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WO2007066068A2 - Antagoniste de recepteur - Google Patents

Antagoniste de recepteur Download PDF

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Publication number
WO2007066068A2
WO2007066068A2 PCT/GB2006/004304 GB2006004304W WO2007066068A2 WO 2007066068 A2 WO2007066068 A2 WO 2007066068A2 GB 2006004304 W GB2006004304 W GB 2006004304W WO 2007066068 A2 WO2007066068 A2 WO 2007066068A2
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Prior art keywords
active agent
nucleic acid
medicament
receptor
substituted
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WO2007066068A3 (fr
Inventor
Alyn Morice
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University of Hull
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University of Hull
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/06—Anti-spasmodics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to pharmaceutically useful agents that antagonize the activity of a vanilloid receptor and their use in the modulation of receptor activation in the treatment of conditions that would benefit from said modulation; and including screening assays to identify antagonists of receptor activation and other subject matter.
  • TRPV 1 transient receptor potential vanilloid receptor 1
  • VR 1 simply vanilloid receptor 1
  • TRPV-1 is a capsaicin response receptor primarily expressed by unmyelinated peripheral nerve fibres. It is predicted to have six transmembrane domains and a short, pore-forming hydrophobic stretch between the fifth and sixth transmembrane domains.
  • TRPV-1 is part of a superfamily of ion channels known as transient receptor potential (TRP) receptors. The superfamily is broadly split into three categories: TRPV receptors, TRPC (transient receptor potential canonical) and TRPM (transient receptor potential melatasin).
  • a related receptor referred to as VRL 3 shows approximately 46% sequence identity to VR 1 and also encodes a calcium ion channel.
  • Both VR 1 and VRL 3 are associated with a number of pain related conditions. These include by way of example, pain, chronic pain, neuropathic pain, post operative pain, rheumatoid pain, osteoarthritic pain, back pain, visceral pain, cancer pain, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HIV related neuropathty, post herpetic neuralgia, fibromyalgia, nerve fibre injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, inflammatory disorders, inflammatory bowel disease, asthma, cystitis, burns and psoriasis. These are not meant to be limiting but merely illustrative of the disease conditions with which these receptors are associated.
  • VR 1 When VR 1 is activated by agonists such as capsaicin, heat or acidosis, calcium enters the cell and pain signals are initiated. When pain receptors (nociceptors) are continually activated through disease or injury the result is chronic pain. When VR1 receptors are continuously activated through exposure to an agonist, for example capsaicin, excessive calcium enters the nerve cell and results in long term but reversible impairment of nociceptor function. This is thought to be the mechanism of pain relief provided by capsaicin.
  • agonists such as capsaicin, heat or acidosis
  • the anti-histamine dexbrompheniramine is a generic drug that is recommended for the control of chronic cough due to upper air ways diseases such as post nasal drip syndrome. It is also used to treat conditions such as sneezing, itching and other symptoms associated with allergies such as hay fever.
  • the present invention relates, amongst other things, to the use of dexbrompheniramine and other agents as a ligand for the TRPV-1 receptor.
  • the present invention relates, at least in part, to clinical applications in the treatment of conditions or diseases that would benefit from the inhibition of TRVP-1 activation.
  • TRPV-1 is representative of the TRP protein superfamily and, as described further below, the disclosure is throughout applicable to all members of this superfamily, i.e. relates inter alia to inhibitors of such proteins.
  • the present disclosure relates in one aspect to the use of an active agent disclosed herein to treat disorders which are treatable by modulation of a calcium ion channel receptor.
  • the calcium ion channel receptor is TRPV-1 (transient receptor potential vanilloid receptor-1) or another TRP protein.
  • TRPV-1 transient receptor potential vanilloid receptor-1
  • the present disclosure also relates to novel combinations of active agents disclosed herein and other therapeutic agents, particularly for use in treating disorders in which inhibition of TRPV-1 activity or other TRP protein activity would be beneficial.
  • a method for the treatment of a disease or condition that would benefit from inhibition of a calcium ion channel receptor comprising administering an effective amount of an active agent selected from dexbrompheniramine and structural variants thereof.
  • the calcium ion channel receptor is a transient receptor potential vanilloid receptor, for example, TRPV-1. In one embodiment, the TRPV is TRPV-1.
  • an active agent which is selected from dexbrompheniramine and structural variants thereof for the manufacture of a medicament for the treatment of a disease or condition that would benefit from inhibition of a calcium ion channel receptor.
  • the active agent is a histamine H 1 receptor antagonist of the alkylamine class.
  • the active agent is a pheniramine or a prodrug or pharmaceutically acceptable salt thereof.
  • references herein to the term "active agent” also encompasses salts and prodrugs (e.g. esters) of the active agent, and also other pharmaceutically acceptable forms of the agent.
  • reference to one such substituted alkylamine, e.g. dexbrompheniramine encompasses salts of dexbrompheniramine, e.g. dexbrompheniramine maleate.
  • the present invention also encompasses use of salts and esters of substituted alkylamines e.g. salts of dexbrompheniramine.
  • products for the treatment of disorders that would benefit from inhibition of a calcium ion channel receptor, e.g. a TRVP-1 protein.
  • Such products include an active agent, as defined herein.
  • the product comprises dexbrompheniramine or a structural variation thereof.
  • the products of the present invention may also include at least one further therapeutic agent.
  • the active agents of the disclosure may be combined and/or co-administered with other therapeutic agents.
  • the choice of the further therapeutic agent(s) will depend on the nature of the disorder to be treated. Such therapeutic agents may be available in commercial use, in clinical evaluation or in pre-clinical development, which could be selected for use with an active agent of the disclosure for the prevention of disorders as described herein by combination drug therapy.
  • the present disclosure teaches that the disclosed active agent, for example, dexbrompheniramine, inhibits capasaicin-induced calcium mobilisation and therefore indicates the inhibition of TRP protein activation by active agents of the disclosure.
  • the disclosed active agent for example, dexbrompheniramine
  • Figure 1 is the nucleic acid sequence of human TRPV-1
  • Figure 2 is the amino acid sequence of human TRPV-1
  • Figure 3 illustrates the antagonistic effect of dexbrompheniramine on TRPV-1 activation in the presence of the TRPV-1 agonist capsaicin
  • Figure 4 is the structure of dexbrompheniramine.
  • Figure 5A is a graph showing the capsaicin concentration effect curve for hTRPV1-HEK following pre-incubation with and without dexbrompheniramine (1mM and 100 ⁇ M). Squares indicate no dexbrompheniramine, triangles represent pre-incubation with dexbrompheniramine at concentration of 100 ⁇ M and diamonds represent pre-incubation with dexbrompheniramine at concentration of 1mM.
  • Figure 5B is a graph showing resiniferatoxin concentration effect curve for hTRPV1-HEK following pre-incubation with and without dexbrompheniramine (100 ⁇ M).). Circles indicate no dexbrompheniramine, crosses represent pre-incubation with dexbrompheniramine at concentration of 100 ⁇ M
  • Figure 6A is a graph showing the capsaicin concentration effect curve for rTRPV1-HEK following pre-incubation with and without dexbrompheniramine (1mM and 100 ⁇ M). Squares indicate no dexbrompheniramine, triangles represent pre-incubation with dexbrompheniramine at concentration of 100 ⁇ M.
  • Figure 6B is a graph showing the resiniferatoxin concentration effect curve for rTRPV1-HEK following pre-incubation with and without dexbrompheniramine (1mM and 100 ⁇ M). Circles indicate no dexbrompheniramine, crosses represent pre-incubation with dexbrompheniramine at concentration of 100 ⁇ M, diamonds represent pre-incubation with dexbrompheniramine at concentration of 1 mM.
  • Figure 6C is a graph showing the capsaicin concentration effect curve for rTRPV1-Pro-5 following pre-incubation with and without dexbrompheniramine (100 ⁇ M). Stars indicate no dexbrompheniramine, Crosses represent pre-incubation with dexbrompheniramine at concentration of 100 ⁇ M.
  • Figure 7A is a graph showing the effect of histamine on TRPV1.
  • Figure 7B is a graph showing the effect of histamine on the capsaicin concentration curve.
  • Figure 8A is a graph showing the effect of diphenhydramine hydrochloride on hTRPV-1-HEK cells in response to capsaicin.
  • Figure 8B is a graph showing the effect of fexofenadine on hTRPV-1-HEK cells in response to capsaicin.
  • Figure 8C is a graph showing the effect of chlorpheniramine on hTRPV-1-HEK cells in response to capsaicin.
  • Figure 9 is a graph showing Inhibition of calcium mobilisation by dexbrompheniramine in rat dorsal root ganglia.
  • DXB dexbrompheniramine maleate
  • VEH phosphate buffer solution
  • CAS capsaicin
  • the present invention provided methods for the treatment of a disease or condition that would benefit from inhibition of a calcium ion channel receptor, comprising administering an effective amount of an active agent as defined herein.
  • the present invention also provides uses of an active agent selected from dexbrompheniramine and structural variants thereof for the manufacture of a medicament for the treatment of a disease or condition that would benefit from inhibition of a calcium ion channel receptor.
  • TRPV-1 is believed to act as a ligand-, proton- and heat-activated molecular integrator of nociceptive stimuli. Activation of TRPV1 leads to central pain and to local "sensory-efferent" effects, which include the release of vasoactive agents
  • calcitonin gene related peptide CGRP
  • vasorelaxation e.g. calcitonin gene related peptide, CGRP
  • active agents disclosed herein are believed to act as an antagonist to the TRPV-1 receptor and therefore it is expected that administration of such agents will reduce or inhibit activation of the TRPV-1 receptor and so prevent or reduce the downstream effects of TRPV-1 activation.
