 g, 99%).
Lithium aluminium hydroxide (3.89g, 27.54mmol) was added to intermediate 102 (3.89g, 27.54mmol) in dry tetrahydrofuran at O0C under argon. After stirring for 30mins, the reaction mixture was heated at reflux overnight. After cooling, sodium decahydrate was added portionwise over 30mins. The reaction was extracted with ethyl acetate (2 x 100ml) and filtered through celite. The mixture was concentrated in vacuo to yield intermediate 103 (2.75 g, 78%).
lndole-3-glyoxylyl chloride (370mg, 1.78mmol) in tetrahydrofuran (5ml) was added to intermediate 103 (267mg, 2.10mmol) and triethylamine (671 μl, 4.82mmol) in tetrahydrofuran (30ml) at O0C. After stirring for 3hr at room temperature the mixture was concentrated in vacuo before partitioning between water (50ml) and ethyl acetate (50ml). The organic layer was collected, dried (MgSO4) and concentrated in vacuo. 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)-Λ/-methyl-2-oxoacetamide (254mg, 47%) 104. Example 43 W-(Cyclohexylmethyl)-Λf-[1H-indol-3-yl(oxo)acetyl]glycine 107
Figure imgf000095_0001
Triethylamine (2mmol) and indole-3-glyoxylyl chloride (2mmol) were added to intermediate 10 in dichloromethane (10ml). The reaction was stirred at room temperature for 24hr. The solvent was removed in vacuo and the reaction mixture quenched with water (20ml). The reaction was extracted with ethyl acetate (3 x 20ml) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was purified by preparative HPLC to yield intermediate 106 as a white solid (14.9mg, 4%).
Intermediate 106 (30mg, O.Oδmmol) was dissolved in 2M NaOH (20ml) and stirred at room temperature for 24hr. The reaction was acidified to pH1 using cone. HCI and the product was extracted with ethyl acetate (3 x 20ml). The combined organic layers were dried over Na2SO4 and the solvent removed in vacuo. The crude reaction mixture was purified by preparative HPLC to yield N- (cyclohexylmethyl)-Λ/-[1 H-indol-3-yl(oxo)acetyl]glycine 107 as an off white solid (14.9mg, 54%).
Example 44 tø-(Cyclohexylmethyl)-2-(1 H-indol-3-yl)-2-oxo-Λ/-(3-pyrrolidin-1 - ylpropyl)acetamide 109
Figure imgf000095_0002
108 Cyclohexanecarboxaldehyde (1.2mmol) and aminopropylpyrroldine (1mmol) were stirred in dichloromethane (10ml) and 4A molecular sieves at room temperature for 16hr. The molecular sieves were removed by filtration and the resulting solution cooled to O0C. NaBH4 (lOmmol) was added and the reaction warmed to room temperature and stirred for 16hr. The reaction was quenched with 2M NaOH (20ml) and the product extracted with dichloromethane (3 x 10ml). The combined organic layers were dried (Na2SO4) and the solvent removed in vacuo to yield intermediate 108.
Intermediate 108 was dissolved in dichloromethane (10ml) before the addition of triethylamine (2mmol) and indole-3-glyoxylyl chloride (2mmol). The reaction was stirred at room temperature for 24hr. The solvent was removed in vacuo and the reaction quenched with water (20ml) and extracted with ethyl acetate (3 x 20ml). The combined organic layers were dried (Na2SO4) and the solvent removed in vacuo before being purified by preparative HPLC to yield Λ/-(cyclohexylmethyl)-2- (1 H-indol-3-yl)-2-oxo-Λ/-(3-pyrrolidin-1-ylpropyl)acetamide 109 an off white solid (51.8mg, 13%).
Example 45 //VV--CC yclohexyl-2-(6-methoxy-1 H-indol-3-yl)-Λ/-methyl-2- oxoacetamide 110
Figure imgf000096_0001
To a stirred mixture of /V-methylcyclohexylamine (222mg, 1.96mmol), triethylamine (0.8ml, 5.89mmol) in tetrahydrofuran (15ml) was added 6-methoxy- indole-3-glyoxylyl chloride (419mg, 1.76mmol) in tetrahydrofuran (10ml) at O0C. The mixture was warmed to room temperature and stirred overnight before being concentrated in vacuo. The reaction was partitioned between dichloromethane (20ml) and 2M HCI (10ml). The organic layer was collected and concentrated in vacuo. The product was purified by column chromatography eluting with DCM 9:1 MeOH/NH3 and further chromatography eluting with hexane:ethyl acetate (1 :1) to yield Λ/-cyclohexyl-2-(6-methoxy-1 H-indol-3-yl)-Λ/-methyl-2-oxoacetamide 110 (145mg, 26%). Example 46 Λ/-Cyclohexyl-Λ/-[(6-methoxy-1 H-indol-3-yl)(oxo)acetyl]glycine 112
Figure imgf000097_0001
To a stirred solution of 97 (200mg, 1.08mmol), triethylamine (451 μl, 3.24mmol) in tetrahydrofuran (25ml) was added 6-methoxy-indole-3-glyoxylyl chloride (230mg, 0.97mmol) in tetrahydrofuran (5ml) at O0C. The mixture was warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo before being partitioned between dichloromethane (20ml) and 2M HCI (10ml). The organic layer was collected, washed with brine (10ml) and concentrated in vacuo. The reaction was purified by column chromatography eluting with DC IWMeO H (9:1) to yield 111 (120mg, 29%).
111 (120mg, 0.31mmol) was stirred in 2M NaOH (5ml) overnight. Diethyl ether (10ml) was added and the reaction was stirred for 10mins. The aqueous layer was collected and acidified with 2M HCI before extracting with ethyl acetate (2 x 10ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude reaction mixture was purified by flash column chromatography eluting with DCM/MeOH/AcOH (9:1) to yield Λ/-cyclohexyl-Λ/-[(6-methoxy-1 H- indol-3-yl)(oxo)acetyl]glycine 112 (98mg, 88%).
Example 47 W-Cyclohexyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-iV-(3- pyrrolidin-1 -ylpropyl)acetamide 113
Figure imgf000097_0002
113 To a stirred mixture of 100 (275mg, 1.30mmol) and triethylamine (455μl, 3.26mmol) in tetrahydrofuran (30ml) was added 6-methoxy-indole-3-glyoxylyl chloride (310mg, 1.30mmol) in tetrahydrofuran (10ml) at O0C. The mixture was warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo and partitioned between ethyl acetate (30ml) and aqueous sodium bicarbonate (30ml). The organic layer was collected, dried (MgSO4) and concentrated in vacuo. The crude reaction mixture was purified by column chromatography eluting with DCM 9:1 MeOH/NH3 to yield Λ/-cyclohexyl-2-(6- methoxy-1 H-indol-3-yl)-2-oxo-Λ/-(3-pyrrolidin-1-ylpropyl)acetamide 113 (92mg, 17%).
Example 48 Λ/-(Cyclohexylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-Λ/-methyl-2- oxoacetamide 114
Figure imgf000098_0001
To a stirred mixture of 103 (228mg, 1.79mmol) and triethylamine (624μl, 4.48mmoi) in tetrahydrofuran (25ml) was added 6-methoxy-indole-3-glyoxylyl chloride (381 mg, 1.61mmol) in tetrahydrofuran (10ml) at O0C. The mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (30ml) and water (30ml). The organic layer was collected, dried (MgSO4) and concentrated in vacuo. The crude reaction mixture was purified by column chromatography eluting with DCM/MeOH (8:2) to yield Λ/-(cyclohexylmethyl)-2-(6-methoxy-1 H- indol-3-yl)-Λ/-methyl-2-oxoacetamide 114 (134mg, 25%). Example 49 /V-(Cyclohexylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-W-(3- pyrrolidin-1 -ylpropyl)acetamide 115
Figure imgf000099_0001
To a stirred mixture of 108 (290mg, 1.29mmol) and triethylamine (449μl, 3.23mmol) in tetrahydrofuran (30ml) was added 6-methoxy-indole-3-glyoxylyl chloride (307mg, 1.29mmol) in tetrahydrofuran (10ml) at O0C. The mixture was warm to room temperature and stirred overnight. The mixture was concentrated in vacuo and partitioned between ethyl acetate (30ml) and aqueous sodium bicarbonate (30ml). The organic layer was collected, dried (MgSO4) and concentrated in vacuo. The crude reaction mixture was purified by column chromatography eluting with DCM 9:1 MeOH/NH3 to yield /V-(cyclohexylmethyl)- 2-(6-methoxy-1 H-indol-3-yl)-2-oxo-Λ/-(3-pyrrolidin-1-ylpropyl)acetamide 115
(189mg, 34%).
Example 50 Λ/2-(Cyclohexylmethyl)-N2-[(6-methoxy-1H-indoI-3- yl)(oxo)acetyl]-L-ornithine 118
Figure imgf000100_0001
DIPEA, THF
Figure imgf000100_0002
116
Figure imgf000100_0003
H-Om(Z)-O1Bu. HCI (638mg, 1.78mmol) and triethylamine (495μl, 3.56mmol) in methanol (1OmI) was added to cyclohexane carboxaldehyde (199mg, 1.78mmol) at O0C. 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 (MgSO4) and concentrated in vacuo to yield 116 (700mg, 94%).
To a stirred mixture of 116 (455mg, 1.09mmol) and DIPEA (377μl, 2,17mmol) in tetrahydrofuran (20ml) was added 6~methoxy-indole-3-glyoxylyl chloride (258mg, 1.09mmol) in tetrahydrofuran (10ml) at O0C. The mixture was warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo and partitioned between ethyl acetate (50ml) and 2M HCI (50ml). The organic layer was collected, dried (MgSO4) and concentrated in vacuo before being purified by preparative HPLC to yield 117 (419mg, 62%).
117 (419mg, 0.68mmol) was strirred in HBr/AcOH (3ml) overnight. The solvent was removed in vacuo and the crude reaction mixture was purified by preparative HPLC to yield A/2-(cyclohexylmethyl)-Λ/2-[(6-methoxy-1 H-indol-3-yl)(oxo)acetyl]- L-ornithine 118 (90mg, 31 %).
Examples 51 to 61
Examples 51 to 61 were prepared according to the general experimental procedure for the formation of amides of structure 14 above.
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0002
Example 62 Λ/-(Cyclohexylmethyl)-2-(6-fluoro-1 H-indol-3-yl)-Λ/-((3-
(methoxymethyl)-1 ,2,4-oxadiazol-5-yl)methyl)-2-oxoacetamide
Figure imgf000104_0001
Cyclohexane carboxaldehyde (708mg) was dissolved in MeOH (20ml) at O0C. Triethylamine (2.6ml) was added followed by 1-[3-methoxymethyl)-1 ,2,4- oxadiazol-5-yl]methanamine.HCI (1g). The reaction was stirred at O0C for 30 minutes and then at room temperature for 2 hours. Sodium triacetoxyborohydride (2.68g) was added to the reaction mixture at O0C and the reaction was left to warm to room temperature overnight. The solvent was removed and the residue was dissolved in EtOAc (25ml). Saturated, aqueous NaHCO3 solution was added until a pH 9 was reached and the product was extracted into EtOAc. The combined organic extracts were dried (MgSO4) and concentrated to give the crude product which was purified by flash column chromatography eluting with DCM - 10% MeOH/NH3/DCM to give cyclohexylmethyl-(3-methoxymethyl- [1 ,2,4]oxadiazol-5-ylmethyl)-amine as a yellow oil (533mg, 35%).
Cyclohexylmethyl-(3-methoxymethyl-[1 ,2,4]oxadiazol-5-ylmethyl)-amine (267mg) was dissolved in THF (15ml) at O0C. Hunig's base (400μl) was added followed by a solution of 6-fluoroindoleglyoxyl chloride (379mg) in THF (5ml). The reaction was stirred at room temperature overnight. The solvent was removed and saturated, aqueous NaHCO3 solution (20ml) was added and the product was extracted into EtOAc. The combined organic extracts were dried (MgSO4) and concentrated to give the crude product which was purified by preparative HPLC to yield 130 as a white solid (59mg, 12%).
Example 63 Λ/-(Cyclohexylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-Λ/-((3- (methoxymethyl)-1,2,4-oxadiazol-5-yl)methyl)-2-oxoacetamide
Figure imgf000105_0001
131
Cyclohexylmethyl^S-methoxymethyl-Ci ^^oxadiazol-δ-ylmethyO-amine (266mg) was dissolved in THF (15ml) at O0C. Hunig's base was added followed by a solution of 6-methoxyindoleglyoxyl chloride (399mg) in THF (5ml). The reaction was stirred at room temperature overnight. The solvent was removed and preparative HPLC to give a brown solid which was triturated with MeOH to give 131 (176mg, 36%).