  • a structural formula herein comprising a chiral centre does not indicate chirality (e.g. where all bonds are shown as lines and there is no "wedge" bond)
  • the structure refers to all corresponding compounds or moieties irrespective of chirality and includes reference to individual compounds or moieties in which the chiral centre is of (R)- configuration, individual compounds or moieties in which the chiral centre is (S)-configuration and mixtures of (R)- and (S)- isomers as, for example, in the case of racemic mixtures, amongst others.
  • hydrocarbyl as used herein includes reference to a moiety consisting exclusively of hydrogen and carbon atoms; such a moiety may comprise an aliphatic and/or an aromatic moiety. The moiety may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
  • hydrocarbyl groups include C 1-6 alkyl (e.g. C 1 , C 2 , C 3 or C 4 alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl); C 1-6 alkyl substituted by aryl (e.g.
  • benzyl or by cycloalkyl (e.g cyclopropylmethyl); cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); aryl (e.g. phenyl, naphthyl or fluorenyl) and the like.
  • cycloalkyl e.g cyclopropylmethyl
  • cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
  • aryl e.g. phenyl, naphthyl or fluorenyl
  • alkyl and 11 C 1-6 alkyl as used herein include reference to a straight or branched chain alkyl moiety having 1, 2, 3, 4, 5 or 6 carbon atoms. This term includes reference to groups such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl or tert-butyl), pentyl, hexyl and the like. In particular, alkyl may have 1, 2, 3 or 4 carbon atoms.
  • aryl or aromatic
  • aromatic as used herein include reference to an aromatic ring system comprising 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring carbon atoms.
  • Aryl is often phenyl but may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes reference to groups such as phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like.
  • heterocyclyl as used herein includes reference to a saturated (e.g. heterocycloalkyl) or unsaturated (e.g. heteroaryl) heterocyclic ring moiety having from 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon and sulphur.
  • heterocyclyl includes a 3- to 10-membered non-aromatic ring or ring system and more particularly a 5- or 6-membered ring, which may be fully or partially saturated.
  • a heterocyclic moiety is, for example, selected from oxiranyl, azirinyl, 1 ,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrroIyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyr- azinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morpholiny
  • Heterocycloalkyl includes reference to a saturated heterocyclic moiety having 3, 4, 5, 6 or 7 ring carbon atoms and 1, 2, 3, 4 or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulphur.
  • the group may be a polycyclic ring system but more often is monocyclic.
  • This term includes reference to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyi, quinolizidinyl and the like.
  • heteroaryl and “heteroaromatic” as used herein include reference to an aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen and sulphur.
  • the group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic, but is more often monocyclic.
  • This term includes reference to groups such as pyrimidinyl, furanyl, benzo[b]thiophenyl, thiophenyl, pyrrolyl, imidazolyl, pyrrolidinyl, pyridinyl, benzo[b]furanyl, pyrazinyl, purinyl, indolyl, benzimidazolyl, quinolinyl, phenothiazinyl, triazinyl, phthalazinyl, 2H-chromenyl, oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl, purinyl, isoquinolinyl, quinazolinyl, pteridinyl and the like.
  • the present invention relates to methods which comprise the use of an active agent selected from dexbrompheniramine and structural variants thereof.
  • the active agent is a histamine Hi receptor antagonist of the alkylamine class.
  • the active agent is a pheniramine or a prodrug or pharmaceutically acceptable salt thereof.
  • Pheniramines are compounds having the skeleton of formula (I) which may be unsubstituted or substituted by one or more substituents:
  • the active agent is pheniramine which is unsubstituted or substituted by one or more substituents selected from the group consisting of trifluoromethyl and species having 1 , 2 or 3 non-hydrogen atoms and optionally one or more hydrogen atoms, or a prodrug or pharmaceutically acceptable salt thereof.
  • the pheniramine can be, for example, a D-pheniramine.
  • D-pheniramine refers to compounds have the skeleton of formula (II) whether substituted or unsubstituted:
  • the one or more substituents of the pheniramine are selected from the group consisting of halogen, hydroxy, methyl, trifluoromethyl, formyl (-CHO), methoxy, amino, methylamino, dimethylamino, amidino, hydroxylamino, cyano, thiol and methylthio.
  • the one or more substituents are selected from chlorine and bromine. Particularly, the one or more substituents can be bromine.
  • the pheniramine is substituted by a single substituent.
  • the disclosure includes pheniramines (for example D- or D/L- pheniramines) substituted at, in an exemplary embodiment, the 2-position of the phenyl group.
  • the disclosure includes pheniramines (for example D- or D/L- pheniramines) substituted at the 3- position of the phenyl group.
  • the disclosure in particular includes pheniramines (for example D- or D/L- pheniramines) substituted at the 4-position of its phenyl group.
  • pheniramines for example D- or D/L- pheniramines substituted at the 4-position of its phenyl group.
  • the active agent has the formula (III):
  • D and E are the same or different and are each a substituted or unsubstituted ring moiety, and wherein D and E are optionally joined together as part of a fused ring system;
  • W is O, S(O) t where t is 0, 1 or 2, or CH 2 , l is O oM, m is 0, 1 ,2, 3 or 4, e.g. 0, 1 or 2,
  • R 10 is a group of Formula (IV):
  • V is a bond, -NR - or, when not linked to SO or SO 2 , is -C(O)-;
  • R 13 is selected from R 18 , -OR 18 , -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -N(R 18 )R 19 , -
  • W is in particular CH 2 .
  • -W-(CH 2 ) m -V- is alkylene ,e.g. having 1 , 2, 3 or 4 carbon atoms. Included is a class of compounds in -W-(CH 2 ) m -V- is alkylene having 2 carbon atoms. Included is a further class of compounds in -W-(CH 2 ) m -V- is alkylene having 3 carbon atoms.
  • -W-(CH 2 ) m -V- is oxyalkylene ,e.g. having, 2 or 3 carbon atoms.
  • R 16 and R 17 together form a ring which is unsubstituted or substituted by one or more R 21 groups.
  • the ring is in some instances mono- or bicyclic; the ring or rings forming the mono- or bicyclic may each have 5 or 6 ring members in some compounds.
  • R 14 and R 15 taken together form NR 20 , wherein R 20 is usually hydrogen or hydroxy.
  • the chiral centre indicated by the symbol * is in particular of (S)-configuration.
  • D and E are each the same or different and in embodiments are mono- or bicyclic rings.
  • Monocyclic rings and each ring of a bicyclic ring may have 5, 6 or 7 ring members, for example.
  • Rings may be aromatic or heteroaromatic; in some embodiments rings are alicyclic.
  • one or both (e.g. exactly one) of D and E is a heterocyclic structure; the heteroatom may be O, S or N, for example, particularly N.
  • Heterocyclic rings may have a heteroatom, e.g. N, at the 2-position.
  • Some heterocycles have one heteroatom, e.g. N; other heterocycles have two heteroatoms, e.g. of which one or both are N; further heterocycles fall outside these categories.
  • D and E are each an aromatic or heteroaromatic 6-membered ring; one may be aromatic and the other heteroaromatic, for example, one may be phenyl and the other pyridyl, e.g. 2-pyridyl.
  • D and E each independently unsubstituted or substituted unsubstituted or substituted by one or more substituents.
  • Substituents may be the same or different and selected from R 21 groups. In embodiments, there are 0, 1, 2 or 3 substituents, e.g. a single substituent. Included are rings, particularly but not exclusively aromatic rings, having a 4- substituent; sometimes the 4-substituent is the sole substituent but sometimes it is not the sole substituent. Exemplary substituents are halogen, e.g. Br or Cl.
  • one of D and E is phenyl which is unsubstituted or substituted as aforesaid (e.g. having a 4-substituent, for example halo and particularly Br or Cl) 1 whilst the other of D and E is pyridyl, particularly 2-pyridyl, which often has 0 or 1 substituents and may for example be unsubstituted.
  • D and E are coupled together as part of a fused ring system, e.g. have a further fused ring (e.g. having 5, 6 or 7 ring-members) fused between them. In other embodiments, D and E are not coupled together as part of a fused ring system.
  • Exemplary compounds are of Formula (V):
  • m is often 1 or 2.
  • -W-(CH 2 ) m - contains 2 or 3 in-chain atoms, e.g. 2. Included are compounds in which W is CH 2 .
  • the active agent has the formula (Vl):
  • a and B are each the same or different and an aromatic or heteroaromatic 6-membered ring, A and B each independently unsubstituted or substituted unsubstituted or substituted by one or more substituents selected from the group consisting of trifluoromethyl and species having 1 , 2 or 3 non-hydrogen atoms and optionally one or more hydrogen atoms, and
  • the one or more substituents are selected from the group consisting of halogen, hydroxy, methyl, trifluoromethyl, formyl (-CHO), methoxy, amino, methylamino, dimethylamino, amidino, hydroxylamino, cyano, thiol and methylthio.
  • the one or more substituents are selected from chlorine and bromine.
  • the one or more substituents can be bromine.
  • exactly one of A and B is substituted by a single substituent.
  • at least one of A and B is phenyl.
  • at least one of A and B may be substituted phenyl.
  • a and B is a heteroaromatic ring. More particularly, a single one of A and B is a heteroaromatic ring.
  • the or each heteroaromatic ring may for example contain one or two heteroatoms.
  • the heteroatom(s) may for example be N, O or S; often, heteroaromatic rings include a nitrogen.
  • the or each heteroaromatic ring contains as heteroatom a single nitrogen. Included are compounds in which the or each heteroaromatic ring has a heteroatom at the 2-position.
  • At least one of A and B is substituted at its 4-position.
  • one of A and B is substituted or unsubstituted phenyl and the other of A and B is substituted or unsubstituted pyridinyl.
  • the pyridinyl group can be pyridin-2-yl. In one embodiment, the pyridinyl group is unsubstituted.
  • the phenyl group is substituted solely at the 4-position.
  • the substituent can be bromine.
  • the substituent can be chlorine.
  • the chiral centre is of (S)-configuration. In an embodiment, neither of A and B is substituted.
  • the disclosure includes compounds of formula (Vl) in which X is CH 2 .
  • Novel compounds of formula (III) are an aspect of the invention, e.g. those which are not pheniramines or not of formula (Vl).
  • the active agent is selected from pheniramine, chlorpheniramine, dexchlorpheniramine, brompheniramine, dexbrompheniramine and triprolidine and prodrugs and pharmaceutically acceptable salts thereof.
  • the active agent is not fexofenadine or diphenhydramine.
  • the active agent is dexbrompheniramine or a prodrug or pharmaceutically acceptable salt thereof.
  • the active agent is not fexofenadine or diphenhydramine.
  • Compounds containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound contains an alkenyl or alkenylene group, geometric cis/trans (or ZJE) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
  • chromatography typically HPLC
  • a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine.
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
  • Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel and S. H. Wilen (Wiley, 1994).
  • the present disclosure includes all pharmaceutically acceptable isotopically-labelled compounds) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • the compounds of the disclosure may be administered in the form of pharmaceutically acceptable salts.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., US, 1985, p.
  • the disclosure thus includes pharmaceutically-acceptable salts of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof, for example the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, to
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl
  • diamyl sulfates long chain halides
  • the invention includes prodrugs for the active pharmaceutical species of the invention, for example in which one or more functional groups are protected or derivatised but can be converted in vivo to the functional group, as in the case of esters of carboxylic acids convertible in vivo to the free acid, or in the case of protected amines, to the free amino group.
  • prodrug represents in particular compounds which are rapidly transformed in vivo to the parent compound, for example, by hydrolysis in blood.
  • Prodrugs therefore include drugs having a functional group which has been transformed into a reversible derivative thereof. Typically, such prodrugs are transformed to the active drug by hydrolysis. As examples may be mentioned the following:
  • Carboxylic acid Esters including e.g. acyloxyalkyl esters, amides
  • Alcohol Esters including e.g. sulfates and phosphates as well as
  • Amine Amides carbamates, imines, enamines,
  • Prodrugs also include compounds convertible to the active drug by an oxidative or reductive reaction. As examples may be mentioned: Oxidative activation
  • metabolic activations of prodrugs are nucleotide activation, phosphorylation activation and decarboxylation activation.
  • TRPV-1 Receptor Antagonist in some embodiments of the invention, use of a TRPV-1 receptor modulator or antagonist is contemplated.
  • the class of TRPV-1 receptor modulators, particularly inhibitors includes, for example, an active agent disclosed herein and an anti-TRPV-1 antibody which modulates, particularly inhibits, TRPV-1 function.
  • the TRPV-1 receptor is a member of the TRP superfamily, which includes for example TRPM proteins, TRPC proteins and other members of the TRPV family e.g. TRPV-2 and TRPV-3.
  • TRPV-I the reader will understand that the teaching may be applied to other members of the TRP protein superfamily and the disclosure of the specification extends accordingly. Therefore a "TRPV-1 antagonist" disclosed herein may be used to modulate, e.g. inhibit other transient receptor potential proteins.
  • the invention is restricted to subject matter relating to the TRPV-1 receptor itself.
  • an anti-TRPV-1 antibody includes, although is not limited to, antibody and antibody fragments which bind to TRPV-1.
  • an anti-TRPV-1 antibody modulates e.g. inhibits the function of TRPV-1.
  • an antibody is a protein which including one or more polypeptides substantially encoded by immunoglobulin genes.
  • the recognized immunoglobulin genes include the kappa, lambda, alpha (IgA), gamma (IgGI, lgG2, lgG3, lgG4), delta (IgD), epsilon (IgE) and mu (IgM) constant region genes, as well as the myriad immunoglobulin variable region genes.
  • Antibodies also exist in a variety of other forms including, for example, Fv, Fab, and
  • the anti-TRPV-1 antibody can be a chimeric antibody.
  • Chimeric antibodies are antibodies whose light and heavy chain genes have been constructed, typically by genetic engineering, from immunoglobulin variable and constant region genes belonging to different species.
  • a therapeutic chimeric antibody is thus a hybrid protein composed of the variable or antigen-binding domain from a mouse antibody and the constant or effector domain from a human antibody although other mammalian species can be used, or the variable region can be produced by molecular techniques. Methods of making chimeric antibodies are well known in the art, e. g. see U. S. Patent No. 5,807, 715, which is herein incorporated by reference.
  • an anti-TRPV-1 antibody which is a "humanized” antibody.
  • a humanized antibody is an immunoglobulin including a human framework region and one or more CDRs from a non-human (such as a mouse, rat, or synthetic) immunoglobulin.
  • the non-human immunoglobulin providing the CDRs is termed a "donor” and the human immunoglobulin providing the framework is termed an "acceptor.”
  • all the CDRs are from the donor immunoglobulin in a humanized immunoglobulin. Constant regions need not be present, but if they are, they must be substantially identical to human immunoglobulin constant regions, i. e. , at least about 85-90%, such as about 95% or more identical.
  • humanized immunoglobulin all parts of a humanized immunoglobulin, except possibly the CDRs, are substantially identical to corresponding parts of natural human immunoglobulin sequences.
  • a "humanized antibody” is an antibody comprising a humanized light chain and a humanized heavy chain immunoglobulin. A humanized antibody binds to the same antigen as the donor antibody that provides the CDRs.
  • the acceptor framework of a humanized immunoglobulin or antibody may have a limited number of substitutions by amino acids taken from the donor framework.
  • Humanized or other monoclonal antibodies can have additional conservative amino acid substitutions which have substantially no effect on antigen binding or other immunoglobulin functions. Exemplary conservative substitutions are those such as gly, ala; val, ile, leu; asp, glu; asn, gin ; ser, thr; lys, arg; and phe, tyr (see U. S. Patent No. 5,585, 089, which is incorporated herein by reference).
  • Humanized immunoglobulins can be constructed by means of genetic engineering, e. g., see U. S. Patent No. 5,225, 539 and U.
  • the anti-TRPV-1 antibody is a human antibody which is an antibody wherein the light and heavy chain genes are of human origin.
  • Human antibodies can be generated using methods known in the art. Human antibodies can be produced by immortalizing a human B cell secreting the antibody of interest. Immortalization can be accomplished, for example, by EBV infection or by fusing a human B cell with a myeloma or hybridoma cell to produce a trioma cell. Human antibodies can also be produced by phage display methods (see, e. g. Dower et al. , PCT Publication No.
  • Human antibodies can also be prepared by using transgenic animals carrying a human immunoglobulin gene (e. g., see Lonberg et al. PCT Publication No. W093/12227 ; and Kucherlapati, PCT Publication No. WO91/10741, which are herein incorporated by reference.)
  • Monoclonal antibodies are antibodies produced by a single clone of B- lymphocytes or by a cell into which the light and heavy chain genes of a single antibody have been transfected. Monoclonal antibodies are produced by methods known to those of skill in the art, for instance by making hybrid antibody- forming cells from a fusion of myeloma cells with immune spleen cells.
  • the anti-TRPV-1 antibody is an antibody fragment. It has been shown that fragments of a whole antibody can perform the function of binding antigens. Various fragments of antibodies have been defined, including Fab, (Fab')2, Fv, single domain antibodies and single- chain Fv (scFv). These antibody fragments are defined as follows: (1) Fab, the fragment that contains a monovalent antigen-binding fragment of an antibody molecule produced by digestion of whole antibody with the enzyme papain to yield an intact light chain and a portion of one heavy chain or equivalently by genetic engineering.
  • the Fab fragment therefore contains VL, VH, CL and CH1 domains; (2) Fab', the fragment of an antibody molecule obtained by treating whole antibody with pepsin, followed by reduction, to yield an intact light chain and a portion of the heavy chain; two Fab 1 fragments are obtained per antibody molecule; (3) (Fab 1 ) 2, the fragment of the antibody obtained by treating whole antibody with the enzyme pepsin without subsequent reduction or equivalents by genetic engineering; (4) F(Ab') 2, a dimer of two FAb' fragments held together by disulfide bonds(5) Fv, a genetically engineered fragment containing the variable region of the light chain and the variable region of the heavy chain expressed as two chains; (6) single domain antibodies; antibodies whose complementary determining regions are part of a single domain polypeptide; and (7) single chain antibody (“scFV”), a genetically engineered molecule containing the variable region of the light chain, the variable region of the heavy chain wherein the VH domain and the VL domain are linked by a peptide linker which allows the
  • the TRPV-1 receptor antagonist is an aptamer.
  • Aptamers have been defined as artificial nucleic acid ligands that can be generated against amino acids, drugs, proteins and other molecules. They are isolated from complex libraries of synthetic nucleic acids by an iterative process of adsorption, recovery and re-amplification.