Example 64 W-(Cyclohexylmethyl)-2-(6-fluoro-1 H-indol-3-yl)-Λ/-((5-methyl- 4H-1 ,2,4-triazol-3-yl)methyl)-2-oxoacetamide
Figure imgf000106_0001
132 133
Cyclohexane carboxaldehyde (388mg) was dissolved in MeOH (15ml) at O0C. Triethylamine (1.9ml) was added followed by (5-methyl-4H-1 ,2,4-triazol-3- yl)methanamine.2HCI (700mg). The reaction was stirred at O0C for 30 minutes then at room temperature for 2 hours. Sodium triacetoxyborohydride (1.47g) was added to the reaction mixture at O0C and the reaction was left to warm to room temperature overnight. The solvent was removed and the residue was dissolved in EtOAc (25ml). Saturated, aqueous NaHCO3 solution was added until a pH 9 was reached. The organic product was extracted into EtOAc and the combined organic extracts were dried (MgSO4) and concentrated to give the crude product which was purified by flash column chromatography eluting with DCM - 10% MeOH/NH3/DCM to yield 132 as a yellow oil (214mg, 30%).
132 (107mg) was dissolved in THF (10 ml) at O0C. Hunig's base (200μl) was added followed by a solution of 6-fluoroindoleglyoxyl chloride (116mg) in THF (5ml). The reaction was stirred at room temperature overnight. The solvent was removed and saturated, aqueous NaHCO3 solution (20 ml) was added and the product was extracted into EtOAc. The combined organic extracts were dried (MgSO4) and concentrated to give the crude product which was purified by preparative HPLC to yield 133 as a solid (25mg, 12%). Example 65 Λ/-(cyclohexylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-/V-((5-methyl- 4H-1 ,2,4-triazol-3-yl)methyl)-2-oxoacetamide
Figure imgf000107_0001
132 134
132 (107mg) was dissolved in THF (10ml) at O0C. Hunig's base (200μl) was added followed by a solution of 6-methoxyindoleglyoxyl chloride (122mg) in THF (5ml). The reaction was stirred at room temperature overnight. The solvent was removed and saturated, aqueous NaHCO3 solution (20ml) was added and the product was extracted into EtOAc. The combined organic extracts were dried (MgSO4) and concentrated to give the crude product which was purified by preparative HPLC to yield 134 as a solid (56mg, 27%).
Example 66 Ethyl 2-(2-(6-methoxy-1H-indol-3-yl)-2-oxo-/V- phenylacetamido)acetate
Figure imgf000107_0002
135
Λ/-Phenylglycine ethyl ester. HCI (0.246g, 1.37mmol, 1 eq) was suspended in THF (5ml) at O0C. Hunig's base (0.47ml, 2.74mmol, 2 eq) was added followed by 6-methoxyindoleglyoxyl chloride (0.49g, 2.06mmol, 1.5 eq) in THF (5ml). The reaction mixture was left to warm up to room temperature overnight. Further 6- methoxyindoleglyoxyl chloride (0.5eq) was added and the reaction was left stirring at room temperature overnight. The solvent was removed and saturated, aqueous NaHCO3 solution (20ml) was added and the product was extracted into EtOAc. The combined organic extracts were dried (MgSO4) and concentrated to give the crude product which was purified by column chromatography eluting with 0-66% EtOAc/hexane followed by preparative HPLC to give 135 as a brown solid (95.1 mg, 0.25mmol, 18%).
Example 67 2-(2-(6-Methoxy-1 H-indol-3-yl)-2-oxo-Λ/-phenylacetamido)acetic acid
Figure imgf000108_0001
Aqueous NaOH (2M; 30ml) was added to 135 (120.4mg, 0.317mmol, 1 eq) and the mixture was left to stir at room temperature over night. The reaction mixture was washed with Et2O (50ml) and the aqueous layer was acidified with aqueous HCI (2M). A fine precipitate was formed which was extracted into EtOAc (30ml). The organic extract was dried (MgSO4) and concentrated to a give 136 as a pale yellow solid (87.0mg, 0.274mmol, 78%).
Example 68 Ethyl 2-(Λ/-(cyclohexylmethyl)-2-(6-fluoro-1 H-indol-3-yl)-2- oxoacetamido)acetate
Figure imgf000109_0001
An excess of ethanol was added to a solution of 64 (200mg), HATU (316mg) and Hunig's base (288μl) in DCM (3ml) which had been stirring for 30 minutes. The reaction was left to stir for 16 hours. Further HATU (0.5 eq), and of Hunig's base (2 eq) were added and the reaction was stirred for a further 16 hours. An aqueous solution of citric acid (10%) was added and mixture was passed through a hydrophobic frit. The organic layer was washed with saturated, aqueous NaHCO3 solution and then passed through a hydrophobic frit. The organics were concentrated to give the crude product which was purified by flash column chromatography eluting from DCM - 10% MeOH/DCM followed by preparative HPLC to give the 137 (38mg, 18%).
Example 69 Ethyl 2-(2-(6-fluoro-1 H-indol-3-yl)-/V-methyl-2- oxoacetamido)acetate
Figure imgf000109_0002
138 139 140
Sarcosine t-butyl ester .HCI (1.Og, 5.34mmol, 1eq) was suspended in THF (10ml) at O0C. Hunig's base (2.77ml, 16.02mmol, 3eq) was added followed by 6- fluoroindoleglyoxyl chloride (1.81g, 8.01 mmol, 1.5 eq) in THF (20ml). The reaction mixture was left to warm up to room temperature overnight. The solvent was removed and saturated, aqueous NaHCO3 solution (20ml) was added and the product was extracted into EtOAc. The combined organic extracts were dried (MgSO4) and concentrated to give the crude product which was purified by column chromatography eluting with 0-66% EtOAc/hexane to give 138 as a yellow/brown solid (1.607g, 4.806mmol, 90%).
HCI.dioxane (5M, 20ml) was added to 138 (1.61g, 4.81 mmol) and the clear yellow solution was left to stir at room temperature over the weekend. A brown precipitate was evident and the reaction mixture was concentrated to give the crude product which was purified using a PE-AX catch and release cartridge to give 139 as a pale brown solid (906mg, 3.26mmol, 68%).
H2SO4 (2 drops) was added to a solution of 139 (200mg, 0.719mmol, 1 eq) in absolute ethanol (20ml). After stirring for 2.5 hours, the reaction was warmed to 350C. Further H2SO4 (2 drops) was added and stirring was continued for a further 2.5 hours. The reaction mixture was concentrated and the residue was purified by column chromatography eluting with 0-66% EtOAc/hexane to give 140 as a white solid (145.5mg, 0.475mmol, 66%).
Example 70 Ethyl 2-(2-(6-fluoro-1 H-indol-3-yl)-2-oxo-iV- phenylacetamido)acetate
Figure imgf000110_0001
141
Λ/-Phenylglycine ethyl ester. HCI (0.246g, 1.37mmol, 1eq) was suspended in THF (5ml) at O0C. Hunig's base (0.47ml, 2.74mmol, 2 eq) was added followed by a solution of 6-fluoroindoleglyoxyl chloride (0.46g, 2.06mmol, 1.5 eq) in THF (5ml). The reaction mixture was left to warm up to room temperature overnight. Further 6-fluoroindoleglyoxyl chloride (0.5 eq) was added and the reaction was left to stir at room temperature overnight. The solvent was removed and saturated, aqueous NaHCO3 solution (20ml) was added and the product was extracted into EtOAc. The combined organic extracts were dried (MgSO4) and concentrated to give the crude product which was purified by column chromatography eluting with 0-66% EtOAc/hexane to give 141 as an off-white solid (328mg, 0.891 mmol, 64.9%).
Example 71 2-(2-(6-Fluoro-1 H-indol-3-yl)-2-oxo-W-phenylacetamido)acetic acid
Figure imgf000111_0001
Aqueous NaOH (2M) (40ml) was added to 141 (229.8mg, 0.624mmol, 1 eq) and the mixture was left to stir at room temperature over the weekend. The reaction mixture was washed with Et2O (50ml) and the aqueous layer was acidified with aqueous HCI (2M). A fine precipitate was formed which was extracted into EtOAc (30ml). The organic extract was dried (MgSO4) and concentrated to a give a solid (200.8mg crude) which was purified using preparative HPLC to give 142 (72.1mg, 0.212mmol, 33.9%).
Example 72 Ethyl 2-(Λ/-benzyl-2-(6-methoxy-1H-indol-3-yl)-2- oxoacetamido)acetate
Figure imgf000112_0001
Λ/-Benzylglycine ethylester (1.Og, 4.97mmol, 1eq) was suspended in THF (10ml) at O0C. Hunig's base (1.72ml, 9.94mmol, 2eq) was added followed by a solution of 6-methoxyindoleglyoxyl chloride (1.77g, 7.452mmol, 1.5 eq) in THF (20ml). The reaction mixture was left to warm up to room temperature overnight. Further 6-methoxyindoleglyoxyl chloride (0.5 eq) was added and the reaction was left to stir at room temperature overnight. The solvent was removed and saturated, aqueous NaHCO3 solution (20ml) was added and the product was extracted into EtOAc. The combined organic extracts were dried (MgSO4) and concentrated to give the crude product which was triturated with MeOH to give 143 as a brown solid (1.02g, 2.59mmol, 52%). Additional 143 was isolated from the filtrate was by column chromatography eluting with 0-66% EtOAc/hexane (0.697g, 1.767mmol, 36%).
Example 73 Ethyl 2-(N-benzyl-2-(6-fluoro-1 H-indol-3-yl)-2- oxoacetamido)acetate
Figure imgf000112_0002
Λ/-Benzylglycineethylester (1.Og, 5.34mmol, 1eq) was suspended in THF (10ml) at O0C. Hunig's base (2.77ml, 16.02mmol, 3eq) was added followed by 6- fluoroindoleglyoxyl chloride (1.68g, 7.45mmol, 1.5eq) in THF (20ml). The reaction mixture was left to warm up to room temperature overnight. The solvent was removed and saturated, aqueous NaHCO3 solution (20ml) was added and the product was extracted into EtOAc. The combined organic extracts were dried (MgSO4) and concentrated to give the crude product which was purified by preparative HPLC to give 144 as a yellow solid (146.2mg)
Example 74 2-(W-(Cyclohexylmethyl)-2-oxo-2-(6-(trifluoromethoxy)-
1 H-indol-3-yl)acetamido)acetic acid
Figure imgf000113_0001
Glyoxyl dimethyl acetal (1.27g) was added to 3-trifluoromethoxyanilne (1g, 5.65mmol) in ethanol (15ml). Pd/C (200mg) was added and the reaction placed under 1 atmosphere of H2. The reaction was left to stir at room temperature for 16 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. Brine (20 ml) was added to the residue and the product was extracted into EtOAc (3 x 20 ml). The organic extract was dried (Na2SO4) and concentrated to yield 145 as a yellow oil (1.43g, 4.88mmol, 86%).
TFAA (1.1 ml) was added to 145 (2.08g, 7.10mmol) and triethylamine (1.2ml) in hexane (20ml) at 00C. The reaction was then left to warm to room temperature for 16 hours. The solvent was removed and water (50ml) was added. The product was extracted into EtOAc (3 x 50ml) and the combined organic extracts were dried (Na2SO4) and concentrated to give the crude product which was purified by flash column chromatography eluting with 100:1 - 10:1 hexane:EtOAc to yield 146 (1.38 g, 3.55mmol, 50%)
TFAA (7ml) and TFA (15ml) were added to 146 (1.38g) and the mixture was heated to reflux for 72 hours. The solvent was removed and the intermediate 147 was isolated by flash column chromatography as a brown oil (~200 mg).
Aqueous KOH (2ml) was added to a solution of 147 (~200 mg, 0.673mmol) in MeOH (2ml) at room temperature and the mixture was stirred for 16 hours. Water (50 ml) was added and the product was extracted with EtOAc (3 x 50ml). The combined organic extracts were dried (Na2SO4) and concentrated to provide the crude product which was purified by flash column chromatography eluting with 10:1 hexane:EtOAc - EtOAc to yield 148 (40 mg, 0.199mmol, -30%).