  • RNA aptamers are nucleic acid molecules with affinities for specific target molecules. They have been likened to antibodies because of their ligand binding properties. They may be considered as useful agents for a variety of reasons. Specifically, they are soluble in a wide variety of solution conditions and concentrations, and their binding specificities are largely undisturbed by reagents such as detergents and other mild denaturants. Moreover, they are relatively cheap to isolate and produce. They may also readily be modified to generate species with improved properties. Extensive studies show that nucleic acids are largely non-toxic and non-immunogenic and aptamers have already found clinical application. Furthermore, it is known how to modulate the activities of aptamers in biological samples by the production of inactive dsRNA molecules in the presence of complementary RNA single strands (Rusconi et al., 2002).
  • RNAs synthesised chemically based on L-ribose sugars will bind the natural target, that is to say the mirror image of the selection target. This process is conveniently referred to as reflection-selection or mirror selection and the L-ribose species produced are significantly more stable in biological environments because they are less susceptible to normal enzymatic cleavage, i.e.they are nuclease resistant.
  • the class of TRPV-1 receptor antagonists also includes an active agent disclosed herein.
  • the TRPV-1 receptor antagonist is dexbrompheniramine or a structural variant thereof.
  • TRPV-1 receptor herein includes reference to other members of the TRP superfamily, e.g. TRPM proteins, TRPC proteins and other members of the TRPV family e.g. TRPV-2 and TRPV-3.
  • TRPM proteins proteins
  • TRPC proteins members of the TRPV family
  • TRPV-1 antagonist disclosed herein may be used to modulate, e.g. inhibit other transient receptor potential proteins. Nonetheless TRPV-1 receptor is a particular receptor disclosed herein.
  • the present invention provided methods for the treatment of a disease or condition that would benefit from inhibition of a calcium ion channel receptor, comprising administering an effective amount of an active agent as defined herein.
  • the method further comprises administering at least one other pharmaceutically active agent.
  • the other pharmaceutically active agent (also referred to herein as "therapeutic agent”) is selected from a group which includes, although is not limited to, an analgesic, a steroid, a corticosteroid, an agent which is indicated for the treatment of epilepsy, an agent which is indicated for the treatment of urinary tract disorders, an agent which is indicated for the treatment of bowel disorders, an anti-inflammatory drug, an anti-depressant, and other pharmaceutically active agents as defined herein under the heading Products.
  • the selection of the at least one therapeutic agent will be determined by the nature of the disorder to be treated.
  • the active agent and the at least one other pharmaceutically active agent can be administered as a fixed combination. Alternatively, or in addition, the active agent and the at least one other pharmaceutically active agent can be administered as components of separate products.
  • the present invention also provides a use of dexbrompheniramine, or a structural variant thereof, for the manufacture of a medicament for the treatment of diseases or conditions that would benefit from inhibition of a calcium ion channel receptor polypeptide encoded by a nucleic acid molecule selected from the group consisting of:
  • nucleic acid molecule comprising a nucleic acid sequence as represented in Figure 1;
  • nucleic acid molecule that hybridizes to a nucleic acid molecule in (i) above and which encodes a calcium ion channel receptor;
  • nucleic acid molecule comprising a nucleic acid sequence which is degenerate as a result of the genetic code to the sequences defined in (i) and (ii) above.
  • dexbrompheniramine or a structural variant thereof, for use in the treatment of diseases or conditions that would benefit from calcium ion receptor polypeptide inhibition.
  • the diseases or conditions would benefit from TRPV-1 inhibition.
  • said nucleic acid molecule hybridizes under stringent hybridisation conditions to the sequences described in (i), (ii) and (iii) above.
  • Hybridization of a nucleic acid molecule occurs when two complementary nucleic acid molecules undergo an amount of hydrogen bonding to each other.
  • the stringency of hybridization can vary according to the environmental conditions surrounding the nucleic acids, the nature of the hybridization method, and the composition and length of the nucleic acid molecules used.
  • the T m is the temperature at which 50% of a given strand of a nucleic acid molecule is hybridized to its complementary strand.
  • the following is an exemplary set of hybridization conditions and is not limiting:
  • the present disclosure provides use of an active agent as defined herein to manufacture a medicament to treat pain.
  • Administration of the active agent can alleviate the pain suffered by the patient.
  • a method for reducing or controlling pain comprising administering an effective amount of an active agent as defined herein or both a said active agent and at least one other pharmaceutically active agent as defined herein.
  • said disease or condition is selected from the group consisting of: chronic pain, neuropathic pain, dental pain, post operative pain, rheumatoid pain, osteoarthritic pain, back pain, visceral pain, cancer pain, neuralgia, migraine, neuropathies, pain relating to diabetic neuropathy, sciatica, HIV related neuropathy, post herpetic neuralgia, fibromyalgia, pain associated with nerve fibre injury, pain associated with ischaemia, pain associated with neurodegeneration, pain associated with stroke, post stroke pain, pain associated with multiple sclerosis, pain which is secondary to inflammatory disorders, pain associated with inflammatory bowel disease, pain associated with cystitis, pain associated with burns and pain associated with psoriasis.
  • a method of reducing or controlling epilepsy comprising administering an effective amount of any TRPV-1 receptor antagonist, whether one disclosed herein or another one, to a patient who has epilepsy.
  • the present invention contemplates a method of reducing the number of seizures suffered by a patient suffering from epilepsy.
  • a TRPV-1 receptor antagonist for the manufacture of a medicament for treating epilepsy.
  • the TRPV-1 receptor antagonist is an active agent as disclosed herein.
  • TRPV-1 in this paragraph does not include reference to other TRP proteins than TRPV-1.
  • the TRPV-1 receptor is considered to mediate glutamatergic synaptic input to neurons (Xing and Li, J. Neurophysiol 2006 Oct 25).
  • Antagonism of the TRPV-1 receptor by a TRPV-1 receptor antagonist as disclosed herein will result in a decrease in the neuronal activity of the neurons which is contemplated for the treatment of epilepsy and epileptic events.
  • the invention therefore includes a method of inhibiting neuronal activity, comprising administering an effective amount of a TRPV-1 receptor antagonist of the disclosure.
  • TRPV-1 also disclosed is a method of modulating, particularly inhibiting glutamatergic synaptic input to neurons, comprising administering an effective amount of a TRPV-1 receptor antagonist of the disclosure.
  • TRPV-1 in this paragraph does not include reference to other TRP proteins than TRPV-1.
  • the TRPV-1 receptor has been identified in the urinary tract of humans and it has been disclosed as being involved in detecting bladder distension (Birder Vascul, Pharmacol 29 Jun. 2006).
  • a method of treating a urinary tract disorder comprising administering an effective amount of a TRPV-1 receptor antagonist as disclosed herein to a patient suffering from a urinary tract disorder.
  • the TRPV-1 receptor antagonist e.g. an active agent as disclosed herein, can be administered alone or in combination with at least one other pharmaceutically active agent (also referred to herein as "therapeutic agent").
  • the urinary tract disorder is, for example, bladder over-activity.
  • Overactive bladder is the most common term currently used in clinical medicine to describe a complex of lower urinary tract symptoms (LUTS) with or without incontinence.
  • the symptoms often include urgency, frequency, nocturia, troublesome or incomplete emptying, and pain.
  • TRPV-1 in this paragraph does not include reference to other TRP proteins than TRPV-1.
  • TRPV-1 receptor antagonist as disclosed herein in the manufacture of a medicament for the treatment of urinary tract disorders.
  • the urinary tract disorder is bladder over-activity.
  • TRPV-1 in this paragraph does not include reference to other TRP proteins than TRPV-1.
  • TRPV1 is involved in faecal urgency and rectal hypersensitivity (Chan et al Lancet 2003 Feb 1;361(9355):385-91).
  • a method of treating a bowel disorder comprising administering an effective amount of a TRPV-1 receptor antagonist of the disclosure, as defined herein, to a patient suffering from a bowel disorder.
  • the present invention also provides the use of a TRPV-1 receptor antagonist e.g. an active agent as disclosed herein, for the manufacture of a medicament to treat a bowel disorder.
  • the bowel disorder is selected from irritable bowel syndrome, inflammatory bowel syndrome, faecal urgency, faecal incontinence, rectal hypersensitivity and combinations thereof.
  • Other bowel disorders may also be treated by the use of dexbrompheniramine and are encompassed by the methods, uses and products of the present invention.
  • the term "TRPV-1" in this paragraph does not include reference to other TRP proteins than TRPV-1.
  • TRPV-1 a method of treating urinary and/or faecal incontinence, comprising administering an effective amount of a TRPV-1 receptor antagonist.
  • the disclosure also provides a method for reducing or preventing bed-wetting, comprising administering an effective amount of a TRPV-1 receptor antagonist e.g. an active agent, both disclosed herein.
  • a TRPV-1 receptor antagonist e.g. an active agent, both disclosed herein.
  • the term "TRPV-1" in this paragraph does not include reference to other TRP proteins than TRPV-1.
  • TRPV1 As well as being expressed by neuronal cells, it has been shown that expression of TRPV1 is up regulated in airways smooth muscle in disease, for example, in patients who have chronic cough
  • TRPV-1 is expressed by for example keratinocytes (Denda et al, Biochem, Biophys Res. Commun 2001 285(5) pp1250-52).
  • the present disclosure provides a method of treating an inflammatory condition or disorder in a patient comprises treating the patient with an effective amount of a TRPV-1 receptor antagonist disclosed herein.
  • the present disclosure also provides use of a TRPV-1 receptor antagonist, e.g. an active agent disclosed herein, for the manufacture of a medicament to treat an inflammatory condition or disorder.
  • a TRPV-1 receptor antagonist e.g. an active agent disclosed herein
  • the term "TRPV-1" in this paragraph does not include reference to other TRP proteins than TRPV-1.