Oxalyl chloride (191 μl) was added to 148 (400mg, 1.99mmol) in Et2O (5ml) at O0C and left to stir for 4 hours. The resulting reaction mixture was filtered to give crude 149 (100mg). The filtrate was evaporated to give further crude 149 which was washed with Et2O (2 x 10ml) to yield 149 as a yellow solid (total 580mg, 1.99mmol, 100%).
6-Trifluoromethoxyindole glyoxylchloride 149 (300 mg) in THF (5ml) was added to 7 (234mg) and Hunig's base (357μl) in THF (5ml) at O0C. The reaction was then allowed to reach room temperature and stirred for 16 hours. The solvent was removed and saturated, aqueous NaHCO3 solution (10ml) was added and the product was extracted into EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated to give the crude product which was purified by flash column chromatography eluting from 5:1 - 1 :1 hexane:EtOAc to yield 150 as a yellow foam (366mg, 76%). HCI in dioxane (4M, 5 ml) was added to 150 (366.7mg) and the mixture was left to stir at room temperature for 16 hours. The mixture was concentrated and the residue was trituration with EtOAc to provide 151 as a light brown solid (273mg, 84%).
Figure imgf000116_0001
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Figure imgf000117_0001
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Figure imgf000119_0001
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Figure imgf000120_0001
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Figure imgf000121_0001
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Figure imgf000122_0001
Figure imgf000122_0002
Figure imgf000123_0001
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Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
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Biological Experimental
Primary dorsal root ganglion neurons were isolated using standard techniques and placed in Ca2+/Mg2+ free phosphate-buffered saline (PBS). Hemisection of the spinal column and cord was performed and the ganglia were uncovered by gently lifting the spinal cord. They were placed in a dissociation solution (PBS) containing 1 mg/ml Collagenase (type Xl) and trypsin (type N-S). Ganglia were incubated in the dissociation solution for 20 minutes at room temperature, followed by 20 minutes at 370C. 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 (370C, 5% CO2) 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; BaCI2, 5; MgCI2, 1 ; HEPES, 10; pH 7.3 adjusted with TEA-OH. Ba2+ was used as a charge carrier to prevent the run-down caused by Ca2+-activated inactivation of Ca2+ channels. Patch pipettes had a resistance of 2-4 MΩ, when filled with a solution containing, in mM: CsCI, 140; EGTA, 5; MgCI2, 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. 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. After stabilization of the high frequency block, 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, ω-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 ω-conotoxin GVIA (100 nM).
Test Examples
Calcium currents were recorded from cultured neonate rat dorsal root ganglion neurons, using the whole-cell configuration of the patch-clamp technique. The compounds 9, and 17 described in the examples above produced a significant use-dependent block of this current at 50 μM.
i Catterall, W A , Perez-Reyes, E , Snutch, T P , Stπessnig, J (2005) International Union of Pharmacology XLVIII Nomenclature and structure-function relationships of voltage-gated calcium channels Pharmacol Rev 57, 411-425
Ii Berrow, N S , Brice, N L , Tedder, I , Page, K M , Dolphin, A C (1997) Properties of cloned rat alphalA calcium channels transiently expressed in the COS-7 cell line Eur J Neurosci 9, 739-748
in Randall, A , Benham, C D (1999) Recent advances in the molecular understanding of voltage-gated Ca2+ channels MoI Cell Neurosci 14, 255-272
iv Birnbaumer, L , Qm, N , Olcese, R , Tareilus, E , Platano, D , Costantin, J , Stefani, E (1998) Structures and functions of calcium channel beta subunits J Bioβnerg Biomβmbr 30, 357-375 v Walker, D , De Waard, M (1998) Subunit interaction sites in voltage-dependent Ca2+ channels role in channel function Trends Neurosci 21 , 148-154
VM Dolphin, A C , Wyatt, C N , Richards, J , Beattie, R E , Craig, P , Lee, J H , Cπbbs, L L , Volsen, S G , Perez-Reyes, E (1999) The effect of alpha2-delta and other accessory subunits on expression and properties of the calcium channel alphai G J Physiol 519, Pt 1 35-45
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Claims

Claims
1. A compound represented by the general formula (1 ) or a pharmacologically acceptable salt or pro-drug thereof, wherein:
Figure imgf000138_0001
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 guanidinoalkyl group;
R2 is an alkyl group, an aryl group or a heteroaryl group which may optionally be substituted with at least one substituent selected from 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 a hydrogen atom, an alkyl group, a cycloalkyl group, saturated or partially unsaturated heterocyclic groups, an alkyl group that is substituted with at least one substituent selected from alkoxy groups, haloalkoxy groups, unsaturated or partially saturated heterocyclic groups, aryloxy groups, alkylsulfonyl groups and alkylsulfinyl groups, 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 hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups;
W is selected from oxygen atoms, sulphur atoms, groups of formula NR7, wherein R7 is a hydrogen atom or alkyl, and groups of formula CR8R9, wherein R8 and R9 are the same or different and each is H or alkyl; and
X is selected from nitrogen atoms and groups of formula CR10, wherein R10 is H or alkyl;
PROVIDED THAT when R1 is an alkyl group, R2 cannot also be an alkyl group.
2. A compound according to claim 1 or a pharmacologically acceptable salt or prodrug thereof, wherein R1 is an alkyl group having from 1 to 6 carbon atoms, an aminoalkyl group having from 1 to 6 carbon atoms, 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 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 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, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, a heteroaryl group which is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, 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, 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 carbonyl groups, a cycloalkylalkyl group which comprises an alkyl group having from 1 to 6 carbon atoms which is substituted with a cycloalkyl group having from 3 to 14 carbon atoms, an aminoalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with at least one amino group, and a guanidinoalkyl group comprising an alkyl group having from 1 to 6 carbon atoms which is substituted with a guanidino group.
3. A compound according to claim 1 or a pharmacologically acceptable salt or prodrug thereof, wherein R1 is an alkyl group having from 1 to 4 carbon atoms, 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.