  • the inflammatory condition is selected from conditions relating to neurogenic inflammation, conditions relating to joint inflammation e.g. arthritis, rheumatoid arthritis, hyperinflammatory conditions, sepsis, vascular inflammation, respiratory inflammation e.g. asthma, intestinal inflammation, conditions relating to chronic inflammation, conditions relating to acute inflammation, nephritis, systemic lupus, erythematosus, inflammatory bowel disease, asthma, Crohn's disease, rheumatoid arthritis, glomerulonephritis, vasculitis and sarcoidosis.
  • the term "TRPV-1" in this paragraph does not include reference to other TRP proteins than TRPV-1.
  • the inflammatory condition is asthma. In one embodiment, the inflammatory condition is arthritis. In a further embodiment, the inflammatory condition is rheumatoid arthritis.
  • dexbrompheniramine or a structural variant thereof, in the treatment of disease conditions that result from the over- expression of a nucleic acid molecule wherein said nucleic acid molecule selected from the group consisting of:
  • nucleic acid molecule comprising a nucleic acid sequence as represented in
  • nucleic acid molecule that hybridizes to a nucleic acid molecule in (i) above and which encodes a calcium ion channel receptor;
  • nucleic acid molecule comprising a nucleic acid sequence which is degenerate as a result of the genetic code to the sequences defined in (i) and (ii) above.
  • said disease condition is an inflammatory disease condition that results from over-expression of a calcium ion channel receptor.
  • an active agent disclosed herein for the manufacture of a medicament for the treatment of a cough that is not caused by post nasal drip syndrome.
  • the present invention also provides a method of treating or alleviating a cough that is not caused by post-nasal drip syndrome in a patient, wherein the method comprises treating the patient with an effective amount of an active agent selected from dexbrompheniramine, or a structural variant thereof.
  • the cough is an acute viral cough. In one embodiment of the invention the cough is the result of gastro-oesophageal reflux. In a further embodiment of the invention the cough is the result of asthma.
  • active agents described herein for the manufacture of a medicament for treating a disease other than cough. Sometimes, this does not apply to active agents other than dexbrompheniramine or, alternatively, other than pheniramines as a class.
  • the patient is human.
  • a method to provide analgesia to a subject in need of pain relief comprising administering an active agent disclosed herein to the subject.
  • a method to treat a cough wherein said cough is not caused by post nasal drip syndrome comprising administering an active agent disclosed herein to a subject in need of treatment.
  • the cough is an acute viral cough.
  • the cough is the result of gastro-oesophageal reflux.
  • the cough is the result of asthma.
  • the subject is human.
  • the subject is a non-human mammal, for example a non-human primate.
  • the non-human mammal is a livestock species, for example a cow, horse, pig or sheep.
  • the non-human mammal is a companion animal, for example a dog, cat or rabbit.
  • the subject is bird species.
  • a method to provide analgesia to a subject in need of pain relief comprising topically applying a wound dressing according to the invention to a wound.
  • the wound is a burn or scald.
  • the wound is a contusion.
  • the wound is an ulcer, for example a diabetic ulcer.
  • the wound is a post-operative wound.
  • the present disclosure also provides pharmaceutically useful products comprising a TRPV-1 receptor antagonist, e.g. an active agent disclosed herein, for treating conditions and disorders which would benefit from inhibition of a calcium ion channel receptor.
  • a TRPV-1 receptor antagonist e.g. an active agent disclosed herein
  • the active agent is dexbrompheniramine or a structural variant thereof.
  • the products are for the treatment of disorders and conditions which would benefit from inhibition of a TRPV receptor.
  • the TRPV receptor is for example TRPV-1.
  • the product comprises the active agent and at least one other pharmaceutically active agent (also referred to herein as "therapeutic agent").
  • the product is a pharmaceutical composition comprising a TRPV-1 receptor antagonist disclosed herein, for example an active agent disclosed herein, and at least one other pharmaceutically active agent.
  • the product comprises dexbrompheniramine and at least one pharmaceutically active agent.
  • the product does not contain pseudoephidrine.
  • a pharmaceutical composition comprising dexbrompheniramine or a structural variant thereof and at least one therapeutic agent which is not pseudoephedrine or dextromethorphan.
  • the invention includes a pharmaceutical composition in unit dosage form (e.g.
  • each unit comprises an active agent of the disclosure in an amount of from about 6mg to about 24mg.
  • the invention also includes a pharmaceutical composition which is for inhaled administration.
  • the amount of active agent in the product can be, for example, about any of the following: 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21 mg, 22mg, 23mg, and 24mg.
  • the amount of active agent e.g.
  • dexbrompheniramine may be differ from the dosage indicated above, for example, the amount of active agent may be from about 1mg to about 100mg, including about any of the following: 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 95mg and 100mg.
  • a combination of an active agent of the disclosure and one or more other pharmaceutically active agents can be used to treat pain.
  • the combination is a fixed combination i.e. comprised within a single product.
  • the combination comprises separate products but is for co-administration, as for example in the case of a package comprising a separate dosage form for each pharmaceutically active agent.
  • the active agent may be supplied in dosage forms as indicated above.
  • the other therapeutic agent is a steroid.
  • the steroid is a corticosteroid, although the present invention also encompasses other steroids as therapeutic agents.
  • the product comprises a steroid, for example, a corticosteroid.
  • a product according to this embodiment may be used in methods to treat or alleviate cough as described herein. In one embodiment, the cough is not caused by post-nasal drip syndrome.
  • Products comprising an active agent disclosed herein and a steroid can be used to treat inflammatory disorders. Such inflammatory disorders include, although are not limited to, those described herein, for example, asthma and inflammatory bowel syndrome.
  • the product comprises the active agent and at least one other therapeutic agent which is an analgesic.
  • the product can be used to treat pain.
  • Analgesics are well known in the art and relates to a diverse group of drugs that are used to relieve pain.
  • Analgesic drugs work in various ways on the peripheral and central nervous system and include paracetamol, non-steroidal anti-inflammatory drugs (for example, sulindac, suli ⁇ dac suifide, sulindac sulfone, aspirin, indomethacin, ibuprofen, meclofenamic acid, flurbiprofen, naproxen or piroxican), and narcotic drugs such as morphine.
  • non-steroidal anti-inflammatory drugs for example, sulindac, suli ⁇ dac suifide, sulindac sulfone, aspirin, indomethacin, ibuprofen, meclofenamic acid, flurbiprofen
  • the analgesic is selected from the class of non-steroidal anti-inflammatory drugs.
  • the therapeutic agent can be aspirin.
  • the analgesic can be paracetamol.
  • the amount of paracetamol per dose can be for example, about any of the following: about 500mg to about 1000mg, and may be for example 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or IOOOmg per dosage form.
  • the therapeutic agent is aspirin.
  • the amount of aspirin per dosage may be for example about 300 to about 1200mg, including, for example, about any of the following:from 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150 and 1200mg.
  • the other therapeutic agent is an anti-depressant.
  • the antidepressant is a tricyclic anti-depressant, for example although not limited to, amitriptyline and nortriptyline. Other tricylic anti-depressants may be used in the products of the disclosure.
  • the other therapeutic agent is amitriptyline.
  • the amount of amitriptyline per dose can be for example from about 75mg to about 200mg, including for example about any of the following: 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 and 200mg.
  • the other therapeutic agent is an opiate.
  • the combination is a combination of dexbrompheniramine and an opiate.
  • the therapeutic agent is selected from a class of morphinomimetics.
  • Other embodiments include a pharmaceutical composition comprising dexbrompheniramine and an opiate.
  • opiates which are encompassed by the present invention include morphine and codeine. Opiates other than those described herein are encompassed by the present invention.
  • the other therapeutic agent is codeine.
  • the amount of codeine can be for example from about 15mg to 60mg per dosage form e.g. about any of the following: 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg and 60mg.
  • the other therapeutic agent in which the product can be used to treat pain, can be morphine wherein the amount of morphine per dosage form may be for example from about 5mg to about 200mg, for example, about any of the following: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 and about 200mg.
  • the other therapeutic agent in which the product can be used to treat pain, is selected from gabapentin and pregabalin. In one embodiment, the other therapeutic agent is gabapentin.
  • the amount of gabapentin or pregabalin per dosage can be for example from about 300 to about 1200mg, including for example, about any of the following: 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150 and 1200mg.
  • the other therapeutic agent may be selected from the class of triptan drugs.
  • the class of triptan compounds include, for example, sumatriptan, which is currently licensed for treatment of migraines.
  • an active agent e.g. dexbrompheniramine
  • sumatriptan is currently licensed for treatment of migraines.
  • an active agent e.g. dexbrompheniramine
  • sumatriptan is also included in the present disclosure.
  • a pharmaceutical composition comprising dexbrompheniramine and sumatriptan.
  • the present disclosure also encompasses pharmaceutical compositions comprising an active agent e.g. dexbrompheniramine and other triptan compounds e.g. zolmitriptan or sumatriptan.
  • the other therapeutic agent is sumatriptan.
  • the amount of sumatriptan per dosage form is from about 50mg to about 300mg for example, about any of the following: 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 and 300mg.
  • the other therapeutic agent is an anti-epileptic drug, for example, sodium valproate or carbamazepine, lamotrigine, oxcarbazepine, topiramate, gabapentin, levetiracetam, phenytoin, tiagabine and vigabatrin.
  • the therapeutic agent is carbamazepine.
  • the amount of carbamazepine per dosage form can be from about 10Omg to about 1200 mg, e.g. about any of the following: 200, 300, 400, 500, 600, 700, 800, 900, 1000, HOOmg and 1200mg.