4. A compound according to claim 1 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.
5. A compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt or prodrug thereof, wherein 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, said group optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur atoms, which is optionally substituted with at least one substituent selected from hydroxyl groups, alkoxyl groups having from 1 to 6 carbon atoms, haloalkoxyl groups having from 1 to 6 carbon atoms, an aryl groups having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, 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 which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, heteroaryl groups which are 5- to 7-membered aromatic heterocyclic groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, cycloalkyl groups having from 3 to 14 carbon atoms, amino groups, alkylamino groups wherein the alkyl substituent has from 1 to 6 carbon atoms, dialkylamino groups wherein each alkyl substituent is the same or different and has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphinyl groups having from 1 to 6 carbon atoms, alysulphonylamino groups having from 1 to 6 carbon atoms, saturated or partially unsaturated heterocyclic groups which are 4- to 8- membered saturated or partially unsaturated heterocyclic groups 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 carbonyl groups, and groups of formula COY,
wherein Y is a hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms, a group of formula NR11 R12 (wherein R11 and R12 are the same or different and each is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group 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 and 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 carbonyl groups, and alkyl groups having from 1 to 6 carbon atom that are substituted with at least one substituent selected from the group consisting of alkoxy groups having from 1 to 6 carbon atoms, haloalkoxy groups having from 1 to 6 carbon atoms, saturated or partially unsaturated heterocyclic groups which are 4- to 8- membered saturated or partially unsaturated heterocyclic groups 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 carbonyl groups, aryloxy groups comprising a an aryl groups having from 5 to 14 carbon atoms which is attached to an oxygen atom, alkylsulfonyl groups having from 1 to 6 carbon atoms and alkylsulfinyl groups having from 1 to 6 carbon atoms, or R1 1 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), or an aminoacid residue.
6. A compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt or prodrug thereof, wherein 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, or R2 is an alkyl group;
(b) 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 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 having from 1 to 4 carbon atoms, and alkyl groups having from 1 to 4 groups that are substituted with unsaturated heterocyclic groups having from 4 to 6 carbon atoms and containing at least one nitrogen, oxygen or sulphur atom.
7. A compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt or prodrug thereof, wherein R2 is an alkyl group having 1 to 4 carbon atoms which is substituted with one or more substituents selected from carboxy groups, amino groups, 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 N-(4-tetrahydro-2H-pyranyl)aminocarbonyl group or a 2-pyrrolidin-1- ylethylaminocarbonyl group.
8. A compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt or prodrug thereof, wherein R3, R4, R5 and R6 are independently selected from hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups comprising a carbonyl group which is substituted with an alkoxy group having from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, nitro groups, amino groups, 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 which is substituted with an alkoxy group having from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups, 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 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, alkylsulphonyiamino groups having from 1 to 6 carbon atoms and cyano groups, aminosulphonyl groups and cyano groups.
9. A compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt or prodrug thereof, wherein 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.
10. A compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt or prodrug thereof, wherein R3, R4, R5 and R6 are independently selected from hydrogen atoms, methyl groups, methoxy groups, fluorine atoms and chlorine atoms.
11. A compound according to any one of claims 1 to 10 or a pharmacologically acceptable salt or prodrug thereof, wherein 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.
12. A compound according to any one of claims 1 to 10 or a pharmacologically acceptable salt or prodrug thereof, wherein X is a group of formula CH.
13. A compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt or prodrug thereof, wherein 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.
14. A compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt or prodrug thereof, wherein W is a group of formula NH.
15. A compound according to claim 1 or a pharmacologically acceptable salt or prodrug thereof, wherein:
R1 is an alkyl group having from 1 to 4 carbon atoms, 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
(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, or R2 is an alkyl group,
(b) 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 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 having from 1 to 4 carbon atoms, and alkyl groups having from 1 to 4 groups that are substituted with unsaturated heterocyclic groups having from 4 to 6 carbon atoms and containing at least one nitrogen, oxygen or sulphur atom;
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 claim 1 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 1 to 4 carbon atoms which is substituted with one or more substituents selected from carboxy groups, amino groups, 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 N-(4-tetrahydro-2H- 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; and
W is a group of formula NH.
17. A compounds according to claim 1 selected from the following compounds, and pharmacologically acceptable salt and prodrugs thereof:
{cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo-acetyl]amino} acetic acid tert-butyl ester,
{cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo-acetyl]amino} acetic acid,
{cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxo-acetyl]amino} acetic acid methyl ester,
A/-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-Λ/-(3-methyl-[1 ,2,4]oxadiazol- 5-ylmethyl)-2-oxo-acetamide,
2-{cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetyl]amino}-2- methylpropionic acid,
(R)-2-{cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetyl]amino}- propionic acid,
(S)-2-{cyclohexylmethyl-[2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetyl]amino}- propionic acid,
/V-cyclohexylmethyl-/V-(2-methoxyethyl)-2-(6-methoxy-1 H-indol-3-yl)-2- oxoacetamide,
Λ/-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-Λ/-(3-methylisoxazol-5- ylmethyl)-2-oxoacetamide,
/V-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-Λ/-(5-methyl-isoxazol-3- ylmethyl)-2-oxo-acetamide, A/-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-Λ/-(5-methyl-isoxazol-3- ylmethyl)-2-oxo-acetamide,
A/-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-Λ/-(1 H-tetrazol-5- ylmethyl)acetamide,
3-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]amino} propionic acid,
4-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino} butyric acid,
{cyclohexylmethyl-[2-(6-fluoro-1 H-indol-3-yl)-2-oxo-acetyl]amino} acetic acid tert-butyl ester,
{cyclohexylmethyi-[2-(6-fluoro-1 H-indol-3-yl)-2-oxo-acetyl]-amino} acetic acid,
Λ/-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-Λ/-pyridin-2-ylmethyl- acetamide,
Λ/-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-Λ/-pyridin-3-ylmethyl- acetamide,
Λ/-cyclohexylmethyl-2-(6-nnethoxy-1 H-indol-3-yl)-2-oxo-/\/-pyridin-4-ylmethyl- acetamide,
Λ/-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-Λ/-pyridin-2-ylmethyl- acetamide,
A/-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-Λ/-pyridin-3-ylmethyl- acetamide,
Λ/-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-/V-pyridin-4-ylmethyl- acetamide,
{[3-(tert-butoxycarbonylamino-methyl)-benzyl]-[2-(1 H-indol-3-yl)-2-oxo-acetyl]- amino}cyclohexyl acetic acid,
[3-({(1-tert-butylcarbamoylethyl)-[2-(1 H-indol-3-yl)-2-oxo-acetyl]amino}- methyl)benzyl]carbamic acid tert-butyl ester, 4-(2-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}ethyl)- piperazine-1-carboxylic acid tert-butyl ester,
Λ/-cyclohexylmethyl-2-(1 H-indol-3-yl)-2-oxo-A/-(2-piperazin-1-ylethyl) acetamide,
(4-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}-butyl)carbamic acid tert-butyl ester,
(4-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino}butyl)carbamic acid tert-butyl ester,
{2-(1 H-indol-3-yl)-2-oxo-acetyl]methylamino} acetic acid,
[3-({cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]amino}methyl)benzyl] carbamic acid tert-butyl ester,
3-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]amino} propionic acid,
4-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]amino} butyric acid,
(S)-5-amino-2-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]amino} pentanoic acid,
(S)-6-amino-2-{cyclohexylmethyl-[2-(1 H-indol-3-yl)-2-oxo-acetyl]-amino} hexanoic acid,
Λ/-cyclohexyl-2-(1 H-indol-3-yl)-Λ/-methyl-2-oxoacetamide,
Λ/-cyclohexyl-Λ/-[1 H-indol-3-yl(oxo)acetyl]glycine,
Λ/-cyclohexyl-2-(1 H-indol-3-yl)-2-oxo-Λ/-(3-pyrrolidin-1-ylpropyl)acetamide,
A/-(cyclohexylmethyl)-2-(1 H-indol-3-yl)-/V-methyl-2-oxoacetamide,
Λ/-(cyclohexylmethyl)-Λ/-[1 H-indol-3-yl(oxo)acetyl]glycine,
Λ/-(cyclohexylmethyl)-2-(1 H-indol-3-yl)-2-oxo-Λ/-(3-pyrrolidin-1- ylpropyl)acetamide, Λ/-cyclohexyl-2-(6-methoxy-1 H-indol-3-yl)-A/-methyl-2-oxoacetamide,
Λ/-cyclohexyl-Λ/-[(6-methoxy-1 H-indol-3-yl)(oxo)acetyl]glycine,
Λ/-cyclohexyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-Λ/-(3-pyrrolidin-1- ylpropyl)acetamide,
A/-(cyclohexylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-Λ/-methyl-2-oxoacetamidθ,
A/-(cyclohexylmethyl)-Λ/-[(6-methoxy-1 H-indol-3-yl)(oxo)acetyl]glycine)
Λ/-(cyclohexylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-Λ/-(3-pyrrolidin-1- ylpropyl)acetamide,
Λ/2-(cyclohexylmethyl)-Λ/2-[(6-methoxy-1 H-indol-3-yl)(oxo)acetyl]-L-omithine;
N-cyclohexylmethyl-N-{[(2-methoxy-θthyl)-methyl-carbamoyl]-methyl}-2-(6- methoxy-1 H-indol-3-yl)-2-oxo-acetamide,
N-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-N-{[methyl-(2-pyrrolidin-1-yl- ethyl )-carbamoyl]-methyl}-2-oxo-acetannide,
N-cyclohexylmethyl-N-[(4-methoxy-cyclohexylcarbamoyl)-methyl]-2-(6- methoxy-1 H-indol-3-yl)-2-oxo-acetamide,
N-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-({[(S)-1-(tetrahydro- furan-2-yl)methyl]-carbamoyl}-methyl)-acetamide,
N-cyclohexylmethyl-2-(6-methoxy-1 H-indol-3-yl)-N-[2-((R)-2-methoxymethyl- pyrrolidin-1 -yl)-2-oxo-ethyl]-2-oxo acetamide,
N-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-N-(2-oxo-2-pyrrolidin-1-yl- ethyl)-acetamide,
N-cyclohexylcarbamoylmethyl-N-cyclohexylmethyl-2-(6-fiuoro-1 H-indol-3-yl)- 2-oxo-acetamide,
N-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-N-[(tetrahydro-pyran-4- ylcarbamoyl)-methyl]-acetamide, N-cyclohexylmethyl-N-dimethylcarbamoylmethyl-2-(6-fluoro-1 H-inclol-3-yl)-2- oxo-acetamide,
N-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-N-[(2-methoxy-ethylcarbamoyl)- methyl]-2-oxo-acetamide,
N-cyclohexylmethyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxo-N-[(2-pyrrolidin-1-yl- ethylcarbamoyl)-methyl]-acetamide,
N-(cyclohexylmethyl)-2-(6-fluoro-1 H-indol-3-yl)-N-((3-(methoxymethyl)-1 ,2,4- oxadiazol-5-yl)methyl)-2-oxoacetamide,
N-(cyclohexylmethyl)-2-(6-methoxy-1 H-indol-3-yl)-N-((3-(methoxymethyl)- i ^^-oxadiazol-δ-yQmethyO^-oxoacetamide,
N-(cyclohexylmethyl)-2-(6-fluoro-1 H-indol-3-yl)-N-((5-methyl-4H-1 ,2,4-triazol- 3-yl)methyl)-2-oxoacetamide,
N-^yclohexylmethyO^-CΘ-methoxy-I H-indol-S-yO-N-^δ-nnethyl^H-i ^^- triazol-3-yl)methyl)-2-oxoacetamide,
ethyl 2-(2-(6-methoxy-1 H-indol-3-yl)-2-oxo-N-phenylacetamido)acetate,
2-(2-(6-Methoxy-1 H-indol-3-yl)-2-oxo-N-phenylacθtamido)acetic acid,
ethyl 2-(N-(cyclohexylmethyl)-2-(6-fluoro-1 H-indol-3-yl)-2- oxoacetamido)acetate,
ethyl 2-(2-(6-fluoro-1 H-indol-3-yl)-N-methyl-2-oxoacetamido)acetate,
ethyl 2-(2-(6-fluoro-1 H-indol-3-yl)-2-oxo-N-phenylacetamido)acetate,
2-(2-(6-fluoro-1 H-indol-3-yl)-2-oxo-N-phenylacetamido)acetic acid,
ethyl 2-(N-benzyl-2-(6-methoxy-1 H-indol-3-yl)-2-oxoacetamido)acetate,
ethyl 2-(N-benzyl-2-(6-fluoro-1 H-indol-3-yl)-2-oxoacetamido)acetate, and
2-(N-(cyclohexylmethyl)-2-oxo-2-(6-(trifluoromethoxy)-1 H-indol-3- yl)acetamido)acetic acid.
18. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and an active ingredient, wherein said active ingredient is a compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof.
19. A compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof for use as a medicament.
20. Use of a compound of general formula (I') or a pharmacologically acceptable salt or pro-drug thereof in the preparation of a medicament for the prophylaxis or treatment of a disease in which Cavx channels are involved:
Figure imgf000153_0001
wherein:
R1 ' is an alkyl group, a cycloalkyl group, an aryl group, an aralkyl 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 heteroaryl group which may optionally be substituted with at least one substituent selected from 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 R121 are the same or different and each is a hydrogen atom, an alkyl group, a cycloalkyl group, saturated or partially unsaturated heterocyclic groups, an alkyl group that is substituted with at least one substituent selected from alkoxy groups, haloalkoxy groups, unsaturated or partially saturated heterocyclic groups, aryloxy groups, alkylsulfonyl groups and alkylsulfinyl groups, 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 hydrogen atoms, alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, nitro groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, arylsulphonyl groups, alkylsulphonylamino groups, arylsulphonylamino groups, aminosulphonyl groups and cyano groups;
W is selected from oxygen atoms, sulphur atoms, groups of formula NR7', wherein R7' is a hydrogen atom or alkyl, and groups of formula CR8'R9', wherein R8' and R9' are the same or different and each is H or alkyl; and
X' is selected from nitrogen atoms and groups of formula CR10', wherein R10' is H or alkyl.
21. Use of a compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel opening.
22. Use of a compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of a condition or disease ameliorated by Cavx channel inhibition.
23. Use of a compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Lower Urinary Tract Disorders.
24. Use of a compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Anxiety and Anxiety-Related Conditions.
25. Use of a compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Epilepsy.
26. Use of a compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Pain Disorders.
27. Use of a compound of general formula (I') according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Gynaecological Pain.
28. Use of a compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiac Arrhythmias.
29. Use of a compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Thromboembolic Events.
30. Use of a compound of general formula (IJ) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cardiovascular Diseases.
31. Use of a compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Disorders of the Auditory System.
32. Use of a compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Migraine.
33. Use of a compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Inflammatory and Immunological Diseases.
34. Use of a compound of general formula (I') according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Gastrointestinal Disorders.
35. Use of a compound of general formula (T) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Vascular and Visceral Smooth Muscle Disorders.
36. Use of a compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Cell Proliferative Disorders.
37. Use of a compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Metabolic Disorders.
38. Use of a compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Memory Loss.
39. Use of a compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders.
40. Use of a compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in the preparation of a medicament for the prophylaxis or treatment of Opthalamic Disorders.
41. 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 general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
42. 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 general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
43. 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 compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
44. A method for the prophylaxis or treatment of Lower Urinary Tract Disorders comprising administering to a patient in need thereof an effective amount of compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
45. A method for the prophylaxis or treatment of Anxiety and Anxiety- Related Conditions comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof.
46. A method for the prophylaxis or treatment of Epilepsy comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof.
47. A method for the prophylaxis or treatment of Pain Disorders comprising administering to a patient in need thereof an effective amount of compound of general formula (I') according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
48. A method for the prophylaxis or treatment of Gynaecological Pain comprising administering to a patient in need thereof an effective amount of compound of general formula (T) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
49. A method for the prophylaxis or treatment of Cardiac Arrhythmias comprising administering to a patient in need thereof an effective amount compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
50. A method for the prophylaxis or treatment of Thromboembolic Events comprising administering to a patient in need thereof an effective amount of compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
51. A method for the prophylaxis or treatment of Cardiovascular Diseases comprising administering to a patient in need thereof an effective amount of compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
52. 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 compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
53. A method for the prophylaxis or treatment of Migraine comprising administering to a patient in need thereof an effective amount of compound of general formula (I') according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
54. A method for the prophylaxis or treatment of Inflammatory and Immunological Diseases comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof.
55. A method for the prophylaxis or treatment of Gastrointestinal Disorders comprising administering to a patient in need thereof an effective amount of compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
56. 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 compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
57. A method for the prophylaxis or treatment of Cell Proliferative Disorders comprising administering to a patient in need thereof an effective amount of compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
58. A method for the prophylaxis or treatment of Metabolic Disorders comprising administering to a patient in need thereof an effective amount of compound of general formula (I') according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
59. A method for the prophylaxis or treatment of Memory Loss comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof.
60. A method for the prophylaxis or treatment of CNS-Mediated Motor Dysfunction Disorders comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof.
61. A method for the prophylaxis or treatment of Opthalamic Disorders comprising administering to a patient in need thereof an effective amount of compound of general formula (V) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof.
62. A compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof for use in the prophylaxis or treatment of any disease or condition recited in any of claims 21 to 23, 26 to 32, 34 to 37 and 40.
63. A compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof for use in the prophylaxis or treatment of any disease or condition recited in any of claims 24, 25, 33, 38 and 39.
64. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and at least two active ingredients, wherein said active ingredients comprise at least one compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof or a compound of general formula (I') according to claim 20 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 α2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists, alpha-1 adrenoceptor antagonists, tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs).
65. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof or a compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof in combination at least one compound selected from the group consisting of muscarinic receptor antagonists, β3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel σ2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and alpha-1 adrenoceptor antagonists.
66. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof or a compound of general formula (I1) according to claim 20 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 a2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs).
67. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof or a compound of general formula (I1) according to claim 20 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 a2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and alpha-1 adrenoceptor antagonists for use in the prophylaxis or treatment of lower urinary tract disorders.
68. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and a combination of active ingredients, wherein said active ingredients comprise at least one compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof or a compound of general formula (I1) according to claim 20 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 a2 δ ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs) for use in the prophylaxis or treatment of pain.
69. Use of at least one compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof or a compound of general formula (I1) according to claim 20 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 α2 δ ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists and alpha-1 adrenoceptor antagonists in the manufacture of a medicament for the prophylaxis or treatment of lower urinary tract disorders.
70. Use of at least one compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt or prodrug thereof or a compound of general formula (I1) according to claim 20 or a pharmacologically acceptable salt or prodrug thereof and at least one compound selected from the group consisting of neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel a2 δ ligands, potassium channel inhibitors, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs) in the manufacture of a medicament for the prophylaxis or treatment of pain.
71. A method for the prophylaxis or treatment of lower urinary tract disorders comprising administering to a patient in need thereof an effective amount of a composition according to claim 65.
72. A method for the prophylaxis or treatment of pain comprising administering to a patient in need thereof an effective amount of a composition according to claim 66.
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