  • the other therapeutic agent is phenytoin.
  • the amount of phenytoin per dosage form can be from about 150mg to about 500mg, e.g., about any of the following: 150, 200, 250, 300, 350, 400, 450 and 500mg.
  • the other therapeutic agent is gabapentin.
  • the active agent may be administered solely or in combination with at least one other therapeutic agent.
  • the other therapeutic agent is a urinary anti-spasmodic.
  • the other therapeutic agent is selected from darifenacin, emepronium, flavoxate, meladrazine, oxybutynin, propiverine, solifenacin, terodiline, tolterodine, trospium and combinations thereof.
  • the other therapeutic agent is selected from oxybutynin, tolterodine and combinations thereof.
  • the other therapeutic agent is oxybutynin.
  • the amount of oxybutynin per dosage can be from about 2.5 to about 20mg, including for example, about any of the following: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or20mg.
  • the other therapeutic agent is tolterodine.
  • the amount of tolterodine per dosage can be from about 1 to about 4mg e.g., about any of the following: 1 , 2, 3 or 4mg.
  • the other therapeutic agent can be an anti-inflammatory agent.
  • the other therapeutic agent can be a bowel-specific anti-inflammatory agent e.g. licensed for use to treat inflammatory conditions of the bowel.
  • the other therapeutic agent is selected from, for example, mesalazine and hyoscine (also referred to as scopolamine). Scopolamine may be in the form of scopolamine hydrobromide.
  • the other therapeutic agent is mesalazine.
  • the amount of mesalazine per dosage can be from about 2 to about 4grammes e.g , about any of the following. 2, 2.5, 3, 3.5 or 4grammes.
  • the other therapeutic agent is hyoscine.
  • the amount of hyoscine per dosage can be from about 30mg to about 80mg e.g. about any of the following: 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or 80mg.
  • the product comprises a combination of an active agent as described herein and at least two other therapeutic agents.
  • the other therapeutic agents are typically therapeutic agents as defined herein.
  • the product in which the product can be used to treat inflammatory disorders, the product comprises the active agent and other therapeutic agents such as montelukast and prednisolone.
  • the amount of montelukast per product in this embodiment can be from about 5mg to about 15mg e.g. , about any of the following: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15mg. In an embodiment, the amount of montelukast per product is about 10mg.
  • the dosage of prednisolone in the product can be from about 2mg to about 60mg e.g. about any of the following: 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or about 60mg.
  • the product in which the product can be used to treat inflammatory disorders for example rheumatoid arthritis, can comprise the active agent, aspirin, ibuprofen, and leflunomide.
  • the amount of aspirin comprised within the product is typically as detailed earlier.
  • the amount of ibuprofen contained within the product may be from about 200mg to about 1800mg, including for example about any of the following: 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700 and 1800mg.
  • the amount of leflunomide per product can be from about 10mg to about 20mg e.g. about any of the following: 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or about 20mg.
  • the other therapeutic agent is anti-asthma drug.
  • the other therapeutic agent is selected from a class of drugs which includes, although is not limited to, leukotriene receptor antagonists e.g. montelukast and salts and prodrugs thereof (e.g. montelukast sodium), pranlukast and salts and prodrugs thereof, and zafirlukast and salts and prodrugs thereof.
  • the other therapeutic agent is selected from a class of drugs (known and future) which includes, although is not limited to, corticosteroids.
  • the corticosteriodal drug is selected from prednisolone and prednisone.
  • the method comprises administering a combination of the active agent as defined herein and at least two therapeutic agents.
  • the combination comprises dexbrompheniramine, a leukotriene receptor antagonist and a corticosteroid.
  • An exemplary combination is, for example, dexbrompheniramine, montelukast and prednisolone.
  • dexbrompheniramine and other therapeutic agents for use in the treatment of an inflammatory disorder is envisaged and encompassed by the present invention.
  • a product which comprises the active agent and at least one therapeutic agent which is an analgesic can be used in methods for the reduction and/or alleviation of pain including, although in no way limited to, the treatment of pain in relation to inflammatory disorders.
  • the product may also be used to treat other types of pain as described herein.
  • the disorders disclosed herein can be treated by co-administration of the active agent in combination with a therapeutic agent, wherein the active agent and the therapeutic agent are not present in the same product.
  • the therapeutic agent may be administered in the dosage amounts indicated above.
  • Co-administration of the active agent and the therapeutic agent can be simultaneous or sequential.
  • the present disclosure also includes use of a product comprising the active agent and an analgesic in methods for treating inflammatory disorders and/ or conditions.
  • the products, medicaments and combined composition include a carrier, adjuvant or excipient.
  • the present disclosure also includes use of a product comprising the active agent and an analgesic in methods for treating cough in a patient.
  • the product comprises the active agent selected from dexbrompheniramine and structural variants thereof and an analgesic selected from codeine, morphine, dextromethorphan and guaiphensin.
  • a combined pharmaceutical composition comprising dexbrompheniramine or a structural variant thereof and at least one analgesic.
  • the active agent is administered with at least one therapeutic agent, either in combination in the medicament or in combination as separate products.
  • the administration may be simultaneous or sequential administration.
  • said therapeutic agent is a steroid; preferably a corticosteroid.
  • said product, medicament or composition is provided as a topical formulation, e.g. a cream adapted for topical application.
  • the products, active agents, compositions and medicaments of the present invention are administered as pharmaceutically acceptable preparations.
  • Such preparations may routinely contain pharmaceutically acceptable concentrations of excipients, diluents, and/or carriers e.g. salt, buffering agents, preservatives, compatible carriers and optionally other therapeutic agents.
  • the products and medicaments of the invention can be administered by any conventional route, including injection or by gradual infusion over time.
  • the administration may, for example, be oral, intravenous, intraperitoneal, intramuscular, intracavity, subcutaneous, inhalation, nasal or transdermal.
  • Medicaments may be administered by aerosol e.g. by inhalation.
  • Techniques for preparing aerosol delivery systems are well known to those of skill in the art. Generally, such systems should utilize components which will not significantly impair the biological properties of the medicaments. Those of skill in the art can readily determine the various parameters and conditions for producing aerosols without resort to undue experimentation.
  • the product is for oral administration.
  • Solid dosage . forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active agent is typically mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or one or more: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cety
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycol, for example.
  • oral formulations contain a dissolution aid.
  • the dissolution aid is not limited as to its identity so long as it is pharmaceutically acceptable. Examples include nonionic surface active agents, such as sucrose fatty acid esters, glycerol fatty acid esters, sorbitan fatty acid esters (e.g.
  • sorbitan trioleate polyethylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, methoxypolyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene alkylamines, polyoxyethylene alkyl thioethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene glycerol fatty acid esters, pentaerythritol fatty acid esters, propylene glycol monofatty acid esters, polyoxyethylene propylene glycol monofatty acid esters, polyoxyethylene sorbitol fatty acid esters, fatty acid alkylolamides, and alkylamine oxides; bile acid and salts thereof (e.g.,
  • ionic surface active agents such as sodium laurylsulfate, fatty acid soaps, alkylsulfonates, alkylphosphates, ether phosphates, fatty acid salts of basic amino acids; triethanolamine soap, and alkyl quaternary ammonium salts; and amphoteric surface active agents, such as betaines and aminocarboxylic acid salts.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, and/or in delayed fashion. Examples of embedding compositions include polymeric substances and waxes.
  • the active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • the active agents may be in finely divided form, for example it may be micronised.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyi alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, is
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active agents, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth and mixtures thereof.
  • the products and medicaments of the invention are administered in effective amounts.
  • An "effective amount" is that amount of a medicament that alone, or together with further doses, produces the desired response.
  • Such amounts will depend, of course, on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.
  • the product is for inhaled administration.
  • Dosage forms for topical administration of an active agent of this invention include powders, sprays, ointments and inhalants.
  • the active agent is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required.
  • Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the products e.g. medicaments used in the foregoing methods preferably are sterile and contain an effective amount of an active agent e.g. dexbrompheniramine or its structural variants as defined herein for producing the desired response in a unit of weight or volume suitable for administration to a patient.
  • the response can, for example, be measured by determining the signal transduction enhanced or inhibited by the product comprising an active agent disclosed herein e.g. dexbrompheniramine or its structural variants via a reporter system, by measuring downstream effects such as gene expression, or by measuring the physiological effects of an active agent disclosed herein e.g. dexbrompheniramine or its structural variants, such as regression of disease symptoms.
  • an active agent disclosed herein e.g. dexbrompheniramine or its structural variants
  • Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions and products of this disclosure may be varied so as to obtain an amount of the active agent(s) that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration (referred to herein as a "therapeutically effective amount").
  • the selected dosage level will depend upon the activity of the particular active agent, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the active agent at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • an active agent disclosed herein e.g. dexbrompheniramine or its structural variants administered to a subject can be chosen in accordance with different parameters, in particular in accordance with the mode of administration used and the state of the subject. Other factors include the desired period of treatment. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits.
  • doses of the active agent e.g. dexbrompheniramine and its structural variants are formulated and administered in doses typically between about 1mg and 36mg.
  • doses of the active agent e.g. dexbrompheniramine and its structural variants are from about 6 to about 24mg.ln one embodiment, which is not limiting, the dose is from about 6mg to aboutabout 12mg, according to any standard procedure in the art.
  • Other protocols for the administration of products comprising the active agent e.g. dexbrompheniramine and its structural variants will be known to one of ordinary skill in the art, in which the dose amount, schedule of injections, sites of injections, mode of administration and the like vary from the foregoing.
  • a subject is a mammal, preferably a human, and including a non-human primate, cow, horse, pig, sheep, goat, dog, cat or rodent.
  • the products e.g. medicaments of the invention are applied in pharmaceutically-acceptable amounts and in pharmaceutically-acceptable compositions.
  • pharmaceutically acceptable j s employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents.
  • the salts When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically-acceptable salts thereof and are not excluded from the scope of the invention.
  • Such pharmacologically and pharmaceutically-acceptable salts include, but are not limited to, . those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like.
  • pharmaceutically-, acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts. . .
  • the active agent e.g. dexbrompheniramine and its structural variants compositions may be combined, if desired, with a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration into a human:
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the components of the pharmaceutical compositions also are capable of being co-mingled with the molecules of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.
  • the products e.g. pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy. All methods include the step of bringing the active agent into association with a carrier which constitutes one or more accessory ingredients. In general, the products e.g. compositions are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • compositions which are suitable for oral administration may be presented as discrete units, such as capsules, tablets, lozenges, each containing a predetermined amount of the active compound.
  • Other compositions include suspensions in aqueous liquids or non-aqueous liquids such as syrup, elixir or an emulsion.
  • Products, including compositions, which are suitable for parenteral administration conveniently comprise a sterile aqueous or non-aqueous preparation of dexbrompheniramine or a structural variant thereof, which is preferably isotonic with the blood of the recipient.
  • This preparation may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation also may be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • a wound dressing that includes dexbrompheniramine, or a structural variant thereof.
  • said wound dressing is a bandage or plaster.
  • said wound dressing is a hydrogel. Hydrogels are also included within the scope of the invention.
  • Hydrogels are amorphous gels or sheet dressings which are crosslinked and which typically consist of a polymer, a humectant and water in varying ratios. Hydrogels are known in the art and are commercially available. Hydrogels/sheets function to maintain a moist wound environment and can be removed without trauma to a wound bed. Examples of commercially available hydrogels are Tegagel 1 " 1 , Nu-Gel tm or FlexiGer.
  • a screening assay for the identification of agents that antagonise the activity of a calcium ion receptor comprising:
  • i) forming a preparation comprising a polypeptide encoded by a nucleic acid molecule selected from the group consisting of:
  • nucleic acid molecule that hybridizes to a nucleic acid molecule in (i) above and which encodes a calcium ion channel receptor
  • nucleic acid molecule comprising a nucleic acid sequence which is degenerate as a result of the genetic code to the sequences defined in (i) and (ii) above and a candidate agent to be tested;
  • the effect of the candidate agent is compared in the presence of an agonist that activates said calcium ion receptor.
  • said agonist is capsaicin or resiniferatoxin.
  • the calcium ion receptor is expressed by a cell, preferably a mammalian cell.
  • the mammalian cell is a human cell.
  • said cell is transfected with a nucleic acid molecule encoding a polypeptide that is a calcium ion channel receptor.
  • the receptor is encoded by a nucleic acid molecule as represented in Figure 1.
  • the candidate agent is based on the structure presented in Figure 4. According to a further aspect of the invention there is provided a method to determine the ligand binding activity of a molecule to associate with a calcium ion channel receptor polypeptide comprising the steps of:
  • the Molecular Similarity application permits comparisons between different structures, different conformations of the same structure, and different parts of the same structure.
  • Each structure is identified by a name.
  • One structure is identified as the target (i.e., the fixed structure); all remaining structures are working structures (i.e., moving structures).
  • the working structure is translated and rotated to obtain an optimum fit with the target structure.
  • the person skilled in the art may use one of several methods to screen chemical entities or fragments for their ability to associate with a target.
  • the screening process may begin by visual inspection of the target on the computer screen, generated from a machine-readable storage medium. Selected fragments or chemical entities may then be positioned in a variety of orientations, or docked, within that binding pocket.
  • Useful programs to aid the person skilled in the art in connecting the individual chemical entities or fragments include: CAVEAT (P. A. Bartlett et al, "CAVEAT: A Program to Facilitate the Structure- Derived Design of Biologically Active Molecules". In Molecular Recognition in Chemical and Biological Problems", Special Pub., Royal Chem. Soc, 78, pp. 182-196 (1989)).
  • wt-rTRPV1 transfected HEK cells were subcloned in geneticin (0.6 mg ml "1 ) containing medium (DMEM containing 10 % FCS, 100 U ml "1 penicillin, 100 ⁇ g ml "1 streptomycin, and 250 ng ml "1 amphotericin B) and propagated for two weeks to allow selection.
  • DMEM fetal calf serum
  • DMEM containing 10 % FCS, 100 U ml "1 penicillin, 100 ⁇ g ml "1 streptomycin, and 250 ng ml "1 amphotericin B
  • transfected cells were plated in 96 well plates (1 cell per well) and colonies grown from single cells were subsequently tested for capsaicin responsiveness by measuring increases in intracellular calcium (see Measurement of Intracellular Calcium). The final clones selected, were taken through three further rounds of single cell cloning to ensure the cell lines were derived from a single cell.
  • the cells were then washed by centrifugation to remove excess Fluo-3 AM and resuspended in Calcium Assay Buffer (CAB) (150 mM sodium chloride, 250 ⁇ M sulphinpyrazone, 3 mM potassium chloride, 10 mM glucose, 20 mM HEPES and 280 mM calcium chloride (CaCI 2 6H 2 O), pH7.4).
  • CAB Calcium Assay Buffer
  • Increases in intracellular calcium levels were measured at room temperature using a fluorospectrometer (Photon Technology International).
  • the fluorospectrometer was set to emit an excitation wavelength of 480 nm and record light emitted with a wavelength of 530 nm.
  • Concentration-effect curves were constructed for each test agonist by adding increasing concentrations of the agonist to separate cell containing cuvettes in half log increments.
  • the increase in fluorescence measured at 530 nm was expressed as a percentage of the maximum fluorescence signal after the addition of 6 ⁇ M calcium ionophore (A23187).
  • For inhibition of capsaicin responses cells were incubated in CAB containing 100 ⁇ M antihistamine for 4 minutes before the addition of capsaicin or resiniferatoxin.
  • hTRPVI Dexbrompheniramine Maleate Inhibits hTRPV1-HEK activation by capsaicin and resiniferatoxin.
  • hTRPVI was successfully cloned from MRC5 cDNA and permanently expressed in HEK293 cells. By measuring agonist triggered increases in intracellular calcium, hTRPVI -HEK cells were characterised. The hTRPVI -HEK cells responded in a concentration dependent manner to capsaicin from 300 pM, reaching a maximum by 300 nM with an EC 50 of 5.5 nM ( Figure 5).
  • hTRPVI -HEK cells also responded in a concentration dependant manner to resiniferatoxin from 3 pM, reaching a maximum by 3 nM with an EC 50 of 85 pM (Figure 6).
  • the two specific TRPV1 agonists, capsaicin and resiniferatoxin had no observable effect on intracellular calcium levels up to the maximum concentration tested (30 ⁇ M and 30 nM respectively, data not shown).
  • Pre-incubation with dexbrompheniramine maleate (4 minutes, 100 ⁇ M) caused the EC 50 values for the hTRPVI -HEK capsaicin and resiniferatoxin concentration effect curves to rise ( Figures 5A and B).
  • rTRPVI Dexbrompheniramine Maleate Inhibits rTRPV1-HEK activation by capsaicin and resiniferatoxin.
  • rTRPVI was cloned from rat dorsal root ganglia and permanently expressed in HEK293 cells (rTRPVI -HEK) and Pro5 cells (rTRPV1-Pro5). Again using agonist triggered increases in intracellular calcium, rTRPV1-HEK cells were characterised. In the rTRPV1-HEK cell line, a concentration-effect curve was observed in response to both resiniferatoxin and capsaicin.
  • Resiniferatoxin induced an increase in intracellular calcium from as low as 30 pM, reaching maximal response at 3 nM with an EC 50 value of ⁇ 168 pM (Figure 6B).
  • Capsaicin induced an increase in intracellular calcium from as low as 10 nM, reaching maximal response at 30 ⁇ M with an EC 5 Q value of -424 nM ( Figure 6A).
  • dexbrompheniramine maleate 100 ⁇ M
  • rTRPV1-Pro5 also responded to capsaicin in a concentration dependent manor from as low as 3 nM reaching a maximum by 300 nM with an EC 50 of 20 nM. Following incubation with dexbrompheniramine (100 ⁇ M), the rTRPV1-Pro5 capsaicin concentration effect curve showed a slight rightward shift and a reduction in maximal response. The cells responded to capsaicin from 30 nM reaching maximal response at 300 nM with an EC 50 of 2OnM.
  • Fexofenadine also had little effect on hTRPV1-HEK activation by capsaicin.
  • hTRPV1-HEK cells pre-exposed to fexofenadine responded to capsaicin from 1 nM reaching a maximum by 300 nM.
  • Fexofenadine (100 ⁇ M) caused a very slight drop in maximal response and EC 50 (3.8 nM, Figure 8B).
  • the ganglia were dissociated into single cells by several passages through a series of syringe needles (23G down to 25G). Finally, the complex of medium and ganglia cells were sieved through a 40 ⁇ m filter to remove debris and topped up with 8 ml of DMEM medium and centrifuged. The final cell pellet were re-suspended in DMEM medium (supplemented with 100 ng/ml mouse Nerve Growth Factor (mouse-NGF-7S) and cytosine-b-D-arabino-furanoside free base (ARA-C) 2.5 mM (van der Stelt M et al., 2005).
  • DMEM medium supplied with 100 ng/ml mouse Nerve Growth Factor (mouse-NGF-7S) and cytosine-b-D-arabino-furanoside free base (ARA-C) 2.5 mM (van der Stelt M et al., 2005).
  • DRG neurons were loaded with Fura-2-AM-ester (3 ⁇ M) in Ca 2+ buffer solution of the following composition (mM): CaCI 2 1.4; KCI 5.4; MgSO 4 0.4; NaCI 135; D-glucose 5; HEPES 10 with BSA 0.1%, at pH 7.4, for 35 min at 37 0 C, washed twice with the Ca 2+ buffer solution and transferred to a chamber on the stage of Nikon eclipse TE300 microscope. The dye was excited at 340 and 380 nm to indicate relative [Ca 2+ ]j changes by the F 340 ZF 38O ratio recorded with a dynamic image analysis system (Laboratory Automation 2.0, RCS, Florence, Italy). Various stimuli or their respective vehicles were directly added to the chamber.
  • mM composition
  • Example 6 indicates the action of dexbrompheniramine on TRPV1 in an alternative cell system.
  • Dexbrompheniramine was administered to 79 chronic cough patients suffering from treatment resistant chronic cough of a wide variety of causes including gastro-oesophageal reflux, asthma and idiopathic (not PNDS). Cough was abolished in 50 out of 79 and mean cough scores reduced from 7.6 out of 10 to 4.8.
  • the subject matter of the following paragraphs also forms part of the present invention:
  • dexbromphe ⁇ iramine or a structural variant thereof, for the manufacture of a medicament for the treatment of diseases or conditions that would benefit from inhibition of a calcium ion channel receptor polypeptide encoded by a nucleic acid molecule selected from the group consisting of.
  • nucleic acid molecule comprising a nucleic acid sequence as represented in
  • nucleic acid molecule that hybridizes to a nucleic acid molecule in (i) above and which encodes a calcium ion channel receptor;
  • nucleic acid molecule comprising a nucleic acid sequence which is degenerate as a result of the genetic code to the sequences defined in (i) and (ii) above.
  • Dexbrompheniramine or a structural variant thereof, for use in the treatment of diseases or conditions that would benefit from calcium ion channel receptor polypeptide inhibition.
  • said disease or condition is selected from the group consisting of: chronic pain, neuropathic pain, post operative pain, rheumatoid pain, osteoarthritic pain, back pain, visceral pain, cancer pain, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HlV related neuropathty, post herpetic neuralgia, fibromyalgia, nerve fibre injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, inflammation, inflammatory disorders, inflammatory bowel disease, cystitis, burns and psoriasis. 6. Use according to any of paragraph 1-5 wherein said medicament includes at least one further therapeutic agent.
  • a combined pharmaceutical composition comprising dexbrompheniramine, or a structural variant thereof and at least one therapeutic agent.
  • a preparation according to paragraph 7 wherein said pharmaceutical composition comprises dexbrompheniramine and an analgesic.
  • said medicament or preparation includes a carrier, adjuvant or excipient.
  • a wound dressing that includes dexbrompheniramine, or a structural variant thereof.
  • a method to administer analgesia to a subject in need of pain relief comprising administering a medicament or pharmaceutical composition according to any of paragraphs 1-15 to said subject.
  • a method to treat a cough wherein said cough is not caused by post nasal drip syndrome comprising administering a medicament or pharmaceutical composition according to any of paragraphs 1-15 to a subject in need of treatment.
  • a method to administer analgesia to a subject in need of pain relief comprising topically applying a wound dressing according to any of paragraphs 21-23 to a wound.
  • a screening assay for the identification of agents that antagonise the activity of a calcium ion receptor comprising:
  • a preparation comprising a polypeptide encoded by a nucleic acid molecule selected from the group consisting of: a) a nucleic acid molecule comprising a nucleic acid sequence as represented in Figure 1;
  • nucleic acid molecule that hybridizes to a nucleic acid molecule in (i) above and which encodes a calcium ion channel receptor
  • nucleic acid molecule comprising a nucleic acid sequence which is degenerate as a result of the genetic code to the sequences defined in (i) and (ii) above and a candidate agent to be tested;
  • a method to determine the ligand binding activity of a molecule to associate with a calcium ion channel receptor polypeptide comprising the steps of:
  • dexbrompheniramine or a structural variant thereof, in the treatment of disease conditions that result from the over-expression of a nucleic acid molecule wherein said nucleic acid molecule selected from the group consisting of:
  • nucleic acid molecule comprising a nucleic acid sequence as represented in
  • nucleic acid molecule that hybridizes to a nucleic acid molecule in (i) above and which encodes a calcium ion channel receptor;
  • nucleic acid molecule comprising a nucleic acid sequence which is degenerate as a result of the genetic code to the sequences defined in (i) and (ii) above.
  • disease condition is an inflammatory disease condition that results from over-expression of a calcium ion channel receptor.
  • a screening assay for the identification of an agent having potential activity for treating epilepsy, a urinary tract disorder, a bowel disorder or pain comprising determining or measuring the effect, or not, of a candidate agent on the activity of the member of the superfamily.

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  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des agents pharmaceutiquement utiles qui s'opposent à l'activité d'un récepteur des canaux calciques, ainsi que leur utilisation dans l'inhibition de l'activation du récepteur dans le traitement d'états qui peuvent bénéficier d'une telle inhibition. L'invention concerne également des criblages permettant d'identifier des antagonistes de l'activation du récepteur et d'autres sujets. L'agent peut être une phéniramine.
PCT/GB2006/004304 2005-12-08 2006-11-17 Antagoniste de recepteur Ceased WO2007066068A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0525029.5A GB0525029D0 (en) 2005-12-08 2005-12-08 Receptor Antagonist
GB0525029.5 2005-12-08

Publications (2)

Publication Number Publication Date
WO2007066068A2 true WO2007066068A2 (fr) 2007-06-14
WO2007066068A3 WO2007066068A3 (fr) 2007-08-23

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PCT/GB2006/004304 Ceased WO2007066068A2 (fr) 2005-12-08 2006-11-17 Antagoniste de recepteur

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GB (1) GB0525029D0 (fr)
WO (1) WO2007066068A2 (fr)

Cited By (2)

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WO2012112969A1 (fr) 2011-02-18 2012-08-23 Endo Pharmaceuticals Inc. Composés d'amino-indane et leur utilisation dans le traitement de la douleur
WO2015095128A1 (fr) 2013-12-16 2015-06-25 Asana Biosciences, Llc Composés de p2x3 et/ou p2x2/3 et procédés

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CN1047308C (zh) * 1995-09-22 1999-12-15 范永昌 一种治疗牙痛的口服丹药
US6124282A (en) * 1997-05-22 2000-09-26 Sellers; Edward M. Drug formulations
CN1181934A (zh) * 1997-10-23 1998-05-20 王书文 适用于肿瘤治疗的镇痛剂
JP2001151677A (ja) * 1999-11-26 2001-06-05 Taisho Pharmaceut Co Ltd 咽頭用組成物
JP2003012514A (ja) * 2001-07-02 2003-01-15 Taisho Pharmaceut Co Ltd 医薬組成物
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WO2003089007A1 (fr) * 2002-04-22 2003-10-30 Adcock Ingram Intellectual Property (Proprietary) Limited Compositions pharmaceutiques comprenant un decongestionnant et d'autres ingredients actifs pour traiter la toux et la grippe
CN1506088A (zh) * 2002-12-05 2004-06-23 上海倍艺医药科技有限公司 一种含有马来酸氯苯那敏的感冒药物
WO2004066960A2 (fr) * 2003-01-28 2004-08-12 Schering Corporation Combinaison d'antagonistes des recepteurs h1, h3 et h4 en vue du traitement d'inflammations pulmonaires allergiques et non allergiques, de congestions et de rhinites allergiques
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012112969A1 (fr) 2011-02-18 2012-08-23 Endo Pharmaceuticals Inc. Composés d'amino-indane et leur utilisation dans le traitement de la douleur
EP3363437A1 (fr) 2011-02-18 2018-08-22 Endo Pharmaceuticals Solutions Inc. Composés d'aminoindane et leur utilisation dans le traitement de la douleur
EP3970723A1 (fr) 2011-02-18 2022-03-23 Asana BioSciences, LLC Composés aminoindane pour utilisation dans le traitement de douleurs urologiques
WO2015095128A1 (fr) 2013-12-16 2015-06-25 Asana Biosciences, Llc Composés de p2x3 et/ou p2x2/3 et procédés
US9908879B2 (en) 2013-12-16 2018-03-06 Asana Biosciences, Llc P2X3 and/or P2X2/3 compounds and methods
US9944637B2 (en) 2013-12-16 2018-04-17 Asana Biosciences, Llc P2X3 and/or P2X2/3 compounds and methods
US10316039B2 (en) 2013-12-16 2019-06-11 Asana Biosciences, Llc P2X3 and/or P2X2/3 compounds and methods
US10544145B2 (en) 2013-12-16 2020-01-28 Asana Biosciences, Llc P2X3 and/or P2X2/3 compounds and methods
US10590127B2 (en) 2013-12-16 2020-03-17 Asana Biosciences, Llc P2X3 and/or P2X2/3 compounds and methods
US11685736B2 (en) 2013-12-16 2023-06-27 Abs Development 1, Inc. P2X3 and/or P2X2/3 compounds and methods

Also Published As

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WO2007066068A3 (fr) 2007-08-23
GB0525029D0 (en) 2006-01-18

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